Manufacturing of eye preparations.

1. Manufacturing of eye preparations.

2. One of the major problems encountered with topical administration is the rapid precorneal loss caused by nasolacrimal drainage and high tear fl uid turnover, which leads to drug concentrations of typically less than 10% of the applied drug.

3. Approaches to improve the ocular bioavailability have been attempted in two directions: to increase the corneal permeability by using penetrations enhancers or prodrugs and to prolong the contact time with the ocular surface by using viscosity - enhancing or in situ gelling polymers

4. Conventional dosage forms such as solutions, suspensions, and ointments account for almost 90% of the currently accessible ophthalmic formulations on the market. They offer some advantages such as their ease of administration by the patient, ease of preparation, and the low production costs. However, there are also signifi cant disadvantages associated with the use of conventional solutions in particular, including the very short contact time with the ocular surface and the fast nasolacrimal drainage, both leading to a poor bioavailability of the drug.

5. Various ophthalmic delivery systems have been investigated to increase the corneal permeability and prolong the contact time with the ocular surface. However, conventional eye drops prepared and administered as aqueous solutions remain the most commonly used dosage form in ocular disease management.

6. Solutions The reasons behind choosing solutions over other dosage forms are their favorable cost advantage, the simplicity of formulation development and production, and the high acceptance by patients. However, there are also a few drawbacks, such as rapid and extensive precorneal loss, high absorption via the conjunctiva and the nasolacrimal duct leading to systemic side effects, as well as the increased installation frequency resulting in low patient compliance.

7. Some of these problems have been encountered by addition of viscosity - enhancing agents such as cellulose derivates, which are believed to increase the viscosity of the preparation and consequently reduce the drainage rate. The use of viscosity enhancers will be discussed later in this section.

8. Suspensions Suspensions of the micronized drug ( < 10 μ m) in a suitable aqueous vehicle are formulated, where the active compound is water insoluble. This is the case for most of the steroids. It is assumed that the drug particles remain in the conjunctival sac, thus promoting a sustained release effect. There have been many studies trying to prove this assumption, but none of them has revealed a pronounced prolonged release profi le.

9. According to Davies, topical ophthalmic suspensions have a number of limitations compared to solutions. They need to be adequately shaken before use to ensure correct dosing, a process which can result in poor patient compliance. In addition, they need to be sterilized, which may cause physical instability of the formulation.

10. Furthermore, the amount of drug required to achieve only a moderate increase in bioavailability is very high, rendering suspensions expensive in terms of their production costs. The drug particle size plays the most important role in the formulation process of suspensions. Particles greater than 10 μ m cause patient discomfort. As they are perceived as foreign substances, they cause refl ex tearing in order to eliminate the particles from the ocular surface. A study by Schoenwald and Stewart showed the infl uence of the particle size of dexamethasone on its bioavailability.a

11. The in vivo dissolution rate decreased with increasing particle size to the point when particles were removed from the conjunctival sac before the dissolution was complete. As a result, achieving a near - solution state with small particles that are easy to resuspend and show minimal sedimentation remains the goal when formulation of a suspension is unavoidable.

12. Ointments Ointments generally consist of a dissolved or dispersed drug in an appropriate vehicle base. They are the most commonly used semisolid preparations as they are well tolerated and fairly safe and increase the ocular bioavailability of the drug. The instilled ointment breaks up into small oily droplets that remain in the cul - de - sac as a drug depot. The drug eventually gets to the ointment – tear interface due to the shearing action of the eyelids.

13. Sieg and Robinson compared the bioavailability of fl uorometholone in a solution, a suspension, and an ointment. They found that the peak concentration (cmax ) of the drug in the aqueous humor of rabbits was comparable with all three formulations, whereas the time to peak concentration ( tmax ) occurred much later with the ointment, leading to a signifi cantly greater total bioavailability of the drug.

14. Overall, ophthalmic ointments offer the following advantages: reduced dilution of the medication via the tear fi lm, resistance to nasolacrimal drainage, and an increased precorneal contact time. However, oily viscous preparations for ophthalmic use (such as ointments) can cause blurred vision and matting of the eyelids and may also be associated with discomfort by the patient as well as occasional ocular mucosal irritation. Ointments are therefore generally used in combination with eye drops, which can be administered during the day, while the ointment is applied at night, when clear vision is not required.

15. Polymeric systems used for ocular drug delivery can be divided into three groups: viscosity - enhancing polymers, which simply increase the formulation viscosity, resulting in decreased lacrimal drainage and enhanced bioavailability; mucoadhesive polymers, which interact with the ocular mucin, therefore increasing the contact time with the ocular tissues; and in situ gelling polymers, which undergo sol - to – gel phase transition upon exposure to the physiological conditions present in the eye.

16. Viscosity -Enhancing Polymers In order to reduce the lacrimal clearance (drainage) of ophthalmic solutions, various polymers have been added to increase the viscosity of conventional eye drops, prolong precorneal contact time, and subsequently improve ocular bioavailability of the drug. Among the range of hydrophilic polymers investigated in the area of ocular drug delivery are polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP), cellulose derivates such as methylcellulose (MC), and polyacrylic acids (carbopols).

17. Chrai and Robinson evaluated the use of an MC solution of pilocarpine in albino rabbits and found a decrease in the drainage rate with increasing viscosity. Patton and Robinson investigated the relationship between the viscosity and the contact time or drainage rate and demonstrated an optimum viscosity of 12 – 15 cps for an MC solution in rabbits. The infl uence of different polymers on the activity of pilocarpine in rabbits and human was reported by Saettone et al.

18. The ocular shear rate ranges from 0.03 s − 1 during interblinking periods to 4250 – 28,500 s − 1 during blinking. It has a great infl uence on the rheological properties of viscous ocular dosage forms and consequently the bioavailability of the incorporated drug. Newtonian systems do not show any real improvement of bioavailability below a certain viscosity and blinking becomes painful, followed by refl ex tearing, if the viscosity is too high. While the viscosity of Newtonian systems is independent from the shear rate, non - Newtonian pseudoplastic or so – called shear - thinning systems exhibit a decrease in viscosity with increasing shear rates.

19. Mucoadhesive Polymers Bioadhesion refers to the attachment of a drug molecule or a delivery system to a specifi c biological tissue by means of interfacial forces. If the surface of the tissue is covered by a mucin fi lm, as is the case for the external globe, it is more commonly referred to as mucoadhesion.

20. In order to be an effective mucoadhesive excipient, polymers must show one or more of the following features: strong hydrogen binding group, strong anionic charge, high molecular weight, suffi cient chain fl exibility, surface energy properties favoring spreading onto the mucus, and near - zero contact angle to allow maximum contact with the mucin coat.

21. The most commonly used bioadhesives are macromolecular hydrocolloids with numerous hydrophilic functional groups capable of forming hydrogen bonds (such as carboxyl, hydroxyl, amide, and sulfate groups). Hui and Robinson were the fi rst to demonstrate the usefulness of bioadhesive polymers in improving the ocular bioavailability of progesterone. Saettone et al. evaluated a series of bioadhesive dosage forms for ocular delivery of pilocarpine and tropicamide and found hyaluronic acid to be the most promising mucoadhesive polymer.

22. Lehr et al. suggested that cationic polymers, which are able to interact with the negative sialic acid residues of the mucin, would probably show better mucoadhesive properties than anionic or neutral polymers. They investigated the polycationic polymer chitosan and demonstrated that the mucoadhesive performance of chitosan was signifi cantly higher in neutral or slightly alkaline pH as it is present in the tear fl uid.a

23. However, according to Park and Robinson, polyanions are better than polycations in terms of binding and potential toxicity. In general, both anionic and cationic charged polymers demonstrate better mucoadhesive properties than nonionic polymer, such as cellulose derivates or PVA.a

24. The mechanism of mucoadhesion involves a series of different steps. First, the mucoadhesive formulation needs to establish an intimate contact with the corneal surface. Prerequisites are either good wetting or swelling of the mucoadhesive polymer as well as suffi cient spreading across the cornea.

25. The second stage involves the penetration of the mucoadhesive polymer chains into the crevices of the tissue surface and also the entanglement with the mucous chains. On a molecular level, mucoadhesion is a results of van - der - Waals forces, electrostatic attractions, hydrogen bonding, and hydrophobic interactions.

26. Mucoadhesive polymers increase the contact time of a formulation with the tear fi lm and simulate the continuous delivery of tears due to a high water – restraining capacity. As such, they allow a decrease in the instillation frequency compared to common eye drops and are therefore useful as artifi cial tear products.

27. In Situ Gelling Systems In situ gelling systems are viscous polymer - based liquids that exhibit sol - to - gel phase transition on the ocular surface due to change in a specifi c physicochemical parameter (ionic strength, temperature, pH, or solvent exchange). They are highly advantageous over preformed gels as they can easily be instilled in liquid form but are capable of prolonging the residence time of the formulation on the surface of the eye due to gelling.

28. The principal advantage of in situ gelling systems is the easy, accurate, and reproducible administration of a dose compared to the application of preformed gels. The concept of forming gels in situ (e.g., in the cul - de - sac of the eye) was fi rst suggested in the early 1980s, and ever since then various triggers of in situ gelling have been further investigated.

29. Polymers that may undergo sol - to - gel transition triggered by a change in pH are cellulose acetate phthalate (CAP) and cross - linked polyacrylic acid derivates such as carbopols, methacrylates and polycarbophils. CAP latex is a free - running solution at pH 4.4 which undergoes sol - to - gel transition when the pH is raised to that of the tear fl uid.

30. This is due to neutralization of the acid groups contained in the polymer chains, which leads to a massive swelling of the particles. The use of pH – sensitive latex nanoparticles has been described by Gurny et al. Carbopols have apparent p Ka values in the range of 4 – 5 resulting in rapid gelation due to rise in pH after ocular administration.

31. Gellan gum is an anionic polysaccharide which undergoes phase transition under the infl uence of an increased ionic strength. In fact, the gel strength increases proportionally with the amount of mono - or divalent cations present in the tear fl uid. As a consequence, the usual refl ex tearing, which leads to a dilution of common viscous solutions, further enhances the viscosity of gellan gum formulations due to the increased amount of tear fl uid and thus higher cation concentration.

32. Shedden et al compared the plasma concentrations of timolol following multiple applications of Timoptic - XE and a timolol maleate solution. They found that a once - daily application of the in situ gelling formulation was suffi cient to reduce the intraocular pressure to levels comparable to a twice - daily application of the solution, leading to better patient compliance as well as a reduction in systemic side effects.

33. Poloxamers or pluronics are block copolymers consisting of poly(oxyethylene) and poly(oxypropylene) units. They rapidly undergo thermal gelation when the temperature is raised to that of the ocaular surface (32 ° C), while they remain liquid at refrigerator temperature. Poloxamers exhibit surface active properties, but even if used in high concentrations (usually between 20 and 30%), Pluronic F127 was found no more damaging to the cornea than a physiological saline solution.

34. In order to reduce the total polymer concentration and achieve better gelling properties, several poloxamer combinations have been tested. Wei et al used a mixture of Pluronic F127 and F68 resulting in a more suitable phase transition temperature with a free - fl owing liquid under 25 ° C. Combining thermal - with pH - dependent gelation, Kumar et al. developed a combination of methylcellulose 15% and carbopol 0.3%.

35. This composition exhibited a sol - to - gel transition between 25 and 37 ° C with a pH increase from 4 to 7.4. A possible mechanism for the thermal effect could be the decrease in the degree of the methylcellulose hydration, while the polyacrylic acid can transform into a gel upon an increase in pH due to the buffering properties of the tear fl uid.

36. Colloidal carriers have been investigated as drug delivery systems for the past 30 years in order to achieve specifi c drug targeting, facilitate the bioavailability of drugs through biological membranes, and protect the drug against enzymatic degradation. Their use in topical administration and especially in ocular delivery however has only been studied for the last two decades.

37. Colloidal carriers are small particulate systems ranging in size from 100 to 400 nm. As they are usually suspended in an aqueous solution, they can easily be administered as eye drops, thus avoiding the potential discomfort resulting from bigger particles present in ocular suspensions or from viscous or sticky preparations.

38. Most efforts in ophthalmic drug delivery have been made with the aim of increasing the corneal penetration of the drug. Calvo et al. have shown that colloidal particles are preferably taken up by the corneal epithelium via endocytosis. It has also been stated by Lallemand and co - workers , that the cornea acts as a drug reservoir, slowly releasing the active compound present in the colloidal delivery system to the surrounding ocular tissues.

39. Nanoparticles Nanoparticles have been among the most widely studied particulate delivery systems over the past three decades. They are defi ned as submicrometer - sized polymeric colloidal particles ranging from 10 to 1000 nm in which the drug can be dissolved, entrapped, encapsulated, or adsorbed.

40. Depending on the preparation process, nanospheres or nanocapsules can be obtained. Nanospheres have a matrixlike structure where the drug can either be fi rmly adsorbed at the surface of the particle or be dispersed/dissolved in the matrix. Nanocapsules, on the other hand, consist of a polymer shell and a core, where the drug can either be dissolved in the inner core or be adsorbed onto the surface.a

41. The fi rst nanoparticulate delivery system studied was Piloplex, consisting of pilocarpine ionically bound to poly(methyl)methacrylate – acrylic acid copolymer nanoparticles. Klein et al. found that a twice - daily application of Piloplex in glaucoma patients was just as effective as three to six instillations of conventional pilocarpine eye drops. However, the formulation was never accepted for commercialization due to various formulation - related problems, including the nonbiodegradability, local toxicity, and diffi culty of preparing a sterile formulation.

42. Another early attempt to formulate a nanoparticulate system for the delivery of pilocarpine was made by Gurny. This formulation was based on pilocarpine dispersed in a hydrogen CAP pseudolatex formulation. Gurny and co - workers compared the formed nanoparticles to a 0.125% solution of hyaluronic acid some years after their fi rst investigation and found that the viscous hyaluronic acid system showed a signifi cantly longer retention time in front of the eye than the pseudolatex formulation.

43. The most commonly used biodegradable polymers in the preparation of nanoparticulate systems for ocular drug delivery are poly - alkylcyanoacrylates, poly - ε - caprolactone, and polylactic - co - glycolic acid copolymers. Marchal - Heussler et al. compared the three particulate delivery systems using antiglaucoma drugs including betaxolol and cartechol. Results showed that poly - ε - caprolactone (nanospheres and nanocapsules) exhibited the highest pharmacological activity when loaded with betaxolol.

44. It seemed that the higher ocular activity was related to the hydrophobic nature of the carrier and that the mechanism of action seemed to be directly linked to the agglomeration of the particles in the conjunctival sac. In general, nanocapsules displayed a much better effect than nanospheres probably due to the fact that the active compound was in its un - ionized form in the oily core and could diffuse faster into the cornea. Diffusion of the drug from the oily core of the nanocapsule to the corneal epithelium seems to be more effective than diffusion from the internal, more hydrophilic matrix of the nanospheres.

45. In order to achieve a sustained drug release and a prolonged therapeutic activity, nanoparticles must be retained in the cul - de - sac and the entrapped drug must be released from the particles at a certain rate. If the release is too fast, there is no sustained release effect. If it is too slow, the concentration of the drug in the tears might be too low to achieve penetration into the ocular tissues. The major limiting issues for the development of nanoparticles include the control of particle size and drug release rate as well as the formulation stability.

46. So far, there is only one microparticulate ocular delivery system on the market. Betoptic S is obtained by binding of betaxolol to ion exchange resin particles. Betoptic S 0.25% was found to be bioequivalent to the Betoptic 0.5% solution in lowering the intraocular pressure.

47. Liposomes Liposomes were fi rst reported by Bangham in the 1960s and have been investigated as drug delivery systems for various routes ever since then. They offer some promising features for ophthalmic drug delivery as they can be administered as eye drops but will localize and maintain the pharmacological activity of the drug at its site of action. Due to the nature of the lipids used, conventional liposomes are completely biodegradable, biocompatible, and relatively nontoxic.

48. A liposome or so - called vesicle consists of one or more concentric spheres of lipid bilayers separated by water compartments with a diameter ranging from 80 nm to 100 μ m. Owing to their amphiphilic nature, liposomes can accommodate both lipohilic (in the lipid bilayer) and hydrophilic (encapsulated in the central aqueous compartment) drugs.

49. According to their size, liposomes are classifi ed as either small unilamellar vesicles (SUVs) (10 – 100 nm) or large unilamellar vesicles (LUVs) (100 – 300 nm). If more than one bilayer is present, they are referred to as multilamellar vesicles (MLVs). Depending on their lipid composition, they can have a positive, negative, or neutral surface charge.

50. Liposomes are potentially valuable as ocular drug delivery systems due to their simplicity of preparation and versatility in physical characteristics. However, their use is limited by instability (due to hydrolysis of the phospholipids), limited drug - loading capacity, technical diffi culties in obtaining sterile preparations, and blurred vision due to their size and opacity.