Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2001-10-03
2003-07-15
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S426000, C424S444000, C424S430000, C424S434000, C424S449000, C424S484000, C525S411000, C525S413000, C525S415000
Reexamination Certificate
active
06592899
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions comprising biodegradable polyester oligomers, and particularly PLA/PLGA oligomers, and water soluble, low molecular weight, biodegradable block copolymers and their use for solubilizing a drug in a hydrophilic environment. Particularly, this invention relates to the use of biodegradable polyester oligomers, and particularly PLA/PLGA oligomers to enhance the solubilizing performance of biodegradable triblock and diblock copolymers that are based on biodegradable polyester and polyethylene glycol (PEG) blocks, which are used as solubilizing agents at physiologically relevant temperatures (temperatures <45° C.).
BACKGROUND OF THE INVENTION
Many important drugs have limited solubility in water, especially hydrophobic drugs. In order to attain the full expected therapeutic effect of such drugs, it is usually required that a solubilized form of the drug be administered to a patient. Recently, many peptide/protein drugs, effective for a variety of therapeutic applications, have become commercially available through advances in recombinant DNA and other technologies. Many peptide drugs are of limited solubility and/or stability in conventional liquid carriers and are therefore difficult to formulate and administer.
A number of methods for solubilizing drugs have been developed that are based on the use of solvents or cosolvents, surfactants, complexation agents (e.g., cyclodextrins, or nicotinamides), or complex drug carriers (e.g., liposomes). Each of the above methods has one or more drawbacks. Conventional surfactants and complexing agents have drawbacks of toxicity, and rapid precipitation of the solubilized drugs once administered to the patient or when otherwise diluted in an aqueous environment. Solvents and cosolvents can be toxic and irritating when injected into humans, such that the use of this solubilization approach is largely restricted to therapies for acute, life threatening diseases where medical experts are constantly in attendance to administer palliative treatments to counteract the adverse effects of the solvents/cosolvents. Water miscible solvents/cosolvents also possess the undesirable feature of allowing the drug to rapidly precipitate when an aqueous environment is contacted. Complex drug carriers, such as liposomes have limited utility due to the unstable nature of the carrier particles and the preferential uptake and localization of liposomal drugs to the reticuloendothelial system, namely, the liver and spleen.
Amphiphilic block copolymers are effective drug carriers that solubilize drugs and particularly hydrophobic drugs into an aqueous environment. For example, there are reports of amphiphilic block copolymers exhibiting self-association properties. EP No. 0 397 307 A2 (See also EP No. 0 583 955 A2 and EP No. 0 552 802 A2.) discloses polymeric micelles of an AB-type amphiphilic diblock copolymer which contains poly(ethylene oxide) as the hydrophilic B-block and poly(amino acids) as the hydrophobic A-block, wherein therapeutically active agents are covalently bonded to the A-block. Although this polymeric micelle is provided as a means of administering a hydrophobic drug, it is highly disadvantageous because it requires the introduction of functional groups into the block copolymer, and the covalent coupling of the drug to the polymeric carrier which creates new chemical entities that are impossible to fully characterize and reproducibly manufacture.
U.S. Pat. No. 4,745,160 discloses water insoluble, amphiphilic, non-crosslinked linear, branched or graft block copolymers having polyethylene glycol as the hydrophilic component and poly(D-, L-, or D, L-lactic acids) as the hydrophobic components. Although the block copolymer is described as an effective dispersing agent or suspending agent for a hydrophobic drug, the block copolymer is insoluble in water and has a molecular weight of 5,000 daltons or more. Furthermore, the hydrophilic component is at least 50% by weight based on the weight of the block copolymer and the molecular weight of the hydrophobic component is 5,000 or less. In the preparation process, a water-miscible and lyophilizable organic solvent is used. When a mixture of the polymer, the drug and an organic solvent are combined with water, precipitates are formed and then the mixture is directly lyophilized to form particles. Therefore, when this particle is dispersed in water, it forms a suspension of macroscopically visible particles.
U.S. Pat. No. 5,543,158 discloses nanoparticles or microparticles formed from a water-insoluble block copolymer consisting essentially of poly(alkylene glycol) and poly(lactic acid). The molecular weight of the block copolymer is high and the copolymer is insoluble in water. In the nanoparticle or microparticle, the biodegradable moieties of the copolymer are in the core of the nanoparticle or microparticle and the poly(alkylene glycol) moieties are on the surface of the nanoparticle or microparticle in an amount effective enough to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system. Nanoparticles are prepared by dissolving the block copolymer and drug in an organic solvent, forming an o/w emulsion by sonication or stirring, and collecting the nanoparticles containing the drug following precipitation. It does not provide for the solubilization of hydrophobic drugs. The nanoparticles are solid particles that are suspended in water.
Currently there are few synthetic or natural polymeric materials that can be used for the controlled delivery of drugs, including peptide and protein drugs, because of strict regulatory compliance requirements such as biocompatibility and low toxicity, having a clearly defined degradation pathway, and safety of the polymers and degradation products. The most widely investigated and advanced biodegradable polymers in regard to available toxicological and clinical data are the aliphatic poly(&agr;-hydroxy acids), such as poly(D-, L-, or D, L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and their copolymers (PLGA). These polymers are commercially available and are presently used as bioresorbable sutures. FDA-approved microsphere systems for controlled release of leuprolide acetate (Lupron Depot™) and human growth hormone (Nutropin Depot™) are also based on PLGA copolymers. Based on this history of use, PLGA copolymers have been the materials of choice in the initial design of parenteral controlled release drug delivery systems using a biodegradable carrier.
Even though there has been some limited success, PLA, PGA, and PLGA polymers present problems as drug carriers that are associated with their physicochemical properties and attendant methods of fabrication. Hydrophilic macromolecules, such as proteins may not readily diffuse through hydrophobic matrices of these polymers. Drug loading and device fabrication using PLA and PLGA often requires use of toxic organic solvents or high temperatures that denature and degrade many drugs. Also, the solid and rigid geometries of the administered solid dosage form may mechanically induce tissue irritation and damage.
There has been no previous disclosure of a composition comprising biodegradable polyester oligomers, and particularly PLA/PLGA oligomers, and low molecular weight, biodegradable triblock or diblock copolymers having a high weight percentage (at least 50 weight percent) of hydrophobic block(s) as solubilizing agents for drugs, or hydrophobic drugs in particular. Accordingly, the present invention represents improved solubilizers that minimize or are free of the problems mentioned above. It has been unexpectedly demonstrated that compositions of biodegradable polyester oligomers, and particularly PLA/PLGA oligomers and amphiphilic, biodegradable triblock or diblock copolymers are more effective in solubilizing drugs and especially hydrophobic drugs than using the triblock or diblock copolymers alone. Biodegradable polyester oligomers, and particularly PLA/PLGA oligomers increase the solubilization capacity and stability of
Fowers Kirk Dee
Piao Ai-Zhi
Shih Chung
Zentner Gaylen M.
Fubara Blessing
Macromed Incorporated
Page Thurman K.
Thorpe North & Western LLP
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