Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2001-01-29
2004-03-02
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S424000, C424S425000, C424S426000, C424S501000, C424S050000
Reexamination Certificate
active
06699504
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to biodegradable compositions for sustained-release drug delivery and methods for administering a biologically active substance via these compositions.
Rapid advances in the fields of genetic engineering and biotechnology have led to the development of an increasing number of proteins and polypeptides that are useful as pharmaceutical agents. The development of methods for administering these new pharmaceutical agents is thus becoming increasingly important.
Most proteins have relatively short half-lives, requiring frequent administration to achieve efficacious blood levels. To increase patient convenience and to improve efficacy and safety by keeping blood levels within the therapeutic range, smoothly releasing injectable depot formulations of protein drugs are highly desirable.
Recent polymer developments have improved the ability to deliver proteins and peptides by allowing for slower and steadier release of the molecule in the patient's system. However, in many cases, the active form of the protein is difficult to formulate in biodegradable polymers. Synthetic materials, such as biodegradable hydrogels, have also been developed for use in delivering proteins. Despite the advances provided by the available polymers and hydrogels, the delivery of protein to the systemic and local circulation is still relatively rapid, in some cases too rapid to allow this route of administration to be used.
SUMMARY OF THE INVENTION
The present invention features articles for delivery of a biologically active substance (hereafter “BAS”), and methods for making such articles. The articles of the invention improve the bioavailability of the BAS by formulating the BAS in an insoluble form. The invention also features methods of treating an animal using the articles for delivery of a BAS.
Accordingly, in a first aspect the invention features a biocompatible therapeutic article for delivery of a BAS, comprising a macromer, a molecule or mixture of molecules which preferentially excludes proteins, and the BAS, wherein the BAS is in an insoluble format upon completion of the formulation of the article comprising the macromer, molecule, or mixture of molecules which preferentially excludes proteins, and BAS.
In a preferred embodiment of the first aspect of the invention, the biocompatible therapeutic article has at least one of the following properties: the BAS is less than 15% aggregated; the article contains at least 10% macromer and at least 5% BAS, as measured by dry weight; the time at which 5% of the releasable BAS is released from the article is greater than {fraction (1/16)} of t
50
; or the t
50
is greater than or equal to ⅝ of t
80
. More preferably the biocompatible therapeutic article has at least two of the above properties. Most preferably, the biocompatible therapeutic article has all of the above properties.
In another embodiment of the first aspect of the invention, the molecule which preferentially excludes proteins is a macromer, poly(ethylene glycol), hyaluronic acid, or poly(vinylpyrrolidone). In yet another embodiment, the macromer is a hydrogel. In still another embodiment, the solubility of a protein in the article comprising the macromer, molecule that preferentially excludes proteins, and BAS is less than 5-10 mg/ml, and more preferably is less than 1 mg/ml.
In another embodiment of the first aspect of the invention, the mixture of molecules comprises a positively charged ion-carrying reagent, for example, triethanolamine or Tris, when the pH is such that the protein is negatively charged. In still another embodiment, the mixture of molecules comprises a negatively charged ion-carrying reagent, such as sodium dodecyl sulfate, when the pH is such that the protein is positively charged. In yet another embodiment, the mixture of molecules comprises a surfactant, for example, Tween 20, Tween 80, or poloxamer F68. In a second aspect, the invention features a method for making a therapeutic article for delivery of a BAS, involving (a) combining the BAS with a molecule or mixture of molecules which preferentially excludes proteins; (b) combining the mixture formed in step (a) with a macromer, wherein the BAS is in an insoluble form and remains insoluble upon combining with the molecule or mixture of molecules which preferentially excludes proteins and the macromer; (c) forming a mixture of the combination formed in step (b); and (d) polymerizing the mixture to form an article.
In one embodiment of the second aspect of the invention, steps (a) and (b) are combined into a single combination step.
In a preferred embodiment of the second aspect of the invention, the biocompatible therapeutic article has at least one of the following properties: the BAS is less than 15% aggregated; the article contains at least 10% macromer and at least 5% BAS, as measured by dry weight; the time at which 5% of the releasable BAS is released from the article is greater than {fraction (1/16)} of t
50
; or the t
50
is greater than or equal to ⅝ of t
80
. More preferably the biocompatible therapeutic article has at least two of the above properties. Most preferably, the biocompatible therapeutic article has all of the above properties.
In another embodiment of the second aspect of the invention, the molecule which preferentially excludes proteins is a macromer, poly(ethylene glycol), hyaluronic acid, or poly(vinylpyrrolidone). In yet another embodiment, the macromer is a hydrogel. In yet another embodiment, the macromer is a hydrogel. In still another embodiment, the solubility of a protein in the article comprising the macromer, molecule that preferentially excludes proteins, and BAS is less than 5-10 mg/ml, and more preferably is less than 1 mg/ml.
In another embodiment of the second aspect of the invention, the mixture of molecules comprises a positively charged ion-carrying reagent, for example, triethanolamine, when the pH is such that the protein is negatively charged. In still another embodiment, the mixture of molecules comprises a negatively charged ion-carrying reagent, such as sodium dodecyl sulfate, when the pH is such that the protein is positively charged. In yet another embodiment, the mixture comprises a surfactant, for example, Tween 20, Tween 80, or poloxamer F68.
In a third aspect the invention features a method of treating an animal, involving administering the biocompatible therapeutic article of the first aspect of the invention to a mammal. Preferably the mammal is a rodent, and most preferably the mammal is a human.
In yet other preferred embodiments, the articles are administered to the lung of the mammal, or are administered intravenously, subcutaneously, intramuscularly, orally, or nasally.
In a preferred embodiment of any of the above aspects of the invention, the macromer comprises: (a) a region forming a central core; (b) at least two degradable regions attached to the core; and (c) at least two polymerizable end groups, where the polymerizable end groups are attached to the degradable regions. In preferred embodiments, the region forming a central core is a water soluble region. The water soluble region may be poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, polysaccharides, carbohydrates, proteins, and combinations thereof. The degradable region is selected from the group consisting of poly(&agr;-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(orthocarbonates), and poly(phosphoesters). Preferably, the poly(&agr;-hydroxy acid) is poly(glycolic acid), poly(DL-lactic acid), or poly(L-lactic acid), and the poly(lactone) is poly(&egr;-caprolactone), poly(&dgr;-valerolactone), or poly(&ggr;-butyrolactone). In another preferred embodiment, the degradable region comprises poly(caprolactone). In yet another embodiment, the polymerizable end groups contain a carbon—carbon double bond capable of polymerizing the macromer.
In other embodiments of
Annavajula Durga
Hubbell Jeffrey A.
Retnarajan Beadle P.
Rowe Stephen C.
Yim Kalvin
Azpuru Carlos A.
Bieker-Brady Kristina
Clark & Elbing LLP
Pelias Technologies, Inc.
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