Note: Descriptions are shown in the official language in which they were submitted.
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METHODS OF USING A SOMATOSTATIN ANALOGUE
Background of the li~,v_~ntion
The present invention is directed to a method of treating one or more of
the following diseases and/or conditions in a patient in need thereof, which
comprises the administration of the compound of the formula H-(3-D-Nal-Cys-
Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (also known as lanreotide), where the two
Cysteines are bonded by 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, such as Crohn's disease, systemic sclerosis, external and internal
pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hyperinsulinism,
gastrinoma, Zollinger-Ellison Syndrome, diarrhea, AIDS related diarrhea,
chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome,
pancreatitis, upper gastrointestinal bleeding, postprandial portal venous
hypertension especially in cirrhotic patients, complications of portal
hypertension, small bowel obstruction, gastroesophageal reflux, duodenogastric
reflux and in treating endocrinological diseases andlor conditions, such as
Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease,
diabetic neuropathy, macular degeneration, hypercalcemia of malignancy,
Paget's disease, and polycystic ovary disease; in treating various types of
cancer such as thyroid cancer, leukemia, meningioma and conditions associated
with cancer such as cancer cachexia; in the treatment of such conditions as
hypotension such as orthostatic hypotension and postprandial hypotension and
panic attacks.
Lanreotide is an analog of somatostatin and is known to inhibit growth
hormone release as well as inhibit insulin, glucagon and pancreatic exocrine
secretion.
U.S. Patent No. 4,853,371 discloses lanreotide, a method for making it
and a method for inhibiting the secretion of growth hormone, insulin, glucagon
and pancreatic exocrine secretion.
U.S. Patent No. 5,147,856 discloses the use of lanreotide of treating
restenosis.
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U.S. Patent No. 5,411,943 discloses the use of lanreotide for treating
hepatoma.
U.S. Patent No. 5,073,541 discloses the use of lanreotide for treating
lung cancer.
U.S. Application No. 08/089,410 filed July 9, 1993 discloses the use of
lanreotide for treating melanoma.
U.S. Patent No. 5,504,069 discloses the use of lanreotide for inhibiting
the accelerated growth of a solid tumor.
U.S. Application No. 08/854,941 filed May 13, 1997, discloses the use of
lanreotide for decreasing body weight.
U.S. Application No. 08/854,943 filed May 13, 1997, discloses the use of
lanreotide for treating insulin resistance and Syndrome X.
U.S. Patent No. 5,688,418 discloses the use of lanreotide for prolonging
the survival of pancreatic cells.
PCT Application No. PCT/US97/14154 discloses the use of lanreotide for
treating fibrosis.
U.S. Application No. 08/855,311 filed May 13, 1997, discloses the use of
lanreotide for treating hyperlipidemia.
U.S. Application No. 08/440,061 filed May 12, 1995, discloses the use of
lanreotide for treating hyperamylinemia.
U.S. Application No. 08/852,221 filed May 7, 1997, discloses the use of
lanreotide for treating hyperprolactinemia and prolactinomas.
The contents of the foregoing patents and applications are incorporated
herein by reference.
Summanr of the Invention
This invention is directed to. a method of treating a disease or condition
which comprises administering to a patient in need thereof an effective amount
of the compound H-(3-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, where the two
Cysteines are bonded by a disulfide bond, or a pharmaceutically acceptable
salt
thereof, wherein the disease or condition is selected from the group
consisting of
systemic sclerosis, pancreatic pseudocysts, pancreatic ascites, VIPoma,
nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome,
hypersecretory diarrhea, scleroderma, irritable bowel syndrome, upper
gastrointestinal bleeding, postprandial portal venous hypertension,
complications
of portal hypertension, small bowel obstruction, duodenogastric reflux,
Cushing's
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Syndrome, gonadotropinoma, hyperparathyroidism, diabetic
neuropathy,
macular degeneration, hypercalcemia of malignancy, Paget's
disease,
meningioma, cancer cachexia, psoriasis, hypotension
and panic attacks.
A preferred method of the immediately foregoing method
is where the
acetate salt of H-~i-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2
is administered.
A preferred method of the immediately foregoing method
is where the
disease or condition is selected from the group consisting
of VIPoma,
nesidoblastosis, hyperinsulinism, gastrinoma, hypersecretory
diarrhea, irritable
bowel syndrome, upper gastrointestinal bleeding, postprandial
portal venous
hypertension, especially in cirrhotic patients, complications
of portal
hypertension, small bowel obstruction, diabetic neuropathy,
meningioma and
cancer cachexia.
A preferred method of the immediately foregoing method
is where the
disease or condition treated is selected from the group
consisting of VIPoma,
nesidoblastosis, hypersecretory diarrhea, irritable
bowel syndrome, small bowel
obstruction and diabetic neuropathy.
In another aspect, the present invention is directed
to a pharmaceutical
composition comprising a pharmaceutically acceptable
carrier and an effective
amount of the acetate salt of H-~i-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NHZ
to
treat a disease or condition wherein the disease or
condition is selected from the
group consisting of systemic sclerosis, pancreatic pseudocysts,
pancreatic
ascites, VIPoma, nesidoblastosis, hyperinsulinism, gastrinoma,
2ollinger-Ellison
Syndrome, hypersecretory diarrhea, scleroderma, irritable
bowel syndrome,
upper gastrointestinal bleeding, postprandial portal
venous hypertension,
especially in cirrhotic patients, complications of portal
hypertension, small bowel
obstruction, duodenogastric reflux, Cushing's Syndrome,
gonadotropinoma,
hyperparathyroidism, diabetic neuropathy, macular degeneration,
hypercalcemia
of malignancy, Paget's disease, meningioma, cancer cachexia,
psoriasis,
hypotension and panic attacks.
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CA 02335654 2001-O1-18
This invention provides a compound of the formula H-~3-D-Nal-Cys-Tyr-D-Trp-
Lys-Val-Cys-Thr-NHz in which the two Cysteines are bonded by a disulfide bond,
a
pharmaceutically acceptable salt thereof, or a pharmaceutical composition
comprising a
pharmaceutically acceptable carrier and the compound or a pharmaceutically
acceptable
salt thereof, for the treatment of a disease or condition selected from the
group consisting
of systemic sclerosis, pancreatic pseudocysts, pancreatic ascites, VIPoma,
nesidoblastosis,
hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, hypersecretory
diarrhea,
scleroderma, irritable bowel syndrome, upper gastrointestinal bleeding,
postprandial portal
venous hypertension, complications of portal hypertension, small bowel
obstruction,
duodenogastric reflux, Cushing's Syndrome, gonadotropinoma,
hyperparathyroidism,
diabetic neuropathy, macular degeneration, hypercalcemia of malignancy,
Paget's disease,
meningioma, cancer cachexia, psoriasis, hypotension and panic attacks.
This invention also provides a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and an effective amount of the acetate
salt of H-~3-D
Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NHz for the treatment of a disease or
condition
wherein the disease or condition is selected from the group consisting of
systemic
sclerosis, pancreatic pseudocysts, pancreatic ascites, VIPoma,
nesidoblastosis,
hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, hypersecretory
diarrhea,
scleroderma, irritable bowel syndrome, upper gastrointestinal bleeding,
postprandial portal
venous hypertension, especially in cirrhotic patients, complications of portal
hypertension,
small bowel obstruction, duodenogastric reflux, Cushing's Syndrome,
gonadotropinoma,
hyperparathyroidism, diabetic neuropathy, macular degeneration, hypercalcemia
of
malignancy, Paget's disease, meningioma, cancer cachexia, psoriasis,
hypotension and
panic attacks.
This invention also provides the use of a compound for the treatment of a
disease
or condition wherein the compound is H-(3-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-
NHz
in which the two Cysteines are bonded by a disulfide bond, or a
pharmaceutically
acceptable salt thereof, and wherein the disease or condition is selected from
the group
consisting of systemic sclerosis, pancreatic pseudocysts, pancreatic ascites,
VIPoma,
nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome,
hypersecretory
diarrhea, scleroderma, irritable bowel syndrome, upper gastrointestinal
bleeding,
postprandial venous hypertension, complications of portal hypertension, small
bowel
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CA 02335654 2001-O1-18
obstruction, duodenogastric reflux, Cushing's Syndrome, gonadotropinoma,
hyperparathyroidism, diabetic neuropathy, macular degeneration, hypercalcemia
of
malignancy, Paget's disease, meningioma, cancer cachexia, psoriasis,
hypotension and
panic attacks.
This invention also provides the use of a pharmaceutical composition
comprising a
pharmaceutically acceptable carrier and an effective amount of the acetate
salt of H-(3-D-
Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NHZ for the treatment of a disease or
condition
wherein the disease or condition is selected from the group consisting of
systemic
sclerosis, pancreatic pseudocysts, pancreatic ascites, VIPoma,
nesidoblastosis,
hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, hypersecretory
diarrhea,
scleroderma, irritable bowel syndrome, upper gastrointestinal bleeding,
postprandial portal
venous hypertension, especially in cirrhotic patients, complications of portal
hypertension,
small bowel obstruction, duodenogastric reflux, Cushing's Syndrome,
gonadotropinoma,
hyperparathyroidism, diabetic neuropathy, macular degeneration, hypercalcemia
of
malignancy, Paget's disease, meningioma, cancer cachexia, psoriasis,
hypotension and
panic attacks.
Detailed Description
Lanreotide is readily prepared according to the procedure disclosed in U.S.
Patent
No. 4,853,371, or the procedure disclosed in U.S. Patent No. 5,411,943, the
teachings of
which are incoporated herein by reference.
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Lanreotide is currently marketed as the acetate salt in a 30 mg long-acting
form
and is available from Ipsen Biotech, Paris, France.
As is well known to those skilled in the art, the known and potential uses
of somatostatin are varied and multitudinous. Somatostatin is known to be
useful
in the treatment of the diseases and/or conditions listed hereinbelow. The
varied
uses of somatostatin may be summarized as follows: Cushings Syndrome (see
Clark, R.V. et al, Clin. Res. ~$, p. 943A, 1990); gonadotropinoma (see Ambrosi
B., et al., Acta Endocr. (Copenh.) 122, 569-576, 1990); hyperparathyroidism
(see Miller, D., et al., Canad. Med. Ass. J., Vol. 145, pp. 227-228, 1991 );
Paget's
disease (see, Palmieri, G.M.A., et af., J. of Bone and Mineral Research, 7,
(Suppl. 1 ), p. S240 (Abs. 591 ), 1992); VIPoma (see Koberstein, B., et al.,
Z.
Gastroenterology, 2$, 295-301, 1990 and Christensen, C., Acta Chir. Scand.
~5, 541-543, 1989); nesidioblastosis and hyperinsulinism (see Laron, Z.,
Israel
J. Med. Sci., ~6_, No. 1, 1-2, 1990, Wilson, D.C., Irish J. Med. Sci., X58,
No. 1,
31-32, 1989 and Micic, D., et al., Digestion, ~_6, Suppl. 1.70. Abs. 193,
1990);
gastrinoma (see Bauer, F.E., et al., Europ. J. Pharmacol., ~, 55 1990);
Zollinger-Ellison Syndrome (see Mozell, E., et al., Surg. Gynec. Obstet., 1~,
476-484, 1990); hypersecretory diarrhea related to AIDS and other conditions
(due to AIDS, see Cello, J.P., et al., Gastroenteroiogy, ~$, No. 5, Part 2,
Suppl.,
A163 1990; due to elevated gastrin-releasing peptide, see Alhindawi, R., et
al.,
Can. J. Surg., ~, 139-142, 1990; secondary to intestinal graft vs. host
disease,
see Bianco J.A., et al., Transplantation, 49, 1194-1195, 1990; diarrhea
associated with chemotherapy, see Petrelli, N., et al., Proc. Amer. Soc. Clin.
Oncol., Vol. 10, P 138, Abstr. No. 417 1991 ); irritable bowel syndrome (see
O'Donnell, L.J.D., et al., Aliment. Pharmacol. Therap., Vol. 4., 177-181,
1990);
pancreatitis (see Tulassay, Z., et al., Gastroenterology, 98, No. 5, Part 2,
Suppl.,
A238, 1990); Crohn's Disease (see Fedorak, R.N., et al., Can. J.
Gastroenterology, $, No. 2, 53-57, 1989); systemic sclerosis (see Soudah, H.,
et
al., Gastroenterology, ~$, No. 5, Part 2, Suppl., A129, 1990); thyroid cancer
(see
Modigliani, E., et al., Ann., Endocr. (Paris), 5Q, 483-488, 1989); psoriasis
(see
Camisa, C., et al., Cleveland Clinic J. Med., ~ ,No. 1, 71-76, 1990);
hypotension (see Hoeldtke, R.D., et al., Arch. Phys. Med. Rehabil., ~9, 895-
898,
1988 and Kooner, J.S., et al., Brit., J. Clin. Pharmacof., ~$, 735P-736P,
1989);
panic attacks (see Abelson, J.L., et al., Clin. Psychopharmacol., 1Q, 128-132,
1990); sclerodoma (see Soudah, H., et al., Clin. Res., Vol. 39, p. 303A, 1991
);
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small bowel obstruction (see Nott, D.M., et al., Brit. J. Surg., Vol. 77, p.
A691,
1990); gastroesophageal reflux (see Branch, M.S., et al., Gastroenterology,
Vol.
100, No. 5, Part 2 Suppl., p. A425, 1991 ); duodenogastric reflux (see Hasler,
W., et al., Gastroenterology, Vol. 100, No. 5, Part 2, Suppl., p. A448, 1991
);
Graves' Disease (see Chang, T.C., et al., Brit. Med. J., 304, p. 158, 1992);
poiycystic ovary disease {see Prelevic, G.M., et al., Metabolism Clinical and
Experimental, 41, Suppl. 2, pp 76-79, 1992); upper gastrointestinal bleeding
(see Jenkins, S.A., et al., Gut., 33, pp. 404-407, 1992 and Arrigoni, A., et
al.,
American Journal of Gastroenterology, 87, p. 1311, (abs. 275), 1992);
pancreatic pseudocysts and ascites (see Hartley, J.E., et al., J. Roy. Soc.
Med.,
85, pp. 107-108, 1992); leukemia (see Santini, et al., 78, (Suppl. 1 ), p.
429A
(Abs. 1708), 1991); meningioma (see Koper, J.W., et al., J. Clin. Endocr.
Metab., 74, pp. 543-547, 1992); and cancer cachexia (see Bartlett, D.L., et
al.,
Surg. Forum., 42, pp. 14-16, 1991 ). The contents of the foregoing references
are incorporated herein by reference.
Surprisingly, the Applicant has now discovered that lanreotide itself was
particularly useful in treating the conditions, disorders and disease noted
hereinabove.
The usefulness of lanreotide in the various disclosed new medical uses
can be better understood through the results of tests relating to the
treatment of
upper gastrointestinal bleeding.
Lanreotide or a pharmaceutically-acceptable salt thereof can be
administered by oral, parenteral (e.g., intramuscular, intraperitoneal,
intravenous
or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or
topical
routes of administration and can be formulated with pharmaceutically
acceptable
carriers to provide dosage forms appropriate for each route of administration.
Solid dosage forms for oral administration include capsules, tablets, pills,
powders and granules. In such solid dosage forms, the active compound is
admixed with at least one inert pharmaceutically acceptable carrier such as
sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal
practice, additional substances other than such inert diluents, e.g.,
lubricating
agents such as magnesium stearate. In the case of capsules, tablets and pills,
the dosage forms may also comprise buffering agents. Tablets and pills can
additionally be prepared with enteric coatings.
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Liquid dosage forms for oral administration include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups, the elixirs containing
inert
diluents commonly used in the art, such as water. Besides such inert diluents,
compositions can also include adjuvants, such as wetting agents, emulsifying
and suspending agents, and sweetening, flavoring and perfuming agents.
Preparations according to this invention for parenteral administration
include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
Examples of non-aqueous solvents or vehicles 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 preserving, wetting, emulsifying, and dispersing
agents. They may be sterilized by, for example, filtration through a bacteria-
retaining filter, by incorporating sterilizing agents into the compositions,
by
irradiating the compositions, or by heating the compositions. They can also be
manufactured in the form of sterile solid compositions which can be dissolved
in
sterile water, or some other sterile injectable medium immediately before use.
Compositions for rectal or vaginal administration are preferably
suppositories which may contain, in addition to the active substance,
excipients
such as coca butter or a suppository wax.
Compositions for nasal or sublingual administration are also prepared
with standard excipients well known in the art.
The dosage of active ingredient in the compositions of this invention may
be varied; however, it is necessary that the amount of the active ingredient
be
such that a suitable dosage form is obtained. The selected dosage depends
upon the desired therapeutic effect, on the route of administration, and on
the
duration of the treatment. Generally, dosage levels of between 25 ?g/kg/day to
100 mg/kg/day of body weight daily are administered as a single dose or
divided
into multiple doses to humans and other animals, e.g., mammals, to obtain the
desired therapeutic effect.
A preferred general dosage range is 250 ?g/kglday to 5.0 mg/kg/day of
body weight daily which can be administered as a single dose or divided into
multiple doses.
Further, Lanreotide can be administered in a sustained release
composition such as those described in the following patents. Among those
formulations, 14-day or 28-day slow release formulations will be preferred.
U.S.
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Patent No. 5,672,659 teaches sustained release compositions comprising
Lanreotide and a polyester. U.S. Patent No. 5,595,760 teaches sustained
release compositions comprising Lanreotide in a getable form. U.S. Application
No. 08/929,363 filed September 9, 1997, teaches polymeric sustained release
compositions comprising Lanreotide and chitosan. U.S. Application No.
081740,778 filed November 1, 1996, teaches sustained release compositions
comprising Lanreotide and cyclodextrin. U.S. Application No. 09/015,394 filed
January 29, 1998, teaches absorbable sustained release compositions of
Lanreotide. The contents of the foregoing patents and applications are
incorporated herein by reference.
The use of immediate or of sustained release compositions depends on
the type of indications aimed at. If the indication consists of an acute or
over-
acute disorder, a treatment with an immediate form will be preferred over the
same with a prolonged release composition. On the contrary, for preventive or
long-term treatments, a prolonged release composition will generally be
preferred.
Typically, to the indication upper gastrointestinal bleeding will correspond
an acute or over-acute treatment with a dosage of 80 to 120 ?g/day per person
during approximately 5 days. After endoscopical treatment, preventive
treatment
against recurrence can be performed using lanreotide sustained release forms
as an adjuvant to usual treatments; for this type of treatment, 14-day
sustained
release forms with a total dosage of approximately 30 mg lanreotide or 28-day
lanreotide forms can be used.
For other indications than upper gastrointestinal bleeding, which
correspond rather long term treatments, 14-day sustained release forms with a
total dosage of approximately 30 mg lanreotide or 28-day lanreotide forms will
be adequate.
7
