1 - Rajiv Gandhi University of Health Sciences



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|6. |BRIEF RESUME OF THE INTENDED WORK |

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| |ENCLOSURE - I |

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| |6.1 NEED FOR THE STUDY |

| |The human eye is a challenging subject for topical administration of drugs. The basis of this can be found in the anatomical arrangement of the surface|

| |tissues and in the permeability of the cornea. The protective operation of the eyelids and lacrimal system is such there is rapid removal of material |

| |instilled into the eye, unless the material is suitably small in volume and chemically and physiologically compatible with surface tissue.¹ Ophthalmic |

| |preparations are sterile liquid, semi-solid or solid preparations intended for administration upon the eyeball and to the conjunctiva or for insertion |

| |in the conjunctival sac.² |

| | |

| |These products may be administered topically (in the form of solutions, suspensions, emulsions, lotions, creams, ointments and gels) or by sub |

| |conjunctival or intraocular (e.g., intravitreal and intracameral) injection³. The sterility of these products, as well as accuracy in the calculation |

| |and preparation of doses is of great importance. It is estimated that only one-tenth of a dose penetrates into the eye. Unless the active ingredient |

| |itself has antimicrobial activity, ophthalmic preparations supplied as multi dose preparations may include a suitable antimicrobial agent. The |

| |antimicrobial activity should remain effective throughout the entire period of use.⁴ |

| | |

| |Pharmaceutical Importance of Sterilization |

| |• Moist heat sterilization is the most efficient biocidal agent. In the pharmaceutical industry it is used for Surgical dressings, Sheets, Surgical and|

| |Diagnostic equipment, Containers, Closures, Aqueous injections, Ophthalmic preparations and Irrigation fluids etc. |

| |• Dry heat sterilization can only be used for thermo stable, moisture sensitive or moisture impermeable pharmaceutical and medicinal. These include |

| |products like; Dry powdered drugs, Suspensions of drug in nonaqueous solvents, Oils, fats waxes, soft hard paraffin silicone, Oily injections, |

| |implants, ophthalmic ointments and ointment bases etc. |

| | |

| |• Gaseous sterilization is used for sterilizing thermolabile substances like; hormones, proteins, various heat sensitive drugs etc. |

| |• U.V light is perhaps the most lethal component in ordinary sunlight used in sanitation of garments or utensils. |

| |• Gamma-rays from Cobalt 60 are used to sterilize antibiotic, hormones, sutures, plastics and catheters etc. |

| |• Filtration sterilizations are used in the treatment of heat sensitive injections and ophthalmic |

| |solutions, biological products, air and other gases for supply to aseptic areas. They are also used in |

| |industry as part of the venting systems on fermentors, centrifuges, autoclaves and freeze driers. |

| |The different categories of ophthalmic preparations include drops consisting of emulsions, solutions or suspensions, and ointments. |

| |The sterilization is the essential process for the preparation of ophthalmic products. |

| |ANTI-INFAMMATORY DRUGS:- A drug which inhibits or suppresses most inflammatory responses of an allergic, bacterial, traumatic or anaphylactic origin, |

| |as well as being immunosuppressant. They include the corticosteroids (e.g. betamethasone, dexamethasone, fluorometholone, hydrocortisone acetate, |

| |loteprednol etabonate, prednisolone, rimexolone, triamcinolone). They are sometimes combined with an antibiotic drug (e.g. betamethasone combined with |

| |neomycin or sulfacetamide, dexamethasone combined with neomycin or polymyxin B). Corticosteroids have side effects, such as enhancing the activity of |

| |herpes simplex virus, fungal overgrowth, raising intraocular pressure or cataract formation. There are other anti-inflammatory drugs that are |

| |non-steroidal (NSAID) and have little toxicity. They act mainly by blocking prostaglandin synthesis. These include diclofenac sodium, flurbiprofen |

| |sodium, indomethacin, ketorolac, nepafenac and oxyphenbutazone. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a type of drug that reduce pain |

| |and inflammation.⁵ |

| | |

| |The nonsteroidal anti-inflammatory drugs are a group of agents inhibiting prostaglandin |

| | |

| |synthetase, thereby reducing the process of inflammation. As a group, they are all effective analgesics. |

| |Some, including the salicylates, ibuprofen, and naproxene, are also useful antipyretics (fever-reducers). |

| |Although the NSAIDs fall into discrete chemical classes, they are usually divided into the nonselective NSAIDs and the COX-2 specific agents. Among the|

| |non-specific NSAIDs are diclofenac (Voltaren), etodolac (Lodine), flurbiprofen (Ansaid), ibuprofen (Motrin, Advil, Rufen), ketorolac (Toradol), |

| |nabumetone (Relafen), naproxen (Naprosyn), naproxen sodium (Aleve, Anaprox, Naprelan), and oxaprozin (Daypro). The COX-2 specific drugs are celecoxib |

| |(Celebrex) and rofecoxib (Vioxx). |

| |Anti-inflammatory drugs and their use in ophthalmic treatment |

| |DRUGS |

| |TREATMENT |

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| |Diclofenac |

| |Treatment of postoperative inflammation in patients after cataract |

| |extraction. |

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| |Temporary relief of pain and photophobia in patients undergoing corneal refractive surgery. |

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| |Flurbiprofen |

| |Inhibition of intraoperative miosis. |

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| |Ketorolac |

| |Temporary relief of ocular itching due to seasonal allergic conjunctivitis. Treatment of postoperative inflammation after cataract extraction. |

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| |Ketorolac LS |

| |Reduction of ocular pain and burning/stinging following corneal refractive surgery. |

| | |

| |Bromfenac |

| |Treatment of postoperative inflammation and reduction in ocular pain after cataract surgery. |

| | |

| |Nepafenac |

| |Treatment of pain and inflammation associated with cataract surgery. |

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| | |

| |Topically administered corticosteroids differ in their ability to penetrate into the corneal stroma. These differences in corneal bioavailability |

| |suggest a corresponding difference in the ability of ophthalmic corticosteroid preparations to suppress inflammation in the cornea. Investigation of |

| |this possibility has documented that dexamethasone formulations do indeed vary in their ability to suppress |

| | |

| |inflammation in the cornea. The present studies demonstrate that different derivatives of prednisolone also are not equivalent in corneal |

| |anti-inflammatory effectiveness following their topical administration to the eye.⁶ |

| | |

| |Veterinary ophthalmologists most commonly use systemic NSAIDs in treating uveitic conditions for which corticosteroids are contraindicated, such as |

| |infectious diseases and diabetes mellitus, and |

| |before cataract surgery for their effects on maintaining mydriasis . Acetylsalicylic acid, phenylbutazone, and flunixin meglumine have traditionally |

| |been the most commonly prescribed. |

| | |

| |NSAIDs in dogs, cats, and horses by veterinary ophthalmologists. With the advent of US Food and Drug Administration (FDA) approval for newer systemic |

| |NSAIDs with fewer reported side effects, however, drugs like carprofen and etodolac are being used with increasing frequency.⁷ |

| | |

| |Ophthalmic suspensions contain solid particles dispersed in a liquid vehicle ; they must be homogeneous when shaken gently and remain sufficiently |

| |dispersed to enable the correct dose to be removed from the container. A sediment may occur, but this should disperse readily when the container is|

| |shaken, and the size of the dispersed particles should be controlled. The active ingredient and any other suspended material must be reduced to a |

| |particle size small enough to prevent irritation and damage to the cornea.⁸ |

| | |

| |The purpose of selecting the category of anti-inflammatory drug used in the formulation and evaluation of ophthalmic product for the treatment of |

| |several eye diseases.(like uveitis, dryness of eye, irritation, sclerosis, glaucoma, cystoid macular, episcleritis, keratitis, conjunctivitis, |

| |blepharitis etc.) |

| | |

| |ENCLOSURE – II |

| |6.2 REVIEW OF LITERATURE |

| | |

| |1. Hanna et al., investigated the anti-inflammatory properties of topical ocular dimethyl sulfoxide (DMSO) by using a standard experimental model of an|

| |acute inflammatory ocular inflammation. In the |

| | |

| |proposed study dimethyl sulfoxide was used for micronizing the prednisolone acetate and it was removed by filtration and the filtrate was washed with |

| |purified water to remove any traces of dimethyl sulfoxide. However if minute traces of dimethyl sulfoxide are found then it does not have any adverse |

| |effect.⁹ |

| | |

| |2. Howard et al., has been reported that Particle-sizeof prednisolone acetate was determined by using a resistance particle counter. Where as in the |

| |present study Particle-size of prednisolone acetate was |

| |determined using Biocular Microscope “Manufacturer Swift” Model # M3300-D, equipped with a micrometer eyepiece.¹⁰ |

| | |

| |3. Kupferman et al., studied that high-viscous Prednisolone acetate was formulated with carboxy polymethylene gel at concentrations of 0.125% and 1.0%.|

| |The ability of these gel preparations to suppress inflammation in the cornea was assessed and compared with the anti-inflammatory capabilities of |

| |conventional commercially available prednisolone acetate ophthalmic suspensions. When administered hourly, the gel formulations produced no greater |

| |anti-inflammatory effect than the conventional suspensions.¹¹ |

| | |

| |4. Yanagawa et al., suggested that a lipid microsphere ophthalmic preparation of various lipophilic drug including steroids might be useful as a drug |

| |delivery system for ophthalmic therapy.¹² |

| | |

| |5. Millichamp et al., found that intravenously administered flunixin meglumine had a significant effect in limiting miosis and reducing production of |

| |PGE2 in the aqueous humor after acute inflammation induction by laser disruption of the anterior lens capsule in normal adult dogs.¹³ |

| | |

| |6. Brown et al., published an evidence-based emergency medicine (EBEM) review of the efficacy of ophthalmic nonsteroidal anti-inflammatory drugs |

| |(NSAIDs) to reduce the pain associated with simple corneal abrasions.¹⁴ |

| | |

| |7. Gamache DA, Graff G, Brady MT, et al., has been reported that nepafenac has been shown to |

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| |penetrate the cornea more rapidly and provides more complete (80 percent versus 50 percent) and longer lasting inhibition of prostaglandin synthesis |

| |(greater than six hours versus three hours) and vascular permeability (eight hours versus four hours) than diclofenac.¹⁵ |

| | |

| |8. Yaylali V, Ozbay D, Tatlipinar S, et al., studied on that rimexolone 1% suspension and prednisolone acetate 1% were compared in 48 patients |

| |undergoing cataract extraction with phaco- |

| |emulsification followed by posterior chamber intraocular lens implantation in a randomized, double-blind trial.148 Both therapies were administered |

| |four times daily for 15 days. Patients were examined |

| |on day one, three, seven, and 15. Efficacy was similar in both groups as defined by anterior chamber cells, anterior chamber flare, and conjunctival |

| |hyperemia. IOP measurements were similar in both groups.¹⁶ |

| | |

| |9. Flach AJ, Dolan BJ, Donahue ME, et al., in a double-masked, randomized trial during the post-operative period of cataract extraction and |

| |implantation of an intraocular lens, a total of 120 patients were treated with either diclofenac 0.1% solution or ketorolac tromethamine 0.5% solution |

| |four times daily for 30 days.136 Treatment began the first post-operative day after surgery. Objective measurements of inflammation and toxicity were |

| |made at three post-operative visits. The anti-inflammatory effects were similar at all three post-operative visits. Both treatments were equally |

| |tolerated.¹⁷ |

| | |

| |10. Herse PR et al., studied that, a history of diabetes mellitus and prior surgery in the affected eye were associated with a worse outcome. |

| |Individuals with diabetes are known to be at increased risk for corneal disorders such as epithelial defects, recurrent erosions, abnormal wound |

| |repair, and increased susceptibility to injury.¹⁸ |

| | |

| |11. Alberti et al., studied that indomethacin 0.1% combined with gentamicin eye drops or gentamicin eye drops alone, which they were instructed to |

| |instill 4 times a day for 5 to 6 days the initial group of patients 80% were followed up to completion. The investigators found a statistically |

| |significant pain reduction at all measured times in the indomethacin group. At 1 hour post treatment, patients receiving indomethacin had a mean pain |

| |intensity reduction (P=.007 for comparison between the 2 groups). |

| | |

| |There was no statistically significant difference in associated symptoms or in the number of patients taking supplemental analgesics.19 |

| | |

| |ENCLOSURE – III |

| |6.3 OBJECTIVES OF THE STUDY |

| |The objectives of the present study are following: |

| |Selection of suitable drug from the anti-inflammatory drug category. |

| |Determination of compatibility between drug and preservatives. |

| |Study on suitable excipients used in the formulations of opthalmics. |

| |Study on optimization of the ophthalmic produtcs by following of several categories like, |

| |a. pH |

| |b. Isotonicity |

| |c. Sterility |

| |d. Viscosity |

| |e . Colour components |

| |Preformulation study on used anti-inflammatory drug and excipients. |

| |To study the stability of the ophthalmic products by using several stabilizers like chelating agents and antioxidants. |

| |To study on maintenance of the efficacy of drug during their shelf life period. |

| |Discuss the strategies for incorporating NSAIDs into cataract and refractive procedure to |

| | |

| |optimize patient result. |

| |To develop fast releasing of NSAIDs drug by using suitable disintegrants. |

| |Evaluation studies |

| |a. Visual clarity and Appearance. |

| |b. pH. |

| |c. Isotonicity |

| |d. Drug content analysis. |

| |e. Rheological Studies. |

| |f. In-vitro release studies. |

| |g. Pharmacokinetic study. |

| |h. Anti-inflammatory efficiency study. |

| |i. Ocular Irritancy study. |

| |j. Sterility testing. |

| | |

| |MATERIALS AND METHODS |

| |MATERIALS |

| |Drug : Anti- inflammatory drug(Diclofenac, Flurbiprofen, Ketorolac etc.) |

| |Polymers : Sodium alginate, HPMC, Carbopol, HPC, Ethyl Cellulose etc. |

| |Water for injection (for eye drop preparation) |

| |METHOD |

| |Ophthalmic anti-inflammatory medicines are used in the eye to lessen problems that can occur |

| |during or after some kinds of eye surgery.The product to be designed as an anti-inflammatory |

| |ophthalmic with reduced particle size to prevent local irritation. Water for injection which is used should be free from contamination & |

| |microbes. During the formulation development it will be considered that the range of excipients will be suitable for large scale |

| |industrial manufacturing . Other parameters like sterility, isotonicity, viscosity, pH, re-dispersibility also will be |

| |considered to make a quality product. |

| | |

| | |

| |ENCLOSURE-IV |

| |7.1 SOURCE OF DATA |

| |Review of literature from: |

| |Journals – such as |

| |Indian Journal of Pharmaceutical Sciences. |

| |European Journal of Pharmaceutical Sciences. |

| |Asian Journal of Pharmaceutics. |

| |International Journal of Pharmaceutics. |

| |Drug development and Industrial pharmacy. |

| |Indian Drugs. |

| |Journal of Pharmaceutical Research. |

| |Egyptian Journal of Pharmaceutical Sciences. |

| |World Wide Web. |

| |J-Gate@ Helinet. |

| | |

| |ENCLOSURE – V |

| | |

| |7.2 METHOD OF COLLECTION OF DATA |

| |1. Data of physiochemical properties of the drug will be collected through literature search such as Solubility in various solvents, pH of the drug |

| |solution and compatibility of the drug with various excipients. |

| |2. Amount of drug released and estimate using the suitable analytical method. |

| |3. Data on drug and excipients will be collected from the drug information center, standard books, catalogs etc. Drug-excipients compatibility studies|

| |can be confirmed by carrying out Infrared light absorption scanning spectroscopy etc. |

| |Statistical significance of collected data. |

| | |

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| | |

| |ENCLOSURE – VI |

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| |7.3 Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, please describe briefly. |

| | |

| |--------------YES -------------- |

| | |

| |7.4 Has ethical clearance been obtained from your institution in case of 7.3? |

| | |

| |------------APPLICABLE ------------ |

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| | |

| |ENCLOSURE - VII |

| |LIST OF REFERENCES |

| | |

| |Gennaro AR, Easton PA . Remington’s Pharm Sci 1990;19:1563-73. |

| | |

| |British Pharmacopoeia. General notice (ph eur monograph 1163) eye preparations comply with the requirements of the European pharmacopoeia 2007. |

| | |

| |Kramer A , Baumann BW . Antiseptic prophylaxis and therapy in ocular infections. Dev. Ophthalmol.,2002; 33: 85-116. |

| | |

| |Hecht G . Ophthalmic Preparations, In Gennaro AR (Editor). Remington: The Sci Practice of Pharm, Mack Publishing Co., Easton PA, USA., |

| |1995;19(89):1563-73. |

| | |

| |Butterworth-Heinemann dictionary of Optometry and Visual Science 2009;7. |

| | |

| |Cox, W V, Kupferman, A, Leibowitz,H ically applied steroids in corneal disease. The role of inflammation in stromal absorption of dexamethasone, |

| |Arch. Ophthalmol 1972; 88: 308. |

| | |

| |Miller TR. Anti-inflammatory therapy of the eye. Int Bonagura J, editor. Kirk’s current veterinary therapy XII, small animal practice. |

| |Philadelphia:WBSaunders; 1995; 1218–22. |

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| |Karthikeyan D, Bhowmick M, Pandey VP, Nandhakumar J, Sengottuvellu S, Sonkar S, Sivakumar T. The Concept Of Ocular Inserts As Drug Delivery System; An |

| |Overview. Asian J Pharm 2008; 2:192-200. |

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| |Hanna C, Fraunfelder FT, Meyer SM . Effects of dimethyl sulfoxide on ocular inflammation. Ann. Ophthalmol., 1977;9: 61-65. |

| | |

| |Howards , Leibowitz HM . Anti-inflammatory effectiveness in the cornea of topically administered prednisolone. Invest. Ophthal. Visual Sci 1974;13: |

| |757-63. |

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| |Kupferman A, Ryan WJ, Leibowitz HM . Prolongation of anti-inflammatory effect of prednisolone acetate. Influence of formulation in high viscosity gel. |

| |Arch. Ophthalmol 1981; 99: 2028-29. |

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| |Yanagawa A, Mizushima Y, Komatsu A, Horiuchi M, Shirasawa E and Igarashi R . Application of a drug delivery system to a steroidal ophthalmic |

| |preparation with lipid microspheres 1987. |

| | |

| |Millichamp NJ, Dziezyc J, Rohde BH, Chiou GC, Smith WB. Acute effects of anti-inflammatory drugs on neodymium:yttrium aluminum garnet laser-induced |

| |uveitis in dogs. Am |

| |J Vet Res 1991;52(8):1279–84. |

| | |

| |Brown MD, Cordell WH, Gee AS. Do ophthalmic nonsteroidal anti-inflammatory drugs reduce the pain associated with simple corneal abrasion without |

| |delaying healing. Ann Emerg Med. 1999;34:526-534. |

| | |

| |Gamache DA, Graff G, Brady MT. Nepafenac, a unique nonsteroidal prodrug with potential |

| | |

| | |

| |utility in the treatment of traumainduced ocular inflammation: I. Assessment of anti-inflammatory efficacy. Inflammation. 2000; 24(4):357-70. |

| | |

| |Yaylali V, Ozbay D, Tatlipinar S. Efficacy and safety of rimexolone 1% versus prednisolone acetate 1% in the control of postoperative inflammation |

| |following phacoemulsification cataract surgery. Int Ophthalmol 2004; 25(1):65-68. |

| | |

| |Flach AJ, Dolan BJ, Donahue ME. Comparative effects of ketorolac 0.5% or diclofenac 0.1% ophthalmic solutions on inflammation after cataract surgery. |

| |Ophthalmology. 1998; 105(9):1775-79. |

| | |

| |Herse PR. A review of manifestations of diabetes mellitus in the anterior eye and cornea. Am J Optom Physiol Opt 1988; 65:224–230. |

| | |

| |Alberti MM, Bouat CG, Allaire CM. Combined indomethacin/gentamicin eye drops to reduce pain after traumatic corneal abrasion. Eur J Ophthalmol. |

| |2001;11:233-39. |

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