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Title:  Agent for ameliorating pancreatic function disorder

United States Patent:  6,689,745

Issued:  February 10, 2004

Inventors:  Itakura; Yasushi (Nara-ken, JP); Taiji; Mutsuo (Takatsuki, JP)

Assignee:  Sumitomo Pharmaceuticals Company, Limited (Osaka, JP)

Appl. No.:  958738

Filed:  October 16, 2001

PCT Filed:  April 7, 2000

PCT NO:  PCT/JP00/02264

PCT PUB.NO.:  WO00/62796

PCT PUB. Date:  October 26, 2000

Abstract

Agents for protecting or ameliorating pancreatic cells and tissues which contains as the active ingredient a neurotrophic factor such as BDNF. By using these drugs, degenerative dropout of pancreatic cells and pancreatic hypofunction caused by diabetes, acute/chronic pancreatitis, etc. can be efficaciously prevented and treated.

DISCLOSURE OF INVENTION

An agent for protecting pancreatic cells or an agent for ameliorating damaged pancreatic cells, an agent for protecting pancreatic cell function or an agent for ameliorating pancreatic cell hypofunction, or an agent for protecting pancreatic tissues or an agent for ameliorating damaged pancreatic tissues, or an agent for protecting pancreatic tissue function or an agent for ameliorating pancreatic tissue hypofunction has been desired in the medical field.

The present inventors have an interest in that the insulin secretion of BDNF-treated type 2 diabetic animal models is kept at high level, and have studied pancreatic function ameliorating activities by using type 2 diabetic animal models. As a result, they have found that BDNF can (1) increase the decreased insulin content in pancreas of type 2 diabetes animal models, (2) reduce the increased glucagon content in pancreas, (3) normalize the localization of A cells and D cells in the pancreatic Langerhans islet, (4) promote the re-granulation of insulin secretory granules of B cells in the pancreatic Langerhans islet, and normalize the organellae. Based on the finding of these pancreatic function ameliorating activity and pancreatic cell protecting activity of BDNF, the present inventors have further studied and have accomplished the present invention.

More particular, the present invention relates to the following:

1. An agent for protecting pancreatic cells or an agent for ameliorating damaged pancreatic cells, which comprises as the active ingredient a neurotrophic factor;

2. An agent for protecting pancreatic cell function or an agent for ameliorating pancreatic cell hypofunction, which comprises as the active ingredient a neurotrophic factor;

3. An agent for protecting pancreatic tissues or an agent for ameliorating damaged pancreatic tissues, which comprises as the active ingredient a neurotrophic factor;

4. An agent for protecting pancreatic tissue function or an agent for ameliorating pancreatic tissue hypofunction, which comprises as the active ingredient a neurotrophic factor;

5. The agent for protection or amelioration of the function according to the above 1 or 2, wherein the pancreatic cell is B cells (.beta. cells), A cells (.alpha. cells), and/or D cells (.delta. cells) of the pancreatic Langerhans islet;

6. The agent for protection or amelioration of the function according to the above 1 or 2, wherein the pancreatic cell is B cells (.beta. cells), A cells (.alpha. cells), D cells (.delta. cells), and/or PP cells of the pancreatic Langerhans islet;

7. The agent for protecting pancreatic tissue function or the agent for ameliorating hypofunction of pancreatic tissue according to the above 3 or 4, wherein the pancreatic tissue is the pancreatic Langerhans islet;

8. The agent for protection or amelioration according to the above 1, 2, 5 or 6, which is an agent for protecting or ameliorating pancreatic endocrine function (insulin secretion ability, glucagon secretion ability and/or somatostatin secretion ability) or an agent for ameliorating pancreatic endocrine function disorder (insulin secretion ability, glucagon secretion ability and/or somatostatin secretion ability);

9. The agent for protection or amelioration according to the above 3, 4 or 7, which is an agent for protecting or ameliorating pancreatic endocrine function (insulin secretion ability, glucagon secretion ability and/or somatostatin secretion ability) or an agent for ameliorating pancreatic endocrine function disorder (insulin secretion ability, glucagon secretion ability and/or somatostatin secretion ability);

10. The agent for protection or amelioration according to the above 1, 2, 5, 6, or 8, wherein the cause for hypofunction or disorder of pancreatic cells is diabetes mellitus;

11. The agent for protection or amelioration according to the above 3, 4, 7 or 9, wherein the cause for hypofunction or disorder of pancreatic tissues is diabetes mellitus;

12. The agent for protection or amelioration according to the above 1, 2, 5, 6, or 8, wherein the cause for hypofunction or disorder of pancreatic cells is acute pancreatitis or chronic pancreatitis;

13. The agent for protection or amelioration according to the above 3, 4, 7 or 9, wherein the cause for hypofunction or disorder of pancreatic tissues is acute pancreatitis or chronic pancreatitis;

14. The agent for protection or amelioration according to the above 1, 2, 5, 6, or 8, wherein the cause for hypofunction or disorder of pancreatic cells is a sulfonylurea derivative;

15. The agent for protection or amelioration according to the above 3, 4, 7 or 9, wherein the cause for hypofunction or disorder of pancreatic tissues is a sulfonylurea derivative;

16. An agent for treating acute pancreatitis or chronic pancreatitis, which comprises as the active ingredient the agent for protection or amelioration as set forth in any one of the above 1, 2, 5, 6, and 8;

17. An agent for treating acute pancreatitis or chronic pancreatitis, which comprises as the active ingredient the agent for protection or amelioration as set forth in any one of the above 3, 4, 7 and 9;

16. An agent for protecting pancreatic endocrine tissues or an agent for ameliorating damaged pancreatic endocrine tissues, which comprises as the active ingredient a neurotrophic factor;

17. An agent for protecting pancreatic endocrine tissue function or an agent for ameliorating hypofunction of pancreatic endocrine tissues, which comprises as the active ingredient a neurotrophic factor;

18. An agent for protecting pancreatic exocrine tissues or an agent for ameliorating damaged pancreatic exocrine tissues, which comprises as the active ingredient a neurotrophic factor;

19. An agent for protecting pancreatic exocrine tissue function or an agent for ameliorating hypofunction of pancreatic exocrine tissues, which comprises as the active ingredient a neurotrophic factor;

20. The agent for protection or amelioration according to any one of the above 1 to 19, wherein the neurotrophic factor of the active ingredient is NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), CNTF (ciliary neurotrophic factor), NT-3 (neurotrophin 3), NT-4 (neurotrophin 4), NT-5 (neurotrophin 5), or NT-6 (neurotrophin 6);

21. The agent for protection or amelioration according to any one of the above 1 to 19, wherein the neurotrophic factor of the active ingredient is BDNF (brain-derived neurotrophic factor);

22. The agent for protection or amelioration according to any one of the above 1 to 19, wherein the neurotrophic factor of the active ingredient is CNTF (ciliary neurotrophic factor);

23. The agent for protection or amelioration according to any one of the above 1 to 19, wherein the neurotrophic factor of the active ingredient is NT-3 (neurotrophin 3);

24. The agent for protection or amelioration according to any one of the above 1 to 19, wherein the neurotrophic factor of the active ingredient is NT-4 (neurotrophin 4);

25. The agent for protection or amelioration according to any one of the above 1 to 19, wherein the neurotrophic factor of the active ingredient is NT-5 (neurotrophin 5);

26. The agent for protection or amelioration according to any one of the above 1 to 19, wherein the neurotrophic factor of the active ingredient is NT-6 (neurotrophin 6);

27. The agent for protection or amelioration according to any one of the above 1 to 19, wherein the neurotrophic factor of the active ingredient is NGF (nerve growth factor);

28. The agent for protection or amelioration according to any one of the above 1 to 19, wherein the neurotrophic factor of the active ingredient is GDNF (glia cell-derived neurotrophic factor);

29. The agent for protection or amelioration according to any one of the above 1 to 19, wherein the neurotrophic factor of the active ingredient is a trkA, a trkB and/or a trkC receptor agonist;

BEST MODE FOR CARRYING OUT THE INVENTION

The neurotrophic factors used as an active ingredient of the present invention may be commercially available ones or can be prepared by the following methods.

The neurotrophic factors used as the active ingredient of the present invention can be any ones prepared by various methods as far as they are purified to such a degree that it could be used as a medicament. The neurotrophic factor can be obtained by cultivating a primary culture cell or an established cell line that can produce the neurotrophic factor, and isolating and purifying it from the culture medium thereof (e.g., culture supernatant, cultured cells). Moreover, a recombinant neurotrophic factor can be obtained by a conventional gene engineering technique, e.g., by inserting a gene encoding a neurotrophic factor into a suitable vector, transforming a suitable host with the recombinant vector, and isolating from a culture supernatant of the resulting transformant. The host cells to be used in the above process are not limited, and may be any conventional host cells which have been used in a gene engineering technique, for example, Escherichia coli, Bacillus subtilis, yeasts, mold fungi, plant cells or animal cells.

The neurotrophic factors obtained in the above method include a modified recombinant neurotrophic factor such as ones produced by a deletion of a part of amino acid sequence, or a substitution by other amino acid(s), or an addition of a part of other amino acid sequence, or ones having one or more amino acids at the N-terminus and/or the C-terminus, or ones wherein the sugar chain is deleted or substituted, as far as they exhibit substantially the same activity.

Method for Preparation of BDNF

When a conventional gene engineering technique is employed, BDNF is prepared by inserting a gene encoding BDNF into a suitable vector, transforming a suitable host with the recombinant vector, and isolating it from a culture supernatant of the resulting transformant (cf., Proc. Natl. Acad. Sci. USA, vol. 88, p. 961 (1991); Biochem. Biophys. Res. Commun., vol. 186, p. 1553 (1992)). The gene engineering technique is suitable for production of BDNF of same quality in a large scale. The host cells mentioned above are not limited, but may be any conventional host cells which have been used in a gene engineering technique, for example, Escherichia coli, Bacillus subtilis, yeasts, plant cells or animal cells.

Method for Preparation of NT-3

NT-3 can be prepared by expressing in various host cells in the same manner as in the preparation of BDNF. The methods for preparing thereof and the methods for assay thereof are disclosed in Neuron, vol. 4, 767-773 (1990), or JP-A-5-161493 (WO 91/3659).

Method for Preparation of NT-4

NT-4 can be prepared by expressing in various host cells in the same manner as in the preparation of BDNF. The methods for expression of the recombinant NT-4 and the methods for assay thereof are disclosed in Proc. Natl. Acad. Sci. USA, vol. 89, p. 3060-3064 (1992.4), JP-A-7-509600 (WO 93/25684), or JP-A-6-501617 (WO 92/5254).

Method for Preparation of CNTF

CNTF can be prepared in a large scale by expressing in various host cells in the same manner as in the preparation of BDNF. The methods for expression of the recombinant CNTF and the methods for assay thereof are disclosed in Biochimica et Biophysica Acta, vol. 1090, p. 70-80 (1991), J. Neurochemistry, vol. 57, p. 1003-1012 (1991). The methods for preparing the recombinant CNTF and the purification thereof are disclosed in JP-A-4-502916 (WO 90/7341).

The agent for protecting or ameliorating pancreatic cell function, or an agent for protecting or ameliorating pancreatic tissue function, which comprise as the active ingredient a neurotrophic factor, can be administered either parenterally or orally.

The precise dosage and the administration schedule of the above agents of the present invention should vary according to the dosage to be required for each patient, the method for treatment, the disease to be treated, or the degree of necessity, and further according to the diagnosis by a physician. When administered parenterally, the dosage and the frequency of the administration may vary according to the conditions, ages, body weights of patients, and administration routes, but when it is administered subcutaneously or intravenously in the form of an injection, then the daily dosage thereof is in the range of about 1 to about 2500 .mu.g, preferably in the range of about 10 to about 500 .mu.g per 1 kg of the body weight in an adult. When it is administered to the air tract in the form of an aerosol spray, the daily dosage thereof is in the range of about 1 .mu.g to about 2500 .mu.g, preferably in the range of about 10 to about 500 .mu.g per 1 kg of the body weight in an adult. The administration schedule is either continuous daily administration, intermittent administration, or a schedule of combining these methods.

When administered orally, the dosage and the frequency of administration may vary according to the conditions, ages, body weights of patients, and administration routes, and the daily dosage thereof is in the range of about 5 to about 2500 .mu.g, preferably in the range of about 10 to about 1000 .mu.g per 1 kg of the body weight in an adult.

A pharmaceutical composition can be prepared by mixing a neurotrophic factor with a pharmaceutically acceptable non-toxic carrier. When a pharmaceutical composition for parenteral administration (subcutaneous injection, intramuscular injection, or intravenous injection) is prepared, it is preferably in the form of a solution preparation or a suspension preparation. When a pharmaceutical composition for intravaginal administration or rectal administration is prepared, it is preferably in the form of a semi-solid preparation such as cream or suppository. When a pharmaceutical composition for intranasal administration is prepared, it is preferably in the form of a powder, a nasal drop, or an aerosol.

The pharmaceutical composition is administered in the form of a single dosage unit, and can be prepared by any conventional method that is known in the pharmaceutical field such as methods disclosed in Remington's Pharmaceutical Science (published by Mack Publishing Company, Easton, Pa., 1970). An injection preparation may optionally contain as a pharmaceutical carrier a protein derived from plasma such as albumin, an amino acid such as glycin, or a carbohydrate such as mannitol, and additionally a buffering agent, a solubilizer, or an isotonic agent, etc. can be contained. When the present pharmaceutical composition is in the form of an aqueous solution preparation or a lyophilized preparation, it may preferably contain a surfactant such as Tween 80 (registered trade mark), Tween 20 (registered trade mark), etc. in order to avoid aggregation. When the present pharmaceutical composition is a composition for parenteral administration other than an injection preparation, then it may contain distilled water or physiological saline solution, polyalkylene glycol such as polyethylene glycol, an oil derived from plant, hydrogenated naphthalene, etc. For example, a pharmaceutical composition such as a suppository for intravaginal administration or rectal administration may contain as a conventional excipient polyalkylene glycol, vaseline, cacao butter, etc. A pharmaceutical composition for intravaginal administration may contain an absorbefacient such as a bile salt, an ethylenediamine salt, a citrate, etc. A pharmaceutical composition for inhalation may be in the form of a solid preparation, and may contain as an excipient lactose, etc., and a pharmaceutical composition for intranasal drop may be in the form of an aqueous solution or an oily solution.

The present pharmaceutical composition is especially preferable in the form of a formulation by which the present compound can persistently be given to a subject by a single administration for a long term, e.g., for one week or one year, and various sustained release preparations, depot preparations, or implant preparations can be employed. For example, a pharmaceutical composition may contain a neurotrophic factor per se, or a pharmaceutically acceptable salt of a neurotrophic factor of which solubility in body fluid is low. Such pharmaceutically acceptable salts are, for example, (1): an acid addition salt such as phosphate, sulfate, citrate, tartrate, tannate, pamoate, alginate, polyglutarate, naphthalenemono- or di-sulfonate, polygalacturonate, etc., (2): a salt or complex with polyvalent metal cation such as zinc, calcium, bismuth, barium, nickel, etc, or a combination of (1) and (2), for example, a tannic acid zinc salt, etc. A neurotrophic factor is preferably converted into a slightly-water-soluble salt thereof, which is mixed with a gel, for example, aluminum monostearate gel and sesame oil, etc. to give a suitable injection preparation. In this case, especially preferable salt is a zinc salt, a tannic acid zinc salt, a pamoate, etc. Another type of a sustained release injection preparation is ones wherein a neurotrophic factor is preferably converted into a slightly-water-soluble salt thereof, which is further enclosed in a slow-disintegrative non-toxic and non-antigenic polymer such as a polymer or a copolymer of polylactic acid/polyglycolic acid. In this case, especially preferable salt is zinc salt, tannic acid zinc salt, pamoate, etc. In addition, a neurotrophic factor or a slightly-water-soluble salt thereof can be enclosed into a cholesterol matrix or collagen matrix to give a sustained release preparation.

The pharmaceutical preparation for oral administration may be ones which are prepared by microencapsulating a neurotrophic factor or a salt thereof with lecithin, cholesterol, a free fatty acid, or ones which are prepared by enclosing said microcapsules into gelatin capsules, or ones which are prepared by enclosing a neurotrophic factor or a salt thereof in enteric capsules, etc. These preparations may additionally contain, for example, an absorbefacient, a stabilizer, a surfactant, etc.

The agent for protecting or ameliorating pancreatic cell function or the agent for protecting or ameliorating pancreatic tissue function can be administered alone or together with insulin to a patient with pancreatic function disorder. The present agents can prevent pancreatic hypofunction of a patient with pancreatitis or pancreatic cancer, and can enable said patient to easily control the blood glucose level or metabolism. When the present agent is administered together with insulin, the dosage of insulin is in the range of 4 to 100 units/human/day in terms of human insulin, and the daily dosage of a neurotrophic factor, which is administered simultaneously or in advance with insulin, is in the range of about 1 to about 2500 .mu.g, preferably in the range of about 10 to about 500 .mu.g per 1 kg of the body weight of an adult.

(Toxicity)

When a neurotrophin, especially BDNF, was administered subcutaneously to rats and cynomolgus monkeys at a dose of 100 mg/kg and 60 mg/kg, respectively, for four weeks, no animal died. With respect to the acute toxicity, BDNF was administered to rats and cynomolgus monkeys at a dose of 200 mg/kg, and no animal died. Therefore, BDNF shows high safety.

Claim 1 of 8 Claims

What is claimed is:

1. A method of protecting pancreatic cell function or of ameliorating hypofunction of pancreatic cells in a subject presenting type II diabetes and a defect in insulin secretion, which comprises administering a brain-derived neurotrophic factor to the subject.



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