barriers and routes of occular drug delivery system.pptx

barriers and routes of occular drug delivery system.pptx

1. BARRIERS AND ROUTES OF OCCULAR DRUG DELIVERY SYSTEM….. 1

2. INTRODUCTION Ocular administration of drug is primarily associated with the need to treat ophthalmic diseases. Eye is the most easily accessible site for topical administration of a medication. Ideal ophthalmic drug delivery must be able to sustain the drug release and to remain in the vicinity of front of the eye for prolong period of time. 2

3. Anatomy of an eye 3 3

4. BARRIER’S OF OCCULAR DRUG DELIVERY SYSTEM…… These barriers can be broadly classified as • Anatomical barriers • Physiological barriers • Blood-ocular barriers 4

5. ANATOMICAL BARRIER… When a dosage form is topically administered there are two routes of entry, either through the cornea or via the non corneal route. • The cornea is a very tight multi-layered tissue that is mainly composed of five sections: epithelium, bowman’s membrane stroma, descemet’s membrane and endothelium. 5

6. CORNIAL CROSS SECTION 6

7. Out of these it’s the epithelium which acts as the principal barrier.. • It acts as a major barrier to hydrophilic drug transport through intercellular spaces. • On the other hand stroma , which consists of multiple layers of hexagonally arranged collagen fibers containing aqueous pores or channels allow hydrophilic drugs to easily pass through but it acts as a significant barrier for lipophilic drugs. Thus for a drug to have optimum bioavailability, it should have the right balance between lipophilicity and hydrophilicity. The remaining layers are leaky and do not act as significant barriers 7

8. Non-corneal route by passes the cornea and involves movement across conjunctiva and sclera. This route is important especially for large and hydrophilic molecules such as peptides, proteins and si RNA (small or short interfering RNA). The conjunctiva is more permeable than cornea especially for hydrophilic molecules due to much lower expression of tight junction proteins relative to corneal epithelium. 8

9. PHYSIOLOGICAL BARRIERS….. The eye’s primary line of defence is its tear film. • Bioavailability of topically administered drugs is further reduced by precorneal factors such as solution drainage , tear dilution, tear turnover, and increased lacrimation. • The lacrimal fluid is an isotonic aqueous solution containing a mixture of proteins (such as lysozyme) as well as lipids. 9

10. Rapid clearance from the precorneal area by lacrimation and through nasolacrimal drainage and spillage further reduces contact time between the tissue and drug molecules. •This in turn lowers the exact time for absorption leading to reduced bioavailability. • The average tear volume is 7-9 μL with a turnover rate of 16% per minute • Thus drugs administered as eye drops need to be isotonic and non Irritating to prevent significant precorneal loss. 10

11. BLOOD – OCCULAR BARRIERS… The blood-ocular barrier normally keeps most drugs out of the eye. However, inflammation breaks down this barrier allowing drugs and large molecules to penetrate into the eye. • Blood-aqueous barrier : It is formed by non pigmented ciliary epithelial cells of ciliary body and endothelial cells of blood vessels in iris. Blood-retinal barrier : Non-fenestrated capillaries of the retinal circulation and tight-junctions between retinal epithelial cells preventing passage of large molecules from chorio-capillaris into the retina. 11

12. BARRIER……. 12 12

13. ROUTES FOR OCCULAR DRUGS….. 13 13

14. ROUTES OF OCCULAR DRUG DELIVERY There are 3 different routes for drug delivery through ocular route are…. Instillation into the conjunctival sac / Topical route Periocular injection / Novel routes Intraocular injection 14

15. INSTILLATION INTO CONJUNCTIVAL SAC…. These are sub divided into Eye drops Ointments Gels Occuserts Soft contact lenses 15

16. PERIOCULAR INJECTION / NOVEL ROUTES……. The different periocular injection are….. Intravitreal injection Sub conjunctival injection Sub tenon injection Retobulbar injection Peribulbar injection 16

17. Intravitreal injection…. Intravitreal injection (IVI) involves delivering of the drug formulation directly into the vitreous humor through pars plana. • This method provides direct access to the vitreous and avoids both the cornea and also the scleral blood vessels. • Formulations such as solution, suspension or a depot formulation can be administered through this route. Mainly given to treat diabetic retinopathy . • IVI administration is associated with adverse effects such as retinal detachment, cataract,etc. 17

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20. Subconjunctival injections…. This injection delivers the drug beneath the conjunctival membrane that lines the inner surface of eyelid. It allows for circumvention of both cornea and conjunctiva allowing the drug direct access to the sclera. • It is much less invasive with lesser side effects when compared to intravitreal injections. • The method is an excellent route for delivering hydrophilic drugs as it bypasses their rate-limiting barriers allowing more drugs to enter into the vitreous. 20

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22. Retrobulbar and peribulbar route Retrobulbar injection is given through eyelid and orbital fascia and it places the drug into retrobulbar space. • This mode administers the drug to the back of the eye ball and is used to deliver drugs such as antibiotics and corticosteroids. • This route is especially applicable for the delivery of anesthetic agents as it causes minor or no change in IOP( intra ocular pressure) though in certain orbital diseases the reverse is also possible. • Yet, it is a very delicate procedure as it may damage the optic nerve and thus requires proper expertise and equipment. 22

23. RETROBULBUR ROUTE 22

24. Peribulbar route……. Peribulbar route : Peribulbar route for drug delivery involves injections above and/or below the globe. It is also a viable route for the delivery of aesthesia especially in cases of cataract surgery, It is a safer route compared to the retrobulbar route with reduced risk of injury. Though it a safer method unlike retrobulbar injection multiple cases of elevated intraocular pressure after peribulbar injections have been reported. 24

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26. Sub- tenon injections…… Sub- tenon injections are administered into a cavity between tenon’s capsule and sclera using a blunt cannula. • Sub- tenon route appears to be a better and safer route for delivering anesthesia relative to retrobulbar and peribulbar administration since it does not require sharp needles. • Steroids injected through this route have also been shown to be effective in the treatment of uveitis, cystoid macular edema. 26

27. SUB - TENON INJECTION 27

28. INTRAOCULAR INJECTION INTRACAMERAL INJECTION : • Intracameral route is similar to intravitreal injections but this injection delivers drug to the anterior chamber . • Drugs administered through this route are limited to anterior chamber with very limited access to the posterior segment. • It is generally employed for anterior segment procedures such as cataract surgery. 28

29. Intracameral route 29

30. Methods to overcome Barriers….. 30 31

31. Bioavailability improvement…. 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 transcorneal 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, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), and hydroxypropyl cellulose. 31

32. B) 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 esterase, ketone reductase, and steroid 6-hydroxylase . 32

33. Some examples of suitable prodrug include the antiviral medications ganciclovir and acyclovir. 33

34. C) 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 par cellular 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 34

35. Controlled and Continuous ocular drug delivery INSERTS CLASSIFICATION : 1 . NON ERODIBLE INSERTS i. Ocusert ii. Contact lens 2 . ERODIBLE INSERTS i. Lacriserts ii. SODI iii. Mindisc 35

36. 1) NON ERODIBLE INSERTS The Ocusert therapeutic system is a flat, flexible, elliptical device designed to be placed in the inferior cul-de-sac between the sclera and the eyelid and to release Pilocarpine continuously at a steady rate for 7 days. Mainly used for treatment of glaucoma . 36

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38. 2) ERODIBLE INSERTS: The solid inserts absorb the aqueous tear fluid and gradually erode or disintegrate. The drug is slowly leached from the hydrophilic matrix. Three types : 1.LACRISERTS 2.SODI 3.MINIDISC 38

39. LACRISERTS: Sterile rod shaped device made up of propyl cellulose without any preservative. For the treatment of dry eye syndromes 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 39

40. SODI SODI: Soluble ocular drug inserts Small oval wafer Sterile thin film of oval shaped of polyacrylamide incorporating drug . SODI of pilocarpine and tetracycline Weighs 15-16 mg Use – glaucoma 40

41. MINIDISC: Countered disc with a convex front and a concave back surface •Diameter – 4 to 5 mm Composition : silicon based polymer Drug release about 170 hrs 41

42. INPLANTS 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: (1) Biodegradable (2) Non biodegradable 42

43. NANOPARTICLE….. •These are polymeric colloidal particles, ranging from 10 nm to 1000 nm, in which the drug is dissolved, entrapped, encapsulated, or adsorbed. •Encapsulation of the drug leads to stabilization of the drug. 43

44. LIPOSOMES…….. The behaviour 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. 44

45. NIOSOMES…. Noisome are bilayered structural vesicles made up of non-ionic 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 45

46. TRANSPORTERS IN EYE The human eye is a complex organ that requires a constant supply of nutrients and oxygen to function properly. This essential task is carried out by a variety of transporters, specialized proteins embedded in the cell membranes that facilitate the movement of molecules across them. 46

47. Major Types of Transporters in the Eye Ion Channels: These proteins create pores in the membrane, allowing specific ions (like sodium, potassium, calcium, and chloride) to pass through. This is crucial for maintaining the electrical balance and signaling within eye cells. Solute Carriers: These transporters use energy (often in the form of ATP) to move molecules across the membrane, often against their concentration gradient. They are involved in transporting a wide range of substances, including glucose, amino acids, and neurotransmitters. Aquaporins: These are specialized channels that allow water to pass through the membrane. They play a vital role in regulating fluid balance in the eye, especially in the aqueous humor and vitreous. 47

48. Key Roles of Transporters in the Eye Nutrient Delivery: Transporters ensure a steady supply of glucose, amino acids, and other essential nutrients to the various cell types of the eye. This is particularly important for the highly metabolically active cells of the retina and lens. Waste Removal: Transporters also help remove metabolic waste products, such as lactate and carbon dioxide, from the eye tissues. This prevents the buildup of toxic substances that could impair vision. Maintaining Intraocular Pressure: Transporters play a crucial role in regulating the balance of fluids within the eye, which is essential for maintaining a healthy intraocular pressure. Visual Signal Transduction: Transporters are involved in the complex processes of phototransduction, the conversion of light into electrical signals in the retina. 48

49. Utilizing Transporters for Enhanced Drug Delivery to the Eye 1. Drug Conjugation: Attaching drugs to transporter substrates: By chemically linking drugs to molecules that are recognized by specific transporters, we can "hitchhike" on these transporters to deliver the drug to its target cells. Example: Conjugating drugs to glucose can leverage the glucose transporter system to deliver them to retinal cells. 2. Modulating Transporter Activity: Enhancing transporter expression: Increasing the number of transporters in the eye can facilitate drug uptake. This can be achieved through gene therapy or by using small molecules that stimulate transporter expression. Inhibiting competing transporters: If other transporters interfere with drug delivery, inhibiting their activity can improve drug uptake by the desired transporter. 49

50. Utilizing Transporters for Enhanced Drug Delivery to the Eye 3. Designing Transporter-Targeted Drug Delivery Systems: Nanoparticle-based delivery: Nanoparticles can be engineered to interact with specific transporters, allowing for targeted drug delivery. Examples: Nanoparticles coated with ligands that bind to specific transporters can be used to deliver drugs to the retina or anterior segment of the eye. 4. Overcoming Transporter-Mediated Efflux: Inhibiting efflux pumps: Some transporters, known as efflux pumps, can remove drugs from cells. Inhibiting these pumps can enhance drug retention in the eye. Example: Using inhibitors of P-glycoprotein, a common efflux pump, can improve the bioavailability of certain eye drugs. 50

51. Utilizing Transporters for Enhanced Drug Delivery to the Eye Personalized Drug Delivery: Genomic analysis: By analyzing a patient's genetic makeup, we can identify variations in transporter genes that may affect drug response. This information can be used to tailor drug delivery strategies. Example: Patients with genetic variations in the glucose transporter system may require different drug formulations or dosages. 51

52. Amino Acid Transporters in the Eye: Crucial for Protein Synthesis and Cellular Function Amino acids are the building blocks of proteins, which are essential for various cellular functions in the eye, including: Protein synthesis: For the formation of structural proteins, enzymes, and signaling molecules. Energy metabolism: As a source of energy through the citric acid cycle. Neurotransmitter synthesis: For the production of neurotransmitters involved in vision and eye movements. 52

53. Roles of Amino Acid Transporters in the Eye Nutrient Supply: Amino acid transporters ensure a steady supply of amino acids to the various cell types of the eye, supporting protein synthesis and other essential functions. Neurotransmitter Synthesis: In the retina, amino acid transporters are involved in the synthesis of neurotransmitters, such as glutamate and GABA, which are crucial for visual signal transduction. Energy Metabolism: Amino acids can be catabolized for energy production, and transporters play a role in supplying these amino acids to the mitochondria. Regulation of Intraocular Pressure: Amino acid transporters may also be involved in regulating fluid balance in the eye, which is important for maintaining intraocular pressure. 53

54. Challenges and Future Directions: While these strategies hold promise, several challenges remain. These include: Off-target effects: Drugs delivered via transporters may also be taken up by cells outside the eye, leading to side effects. Drug resistance: Over time, cells may develop resistance to transporter-mediated drug delivery. Cost and complexity: Developing and implementing transporter-targeted drug delivery systems can be expensive and complex. 54

55. REFERENCES…. Bio pharmaceutics and Pharmacokinetics, Brahmankar and jaiswal,1 st edt . Novel drug delivery system, Y.W.Chien, 2 nd edt. Controlled and novel drug delivery, N.k.Jain,1 st edition World J Pharmacol 2013 December 9; 2(4): 78-83 ISSN 2220-3192 (online)© 2013 Baishideng Publishing Group Co., Limited. All rights reservedWJP | www . 55

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