Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-10-31
2004-03-16
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S423000, C424S489000, C424S502000, C514S772300
Reexamination Certificate
active
06706289
ABSTRACT:
BACKGROUND OF THE INVENTION
Encapsulation of pharmaceuticals in biodegradable polymer microspheres and nanospheres can prolong the maintenance of therapeutic drug levels relative to administration of the drug itself. Sustained release may be extended up to several months depending on the formulation and the active molecule encapsulated. However many bioactive molecules, and especially proteins, are damaged or made unstable by the procedures required to encapsulate them in the polymeric carriers. Furthermore, the charged, polar nature of many proteins may limit the extent of encapsulation in polymer drug carriers and may lead to rapid loss of a fraction of the encapsulated bioactive molecule when first administered (“burst”).
Encapsulation of bioactive molecules in biodegradable polymer delivery systems has been used to stimulate an immune response when administered to a patient (see U.S. Pat. No. 5,942,253 to Gombotz et al.). While this is a desired result in certain cases, it is undesirable when the purpose is delivery of the bioactive molecule for therapeutic purposes. Thus, diminished recognition by the immune system of bioactive molecules delivered using biodegradable polymers would be beneficial in a therapeutic setting.
Bioactive molecules, especially therapeutic proteins (drugs), may be modified with hydrophilic polymers (a process generally known as “pegylation”), such as polyethylene glycol, covalently attached to one or more amino acid side chains (see e.g., U.S. Pat. No. 4,179,337 to Davis et al.; U.S. Pat. No. 5,446,090 to Harris; U.S. Pat. No. 5,880,255 to Delgado et al.). While it is known in the art that such attachment may lead to an apparent increase in molecular mass and decreased blood clearance rate for the modified therapeutic protein (see e.g., U.S. Pat. No. 5,320,840 to Camble et al.), the prior art does not teach that diminished immunogenicity can be achieved or that the duration of release from biodegradable polymer drug delivery systems can be extended using pegylated proteins. The prior art does not teach that pegylation can increase the drug loading achievable in a biodegradable drug delivery system relative to the unpegylated drug, nor does it teach that reduced burst of drug is achievable for the pegylated moiety relative to the unpegylated drug.
SUMMARY OF THE INVENTION
The present invention provides novel formulations for controlled, prolonged release of bioactive molecules such as therapeutic proteins, peptides and oligonucleotides. The formulations are based on microparticles or nanoparticles formed of the combination of biodegradable, polymers such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and copolymers thereof. Bioactive molecules are coupled to hydrophilic polymers such as polyethylene glycol or polypropylene glycol and then formulated with the solid microparticles or nanoparticles to provide controlled release. The controlled release formulations can be administered by injection, by inhalation, nasally, or orally.
Accordingly, as part of the present invention, it has been discovered that attachment of hydrophilic polymers to bioactive molecules, such as drugs and therapeutic proteins, has several beneficial effects, including providing protection from degradation and denaturation under the conditions of encapsulation in drug carriers. Additionally the amount of modified protein that can be encapsulated is increased relative to the unmodified protein, thus providing a lower total dose of material, benefiting both the patient and producer.
In addition, the present invention is further based on the discovery that immunogenicity of peglyated bioactive molecules encapsulated in biodegradable polymer drug delivery carriers is decreased relative to non-peglyated bioactive molecules in the carriers, particularly when administered by subcutaneous or intramuscular injection or inhalation or mucosal delivery (e.g., oral or nasal delivery). Such diminished immunogenicity is particularly advantageous when biodegradable polymers are used for oral delivery, since this is a typical method for mucosal vaccination.
In another aspect, the present invention is based on the discovery that pegylated proteins, peptides, oligosaccharides and oligonucleotides, which normally are not absorbed from the gastro-intestinal tract, are made bioavailable by administration in biodegradable polymer systems, particularly nanospheres. The term “bioavailable”, as used herein, refers to the fraction of bioactive molecule that enters the blood stream following administration to a subject. The controlled release formulations of the invention increase the bioavailability of bioactive molecules and, in particular, the nanosphere formulations described herein when administered orally. For example, blood levels can be maintained for up to several days following a single oral administration of nanosphere encapsulated peglyated bioactive molecule. Additionally the polyethylene glycol chains protect the bioactive molecules from degradation and denaturation in the process of forming the nanospheres, contribute to increased entrapment of active material, and diminish the “burst” effect.
Thus, in a preferred embodiment, the invention provides a pharmaceutical composition for controlled, sustained release and increased bioavailability of a bioactive molecule, which includes a polymer (e.g., PEG) conjugated therapeutic agent encapsulated into nanospheres. In a particularly preferred embodiment, the composition is administered orally.
In a preferred embodiment, the bioactive molecule is selected from the group consisting of &agr;-interferon, &bgr;-interferon, &ggr;-interferon, erythropoietins, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, interleukin 1, interleukin 2, interleukin 3, interleukin 12, asparaginase, adenosine deaminase, insulin, ACTH, glucagon, somatostatin, somatotropin, thymosin, parathyroid hormone, pigmentary hormones, somatomedin, leuteinizing hormone, chorionic gonadotropin, hypothalmic releasing factors, antidiuretic hormones, thyroid stimulating hormone, endorphins, enkephalins, biphalin, prolactin, monoclonal antibodies, polyclonal antibodies, antisense oligonucleotides, aptamers, therapeutic genes, heparin, low molecular weight heparin and small bioactive molecules.
Accordingly, the compositions of the present invention can be used to improve in vivo delivery of therapeutic bioactive molecules in several respects. In particular, the invention provides the advantages of reduced immunogenicity, increased bioavailability, increased duration, increased stability, decreased burst and controlled, sustained release of bioactive molecules in vivo.
DETAILED DESCRIPTION OF THE INVENTION
I. Bioactive Molecules
The term “bioactive molecule”, as used herein, refers to any therapeutic protein, peptide, polysaccharide, nucleic acid or other biologically active compound for administration to a subject, such as a human or other mammal. Suitable therapeutic proteins for use in the invention include, but are not limited to, interferon-alphas, interferon-betas, interferon-gamma, erythropoetins, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor (GM-CSF), interleukin 1, interleukin 2, interleukin 3, interleukin 12, asparaginase, adenosine deaminase and insulin.
Suitable therapeutic peptides also include hormones, such as ACTH, glucagon, somatostatin, somatotropin, thymosin, parathyroid hormone, pigmentary hormones, somatomedin, luteinizing hormone, chorionic gonadotropin, hypothalmic releasing factors, antidiuretic hormones, thyroid stimulating hormone, endorphins, enkephalins, biphalin and prolactin.
Additional suitable therapeutic proteins include monoclonal and polyclonal antibodies, single-chain antibodies, other antibody fragments, analogs and derivatives. Therapeutic polynucleotides, including antisense oligonucleotides, aptamers and therapeutic genes also can be delivered using the methods and compositions of the invention.
Anticoagulant therapeutics, such as heparin and low molecular weigh
Hinds Kenneth
Lewis Danny
Schmidt Paul
Azpuru Carlos A.
Hathaway Pease Russell, Esq.
Jane E. Remillard, Esq.
Lahive & Cockfield LLP
PR Pharmaceuticals, Inc.
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