Saurabh, Gupta (2010) Studies on in situ gelling system for better ocular drug therapy. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.
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Abstract
Currently, very few new ophthalmic drug delivery systems have been commercialized. Effective treatment of ocular diseases is a formidable challenge for scientists in the field especially because of the nature of diseases and presence of the multiple ocular barriers imposed by the eye against the entry of xenobiotics. There is a multiplicity of reasons for increased interest in alternate dosage forms. A basic concept shared by most scientists in ophthalmic research and development is that the therapeutic efficacy of an ophthalmic drug can be greatly improved by prolonging its contact with corneal surface. For achieving this purpose, viscosity enhancing agents such as methyl cellulose are added into eye drop preparations, or the ophthalmic drug is provided as an ointment to sustain the duration of intimate drug/eye contact. Unfortunately, these dosage forms give only marginally more sustained drug/eye contact than the eye drop solutions and do not yield a constant drug bioavailability as originally hoped. Repeated medications are still required throughout the day. As the pharmaceutical companies adjust their strategies to one of disease management, novel drug delivery offers us the capability of developing a series of niche and line extensions to enhance the product line offered around the disease focused. In addition to cost containment, novel drug delivery systems can impart important advantages such as extending the duration of drug activity, which allows greater patient compliance owing to elimination of multiple dosing schedules; reducing side effects due to optimization of the blood concentration-time profile; addressing chronological issues by temporal optimization of dosing and by using feedback control self-regulatory polymers and other systems. The principal categories of products in the ophthalmic market are glaucoma treatments, anti-inflammatories, anti-infectives, surgical adjuncts and artificial tear products. Glaucoma is the leading cause of preventable blindness and Conjunctivitis is the most common ocular infection out of all in the world which is treatable by medications. Glaucoma treatment is the largest ophthalmic drug category, accounting for approximately 45% of U.S. ophthalmic prescription sales. This project is an endeavor to formulate a liquid dosage form that can sustain drug release and remain in contact with the cornea of the eye for extended periods of time which will overcome the atrocities of conventional dosage forms like nasolacrymal drainage, reducing dose related adverse effects, etc. It was also set out to establish the role of some anti-glaucoma drugs (Forskolin, Timolol Maleate, Betaxolol HCl, Pilocarpine Nitrate, Dorzolamide HCl) in the form of ophthalmic in situ gels in the modulation of IOP, the duration of IOP-lowering effect. To explore the acceptance and compatibility of developed in situ gel with broad variety of drugs, the role of some antibiotics (Ciprofloxacin and Ofloxacin) in the form of ophthalmic in situ gels were also studied. The bioavailability of forskolin is limited when given as a conventional ophthalmic suspension. To overcome the problem of poor bioavailability caused by poor aqueous solubility and rapid nasolachrymal drainage, forskolin was also formulated as in situ gel forming nanosuspension, i.e. combining the properties of mucoadhesive drug delivery systems, in this case hydrogels, with nanosuspensions. The selected ideal batches, exhibited excellent sustained release of drug in the eyes and exhibited increased corneal residence time than marketed conventional eye drops dosage form. Our efforts to formulate and develop ophthalmic in situ gels intended at improving the corneal availability of wide variety of drugs brought out various observations which led to the following conclusions. • Preformulation studies revealed satisfactory purity of the drug compatibility of the selected polymers (Noveon AA-1 Polycarbophil and Poloxamer 407) with selected drugs (Forskolin, Timolol Maleate, Betaxolol HCl, Pilocarpine Nitrate, Dorzolamide HCl, Ciprofloxacin and Ofloxacin). • After preparation of a number of batches, the effect of formulation, an ideal batch of pH-triggered, Temperature-triggered and pH/Temperature-triggered ophthalmic in situ gels based on sol-gel phase transition (gelling) temperature, rheological study at different temperature, pH, isotonicity, in vitro drug release were selected. • pH-triggered, Temperature-triggered and pH/Temperature-triggered ophthalmic in situ gels were prepared and studied with wide variety of drugs (Forskolin, Timolol Maleate, Betaxolol HCl, Pilocarpine Nitrate, Dorzolamide HCl, Ciprofloxacin and Ofloxacin). • pH and thermoreversible in situ gel formulation were prepared using Noveon® AA-1 Polycarbophil/ Poloxamer 407 with the nano size forskolin crystals which can be effectively produced with the wet crushing method by the high performance disperser for better glaucoma therapy. • The particle size obtained was suitable for ophthalmic administration. • To overcome the drug particle growth, the surface of crystal was stabilized by poloxamer 407. • High performance disperser was shown to be a simple and adequate technique for drug particle size reduction and did not seem to alter the crystalline state of the drug, which should be highly relevant when considering drug stability during the storage over a period of 6 months. • The formulation was liquid at room temperature 20°C ± 10°C which underwent rapid gelation upon raising the eye pH (7.4) and temperature (35°C). • The in vitro release results indicated that the developed forskolin in situ gel was able to prolong and control forskolin release for more than 5 h, thus maintaining concentrations for a longer duration. • The formulations were capable of sustaining drug release and remain in contact with the cornea of the eye for 6 h. • The formulation was therapeutically efficacious capable of reducing IOP for 12 h. • The developed forskolin in situ gel forming nanosuspension in vivo studies on glaucomatous rabbits indicated that the IOP lowering efficacy for nanosuspension/hydrogel systems was 31% and lasted for 12 h, which is significantly better than the effect of traditional eye suspension (18%, 4-6 h). • In situ gel containing forskolin nanocrystals may produce added value by allowing a reduction in either the dose or its frequency of administration. It is not possible to guess whether this subtle but significant IOP reducing effect of topically applied drugs on the IOP of rabbits has any clinical significance for humans or not. Some workers have reported better results with viscous vehicles in the human eye, in comparison to those obtained with rabbits (Saettone [et al.], 1986). The developed formulation is a viable alternative to conventional eye solution/ suspension by virtue of its ability to enhance bioavailability by the formulation of in situ gel/nanosuspension. Main advantages of nanosuspensions are their increase of saturation solubility and dissolution velocity, improving the bioavailability of drugs. To further prolong the precorneal residence time of the forskolin nanosuspension in the eye, the nanosuspension was formulated with hydrogels made from thermoreversible and pHtriggered mucoadhesive polymers. The developed in situ gel forming system will have good patient acceptance because it is easy to instill into eye and gradually erodes by dissolution of the gel, obviating the need for removal. Thus, it is inevitable that the intention behind the development of this formulation, i.e., reduce the dose intake, thereby increasing the cost effectiveness, dosing frequency, nasolachrymal drainage and ultimately improve the pharmacotherapy of glaucoma and conjunctivitis has been fulfilled. Hence, in vivo study confirmed our hypothesis of increased corneal residence with sustained drug release of the formulated ophthalmic in situ gels drug delivery systems. Hence, it can be concluded that the formulated ophthalmic in situ gelling system will be good alternatives, than conventional eye drops for delivering the drug for ocular disorders.
| Item Type: | Thesis (Doctoral) |
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| Uncontrolled Keywords: | in situ gelling system, ocular drug therapy. |
| Subjects: | PHARMACY > Pharmaceutics |
| Depositing User: | Devi S |
| Date Deposited: | 27 Jun 2017 06:33 |
| Last Modified: | 16 Sep 2022 02:22 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/408 |
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