Technology of parenteral preparations.
INTRODUCTION
Parenteral is derived from the two words ‘‘para’’ and ‘‘enteron’’ meaning to avoid the intestine. Parenteral articles are defined according to the USP 24/NF19
‘‘as those preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal, so that the active substances they contain are administered using gravity or force directly into a blood vessel, organ, tissue, or lesion. Parenteral products are prepared scrupulously by methods designed to ensure that they meet pharmacopeial requirements for sterility, pyrogens, particulate matter, and other contaminants, and, where appropriate, contain inhibitors of growth of microorganisms.
An injection is a preparation intended for parenteral administration and/or for constituting or diluting a parenteral article prior to administration.’’[1]
Parenteral drug administration is an attractive route of administration when oral administration is contraindicated, and it has been traditionally used in institutional
settings. With an increasing interest in reducing overall health care costs and with the development of new biotechnologically derived compounds and improved and novel infusion-related technologies, parenteral products have become an important component in the care of patients in hospitals and the home health care setting. In the present article, information will be presented on history and the following: the use of
parenterals in health care, the advantages and disadvantages of using parenterals, routes of administration, vascular access devices and infusion sets, types of parenteral
products, components of parenteral products, parenteral packaging, convenience and needleless systems, needleless injection, extemporaneous compounding of parenteral products, infusion pumps and devices, and future parenteral dosage forms.
HISTORY AND USE OF PARENTERALS
A detailed history of early parenteral medications can be found in the first edition of this encyclopedia. One of the first historical references to the parenteral administration of a compound was in the late 15th century when a blood transfusion from three young boys was given to Pope Innocent VIII, resulting in the death of all four individuals. These deaths led to a ban in the use of this type of medical treatment, namely an infusion, for several centuries. It was not until the 17th century that studies on the parenteral administration of compounds was first studied in animals. The development of the hypodermic needle and the use of parenterally injected drugs in humans is first reported in the mid-19th century. By the end of this century, there was an increased interest in the use of intravenous administration of glucose and normal saline solutions. Baxter produced the first commercially prepared
intravenous solutions in 1931. However, parenteral products and their administration became acceptable and a mainstay in the treatment of patients in the mid 20th century. This could be attributed, in part, to our increased understanding of microbial
and viral agents, increased recognition of the dangers associated with parenteral therapy, the development of antibiotics and other drug classes, and the availability
of new systems or infusion technologies. In the mid 1960s, many hospitals introduced intravenous admixture services. In the last 20 years, the area of infusion pumps and systems and improved vascular access devices has enabled parenteral therapy to extend beyond the institutional setting to clinics, ambulatory infusion centers, and home health care. In addition, the administration of parenteral drugs is also frequently
utilized in basic and clinical research in animals and humans.
Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-100001047
Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved. 1001
In today’s health care environment, parenteral products are a key component of therapy for hospitalized patients. Vascular access for parenteral infusion therapy is obtained in the vast majority of hospitalized patients at some point in their therapy. There are very little data as to the use of parenteral products in today’s health care environment. It was suggested that 40% of all pharmaceutical dosage forms are administered as a type of injection and that over 350 million units of large volume parenterals and 100 million units of IV admixtures (piggybacks) were used annually in the late 1980s.[2] These numbers have certainly increased since that time with the advent of new drugs and infusion methodologies. Infusion therapy in home health care continues to have a strong market in the
a valuable source of current information, including available parenteral products, infusion sets and ports, devices and infusion pumps. A list of useful worldwide
websites is shown in Table 1.
ADVANTAGES AND DISADVANTAGES
OF PARENTERAL PRODUCTS
The advantages and disadvantages of parenteral drugs and administration are shown in Table 2. Generally, parenterally administered drugs are advantageous because they can provide rapid and reliable drug systemic effects, long-term drug delivery, and targeted drug delivery. The disadvantages of parenteral products are predominately associated with safety issues related to infection and thrombosis, tissue damage and/or pain upon injection, and the use of requirements for specific equipment, devices, and techniques.
ROUTES OF ADMINISTRATION
The routes of administration for parenteral products are shown in Fig. 1. The most commonly used routes are intravenous, intramuscular, subcutaneous, and intradermal. Formulations intended for administration into the central nervous system should not include preservatives.
For intramuscular, intradermal, and subcutaneous, a single needle and syringe is generally used to administer the drugs. For intravenous and intraarterial, drugs are administered using vascular access or port devices. Other parenteral routes of administration (e.g., epidural, intra-articular, and intrathecal) usually require specialized delivery sets. In some cases, the specific drug requires a specialized delivery set be utilized due to the dose of the drug or the physicochemical properties of the drug (e.g., nitroglycerin).
VASCULAR ACCESS DEVICES
AND INFUSION SETS
Vascular access can be achieved through short peripheral, long dwell peripheral, central lines, and ports.[7,10]
These various devices differ in their insertion, characteristics, dwell time or time they should be in place, and usage and safety features. In peripheral access, the distal veins on the hand and arm are often used, with the basilic and cephalic veins in the arms being the most common site for peripheral infusions. Alternatively, the metacarpal veins can also be utilized.
The basic devices are a winged infusion device or the over-the-catheter needle, with needle sizes ranging from 16 to 26G (20- or 22-gauge being the most common size). These catheters are usually utilized only for 48 h. A midline catheter is usually inserted into a large vein and is intended to be used over a 2- to 4- week period (
Central venous catheters (CVC) are inserted into the subclavian or jugular vein and threaded until the tip is located in the superior vena cava. The types of central venous catheter are a non-tunneled, Groshong, Hickman, and Brovaic. A non-tunneled CVC can be inserted at the bedside, whereas the Groshan, Hickman, and Brovaic require surgical insertion. Vascular access ports (VAP) are an alternative to central venous access.
These devices are surgically implanted usually into the chest wall or arm subcutaneous tissue and are composed of a rigid reservoir with a self-sealing rubber septum, and the tip of the catheter is placed into a central vein.
The drug is placed into the reservoir via an injection. A VAP allows repeated, intermittent access and drug delivery (in some cases up to 2000 times), depending
upon the size of the needle. Examples of these types of ports include a P.A.S Port_ (SIMS Deltec), Vital-Port_ (Cook Incorporated), and BardPort_ and CathLink_ (Bard Medical Division).
There are three basic types of intravenous administration:
1) primary set; 2) secondary set; and 3) a volume control set (Fig. 2).[7] The basic components of all these sets include a piercing spike (to insert into the bag or bottle), drip chamber and drip orifice, tubing ranging in length from 160 to
Table 2 Advantages and disadvantages of parenteral drugs and administration
Advantages Disadvantages
Useful for patients who cannot take drugs orally Useful for drugs that require a rapid onset of action (primarily intravenous administration) Useful for emergency situations Useful for providing sustained drug delivery (implants, intramuscular depot injections) Can be used for self-delivery of drugs (subcutaneous) Useful for drugs that are inactivated in the gastrointestinal tract or susceptible to first-pass metabolism by the liver Useful for injection of drugs directly into a tissue (targeted drug delivery)
Useful for delivering fluids, electrolytes, or nutrients (total parenteral nutrition to patients) Useful for providing precise drug delivery by intravenous injection or infusion utilizing pharmacokinetic techniques Can be done in hospitals, ambulatory infusion centers, and in home health care More expensive and costly to produce Potential for infection at site of injection Potential for sepsis Potential for thrombophlebitis Potential for fluid overload Potential for air embolism Potential for extravasation Psychological distress by the patient Require specialized equipment, devices, and techniques to prepare and administer drugs Potential for pain upon injection Potential for tissue damage upon injection Risk of needlestick injuries and exposure to blood-borne pathogens by health care worker Increased morbidity associated with long-term vascular access devices Disposal of needles, syringes, and other infusion devices requires special consideration a Y-site for infusion of other components, an in-line filter (ranging from 0.2 to
TYPES OF PARENTERAL PRODUCTS
Parenteral products can be divided into two general classes according to the volume of the product. All parenteral products are sterilized and must meet all the requirements for sterility and particulate matter and must be pyrogen-free.[2,5] They must be prepared using strict sanitation standards in environmentally controlled areas by individuals trained to meet these standards. The injections are overfilled with a small excess over the labeled volume to ensure that the required volume can be obtained from the product.
Small-volume parenterals (SVP) or injections are 100 ml or less and can be provided as a single- or multidose product. In contrast, large-volume parenterals (LVP) are intended to be used intravenously as a single-dose injection and contain more than 100 ml of solution. SVPs and LVPs are often combined during the extemporaneous preparation of intravenous admixtures, to be discussed later in this article.
The U.S. Pharmacopoeia (USP) classifies injections into five different types. The dosage form selected for a particular drug product is dependent upon the characteristics of the drug molecule (e.g., stability in solution, solubility, and injectability), the desired therapeutic effect of the product (e.g., immediate vs. Sustained release), and the desired route of administration. Solutions and some emulsions (e.g., miscible with blood) can be injected via most parenteral routes of administration.
Suspensions and solutions that are not miscible with blood (e.g., injections employing oleaginous vehicles) can be administered via intramuscular or subcutaneous injection but should not be given intravenously.
Parenteral products contain excipients such as buffers, solvents, non-aqueous solvents, antimicrobial preservatives, antioxidants, and chelating agents.
Coloring agents are prohibited in parenteral products. All excipients must meet compendial standards, and the excipients must not interfere with the efficacy of the product (to be discussed more in detail later in this article). Parenterals are packaged in airtight containers using specific, high quality materials so that they do not interact with the product and to maintain the sterility of the product. For example, the type of glass to be used in a specific parenteral drug product is indicated in the monograph. The types of packaging and containers for SVPs and LVPs will be discussed later in this article.
A SVP product is available for most of the major therapeutic classes of drug. It is often desirable for a manufacturer to provide both an oral and parenteral dosage form for a specific drug product. A ‘‘drug injection’’ is a liquid preparation that is composed of drug substances and or solutions. A ‘‘drug for injection’’ is a dry solid that upon the addition of a suitable vehicle (usually a vehicle in which the drug is stable and soluble) provides a solution that conforms to the requirements for an injection.
Drugs for injection are often lyophilized or freezedried to assist in the reconstitution of the solid.
A ‘‘drug injectable emulsion’’ is a liquid preparation of a drug or drug substances dissolved in a suitable emulsion vehicle. A ‘‘drug injectable suspension’’ is a liquid preparation of solids suspended in a suitable vehicle. A ‘‘drug for injectable suspension’’ is a dry solid (often lyophilized) that is intended, upon the addition of a suitable vehicle, to yield a preparation that in all aspects meets the requirements for an injectable suspension.
LVPs are often administered via intravenous infusion in a large single-dose container. The therapeutic goal of these products is to provide electrolytes, body fluids, and nutrition. These solutions may or may not be isotonic with blood depending upon the concentration of the components, which include sodium hloride, dextrose, mannitol, Ringers (sodium, potassium, calcium, and chloride) and Lactated Ringers (calcium, potassium, sodium, and lactate), sodium bicarbonate, ammonium chloride, sodium lactate, fructose, alcohol, dextran, and amino acids. Other drugs (small volume injectables) are often combined to these LVPs, provided that these two products are compatible during the extemporaneous preparation of intravenous admixtures (discussed later).
COMPONENTS OF PARENTERAL
PRODUCTS
Parenteral products are optimized during their development provide the requisite solubility (per the required dose), stability, and syringeability. In addition, these products must meet the desired requirements for the rate of drug release based upon the dosage form and biopharmaceutical properties. Finally, it is important that parenteral products also be evaluated for their potential to cause tissue damage and/or
pain associated with the injection of the formulation.
The adjuvants in parenteral products can include solvents, vehicles, cosolvents, buffers, preservatives, antioxidants, inert gases, surfactants, complexation agents,
and chelating agents.
It is important to understand the various types of waters used in parenteral products. The most frequently used solvent in parenteral products is Water for Injection, USP, which is not required to be sterile but must be pyrogen-free. In contrast, Sterile Water
for Injection, USP is water that has been sterilized, does not include a preservative or antimicrobial agent, is pyrogen-free, and is provided in single containers no larger than 1000 ml. The use of this product is for the reconstitution of other parenteral products, in most cases antibiotics. This product must not be given alone.
Bacteriostatic Water for Injection, USP is sterile water that can contain one or more preservative or antimicrobial agent (specified on the label) and is packaged in prefilled syringes or vials that are no larger than 30 ml. It is also used in the reconstitution of SVPs.
USP is the presence of the antimicrobial agent that is contraindicated iewborns. Other solvents used for parenteral formulations are Sodium Chloride Injection, USP and Bacteriostatic Sodium Chloride Injection, USP, Ringers Injection, USP, and Lactated Ringer’s, USP.
Other vehicles may be added to parenteral products if the aqueous solubility is limited. However, these vehicles must be non-toxic, non-sensitizing, and non-irritating.[2,5] In addition, these solvents must be compatible with the drug and other components in the formulation. Cosolvents often used in parenteral formulations include propylene glycol, ethanol, polyethylene glycols, glycerin, and dimethylacetamide. In addition, fixed vegetable oils, such as peanut, cottonseed, sesame and castor oil, can be used; however the USP provides clear restrictions on their use in parenteral products.
Buffers can also be provided in parenteral formulations to ensure the required pH needed for solubility and/or stability considerations. Other excipients included in parenteral products are preservatives (e.g., benzyl alcohol, r-hydroxybenzoate esters, and phenol), antioxidants (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, cysteine, and butyl hydroxyl anisole), surfactants (e.g., polyoxyethylene sorbitan monooleate), and emulsifying agents (e.g., polysorbates).
An inert gas (such as nitrogen) can also be used to enhance drug stability. Stability and solubility can also be enhanced by the addition of complexation and chelating agents such as the ethylenediaminetetraacetic acid salts. For a more detailed list of approved excipients in parenteral products, the reader should consult the monographs within the USP.
PARENTERAL PACKAGING
In general, all parenteral products must be manufactured under strict, current good manufacturing processes (cGMP) to ensure the final product is sterile and pyrogen-free. Sterilization is defined as the complete destruction of all living organisms or their spores or the complete removal from the product.[5]
Pharmaceutical products can be sterilized by steam sterilization, dry-heat sterilization, filtration sterilization, gas sterilization, and ionizing-radiation sterilization.
The USP provides monographs and standards for biological indicators required to test the validity of the sterilization process. These products must also be tested for pyrogens—fever-producing substances that arise from microbial contamination most likely thought to be endotoxins or lipopolysaccharide in the bacterial outer cell membrane.
Injections are provided in either multiple-dose containers or single-dose containers. A multiple-dose container is often a vial that will allow the withdrawal of successive portions of the contents without a change in the strength of the product and while maintaining the sterility. A single-dose product is intended for a single parenteral administration. These products can be an ampul, vial, or a syringe. For some drugs, there are specific double-chambered vials that contain the reconstitution solvent and the powdered drug (e.g., Mix-O-Vial—to be discussed later). Types I, II, and III glass are required for parenteral products and are specified in the individual monograph for a given drug.
Ampuls are utilized for a single dose and, as such, do not require a preservative. However, in many cases, the manufacturer will include a preservative, as the drug formulation is the same for both the ampul and multiple-dose vial. The disadvantages of ampuls are that these containers become contaminated with glass particles when opened and require the use of a syringe to remove the drug solution. A filter needle must be used sometime during the withdrawal of the solution or delivery of the drug solution to a flexible bag or other intravenous solution to ensure the glass is removed from the solution. Ampuls are opened via breaking the neck at a prescored position.
Vials can be used for single or multiple doses. The glass containers are sealed with rubber closures that permit the withdrawal of the drug solution via a syringe.
The disadvantage of these systems is associated with ensuring that the drug solution is compatible with the rubber closure. Furthermore, when utilizing vials in the extemporaneous preparation of sterile intravenous admixtures, the health care practitioner must minimize the potential of coring during the introduction of the needle through the rubber seal. Furthermore, there is always the concern of contamination of the solution with repeated withdrawals. The potential for contamination can be minimized by the use of single-dose vials.
Parenteral solutions can also be packaged in syringe dosage forms for a single-dose use. As such, they can be considered a type of convenience container (to be discussed later). The syringe and needle are sterile until opened. They are ideal for emergency situations or the home health care environment.
LVPs are usually provided in glass containers, flexible plastic bags, or semirigid containers. These systems are also classified as open systems (non-vacuum) and closed systems (vacuum). The largest manufacturers of LVPs are Abbott Laboratories, Baxter Healthcare Corporation, and B. Braun.
Glass containers are sealed with a thick rubber disk and a target in the center for the piercing spike. Glass bottles can be either vented with a plastic venting tube or non-vented, thereby requiring either a non-vented administration set or a vented administration set, respectively. The advantages of glass containers for parenterals are that they are easy to sterilize, can be accurately read, and are generally inert and less susceptible to incompatibilities with drugs or leaching of components compared to the plastic flexible intravenous bags. The disadvantage of glass is associated with handling the glass bottles and the potential for breakage.[9]
Plastic intravenous fluid containers were first introduced due to the need to start intravenous therapy while transporting soldiers from the battlefield or triage area to the hospitals. These containers are flexible due to the presence of plasticizers, with the bags being composed of polyvinyl chloride. In contrast, semirigid containers are often composed of polyolefin. Some representative shapes of these various types of containers are shown in Fig. 3. The most common manufacturers of intravenous solutions are Abbott Laboratories—Lifecare, Baxter Healthcare—Viaflex, and B. Braun Medical—Excel. The major advantages of plastic flexible bag systems for parenterals are that they do not require the use of a vented administration set as they collapse when empty, and they are less susceptible to breakage. It is also easier to store and transport these bags. The difficulties with these flexible plastic bags for infusions solutions are the potential for incompatibilities of the drug substance with the components in the bag (see later), the potential for the bag to get perforated during its use, thus compromising the sterility of the solution, and the difficulty in reading the volume remaining in the bag. One major concern with the use of flexible plastic bags is the potential for the drug compound to leach out the plasticizers from the systems.
Semirigid containers are similar to flexible plastic containers in that they are lightweight and nonbreakable and can be easily transported and stored.
These containers are less likely to be perforated during their use. More importantly, these containers do not contain plasticizers and, as such, may be more compatible with drug substances. The disadvantages are related to their similar properties to glass containers, in that they require venting, can be more susceptible to cracking upon extreme changes in temperature, should not be frozen, and do not adapt well for ambulatory care.
CONVENIENCE AND NEEDLELESS
SYSTEMS
Whereas the compounding and administration of parenteral products and intravenous admixtures continues to be a vital and important component in the care of hospitalized and home health care patients, there is continued interest in easing the preparation, storage, and administration of these products with respect to controlling contamination of the finished product and protecting the health care providers from needlestick injuries. It is estimated that more than 750,000 needlestick injuries occur every year. Commonly used convenience and/or needleless systems include premixes, bags, and vial systems (e.g., Add-Vantage and Mini-Bag Plus_), prefilled syringe systems (Carpuject_—Abbott and Tubex_—Wyeth-Ayerst) and double-chambered vial systems (Mix-O-Vial—Pharmacia-Upjohn and Redi-Vial_—Lilly).
For drugs with suitable stability in intravenous solutions, premixes provide an alternative to the extemporaneous compounding of admixtures. These products are ready to administer, reduce the chance for a medication error, reduce the potential for infection, and decrease the chance for needlestick injuries. In addition, there is an advantage in using these products with respect to the shelf-life of the product. The stability and storage requirements for each product is provided by the manufacturer. For example, the FirstChoice_ Premix products (Abbott) in the overwrap have a shelf-life of, typically, 18 months, whereas those products in which the overwrap has been removed and which are stored at room temperature can be stable for up to 30 days, provided no additional drugs or additives have been added to the product. The
diluents in these premix products include 0.45 or 0.9% sodium chloride, 5% dextrose, water for injection, Lactated Ringers, and combinations of these diluents in volumes ranging from 50 to 1000 ml in plastic or glass containers. Drug classes that are currently formulated as premixes include amino acids, dextrans, electrolytes, cardiovascular, anti-infectives, analgesics, and gastrointestinal and respiratory compounds.
The Add-Vantage_ system (Abbott Laboratories) and the Mini-Bag_ Plus system (Baxter Healthcare) are needleless drug delivery systems composed of a drug-containing vial and a diluent in a flexible plastic intravenous bag. A schematic of these type of systems is shown in Fig. 3B. The drug in the vial comes in contact with the diluent, followed by the drug being transferred back into the bag with the vial still attached; this system can then be attached directly to the infusion equipment. In the Add-Vantage system_, there are specialized vials and intravenous bags and it is necessary for the health care professional to activate the system by removing the vial stopper, thus allowing the diluent to enter the vial. The Mini-Bag Plus_ system is designed to allow the simple reconstitution of standard 20mm powdered drug vials. The Monovial Safety Guard_ (Becton, Dickinson and Company) is an integrated, self-contained system that allows the transfer of a reconstitution solution from a flexible intravenous bag or vial into a drug-containing vial, and it is only available for a limited number of drugs.
As such, the advantages of these systems are that the product can be easily stored and quickly prepared A B C D without the need for calculations, specialized equipment (such as laminar airflow hoods) or needles and syringes. They also allow for a quicker turnaround time for the first dose. These products enhance safety for both the patient, by reducing the chance for medication errors (e.g., the wrong drug added to the vial, the incorrect amount of drug to be added to the bag, or a product being incorrectly labeled), and for the health care practitioner, by minimizing the chance for a needlestick injury. In addition, these products can help to reduce costs associated with unused doses because the unwrapped products can be redistributed for short periods of time. At present, a variety of therapeutic classes of drugs from anti-infectives to cardiovascular agents to pain management at various doses are available for reconstitution in bags containing 0.9 or 0.45% sodium chloride or 5% dextrose in 50 to 250 ml bags.
Prefilled syringes (Carpuject_—Abbott and Tubex_—Wyeth-Ayerst) are composed of drug solutions placed in a syringe with a needle and needleless systems. The advantages of these systems are the convenience associated with a standard dose, less chance for medication error associated with extemporaneous compounding of these syringes, usefulness in emergency situations, and ease of storage. The needle and syringe are sterile until opened. Prefilled syringes are available for drugs ranging from anti-infectives, analgesics, and antipsychotics to antiemetics.
Doubled-chambered vials are advantageous in that the reconstitution solution is separated from the drug until desired by the health care practitioner. The Mix-O-Vial_ (Pharmacia-Upjohn) system is a combination of a powdered or lyophilized drug in a lower container and an appropriate diluent with a preservative and other active ingredients in an upper container.
Following removal of the dust cover and upon pressure on the top plunger, the solution comes in contact with the drug and the vial is shaken until a solution is obtained. The upper plunger can then be swabbed with a disinfectant and the appropriate volume of drug removed with a needle as in the standard preparation of an intravenous admixture using a vial.
With an increased interest in eliminating needlestick injuries associated with parenteral drug administration in health care workers, needleless systems are becoming more common in patient care. For example, the Interlink_ System (Baxter) is designed for needleless access during intravenous therapy.
These types of products are available for injection sites, Y-sites, vial adapters, infusion and vein access, syringe products and catheter extension sets. Other needleless catheters and infusion sites include the Introcan_ Safety IV catheter and the Sifesite_ injection aps (B. Braun).
NEEDLELESS INJECTION
The concept of needleless injection is not a new one and has been thought about since the 1940s. Current products utilize either spring action or compressed gas (e.g., helium or carbon dioxide) as a propellant to deliver a drug through the skin. These needleless systems offer several advantages. The first potential advantage is reduced pain and anxiety, an advantage for use in children. The second advantage is that needleless injection causes less tissue damage than conventional needles.[11] Finally, a needleless system results in a diffuse pattern of exposure and, therefore, increases surface area and absorption rate.[11] The main disadvantage of this system is unreliability in reference to pain and discomfort and skin characteristics that can influence the amount of drug entering the body.[11]
This system has been used to administer vaccines, insulin, [11] and drugs for topical applications (e.g., penile erectile dysfunction)[12] and as a means to deliver DNA for gene therapy.[13]
EXTEMPORANEOUS COMPOUNDING
OF PARENTERAL PRODUCTS
Whereas the presence of the various convenience parenteral products has assisted health care practitioners in safely and accurately delivering drugs to the patients, the extemporaneous compounding of parenteral products continues to be an important component in institutional settings and home health care.[2,4,14] Parenteral intravenous admixtures include the withdrawing of the drug solution from an ampul(s) or vial(s) and placing it into various large volume solutions, syringe dosage forms for patients, total parenteral nutrition solutions and cassettes, or other delivery systems for home health care patients. The American Society of Health-System Pharmacists, the National Association of Boards of Pharmacy, and the USP provide practitioners with useful technical assistance bulletins, rules, and standards for the preparation of parenteral products.[1,2] The concerns associated with the extemporaneous preparation of parenteral products are maintaining sterility of the products through proper aseptic techniques, calculating and providing the correct dosage, preventing or reducing drug–drug, drug–solution, or drug–container incompatibilities during the preparation or administration of the product, and maintaining and providing drug stability and quality control.
The majority of extemporaneous parenteral products are prepared by pharmacists working in hospitals, home health care, or long-term care facilities.
These products must be prepared using aseptic technique and using the appropriate supplies (e.g., syringes, needles, and filter needles, and caps) and equipment (Class 100 laminar airflow hoods enclosed within a class 10,000 clean room). Aseptic technique which differs from sterilization, is a process by which an individual can manipulate sterile products and containers to prevent microbial contamination. Pharmacists and other personnel involved in the extemporaneous preparation of parenteral products require special knowledge and training and should receive additional training and education on a routine basis to ensure proper aseptic techniques are being followed consistently.
In addition, these individuals must be able to perform the required calculations (e.g., dosing, milliequivalents, milliosmoles, and powder volume) needed to prepare intravenous admixtures. Equally important to the safe preparation of intravenous admixtures is an understanding of general principles and concepts related to drug and solution or container incompatibilities and to drug stability and also specific knowledge as to whether a specific drug is compatible or stable with another drug, solution, or container. For example, general and specific information on intravenous
admixture incompatibilities can be found in books such as Handbook on Injectable Drugs[15,16] and King Guide to Parenteral Admixtures[17] and in primary literature sources such as the American Journal of Health-System Pharmacy and the International Journal of Pharmaceutical Compounding.
INFUSION PUMPS AND DEVICES
Infusion pumps and devices are an essential component to the delivery of parenteral drugs, particularly those given by the intravenous route. For drugs that are administered via intravenous infusion, there are two forces that control fluid flow: 1) the pressure of an active force of the liquid that can be generated via gravity flow (viz., hydrostatic pressure) or mechanically via a positive pressure pump and 2) resistance, or an opposing force, that is generated via the infusion sets, a vascular access device and/or blood vessels. The maximum flow rate will depend upon the ratio of the change in pressure exerted by the liquid to that of the change in resistance.
An infusion control device (ICD) is a device that maintains a constant infusion rate in a gravity flow system (controller) or via a positive pressure pump. A positive pressure pump is a device that provides mechanical pressure (2–12 psi) to overcome the resistance to flow in the vessels. The types of positive pressure pumps are categorized according to how they deliver the solution and their degree of precision in the flow rate. Positive pressure pumps include peristaltic pumps, cassette pumps, syringe pumps, non-electric or disposable pumps, and patient-controlled analgesic pumps (PCA). Syringe pumps are usually the most accurate pumps, with flow variances at 2% or less.
Non-electric or disposable syringe and PCA pumps are useful for ambulatory care. PCA pumps are very useful for the parenteral administration of analgesics (viz., morphine) and can be easily programmed to deliver bolus doses and provide a dosing history.
Non-electric or disposable pumps (e.g., Homepump _—I-Flow Corporation, Readymed_—Alaris Medical Systems, and SmartDose_—ProMed) are lightweight, and the solution is delivered based upon a vacuum or through the generation of a gas in the system.
A recent consensus development conference on the safety, cost, simplicity of use, and training of intravenous drug delivery systems, focusing on acute care and non-electronic devices, reviewed the use of manufacturer-prepared (e.g., premixed or frozen products), point-of-care activated systems (manufacturerprepared products that require the drug and diluents to be mixed at the point of care), pharmacy-based intravenous admixture, intravenous push medications in prepared or premade syringes, augmented iv push systems (syringe pumps), and volume control chambers.[18] Manufacturer-prepared products, point-of-care activated products, and pharmacy-based intravenous admixture programs were recommended as being superior intravenous drug delivery systems, with the manufactured products being considered the safest systems due to the quality assurance in the preparation of these products.
FUTURE PARENTERAL DOSAGE FORMS
Current research is leading to newer types of parenteral dosage forms that will be useful for both immediate and sustained drug delivery, for systemic and targeted drug delivery, and for the delivery of small molecules and macromolecules (e.g., proteins, peptides, and DNA). There has been an increased interest in developing a wide variety of particulate drug delivery systems for parenteral products, which have included liposomes or other phospholipid vesicles, microspheres, microcapsules, nanoparticles, or microemulsions.[19–22]
The development of new biomaterials, such as the linear and branched biodegradable polyesters, has increased the interest in the development of these systems for microsphere formulations for parenteral drugs. [23,24]
An advantage is that drug molecules can be incorporated into these particulate carriers, and, as such, the rate of drug release can be modified, cellular uptake can be facilitated, or the degree of tissue damage or pain can be reduced.
Microemulsions, defined as clear solutions obtained by tritrating normal coarse oil-in-water emulsions with a medium chain alcohol and composed of the non-polar phase, surfactant and cosurfactant, appear to be potentially useful for parenteral administration, as these are clear and stable formulations that are able to be filtered and might besuitable for intravenous administration.[20,21] In addition, other researchers are investigating in situ forming gel or implants that can be easily injected intramuscularly or subcutaneously and that result in the formation of a depot at the site of injection with the potential to modify or extend the release of the drug or macromolecule.[24–26]
CONCLUSIONS
Parenteral products will continue to play a vital role in the treatment of patients when the oral route is contraindicated, when it is necessary to carefully control drug blood levels in response to therapeutic effects, when a prolonged therapeutic effect is needed through a long-acting injectable, or when a drug effect is to be targeted to a specific tissue or organ, to name a few instances. Advances in the technology required for the administration of parenteral dosage forms in the last 100 years have expanded their clinical uses for in-patient and out-patient settings. In addition, there is improved convenience and safety for the health care roviders who prepare and administer these products.
It seems likely that more parenteral dosage forms will become available in the marketplace in response to the compounds being developed through biotechnology.
Dosage Regimens and Dose-Response
Chyung S. Cook
Aziz Karim
Pharmacia Corporation,
INTRODUCTION
Drugs are administered for their pharmacological effects. In some cases, however, drug therapy includes the risk of undesirable side effects, with each drug having inherently different risks associated with its use. Therefore, it is the objective of physicians to administer a drug with an optimal dosing regimen by selecting the appropriate dosage, route, and frequency of administration to achieve maximal pharmacological efficacy with minimal side effects.
In most clinical situations, drugs are administered either repetitively, at time intervals, or as a continuous infusion to maintain a certain blood concentration at steady state within the known therapeutic concentration range for a given drug. A loading dose may be desirable in order to achieve the target concentration rapidly at the onset of therapy for a drug with a long half-life. These maintenance and loading doses as well as dosing frequency can be determined using pharmacokinetic principles.
DETERMINATION OF DOSE
Maintenance Dose
The general principle that is used to select the appropriate maintenance dose and dosing interval for the average patient is as follows: to maintain a target concentration at the steady state, the rate of drug administration should be equal to the rate of elimination.
This can be expressed by the following equation [Eq. (1)] using the clearance concept: Dosing rate ј рCLFЮ _ Css р1Ю where CL is clearance, Css is the steady state concentration of drug, and F is the fraction of the dose that is systemically available. Therefore, if CL, F, and Css are known, then the appropriate dose and dosing interval can be calculated.
For example, for theophylline, the clearance value is 0.65 mL/min/kg (2.34 L/h for a
Using theophylline as an example again, if the targeted average plasma concentration is 10mg/L, the dose calculated in the above example is 23.4mg/h. Therefore, to maintain this concentration as an average concentration, IV bolus doses can be given at 140mg every 6 h (qid), 187mg every 8 h (tid), 280mg every 12 h (bid), or 560mg once a day (qd). The average concentration for a non-infusion dose regimen is defined as Average plasma concentration ј AUC=t р2Ю where AUC is the area under the plasma concentration–time curve and t is dosing interval.
Although all these dose regimens will give the same target average plasma concentration, both Css, max and Css, min values will be markedly different. For a given dose, Css, max and Css, min values can be estimated using the following dose that will give the targeted maximal and minimal concentrations can be estimated using these equations: K is the elimination rate constant (equal to 0.693 divided by the clinically relevant half-life). Ka is the absorption rate constant. Tmax is the time to reach Cmax. Vss is the volume of distribution at steady state.
For an IV dose, Tmax is 0, and the term e_KTmax ecomes
For theophylline (Vss for
As can be seen in the table, the more frequently a drug is given, the smaller the ratio of peak-to-trough plasma concentrations will be. These phenomena are also demonstrated by the computer-simulated plasma concentration-time curves (Fig. 1). If the dosing interval is equal to or smaller than the half-life, then the fluctuation between Cmax and Cmin is usually acceptable even for a drug with a narrow therapeutic window. If the dosing interval is greater than the half-life, a large fluctuation is expected, which may not be desirable for drugs with a narrow therapeutic window. However, if the half-life is very short, dosing at every half-life is not practical. Therefore, different formulations (e.g., extended-release or controlled release) are often used.
For drugs with a long half-life (greater than 12 h), the dose can be given once or twice a day to maintain appropriate therapeutic levels.
Following multiple oral doses of a drug that obeys bi-exponential kinetics after IV administration (two-compartment model), the estimation of the Css, max and Css,min involves a complicated set of exponential constants for absorption and distribution, as shown below. Where a and b are rate constants for distribution and elimination phases, respectively, and K21 is the rate constant rom tissue to plasma compartment.
As with the one compartment model, Tmax is 0 for an IV bolus dose or rapid oral absorption, and both terms e_aTmax and e_bTmax become
If both the absorption and distribution are very rapid, these terms can be ignored for simplicity, and a maximal steady state concentration can be easily predicted by omitting the e_KTmax term in the numerator of the above Eq. (3) even for the two compartment model. Because of this approximation, the predicted maximal concentration from this equation will be greater than that actually observed.
As discussed above, it is possible to design a dose with pharmacokinetic parameters alone. However, in some cases, pharmacodynamic considerations make the selection of the dose regimen deviate from this principle. If pharmacological half-life is substantially different from pharmacokinetic half-life, then pharmacodynamic half-life (instead of pharmacokinetic halflife) should be used. For example, aspirin is rapidly hydrolyzed to salicylic acid, but the half-life for antiplatelet activity is in days. Therefore, a small amount of aspirin once a day is a good dose regimen in order to achieve the desired pharmacological response.
Another exceptional case is for the drugs that are relatively non-toxic even though the pharmacological activity is directly related to plasma concentrations (i.e., there is a large therapeutic index). In this case, a high dose can be given so that the dosing interval can be much longer than the elimination half-life.
The half-life of penicillin G is less than 1 h, but it is given at very large doses every 6 or 12 h.
If absorption is slow, and the apparent absorption half-life is much longer than the elimination half-life, hen the dose regimen can be based on the apparent half-life of the absorption phase. Changing the formulation is a relatively common approach that is taken for short-acting drugs to extend the duration of absorption. The elimination half-life of nitroglycerin is approximately 2 min. However, nitroglycerin from a transdermal formulation is slowly released, and therapeutic plasma concentrations can be maintained for 24 h.
Another question regarding dose regimen is how often the dosage has to be changed and by how much.
This can be usually determined using simple pharmacokinetic principles. The dose will not change by more than 50% and no more often than every 3 to 4 half-lives. Regardless of the half-life and frequency of dosing, it will take 3 half-lives to reach 87.5% of the steady state plasma concentration if the elimination rate constant is smaller than the absorption rate constant (Fig. 2). However, if the elimination rate constant is much greater than the absorption rate constant, the time to reach steady state will depend on the absorption rate constant and not on the elimination constant.
Loading Dose
The appropriate magnitude for the loading dose can be calculated as follows: Loading dose ј Target plasma concentration To achieve steady-state plasma concentrations, it takes approximately 4 elimination half-lives. If the half-life is long and the drug effects are immediately required for treatment of a life-threatening condition, then single or multiple loading doses are sometimes inevitable. For example, the half-life of lidocaine is greater than 1 h.
However, a patient with arrhythmia after a myocardial infarction cannot wait 4–6 h to achieve therapeutic concentrations of the drug by IV infusion. Thus, the use of a loading dose of lidocaine in the coronary unit is a standard therapy.
For oral doses, the loading dose is usually twice that of the single dose. This is based on the pharmacokinetic principle that the accumulation factor is two when a drug is administered at every half-life. However, a loading dose should be cautiously used, particularly for those drugs with a narrow therapeutic window, because the sensitive individual may be exposed to toxic concentrations.
Furthermore, for drugs with long half-lives, it will take a long time to eliminate a large loading dose from the body.
DOSE- (OR CONCENTRATION-)
RESPONSE RELATIONSHIP
A drug is primarily carried by the blood from the absorption site to the target organ/tissue or blood component where the drug interacts with a receptor to produce its effect. Consequently, for many drugs, various types of relationships exist between the plasma or serum concentration of a drug and its clinical efficacy and toxicity. Much effort has been directed toward establishing reliable mathematical relationships between drug bioavailability input (plasma concentrations) and pharmacological output (response). [1–3]
Although the relationship is far from being completely understood, this dose-response relationship is very important in therapeutic decisions, and optimal dosage regimens can be deliberately planned for many drug therapies using the plasma concentration as a reasonable marker, particularly when pharmacological effects are easily measurable (e.g., blood pressure). This doseresponse relationship generally depends on whether the plasma concentration is directly or indirectly related to response and whether a drug interacts with its receptor in a reversible or irreversible manner. If there is no apparent correlation between plasma/serum concentrations and the pharmacological effects and/or the effects are not easily measurable, the trial-and-error approach may be more practical.
Directly Reversible Pharmacological Response The concept of a direct and rapidly reversible pharmacological response implies that the intensity of response is directly associated with the drug concentrationat the site of action. In this category, two models (pharmacodynamic and pharmacokinetic–pharmacodynamic) are discussed.
In the pharmacodynamic model, the drug concentration at the receptor site is proportional to the drug concentration in the plasma, regardless of the pharmacokinetic model (one compartment or multicompartment), and the interaction between the drug and receptor is directly and rapidly reversible after drug administration.
Plasma concentration (C) and intensity (I) of the pharmacological response often follow an empirical relationship, known as the Hill equation: where Imax is the maximal effect attributable to the drug and C50 is the concentration producing 50% of the maximum effect. Two examples of this are the in vivo effect of d-tubocurarine on muscle strength in patients and the plasma concentration–antiarrhythmic effect of tocainide in humans.
Another common and empirical relationship between concentration and response is the sigmoidal plot of response vs. logarithm of dose, plasma concentration, or drug concentration in the body. Very often, this curve shows excellent linearity from at least 20–80% of the maximum attainable intensity of response, which is a region of particular interest in drug therapy. Such apparent linearity between response and log plasma concentration has been demonstrated for a number of drugs, such as theophylline and propranolol.
Relating response to the logarithm of plasma concentration rather than to the logarithm of dose reduces the variability in response due to differences in absorption, metabolism, and excretion among patients.
The pharmacokinetic–pharmacodynamic model is one in which drug concentrations at the effect site are not known or cannot be estimated without knowledge of the drug effect. If the pharmacological response is associated with a peripheral compartment (not with a central compartment) that receives a substantial mass of drug, a linear, log-linear, or sigmoidal relationship may also be obtained when the response is plotted against the calculated concentrations of the drug in the peripheral compartment (not plasma concentrations). A linear relationship was obtained between behavior response and the predicted concentration of the drug in the tissue compartment after IV administration of d-lysergic acid diethylamide (LSD) to humans.
Indirect Pharmacological Response In contrast to the direct pharmacological responses discussed above, some pharmacological responses are indirect and represent the net result of several processes of which only one is influenced by the drug.
In this case, a direct relationship between plasma concentration and pharmacological response may not be obtained. However, if the process influenced by the drug can be identified, then the drug concentration may relate to changes in this process. This concept is illustrated by the effects of oral anticoagulants such as warfarin.
Warfarin inhibits the synthesis of certain vitamin K-dependent clotting factors. However, warfarin has no effect on the physiological degradation of these factors.
Therefore, the pharmacological response of warfarin should be based on the inhibitory effect on the synthesis of the clotting factor (prothrombin) rather than on the change in clotting time. These mechanism-based models were found to be relevant for the clinical effects of numerous drugs.[4] Many metabolic and endocrine systems provide similar modeling strategies.[5]
Irreversible Pharmacological Response Most drugs produce a reversible pharmacological response. However, some antibiotics, irreversible enzyme inhibitors, and anticancer agents incorporate irreversibly or covalently into a cell’s metabolic pathway.
This results in an irreversible effect—cell death. Complex kinetic models are used to explain the relationship of dose-chemotherapeutic effects for some drugs, such as methotrexate, cyclophosphamide, and arabinosylcytosine.[2]
FACTORS AFFECTING DRUG RESPONSE
Dosage regimens are generally derived using average pharmacokinetic parameters to maintain plasma concentrations of the drug within the therapeutic window.
For many drugs, both therapeutic range and toxic concentrations have been established.[6] However, for a fixed dose, the plasma concentration of a drug within a patient can be influenced by many pharmacodynamic and pharmacokinetic factors. Therefore, these factors must also be taken into consideration for maintaining desired therapeutic concentrations of a drug.
Pharmacokinetic Factors Factors affecting absorption Factors affecting drug absorption include formulation, disease state, food effect, and drug–drug interaction.
Formulations used for oral administration include solutions, suspensions, capsules, and uncoated and coated tablets. Depending on the formulation of a drug, the absorption characteristics may differ substantially.
Slow-release oral formulations are often used to prolong the drug’s activity and to reduce the fluctuation between Cmax and Cmin values.
Intestinal surgery and disease states have been shown to alter the absorption of some drugs, although information on this subject is limited. For a given disease state orsurgery, drug absorption may be increased, unchanged, or decreased, depending on the drug.
Therefore, the effect of a particular disease condition on drug absorption cannot usually be predicted from the existing information.
The effect of food on the absorption of a drug from the gastrointestinal (GI) tract is quite variable and depends on the physicochemical properties of the drug substance and the mechanism by which it is absorbed.
The presence of solid food in the stomach will tend to decrease the rate of stomach emptying and thus delay the absorption of the drug, which often results in decreased systemic availability of the drug. The relative bioavailability of lincomycin is reduced to about 60% when given 1 h before breakfast and to about 20% when given immediately after breakfast, compared with that observed after oral administration to fasting subjects. A potentially dangerous situation may arise owing to delayed absorption of hypnotic agents in non-fasting patients. With the hypnotic capuride, a
42-min difference in onset of absorption has been observed between fasting and non-fasting subjects.
The presence of food is also found to increase gastrointestinal motility and splanchnic blood flow up to 30%. Consequently, the absorption of some drugs is either unaffected or increased by food. Among the beta-blocking agents, absorption of bevantolol and oxprenolol was unchanged with food, whereas absorption of metoprolol, labetalol, and propranolol was increased, but the absorption of atenolol and sotalol was decreased. The oral absorption in humans of the antifungal antibiotic griseofulvin is substantially greater with food of high fat content than without food.
Because a high fat concentration in the small intestine stimulates bile secretion, absorption of the relatively lipophilic drug may be increased by enhancing its dissolution in the GI tract. Furthermore, the increase in splanchnic blood flow resulting from food consumption may contribute to the enhanced absorption. However, relatively polar and poorly permeable drugs show a tendency toward reduced absorption in the presence of food.[7] Food decreases absorption of alendronate, astemizole, captopril, didanosine, and penicillamine.
Food effects on drug absorption will depend not only on the physical and chemical properties of the drug substance but also on the formulation. Following oral administration of theophylline, the absorption rate of the drug can be either increased or decreased with food, depending on the formulation.[8] Generally, the greatest food effect is observed when the drug is taken immediately after a meal; the degree of interaction decreases as the time between eating and drugdosing increases.[9] Extensive reviews of the effect of food on drug absorption can be found in the literature.[10–12]
Drug interaction is another important factor affecting absorption. In general, interactions that interfere with absorption either involve binding or chelation of drugs in the GI tract, rendering them non-absorbable, or involve effects on gastric emptying or gastrointestinal motility. In addition, gastric pH changes may affect on the absorption of some drugs.
Antacids, particularly aluminum hydroxide gel, reduce the absorption of most tetracycline drugs by forming an insoluble complex in the gut. Simultaneous administration of iron (ferrous sulfate) with tetracycline, oxytetracycline, methacycline, or doxycycline seriously impairs the absorption of these antibiotics.
Adsorbants such as kaolin (an antidiarrheal agent) substantially reduce the absorption of lincomycin and promazine. Ion-exchange resins, such as cholestyramine, strongly bind many anionic and neutral drugs in the GI tract and interfere with the absorption of anticoagulants and thyroxine. Imipramine significantly reduces bioavailability of levodopa in humans, presumably because delayed absorption by reducing gastric emptying time enhances metabolism of levodopa in the gut. Orally administered ketoconazole requires an acidic medium to dissolve adequately and, therefore, antacids, anticholinergic drugs, H2 blockers, or acid pump inhibitors (e.g., omeprazole) will reduce the bioavailability of this drug. Metoclopramide, cisapride, and cathartics increase GI motility and may decrease the absorption of drugs that require prolonged contact with the absorbing surface and those that are absorbed only at a particular site along the GI tract. Anticholinergics decrease GI motility and may increase absorption by prolonging contact with the area of optimal absorption or may reduce absorption by slowing dissolution and gastric emptying. The interactions between drugs have been reviewed in detail.[13–15]
Factors affecting distribution After entering the general circulation, a drug is carried throughout the body and is distributed to various tissues. The drug distribution depends on the relative affinity of binding to plasma protein, red blood cells, and tissues. However, it can be altered in the presence of other drugs, in some disease states, and due to the age of the patient.
The risk of interactions resulting from the displacement of the drug from proteins is significant, primarily with drugs that are highly protein-bound (>90%) and that have a small apparent volume of distribution and a relatively narrow therapeutic window. This can result in a high concentration of unbound drug temporally (the first few days), which may have clinically important effects. Trichloroacetic acid, a major metabolite of chloral hydrate, displaces warfarin from its binding sites on plasma albumin. This displacement temporarily elevates plasma levels of warfarin and, thereby, increases the pharmacological effect per unit dose. Administration of
Disease states are another factor that may affect the binding of drugs to proteins in plasma and other tissues. Unusually low binding of drugs to plasma proteins has been observed in various diseases. For xample, the percentage of unbound phenytoin in plasma was 5.8–7.3% iormal subjects, whereas the percentages of unbound drug in patients with renal diseases (azotemia or uremia) were 8–25%. In addition to renal diseases, liver diseases, hyperbilirubinemia, and hyperlipidemia are reported to lower plasma protein binding of some drugs. However, during physiological stress (e.g., myocardial infarction, surgery, ulcerative colitis, and Crohn’s disease), the plasma protein binding of basic drugs (e.g., propranolol, quinidine, and disopyramide) increases, and volume of distribution decreases accordingly due to the increase in concentrations of the a1-acid glycoprotein.
Age-related changes in drug distribution have been reported. The apparent volume of distribution is somewhat larger iewborns and infants than in adults. The estimated volume of distribution of sulfamethoxypyridazine iewborns and infants is 0.47 and 0.36 L/kg, respectively, whereas the values are 0.20–0.26 L/kg in children, adults, and elderly subjects.
The volume of distribution of chlordiazepoxide is substantially larger in the elderly (0.52 L/kg) than in the young (0.42 L/kg). The age-related difference in the volume of distribution may be due to a difference in plasma protein binding and/or in the relative size of body compartments.
Drug Delivery: Parenteral Route
Michael J. Akers
Martinsville, Indiana, U.S.A.
INTRODUCTION
The United States Pharmacopoeia 24[1] defines a smallvolume injectable (SVI) as ‘‘an injection that is packaged in containers labeled as containing 100 ml or less.’’ Therefore, all sterile products packaged in vials, ampuls, syringes, cartridges, bottles, or any other container that is 100 ml or less fall under this classification.
Ophthalmic products packaged in squeezable plastic containers, although topically applied to the eye rather than administered by injection, also fall under the classification of small-volume injections as long as the container size is 100 ml or less. (See the article Ocular Drug Formulation and Delivery in this encyclopedia). Large-volume injectables (LVI) have to be terminally sterilized, whereas SVIs can be
sterilized terminally or by aseptic filtration and processing.
In fact, 80% or greater of all SVIs commercially available are prepared by aseptic processing. LVIs usually involve intravenous infusion, dialysis, or irrigation fluids containing electrolytes, sugar, amino acids, blood, blood products, and fatty lipid emulsions[2] LVIs must be administered by intravenous administration.
Small-volume injections may be injected by intravenous, subcutaneous, or intramuscular routes (primary routes of parenteral administration) or by various secondary routes such as intra-abdominal, intra-arterial, intraarticular, intracardiac, intracisternal, intradermal, intraocular, intrapleural, intrathecal, intrauterine, or intraventricular injections.
SVI formulations are relatively simple, composed of the active ingredient, a solvent system (preferably aqueous), a minimal number of excipients present for reasons described later in this chapter, and the appropriate container and closure packaging system.
If the active ingredient is unstable in solution or suspension, the product can be a dry powder, processed either by lyophilization or by sterile crystallization.
This chapter introduces the basic aspects of smallvolume injectable products—their use, types and primary characteristics of dosage forms, formulation ingredients, and packaging systems. Additional information is available in a variety of reference texts and book chapters.[2–7] Only conventional SVI formulations are addressed in this chapter. Advanced, long-acting (depot) formulations are not covered.
PRIMARY USES OF SMALL-VOLUME
INJECTABLES
Small-volume injectables can be therapeutic injections, ophthalmics, diagnostics, radiopharmaceuticals, or allergenic extracts. The active ingredients can be intended
for human or animal therapy and can be small molecules, proteins and other large molecules, biologics, accines, monoclonal antibodies, antisense oligonucleotides,
and, in the future, genes.
Therapeutic Injections Injections include a wide variety of therapeutic agents, e.g., for the treatment of cancer, infection, cardiovascular disease, arthritis and other inflammatory diseases, diabetes, hormonal deficiencies, central nervous system problems, and many other disease states. There are more than 400 injection products listed in the USP and, because of the huge number of biotechnology molecules in clinical study, this number will continue to grow rapidly over the next several years. Injections are primarily solutions containing the active ingredient and other substances. Product solutions are available either as ‘‘ready-to-use’’ (e.g., amobarbital sodium for injection) or solutions after reconstituting lyophilized (e.g., Gemzar_) or crystallized dry powder products (including many injectable cephalosporins). Some solutions may contain only the drug, e.g., vancomycin hydrochloride solution after reconstitution. Some products are suspensions in which the drug is suspended in a suitable medium, again either commercially available as a readyto-use suspension (e.g., Humulin_ N) or reconstituted as a suspension rather than as a solution (e.g., amoxicillin for injectable suspension). Injections can also be commercially available as concentrated liquids (e.g., potassium chloride for injection concentrate) that must be diluted before administration. Injectable products are either single dose or multiple dose. Multiple-dose Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-100000368 1266 Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved.
Injections must contain an antimicrobial preservative agent(s), and the volume of injection should not exceed 30 ml.[8]
Ophthalmic Products[9]
Ophthalmic drug products include drugs in solution, suspension, gel, or ointment, administered topically to the corneal surface of the eye. Ophthalmic products also include irrigating solutions in LVI sizes. There are many different types of ophthalmic drug products to treat glaucoma, infection, inflammation, and other diseases of the eye. Ophthalmic products must be sterile, but because they are topically applied, they are not required to be pyrogen-free. Ophthalmic solutions
and suspensions are usually packaged in squeezeable low-density polyethylene containers for easy administration.
Ophthalmic ointments are also sterile and must be free from metallic particles; they are packaged in ointment tubes. Because ophthalmic products are multiple-dose products, they must contain antimicrobial preservative agents. Because of plastic packaging, most ophthalmic products are aseptically processed. Diagnostic Agents Including Diagnostic Radiopharmaceuticals[10]
There are many SVI diagnostic agents available including solutions containing contrast media and solutions containing radioactive iodine, chromium, technetium,
iron, and other radioactive elements. These products are used primarily to evaluate organ functions. Contrast media solutions are stable in solution and, in fact, can be terminally sterilized. Most radioactive agents are produced to be used within hours of preparation because of the very short half-lives of the radioactive element. As with other sterile dosage forms, diagnostic agent products are to be sterile, pyrogen-free, and particulate-free.
Allergenic Extracts[11]
Allergenic extracts are sterile concentrates (solutions or suspensions) of the substances (allergens) responsible for unusual sensitivities in humans. These products
can be used for therapeutic or diagnostic purposes. Extracts are aqueous (0.9% sodium chloride used as the diluent) or glycerinated (50% glycerin as the diluent). Most preparations are buffered at pH 8 and contain phenol (_0.4%) as an antimicrobial preservative.
They are sterilized by aseptic filtration.
FORMULATIONS
Small-volume injectables are usually considered smallvolume solutions in vials or ampuls but are available in a variety of dosage forms and packaging systems.
Liquids Small-volume injectable liquids are primarily aqueous solutions. However, because many important therapeutic agents are poorly soluble or totally insoluble
in water, oily solvents and water-miscible cosolvents are used to produce ready-to-use solutions.
Aqueous solutions
Aqueous ready-to-use SVIs contain the active ingredient, additional substances, if necessary, and water as he solvent. Water-for-injection (WFI), USP, is the solvent of choice for aqueous SVIs. WFI is prepared by distillation or reverse osmosis techniques. Of all the USP types of water (Table 1), WFI is the purest form of water available for sterile products. An essential requirement of WFI is its freedom from pyrogenic contamination. WFI and other USP types of water are now required to pass a certain specification for endotoxin concentration (Table 1). Endotoxins are pyrogens with pyrogens being metabolic byproducts of microbial growth and death that cannot be destroyed by autoclaving or by sterilizing membrane filters. Aqueous SVI solutions are prepared either by illing the product into containers, sealing, and terminally sterilizing the finished product or, for drugs that cannot physically or chemically withstand high temperatures or radiation doses required for terminal sterilization, the drug product is sterile-filtered and aseptically filled into the final container and the container sealed by aseptic processing.
Non-aqueous solutions Several SVIs are marketed as oily solutions (Table 2).
The oil must be of vegetable origin (sesame, olive, or cottonseed oils are most commonly used) because of safety, purity, and biocompatiblity considerations. Oils
for injection must meet USP requirements:[12]
1. Solid paraffin test (measurement of oil clarity);
2. Saponification value between 185 and 200;
3. Iodine value between 79 and 128; and
4. Test for unsaponifiable matter and free fatty acids.
Oily solutions are prepared by separately sterilizing the solvent, usually using dry heat, and the drug (dry Drug Delivery: Parenteral Route 1267 heat or a gas such as ethylene oxide), then combining the solvent and drug aseptically. Terminal sterilization cannot be used for oily solutions because of the lack of moisture in the product necessary to generate saturated steam under pressure required to destroy microbial life.
Practical development experiences with oily injection formulations have been reported by Sims and Worthington[13] and Radd et al.[14].
Cosolvent A fairly large number of SVIs contain cosolvent systems; a partial listing of commercial products is given in Table 3. Cosolvents are used to increase the solubility of the poorly soluble drug in water. Cosolvents also tend to minimize or even prevent drug chemical degradation by hydrolysis, obviously because of the
reduction in the percentage of water in the system.
Water-miscible cosolvents operate on the principle of lowering the dielectric constant property of water, thereby increasing the aqueous solubility of poorly water-soluble drugs. Depending on drug stability, products containing cosolvents can be sterililized terminally using saturated steam under pressure. Otherwise, such products are prepared by aseptic processing. A primary concern in using cosolvents in injectable formulations is their potential to cause lysis of red blood cells when administered intravenously.[15] Therefore, any addition of a cosolvent to a formulation intended
for parenteral administration must be studied for its safety and potential toxicological effects.
Solids
SVIs are available as sterile dry solids that must be reconstituted with a diluent, usually sterile water for injection, USP, before being administered as a solution or suspension. Sterile dry SVIs are prepared using two primary methods.
Freeze-drying Most commercial sterile dry powders are manufactured by freeze-drying, also called lyophilization. In this process, under strict aseptic conditions, the product is Table 1 Types of water described in the United States Pharmacopeia Type Preparation Pryogen-free Comments Purified water USP Distillation or ion exchange No Pharmaceutical solvent Water for injection USP (WFI) Distillation or reverse osmosis Yesa Not sterile. Must be used within 24 h rstored below 5_C or _80_C; used for manuf. of parenteral products tobe sterilized Sterile water for injection USP
Distillation or reverse osmosis Yesa Same as WFI; single-dose containers; also used to reconstitute sterile solids and dilute sterile solutions Bacteriostatic water for injection USP Distillation or reverse osmosis Yesa Multiple and single dose Sterile water for irrigation USP Distillation or reverse osmosis Yesa
Table 2 Small-volume parenteral products containing oil(s) as the solvent system
Product, USP XXII Oil Ampicillin (suspension) Vegetable Desoxycorticosterone acetate Sesame Diethylstilbestrol Sesame, cottonseed Dimercaprol (suspension) Peanut Epinephrine (suspension) Sesame Estradiol benzoate Sesame Estradiol cypionate Cottonseed Estradiol valerate Sesame Estrone Sesame Ethiodized iodine Poppyseed Fluphenazine enanthate Sesame Hydroxyprogesterone caproate Sesame
Menadione Sesame Nandrolone decanoate Sesame Penicillin G procaine (suspension) Vegetable Propyliodone (suspension) Peanut Testosterone cypionate Cottonseed
Testosterone enanthate Sesame Testosterone propionate Sesame (From Ref.[4].)
1268 Drug Delivery: Parenteral Route aseptically filtered and filled as a solution. Special slotted rubber closures are inserted partially onto the vials, which are then transferred to a freeze dryer. Freezedrying involves three primary operations:
1. Freezing the product below its eutectic temperature (for crystalline materials) or below its glass transition temperature (for amorphousmaterials);
2. Primary drying in which the frozen solvent is sublimed, a phase transition from a solid directly to a gas; and
3. Secondary drying in which solute bound water is removed to an acceptable product moisture level for long-term stability.
At the completion of the freeze-dry cycle, the partially inserted rubber closures are fully seated in the vials. The finished product contains a white or offwhite sterile dry powder.
Freeze-drying operations are used because of limited stability of certain drugs in solution. Most therapeutic proteins are unstable in solution and can only be commercial products if they are freeze-dried. Freeze-dried formulations usually contain bulking agents (e.g., mannitol) that provide an esthetic dry solid matrix
and can help in stabilizing the drug in the solid state.
Other excipients are added to the freeze-dried formulation for various reasons, primarily to aid in product chemical and/or physical stabilization (e.g., buffers, antioxidants, cyroprotectants). Freeze-dried vials are usually stable for at least 2 years at ambient conditions, except for some protein products that might need to be refrigerated and have a shorter shelf life. Once the freeze-dried product is reconstituted, normal shelf-life storage conditions are 24 h at room temperature and
up to 1 week under refrigeration. Excellent freeze-drying science and technology reviews are available.[16]
Powder-filled SVIs
Many SVI antibiotics, particularly the injectable cephalosporins, as well as other molecules are manufactured by sterile crystallization of the active ingredient and aseptically filling the sterile powder into the final container. The drug is dissolved in an appropriate solvent, then filtered through a 0.2-mm membrane filter. Several techniques can be used for sterile crystallization, including adding sterile seed crystals and adjusting the pH level or adding a sterile antisolvent in which the drug is insoluble. The resultant slurry is collected on a filter system (e.g., the Buchner funnel) and dried, then the dried crystals are milled and blended. Obviously, for this approach to work, the drug must be able to be crystallized. Several variables are critical in controlling the purity and quality of the final crystals, including temperature, rate of addition of solvent, adjustment of pH level, mixing rate and time, and the quality of the seed crystals. Sterile crystallization followed by powder-filling is much more economical than freeze-drying. However, sterile powder-filling offers greater challenges with respect to process variability, microbial and particulate contamination, and operator sensitivity.
Suspensions[17]
With sterile suspensions, the active drug ingredient is suspended in a liquid carrier before administration.Parent–Vaginal
Commercial suspensions are either ready to use or dry powders reconstituted as suspensions. Drugs are formulated as suspension dosage forms for one of two reasons: poor solubility in aqueous solution but the product does not need to be administered iv, and the need for a long-acting depot injection.
Suspension products (Table 4) are prepared by combining sterile vehicle and sterile drug powder aseptically or by combining two sterile solutions, with the drug solution precipitating in the diluent solution.
Major concerns with the suspension dosage form are:
1. Resuspendability of the drug in the vehicle to permit homogeneous filling of the product into the container and to provide homogeneous dosing when withdrawing from the container;
2. Caking or settling of the drug, resulting in a physically unstable product; and
3. Syringeability (the ability to withdraw a homogeneous dose from the vial into a syringe) and injectability (the ability to eject the product through the needle into the patient).
Formulation ingredients include the suspending agent, a wetting agent (if the suspending agent does not also serve this purpose), a buffer, and an antimicrobial
preservative for multiple-dose products.
Emulsions[18]
Emulsions are mixtures of oil- and water-based vehicles with an appropriate surface-active agent to facilitate and maintain the miscibility of the oil-in-water phase. Diprivan_ (propofol, a local anesthetic agent) s a primary example of an SVI emulsion. The formulation contains soybean oil, glycerol, and egg lecithin.
BASIC CHARACTERISTICS OF SVIS
SVIs must be sterile and free from pyrogens and foreign particulate matter. These three major characteristics distinguish sterile dosage forms from any other pharmaceutical product.
Sterility[19]
Sterility is a state of absolute freedom from microbial contamination. Interestingly, the word sterile on the label of a sterile product has had a historic meaning that a sample of the product lot passed the compendial test for sterility.[20] Today, to claim that a product is sterile involves much more than passing a sterility test.
Achievement of sterility involves the combination and coordination of a wide range of activities and processes such as:
– Cleaning and sanitization of all facilities and equipment
– Cleaning and sterilization of equipment, packaging, and all other items to be in contact with the sterile product
– Installation and certification of laminar air flow areas where sterile air is provide via high-efficiency particulate air (HEPA) filters
– Environmental monitoring of the facility, equipment, water, and personnel for strict microbiological and particulate control–Vaginal
– Appropriate gowning and training of personnel in aseptic techniques
– Validation of sterilization processes
– Validation of the filter system
– Integrity testing of the filter system before and after filtration
– Integrity testing of the container-closure system to maintain sterility of the product
– Conductance of the sterility test initially for all lots and at the end of the shelf-life expiration dating period for the product lot under stability testing The end-product sterility test suffers from at least three serious limitations that minimize its dependability as a sole indicator of the sterility of a lot of product.
1. Concern that the small sample (usually 20containers per lot) truly represents the entire lot. Probability statistics reveal that with such a small sample size, the extent of contamination must be significant (on the order of at least 1% of the lot) for the sample to fail the sterility test.
2. Concern that the culture test media used for sterility testing can support the growth of low to high levels of any microbial life possibly contaminating the product.
3. Concern that no accidental contamination was introduced during the performance of the sterility test. There is a finite probability that personnel, testing environment, and/or testing materials may introduce contamination, resulting in a false-positive sterility test result. This concern has been alleviated to a great degree by the advent and successful application of barrier isolator technology systems. Such systems remove direct human contact with the sterile product samples and provide a testing environment that is validated as truly sterile.
Freedom from Pyrogens
Pyrogens are metabolic byproducts of microbial growth. Injected in sufficient amounts in humans (in fact, in any mammal), pyrogens can react with the hypothalamus of the brain to raise the body temperature.
In addition, they can cause a number of other adverse physiological effects, including death. The serious problems with sepsis are a result of high levels of endotoxins, endotoxins being a major type of pyrogen.
Pyrogens are very small, water-soluble, heat-resistant lipopolysaccharides that cannot be destroyed by typical steam-sterilization cycles or removed by 0.2-mm membrane filters. Prevention rather than elimination is the key for pyrogen removal. The primary source of pyrogenic contamination in parenteral products is water. Fortunately, pyrogens are destroyed by distillation.
Water used to clean containers and closures can also be a source of pyrogens. However, glass is sterilized by dry heat at temperatures hot enough (usually >250_C to destroy pyrogens). Rubber closures are steam-sterilized, which does not destroy pyrogens.
Closures are depyrogenated by the cleaning and rinsing process using pyrogen-free water. Chemical raw materials used in parenteral formulations must be crystallized
using pyrogen-free water or other solvents.
Some raw materials, e.g., sucrose, mannitol, amino acids, etc. must now be tested by incoming quality control for the presence of endotoxins. If the parenteral product is contaminated with pyrogens, there is no practical way to remove or destroy them. Ultrafiltration (nanometer; nominal molecular-weight filters) will depyrogenate and is used in bioprocessing for separating the smallest unit of lipopolysaccharide from therapeutic proteins. However, ultrafiltration is not a practical pyrogen-removal process for commercial processing of parenteral products.
Pyrogenic contamination is detected using two tests. In the older method, rabbits are injected with product samples, and rectal temperature is measured. Compendial limits are established with respect to how much temperature increase is permitted before the product is judged to be free or contaminated with pyrogens.
The newer method involves a relatively simple in vitro technique called the Limulus Amebocyte Lysate (LAL) test. It is based on the high senstivity of amebocytes of the horseshoe crab (Limulus) to the lipopolysaccharide component of endotoxins originating from Gramnegative bacteria. The LAL test is now the USP method of choice with endotoxin limits established for most SVIs.[21]
Freedom from Particulate Matter Particulate matter is viewed as unacceptable contamination in parenteral solutions. It is recognized that subvisible particulate matter will exist in certain amounts, but the USP now has limits for acceptable levels of particulate matter for SVIs (no more than 6000 particles per container _0.5 mm; no more than 600 particles per container _25 mm). The USP is the only compendium in the world that contains limits for subvisible particulates in SVIs. All worldwide compendia have subvisible particle limits (particles per milliliter) for large-volume injections. SVI solutions with visible particulate matter should not used. Particulate
matter creates problems in product quality and clinical safety. The primary sources of particulate matter are the container-closure systems and personnel.
Stability
Drugs in SVIs are generally unstable. Many drugs are so unstable that they cannot be marketed as ready-touse solutions. Drugs with sufficient solution stability will still require certain formulation, packaging, and storage conditions to maintain stability during shelflife storage and use. The primary pathways of drug degradation involves oxidation (reaction with molecular oxygen catalyzed by various factors including high temperature, high pH level, heavy metals, light, and peroxide contaminants) and hydrolysis (reaction with water catalyzed by high temperature and extremes in pH). For protein pharmaceuticals, aggregation of the protein, resulting in a loss of potency, can be a major degradation pathway. Drugs can also react with packaging and formulation components, resulting in physical and chemical degradation.
Oxidation involves the reaction of free radicals with molecular oxygen so the combination of functional groups that can easily form free radicals, e.g., phenolic
or sulfhydryl groups, catalysts (see above), and molecular oxygen, will cause a propagation of the selfoxidation process. Many SVI products are packaged in light-protective packaging, require storage at controlled room or lower (refrigeration) temperatures, are rmulated at low pH, contain antioxidants and/or metal chelating agents, and are processed in ‘‘oxygenfree’’ conditions where water is saturated with an inert gas, and, before to sealing the container, the product is overlayed with an inert gas to remove oxygen from the headspace of the container.
Many drugs in liquid SVIs will react with water and form hydrolytic degradation products. Hydrolysis and decomposition occur as solution pH may change and are catalyzed by resulting hydrogen and/or hydroxyl ions. Buffers play an important role in certain injectable products to achieve tight control of solution pH. Hydrolysis of solid-state injectables can occur with moisture from the headspace in the container, moisture remaining in the solid product, and/or moisture originating from or through the rubber closure. Control of residual moisture during and after processing and the use of effective container-closure systems to minimize moisture ingress are very important to protect dried powders from hydrolytic degradation.
Isotonicity
SVIs should be isotonic with blood, tears, spinal fluid, and other biological fluids into which the product is injected or instilled. This means that the injected or instilled solution contains the same ‘‘number’’ of solute ‘‘particles’’ in solution as is contained in the biological cell. Isotonicity means that the ‘‘tone’’ of the cell will not be disturbed, either by the ingress of water from the injected solution (if the solution is hypotonic) or egress of water from the cell (if the solution is hypertonic).
Solution tonicity can be ascertained by measurement of a colligative property such as osmostic pressure or freezing-point depression. Biological cells are semipermeable membranes, meaning that they allow the passage of water (and some solutes such as
boric acid) but do not allow passage of most solutes.
Thus, for example, if a hypotonic solution is injected or instilled, there are fewer solute ‘‘particles’’ in the solution than there are in the cell, forcing water from the injected solution to pass through the cell membrane in an attempt to equalize pressure on both sides of the cell membrane. Increasing the water level of the cell may lead to the cell bursting, which, for red blood cells, is a phenomenon called hemolysis. Hypertonic solutions administered cause the opposite effect, whereby water from the cells permeate the membrane to equalize pressure, and the cells shrink (crenation). In either case, cellular damage can occur causing pain and tissue irritation or damage. Blood, muscle, and subcutaneous cells can withstand a fairly wide range of osmotic pressures from injected solutions (e.g., 250–350 mOsm/kg), whereas tear and spinal fluid cells are much more sensitive to slight differences in the osmotic pressure of
injected or instilled solutions. In practice, wide osmolality ranges of SVIs can be tolerated when injected except for injections in cerebrospinal fluid (intrathecal, intraspinal, intracisternal injections). However, it is also true that for all injections, achieving isotonicity should be a goal of the product formulation scientist.
FORMULATION INGREDIENTS
SVIs are simple formulations compared with other pharmaceutical dosage forms. Solution SVIs contain water, the active ingredient, and a minimal number of inactive added ingredients. Solid SVIs contain the active ingredient and usually one or two added ingredients.
Formulation scientists have severe restrictions in number and choice of added substances because of safety considerations.
Solvent
The most widely used solvent for SVIs is water for injection (WFI), USP. As a solvent, WFI is used in preparing the bulk solution (compounding) and as a final rinse for equipment and packaging preparation. WFI is prepared by distillation or reverse osmosis, although only distillation is permitted for sterile water for injection, USP. Sterile water for injection is used as a vehicle for reconstitution of sterile solid products before administration and is terminally sterilized by autoclaving. Bacteriostatic water for injection, USP, is commercially available as a reconstitution vehicle for solid products intended for multiple-dose use. Benzyl alchohol is a common antimicrobial preservative used in bacteriostatic water for injection.
Sesame oil, cottonseed oil, and other vegetable oils are used as vehicles for water-insoluble drugs such as corticosteroids and oil-soluble vitamins. Oily solutions can be administered only by intramuscular injection.
Solubilizers
Solubilizers are used to enhance and maintain the aqueous solubility of poorly water-soluble drugs.[22–26] Examples of solubilizing agents used in sterile products include:
1. Liquid cosolvents: glycerin, polyethylene glycol (300, 400, 3350), propylene alcohol, and ethanol, Cremophor EL, sorbitol.
2. Surface active agents: polysorbate 80 (polyoxyethylene orbitan monooleate), polysorbate 20, Pluronic 68, lecithin.
3. Complexing agents: b-Cyclodextrins, Captisol_, polyvinylpyrrolidone, carboxymethylcellulose sodium.
Liquid solubilizers act by reducing the dielectric constant properties of the solvent system, thereby reducing the electrical conductance capabilities of the solvent and increasing the solubility of hydrophobic or non-polar drugs. Lanoxin,_ Valium,_ and Nembutal_are examples of commercially available sterile solutions containing cosolvent solubilizers. A popular combination consists of 40% propylene glycol and 10% ethanol in water.
Surface active agents increase the dispersability and water solubility of poorly soluble drugs owing to their unique chemical properties of possessing both hydrophilic and hydrophobic functional groups in the same molecule (the same is true of b-cyclodextrins, addressed below). The hydrophobic groups adsorb to surface molecules of the drug, whereas the hydrophilic groups interact with the water-solvent molecules.
Therefore, the drug molecules locate within the hydrophobic core of the surface active agent (sometimes called a micelle) while the polar molecules of the surface active agent are oriented with water, and the drug is solubilized within the surface active agent dissolved in water.
Solid solubilizers such as the b-cyclodextrins act by forming soluble inclusion complexes in aqueous solution.
These molecules, as with surface active agents, are amphiphilic, meaning that they contain hydrophobic interior functional groups and hydrophilic hydroxy exterior functional groups that enable insoluble drugs to remain in the interior core and be solubilized in water.
Loftsson and Brewster[27] reviewed the application of cyclodextrins in parenteral formulations, particularly for the solubilization and stabilization of proteins and peptides. A relatively new cyclodextrin, Captisol_, has gained prominence as a safe and effective solubilizer and stabilizer.[28] It is an anionic b-cyclodextrin with a sulfobutyl ether substituent.
Antimicrobial Preservative Agents
Antimicrobial preservatives serve to maintain the sterility of the product during its shelf life and use. They are required in preparations intended for multiple dosing from the same container because of the finite probability of accidental contamination during repeated use. They also are included, although this is quite controversial, in some single-dose products that are aseptically manufactured to provide additional assurance of product sterility. The combination of antimicrobial preservative agents and adjunctive heat treatment (usually temperatures below 110_C) also is used to
increase assurance of sterility for products that cannot be terminally sterilized. Very few antimicrobial preservative agents are acceptable (Table 5), with this list decreasing as agents such as thimerosal (and other mercury-containing preservatives) and chlorobutanol are no longer being used. Most substances with antimicrobial activity are irritating and toxic at relatively ow concentrations and usually have stability limitations (hydrolytic or oxidative degradation). They can be incompatible with the drug and formulation ingredients and can interact adversely with packaging
components. Most commonly used parenteral antimicrobial preservatives are alcoholic or phenolic chemicals.
These are highly toxic even at low concentrations and easily oxidizable, and their volatility can cause problems with rubber closure permeation. Formulation scientists must also be aware of significant differences comparing USP and EP requirements for preservative efficacy. Basically, the USP requires a bacteriostatic preservative system, whereas the EP requires a bacteriocidal preservative system. For example, whereas the USP requires a 1-log reduction 7 days after a bacterial challenge population is added to the product containing the antimicrobial preservative, the EP Criteria A requirement is a 3-log reduction in bacterial population after 1 day.
Buffers
Buffers are used to maintain the pH level of a solution in the range that provides either maximum stability of the drug against hydrolytic degradation or maximum
or optimal solubility of the drug in solution. The most common buffer systems used in SVIs are listed in Table 6. Buffers are composed of simple weak acids and their corresponding salt forms. The appropriate choice of buffer depends on the pH range in which the drug in question is most stable (or most soluble) that matches the pKa (dissociation constant) of the buffer species. For example, if a pH of 4.5 is most desirable, the correct choice of buffer would be an acetate buffer because the pKa of acetic acid is 4.76. At pH 4.76, acetic acid exists 50% as the acid (un-ionized form) and 50% as the salt (ionized form). Sufficient acid and salt species exist at this pH level to compensate or any potential drifts in solution pH and maintain the desired pH level. The concentration of buffer depends on strength of buffer capacity required
to maintain the pH level within the desired range.
Obviously, the higher the concentration, the greater the buffer capacity. However, high buffer concentrations can lead to other problems such as general acid/base catalysis of drug hydrolytic reactions.
Antioxidants
Antioxidants function by reacting preferentially with molecular oxygen and minimizing or terminating the free radical auto-oxidation reaction. Many drugs are
sensitive to the presence of oxygen and will degrade very rapidly in the absence of protection. In addition to the use of antioxidants, other precautions must be taken. These include protection from light, heat, heavy metal and peroxide contamination, and excessive exposure to air. Formulating the product at low pH is preferable if the product is stable and soluble at low pH. Common antioxidants are shown in Table 7.
The most widely used agent is sodium bisulfite because its oxidation-reduction potential lies in the range at which it does not preferentially oxidize too slowly or too rapidly. Other sulfurous acid salts also are effective antioxidants, as are ascorbic acid and sodium ascorbate. Sometimes, combinations of antioxidants strengthen oxidative drug protection as well as the combination of an antioxidant and a chelating agent.
The most common chelating agent used in parenterals is disodium ethylenediaminetetraacetic acid (DSEDTA).
Protein Stabilizers
Therapeutic proteins and peptides have exploded on the pharmaceutical scene in recent years. There are at least 30 commercial protein products currently marketed
and hundreds more in clinical study. Proteins are very reactive with their environment, with such reactions causing protein degradation. In pharmaceutical dosage forms, proteins are potentially quite reactive with water, formulation components, packaging components, and air. Environmental conditions that promote
protein degradation include high temperature, pH excursions, light, oxygen, moisture, and mechanical stress. Degradation reactions are both chemical and hysical, with physical stabilization often more challenging than chemical stabilization. Proteins easily aggregate under a variety of conditions, particularly at temperature extremes and with excessive mechanical manipulations. Denaturation in the form of aggregation can occur during the freezing and/or drying and subsequent storage of proteins processed by lyophilization. A number of ingredients have been shown to stabilize proteins both in the solution state and in the dry state.[29–32] Serum albumin will compete with therapeutic proteins for binding sites in glass and other surfaces and minimizes loss of the protein caused by surface binding. With concern about viral contamination iatural substances like albumin, other competitive binding agents are being investigated (e.g., hetastarch). A number of different types of substances are used as cryoprotectants and lyoprotectants to minimize protein denaturation during freeze-drying.
Primary examples include amino acids (glycine, lysine, glutamine); polyhydric alcohols (sorbitol, glycerol, polyethylene glycol); non-reducing sugars (sucrose, trehalose); and polymers such as polyvinylpyrolidone, methylcellulose, and dextran. Surface active agents, such as polysorbate 80, polysorbate 20, and poloxamer 188 (Pluronic 68), are widely used to minimize protein aggregation at air/water and water/solid interfaces.
Buffers, antioxidants, and chelating agents also are used to stabilize proteins in solution wheecessary.
Tonicity Adjusters
A variety of agents are used in sterile products to adjust tonicity. Most common are simple electrolytes such as sodium chloride or other sodium salts and non-electrolytes such as glycerin and lactose. Tonicity adjusters are usually the last ingredient added to the formulation after other ingredients in the formulation are established and the osmolality of the formulation measured. If the formulation is still hypotonic (i.e., <280 mOsm/kg as measured by a commonly used osmometer instrument), tonicity adjusting agents are added until the formulation is isotonic. If the formulation is hypertonic, the degree of hypertonicity and the intended route of drug administratioeed to be considered. For intravenous administration, hypertonicity values up to approximately 360 mOsm/kg are not considered harmful. However, for other routes of administration, efforts should be made to make the final product isotonic before administration. This can be accomplished either by reducing concentrations of ingredients, if acceptable, or by diluting the product before administration.
Other Ingredients
Bulking agents are used in freeze-dried preparations to increase the solid content of the ‘‘plug’’ in the container after the sublimation process during the freezedrying cycle. Bulking agents not only serve to enhance the elegance of the product but also can serve as stabilizers in adsorbing excess moisture during shelf life.
Suspending agents keep the drug suspended in the solvent after shaking and allow homogeneous dosing of the suspended drug from the container. Emulsifying agents lower the interfacial tension of an oil and water interface to allow the two immiscible solvents to mix and form a stable emulsion dosage form. Semisolid agents aid in the dispersibility of the drug in ophthalmic ointments and provide the ointment base. Examples of these different additives are:
1. Bulking agents: mannitol, lactose, sucrose, dextran.
2. Suspending agents: carboxymethylcellulose, ethylcellulose, gelatin, sorbitol.
3. Emulsifying agents: lecithin, polysorbate 80.
4. Ophthalmic ointment bases: petrolatum.
Two comprehensive references are available that ist type and concentration of all excipients used in commercial sterile formulations that should be part of every sterile formulation scientist’s library.
PACKAGING
The packaging system obviously is an integral part of the parenteral product, providing long-term protection and maintenance of physical and chemical stability of
the product formulation. Packaging can also be used as a drug delivery tool by providing more convenient delivery of the drug product (e.g., syringes, dual chamber
vials) and offering better control of drug dosing (e.g., cartridges). Packaging is a major source of particulate contamination and can contribute to physical and chemical degradation of the product. Packaging constituents can leach into the product or the product can be adsorbed or absorbed. The primary types of packaging systems are glass, rubber, and plastic. Metal tubes for ophthalmic ointments are not addressed here.
Primary SVI packaging systems include glass sealed ampuls, rubber closed vials, prefilled syringes, cartridges, and small- and large-volume bottles made either of glass or plastic.
Glass[34]
Glass used for parenteral products is classified as type I, type II, and type III (Table 8). Type I is the highest quality grade, composed almost exclusively of borosilicate
(silicon dioxide), making it chemically resistant to extreme acidic and alkaline conditions. Type I glass, although more expensive, is preferred for most parenteral
products. Often, even type I glass must be surface treated with agents such as ammonium sulfate or silica dioxide to remove surface leachates. Type II glass is made of soda-lime glass but is treated with sodium sulfite or sulfide to neutralize surface alkaline oxides.
Type III glass is untreated soda-lime glass. Type II glass generally is used for large-volume injectables and for small-volume products if the solution pH level is less than 7.0. Type III glass can only be used for oily solutions and dry powders. The USP[35] and other compendia provide requirements and tests necessary to qualify the different types of glass.
Formulation scientists must be aware that glass can and will leach out various elements such as boron, sodium, potassium, calcium, iron, and magnesium.
Glass leachates can affect solution pH and cause precipitation problems if the drug or other formulation component forms insoluble salts when combined with these leachates. Solutions of high pH level are notorious for causing alkali leachates. Quality control of each lot of glass must be consistent to control these potential difficulties with leachates. Glass particulates can also be a problem owing to delamination of the inner surface of the glass.
Amber glass containers can be used for lightsensitive SVIs. The amber color is produced by the addition of iron and manganese oxides to the glass formulation. Oxide leachates can occur and catalyze oxidation reactions.
Rubber[36]
Rubber formulations are used as rubber closures (vials, cartridges); rubber plungers (syringes, cartridges); and other applications (rubber septum in dual chamber vials, rubber septum for needle introduction in administration set tubing). The formulations can be very complex. Not only do they contain the basic rubber polymer, but also they may contain many additives such as plasticizers, fillers, vulcanizing agents, pigments, activators, accelerants, and antioxidants. Many of these additives are not fully characterized for content or purity and can be sources of physical and chemical degradation problems in parenteral products.
The formulation scientist must work as closely with the rubber manufacturer as with the glass manufacturer to choose the appropriate rubber formulation having consistent specifications and characteristics to maintain product stability.
The most common rubber polymers used in SVI closures are natural and butyl rubber (Table 9). Silicone and neoprene also are used but less frequently in sterile products. Butyl rubber has great advantages over natural rubber in that butyl rubber requires fewer additives, has low water vapor permeation properties, and has good characteristics with respect to gaseous (e.g., oxygen) permeation and reactivity with the active ingredient.
Problems with rubber materials include leaching of constituents (e.g., zinc) into the product, adsorption of active ingredients or antimicrobial preservatives, and coring of the rubber by repeated insertion of a needle.
Coring produces rubber particulates that affect the quality and, potentially, the safety of the product.
Siliconization of rubber closure is a common practice in manufacturing to facilitate movement of the closure through stainless steel equipment on the filling lines. However, silicone is incompatible with hydrophobic drugs. Excessive silicone on rubber can potentiate protein aggregation and cause precipitation problems with certain drugs. Elastomer manufacturers have developed rubber formulations with specially bonded coatings that provide ‘‘slippery’’ rubber surfaces and, thus, do not require the need to apply silicone for high-speed processing equipment.
Plastic
Plastic packaging has always been important for ophthalmic drug dosage forms and is gaining in popularity for injectable dosage forms. Plastic bottles are used to enable people to apply droplets of medication into the eye. Plastic bottles for LVIs have been used for many years. Plastic vials for SVIs may be a wave of the future. Plastic packaging offers such advantages of cost savings, elimination of the problems caused by breakage of glass, and increase convenience of use.
As with other packaging systems, plastic formulations can interact with the product, causing physical and chemical stability problems. Plastic formulations are less complicated than are rubber formulations and tend to have a lower potential for leachability of its constituents. However, plasticizer leachates are wellknown with polymers such as polyvinyl chloride containers used for LVI bags and administration
devices. The most commonly used plastic polymer for ophthalmic products is low-density polyethylene. For other SVIs, polyolefin formulations are widely used as well as polyvinyl chloride, polypropylene, polyamide (nylon), polycarbonate, and copolymers such as ethylene vinyl acetate.
STORAGE
Proper storage of SVIs is critical for the safety and potency of the active ingredient(s) contained in the packaging system. Long-term stability studies are necessary for the appropriate storage conditions. Stability studies involve storing the product at various temperatures, exposing to light, exposing to various relative humidities, and assessing the effect of mechanical stress during transportation and handling. Studies on proper storage conditions and appropriate handling are extremely important in this age of global distribution of drug products, particularly products containing temperature- and stress-sensitive biomolecules. In addition to concerns regarding the maintenance of chemical and physical stability of the drug product during distribution and storage, there is also concern that the container-closure system is adequate to maintain sterility and other microbiological quality attributes of the sterile product. Container-closure integrity studies in recent years have taken on greater prominence as require these data in registration approvals and in the routine conducting of stability studies. Excellent references on container-closure integrity methods are available.[37,38]
ARTICLES OF FURTHER INTEREST
Autoxidation and Antioxidants, p. 139.
Freeze Drying, p. 1807. Excipients: Parenteral Dosage Forms and Their Role Sandeep Nema Pharmacia Corp., Skokie, Illinois, U.S.A. Ron J. Brendel Mallinckrodt, Inc., St. Louis, Missouri, U.S.A. Richard Washkuhn Consultant, Lexington, Kentucky, U.S.A.
INTRODUCTION
The term pharmaceutical excipient or additive denotes compounds that are added to the finished drug product for a variety of reasons. Most often excipients are major components of the drug product, with the active drug molecule present in a small percentage. Excipients also have been referred to as inactive or inert ingredients to distinguish them from the active pharmaceutical ingredients. However, in many instances excipients may not be as inert as some scientists believe. Several countries have restrictions on the type or the amount of excipient that can be included in the formulation of parenteral drug products due to safety issues. For example, in Japan, amino mercuric chloride, or thimerosal use is prohibited, even though these excipients are present in several products in the United States.
As defined in the European Pharmacopoeia (EP) 1997 and the British Pharmacopoeia (BP) 1999, ‘‘Parenteral preparations are sterile preparations intended for administration by injection, infusion, or implantation into the human or animal body.’’[1,2] However, for the purposes of this article, only sterile preparations for administration by injection or infusion into the human body will be surveyed. Injectable products require a unique formulation strategy. The formulated product has to be sterile, pyrogen free, and in the case of solutions, free of particulate matter. No coloring agent may be added solely for the purpose of coloring the parenteral preparation. Preferably, the formulation should be isotonic, and depending on the route of administration, certain excipients may not be allowed.
For a given drug, the risk of an adverse event may be higher or the effects may be difficult to reverse if it is administered as an injection versus a non-parenteral route, since the injected drug bypasses natural defense barriers. The requirement for sterility demands that the excipient be able to withstand terminal sterilization or aseptic processing. These factors limit the choice of excipients available to the formulator.
Generally, a knowledge of which excipients have been deemed safe by the Food and Drug Administration (FDA) or are already present in a marketed product provides increased assurance to the formulator hat these excipients will probably be safe for their new drug product. However, there is no guarantee that the new drug product will be safe as excipients are combined with other additives and/or with a new drug
molecule, creating unforeseen potentiation or synergistic toxic effects. Regulatory bodies may view favorably an excipient previously approved in an injectable dosage form and will frequently require less safety data. A new additive in a formulated product will always require additional studies adding to the cost and timeline of product development.
In Japan, if the drug product contains an excipient with no precedence of use in that country, then the quality and safety attributes of the excipient must be evaluated by the Subcommittee on Pharmaceutical Excipients of the Central Pharmaceutical Affairs Council concurrently with the evaluation of the drug product application.[3] Precedence of use means that the excipient has been used in a drug product in Japan,
and will be administered via the same route and in a dose level equal to or greater than the excipient in uestion in the new application.
This chapter is a comprehensive review of the excipients included in the injectable products marketed in the United States, Europe, and Japan. A review of the literature indicates that only a few articles that specifically deal with the selection of parenteral excipients have been published.[4–9] However, excipients included in other sterile dosage forms not administered parenterally, such as solutions for irrigation, ophthalmic or otic drops, and ointments, will not be covered.
Several sources of information were used to summarize the information compiled in this chapter.[4–7,10–14]
Formulation information on the commercially available injectable products was entered in a worksheet.
Tables presented in this chapter are condensed from this worksheet. Each table is categorized based on the Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-100001054 1622 Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved.
Primary function of the excipient in the formulation. For example, citrates are classified as buffers and not as chelating agents, and ascorbates are categorized as antioxidants, although they can serve as buffers.
This classification system minimizes redundancy and provides a reader-friendly format. The concentration of excipients is listed as percent weight by volume (w/v) or volume by volume (vol%). If the product was listed as lyophilized or powder, the percentages were derived based on the reconstitution volume commonly used. The tables list the range of concentration and examples of products containing the excipient, especially those that use an extremely low or high concentration.
TYPES OF EXCIPIENTS
Solvents and Cosolvents
Table 1 list solvents and cosolvents used in parenteral products. Water for injection is the most common solvent but may be combined or substituted with a cosolvent to improve the solubility or stability of drugs.[15,16] The dielectric constant and solubility parameters are among the most common polarity indices used for solvent blending.[17,18] Ethanol and propylene lycol are used either alone or in combination with other solvents in more than 50% of parenteral cosolvent systems. Surprisingly, propylene glycol is used more often than polyethylene glycols (PEGs) in spite of its
higher myotoxicity and hemolyzing effects.[19–22] The hemolytic potential of cosolvents is as follows:[19] Dimethyl acetamide < PGE400 < Ethonal < Propylene glycol < Dimethyloxide It is possible that the presence of residual peroxide from the bleaching of PEG or the generation of peroxides in PEG may result in the degradation of the drug in the cosolvent system. It is important to use unbleached
and/or peroxide–free PEGs in the formulation.
Oils such as safflower and soybean are used in total parenteral nutrition products, where they serve as a fat source and as carriers for fat-soluble vitamins. The U.S. Pharmacopeia (USP) requirement for injectable oils is as follows:
A. Fixed oils (of vegetable origin)
_ Saponification value (185–200)
_ Iodine number (79–128). (The Japanese Pharmacopoeia (JP) recommends value between 79–137.)
_ Test for unsaponifiable matter
_ Test for free fatty acid
_ Solid paraffin test at 10_C
_ Acid value NMT 0.56 (JP only)
B. Synthetic mono-and diglycerides of fatty acids (which are liquid and remain so when cooled to 10_C)
_ Iodine number (<140)
_ Solid paraffin test at 10_C
The oils also are used to dissolve drugs with low aqueous solubility and provide a mechanism to slowly release drug over a long period of time. Deterioration of fixed oils, which leads to rancidity and production of free fatty acids, must be avoided in injectable products.
Also the fixed oils or fatty acid esters must not contain mineral oil or paraffin which the body cannot metabolize.
Polymeric and Surface Active Compounds
Table 2 includes a broad category of excipients whose function in formulation could be as follows:
1. To impart viscosity or act as suspending agents such as carboxy methyl cellulose, sodium carboxy methyl cellulose, acacia, Povidone, hydrolyzed gelatin, and sorbitol.
2. To act as solubilizing, wetting, or emulsifying agents such as Cremophor EL, sodium desoxycholate, Polysorbate 20 or 80, PEG 40 castor oil, PEG 60 castor oil, sodium dodecyl sulfate, lecithin, or egg yolk phospholipid.
3. To form gels such as when aluminum monostearate is added to fixed oil to form a viscous or gel-like suspension medium.
Polysorbate 80 is the most common and versatile solubilizing, wetting and emulsifying agent. Again, one must be concerned about the level of residual peroxides present in polysorbates and protecting them from air to prevent further oxidation. Polysorbate 80 is polyoxyethylene sorbitan ester of oleic acid (unsaturated fatty acid) while polyoxyethylene Polysorbate 20 is sorbitan ester of lauric acid (saturated fatty acid). Thus, stability differences could occur in the drug product formulated with Polysorbate 80 vs. Polysorbate 20. One example is Neupogen_
which when exposed to a high concentration of Polysorbate 20 exhibited substantially less oxidation than when exposed to a similar concentration of Polysorbate 80.
Chelating Agents
Only a limited number of chelating agents are used in parenteral products (Table 3). They serve to complex heavy metals and therefore can improve the efficacy of antioxidants or preservatives. Citric acid, tartaric acid and some amino acids also can act as chelating agents. There have been some misunderstandings concerning the use of EDTA (as calcium salt) as an approved injectable product in Japan. Currently in
Japan, some drug products that contain calcium disodium EDTA are on the market and this excipient is also listed as an official excipient (Table 11). An advantage of calcium EDTA over tetrasodium salt is that calcium EDTA does not contribute sodium and does not chelate as much calcium from the blood.
A complexing agent should not be used in metalloprotein formulations, where the protein subunits are held by the metal.[24] The EDTA, in rare instances, can increase the oxidation rate due to binding of the EDTA–metal complex to protein, resulting in sitespecific generation of radicals.[25]
Antioxidants
Antioxidants are used to prevent the oxidation of active substances and excipients in the finished product.
There are three main types of antioxidants:
1. True Antioxidants: They act by a chaintermination mechanism by reacting with free radicals, e.g., butylated hydroxytoluene.
2. Reducing Agents: They have a lower redox potential than the drug and get preferentially oxidized, e.g., ascorbic acid. Thus, they can be consumed during the shelf-life of the product.
3. Antioxidant Synergists: These enhance the effect of antioxidants, e.g., EDTA.
Table 4 summarizes the antioxidants, their frequency of use, concentration range, and examples of products containing them. Sulfite, bisulfite, and metabisulfite constitute the majority of antioxidants used in parenteral products despite several reports of
incompatibility and toxicity.[26,27] Butylated hydroxy anisole, butylated hydroxy toluene, alpha tocopherol, and propyl gallate are primarily used in semi/nonaqueous
vehicles because of their low aqueous solubility.[28] Ascorbic acid/sodium ascorbate may serve as an antioxidant, buffer and chelating agent in the same formulation. Some amino acids such as cysteine also function as effective antioxidants.
The Committee for Proprietary Medicinal Products (CPMP) guideline calls for a full explanation and justification for including antioxidants in the formulation.[29] It further states that antioxidants should only be included in a formulation if it has been proven that their use cannot be avoided. Thus, it is imperative to first try inert gas (nitrogen or argon) in the headspace to prevent oxidation. If the antioxidant has to
be included, its concentration must be justified in terms of efficacy and safety. Antioxidants such as sulfites and metabisulfites are especially undesirable.
Some antioxidants possess antimicrobial properties, such as propyl gallate and butylated hydroxy anisole, which are somewhat effective against bacteria. Butylated
hydroxy toluene has demonstrated some antiviral activity. Compatibility of antioxidants with the drug, packaging system and the body should be studied carefully.
For example, tocopherols may be absorbed onto plastics; ascorbic acid is incompatible with alkalis, heavy metals, and oxidizing materials such as phenylephrine, and sodium nitrite; and propyl gallate forms complexes with metal ions such as sodium, potassium and iron.
Preservatives
Benzyl alcohol is the most common antimicrobial preservative present in parenteral formulations (Table 5).
This observation is consistent with other surveys.[6,30] Parabens are the second most common preservatives.
Surprisingly, thimerosal is also common, especially in vaccines, even though some individuals are sensitive to mercurics. Several preservatives can volatilize easily (such as benzyl alcohol, and phenol) and, therefore, should not be used for lyophilized dosage form.
Chlorocresol is purported to be a good preservative for parenterals, but our survey did not find any examples of commercial products containing chlorocresol.
The British Pharmaceutical Codex and Martindale list chlorocresol as a preservative to be used in multidose aqueous injections at concentrations of 0.1% but no examples of injectable products have been provided.[31,32]
Antimicrobial preservatives are allowed in multidose injections to prevent growth of microorganisms that may accidentally enter the container during withdrawal of the dose. However, they are discouraged from being used in single-dose injections in the United States while the EP and BP allow aqueous preparations, that are manufactured using aseptic techniques, to contain suitable preservatives. It should be emphasized that preservatives should never be used as a substitute for inadequate good manufacturing practices (GMP).
BP and EP prohibit antimicrobials from single-dose injections where the dose volume is greater than 15mL or if the drug product is to be injected via intracisternal, or any route which gives access to the cerebrospinal fluid (CSF). Toxicity is the primary
reason for minimizing the use of antimicrobial preservatives.
For example, many individuals are allergic to mercury preservatives while benzyl alcohol is contraindicated in children under the age of 2. USP has also placed some restrictions on the maximum concentration of preservatives allowed in the formulation to address toxicity and allergic reactions (Table 6). The World Health Organization (WHO) has set an estimated total acceptable daily intake for sorbate (as
acid, calcium, potassium and sodium salts) as not more than 25 mg/kg body weight. The efficacy of the preservative should be assessed during product development using Antimicrobial Preservative Effectiveness Testing (PET).[33–35] Thus, an aqueous-preserved parenteral product can be used up to a maximum of 28 days after the container has been opened.[36] Obviously, 28 days has to be justified by performing PET on the finished product in the final package. On the other hand, unpreserved products preferably should be used immediately following opening, reconstitution, or dilution.
Buffers
Buffers are added to a formulation to adjust the pH in order to optimize solubility and stability. For parenteral preparations, the pH of the product should be close to physiologic pH. The selection of buffer concentration (ionic strength) and buffer species is important. For example, 5–15mM of citrate buffers are used in the formulation but increasing buffer concentration to >50mM will result in excessive pain on subcutaneous injection and toxic effects due to the chelation of calcium in the blood.
Buffers have maximum buffer capacities near their pKa. For products that may be subjected to excessive temperature fluctuations during processing (such as sterilization or lyophilization), it is important to select buffers with a small DpKa/_C. Thus, Tris, whose DpKa/_C is large (_0.028/_C), the pH of buffer made at 25_C will change from 7.1 to 5.0 at 100_C. This may dramatically alter the stability or solubility of the drug.
Similarly, the best buffers for a lyophilized product may be those that show the least pH change upon cooling, that do not crystallize out, and that can remain in the amorphous state protecting the drug. For example, replacing succinate with glycolate buffer improves the stability of lyophilized interferon-g.[37] During the lyophilization of mannitol that contains succinate buffer at pH 5, monosodium succinate crystallizes, reducing the pH and resulting in the unfolding of interferon-g.
This pH shift is not seen with glycolate buffer.
Table 7 lists buffers and chemicals used to adjust the pH of formulations and the product pH range. Phosphate, citrate, and acetate are the most common buffers used in parenteral products. Mono- and diethanolamines are added to adjust pH and form salts. Hydrogen bromide, sulfuric acid, benzene sulfonic acid, and methane sulfonic acids are added to drugs which are salts of bromide (Scopolamine HBr, Hyoscine HBr), sulfate (Nebcin, Tobramycin sulfate), besylate (Tracrium Injection, Atracurium
besylate) or mesylate (DHE 45 Injection, Dihydroergotamine mesylate). Glucono delta lactone is used to adjust the pH of Quinidine gluconate. Benzoate buffer, at a concentration of 5%, is used in Valium Injection.
Citrates are a common buffer that can have a dual role as chelating agents. The amino acids lysine and glycine, function as buffers and stabilize proteins and peptide formulations. These amino acids are also used as lyoadditives and may prevent cold denaturation. Lactate and tartrate are occasionally used as buffer systems.
Acetates are good buffers at low pH, but they are not generally used for lyophilization because of potential sublimation of acetates.
Bulking Agents, Protectants, and Tonicity Adjusters
Table 8 lists additives that are used to modify osmolality, and as bulking or lyo/cryoprotective agents.
Dextrose and sodium chloride are used to adjust tonicity in the majority of formulations. Some amino acids such as glycine, alanine, histidine, imidazole, arginine, asparagine, and aspartic acid are used as bulking agents for lyophilization and also can serve as stabilizers, and/or as buffers. Monosaccharides (dextrose, glucose, maltose, lactose), disaccharides (sucrose, trehalose), polyhydric alcohols (inositol, mannitol, sorbitol), glycols (PEG 3350), Povidone (polyvinylpyrrolidone,
PVP) and proteins (albumin, gelatin) are commonly used as lyo-additives. Hydroxyethyl starch (hetastarch) and pentastarch, which are currently used as plasma expanders in commercial injectable roducts such as Hespan and Pentaspan, also are
being evaluated as protectants during freeze-drying of proteins.
PVP has been used in injectable products as a solubilizing agent, a protectant and as a bulking agent.
Only pyrogen-free grade, with low molecular weight (K value less than 18) should be used in parenteral products to allow for rapid renal elimination. PVP not only solubilizes drugs such as rifampicin, but it also can reduce the local toxicity as seen in oxytetracycline injection.
Many proteins can be stabilized in the lyophilized state if the stabilizer and protein do not phase separate during freezing or the stabilizer does not crystallize out.
In the case of Neupogen_ (GCSF), the original formulation was modified by replacing mannitol with sorbitol to prevent the loss of activity of liquid formulation
in case of accidental freezing.[23] Mannitol crystallizes if the solution freezes while sorbitol remains in an amorphous state protecting GCSF. Similarly, it is useful that the drug remains dispersed in the stabilizer upon freezing of the solution. Thus, Cefoxitin, a cephalosporin, is more stable when freeze-dried with sucrose than with trehalose, although the glass transition temperature and structural relaxation time is much greater for trehalose than sucrose.[38] FTIR data indicated that the trehalose–cefoxitin system phase separated into two nearly pure components, resulting io protection (stability). Similarly, dextran was not found to be as useful a cryoprotectant for protein as sucrose because dextran and protein underwent phase segregation as the solution started to freeze. The mechanism of cryoprotection in the solution has been explained by the preferential exclusion hypothesis.[39]
Trehalose is a non-reducing disaccharide composed of two D-glucose monomers. It is found in several animals that can withstand dehydration and therefore was suggested as a stabilizer of drugs that undergo denaturation during spray or freeze-drying.[40] Herceptin_ (Trastuzumab) is a recombinant DNA-derived monoclonal antibody (MAb) that is used for treating metastatic breast cancer. The MAb has been stabilized in the lyophilized formulation using a,a-trehalose dihydrate.
Trehalose has also been used as a cryoprotectant to prevent liposomal aggregation and leakage. In the dried state, carbohydrates such as trehalose, and inositol, exert their protective effect by acting as a water substitute.[41]
Additives may have to be included in the formulation to adjust the specific gravity. This is important for drugs that upon administration may come in contact with CSF. CSF has a specific gravity of 1.0059 at 37_C. Solutions that have the same specific gravity as that of CSF are termed isobaric, while those solutions that have specific gravity greater than that of CSF are called hyperbaric. Upon administration of a hyperbaric solution in the spinal cord, the injected solution will settle and will affect spinal nerves at the end of the spinal cord. For example, Dibucaine hydrochloride
solution (Nupercaine_ 1 : 200) is isobaric, while Nupercaine 1 : 500 is hypobaric (specific gravity of 1.0036 at 37_C). Nupercaine heavy solution is made hyperbaric by addition of 5% dextrose solution, and this solution will block (anesthetize) the lower spinal nerves as it settles in the spinal cord.
Special Additives
Special additives serve special functions in pharmaceutical formulations (Table 9). The following is a summary of special additives along with their intended use:
1. Calcium gluconate injection (American Regent) is a saturated solution of 10% w/v. Calcium D-saccharate tetrahydrate 0.46% w/v is added to prevent crystallization during temperature fluctuations.
2. Cipro IV_ (Ciprofloxacin, Bayer) contains lactic acid as a solubilizing agent for the antibiotic.
3. Premarin Injection_ (Conjugated Estrogens, Wyeth-Ayerst Labs) is a lyophilized product that contains simethicone to prevent the formation of foam during reconstitution.
4. Dexamethasone acetate (Dalalone DP, Forest, Decadron-LA, Merck) and Dexamethasone sodium phosphate (Merck) are available as a suspension or a solution. These dexamethasone formulations contain creatine or creatinine as additives.
5. Adriamycin RDF_ (Doxorubicin hydrochloride, Pharmacia-Upjohn) contains methyl paraben, 0.2 mg/ml to increase dissolution.[42]
6. Ergotrate maleate (Ergonovine maleate, Lilly) contains 0.1% ethyl lactate as a solubilizing agent.
7. Estradurin Injection_ (Polyestradiol phosphate, Wyeth-Ayerst Labs) uses Niacinamide (12.5mg/ ml) as a solubilizing agent. Hydeltrasol_ also contains niacinamide. The concept of hydrotropic agents to increase water solubility has been tried on several compounds, including proteins.[43,44]
8. Aluminum, in the form of aluminum hydroxide, aluminum phosphate or aluminum potassium sulfate, is used as adjuvant in various vaccine formulations to elicit an increased immunogenic response.
9. Lupron Depot Injection_ is lyophilized microspheres of gelatin and glycolic–lactic acid for intramuscular (IM) injection. Nutropin Depot consists of polylactate–glycolate microspheres.
10. Gamma cyclodextrin is used as a stabilizer in Cardiotec_ at a concentration of 50 mg/ml.
11. Alprostadil (Edex_, Schwartz) is a lyophilized product of Prostaglandin E1 in a-cyclodextrin inclusion complex. The complex has better stability and aqueous solubility than the drug itself.
12. Itraconazole (Sporanox_, Janssen) is solubilized as a molecular inclusion complex using hydroxypropyl- b-cyclodextrin.
13. Sodium caprylate (sodium octoate) has antifungal properties, but it is also used to improve the stability of albumin solution against the effects of heat. Albumin solution can be pasteurized by heating at 60_C for 10 h in the presence of sodium caprylate. Acetyl tryptophanate sodium is also added to albumin formulations.
14. Meglumine (N-methylglucamine) is used to form in situ salt. For example, diatrizoic acid, an X-ray contrast agent, is more stable when autoclaved as meglumine salt than as sodium salt.[45]
Meglumine is also added to Magnevist_, a magnetic resonance contrast agent.
15. Tri-n-butyl phosphate is present as an excipient in human immune globulin solution (Venoglobulin_).
Its exact function in the formulation is not known, but it may serve as a scavenging agent.
16. von Willebrand factor is used to stabilize recombinant antihemophilic factor (Bioclate_).
17. Maltose serves as a tonicity adjuster and stabilizer in immune globulin formulation (GamimuneN_).
18. Epsilon amino caproic acid (6-amino hexanoic acid) is used as a stabilizer in anistreplase (Eminase Injection_).
19. Zinc and protamine have been added to insulin to form complexes and control the duration of action.
The FDA has published the ‘‘Inactive Ingredient Guide’’ which lists all excipients in alphabetical order.[14] Each ingredient is followed by the route of administration, and in some cases, the range of concentration used in the approved drug product. However, this list does not provide the name of commercial product(s) corresponding to each excipient. Table 10 summarizes all the excipients included in the ‘‘Inactive
Ingredient Guide’’ that do not appear in the Physician’s Desk Reference (PDR), GenRx, or Handbook of Injectable Drugs.
Similarly, in Japan the ‘‘Japanese Pharmaceutical Excipients Directory’’ is published by the Japanese Pharmaceutical Excipients Council, with the cooperation and guidance of the Ministry of Health and Welfare.[46]
This directory divides the excipients into:
1. Official. Those 590 excipients that have been recognized in the JP, Japanese Pharmaceutical Codex, and Japanese Pharmaceutical Excipients, and for which testing methods and standards have been determined. Table 11 summarizes official excipients used in parenteral products.
2. Non-Official Excipients. These 522 excipients are used in pharmaceutical products sold in Japan and will be included in the official book or in supplemental editions. The non-official excipients, used in parenteral products, are listed in Table 12.
REGULATORY PERSPECTIVE
The International Pharmaceutical Excipients Council (IPEC) has classified excipients into the following four classes, based on available safety testing information:[47]
1. New Chemical Excipients: Require a full safety evaluation program. The estimated cost of safety studies for a new chemical excipient is approximately $35 million over 4–5 years.
European Union (EU) directive 75/318/EEC states that new chemical excipients will be treated in the same way as new actives. In the United States a new excipient requires a Drug Master File (DMF) to be filed with the FDA. Similarly, in Europe a dossier needs to be established. Both the DMF and dossier contain relevant safety
information. The IPEC Europe has issued a draft guideline (Compilation of Excipient Masterfiles Guidelines) which provides guidance to excipient producers on how to construct a dossier that will support a Marketing Authorization Application (MAA) while maintaining the confidentiality of the data.
2. Existing Chemical Excipient—First Use in Man: Implies that animal safety data exist since data may have been used in some other application. Additional safety information may have to be gathered to justify its use in humans.
3. Existing Chemical Excipient: Indicates that it has been used in humans but change in route of administration (say from oral to parenteral), new dosage form, higher dose, etc. may require additional safety information.
4. New Modifications or Combinations of Existing Excipients: A physical interaction NOT a chemical reaction. No safety evaluation is necessary in this case.
Simply because an excipient is listed as Generally Recognized As Safe (GRAS) does not mean that it can be used in parenteral dosage form. The GRAS list may include materials that have been proven safe for food (oral administration) but have not been
deemed safe for use in an injectable product. This makes it difficult for the formulation development scientist to choose additives during the dosage form development.
Many pharmacopeial monographs for identical excipients differ considerably with regards to specifications, test criteria, and analytical methods. Thus, if a pharmaceutical manufacturer is going to supply a product throughout the world, the manufacturer will have to repeat testing on the same excipient several times in order to meet USP, JP, EP, BP, and other pharmacopoeias.
EP, JP and USP are the main driving bodies within the International Conference on Harmonization (ICH) that are working on several of the commonly used excipients in order to achieve a single monograph for each excipient. For example, benzyl alcohol undergoes degradation by a free radical mechanism to form benzaldehyde and hydrogen peroxide.
The degradation products are much more toxic than the parent molecule. The USP, JP, and EP require three different chromatographic systems to test for organic impurity (mainly benzaldehyde). The harmonized monograph of benzyl alcohol will eliminate unnecessary repetition, which does not contribute to the overall quality of the product.[48] The following 11 pharmacopoeialtests can be substituted by a single gas chromatography (GC) method: EP:
_ Benzaldehyde, related substance (GC)
_ Halogenated compounds and halides (colorimetrictest)
_ Assay (hydroxyl value)JP:
_ Limit test for benzaldehyde
_ Limit test for chlorinated compounds
_ Distillation rangeAssay (hydroxyl value)NF/USP:
_ Benzaldehyde (HPLC)
_ Halogenated compounds and halides (colorimetrictest)
_ Organic volatile impurities (GC)
_ Assay (hydroxyl value)
The harmonization process is just beginning and is amajor step in the right direction.
Another area where regulatory bodies are focusingtheir attention is the manufacturing process used toproduce excipients. The IPEC has undertaken majorinitiatives to improve the quality of additives and haspublished ‘‘Good Manufacturing Practices Guide forBulk Pharmaceutical Excipients.’’[49] The excipientsmay be manufactured for the food, cosmetic, chemical,agriculture, or pharmaceutical industries, and the
requirements for each area are different. The purposeof this guide is twofold:
1) to develop a quality system framework that can be used for suppliers of excipients
and which will be acceptable to the pharmaceutical industry and 2) to harmonize the requirements in the United States, Europe, and Japan.
The United States, Europe, and Japan require that all excipients be declared on the label if the product is an injectable preparation. The European guide for the label and package leaflet also lists excipients, that have special issues. These are addressed in an Annex.[50] Table 13 contains a summary of some of these ingredients, which are commonly used as parenteral excipients and the corresponding safety information
that should be included in the leaflet.
Similarly, 21 CFR 201.22 requires prescription drugs containing sulfites to be labeled with a warning statement about possible hypersensitivity. An informational chapter in USP h1091i entitled ‘‘Labeling of Inactive\Ingredients’’ provides guidelines for labeling of inactive ingredients present in dosage forms.
CRITERIA FOR THE SELECTION
OF EXCIPIENT AND SUPPLIER
During the development of parenteral dosage forms, the formulator selects excipients that will provide a stable, efficacious, and functional product. The choice, and the characteristics of excipients should be appropriate for the intended purpose.
An explanation should be provided with regard to the function of all constituents in the formulation, with justification for their inclusion. In some cases, experimental data may be necessary to justify such inclusion, e.g., preservatives. The choice of the quality of the excipient should be guided by its role in the formulation and by the proposed manufacturing process.
In some cases, it may be necessary to address and justify the quality of certain excipients in the formulation.[51]
Normally, a pharmaceutical development report iswritten in the United States, which should be available at the time of Pre-Approval Inspection (PAI). The development report contains the choice of excipients, their purpose and levels in the drug product, compatibility with other excipients, drug or package system, and how they may influence the stability and efficacy of the finished product.
The following key points should be considered in selecting an excipient and its supplier for parenteral products:
1. Influence of excipient on the overall quality, stability, and effectiveness of drug product.
2. Compatibility of excipient with drug and the packaging system.
3. Compatibility of excipient with the manufacturing process. For example, preservatives may be adsorbed by rubber tubes or filters, acetate buffers will be lost during lyophilization process, etc.
4. The amount or percentage of excipients that can be added to the drug product. Table 6 summarizes the maximum amount of preservatives and antioxidants allowed by various pharmacopoeias.
5. Route of administration. The USP, EP, and BP do not allow preservatives to be present in injections intended to come in contact with brain tissues or CSF. Thus intracisternal, epidural, and intradural injections should be preservative free. Also, it is preferred that a drug product to be administered via intravenous (iv) route be free of particulate matter. However, if the size of the particle is well controlled, like in fat
emulsion or colloidal albumin or amphotericin B dispersion, it can be administered by iv infusion.
6. Dose volume. All LVPs and those SVPs where the single dose injection volume can be greater than 15 ml are required by the EP/BP to be preservative free (unless justified). The USP recommends that special care be observed in the choice and the use of added substances in preparations for injections that are administered in volumes exceeding 5 ml.
7. Whether the product is intended for single or multiple dose use. According to USP, single dose injections should be free of preservative.
The FDA takes the position that even though a single dose injection may have to be aseptically processed, the manufacturer should not use a preservative to prevent microbial growth.
European agencies have taken a more lenient attitude on this subject.
8. The length or duration of time that the drug product will be used once the multidose injection is opened.
9. How safe is the excipient?
10. Does the parenteral excipient contain very low levels of lead, aluminum, or other heavy metals?
11. Does a dossier or DMF exist for the excipient?
12. Has the excipient been used in humans? Has it been used via a parenteral route and in the amount and concentration that is being planned?
13. Has the drug product that contains this excipient been approved throughout the world?
14. What is the cost of the excipient and is it readily available?
15. Is the excipient vendor following the IPEC GMP guide? Is the vendor ISO 9000 certified?
16. Will the excipient supplier certify the material to meet USP, BP, EP, JP, and other
pharmacopoeias?
17. Has the supplier been audited by the FDA or the company’s audit group? How did it fare?
Presence of impurities in excipients can have a dramatic influence on the safety, efficacy or stability of the drug product. Monomers or metal catalysts used during
a polymerization process are toxic and can also destabilize the drug product if present in trace amounts. Due to safety concerns, the limit of vinyl chloride (monomer) in polyvinyl pyrrolidone is nmt 10 ppm, and for hydrazine (a side product of polymerization reaction) nmt 1 ppm. Monomeric ethylene oxide is highly toxic and can be present in ethoxylated excipients such as PEGs, ethoxylated fatty acids, etc.
The FDA has issued a guidance suggesting that animal-derived materials such as egg yolk lecithin, and egg phospholipid) used in drug products, originating from Belgium, France, and the Netherlands between January and June 1999 should be investigated for the presence of dioxin and polychlorinated biphenyls.
The contamination in the animal-derived product was probably due to contaminated animal feed.
Excipients manufactured by fermentation processes, such as dextrose, citric acid, mannitol, and trehalose, should be specially controlled for endotoxin levels.
Mycotoxin (highly toxic metabolic products of certain fungi species) contamination of an excipient derived from natural material has not been specifically addressed by regulatory authorities. The German health authority issued a draft guideline in 1997 where a limit was specified for Aflotoxins M1, B1, and the sum of B1, B2, G1, and G2 in the starting material for pharmaceutical products.
Heavy metal contamination of excipients is a concern, especially for sugars, phosphate, and citrate. Several rules have been proposed or established. For example, the EP sets a limit of nmt 1 ppm of nickel in polyols. California Proposition 65 specifies a limit of nmt 0.5 mg of lead per day per product.[52] Similarly, the FDA has proposed a guideline that would limit the aluminum content for all LVPs used in TPN therapy to 25 mg/L.[53] Furthermore, it requires that the maximum level of aluminum in SVPs intended to be added to LVPs and pharmacy bulk packages, at expiration date, be stated on the immediate container label.
Physical and chemical stability of the excipient should be considered in assigning a reevaluation date.
Since many drug products have a small amount of active and a comparatively high amount of excipients, degradation of even a small percentage of excipient can lead to levels of impurities sufficient to react or degrade a large percentage of active material. For example, benzyl alcohol decomposes via free radical mechanism in the presence of light and oxygen, to form benzaldehyde (x% of benzaldehyde is approximately equivalent to 1/3 x% of hydrogen peroxide). Hydrogen peroxide can rapidly oxidize sulfhydryl groups of amino acids such as cysteine present in peptides or proteins.
It is essential that adequate research and thought be given in the selection of a pharmaceutical excipient supplier. It is not uncommon for the supplier to change its manufacturing process to make products more efficiently (i.e., less costly). Normally, excipients are low-value, high-volume products that are used by several industries. The pharmaceutical industry, in general, is not the major customer of excipients (in terms of volume of material purchased). For example, the pharmaceutical industry uses approximately 20% of gelatin produced. Of this 20%, most is for production
of oral dosage forms. The parenteral portion is approximately 5% of this 20%. Therefore, it is extremely important that the drug manufacturer has a contract with the excipient supplier, that prohibits the supplier from making any change in the process/quality of the material without informing their customers well in advance. Also, the pharmaceutical manufacturer should investigate all the alternate sources that could be used in case of an emergency. A change in the supplier should not be made without consulting the pertinent regulatory bodies, since such an event may
require prior regulatory approval.
The pharmaceutical manufacturer should have an active Vendor Certification Program. The manufacturer also should assure that the vendor is ISO 9000 certified. An audit of the excipient manufacturer is essential, since the pharmaceutical industry is ultimately responsible for the quality of the drug product that includes the excipient(s) as one of the components.
The IPEC GMP guide may be used as an audit tool, since it is written in the format of ISO 9000 using identical nomenclature and paragraph numbering. The audit may ensure that the quality is being built into the excipient that may be difficult to measure later by quality control on receipt of the material. This is especially true for parenteral excipients where not only chemical, but also microbiological attributes are critical.
Bioburden and endotoxin limits may be needed for each of the excipients and several guidelines are available to establish the specifications.[54,55]
Recent events in Haiti highlight the importance of assuring the quality of excipients to the same degree that one normally does for active ingredients. From November 1995 through June 1996, acute anuric renal failure was diagnosed in 86 children. This was associated with the use of diethylene glycol-contaminated glycerin used to manufacture acetaminophen syrup.[56]
SAFETY ISSUES
Reference[57] is an excellent resource on the safety and adverse reaction to several excipients. Sensitization reactions have been reported for the parabens, thimerosal, and propyl gallate. Sorbitol is metabolized Excipients: Parenteral Dosage Forms and Their Role 1641 to fructose and can be dangerous when administered to fructose-intolerant patients. Table 13 also lists safety concerns.
Progress in drug delivery systems and new proteins/peptides being developed for parenteral administration has created a need to expand the list of excipients that can be safely used. An informational chapter included in the USP 24, presents a scientifically based approach for safety assessment of new pharmaceutical excipients.[58] This chapter is based on the excipient safety evaluation guidelines prepared by The Safety Committee of the International Pharmaceutical Excipient
Council, with appropriate reaction. Table 14 summarizes the approach in developing a new excipient.
Currently, there are some concerns regarding Transmissible Spongiform Encephalopathies (TSE) via animal-derived excipients such as gelatin. TSEs are caused by prions that are extremely resistant to heat and normal sterilization processes. TSEs have a very long incubation time with no cure and include diseases
such as the following:
_ Scrapies in sheep and goats
_ Bovine spongiform encephalopathy (BSE), otherwise known as Mad Cow Disease, in cattle
_ Kuru disease in humans
_ Creutzfeld-Jacob disease (CJD) in humans, which has been attributed to repeated parenteral administration of growth hormone and gonadotropin derived from human pituitary glands.
Several guidelines have been issued that address the issue of animal-derived excipients and scientific principles to minimize the possible transmission of TSEs via
medicinal products.[59,60] The current situation indicates that there are negligible concerns for lactose, glycerol, fatty acids, and their esters, but the situation is less clear for gelatin. In this scenario, if one has a choice, then it may be beneficial to select nonanimalderived excipients. The use of bovine serum albumin (BSA) or human serum albumin (HSA) is of concern because they can be derived from virus-contaminated blood. The risk of TSEs from excipients can be greatly reduced by controlling the following parameters:
1. Source of animal should be from countries where BSE has not been reported.
2. Animals used should be young.
3. Category III or IV animal tissue should be used in manufacture.[59]
Amendment to the European Commission directive 75/318/EEC would require manufacturers to provide a ‘‘Certificate of Suitability’’ or the underlying ‘‘scientific
information’’ in the form of a marketing variation to attest that their pharmaceuticals are free of TSEs.
FUTURE DIRECTION
Several new excipients are being evaluated in order to increase the solubility or improve the stability of parenteral drugs. Cyclodextrins have been tried for the above reasons. Currently, there are two FDA approved parenteral products that have utilized
a and g-cyclodextrins. b-cyclodextrin is unsuitable for parenteral administration because it causes necrosis of the proximal kidney tubules upon IV and subcutaneous
administration.[61] Hydroxypropyl b-cyclodextrin (HPbCD) and sulfobutylether b-cyclodextrin (SBE-7- b-CD) have shown the most promise. CaptisolTM is the trade name of SBE-7-b-CD and is anionic. Currently, two CaptisolTM based small molecule IV and IM drug formulations are in Phase III clinical trials in the United States. One parenteral formulation that utilizes HPbCD (Cavitron_) is in Phase II/III clinical trials, and another (Sporanox) has been approved by the FDA. Manufacturers of HPbCD and SBE-7-b-CD have established a DMF with the FDA. A detailed review of cyclodextrins was recently published.[62,63] It should be noted, however, that cyclodextrin also can accelerate the degradation of drug product[64] and can
sequester preservatives, rendering them ineffective.[65]
Chitosan, b-1,4-linked glucosamine, is a naturally occurring, biodegradable, non-toxic polycationic biopolymer.
It is being investigated for its potential as a cross-linked matrix of microspheres to deliver antineoplastic drugs. Because of its charge, it can trap several drugs and can bind strongly with cancer cells, thereby minimizing drug toxicity and enhancing therapeutic efficacy.[66] Chitosan also has been shown to stabilize liposomes.
Biodegradable polymeric materials such as polylactic acid, polyglycolic acid, and other poly-alphahydroxy acids have been used as medical devices and as biodegradable sutures since the 1960s.[67] Currently, the FDA has approved for marketing, only devices made from homopolymers or copolymers of glycolide, lactide, caprolactone, p-dioxanone, and trimethylene carbonate.[68] Such biopolymers are finding increased application as a matrix to deliver parenteral drugs
for prolonged delivery.[69] At least four drug products—Lupron Depot_, Decapeptyl_, Nutropin Depot_, and Zoladex_—have been approved. These four drug products are microspheres in PLG, polylactic acid (PLA), or the PLGA matrix. Polyglycolic acid (PGA) is highly crystalline (approximately 50%) with a high melting point (220–225_C). PLA can be produced by the polymerization of L-lactic acid (LPLA), D-lactic acid (DPLA), or a blend of D- and L- lactic acid (DLPLA). LPLA is 37% crystalline while DLPLA, is amorphous. The degradation time of LPLA is much slower than that of DPLA requiring more than 2 years.
By copolymerizing lactic and glycolic acid, polymeric matrices with a wide range of properties (tensile strength, crystallinity, and degradation rate) can be obtained. Decapeptyl_ is approved in France and is a microsphere for IM administration. It contains drug in a matrix of PLGA and Carboxymethyl cellulose with mannitol and polysorbate 80.
Polyanhydrides degrade primarily by surface erosion and possess excellent in vivo compatibility. In 1996 the FDA approved a polyanhydride-based drug delivery system to the brain of chemotherapeutic agent BCNU, which is currently being manufactured by Guilford Pharmaceutical, Inc.
Several phospholipid-based excipients are finding increased application as solubilizing agents, emulsifying agents, or as components of liposomal formulation.
The phospholipids occur naturally and are biocompatible and biodegradable. Examples include egg phosphatidylcholine, soybean phosphatidylcholine, hydrogenated soybean phosphatidylcholine (HSPC), DMPC, DSPC, DOPC, DSPE, DMPG, DPPG, and DSPG. SpartajectTM technology uses a mixture of phospholipids, to encapsulate poorly water-soluble drugs, to form micro-suspensions that can be injected intravenously. Busulfan_ drug product uses this technology and is currently undergoing Phase I clinical trials. Many liposomal and liposomal-like formulations (DepoFoam_) are either approved (DepoCyt_) or are undergoing clinical trials to reduce drug toxicity, improve drug stability, prolong the duration of action, or to deliver drug to the central nervous system.[70]
Two amphotericin formulations have been approved in the United States, They are liposomal, or a lipid complex between the antifungal drug and positively charged lipid. Amphotec_ is a 1 : 1 molar ratio complex of amphotericin B and cholesteryl sulfate while Abelcet_ is a 1 : 1 molar complex of amphotericin B with phospholipids
(seven parts of L-a-dimyristoylphosphatidylcholine and L-a-dimyristoylphosphatidyl glycerol).
Poloxamers or pluronics are block copolymers comprised of polyoxyethylene and polyoxypropylene segments.
They exhibit reverse thermal gelation and are being tried as solubilizing, emulsifying, and stabilizing agents. Thus, a depot drug delivery system can be created using pluronics whereby the product is a viscous injection that gels upon IM injection.[71] Pluronics can prevent protein aggregation or adsorption/absorption and can help in the reconstitution of lyophilized products. Pluronic F68 (Polaxamer-188), F38 (Poloxamer-108), and F127 (Poloxamer-407) are the most commonly used pluronics. For example, liquid formulation of human growth hormone and Factor VIII can be stabilized using pluronics. Fluosol_ is a complex mixture of perfluorocarbons, with a high oxygencarrying capacity emulsified with Pluronic F-68, and various lipids. It was recently approved by the FDA for adjuvant therapy to reduce myocardial ischemia during coronary angioplasty. A highly purified form of Poloxamer 188 (FlocorTM), intended for IV administration, is undergoing Phase III clinical trials for various cardiovascular diseases. Purification of Poloxamer 188 has been shown to reduce nephrotoxicity.
Poloxamers and other polymeric materials such as albumin may coat the micro- or nano particle, alter their surface characteristics and reduce their phagocytosis and opsonization by the reticuloendothelial system following IV injection. Such surface modifications often result in prolongation in the circulation time of intravenously injected colloidal dispersions.[72] Poloxamers also have been used to stabilize suspension such as NanoCrystalTM.[73]
The first successful development of an injectable perfluorocarbon-based commercial product was achieved by the Green Cross Corporation in Japan, when it made Fluosol-DA_, a dilute (20% w/v) emulsion based on perfluorodecalin and perflurotripropylamine emulsified Excipients: Parenteral Dosage Forms and Their Role 1643 with potassium oleate, Pluronic F-68, and egg yolk lecithin. These perfluorocarbons are inert and also can be used to formulate non-aqueous preparations of insoluble proteins and small molecules.[74] Perfluorocarbons also have been approved by the FDA for use in one ultrasound contrast agent, Optison_, which is administered via the IV route. Optison_ is a suspension of microspheres of HSA with octafluoropropane.
Heat treatment and sonication of appropriately diluted human albumin, in the presence of octafluoropropane gas, is used to manufacture microspheres in the Optison_injection. The protein in the microsphere shell makes upapproximately 5–7 (wt%) of the total protein in theliquid. The microspheres have a mean diameter range
of 2.0–4.5 mm with 93% of the microsphere being lessthan
Sucrose acetate isobutyrate (SAIB) is a high viscosity liquid system that converts into free-flowing liquid when mixed with 10–15% ethanol.[75] On subcutaneous or IM injection, the matrix rapidly converts to a water-insoluble semi-solid, that is capable of delivering proteins and small molecules for a prolonged period. SAIB is biocompatible, and biodegrades to natural metabolites. This is a fairly new matrix and three INDs have been filed for veterinary applications.
It has not been used in humans.
Several other biodegradable, biocompatible, injectable polymers are being investigated for drug delivery systems. They include polyvinyl alcohol, block copolymer of PLA–PEG, polycyanoacrylate, polyanhydrides, cellulose, alginate, collagen, gelatin, albumin, starches, dextrans, hyaluronic acid and its derivatives, and
hydroxyapatite.[76]
