Ocular bioavailability

Ocular Bioavailability

1. Ocular Bioavailability Prepared By Sneha Arun Chavan Department Of Pharmaceutics M Pharmacy 1 st year IInd semester 1

2. Factor Affecting Bioavailability 2

3. PHYSICOCHEMICAL FACTOR Particle size Molecular weight Concentration Solubility Lipophilicity Partition coefficient Ionization constant pH Tonicity Viscosity 3

4. Molecular weight Compound with MW > 500 Da offer poor corneal penetration, because passive diffusion does not occur . Compound with MW < 500 Da generally diffuse through membrane. Transcorneal permeability of hydrophobic drug are not govern by their molecular weight but by their lipid solubility . While hydrophilic substance govern by their MW 4

5. Particle size Drug particle deposited in eye surface are moved by eyelid at each blink, which cause an abrasion of outer epithelial layer. Also cause irritation of sensory nerve in epithelium. Irritation elicit reflex blink and reflex lacrimation . Concentration, shape, particle size together interact to determine irritation potential of suspended drug particle. Commercial suspension are formulated to contain nearly spherical particle less than 10 µm in size. 5

6. Concentration and Osmolality Tears are slightly hypertonic at about 330 mOsm. Hypertonic solutions above 400 mOsm can produce discomfort and lacrimation , increasing loss of drug. Hypotonic solutions as low as 100 mOsm are still comfortable in the eye and may improve bioavailability of water-soluble drugs through the solvent-drag effect. 6

7. Partition coefficient Measure corneal penetration efficiency of drug For hydrophilic drug (log partition coefficient < 0), the epithelium provide large % of the resistance to corneal penetration. For lipophilic drug, with log partition coefficient between 1.6-2.5, stroma contribute significant % of resistance. Drug with log partition coefficient between 0 – 1.6 the sum of stromal and endothelial resistance equal the epithelial resistance. Optimal HLB in the molecular structure of penetrant must be achieve to affect rapid penetration through the lipophilic and hydrophilic barrier of the cornea. 7

8. Ionization constant Degree of ionization influence the extent of diffusion across a membrane. The ionized form of drug is minimally lipid soluble and if this molecule is too large, the rate of corneal penetration may not be sufficient to produce therapeutic level of drug in the eye. These H enderson H asselbalch equation, determine amount of unionized drug available for transcorneal movement. Greater fraction of drug available in unionized form, the greater extent of passive diffusion. 8

9. Lipophilicity and Solubility Altering the lipophilicity and solubility of a compound can also enhance its ability to reach the target tissue. E.g., moxifloxacin , highly lipophilic, highly soluble in water. Elevated lipophilicity compared to other fluoroquinolones allows moxifloxacin to pass more easily through the corneal tissues, while the enhanced aqueous solubility increases absorption by creating a strong concentration gradient between the tear film and corneal epithelium . If drug is poorly soluble, its concentration in precorneal tear film may be limited and therefore its rate of absorption may not be high enough to achieve adequate concentration for therapeutic activity and reverse is true. 9

10. pH The average pH of tears is 7.2 and eyes can tolerate pH of 6.5-8.0 without much discomfort 0.3% w/v concentration of Ofloxacin at pH 7.2 yields a slightly turbid solution which becomes clear when pH is reduced to 6.4. Increasing the pH of the formulation to physiological pH will reduce its irritation potential. So , in order to enhance the solubility of ofloxacin at pH 7.2 , hydroxypropyl-β-cyclodextrin was employed . Cornea has an isoelectric point (pI) of 3.2 , and above this pH, cornea is negatively charged, and thus becomes selectively permeable to cations. 10

11. Cont… Ofloxacin pKa1 of 5.5 (for the carboxyl group), pKa2 of 8.0 ( for the piperazinyl group) and pI of 6.75. Thus, increasing the pH of ofloxacin solution from 6.4 to 7.2 will increase the unionized fraction of ofloxacin, which should increase its corneal permeation. But the unionized drug concentration exceeds the solubility of drug in water at pH 7.2; as a result it gives a cloudy solution. Inclusion of cyclodextrin improved the solubility of drug at pH 7.2. Cyclodextrins have earlier been reported to enhance the corneal permeation of drugs. 11

12. PHYSIOLOGICAL FACTOR Instilled Solution Drainage Instilled Volume Dilution of drug by tear turnover Protein Binding Enzymatic metabolism Non productive drug absorption Membrane Factor Blood retinal barrier Blood aqueous layer Cornea Tear Film Active ion Transport 12

13. 1. Instilled Solution Drainage Normal volume of tear 7µl. (under normal condition) If blinking doesn’t occur the human eye can accommodate 30 µl without spillage from palpebral fissure. With an estimated drop volume of 50 µl Due to overflow 70% of administered dose is expelled. If blinking occur, then the residual volume left is 10 µl. ( 90% OF DOSE IS EXPELLED ) Excess instilled either spill or rapidly drain into nasolacrimal duct with subsequent absorption into systemic circulation. Rate of drainage depend on volume of drug solution instilled and increases with increase in volume. Drainage rate 100 times faster than rate of corneal absorption rate. 13

14. Cont… Lee and Robinson gave following equation to predict drainage 14

15. 2. Instilled Volume More instilled volume of drug, more loss due to spillage or overflow thus less absorption, less bioavailability. To overcome this, Reduction in dose volume and simultaneous increase in instilled drug concentration , less drug loss thus increase in bioavailability. M ultiple dosing is more efficient when sufficient time allowed to elapsed between instillation. 3. Dilution of drug by tear turnover Normal human Tear turnover is approx. 16% per minute except during period of sleep and during anesthesia. Which is stimulated by factor drug entity, pH, tonicity of dosage form. 15

16. Cont… 4. Protein Binding Tears contain about 0.7% of protein. Its level increases during inflammation and infection. Unlike the blood, where the drug protein complex is continued to circulate, tears are replaced quickly thus removing both free and bound form of the drug. Miotic response to topically applied pilocarpine was reduced about 2 times as albumin concentration in precorneal fluid was increased from 0 – 3%. 16

17. 5. Enzymatic metabolism Occur in Precorneal space or in the cornea Reduced bioavaibility of instilled dose To overcome this, frequent dose of drug at high conc. are recommended . 6. Non productive drug absorption Upon instillation drug is absorbed into cornea and conjunctiva. Surface area of conjunctiva is about 17 times that of the cornea with 2 – 30 times greater permeability of many drug. Drug absorption in tissue other than cornea is non productive loss (systemic drug absorption). Loss can be minimized by two way : varying drug lipophilicity or changing the drug formulation. 17

18. 7. Membrane Factor Area available for absorption, thickness, porosity and tortuosity of the cornea and hydrophilic lipophilic balance. Cornea consist of three layer: Epithelial, stroma and endothelium Epithelial is lipophilic, low in porosity and high in tortuosity and thickness, a rapidly penetrating drug must possess log partition coefficient is greater than 1in order to achieve sufficient penetration rate. Stroma is acellular, hydrophilic in nature, high in porosity, low in tortuosity and it represent 90% of thickness of cornea. Endothelium and epithelium are lipophilic but, endothelium is 2.7 times more permeable than the epithelium. 18

19. Cont… Low corneal permeability (act as lipid barrier) Lipophilic agents of low molecular weight follow transcorneal transport by passive diffusion and obey Fick's first law of diffusion: J = - D . d Cm / dx J = The flux rate across the membrane D = diffusion coefficient The diffusion coefficient increases, as the molecular size of the drug decreases. Cm = concentration gradient As the drug solubility increases, the gradient increases, the driving force for drug entry into the aqueous humor increases. the drug should have dual solubility (oil and water soluble) to traverse the corneal epithelium (lipid barrier) then the aqueous humor. 19

20. 20

21. Ion transport Corneal epithelial contains ionic channel that selective for cation over anion. active transport is saturable and it's possible that once it's at full capacity, passive diffusion prevails . Also contain anion channel in apical membrane and conductive for potassium channel in basal cell. Two types of transporters that have been found to move drugs into and out of the cornea are multidrug resistance proteins (MRPs ) – Efflux Transporter and protein-coupled oligopeptide transporter (POT) superfamily .- Influx Transporter Unfortunately, corneal transporter-mediated uptake and elimination can differ greatly between species, making it more difficult to apply animal models of corneal absorption to humans 21

22. Physiological condition The tear film is also highly variable between individuals as there is up to a six fold difference in tear flow. For example, dry-eye patients, who by definition have a deficiency in the quantity and/or quality of the tear film, may experience enhanced drug absorption due to the failure of this barrier function . E ffect of a drug in normal subjects can be increased by administration after tear-film breakup. 22

23. Approaches to Improve Bioavailability Approaches to prolong the contact time of drug with corneal surface Approaches to enhance corneal permeability either by mild or transient structural alteration of corneal epithelium or by modification of chemical structure of the drug molecule 23

24. Viscosity enhancers I ncreased 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. The polymers used include polyvinyl alcohol (PVA), Polyvinylpyrrolidone (PVP), methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), and hydroxypropyl cellulose . T he retention of drug in the precorneal tear film is related to the viscosity of the vehicle, the surface spreading characteristics of the vehicle and the ability of a polymer to drag water as the vehicle spreads over the ocular surface with each blink. 24

25. Cont… E.g., Eye ointments, Gel, Polymeric Solution improving drug bioavailability and in sustaining drug release. Prolonged residence time, reduced systemic exposure . the dosing frequency can be decreased to once a day at most. blurred vision and matted eyelids, which substantially reduce patient acceptability . 25

26. Phase Transition System or In- Situ Activated Gel Forming Agent 26 Polymer like Lutrol FC – 127 and poloxamer 407 whose viscosity increases when its temperature raised to 37 ºC Cellulose acetate phthalate (CAP) coagulate when its pH of 4.5 is raised by tear fluid to pH 7.4 Low acetyl gellan gum which gel clearly in presence of sodium ion in tear. Concentration of sodium ion in tear is 2.6g/L. That cause gelation of material when topically instilled into the conjunctival sac.

27. Xanthan gum has capacity to form gel with the enzyme LYSOZYME which is present in the tear fluid. Sodium alginate:- Alginate is the block copolymer of the ß – D – mannuronic acid and alpha- d – glucoronic acid. But only the glucoronic acid content is responsible for the gelling capacity. it forms 3D gel in presence of calcium ions. Calcium linked alginate gels have good mechanical properties even if prepared from very less concentration ( i.e. 0.5 % concentration ) and they can physically entrap whole molecules and sustained release. 27

28. Cont… Recent trends in sol-gel transition (graft copolymers):- Graft copolymers are the polymers which are made up by grafting one polymer of desired characteristics. On the another one. For example, poloxamer is thermo gelling polymer which is 1st converted in to monoamine terminated poloxamer and then its amine terminated part is grafted with the hyaluronic acid. and the generated polymer is called poloxamer-g-hyaluronic acid which has dual properties means it has thermo gelling properties as well as penetration enhancing properties. Another example is poloxamer-g-c6s (c6s = chondroitoin -6 – sulphate). 28

29. Ocular Penetration Enhancers The use of substances facilitating drug penetration through the corneal to improve ophthalmic bioavailability . Penetration enhancer like actin filament inhibitor, bile salts, chelator and organic compound also used to increase bioavailability of topically applied peptides and protein. Protein is poorly absorbed due to molecular size, hydrophilicity, susceptible to degradation by an peptidase enzyme. Limitation:- cause tissue irritation and damage. 29

30. Cont… Actin cytoskeleton inhibitor (cytochalasin B) Act by disruption of actin microfilament at tight junction of corneal epithelium resulting in increase permeability at these junction. chelator EDTA bind to calcium ion present in tight junction of epithelium result in decrease in calcium ion concentration in these junction and thus decreasing the transepithelial resistance to water soluble compound. Also cause corneal damage. 30

31. Surfactant Breakdown in cohesion of epithelium by increasing the width of intercellular space Also disruption of cell cytoplasm resulting in increased permeability. The order of surfactant toxicity is: Anionic > cationic » nonionic Nonionic surfactants preferred for ophthalmic use Bile salt Sodium taurocholate (TC-Na), sodium Taurodeoxycholate (TDC-Na) etc. Loosening of tight junction of corneal epithelial barrier resulting in increased permeability TDC- Na and sodium ursodeoxycholate used as ocular permeation enhancer for atenolol and timolol. 31

32. Preservative Chlorobutanol reduces oxygen utilization in cornea result in loosened epithelial adhesion. Organomercurial (phenyl mercuric acetate, phenyl mercuric nitrate) react with membrane sulfhydryl group and alter membrane permeability and transport system Benzalkonium chloride has a high affinity for membrane proteins and can insert itself into the cellular membrane, possibly altering corneal ionic resistance.  Ion pairing salt Tetraphenylphosphonium chloride, tetraphenylarsonium chloride, trimethylphenylammonium chloride etc. Association of an drug ion with counter ion give rise to an ion pair Ion pair posses no net charge and more lipid soluble than constituent ion hence permeability is enhanced. 32

33. Prodrug chemically or enzymatically metabolized to the active parent compound. Epinephrine Prodrugs Dipivefrine, a dipivalyl prodrug-ester of epinephrine, has currently replaced epinephrine in the treatment of glaucoma. Dipivalyl epinephrine (dipivefrine) is a dipivalic acid diester of epinephrine which releases epinephrine after cornea absorption. Dipivefrine penetrates the human cornea 17 times better than epinephrine due to fact that dipivefrine is 600 times more lipophilic (at pH 7.2) than epinephrine. As compared to the conventional 2% epinephrine hydrochloride eye drop, a 0.1% dipivefrine eye drop is slightly less effective on IOP lowering effect, while side-effects are greatly reduced. 33

34. Mucoadhesive / Bioadhesive Dosage Form Cornea and conjunctival surface covers with mucin. If polymer adheres to mucin, the interaction referred as mucoadhesion. Mucoadhesive system can either be polymeric solution or microparticle suspension. They retained in cul-de-sac through adhesive bond with mucin or epithelium thus increasing corneal contact time. Water soluble polymer having short half life. Polycarbophil is an acrylic acid based polymer and able to pickup water 100 times its weight at neutral pH Mucoadhesive polymer with numerous hydrophilic functional group. Established electrostatic and hydrophobic interaction and hydrogen bonding with underlying surface. 34

35. P seudolatices New class of polymeric colloidal dispersion and film forming agent, for sustaining drug activity in vivo. What is pseudolatices ? Organic solution of polymer is disperse in an aqueous phase to form O/W emulsion subsequently using appropriate means, i.e., by applying vacuum or by using controlled temperature. Water is removed partially to an extent that residual water is sufficient enough to keep polymeric phase discrete and dispersed, such dispersion is called pseudolatices. Which on application leave an intact non invasive continuous polymeric film which reserve the drug. Drug from such system release slowly over prolonged period of time. Ensuring better ocular bioavailability. Patient compliance by avoiding frequent instillation of preparation. 35

36. Collagen shields Collagen (protein) that promote wound healing. Deliver variety of medicament to cornea and other ocular tissue. Bloomfeild and coworker first suggest the use of collagen insert as tear substitute and as delivery system for gentamycin. Collagen corneal bandage in shape of contact lens as an alternative to soft contact lens to protect the healing of corneal epithelium after surgery. For drug delivery, the shield (package in sterile, dehydrated form) are rehydrated in a water solution of the drug, whereby the drug is absorbed by the protein matrix and released once the shield dissolve in the eye. 36

37. Cont… Drawback Application of shield require to anaesthetize the cornea and produce some discomfort and interfere with vision. A new preparation referred to as COLLASOMES consist of small pieces (1mm×2mm × 0.1mm) of collagen suspended in 1% methylcellulose vehicle. It has same therapeutic advantage as that of shields. Shields disadvantage are circumvented. Marketed products:- 1) Medi lens ® ( Chiron, irvine , ca) 2) Pro shield® ( alcon , fortworth , tx ) 37

38. Novel Drug Delivery System Liposome Niosome Microemulsion Nanosuspension Cyclodextrin Discomes Microneedle 38

39. DISCOMES Disc shaped niosomes are known as discomes . large size may prevent their drainage into the systemic pool. Furthermore, their ‘‘disc’’ shape provides for a better fit in the cul-de-sac of the eye. USE OF CYCLODEXTRIN hydrophilic cyclodextrins act as true carriers by keeping the lipophilic water-insoluble drug molecules in solution and delivering them to the membrane surface where they partition from the cyclodextrin cavity into the lipophilic membrane. 39

40. 40

41. M icroneedle Deliver the drug to back of eye tissue in minimally non invasive manner. May reduce the risk and complication associated with IVT injection such as retinal detachment, cataract, hemorrhage, endophthalmitis. Circumvent BRB and provide efficient treatment strategy for age related macular degeneration (AMD), diabetic retinopathy and posterior uveitis. These are penetrate into the sclera or subarchoroidal space (SCS), the region between sclera and choroid Also used for anterior segment of ocular drug delivery. 41

42. Cont… Sclera is static barrier to microneedle. After microneedle scleral penetration, surface coated drug rapidly accumulated in the microneedle penetration region, forming depot. This depot formation increase bioavailability. Carrier system if placed near the back of eye tissue (i.e., in SCS) can deliver high drug concentration to the retina choroid. 42

43. Micro Emulsions w/o Micro emulsions offer a promising alternative. They are thermodynamically stable and optically isotropic colloidal systems with excellent wetting and spreading properties Moreover, they are comprised of aqueous and oily components and therefore can accommodate both hydrophilic as well as lipophilic drugs. w/o micro emulsions where administered in the eye; converted into the LC state which releases the drug slowly and produce a sustained release preparation for eye. Cationic emulsions:- They are developed by the Novagali pharmaceuticals for ophthalmic applications. The topical administration of a cationic emulsion onto the eye has shown to increase the residence time of the drug on the cornea, with a lower contact angle and an increased spreading coefficient in comparison with conventional eye drops and anionic emulsions. 43

44. 44

45. 45

46. Matrix Type Of DDS Hydrophilic soft contact lens Made up of hydrogel that absorb aqueous solution Drug delivery to anterior segment of the eye. E.g., polymixin B, pilocarpine, antiviral idoxuridine Soluble ocular insert Such as polyvinyl alcohol insert (PVAI) soluble opthalamic drug insert (SODI) Thin, elastic and oval shaped plates are impregnated with drug (antibiotics, pilocarpine, atropine etc.) After insertion into conjunctival sac, absorb tear and swells, dissolve in about 30 – 90 min Difficulty of self insertion, but free the patient from task of removing the device. Controlled release, enhanced drug absorption, enhanced BIOAVAILABILITY 46

47. Scleral Buckling Material Used in retinal detachment surgery. Cause pre and postoperative infection Common scleral buckling material, gelatine film and solid silicone rubber impregnated with antibiotics, and biological activity evaluated using agar plate method. Sustain release of drug help to cure infection. Novel Metered Delivery System Another novel metered delivery system in development is a small-volume nebulizer that delivers a mist to the eye.  In a clinical study, the nebulizer system produced a significantly higher bioavailability of vitamin B12 than standard topical delivery 47

48. 48

49. The New Opthalamic Delivery System (Nods) Drug-incorporated-water soluble polyvinyl alcohol film Each NODS consists of a drug loaded film or (flag) attached to a handle by means of thin membrane On contact with the tear film in the lower conjunctival sac the membrane-quickly dissolves-releases the flag into the tear film Flag-hydrates-disperses allowing diffusion and absorption of the drug Handle provided with paper backing for strength Both soluble drugs such as pilocarpine and insoluble drugs such as tropicamide can be formulated into the NODS NODS containing 40,80 and 170 μg pilocarpine nitrate showed eight fold increase in bioavailability compared with a standard 2% eye drops 49

50. Intravitreal Injections/Implants Two antivirals have been approved for treatment of the ocular sequelae of AIDS with direct emplacement in the vitreous cavity so as to provide high localized ocular therapeutic concentrations. A polymer-coated sterile tablet containing ganciclovir , called a Vitrasert,47 is implanted by the surgeon in the vitreous cavity , where it releases drug over a period of several months and then is removed and replaced with a new tablet. The tablet is formulated with magnesium stearate as the drug carrier and coated with polymers that provide the prolonged drug release. during handling, this polymer coating is not damaged and the special sterile packaging not be compromised. A sterile solution of fomivirsen is also available for intravitreal injection to treat cytomegalovirus retinitis. It is supplied in single-use vials and is injected intravitreal without requiring surgery but must be repeated every 2 to 4 weeks. 50

51. CHEMICAL APPROACHES FOR OCULAR DRUG DELIVERY A) CHEMICAL DRUG DELIVERY SYSTEM A chemical delivery system (CDS), is an inactive species obtained by chemical modifications of the active agent based on metabolic considerations. Conceptually, a CDS upon its administration will undergo several predictable enzymatic transformations via inactive intermediates and finally deliver the active species to the target site. B) SOFT DRUG APPROACH:- It Produce the desired pharmacological activity at the site of application but at other sites do not show any action even though the same receptor is present. 51

52. 52

53. IONTOPHORESIS noninvasive nature of delivery to both anterior and posterior segment . Transferring ionized drugs through membranes with low electrical current . The drugs are moved across the membranes by two mechanisms: migration and electro-osmosis. Ocular iontophoresis is classified into transcorneal, corneoscleral, or trans-scleral iontophoresis, The sclera has larger surface area than the cornea ( about 17 cm2 vs 1.3 cm2), high degree of hydration, low number of cells, and it is permeable to large molecular weight compounds. noninvasive method, easy to use, less risk of toxicity, a broad applicability to deliver a broad range of drugs or genes to treat several ophthalmic diseases in the posterior segment of the eye, and good acceptance by patients. 53

54. Disadvantage no sustained half-life, requires repeated administrations, side effects include mild pain in some cases, but no risk of infections or ulcerations , risk of low patient compliance because the frequent administrations that may be needed. OcuPhor™ system has been designed with an applicator, dispersive electrode , and a dose controller for trans scleral iontophoresis (DDT). This device releases the active drug into retina-choroid as well . A similar device has been designed called Visulex ™ to allow selective transport of ionized molecules through sclera. Examples of antibiotics successfully employed are gentamicin, tobramycin, ciprofloxacin and steroid. 54

55. REFERENCE Remington Essential of Pharmaceutics, edited by Linda Felton, page no. 545 - 562 Ophthalmic Drug Delivery System: Challenges and Approaches Patel PB, Shastri DH, Shelat PK, Shukla AK Systematic Reviews in Pharmacy | July-December 2010 | Vol 1 | Issue 2 Progress and Problems in Ophthalmic Drug Delivery, a report by Professor Marco Fabrizio Saettone Ocular drug delivery, Aswani Dutt Vadlapudi, Kishore Cholkar, supriya Reddy Desari, and Ashim K. Mitra https:// www.reviewofophthalmology.com/article/the-secret-world-of-pharmacokinetics Indian Journal of experimental of biology Vol. 39, January 2001, pp 11-24 Review Article, Permeation through Cornea, by Majusha Malhotra and D. K. Mujumdar 55