Title:  Prolonging survival of transplanted pancreatic cells

United States Patent:  6,342,479

Assignee:   Societe de Counseils de Recherches et d'Applications Scientifiques, SAS (Paris, FR)

Filed:  March 1, 1999

PCT NO:  PCT/US97/05722

102(e) Date:  March 1, 1999

PCT PUB. Date:  October 16, 1997

A method of prolonging the survival of pancreatic cells transplanted in a patient. The method includes the step of administering a therapeutically effective amount of somatostatin or a somatostatin agonist to the patient.

SUMMARY OF THE INVENTION

The present invention relates to a method of prolonging the survival of transplanted pancreatic cells in a patient (e.g., a mammal such as a human). The method includes the step of administering a therapeutically effective amount of somatostatin or a somatostatin agonist to the patient. What is meant by "survival" is either the viability or the biological function (e.g., the insulin response to hyperglycemia) of the transplanted pancreatic cells. The somatostatin or somatostatin agonist may be administered parenterally, e.g., administered intravenously, subcutaneously, or by implantation of a sustained release formulation. The transplanted pancreatic cells may be a whole or partially intact pancreas, pancreatic islets, or isolated pancreatic cells. The cells may be autograft cells, allograft cells, or xenograft cells. In one embodiment, the patient is an insulin-dependent (e.g., Type I or late Type II diabetic).

Definition of "somatostatin agonist" will be defined below. A therapeutically effective amount depends upon the condition being treated, the route of administration chosen, and the specific activity of the compound used and ultimately will be decided by the attending physician or veterinarian. In one embodiment, the somatostatin agonist is administered to the patient during the pancreatic cell transplantation and continued until the transplanted cells have become established and fully functional in the patient. In another embodiment, the somatostatin agonist is administered for the lifetime of the cells (e.g., potentially the lifetime of the patient).

The somatostatin agonist may be injected parenterally, e.g., intravenously, into the bloodstream of the subject being treated. However, it will be readily appreciated by those skilled in the art that the route, such as intravenous, subcutaneous, intramuscular, intraperitoneal, enterally, transdermally, transmucously, sustained released polymer compositions (e.g., a lactide polymer or copolymer microparticle or implant), profusion, nasal, oral, etc., will vary with the condition being treated and the activity and bioavailability of the somatostatin agonist being used.

While it is possible for the somatostatin agonist to be administered as the pure or substantially pure compound, it may also be presented as a pharmaceutical formulation or preparation. The formulations to be used in the present invention, for both humans and animals, comprise any of the somatostatin agonists to be described below, together with one or more pharmaceutically acceptable carriers thereof, and optionally other therapeutic ingredients.

The carrier must be "acceptable" in the sense of being compatible with the active ingredient(s) of the formulation (e.g., capable of stabilizing peptides) and not deleterious to the subject to be treated. Desirably, the formulation should not include oxidizing agents or other substances with which peptides are known to be incompatible. For example, somatostatin agonists in the cyclized form (e.g., internal cysteine disulfide bond) are oxidized; thus, the presence of reducing agents as excipients could lead to an opening of the cysteine disulfide bridge. On the other hand, highly oxidative conditions can lead to the formation of cysteine sulfoxide and to the oxidation of tryptophane. Consequently, it is important to carefully select the excipient. pH is another key factor, and it may be necessary to buffer the product under slightly acidic conditions (pH 5 to 6).

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient(s) into association with the carrier which constitutes one or more accessory ingredients.

In general, the formulations for tablets or powders are prepared by uniformly and intimately blending the active ingredient with finely divided solid carriers, and then, if necessary, as in the case of tablets, forming the product into the desired shape and size.

Formulations suitable for parenteral (e.g., intravenous) administration, on the other hand, conveniently comprise sterile aqueous solutions of the active ingredient(s). Preferably, the solutions are isotonic with the blood of the subject to be treated. Such formulations may be conveniently prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution, and rendering the solution sterile. The formulation may be presented in unit or multi-dose containers, for example, sealed ampoules or vials.

Formulations suitable for sustained release parenteral administrations (e.g., biodegradable polymer formulations) are also well known in the art. See, e.g., U.S. Pat. Nos. 3,773,919 and 4,767,628 and PCT Publication No. WO 94/15587.

The somatostatin or somatostatin agonist may also be administered with an immunosuppressive agent or insulin. Examples of immunosuppressive agents include cyclosporin, FK-506 glucocorticoids, and antibodies to T-cells.

Claim 1 of 16 Claims

What is claimed is:

1. A method of prolonging the survival of pancreatic cells transplanted in a patient said method comprising administering a therapeutically effective amount of a somatostatin agonist selected from the group consisting of

D-.beta.-Nal-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH₂,

D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-.beta.-Nal-NH₂,

D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-.beta.-Nal-NH₂,

D-.beta.-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH₂,

D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-NH₂,

D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH,

D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH,

Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH,

Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH,

Phe-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr-OH,

H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol,

H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,

H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,

H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH₂,

H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,

Ac-D-Phe-Lys*-Tyr-D-Trp-Lys-Val-Asp-Thr-NH₂ (an amide bridge formed between Lys* and Asp),

Ac-hArg(Et)₂ -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-D-hArg(Et)₂ -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-D-hArg(Bu)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-D-hArg(Et)₂ -Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-L-hArg(Et)₂ -Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-D-hArg(CH₂ CF₃)₂ -Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-D-hArg(CH₂ CF₃)₂ -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-D-hArg(CH₂ CF₃)₂ -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH₂,

Ac-D-hArg(CH₂ CF₃)₂ -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt,

Ac-L-hArg(CH₂ CF₃)₂ -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-D-hArg(CH₂ CF₃)₂ -Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NH₂,

Ac-D-hArg(CH₂ CF₃)₂ -Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NHEt,

Ac-hArg(CH₃, hexyl)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

H-hArg(hexyl₂)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-D-hArg(Et)₂ -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt,

Ac-D-hArg(Et)₂ -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH₂,

Propionyl-D-hArg(Et)₂ -Gly-Cys-Phe-D-Trp-Lys(iPr)-Thr-Cys-Thr-NH₂,

Ac-D-.beta.-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg(Et)₂ -NH₂,

Ac-D-Lys(iPr)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-D-hArg(CH₂ CF₃)₂ -D-hArg(CH₂ CF₃)₂ -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-D-hArg(CH₂ CF₃)₂ -D-hArg(CH₂ CF₃)₂ -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH₂,

Ac-D-hArg(Et)₂ -D-hArg(Et)₂ -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,

Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH₂,

Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,

Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH₂,

Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH₂,

Bmp-Tyr-D-Trp-Lys-Val-Cys-.beta.-Nal-NH₂,

H-D-.beta.-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,

H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂,

H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-.beta.-Nal-NH₂,

H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,

Ac-D-.beta.-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH₂,

H-D-.beta.-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-.beta.-Nal-NH₂,

H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-.beta.-Nal-NH₂,

H-D-.beta.-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂,

H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂,

Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂,

H-D-Phe-Cys-.beta.-Nal-D-Trp-Lys-Val-Cys-Thr-NH₂,

H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH₂,

cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe),

cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe),

cyclo(Pro-Phe-D-Trp-Lys-Thr-N-Me-Phe),

cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe),

cyclo(Pro-Tyr-D-Trp-Lys-Thr-Phe),

cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe),

cyclo(Pro-Phe-L-Trp-Lys-Thr-Phe),

cyclo(Pro-Phe-D-Trp(F)-Lys-Thr-Phe),

cyclo(Pro-Phe-Trp(F)-Lys-Thr-Phe),

cyclo(Pro-Phe-D-Trp-Lys-Ser-Phe),

cyclo(Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe),

cyclo(D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe),

cyclo(D-Ala-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Phe),

cyclo(D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe),

cyclo(D-Abu-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Tyr),

cyclo(Pr-Tyr-D-Trp-t-4-AchxAla-Thr-Phe),

cyclo(Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe),

cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe),

cyclo(N-Me-Ala-Tyr-D-Trp-t-4-AchxAla-Thr-Phe),

cyclo(Pro-Tyr-D-Trp-4-Amphe-Thr-Phe),

cyclo(Pro-Phe-D-Trp-4-Amphe-Thr-Phe),

cyclo(N-Me-Ala-Tyr-D-Trp-4-Amphe-Thr-Phe),

cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),

cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba),

cyclo(Asn-Phe-D-Trp-Lys-Thr-Phe),

cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH(CH₂)₄ CO),

cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-.beta.-Ala),

cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu)-OH,

cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe),

cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gly),

cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),

cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly),

cyclo(Asn-Phe-Phe-D-Trp(F)-Lys-Thr-Phe-Gaba),

cyclo(Asn-Phe-Phe-D-Trp(NO₂)-Lys-Thr-Phe-Gaba),

cyclo(Asn-Phe-Phe-Trp(Br)-Lys-Thr-Phe-Gaba),

cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe(I)-Gaba),

cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr(But)-Gaba),

cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH,

cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH,

cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys)-OH,

cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-MeLeu-Cys)-OH,

cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba),

cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba),

cyclo(Phe-Phe-D-Trp(5F)-Lys-Thr-Phe-Phe-Gaba),

cyclo(Asn-Phe-Phe-D-Trp-Lys(Ac)-Thr-Phe-NH--(CH₂)₃ --CO),

cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),

cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),

cyclo(Orn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba) and

H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH₂

wherein a disulfide bond exists in the somatostatin agonists having two Cys residues.

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