Ocular Drug Delivery Systems: Advances, Challenges, and Pharmaceutical Applications Computer-Aided Formulation Development (CADD): Optimization, DOE, and Pharma Applications

Ocular drug delivery is one of the most complex and fascinating areas of pharmaceutics due to the protective barriers of the eye. This presentation provides a detailed overview of the anatomy and physiology of the eye, tear film composition, nasolacrimal drainage, and ocular barriers. It explains conventional ophthalmic dosage forms such as solutions and suspensions, while emphasizing novel systems like ocular inserts, implants, gels, and intravitreal injections. Challenges in bioavailability, strategies for improvement (viscosity enhancers, penetration enhancers, prodrugs), and controlled release systems like Ocusert are discussed in depth. This serves as a strong reference for students exploring ophthalmic formulation development.

1. OCCULAR DRUG DELIVERY SYSTEM Presented by, Ayushi P. Jain 1

2. INTRODUCTION “ophthalmic drug delivery is one of the most interesting and challenging endeavor's facing the pharmaceutical scientist. The anatomy, physiology and biochemistry of the eye render this organ exquisitely impervious to foreign substances. The challenge to the formulator is to circumvent the protective barriers of the eye without causing permanent tissue damage. The primitive ophthalmic solutions, suspensions and ointment dosage forms are clearly no longer sufficient to combat some present virulent diseases. 2

3. Definition They are specialized dosage forms designed to be instilled onto the external surface of the eye (topical), administered inside (intra-ocular) or adjacent (per -ocular) to the eye or used in conjunction with an ophthalmic device. The novel approach of drug delivery system in which drug can be instilled on the cul-de-sac cavity of eye is known as ocular drug delivery system. Ocular administration of drug is primarily associated with the need to treat ophthalmic diseases. The newest forms are gels, gel-forming solutions, ocular inserts, intra- vitreal injections & implants. 3

4. Difference between ophthalmic & ocular drug delivery system Ophthalmic DDS Conventional system Old concept Addition of preservatives High dosing frequency Minimum release rate of drug Limited flexibility Minimum absorption rate Minimum bioavailability Ocular DDS Novel system New concept No addition of preservatives Low dosing frequency Maximum release rate of drug Extreme flexibility Maximum absorption rate Maximum bioavailability 4

5. Major classes of drug used are Miotics - e.g. Pilocarpine Hcl Mydriatics – e.g. Atropine Cycloplegics – e.g. Atropine Anti-Inflammatory - e.g. Corticosteroids Anti-Infective – e.g. Antibiotics, Antiviral , Antibacterial Anti-glaucoma drugs – e.g. Pilocarpine Hcl Surgical adjuncts – e.g. Irrigating solutions Diagnostic drugs – e.g. Sodium fluorescein Anaesthetics – e.g. Tetra Caine 5

6. Anatomy and physiology of eye 6

7. Eye is a unique and very valuable organ. This is considered a window hinge. We can enjoy it and look at the world body. The eye is composed of two components Anterior segment consist of front 1/3 rd of eye that mainly includes pupil, cornea, iris, ciliary body, aqueous humor & lens. Posterior segment consist of the back 2/3 rd of eye that includes vitreous humor, retina, choroid, macula & optic nerve 7

8. Composition of tears The secretion is a clear watery fluid containing numerous salts, glucose, other organic compounds approximately 0.7% protein and the enzymes lysozyme Water-98.2% Solid-1.8% NPN- .05% Organic elements:- Protien-0.67% Sugar-0.65% Nacl-0.66% Urea-0.03% Other mineral elements are : sodium, potassium & ammonia-0.79% Normal volume in humans is 7µl and fluid pH 7.4 and of blinking doesn’t take place, the volume may go up to 30µl without spillage. The cul-de-sac is sterile due to partially of the action of lysozyme in tears 8

9. Human eye- Diameter- 23mm Structure- comprises of 3 layers 1. outermost coat- the clear, transparent cornea and the white, opaque sclera 2. Middle layer- the iris anteriorly, the choroid posteriorly, and the ciliary body at the intermediate part 3. Inner layer- retina (extension of CNS) CORNEA (types) Epithelium Stroma Endothelium ( fat-water-fat structure) Function- penetration of the drug depends on oil-water partition co-efficient 9

10. Fluids system in the eye Aqueous humor Secreted from blood through epithelium of the ciliary body. Secreted in posterior chamber and transported to anterior chamber. Vitreous humor Secreted from blood through epithelium of the ciliary body. Diffused through the vitreous body. Lacrimal glands Secreted from tears and bosh foreign bodies. Moistens the cornea and from drying out. The sclera- the protective outer layer of the eye, refer to ask white of the eye and that maintains the shape of the eye. 10

11. The cornea : The front portion of the sclera, is transparent and allows light to enter the eye . The cornea is a powerful refracting surface, providing much of the eye's focusing power. The choroid : is the second layer of the eye and lies between the sclera and the retina . It contains the blood vessels that provide nourishment to the outer layers of the retina. The iris : is the part of the eye that gives it color . It consists of muscular tissue that responds to surrounding light, making the pupil, or circular opening in the center of the iris, larger or smaller depending on the brightness of the light. 11

12. The lens is a transparent, biconvex structure, encased in a thin transparent covering. The function of the lens is to refract and focus incoming light onto the retina. The retina is the innermost layer in the eye. It converts images into electrical impulses that are sent along the optic nerve to the brain where the images are interpreted. The macula is located in the back of the eye, in the center of the retina. This area produces the sharpest vision. 12

13. Anatomical & physiological considerations Precordial area Precordial tear film Nasolacrimal drainage Transport barriers in the eye Cornea Sclera Iris-ciliary body Lens Blood-ocular barrier (aqueous & retinal) 13

14. Nasolacrimal drainage system 14

15. The nasolacrimal drainage system consists of three parts: 1.The secretory system, 2.The distributive system 3.The excretory system. The secretory system consists of basic secretors that are stimulated by blinking and temperature change This includes the effect of tear evaporation and reflex secretors that have an efferent parasympathetic nerve supply and secrete in response to physical or emotional stimulation. The distributive system consists of the eyelids and the tear meniscus around the lid edges of the open eye, which spread tears over the ocular surface by blinking, thus preventing dry areas from developing. 15

16. The excretory part of the nasolacrimal drainage system consists of: the lachrymal punctate, the superior, inferior and common canaliculi; the lachrymal sac and the nasolacrimal duct. It is thought that tears are largely absorbed by the mucous membrane that lines the ducts and the lachrymal sac and that only a small amount reaches the nasal passage. 16

17. Routes of ocular drug delivery system 17

18. Subconjunctival administration: Traditionally Subconjunctival injections have been used to deliver drugs at increased levels to the uvea. The progress in materials sciences and pharmaceutical formulation have provided possibilities to develop controlled release formulations to deliver drugs to the posterior segment and to guide the healing process after surgery. 18

19. Intravitreal administration Direct drug administration into the vitreous offers distinct advantage of more straightforward access to the vitreous and retina. Small molecules are able to diffuse rapidly in the vitreous but the mobility of large molecules, particularly positively charged, is restricted. 19

20. Advantages 1. Increased accurate dosing, To overcome the side effects of pulsed dosing produced by conventional systems. 2. To provide sustained and controlled drug delivery. 3. To increase the ocular bioavailability of drug by increasing the corneal contact time. This can be achieved by effective adherence to corneal surface. 4. To provide targeting within the ocular globe so as to prevent the loss to other ocular tissues. 5. To circumvent the protective barriers like drainage, lacrimation and conjunctiva absorption. 6. To provide comfort, better compliance to the patient and to improve therapeutic performance of drug. 7. To provide better housing of delivery system. 20

21. Limitations of ophthalmic drug delivery Dosage form cannot be terminated during emergency. Interference with vision. Difficulty in placement and removal. Occasional loss during sleep or while rubbing eyes. Movement around the eye Less bioavailability Protein binding Lacrimation Peak valley profile Less intimate contact Patient incompliance 21

22. Ideal requirements of ocular drug delivery system Sterility Isotonicity e.g. 0.9% Nacl, 1.9% boric acid Buffer/pH Less drainage system Minimum protein binding i.e. prolong contact time with corneal tissue Simplicity of instillation for the patient Non irritative & comfortable form Appropriate rheological properties Inert & stable 22

23. CLASSIFICATION OF OCULAR DDS

24. Formulation consideration Physicochemical properties of drug – Ko /w :- 10 to 100 Molecular size Corneal transport Conjunctiva transport < 20000Da   Nature Ko / w barrier transport Absorption mechanism Hydrophilic drug Low epithelial Paracellular Diffusion, active transport, endocytosis Lipophilic drug high stroma Transcellular Passive transport 24

25. Buffer capacity & pH Normal pH 7.4 Tear fluid has limited buffering capacity Formulation pH 7 to 7.4 Osmotic pressure Osmoticaly depends on number of ions dissolved in aqueous layer of tear film Normal 310 to 350 osm /kg Hypotonic solutions better tolerated than hypertonic Below 260 & above 480 osm /kg- irritation 25

26. Instillation volume Cul-de-sac capacity :- holds 7 to 9 . Eye dropper delivers 50-70𝜇𝑙. Excess volume rapidly removed through nasolacrimal drainage Rate of drainage follows 1 st order kinetics with instillation volume. Keep constant dose with low instillation volume Required partition coefficient (o/w) 10 to 100 Required molecular weight Transport through cornea below 5000Da Transport through conjunctiva below 20000Da Osmotic pressure 310 to 370   26

27. Role of polymers To increase the viscosity of solution ultimately reduce solution drainage e.g. : PVP, PVA & poloxamers. The polysaccharides such as hyaluronic acid, cellulose derivatives such as MC, HMC, CMC, HPC & dextran, xanthan & Gellan. By improving contact time with cornea & bioavailability is also increased. High molecular weight, hydrophilic molecules that are unlikely to cross biological barriers. Prolong residence time with an extended duration of action. Optimal viscosity is 12-15 cps. 27

28. MUCOADHESIVE DOSAGE FORMS Any polymer solution/ suspension placed in the eye first encounters mucin at the corneal and conjunctival surface. The interaction of polymer with the mucin (a thin film of glycoprotein) at the corneal & conjunctival surface by non- covalent bonds is called as mucoadhesion. Bio adhesive/ mucoadhesive systems can be either polymeric solution or micro particle suspensions. They are retained in the cul-de-sac through adhesive bonds established with the mucin or epithelium thus increasing the corneal contact time until mucin turnover causes elimination of polymer. They help in prolonging the release of drug from dosage form. Mucoadhesive polymers are usually macromolecular hydrocolloids with numerous hydrophilic functional groups like carboxyl, hydroxyl, amide & Sulphate groups. They exhibit electrostatic, hydrophobic interactions & hydrogen bonding. Eg: lectins, carbopol, poly acrylic acid, CMC, poly acrylamide. 28

29. Factors affecting intraocular bioavailability Efficient nasolacrimal drainage (increase viscosity) Spillage from eye Ocular metabolism Continual inflow & outflow of lacrimal fluid reducing concentration gradient (driving force for absorption) Drug-protein interaction lacrimal fluid Dilution of drug in tears Absorption of drug into various ocular tissue i.e. cornea & conjunctiva 29

30. EXAMPLES

31. Barriers in ocular absorption Pre-corneal constraints Solution drainage Cornea as rate limiting barrier Lachrymation Anatomy of cornea Tear dilution Corneal constraints Cornea as rate limiting barrier Anatomy of cornea 1.Outer-Epithelium(lipophilic), 2.Middle-Stroma(hydrophilic), 3 . I nner E ndot h e liu m (l i p op h i l i c) 31

32. 32

33. General Pathway For Ocular Absorption 33

34. Drug loss from the ocular surface Instillation, the flow of lacrimal fluid removes instilled compounds from the surface of eye. Even though the lacrimal turnover rate is only 1 µl/min the excess volume of the instilled fluid is flown to the nasolacrimal duct rapidly in a couple of minutes. Another source of non-productive drug removal is its systemic absorption instead of ocular absorption. Systemic absorption may take place either directly from the conjunctiva sac via local blood capillaries or after the solution flow to the nasal cavity. 34

35. Lacrimal fluid – eye barrier Corneal epithelium limits drug absorption from the lacrimal fluid into the eye. The corneal epithelial cells form tight junctions that limit the paracellular drug permeation. Lipophilic drugs have typically higher permeability in the cornea than the hydrophilic drugs. The conjunctiva is a leakier epithelium than the cornea and its surface area is also nearly 20 times greater than that of the cornea. 35

36. Tear One of the pre-corneal barriers is Tear Film which reduces the effective concentration of the administrated drugs due to dilution by the tear turnover (approximately 1 uL /min), accelerated clearance, and binding of the drug molecule to the tear proteins. In addition the dosing volume of instillation is usually 20–50 uL whereas the size of cul-de-sac is only 7–10 uL. The excess volume may spill out on the cheek or exit through the nasolacrimal duct. Conjunctiva Conjunctiva of the eyelids and globe is a thin and transparent membrane, which is involved in the formation and maintenance of the tear film. In addition, conjunctiva or episcleral has a rich supply of capillaries and lymphatic's, therefore, administrated drugs in the conjunctiva or episcleral space may be cleared through blood and lymph. The conjunctiva blood vessels do not form a tight junction barrier, which means drug molecules can enter into the blood circulation by convective transport through paracellular pores in the vascular endothelial layer . 36

37. Blood-ocular barriers Conventionally, blood-ocular barriers are the blood-aqueous and the blood-retinal barriers. “blood-aqueous barrier” refers to the tight junctions of the non-pigmented epithelium of the ciliary body, the junctions of the iris tissues, and the iris blood vessels. due to its anatomic position, this barrier limits access by drug solutes to the anterior segment of the eye. “blood-retinal barrier” refers to the tight junctions between retinal capillary endothelial cells and the tight junctions between retinal pigment epithelial cells, the inner and the outer components of the blood-retinal barrier, respectively. Due to its anatomic position, it restricts access by therapeutic agents from the blood to the posterior segment of the eye. aqueous humor is secreted into the posterior chamber and then flows into the anterior chamber, crossing the iris diaphragm. 37

38. Methods to overcome barriers bioavailability improvement Viscosity adjustment Penetration enhancers Prodrug controlled release drug delivery Implants Inserts Micro particulates Colloids 38

39. Bioavailability Improvements a ) Viscosity adjustment Viscosity-increasing polymers are usually added to ophthalmic drug solutions on the premise that an increased vehicle viscosity should correspond to a slower elimination from the preocular area, which lead to improved Precorneal residence time and hence a greater trans corneal penetration of the drug into the anterior chamber. It has minimal effects in humans in terms of improvement in bioavailability. The polymers used include polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), methylcellulose, hydroxyl ethyl cellulose, hydroxyl propyl methylcellulose (HPMC), and hydroxyl propyl cellulose. 39

40. b) penetration enhancers The transport characteristics across the cornea can be maximized by increasing the permeability of the corneal epithelial membrane. The stratified corneal epithelial cell layer is a ‘tight’ ion-transporting tissue, because of the high resistance being exhibited by the paracellular pathway. So, one of the approaches used to improve ophthalmic drug bioavailability lies in increasing transiently the permeability characteristics of the cornea with appropriate substances known as penetration enhancers or absorption promoters. It has disadvantages like ocular irritation and toxicity. This includes agents such as cetylpyridinium chloride, ionophore such as lasalocid,Tween 20, saponins , Brij 35, Brij 78, Brij 98, ethylenediaminetetraacetic acid, bile salts, In different formulations, these have shown a significant enhancement in corneal drug absorption. Mechnism : the principle is ficks diffusion J=-DA DC/DX 40

41. c) Prodrug The principle of prodrug is to enhance corneal drug permeability through modification of the hydrophilicity (or lipophilicity ) of the drug. Within the cornea or after corneal penetration, the prodrug is either chemically or enzymatically metabolized to the active parent compound. Thus, the ideal prodrug should not only have increased lipophilicity and a high partition coefficient, but it must also have high enzyme susceptibility. Enzyme systems identified in ocular tissues include Esterases , ketone Reductase , and steroid 6-hydroxylase. Some examples of suitable prodrug include the antiviral medications ganciclovir and acyclovir. An acyl ester prodrug formulation of ganciclovir , a drug with a relatively low partition coefficient, substantially increased the amount of drug that can penetrate the cornea. 41

42. Ophthalmic inserts Ophthalmic inserts are defined as sterile solid or semisolid preparations with a thin, flexible & multi-layered structure, for insertion in the conjunctival sac. The system is flat, flexible, eliptical device designed to place in the cul-de-sac between the sclera & eyelid & to release the drug 42

43. ADVANTAGES Reduced local side effects and toxicity. Around the clock control of drug. Improved patient compliance. Reduced dosing frequency. DISADVANTAGES Retention in the eye for the full 7 days. Periodical check of unit. Replacement of contaminated unit Expensive. 43

44. Hence utilization of the principles of controlled release as embodied by ocular inserts offers an attractive approach to the problem of prolonging Precorneal drug residence times. The desired criteria for the controlled release ocular inserts are : Comfort Lack of explosion Ease of handling & insertion Non interference with vision & oxygen permeability Reproducibility of release kinetics Sterility Stability Ease of manufacture 44

45. Ocusert Developed by Alza Corporation, Oval flexible ocular insert, Release Rate:20 or 40mg/ hr (Pilocarpine) for consecutive 7 days. Uses : chronic glaucoma The device consists of three layers Outer layer – ethylene vinyl acetate copolymer layer. Inner core – Pilocarpine gelled with alginate main polymer. A retaining ring – of EVA impregnated with titanium dioxide . 45

46. Part Material Drug Reservoir Carrier material Rate controller Energy Source Delivery Portal Material Pilocarpine Alginic acid Ethylene vinyl acetate copolymer Conc. Of Pilocarpine Copolymer membrane 46

47. Insoluble insert is a multilayered structure consisting of a drug containing core surrounded on each side by a layer of copolymer membranes through which the drug diffuses at a constant rate. The rate of drug diffusion is controlled b: The polymer composition The membrane thickness The solubility of the drug Diffusion controlled ocular inserts These consists of a medicated core prepared out of a hydrogel polymer like alginates, sandwiched between two sheets of transparent lipophilic, rate controlling polymer. The drug molecule penetrate through the membranes at zero order controlling rate process. dQ / dt = Dp Km (Cr-Ct)/ δ m 47

48. Difference between Pilo-20 and Pilo-40 Ocular system Pilo-20 Pilocarpine nitrate 20 5 mg of drug 20 ug drug is releases per hours for next seven days thick Barrier functioning Drug release rate is less Rate of Absorption is less Limited Flexibility Permeation Enhancers are not applicable Minimum Bioavailability Pilo-40 Pilocarpine nitrate 40 11 mg of drug 40 ug drug is releases per hours for next seven days thin No Barrier functioning Drug release rate is less Rate of Absorption is more Extreme Flexibility Permeation Enhancers are applicable Maximum Bioavailability 48

49. Synthetic & semi-synthetic polymers offer additional advantage of simple design & easily processed Soluble synthetic polymers Such as cellulose derivatives – HPC, MC, HEC, HPMC, Na CMC Others – PVA, EVA copolymer. Additives Plasticizers – PEG, Glycerin, PG Complexing agent – PVP Bio adhesives – poly acrylic acids, methyl hydroxyl ethyl cellulose. Soluble cellulose derivative inserts are composed of 30% of water, presence of water is unfavorable from stand [point of stability of drug. Inserts can be sterilized by exposure to gamma radiation without the cellulose component being altered. 49

50. CONTACT LENS Contact lenses can be a way of providing extended release of drugs into the eye. Conventional hydrogel soft contact lenses have the ability to absorb some drugs and release them into the post lens lachrymal fluid, minimizing clearance and sorption through the conjunctiva. Their ability to be a drug reservoir strongly depends on the water content and thickness of the lens, the molecular weight of the drug, the concentration of the drug loading solution and the time the lens remains in it. 50

51. The ability of contact lens to load drugs and to control their release is in general inadequate and the following approaches, based on modifications of the polymer network, are under evaluation. Covalent binding of the drug to the lens network via labile bonds. Inclusion of the drug in colloidal structures that are dispersed in the lens and are responsible for controlling drug release. Functionalization of the network with chemical groups that work as ion-exchange resins. and Creation in the lens structure of imprinted pockets that memorize the spatial features and bonding preferences of the drug and provide the lens with a high affinity and selectivity for a given drug . 51

52. Types of contact lenses 1- Hard contact lenses Made of rigid plastic resin polymethylmethacrylate Impermeable to oxygen and moisture 2- Soft contact lenses Made of hydrophilic transparent plastic, hydroxyethylmethacrylate Contain 30 – 80% water so are permeable to oxygen Have two types: daily wear and extended wear 52

53. 3- Rigid gas permeable (RGP) -Take the advantages of both soft and hard lenses, they are hydrophobic and oxygen permeable. Advantages of hard contact lenses and RGP lenses: strength durability resistant to absorption of medications and environmental contaminants visual acurity Disadvantages: require adjustment period of the wearer more easily dislodged from the eye 53

54. Advantages of soft contact lenses : worn for longer periods Do not dislodge easily Disadvantages: Have a shorter life span and the wearer must ensure that the lenses Do not dry out 54

55. Lens Type Chemical Classification Major Characteristics Hard, Rigid, Hydrophobic PMMA ( Polymethylmethacrylate ) Negligible gas permeability Low water content Medium wettability Soft, flexible, Hydrophilic HEMA ( Hydroxylethylmethylmethacr ylate ) High water Content Iow gas permeability Good wettability Flexible, Hydrophobic Silicon vinylpyrolidone Good gas permeability Good wettability Rigid Hydrophilic CAB (Cellulose acetate butyrate) Good gas permeability Good wettability 55

56. Rinsing and storage solutions : Remove the cleaning solution, facilitate lens hydration, inactivation of microbial contamination and prevent the lens from drying out Formulation: 1. 0.9% Nacl (isotonic) 2. Antibacterial- 3% hydrogen peroxide for 30 min followed by inactivation with sodium pyruvate 3. Enzyme protein digest : For occasional cleaning followed by washing before wearing Formulation. Proteolytic enzyme: papain solution tablet to produce a solution when dissolved in water 4. Wetting solutions0.01% benzalkonium chloride + 0.1% sodium edetate . To achieve rapid wetting by the lachrymal fluid and promote comfort Facilitate insertion of the lens & provide lubrication. 5. viscosity-increasing agent ( hydroxy ethyl cellulose + wetting agent (polyvinyl alcohol) + preservatives ( benzalknonium chloride or sodium edetate + buffers and salts to adjust pH and tonicity. 56

57. 57

58. ERODIBLE INSERTS The solid inserts absorb the aqueous tear fluid and gradually erode or disintegrate. The drug is slowly leached from the hydrophilic matrix. It is Biologically Stable, Biodegradable, Biocompatible, Bio erodible. They quickly lose their solid integrity and are squeezed out of the eye with eye movement and blinking. Do not have to be removed at the end of their use. Three types : Lacriserts SODI Minidisc 58

59. LACRISERTS Sterile rod shaped device made up of hydroxyl propyl cellulose without any preservative. For the treatment of dry eye syndromes and is usually recommended for patients unable to obtain symptomatic relief with artificial tear solutions. It weighs 5 mg and measures 1.27 mm in diameter with a length of 3.5 mm. It is inserted into the inferior fornix . consists of all monolytic polymeric devices that at the end of their release, the device dissolve or erode. 59

60. Types of lacriserts : Based on natural polymers e.g. collagen. 1. synthetic or semi synthetic polymers e.g. Cellulose derivatives – Hydroxypropyl cellulose, methylcellulose or Polyvinyl alcohol, ethylene vinyl acetate copolymer. The system soften in 10-15 sec after introduction into the upper conjunctival sac, gradually dissolves within 1h, while releasing the drug. Advantage: Being entirely soluble so that they do not need to be removed from their site of application. 60

61. 2. Bioerodible polymers Hence called bioerodible inserts. They undergoes hydrolysis of chemical bonds & hence dissolution. Bio-erodible matrix controlling the release rate of the drug ensures zero order release rate. E.g. poly ( ortho esters), poly ( ortho carbonates) Great advantage of these bio-erodible polymers is the possibility of modulating their erosion rate by modifying their final structure during synthesis. 61

62. SODI Soluble ocular drug inserts. Small oval wafer. Sterile thin film of oval shape. Weighs 15-16 mg. Use – glaucoma. Advantage – Single application can replce 4-12 drops instillation & 3-6 application of ointment. The first soluble ophthalmic drug insert (SODI) developed was of soluble co -polymer of acrylamide, N- vinyl pyrrolidone & ethyl acetate. Anew type of ophthalmic insert incorporating a water-soluble bio-adhesive component in its formulation has been developed to decrease risk of expulsion & ensure prolonged residence in eye, combined with the controlled release. These inserts, named bio-adhesive ophthalmic drug inserts (BODI) 62

63. Minidisc Also known as OTS (ocular therapeutic system) Consist of contoured disc with a convex front and a concave back surface in contact with eye ball. Diameter – 4 to 5 mm. Composition Silicone based polymer-alpha-w-dis (4-methacryloxy)-butyl poly di methyl siloxane . (M2DX) M - Methyl acryloxy butyl functionalities, D - Di methyl siloxane functionalities. Sulfisoxazole , a poorly water soluble drug incorporated in a hydrophilic matrix. It release is 170h. Whereas gentamicin sulphate more than 320h Gamma irradiation & heat exposure of the system were found to slow down the drug release rates because of cross linking of polymer matrix. 63

64. Other devices are : Implantable silicone devices Developed for the local delivery of an anti-neoplastic drug to the intra-ocular site. Composed of 2 sheets of silicone rubber glued to the edge with adhesive to form a balloon like sac through which a silicone tubing (0.3 mm d) is inserted. Such devices have significant potential for local controlled delivery of anti- bacterial, anti-cancer, & anti-viral drugs to anterior chamber of eye. Ocufit is a sustained release rod shape device made up of silicone elastomer. It is designed to fit the shape and size of the human conjunctival fornix. Its diameter is 1.9mm and length is 25-30mm. New ophthalmic delivery system (NODS) - It is a method for delivering precise amounts of drugs to eye within a water soluble, drug-loaded film. When evaluated in humans, the NODS produced an 8 fold increase in BA for pilocarpine with respect to std. eye drop formulations 64

65. EVALUATION OF OCUSERTS Sr. No. Evaluation Parameters No of Units 1 Percentage of Moisture Absorption 3 2 Percentage of Moisture Loss 3 3 Thickness of Film 6 4 Weight Variation 10 5 Drug Content 3 6 In vitro drug release study 3 7 In vivo drug release study Not Fixed 8 Stability test Not Fixed 9 Sterility test Not Fixed 10 Tensile strength 3 11 Water Absorption test 3

66. Advantages And Disadvantages of Ocular Inserts Type Advantages Disadvantages Erodible inserts Effective. Flexibility in drug type & dissolution rate. Need only be introduced into eye & not removed Patient discomfort . Requiers patient insertion. Occasional Product. Non-erodible inserts Controlled rate of release. Prolonged delivery. Flexibility for type of drug selected. Sustained release. Patient discomfort. Irritation to eye. Tissue fibrosis. 66

67. Implants Implants have been widely employed to extend the release of drugs in ocular fluids and tissues particularly in the posterior segment. Implants can be broadly classified into two categories based on their degradation properties: -Biodegradable - Nonbiodegradable 67

68. PARTICULATE ( nanoparticles ) One of the conventional form containing sparingly soluble drug in a finely divided particulate form which is suspended in saturated solution of drug. These are polymeric colloidal particles, ranging from 10 - 1000 nm, in which the drug is dissolved, entrapped, encapsulated, or adsorbed. Encapsulation of the drug leads to stabilization of the drug. Material used polyalkylcyanoacrylates Polymerization is done Biodegradable polymer is used Miosis time was prolonged from 180to 240min in comparison to Pilocarpine solution e.g. khopade & jain prepared Eudragit self assembling nanoparticles of diclofenac diethylammonium & showed improved efficacy against turpentine induced inflammation. 68

69. LIPOSOMES The behavior of liposomes as an ocular drug delivery system has been observed to be, in part, due to their surface charge. Positively charged liposomes seem to be preferentially captured at the negatively charged corneal surface as compared with neutral or negatively charged liposomes. It reduced the toxicity of the drug. It provides the sustained release and site specific delivery 69

70. NIOSOMES Niosomes are bilayered structural vesicles made up of nonionic surfactant which are capable of encapsulating both lipophilic and hydrophilic compounds. It was noted that when vesicular systems were formed when a mixture of cholesterol and single alkyl chain non ionic surfactant was hydrated Niosomes reduce the systemic drainage and improve the residence time, which leads to increase ocular bioavailability. 70

71. Eye Drops Drugs which are active at eye or eye surface are widely administered in the form of Solutions, Emulsion and Suspension. Various properties of eye drops like hydrogen ion concentration, osmolality, viscosity and instilled volume can influence retention of a solution in the eye. Less than 5 % of the dose is absorbed after topical administration into the eye. The dose is mostly absorbed to the systemic blood circulation via the conjunctival and nasal blood vessels. Examples of topical eye drops: Atropine Sulphate eye drops. Pilocarpine eye drops. Silver nitrate eye drops. Zinc Sulphate eye drops. 71

72. 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 and efficacy. The major topical ophthalmic suspensions are the steroid anti- inflammatory agents. An ophthalmic suspension should use the drug in a micro fine form; usually 95% or more of the particles have Diameter of 10µm or less. Examples, Prednisolone acetate suspension. Besifloxacin suspension. Blephamide suspension. Fluorometholone . 72

73. Emulsions Topical ophthalmic emulsions generally are prepared by dissolving or dispersing the active ingredients into an oil phase, adding suitable emulsifying and suspending agents and mixing with water vigorously to form a uniform oil-in-water emulsion. Each phase is typically sterilized prior to or during charging into the mixing vessel. High-shear homogenation may be employed to reduce oil droplet size to sub-micron size which may improve the physical stability of the oil micelles so they do not coalesce. The resulting dosage form should contain small oil droplets, uniformly suspended, to prevent flocculation, creaming and coalescence of the emulsions, manufacturers commonly add surfactants to increase the kinetic stability of the emulsion so that the emulsion does not change significantly with time. 73

74. Advantages And Disadvantages of Eye Drops Dosage form Advantages Disadvantages Solutions Convenience Usually do not interfere with vision of patient. Rapid Precorneal elimination. Non sustained action. To be Administered at frequent intervals. Suspension Patient compliance. Best for drug with slow dissolution. Longer contact time Drug properties decide performance loss of both solutions and suspended particles. Irritation potential due to the particle size of the drug. Emulsion 1. Prolonged release of drug from vehicle Blurred vision. patient non compliance. 74

75. Ointment Prolongation of drug contact time with the external ocular surface can be achieved using ophthalmic ointment vehicle. The ointment base is sterilized by heat and appropriately filtered while molten to remove foreign particulate matter. Ointment base is sterilized by heat and filtered while molten to remove foreign particulate matter. It is then placed into a sterile steam jacketed to maintain the ointment in a molten state and excipients are added. The entire ointment may be passed through a previously sterilized colloid mill. 75

76. Examples Chloramphenicol ointment. Tetracycline ointment. Hydrocortisone ointment Advantages Disadvantages Longer contact time and greater storage stability. Sticking of eyes lids. Matting of eyelids Flexibility in drug choice. Blurred vision. Improved drug stability. Poor patient compliance Interfere with the attachment of new corneal epithelial cells to their normal base. 76

77. Gels Ophthalmic gels are composed of mucoadhesive polymers that provide localized delivery of an active ingredient to the eye. Such polymers have a property known as bioadhesion . These polymers are able to extend the contact time of the drug with the biological tissues and there by improve ocular bioavailability. Advantages Disadvantages Longer contact time. Blurred vision but less then ointment. Greater storage stability. Poor patient compliance. 77

78. Gel-Forming Solutions Solution that are liquid in the container and thus can be instilled as eye drops but forms gel on contact with the tear fluid and provide increased contact time with the possibility of improved drug absorption and Duration of therapeutic effect. liquid-gel phase transition-dependent delivery system vary according to the particular polymers employed and their mechanisms for triggering the Transition to a gel phase in the eye. Take the advantage of changes in temperature , pH, ion sensitivity, lysozymes upon contact with tear fluid. 78

79. Different mucoadhesive polymers were added to poloxamer Carbopol 940 Hydroxypropylmethyl cellulose (HPMC) Hydroxyethyl cellulose (HEC) 79

80. Packaging Ophthalmic ointment are packaged in : Small collapsible tin tube usually holding 3.5g of product. The pure tin tube is compatible with a wide range of drugs in petrolatum-based ointments. Aluminum tubes have been used because of their lower cost and as an alternative should the supply of tin. 80

81. Plastic tubes made from flexible LDPE resins have also been considered as an alternative material. Filled tubes may be tested for leakers. The screw cap is made of polyethylene or polypropylene. The tube can be a source of metal particles and must be cleaned carefully before sterilization (by autoclaving or ethylene oxide). 81

82. Strips Ophthalmic strips are made of filter paper and are individually packed to ensure sterility until the time of use. They can be used in the measurement of tear production in dry eye conditions. E.g. fluorescein sodium used as a diagnostic strips to visualize defects or aberrations in the corneal epithelium by staining the areas of cellular loss. 82

83. Injections While injections are considered a dosage form for nomenclature purposes, they are not treated as a dosage form in this paper. Instead, refer to the appropriate physical form, such as, suspension, etc., for general information. 83

84. EVALUATION OF OCCULAR DDS Evaluation test Eye Drops Eye Suspension Eye Ointment Organolaptic Characters Colour Odour Yes Yes Yes pH Yes Yes Yes Isotonicity Yes Yes No Viscosity Yes Yes Yes (Visco-elastic) Volume fill Yes Yes No (Minimum fill) Clearity test Yes No No (Penetration Test i.e. Consistency or Hardness test by using penetrometer) Leaker Test Yes (Mulitidose container never subjected) No (Particle size measured) No

85. Sr. no . Evaluation test Eye Drops Eye S u s p ension Eye Ointment 8 Drug Content Yes Yes Yes 9 In vitro drug release Yes Yes Yes 10 In vivo drug release Yes Yes Yes 11 Ex vivo drug release Yes Yes Yes 12 Sterility test Yes Yes Yes 13 Stability test Yes Yes Yes (R.T. 70ºF & Elevated Temp. 105º F to 120ºF) 14 Metal Test No No Yes 15 Irritant Test No No Yes 85

86. Thickness Of The Film Measured by dial caliper at different points and the mean value is calculated. Drug Content Uniformity The cast film cut at different places and tested for drug as per monograph. Uniformity Of Weight Here, three patches are weighed. IN – VITRO EVALUATION METHODS a) Bottle Method: In this, dosage forms are placed in the bottle containing dissolution medium maintained at specified temperature and pH. The bottle is then shaken. A sample of medium is taken out at appropriate intervals and analyzed for the drug content. b) Diffusion Method: Drug solution is placed in the donor compartment and buffer medium is placed in between donor and receptor compartment. Drug diffused in receptor compartment is measured at various time intervals. 86

87. c) Modified Rotating Basket Method: Dosage form is placed in a basket assembly connected to a stirrer. The assembly is lowered into a jacketed beaker containing buffer medium and temperature 37 . Samples are taken at appropriate time intervals and analyzed for drug content. d) Modified Rotating Paddle Apparatus: Here, dosage form is placed into a diffusion cell which is placed in the flask of rotating paddle apparatus. The buffer medium is placed in the flask and paddle is rotated at 50 rpm. The entire unit is maintained at 37 . Aliquots of sample are removed at appropriate time intervals and analyzed for drug content.   87

88. In- Vivo Study Here, the dosage form is applied to one eye of animals and the other eye serves as control. Then the dosage form is removed carefully at regular time interval and are analyzed for drug content. The drug remaining is subtracted from the initial drug content, which will give the amount of the drug absorbed in the eye of animal at particular time. After one week of washed period, the experiment was repeated for two time as before. 88

89. Accelerated Stability Studies These are carried out to predict the breakdown that may occur over prolonged periods of storage at normal shelf condition. Here, the dosage form is kept at elevated temperature or humidity or intensity of light, or oxygen. Then after regular intervals of time sample is taken and analyzed for drug content. From these results, graphical data treatment is plotted and shelf life and expiry date are determined 89

90. Metal Particles Test This test is required only for ophthalmic ointments It is performed using 10 ointment tubes. The content from each tube is completely removed onto a clean 60mm diameter Petri dish which possesses a flat bottom. The lid is closed and the product is heated at 85 ° C for 2 h. Once the product is melted and distributed uniformly, it is cooled to room temperature. The lid is removed after solidification. The bottom surface is then viewed through an optical microscope at 30X magnification. The viewing surface is illuminated using an external light source positioned at 45 °C on the top. 90

91. The entire bottom surface of the ointment is examined, And the number of particles 50 μm or above are counted using a calibrated eyepiece micrometer. The USP recommends that the number of such particles in 10 tubes should not exceed 50, with not more than 8 particles in any individual tube. limits are not met, the test is repeated with an additional 20 tubes. In this case, the total number of particles in 30 tubes should not exceed 150, and not more than 3 tubes are allowed to contain more than 8 particles . 91

92. Leakage test This test is mandatory for ophthalmic ointments, which evaluates the intactness of the ointment tube and its seal. Ten sealed containers are selected, and their exterior surfaces are cleaned. They are horizontally placed over absorbent blotting paper . Maintained at 60 ± 3 ° C for 8 h. The test passes if leakage is not observed from any tube. If leakage is observed, the test is repeated with an additional 20 tubes. The test passes if not more than 1 tube shows leakage out of 30 tubes . 92

93. Sterility Tests Ophthalmic semisolids should be free from anaerobic and aerobic bacteria and fungi. Sterility tests are therefore performed by the: Membrane filtration technique . Direct - inoculation techniques. 93

94. Membrane filtration method: A solution of test product (1%) is prepared in isopropyl myristate and allowed to penetrate through cellulose nitrate filter with pore size less than 0.45 μ m. If necessary, gradual suction or pressure is applied to aid filtration. The membrane is then washed three times with 100mL quantities of sterile diluting and rinsing fluid and transferred aseptically into fluid thioglycolate (FTG) and soybean – casein digest medium (SBCD) . The membrane is finally incubated for 14 days. Growth on FTG medium indicates the presence of anaerobic and aerobic bacteria. Soybean casein digest medium indicates fungi and aerobic bacteria. Absence of any growth in both these media establishes the sterility of the product 94

95. Direct - inoculation technique : 1 part of the product is diluted with 10 parts of sterile diluting and rinsing fluid with the help of an emulsifying agent Incubated in Fluid thioglycolate (FTG) and soybean-casein digest medium (SBCD) media for 14 days . In both techniques, the number of test articles is based on the batch size of the product. If the batch size is less than 200 the containers, either 5% of the containers or 2 containers (whichever is greater) are used. If the batch size is more than 200, 10 containers are used for sterility testing . 95

96. QUESTIONS Write a short note on ocular DDS ? 8m Write a short note on Liposomes & Niosomes ? 5m Write a short note on Formulation and evaluation of ocular DDS ? 10m What are the causes of poor bioavailability from conventional ophthalmic preparation ? Explain design mechanism & advantages of ocuserts ? 10m Discuss the design of controlled ocular DDS ? 5m 96

97. THANK YOU 97

98. References Ophthalmic drug delivery system by mittal , marcel dekker series NY 1992. Remington: The Science And Practice Of Pharmacy. Volume 120TH edition pg no 821-835. The Theory and Practice of Industrial Pharmacy. Leon Lachman , Herbert A.Liberman , Joseph l. Kanig . Third edition pg no 653-656. Y.W.Chein , Novel drug delivery systems, second edition, pg 269-300. Dispensing for pharmaceutical by Cooper and gunn’s pg : 634-661 Modern dispensing pharmacy : N K Jain pg : 13.3-14.9 N.K.Jain , Advances in Controlled & Novel Drug Delivery, CBS Publication, & distributor, New Delhi, pg No.219-223. S.P.Vyas Roop K.Khar ; Controlled Drug Delivery, concepts and advances, Pg No: 383-410. 98