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CROSS REFERENCE TO RELATED APPLICATIONS This is a continuation application and claims priority under 35 U.S.C. §120 of co-pending U.S. Patent application Ser. 10/745,069 filed Dec. 23, 2003, which is a continuation-in-part of U.S.
Patent application Ser. 10/322,266, filed Dec. 17, 2002, and claims priority under 35 U.S.C. §119 (e) of U.S. Provisional Application No. 60/493,226, filed Aug. 7, 2003, U.S.
Provisional Application No. 60/501,170, filed Sep. 8, 2003, U.S. Provisional Application No. 60/510,785, filed Oct. 10, 2003, U.S. Provisional Application No.
60/517,290, filed Nov. 4, 2003; U.S. Provisional Application No. 60/518,812, filed on Nov. 10, 2003; and PCT/US03/40538, filed on Dec. 17, 2003; the entire contents of these applications are incorporated herein by reference. BACKGROUND OF THE INVENTION The teachings of all the references cited in the present specification are incorporated in their entirety by reference.
Obesity and its associated disorders are common and very serious public health problems in the United States and throughout the world. Upper body obesity is the strongest risk factor known for type-2 diabetes mellitus, and is a strong risk factor for cardiovascular disease.
Obesity is a recognized risk factor for hypertension, arteriosclerosis, congestive heart failure, stroke, gallbladder disease, osteoarthritis, sleep apnea, reproductive disorders such as polycystic ovarian syndrome, cancers of the breast, prostate, and colon, and increased incidence of complications of general anesthesia. It reduces life-span and carries a serious risk of co-morbidities above, as well disorders such as infections, varicose veins, acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertension hypercholesterolemia, cholelithiasis, orthopedic injury, and thromboembolic disease. Obesity is also a risk factor for the group of conditions called insulin resistance syndrome, or “Syndrome X.” It has been shown that certain peptides that bind to the Y2 receptor when administered peripherally to a mammal induce weight loss. The Y2 receptor-binding peptides are neuropeptides that bind to the Y2 receptor. Neuropeptides are small peptides originating from large precursor proteins synthesized by peptidergic neurons and endocrine/paracrine cells. Often the precursors contain multiple biologically active peptides. There is great diversity of neuropeptides in the brain caused by alternative splicing of primary gene transcripts and differential precursor processing.
The neuropeptide receptors serve to discriminate between ligands and to activate the appropriate signals. These Y2 receptor-binding peptides belong to a family of peptides including peptide YY (PYY), neuropeptide Y (NPY) and pancreatic peptide (PP). NPY is a 36-amino acid peptide and is the most abundant neuropeptide to be identified in mammalian brain. NPY is an important regulator in both the central and peripheral nervous systems and influences a diverse range of physiological parameters, including effects on psychomotor activity, food intake, central endocrine secretion, and vasoactivity in the cardiovascular system. High concentrations of NPY are found in the sympathetic nerves supplying the coronary, cerebral, and renal vasculature and have contributed to vasoconstriction. NPY binding sites have been identified in a variety of tissues, including spleen, intestinal membranes, brain, aortic smooth muscle, kidney, testis, and placenta.
Neuropeptide Y (NPY) receptor pharmacology is currently defined by structure activity relationships within the pancreatic polypeptide family. This family includes NPY, which is synthesized primarily in neurons; PYY, which is synthesized primarily by endocrine cells in the gut; and PP, which is synthesized primarily by endocrine cells in the pancreas.
These approximately 36 amino acid peptides have a compact helical structure involving a “PP-fold” in the middle of the peptide. Specific features include a polyproline helix in residues 1 through 8, a β-turn in residues 9 through 14, an α-helix in residues 15 through 30, an outward-projecting C-terminus in residues 30 through 36, and a carboxyl terminal amide, which appears to be critical for biological activity. The peptides have been used to define at least five receptor subtypes known as Y1, Y2, Y3, Y4 and Y5. Y1 receptor recognition by NPY involves both N- and C-terminal regions of the peptide; exchange of Gln 34 with Pro 34 is fairly well tolerated. Y2 receptor recognition by NPY depends primarily upon the four C-terminal residues of the peptide (Arg 33-Gln 34-Arg 35-Tyr 36-NH 2) preceded by an amphipathic an α-helix; exchange of Gln 34 with Pro 34 is not well tolerated. One of the key pharmacological features which distinguish Y1 and Y2 is the fact that the Y2 receptor (and not the Y1 receptor) has high affinity for the NPY peptide carboxyl-terminal fragment NPY-(13–36) and the PYY fragment PYY(22–36). It has been shown that a 36 amino acid peptide called Peptide YY(1–36)PYY(1–36) YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY, SEQ ID NO.: 1.
When administered peripherally by injection to an individual produces weight loss and thus can be used as a drug to treat obesity and related diseases, Morley, J. Neuropsychobiology 21:22–30 (1989). It was later found that to produce this effect PYY bound to a Y2 receptor, and the binding of a Y2 agonist to the Y2 receptor caused a decrease in the ingestion of carbohydrate, protein and meal size, Leibowitz, S. Peptides, 12:1251–1260 (1991). An alternate molecular form of PYY is PYY(3–36) IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY SEQ ID NO.: 2, Eberlein, Eysselein et al.
Peptides 10: 797–803, 1989). This fragment constitutes approximately 40% of total PYY-like immunoreactivity in human and canine intestinal extracts and about 36% of total plasma PYY immunoreactivity in a fasting state to slightly over 50% following a meal. It is apparently a dipeptidyl peptidase-IV (DPP4) cleavage product of PYY. PYY3–36 is reportedly a selective ligand at the Y2 and Y5 receptors, which appear pharmacologically unique in preferring N-terminally truncated (i.e.
C-terminal fragments of) NPY analogs. It has also been shown that a PYY fragment having only residues 22–36 will still bind to the Y2 receptor. However, if any of the carboxyl terminus of the peptide is cleaved, the peptide looses its ability to bind to the Y2 receptor. Hence a PYY agonist is a peptide, which has a partial sequence of full-length PYY and is able to bind to a Y2 receptor in the arcuate nucleus of the hypothalamus. Hereinafter the term PYY refers to full-length PYY and any fragment of PYY that binds to a Y2 receptor. It is known that PYY and PYY3–36 can be administered by intravenous infusion or injection to treat life-threatening hypotension as encountered in shock, especially that caused by endotoxins (U.S. 4,839,343), to inhibit proliferation of pancreatic tumors in mammals by perfusion, parenteral, intravenous, or subcutaneous administration, and by implantation (U.S.
5,574,010) and to treat obesity (Morley, J. Neuropsychobiology 21:22–30 (1989) and U.S. Patent Application No. It is also claimed that PYY can be administered by parenteral, oral, nasal, rectal and topical routes to domesticated animals or humans in an amount effective to increase weight gain of said subject by enhancing gastrointestinal absorption of a sodium-dependent cotransported nutrient (U.S. However, for the treatment of obesity and related diseases, including diabetes, the mode of administration has been limited to intravenous IV infusion with no effective formulations optimized for alternative administration of PYY3–36. None of these prior art teachings provide formulations that contain PYY or PYY(3–36) combined with excipients designed to enhance mucosal (i.e., nasal, buccal, oral) delivery nor do they teach the value of endotoxin-free Y2-receptor binding peptide formulations for non-infused administration.
Thus, there is a need to develop formulations and methods for administering PYY3–36. SUMMARY OF THE INVENTION The present invention fulfills the foregoing needs and satisfies additional objects and advantages by providing novel, effective methods and compositions for mucosal, especially intranasal, delivery of a Y2 receptor-binding peptide such as PYY, Pancreatic Peptide (PP) and NPY, to treat obesity, induce satiety in an individual and to promote weight-loss in an individual and prevent or cure diabetes. In certain aspects of the invention, the Y2 receptor-binding peptide is delivered in formulations to the intranasal mucosa so as to be able to increase the concentration of the Y2 receptor-binding peptide by at least 5 pmol, preferably by at least 10 pmol, in the blood plasma of a mammal when a dose of the formulations of the Y2 receptor agonist is administered intranasally. Furthermore preferred formulations would be able to raise the concentration of the Y2 receptor-binding peptide in the plasma of a mammal by 10 pmol, preferably 20 pmol, when the Y2 receptor-binding peptide is administered intranasally.
When 150 μg is administered intranasally the preferred formulation would be able to raise the concentration of the Y2 receptor agonist in the plasma of the mammal by at least 40 pmol per liter of plasma. When 200 μg of the Y2 receptor-binding peptide is administered intranasally, the formulations of the present invention induce at least 80 pmol, per liter of plasma increase of the Y2 receptor-binding peptide. In preferred embodiments, the elevated concentrations of the Y2-receptor-binding peptide remains elevated in the plasma of the mammal for at least 30 minutes, preferably at least 60 minutes following a single intranasal dose of the Y2 receptor-binding peptide. Preferably the Y2 receptor-binding peptide is a PP, PYY or NPY peptide and the mammal is a human. In a most preferred embodiment the Y2 receptor-binding peptide is a PYY peptide, preferably PYY(3–36) and the mammal is human. The present invention is also related to a Y2 receptor-binding peptide formulation that is able to raise the concentration of the Y2 receptor-binding peptide in the blood plasma of a mammal by at least 5 pM when a dose containing at least 50 μg of the Y2 receptor-binding peptide is administered to the mammal. In preferred embodiments, the elevated concentrations of the Y2-receptor-binding peptide remains elevated in the plasma of the mammal for at least 30 minutes, preferably at least 60 minutes following a single intranasal dose of the Y2 receptor-binding peptide.
The present invention is also related to a Y2 receptor-binding peptide formulation that is able to raise the concentration of the Y2 receptor-binding peptide in the blood-plasma of a mammal by at least 20 pM when a dose containing at least 100 μg of the Y2 receptor-binding peptide is administered to the mammal. In preferred embodiments, the elevated concentrations of the Y2-receptor-binding peptide remains elevated in the plasma of the mammal for at least 30 minutes, preferably at least 60 minutes following a single intranasal dose of the Y2 receptor-binding peptide.
The present invention is also related to a Y2 receptor-binding peptide formulation that when administered intranasally to a mammal is able to raise the concentration of the Y2 receptor-binding peptide in blood plasma of the mammal by at least 30 pM when a dose containing at least 150 μg of the Y2 receptor-binding peptide is administered. In preferred embodiments, the elevated concentrations of the Y2-receptor-binding peptide remains elevated in the plasma of the mammal for at least 30 minutes, preferably at least 60 minutes following a single intranasal dose of the Y2 receptor-binding peptide. Preferably the mammal is a human. The present invention is also related to a Y2 receptor-binding peptide formulation that when administered intranasally to a mammal is able to raise the concentration of the Y2 receptor-binding peptide by at least 60 pM when a dose containing at least 200 μg is administered to the mammal. In preferred embodiments, the elevated concentrations of the Y2-receptor-binding peptide remains elevated in the plasma of the mammal for at least 30 minutes, preferably at least 60 minutes following a single intranasal dose of the Y2 receptor-binding peptide.
Preferably the mammal is a human. The present invention is also directed to an intranasal formulation of a Y2 receptor-agonist that is substantially free of proteins or polypeptides that stabilize the formulation. In particular, the preferred formulation is free of such proteins as albumin, and collagen-derived proteins such as gelatin.
In other aspects of the present invention a transmucosal Y2 receptor-binding peptide formulation is comprised of a Y2 receptor-binding peptide, water and a solubilizing agent having a pH of 3–6.5. In a preferred embodiment, the solubilization agent is a cyclodextrin.
In another embodiment of the present invention a transmucosal Y2 receptor-binding peptide formulation is comprised of a Y2 receptor-binding peptide, water, a solubilizing agent, preferably a cyclodextrin, and at least one polyol, preferably 2 polyols. In alternate embodiments the formulation may contain one or all of the following: a chelating agent, a surface-acting agent and a buffering agent. In another embodiment of the present invention the formulation is comprised of a Y2 receptor-binding peptide, water, chelating agent and a solubilization agent. In another embodiment of the present invention the formulation is comprised of a Y2 receptor-binding peptide, water and a chelating agent having a pH of 3–6.5.
In another embodiment of the present invention the formulation is comprised of a Y2 receptor-binding peptide, water, chelating agent and at least one polyol, preferably two polyols. Additional embodiments may include one or more of the following: a surface-active agent, a solubilizing agent and a buffering agent. In another embodiment of the present invention the formulation is comprised of a Y2 receptor-binding peptide, water, and at least two polyols, such as lactose and sorbitol. Additional agents, which can be added to the formulation, include, but are not limited to, a solubilization agent, a chelating agent, one or more buffering agents and a surface-acting agent.
The enhancement of intranasal delivery of a Y2 receptor-binding peptide agonist according to the methods and compositions of the invention allows for the effective pharmaceutical use of these agents to treat a variety of diseases and conditions in mammalian subjects. The present invention fills this need by providing for a liquid or dehydrated Y2 receptor-binding peptide formulation wherein the formulation is substantially free of a stabilizer that is a polypeptide or a protein. The liquid PYY formulation is comprised of water, PYY and at least one of the following additives selected from the group consisting of polyols, surface-active agents, solubilizing agents and chelating agents.
The pH of the formulation is preferably 3 to about 7.0, referably 4.5 to about 6.0, most preferably about 5.0±0.03. Another embodiment of the present invention is an aqueous Y2 receptor-binding formulation of the present invention is comprised of water, a Y2 receptor-binding peptide, a polyol and a surface-active agent wherein the formulation has a pH of about 3 to about 6.5, and the formulation is substantially free of a stabilizer that is a protein or polypeptide.
Another embodiment of the present invention is an aqueous Y2 receptor-binding peptide formulation comprised of water, Y2 receptor-binding peptide, a polyol and a solubilizing agent wherein the formulation has a pH of about 3.0 to about 6.5, and the formulation is substantially free of a stabilizer that is a protein or polypeptide. Another embodiment of the present invention is an aqueous Y2 receptor-binding peptide formulation comprised of water, Y2 receptor-binding peptide, a solubilizing agent and a surface-active agent wherein the formulation has a pH of about 3.0 to about 6.5, and the formulation is substantially free of a stabilizer that is a protein or polypeptide. Another embodiment of the invention is a aqueous Y2 receptor-binding peptide formulation comprised of water, a Y2 receptor-binding peptide, a solubilizing agent, a polyol and a surface-active agent wherein the formulation has a pH of about 3.0 to about 6.5, and the formulation is substantially free of a stabilizer that is a protein or polypeptide. In another aspect of the present invention, the stable aqueous formulation is dehydrated to produce a dehydrated Y2 receptor-binding peptide formulation comprised of Y2 receptor-binding peptide and at least one of the following additives selected from the group consisting of polyols, surface-active agents, solubilizing agents and chelating agents, wherein said dehydrated Y2 receptor-binding peptide formulation is substantially free of a stabilizer that is a protein or polypeptide such as albumin, collagen or collagen-derived protein such as gelatin.
The dehydration can be achieved by various means such as lyophilization, spray-drying, salt-induced precipitation and drying, vacuum drying, rotary evaporation, or supercritical CO 2 precipitation. In one embodiment, the dehydrated Y2 receptor-binding peptide is comprised of Y2 receptor-binding peptide, a polyol and a solubilizing agent, wherein the formulation is substantially free of a stabilizer that is a protein. In another embodiment, the dehydrated Y2 receptor-binding peptide formulation is comprised of a Y2 receptor-binding peptide, a polyol, and a surface-active agent wherein the Y2 receptor-binding peptide formulation is substantially free of a stabilizer that is a protein or polypeptide. In another embodiment, the dehydrated Y2 receptor-binding peptide formulation is comprised of a Y2 receptor-binding peptide, a surface-active agent, and a solubilizing agent wherein the Y2 receptor-binding peptide formulation is substantially free of a stabilizer that is a protein or polypeptide.
In another embodiment of the present invention, the dehydrated Y2 receptor-binding peptide formulation is comprised of a Y2 receptor-binding peptide, a polyol, a surface-active agent and a solubilizing agent wherein the Y2 receptor-binding peptide formulation is substantially free of a stabilizer that is a protein or polypeptide. Any solubilizing agent can be used but a preferred one is selected from the group consisting of hydroxypropyl-β-cyclodextran, sulfobutylether-β-cyclodextran, methyl-β-cyclodextrin and chitosan. Generally a polyol is selected from the group consisting of lactose, sorbitol, trehalose, sucrose, mannose and maltose and derivatives and homologs thereof. A satisfactory surface-active agent is selected from the group consisting of L-α-Phospharidycholine didecanoyl (DDPC), polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), polyethylene glycol (PEG), cetyl alcohol, polyvinylpyrolidone (PVP), polyvinyl alcohol (PVA), lanolin alcohol, and sorbitan monooleate. In a preferred formulation, the Y2 receptor-binding peptide formulation is also comprised of a chelating agent such as ethylene diamine tetraacetic acid (EDTA) or ethylene glycol tetraacetic acid (EGTA).
Also a preservative such as chlorobutanol or benzylkonium chloride can be added to the formulation to inhibit microbial growth. The pH is generally regulated using a buffer such as sodium citrate and citric acid, and sodium acetate and acetic acid. An alternative buffer would be acetic acid and sodium acetate or succinic acid and sodium hydroxide. The preferred Y2 receptor-binding peptide is a PYY, PP or NPY peptide, preferably a PYY(3–36) peptide. The present invention also comprehends a formulation wherein the concentration of the Y2 receptor-binding peptide is 0.1–15.0 mg/mL, preferably 1.0–2 mg/mL and the pH of the aqueous solution is 3.0–6.5 preferably about 5.0±0.3. The present invention further includes Y2 receptor-binding peptide formulation wherein the concentration of the polyol is between about 0.1% and 10% (w/v) and additionally wherein the concentration of the polyol is in the range from about 0.1% to about 3% (w/v).
The instant invention also includes a formulation, wherein the concentration of the surface-active agent is between about 0.00001% and about 5%(w/v), and wherein the concentration of the surface-active agent is between about 0.0002% and about 0.1% (w/v). The instant invention also includes a formulation, wherein the concentration of the solubilzation agent is 1%–10% (w/v), and wherein the concentration of the solubilizing agent is 2% to 5% (w/v). The finished solution can be filtered and freeze-dried, lyophilized, using methods well known to one of ordinary skill in the art, and by following the instructions of the manufacturer of the lyophilizing equipment. This produces a dehydrated Y2 receptor-binding peptide formulation substantially free of a stabilizer that is a protein. In another embodiment of the present invention, a Y2 receptor-binding peptide formulation is comprised of an Y2 receptor-binding peptide and a pharmaceutically acceptable carrier wherein the Y2 receptor-bind peptide formulation has at least 1%, preferably 3% and most preferably at least 6% higher permeation in an in vitro tissue permeation assay than a control formulation consisting of water, sodium chloride, a buffer and the Y2 receptor-binding peptide, as determined by the transepithelial electrical resistance assay shown in Examples 2 & 7.
In a preferred embodiment, the Y2 receptor-binding formulation is further comprised of at least one excipient selected from the group consisting of a surface-active agent, a solubilization agent, a polyol, and a chelating agent. Preferably the Y2 receptor-binding peptide is a PYY peptide, an NPY peptide or a PP peptide. In another embodiment of the present invention a Y2 receptor-binding petide formulation is provided that is capable of raising the concentration of the Y2 receptor-binding peptide in the plasma of a mammal by at least 5 preferably 10, 20 40, 60, 80 or more pmoles per liter of plasma when 100 μL of the formulation is administered intranasally to said mammal.
In exemplary embodiments, the enhanced delivery methods and compositions of the present invention provide for therapeutically effective mucosal delivery of the Y2 receptor-binding peptide agonist for prevention or treatment of obesity and eating disorders in mammalian subjects. In one aspect of the invention, pharmaceutical formulations suitable for intranasal administration are provided that comprise a therapeutically effective amount of a Y2 receptor-binding peptide and one or more intranasal delivery-enhancing agents as described herein, which formulations are effective in a nasal mucosal delivery method of the invention to prevent the onset or progression of obesity or eating disorders in a mammalian subject. Nasal mucosal delivery of a therapeutically effective amount of a Y2 receptor-binding peptide agonist and one or more intranasal delivery-enhancing agents yields elevated therapeutic levels of the Y2 receptor-binding peptide agonist in the subject and inhibits food intake in the mammalian subject, reducing symptoms of obesity or an eating disorder. The enhanced delivery methods and compositions of the present invention provide for therapeutically effective mucosal delivery of a Y2 receptor-binding peptide for prevention or treatment of a variety of diseases and conditions in mammalian subjects. Y2 receptor-binding peptide can be administered via a variety of mucosal routes, for example by contacting the Y2 receptor-binding peptide to a nasal mucosal epithelium, a bronchial or pulmonary mucosal epithelium, the oral buccal surface or the oral and small intestinal mucosal surface. In exemplary embodiments, the methods and compositions are directed to or formulated for intranasal delivery (e.g., nasal mucosal delivery or intranasal mucosal delivery).
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