Drug – bio-affecting and body treating compositions – Topical body preparation containing solid synthetic organic... – Ophthalmic preparation
Reexamination Certificate
2001-09-18
2003-06-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Topical body preparation containing solid synthetic organic...
Ophthalmic preparation
C424S078040, C424S405000, C424S406000, C424S486000, C424S489000
Reexamination Certificate
active
06579519
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a sustained release and long residing ophthalmic formulation and the process of preparing the same.
BACKGROUND OF THE INVENTION
Medication of the eyes is done for two purposes—to treat the outside of the eyes for such infections as conjunctivitis, blepharitis, keratitis sicca etc and to provide intraocular treatment through the cornea for diseases such as glaucoma or uveitis. Most ocular diseases are treated with topical application of solutions administered as eye drops. One of the major problems encountered with the topical delivery of ophthalmic drugs is the rapid and extensive precorneal loss caused by drainage and high tear fluid turn over. After instillation of an eye-drop, typically less than 2-3% of the applied drug penetrates the cornea and reaches the intra-ocular tissue, while a major fraction of the instilled dose is often absorbed systematically via the conjunctiva and nasolacrimal duct. Another limitation is relatively impermeable corneal barrier that limits ocular absorption.
Because of the inherent problems associated with the conventional eye-drops there is a significant efforts directed towards new drug delivery systems for ophthalmic administration such as hydrogels, micro- and nanoparticles, liposomes and collagen shields. Ocular drug delivery is an approach to controlling and ultimately optimizing delivery of the drug to its target tissue in the eye. Most of the formulation efforts aim at maximizing ocular drug absorption through prolongation of the drug residence time in the cornea and conjunctival sac as well as to slow drug release from the delivery system and minimizing precorneal drug loss.
To solve the above mentioned problem associated with the ocular delivery of drugs. WO 9405257 A1 940317 discloses a method for preparing a bioerodible drug delivery vehicle composed of solid polymeric matrix formed from derivatised cellulose and methacrylic acid copolymer and incorporating ophthalmic drugs in it. The inventors have demonstrated that such formulation when instilled in eyes the polymeric materials bio-erodes and dispenses the incorporated drug on the cornea surface. However, the problem always associated with the use of such bulk gel is the blurring effect and bio-compatibility of the polymeric material. Moreover, the long residence time and sustained release of drug on cornea surface have not been achieved.
There have been reported other studies on the use of co-polymeric materials as earners for ophthalmic drugs and particularly noteworthy are the attempts to incorporate hydrophobic drugs into the hydrophobic core of the copolymer micelles. The pharmaceutical efficacy of these formulations depends on the specific nature and properties of the co-polymeric materials.
For example, EP 0744938 A1 961204 discloses sustained release liquid aqueous ophthalmic delivery system. The method provides a slow and sustained release of treating agents. The polymer used was chitosan and was applied in the form of bulk material. However, it is difficult for such bulk polymer to penetrate the conceal membrane and the liquid formulation remain in the liquid form even at body temperature so that there exists every possibility to be washed away by tears. There also exists a problem of this formulation. The acidic pH of the liquid pH 3.0 to 6.2, is not very much patient compliance. The other patents with related formulation with chitosan is WO 9522315 A1 950824 and EP 0594760.
A1 940504 discloses a method for entrapping ophthalmic drugs in polyacryl acid polymer to obtain a fluid aqueous gel having a pH of between 6.5 and 8. The formulation is claimed to be useful for treating various pathological ocular conditions. This method, thus solves the potential muco-adhesive problem of the polymer by using poly-acrylic acid gels. However, pure polyacryl acid is so much sticky that a permanent polymer layer on the cornea surface may cause blurred vision. Moreover, being bulk gel, these polymeric composition may not have sufficient penetration and subsequently less bio-availability. The same is the comment for other patents: WO 9300887 A1 930121 and WO 9922713 A1 19990514 and WO 9405257 A1 940317.
There are reported studies on formulations of non-steroidal anti-inflammatory drugs (NSAID) using different carriers particularly directed towards oral delivery to avoid the adverse effects on the gastrointestinal tract.
A patent WO 93/25190 has disclosed surface modified NSAID nanoparticles by taking crystalline NSAID having surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400 nm.
One patent, EP 0274870 A2 880720, has disclosed the micelles containing polyethoxylated nonionic surfactant as carrier for certain NSAIDs. Other patents. EP 0818992 A1 980121 and WO 9505166 A1 950223 disclose the similar type of micellar encapsulation of NSAIDs using cellular acetate phthalate and gelatin.
Another patent, WO 9702017 A1 970123 used hydrophilic poloxamer for encapsulating NSAIDs. These are some of the patents, which are mainly directed towards oral delivery formulations so that these NSAIDs cannot be exposed in GI tract. These formulations do not have any relevance to eye drop preparations.
To overcome the problem of blurred vision and poor bio-availability of drug by using bulk gel in ophthalmic formulations, it has been suggested that colloidal carriers would have better effect. Colloidal carriers which have been studied for ocular delivery are mainly liposomes and nanoparticles because of their extremely small size. The main limitation of liposomes as ocular drug delivery system is its surface charge. Positively charged liposomes seemed to be preferentially captured at the negatively charged corneal surface compared to neutral and negatively charged liposomes. Another limitation of liposomes is the instability of the lipid aggregates on the mucine surface. The vesicular aggregates of positively charged lipids are completely disintegrated on the negatively charged mucine membrane surface.
Nanoparticles as drug carriers for ocular delivery have been revealed to be more efficient than liposomes and in addition to all positive points of liposomes, these nanoparticles are exceptionally stable entity and the sustained release of drug can be modulated.
Some studies have been reported in the literature as well as patents on the use of nanoparticles carriers for encapsulating water insoluble drugs. For example, a U.S. Pat. No. 5,510,103 disclose the entrapment of water-insoluble drugs including NSAIDs in the hydrophobic core of polymeric micelles of different block copolymers. Another U.S. Pat. No. 5,449,513 has also disclosed the use of various amphiphilic copolymers in the form of micelles to physically entrap water-insoluble drugs. The other patents of similar type are U.S. Pat. No. 5,510,103, U.S. Pat. No. 5,449,513, U.S. Pat. No. 5,124,151.
All these patents described the method of preparation of amphiphilic copolymers of random compositions of two or three different types of amphiphilic monomers and aggregating them in aqueous solutions and dissolving the water-insoluble drugs inside the hydrophobic core of these polymeric micelles. The properties of these copolymers are governed by the composition of them. But none of the polymers could comply the overall requirements of best ophthalmic formulation—hydrogel formation, mucoadhesiveness, thermosensitivity and small particle size—in a single formulation.
THE OBJECT AND SUMMARY OF THE INVENTION
The object of the present invention is to obviate the above-mentioned drawbacks and to provide a formulation having thermosensitivity, mucoadhesiveness, hydrogel properties and small particle size all together in a single composition.
Still further object of this invention is to provide sustained release and long residing ophthalmic formulation, so that the release of the entrapped drug can be controlled and the process of preparing the same.
To achieve the said objectives, this invention provides a sustained rele
Gupta Ajay Kumar
Madan Sumit
Maitra Amarnath
Majumdar Dipak
Page Thurman K.
Registrar, University of Delhi
Sidley Austin Brown & Wood LLP
Young Micah-Paul
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