MANUFACTURING OF SEMI-SOLID DOSAGE FORMS. SUPPOSITORIES. PATCHES.

MANUFACTURING OF SEMI-SOLID DOSAGE FORMS. SUPPOSITORIES. PATCHES.

Semisolid dosage forms are traditionally used for treating topical ailments. The vast majority of them are meant for skin applications. They are also used for treating ophthalmic, nasal, buccal, rectal, and vaginal ailments. Various categories of drugs such as antibacterials, antifungals, antivirals, antipruritics, local anesthetics, anti – infl ammatories, analgesics, keratolytics, astringents, and mydriatic agents are incorporated into these products. Drugs incorporated into semisolids either show their

activity on the surface layers of tissues or penetrate into internal layers to reach the site of action. For example, an antiseptic ointment should be able to penetrate the skin layers and reach the deep – seated infections in order to prevent the growth of microbes and heal the wound.

Systemic entry of drugs from these products is limited due to various physicochemical properties of dosage forms and biological factors. The barrier nature of most surface biological layers such as skin, cornea and conjunctiva of the eye, and

mucosa of nose, mouth, rectum, and vagina greatly limits their entry into the systemic circulation. Systemic delivery of drugs from topical dosages is however feasible by suitable formulation modifi cations. Semisolid dosage forms are also used in nontherapeutic conditions for providing protective and lubricating functions. They protect the skin against external environments such as air, moisture, and sun rays and hence their components do not necessarily penetrate the skin layers. Cold creams and vanishing creams are classic examples of such semisolid preparations.

OINTMENTS AND CREAMS

Ointments are semisolid preparations intended for topical application. They are used to provide protective and emollient effects on the skin or carry medicaments for treating certain topical ailments. They are also used to deliver drugs into eye, nose, vagina, and rectum. Ointments intended for ophthalmic purposes are required to be sterile. When applied to the eyes, they reside in the conjunctival sac for prolonged

periods compared to solutions and suspensions and improve the fraction of drug absorbed across ocular tissues. Ophthalmic ointments are preferred for nighttime applications as they spread over the entire corneal and conjunctival surface and cause blurred vision.

Creams are basically ointments which are made less greasy by incorporation of water. Presence of water in creams makes them act as emulsions and therefore are

sometimes referred as semisolid emulsions. Hydrophilic creams contain large amounts of water in their external phase (e.g., vanishing cream) and hydrophobic creams contain water in the internal phase (e.g., cold cream). An emulsifying agent is used to disperse the aqueous phase in the oily phase or vice versa. As with ointments,

creams are formulated to provide protective, emollient actions or deliver drugs to surface or interior layers of skin, rectum, and vagina. Creams are softer than ointments and are preferred because of their easy removal from containers and good spreadability over the absorption site.

Bases

Bases are classifi ed based on their composition and physical characteristics. The U.S.

Pharmacopeia (USP) classifi es ointment bases as hydrocarbon bases (oleaginous bases), absorption bases, water – removable bases, and water – soluble bases (water – miscible bases) [1] .

Hydrocarbon bases are made of oleaginous materials. They provide emollient

and protective properties and remain in the skin for prolonged periods. It is diffi cult to incorporate aqueous phases into hydrocarbon bases. However, powders can be incorporated into these bases with the aid of liquid petrolatum. Removal of hydrocarbon bases from the skin is diffi cult due to their oily nature. Petrolatum USP, white petrolatum USP, yellow ointment USP, and white ointment USP are examples of hydrocarbon bases.

Absorption bases contain small amounts of water. They provide relatively less emollient properties than hydrocarbon bases. Similar to hydrocarbon bases, absorption bases are also diffi cult to remove from the skin due to their hydrophobic nature.

Hydrophilic petrolatum USP and lanolin USP are examples of absorption bases.

Water – removable bases are basically oil – in – water emulsions. Unlike hydrocarbon and absorption bases, a large proportion of aqueous phase can be incorporated into water – removable bases with the aid of suitable emulsifying agents. It is easy to remove these bases from the skin due to their hydrophilic nature. Hydrophilic ointment USP is an example of a water – removable ointment base.

Water – soluble bases do not contain any oily or oleaginous phase. Solids can be easily incorporated into these bases. They may be completely removed from the skin due to their water solubility. Polyethylene glycol (PEG) ointment National

Formulary (NF) is an example of a water – soluble base.

Selection of an appropriate base for an ointment or cream formulation depends on the type of activity desired (e.g., topical or percutaneous absorption), compatibility with other components, physicochemical and microbial stability of the product, ease of manufacture, pourability and spreadability of the formulation, duration of contact, chances of hypersensitivity reactions, and ease of washing from the site of application. In addition, bases that are used in ophthalmic preparations should be nonirritating and should soften at body temperatures. White petrolatum and liquid petrolatum are generally used in ophthalmic preparations. Table 1 summarizes compendial status, synonym, and specifi cations of some of the bases used in ointments and creams.

The following sections describe the source, physicochemical properties, formulation considerations, stability, incompatibility, storage, and hypersensitivity reactions of some of these bases.

Lanolin Lanolin is a refi ned, decolorized, and deodorized material obtained from sheep wool. It is available as a pale yellow, waxy material with a characteristic odor.

It is extensively used in the preparation of hydrophobic ointments and water – in – oil creams. As lanolin is prone to oxidation, antioxidants such as butylated hydroxytoluene are generally included. Although lanolin is insoluble in water, it is miscible with water up to 1 : 2 ratio. This property favors in preparing physically stable creams.

Addition of soft paraffior vegetable oil improves the emollient property of lanolin preparations. Exposure of lanolin to higher temperature usually leads to discoloration and rancidlike odor, and hence prolonged heating is avoided during the

preparation and preservation of lanolin – containing preparations. Gamma sterilization or fi ltration sterilization is usually employed for sterilizing ophthalmic ointments containing lanolin. Lanolin and some of its derivatives are reported to cause hypersensitivity reactions and therefore are avoided in patients with known hypersensitivity.

One of the reasons for hypersensitivity reactions is free fatty alcohols.

Modifi ed lanolins containing reduced levels of free fatty alcohols are commercially available [2, 3] .

Hydrous Lanolin Incorporation of about 25 – 30% of water into lanolin gives

hydrous lanolin. Gradual addition of water into molten lanolin with constant stirring helps in water incorporation. It is available as a pale yellow, oily material with a characteristic odor. The water uptake capacity of hydrous lanolin is higher than lanolin, and it is used for preparing topical hydrophobic ointments or water – in – oil creams with larger aqueous phase. Exposure of these preparations to higher temperatures results in separations of oily and aqueous layers. Addition of antioxidants and preservation in well – fi lled, airtight, light – resistant containers in a cool and dry place improve the stability of lanolin products. Well – preserved preparations can be stored up to two years. Hydrous lanolin that contains free fatty alcohols is avoided in hypersensitive patients [2, 3] .

Lanolin Alcohols Lanolin alcohol is prepared from lanolin by the saponifi cation process and is used as a hydrophobic vehicle in pharmaceutical ointments and

creams. It is composed of steroidal and triterpene alcohols and is available as a brittle solid material pale yellow in color with a faint characteristic odor. The brittle powder becomes plastic under warm conditions. It is practically insoluble in water and soluble in boiling ethanol. Lanolin alcohol possesses emollient properties, which makes it suitable for preparing dry – skin ointments, eye ointments, and water – in – oil creams. Creams containing lanolin alcohols do not show surface darkening and do not produce objectionable odor compared to lanolin – containing preparations.

Inclusion of about 0.1% antioxidant, however, minimizes the oxidation on storage.

Preparations containing lanolin alcohols can be stored up to two years if preserved in well – fi lled, well – closed, light – resistant containers in a cool and dry place. As with other lanolin bases, hypersensitivity reactions may occur in some individuals while using preparations containing lanolin alcohols [2, 3] .

Petrolatum Petrolatum is also known as yellow soft paraffi n. It is an inert material obtained from petroleum, which contains branched and unbranched hydrocarbons.

It is available as soft oily material and appears pale yellow to yellow in color. Various grades of petrolatum are commercially available with varying physical properties.

All these grades are generally insoluble in water and possess emollient properties.

Concentrations up to 30% are used in creams. Petrolatum shows phase transitions on heating to about 35 ° C. As it possesses a higher coeffi cient of thermal expansion, prolonged heating is avoided during processing. The presence of minor impurities can oxidize petrolatum and discolor the product. Antioxidants are therefore added to prevent such physical changes in preparations during storage. Butylated hydroxyanisole, butylated hydroxytoluene, or - tocopherol is generally incorporated as an antioxidant in petrolatum products. In addition, use of well – closed, airtight, light – resistant containers and storage in a cool and dry place improve stability of preparations.

Minor quantities of polycyclic aromatic hydrocarbon impurities in petrolatum

sometimes cause hypersensitivity reactions. Substituting yellow soft paraffiwith white soft paraffireduces such reactions [4] .

Petrolatum and Lanolin Alcohols Various quantities of lanolin alcohols are mixed with petrolatum to form these mixtures. Wool ointment British Pharmacopoeia (BP) 2001 contains 6% lanolin alcohols and 10% petrolatum. These proportions can be varied to alter physical properties such as consistency and melting range. They are

available as soft solids pale ivory in color and possess a characteristic odor. These mixtures are insoluble in water, and concentrations ranging 5 – 50% are used for preparing hydrophobic ointments. They are also used for preparing water – in – oil emollient creams. Preparations containing petrolatum and lanolin alcohols need to be preserved in airtight, well – closed, light – resistant containers in a cool and dry place to avoid oxidation of impurities and discoloration. Antioxidants improve the stability

of these products. Although these mixtures are safe for topical applications, hypersensitivity reactions may occur in some individuals due to the presence of lanolin alcohol [5] .

ParaffiParaffiis obtained by distillation of crude petroleum followed by purifi cation processes. The purifi ed fraction contains saturated hydrocarbons. Paraffiis available as a white color solid and does not possess any specifi c odor or taste. Different purity grades are available. Use of highly purifi ed grades can avoid batch – to – batch variations in formulations, especially the hardness, melting behavior, and malleability. Paraffiis insoluble in water and is generally used to prepare hydrophobic topical ointments and water – in – oil creams. Repeated heating and congealing are avoided during formulation as they change the physical properties of paraffi n.

These preparations need to be preserved in well – closed container at room temperature.

Synthetic paraffi ns, which melt between 96 and 105 ° C, are sometimes used to increase the melting point and stiffness of formulations [6] .

Polyethylene Glycol Also known as macrogol, PEG is synthesized by condensation of ethylene oxide and water under suitable reaction conditions. Based on the number of oxyethylene groups present, their molecular weights vary from few hundreds to several thousands. Usually the number that follows PEG represents their

average molecular weight. They are available as liquids or solids based on molecular weight. PEGs 600 or less are liquids, whereas PEGs above 1000 are solids. PEG liquids are usually clear or pale yellow in color. Their viscosity increases with increase in molecular weight. Solid PEGs are usually white in color and available as pastes, waxy fl akes, or free – fl owing solids based on their molecular weight. Table 2 shows the physicochemical properties of some PEGs.

PEGs are hydrophilic materials and are extensively used in the preparation of

hydrophilic ointments and creams. They are nonirritants and are easily washed from skin surfaces. Products with varying consistency are prepared by mixing different grades of PEGs. Excessive heating is avoided while melting PEGs. This will prevent oxidation and discoloration of products. In addition, use of purifi ed grades that are free from peroxide impurities, inclusion of suitable antioxidants, and heating under nitrogen atmosphere can minimize the oxidation. PEGs are prone to etherifi cation or esterfi cation reactions due to the presence of two terminal hydroxyl groups. They are incompatible with some antibiotics, antimicrobial preservatives, iron, tannic acid, and salicylic acid and also interact with plastic containers made of polyvinyl chloride and polyethylene. PEG – containing products are usually packed in aluminum, glass, or stainless steel containers to avoid such interactions.

Although low – molecular – weight PEGs are hygroscopic, they do not promote microbial growth. PEG – containing products are generally stored in well – closed containers in a cool, dry place. These products can cause stinging sensation on mucus and some hypersensitivity reactions, especially when applied onto open wounds [7, 8].

Stearic Acid Stearic acid is obtained by hydrolysis of fat or hydrogenation of

vegetable oils. Compendial stearic acid contains a mixture of stearic acid and palmitic

acids. It is available as powder or crystalline solid which is white to yellowish white in color and possesses a characteristic odor. Although stearic acid is insoluble in water, partially neutralized grades form a cream base when combined with about 10 times its weight of aqueous solvents. The appearance and consistency of these grades are based on the proportion of alkali or triethanolamine used for neutralization.

Concentrations up to 20% are used for formulating creams and ointments. Different grades of stearic acids are commercially available with varying stearic acid

content, melting temperature, and other physical properties. A suitable antioxidant is included in formulations containing stearic acid. As stearic acid interacts with metals, it is avoided in preparations which contain salts, especially divalent metals such as calcium and zinc. It also reacts with metal hydroxides and some drugs. Compatibility evaluation between stearic acid and other formulation components is therefore essential when formulating newer products with stearic acid [9] .

Carnauba Wax Carnauba wax contains a mixture of esters of acids and hydroxyacids isolated from Brazilian carnauba palm. It also contains various resins, hydrocarbons, acids, polyhydric alcohols, and water. It is available as lumps, powder, or fl akes which are brown to pale yellow in color and possesses a characteristic odor.

Carnauba wax is practically insoluble in water and melts at 80 – 88 ° C. Being a hard material, it improves the stiffness of topical preparations [6] .

Cetyl Alcohol Cetyl alcohol is obtained by hydrogenolysis or esterfi cation of fatty acids and contains not less than 90% cetyl alcohol along with other aliphatic alcohols.

It is available as fl akes or granules white in color and possesses a characteristic odor. Different grades are commercially available with varying proportions of cetyl alcohol, stearyl alcohol, and related alcohols. Although insoluble in water, cetyl alcohol has good water – absorptive and emulsifying properties. This property makes it suitable for preparing emollient ointments and creams. Its viscosity – enhancing properties reduce coalescence of dispersed phase and improves the physical stability of creams. Concentrations ranging from 2 to 10% are used in topical preparations to impart emollient, emulsifying, water – absorptive, and stiffening properties. Mixtures of petrolatum and cetyl alcohol are sometimes used for preparing creams. Such mixtures minimize the quantity of additional emulsifying agents in preparations.

Although cetyl alcohol forms stable preparations, it is incompatible with strong oxidizing materials and some drugs. Compatibility studies are therefore conducted when including cetyl alcohol into formulations. Highly purifi ed grades are free from hypersensitivity reactions [3, 10] .

Emulsifying Wax Emulsifying wax, also known as anionic emulsifying wax, is a mixture of cetostearyl alcohol, sodium lauryl sulfate, and purifi ed water. Emulsifying wax BP contains about 90% cetostearyl alcohol, 10% sodium lauryl sulfate, and 4% purifi ed water. Emulsifying wax USP contains nonionic surfactants. It is available as fl akes or solids which are white to pale yellow in color and possesses a characteristic odor. Although emulsifying wax is insoluble in water, its emulsifying properties help in preparing hydrophilic oil – in – water emulsions. Ointment bases are prepared by mixing up to 50% emulsifying wax with liquid or soft paraffi ns. At concentrations up to 10%, it forms creams. Although emulsifying wax is compatible with many acids and alkalis, it is incompatible with many cationic materials and polyvalent metal salts. Stainless steel vessels are preferred for mixing operations.

Preparations containing emulsifying wax are preserved in well – closed container in a cool, dry place [11] .

Cetyl Esters Wax Cetyl esters wax is obtained by esterifi cation of some fatty alcohols and fatty acids. It is available as crystalline fl akes which are white to off – white in color and possesses a characteristic aromatic odor. It is insoluble in water and has emollient and stiffening properties. About 10% of cetyl ester wax is used for preparing hydrophobic creams and about 20% is used for preparing topical ointments.

Various grades of cetyl esters wax are available commercially and vary in their fatty alcohol and fatty acids content and melting range. As this wax is incompatible with strong acids and bases, it should be avoided in certain formulations.

Cetyl ester wax – containing products are stored in well – closed containers in a cool, dry place [6] .

Hydrogenated Castor Oil It is used as stiffening agent in hydrophobic ointments and creams due to its higher melting point. Hydrogenated castor oil contains triglyceride of hydroxystearic acid and is available as white color fl akes or powder. It is insoluble in water and melts at 85 – 88 ° C. Different grades with varying compositions and physical properties are commercially available. Products can be prepared at higher temperatures, as hydrogenated castor oil is stable up to 150 ° C. It is compatible with other waxes obtained from vegetable and animal sources. Preparations containing hydrogenated castor oil need to be preserved in well – closed containers in a cool and dry place [12] .

Microcrystalline Wax Microcrystalline wax is obtained from petroleum by solvent fractionation and dewaxing procedures. It contains many straight – chain and

branched – chain alkanes, with carbon chain lengths ranging from 41 to 57. It is available as fi ne fl akes or crystals which are white or yellow in color. Microcrystalline wax is insoluble in water and possesses a wide melting range (54 – 102 ° C). High – melting and stiffening properties of microcrystalline wax make it suitable for preparing ointments and cream with higher consistency. Acids, alkalis, oxygen, and light do not affect its stability [6] .

Stearyl Alcohol Reduction of ethyl stearate in the presence of lithium aluminum hydride yields stearyl alcohol, which contains not less than 90% of 1 – octadecanol.

It is available as fl akes or granules which are white in color and possesses a characteristic odor. It is insoluble in water and melts at 55 – 60 ° C. Stearyl alcohol has stiffening, viscosity – enhancing, and emollient properties and hence is used in the preparation of hydrophobic ointments and creams. Its weak emulsifying properties help in improving the water – holding capacity of ointments. Hypersensitivity reactions are sometimes observed due to the presence of some minor impurities.

Stearyl alcohol preparations are compatible with acids and alkalis and are preserved in well – closed containers in a cool and dry place [6] .

White Wax White wax is a bleached form of yellow wax which is usually obtained from the honeycomb of bees and hence is known as bleached wax or white bees wax .

It contains about 70% esters of straight – chain monohydric alcohols, 15% free acids, 12% carbohydrates, and 1% free wax alcohols and stearic esters of fatty acids. It is available as granules or sheets which are white in color and possesses a characteristic odor. White wax is insoluble in water and melts between 61 and 65 ° C. It has stiffening and viscosity – enhancing properties and therefore is used in hydrophobic ointments and oil – in – water creams. Although it is thermally stable, heating to above 150 ° C results in reduction of its acid value. White wax is incompatible with oxidizing agents. The presence of small quantities of impurities results in hypersensitivity reactions in rare occasions. Preparations are stored in well – closed, light – resistant containers in a cool, dry place [13] .

Yellow Wax Yellow wax, also known as yellow beeswax, is obtained from honey combs. It contains about 70% esters of straight – chain monohydric alcohols, 15% free acids, 12% carbohydrates, and 1% free wax alcohols and stearic esters of fatty acids. It is available as noncrystalline pieces which are yellow in color and possesses a characteristic odor. It is practically insoluble in water and melts at 61 – 65 ° C. It is used in the preparation of hydrophobic ointments and water – in – oil creams because of its viscosity – enhancing properties. Concentrations up to 20% are used for producing ointments and creams. It is incompatible with oxidizing agents.

Esterifi cation occurs while heating to 150 ° C and hence should be avoided during preparation.

Hypersensitivity reactions sometimes occur on topical application of yellow wax – containing ointments and creams due to the presence of some minor impurities.

These products are preserved in well – closed, light – resistant containers [13] .

Combinations of bases are sometimes used to acquire better stability. Gelling agents such as carbomers and PEG are also included in some ointment and cream preparations. Table 3 shows examples of cream bases used in some commercial cream preparations.

Preparation and Packaging

In addition to the base and drug, ointments and creams may also contain other

components such as stabilizers, preservatives, and levigating agents. Usually levigation and fusion methods are employed for incorporating these components into the base. Levigation involves simple mixing of base and other components over an ointment slab using a stainless steel ointment spatula. A fusion process is employed only when the components are stable at fusion temperatures. Ointments and creams containing white wax, yellow wax, paraffi n, stearyl alcohol, and high – molecular – weight PEGs are generally prepared by the fusion process. Selection of levigation or the fusion method depends on the type base, the quantity of other components, and their solubility and stability characteristics.

Oleaginous ointments are prepared by both levigation and fusion processes.

Small quantities of powders are incorporated into hydrocarbon bases with the aid of a levigating agent such as liquid petrolatum, which helps in wetting of powders.

The powder component is mixed with the levigating agent by trituration and is then incorporated into the base by spatulation. All solid components are milled to fi ner size and screened before incorporating into the base to avoid gritty sensation of the fi nal product. Roller mills are used for producing large quantities of ointments in

pharmaceutical industries. Uniform mixing can be obtained by the geometric dilution procedure, which usually involves stepwise dilution of solids into the ointment base. The fusion method is followed when the drugs and other solids are soluble in the ointment bases. The base is liquefi ed, and the soluble components are dissolved in the molten base. The mixture is then allowed to congeal by cooling. Fusion is performed using steam – jacketed vessels or a porcelain dish. The congealed mixture is then spatulated or triturated to obtain a smooth texture. Care is taken to avoid thermal degradation of the base or other components during the fusion process.

Absorption – type ointments and creams are prepared by incorporating large quantities of water into hydrocarbon bases with the aid of a hydrophobic emulsifying agent. Water – insoluble drugs are added by mechanical addition or fusion methods.

As with oleaginous ointments, levigating agents are also included to improve wetting of solids. Water – soluble or water – miscible agents such as alcohol, glycerin, or propylene glycol are used if the drug needs to be incorporated into the internal aqueous phase. If the drug needs to be incorporated into the external oily phase, mineral oils are used as the levigating agent. Incorporation of water – soluble components is achieved by slowly adding the aqueous drug solution to the hydrophobic base using pill tile and spatula. If the proportion of aqueous phase is larger, inclusion of additional quantities of emulsifi er and application of heat may be needed to achieve uniform dispersion. Care must be taken to avoid excessive heating as it can result in evaporation aqueous phase and precipitation of water – soluble components and formation of stiff and waxy product.

Water – removable ointments and creams are basically hydrophilic – type emulsions.

They are prepared by fusion followed by mechanical addition approach. Hydrocarbon components are melted together and added to the aqueous phase that contains water – soluble components with constant stirring until the mixture congeals.

A hydrophilic emulsifying agent is included in the aqueous phase in order to obtain stable oil – in – water dispersion. Sodium lauryl sulfate is used in the preparation of hydrophilic ointment USP.

Water – soluble ointments and creams do not contain any oily phase. Both water – soluble and water – insoluble components are incorporated into water – soluble bases by both levigation and fusion methods. If the drug and other components are water soluble, they are dissolved in a small quantity of water and incorporated into the base by simple mixing over an ointment slab. If the components are insoluble in water, aqueous levigating agents such as glycerin, propylene glycol, or a liquid PEG are used. The hydrophobic components are mixed with the levigating agent and then incorporated into the base. Heat aids incorporation of a large quantity of hydrophobic components.

A wide range of machines are available for the large – scale production of ointments and creams. Each of these machines is designed to perform certain unit operations, such as milling, separation, mixing, emulsifi cation, and deaeration.

Milling is performed to reduce the size of actives and other additives. Various fl uid energy mills, impact mills, cutter mills, compression mills, screening mills, and tumbling mills are used for this purpose. Alpine, Bepex, Fluid Air, and Sturtevant are

some of the manufacturers of these mills. Separators are employed for separating materials of different size, shape, and densities. Either centrifugal separators or vibratory shakers are used for separation. Mixing of the actives and other formulation components with the ointment or cream base is performed using various types of low – shear mixers, high – shear mixers, roller mills, and static mixers. Mixers with heating provisions are also used to aid in the melting of bases and mixing of components.

Chemineer, Fryma, Gate, IKA, Koruma (Romaco), Moorhouse – Cowles, Ross, and Stokes Merrill are some of the manufacturers of semisolids mixers. Creams are produced with the help of low – shear and high – shear emulsifi ers.

These emulsifi ers are used to disperse the hydrophilic components in the hydrophobic dispersion phase (e.g., water – in – oil creams) or oleaginous materials in aqueous dispersion medium (oil – in – water creams). Bematek, Fryma, Koruma (Romaco), Lightnin, Moorhouse, and Ross supply various types of emulsifi ers. Entrapment of air into the fi nal product due to mixing processes is a common issue in the large – scale manufacturing of semisolid dosage forms. Various offl ine and in – line deaeration procedures are adopted to minimize this issue. Effective deaeration is generally achieved by using vacuum vessel deaerators. Some of the recent large – scale machines are designed to perform heating, high – shear mixing, scrapping, and deaeration processes in a single vessel. Figure 1 shows the design feature of a semisolid production machine manufactured by Ross.

Various low – and high – shear shifters are used to transfer materials from the production vessel to the packaging machines. In the packaging area, various types of holders (e.g., pneumatic, gravity, and auger holders), fi llers (e.g., piston, peristaltic pump, gear pump, orifi ce, and auger fi llers), and sealers (e.g., heat, torque, microwave, indication, and mechanical crimping sealers) are used to complete the unit

 

FIGURE 1 Semisolid production machine with heat jacketed vessel, high – shear mixer,

scrapper, vacuum attachments, and control station. (Courtesy of Ross, Inc.) operations. These equipments are supplied by various manufacturers, namely Bosch, Bonafacci, Erweka, Fryma – Maschinenbau, IWKA, Kalish, and Norden.

Sterility of ointments, especially those intended for ophthalmic use, is achieved by aseptic handling and processing. Improper processing, handling, packing, or use of ophthalmic ointments lead to microbial contaminations and eventually result in ocular infections. In general, the empty containers are separately sterilized and fi lled under aseptic condition. Final product sterilization by moist heat sterilization or gaseous sterilization is ineffective because of product viscosity. Dry – heat sterilization is associated with stability issues. Strict aseptic procedures are therefore practiced when processing ophthalmic preparations. Antimicrobial preservatives such as benzalkonium chloride, phenyl mercuric acetate, chlorobutanol, or a combination of methyl paraben and propyl paraben are included in ophthalmic ointments to retain microbial stability.

Packaging An ideal container should protect the product from the external atmosphere such as heat, humidity, and particulates, be nonreactive with the product components, and be easy to use, light in weight, and economic [14] . As tubes made of aluminum and plastic meet most of these qualities, they are extensively used for packaging semisolids. Aluminum tubes with special internal epoxy coatings are commercially available for improving the compatibility and stability of products.

Various modifi ed plastic materials are used for making ointment tubes. Tubes made

 

FIGURE 2 Custom – designed LDPE containers made by BFS process for packaging topical products. (Courtesy of Rommelag USA, Inc.)

 

of low – density polyethylene (LDPE) are generally soft and fl exible and offer good moisture protection. Tubes made of high – density polyethylene (HDPE) are relatively harder but offer high moisture protection. Polypropylene containers offer high heat resistance. Plastic containers made of polyethylene terephthalate (PET) are transparent and provide superior chemical compatibility. Ointments meant for ophthalmic, nasal, rectal, and vaginal applications are supplied with special application tips for the ease of product administration.

A recent method known as blow fi ll sealing (BFS) performs fabrication of container, fi lling of product, and sealing operations in a single stage and hence is gaining greater attention. The products can be sterile fi lled, which makes BFS a cost – effective alternative for aseptic fi lling. All plastic materials are suitable for BFS processing. In most cases, monolayered LDPE materials are used for making small – size containers. If the product is not compatible with the LDPE or sensitive to oxygen, barrier layers are added to the container wall by coextrusion methods.

As the container is formed inside the BFS machine, upstream handling problems are avoided. The BFS machine can hand the container off to any secondary packaging operation that needs to be performed. Typically a secondary overwrap is added to the containers prior to cartooning. An additional advantage of BFS containers is the integrated design of the applicator into the product container. Figure 2 shows some of the custom – designed BFS containers for topical products.

Evaluation

Ointments and creams are evaluated for various pharmacopeial and nonpharmacopeial tests to ascertain their physicochemical, microbial, in vitro, and in vivo characteristics. These tests help in retaining their quality and minimizing the batch – to – batch variations. The USP recommends storage and labeling, microbial screening, minimum fi ll, and assays for most ointments and creams. Tables 4 and 5 summarize the compendial requirements for some pharmacopeial ointments and creams.

Packaging and Storage The USP recommends packaging and storage requirements for each offi cial ointment and cream. Generally collapsible tubes, tight containers, or other well – closed containers are recommended for packing. They are stored in either a cool place or at controlled room temperatures. In some cases, special storage conditions are recommended: for example, protect from light, avoid exposure to excessive heat, avoid exposure to direct sunlight, avoid strong fl uorescent lighting, do not refrigerate, and avoid prolonged exposure to temperatures exceeding 30 ° C.

Minimum Fill This test is performed to compare the weight or volume of product fi lled into each container with their labeled weight or volume. It helps in assessing the content uniformity of product. A minimum – fi ll test is applied only to those containers that contaiot more than 150 g or mL of preparation. It is performed in two steps. Initially, labels from the product containers are removed. After washing and drying the surface, their weights are recorded ( W1 ). In the second step, the entire product from each container is removed. After cleaning and drying, the weight of empty containers is recorded ( W2 ). The difference between total weight ( W1 ) and empty – container weight ( W2 ) gives the weight of product. The USP recommends that the average net content of 10 containers should not be less than the labeled amount. If the product weight is less than 60 g or mL, the net content of any single container should not be less than 90% of the labeled amount. If the product weight is between 60 and 150 g or mL, the net content of any single container should not be less than 95% of the labeled amount. If these limits are not met, the test is repeated with an additional 20 containers. All semisolid topical preparations should meet these specifi cations [15] .

Water Content The presence of minor quantities of water may alter the microbial, physical, and chemical stability of ointments and creams. Titrimetric methods (method I) are usually performed for determining the water content in these preparations.

These methods are based on the quantitative reaction between water and anhydrous solution of sulfur and iodine in the presence of a buffer that can react with hydrogen ions. Special titration setups and reagents (Karl Fischer, KF) are used in these determinations. In the direct method (method Ia), about 35 mL of methanol is titrated with suffi cient quantity of KF reagent to the electrometric or visual endpoint

(color change from canary yellow to amber). This blank titration helps to consume any moisture that may be present in the reaction medium. A known quantity of test material (ointment or cream) is added to the reaction medium, mixed, and again titrated with KF reagent to the reaction endpoint. The water content is determined by considering the volume of KF reagent consumed and its water equivalence factor. In the residual titration method (method Ib), a known excess quantity of KF reagent is added to the titration vessel, which is then back titrated with standardized water to the electrometric or visual endpoint. In the coulometric titration method (method Ic), the sample is dissolved in anhydrous methanol and injected into the reaction vessel that contains the anolyte, and the coulometric reaction is performed until the reaction endpoint. In some cases, methanol is replaced with other solvents. The maximum allowable limit of water in ointment preparations varies between 0.5 and 1.0%. The limit of water in bacitracin, chlortetracycline hydrochloride, and nystatin ointments is not more than 0.5%, whereas amphotericin B, erythromycin, gentamycin sulfate, neomycin sulfate, and tetracycline hydrochloride ointments may contain up to 1% moisture [15] .

Metal Particles This test is required only for ophthalmic ointments. The presence of metal particles will irritate the corneal or conjunctival surfaces of the eye. It is performed using 10 ointment tubes. The content from each tube is completely removed onto a clean 60 – mm – diameter petridish which possesses a fl at bottom.

The lid is closed and the product is heated at 85 ° C for 2 h. Once the product is melted and distributed uniformly, it is cooled to room temperature. The lid is removed after solidifi cation. The bottom surface is then viewed through an optical microscope at 30magnifi cation. The viewing surface is illuminated using an external light source positioned at 45 ° on the top. The entire bottom surface of the ointment is examined, and the number of particles 50 m or above are counted using a calibrated eyepiece micrometer. The USP recommends that the number of such particles in 10 tubes should not exceed 50, with not more than 8 particles in any individual tube. If these limits are not met, the test is repeated with an additional 20 tubes. In this case, the total number of particles in 30 tubes should not exceed 150, and not more than 3 tubes are allowed to contain more than 8 particles [15] .

Leakage Test This test is mandatory for ophthalmic ointments, which evaluates the intactness of the ointment tube and its seal. Ten sealed containers are selected, and their exterior surfaces are cleaned. They are horizontally placed over absorbent blotting paper and maintained at 60 3 ° C for 8 h. The test passes if leakage is not observed from any tube. If leakage is observed, the test is repeated with an additional 20 tubes. The test passes if not more than 1 tube shows leakage out of 30 tubes [15] .

Sterility Tests Ophthalmic semisolids should be free from anaerobic and aerobic bacteria and fungi. Sterility tests are therefore performed by the membrane fi ltration technique or direct – inoculation techniques. In the membrane fi ltration method, a solution of test product (1%) is prepared in isopropyl myristate and allowed to penetrate through cellulose nitrate fi lter with pore size less than 0.45 m. If necessary, gradual suction or pressure is applied to aid fi ltration. The membrane is then washed three times with 100 – mL quantities of sterile diluting and rinsing fl uid and transferred aseptically into fl uid thioglycolate (FTG) and soybean – casein digest (SBCD) medium. The membrane is fi nally incubated for 14 days.

Growth on FTG medium indicates the presence of anaerobic and aerobic bacteria, and SBCD medium indicates fungi and aerobic bacteria. Absence of any growth in both these media establishes the sterility of the product. In the direct – inoculation technique, 1 part of the product is diluted with 10 parts of sterile diluting and rinsing fl uid with the help of an emulsifying agent and incubated in FTG and SBCD media for 14 days. In both techniques, the number of test articles is based on the batch size of the product. If the batch size is less than 200 the containers, either 5% of the containers or 2 containers (whichever is greater) are used. If the batch size is more than 200, 10 containers are used for sterility testing [15] .

Microbial Screening Semisolid preparations are required to be free from any

microbial contamination. Hence, most of the topical ointments are screened for the presence of Staphylococcus aureus and Pseudomonas aeruginosa . In some cases, screening for Escherichia coli, Salmonella species, and total aerobic microbial counts is recommended by the USP. For instance, clobetasol propionate ointment USP and mometasone furoate ointment USP are screened for all these organisms. In addition, preparations meant for rectal, vaginal, and urethral applications are tested for yeasts and molds [15] .

Test for S. aureus and P. aeruginosa The test sample is mixed with about 100 mL of fl uid soybean – casein digest (FSBCD) medium and incubated. If microbial growth is observed, it is inoculated in agar medium by the streaking technique. Vogel – ohnson agar (VJA) medium is used for S. aureus screening, and cetrimide agar (CA) medium is used for screening P. aeruginosa . The petridishes are then closed, inverted, and incubated under appropriate conditions. The appearance of black colonies surrounded by a yellow zone over VJA medium and greenish colonies in CA medium indicates the presence of S. aureus and P. aeruginosa , respectively.

Various other agar media are also available for screening these organisms. A coagulase test is then performed for confi rming the presence of S. aureus and oxidase and pigment tests for confi rming P. aeruginosa .

Test for Salmonella Species and E. coli The test sample is mixed with about 100 mL of fl uid lactose (FL) medium and incubated. If microbial growth is observed, the contents are mixed and 1 mL is transferred to vessels containing 10 mL of fl uid selinite cystine (FSC) medium and fl uid tetrathionate (FT) medium and incubated for 12 – 24 h under appropriate conditions. To identify the presence of Salmonella , samples from the above two media are streaked over brilliant green agar (BGA) medium, xylose lysine desoxycholate agar (XLDA) medium, and bismuth sulfi te agar (BSA) medium and incubated. The appearance of small, transparent or pink – to – white opaque colonies over BGA medium, red colonies with or without black centers over XLDA medium, and black or green colonies over BSA medium indicates the presence of Salmonella . It is further confi rmed in triple sugar iron agar

medium. The presence of E. coli is screened by streaking the samples from FL medium over MacConkey agar medium. The appearance of brick red colonies indicates the presence of E. coli . It is further confi rmed using Levine eosin methylene blue agar medium. total aerobic microbial counts The plate method or multiple – tube method is performed to estimate the total count. About 10 g or 10 mL of the test sample is dissolved or suspended in suffi cient volume of phosphate buffer (pH 7.2), fl uid soybean casein digest (FSBCD) medium, or fl uid casein digest – soy lecithin – polysorbate 20 medium to make the fi nal volume 100 mL. In the plate method, about 1 mL of this diluted sample is mixed with molten soybean – casein digest agar (SBCDA) medium and solidifi ed at room temperature. The plates are inverted and incubated for two to three days. The number of colonies that are on the surface of nutrient media are counted. The multiple tube method is performed using sterile fl uid SBCD medium. The number of colonies formed should not exceed the limits specifi ed in an individual monograph. For example, clobetasol propionate ointment USP and hydrocortisone valerate ointment USP contains less than 100 colony – forming units (CFU) per gram of sample.

Test for Yeasts and Molds The plate method is used for testing molds and yeast in semisolids. The procedure is similar to that of the total count test. Instead of SBCDA medium, Sabouraud dextrose agar (SDA) medium or potato dextrose agar (PDA) medium is used. Samples are incubated for fi ve to seven days at 20 – 25 ° C to identify the presence of yeasts and molds.

Assay The quantity of drug present in a unit weight or volume of ointment or cream is determined by various methods. Spectrophotometric, titrimetric, chromatographic, and in some cases microbial assays are performed. Selection of a particular method is based on the nature of drug, its concentration in the product, interference between the drug and other formulation components, and offi cial requirements.

Although spectrophotometric methods are accurate and easy to perform, the complexity of ointment matrix sometimes reduced the specifi city of analysis compare to liquid chromatographic methods. The USP prescribes high – performance liquid chromatographic (HPLC) assays for many offi cial ointments due to its specifi city, accuracy, and precision. For example, amcinonide, anthralin, betamethasone dipropionate, clobetasol propionate, dibucaine, nitroglycerine, hydrocortisone, and triamcinolone acetonide are assayed by HPLC methods. These methods involve extraction of drug from the formulation matrix using suitable solvents followed by chromatographic separation using suitable reversed – phase columns followed by ultraviolet (UV) detection. Clioquinol preparation is assayed by gas chromatography. The USP also recommends potentiometric titrations (benzocaine, lidocaine, and ichthammol) and complexometric titrations (zinc oxide) for some semisolid preparations.

Microbial assays are recommended for certain preparations containing antibiotics such as amphotericin B, bacitracin, chlortetracycline hydrochloride, gentamycin sulfate, neomycin sulfate, and nystatin. These tests evaluate the potency of an antibiotic by means of its inhibitory effects on specifi c microorganism. Two types of microbial assays are performed to determine the antibiotic potency. They are known as cylindrical plate or plate assays and turbidimetric or tube assays. The plate method measures the extent of growth inhibition of a particular microorganism in solidifi ed agar medium in the presence of the test antibiotic (commonly known as zone of inhibition ). The tube method measures the turbidity of a liquid medium that contains a particular organism in the presence and absence of the test antibiotic.

These methods involve extracting drug from the formulation matrix, diluting the drug to a known concentration, and measuring the zone of inhibition or turbidity.

In Vitro Drug Release Studies These studies are conducted to ascertain release of drug from the formulation matrix. Open – chamber diffusion cells such as Franz cells are used for performing in vitro studies. These cells consist of a donor side and a receiver side separated by a synthetic membrane such as cellulose acetate/nitrate mixed ester, polysulfone, or polytetrafl uoroethylene. The membranes are usually pretreated with the receiver fl uid to avoid any lag phase in drug release.

The receiver side is fi lled with a known volume of release medium and is heated to 32 0.5 ° C by circulating warm water through an outer jacket. Aqueous buffers are used for water – soluble drugs. Phosphate buffer solution of pH 5.4 is considered most appropriate for dermatological products as it mimics the pH of skin. Hydroalcoholic or other suitable medium may also be used for sparingly water soluble drugs. A known quantity of the test product is applied uniformly over the membrane on the donor side and samples are withdrawn from the receiver side at different time intervals.

After each sampling, an equal volume of fresh medium is replaced to the receiver side. The sampling time points are different for different formulations; however, at least fi ve samples are withdrawn during the study period for determining the release rate. A typical sample time sequence for a 6 – h study is 0.5, 1.0, 2.0, 4.0, and 6.0 h.

The receiver samples are analyzed by a suitable analytical method to quantify the amount of drug released from the formulation at different time intervals. The slope of the straight line which is obtained from a plot of cumulative amount drug release across 1 – cm 2 membrane versus the square root of time represents the release rate.

Experiments are conducted in hexaplicate to obtain statistically signifi cant results [16] .

In Vivo Bioequivalence Studies In vivo studies are conducted to establish the

biological availability or activity of the drug from a topically applied semisolid formulation.

Dermatopharmacokinetic studies, pharmacodynamic studies, or comparative clinical trials are generally conducted to assess the bioequivalence of topical products [16, 17] .

Dermatopharmacokinetic (DPK) studies are applicable for topical semisolid products that contain antifungals, antivirals, corticosteroids, and antibiotics and vaginally applied products. They are not applicable for ophthalmic, otic, and other products that damage stratum corneum. DPK studies involve measurement of drug concentrations in stratum corneum, drug uptake, apparent steady state, and elimination after application of the test product onto skin. These studies are conducted in healthy human subjects adopting crossover design. The test and the reference products are applied onto eight to nine sites in the forearm. The surface area of each site is based on the strength of drug, extent of drug diffusion, exposure time, and sensitivity of the analytical technique. The application site is washed and allowed to normalize for at least 2 h prior to drug application. A known amount of product is applied onto these selected sites. At appropriate time intervals, the excess of drug from each area is removed using cotton swabs or soft tissue papers. Care is taken to avoid stratum corneum damage during sample collection. Stripping of stratum corneum is performed using adhesive tape – strips (e.g., D – Squame, Transpore). In the elimination phase, the excess drug is removed at the steady – state time point, and

the stratum corneum is harvested at succeeding times over 24 h. The drug content from strips from each time point are extracted using suitable solvents and quantifi ed by a validated analytical method. A stratum corneum drug levels – time curve is developed, and pharmacokinetic parameters such as maximum concentration at steady state ( Cmax – ss ), time to reach Cmax – ss ( Tmax – ss ), and areas under the curve for the test and standard (AUC test and AUC reference ) are computed. DPK studies are performed in either one or two occasions. If performed in one occasion, both arms of a single subject are used to compare the test and reference products. If performed in two occasions, a wash – out period of at least 28 days is allowed to rejuvenate the harvested stratum corneum.

Pharmacodynamic (PD) studies are also performed to estimate the bioavailability and bioequivalence of drugs from topically applied semisolids. In this case, known therapeutic responses from drug products such as skin blanching due to vasoconstrictor effects caused by corticosteroids and transepidermal water loss caused by retinoids are measured and compared between the test and reference products. Comparative clinical studies are rarely conducted due to the diffi culties involved in performing the study, variability in study results, and their poor sensitivity.

Typical Pharmacopeial/Commercial Examples

The vast majority of topical ointments and creams are meant for dermatological applications. They are used to treat various skin conditions such as eczema, dermatitis, allergies, infl ammatory and pruritic manifestations, minor skin wounds, pain, insect bites, psoriasis, herpes and other infections of the skin (e.g., impetigo), acne, and precancerous and cancerous skin growths. Similarly, ophthalmic conditions such as infections, infl ammation, allergy, and dry – eye symptoms are treated with semisolid preparations. Products are also available for certain eye examinations. Vaginal preparations are available for treating genital herpes, yeast infections, and vaginosis caused by bacteria and to reduce menopausal symptoms (e.g., vaginal dryness), and rectal preparations are available for treating minor pain, itching, swelling, and discomfort caused by hemorrhoids and other problems of the anal area. Tables 6 and 7 show some of the commercially available compendial ointment and cream preparations used for treating various topical ailments.

 GELS

Gels are semisolid preparations that contain small inorganic particles or large organic molecules interpenetrated by a liquid. Gels made of inorganic materials are usually two – phase systems where small discrete particles are dispersed throughout the dispersion medium. When the particle size of the dispersed phase is larger, they are referred to as magmas. Gels made of organic molecules are single – phase systems, where no apparent physical boundary is seen between the dispersed phase and the dispersion medium. In most cases, the dispersion medium is aqueous.

Hydroalcoholic or oleaginous dispersion media are also used in some cases. Unlike dispersed systems like suspensions and emulsions, movement of the dispersed phase is restricted in gels because of the solvated organic macromolecules or interconnecting three – dimensional networks of particles.

Gels are attractive delivery systems as they are simple to manufacture and suitable for administering drugs through skin, oral, buccal, ophthalmic, nasal, otic, and vaginal routes. They also provide intimate contact between the drug and the site of action or absorption. With the advancement in polymer science, gel – based systems that respond to specifi c biological or external stimuli like pH, temperature, ionic strength, enzymes, antigens, light, magnetic fi eld, ultrasound, and electric current are being designed and evaluated as smart delivery systems for various applications.

Characteristics

Gels may appear transparent or turbid based on the type of gelling agent used. They exhibit different physical properties, namely, imbibition, swelling, syneresis, and thixotropy. Imbibition refers to the uptake of water or other liquids by gels without any considerable increase in its volume. Swelling refers to the increase in the volume of gel by uptake of water or other liquids. This property of most gels is infl uenced by temperature, pH, presence of electrolytes, and other formulation ingredients.

Syneresis refers to the contraction or shrinkage of gels as a result of squeezing out of dispersion medium from the gel matrix. It is due to the excessive stretching of macromolecules and expansion of elastic forces during swelling. At equilibrium, the system still maintains its physical stability because the osmotic forces of swelling balance the expanded elastic forces of macromolecules. On cooling, the osmotic pressure of the system decreases and therefore the expanded elastic forces return to normal. This results in shrinkage of the stretched molecules and squeezing of dispersion medium from the gel matrix. Addition of osmotic agents such as sucrose, glucose, and other electrolytes helps in retaining higher osmotic pressure even at lower temperatures and avoids syneresis of gels. Thixotropy refers to the non – Newtonian fl ow nature of gels, which is characterized by a reversible gel – to – sol formation with no change in volume or temperature [18] .

Classifi cation

Gels are classifi ed as hydrogels and organogels based on the physical state of the gelling agent in the dispersion. Hydrogels are prepared with water – soluble materials or water – dispersible colloids. Organogels are prepared using water – insoluble oleaginous materials.

Hydrogels Natural and synthetic gums such as tragacanth, sodium alginate, and pectin, inorganic materials such as alumina, bentonite, silica, and veegum, and organic materials such as cellulose polymers form hydrogels in water. They may either be dispersed as fi ne colloidal particles in aqueous phase or completely dissolve in water to gain gel structure. Gums and inorganic gelling agents form gel structure due to their viscosity – increasing nature. Organic gelling agents which are generally high – molecular – weight cellulose polymer derivatives produce gel structure because of their swelling and chain entanglement properties. The swollen molecular chains are held together by secondary valence forces, which help in retaining their gel structure. The physical strength of the gel structure is based on the quantity of gelling agent, nature and molecular weight of gelling agent, product pH, and gelling temperature. Generally high – molecular – weight polymers at higher concentrations produce thick gels. The gel – forming temperature ( gel point ) varies with different polymers. Generally natural gums form gel at lower temperatures. Gelatin, a natural protein polymer, forms gel at about 30 ° C. If the temperature is increased, gel consistency is not obtained even at higher concentrations of gelatin. On the other hand, polymers such as methylcellulose gain gel structure only when the temperature is above 50 ° C due to its decreased solubility and precipitation. Knowledge of the gel point for each gelling agent is therefore essential for preparing physically stable hydrogels.

Organogels Organogels are also known as oleaginous gels. They are prepared using water – insoluble lipids such as glycerol esters of fatty acids, which swell in water and form different types of lyotropic liquid crystals. Widely used glycerol esters of fatty acids include glycerol monooleate, glycerol monopalmito stearete, and glycerol monolinoleate. They generally exist as waxes at room temperature and form cubic liquid crystals in water and increase the viscosity of dispersion. Waxes such as carnauba wax, esparto wax, wool wax, and spermaceti are used in cosmetic organogel preparations. A large quantity of water is entrapped between the three – dimensional lipid bilayers. The equilibrium water content in organogels is about 35%. The structural properties of the lipid, quantity of water in the system, solubility of drug incorporated, and external temperature infl uence the nature of the liquid crystalline phase. The bipolar nature of organogels allows incorporation of both hydrophilic and lipophilic drugs. Release rates can be controlled by altering the hydrophilic and hydrophobic components. Biodegradability of these waxes by the lipase enzyme in the body makes organogels suitable for parenteral administration.

The water present in the gel framework can be completely removed with some gelling agents. Gelatin sheets, acacia tears, and tragacanth ribbons are generally prepared by removal of water from their respective gel matrix. These dehydrated gel frameworks are called as xerogels.

Stimuli – Responsive Hydrogels

The three – dimensional networks of hydrophilic polymers absorb a large quantity of water and form soft structures which resemble biological tissues. Swelling properties of these hydrogels can be altered by various physicochemical parameters.

Physical factors such as temperature, pH, and ionic strength of the swelling medium and chemical factors such as the structure of polymer (linear/branched) and chemical modifi cations (cross – linking) can be altered to tailor their swelling rate.

This feature makes them very attractive for drug delivery and biomedical applications [19 – 23] . pH-Responsive Hydrogels Some polymers show pH – dependent swelling and gelling characteristics in aqueous media. A polymer that exhibits such phase transition properties is very useful from the point of drug delivery. Methacrylic acids (e.g., carbomers) that contain many carboxylic acid groups exist as solution at lower pH conditions. When the pH is increased, they undergo a sol – to – gel transition. This is because of the increase in the degree of ionization of acidic carboxylic groups at higher pH conditions, which in turn results in electrostatic repulsions between chains and, increased hydrophilicity and swelling.

Conversely, polymers that contain amine – pendant groups swell at lower pH environment due to ionization and repulsion between polymer chains. The ionic strength of surrounding fl uids signifi cantly infl uences the equilibrium swelling of these pH – responsive polymers. Higher ionic strength favors gel – counter ionic interactions and reduces the osmotic swelling forces.

Thermoresponsive Hydrogels A dispersion which exists as solution at room temperature and transforms into gel on instillation into a body cavity can improve the administration mode and help in modulating the drug release. Many polymers with thermoresponsive gelling properties are currently being synthesized and evaluated.

A triblock copolymer that consists of polyethylene glycol – polylactic acid, glycolic acid – polyethylene glycerol (PEG – PLGA – PEG) is solution at room temperature and gels at body temperature. Poloxamers, which are made of triblock poly(ethylene oxide) – poly(propylene oxide) – poly(ethylene oxide), exhibit gelatin properties at body temperatures. Similarly, xyloglucan and xanthan gum aqueous dispersions are solutions at room temperature and become gel at body temperature

These are considered convenient alternatives for rectal suppository formulations which usually cause mucosal irritations due to their physical state. The physicochemical properties of these chemically modifi ed thermoresponsive hydrogels are altered by changing the ratio of hydrophilic and hydrophobic segments, block length, and polydispersity.

ReGel by MacroMed contains a triblock copolymer PLGA – PEG – PLGA, undergoes sol – to – gel transition on intratumoral injection, and releases paclitaxel for six weeks.

Ionic-Responsive Hydrogels Administration of sodium alginate aqueous drops into the eye results in alginate gelation due to its interaction with calcium ions in the tear fl uid. Alginate with high guluronic acid and deacetylated gellan gum (Gelrite) show sol – to – gel conversions in the eye due to their interaction with cations in the tear fl uid. Timolol maleate sterile ophthalmic gel – forming solution (Timoptic – XE) that contains Gelrite gellan gum is commercially available.

Gelling Agents

A large number of gelling agents are commercially available for the preparation of pharmaceutical gels. In general, these materials are high – molecular – weight compounds obtained from either natural sources or synthetic pathways. They are water dispersible, possess swelling properties, and improve the viscosity of dispersions. An ideal gelling agent should not interact with other formulation components and should be free from microbial attack. Changes in the temperature and pH during preparation and preservation should not alter its rheological properties. In addition, it should be economic, readily available, form colorless gels, provide cooling sensation on the site of application, and possess a pleasant odor. Based on these factors, gelling agents are selected for different formulations. Table 8 summarizes the molecular weight, gelling strength, synonyms, and compendial status of some of these agents.

The following sections briefl y describe the source, physicochemical properties, formulation, and preservation of some pharmacopeial gelling agents.

Alginic Acid Alginic acid is tasteless and odorless and occurs as a yellowish white fi brous powder. The main source for this naturally occurring hydrophilic colloidal polysaccharide is different species of brown sea weed, known as Phaeophyceae. It consists of a mixture of d – mannuronic acid and l – glucuronic acids. It is used in gels due to its thickening and swelling properties. Alginic acid is insoluble in water; however, it absorbs 200 – 300 times its own weight of water and swells. The viscosity of alginic acid gels can be altered by changing the molecular weight and concentration.

Addition of calcium salts increases the viscosity of alginic acid gels. Its viscosity decreases at higher temperature. Depolymerization due to microbial attack also results in viscosity reduction. Inclusion of an antimicrobial preservative avoids depolymerization and viscosity reduction during storage [6] .

Bentonite Bentonite is a naturally occurring colloidal hydrated aluminum silicate and contains traces of calcium, magnesium, and iron. It is odorless, available as fi ne crystalline powder, and is cream to grayish in color. The particles are negatively charged. Its high water uptake and swelling and thickening properties make it suitable for preparing gels. It swells to about 12 – fold when it comes in contact with water. The viscosity of bentonite dispersion increases with increase in concentration.

The gel – forming properties increase with addition of alkaline materials such as magnesium oxide and decrease with addition of alcohol or electrolytes. Use of hot water and stirring improve wetting and dispersion of bentonite particles in the preparation of the gel. Mixing with magnesium oxide or zinc oxide prior to addition helps in dispersion of bentonite in water. Prior trituration of bentonite with glycerin also helps in easy dispersibility in water. These dispersions are generally left for about 24 h to complete the swelling process. At lower concentration (10%) bentonite suspension exhibits the properties of shear thinning systems and at high concentrations (about 50 – 60%) it forms gel with fi nite yield strength [24] .

Carbomer Carbomers are one of the widely used gelling agents in topical preparations due to their extensive swelling properties. They are obtained by cross – linking acrylic acid with allyl sucrose or allyl pentaerythritol. Various grades with varying degree of cross – linking and molecular weight are commercially available.

Carbomers are generally available as hygroscopic powders, are white in color, and possess a characteristic odor. Presence of about 60% carboxylic acid in its composition makes them acidic. Carbomer 934P, 971P, 974P, and so on, are used for preparing clear gels. Aqueous dispersions of carbomers are usually low viscous, and oeutralization they form high – viscous gels. Basic materials such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, and borax are being used for neutralizing carbomer dispersions. About 0.4 g of sodium hydroxide is used to neutralize 1 g of carbomer dispersion. The viscosity of gels depends on the molecular weight of carbomer and its degree of cross – linking. Inclusion of antioxidants, protection from light, and preservation at room temperature help in retaining their viscosity for prolonged periods. Microbial stability of carbopol gels can be improved by adding antimicrobial preservatives. These gels are prone to discoloration in the presence of large amounts of electrolytes, strong acids, and cationic polymers. Glass, plastic, and resin – lined containers which possess good corrosion – resistant properties are used for packing carbomer gels [6] .

Carboxymethylcellulose Calcium (Calcium CMC) A calcium salt of polycarboxymethyl ether of cellulose, calcium CMC is obtained by carboxymethylation of cellulose and conversion into calcium salt. Different molecular grades are prepared by changing the degree of carboxymethylation. It is available as a fi ne powder, white to yellowish white in color, and hygroscopic iature. Calcium CMC has swelling and viscosity – enhancing properties in water. It can swell twice its volume in water [25] .

Carboxymethylcellulose Sodium (Sodium CMC) A sodium salt of polycarboxymethyl ether of cellulose, sodium CMC is obtained by treating alkaline cellulose with sodium monochloroacetate. It is available as white – colored granular powder.

Various viscosity grades of sodium CMC commercially available basically differ in their degree of substitution. The degree of substitution represents the average number of hydroxyl groups that are substituted per anhydroglucose unit. It is readily dispersible in water and forms clear gels. The aqueous solubility of CMC sodium is governed by the degree of substitution. Higher concentrations generally yield thicker gels. Although the viscosity of gels is stable over a wide range of pH (4 – 10), a fall in pH below 2 or a rise to above 10 results in physical instability and viscosity reduction. Higher viscosity is obtained at neutral pH conditions. Exposure of gels to higher temperature also results in viscosity reduction. Preservation at optimum temperature and inclusion of an antimicrobial preservative improve the physical and microbial stability of CMC sodium gels [25] .

Carrageenan Extraction of some red seaweed belonging to the Rhodophyceae – class with water or aqueous alkali yields carrageenan. It is a hydrocolloid and mainly contains sodium, potassium, calcium, magnesium, and ammonium sulfate esters of galactose and copolymers of 3, 6 – anhydrogalactose.

They differ in their ester sulfate and anhydrogalactose content. It is available as a coarse to fi ne powder which is yellow to brown in color. It is odorless and tasteless. Carrageenan is soluble in hot water and forms gels at 0.3 – 2.0%. - Carrageenan and – carrageenan show good gelling properties [26] .

Colloidal Silicon Dioxide Colloidal silicon dioxide is a fumed silica obtained by vapor hydrolysis of chlorosilanes. It is available as nongritty amorphous powder which is bluish white in color. It is tasteless and odorless and possesses low tapped density. Although insoluble in water, it readily forms a colloidal dispersion due to its fi ne particle size, higher surface area, and water – adsorbing properties. The bulk density and particle size of colloidal silicon dioxide can be altered by changing the method of manufacture. Transparent gels can be formed by mixing with other materials that possess similar refractive index. Under acidic and neutral pH conditions, it shows viscosity – increasing properties. This property is lost at higher pH conditions because of its dissolution. Viscosity of gels is not generally affected by temperature [27] .

Ethylcellulose Ethylcellulose is a synthetic polymer made of  anhydroglucose units connected by acetyl linkages. It is obtained by ethylating alkaline cellulose solution with chloroethane. Ethylcellulose is available as a free – fl owing powder which is tasteless and white in color. Although it is insoluble in water, it is incorporated into topical preparations due to its viscosity – enhancing properties.

Ethanol or a mixture of ethanol and toluene (2 : 8) is used as a solvent. A decrease in the ratio of alcohol increases the viscosity. The viscosity of the dispersion is increased by increasing the concentration of ethylcellulose or by using a high – molecular – weight material. As ethylcellulose is prone to photo – oxidation at higher temperature, and gels are prepared and preserved at room temperature and dispensed in airtight containers [28] .

Gelatin Gelatin is a protein obtained by acid or alkali hydrolysis of animal tissues that contain large amounts of collagen. Based on the method of manufacture, it is named type A or type B gelatin. Type A is obtained by partial acid hydrolysis and type B is obtained by partial alkaline hydrolysis. They differ in their pH, density, and isoelectric point. Gelatin is available as yellow – colored powder or granules. It swells in water and improves the viscosity of dispersions. Different molecular weights and particle size grades are commercially available. Gels can be prepared by dissolving gelatin in hot water and cooling to 35 ° C. Temperature greatly infl uences the viscosity and stability of gelatin dispersions. It transforms to a gel at temperatures above 40 ° C and undergoes depolymerization above 50 ° C. The viscosity of gelatin gel is also affected by microbes [29] .

Guar Gum Guar gum is a high – molecular – weight polysaccharide obtained from the endosperms of guar plant. It mainly contains d – galactan and d – mannan. It is available as powder which is odorless and white to yellowish white in color. It readily disperses in water and forms viscous gels. The viscosity of gel is infl uenced by the particle size of material, pH of the dispersion, rate of agitation, swelling time, and temperature. Viscosity reduces on long – time heating. Maximum viscosity can be achieved within 2 – 4 h. Gels are stable at pH between 7 and 9 and show liquifi cation below pH 7. Addition of antimicrobial preservatives improves the microbial stability of guar gum gels. Rheological properties of these gels can be modifi ed by incorporating other plant hydrocolloids such as tragacanth and xanthan gum [30] .

Hydroxyethyl Cellulose ( HEC) HEC is a partially substituted poly(hydroxyethyl) ether of cellulose. It is obtained by treating alkali cellulose with ethylene oxide. HEC is available as a powder and appears light tan to white in color.

Different viscosity grades of HEC are commercially available which differ in their molecular weights.

Clear gels are prepared by dissolving HEC in hot or cold water. Dispersions can be prepared quickly by altering the stirring rate of dispersion, temperature, and pH.

Slow stirring at room temperature during the initial stages favors wetting. Increasing the temperature at this stage increases the rate of dispersion. Although HEC dispersions are stable over a wide pH range, maintaining basic pH improves the dispersion.

The preservation temperature, formulation pH, and microbial attack infl uence the rheological properties of HEC dispersions. Viscosity reduces at higher temperature, but reverts to the original value on returning to room temperature. Lower and higher pH of the vehicle usually results in hydrolysis or oxidation of HEC, respectively. Some of the enzymes secreted by microbes decrease the viscosity of HEC dispersions. The presence of higher levels of electrolytes may also destabilize HEC dispersions. Inclusion of a suitable antimicrobial preservative is essential to retain the viscosity of HEC gels [31] .

Hydroxyethylmethyl Cellulose ( HEMC) HEMC is a partially o – methylated and o – (2 – hydroxyethylated) cellulose. It is available as powder or granules which are white, grayish white, or yellowish white in color. Various viscosity grades of HEMC are commercially available, and form viscous colloidal dispersions or gels in cold water which has a pH in the range of 5.5 – 8 [6] .

Hydroxypropyl Cellulose ( HPC) HPC is a partially substituted poly(hydroxypropyl) ether of cellulose. It is obtained by treating alkali cellulose with propylene oxide at higher temperatures. It is available as tasteless and odorless powder which is yellowish or white in color. Different viscosity grades are commercially available.

Gradual addition of HPC powder into vigorously stirred water yields clear viscous dispersions or gels below 38 ° C. Increase in temperature destabilizes the dispersion and leads to precipitation. The viscosity of dispersions can be increased by increasing the concentration of HPC or by using high – molecular – weight grades.

Inclusion of a cosolvent such as dichloromethane or methane produces viscous dispersion or gels with modifi ed texture. The viscosity of HPC dispersions can be increased by mixing with an anionic polymer. High concentrations of electrolytes destabilize HPC dispersions. HPC dispersions are neutral in pH (6 – 8).

They undergo acid hydrolysis at lower pH and oxidation at higher pH. Both processes decrease the dispersion viscosity. In addition, certain enzymes produced by microbes degrade HPC and reduce its viscosity. Addition of an antimicrobial preservative is therefore recommended for HPC gels. Preservation of these gels from light can further improve its physical stability [25] .

Hydroxypropylmethyl Cellulose ( HPMC) HPMC is a partly o – methylated and o – (2 – hydroxypropylated) cellulose obtained by treating alkali cellulose with chloromethane and propylene oxide. It is available as odorless and tasteless granular or fi brous powder which is creamy white or white in color. HPMC is soluble in cold water. Aqueous dispersions are prepared by dispersing material in about 25% hot water (80 ° C) under vigorous stirring. On complete hydration of HPMC, a suffi cient quantity of cold water is added and mixed. The gel point of HPMC dispersions varies from 50 to 90 ° C. Gels are stable over a wide pH range (3 – 11). The viscosity HPMC dispersions depends on the concentration of material used, its molecular weight, vehicle composition, presence of preservatives, and so on. Viscous gels can be prepared using high concentrations of high – molecular – weight grades. Inclusion of organic solvents such as ethanol or dichloromethane improves the viscosity.

Addition of an antimicrobial preservative (e.g., benzalkonium chloride) minimizes microbial spoilage of HPMC gels [25] .

Glyceryl Behenate Glyceryl behenate is a mixture of glycerides of fatty acids which is obtained by esterifi cation of glycerin with behenic acid. It may also contain arachidic acid, stearic acid, erucic acid, lignoceric acid, and palmitic acid. It is available as a waxy mass or powder, possesses a faint odor, and is white in color. It is practically insoluble in water and soluble in dichloromethane and chloroform. It is used as a viscosity – increasing agent in silicon gels [6] .

Glyceryl Monooleate ( GMO) GMO is a mixture of glycerides of fatty acids obtained by esterifi cation of glycerol with oleic acid. It may also contain linoleic acid, palmitic acid, stearic acid, linolenic acid, arachidic acid, and eicosenoic acid. It is available as a partially solidifi ed or oily liquid. GMO is insoluble in water. Self – emulsifying grades that contain an anionic surfactant disperse easily and swell in water. The nonemulsifying grades are used as emollients in topical preparations and self – emulsifying grades are used as emulsifi ers in aqueous emulsions [6] .

Magnesium Aluminum Silicate ( MAS) MAS is also known as veegum. It is a polymeric complex of magnesium, aluminum, silicon, oxygen, and water and is obtained from silicate ores. Based on the ratio of aluminum and magnesium and viscosity, it is classifi ed as types IA, IB, IC, and IIA. It is available as fi ne powder that is odorless, tasteless, and off – white to creamy white in color. Although MAS is insoluble in water, it swells to a large extent and produces viscous colloidal dispersions.

Use of higher concentration, addition of electrolytes, and heating of dispersion usually improve the viscosity [32] .

Methylcellulose ( MC) MC is a long – chain cellulose polymer with methoxyl substitutions at positions 2, 3, and 6 of the anhydroglucose ring. It is synthesized by methylating alkali cellulose with methyl chloride. The degree of substitution of methoxy groups infl uences the molecular weight, viscosity, and solubility characteristics of MC. It is available as powder or granules and is odorless, tasteless, and white to yellowish white in color. MC is insoluble in hot water but slowly swells and forms viscous colloidal dispersions in cold water. Gels can be prepared by initially mixing the methylcellulose with half the volume of hot water ( ≈70 ° C) followed by addition of the remaining volume of cold water. Viscosity of these dispersions can be increased by using high – concentration or high – molecular – weight grades of methylcellulose.

Higher processing or preservation temperatures reduce the viscosity of formulations, which regain their original state on cooling to room temperature. MC aqueous dispersions show pH values of 5 – 8. Reduction in pH to less than 3 leads to acid – catalyzed hydrolysis of glucose – glucose linkages and results in low viscosity.

Antimicrobial preservatives are generally included to enhance the microbial stability of dispersions. Salting out is observed when high concentrations of electrolytes are added to methylcellulose dispersions. The viscosity of methylcellulose dispersions is also infl uenced by the presence of formulation excipients and drugs [25] .

Poloxamer Poloxamers are copolymers of ethylene oxide and propylene oxide.

Different molecular weight grades that are different in physical form, solubility, and melting point are available. Poloxamer 124 is a colorless liquid, whereas poloxamers 188, 237, 338, and 407 are solids at room temperature. All poloxamer grades are freely soluble in water and form gels at higher concentrations. The pH of aqueous liquids ranges between 5 and 7.5 [33] .

Polyethylene Oxide Polyethylene oxide is a nonionic homopolymer of ethylene oxide synthesized by polymerization of ethylene oxide. It is available as a free – fl owing powder white to off – white in color with a slight ammonia odor.

Various molecular weight grades of polyethylene oxide are commercially available. They swell in water and form viscous dispersions or gels based on the concentration and grade used. Inclusion of alcohol improves the rheological stability of polyethylene oxide dispersions [6] .

Polyvinyl Alcohol ( PVA ) PVA is a synthetic polymer prepared by hydrolysis of polyvinyl acetate. It is available as a granular powder which is odorless and white in color. Mixing with water at room temperature, heating for about 5 min at 90 ° C, followed by cooling with constant mixing yield aqueous dispersions or gels. Higher viscosities can be obtained by using high – viscosity grades. Addition of borax improves the gelling properties of PVA, whereas inorganic salts destabilize these dispersions.

The pH of PVA dispersions ranges between 5 and 8. Physical and chemical decompositions occur at lower and higher pH conditions. Incorporation of an antimicrobial preservative and storage at room temperature improve its stability [6] .

Povidone Povidone is a synthetic polymer consisting of 1 – vinyl – 2 – pyrrolidinone units. It is available as a fi ne powder and appears white to creamy – white in color.

Various molecular weight grades of povidone are available which differ in their degree of polymerization. Povidone is soluble in water and forms viscous solutions and gels based on the concentration and viscosity grade used.

Decomposition occurs when dispersions are heated to about 150 ° C. The pH of aqueous dispersions ranges from 3 to 7. The microbial stability of povidone aqueous dispersions can be increased by adding preservatives [6] .

Propylene Carbonate ( PC) PC is prepared by reacting propylene chlorohydrin with sodium bicarbonate. It is available as a clear liquid with a faint odor. Mixtures of PC and propylene glycol are good solvents for corticosteroids in topical preparations.

It is incompatible with strong acids, bases, and amines. The pH of 10% aqueous dispersion is 6.0 – 7.5 [34] .

Propylene Glycol Alginate ( PGA) PGA is a propylene glycol ester of alginic acid obtained by treating alginic acid with propylene oxide. It is available as granular or fi brous powder which is odorless, tasteless, and white to yellowish – white in color.

PGA is soluble in water and forms viscous colloidal dispersions. The viscosity of these dispersions is based on the concentration of PGA, temperature, and pH. Its aqueous solubility decreases at higher temperatures. The aqueous dispersions are acidic iature and more stable at pH 3 – 6. Higher pH leads to saponifi cation. As these dispersions are prone to microbial spoilage, antimicrobial preservatives are generally included [6] .

Sodium Alginate Sodium alginate is obtained by extraction of alginic acid from brown seaweed followed by neutralization with sodium bicarbonate. Alginic acid is composed of d – mannuronic acid and l – guluronic acid. It is available as a powder which is tasteless, odorless, and white to yellowish – brown in color. Sodium alginate forms viscous gels in water. Dispersing agents such as glycerol, propylene glycol, sucrose, and alcohol are added to improve dispersion. The presence of low concentration of electrolytes improves the viscosity, whereas at high concentrations salting out takes place. The viscosity of gel is based on the concentration of sodium alginate, temperature, pH, and other additives. Various viscosity grades of sodium alginate are commercially available. Aqueous dispersions are stable at pH 4 – 10.

Precipitation or decrease in viscosity is observed when the pH is below or above these values.

Autoclaving or heating above 70 ° C results in depolymerization and decrease in viscosity. Inclusion of preservative is essential to maintain the microbial stability of sodium alginate topical gels [35] .

Tragacanth Tragacanth is a polysaccharide polymer obtained from some Astragalus species. It is composed of two polysaccharides: bassorin (water insoluble) and tragacanthin (water soluble). It is available as odorless powder white to yellowish in color and possesses mucilaginous taste. Tragacanth swells about 10 times its weight in water and forms viscous solutions or gels. Tragacanth is usually added with vigorous stirring to avoid lump formation. Wetting agents such as glycerin, propylene glycol, and 95% ethanol are used in initial stages to improve wetting and dispersion of tragacanth in water. The viscosity of tragacanth dispersions is infl uenced by the processing temperature and formulation pH. High temperature usually increases the viscosity of gels. Tragacanth dispersions show higher viscosity at pH 8 and starts decreasing at higher pH. These gels usually contain preservatives such as benzoic acid or a combination of methyl and propyl parabens for effective preservation from microbial attack. The viscosity of tragacanth dispersions reduces in the presence of strong mineral and organic acids and sodium chloride [6] .

Preparation and Packaging

Gels are relatively easier to prepare compare to ointments and creams. In addition to the gelling agent, medicated gels contain drug, antimicrobial preservatives, stabilizers, dispersing agents, and permeation enhancers. Some of the factors discussed below are essential to obtain a uniform gel preparation.

Order of Mixing The order of mixing of these ingredients with the gelling agent is based on their infl uence on the gelling process. If they are likely to infl uence the rate and extent of swelling of the gelling agent, they are mixed after the formation of gel. In the absence of such interference, the drug and other additives are mixed prior to the swelling process. In this case, the effects of mixing temperature, swelling duration, and other processing conditions on the physicochemical stability of the drug and additives are also considered. Ideally the drug and other additives are dissolved in the swelling solvent, and the swelling agent is added to this solution and allowed to swell.

Gelling Medium Purifi ed water is the most widely used dispersion medium in the preparation of gels. Under certain circumstances, gels may also contain cosolvents or dispersing agents. A mixture of ethanol and toluene improves the dispersion of ethylcellulose, dichloromethane and methanol increase the viscosity of hydroxypropyl cellulose dispersions, alcohol improves the rheological stability of polyethylene oxide gels, and inclusion of glycerin, propylene glycol, sucrose, and alcohol improves the dispersion of sodium alginate dispersions. Borax is included in polyvinyl alcohol gels and magnesium oxide, zinc oxide, and glycerin are included in bentonite gel as dispersing agents. Care should be taken to avoid the evaporation or degradation of these cosolvents and dispersing agents during the preparation of gels.

Processing Conditions and Duration of Swelling The processing temperature, pH of the dispersion, and duration of swelling are critical parameters in the preparation of gels. These conditions vary with each gelling agent. For instance, hot water is preferred for gelatin and polyvinyl alcohol, and cold water is preferred for methylcellulose dispersions. Carbomers, guar gum, hydroxypropyl cellulose, poloxamer, and tragacanth form gels at weakly acidic or near – neutral pH conditions (pH 5 – 8).

Gelling agents such as carboxymethyl cellulose sodium, hydroxypropylmethyl cellulose, and sodium alginate form gels over a wide pH range (4 – 10). Hydroxyethyl cellulose forms gel at alkaline pH condition. A swelling duration of about 24 – 48 h generally helps in obtaining homogeneous gels. Natural gums need about 24 h and cellulose polymers require about 48 h for complete hydration.

Removal of Entrapped Air Entrapment of air bubbles in the gel matrix is a common issue, especially when the swelling process involves a mixing procedure or the drug and other additives are added after the swelling process. Positioning the propeller at the bottom of the mixing container minimizes this issue to a larger extent. Further removal of air bubbles can be achieved by long – term standing, low – temperature storage, sonication, or inclusion of silicon antifoaming agents. In large – scale production, vacuum vessel deaerators are used to remove the entrapped air.

Packaging Being viscous and non – Newtonian systems, gels need high attention during packing into containers. Usually they are packed into squeeze tubes or jars made of plastic materials. Aluminum containers are also used when the product pH is slightly acidic. Pump dispensers and prefi lled syringes are sometimes used for packing gels. As most of the gels contain an aqueous phase, preservation in airtight containers helps in protecting them from microbial attack. Usually they are preserved at room temperature and protected from direct sunlight and moisture.

In large – scale production, different mills, separators, mixers, deaerators, shifters, and packaging machines are used. Most of this equipment is similar to those discussed under ointments and creams. Figure 3 shows a “ one – bowl ” vacuum processing machine manufactured by FrymaKoruma – Rheinfelden (Romaco) for the preparation gels. Batch sizes ranging from 15 to 160 L are processed using this machine. It uses an extremely effi cient high – shear rotor/stator system for homogenizing and a counterrotating mixing system for macromixing. The raw materials are drawn into the multichamber system of the homogenizer by vacuum and then mixed and pumped into the homogenizing zone. The product which enters the vessel is mixed, sheared, and recirculated. All the entrapped air is removed during the recirculation.

The machine also has an insulated jacket for controlling the processing temperature.

Evaluation

Various pharmacopeial and nonpharmacopeial tests are carried out to evaluate the physicochemical, microbial, in vitro, and in vivo characteristics of gels. These tests are meant for assessing the quality of gel formulations and minimizing the batch –

FIGURE 3 Vacuum processing machine used for preparation of gels. (Courtesy of

FrymaKoruma – Rheinfelden, Switzerland.)

to – batch variations. Some of the tests recommended by the USP for gels include minimum fi ll, pH, viscosity, microbial screening, and assay. In some cases sterility and alcohol content are also specifi ed. The USP also recommends storage for each compendial gel formulation. Table 9 shows the quality control tests and storage requirements that are specifi ed for some pharmacopeial gels. The procedures for minimum fi ll, microbial screening, sterility, assay, in vitro drug release, and in vivo bioequivalence are similar to those of ointments and creams. The procedures for additional tests such as homogeneity, surface morphology, pH, alcohol content, rheological properties, bioadhesion, stability, and ex vivo penetration are described below.

Homogeneity and Surface Morphology The homogeneity of gel formulations is usually assessed by visual inspection and the surface morphology by using scanning electron microscopy. Generally, the swollen gel is allowed to freeze in liquid nitrogen and then lyophilized by freeze drying. It is assumed that the morphologies of the swollen samples are retained during this process. The lyophilized hydrogel is gold sputter coated and viewed under an electron microscope. pH Many gelling agents show pH – dependent gelling behavior. They show highest viscosity at their gel point. Determination of pH is therefore important to maintain consistent quality. As conventional pH measurements are diffi cult and often give erratic results, special pH electrodes are used for viscous gels. Flat – surface digital pH electrodes from Crison, combination electrodes that contain a built – in temperature probe, a bridge electrolyte chamber and movable sleeve junction from Mettler, and combination pH puncture electrodes with spear – shaped tip from Mettler are some commercially available pH measurement systems for semisolid formulations.

Alcohol Content Alcohol levels in some gel preparations are determined by gas chromatographic (GC) methods. Desoxymetasone gel USP and naftifi ne hydrochloride gel USP contain 18 – 24% and 40 – 45% (w/w) of ethyl alcohol, respectively. In a desoxymetasone gel, the sample is dissolved in methanol and injected into a gas chramatograph for quantitative analysis. Isopropyl alcohol is used as an internal standard. Iaftifi ne hydrochloride gel, n – propyl alcohol is used as an internal standard and water is used as the diluting solvent [15] .

Rheological Studies Viscosity measurement is often the quickest, most accurate, reliable method to charactreize gels. It gives an idea about the ease with which gels can be processed, handled, or used. Some of the commonly used tests for characterizing rheology of gels are yield stress, critical strain, and creep. Yield stress refers to the stress that must be exceeded to induce fl ow. This helps in characterizing the fl ow nature of non – Newtonian systems. Critical strain or gel strength refers to the minimum energy needed to disrupt the gel structure. When samples are subjected to increasing stress, viscosity is maintained as long as the gel structure is maintained.

When the gel ’ s intermolecular forces are overcome by the oscillation stress, the sample breaks down and the viscosity falls. The higher the critical strain, the better the physical integrity of gel systems. Creep or recovery helps in assessing the strength of bonds in a gel structure. This is assessed by determining relaxation times, zero – shear viscosity, and viscoelastic properties.

Based on the nature of the test material, different techniques are employed to measure the rheological parametrs of gels. Very sophisticated automatic equipment is commercially available for measurements. Cup – and – bob viscometers and cone – and – plate viscometers are widely used for viscous liquids and gels. They measure the frictional force that is created when gels start fl owing. These viscometers are usually calibrated with certifi ed viscosity standards before each measurement.

General – purpose silicone fl uids which are less sensitive to temperature change are used as standards. The viscosity of gels is affected by the experimental temperature and shear rate and the gels exhibit liquid – or solidlike properties. Hence the viscosity of these non – Newtonian systems are recorded at several shear rates under controlled temperatures. The USP specifi es the operating conditions for each gel formulation.

Commercially available viscometers include Brookfi eld rotational viscometers, Haake rheometers, Schott viscoeasy rotational viscometers, Malvern viscometers, and Ferranti – Shirley cone – and – plate viscometers.

Bioadhesion This test is performed to assess the force of adhesion of a gel with biological membranes. The bioadhesive property is preferred for ophthalmic, nasal buccal, and gastroretentive gel formulations. Drugs applied as solutions, viscous solutions, and suspensions drain out from these biological locations within a short time and only a limited fraction of drug elicits the pharmacological activity.

Products with higher bioadhesion thus help in increasing the contact time between drugs and absorbing surface and improve their availability. The bioadhesive properties of gels are measured using various custom – designed equipment. All the equipment, however, measures the force required to detach the gel from a biological surface under controlled experimental conditions (e.g., temperature, wetting level, contact time, contact force, surface area of tissue). A typical bioadhesion measurement system consists of a moving platform and a static platform. A tissue from a particular biological region is fi xed onto these platforms and a known quantity of the test product is uniformly applied to the tissue surface of the lower static platform. The upper moving platform is allowed to contact with the product surface with a known contact force. After allowing for a short contact time, the moving platform is separated from the product with a constant rate. The force required to detach the mucosal surface from the product is recorded. The analog signals generated by precision load cells are then converted to digital signals through data acquisition systems and processed using specifi c software programs.

Stability Studies Being dispersed systems containing water in their matrix, gels are prone to physical, chemical, and microbial stability issues. Syneresis is a commonly observed physical stability problem with gels. It involves squeezing out dispersion medium due to elastic contraction of polymeric gelling agents. This results in shrinkage of gels. Syneresis can be determined by heating the gels to a higher temperature followed by rapid cooling using an ice water bath at room temperature.

The sample is preserved at 4 ° C for about a week, and water loss from the gel matrix is measured. Water loss is measured by weighing the mass of the gel matrix after centrifugation. Absence of syneresis indicates higher physical stability of gels.

The chemical stability of drugs in the gel matrix is determined using stability – indicating analytical methods. Studies are conducted at accelerated temperature, moisture, and light conditions to determine the possible degradation of drug in the gel.

Ex Vivo Penetration Ex vivo studies are carried out to examine the permeation of drug from gels through the skin or any other biological membrane. As with in vitro release studies, ex vivo penetration is conducted using vertical diffusion cells or modifi ed cells with fl ow – through design. In this case, the receiver side is fi lled with phosphate buffer solution of pH 7.4 to simulate the biological pH of human blood. Skin samples from different animal sources such as rats, rabbits, pigs, and human cadavers are used for screening dermatological products. The stratum corneum layer of the skin is separated from the dermis before mounting onto the diffusion cells. The epidermis is separated by immersing the skin sample iormal saline or purifi ed water which is maintained at 60 ° C for 2 min followed by immersion into cold water for 30 s. Careful peeling helps in the separation of the epidermis layer from the dermis. This layer is mounted between the donor and receiver sides and studies are conducted after application of test gel over the surface of the stratum corneum in the donor side. Samples are withdrawn at different time intervals and analyzed for drug permeation by suitable analytical techniques.

Typical Pharmacopeial and Commercial Examples

Gels are becoming popular dosage forms for delivering various categories of drugs for treating dermatological, oral, ophthalmic, vaginal, and other conditions. Many dermatological gels are used for treating mild to moderate acne, eczema, dermatitis, allergies, rash, and psoriasis and for removal of common warts. Oral gels are available for relieving painful mouth sores, treating tooth decay, preventing tooth plaque, and relieving infl ammation of the gums, and vaginal gels are available for treating certain type of vaginal infections (e.g., bacterial vaginosis). Some special types of gels are available for preventing or controlling pain during certain medical procedures, numbing and treating urinary tract infl ammation (urethritis), and numbing mucous membranes. Table 10 shows some of the commercially available compendial gels.

The vagina has been used for a long time as a route for drug administration, being as old as medicine and pharmacy themselves. Throughout the history of human

civilization, vaginal administration of drugs has been practiced and recorded until the modern era. Some of the fi rst records were found in Egypt, where the Kahun Papyrus, the oldest of the surviving medical papyri (ca. 1850 b . c .), included references to vaginal “ preparations ” containing substances such as mud, frankincense, oil, malachite, ass urine, myrrh, crocodile dung, honey, and sour milk, normally used in female genitalia – related conditions and contraception [1] . Latter papyri such as the Ramesseum Papyrus (ca. 1700 b . c .), the Ebers Papyrus (ca. 1550 b . c .), and the Greater Berlin Papyrus (ca. 1300 b . c .) also contained drug formulations to be administered in the vagina. Vaginal administration of drugs continued to be carried out by other civilizations from ancient Greece and Rome to the Middle Ages, in the Arabic and Oriental cultures, passing through the Renaissance, until our days [1, 2] .

Although traditionally used for local action, some drugs can permeate the vaginal mucosa and reach the bloodstream in suffi cient concentrations to have systemic effects. Current understanding of the vaginal anatomy, physiology, and pathophysiology is very considerable, contrasting with the still limited knowledge of the possibilities of vaginal drug delivery. Nonetheless, interest and contribution of pharmaceutical scientists toward vaginal drug delivery development have increased in the last years in response to the specifi c needs of this route of drug administration.

Indeed, vaginal drug delivery has seen recent advances that make it very promising, in particular therapeutic fi elds such as the prevention of human immunodefi ciency virus (HIV) and other sexually transmitted infections, contraception, hormone replacement therapy in menopausal women, and labor induction.

Therefore, this chapter discusses the main features of vaginal anatomy, physiology, and histology related to drug delivery as well as vaginal drug delivery systems and their evaluation. Also, past and current usage of the vagina as a route of drug administration, ongoing investigation, and promising strategies in this fi eld are addressed.

A wide range of drug delivery systems have been used, although many of them are not specifi cally designed for intravaginal administration. Traditionally used vaginal drug delivery systems include solutions, ointments, creams, vaginal suppositories, and tablets. Recently, others, such as vaginal rings or vaginal fi lms, have been developed.

Also, several strategies and improvements have been tested in order to overcome natural limitations of drug delivery through this route, particularly low retention, limited absorption, and cyclic variations.

Most of the currently available vaginal formulations, particularly those that have been marketed for a longer period of time, have serious limitations such as poor spreadability, messiness, and small capacity of retention in the vagina. Nonetheless, recent advances allowed circumventing some of the major diffi culties that hold back the use of this route of drug delivery as a serious alternative to the most traditional ones, with the consequent increase of commercially available drug delivery systems [39] . Drug release of most traditional formulations is rapid, needing frequent administrations to sustain therapeutic drug concentrations. Thus, in recent years, sustained release has been a new approach to deliver several active substances through the vaginal route. Also, vaginal drug delivery systems should ensure either an adequate penetration of the drug within the mucosa, in order to enhance the local effects and reduce systemic absorption, or an ideal permeation of the active substances into the bloodstream in order to assure an effective systemic response.

Before formulators choose a delivery system for a selected drug, several issues should be taken into consideration: physicochemical properties of the active substance, intended effect of the active substance, required drug release profi le, excipients to be used and their compatibility with the active substance and vaginal mucosa, women ’ s preferences, and economical implications.

Excipients

When vaginal drug delivery is considered, formulators must select a number of suitable excipients in order to design a drug delivery system able to ensure the therapeutic success of the active substance(s). In fact, it is known that excipients used in vaginal formulations can infl uence the pharmacological performance of active substances, being able to improve or diminish their activity [68, 69] . The decision of which excipients to use depends to a great extent on the fi nal dosage form and desired characteristics of the drug delivery system. Some excipients can infl uence drug delivery system performance by changing some properties, such as viscosity, mucoadhesion, and distribution [70] . Although these variations do not interfere directly with the pharmacological effect of the active substances, their availability and thus the formulation clinical outcome can be compromised. Thus, excipient selection must be performed with utmost caution, taking into consideration the quality, safety, and functionality aspects of these materials. Indeed, Garg et al. recently compiled a list of excipients that are currently approved or have already been investigated for vaginal administration [71] .

Although by defi nition excipients are deprived of pharmacological effects, some have showed that this is not always true. For instance, chitosan, an excipient that has attracted a lot of interest in the formulation of vaginal drug delivery systems, exhibits antimycotic effects, particularly against the common vaginal pathogen

Candida albicans [72] . Also, other polymers commonly used in tablets and capsules, such as cellulose acetate phthalate, have been investigated in the formulation of vaginal microbicides, due to their antiviral effects against HIV [73] .

Some commonly used excipients can interact with vaginal and cervical fl uids, altering their properties. These interactions should be taken into consideration when designing a drug delivery system, as they can infl uence in vivo performance.

For example, small amounts of nonionic (e.g., polyethylene glycol) and cationic (e.g., polyvinylpyridine) polymers are able to modify the gel structure of the cervical mucus, altering its barrier properties, while like – charged molecules (e.g., polyacrylic acid) interact little with this biological fl uid. This approach has been taken into account, particularly as a new prevention strategy for pathogens that infect via the mucosa, as a new treatment option for diseases that affect the mucous layer itself or even as a strategy for systemic drug delivery routes [74, 75] .

Solid Systems

Solid systems commonly administered by the vaginal route include tablets, capsules, and vaginal suppositories.

Tablets are frequently used as vaginal drug delivery systems, being inexpensive and easy to manufacture. They are also easily administered in the vagina, allowing a “ clean ” insertion that contrasts with the typical messiness of semisolid drug delivery systems. Although very similar to oral tablets, these systems have some particularities, such as being round or oval shaped and devoid of sharp edges, in order to avoid damage of mucosal tissue. These drug delivery systems are usually designed to rapidly release their active substances after being placed in the vagina. In fact, disintegration or dissolution problems, mainly due to the scarce amount of vaginal fl uid, are important issues to be managed by formulators. This rapid release and solubility enhancement of the active substances can be important because of the rapid vaginal wash – off and low in situ retention. Increased and faster release of drug content has been achieved using effervescent tablets [76] or including specifi c excipients that can enhance its disintegration in vaginal fl uids [77] . For instance, Karasulu et al. proposed an effervescent tablet made of a mixture of mucoadhesive microcapsules loaded with ketoconazole and effervescent granules [76] . This combination showed ability to improve retention with rapid onset of action.

Additionally, other strategies have been used, such as inclusion complexes of poorly soluble drugs with cyclodextrins, in order to improve drug solubility, allowing a rapid onset of the pharmacological effect.

Although fast release of the active substances is a frequent goal, controlled – release tablets can be used in order to enhance their effi cacy, because of their prolonged release, and prevent the irritation of the vaginal mucosa that may be caused by some drugs [78] . Nonoxynol – 9, a commonly used microbicide and spermicide, known for its irritability when administered in the vagina, is a good example of a drug that can benefi t from controlled release. Formulation of double – layer tablets (fast – release outer layer and slow – release core) obtained from coprecipitates of nonoxynol – 9 with polyvinylpyrrolidone, can provide extended drug release, allowing a more prolonged spermicidal effect while reducing its irritating effect [79] . Also, controlled release prevents peaks in serum concentration of absorbable drugs, limiting possible systemic effects [80] .

Vaginal tablets containing lactobacilli have been used in order to restore the normal vaginal fl ora. Formulation of these delivery systems requires specifi c proceedings in order to provide viability of lactobacilli and stability of the fi nal product.

Freeze drying of bacterial suspensions has been tested to obtain lyophilized powders for tablet production [81] . These powders were shown to be processable and tablet production was easy and reproducible. Also, the use of double – layer tablets (fast – release layer and slow – release layer) seems to be an interesting approach to lactobacilli administration.

It is common to use tablets designed for the oral route in order to deliver drugs through the vagina. Nonetheless, issues such as delivery system retention an distribution and drug release can infl uence the fi nal performance of the formulation, being preferable to use specifi cally vaginal designed drug delivery systems, or at least study the pharmacokinetics of oral tablets after vaginal administration [82] .

Capsules, particularly soft capsules, have been used as vaginal drug delivery systems, but with modest popularity. These systems are relatively stable, particularly when compared with semisolid formulations or vaginal suppositories, being an adequate way to deliver liquid drugs within a solid dosage form.

Vaginal suppositories, also referred as ovules or pessaries, are ovoid – shaped, solid (but generally malleable) dosage forms specifi cally designed for vaginal administration.

These systems usually weigh 2 – 3 g, although formulations with up to 16 g have been used in the past [83] . Vaginal suppositories have a long history of use as vaginal drug delivery systems, mainly in the management of local conditions. Major advantages are their reduced price and ease of manufacture. However, they present some inconveniences, such as messiness, low retention in the vagina, and poor stability, the last feature due to their temperature and moisture sensibility.

Vaginal suppositories are very close to rectal suppositories in terms of excipient nature and manufacturing process. Thus, they are usually prepared by fusion of the excipient(s) (referred as “ base ” ) and incorporation of the active substance(s), this mixture being subsequently poured into molds and allowed to solidify. Other methods, such as by compression, can also be used. Several substances have been utilized as bases for the formulation of vaginal suppositories: gelatin and glycerin, cocoa butter, semisynthetic glycerides, and polyethylene glycol, among others [83] .

Composition of vaginal suppositories is importantly related to their melting or dissolution, thus infl uencing drug release profi le. Generally, it can be stated that drug release rate increases as the melting temperature of a suppository decreases or as its dissolution time in vaginal fl uids increases. Also, affi nity of the drug for the base infl uences its release from vaginal suppositories: Greater release of drug is expected when there is less affi nity between the active substance(s) and the base [84] . The melting temperature and melting process of vaginal suppositories can be characterized by several techniques, such as differential scanning calorimetry and viscosity and dilatometry methods, among others [85] . Specifi c pharmaceutical characterization of vaginal suppositories includes the determination of disintegration time and breaking hardness. Also, other standard quality control tests include appearance description, surface texture evaluation, pH determination, uniformity of content, and microbial limit testing [86, 87] .

Recently, sustained – release vaginal suppositories have been developed in order to attain drug delivery systems with improved performance. Sustained release can reduce the number of administrations, thus improving patient compliance. A base

composition consisting of a polymeric gum (carboxymethylcellulose and xanthan gum), a dispersing agent (colloidal silicone dioxide), and polyethylene glycol, referred as long acting, sustained release of spermicide (LASRS), has recently been studied by Zaneveld et al. in order to deliver contraceptives and microbicides [88] .

Results showed that a LASRS base is able to spread quickly and evenly over the mucosa, being retained in place for prolonged periods of time and allowing long – lasting effi cacy for several active drugs. Preliminary human trials have confi rmed these results [89] . In another study, Mandal developed hydrophilic vaginal suppositories comprising mixtures of miconazole cross – linked with poly(vinyl alcohol) by freeze thawing and different polyethylene glycols that were able to sustain release this antifungal drug for up to 108 h [90] .

Semisolid Systems

Semisolid systems present several advantages over other drug delivery systems: They are easy to use and generally inexpensive and have good acceptability. Among their disadvantages, leakage has been one of the most disturbing, mainly because many conventional formulations are not mucoadhesive. The simplest way of dealing with this problem has been the recommendation for night administration, as the supine position diminishes leakage. Also, messiness and discomfort upon application and diffi culties in dispensing an accurate dose are important limitations.

Once widely used, ointments have been largely substituted by creams and gels.

Nonetheless, some of these drug delivery systems may still be encountered, particularly as hydrophilic bases.

Creams have been used for quite some time as vaginal drug delivery systems, particularly for the administration of sexual hormones and antimicrobials. The main advantage of creams over other semisolid systems is their ability to easily dissolve both hydrophobic and hydrophilic drugs. As most conventional creams do not possess bioadhesive properties, incorporation of bioadhesive polymers is an effective approach to improve their retention in the vagina. Recently, a new approach to vaginal drug delivery was developed using Site Release (SR) technology (KV Pharmaceutical, St. Louis, MO). This technology is based on bioadhesive controlled – release water – in – oil emulsions, being formulated as a vaginal cream (SR cream).

The outer oily phase repels moisture (thereby resisting dilution) and retains the dispersed water phase containing the drug (allowing controlled release) [91] . The SR cream allows minimizing leakage and enhancing clinical outcome, requiring less total drug exposure per course of therapy. Site Release technology is currently available in the United States in two commercial products: one containing butoconazole nitrate 2% (Gynazole – 1, Ther – Rx Co., St. Louis, MO) and the other containing clindamycin phosphate 2% (Clindesse, Ther – Rx Co.). Clinical fi ndings demonstrated that a single application of Gynazole – 1 makes it possible to achieve more rapid relief of vaginal candidiasis symptoms than standard oral therapy with fl uconazole [92] .

Similarly, Clindesse was show to be able to achieve prolonged local effective concentrations while presenting lower systemic bioavailability and thus less systemic adverse effects when compared with conventional formulations in the treatment of bacterial vaginitis [93] . Also, other drugs have been studied in order to further evaluate the potential of this versatile technology [94] .

Since the pioneer work by Wichterle and Lim in the 1960s [95] , gels have evolved greatly from simple formulations to advanced drug delivery systems. These systems were soon demonstrated to be good candidates to deliver drugs in the vagina, particularly because of their high bioavailability (mainly because of mucoadhesive properties), biocompatibility, spreadability, ease of usage, and economical savings [96] . Gels are extremely versatile, being used to deliver most of the currently used drugs through the vaginal route.

Recent advances in gel and polymer technology boosted research, opening new possibilities for vaginal drug delivery [97] . Indeed, the development of new and improved gelling agents, particularly concerning to their mucoadhesive properties, has been of great importance. For example, polycarbophil (Noveon AA – 1, Noveon, Cleveland, OH), a mucoadhesive polyacrilic acid polymer, has been widely used as a gelling agent in vaginal gel formulations. This polymer is acidic iature, which can be useful in reducing the elevated pH associated with bacterial vaginosis [98] .

Additionally, acidic polycarbophil gels may be used in the treatment of dry vagina and menopause – related stress incontinence [99] .

Also, gel microemulsions have been recently reported as safe and devoid of mucosal toxicity drug delivery systems, presenting intrinsic spermicide activity and the possibility of improving vaginal bioavailability of poorly soluble antimicrobial agents [100] .

Although most currently available vaginal gels rapidly release their active substance(s), they can also be formulated to achieve modifi ed drug release profi les [101] . It is not clear how controlled release is achieved, but the analysis of most formulations that claim to possess this feature suggests a combination of dissolution and diffusion control [102] . Gels are also known to be promising drug delivery systems in protein and peptide administration through the vagina, proving to be adequate to accommodate and stabilize sensible molecules such as leuprolide [103] .

Liquid Systems

Vaginal douching with liquids containing antimicrobial drugs such as povidone – iodine has been a common practice among women, with the intention of improving personal hygiene and treat vaginitis [104] . These liquids are almost immediately removed from the vagina after administration, thus being inadequate for controlled release. Although vaginal washing is frequently performed by women all over the world, its practice is discouraged, as it is associated with increased risk of acquiring HIV, particularly when soap or other substances rather than water are used [105, 106] . Also, bacterial vaginitis and other adverse reproductive health effects are possible when vaginal douching is a frequent practice [107, 108] .

In addition, several solutions are utilized by gynecologists in their offi ce practice.

For example, glacial acetic acid solutions (3 – 5%) are used to identify cervical dysplasia during colposcopy, and Lugol solution is employed to perform Schiller ’ s test (diagnosis of cervix cancer).

Vaginal Rings

Vaginal rings are doughnut – shaped drug delivery systems designed to provide controlled release of drugs. Developed systems are made of fl exible, inert, and nonirritating polymeric materials, presenting different dimensions, usually 54 – 58 mm in diameter and 4 – 9.5 mm in cross – sectional diameter [109, 110] . Vaginal rings present several advantages particularly important for hormonal contraceptives delivery: (1) They do not require daily attention, allowing higher compliance than with daily dosage forms; (2) fl exibility of current rings allow them to be easily inserted and removed by the woman herself, not requiring medical assistance as in the case of subcutaneous or intrauterine devices; (3) the continuous and prolonged delivery (three weeks to one year) of hormones avoids the high peak concentrations and fl uctuations seen with daily oral administration; (4) rings are not associated with adverse local effects, including cytological and normal fl ora changes; and (5) contraceptive rings may be removed from the vagina during sexual intercourse and up to 2 h, without compromising their pharmacological effect [110 – 112] . Although vaginal rings have been essentially investigated and used for the delivery of sexual hormones with contraceptive purposes or as hormone replacement therapy, these drug delivery systems can be also useful for the administration of other drugs such as bromocriptine mesylate, danazol, oxybutynin, antigens, and microbicides [113 – 117].

In the 1960s, fi rst reports that implants made of polysiloxane, containing sexual steroids, could release their content at constant rates in saline solutions provided early information that led to the development of the fi rst vaginal rings [118] . Vaginal rings were initially developed in the 1970s as contraceptives. The fi rst system was composed of a silicone rubber ring containing medroxyprogesterone acetate as the active substance [119] . Nonetheless, the fi rst vaginal rings have just recently reached the market, due to several unpredictable obstacles such as formulation diffi culties, safety issues, and poor ovulation suppression [120, 121] . Table 3 presents some vaginal rings currently available in the market. Vaginal rings may present several designs, as seen in Figure 4 . The fi rst vaginal rings were made of a homogeneous matrix containing the mixture of poly(dimethylsiloxane) (matrix – forming polymer) and the active drug, usually referred as a matrix design. Unfortunately, these rings showed an initial burst effect due to rapid release of the drug contained in the system ’ s surface followed by persistent linear decrease of the drug release rate. This later phenomenon is related to the gradually thickening of a drug – depleted boundary between the inner drug – loaded region and the release surface, which is created by continuous drug release from the outer layers. Thus, their use in clinical practice was compromised, namely

FIGURE 4 Cross sections of three vaginal rings presenting different designs: matrix design (left), core or reservoir design (center), and sandwich or shell design (right).

 

Light gray represents drug – polymer mixture and dark gray represents polymer only. as contraceptive devices. Later, and in order to improve control of the drug release, a layer of poly(dimethylsiloxane) without active substance was applied over the core containing the drug, acting as a drug release – limiting sheath (core or reservoir design). This strategy allowed achieving a near zero – order drug release profi le. The diffusion rate of reservoir design rings is dependent on the drug concentration in the core, its partition coeffi cient between the core and membrane, the thickness and surface area of the membrane, and the diffusion coeffi cient of the drug in the membrane.

In order to achieve a constant release rate, the drug should be much more permeable through the core than through the membrane [122] . Rings with several independent reservoirs containing different drugs have been obtained, thereby allowing the administration of two or more active substances from the same device.

Also, another design has been developed in order to overcome drug release drawbacks, comprising a core of poly(dimethylsiloxane), an intermediate layer of poly(dimethylsiloxane) containing the active substance, and an outer drug release – limiting membrane of poly(dimethylsiloxane) (sandwich or shell design). As the drug is closer to the releasing surface, this strategy is particularly suited for substances presenting poor polymer diffusion characteristics [123] . As with reservoir design rings, a near zero – order drug release profi le is obtained.

Besides poly(dimethylsiloxane), other elastomeric polymers have been employed in the manufacturing of vaginal rings, such as poly(dimethylsiloxane/vinylmethylsiloxane), styrene – butadiene – styrene block copolymer, and poly(ethylene – co – vinyl acetate) [123 – 125] . In fact, poly(ethylene – co – vinyl acetate) (commonly referred as EVA) appeared in the mid 1990s as an alternative to poly(dimethylsiloxane), when the manufacturer of this last material stopped supplying it for human use, demonstrating it to be very suitable for the production of controlled – release systems.

At the laboratory scale, silicone vaginal rings are usually obtained by injection molding, where poly(dimethylsiloxane) is mixed with a polymerization catalyst and the drug, being subsequently injected in ring – shaped molds. The mixture is allowed to cure for a period of time at a preestablished temperature, which can range from room temperature to 150 ° C and over (higher temperatures allow increasing the speed of the ring curing). In fact, curing time and temperature should be optimized as they infl uence the fi nal performance of the ring, particularly drug release (Figure5 ). This step leads to the formation of a three – dimensional network by means of a cross – linking reaction between polymer chains [126] . Afterward, other layers can be added, a step that is usually performed by injection molding or a dipping process.

Although vaginal rings produced at the laboratory scale are useful during preclinical and clinical experimentation, the pharmaceutical industry needs other manufacture solutions to allow large – scale and fi nancially viable production of these drug delivery systems. This process scale – up requires proof of bioequivalence between rings obtained by both processes [109] .

The most common process of obtaining vaginal rings in the pharmaceutical industry is hot – melt extrusion (or hot – melt spinning), where the polymer, either alone or mixed with drugs or other additives, is melted (usually between 105 and 120 ° C) and forced by single – or twin – extrusion screws to pass through a die. After leaving the die, the obtained coaxial fi ber is cooled and cut, the obtained fragments being shaped as rings by gluing both ends with an adequate pharmaceutical adhesive. Figure 6 presents a simplifi ed scheme of the manufacturing process of a reservoir design ring similar to one used to produce Nuvaring (NV Organon, Oss, The Netherlands), an EVA vaginal ring containing etonogestrel and ethiny lestradiol.

The core [polymer and active substance(s)] and the surrounding membrane polymer mixtures are extruded separately through two single – screw extruders (coextrusion)

FIGURE 6 Schematic of manufacturing process of reservoir design ring by hot – melt extrusion.

 

that are connected to a spinning pump. In these cylindrical pipelines the polymers are melted and extruded through a die at an accurate fl ow rate. Then, the core and membrane polymers are combined in a spinneret, forming a coaxial fi ber. The ratio between fl ow rates of both spinning pumps determines the thickness of the membrane.

After leaving the spinneret, this fi ber is cooled, fi rst by air exposure and then by immersion in a water bath. At this stage, the fi ber diameter is adjusted to the desired value by elongation with take – up rolls. In fact, after leaving the die, the obtained fi ber expands its diameter as a result of the viscoelastic behavior of the polymers used [122, 127] .

The drug release profi le is conditioned by the polymeric structure of the systems, which is infl uenced by several parameters such as polymer composition, melt spinning process variables (namely feeding of polymer mixture and spinning velocity, extrusion temperature, spinline stress, cooling rate, and drawing back elongating force), and storage conditions [122, 128] . Also, drug release characteristics are largely infl uenced by the active substances ’ molecular weight and diffusion coeffi cient and solubility in the polymer. For example, extremely hydrophobic drugs and molecules with molecular weight above 450 Da are poorly released from silicone. Modulation of the drug solubility by adding various excipients (e.g., propylene glycol, polyethylene glycol, gelatin, and fl uid silicone) can be used to change the release profi le [129, 130] . The physical state of the drug is also an important parameter related to drug release. Taking the example of steroids, these compounds can be either in a solid crystalline state or in a molecularly dissolved state. In the fi rst case, the concentration of the drug is fi xed by its saturation solubility, making it possible to control the release rate by the thickness and the permeability of an outer membrane. When two drugs are present, this concept cannot be used: Both drugs need to be completely dissolved, their release rates being controlled by their concentrations [123] .

Vaginal Films

Vaginal fi lms are polymeric drug delivery systems shaped as thin sheets, usually ranging from 220 to 240 m in thickness. These systems are often square (approximately 5 cm 5 cm), colorless, and soft, presenting a homogenous surface. Vaginal fi lms have some advantages, such as portability, ease of application, long time of retention in the vagina, and good drug stability [131] . Once placed in the vagina, the fl uid present in the mucosa hydrates the polymer, covering the mucosa with the active substance. This coating may also be helped during sexual intercourse due to the spreading motion of the male penis.

Vaginal fi lms are produced with polymers such as polyacrylates, polyethylene glycol, polyvinyl alcohol, and cellulose derivatives. Proper combination of these polymer is essential to achieve adequate mucoadhesion and optimal drug release profi les. Vaginal fi lms can be produced by casting [132] , in which polymer solutions containing the active substance(s) are poured into adequate molds and dried until a thin, solid, and fl exible polymeric sheet is formed. Afterward, the sheet is cut in small pieces (individual fi lms) and peeled off.

Vaginal fi lms have been mostly used as spermicides, although they present inferior contraceptive success than hormonal methods, condoms, and intrauterine devices. A contraceptive fi lm containing 28% nonoxynol – 9 in a polyvinyl alcohol base (VCF, Apothecus Pharmaceutical) is currently available in the United States.

Alternative contraceptive fi lms containing different drugs and fi lm – forming polymers have also been investigated, in order to obtain more effective and acceptable formulations [133] .

Medicated Vaginal Tampons

Vaginal tampons have been studied for their feasibility as vaginal drug delivery systems. First experiments used commercially available tampons that were impregnated with active substances by a simple dipping process [134] . Currently, a medicated vaginal tampon, approved as a medical device by the Food and Drug

Administration (FDA), is available (Ela Tampon, Rostam, Israel). This bifunctional tampon contains a polymeric delivery system (strips) that absorbs menstrual fl uid while gradually releasing lactic acid and citric acid. These two drugs act by preserving the acid vaginal milieu, preventing the proliferation of potential pathogenic bacteria [135] .

Vaginal Foams

Vaginal foams have been tested to deliver drugs in the vagina, mainly microbicides or spermicides [136, 137] . The effi cacy of these systems was shows to be limited when compared to other available options, leading to a decline of their use.

Nonetheless, foams are easy to use, providing a good coverage of the vaginal mucosa with minimal leaking. Also, most foam bases are nonirritating, unlike some other conventional formulations which are reported to cause burning and itching. Thus, improving their formulation can be an interesting approach to obtaining new vaginal drug delivery systems. In fact, foams containing antimicrobials, local anesthetics, and hormones have the potential to gradually substitute several currently available dosage forms, namely creams and ovules.

Vaginal Sponges

Vaginal sponges were once widely used as vaginal contraceptives, the oldest reference to their use in the Talmud (c. 500 b . c. ), where a sponge soaked in vinegar was recommended in order to prevent pregnancy [138] . Although these devices have been disapproved by some researchers, since their use encouraged colonization and proliferation of bacteria in the vagina, predisposing women to vaginitis and other genital disorders [139] , sponges containing spermicides are still used as contraceptives.

These contraceptive devices have the ability to deliver the active drugs while absorbing semen and blocking the cervical canal. Also, vaginal sponges are inexpensivedevices; less messy than creams, gels, and foams; and easier to insert and remove than diaphragms [140] . Nonetheless, these systems have demonstrated less effi cacy than other contraceptive methods, such as the diaphragm [141] .

A vaginal sponge (Today, Whitehall Robins) made of soft polyurethane foam (diameter of 5.5 cm and 2.5 cm thick) and saturated with 1 g of nonoxynol – 9 was authorized as a spermicide in the United States in 1983 [140] . Advantages of this formulation include the possibility of being used up to 24 h without requiring additional application of spermicide. Although in 1995 the manufacturer discontinued its production because of increased costs related to FDA guideline compliance,

Allendale Pharmaceuticals purchased the rights to the sponge, reintroducing the product in U.S. and Canadian markets [142] . Similar sponges are available outside the United States containing benzalkonium chloride alone (Pharmatex, Innotech International) or a combination of nonoxynol – 9 and sodium cholate (Protectaid, Pirri Pharma).