Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1994-04-22
2002-04-16
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S428000, C424S400000, C514S912000
Reexamination Certificate
active
06372245
ABSTRACT:
FIELD OF THE INVENTION
The present invention is concerned with sustained release delivery systems for medicaments, especially topical ophthalmic delivery systems, More particularly, the present invention relates to a sustained release drug delivery system based on a flowable, plasticized bioerodible polymeric matrix material.
BACKGROUND
In topical administration of medicaments to the eye, a variety of factors can be important, among them: comfort, consistency and accuracy of dosage, type and time of any vision interference, ease of administration, and timing of delivery. Prior ophthalmic delivery vehicles have suffered drawbacks in one or more of those areas.
For example, eyedrops in the form of aqueous solutions or suspensions can be rapidly washed away by the eye's tear fluid. Ointments or creams can blur the vision and oftentimes can result in other undesirable side effects. Gelatin lamellae or other films or sheets, ocular inserts and non-aqueous suspensions and emulsions all can cause immediate pain and continuing discomfort and can also interfere with vision. A number of drug delivery systems or formulations have been developed in an attempt to ameliorate or to avoid the foregoing problems.
One group of polymers found useful in the eye are disclosed in Choi et al, U.S. Pat. No. 4,138,344, issued Feb. 6, 1979. In particular, Choi et al disclose orthoester and orthocarbonate polymers having a repeating mer comprising a hydrocarbon radical and a symmetrical dioxycarbon unit. The polymers are generally highly viscous or solid and have been prepared for use in the form of a bioerodible insert encapsulated by another polymer.
The bioerodible ocular insert of Choi et al consists of a bioerodible polymer comprising a continuous matrix in which particles of drug are dispersed. When the ocular insert is placed in the environment of the eye, the polymer gradually bioerodes and releases drug to the eye and surrounding tissues. Until now, it is believed that the polymers have been suitable for administration to the eye only as an insert because of their tackiness and poor handling ability.
The present invention, which is based on a flowable, plasticized, bioerodible polymeric matrix material, evolved from efforts to obtain sustained release benefits from such polymers without constraints and disadvantages associated with inserts. It is believed that before the present invention, very small amounts of polyethylene glycol were added to a Choi et al. material for a different purpose, i.e., in an attempt to combat its tackiness while still maintaining it as a solid.
OBJECTS AND SUMMARY
It is an object of the present invention to provide novel sustained release delivery systems.
It is a particular object of this invention to provide novel sustained release delivery systems for topical ophthalmic delivery of medicaments.
A further object of this invention is to provide novel, sustained release, topical ophthalmic delivery systems suitable for administration of medicaments at intervals of once daily or even longer.
Yet another object of this invention is to provide a method for convenient therapeutic treatment using a delivery system which has a prolonged release time for medicaments.
A still further object of this invention is to provide novel methods for the preparation of sustained release delivery systems.
In accordance with a preferred form of the invention intended to accomplish at least some of the foregoing objects, a sustained release medicament delivery system comprises, and more preferably consists essentially of, a plasticized, bioerodible polymer for carrying medicament.
When formulated as a topical ophthalmic delivery system, the viscosity of the composition is desirably in a range suitable for administration to the eye in ribbon form or in drop form. Preferably that viscosity is from about 1,000 to about 55,000 cps. For drops the viscosity is more preferably from about 5,000 to about 30,000 cps, and for administration in ribbon form the viscosity is more preferably from about 40,000 to about 55,000 cps. There can, however, be overlap in the drop and ribbon viscosity ranges by reason of variations in formulation techniques and ingredients. When formulated for injection, the viscosity of the injectable liquid can be substantially greater than 100,000 cps, but still preferably such that the liquid can be passed through an 18 gauge or smaller needle at room temperature (about 20 °C.).
The delivery system comprises a plasticized bioerodible polymer. As used herein “erodible” and “bioerodible” refer to the property of the polymer to break down as a unit structure by chemical decomposition, as opposed to physical degradation, e.g., by the polymer reacting with water or through polymer reaction with enzymes, water in tear fluids or other biological materials. Preferably, however the bioerodible polymer is a polyorthoester.
Preferred plasticizers are, polyethylene glycol, glycerin (glycerol), propylene glycol, polypropylene glycol, ethylene glycol, cetyl alcohol and polyvinyl alcohol. In topical ophthalmic preparations only small amounts of ethylene glycol should be used because of potential toxicity in the eye.
The plasticizers are preferably present in systems of the present invention in an amount from about 5% to about 70% of the total weight of the bioerodible polymer and plasticizer (excluding medicament), more preferably about 5% to about 40% and for some formulations preferably about 10% to about 30% by weight. In any event, the amount of plasticizer or any other constituent is such that the system is flowable and remains essentially bioerodible.
The bioerodible polymeric material is preferably selected from the group consisting of polysaccharides, proteinaceous polymers and their soluble derivatives, polypeptides, polyesters, polylactic acid polymers, polyglycolic acid polymers, poly(lactic/glycolic) copolymers and polyorthoesters. The most preferred materials are plasticized and unplasticized polyorthoesters, especially poly(2,2 dioxo-trans-1,4 cyclohexane dimethylene tetrahydrofuran), of the type disclosed by Choi et al, U.S. Pat. No. 4,128,344 which is hereby incorporated by reference.
The flowable bioerodible material of the delivery system is preferably present in an amount within a range of about 30% to about 95%, by weight based on the total weight of the bioerodible polymer and plasticizer (excluding medicament), more preferably about 60% to about 95%, by weight of the bioerodible polymer and plasticizer (excluding medicament).
Where topical ophthalmic compositions useful to ameliorate “dry eye” conditions are formulated, the medicament, as that term is here used, may be a demulcent. Of course, the term medicament also includes, and in most instances will be constituted by, what are often referred to a over the counter or prescription drugs. Drugs administered by means of the controlled release drug delivery systems of the present invention preferably include an adrenocorticotrophic hormone, insulin, vitamin, steroid, narcotic antagonist, antibiotic, anticancer drug, antihypotensive drug, aminosteriod or protein. The drugs may be in either the free base or the acid form. Particular advantages are perceived for administering water soluble drugs inasmuch as they are believed less likely to diffuse out of the system. Therefore, their administration is more erosion controlled.
The present invention also includes a process for making a sustained release medicament system which comprises the steps of mixing a plasticizer with the bioerodible polymer at a temperature and time sufficient to form a substantially homogenous mixture at room temperature. The time and temperature of mixing will depend on factors such as molecular weight of the polymer, viscosity, and temperature stability of the components. The medicament is added to the mixture with mixing at a temperature compatible with the stability of the material.
Depending on its molecular weight, the bioerodible polymer employed can be at room temperature a tacky, solid or semi-solid substance, or a tacky, extremely v
Bowman Lyle M.
Chandrasekaran Santosh Kumar
Patel Rajesh
Vo Hoa Vinh
Arnold & Porter
Insite Vision Incorporated
Webman Edward J.
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