MODULE 2. SOFT AND ASEPTIC DOSAGE FORMS. PHARMACEUTICAL INCOMPATIBILITIES.

CONTENT MODULE 4.  MEDICINAL FORMS THAT REQUIRE ASEPTIC MANUFACTURING CONDITIONS. PHARMACEUTICAL INCOMPATIBILITIES.

LESSON 24. EYE DOSAGE FORMS.

 

EYE MEDICAL FORMS

Classification of eye medical forms

Solid medical forms:  pills, lamels, pencils, powders, tapes.

Liquid medical forms: eye drops, washes, washings, solutions for injections and electrophoresis.

Soft medical forms: ointments homogeneous and heterogeneous.

Gaseous medical forms: aerosols.

Eye drops (Guttae ophthalmіcae ) – are medical form, which shows by itself hydrogen’s or oil solutions, and also suspensions which are intended for installation in a conjunctive sac in a negligible quantity.

Requirements for eye drops:

·        sterility

·        isotonicity

·        stability

·        exactness of

·        concentration of operating substances;

·        transparency;

·        absence of irritating and allergenic actions

·        to find out maximal biological activity

·        in some cases do prolonged therapeutic effect.

Aseptic terms – it the certain terms of work, and also complex of obligatory organizational measures which allow maximally to save medications, from a hit in them of microorganisms.

Sterility – arrived at by preparation of eye drops in aseptic terms and their next sterilization.

Stability is arrived by the use of buffer solutions, stabilizations and by the correct selection of tableware, made from glass of brand NG (neutral glass)-1, NG-2, NG-3.

Absence of mechanical inclusions provided by filtration

Isotones of eye drops conduct on principle of the same name of ions.

Use:

·        sodium chloride

·        sodium sulfate

·        sodium nitrate

·        boric acid (only on a concordance with a doctor)

·        glucose (only on a concordance with a doctor)

For isotones use the isotonic equivalents of medicinal substances by sodium chloride.

Rp.:  Sol. Pіlocarpіnі hydrochlorіdі      1% 10 ml

іsotonіcae

D. S. For 2 drops in eyes

Technology depends on solubility of substances

·        If a medical substance is well soluble in a solvent, dissolve in the half amount of solvent and filter in a small bottle for dispense through washed by water purificate filter and cotton wool, and then a filter washed by other part of solvent.

Technology depends on solubility of substances

·        If a medical substance is difficult soluble, dissolve in totally of solvent and filter in the measured cylinder through a dry filter and cotton wool, and amount of water, that it is not enough, add through the same filter and cotton wool to the necessary volume of solution.

 

Rp.: Sol. Zinci sulfatis 0,25 % 20 ml

 M. D. S. For 2 drops in an eye.

WCP (r.s.)

Zinci sulfatis 0,05

Aque purificatae 20 ml

Natrii sulfatis 0,76

 

а)  with the use of equivalents of zinc sulfate and sodium sulfate at sodium by a chloride:

Amount of zinc sulfate :

0,25 – 100 ml  

Х – 20 ml                       Х =  0,05

Amount of sodium of chloride which equal the amount of zinc sulfate :

1,0 – 0,12

0,05 – Х                         Х = 0,006

4. Amount of sodium chloride, necessity for isotones of eye drops:

0,18 – 0,006 = 0,174

Amount of sodium sulfate, necessity for isotones of eye drops :

0,23 sodium chloride – 1,0 sodium  sulfate

0,174 sodium chloride – Х        Х = 0,76

WCP (f.s.)

Date                     № of recipe     

Aquae purificatae 10 ml

Zinci sulfatis 0,05
    Natrii sulfatis 0,76

 V = 20 ml

10 ml №2

  Sterilis                 

Prepared                  

Checked

 

Registration to dispense.

Labels: the “Eye drops”, “Sterile”, to “Save from children”.

 

Rp.: Ung. Thiamini bromidi 0,5% 10,0

 D. S. To mortgage for an eyelid.

WCP (f.s.)

Date                             № of

Thiamini bromidi 0,05 (0,1)

Aquae purificatae q.s.

Basis pro oculi sterile (8:2) 10,0

m = 10,0

Addita aseptice

Prepared                  

Checked

 

Many ophthalmic preparations are used in the practice of medicine. You probably know solutions, suspensions, and ointments are commonly used as ophthalmic products. Most ophthalmic products are no longer prepared in the pharmacy. However, you should be familiar with some of the characteristics of these important products.

DEFINITION OF OPHTHALMIC PREPARATIONS

Ophthalmic preparations are sterile products that are intended to be applied to the eyelids or placed in the space between the eyelids and the eyeball.

TYPES OF OPHTHALMIC PREPARATIONS

Three types of ophthalmic preparations are commonly encountered in the pharmacy. Each type of preparation has its advantages and disadvantages.

a. Solutions. Ophthalmic solutions are rather easily placed into the eye. However, care must be taken to ensure the solution remains in the eye in order to produce the desired therapeutic effect. Ophthalmic solutions usually do not impair of interfere with the vision of the patient.

b. Suspensions. Ophthalmic suspensions are also easily placed into the eye. In general, suspensions produce a longer effect than do solutions. Suspensions do

have one disadvantage; it is difficult to ensure that the suspension does not contain particles large enough to produce eye irritation.

c. Ointments. Ophthalmic ointments (for example, certain antibiotic ointments)

are commonly used. They are relatively easy to apply (except in the eyes of children).

Ophthalmic ointments remain in contact with the eye tissues for an extended period.

Hence, they usually produce a therapeutic effect of long duration. One major disadvantage of ointments is that they leave a film over the patient’s eye. Thus, the

patient’s vision can be impaired.

CHARACTERISTICS OF OPHTHALMIC PREPARATIONS

a. Solutions. Ophthalmic solutions must be sterile and particle-free. Moreover,

 phthalmic solutions should be isotonic, if possible.

b. Suspensions. Ophthalmic suspensions must be sterile and free from large

particles that might irritate the eye.

 

 

Learning Objectives

Upon completion of this exercise, you should be able to:

Define buffers, buffer capacity, isotonicity, iso-osmoticity, osmotic pressure, hypertonicity, hypotonicity.

Describe the use buffers in pharmaceutical solutions.

Identify the range of solution pH considered safe for ophthalmic solutions.

Formulate and analyze a buffer solution of desired pH and buffer capacity.

Explain the importance of isotonicity in ophthalmic solutions.

Explain the importance of sterility in ophthalmic solutions.

Explain the role of preservatives in pharmaceutical solutions.

Formulate and prepare pharmaceutically and physiologically acceptable ophthalmic solutions.

Introduction

Drugs are administered to the eye for local effects such as miosis, mydriasis, and anesthesia, or to reduce intraocular pressure in treating glaucoma. The ophthalmic formulation delivers the drug on the eye, into the eye, or onto the conjunctiva. Transcorneal transport (i.e., drug penetration into the eye) is not an effective process. It is estimated that only one-tenth of a dose penetrates into the eye.

 Formulations used include aqueous solutions, aqueous suspensions, ointments, and inserts. Every ophthalmic product must be sterile in its final container to prevent microbial contamination of the eye. Preservatives are added to the formulation to maintain sterility once the container has been opened. Ophthalmic formulations also require that the pH, buffer capacity, viscosity, and tonicity of the formulation is carefully controlled.

ASHP has prepared a Technical Assistance Bulletin entitled, “Pharmacy-Prepared Ophthalmic Products.” The bulletin gives a sketch of the many considerations that are inherent in compounding ophthalmic formulations. The bulletin then stresses the need for established policies and procedures. It states that all compounding must be performed in a laminar air flow hood, and gives some general information about how to filtration sterilize solutions. Ophthalmic suspensions and ointments cannot be filtration sterilized and must either be sterilized as a finished product, or have each component separately sterilized and then combined using aseptic techniques.

Solutions and Suspensions

 

Ophthalmic solutions are sterile, free from foreign particles, and specially prepared for instillation in the eye. Most ophthalmic solutions are dispensed in eye dropper bottles. Patients should be shown how to properly instill the drops in their eyes, and every effort should be made to emphasize the need for instilling only one drop per administration, not two or three. When more than one drop is to be administered, wait at least five minutes between administrations. Immediately after instilling a drop on the eye, place pressure on the lacrimal sac for one or two minutes. This will reduce the rate of drug loss through this pathway.

Ophthalmic suspensions are aqueous formulations that contain solid particles. The particle size must be kept to a minimum to prevent irritation of the eye. It has been recommended that particles be less than 10 microns in size to minimize irritation to the eye. The micronized form of the drug can be used to meet this requirement. There is a tendency of the solid undissolved particles to adhere to the conjunctiva. As drug is absorbed, these solid particles will dissolve to replenish the absorbed drug. This reservoir effect increases the contact time and duration of action of a suspension compared to a solution.

Administering Ophthalmic Dosage Forms

How to Use Ophthalmic Drops

Wash your hands carefully with soap and warm water.

If the product container is transparent, check the solution before use. If it is discolored or has changed in any way since it was purchased (e.g., particles in the solution, color change), do not use the solution.

If the product container has a depressible rubber bulb, draw up a small amount of medication into the eye dropper by first squeezing, then relieving pressure on the bulb.

Tilt the head back with chin tilted up and look toward the ceiling.

With both eyes open, gently draw down the lower lid of the affected eye with your index finger.

In the “gutter” formed, place one drop of the solution.

IMPORTANT: The dropper or administration tip should be held as near as possible to the lid without actually touching the eye. DO NOT allow the dropper or administration tip to touch any surface.

If possible, hold the eyelid open and do not blink for 30 seconds.

You may want to press your finger against the inner corner of your eye for one minute. This will keep the medication in your eye.

Tightly cap the bottle.

Comments

 

This is a sterile solution. Contamination of the dropper or eye solution can lead to a serious eye infection.

If irritation persists or increases, discontinue use immediately.

Generally, eye makeup should be avoided while using eye solutions.

You may want to use a mirror when applying the drops, or it may be much easier to have someone help you instill your eye drops.

How To Administer An Ophthalmic Ointment

Wash your hands carefully with soap and warm water.

You may want to hold the ointment tube in your hand for a few minutes to warm and soften the ointment.

Gently cleanse the affected eyelid with warm water and a soft cloth before applying the ointment.

In front of a mirror, with the affected eye looking upward, gently pull the lower eyelid downward with your index finger to form a pouch.

Squeeze a thin line (approximately ¼ – ½ inch) of the ointment along the pouch.

IMPORTANT: Be very careful when applying this ointment. DO NOT allow the tip of the ointment tube to touch the eyelid, the eyeball, your finger, or any surface.

Close the eye gently and rotate the eyeball to distribute the ointment. You may blink several times to evenly spread the ointment.

Replace the cap on the ointment tube.

After you apply the ointment, your vision may be blurred temporarily. Do not be alarmed. This will clear up in a short while, but do not drive a car or operate machinery until your vision has cleared.

Comments

This is a sterile ointment. Contamination of the tip or the cap of the tube can lead to a serious eye infection.

If irritation persists or increases, discontinue use immediately.

Generally, eye makeup should be avoided while using eye ointments.

It may be much easier to have someone help you apply your eye ointment

Ointments and Inserts

In an effort to maintain longer contact between the drug and ocular tissue, ointments and inserts have been used.

 Ophthalmic ointments tend to keep the drug in contact with the eye longer than suspensions. Most ophthalmic ointment bases are a mixture of mineral oil and white petrolatum and have a melting point close to body temperature. Sometimes anhydrous lanolin is used to take up an ingredient that was dissolved in a small amount of water to affect dissolution. The aqueous solution is incorporated into the lanolin and then the lanolin is mixed with the remaining ointment base ingredients.

Ointments must be nonirritating and free from grittiness so the micronized form of the ingredients is required. Sterile ointments are prepared by first sterilizing all of the individual ingredients and then combining them under aseptic conditions. The prepared ointment is then packaged in a sterile container such as an ointment tube.

 Most ointments tend to blur patient vision as they remain viscous and are not removed easily by the tear fluid. Thus ointments are generally used at night as adjunctive therapy to eye drops used during the day. Ophthalmic ointment tubes are typically small holding approximately 3.5 g of ointment and fitted with narrow gauge tips which permit the extrusion of narrow bands of ointment.

Ocular inserts are not compounded but must be manufactured. Ocusert® is a nonerodible device designed to deliver pilocarpine for several days in the treatment of glaucoma. Some inserts are designed to dissolve in tear fluid. These inserts are made of dried polymeric solutions that have been fashioned into a film or rod. An example of this type of insert is Lacrisert® used to treat moderate to severe dry eye syndrome. Inserts are placed in the cul-de-sac between the eyeball and the eyelid. The biggest disadvantage of inserts is their tendency to float on the eyeball, particularly in the morning upon arising.

Formulation Factors to Consider

Solution pH

The physiologic pH of blood and tears is approximately 7.4. Thus, from a comfort and safety standpoint, this would be the optimal pH of ophthalmic and parenteral solutions. This may not be possible, however, from a perspective of solubility, chemical stability or therapeutic activity. Thus, some compromise must be made and product stability must be considered paramount.

 When a formulation is administered to the eye, it stimulates the flow of tears. Tear fluid is capable of quickly diluting and buffering small volumes of added substances, thus the eye can tolerate a fairly wide pH range. Ophthalmic solutions may range from pH 4.5 – 11.5. But the useful range to prevent corneal damage is 6.5 to 8.5.

Once we have determined the optimal pH of a product, we need a mechanism for adjusting and maintaining the pH of the solution.

Buffers and Buffer Capacity

Buffers are compounds that resist changes in pH upon the addition of limited amounts of acids or bases. Buffer systems are usually composed of a weak acid or base and its conjugate salt. The components act in such a way that addition of an acid or base results in the formulation of a salt causing only a small change in pH.

 

The pH of a buffer system is given by the Henderson-Hasselbach equation:

 (for a weak acid and its salt)

 (for a weak base and its salt)

where [salt], [acid] and [base] are the molar concentrations of salt, acid and base.

Buffer capacity is a measure of the efficiency of a buffer in resisting changes in pH. Conventionally, the buffer capacity () is expressed as the amount of strong acid or base, in gram-equivalents, that must be added to 1 liter of the solution to change its pH by one unit.

Calculate the buffer capacity as:

 

                 = gram equivalent of strong acid/base to change pH of 1 liter of buffer solution

               = the pH change caused by the addition of strong acid/base

In practice, smaller pH changes are measured and the buffer capacity is quantitatively expressed as the ratio of acid or base added to the change in pH produced (e.g., mEq./pH for x volume). The buffer capacity depends essentially on 2 factors:

Ratio of the salt to the acid or base. The buffer capacity is optimal when the ratio is 1:1; that is, when pH = pKa

Total buffer concentration. For example, it will take more acid or base to deplete a 0.5 M buffer than a 0.05 M buffer.

The relationship between buffer capacity and buffer concentrations is given by the Van Slyke equation:

 

 

where C = the total buffer concentration (i.e. the sum of the molar concentrations of acid and salt).

Just as we must often compromise the optimal pH for a product, so must we compromise on the optimal buffer capacity of our solution. On the one hand, buffer capacity must be large enough to maintain the product pH for a reasonably long shelf-life. Changes in product pH may result from interaction of solution components with one another or with the product package (glass, plastic, rubber closures, etc.). On the other hand, the buffer capacity of ophthalmic and parenteral products must be low enough to allow rapid readjustment of the product to physiologic pH upon administration. The pH, chemical nature, and volume of the solution to be administered must all be considered. Buffer capacities ranging from 0.01 – 0.1 are usually adequate for most pharmaceutical solutions.

Preparing a Buffer

Determine the optimal pH for the product, based on physical and chemical stability, therapeutic activity and patient comfort and safety (must consider chemical and physical nature of the active and other ingredients and the route administration).

Select a weak acid with a pKa near the desired pH (must be nontoxic and physically/chemically compatible with other solution additives).

Calculate the ratio of salt to acid required to produce the desired pH (Henderson-Hasselbach equation).

Determine the desired buffer capacity of the product (consider stability of product, route of administration, volume of dose, chemical nature of product).

Calculate the total buffer concentration required to produce this buffer capacity (Van Slyke equation).

Determine the pH and the buffer capacity of the completed buffer solution by using a reliable pH meter or pH paper. (This may not always be practical, especially when small volume, sterile products are prepared.)

 

Sample calculation:

Using Acetic Acid and Sodium Acetate prepare 500 ml of a buffer solution at pH 4.5 with a buffer capacity of 0.05.

Salt to Acid Ratio:

 

Total Buffer Concentration:

Final Calculations:

Iso-osmoticity and Isotonicity

If a semi-permeable membrane (one that is permeable only to solvent molecules) is used to separate solutions of different solute concentrations, a phenomenon known as osmosis occurs in which solvent molecules cross the membrane from lower to higher concentration to establish a concentration equilibrium. The pressure driving this movement is called osmotic pressure and is governed by the number of “particles” of solute in solution. If the solute is a nonelectrolyte, the number of particles is determined solely by the solute concentration. If the solute is an electrolyte, the number of particles will be governed by both the concentration and degree of dissociation of the substance.

 Solutions containing the same concentration of particles and thus exerting equal osmotic pressures are called iso-osmotic. A 0.9% solution of NaCl (Normal Saline) is iso-osmotic with blood and tears. The term isotonic, meaning equal tone, is sometimes used interchangeably with the term iso-osmotic. The distinction between these terms comes with the realization that red blood cell membranes are not perfect semipermeable membranes, but allow passage of some solutes, such as alcohol, boric acid, ammonium chloride, glycerin, ascorbic acid, and lactic acid. Hence, a 2% solution of boric acid while physically measured to be iso-osmotic (containing same number of particles) with blood, will not be isotonic (exerting equal pressure or tone) with blood but is isotonic with tears. Practically speaking, this differentiation is rarely of significance and isotonicity values calculated on the basis of the number of particles in solution is usually sufficient.

The clinical significance of all this is to insure that isotonic or iso-osmotic solutions do not damage tissue or produce pain when administered. Solutions which contain fewer particles and exert a lower osmotic pressure than 0.9% saline are called hypotonic and those exerting higher osmotic pressures are referred to as hypertonic. Administration of a hypotonic solution produces painful swelling of tissues as water passes from the administration site into the tissues or blood cells. Hypertonic solutions produce shrinking of tissues as water is pulled from the biological cells in an attempt to dilute the hypertonic solution. The effects of administering a hypotonic solution are generally more severe than with hypertonic solutions, since ruptured cells caever be repaired. The eye can tolerate a range of tonicities as low as 0.6% and as high as 1.8% sodium chloride solution.

 Several methods are used to adjust isotonicity of pharmaceutical solutions. One of the most widely used method is the sodium chloride equivalent method. The NaCl equivalent (E) is the amount of NaCl which has the same osmotic effect (based oumber of particles) as 1 gm of the drug.

Sample calculation: Calculate the amount of NaCl required to make the following ophthalmic solution isotonic.

Rx

Atropine Sulfate 2%

 NaCl qs

 Aqua. dist. q.s. ad. 30 ml

 M.ft. isotonic solution

 

1. Determine the amount of NaCl to make 30 ml of an isotonic solution

 

2. Calculate the contribution of atropine sulfate to the NaCl equivalent

3. Determine the amount of NaCl to add to make the solution isotonic by subtracting (2) from (1)

Other substances may be used, in addition to or in place of NaCl, to render solutions isotonic. This is done by taking the process one step further and calculating the amount of the substance that is equivalent to the amount of NaCl calculated in step 3.

For example, boric acid is often used to adjust isotonicity in ophthalmic solutions because of its buffering and anti-infective properties. If E for boric acid is 0.50, then the amount of boric acid needed to replace the NaCl in step 3 can be calculated:

 

or 

or, more simply: 

Thus, 0.38 g or 380 mg of boric acid would be required to render the previous ophthalmic solution isotonic.

 Isotonic Buffers

The addition of any compound to a solution will affect the isotonicity since isotonicity is a property of the number of particles in solution. So the osmotic pressure of a solution will be affected not only by the drug but also by any buffer compounds that are included in the formulation. But after these compounds have been added, it is still possible that the solution will not be isotonic. It may be necessary to add additional sodium chloride to bring the solution to isotonicity, but that would require doing the calculations as shown above.

 An alternative to this approach is to use an isotonic buffer. There are two approaches to using isotonic buffers.

Approach 1

 In the first approach, the drug is dissolved in an appropriate volume of water (V-value) to make the solution isotonic. Then the remaining volume needed in the formulation is supplied by an isotonic buffer

 

 An example:Rx

 Procaine HCl 2%

 Aqua. dest. q.s. ad 15 ml

 M.Ft. Isotonic, buffered injection

The formulation requires 0.3 g of Procaine HCl. V-value tables can been found in standard references and are tabulated to tell how many ml of water, when added to 0.3 g of drug, will result in an isotonic solution. For Procaine HCl, 7 ml of water added to 0.3 g of drug will make an isotonic solution. Therefore 0.3 g Procaine HCl is dissolved in 7 ml water, and then sufficient buffered, isotonic vehicle of appropriate pH is added to make 15 ml.

The pH of an isotonic Procaine HCl solution is 5.6. Therefore, an isotonic buffer of approximately that pH would be used. One commonly used isotonic buffer is the Sorenson’s Modified Phosphate Buffer.

Sorensen’s Phosphate Vehicleml of 0.0667 M

 NaH2PO4   ml of 0.0667 M

 Na2HPO4   Resulting pH       NaCl required for

 isotonicity (g/100ml)

90       10     5.9    0.52

80       20     6.2    0.51

70       30     6.5    9.5.

60       40     6.6    0.49

50       50     6.8    0.48

40       60     7.0    0.46

30       70     7.2    0.45

20       80     7.4    0.44

10       90     7.7    0.43

5         95     8.0    0.42

 (from USP XXI, p. 1338)

 

The closest Sorenson’s buffer to pH 5.6 would be pH 5.9. So to complete the formulation, 8 ml of pH 5.9 Sorensen’s buffer would be added to the 7 ml of Procaine HCl solution. The individual amounts of the Sorenson’s buffer to add can be determined:

Therefore, the compounding procedure would be to weigh 0.3 g Procaine HCl and 0.04 g NaCl, add 7 ml of H2O, 7.2 ml of 0.0667 M NaH2PO4, and 0.8 ml of 0.0667 M Na2HPO4. Filtration sterilize the solution and package in a sterile final container.

The limitation to this approach is that the final formulation pH may be different than the desired pH. The final pH will depend on the two pHs and buffer capacities of the Sorensen’s buffer and the aqueous drug solution.

Approach 2

The second method is to use the Sorensen’s buffer as the entire solvent of the formulation. In this situation, the sodium chloride equivalent of the active drug is subtracted from the “NaCl required for isotonicity” listed in the table. This method has the advantage that the pH of the final solution will be the pH of the selected Sorensen’s buffer.

An example:

Ampicillin Sodium                     30 mg/ml

 Sodium Chloride                       q.s.

 Make 15 ml of sterile, buffered, isotonic solution at pH 6.6

1. A ratio calculation will show that 0.45 g of Ampicillin Sodium is needed for this formulation.

2. The sodium chloride equivalent for Ampicillin Sodium is 0.16. Therefore, the drug will contribute osmotic pressure as if it was 0.072 g of sodium chloride.

3. To have a pH of 6.6, 9.0 ml of monobasic sodium phosphate solution and 6.0 ml of dibasic sodium phosphate solution are needed. Then to adjust the isotonicity, 0.0735 g of sodium chloride is needed, but the Ampicillin Sodium equivalent will account for 0.072 g. So an additional 0.0015 g of sodium chloride must be added.

Therefore, the compounding procedure would be to weigh 0.45 g of Ampicillin Sodium and 0.0015 g of sodium chloride. Add 9.0 ml of monobasic sodium phosphate solution and 6.0 ml of dibasic sodium phosphate solution. Filtration sterilize the solution and package in a sterile final container.

Preservatives

Ophthalmic solutions are generally packaged in multiple dose containers. Since there is the possibility of inadvertent bacterial contamination of the formulation with repeated patient use, a preservative should be added. Preservatives should be used that do not cause patient sensitivity or that are incompatible with the other ingredients in the formulation.

Preservatives that are commonly used in ophthalmic formulations are listed in the table below. The FDA Advisory Review Panel on OTC Ophthalmic Drug Products (Dec. 1979) established that the concentrations are for formulations that will have direct contact with the eye and not for ocular devices such as contact lens products.

Maximum Concentration of Preservatives Approved for Use in Ophthalmic

Solutions Agent	Maximum Concentration
Benzalkonium chloride  Benzethonium chloride  Chlorobutanol  Phenylmercuric acetate  Phenylmercuric nitrate  Thimerosal Methylparaben  Propylparabens	0.01%  0.5%  0.004%  0.004%  0.01%  0.1- 0.2%  0.04% 0.013%

 

 FDA Advisory Review Panel on OTC Ophthalmic Drug Products, Final report, Dec. 1979.

Preservatives do not immediately produce sterility and should not be the sole means of sterilizing a product. Patients should be counseled that the product may be easily contaminated by touching it to the eyes. Self-contained dropper bottles are less likely to be contaminated than those which must be opened and the dropper removed. However, the plastics used to make these are reactive with a number of solutions and may not be as acceptable as glass bottles.

Antioxidants

 Some drugs can be chemically degraded by oxidation. If such a drug is present in the formulation, an antioxidant should be added. The common agents and their maximum concentration used in ophthalmic formulations are in the table below. Sulfites can cause allergic-type reactions in certain people and so patients should be questioned about this potential reaction before the antioxidant is included in the formulation. Ethylenediaminetetraacetic acid (also known as Edetic Acid or EDTA) is not often used in ophthalmic formulations because of its low water solubility. However, disodium Edetate, the disodium salt of EDTA, is used instead because of its high water solubility.

Antioxidant	Maximum Concentration (%)
Ethylenediaminetetraacetic acid	0.1
Sodium metabisulfite	0.1
Thiourea	0.1
Sodium bisulfite	0.1

 

Viscosity

 Viscosity measures the resistance of a solution to flow when a stress is applied. The viscosity of a solution is given in poise units. The unit centipoise (cp or the plural cps) is equal to 0.01 poise and is most often used in pharmaceutical applications. Compounds used to enhance viscosity are available in various grades such as 15 cps, 100 cps, etc. The grade number refers to the viscosity that results when a fixed percentage aqueous solution is made. Generally the solutions are 1% or 2% and the viscosity is measured at 20oC.

 Viscosity enhancers are used in ophthalmic solutions to increase their viscosity. This enables the formulation to remain in the eye longer and gives more time for the drug to exert its therapeutic activity or undergo absorption. Commonly used viscosity enhancers and their maximum concentrations are given in the table below.

Viscosity Enhancer	Maximum Concentration (%)
Hydroxyethylcellulose	0.8
Hydroxypropylmethylcellulose	1.0
Methylcellulose	2.0
Polyvinyl alcohol	1.4
Polyvinylpyrrolidone	1.7

 

The most common viscosity desired in an ophthalmic solution is between 25 and 50 cps. The actual concentration of the enhancer required to produce that viscosity will depend on the grade of the enhancer. For example, if methylcelluse 25 cps is used, a 1% solution will create a viscosity of 25 cps. If methylcellulose 4000 cps is used, a 0.25% solution provides the desired viscosity. Standard references give tables of viscosities produced by percentage solutions and grades of ingredients.

 

  Sterility

Sterility is defined as the absence of viable microbial contamination. Sterility is an absolute requirement of all ophthalmic formulations. Contaminated ophthalmic formulations may result in eye infections that could ultimately cause blindness, especially if the Pseudomonas aeruginosa microbe is involved. Therefore, ophthalmic formulations must be prepared in a laminar flow hood using aseptic techniques just the same as intravenous formulations. The sterile formulations must be packaged in sterile containers.

Suspensions should not be filtered as the drug will be removed by the filter. Obviously, ointments cannot be filtered. For these formulations, the individual ingredients are sterilized separately and then they are formulated using aseptic techniques.

 

Preparation of eye drops involves the following:

• Preparation of the solution

• Clarification

• Filling and sterilization

Preparation of the solution

• The aqueous eye drop vehicle containing any necessary preservative, antioxidant, stabilizer, tonicity modifier, viscosity modifier or buffer should be prepared first. Then the active ingredient is added and the vehicle made up to volume.

Characteristics, Properties and Requirements of Eye Drop Preparations

Clarity
Eye solution has to be free from foreign particles and clear, obtained by filtration.
Therefore, filtration equipment is very important and well washed, so free from foreign material. Work on eye preparations should also be in a clean environment.

Use of Laminar Air Flow and must not be spilled and leak, will give unity to the preparation of clear solution free of foreign particles. In some problems, clarity and sterility done in the same filtration step. Containers and lids must be clean, sterile and does not shed. Containers and lids are not carrying particles in solution during prolonged contact during storage. Sterility test is normally done.

Stability
Stability of drug in solution depends on the chemical properties of ingredients, product pH, storage methods (especially the temperature), other additive and type of packaging

Drugs such as pilocarpine and fisostigmin active and fit on the eye at pH 6.8 however, the pH of the chemical stability (or stability) can be measured within a few days or months. With this drug, the material loses chemical stability of less than 1 year. Conversely pH 5, both drugs stable in recent years.

If the oxygen sensitivity is a factor, to improve stability adequate antioxidant is desirable. Plastic packaging, low density polyethylene “Droptainer” provide patient comfort, can increase deksimental for stability with the release of oxygen produces oxidative decomposition of medicinal materials.

Buffer and pH

Ideally, eye preparations preferably at a pH that is equivalent to the eye fluid is 7.4. In practice, this is rarely achieved. majority of the active ingredient in ophthalmology are the salt of a weak base and the most stable at acidic pH. This can generally be made isoluble corticosteroid suspension, usually most stable at acidic pH.

Buffer systems were selected in order to have adequate capacities to obtain a pH range of stability for the duration of life of the product. Buffer capacity is the key.

Tonicity
Tonicity means that the osmotic pressure given by the salts in aqueous solution, the solution is isotonic with the eyes of others when magnefudosifat colligative solution is the same solution. isotonic eye solution to be considered when solution tonicity equal to 0.9% Na Cl.

Actually, the eye is more tolerant of variations in tonicity. Then, it can usually tolerate the same solution for the range 0.5% -1.8% NaCl. Provide choice, isotonicity always desirable and is particularly important in intraocular solution. However, this is not required when the total stability of the products considered.

Viscosity
USP allows the use of viscosity chelating material to extend the contact time in the eye and for absorption of the drug and its activities. Materials such as methylcellulose, polyvinyl alcohol and hydroxy methyl cellulose is added periodically to increase the viscosity.

Researchers have studied the effect of increased viscosity in the contact time in the eye. 25-50 cps viscosity generally increased significantly improved long-range contacts in the eye.

Additives
The use of additives in solution allowed, however, the selection of a certain amount. Antioxidants, especially sodium bisulfate or metabisulfat, used with concentrations up to 0.3%, especially in saline solution containing epinephrine. Other antioxidants such as ascorbic acid or acetylcysteine are also used. Antioxidant effect as a stabilizer to minimize oxidation of epinephrine.

The use of surfactants in the preparation of the eye is restricted. Nonionic surfactants, such small toxic class of compounds used in low concentrations, especially the suspension and is associated with the clarity of the solution.

Nonionic surfactants, in particular can react with the adsorption with antimicrobial preservatives and inactive components of the preservative system.

Cationic surfactants are used gradually in the eye solution but almost invariable as an antimicrobial preservative. benzalkonium chloride in the range 0.01 to 0.02% with concentrations of toxicity limiting factor. Benzalkonium chloride as a preservative is used in large quantities in commercial eye solution and suspension.

Clarification
• The BP has stringent requirements for the absence of particulate matter in eye drop solutions. Sintered glass filters or membrane filters of 0.45 – 1.2 micron pore sizes are suitable. The clarified solution is either filled directly into the final containers which are sealed prior to heat sterilization or filled into a suitable container prior to filtration sterilization. Clarified vehicle is used to prepare eye drop suspensions which are filled into final containers and sealed prior to sterilization.

Sterilization
This can take the form of:

• Autoclaving at 115°C for 30 minutes or 121°C for 15 minutes

• Heating at 98 – 100°C for 30 minutes together with either benzalkonium chloride 0.01% w/v or chlorhexidine acetate 0.01% w/v or phenylmercuric acetate or nitrate 0.002% w/v or thiomersal 0.01% w/v. This method is described in the BP (1980) but is no longer a pharmacopoeial recommended method.

• Filtration through a membrane filter having a 0.22micron pore size into sterile containers using strict aseptic technique. Filling should take place under Grade A laminar airflow conditions. A suitable filter holder for extemporaneous preparation is illustrated in Figure 4. The filter assembly is sterilized by autoclaving before use.

• Dry heat sterilization at 160°C for 2 hours is employed for non-aqueous preparations such as liquid paraffin eye drops. Silicone rubber teats must be used.

Immediately following sterilization the eye drop containers must be converted with readily breakable seal, such as a viskring, to distinguish between opened and unopened containers.

 

General Labelling requirements for eye drop containers

Requirement	Include on label
Fully identify the product	Title, either name and concentration of active ingredients or reference to official monograph giving these details. If monograph allows more than one concentration then state the one used
Specify storage conditions	“Store in a cool place” or “Protect from light”
State product expiry date	Month and year of expiry
Warning label	“Not to be taken”
Specify volume	e.g. 5mL
Ensure correct use	e.g. “Shake the bottle” for a suspension

 

Eye Drops Ingredients, Composition and Manufacturing

Composition of Eye Drops

Besides medicines, eye drops may contain a number of additional material to maintain potency and prevent decomposition. Additional ingredients include:

Preservative
There is material to prevent the development of microorganisms that may be present during the use of eye drops. The most used preservative is phenyl mercury nitrate, phenyl ethyl alcohol and benzalkonium chloride.

 

Isotonicity with lacrimal secretions
NaCl is normally used to reach the osmotic pressure within their ophthalmic solution.

Oxidation of Drugs
Many eye medication immediately oxidized and usually in some cases including a reducing agent. Metasulfit sodium in concentrations of 0.1% is generally used for this purpose.

Hydrogen Ion Concentration

Need for stability of the hydrogen ion concentration, and several buffers have been described. Sodium citrate is used in ophthalmic phenylephrine.

Chelating material
When the ions and heavy metals can cause decomposition of the drug in a solution of the material used chelators that bind ions in organic complexes, will provide protection. Na2EDTA, one of the most well known as chelators.

Viscosity
To prepare the viscous solution by giving the action a long time in solution with a fixed eye contact longer on the surface of the eye, thickeners can be used, methylcellulose 1% was used for this purpose.

 

Eye Fluid pH

Lacrimal secretions have a pH value between 7.2 to 7.4 and have high capacity of buffering. As a result, the eye can tolerate a solution having a pH value of 3.5 to 10, they not buffered strongly because liquid eye will quickly improve the value of the normal pH of the eye.

Eye Preparations pH

Solution of normal lacrimal pH 7.4 with a range from 5.2 to 8.3. It can still be tolerated by the eye solution with this pH range, due to (1) small volume of solution, (2) buffer liquid eyes, and (3) increased production of tears. pH of the solution of the eyes should be between 4.5 and 9.

 

Container
Containers for the solution of the eyes. Eye solution should be used in small units, is never greater than 15 ml and preferably smaller. 7.5 ml bottle is a nice size to use eye solution. The use of small containers to shorten the treatment time will be kept by the patient and minimize the amount of exposure to contamination.

Eye solution prepared continuously packed in the container drops (droptainers) polyethylene or drops in a glass bottle. To maintain sterility of the solution, the container must be sterile. Polyethylene container sterilized with ethylene oxide, while the glass dropper can be wrapped and autoclaved. Commercially prepared single dose units with a volume of 0.3 ml or less packed in sterile polyethylene tubes and sealed by heating.

 

Why Eye Drops Must Sterile

Sterilization is critical. Eye solution that made can carry many organisms, the most dangerous is Pseudomonas aeruginosa. eye infections from this organism can cause blindness. This is especially dangerous to use nonsterile products in the eye when the cornea is opened, particulate materials can irritate the eyes, and make patients very discomfort.

Pseudomonas aeruginas (B. pyocyaneus; P. pyocyanea; Blue pas bacillus) is a dangerous and upportunis microorganisms that grow well in culture media that produce toxins and substances / antibacterial products, tend to kill other contaminants and leave the Pseudomonas aeruginosa to grow in pure culture . Gram-negative bacillus becomes a source of serious infection of the cornea. This can cause loss of vision in 24-48 hours. At concentrations that are tolerated by the eye tissues, suggesting that all antimicrobial agents are discussed in the following section may not be effective against some strains of this organism.

Why Eye Drops Must Isotonic

Tonicity means that the osmotic pressure generated by the existence of a solution of dissolved solids or insoluble. Liquid eyes and other body fluids provide the same osmotic pressure with normal saline or 0.9% NaCl solution. Solution that has a larger amount of dissolved material than the eye is called hypertonic fluid. Instead, the fluid has little solute has a lower osmotic pressure are called hypotonic. Eye can tolerate a solution that has a value equivalent tonicity in the range of 0.5% to 1.6% NaCl without great inconvenience.

Tonicity eyewash have more important things than eye drops because of the volume of solution used. With the help of an eyewash and eye patch, eye washed with a solution and then overwhelming the ability of the eye fluid to set some differences in tonicity. If the tonicity eyewash fluid is not approaching the eye, can produce pain and irritation.

In making eye solution, the solution tonicity can be set equal againts lacrimal fluid with the addition of suitable solutes such as NaCl. If the osmotic pressure of the desired drug concentration exceeds the liquid eyes, nothing can be done. Examples 10 and 30% solution of sodium sulfasetamid is hypertonic, the concentration is less than 10% did not give the desired clinical effect. For the hypotonic solution was prepared a number of methods for calculating the amount of NaCl to adjust the tonicity of the eye solution, one method is a method of freezing point depression.

Isotonicity value. Eye fluid isotonic with the blood and have isotonicity values correspond to a solution of Sodium Chloride 0.9% P. Ideally, eye drug solution must have that isotonic value, but the eyes are resistant to isotonic low value which is equivalent to P 2.0% NaCl solution without real nuisance.

Some eye medicines solutioeed to be hypertonic to increase the absorptive capacity and provide the active ingredient content is high enough to produce the effect of rapid and effective drugs. If the solution of such drugs are used in small quantities, dilution with tears occur rapidly so that the pain caused by hipertonicity only temporary. But, isotonicity adjustment by dilution with tears does not mean, if the hypertonic solution is used in large quantities as koliria to moisten the eyes. So important is the solution of the eye drug for this purpose should be close to isotonic.

 

Definition of Eye Drop

Eye drops are sterile preparations in the form of a solution or suspension which is used by dripping the drug on the mucous membranes around the eyelid from the eyeball. They can contain antimicrobial substances such as antibiotics, anti-inflammatory ingredients such as corticosteroids, medications such mioti fisostigmin midriatik sulfate or drugs such as atropine sulfate

Solution of the eyes (colluria / singular collyrium)
Drugs are inserted into the eye should be formulated and prepared with consideration given to the tonicity, pH, stability, viscosity and sterilization. Sterilization is desirable because the cornea and anterior chamber network nodes is a good medium for microorganisms and the entry of contaminated eye solutions into the eyes of trauma due to accidents or surgery can cause vision loss.

Terms of Good Eye Drops

The factors below will be most important in the preparation of a eye drop:

1.     Precision and cleanliness in the preparation of the solution; included free of foreign particles

2.     The sterility of the end of collyrium and the presence of antimicrobial agents effective for inhibiting the growth of many microorganisms during use of the preparation;

3.     Isotonicity of the solution;

4.     Appropriate pH in the carrier to produce an optimum stability

5.     The preparation of eye drops does not irritate the eyes

Sterilization is desirable because the cornea and anterior chamber network nodes is a good medium for the growth of microorganisms and the entry of contaminated eye fluid in the eye by accident trauma or surgery can cause vision loss.

The Advantages Eye Drops

• In general, the aqueous solution is more stable than the ointment, though ointment with fat-soluble drug is better absorbed than solution / ointment which drug soluble in water.

• Not disturbing visions when used

• eye ointment generally produces a greater bioavailability than the aqueous solution.

The Disadvantages Eye Drops

• relatively, had short contact time between drug and absorbed surface.

• Bioavailability of eye drugs approved worse if the solution is used topically for most drugs is less than 1-3% of the dose that is inserted through the cornea to the anterior chamber. Since drug bioavailability very slow, the patient adhere to the rules and techniques of proper usage.

Use of Eye Drops

• Wash hands

• With one hand, gently pull the lower eyelid

• If the dropping applicator separated apart, hit the rubber once when the dropper is inserted into the bottle to bring the solution into the dropper

• Place the dropper above the eye, drops a drug into the lower eyelid while looking up do not touch dropper to eye or finger.

• Release the eyelid, try to keep the eyes open and do not blink at least 30 seconds

• If the dropping applicator separated apart, put back on the bottle and cover tightly

• Never use eye drops that have become discolored

• If you have more than one bottle of the same drops, open only one bottle

• If you use more than one type of drops at the same time, wait several minutes before using other eye drops

• After using the eye drops do not close your eyes too tight and not blink more often than usual because it can eliminate the drugs work.

 

 

Eye Preparations of the British Pharmacopoeia

General Notices

In addition to the above requirements of the European Pharmacopoeia, the following statements apply to any eye drops, eye lotion or eye ointment that is the subject of an individual monograph in the British Pharmacopoeia.

EYE DROPS

DEFINITION

Definition of particular Eye Drops as a solution or suspension in Purified Water does not preclude the inclusion of suitable additional substances where necessary for the purposes referred to above under the requirements of the European Pharmacopoeia. However of buffering agents are used in preparations intended for use in surgical procedures great care should be taken to ensure that the nature and concentration of the chosen agent are suitable.

Where the active ingredient is susceptible to oxidative degradation appropriate precautions such as the addition of a suitable antioxidant should be taken. If an antioxidant is added care should be taken to ensure compatibility between the antioxidant and the antimicrobial preservative.

PRODUCTION

Methods of sterilisation that may be used in the manufacture of Eye Drops are described in Appendix XVIII.

STORAGE

Eye Drops are supplied in tamper-evident containers. The compatibility of plastic or rubber components should be confirmed before use.

Containers for multi-dose Eye Drops are fitted with an integral dropper or with a sterile screw cap of suitable materials incorporating a dropper and rubber or plastic teat. Alternatively such a cap assembly is supplied, sterilised, separately.

LABELLING

The label states (1) the names and percentages of the active ingredients; (2) the date after which the Eye Drops are not intended to be used; (3) the conditions under which the Eye Drops should be stored.

For multi-dose containers the label states that care should be taken to avoid contamination of the contents during use.

Single-dose containers that because of their size bear only an indication of the active ingredient and the strength of the preparation do so by use of an approved code, Appendix XXI C, together with an expression of the percentage present. When a code is used on the container, the code is also stated on the package.

EYE OINTMENTS

DEFINITION

Eye Ointments of the British Pharmacopoeia that are intended to be used solely or primarily as a suitable eye-ointment basis contaio active ingredient.

PRODUCTION

Methods of sterilisation that may be used in the manufacture of Eye Ointments are described in Appendix XVIII.

In preparing Eye Ointments in tropical or subtropical countries where the prevailing high temperatures otherwise make the basis too soft for convenient use, the proportions of Yellow Soft Paraffin and Liquid Paraffin specified in the individual monograph may be varied, or Hard Paraffin may be added but the proportions of active ingredients must not be changed.

STORAGE

Single-dose containers for Eye Ointments, or the nozzles of tubes, are of such a shape as to facilitate administration without contamination. The former type of container is individually wrapped. Tubes are tamper-evident.

LABELLING

The label states (1) the names and percentages of the active ingredients; (2) the date after which the Eye Ointment is not intended to be used; (3) the conditions under which the Eye Ointment should be stored.

EYE PREPARATIONS

General Notices

(Ph Eur monograph 1163)

Eye Preparations comply with the requirements of the European Pharmacopoeia. These requirements are reproduced below.

DEFINITION

Eye preparations are sterile liquid, semi-solid or solid preparations intended for administration upon the eyeball and/or to the conjunctiva, or for insertion in the conjunctival sac.

Where applicable, containers for eye preparations comply with the requirements of materials used for the manufacture of containers (3.1 and subsections) and containers (3.2 and subsections).

Several categories of eye preparations may be distinguished:

ı— eye drops;

ı— eye lotions;

ı— powders for eye drops and powders for eye lotions;

ı— semi-solid eye preparations;

ı— ophthalmic inserts.

PRODUCTION

During the development of an eye preparation whose formulation contains an antimicrobial preservative, the necessity for and the efficacy of the chosen preservative shall be demonstrated to the satisfaction of the competent authority. A suitable test method together with criteria for judging the preservative properties of the formulation are provided in chapter

5.1.3. Efficacy of antimicrobial preservation.

Eye preparations are prepared using materials and methods designed to ensure sterility and to avoid the introduction of contaminants and the growth of micro-organisms;

recommendations on this aspect are provided in chapter 5.1.1. Methods of preparation of sterile products.

In the manufacture of eye preparations containing dispersed particles, measures are taken to ensure a suitable and controlled particle size with regard to the intended use.

During development, it must be demonstrated that the nominal contents can be withdrawn from the container of liquid and semi-solid eye preparations supplied in single-dose containers.

TESTS

Sterility (2.6.1)

Eye preparations comply with the test. Applicators supplied separately also comply with the test. Remove the applicator with aseptic precautions from its package and transfer it to a tube of culture medium so that it is completely immersed. Incubate and interpret the results as described in the test.

STORAGE

Unless otherwise justified and authorised, store in a sterile, tamper-proof container .

LABELLING

The label states the name of any added antimicrobial preservative.

EYE DROPS

DEFINITION

Eye drops are sterile aqueous or oily solutions, emulsions or suspensions of one or more active substances intended for instillation into the eye.

Eye drops may contain excipients, for example, to adjust the tonicity or the viscosity of the preparation, to adjust or stabilise the pH, to increase the solubility of the active substance, of to stabilise the preparation. These substances do not adversely affect the intended medicinal action or, at the concentrations used, cause undue local irritation.

Aqueous preparations supplied in multidose containers contain a suitable antimicrobial preservative in appropriate concentration except when the preparation itself has adequate antimicrobial properties. The antimicrobial preservative chosen must be compatible with the other ingredients of the preparation and must remain effective throughout the period of time during which eye drops are in use.

If eye drops do not contain antimicrobial preservatives they are supplied in single-dose containers or in multidose containers preventing microbial contamination of the contents after opening.

Eye drops intended for use in surgical procedures do not contain antimicrobial preservatives.

Eye drops that are solutions, examined under suitable conditions of visibility, are practically clear and practically free from particles.

Eye drops that are suspensions may show a sediment that is readily redispersed on shaking to give a suspension which remains sufficiently stable to enable the correct dose to be delivered.

Multidose preparations are supplied in containers that allow successive drops of the preparation to be administered. The containers contain at most 10 ml of the preparation, unless otherwise justified and authorised.

TESTS

Particle size

Unless otherwise justified and authorised, eye drops in the form of a suspension comply with the following test: introduce a suitable quantity of the suspension into a counting cell or with a micropipette onto a slide, as appropriate, and scan under a microscope an area corresponding to 10 μg of the solid phase. For practical reasons, it is recommended that the whole sample is first scanned at low magnification (e.g. × 50) and particles greater than 25 μm are identified. These larger particles can then be measured at a larger magnification (e.g. × 200 to × 500). For each 10 μg of solid active substance, not more than 20 particles have a

maximum dimension greater than 25 μm, and not more than 2 of these particles have a maximum dimension greater than 50 μm. None of the particles has a maximum dimension greater than 90 μm.

LABELLING

The label states, for multidose containers, the period after opening the container after which the contents must not be used. This period does not exceed 4 weeks, unless otherwise justified and authorised.

EYE LOTIONS

DEFINITION

Eye lotions are sterile aqueous solutions intended for use in rinsing or bathing the eye or for impregnating eye dressings.

Eye lotions may contain excipients, for example to adjust the tonicity or the viscosity of the preparation or to adjust or stabilise the pH. These substances do not adversely affect the intended action or, at the concentrations used, cause undue local irritation.

Eye lotions supplied in multidose containers contain a suitable antimicrobial preservative in appropriate concentration except when the preparation itself has adequate antimicrobial properties. The antimicrobial preservative chosen is compatible with the other ingredients of the preparation and remains effective throughout the period of time during which the eye lotions are in use.

If eye lotions do not contain antimicrobial preservatives, they are supplied in single-dose containers. Eye lotions intended for use in surgical procedures or in first-aid treatment do not contain an antimicrobial preservative and are supplied in single-dose containers.

Eye lotions, examined under suitable conditions of visibility, are practically clear and practically free from particles.

The containers for multidose preparations do not contain more than 200 ml of eye lotion, unless otherwise justified and authorised.

LABELLING

The label states:

ı— where applicable, that the contents are to be used on one occasion only;

ı— for multidose containers, the period after opening the container after which the contents must not be used; this period does not exceed 4 weeks, unless otherwise justified and authorised.

POWDERS FOR EYE DROPS AND POWDERS FOR EYE LOTIONS

DEFINITION

Powders for the preparation of eye drops and eye lotions are supplied in a dry, sterile form to be dissolved or suspended in an appropriate liquid vehicle at the time of administration. They may contain excipients to facilitate dissolution or dispersion, to prevent caking, to adjust the tonicity, to adjust or stabilise the pH or to stabilise the preparation.

After dissolution or suspension in the prescribed liquid, they comply with the requirements for eye drops or eye lotions, as appropriate.

TESTS

Uniformity of dosage units (2.9.40)

Single-dose powders for eye drops and eye lotions comply with the test or, where justified and authorised, with the tests for uniformity of content and/or uniformity of mass shown below.

Herbal drugs and herbal drug preparations present in the dosage form are not subject to the provisions of this paragraph.

Uniformity of content (2.9.6)

Unless otherwise prescribed or justified and authorised, single-dose powders for eye drops and eye lotions with a content of active substance less then 2 mg or less than 2 per cent of the total mass comply with test B. If the preparation has more than one active substance, the requirement applies only to those substances that correspond to the above condition.

Uniformity of mass (2.9.5)

Single-dose powders for eye drops and eye lotions comply with the test. If the test for uniformity of content is prescribed for all the active substances, the test for uniformity of mass is not required.

SEMI-SOLID EYE PREPARATIONS

DEFINITION

Semi-solid eye preparations are sterile ointments, creams or gels intended for application to the conjunctiva or to the eyelids. They contain one or more active substances dissolved of dispersed in a suitable basis. They have a homogeneous appearance.

Semi-solid eye preparations comply with the requirements of the monograph Semi-solid preparations for cutaneous application (0132). The basis is non-irritant to the conjunctiva.

Semi-solid eye preparations are packed in small, sterilised collapsible tubes fitted or provided with a sterilised cannula. The containers contain at most 10 g of the preparation, unless otherwise justified and authorised. The tubes must be well-closed to prevent microbial contamination. Semi-solid eye preparations may also be packed in suitably designed singledose containers. The containers, or the nozzles of tubes, are of such a shape as to facilitate administration without contamination.

TESTS

Particle size

Semi-solid eye preparations containing dispersed solid particles comply with the following test: spread gently a quantity of the preparation corresponding to at least 10 μg of solid active substance as a thin layer. Scan under a microscope the whole area of the sample. For practical reasons, it is recommended that the whole sample is first scanned at a small magnification (e.g. × 50) and particles greater than 25 μm are identified. These larger particles can then be measured at a larger magnification (e.g. × 200 to × 500). For each 10 μg of solid active substance, not more than 20 particles have a maximum dimension greater than 25 μm, and not more than 2 of these particles have a maximum dimension greater than 50 μm. None of the particles has a maximum dimension greater than 90 μm.

LABELLING

The label states, for multidose containers, the period after opening the container after which the contents must not be used. This period does not exceed 4 weeks, unless otherwise justified and authorised.

OPHTHALMIC INSERTS

DEFINITION

Ophthalmic inserts are sterile, solid or semi-solid preparations of suitable size and shape, designed to be inserted in the conjunctival sac, to produce an ocular effect. They generally consist of a reservoir of active substance embedded in a matrix or bounded by a ratecontrolling membrane. The active substance, which is more or less soluble in lacrymal liquid, is released over a determined period of time.

Ophthalmic inserts are individually distributed into sterile containers.

PRODUCTION

In the manufacture of ophthalmic inserts, measures are taken to ensure a suitable dissolution behaviour.

TESTS

Uniformity of dosage units (2.9.40)

Ophthalmic inserts comply with the test or, where justified and authorised, with the test for uniformity of content shown below. Herbal drugs and herbal drug preparations present in the dosage form are not subject to the provisions of this paragraph.

Uniformity of content (2.9.6)

Ophthalmic inserts comply, where applicable, with test A.

LABELLING

The label states:

ı— where applicable, the total quantity of active substance per insert;

ı— where applicable, the dose released per unit time.

 

1. INTRODUCTION : 

1. INTRODUCTION 1.

DEFINITION: “ophthalmic preparation are sterile Product that are intended to be applied to the eyelids or placed in the space between the eyelids and the eyeball.

Ophthalmic preparation are similar to parenteral dosage forms in their requirement for:

1.Sterility

2.Tonicity (osmotic pressure)

3.Preservation

4.Tissue compatibility

5.Particulate matter

6.Avoidance of pyrogens (not as critical as other parenteral products)

7.Suitable packaging

 

TYPES/CLASSES OF OPHTHALMIC DOSAGE FORMS :

2. Manufacturing considerations in design of ophthalmic production facility: : 

2. Manufacturing considerations in design of ophthalmic production facility: Because the official compendia require all topically administered ophthalmic medication to be sterile, the manufacturer of such medication must consider all the current concepts in the manufacture of sterile pharmaceuticals in designing a manufacturing procedure for sterile ophthalmic pharmaceutical products.

The manufacture of sterile ophthalmic pharmaceutical products requires special attention to:

1. Environment

2. Personnel Requirements

3. Equipments

4. Raw Material

5. PAT (Process Analytical Technology)

 

1 ENVIRONMENT: : 

1 ENVIRONMENT: Current U.S. std. for GMP provide for the use of specially designed environmentally controlled areas for the manufacturing of sterile large & small volume injections for terminal sterilization.

Note : Grade A and B correspond to with class 100 Grade C correspond to with class 10000 Grade D correspond to with class 100000 (Class 100 : NMT 100 particles /ft3 of air of diameter of 0.5 µm or larger)

 

a)Walls, ceiling & floors Constructed of material →hard ,non flaking , smooth & unaffected by surface cleaning agents & disinfectants. For that epoxy or vinyl ceiling coat for finishing avoids holes on surface.b)All lights & windows Should be flush mounted in walls & ceilings for ease of cleaning & disinfectionc)U.V. lamps May be provided in recessed , flush mounted fixtures to maintain surface disinfection.(difficult to validate)d)Separate entrance For both personnel & equipments (specially designed air locks maintained at negative pressure relative to aseptic manufacturing area & at positive pressure relative to non-environmentally controlled area. : 

a)Walls, ceiling & floors Constructed of material →hard ,non flaking , smooth & unaffected by surface cleaning agents & disinfectants. For that epoxy or vinyl ceiling coat for finishing avoids holes on surface.

b)All lights & windows Should be flush mounted in walls & ceilings for ease of cleaning & disinfectionc)U.V. lamps May be provided in recessed , flush mounted fixtures to maintain surface disinfection.(difficult to validate)d)Separate entrance For both personnel & equipments (specially designed air locks maintained at negative pressure relative to aseptic manufacturing area & at positive pressure relative to non-environmentally controlled area.

 

2 PERSONNEL REQUIREMENTS : 

2 PERSONNEL REQUIREMENTS No. of workers should kept to a minimum. Training of personal Personal hygiene:- All employees should be in good health, Subjected to Physical examination, Understood their responsibilities to report own illness like cold, a sore throat, or other infection.

 

3 EQUIPMENTS : : 

3 EQUIPMENTS : All tanks , valves , pipings →best available grade of corrosion-resistant stainless steel.(S.S. type 304 or 316) is preferable. All the product contact surface should be finished either mechanically or by electro polishing to provide a surface as free as possible from scratches or defects. For the equipment that will reside in aseptic filling areas such as filling & capping machine, care should be taken in their design to yield equipment as free as possible from particle generating mechanisms.

 

4 RAW MATERIAL : : 

4 RAW MATERIAL : Highest quality In most sterile dosage form largest proportion is of “water” which is main source of contamination. For the preparation intended for parenteral administration ,U.S.P. xxii requires the use of → WFI → SWFI → BWFI All of above are produced by distillation or reverse osmosis & kept in circulation at relatively high temperature up to 800c, or alternatively its disposal at every 24 hrs, in all S.S. equipment of highest attainable , corrosion resistant quality

 

5 PAT (PROCESS ANALYTICAL TECHNOLOGY) : 

5 PAT (PROCESS ANALYTICAL TECHNOLOGY) The product manufacturing & quality control is governed by the c GMP regulation. For better output ,PAT is to be followed. “System for designing ,analyzing & controlling manufacturing through timely measurements (during process) of critical quality & performance attribute of raw & in process material & process with a goal of ensuring final product quality. ”

 

3. Manufacturing operation : 

3. Manufacturing operation A. AREA REQUIREMENT Minimum of 10 m2 → for ancillary area Minimum of 25 m2 → for basic installation Manufacturing & filling shall be carried out in air –conditioned areas under aseptic condition The rooms shall be further dehumidified as considered necessary if preparation containing antibiotics are manufactured.

 

B. LIST OF EQUIPMETNS AS PER SCHEDULE M : 

B. LIST OF EQUIPMETNS AS PER SCHEDULE M For Ophthalmic solutions & suspensions Jacketed kettle/stainless steel tanks(steam gases electrically heated) Mixing & storage tanks of stainless steel/planetary mixer Sintered glass funnel , Seitz filter or filter candle(preferably cartridge & membrane filter) Liquid filling equipments (semi automatic & automatic filling machine) For Ophthalmic Ointments Colloid mill/ointment mill Tube filling & crimping equipment(semi automatic & automatic filling machine) Tube cleaning equipments (air jet type) Tube washing & drying equipments

 

EQUIPMETNS : 

EQUIPMETNS Thermostatically controlled Hot air oven. (preferably double ended) Autoclave (preferably ventilator autoclave) Air conditioning & dehumidification arrangement Laminar air flow units. Automatic vial washing machine Vial drying oven Distillation unit Packaging & labeling Inspection machine

 

Multicolumn distillation unit : 

Multicolumn distillation unit It consist of specially designed columns which make optimum use of the principles of inter stage heat exchange (Multi effect distillation method) to produce pure pyrogen free sterile distilled water for injectables as per IP/BP specification.

 

Mixing & Storage Tanks : 

Mixing & Storage Tanks

 

SS Tank with Stirrer / Manufacturing vessel : 

SS Tank with Stirrer / Manufacturing vessel With SS steam jacketed & insulation with SS cladding. Different type of stirrer (paddle/ anchor/propeller) available. Electric heating also possible for small scale.

 

Jacketed kettle / SS Tank (steam, gas or electrically heated) : 

Jacketed kettle / SS Tank (steam, gas or electrically heated)

 

Triple roller mill : 

Triple roller mill It’s used for grinding ointment, pastes, paints, etc. Side scrappers moves up and down with compression spring and knob to secure appropriate working pressure

 

ROTARY TUBE FILLING MACHINE : 

ROTARY TUBE FILLING MACHINE Rotary tube filling & closing (crimping) machine with coding device. Speed :- 30 to 80 TPM Another TWIN HEAD machine also available in market.

 

Vial filling machine : 

Vial filling machine . Suitable for 2 ml to 30 ml vials Output Speed up to 120 VPM

 

Fully Automatic Labeling Machine SBSL-120F : 

Fully Automatic Labeling Machine SBSL-120F Fully Automatic, User Friendly, Sticker (Self-Adhesive) Labeling Machine Model SBSL-120F, Suitable to apply accurate Labels on Double Side (Front & Back) of Flat/Oval/Square shaped products .

 

Manual Vial & Bottle Inspection machine : 

Manual Vial & Bottle Inspection machine

 

Automatic Packaging Conveyor : 

Automatic Packaging Conveyor Conveyor belt is used as a PVC coated canvas belt / endless rubberised belt. The Reduction Gear Box provides jerk less & noiseless performance for long time.

 

STEAM STERILIZER or AUTOCLAVE : 

STEAM STERILIZER or AUTOCLAVE used for sterilizing • Solutions in glass containers like ampoules, vials, glass bottles etc.

 

C. PROCESS FLOW CHART : 

C. PROCESS FLOW CHART

 

D. FLOW DIAGRAM SHOWING ARRANGEMENT OF DIFFERENT AREA : 

D. FLOW DIAGRAM SHOWING ARRANGEMENT OF DIFFERENT AREA OPHTHALMIC– MANUFACTURING PLANT LAYOUT

 

E. MANUFACTURING OPERATION OF OPHTHALMIC PREPARATIONS : 

E. MANUFACTURING OPERATION OF OPHTHALMIC PREPARATIONS Divided in to two separate areas:-

1. Ophthalmic preparation in glass container.

2. Ophthalmic preparation in plastic container.

 

1. OPHTHALMIC PREPARATIONS IN GLASS CONTAINER : 

1. OPHTHALMIC PREPARATIONS IN GLASS CONTAINER

 

2. OPHTHALMIC PREPARATIONS IN PLASTIC CONTAINER : 

2. OPHTHALMIC PREPARATIONS IN PLASTIC CONTAINER FORM-FILL-SEAL TECHNOLOGY OR BLOW-FILL-SEAL TECHNOLOGY SIMPLE FILL-SEAL TECHNOLOGY Form-Fill-Seal units are specially built automated machines in which through one continuous operation, container’s are formed from thermoplastic granules, filled and then sealed . Fill-seal units are machines in which containers are molded (preformed) in separate clean rooms by non continuous operation then filling & sealing is carried out.

 

FORM-FILL-SEAL OR BLOW-FILL-SEAL MACHINE : 

FORM-FILL-SEAL OR BLOW-FILL-SEAL MACHINE

 

PACKAGING : 

PACKAGING Plastic containers → ease of use → little breakage → less spoilage Large volume intraocular solutions of 250ml &500ml have been packaged in glass, but even this parenteral type products are beginning to be packaged in specially fabricated polyethylene/polypropylene containers or flexible bags. Type 1 glass vials with appropriate stoppers are used for intraocular ophthalmic products administered by injection. Different ophthalmic cap color coding are given by the cooperative efforts of FDA , the ophthalmic industry & academy of ophthalmology.

 

OPHTHALMIC CAP COLOR CODING : 

OPHTHALMIC CAP COLOR CODING

4. Ophthalmic preparation characteristics : 

4. Ophthalmic preparation characteristics 1) Clarity: Ophthalmic solutions by definition contaio undissolved ingredients & are essentially free from foreign particles. But solution containing viscosity imparting polymers diminish clarity. In these situation it may be important to define both the visual clarity of the product & monitor its stability. The E.P. describes visual clarity & recommended standards that can be used for clarity specifications.

 

2) Stability: : 

2) Stability: The stability of a drug in an ophthalmic product depends on a number of factors including the chemical nature of the drug substance, product pH, method of preparation (particularly temperature exposure), solution additives, &type of packaging. Pharmaceutical manufacturers conduct comprehensive stability programs to assure the assigned expiration dating for each product. The stability of the preservative is also monitored by chemical means or by actual challenge of the preservative efficacy with appropriate test organisms.

 

3) Sterility: : 

3) Sterility: The important property of ophthalmic formulations is that they must be sterile. The USP-22 listed five methods of achieving sterility. a) Steam sterilization at 1210c b) Dry heat sterilization c) Gas sterilization d) Sterilization using ionizing radiation e) Sterilization by filtration The method chosen is often depends on resistance of the active ingredient & the resultant product to heat & to the type of packaging(i.e. container) used.

 

4) pH adjustment & buffers: : 

4) pH adjustment & buffers: The adjustment of ophthalmic solution pH by the appropriate choice of a buffer is one of the most important considerations. Ideally, ophthalmic preparations should be formulated at a pH equivalent to the tear fluid value of 7.4 5) Tonicity: Tonicity refers to the osmotic pressure exerted by salts in aqueous solution. An ophthalmic solution is isotonic with another solution when the magnitudes of the colligative properties of the solutions are equal.

 

5. QUALITY CONTROL SPECIFICATION : 

5. QUALITY CONTROL SPECIFICATION 1) Raw material 2) packing material – Description – Compatibility – Moisture content – Stability – Assay of ingredient – Purity 3) In process Product a) Mixing b) Filling – Assay – weight variation – Grittiness – content uniformity – Viscosity – Density – pH

 

4) Product Specification : 

4) Product Specification a) Microbial specification – limit for total microbial count – Absence of specific microorganism as per pharmacopoeia b) Chemical specification – pH – Content uniformity – Chemical potency c) Physical specification – clarity – Particle size – Density – Viscosity

 

Compendial requirements for semi-solid product : 

Compendial requirements for semi-solid product Semi-solid product must meet USP tests for, 1) Microbial content 2) Minimum fill 3) Packing 4) Storage 5) Labeling Ophthalmic ointment must meet to the, – USP sterility tests – Test for metal particles USP directs the ophthalmic ointment must be packed in collapsible tube with narrow tip.

 

6. Documentation : 

6. Documentation Master formula records Batch formula records Equipment & containers records Filtration & filling records Batch Packaging & Labeling Records IPQC records