Ophthalmic Dosage Form Development: From Benchtop to Clinic

Transcription

1 1 Ophthalmic Dosage Form Development: From Benchtop to Clinic

2 2 There s More to Topical Formulations Than Putting an Active into Solution

3 Overall Goal Achieving effective drug concentration at the target tissue for the appropriate duration of effect All while... Maintaining tissue specificity Minimizing toxicity and side effects Ensuring comfort and tolerability and ease of use for patients Maintaining potency and stability of active ingredient Preventing contamination 4

4 Advantages of Topical versus Systemic Ophthalmic Drug Delivery vs Eyedrops allow therapeutic concentrations of drug to be achieved selectively in aqueous humor/ocular tissues Topical administration effective for molecules with poor ocular uptake or poor efficacy-to-safety ratio when given systemically Less incidental exposure of drug to nontarget tissues = fewer systemic AEs 5

5 Disadvantages of Topical Drug Delivery Major formulation challenge: poor bioavailability Short ocular surface retention time At least 75% loss via nasolacrimal drainage Dilution of applied dose through lacrimation (lower driving force for corneal penetration) Protein binding and conjunctival absorption Requires frequent (at least once daily) dosing for extended periods Typical ocular bioavailability is only a few percent 6

6 Factors Affecting Bioavailability/Short Ocular Retention Time Blinking Reflex lacrimation Nasolacrimal drainage Gravity 7

7 Factors Affecting Bioavailability: Corneal Barriers Low corneal permeability LogP of compounds should be optimized Anatomy of the cornea (Image used with permission. Source: Ghate and Edelhauser 2008) Superficial absorption of drug into conjunctiva and sclera and rapid removal by peripheral blood flow 8

8 Factors Affecting Drug Bioavailability In general: Transport of hydrophilic and macromolecular drugs occurs through scleral route Compounds that can permeate the cornea, liophlic small molecules, penetrate into the aqueous humor via Fickian diffusion: J = - D. d C m /dx dc/dt = ADΓ/h (C t -C a ) Drug needs dual solubility (oil and water soluble) to traverse the corneal epithelium (lipid barrier) then the aqueous humour 9

9 P app (x10-6 cm/sec) Drug Lipophilicity and RCECL Permeability Solubility Issue? Log P

10 Other Formulation Challenges Need to stabilize active ingredients and formulation Necessity of using preservatives Suboptimal compliance Many contributing factors including poor patient dexterity with squeezing bottle and instilling the drop into the eye correctly 11

11 Target Product Characteristics Adequate corneal penetration 1-3 Sufficient precorneal retention and optimal viscosity 1-3 Nonirritating and comfortable 2 Minimal systemic absorption 1-3 Ease of administration 1,3 Sterile dosage formula Ghate and Edelhauser. J Glaucoma. 2008;17(2): Novack. Pharmacol Ther May;85(5): Janoria et al. Recent Pat Drug Deliv Formul. 2007;1(2): Kaufman and Novack. Ocul Surf Apr;1(2):80-5.

12 Key Components Active ingredient(s) Vehicle Inactive ingredients: Tonicity adjustment Buffer and adjust ph Anti-oxidants Solubilizers Suspending agents and viscosifiers Prevent microbial contamination 13

13 Stability of Active Ingredient Degradation of active ingredient, due to excessive heat, light exposure, or contamination, can compromise efficacy 1-3 For example, bimatoprost is more stable than other PGAs; differs with respect to: Stable at room temperature (refrigeration not required) Not sensitive to light or air exposure (storage in colored bottle or lightproof, airtight foil pouch not required) Cantor. Expert Opin Pharmacother. 2002;3(12): Paolera et al. BMC Ophthalmol. 2008;8: Johnson et al. J Ocul Pharmacol Ther. 2011;27(1):51-59.

14 Role of Preservatives Antimicrobial preservatives are necessary for most multidose preparations to prevent contamination of the product 1,2 Bottle tips often inadvertently touch the skin and ocular surface during drop application, which can lead to contamination 1 Preservatives prevent the growth of bacteria, yeast, and mold Help to prevent contamination of the bottle contents over the course of multiple uses By preventing contamination, preservatives may help ensure product stability 1 Preservatives must meet USP and EP antimicrobial preservative efficacy requirements to meet global regulatory requirements Samalonis. Rev Ophthalmol. 2006:13(9): US Pharmacopeia. April 2007.

15 Preservatives in Ophthalmic Formulations Commonly Used Benzalkonium chloride (BAK or BAC) PURITE (stabilized oxychloro complex) Polyquad (polyquaternium-1) Sodium perborate sofzia Polyhexamethylene biguanide (PHMB) OPHTHALMIC PRESERVATIVES Historically Used Sorbic acid Thiomersal Benzododecinium bromide Chlorobutanol/phenylethanol Parabens Phenylmercuric acetate or nitrate Preservatives differ in their mechanism of action, antimicrobial specificities, and safety profiles BAK is the most commonly used ophthalmic preservative and is used in 72% of ophthalmic solutions 1, Abelson and Fink. Rev Ophthalmol. 2002;9(12): Noecker. Adv Ther. 2001;18(5):

16 Little Relationship Between Type of Preservative and Tolerability Three-month clinical trial results show no difference in tolerability or AEs between BAK-preserved and sofzia preserved PGA 1 Travoprost preserved with Polyquad found to have similar safety and efficacy as BAK-preserved travoprost 2 Daily dose of BAK (ie, number of drops/day) is predictive of ocular surface disease, but only when the dose exceeds 2 drops per day Lewis et al. J Glaucoma. 2007;16(1): Gandolfi et al. Eur J Ophthalmol. 2012;22(1): Skalicky et al. Am J Ophthalmol.2012;153:1-9.

17 Tonicity and Tonicity-Adjusting Agents Tonicity of an ophthalmic solution needs to be adjusted so that it Exerts an osmotic pressure equal to that of tear fluids (roughly equivalent to 0.9% NaCl ideally) Some ophthalmic solutions are necessarily hypotonic to enhance absorption and provide concentration of active ingredient sufficient to achieve efficacy Hypotonic solutions are better tolerated than hypertonic solutions 1 Common tonicity-adjusting ingredients include: NaCl, Cl, buffer salts, dextrose, glycerin, propylene glycol, and d-mannitol Propylene glycol Glycerin D-mannitol Dextrose Ghate and Edelhauser. J Glaucoma. 2008;17(2):

18 ph Critical for Topical Ophthalmics ph adjustment is an important step in formulation: Influences the comfort and tolerability of the drug product Affects bioavailability Optimizes solubility and permeability Minimizes lacrimation and tear dilution/ drainage of active Provides stability for the active Buffer capacity greatly affects ph tolerability 21

19 ph Adjustment and Buffers Normal tears have a ph of 7.4 and possess some buffer capacity ph should be chosen to optimize stability and permeability (bioavailability, especially important for ionizable drugs) Where ph deviates from 7.4 it is important to be aware of buffer capacity to minimize lacrimation and irritation 22

20 Antioxidants Antioxidants are commonly added to topical ophthalmics to mitigate oxidation issues: Epinephrine solutions are the classic example Sodium bisulfite or metabisulfite is used in concentrations up to 0.3% in epinephrine hydrochloride and bitartrate solutions Several antioxidant systems have been developed Consist of ascorbic acid and acetyl-cysteine and sodium thiosulfate 24 Modern Pharmaceutics 4 th ed 2006

21 Surfactants Several nonionic surfactants are used in relatively low concentrations to: Aid in dispersing steroids in suspensions To achieve drug solubility or to improve solution clarity Polysorbate, tyloxapol, polyoxyl 40 stearate The order of surfactant toxicity is: Anionic > cationic» nonionic Nonionic surfactants preferred for ophthalmic use 25 Modern Pharmaceutics 4 th ed 2006

22 Viscosifiers Viscosity-imparting agents are commonly used to increase the viscosity of ophthalmic solutions and suspensions Improve suspension stability Increase precorneal residence time by decreasing drainage rate and increasing mucoadhesiveness, resulting in potentially increased drug bioavailability Act as a demulcent (protects ocular surface and relieves dryness/irritation) Provide lubrication of the corneal surface Commonly used viscosifiers include: polyvinyl alcohol, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, and carbomers 26

23 Viscosity-Imparting Agents Potential disadvantages Can produce blurring of vision, dry-film formation, and crusting on the bottle tip Makes sterile filtration more difficult in the manufacturing process Some polymers interact with commonly used preservatives; eg, CMC may precipitate BAK 27

24 28 Brimonidine Tartrate: Effect of ph

25 Formulation Evolution and Optimization: Effect of ph Ingredient Function (%w/v) Brimonidine 0.2% BAK Brimonidine 0.2% Purite Brimonidine 0.2% PF Active Agent Brimonidine tartrate (0.2%) Brimonidine tartrate (0.2%) Brimonidine tartrate (0.2%) Preservative BAK PURITE N/A Viscosity Agent Polyvinyl alcohol Polyvinyl alcohol Polyvinyl alcohol Formulation ph JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 18, Number 4,

26 Brimonidine: Effect of ph Brimonidine % Free Base or Salt Form vs. ph % Free Base % Salt Form % (relative) According to the Henderson Hasselbalch equation: pka ph = log ([salt form]/[free base form]) Brimonidine tartrate pka = 7.8 ph 30

27 Brimonidine: Effect of ph OH HN N NH 2 + Br -OOC N OH COOH pka = 7.8 HN N NH Br N N N Brimonidine Tartrate (salt form) ph 6.4: 96.2% ph 7.2: 80% Brimonidine (non-ionized form) 3.8% 20% 31

28 BRIMONIDINE TARTRATE 0.2%: PK Study on Effect of ph on Aqueous Drug Levels Comparison of brimonidine aqueous humor AUC0 4hr for 0.2% Brimonidine-Purite, 0.2%Alphagan and 0.2% Brimonidine-PF formulations in rabbits 32

29 Summary and Conclusions Formulating topical glaucoma medications is complex and requires extensive development studies to ensure an optimized product meets all requirements Always the challenge is to maximize efficacy while minimizing adverse events and tolerability issues All products are subject to rigorous regulatory review and approval processes Wide-ranging expertise and experience required for optimal results 33