Methods and compositions for administration of therapeutic...

Details Methods and compositions for administration of therapeutic... Methods and compositions for administration of therapeutic...

1999-07-09

2003-04-01

Stucker, Jeffrey (Department: 1648)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S486000, C514S002600, C514S054000, C514S057000, C530S323000, C530S326000

Reexamination Certificate

active

06541020

ABSTRACT:

1. FIELD OF THE INVENTION
The present invention relates to compositions and methods for the administration of therapeutic reagents. In particular, the invention relates to compositions and methods for the administration of the peptides known as T20 and T1249.
2. BACKGROUND
Peptide products have a wide range of uses as therapeutic and/or prophylactic reagents for prevention and treatment of disease. For example, many peptides are able to regulate biochemical or physiological processes to either prevent disease or to provide relief from symptoms associated with disease. For example, peptides such as viral or bacterial peptides have been utilized successfully as vaccines for prevention of pathological diseases. Additionally, peptides have been successfully utilized as therapeutic agents for treatment of disease symptoms. Such peptides fall into diverse categories such as, for example, hormones, enzymes, immunomodulators, serum proteins and cytokines.
For peptides to manifest their proper biological and therapeutic affect in patients, they must be present in appropriate concentrations at their sites of action in vivo. More specifically, the pharmacokinetics of any particular compound, including any particular peptide, is dependent on the bioavailability, distribution and clearance of that compound in vivo. However, the chemical nature and characteristics of peptides, such as size, complexity, conformational requirements and solubility profiles, tend to cause peptides to have pharmakokinetic profiles that are suboptimal compared to the pharmakokinetic profiles of other compounds.
Accordingly, there has been considerable effort in the art to attempt to develop ways to administer therapeutic reagents such as peptides so that both the bioavailability and the half-life of the therapeutic reagents are increased. For example, drug loaded biodegradable controlled release devices fabricated from polyglycolic acid (PGA) and polylactic acid (PLA) polymers have been described. One such device, the Lupron Depot™, consists of injectable microcapsules which release a therapeutic reagent, leuprolide acetate, over a prolonged period of time (e.g., about 30 days). However, due to the hydrophobic properties of these polymers, drug loading and device manufacturing using these methods requires organic solvents such as methylene chloride, chloroform, acetic acid or dimethyl formamide, which may induce tissue irritation in patients. Further, the final product requires extensive drying and exists as a distinct solid shape. Thus, such devices must be administered either as implants or injected as solid microspheres. Such solid dosage forms may cause additional tissue irritation, and administration as implants requires invasive surgery. In addition, hydrophilic molecules such as certain peptides cannot diffuse out through the hydrophobic matrix of these materials.
Injectable systems for delivering therapeutic reagents such as peptides have also been proposed. For example, Dunn et al., U.S. Pat. Nos. 4,938,763 and 5,278,202, describe thermoplastic and/or thermosetting polymer systems which may be mixed with a drug injected in a liquid form and which, upon injection and exposure to body fluids or water, coagulate into a gel polymer matrix encapsulating the drug. The gel polymer matrix releases the drug in a controlled manner and degrades to products that are readily metabolized and excreted. However, the solutions require the use of organic solvents, such as N-methyl-2-pyrrolidone, methyl ethyl ketone, dimethylformamide, propylene glycol, THF, DMSO, dodecylazacycloheptan-2-one and the like, that may be toxic or irritating to body tissues. Further, preparation of these systems is quite complicated and unwieldily; the drug must be admixed with the prepolymer solution followed by addition of a curing reagent. The preparation must be injected almost immediately after the addition of the curing reagent and cannot be stored.
Cha et al., U.S. Pat. No. 5,702,717, also describes an injectable system and method for delivering drugs, including peptides, dissolved or dispersed in a biodegradable block copolymer that has a reverse gelation temperature below the physiological temperature of a patient. Specifically, the copolymer consist of a hydrophobic polymer block composed of poly(&agr;-hydroxy acids) or poly(ethylene carbonates), and a hydrophilic polymer block composed of polyethylene glycol. The composition may be loaded with a drug and stored as a liquid at a temperature below its gelation temperature. However, upon injection into a patient, the temperature is increased and the composition undergoes a phase change to form a hydrogel.
Poloxamer compounds, which are block copolymer systems composed of two different polymer blocks, i.e., hydrophilic poly(ethylene oxide) blocks and hydrophobic poly(propylene oxide) blocks, are also known and may be used to administer certain compounds. These polymer blocks are synthesized to make a triblock of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) and marketed under the Pluronic™ tradenames. The compositions known as Pluronic F-127™ or Poloxamer 407™ is of particular interest for drug delivery. Pluronic F-127™ consists of approximately 70% ethylene oxide and 30% propylene oxide by weight, and has an average molecular weight of 11500. The copolymer has reverse thermal gelation properties, and is liquid at low temperature (under 10° C.) while forming a soft gel at physiological temperatures. Studies have been performed to investigate whether Pluronic F-127™ gels may be utilized as an injectable sustained release depot (see, e.g., Johnson et al., 1985
, J. Parenteral Sci
. &
Tech
. 39:83-88; Fults and Johnson, 1990
, J. Parenteral Sci
. &
Tech
. 44:58-65; Johnson et al., 1992
, Pharmaceutical Research
9:425-434; Morikawa et al., 1987
, Cancer Res
. 47:37-41; and Johnson and Miller, 1989
, J. Parental Sci
. &
Tech
. 43:279-285; Xu et al., 1993
, Pharmaceutical Research
10:1144-1152).
3. SUMMARY OF THE INVENTION
The present invention provides, first, carrier hydrogel compositions which may be used to administer bioactive molecules to a patient. Specifically, the carrier hydrogel compositions of the invention are compositions comprising a polymer material that forms a hydrogel at physiological temperatures and a polypeptide which is either T20 or T1249. The carrier hydrogel compositions of the invention are ideally suited for administering the specific peptides, referred to as T20 and T1249, which are described herein, as well as derivatives of the T20 and T1249 peptides described herein.
The carrier hydrogel compositions comprise gelling materials that possess a reverse thermal gelation property, and at least one peptide, i.e., T20, T1249 or a derivative thereof. The carrier hydrogel compositions exist as liquid, aqueous solutions at temperatures that are below physiological temperatures. However, when the gelling materials are exposed to physiological temperatures (e.g., temperatures of about 37° C.) they form a polymer gel which is biodegradable or at least bioerodible. Such carrier hydrogel compositions can be stored indefinitely in an aqueous state. The carrier hydrogel composition can then be administered to a patient in liquid form, e.g., by subcutaneous injection. Upon administration, the carrier hydrogel composition is heated to the patient's body temperature and forms a polymer gel which then acts as a sustained-release matrix for the peptides.
The carrier hydrogel compositions of the invention contain at least one polymer material in sufficient amounts (i.e., at sufficient concentrations in an aqueous solution) to form a gel. Preferably, the polymer material is Poloxamer 407™ or Methyl cellulose. The carrier hydrogel compositions of the invention also contain a T20 or T1249 peptide, or a derivative thereof, e.g., for administration to a patient. Preferably, the carrier hydrogel compositions of the invention contain a sufficient concentration of peptide such that an effective dose of the peptide is released.
The invention is based, at least in p

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