can be formulated as water-soluble salts. A homogeneous solution offers the assurance of greater uniformity of dosage and bioavailability and simplifies large-scale manufacture. The selection of the appropriate salt form depends on its solubility, therapeutic concentrations required, ocular toxicity, the effect of pH, tonicity, buffer capacity, its compatibility with the total formulation, and the intensity of any possible stinging or burning sensations (i.e., discomfort reactions). The most common salt forms used are the hydrochloride, sulfate, nitrate, and phosphate. Salicylate, hydrobromide, and bitartrate salts are also used. For drugs that are acidic, such as the sulfonamides, sodium and diethanolamine salts are used. The effect that choice of salt form can have on resulting product properties is exemplified by the epinephrine solutions available, as shown in Table 3. The bitartrate form is a 1:1 salt and may cause considerable stinging, and the free carboxyl group acts as a strong buffer, resisting neutralization by the tears. The borate form results in a solution with lower buffer capacity, a more nearly physiological pH, and better patient tolerance; however, it is less stable than the other two salts. The hydrochloride salt combines better stability than the borate with acceptable patient tolerance.
Gel-forming solutions One disadvantage of solutions is their relatively short residence time in the eye. This has been overcome to some degree by the development of solutions that are liquid in the container and thus can be instilled as eyedrops but gel on contact with the tear fluid and provide increased contact time with the possibility of improved drug absorption and increased duration of therapeutic effect.
A number of liquid-gel phase transition-dependent delivery systems have been researched and patented. They vary according to the particular polymer(s) employed and their mechanism(s) for triggering the transition to a gel phase in the eye. The mechanisms that make them useful for the eye take advantage of changes in temperature, pH, ion sensitivity, or ionic strength upon contact with tear fluid or the presence of proteins such as lysozyme in the tear fluid. Thermally sensitive systems, which are transformed to a gel phase by the change in temperature associated with reaching body temperature, have the disadvantage of possibly gelling in the container when subjected to warmer climatic conditions. The pH-sensitive systems may have limited use for drugs that require a neutral to slightly alkaline environment for stability, solubility, etc.
Gel-forming ophthalmic solutions have been developed and approved by the FDA for timolol maleate, which is used to reduce elevated IOP in the management of glaucoma. Timolol maleate ophthalmic solutions, as initially developed, require twice-a-day dosage for most patients. With the gel-forming solutions, IOP-lowering efficacy was extended from 12 to 24 hours and thus required only once-a-day dosing. This extended duration of efficacy was demonstrated for both gel-forming products in controlled clinical trials. The first gel-forming product, Timolol®-XE, uses the polysaccharide gellan gum and is reported to gel in situ in response to the higher ionic strength of tear fluid (U.S. patent 4,861,760). Alternative ion-sensitive gelling systems have been patented (3-7). The second product, Alcon's timolol gel-forming solution (timolol maleate), uses the polysaccharide xanthan gum as the gelling agent and is reported to gel upon contact with the tear fluid, at least in part, due to the presence of tear protein lysozyme (PCT Application WO 99/51273). Another more recent application of a gel-forming product is the ocular lubricant eyedrop SYSTANE that contains hydroxypropyl guar (343).
Suspensions If the drug is not sufficiently soluble, it can be formulated as a suspension. A suspension may also be desired to improve stability, bioavailability, or efficacy. The major topical ophthalmic suspensions include but are not limited to steroid anti-inflammatory agents and IOP-lowering agents: prednisolone acetate, dexamethasone, fluorometholone, nepafenac, brinzolamide, betaxolol hydrochloride, and rimexolone. Water-soluble salts of prednisolone phosphate and dexamethasone phosphate are available; however, they have a lower steroid potency and are poorly absorbed.
An ophthalmic suspension should use the drug in a microflne form; usually 95% or more of the particles have a diameter of 10 |im or less. This is to ensure that the particles do not cause irritation of the sensitive ocular tissues and that a uniform dosage is delivered to the eye. Since a suspension is made up of solid particles, it is at least theoretically possible that they may provide a reservoir in the cul-de-sac for slightly prolonged activity. However, it appears that this is not so, since the drug particles are extremely small, and with the rapid tear turnover rate, they are washed out of the eye relatively quickly.
Pharmaceutical scientists have developed improved suspension dosage forms to overcome problems of poor physical stability and patient-perceived discomfort attributed to some active ingredients. An important development and compendial aspect of any suspension is the ability to resuspend easily any settled particles prior to instillation in the eye and ensure a uniform dose is delivered. It would be ideal to formulate a suspension that does not settle since the patient may not always follow the labeled instructions to shake well before using. However, this is usually not feasible or desirable since the viscosity required to retard settling of the insoluble particles completely would likely be excessive for a liquid eyedrop. The opposite extreme, of allowing complete settling between doses, usually leads to a dense layer of agglomerated particles that are difficult to resuspend.
An improved suspension has been developed, which controls the flocculation of the insoluble active ingredient particles, such that they will remain substantially resuspended (95%) for many months, and any settled particles can be easily resuspended with only a few seconds of gentle handshaking. This improved vehicle utilizes a charged water-soluble polymer and oppositely charged electrolyte such as negatively charged carbomer polymer of very high molecular weight and large dimension and a cation such as sodium or potassium. The negatively charged carboxy vinyl polymer is involved in controlling the flocculation of the insoluble particles, such as the steroid rimexolone, and the cation assists in controlling the viscosity of the vehicle such that the settling is substantially retarded, yet can be easily and uniformly resuspended and can be dispensed from a conventional plastic eyedrop container (U.S. patent 5,461,081).
In some cases it may be advantageous to convert a water-soluble active ingredient to an insoluble form for development as an ophthalmic suspension dosage form. This could be the case when it is beneficial to extend the practical shelf life of the water-soluble form to improve the compatibility with other necessary compositional ingredients or to improve its ocular tolerability. Such an example is the P-blocker betaxolol hydrochloride, which is an effective IOP-lowering agent with clinically significant safety advantages for many asthmatic patients. With the ophthalmic solution dosage form some patients experienced discomfort characterized as a transient stinging or burning upon instillation. Although, this did not interfere with the safety or efficacy of the product, it was desirable to improve the patient tolerability. Many solution-based formulations were tried but with limited success. It was discovered that an insoluble form of betaxolol (Betoptic® S) could be produced in situ with the use of a combination of a high-molecular-weight polyanionic polymer such as carbomer and a sulfonic acid cation exchange resin. The resultant optimized suspension increased the ocular bioavailability of betaxolol such that the drug concentration required to achieve equivalent efficacy to the solution dosage form was reduced by one-half and the ocular tolerance was improved significantly. It would appear that the sustained release of the active betaxolol occurs through exchange with cations such as sodium and potassium in tear fluid, resulting in prolonged tear levels of the drug and substantial increase in ocular bioavailability (U.S. patent 4,911,920).
Powders for reconstitution Drugs that have only limited stability in liquid form are prepared as sterile powders for reconstitution by the pharmacist prior to dispensing to the patient. In ophthalmology, these drugs include a-chymotrypsin, echothiophate iodide (Phospholine Iodide®), dapiprazole HC1 (Rev-Eyes®), and acetylcholine (Miochol®). The sterile powder is usually manufactured by lyophilization in the individual glass vials. In powder form these drugs have a much longer shelf life than in solution. Mannitol is usually used as a bulking agent and lyophilization aid and is dissolved in the solution with the drug prior to drying. In the case of echothiophate iodide, it was found that potassium acetate used in place of mannitol as a drying aid produced a more stable product. Apparently the presence of potassium acetate with the drug allows freeze-drying to lower residual moisture content (U.S. patent 3,681,495). A stable echothiophate product has also been produced by freeze-drying from an alcoholic solution without a codrying or bulking agent, but the product is no longer marketed.
A separately packaged sterile diluent and sterile dropper assembly is provided with the sterile powder and requires aseptic technique to reconstitute. The pharmacist should only use the diluent supplied by the manufacturer since it has been developed to maintain the optimum potency and preservation of the reconstituted solution. The storage conditions and expiration dating for the final solution should be emphasized to the patient.
The therapeutically inactive ingredients in ophthalmic solution and suspension dosage forms are necessary to perform one or more of the following functions: adjust concentration and tonicity, buffer and adjust pH, stabilize the active ingredients against decomposition, increase solubility, impart viscosity, and act as solvent. The use of unnecessary ingredients is to be avoided, and the use of ingredients solely to impart a color, odor, or flavor is prohibited.
The choice of a particular inactive ingredient and its concentration is based not only on physical and chemical compatibility but also on biocompatibility with the sensitive and delicate ocular tissues. Because of the latter requirement, the use of inactive ingredients is greatly restricted in ophthalmic dosage forms.
The possibility of systemic effects due to nasolacrimal drainage as previously discussed should also be kept in mind. FDA has cataloged all inactive ingredients in approved drug products and provides this information in a searchable database at http:// www.accessdata.fda.gov/scripts/cder/iig/index.cfm. The FDA database provides route and dosage form, CAS number, UNII, and maximum potency for each listed inactive ingredient.
Tonicity and tonicity-adjusting agents In the past a great deal of emphasis was placed on teaching the pharmacist to adjust the tonicity of an ophthalmic solution correctly (i.e., exert an osmotic pressure equal to that of tear fluids, generally agreed to be equal to 0.9% NaCl). In compounding an eye solution, it is more important to consider the sterility, stability, and preservative aspects, and not jeopardize these aspects to obtain a precisely isotonic solution. A range of 0.5% to 2.0% NaCl equivalency does not cause a marked pain response, and a range of about 0.7% to 1.5% should be acceptable to most persons. Manufacturers are in a much better position to make a precise adjustment, and thus their products will be close to isotonic, since they are in a competitive situation and are interested in a high percentage of patient acceptance for their products. In certain instances, the therapeutic concentration of the drug will necessitate using what might otherwise be considered an unacceptable tonicity. This is the case for sodium sulfacetamide, for which the isotonic concentration is about 3.5%, but the drug is used in 10% to 30% concentrations. Fortunately, the eye seems to tolerate hypertonic solutions better than hypotonic ones. Various textbooks deal with the subject of precise tonicity calculations and determination. Several articles (344) have recommended practical methods of obtaining an acceptable tonicity in extemporaneous compounding. Common tonicity-adjusting ingredients include NaCl, KC1, buffer salts, dextrose, glycerin, propylene glycol, and mannitol.
pH adjustment and buffers The pH and buffering of an ophthalmic solution is probably of equal importance to proper preservation, since the stability of most commonly used ophthalmic drugs is largely controlled by the pH of their environment. Manufacturers place particular emphasis on this aspect, since economics indicates that they produce products with long shelf lives that will retain their labeled potency and product characteristics under the many and varied storage conditions outside the makers' control. The pharmacist and wholesaler must become familiar with labeled storage directions for each product and ensure that it is properly stored. Particular attention should be paid to products requiring refrigeration. The stability of nearly all products can be enhanced by refrigeration, except for those few in which a decrease in solubility and precipitation might occur. Freezing of ophthalmic products, particularly suspensions, should be avoided. A freeze-thaw cycle can induce particle growth or crystallization of a suspension and increase the chance of ocular irritation and loss of dosage uniformity. Glass-packaged liquid products may break owing to the volume expansion of the solution when it freezes. It is especially important that the pharmacist fully advise the patient on proper storage and use of ophthalmic products to ensure their integrity and safe and efficacious use.
In addition to stability effects, pH adjustment can influence comfort, safety, and activity of the product. Comfort can be described as the subjective response of the patient after instillation of the product in the cul-de-sac (i.e., whether it may cause a pain response such as stinging or burning). Eye irritation is normally accompanied by an increase in tear fluid secretion (a defense mechanism) to aid in the restoration of normal physiological conditions. Accordingly, in addition to the discomfort encountered, products that produce irritation will tend to be flushed from the eye, and hence a more rapid loss of medication may occur with a probable reduction in the therapeutic response (11).
Ideally, every product would be buffered to a pH of 7.4, considered the normal physiological pH of tear fluid. The argument for this concept is that the product would be comfortable and have optimum therapeutic activity. Various experiments, primarily in rabbits, have shown an enhanced effect when the pH was increased, owing to the solution containing a higher concentration of the nonionized lipid-soluble drug base, which is the species that can more rapidly penetrate the corneal epithelial barrier. This would not be true if the drug were an acidic moiety. The tears have some buffer capacity of their own, and it is believed that they can neutralize the pH of an instilled solution if the quantity of solutions is not excessive and if the solution does not have a strong resistance to neutralization. Pilocarpine activity is apparently the same whether applied from vehicles with nearly physiological pH values or from more acidic vehicles, provided the latter are not strongly buffered (345). A pH difference of 6.6 versus 4.2 produced a statistically insignificant difference in pilocarpine miosis (346). The pH values of ophthalmic solutions are adjusted within a range to provide an acceptable shelf life. When necessary, they are buffered adequately to maintain stability within this range for at least two years. If buffers are required, their capacity is controlled to be as low as possible, thus enabling the tears to bring the pH of the eye back to the physiological range. Since the buffer capacity is determined by buffer concentration, the effect of buffers on tonicity must also be taken into account and is another reason that ophthalmic products are usually only lightly buffered.
The pH value is not the sole contributing factor to discomfort of some ophthalmic solutions. It is possible to have a product with a low pH and little buffer capacity that is more comfortable than a similar product with a higher pH and a stronger buffer capacity. Epinephrine hydrochloride and dipivefrin hydrochloride solutions, used for treatment of glaucoma, have a pH of about 3, yet they have sufficiently acceptable comfort to have been used daily for many years. The same pH solution of epinephrine bitartrate has an intrinsically higher buffer capacity and will produce much more discomfort.
The acidic nonsteroidal anti-inflammatory agents produce significant stinging and burning upon topical ocular instillation, and this limits the concentration of drug that can be developed. Caffeine, a xanthine derivative, has been found to improve significantly the comfort of drugs such as suprofen (Profenal®) by forming in situ weak complexes with the NSAID (U.S. patent 4,559,343).
Stabilizers Stabilizers are ingredients added to a formula to decrease the rate of decomposition of the active ingredients. Antioxidants are the principal stabilizers added to some ophthalmic solutions, primarily those containing epinephrine and other oxidizable drugs. Sodium bisulfite or metabisulfite are used in concentration up to 0.3% in epinephrine hydrochloride and bitartrate solutions. Epinephrine borate solutions have a pH in the range 5.5 to 7.5 and offer a more difficult challenge to formulators who seek to prevent oxidation. Several patented antioxidant systems have been developed specifically for this compound. These consist of ascorbic acid and acetylcysteine and sodium bisulfite and 8-hydroxyquinoline. Isoascorbic acid is also an effective antioxidant for this drug. Sodium thiosulfate is used with sodium sulfacetamide solutions.
Surfactants The use of surfactants is greatly restricted in formulating ophthalmic solutions. The order of surfactant toxicity is anionic > cationic » nonionic. Several nonionic surfactants are used in relatively low concentrations to aid in dispersing steroids in suspensions and to achieve or to improve solution clarity. Those principally used are the sorbitan ether esters of oleic acid (polysorbate or Tween 20 and 80), polymers of oxyethylated octyl phenol (tyloxapol), and polyoxyl 40 stearate. The lowest concentration possible is used to perform the desired function. Their effect on preservative efficacy and possible binding by macromolecules as well as effect on ocular irritation must be taken into account. The use of surfactants as cosolvents for an ophthalmic solution of chloramphenicol has been described (347). This composition includes polyoxyl 40 stearate and polyethylene glycol to solubilize 0.5% chloramphenicol. These surfactants-cosolvents provide a clear aqueous solution of chloramphenicol and a stabilization of the antibiotic in aqueous solution. Polyethoxylated ethers of castor oil are used reportedly for solubilization in Voltaren® (diclofenac sodium) ophthalmic solution (U.S. patent 4,960,799).
Viscosity-imparting agents Polyvinyl alcohol, methylcellulose, hydroxypropyl methyl-cellulose, hydroxyethylcellulose, and one of the several high-molecular-weight cross-lined polymers of acrylic acid, known as carbomers (346), are commonly used to increase the viscosity of ophthalmic solutions and suspensions. Although they reduce surface tension significantly, their primary benefit is to increase the ocular contact time, thereby decreasing the drainage rate and increasing drug bioavailability. A secondary benefit of the polymer solutions is a lubricating effect that is largely subjective, but noticeable to many patients. One disadvantage to the use of the polymers is their tendency to dry to a film on the eyelids and eyelashes; however, this can be easily removed by wiping with a damp tissue.
Numerous studies have shown that increasing the viscosity of ophthalmic products increases contact time and pharmacological effect, but there is a plateau reached after which further increases in viscosity produce only slight or no increases in effect. The location of the plateau is drug and formulation dependent. Blaugh and Canada (347) using methylcellulose solutions found increased contact time in rabbits up to 25 cP and a leveling off at 55 cP. Lynn and Jones (348) studied the rate of lacrimal excretion in humans using a dye solution in methylcellulose concentration from 0.25% to 2.5%, corresponding to viscosities of 6 to 30,000 cP, the latter being a thick gel.
Chrai and Robinson (42) conducted studies in rabbits and found that over a range of 1.0 to 12.5 cP viscosity there is a threefold decrease in the drainage rate constant and a further threefold decrease over the viscosity range of 12.5 to 100 cP. This decrease in drainage rate increased the concentration of drug in the precorneal tear film at zero time and subsequent time periods, which resulted in a higher aqueous humor drug concentration. The magnitude of the increase in drug concentration in the aqueous humor was smaller than the increase in viscosity, about 1.7 times, for the range 1.0 to 12.5 cP, and only a further 1.2-fold increase at 100 cP. Since direct determination of ophthalmic bioavailability in humans is not possible without endangering the eye, investigators have used fluorescein to study factors affecting bioavailability in the eye, because its penetration can be quantified in humans through the use of slit-lamp fluorophotometer. Adler (349), using this technology, found only small increases in dye penetration over a wide range of viscosities. The use of fluorescein data to extrapolate vehicle effects to ophthalmic drugs in general would be questionable owing to the large differences in chemical structure, properties, and permeability existing between fluorescein and most ophthalmic drugs.
The major commercial viscous vehicles are hydroxypropyl methylcellulose (Isopto®) and polyvinyl alcohol (Liquifilm®). Isopto products most often use 0.5% of the cellulosic and range from 10 to 30 cP in viscosity. Liquifilm products have viscosities of about 4 to 6 cP and use 1.4% polymer.
Although usually considered to be inactive ingredients in ophthalmic formulations added because they impart viscosity, many of these polymers function as ocular lubricants. They are marketed as the active ingredients in OTC ocular lubricants used to provide relief from dry eye conditions. The regulatory requirements for these OTC products are found in the FDA CFR (21 CFR 349 Ophthalmic Drug Products for Over-the-Counter Human Use), and their formulations are presented in the 15th edition of the APhA Handbook of Nonprescription Drugs.
In summary, there are numerous variables to be adjusted and many choices of excipients required when tailoring a formulation of a particular therapeutic agent for ophthalmic application. But ultimately the choice rests on finding an economically viable formulation, which clinically enhances the therapeutic index for that drug.
Vehicles Ophthalmic drops are, with few exceptions, aqueous fluids using purified water USP as the solvent. WFI is not required as it is in parenterals. Purified water meeting USP standards may be obtained by distillation, deionization, or reverse osmosis.
Oils have been used as vehicles for several topical eyedrop products that are extremely sensitive to moisture. Tetracycline HC1 is an antibiotic that is stable for only a few days in aqueous solution. It is supplied as a 1% sterile suspension with Plastibase 50W and light liquid petrolatum. White petrolatum and its combination with liquid petrolatum to obtain a proper consistency is routinely used as the vehicle for ophthalmic ointments.
When oils are used as vehicles in ophthalmic fluids, they must be of the highest purity. Vegetable oils such as olive oil, castor oil, and sesame oil have been used for extemporaneous compounding. These oils are subject to rancidity and, therefore, must be used carefully. Some commercial oils, such as peanut oil, contain stabilizers that could be irritating. The purest grade of oil, such as that used for parenteral products would be advisable for ophthalmics.
Eyedrops have been packaged almost entirely in plastic dropper bottles since the introduction of the Drop-Tainer® plastic dispenser in the 1950s. A few products still remain in glass dropper bottles because of special stability considerations. The main advantage of the Drop-Tainer and similarly designed plastic dropper bottles are convenience of use by the patient, decreased contamination potential, lower weight, and lower cost. The plastic bottle has the dispensing tips as an integral part of the package. The patient simply removes the cap and turns the bottle upside down and squeezes gently to form a single drop that falls into the eye. The dispensing tip will deliver only one drop or a stream of fluid for irrigation, depending on the tip design and pressure applied. When used properly, the solution remaining in the bottle is only minimally exposed to airborne contaminants during administration; thus, it will maintain very low to nonexistent microbial content compared with the old-style glass bottle with its separate dropper assembly.
The plastic bottle and dispensing tip are made of low-density polyethylene (LDPE) resin, medium-density polyethylene (MDPE), or a high-density polyethylene (HDPE) resin, which provides the necessary flexibility and inertness. Because these components are in contact with the product during its shelf life, they must be carefully chosen and tested for their suitability for ophthalmic use. In addition to stability studies on the product in the container over a range of normal and accelerated temperatures, the plastic resins must pass the USP biological and chemical tests for suitability. The LDPE resins are by far the most commonly used and are compatible with a very wide range of drugs and formulation components. Their one disadvantage is their sorption and permeability characteristics. Volatile ingredients, such as the preservatives chlorobutanol and phenylethyl alcohol, can migrate into the plastic and eventually permeate through the walls of the container. The sorption and permeation can be detected by stability studies if it is significant. If the permeating component is a preservative, a repeat test of the preservative effectiveness with time will determine if the loss is significant. If necessary, a safe and reasonable excess of the permeable component may be added to balance the loss during the product's shelf life. Another means of overcoming permeation effects is to employ a secondary package, such as a peel-apart blister or pouch composed of nonpermeable materials (e.g., aluminum foil or vinyl). The plastic dropper bottles are also permeable to water, but weight loss by water vapor transmission has a decreasing significance as the size of the bottle increases. The consequences of water vapor transmission must be taken into consideration when assessing the stability of a product.
The LDPE resins are translucent, and if the drug is light sensitive, additional package protection may be required. This can be achieved by using a resin containing an opacifying agent such as titanium dioxide, by placing an opaque sleeve over the exterior of the container, or by placing the bottle in a cardboard carton. Extremely light-sensitive drugs, such as epinephrine and proparacaine, may require a combination of these protective measures.
The MDPE and HDPE resins were developed to address formulator's needs when an LDPE resin was not adequate; on the basis of parameters such as weight loss, adsorption, or additional package rigidity is required. The MDPE resins provide intermediate properties between low- and high-density polyethylene, where more rigidity than LDPE and less rigidity than HDPE are required. The HDPE resins are of a natural milky color with much better barrier properties than LDPE and MDPE.
Colorants, other than titanium dioxide, are rarely used in plastic containers; however, the use of colorants is required for the cap. The American Academy of Ophthalmology (AAO) recommended to the FDA that a uniform color coding system be established for the caps and labels of all topical ocular medications. Industry new drug applicants are required to either follow this system or provide an adequate justification for any deviations from the system. The AAO color codes, as revised and approved by the AAO Board of Trustees in June 1996, are shown in Table 4. The FDA and AAO have extended the cap color scheme to differentiate different classes of newer Rx drugs for the benefit of the patient who may be using more than one product. The intent is to help prevent errors in medication and improve patient compliance. It is important for the pharmacist to explain this color coding to the patient and/or caregiver since it can be defeated if the cap is not returned to the proper container after each use.
The pharmacist should dispense the sterile ophthalmic product only in the original unopened container. A tamper-evident feature such as a cellulosic or metal band around
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