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Pharmaceutical composition comprising cyclic somatostatin analoguesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, CyclopeptidesPharmaceutical composition comprising cyclic somatostatin analogues description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070093412, Pharmaceutical composition comprising cyclic somatostatin analogues. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to parenteral pharmaceutical compositions comprising a somatostatin analogue and to novel somatostatin analogues. [0002] Somatostatin is a tetradecapeptide having the structure [0003] Since the isolation and characterization of somatostatin, an extensive search for more potent and more stable analogues has continued. [0004] Somatostatin analogues have been described e.g. in WO 97/25977. Said somatostatin analogues comprise the amino acid sequence of formula I -(D/L)Trp-Lys-X.sub.1-X.sub.2- I wherein X.sub.1 is a radical of formula (a) or (b) wherein R.sub.1 is optionally substituted phenyl, wherein Z.sub.1 is O or S, and [0005] X.sub.2 is an .alpha.-amino acid having an aromatic residue on the C.sub..alpha. side chain, or an amino acid unit selected from Dab, Dpr, Dpm, His,(Bzl)HyPro, thienyl-Ala, cyclohexyl-Ala and t-butyl-Ala, the residue Lys of said sequence corresponding to the residue Lys.sup.9 of the native somatostatin-14. [0006] By somatostatin analogue as used herein is meant a straight-chain or cyclic peptide derived from that of the naturally occurring somatostatin-14, comprising the sequence of formula I and wherein additionally one or more amino acid units have been omitted and/or replaced by one or more other amino acid radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups. In general the term covers all modified derivatives of the native somatostatin-14 comprising the above sequence of formula I which have binding affinity in the nM range to at least one somatostatin receptor subtype as defined hereinafter. [0007] Preferred are somatostatin analogues in which the residues at positions 8 through 11 of the somatostatin-14 are represented by the sequence of formula I as defined above. [0008] More preferred are somatostatin analogues as disclosed above comprising a hexapeptide unit, the residues at positions 3 through 6 of said hexapeptide unit comprising the sequence of formula I. Even more preferably the residues at positions 1 and 2 of the hexapeptide unit of the somatostatin hexapeptide may be any of those as known in the art, e.g. as disclosed by A. S. Dutta in Small Peptides, Vol. 19, 292-354, Elsevier, 1993, or as substituents for, Phe.sup.6 and/or Phe.sup.7 of somatostatin-14. [0009] Even more preferred are cyclic somatostatin hexapeptides, e.g. cyclic somatostatin hexapeptides comprising a hexapeptide unit numbered from 1 to 6, the residues at positions 3 through 6 of said hexapeptide unit having the amino sequence of formula I as indicated above, e.g. a compound of formula Ia wherein X.sub.1 and X2 are as defined above, [0010] A is a divalent residue selected from Pro, wherein R.sub.3 is NR.sub.8R.sub.9--C.sub.2-6alkylene, guanidino-C.sub.2-6alkylene or C.sub.2-6alkylene-COOH, R.sub.3a is H, C.sub.1-4alkyl or has independently one of the significances given for R.sub.3, R.sub.3b is H or C.sub.1-4alkyl, R.sub.a is OH or NR.sub.5R.sub.6, R.sub.b is --(CH.sub.2).sub.1-3-- or --CH(CH.sub.3)--, R.sub.4 is H or CH.sub.3, R.sub.4a is optionally ring-substituted benzyl, each of R.sub.5 and R.sub.6 independently is H, C.sub.1-4alkyl, .omega.-amino-C.sub.1-4alkylene, .omega.-hydroxy-C.sub.1alkylene or acyl, R.sub.7 is a direct bond or C.sub.1-6alkylene, each of R.sub.8 and R.sub.9 independently is H, C.sub.1-4alkyl, .omega.-hydroxy-C.sub.2-4alkylene, acyl or CH.sub.2OH--(CHOH).sub.c--CH.sub.2-- wherein c is 0, 1, 2, 3 or 4, or R.sub.8 and R.sub.9 form together with the nitrogen atom to which they are attached a heterocyclic group which may comprise a further heteroatom, and R.sub.11 is optionally ring-substituted benzyl, --(CH.sub.2).sub.1-3--OH, CH.sub.3--CH(OH)-- or --(CH.sub.2).sub.1-5--NR.sub.5R.sub.6, and ZZ.sub.a, is a natural or unnatural .alpha.-amino acid unit. [0011] Particularly preferred are compounds of formula II wherein the configuration at C-2 is (R) or (S) or a mixture thereof, and wherein R is NR.sub.1R.sub.2--C.sub.2-6alkylene or guanidine-C.sub.2-6alkylene, and each of R.sub.1 and R.sub.2 independently is H or C.sub.1-4alkyl, in free form, in salt form or protected form. [0012] Preferably R is NR.sub.1R.sub.2--C.sub.2-6alkylene. Preferred compounds of formula II are the compounds wherein R is 2-amino-ethyl, namely cyclo[{4-(NH.sub.2--C.sub.2H.sub.4--NH--CO--O--)Pro}-Phg-DTrp-Lys-- Tyr(4-Bzl)-Phe] (referred herein to as Compound A) and cyclo[{4-(NH.sub.2--C.sub.2H.sub.4--NH--CO--O--)Pro}-DPhg-DTrp-Lys-Tyr(4-- Bzl)-Phe], in free form, salt form or protected form. Phg means --HN--CH(C.sub.6H.sub.5)--CO-- and Bzl means benzyl. [0013] These compounds in free form, salt form or protected form are referred to hereinafter as "compounds of the invention". [0014] Due to proteolytic degradation of the somatostatin analogues of the present invention, systemic delivery, e.g. parenteral administration, is highly desirable. However, parenteral administration may be very painful at the site of administration, especially in repeated administration. [0015] It has now been found that parenteral compositions comprising a compound of the invention, and tartaric acid show particularly interesting properties, e.g. good tolerability and high stability. [0016] A compound of the invention in protected form corresponds to a somatostatin analogue wherein at least one of the amino groups is protected and which by deprotection leads to a compound of formula II , preferably physiologically removable. Suitable amino protecting groups are e.g. as disclosed in "Protective Groups in Organic Synthesis", T. W. Greene, J. Wiley & Sons NY (1981), 219-287, the contents of which being incorporated herein by reference. Example of such an amino protecting group is acetyl. [0017] A compound of the invention may exist e.g. in free or salt form. Salts include acid addition salts with e.g. inorganic acids, polymeric acids or organic acids, for example with hydrochloric acid, acetic acid, lactic acid, aspartic acid, benzoic acid, succinic acid or pamoic acid. Acid addition salts may exist as mono- or divalent salts, e.g. depending whether 1 or 2 acid equivalents are added. Preferred salts are the lactate, aspartate, benzoate, succinate and pamoate including mono- and di-salts, more preferably the aspartate di-salt and the pamoate monosalt. [0018] The compounds of the invention may be prepared in accordance with conventional methods. [0019] In a first aspect, the present invention provides a parenteral composition comprising a compound of the invention and tartaric acid. [0020] According to the invention, typically the concentration of the compound of the invention in the composition of the invention is from about 0.05 to about 1 mg per ml composition, particularly 0.1 to 1 mg/ml. [0021] Conveniently, the ratio of the compound of the invention (amount corresponding to free form) to tartaric acid is about 0.001 to about 2 weight in weight, preferably about 0.05 to about 0.6. [0022] The amount of the compound of the invention in the composition of the invention is from about 0.005% to about 0.1% based on a total weight of the formulation. [0023] Preferably, the tartaric acid is in fine crystalline form. More preferably, crystalline D(-) or L(+) tartaric acid is used. The amount of tartaric acid is preferably from about 0.01% to about 1.5% w/w of the formulation, preferably about 0.01% to about 0.3%, more preferably about 0.15%. Preferably, the molarity of tartaric acid in the final composition is about 10 mM. [0024] In accordance with the present invention, in addition to the tartaric acid and a compound of the invention, the pharmaceutical composition preferably comprises also a basic component selected and added to the composition in such a way that the pH of the tartaric acid buffered pharmaceutical composition is adjusted to a pH of about 4 to about 4.5, preferably about 4.2. Continue reading about Pharmaceutical composition comprising cyclic somatostatin analogues... Full patent description for Pharmaceutical composition comprising cyclic somatostatin analogues Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Pharmaceutical composition comprising cyclic somatostatin analogues patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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