Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-03-18
2004-05-11
Travers, Russell (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S424000, C424S425000, C424S422000, C424S457000, C424S458000, C424S459000, C424S489000, C424S423000, C604S891100
Reexamination Certificate
active
06733767
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to liquid polymeric compositions; for instance, such compositions for controlled release of at least one bioactive substance, e.g., at least one hydrophobic bioactive substance, such as a liquid polymeric composition which can form a film encapsulated liquid, e.g., in situ and/or which can achieve a long-term sustained release in a patient or host (e.g., animal or human) such as plasma profiles showing high efficacy (greater than about 70%, such as at least about 80%, preferably at least about 90%, e.g., about 100% efficacy for greater than about 12 months and/or plasma levels sustained for at least about 50 or about 60 days or at least about two months or at least about eight weeks, e.g., at least about 90 days or about three months or about 12 weeks or at least about 120 days or about four months or about 16 weeks, or at least about 150 days or about five months or about 20 weeks, or even longer, e.g., up to about a year or more; for instance, from 1 to 12 months.
The present invention further relates to a liquid polymeric composition comprising: (1) about 1-30% w/v bioactive substance (e.g., hydrophobic bioactive substance); (2) about 1-20% w/v of a biologically acceptable “polymer” (including “copolymer”, a polymer polymerized by at least two comonomers) (e.g., poly(lactide-co-glycolide) copolymer), for instance, wherein the weight ratio of the polymer to the bioactive substance can be 1:1 or less, e.g., 0.3:1 to 1:1; and (3) at least one lipophilic solvent or a mixture of hydrophilic and lipophilic solvents wherein the volume ratio of the hydrophilic and lipophilic solvents is from about about 80:20 to about 0:100, for instance about 80:20 to about 10:90 or 5:95, hydrophilic and lipophilic solvents, e.g., about 65:35 to about 35:65, and/or wherein the the water immiscible or lipophilic solvent is present in an amount of at least about 16.5% by weight (e.g., including about 16.465% by weight), such as at least about 16.5% to about 45% by weight, for instance at least about 16.5% to about 30% by weight (e.g., at least about 29% by weight) or at least greater than 40% by weight (for instance and at least about 42-45% by weight); e.g., such compositions wherein there is less than 10% of the polymer and 1 to 10% of the bioactive active substance or about less than 7% (e.g., 6.7%) or 5% or less polymer, with the bioactive substance content at less than or equal to about 10% or 5%.
The present invention yet further relates to a liquid polymeric composition consisting essentially of the foregoing, wherein the liquid polymeric composition is capable of forming a film encapsulated liquid, e.g., in situ, and/or having long-term sustained release, wherein the term “consisting essentially of” is used in the sense attributed to it in patent documents, and the term is exclusionary as to ingredients which may impede the capability of the composition to so form a film encapsulated liquid.
The present invention still further relates to methods for making and using such compositions. For example, a method of making such compositions comprising admixing the aforementioned ingredients; for instance, preferably dissolving both the polymer and the bioactive substance (as opposed to suspending, encapsulating, or having present as a solid, the bioactive substance, which, while not necessarily excluded by the invention, may be less preferable to dissolving). Or, a method for using such compositions comprising administering to a patient or host (animal, e.g., mammal such as domesticated animal, for instance companion animal or feedstock animal, or human) an inventive composition.
These and other areas to which the invention relates will be apparent from the following text. Various documents are cited in the following text, without any admission that any of these documents are prior art as to the invention. All documents cited in this text, as well as all documents referenced in documents cited in this text, are hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
Biodegradable polymers have been used in parenteral controlled release formulations of bioactive compounds. In one approach the polymer is fabricated into microspheres that may be injected via syringe, and the bioative compound is entrapped within the microspheres. This approach has not proved to be practical in part due to the difficulty in the manufacturing procedure for producing sterile and reproducible products, and the high cost of manufacturing. In another approach the biodegradable polymer and the bioactive material are dissolved in a biocompatible water-miscible solvent to provide a liquid composition. When the liquid composition is injected into the body, the solvent dissipates into the surrounding aqueous environment, and the polymer forms a solid depot from which the bioactive material is released.
European Patent Application 0537559 concerns polymeric compositions having a thermoplastic polymer, rate modifying agent, water soluble bioactive material and water-miscible organic solvent. Upon exposure to an aqueous environment (e.g. body fluids) the liquid composition is capable of forming a biodegradable microporous, solid polymer matrix for controlled release of water soluble or dispersible bioactive materials over about four weeks. The thermoplastic polymer may be, among many listed, polylactide, polyglycolide, polycaprolactone or copolymers thereof, and is used in high concentration (45 to 50%). The rate modifying agent may be, among many others listed, glycerol triacetate (triacetin); however, only ethyl heptanoate is exemplified; and the amount of the rate modifying agent is no more than 15%.
Indeed, with respect to the patent literature, reference is made to:
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These documents tend to provide compositions that form a solid, gel or coagulated mass; for instance, a significant amount of polymer is contemplated in these documents, akin to European Patent Application 0537559.
Mention is also made of: Shah et al (
J. Controlled Release,
1993, 27:139-147), as relating to formulations for sustained release of bioactive compounds containing various concentrations of poly(lactic-co-glycolic) acid copolymer (PLGA) dissolved in vehicles such as triacetin; Lambert and Peck (
J. Controlled Release,
1995, 33:189-195), as a study of the release of protein from a 20% PLGA solution in N-methylpyrrolidone exposed to aqueous fluid; and Shivley et al (
J. Controlled Release,
1995, 33:237-243), as a study of the solubility parameter of poly(lactide-co-glycolide) copolymer in a variety of solvents, and the in vivo release of naltrexone from two injectable implants (5% naltrexone in either 57% PLGA and 38% N-methylpyrrolidone or 35% PLGA and 60% N-methylpyrrolidone).
There is nonetheless a need fo
Chern Rey T.
Zingerman Joel R.
Desai Mitul I.
Merck & Co. , Inc.
Rose David L.
Sharareh Shahnam
Travers Russell
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