WO2008132732A2

WO2008132732A2 - Methods and compositions for rectal administration of proteins

Info

Publication number: WO2008132732A2
Application number: PCT/IL2008/000547
Authority: WO
Inventors: Miriam Kidron
Original assignee: Oramed Pharmaceuticals Inc
Priority date: 2007-04-26
Filing date: 2008-04-27
Publication date: 2008-11-06
Also published as: WO2008132732A3

Abstract

This invention provides compositions comprising a protein and an absorption enhancer, methods for treating a disease, comprising administering same, and methods for rectal administration of a protein.

Description

METHODS AND COMPOSITIONS FOR RECTAL ADMINISTRATION OF

PROTEINS

FIELD OF INVENTION

[001] This invention provides methods and compositions comprising a protein and a chelating agent for treating a disease.

BACKGROUND OF THE INVENTION

[002] Peptides are made up of groups of amino acid linked together by amide bonds. Proteins also are groups of amino acids linked by amide bonds; proteins and peptides are separated by molecular weight or the number of amino acids in the chain. The technology for synthetically producing peptides has been improving, as has the technology for producing them biologically via recombinant DNA methods using bacteria.

[003] Peptides play a crucial role in many physiological processes, including actions as neurotransmitters, hormones, and antibiotics. Research has shown their importance in such fields as neuroscience, immunology, pharmacology, and cell biology.

[004] Their potent specific activity makes them good candidates for drug development, but the lack of in-vivo stability has restricted their therapeutic value. The low level of bioavailability of small peptides coupled to the high cost of synthesis also prohibited their use in cosmetic applications.

[005] Due to improved biotechnology, the accessibility of biologically active peptides to the pharmaceutical industry has increased considerably. However, a limiting factor in the development of peptide drugs is the relative ineffectiveness when given rectally. Almost all peptide drugs are parenterally administered, although parenterally administered peptide drugs are often connected with low patient compliance.

[006] The advent of genetic engineering and especially recombinant DNA technology has made available many biologically active peptides that previously were laboratory curiosities. The peptides include human insulin, human growth hormone, bovine growth hormone, endorphins and enkephalines, calcitonin, interferons, interleukins and other lymphokines, TPA, vasopressin, oxytocin and many others.

[007] Use of these biologically active peptides in medical practice is prone to difficulties. Because of the nature of the peptide bond, they are not stable in the acidic conditions of the stomach and thus have very poor oral activity. The most common route of administering biologically active peptides is by the intravenous route, which is not amenable to out-patient treatment.

SUMMARY OF THE INVENTION

[008] This invention provides, in one embodiment, a composition comprising a protein having a molecular weight of up to 100,000 Daltons and a chelating agent.

[009] In another embodiment, the present invention provides a method for rectal administration of a protein having a molecular weight of up to 100,000 Daltons to a subject, whereby a substantial fraction of the protein retains its activity after absorption through a rectal mucosal barrier of a subject, comprising administering rectally to a subject a pharmaceutical composition comprising a protein and a chelating agent

[0010] In another embodiment, the present invention provides a method for treating a disease in a subject, comprising administering rectally to a subject a pharmaceutical composition comprising a protein having a molecular weight of up to 100,000 Daltons and a chelating agent, thereby treating a disease.

BRIEF DESCRIPTION OF THE FIGURES

[0011] Figure 1 is a graph demonstrating the Glucose lowering effect of the intra-rectal insulin preparation of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0012] This invention provides compositions and methods comprising a protein having a molecular weight of up to 100,000 Daltons and a chelating agent. In another embodiment, the protein of the present invention is a peptide. In another embodiment, the present invention further provides an enhancer which enhances absorption through a rectal mucosal barrier of a subject. In one embodiment, as provided herein a composition comprising a protein having a molecular weight of up to 100,000 Daltons and a chelating agent have utility in the rectal administration of a protein having a molecular weight of up to 100,000 Daltons, whereby the protein is absorbed by the rectal mucosa into the bloodstream in an active form.

[0013] In another embodiment, this invention provides compositions and methods comprising a protein having a molecular weight of up to 100,000 Daltons and an enhancing agent. In another embodiment, the protein of the present invention is a peptide. In another embodiment, the absorption enhancer enhances absorption through a rectal mucosal barrier of a subject. In one embodiment, as provided herein the absorption enhancer is a chelating agent having utility in the rectal administration of a protein having a molecular weight of up to 100,000 Daltons, whereby the protein is absorbed by the rectal mucosa into the bloodstream in an active form.

[0014] In another embodiment, the methods and compositions of the present invention comprise a human protein having a molecular weight of up to 100,000 Daltons. In another embodiment, the human protein having a molecular weight of up to 100,000 Daltons is a recombinant human protein. In another embodiment, the protein of the present invention is a bovine protein. In another embodiment, the protein of the present invention is a porcine protein. In another embodiment, the protein of the present invention is a rat protein. In another embodiment, the protein of the present invention is a mouse protein. In another embodiment, the protein of the present invention is a guinea pig protein. In another embodiment, the protein of the present invention is a chicken protein. In another embodiment, the protein of the present invention is a worm protein. In another embodiment, the protein of the present invention is a Drosophila melanogaster protein. In another embodiment, the protein of the present invention is a whale protein. In another embodiment, the protein of the present invention is a metal complex protein (e.g. a zinc complex, protamine zinc, or globin zinc).

[0015] In another embodiment, the protein of the present invention is a regular-acting protein. In another embodiment, protein of the present invention is a fast-acting protein. In another embodiment, the protein of the present invention is a short-acting protein. In another embodiment, the protein of the present invention is a mixture of long-acting and short-acting protein. [0016] In another embodiment, the protein of the present invention is a native protein. In another embodiment, native protein is the wild-type form of a protein. In another embodiment, the protein of the present invention is a modified protein

[0017] In another embodiment, the protein of the present invention is a full length protein. In another embodiment, the protein of the present invention is a fragment with enzymatic activity. In another embodiment, the protein of the present invention is a homologue. In another embodiment the protein of the present invention is an orthologue. In another embodiment, the protein of the present invention is a sequence-modified with enzymatic activity. In another embodiment, the protein of the present invention is modified by man. In another embodiment, the protein of the present invention is chemically modified. In another embodiment, the protein of the present invention is chemically protected. Each possibility represents a separate embodiment of the present invention.

[0018] In another embodiment, the protein is an enzyme. In another embodiment, the protein is a receptor ligand, transporter, or a storage protein. In another embodiment, the protein is a structural protein.

[0019] In another embodiment, the enzyme is an oxidoreductase. In another embodiment, the enzyme is a transferase. In another embodiment, the enzyme is a hydrolase. In another embodiment, the enzyme is a lyase. In another embodiment, the enzyme is an isomerase. In another embodiment, the enzyme is a ligase.

[0020] In another embodiment, oxidoreductases act on the aldehyde or oxo group of donors, on the CH-CH group of donors, on the CH-NH(2) group of donors, on the CH-NH group of donors, on NADH or NADPH, on the CH-OH group of donors, on nitrogenous compounds as donors, on a sulfur group of donors, on a heme group of donors, on diphenols and related substances as donors, on a peroxide as acceptor, on hydrogen as donor, on single donors with incorporation of molecular oxygen, on paired donors, on superoxide as acceptor, oxidizing metal ions, on CH or CH(2) groups, on iron-sulfur proteins as donors, on reduced flavodoxin as donor, on phosphorus or arsenic in donors, or on x-H and y-H to form an x-y bond.

[0021] In another embodiment, transferases are acyltransferases or glycosyltransferases. In some embodiments, transferases transfer aldehyde or ketone residues. In another embodiment, transferases transfer alkyl or aryl groups, other than methyl groups. In another embodiment, transferases transfer nitrogenous, phosphorous, sulfur or selenium containing groups.

[0022] In another embodiment, hydrolases are glycosylases or act on ether bonds, on peptide bonds, on carbon-nitrogen bonds, other tha peptide bonds, on acid anhydrides, on carbon-carbon bonds, on halide bonds, on phosphorus-nitrogen bonds, on sulfur-nitrogen bonds, on carbon- phosphorus bonds, on sulfur-sulfur bonds, or on carbon-sulfur bonds.

[0023] In another embodiment, lyases are carbon-carbon lyases, carbon-oxygen lyases, carbon- nitrogen lyases, carbon-sulfur lyases, carbon-halide lyases, phosphorus-oxygen lyases, or other lyases.

[0024] In another embodiment, isomerases are racemases or epimerases, cis-trans-isomerases, intramolecular oxidoreductases, intramolecular transferases, intramolecular lyases, or other isomerases.

[0025] In another embodiment, ligases form carbon-sulfur bonds, carbon-nitrogen bonds, carbon- carbon bonds, phosphoric ester bonds, or nitrogen-metal bonds. PIs fix formatting

[0026] In another embodiment, transporter proteins are annexins, ATP-binding cassette transporters, hemoglobin, ATPases, calcium channels, potassium channels, sodium channels, or solute carriers.

[0027] In another embodiment, storage proteins comprise albumins, lactoglobulins, casein ovomucin, ferritin, phosvitin, lactoferrin, or vitellogenin. In one embodiment, albumins comprise avidin, ovalbumin, serum albumin, parvalbumin, c-reactive protein prealbumin, conalbumin, ricin, lactalbumin, methemalbumin, or transthyretin. Each possibility represents a separate embodiment of the present invention.

[0028] In another embodiment, structural proteins comprise amyloid, collagen elastin, or fibrillin.

[0029] In another embodiment, the protein is a viral protein, bacterial protein, invertebrate protein, or vertebrate protein. In some embodiments, the protein is a recombinant protein. In one embodiment, the protein is a recombinant protein. In one embodiment, the recombinant protein is a recombinant human protein.

[0030] In another embodiment, the protein of the present invention is a crystalline protein. In another embodiment, the protein of the present invention is an amorphous protein. In another embodiment, the protein of the present invention is a mixture of the protein in a crystal and an amorphous form. In another embodiment, the activity of the protein of the present invention is influenced by the physical state and size of the protein particles. In another embodiment, the duration of action of the protein is influenced by the physical state and size of the protein particles. Each possibility represents a separate embodiment of the present invention.

[0031 ] In some embodiments, the protein of the present invention exists in rhombohedral crystals as hexamers. In another embodiment, a crystalline protein of the present invention comprises protein-protamine complexes, such as neutral protamine Hagedorn (NPH).

[0032] In another embodiment, a crystalline protein of the present invention is over 70% pure as measured by rpHPLC. In another embodiment, a crystalline protein of the present invention is over 75% pure as measured by rpHPLC. In another embodiment, a crystalline protein of the present invention is over 80% pure as measured by rpHPLC. In another embodiment, a crystalline protein of the present invention is over 85% pure as measured by rpHPLC. In another embodiment, a crystalline protein of the present invention is over 90% pure as measured by rpHPLC. In another embodiment, a crystalline protein of the present invention is over 95% pure as measured by rpHPLC. In another embodiment, crystalline human zinc protein of the present invention is over 99% pure as measured by rpHPLC.

[0033] In some embodiments, a crystalline dry powder of the protein of the present invention may be formed by grinding or jet milling of bulk crystalline protein.

[0034] In another embodiment, a recombinant human protein of the present invention is produced in bacterial cells. In another embodiment, a recombinant human protein of the present invention is produced in Escherichia coli. In another embodiment, a recombinant human protein of the present invention is produced in yeast cells. In another embodiment, a recombinant human protein of the present invention is produced in Saccharomyces cerevisiae. In another embodiment, a recombinant human protein of the present invention is a modified protein synthesized by mutation of the genes used in E. coli or S. cerevisiae. In another embodiment, a recombinant human protein of the present invention is produced in insect. In another embodiment, a recombinant human protein of the present invention is produced in a cell line. In another embodiment, a recombinant human protein of the present invention is produced in CHO cells. Each possibility represents a separate embodiment of the present invention.

[0035] In another embodiment, the protein of the present invention is a plant protein. In another embodiment, a plant protein is a peptide. In another embodiment, the protein of the present invention is a bacterial peptide. In another embodiment, the bacterial peptide is a cationic antimicrobial peptide. In another embodiment, the bacterial peptide is cathelicidin. In another embodiment, the bacterial peptide is a microcin. In another embodiment, the bacterial peptide is a Peptaibol. In another embodiment, the bacterial peptide is a nonribosomally synthesized microbial macrocyclic peptide. In another embodiment, the bacterial peptide is a Iantibiotic Ih another embodiment, the bacterial peptide is a gram-positive peptide. In another embodiment, the bacterial peptide is a gram-negative peptide. In another embodiment, the bacterial peptide is a colicin.

[0036] In another embodiment, the protein of the present invention is a fungal peptide. In another embodiment, the fungal peptide possesses antifungal activity. In another embodiment, the fungal peptide is an amatoxin. In another embodiment, the fungal peptide is a phallotoxin. In another embodiment, the fungal peptide is a virotoxin. In another embodiment, the fungal peptide possesses ribonuclease activity. In another embodiment, the fungal peptide is a ribosome inactivating protein.

[0037] In another embodiment, the protein of the present invention is an invertebrate peptide. In another embodiment, the invertebrate peptide is an insect diuretic peptide. In another embodiment, the invertebrate peptide is an insect antidiuretic peptide.

[0038] In another embodiment, the protein of the present invention is a hormone. In another embodiment, the protein of the present invention is a developmental peptide. In another embodiment, the peptide of the present invention is ETH. In another embodiment, the peptide of the present invention is corazonin. In another embodiment, the peptide of the present invention is PTTH. In another embodiment, the peptide of the present invention is a tachykinin. In another embodiment, the peptide of the present invention is a tachykinin-related peptides. In another embodiment, the peptide of the present invention is proctolin. In another embodiment, the peptide of the present invention is sulf akinins . In another embodiment, the peptide of the present invention is myosuppressin. In another embodiment, the peptide of the present invention is an allatostatin. Each possibility represents a separate embodiment of the present invention.

[0039] In another embodiment, the peptide of the present invention is a Crustacea peptide. In another embodiment, the Crustacea peptide is a chromatophorotrophin. In another embodiment, the Crustacea peptide is a hyperglycemic hormone peptide.

[0040] In another embodiment, the peptide of the present invention is an amphibia peptide. In another embodiment, the amphibia peptide is an opioid Peptide from frog skin.

[0041] In another embodiment, the peptide of the present invention is a neuropeptides. In another embodiment, the peptide of the present invention is a bradykinin. In another embodiment, the peptide of the present invention is a bradykinin related peptide. In another embodiment, the peptide of the present invention is a snake venom peptide. In another embodiment, the peptide of the present invention is a sea anemone venom peptide. In another embodiment, the peptide of the present invention is a spider venom peptide. In another embodiment, the peptide of the present invention is a conus snail venom peptide.

[0042] In another embodiment, the peptide of the present invention is a Luteinizing Hormone- Releasing Hormone (LHRH). In another embodiment, the peptide of the present invention is an analogue of Luteinizing Hormone-Releasing Hormone (LHRH). in Cancer 61. In another embodiment, the peptide of the present invention is a bombesin-related peptides. In another embodiment, the peptide of the present invention is neurotensin. In another embodiment, the peptide of the present invention is endothelin. In another embodiment, the peptide of the present invention is adrenomedullin. In another embodiment, the peptide of the present invention is an angiotensin peptide. In another embodiment, the peptide of the present invention is gastrin.

[0043] In another embodiment, the peptide of the present invention is a growth factor. In another embodiment, the peptide of the present invention is an autocrine growth factor. In another embodiment, the peptide of the present invention is a paracrine growth factor. In another embodiment, the peptide of the present invention is an endocrine growth factor. In another embodiment, the peptide of the present invention is oxytocin. In another embodiment, the peptide of the present invention is an antagonists of growth hormone/releasing hormone (GHRH).

[0044] In another embodiment, the peptide of the present invention is a vaccine. In another embodiment, the peptide of the present invention is a cancer vaccine. In another embodiment, the peptide of the present invention is a synthetic peptide. In another embodiment, the peptide of the present invention is antiadhesin. In another embodiment, the peptide of the present invention is an antiadhesin synthetic peptide.

[0045] In another embodiment, the protein of the present invention is an antibody. In another embodiment, the peptide of the present invention is a peptide vaccine for malaria. In another embodiment, the peptide of the present invention is a peptide vaccine for otitis media. In another embodiment, the peptide of the present invention is a peptide vaccine for Alzheimer's disease. In another embodiment, the peptide of the present invention is a peptide dendrimer. In another embodiment, the peptide of the present invention is an immunogen.

[0046] In another embodiment, the peptide of the present invention is a pro- inflammatory peptide. In another embodiment, the peptide of the present invention is an anti-inflammatory peptide. In another embodiment, the peptide of the present invention is a chemotactic peptide. In another embodiment, the peptide of the present invention is a ligand for formylpeptide receptors influencing inflammation. In another embodiment, the peptide of the present invention is a complement-derived inflammatory peptide. In another embodiment, the peptide of the present invention is an anaphylatoxin. In another embodiment, the peptide of the present invention is a chemokine. In another embodiment, the peptide of the present invention is a neuromodulator. In another embodiment, the peptide of the present invention is a dipeptidyl aminopeptidase. In another embodiment, the peptide of the present invention is an RGD-peptide. In another embodiment, the peptide of the present invention is a neuropeptide that regulates an immune response. In another embodiment, the peptide of the present invention is a peptide that serves as a target of T cell-mediated immune response.

[0047] In another embodiment, the peptide of the present invention is derived from the use of positional scanning synthetic peptide combinatorial libraries that identify immunological relevant peptides. In another embodiment, the peptide of the present invention is a copolymer. In another embodiment, the peptide of the present invention is copolymer 1. In another embodiment, the peptide of the present invention is an immunomodulating peptide.

[0048] Ih another embodiment, the peptide of the present invention is a multifunctional MHC associated peptide. In another embodiment, the peptide of the present invention is an MHC Class II associated self-peptide.

[0049] In another embodiment, the peptide of the present invention is a brain related peptide. Ih another embodiment, the peptide of the present invention is vasopressin. In another embodiment, the peptide of the present invention is oxytocin. In another embodiment, the peptide of the present invention is thyrotrophin-releasing hormone. In another embodiment, the peptide of the present invention is gonadotrophin releasing hormone. In another embodiment, the peptide of the present invention is a brain somatostatin-related peptide. In another embodiment, the peptide of the present invention is a corticotrophin-releasing hormone (CRH) peptide. In another embodiment, the peptide of the present invention is a growth hormone-releasing hormone.

[0050] In another embodiment, the peptide of the present invention is a melanocortin. In another embodiment, the peptide of the present invention is a cocaine- and amphetamine-regulated transcript. In another embodiment, the peptide of the present invention is a melanin-concentrating hormone. In another embodiment, the peptide of the present invention is gastrin. In another embodiment, the peptide of the present invention is a hypocretins (Orexin). In another embodiment, the peptide of the present invention is a ghrelin. In another embodiment, the peptide of the present invention is a neurotensin. In another embodiment, the peptide of the present invention is a neuromedin. In another embodiment, the peptide of the present invention is a galanin peptide. In another embodiment, the peptide of the present invention is a GALP Systems peptide. In another embodiment, the peptide of the present invention is an adrenomedullin. In another embodiment, the peptide of the present invention is an RF amide-related peptide. In another embodiment, the peptide of the present invention is apelin. In another embodiment, the peptide of the present invention is urotensin. In another embodiment, the peptide of the present invention is urotensin related Peptide. In another embodiment, the peptide of the present invention is a natriuretic peptide (BNP). In another embodiment, the peptide of the present invention is a C-Type natriuretic peptide (CNP). In another embodiment, the peptide of the present invention is an endozepine. In another embodiment, the peptide of the present invention is a metastin.

[0051] In another embodiment, the peptide of the present invention is an opioid peptide regulating endocrine glands. In another embodiment, the peptide of the present invention is a neuropeptide Y. In another embodiment, the peptide of the present invention is PACAP. In another embodiment, the peptide of the present invention is an endothelin. In another embodiment, the peptide of the present invention is an adrenomedullin. In another embodiment, the peptide of the present invention is an adrenomedullin related peptide. In another embodiment, the peptide of the present invention is an atrial natriuretic peptide. In another embodiment, the peptide of the present invention is galanin. In another embodiment, the peptide of the present invention is a neuromedin.

[0052] In another embodiment, the peptide of the present invention is an ingestive peptide. In another embodiment, the peptide of the present invention is neuropeptide Y which acts as a conductor of the appetite-regulating orchestra in the hypothalamus. In another embodiment, the peptide of the present invention is a hypothalamic galaninln another embodiment, the peptide of the present invention is a melanocortin. In another embodiment, the peptide of the present invention is a melanin-concentrating hormone. In another embodiment, the peptide of the present invention is a corticotrophin-releasing hormone (CRH). In another embodiment, the peptide of the present invention is peptide YY (PYY). In another embodiment, the peptide of the present invention is Neuromedin MG (NMU). In another embodiment, the peptide of the present invention is cholecystokinin. In another embodiment, the peptide of the present invention is enterostatin. In another embodiment, the peptide of the present invention is glucagon like Peptide 1 (GLP-I). In another embodiment, the peptide of the present invention is Amylin. In another embodiment, the peptide of the present invention is calcitonin. In another embodiment, the peptide of the present invention is leptin. In another embodiment, the peptide of the present invention is insulin.

[0053] In another embodiment, the peptide of the present invention is a gastrointestinal peptide.

In another embodiment, the peptide of the present invention is adrenomedullin. In another embodiment, the peptide of the present invention is a corticotrophin-releasing hormone (CRH). In another embodiment, the peptide of the present invention is a defensin. In another embodiment, the peptide of the present invention is a gastrin-releasing peptide. In another embodiment, the peptide of the present invention is glucagon like Peptides 2 (GLP-2) . In another embodiment, the peptide of the present invention is enteroglucagon. In another embodiment, the peptide of the present invention is glicentin. In another embodiment, the peptide of the present invention is oxyntomodulin. In another embodiment, the peptide of the present invention is motilin.

[0054] In another embodiment, the peptide of the present invention is a pituitary adenylate cyclase activating polypeptide (PACAP). In another embodiment, the peptide of the present invention is a pancreatic peptide. In another embodiment, the peptide of the present invention is somatostatin. In another embodiment, the peptide of the present invention is a somatostatin analogue. In another embodiment, the peptide of the present invention is substance P. In another embodiment, the peptide of the present invention is a TFF (Trefoil Factor Family) Peptide.

[0055] In another embodiment, the peptide of the present invention is a vasoactive intestinal peptide. In another embodiment, the peptide of the present invention is a cardiovascular peptide. In another embodiment, the peptide of the present invention is adrenomedullin. In another embodiment, the peptide of the present invention is angiotensin II and its related peptides. In another embodiment, the peptide of the present invention is a natriuretic peptide in the cardiovascular system. In another embodiment, the peptide of the present invention is vasopressin.

[0056] In another embodiment, the peptide of the present invention is a renal peptide. In another embodiment, the peptide of the present invention is a neurohypophyseal peptide. In another embodiment, the peptide of the present invention is a renal renin-angiotensin system peptide. In another embodiment, the peptide of the present invention is urodilatin. In another embodiment, the peptide of the present invention is ANP. In another embodiment, the peptide of the present invention regulates renal tubular transport processes. In another embodiment, the peptide of the present invention is intermedin. In another embodiment, the peptide of the present invention is prolactin.

[0057] In another embodiment, the peptide of the present invention is a proenkephalin-derived opioid peptide. In another embodiment, the peptide of the present invention is a prodynorphin- derived opioid peptide. In another embodiment, the peptide of the present invention is a POMC opioid peptide. In another embodiment, the peptide of the present invention is an endomorphin. In another embodiment, the peptide of the present invention is a casomorphin. In another embodiment, the peptide of the present invention is a hemorphin. [0058] In another embodiment, the peptide of the present invention is an anti-opioid peptide. In another embodiment, the peptide of the present invention is nociceptin. In another embodiment, the peptide of the present invention is an exorphin-opioid active peptide. In another embodiment, the peptide of the present invention is a neurotrophic peptide. In another embodiment, the peptide of the present invention is insulin-like growth factor 1. In another embodiment, the peptide of the present invention is erythropoietin. In another embodiment, the peptide of the present invention is a neuregulin.

[0059] In another embodiment, the peptide of the present invention is a blood-brain barrier modulator peptide. In another embodiment, the peptide of the present invention is an oligopeptide transport peptide. In another embodiment, the peptide of the present invention is a fibroblast growth factor peptide.

[0060] In another embodiment, the peptide of the present invention is a prebiotic peptide. In another embodiment, the peptides of the present invention are mixture-based combinatorial libraries of synthetic peptides for Structural and functional analyses of viruses. In another embodiment, the peptides of the present invention are mixture-based combinatorial libraries of synthetic peptides for Structural and functional analyses of HIV. In another embodiment, the peptide of the present invention is a pheromone. In another embodiment, the peptide of the present invention is a fish peptide. In another embodiment, the peptide of the present invention is a sleep peptide. Each possibility represents a separate embodiment of the present invention.

[0061 ] In another embodiment, the peptide of the present invention is used for treating a disease. In another embodiment, the term "disease" according to the present invention comprises disorder. In another embodiment, the peptide of the present invention is used for abrogating a disease. In another embodiment, the peptide of the present invention is used for inhibiting a disease. In another embodiment, the peptide of the present invention is used for preventing a disease.

[0062] In another embodiment, the peptide of the present invention is an anti-cancer peptide. In another embodiment, the anti-cancer peptide is a monoclonal antibody. In another embodiment, the monoclonal antibodies are used for treatment of cancer. Ih another embodiment, monoclonal antibodies react against specific antigens on cancer cells. In another embodiment, the monoclonal antibody acts as a cancer cell receptor antagonist. In another embodiment, monoclonal antibodies enhance the patient's immune response. Ih another embodiment, monoclonal antibodies act against cell growth factors, thus blocking cancer cell growth. In another embodiment, anti-cancer monoclonal antibodies are conjugated or linked to anti-cancer drugs, radioisotopes, other biologic response modifiers, other toxins, or a combination thereof.

[0063] In another embodiment, the peptide of the present invention is a selective tyrosine kinase inhibitor. In another embodiment, the selective tyrosine kinase inhibitor inhibits catalytic sites of cancer promoting receptors thereby inhibiting tumor growth. In another embodiment, a selective tyrosine kinase inhibitor modulates growth factor signaling. In another embodiment, the selective tyrosine kinase inhibitor targets EGFR (ERB B/HER) family members. In another embodiment, the selective tyrosine kinase inhibitor is a BCR-ABL tyrosine kinase inhibitor. In another embodiment, the selective tyrosine kinase inhibitor is an epidermal growth factor receptor tyrosine kinase inhibitor. In another embodiment, the selective tyrosine kinase inhibitor is a vascular endothelial growth factor tyrosine kinase inhibitor. In another embodiment, the selective tyrosine kinase inhibitor is a Platelet Derived Growth Factor (PDGF) inhibitor.

[0064] In another embodiment, the peptide of the present invention is a cancer vaccine. In another embodiment, the cancer vaccine is a therapeutic vaccine thus, treating an existing cancer. In another embodiment, the cancer vaccine is a prophylactic vaccine thus, preventing the development of cancer. In another embodiment, both types of vaccines have the potential to reduce the burden of cancer. In another embodiment, treatment or therapeutic vaccines are administered to cancer patients and are designed to strengthen the body's natural defenses against cancers that have already developed. In another embodiment, therapeutic vaccines may prevent additional growth of existing cancers, prevent the recurrence of treated cancers, or eliminate cancer cells not killed by prior treatments. In another embodiment, prevention or prophylactic vaccines are administered to healthy individuals and are designed to target cancer in individuals who present high risk for the disease. In another embodiment, the cancer vaccine is an antigen/adjuvant vaccine. In another embodiment, the cancer vaccine is a whole cell tumor vaccine. In another embodiment, the cancer vaccine is a dendritic cell vaccine. In another embodiment, the cancer vaccine comprises viral vectors and/or DNA vaccines. In another embodiment, the cancer vaccine is an idiotype vaccine. [0065] In another embodiment, the peptide of the present invention is an anti-cancer chemotherapeutic peptide. In another embodiment, the anti-cancer chemotherapeutic peptide is a cytotoxic antibiotic. In another embodiment, the anti-cancer chemotherapeutic peptide is an antimetabolite. In another embodiment, the anti-cancer chemotherapeutic peptide is an aromatase inhibitor.

[0066] In another embodiment, the peptide of the present invention is a Bax activity modulator. In another embodiment, the peptide of the present invention is an angiotensin π receptor modifier.

[0067] In another embodiment, the peptide of the present invention is an immunomodulating peptide. In another embodiment, the immunomodulating peptide is an immunosuppressive peptide.

[0068] In another embodiment, the peptide of the present invention is an immunostimulatory peptide. In another embodiment, the immunostimulatory peptide is a specific immunostimulator thus, provides antigenic specificity during an immune response, such as a vaccine or any antigen. In another embodiment, the immunostimulatory peptide is a non-specific immunostimulator thus, acting irrespective of antigenic specificity to augment immune response of other antigen or stimulate components of the immune system without antigenic specificity. In another embodiment, the non-specific immunostimulator is Freund's complete adjuvant. In another embodiment, the non-specific immunostimulator is Freund's incomplete adjuvant.

[0069] In another embodiment, the immunomodulating peptide is an anti-inflammatory peptide. In another embodiment, the anti-inflammatory peptide is a non-steroidal anti-inflammatory peptide. In another embodiment, the non-steroidal anti-inflammatory peptide is a cox-1 inhibitor. In one embodiment, the non-steroidal anti-inflammatory peptide is a cox-2 inhibitor. In one embodiment, the non-steroidal anti-inflammatory peptide is a cox-1 and cox-2 inhibitor.

[0070] In another embodiment, the immunomodulating peptide is an anti-rheumatic peptide. In another embodiment, the anti-rheumatic peptide is a disease modifying anti-rheumatic drug. In another embodiment, the disease modifying anti-rheumatic drug is a slow-acting anti-rheumatic drug. In another embodiment, the disease modifying anti-rheumatic drug is an antimalarial peptide. [0071] In another embodiment, the peptide of the present invention is an antidiabetic peptide. In another embodiment, the antidiabetic peptide is an alpha glucosidase inhibitor. In another embodiment, the antidiabetic peptide is insulin. In another embodiment, the insulin is rapid-acting insulin. In another embodiment, the insulin is short-acting insulin. In another embodiment, the insulin is intermediate-acting insulin. In another embodiment, the insulin is intermediate- and short-acting insulin mixtures. In another embodiment, the insulin is long-acting insulin. In one embodiment, the antidiabetic peptides are inhibitors of fatty acid binding protein (aP2) such as glucagon-like peptide-1 (GLP-I), and dipeptidyl peptidase IV (DPP4) inhibitors.

[0072] In another embodiment, the peptide of the present invention is a peptide used for treating the nervous system. In another embodiment, the peptide used for treating the nervous system is a peptide treating the autonomic nervous system. In another embodiment, the peptide used for treating the autonomic nervous system is an adrenomimetic drug. In another embodiment, the adrenomimetic drug is a beta-adrenoceptor agonist,. In another embodiment, the adrenomimetic drug is an alpha-adrenoceptor agonist. In another embodiment, the adrenomimetic drug is a combination of a beta-adrenoceptor agonist and an alpha-adrenoceptor agonist.

[0073] In another embodiment, the peptide used for treating the autonomic nervous system is an adrenoceptor antagonist. In another embodiment, the peptide used for treating the autonomic nervous system is a cholinomimetic peptide. In another embodiment, the cholinomimetic peptide is a direct-acting parasympathomimetic drug. In another embodiment, the peptide used for treating the autonomic nervous system is a cholinesterase inhibitor. In another embodiment, the peptide used for treating the autonomic nervous system is a muscarinic blocking peptide. In another embodiment, the peptide used for treating the autonomic nervous system is a gangilionic blocking peptide. In another embodiment, the peptide used for treating the nervous system is a peptide treating the central nervous system. In another embodiment, the peptide used for treating the central nervous system is a local anesthetic peptide. In another embodiment, the peptide used for treating the central nervous system is an analgesic peptide. In another embodiment, the peptide used for treating the central nervous system is a muscle relaxant or vasoconstrictor peptide. In another embodiment, the peptide used for treating the central nervous system is an antiemetic drug. In another embodiment, the antiemetic drug is a 5-HT3 receptor antagonist. In another embodiment, the peptide used for treating the central nervous system is a sedative peptide. In another embodiment, the sedative peptide is an antidepressant peptide. In another embodiment, the peptide used for treating the central nervous system is a neurodegenerative disorder medication. In another embodiment, the neurodegenerative disorder medication is an acetylcholinesterase inhibitor. In another embodiment, the neurodegenerative disorder medication is an N-methyl-D- aspartate (NMDA) antagonist. In another embodiment, the neurodegenerative disorder medication reduces damage to motor neurons such as riluzole. In another embodiment, the neurodegenerative disorder medication silences the gene that causes the progression of the disease.

[0074] In another embodiment, the peptide used for treating the central nervous system is an antiepileptic drug (AED). In another embodiment, antiepileptic peptides include sodium channel blockers, GABA receptor agonists, GABA reuptake inhibitors, GABA transaminase inhibitor, AEDs with a potential GABA mechanism of action, glutamate blockers, or AEDs with other mechanisms of action. In another embodiment, the peptide used for treating the central nervous system is an anti-addiction drug. In another embodiment, the anti-addiction is an anti-alcoholism drug. In another embodiment, the anti-addiction drug is a serotonin uptake inhibitor, dopaminergic agonist, or opioid antagonist.

[0075] In another embodiment, the peptide used for treating the central nervous system is a peptide treating Alzheimer disease. In another embodiment, peptides treating Alzheimer's disease include but are not limited to a cholinesterase inhibitor, gamma secreatse inhibitor, or a beta lowering drug.

[0076] In another embodiment, the peptide used for treating the central nervous system is a peptide treating mild cognitive impairment. In another embodiment, peptides treating mild cognitive impairment include but are not limited to an AMPA regulator.

[0077] In another embodiment, the peptide used for treating the central nervous system is a peptide treating Parkinson's disease. In another embodiment, peptides treating Parkinson's disease include but are not limited to a dopaminergic drugs.

[0078] In another embodiment, the peptide used for treating the central nervous system is a peptide treating sexual dysfunction. In another embodiment, peptides treating sexual dysfunction include but are not limited to PDE5 inhibitors, [0079] In another embodiment, the peptide of the present invention is a peptide treating the cardiovascular system. In another embodiment, the peptide used for treating the cardiovascular system is treating a congestive heart failure. In another embodiment, the peptide used for treating congestive heart failure is an angiotensin converting enzyme (ACE) inhibitor.

[0080] In another embodiment, the peptide used for treating the cardiovascular system is an antiarrhythmic peptide. In another embodiment, the anti-arrhythmic peptide is a sodium channel blocker, beta-adrenergic blocker, calcium channel blocker, or a peptide that prolong repolarization.

[0081] In another embodiment, the peptide used for treating the cardiovascular system is an antianginal peptide. In another embodiment, the anti-anginal peptide is an antiplatelet peptide, adrenoceptor antagonist, calcium channel blocker, or a vasodilator.

[0082] In another embodiment, the peptide used for treating the cardiovascular system is a vasocative peptide or an inotrope.

[0083] In another embodiment, the peptide used for treating the cardiovascular system is an anticoagulant peptide. In another embodiment, the anticoagulant peptide is unfractionated heparin. In another embodiment, the peptide used for treating the cardiovascular system is fibrinolytic. In another embodiment, the peptide used for treating the cardiovascular system is a hypercholesterolemic peptide.

[0084] In another embodiment, the peptide of the present invention is a peptide treating the gastrointestinal system. In another embodiment, the peptide used for treating the gastrointestinal (GI) system is enhancing GI motility. In one embodiment, the peptide enhancing GI motility is a prokinetic peptide.

[0085] In another embodiment, the peptide used for treating the GI system is an emetic peptide. Ih another embodiment, the peptide used for treating the GI system is an H2-receptor antagonist. In another embodiment, the peptide used for treating the GI system is a proton pump inhibitor. In another embodiment, the peptide used for treating the GI system is a peptide treating inflammation. [0086] In another embodiment, the peptide of the present invention is a peptide treating a dermatological disorder. In another embodiment, the peptide used for treating a dermatological disorder is a photochemotherapy peptide. In another embodiment, the peptide treating a dermatological disorder is a photodynamic peptide such as porphyrin. In another embodiment, the peptide used for treating a dermatological disorder is an anti-malarial peptide, antimicrobial peptide, or antifungal peptide. In another embodiment, the peptide used for treating a dermatological disorder is an antibiotic. In another embodiment, the antibiotic is a systemic antibiotic. In another embodiment, the peptide used for treating a dermatological disorder is an antiviral peptide such as interferon alpha. In another embodiment, the peptide used for treating a dermatological disorder is an antiscabies peptide. In another embodiment, the peptide used for treating a dermatological disorder is an immunosuppressive peptide. In another embodiment, the peptide used for treating a dermatological disorder is a topical immunosuppressive peptide. In another embodiment, the peptide used for treating a dermatological disorder is an antihistamine. In another embodiment, the peptide used for treating a dermatological disorder is becaplermin, etanercept, denileukin diftitox, or botulinum toxin.

[0087] In another embodiment, the peptide used for treating a dermatological disorder is a growth factor such as epidermal growth factor (EGF), transforming growth factor-α (TGF-α), platelet derived growth factor (PDGF), fibroblast growth factors (FGFs) including acidic fibroblast growth factor (α-FGF) and basic fibroblast growth factor (β-FGF), transforming growth factor-β (TGF-β) and insulin like growth factors (IGF-I and IGF-2), or any combination thereof.

[0088] In another embodiment, the peptide of the present invention is an anti-infective peptide. In another embodiment, the anti-infective peptide is an antibiotic peptide. In another embodiment, the antibiotic is a cyclic peptide antibiotic. In another embodiment cyclic peptide antibiotics include but are not limited to vancomycin, streptogramins, Microcin J25, Bacteriocin AS-48, RTD-I, or polymyxins.

[0089] In another embodiment, the antibiotic is an anti-tuberculosis peptide. In another embodiment, the antibiotic is an antifungal peptide. In another embodiment, the antibiotic is an antiprotozoal peptide. In another embodiment, the antibiotic is an antimalarial peptide. In another embodiment, the antibiotic is an antiviral peptide. [0090] In another embodiment, the peptide of the present invention is a peptide treating the liver. In another embodiment, the peptide of the present invention is a bile acid sequestrant. In another embodiment, the peptide of the present invention is a cholesterol absorption inhibitor.

[0091] In another embodiment, the peptide of the present invention is a peptide treating the kidney. In another embodiment, the peptide used for treating the kidney is a diuretic peptide.

[0092] In another embodiment, the peptide used for treating the kidney is erythropoietin. In another embodiment, erythropoietin is obtained from natural sources, or recombinantly produced protein and analogs thereof, as well as human erythropoietin analogs with increased glycosylation and/or changes in the amino acid and the hyperglycosylated analogs having 1-14 sialic acid groups and changes in the amino acid sequence.

[0093] In another embodiment, the peptide of the present invention is a peptide treating a metabolic disease. In another embodiment, the peptide used for treating a metabolic disease is a pancreatic lipase inhibitor or norepinephrine reuptake inhibitor, insulin-sensitizers, PPAR agonist, Dual-acting PPAR agonist, PPAR-delta agonist, DPP-IV Inhibitor, alpha glucosidase inhibitors, AT-H receptor antagonists, cannabinoid receptor antagonists, cholesteryl ester transfer protein or CETP Inhibitors, or beta-3 adrenergic agonist.

[0094] In another embodiment, the peptide of the present invention is a peptide treating the endocrine system. In another embodiment, the peptide used for treating the endocrine system is a 5-alpha-reductase inhibitor.

[0095] In another embodiment, the peptide used for treating the endocrine system is a gonadotropin-releasing hormone agonist or antagonist. In another embodiment, the peptide used for treating the endocrine system is a luteinizing hormone agonist or

[0096] In another embodiment, human growth hormone treats the endocrine system is a. In another embodiment, human growth hormones include but are not limited to somatotropin or analogues. Ih another embodiment, the peptide used for treating the endocrine system is a ghrelin. In another embodiment, ghrelins include but are not limited to human ghrelin, CYT-009-GhrQb, L-692429, GHRP-6, SK&F-l 10679, or U-75799E. [0097] In another embodiment, the peptide used for treating the endocrine system is a leptin. In another embodiment, leptins include but are not limited to metreleptin or pegylated leptin. In another embodiment, a peptide treating the endocrine system is a leptin receptor agonist.

[0098] In another embodiment, the peptide of the present invention is a behavior-modulating peptide. In another embodiment, behavior-modulating peptides include but are not limited to antianxiety peptides, anti-psychotic peptides, anti-depressants, beta-blockers, beta-2 agonists, anticholinergic bronchodilators, or a neuraminidase inhibitor.

[0099] In another embodiment, the peptide of the present invention is a peptide treating a connective tissue disease. In another embodiment, peptides treating a connective tissue include but are not limited to an anti-malaria peptide, cytotoxic peptides, lupus medications, anti-rheumatic peptides, or anti-inflammatory peptides.

[00100] In another embodiment, the peptide of the present invention is a peptide treating an ophthalmic disease.

[00101] Each disease or disorder and the peptides treating these diseases represent a separate embodiment of the present invention.

[00102] In another embodiment, the amount of protein of the present invention utilized in methods and compositions of the present invention is about 0.0001-100 mg/kg in humans.

[00103] In another embodiment, the amount of protein of the present invention is about 0.0001-100 mg/kg. In another embodiment, the amount is about 0.001-100 mg/kg. In another embodiment, the amount is aboutO.001-100 mg/kg. In another embodiment, the amount is aboutO.01-100 mg/kg. In another embodiment, the amount is about 0.001 - 100 mg/kg. In another embodiment, the amount is about 0.1-100 mg/kg. In another embodiment, the amount is about 0.001-100 mg/kg. In another embodiment, the amount is about 1-100 mg/kg. In another embodiment, the amount is about 0.001-100 mg/kg. In another embodiment, the amount is about 10-100 mg/kg. In another embodiment, the amount is about 0.001-100 mg/kg. In another embodiment, the amount is about 20-100 mg/kg. In another embodiment, the amount is about 40-100 mg/kg. In another embodiment, the amount is about 1-2.5 mg/kg. In another embodiment, the amount is about 50- 100 mg/kg. In another embodiment, the amount is about 2-3 mg/kg. In another embodiment, the amount is 20-70 mg/kg. In another embodiment, the amount is about 2-5 mg/kg. In another embodiment, the amount is 30-80 mg/kg.

[00104] Ih another embodiment, the amount of protein in a composition of the present invention is

0.001-2 mg/kg. In another embodiment, the amount is 0.01-2 mg/kg. In another embodiment, the amount is 0.001-5 mg/kg. In another embodiment, the amount is 0.04-2 mg/kg. In another embodiment, the amount is 0.001-10 mg/kg. In another embodiment, the amount is 0.6-2 mg/kg.

In another embodiment, the amount is 0.001-15 mg/kg. In another embodiment, the amount is 1-

10 mg/kg. In another embodiment, the amount is 0.001-20 mg/kg. In another embodiment, the amount is 0.001-30 mg/kg. In another embodiment, the amount is 1.6 mg/kg. In another embodiment, the amount is 0.001-40mg/kg. In another embodiment, the amount is 2 mg/kg. In another embodiment, the amount is 0.001-50 mg/kg. In another embodiment, the amount is 2.5 mg/kg. In another embodiment, the amount is 0.001-80 mg/kg.

[00105] In another embodiment, the amount of protein in a composition of the present invention is administered in a single dosage. In another embodiment, the amount of protein of the present invention is administered twice daily. In another embodiment, the amount of protein of the present invention is administered three timed daily. In another embodiment, the amount of protein of the present invention is administered in multiple dosages. In another embodiment, the amount of protein of the present invention is administered once a week. In another embodiment, the amount of protein of the present invention is administered once a month. In another embodiment, the amount of protein of the present invention is administered once a week.

[00106] In another embodiment, the amount of protein in a composition of the present invention is 0.1-0.5 mg. In another embodiment, the amount is 0.1 -0.5 mg. Li another embodiment, the amount is 100-150 mg. In another embodiment, the amount is 0.3-1 mg. In another embodiment, the amount is 1-3 mg. In another embodiment, the amount is 2-10 mg. In another embodiment, the amount is 3-10 mg. In another embodiment, the amount is 5-10 mg. In another embodiment, the amount is 1-20 mg. In another embodiment, the amount is 2-20 mg. In another embodiment, the amount is 3-20 mg. In another embodiment, the amount is 5-20 mg. In another embodiment, the amount is 7-20 mg. In another embodiment, the amount is 10-20 mg. In another embodiment, the amount is 12-20 mg. In another embodiment, the amount is 10-12 mg. Ih another embodiment, the amount is 10- 15 mg. In another embodiment, the amount is 10-25 mg. In another embodiment, the amount is 10-30 mg. In another embodiment, the amount is 20-30 mg. In another embodiment, the amount is 10-50 mg. In another embodiment, the amount is 20-50 mg. In another embodiment, the amount is 30-50 mg. In another embodiment, the amount is 20-100 mg. In another embodiment, the amount is 100-150 mg. In another embodiment, the amount is 150-200 mg. In another embodiment, the amount is 300-1000 mg.

[00107] In another embodiment, the amount of protein in a composition of the present invention is 1000- 1200 mg. In another embodiment, the amount is 300-1000 mg. In another embodiment, the amount is 1200-1500 mg. In another embodiment, the amount is 300-1000 mg. In another embodiment, the amount is 1500-2000 mg. In another embodiment, the amount is 2000-2500 mg. In another embodiment, the amount is 1000-1200 mg. In another embodiment, the amount is 2500-3000 mg. In another embodiment, the amount is 3000-3500 mg. In another embodiment, the amount is 300-1000 mg. In another embodiment, the amount is 3500-4000 mg. In another embodiment, the amount is 300-1000 mg. In another embodiment, the amount is 4000-4500 mg. In another embodiment, the amount is 4500-5000 mg. In another embodiment, the amount is 1000-1200 mg.

[00108] In another embodiment, the use of sustained release dosage forms (e.g. sustained release microencapsulation) enables the treatment frequency to be reduced. In another embodiment, the use of sustained release dosage forms enables the treatment frequency to be reduced to once or twice a day. In another embodiment, the protein of the present invention dosage is increased correspondingly with decreasing frequency of administration.

[00109] Each amount of protein of the present invention represents a separate embodiment of the present invention.

[00110] Methods of measuring the protein of the present invention levels are well known in the art. In another embodiment, levels of recombinant protein of the present invention are measured using a radio-immunoassay (RIA) kit. In another embodiment, protein of the present invention ELISA kits are used. In another embodiment, proteins of the present invention levels are measured by any other method known in the art. Each possibility represents a separate embodiment of the present invention. [00111] In another embodiment, the compositions of the present invention further comprise pharmaceutical excipients. In another embodiment, pharmaceutical excipients comprise chelating agents. In another embodiment, pharmaceutical excipients comprise a substance that enhances absorption of the protein of the present invention through a rectal mucosal barrier. In another embodiment, a substance that enhances absorption of the protein of the present invention through a rectal mucosal barrier is a rectal absorption enhancer. In another embodiment, the terms "rectal absorption enhancer" and "absorption enhancer" are used interchangeably. In another embodiment, a substance that enhances absorption of the protein of the present invention through a rectal mucosal barrier is a protein of the present invention rectal absorption enhancer. In another embodiment, a substance that enhances absorption of recombinant protein of the present invention through a rectal mucosal barrier is a rectal absorption enhancer. In another embodiment, the absorption enhancer of the present invention is a chelating agent. In another embodiment, the absorption enhancer, when administered to the rectum in a composition comprising crystalline protein of the present invention, acts within the rectum in such a way as to induce absorption of crystalline protein of the present invention into the living body through the rectal mucous membrane.

[00112] In another embodiment, the compositions of the present invention further comprise a chelating agent. In another embodiment, a chelating agent enhances absorption of protein of the present invention. In another embodiment, as provided herein, enhancers, when used in a composition comprising protein of the present invention, enhance its ability to be absorbed in the blood.

[00113] In another embodiment, the compositions of the present invention further comprise a poly unsaturated fatty acid (PUFA). In another embodiment, a PUFA of the present invention acts as an absorption enhancer. In another embodiment, the compositions of the present invention further comprise didecanoylphosphatidylcholine (DDPC). In another embodiment, the compositions of the present invention further comprise an aminopolycarboxylate. In another embodiment, the compositions of the present invention further comprise a chelating agent. In another embodiment, the absorption enhancer is a chelating agent. In another embodiment, the chelating agents of the present invention comprise ethylenediaminetetraacetic acid (EDTA) or egtazic acid EGTA. In another embodiment, the EDTA is sodium-EDTA. In another embodiment, the chelating agent is Sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC). Li another embodiment, the chelating agent is diethylene triamine pentaacetic acid (DTPA). In another embodiment, the chelating agent is nitrilotriacetic acid (NTA). In another embodiment, NTA is combined with His-tags. In another embodiment, the chelating agent is aphosphonate. In another embodiment, the chelating agent is phosphonic acid. In another embodiment, the phosphonate is a bisphosphonate. In another embodiment, the bisphosphonate is HEDP. In another embodiment, phosphonic acids of the invention comprise an amine group which, in some embodiments increases the metal binding abilities of the phosphonate.

[00114] Ih another embodiment, the compositions of the present invention further comprise tolmetin. In another embodiment, tolmetin acts as an absorption enhancer. In another embodiment, tolmetin of the present invention comprise tolmetin salt. In another embodiment, the compositions of the present invention further comprise sodium caprate. In another embodiment, sodium caprate acts as an absorption enhancer. In another embodiment, the compositions of the present invention further comprise salicylic acid. In another embodiment, salicylic acid acts as an absorption enhancer. In another embodiment, the compositions of the present invention further comprise oleic acid. In another embodiment, oleic acid acts as an absorption enhancer. In another embodiment, the compositions of the present invention further comprise linoleic acid. In another embodiment, linoleic acid acts as an absorption enhancer. In another embodiment, the compositions of the present invention further comprise linolenic acid. In another embodiment, linolenic acid acts as an absorption enhancer. In another embodiment, the compositions of the present invention further comprise eicosapentaenoic Acid (EPA). In another embodiment, EPA acts as an absorption enhancer. In another embodiment, the compositions of the present invention further comprise docahexaenoic Acid (DHA). In another embodiment, DHA acts as an absorption enhancer. In another embodiment, the compositions of the present invention further comprise benzilic acid. In another embodiment, benzilic acid acts as an absorption enhancer. In another embodiment, the compositions of the present invention further comprise lecithin. In another embodiment, lecithin acts as an absorption enhancer. .

[00115] In some embodiments, the compositions of the present invention further comprise a nitric oxide (NO) donor. In some embodiments, the compositions of the present invention further comprise a bile acid, glycine-conjugated form of a bile acid, or an alkali metal salt. In another embodiment, the compositions of the present invention further comprise an ascorbic acid. In another embodiment, the ascorbic acid is sodium ascorbate or potassium ascorbate. In another embodiment, the compositions of the present invention further comprise a salicyclic acid. In another embodiment, the compositions of the present invention further comprise sodium salicylate, potassium salicylate, acetyl-salicylic acid, salicylosalicylic acid, aluminum acetylsalicylate, choline salicylate, salicylamide, or lysine acetylsalicylate. In another embodiment, the compositions of the present invention further comprise exalamide. In another embodiment, the compositions of the present invention further comprise diflunisal. In another embodiment, the compositions of the present invention further comprise ethenzamide. In another embodiment, an NO donor, a bile acid, a glycine-conjugated form of a bile acid, an alkali metal salt, sodium ascorbate, potassium ascorbate, salicyclic acid, sodium salicylate, potassium salicylate, acetyl- salicylic acid, salicylosalicylic acid, aluminum acetylsalicylate, choline salicylate, salicylamide, lysine acetylsalicylate, exalamide, diflunisal, or ethenzamide act as an absorption enhancer.

[00116] In another embodiment, the absorption enhancer is characterized by being substantially nontoxic to living organisms. In another embodiment, the absorption enhancer contains in the molecule at least two hydrophilic groups selected from the class consisting of carboxyl groups, acidic hydroxyl groups, carboxyl groups in the form of pharmaceutically acceptable salts, acidic hydroxyl groups in the form of pharmaceutically acceptable salts, carboxyl groups in the form of amides and acidic hydroxyl groups in the form of esters. In another embodiment, the absorption enhancer contains at least two lipophilic groups.

[00117] In another embodiment, the absorption enhancer comprises an amino group, or acidic amino acids. In another embodiment, the compositions of the present invention further comprise glutamic acid. In another embodiment, the compositions of the present invention further comprise sodium glutamate. In another embodiment, the compositions of the present invention further comprise potassium glutamate. In another embodiment, the compositions of the present invention further comprise glutamine. In another embodiment, the compositions of the present invention further comprise pyroglutamic acid. In another embodiment, the compositions of the present invention further comprise sodium pyroglutamate. In another embodiment, the compositions of the present invention further comprise potassium pyroglutamate. In another embodiment, the compositions of the present invention further comprise pyroglutamic acid triethanolamine salt. In another embodiment, the compositions of the present invention further comprise aspartic acid. In another embodiment, the compositions of the present invention further comprise sodium aspartate. In another embodiment, the compositions of the present invention further comprise potassium aspartate. In another embodiment, the compositions of the present invention further comprise asparagine.

[00118] In another embodiment, absorption enhancement is achieved through utilization of a combination of α-galactosidase and β-mannanase. In some embodiments, the compositions of the present invention further comprise a fatty acid such as sodium caprate. In another embodiment, the compositions of the present invention further comprise sodium glycocholate. In another embodiment, the compositions of the present invention further comprise sodium salicylate. In another embodiment, the compositions of the present invention further comprise n-dodecyl- β-D- maltopyranoside. In some embodiments, surfactants serve as absorption enhancer. In another embodiment, the compositions of the present invention further comprise chitisan such as N,N,N - trimethyl chitosan chloride (TMC).

[00119] In another embodiment, NO donors of the present invention comprise 3-(2-Hydroxy-l-(l- methylethyl)-2-nitrosohydrazino)- 1 -propanamine, N-ethyl-2-( 1 -ethyl-hydroxy-2- nitrosohydrazino)-ethanamine, or S-Nitroso-N-acetylpenicillamine

[00120] In another embodiment, the bile acid of the present invention is a cholic acid. In another embodiment, the bile acid of the present invention is a chenodeoxycholic acid. In another embodiment, the bile acid of the present invention is a taurocholic acid. In another embodiment, the bile acid of the present invention is a taurochenodeoxycholic acid. In another embodiment, the bile acid of the present invention is a glycocholic acid. In another embodiment, the bile acid of the present invention is a glycochenocholic acid. In another embodiment, the bile acid of the present invention is a 3 beta-monohydroxychloric acid. In another embodiment, the bile acid of the present invention is a lithocholic acid. In another embodiment, the bile acid of the present invention is a 5 beta-cholanic acid. In another embodiment, the bile acid of the present invention is a 3, 12-diol-7- another-5 beta-cholanic acid. In another embodiment, the bile acid of the present invention is a 3 alpha-hydroxy-12-ketocholic acid. In another embodiment, the bile acid of the present invention is a 3 beta-hydroxy-12-ketocholic acid. In another embodiment, the bile acid of the present invention is a 12 alpha-3 beta-dihydrocholic acid. In another embodiment, the bile acid of the present invention is an ursodesoxycholic acid.

[00121] In another embodiment, pharmaceutical excipients of the present invention further comprise a nonionic surfactant. In another embodiment, the compositions of the present invention further comprise a nonionic surfactant. In another embodiment, the compositions of the present invention further comprise a nonionic polyoxyethylene ether surface active agent (e.g. another having an HLB value of 6 to 19, wherein the average number of polyoxyethylene units is 4 to 30).

In another embodiment, the compositions of the present invention further comprise anionic surface active agents. In another embodiment, the compositions of the present invention further comprise a cationic surface active agent. In another embodiment, the compositions of the present invention further comprise an ampholytic surface active agent. In another embodiment, zwitteruionic surfactants such as acylcarnitines serve as absorption enhancers.

[00122] In another embodiment, the amount of an absorption enhancer utilized in methods and compositions of the present invention is 0.1 mg/dosage unit. In another embodiment, the amount of enhancer is 0.2 mg/dosage unit. In another embodiment, the amount is 0.3 mg/dosage unit. In another embodiment, the amount is 0.4 mg/dosage unit. In another embodiment, the amount is 0.6 mg/dosage unit. In another embodiment, the amount is 0.8 mg/dosage unit. In another embodiment, the amount is 1 mg/dosage unit. In another embodiment, the amount is 1.5 mg/dosage unit. In another embodiment, the amount is 2 mg/dosage unit. In another embodiment, the amount is 2.5 mg/dosage unit. In another embodiment, the amount is 3 mg/dosage unit. In another embodiment, the amount is 5 mg/dosage unit. In another embodiment, the amount is 7 mg/dosage unit. In another embodiment, the amount is 10 mg/dosage unit. In another embodiment, the amount is 12 mg/dosage unit. In another embodiment, the amount is 15 mg/dosage unit. In another embodiment, the amount is 20 mg/dosage unit. In another embodiment, the amount is 30 mg/dosage unit. In another embodiment, the amount is 50 mg/dosage unit. In another embodiment, the amount is 70 mg/dosage unit. In another embodiment, the amount is 100 mg/dosage unit. In another embodiment, the absorption enhancer of the present invention is a chelating agent.

[00123] In another embodiment, the amount of an absorption enhancer is 0.1-1 mg/dosage unit. In another embodiment, the amount of enhancer is 0.2-1 mg/dosage unit. In another embodiment, the amount is 0.3-1 mg/dosage unit. Bi another embodiment, the amount is 0.5-1 mg/dosage unit. In another embodiment, the amount is 0.1-2 mg/dosage unit. Ih another embodiment, the amount is 0.2-2 mg/dosage unit. In another embodiment, the amount is 0.3-2 mg/dosage unit. In another embodiment, the amount is 0.5-2 mg/dosage unit. In another embodiment, the amount is 1-2 mg/dosage unit. In another embodiment, the amount is 1-10 mg/dosage unit. In another embodiment, the amount is 2-10 mg/dosage unit. In another embodiment, the amount is 3-10 mg/dosage unit. In another embodiment, the amount is 5-10 mg/dosage unit. In another embodiment, the amount is 1-20 mg/dosage unit. In another embodiment, the amount is 2-20 mg/dosage unit. In another embodiment, the amount is 3-20 mg/dosage unit. In another embodiment, the amount is 5-20 mg/dosage unit. In another embodiment, the amount is 10-20 mg/dosage unit. In another embodiment, the amount is 10-100 mg/dosage unit. In another embodiment, the amount is 20-100 mg/dosage unit. In another embodiment, die amount is 30-100 mg/dosage unit. In another embodiment, the amount is 50-100 mg/dosage unit. In another embodiment, the amount is 10-200 mg/dosage unit. In another embodiment, the amount is 20-200 mg/dosage unit. In another embodiment, the amount is 30-200 mg/dosage unit. In another embodiment, the amount is 50-200 mg/dosage unit. In another embodiment, the amount is 100- 200 mg/dosage unit. In another embodiment, the absorption enhancer of the present invention is a chelating agent.

[00124] In another embodiment, the amount of an absorption enhancer is 0.1 - 1000 mg/dosage unit. In another embodiment, the amount of enhancer is 1-1000 mg/dosage unit. In another embodiment, the amount is 10- 1000 mg/dosage unit. Ih another embodiment, the amount is 100- 1000 mg/dosage unit. In another embodiment, the amount is 200-1000 mg/dosage unit. In another embodiment, the amount is 300- 1000 mg/dosage unit. In another embodiment, the amount is 500- 100 mg/dosage unit. In another embodiment, the amount is 300-900 mg/dosage unit. In another embodiment, the amount is 500-900 mg/dosage unit. In another embodiment, the amount is 600- 900 mg/dosage unit. In another embodiment, the absorption enhancer of the present invention is a chelating agent.

[00125] In another embodiment, the amount EDTA 0.1-1000 mg/dosage unit. In another embodiment, the amount of EDTA is 1-1000 mg/dosage unit. In another embodiment, the amount is 10-1000 mg/dosage unit. Li another embodiment, the amount is 100-1000 mg/dosage unit. In another embodiment, the amount is 200-1000 mg/dosage unit. In another embodiment, the amount is 300-1000 mg/dosage unit. In another embodiment, the amount is 500-100 mg/dosage unit. In another embodiment, the amount is 300-900 mg/dosage unit. In another embodiment, the amount is 500-900 mg/dosage unit. In another embodiment, the amount is 600-900 mg/dosage unit. In another embodiment, the amount is 750 mg/dosage unit. In another embodiment, the daily amount is 1.5 g.

[00126] In another embodiment, the composition of the present invention further comprises a surfactant. In another embodiment, the surfactant is sodium lauryl sulfate. In another embodiment, the surfactant is polyoxyethylene lauryl ether. In another embodiment, the surfactant is an antioxidant. In another embodiment, the antioxidant is butylhydroxytoluene. In another embodiment, the present invention further comprises preservatives. In another embodiment, the preservative is paraoxybenzoates.

[00127] Each type and amount of enhancer represents a separate embodiment of the present invention.

[00128] In another embodiment, the formulation of the present invention further comprises a base. In another embodiment, the base used in the pharmaceutical composition of this invention may be those which are known as bases of suppositories for intrarectal administration. In some embodiments, base include oils and fats comprising triglycerides as main companothernts such as cacao butter, palm fat, palm kernel oil, coconut oil, fractionated coconut oil, lard and WITEPSOL.RTM., waxes such as lanolin and reduced lanolin; hydrocarbons such as Vaseline, squalene, squalane and liquid paraffin; long to medium chain fatty acids such as caprylic acid, lauric acid, stearic acid and oleic acid; higher alcohols such as lauryl alcohol, cetanol and stearyl alcohol; fatty acid esters such as butyl stearate and dilauryl malonate; medium to long chain carboxylic acid esters of glycerin such as triolein and tristearin; glycerin-substituted carboxylic acid esters such as glycerin acetoacetate; and polyethylene glycols and its derivatives such as macrogols and cetomacrogol. They may be used either singly or in combination of two or more.

[00129] In some embodiments, the composition of this invention may further include a surface- active agent, preservative, and coloring agent, which are ordinarily used in suppositories.

[00130] In another embodiment, the unit dosage forms of the pharmaceutical composition of this invention include a solid suppository having as a base a solid fat which when administered to the rectum, becomes flowable within the rectum, such as cacao butter and WITEPSOL, a solid suppository having as a base a hydrophilic solid substance which becomes flowable in the rectum in the same way, such as macrogol, and a gelatin capsule suppository having a nomally liquid substance (liquid at room temperature) such as neutral fatty acid triglycerides and vegetable oils as a base and coated with a gelatin film.

[00131] In another embodiment, a gelatin capsule shell of the present invention comprises 50-500 mg gelatin. In another embodiment, a gelatin capsule shell of the present invention comprises 100- 300 mg gelatin. In another embodiment, a gelatin capsule shell of the present invention comprises 150-250 mg gelatin. In another embodiment, a gelatin capsule shell of the present invention comprises 100-200 mg gelatin. In another embodiment, a gelatin capsule shell of the present invention comprises 100-150 mg gelatin. In another embodiment, a gelatin capsule shell of the present invention comprises 150-200 mg gelatin.

[00132] In another embodiment, a gelatin capsule shell of the present invention comprises 20-300 mg glycerol, hi another embodiment, a gelatin capsule shell of the present invention comprises 50- 300 mg glycerol. In another embodiment, a gelatin capsule shell of the present invention comprises 50-200 mg glycerol. In another embodiment, a gelatin capsule shell of the present invention comprises 100-300 mg glycerol. In another embodiment, a gelatin capsule shell of the present invention comprises 80-200 mg glycerol. In another embodiment, a gelatin capsule shell of the present invention comprises 80-150 mg glycerol. In another embodiment, a gelatin capsule shell of the present invention comprises 80-120 mg glycerol.

[00133] In another embodiment, a gelatin capsule shell of the present invention comprises 10-100 ml purified water. In another embodiment, a gelatin capsule shell of the present invention comprises 10-50 ml purified water. In another embodiment, a gelatin capsule shell of the present invention comprises 20-100 ml purified water. In another embodiment, a gelatin capsule shell of the present invention comprises 50-100 ml purified water. In another embodiment, a gelatin capsule shell of the present invention comprises 20-80 ml purified water. In another embodiment, a gelatin capsule shell of the present invention comprises 30-60 ml purified water. In another embodiment, a gelatin capsule shell of the present invention comprises 30-50 ml purified water.

[00134] In another embodiment, a gelatin capsule shell of the present invention comprises 0.5-30 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 0.5-10 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 10-30 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 15-30 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 0.5-10 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 1-10 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 3-6 mg titanium oxide.

[00135] In another embodiment, a gelatin capsule shell of the present invention comprises 0.1-1.5 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.5-1.5 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 1-1.5 mg D&C yellow No.

Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.1 - 1 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.2- 1 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.1-0.6 mg D&C yellow

No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.2-0.6 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.3-0.6 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.4-0.5 mg

D&C yellow No. Quinoline Yellow.

[00136] In another embodiment, the capsule fill comprises 50-5000 mg soybean oil. In another embodiment, the capsule fill comprises 500-5000 mg soybean oil. In another embodiment, the capsule fill comprises 50-500 mg soybean oil. In another embodiment, the capsule fill comprises 500-3000 mg soybean oil. In another embodiment, the capsule fill comprises 50-5000 mg soybean oil. In another embodiment, the capsule fill comprises 500-2500 mg soybean oil. In another embodiment, the capsule fill comprises 1000-1500 mg soybean oil. In another embodiment, the capsule fill comprises 500-1000 mg soybean oil. In another embodiment, the capsule fill comprises 700-1200 mg soybean oil. In another embodiment, the capsule fill comprises 700-1000 mg soybean oil. In another embodiment, the capsule fill comprises 600-900 mg soybean oil. [00137] In another embodiment, the capsule fill comprises 10-1000 mg SNAC. In another embodiment, the capsule fill comprises 300-1000 mg SNAC. In another embodiment, the capsule fill comprises 500-1000 mg SNAC. In another embodiment, the capsule fill comprises 10-1000 mg SNAC. In another embodiment, the capsule fill comprises 10-500 mg SNAC. In another embodiment, the capsule fill comprises 10-300 mg SNAC. In another embodiment, the capsule fill comprises 50-250 mg SNAC. In another embodiment, the capsule fill comprises 10-1000 mg SNAC. In another embodiment, the capsule fill comprises 50-150 mg SNAC. In another embodiment, the capsule fill comprises 80-120 mg SNAC.

[00138] In another embodiment, the capsule fill comprises 10-1000 mg EDTA. In another embodiment, the capsule fill comprises 300- 1000 mg EDTA. In another embodiment, the capsule fill comprises 500-1000 mg EDTA. In another embodiment, the capsule fill comprises 10-1000 mg EDTA. In another embodiment, the capsule fill comprises 10-500 mg SNAC. In another embodiment, the capsule fill comprises 10-300 mg EDTA. In another embodiment, the capsule fill comprises 50-250 mg EDTA. In another embodiment, the capsule fill comprises 10-1000 mg SNAC. In another embodiment, the capsule fill comprises 100-250 mg EDTA. In another embodiment, the capsule fill comprises 100-200 mg EDTA.

[00139] In another embodiment, the capsule fill comprises 1-50 mg protein of the present invention. In another embodiment, the capsule fill comprises 10-50 mg protein of the present invention. In another embodiment, the capsule fill comprises 15-50 mg protein of the present invention. In another embodiment, the capsule fill comprises 30-50 mg protein of the present invention. In another embodiment, the capsule fill comprises 1-30 mg protein of the present invention. In another embodiment, the capsule fill comprises 10-30 mg protein of the present invention. In another embodiment, the capsule fill comprises 1-20 mg protein of the present invention. In another embodiment, the capsule fill comprises 2-15 mg protein of the present invention. In another embodiment, the capsule fill comprises 2-10 mg protein of the present invention. In another embodiment, the capsule fill comprises 3-5 mg protein of the present invention.

[00140] In another embodiment, the capsule fill comprises 50-500 mg protein of the present invention. In another embodiment, the capsule fill comprises 50-100 mg protein of the present invention. In another embodiment, the capsule fill comprises 100-150 mg protein of the present invention. In another embodiment, the capsule fill comprises 150-200 mg protein of the present invention. In another embodiment, the capsule fill comprises 200-250 mg protein of the present invention. In another embodiment, the capsule fill comprises 250-300 mg protein of the present invention. In another embodiment, the capsule fill comprises 300-350 mg protein of the present invention. In another embodiment, the capsule fill comprises 350-400 mg protein of the present invention. In another embodiment, the capsule fill comprises 400-450 mg protein of the present invention. In another embodiment, the capsule fill comprises 450-500 mg protein of the present invention.

[00141] In another embodiment, the capsule fill comprises 500-1000 mg protein of the present invention. In another embodiment, the capsule fill comprises 500-550 mg protein of the present invention. In another embodiment, the capsule fill comprises 550-600 mg protein of the present invention. In another embodiment, the capsule fill comprises 650-700 mg protein of the present invention. In another embodiment, the capsule fill comprises 700-750 mg protein of the present invention. In another embodiment, the capsule fill comprises 750-800 mg protein of the present invention. In another embodiment, the capsule fill comprises 800-850 mg protein of the present invention. In another embodiment, the capsule fill comprises 850-900 mg protein of the present invention. In another embodiment, the capsule fill comprises 900-950 mg protein of the present invention. In another embodiment, the capsule fill comprises 950-1000 mg protein of the present invention.

[00142] In another embodiment, the capsule fill comprises 1000-5000 mg protein of the present invention. In another embodiment, the capsule fill comprises 1000-1500 mg protein of the present invention. In another embodiment, the capsule fill comprises 1500-2000 mg protein of the present invention. In another embodiment, the capsule fill comprises 2000-2500 mg protein of the present invention. In another embodiment, the capsule fill comprises 2500-3000 mg protein of the present invention. In another embodiment, the capsule fill comprises 3000-3500 mg protein of the present invention. In another embodiment, the capsule fill comprises 3500-4000 mg protein of the present invention. In another embodiment, the capsule fill comprises 4000-4500 mg protein of the present invention. In another embodiment, the capsule fill comprises 4500-5000 mg protein of the present invention.

[00143] In another embodiment, suppositories of the present invention are prepared by mixing the protein of the present invention with a wax-like substance to form a semi-solid, bullet-shaped form that will melt after insertion into the rectum.

[00144] In another embodiment, composition of the present invention is formulated into insertable liquids for use as retention enemas.

[00145] In another embodiment, the present invention comprises capsules of gelatin comprising the composition of the present invention. In another embodiment, gelatin capsules comprising the composition of the present invention are for pediatric use.

[00146] In another embodiment, the present invention comprises rectal ointments that incorporate the composition of the present invention. In another embodiment, the present invention comprises rectal creams that incorporate the composition of the present invention. In some embodiments, ointments and creams of the invention further comprise rectal insertion and delivery tips.

[00147] In another embodiment, administration of internal rectal medicated cream or ointment requires placement of the applicator's lubricated tip at the rectal opening. In another embodiment, the correct dosage of the composition of the present invention is squeezed into the rectum.

[00148] In another embodiment, the present invention comprises rectal aerosol foams (oil-in-water emulsions resembling light creams, non-greasy) that incorporate the composition of the present invention. In another embodiment, the present invention comprises rectal coherent gel matrix that incorporate the composition of the present invention.

[00149] In another embodiment, the present invention comprises a non-dissolving, non- disintegrating slow-release suppository base consisting essentially of a linear polymer, such as methyl cellulose, and water in an amount of more than 35 parts by weight and less than 65 parts by weight of linear polymer.

[00150] In another embodiment, the present invention comprises a non-dissolving, non- disintegrating, slow-release, shaped suppository consisting essentially of polyvinyl pyrrolidanother and water, wherein the water is present in an amount of more than 35 parts by weight wherein the suppository has flexibility and becomes slippery when moistened. [00151] In another embodiment, the present invention comprises a suppository applicator which is a another-piece injection molded suppository applicator for ejecting medicament comprising a protein of the present invention into a body cavity comprising a cylindrical main body portion having a distal end and a proximal end. In another embodiment, the main body portion further comprises: an integral flexible chamber means at the distal end; a flexible junction means adjacent, integral to and at least partially the flexible chamber means; a plunger means adjacent and integral to the flexible chamber means; and a barrel stem; wherein the flexible junction means integrally joins the plunger means and flexible chamber means within the barrel stem.

[00152] In another embodiment, the present invention comprises a urethral suppository. In another embodiment, a urethral suppository comprises i) a relatively long, relatively small diameter shaft, ii) a bulbous head extending from a rounded nose through a relatively gradually outwardly curving insertion surface having an axial length equaling about two thirds of the overall length of the head and a relatively sharply curving retention surface extending from the intersection with the insertion surface which is the maximum diameter of the head to an intersection with the shaft, the intersection between the retention surface and the insertion surface not comprising a sharp edge or corner, and iii) a conical tail including an outwardly tapered retaining surface extending from the shaft to a base having a diameter substantially greater than the maximum diameter of the bulbous head, wherein shaft, head, and tail comprises predetermined dimensions and a unitary structure and are formed entirely from the protein of the present invention.

[00153] In another embodiment, the protein of the present invention is combined in a dissolvable element containing an agent material that is used for local administration of an agent material in an internal body area. In another embodiment, the dissolvable element is made of a dissolvable polymer material and/or complex carbohydrate material which dissolve due to human body temperatures and moisture during use to release the agent material in a desired timed release and dosage.

[00154] In another embodiment, the present invention comprises a sustained release suppository comprising a fat having a melting range of from 29⁰C to 40⁰C. In another embodiment, the sustained release suppository further comprises a physiologically acceptable organic substance that is swellable in contact with water. In another embodiment, the organic substance that is swellable in contact with water is hydroxypropylmethylcellulose. In some embodiments, the sustained release suppository further comprises hydrophobic silicium dioxide.

[00155] In some embodiments, the present invention comprises a suppository for use in the vaginal or rectal cavity comprising the protein of the present invention and a mixture of triglycerides of fatty acids. In some embodiments, the vaginal or rectal suppository further comprises a gel forming agent and a gel dispersing agent.

[00156] In some embodiments, the present invention comprises an effervescent vaginal suppository composition containing a stabilizer. In some embodiments, the stabilizer is selected from compounds such as anhydrous sodium sulfate, anhydrous silica gel, dried magnesium silicate, dried aluminum silicate, dried calcium carboxymethylcellulose, dried microcrystalline cellulose, dried starch and dried calcium phosphate, or mixtures thereof.

[00157] In some embodiments, the present invention comprises the protein of the present invention capsule. In another embodiment, the protein of the present invention capsule is formed of a hard capsule shell. In some embodiments, hard capsule shell is made of a mixed ester of cellulose ether, e.g. alkyl-, hydroxyalkyl- and hydroxyalkyl alkylcelluloses, esterified with aliphatic monacyl groups and acidic succinyl groups . In another embodiment, the capsule is inserted into the rectum. In some embodiments, the capsule shell is disintegrated and the rectally absorbable effective protein of the present invention is released into the rectum.

[00158] In another embodiment, the suppository of the present invention comprises a biocompatible material in the form of a polymer. In another embodiment, the biocompatible polymer is polyurethane. In another embodiment, the polymer is cellulose acetate. In another embodiment, the biocompatible polymer is polyamide. In another embodiment, the polymer is polyethylene. In another embodiment, the polymer is polyethylene terephthalate. In another embodiment, the polymer is polypropylene. In another embodiment, the polymer is polyvinyl acetate. In another embodiment, the polymer is polyvinyl chloride. In another embodiment, the polymer is silicanother rubber. In another embodiment, the polymer is latex. In another embodiment, the polymer is polyhydroxybutyrate. In another embodiment, the polymer is polyhydroxyvalerate. In another embodiment, the polymer is Teflon. In another embodiment, the polymer is polylactic acid. In another embodiment, the polymer is polyglycolic acid.

[00159] In another embodiment, the biocompatible polymer erodes at a substantially slower rate than the rest of the matrix. In another embodiment, the biocompatible polymer comprises a matrix of another or more substantially water soluble crystalline polymers.

[00160] In another embodiment, the pharmaceutical composition of this invention may be prepared by uniformly mixing predetermined amounts of the active ingredient, the absorption aid and optionally the base, etc. in a stirrer or a grinding mill, if required at an elevated temperature. In another embodiment, the resulting composition may be formed into a suppository in unit dosage form by, for example, casting the mixture in a mold, or by forming it into a gelatin capsule using a capsule filling machine.

[00161] In another embodiment, the coating is a gelatin coating. In another embodiment, microencapsulation is used to protect the protein of the present invention against decomposition in the rectum. In some embodiments, methods for applying a gelatin coating and for microencapsulation are well known in the art. Each method represents a separate embodiment of the present invention.

[00162] In another embodiment, the coating is a film-coating. In another embodiment, the coating is ethylcellulose. In another embodiment, the coating is a water-based dispersion of ethylcellulose, e.g. hydroxypropylmethylcelullose (HPMC) E15. In another embodiment, the coating is a monolithic matrix. In another embodiment, the coating is cellulose ether (e.g. hypromellose

(HPMC). Each type of coating represents a separate embodiment of the present invention.

[00163] In another embodiment, a multiparticulate dosage forms is used to inhibit digestion of the composition in the stomach.

[00164] Each type of coating, dosage form, etc, that inhibits digestion of the composition in the stomach represents a separate embodiment of the present invention.

[00165] In another embodiment, methods and compositions of the present invention have the advantage of more closely mimicking physiological secretion of the protein of the present invention. When the protein of the present invention is secreted into the portal vein, the liver is exposed to a greater the protein of the present invention concentration than peripheral tissues. Similarly, the protein of the present invention administered according to the present invention reaches the intestine and is absorbed in the body through the intestine and through the portal system to the liver. This absorption route thus resembles the physiological secretion of the protein of the present invention, enabling, in this embodiment, delicate control and the metabolic activities of the liver and the peripheral organs controlled by the protein of the present invention.

[00166] In another embodiment, different constituents of compositions of the present composition are absorbed at different rates into the blood stream.

[00167] In another embodiment, a treatment protocol of the present invention is therapeutic. In another embodiment, the protocol is prophylactic. Each possibility represents a separate embodiment of the present invention.

[00168] In another embodiment, the compositions further comprise binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidanother), disintegrating agents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidanother, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCL, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosity increasing agents(e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g. aspartame, citric acid), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants. Each of the above excipients represents a separate embodiment of the present invention.

[00169] In some embodiments, the dosage forms of the present invention are formulated to achieve an immediate release profile, an extended release profile, or a delayed release profile. In some embodiments, the release profile of the composition is determined by using specific excipients that serve for example as binders, disintegrants, fillers, or coating materials. In another embodiment, the composition will be formulated to achieve a particular release profile as known to another skilled in the art.

[00170] In other embodiments, controlled- or sustained-release coatings utilized in methods and compositions of the present invention include formulation in lipophilic depots (e.g. fatty acids, waxes, oils).

[00171 ] The compositions also include, in another embodiment, incorporation of crystalline protein of the present invention into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.) Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance. In another embodiment, particulate compositions of the active ingredients are coated with polymers (e.g. poloxamers or poloxamines)

[00172] In another embodiment, the compositions containing protein of the present invention and an absorption enhancer are delivered in a vesicle, e.g. a liposome (see Langer, Science 249: 1527- 1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-

Berestein andFidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp.317-

327; see generally ibid).

[00173] Each of the above additives, excipients, formulations and methods of administration represents a separate embodiment of the present invention.

[00174] In another embodiment, the term "treating" refers to curing a disease. In another embodiment, "treating" refers to preventing a disease. In another embodiment, "treating" refers to reducing the incidence of a disease. In another embodiment, "treating" refers to ameliorating symptoms of a disease. Li another embodiment, "treating" refers to inducing remission. In another embodiment, "treating" refers to slowing the progression of a disease.

EXPERIMENTAL DETAILS SECTION

EXAMPLE 1

RECTAL INSULIN PREPARATION MATERIALS AND EXPERIMENTAL METHODS

Formulation

EXPERIMENTAL DESIGN

[00175] To test whether insulin can be absorbed via the rectum, a gelatin capsule composition containing insulin, SNAC, and soybean oil was administered directly to rectum of an 11.0 kg beagle dog. Blood glucose was measured every 10 minutes following administration. Thus, the compositions of the present enable direct absorption of rectally administered insulin.

Table 1. Blood glucose concentrations following rectal administration of insulin.

RESULTS

[00176] According to the results obtained in Example, 1 intra-rectal insulin preparations of the present invention are effective in lowering blood glucose levels (Figure 1). Additionally, the intra- rectal insulin preparations of the present invention have comparable efficacy in lowering blood glucose levels to the oral insulin formulations presented in Example 2.

EXAMPLE 2

ORAL INSULIN PREPARATIONS

[00177] To test whether insulin can be protected from proteases and absorbed via the duodenum, a composition containing insulin, SBTI, EDTA, and fish oil was administered directly to the duodenum of an 8.8 kg beagle dog. Blood glucose was measured every 10 minutes following administration. As depicted below in Table 1, blood glucose levels were significantly reduced in response to the insulin.

[00178] Thus, compositions comprising an omega-3 fatty acid can protect insulin from proteases in the small intestine and enable direct absorption of orally administered insulin.

Table 1. Blood glucose concentrations following administration of insulin to the duodenum in experiment #1.

EXAMPLE 3

PREPARATION OF RECTAL CAPSULE FILL

[00179] The raw materials of example 1 were weighed on electronic balances within the pilot plant area. The soybean oil was weighed into a 300 mL beaker and heated to 6O⁰C on a heatable magnetic stirrer. The fat companothernts were weighed onto PE foil and added to the heated oil.

After melting and dissolving in the soybean oil the mixture was let cooling to room temperature.

Then SNAC or EDTA was added under intense manual stirring. Finally, insulin was added to the bulk fill and mixed thoroughly. The appearance of the bulk fill was a stable suspension. The bulk fill was then homogenized on a rolling mill at 2O⁰C and sealed with aluminum foil and stored at 2-

8⁰C until used for encapsulation.

[00180] After encapsulation the capsules were mechanically cleaned from lubricating oil in a tumble dryer for about 20 minutes. Last, the capsules were coated and stored in polyethylene boxes at 2-8⁰C.

EXAMPLE 4

OPTIMIZATION OF ENHANCER

[00181] Various enhancers (e.g. those listed above in the specification) are compared for their ability to facilitate absorption of FGF following rectal administration in methods and compositions of the present invention. FGF rectal capsules and suppositories are formulated as described, except that the alternate enhancers are substituted for EDTA or SNAC. Amounts of the enhancers are also varied, to determine the optimal amounts. FGF rectal capsules are administered twice daily, every twelve hours. The amount of blood FGF is measured every two days using RIA according to the methods of the present invention. The most effective enhancer/amount is used in subsequent experiments.

EXAMPLE 5

OPTIMIZATION OF TYPE AND AMOUNT OF HEPARIN [00182] Various types and amounts of heparin e.g. low, high, and intermediate molecular weight heparins, modified and unmodified, are compared for their ability to regulate blood coagulation according to the methods and compositions of the present invention. Heparin rectal capsules and suppositories are formulated as described hereinabove, except that the type and amount of heparin is varied. The most effective type/amount of heparin is used in clinical trials.

EXAMPLE 6

EFFICACY OF RECTALLY ADMINISTERED INSULIN IN HUMANS

Formulation

[00183] Formulations comprising EDTA or SNAC and crystalline insulin were formulated as follows: (1) formulation containing 200 mg EDTA, 100 MG (4mg) crystalline insulin, 876 mg soybean oil in a rectal gelatin capsule composed of 186 mg gelatin, 102.3 mg glycerol (98%), 5 mg titanium oxide, and 36.7 mg water; (2) formulation containing 100 mg SNAC, 100 MG (4 mg) crystalline insulin, 876 mg soybean oil in a rectal gelatin capsule composed of 186 mg gelatin, 102.3 mg glycerol (98%), 5 mg titanium oxide, and 36.7 mg water.

[00184] Formulations (1) and (2) are administered rectally to 8 healthy volunteers divided to two groups (4 healthy volunteers in each group) entering the clinic on the morning of dosing after an 8 hour overnight fast. No food is allowed until the last blood sample is collected (approximately 3.0 hours post study drug administration).

[00185] Blood samples are collected 15 minutes prior to study drug administration, at 0 min, and then every 10 min for the first 60 min and every 15 minutes after drug administration up to 180 minutes. Treatment Phase will consist of two periods and will be approximately 10 days in duration.

[00186] Glucose tests (another-drop) to monitor real-time glucose values are performed using 2 gluco-meters.

[00187] The Treatment Phase consists of two periods and is 10 days in duration. At each study period prior to study drug administration an indwelling catheter is inserted for blood sample collection; glucose test (another drop) is performed 15 minutes prior to study drug administration; vital signs (blood pressure, heart rate) are recorded 20 minutes prior to study drug administration. Vital signs are measured in the sitting position after at least 5 minutes of rest; blood samples for insulin, plasma glucose and C-peptide analysis are collected 15 minutes prior to study drug administration; vital signs (blood pressure, heart rate) are recorded at approximately 1 and 3 hours post study drug administration. Vital signs are measured in the sitting position. Same.

Claims

WHAT IS CLAIMED IS:

1. A composition comprising a protein having a molecular weight of up to 100,000 Daltons and a chelating agent.

2. The composition of claim 1 , wherein said chelating agent is an EDTA or a SNAC.

3. The composition of claim 1 , wherein said protein is a recombinant protein.

4. The composition of claim 3 , wherein said recombinant protein is a human recombinant protein.

5. The composition of claim 1, further comprising: tolmetin or a salt thereof, sodium caprate, salicylic acid, oleic acid, lecithin, linoleic acid, linolenic acid, EPA, DHA, benzilic acid, or a mixture thereof.

6. The composition of claim 1, wherein said composition further comprises a pharmaceutical excipient suitable for rectal administration.

7. The composition of claim 1 , wherein said composition is in the form of a suppository.

8. The composition of claim 1, wherein said composition is in the form of a capsule.

9. The composition of claim 8, wherein said capsule is a gelatin capsule.

10. A method for rectal administration of a protein to a subject, comprising administering rectally to said subj ect a pharmaceutical composition comprising a protein having a molecular weight of up to 100,000 Daltons and a chelating agent, whereby a substantial fraction of said protein retains its activity after absorption through a rectal mucosal barrier of said subject.

11. The method of claim 10, wherein said chelating agent is EDTA or SNAC.

12. The method of claim 10, wherein said protein is a recombinant protein.

13. The method of claim 10, wherein said recombinant protein is a human recombinant protein.

14. The method of claim 10, wherein said pharmaceutical composition further comprises: tolmetin or a salt thereof, sodium caprate, salicylic acid, oleic acid, lecithin, linoleic acid, linolenic acid, EPA, DHA, benzilic acid, or a mixture thereof.

15. The method of claim 10, wherein said pharmaceutical composition form is a suppository.

16. The method of claim 10, wherein said pharmaceutical composition form is a capsule.

17. The method of claim 16, wherein said capsule is a gelatin capsule.

18. A method for treating a disease in a subject, comprising administering rectally to said subject a pharmaceutical composition comprising a protein having a molecular weight of up to 100,000 Daltons and a chelating agent, thereby treating said disease.

19. The method of claim 18, wherein said disease is selected from an immunological disease, an inflammatory disease, a rheumatic disease, diabetes mellitus, a neuronal disease, a cardiovascular disease, a gastrointestinal disease, a dermatological disease, an infective disease, a liver disease, a kidney disease, a metabolic disease, an endocrine disease, a behavior disease, or a connective tissue disease.

20. The method of claim 18, wherein said chelating agent is EDTA or SNAC.

21. The method of claim 18, wherein said protein is a recombinant protein.

22. The method of claim 18, wherein said recombinant protein is a human recombinant protein.

23. The method of claim 18, wherein said pharmaceutical composition further comprises: tolmetin or a salt thereof, sodium caprate, salicylic acid, oleic acid, lecithin, linoleic acid, linolenic acid, EPA, DHA, benzilic acid, or a mixture thereof.

24. The method of claim 18, wherein said pharmaceutical composition form is a suppository.

25. The method of claim 18, wherein said pharmaceutical composition form is a capsule.

26. The method of claim 25, wherein said capsule is a gelatin capsule.