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Publication Number
US-9421271-B2
Publication Date
2016-08-23
Expiration Date
Abstract
The present invention provides compositions for extended release of an active ingredient, comprising a lipid-saturated matrix formed from a biodegradable polymer. The present invention also provides methods of producing the matrix compositions and methods for using the matrix compositions to provide controlled release of an active ingredient in the body of a subject in need thereof.
Core Innovation
The invention provides a matrix composition in which a biodegradable polymer is in non-covalent association with a first lipid comprising cholesterol and with a second lipid comprising at least one phosphatidylcholine selected from DMPC, DPPC, DSPC, DOPC and any combination thereof. A pharmaceutical active agent is included in the matrix, and the composition comprises at least 50% (ww) of lipids, with the at least one phosphatidylcholine constituting at least 50% (ww) of the total lipid content, and a weight ratio of total lipids to the biodegradable polymer between 1.5:1 and 9:1 inclusive.
The matrix composition has an ordered multilayer structure in which the biodegradable polymer and lipid are ordered in the form of layers. When maintained in an aqueous environment, the ordered multilayer structure provides sustained release of the pharmaceutical active agent.
Dependent refinements further specify phosphatidylcholine proportion, cholesterol content, and release behavior criteria, including release of at least 50% of the agent under zero-order kinetics. The disclosed approach emphasizes sustained/controlled release drug carrier matrices in aqueous environments, with ordered multilayer structures verified by electron microscopy and SAXS.
Claims Coverage
The independent claim covers a cholesterol-containing, non-covalently associated biodegradable polymer-lipid matrix with phosphatidylcholine, quantitative lipid fraction constraints, and an ordered multilayer structure that provides sustained release in an aqueous environment. Dependent claims further specify phosphatidylcholine and cholesterol thresholds, a zero-order release criterion, and coated substrates.
Lipid-associated ordered multilayer sustained-release matrix
A matrix composition comprising a biodegradable polymer in non-covalent association with a first lipid comprising cholesterol and a second lipid comprising at least one phosphatidylcholine selected from DMPC, DPPC, DSPC, DOPC and any combination thereof, together with a pharmaceutical active agent, wherein the matrix composition comprises at least 50% (ww) of lipids, the at least one phosphatidylcholine constitutes at least 50% (ww) of the total lipid content, and the weight ratio of total lipids to the biodegradable polymer is between 1.5:1 and 9:1 inclusive, the matrix composition having an ordered multilayer structure in which the biodegradable polymer and lipid are ordered in the form of layers and, when maintained in an aqueous environment, provides sustained release of the pharmaceutical active agent.
High phosphatidylcholine fraction
A matrix composition wherein at least one phosphatidylcholine makes up at least 60% (w/w) of the total lipid content.
Cholesterol content range within total lipids
A matrix composition in which cholesterol is 10–40 percent (w/w) of the total lipid content.
Zero-order kinetics release criterion
A matrix composition for sustained release of a pharmaceutical active agent that, when kept in an aqueous environment, releases at least 50% of the agent under zero-order kinetics.
Coated substrate with specified materials
A substrate coated on at least part of its surface with a matrix composition, wherein the substrate includes at least one material selected from hydroxyapatite, stainless steel, cobalt-chromium, titanium alloy, tantalum, ceramic, and gelatin.
Coverage centers on a cholesterol-containing, non-covalently associated biodegradable polymer-lipid matrix with phosphatidylcholine, quantitative lipid fraction constraints, and an ordered multilayer structure that provides sustained release in aqueous environments, with dependent refinements adding stricter cholesterol and phosphatidylcholine thresholds, a zero-order release criterion, and coated substrates on specified material types.
Stated Advantages
Sustained release of the pharmaceutical active agent when maintained in an aqueous environment.
Ordered multilayer structure in which the biodegradable polymer and lipid are ordered in the form of layers.
Release of at least 50% of the agent under zero-order kinetics when kept in an aqueous environment.
Documented Applications
A bone filler/implant application providing doxycycline hyclate release from bone filler/implants.
Substrate coatings including orthopedic/dental and medical device materials, including bone particles, gelatin sponge, and specified metal/ceramic substrates.
Use as sustained/controlled release drug carrier matrices for pharmaceutical active agents including antibiotics, antifungals, NSAIDs, steroids, anticancer agents, osteogenic factors, and bone resorption inhibitors.
Periodontitis, bone augmentation, surgical regenerative procedures, orthopedic recovery, and osteomyelitis using therapeutic agent-loaded implants/microspheres.
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