NO324123B1 - Use of lanreotide, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition - Google Patents

Abstract

The present invention is directed to a method of treating one or more diseases and / or conditions, which comprises administering to a patient in need thereof the compound Hg (b) -D-Nal-Cys-Tyr-D-Trp-Lys -Val-Cys-Thr-NH, wherein the cysteines are linked together via a disulfide bond, or a pharmaceutically acceptable salt thereof, most preferably the acetate salt of the compound, in the treatment of certain diseases and / or conditions such as gastroenterological conditions and / or diseases, endocrinological diseases and / or conditions, various cancers and conditions associated with cancer such as cancer cachexia, and in the treatment of hypotension and panic attacks.

Description

The present invention relates to the use of lanreotide, or a pharmaceutically acceptable salt thereof, for the production of a pharmaceutical preparation. The invention is directed to the use of the compound of formula H-p-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (also known as lanreotide), where the two cysteines are bound together by a disulfide bond, or a pharmaceutically acceptable salt thereof, most preferably the acetate salt of the compound, which is suitable for the treatment of certain diseases and/or conditions such as pancreatic pseudocysts and ascites, nesidioblastosis, Zollinger-Ellison syndrome, small bowel obstruction, duodenogastric reflux, Cushing's syndrome, gonadotropinoma, hyperparathyroidism, diabetic neuropathy, macular degeneration, Paget's disease, meningion, cancer cachexia; psoriasis, hypotension and panic attacks.

Lanreotide is an analogue of somatostatin and is known to inhibit growth hormone release as well as inhibit insulin, glucagon and pancreatic exocrine secretion.

D1=US Patent No. 4,853,371 describes lanreotide, a method for its preparation and a method for inhibiting the secretion of growth hormone, insulin and glucagon, as well as pancreatic exocrine secretion.

US Patent No. 5,147,856 describes the use of lanreotide for the treatment of restenosis.

US Patent No. 5,411,943 describes the use of lanreotide for the treatment of hepatoma.

US Patent No. 5,073,541 describes the use of lanreotide for the treatment of lung cancer.

US Patent Application No. 08/089,410, filed July 9, 1993, describes the use of lanreotide for the treatment of melanoma.

US Patent No. 5,504,069 describes the use of lanreotide for inhibiting the accelerated growth of a massive tumor.

US Patent Application No. 08/854,941, filed May 13, 1997, describes the use of lanreotide for reducing body weight.

US Patent Application No. 08/854,943, filed May 13, 1997, describes the use of lanreotide for the treatment of insulin resistance and syndrome X.

US Patent No. 5,688,418 describes the use of lanreotide for prolonging the survival of pancreatic cells.

PCT Patent Application No. PCT/US97/14154 describes the use of lanreotide for the treatment of fibrosis.

US Patent Application No. 08/855,311, filed May 13, 1997, describes the use of lanreotide for the treatment of hyperlipidemia.

US Patent Application No. 08/440,061, filed May 12, 1995, describes the use of lanreotide for the treatment of hyperamylinemia.

US Patent Application No. 08/852,221, filed May 7, 1997, describes the use of lanreotide for the treatment of hyperprolactinemia and prolactinomas.

US 5,688,530 describes sustained release formulations which are microparticles comprising Octreotide® or certain other specified structures described as somatostatin analogs and polymeric matrices of copolymers of polylactide-co-glycolide molecules. The acetate salt of Octreotide and the other compounds are preferred for use in the microparticles. The microparticle formulations of US 5,688,530 can be used to treat certain disorders, especially acromegaly.

WO 98/10786 describes pharmaceutical compositions comprising specific compounds including Lanreotide® for the treatment of syndrome X of Raven.

Hepatology, vol 27, no. 4, 1998, pp. 920-925, Mottet, C. et al. notes the increased use of somatostatin and its analogs to manage complications of chronic liver disease such as variceal bleeding. Mottet describes a study of hemodynamic effects of administering lanreotide in healthy individuals. Mottet concludes that intravenous administration of lanreotide in healthy subjects inhibits food-induced hyperemia and attenuates normal food-induced systemic hemodynamic changes.

British Journal of Clinical Pharmacology, vol.41, no.2, 1996, pp.109-114, Sobhani, I. et al. cites the previous use of somatostatin to treat VIP-induced watery diarrhea and describes a study of the effect of lanreotide on stimulated intestinal cells as assessed by secretion of water and ions in the jejunum in ten healthy men and two men with AIDS (suffering from watery diarrhea ), that is, to look for beneficial effects in controlling VIP secretory diarrhea.

The American Journal of the Medicial Sciences, vol.309, no.6, 1995, p.312-314, Anthony, L.B. et al describe a study for the use of lanreotide in the treatment of a patient for hypercalcemia of malignancy (HCM) associated with overexpression of parathyroid hormone-related protein (PTHrP) by a tumor.

The contents of the aforementioned patents and patent applications are included herein as a reference.

This invention is directed to the use of an effective amount of the compound H-p-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, where the two cysteines are linked together via a disulfide bond, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical preparation for the treatment of a disease or condition selected from the group consisting of pancreatic pseudocysts, pancreatic ascites, nesidioblastosis, Zollinger-EHison syndrome, small bowel obstruction, duodenogastric reflux, Cushing's syndrome, gonadotropinoma, hyperparathyroidism, diabetic neuropathy, macular degeneration, Paget's disease, meningion, cancer cachexia; psoriasis, hypotension and panic attacks.

A preferred application for the application described immediately above is where the acetate salt of H-P-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 is used.

A preferred application of the application described immediately above is where the disease or condition is selected from the group consisting of nesidioblastosis, small bowel obstruction, diabetic neuropathy, meningioma and cancer cachexia.

A preferred application of the immediately above application is where the disease or condition being treated is selected from the group consisting of nesidioblastosis, small bowel obstruction and diabetic neuropathy. Lanreotide is readily prepared according to the method described in US Patent No. 4,853,371, or the method described in US Patent No. 5,411,943. Lanreotide was previously marketed as the acetate salt in a 30 mg long-acting form and supplied by Ipsen Biotech, Paris, France.

As is well known to those skilled in the art, the known and potential uses of somatostatin are varied and diverse. Somastatin is known to be useful in the treatment of the diseases and/or conditions listed below. The varied uses of somatostatin can be summarized as follows: Cushing's syndrome (see R.V. Clark et al., Clin. Res. 38, p. 943A, 1990); gonadotropinoma (see B. Ambrosi et al., Acta Endocr. (Copenhagen) 122, 569-576, 1990); hyperparathyroidism (see D. Miller et al., Canad. Med. Ass. J., vol. 145, pp. 227-228, 1991); Paget's disease (see G.M.A. Palmieri et al., J. of Bone and Mineral Research, 7, (Suppl. 1), p. S240 (Smdr. 591), 1992); VIPom (see B. Koberstein et al., Z. Gastroenterology, 28, 295-301, 1990 and C. Christensen, Acta Chir. Scand. 155, 541-543, 1989); nesidioblastosis and hyperinsulinism (see Z. Laron, Israel J. Med. Sei., 26, No. 1,1-2, 1990, D.C. Wilson, Irish J. Med. Sei., 158, No. 1, 31-32, 1989 and D. Micic et al., Digestion, 16, Suppl. 1.70. Smdr. 193, 1990); gastrinoma (see F.E. Bauer et al., Europ. J. Pharmacol., 183, 55 1990); Zollinger-Ellison syndrome (see E. Mozell et al., Surg. Gynec. Obstet., 170, 476-484, 1990); hypersecretory diarrhea associated with AIDS and other conditions (due to AIDS, see J.P. Cello et al., Gastroenterology, 98, No. 5, Part 2, Suppl., A 163 1990; due to elevated gastrin-releasing peptide, see R Alhindawi et al., Can. J. Surg., 33, 139-142, 1990; secondary to intestinal graft-versus-host disease, see J. A. Bianco et al., Transplantation, 49, 1194-1195, 1990; diarrhea associated with chemotherapy, see N. Petrelli et al., Proe. Amer. Soc. Clin. Oncol., vol. 10, P 138, Smdr. no. 417 1991); irritable bowel syndrome (see L.J.D. O'Donnell et al., Aliment. Pharmacol. Therap., vol. 4, 177-181, 1990); pancreatitis (see Z. Tulassay et al., Gastroenterology, 98, No. 5, Part 2, Suppl., A238, 1990); Crohn's disease (see R.N. Fedorak et al., Can. J. Gastroenterology, 3, No. 2, 53-57, 1989); systemic sclerosis (see H. Soudah et al., Gastroenterology, 98, No. 5, Part 2, Suppl., A129, 1990); thyroid cancer (see E. Modigliani et al., Ann., Endocr. (Paris), 50, 483-388, 1989); psoriasis (see C. Camisa et al., Cleveland Clinic J. Med., 57, No. 1, 71-76, 1990); hypotension (see R.D. Hoeldtke et al., Arch. Phys. Med. Rehabil., 69, 895-898, 1988 and J.S. Kooner et al., Brit. J. Clin. Pharmacol., 28, 745P-736P, 1989); panic attacks (see J.L. Abelson et al., Clin. Psychopharmacol., 10,128-132,1990); scleroderma (see H. Soudah et al., Clin. Res., vol. 39, p. 303A, 1991); small bowel obstruction (see D.M. Nott et al., Brit. J. Surg., vol. 77, p. A691, 1990); gastroesophageal reflux (see M.S. Branch et al., Gastroenterology, vol. 100, no. 5, part 2 Suppl., p. A425, 1991); duodenogastric reflux (see W. Hasler et al., Gastroenterology, vol. 100, no. 5, part 2, Suppl., p. A448, 1991); Graves' disease (see T.C. Chang et al., Brit. Med. J., 304, p. 158, 1992); polycystic ovary disease (see G.M. Prelevic et al., Metabolism Clinical and Experimental, 41, Suppl. 2, pp. 76-79, 1992), bleeding in the upper gastrointestinal system (see S.A. Jenkins et al., Gut., 33, p. 404-407,1992 and A. Arrigoni et al., American Journal of Gastroenterology, 87, p. 1311, (smdr. 275), 1992); pancreatic pseudocysts and ascites (see J.E. Hartley et al., J. Roy. Soc. Med., 85, pp. 107-108, 1992); leukemia (see Santini et al., 78, (Suppl. 1), p. 429A (Smdr. 1708), 1991); meningioma (see J.W. Koper et al., J. Clin. Endocr. Metab., 74, pp. 543-547,1992) and cancer cachexia (see D.L. Bartlett et al., Surg. Forum., 42, pp. 14- 16, 1991).

The applicant has now surprisingly discovered that lanreotide itself was particularly useful in the treatment of the conditions, disorders and diseases indicated above.

The usefulness of lanreotide in the various described new medical applications can be better understood via the results of tests in connection with the treatment of bleeding in the upper gastrointestinal system.

Lanreotide or a pharmaceutically acceptable salt thereof may be administered orally, parenterally (eg, intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasally, vaginally, rectally, sublingually, or topically, and may be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for h<y>er mode of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. Such dosage forms can also, as is normal practice, include additional substances other than such inert diluents, e.g. lubricants such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also include buffering agents. Tablets and pills can also be produced with enteric coatings.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the field, such as water. In addition to such inert diluents, the preparations can also include adjuvants, such as wetting agents, emulsifying agents and suspending agents, as well as sweeteners, flavoring agents and perfumes.

Preparations used for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or carrier materials are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. They can be sterilized, for example, by filtering through a filter that retains bacteria, by incorporating sterilizing agents into the preparations, by irradiating the preparations or by heating the preparations. They can also be produced in the form of sterile solid preparations that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.

Preparations for rectal or vaginal administration are preferably suppositories which, in addition to the active substance, may contain excipients such as cocoa butter or a suppository wax.

Preparations for nasal or sublingual administration are also prepared with standard excipients which are well known in the field.

The dosage of active ingredient in the preparations used can be varied; however, it is necessary that the amount of the active ingredient is such that a suitable dosage form is obtained. The chosen dosage depends on the desired therapeutic effect, on the method of administration and on the duration of the treatment. Typically, dosage levels of between 25 µg and 100 mg per kg body weight per day as a single dose or divided into multiple doses for humans and other animals, e.g. mammals, to achieve the desired therapeutic effect.

A preferred general dosage range is from 250 u.g to 5.0 mg per kg body weight per day, which can be administered as a single dose or divided into multiple doses.

Lanreotide can further be administered in a sustained release formulation, such as those described in the following patents. Among these prolonged release formulations, formulations with 14 day or 28 day release will be preferred. US Patent No. 5,672,659 teaches sustained release formulations comprising lanreotide and a polyester. US Patent No. 5,595,760 teaches sustained release formulations comprising lanreotide in a form that can form a gel. US Patent Application No. 08/929,363, filed September 9, 1997, teaches sustained release polymeric compositions comprising lanreotide and chitosan. US Patent Application No. 08/740,778, filed November 1, 1996, teaches sustained release formulations comprising lanreotide and cyclodextrin. US Patent Application No. 09/015,394, filed January 29, 1998, teaches absorbable sustained release preparations of lanreotide.

The use of preparations with immediate or prolonged release depends on the type of indications sought. If the indication consists of an acute or super-acute disorder, a treatment with an immediate form will be preferred over the same with a preparation with prolonged release. For preventive or long-term treatments, however, a preparation with a long-term release will usually be preferred.

The indication that includes bleeding in the upper gastrointestinal system will typically correspond to an acute or super-acute treatment with a dosage of 80-120 µg/day per person during approx. 5 days. After endoscopic treatment, preventive treatment against recurrence can be carried out using forms with prolonged release of lanreotide as an aid to usual treatments; for this type of treatment, long-term release forms with a 14-day release can be used, with a total dosage of approx. 30 mg lanreotide, or 28-day forms of lanreotide.

For indications other than bleeding in the upper gastrointestinal system, which correspond to fairly long-term treatments, 14-day long-term release forms with a total dosage of approx. 30 mg lanreotide or 28 day forms of lanreotide may be appropriate.

Claims (4)

1. Use of an effective amount of the compound H-p-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, where the two cysteines are linked together via a disulfide bond, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a disease or condition selected from the group consisting of pancreatic pseudocysts, pancreatic ascites, nesidioblastosis, Zollinger-Ellison syndrome, small bowel obstruction, duodenogastric reflux, Cushing's syndrome, gonadotropinoma, hyperparathyroidism, diabetic neuropathy, macular degeneration , Paget's disease, meningion, cancer cachexia; psoriasis, hypotension and panic attacks. 2. Use according to claim 1, where the compound is the acetate salt of H-p-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2. 3. Use according to claim 2, where the disease or condition is selected from the group consisting of nesidioblastosis, small bowel obstruction, diabetic neuropathy, meningioma and cancer cachexia. 4. Use according to claim 3, where the disease or condition being treated is selected from the group consisting of nesidioblastosis, small bowel obstruction and diabetic neuropathy.