Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-09-15
2003-01-07
Dodson, Shelley A. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S422000, C424S484000, C424S488000
Reexamination Certificate
active
06503534
ABSTRACT:
The invention relates to new pharmaceutical compositions intended for the sustained release of peptides and to the process for their preparation. U.S. Pat. No. 5,595,760 has already described solid and semisolid pharmaceutical compositions intended for the sustained release of peptides, which are composed of a gellable and water-soluble peptide salt optionally combined with an appropriate monomeric excipient. After administration to a patient, these compositions gel and allow a sustained release over a period of at least three days.
These compositions brought a considerable advantage compared with the prior art in terms of the simplicity of their manufacture and use.
The Applicant has now discovered, unexpectedly, that improved compositions can be obtained which, while utilizing the same principle, make it possible to obtain a slower release than the conventional compositions, it being possible for said release to extend over one, two, three months or more in some cases. In particular, the initial peak (or burst) is reduced.
Furthermore, the compositions of the invention are easier to prepare. In particular, the peptide grinding time and the force required for mixing can be greatly reduced. Also, the characteristics of the compositions of the invention are more homogeneous.
Apart from the advantages mentioned above, for the same amount of peptide, some of these compositions have the advantage of requiring a smaller injection force, so they are more convenient to use. This therefore makes it possible to use syringes with a smaller needle diameter than that which would be necessary for the equivalent compositions of the prior art.
It is found moreover that these compositions give very good results in the in vivo tests and that the individual experimental deviations are reduced, making it possible to treat a greater proportion of patients effectively.
All these advantages are obtained by giving the peptide a higher specific surface area than that of the non-matrix (gellable) compositions known a person skilled in the art and described in the U.S. Pat. No. 5,595,760. The gellable compositions according to the invention preferably use peptides whose specific surface area has been increased to at least 4 m
2
/g, and more preferably to 8 m
2
/g or more, this characteristic giving them a slower and more regular release profile. The compositions according to the invention are obtained by using a special lyophilization process comprising a flash-freezing phase of a peptide solution, said process being described below.
The invention therefore relates first and foremost to a solid or semisolid pharmaceutical composition comprising a gellable and soluble peptide salt optionally combined with an appropriate excipient, said pharmaceutical composition being characterized in that the peptide salt has a high specific surface area and in that, once injected into a patient, it forms a gel in contact with this patient's body substances, said gel being capable of releasing the peptide over a prolonged period of at least 15 days.
High specific surface area is understood as meaning a specific surface area greater than that which would be obtained by a lyophilization involving the slow freezing of a solution of a peptide salt. Slow freezing is understood as meaning a freezing which is not a flash freezing as describe hereafter or in the PCT Patent Application WO 98/47489.
Preferably, the peptide salt has a specific surface area of at least 8 m
2
/g and, once injected into a patient, it forms a gel in contact with this patient's body substances, said gel being capable of releasing the peptide over a prolonged period of at least 15 days.
The invention therefore preferably relates to a solid or semisolid pharmaceutical composition comprising a gellable and soluble peptide salt optionally combined with an appropriate excipient, said pharmaceutical composition being characterized in that the peptide salt has a specific surface area of at least 4 or 5 m
2
/g, preferably 8 m
2
/g, and in that, once injected into a patient, it forms a gel in contact with this patient's body substances, said gel being capable of releasing the peptide over a prolonged period of at least 15 days.
Peptide is understood as meaning either a peptide or a protein. The peptide salts which can be used for the invention may be selected in particular from a group comprising the salts of the following substances: triptorelin, lanreotide, octreotide (as described for example in Patent EP 29,579), a compound with LH−RH activity, such as triptorelin, goserelin, leuprorelin or buserelin, an LH—RH antagonist, a GPIIb/IIIa antagonist, a compound with a similar activity to a GPIIb/IIIa antagonist, erythropoietin (EPO) or one of its analogues, the various types of interferon-&agr;, interferon-&bgr; or -&ggr;, somatostatin, a somatostatin derivative such as that described in the European Patent EP 215,171, a somatostatin analogue such as that described in the U.S. Pat. No. 5,552,520 (this patent itself includes a list of other patents describing somatostatin analogues, which are incorporated in the present application by way of reference), insulin, a growth hormone (GH), a growth hormone releasing factor (GHRF), a growth hormone releasing peptide (GHRP), an epidermal growth factor (EGF), a melanocyte stimulating hormone (MSH), a thyrotropin releasing hormone (TRH) or one of its derivatives, a thyroid stimulating hormone (TSH), a luteinizing hormone (LH), a follicle stimulating hormone (FSH), a parathyroid hormone (PTH) or one of its derivatives, a lysozyme hydrochloride, a parathyroid hormone related peptide (PTHrp), an N-terminal peptide fragment (position 1→34) of human PTH, vasopressin or one of its derivatives, oxytocin, calcitonin, a calcitonin derivative with a similar activity to that of calcitonin, a calcitonin gene related peptide (CGRP), glucagon, a peptide similar to glucagon (GLP), gastrin, a gastrin releasing peptide (GRP), secretin, pancreozymin, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enkephalin, an enkephalin derivative, colony stimulating factor (CSF), endorphin, kyotorphin, interleukins, for example interleukin-2, tuftsin, thymopoietin, thymostimulin, thymic humoral factor (THF), thymic serum factor (TSF), a derivative of thymic serum factor (TSF), thymosin, thymic factor X, tumour necrosis factor (TNF), motilin, bombesin or one of its derivatives, such as those described in the U.S. Pat. No. 5,552,520 (this patent itself includes a list of other patents describing bombesin derivatives, which are incorporated in the present application by way of reference), prolactin, neurotensin, dynorphin, caerulein, substance P, urokinase, asparaginase, bradykinin, kallikrein, nerve growth factor, a blood clotting factor, polymixin B, colistin, gramicidin, bacitracin, a protein synthesis stimulating peptide, an endothelin antagonist or one of its derivatives, a vasoactive intestinal polypeptide (VIP), adrenocorticotropic hormone (ACTH) or one of its fragments, a platelet derived growth factor (PDGF), a bone morphogenetic protein (BMP), a pituitary adenylate cyclase activating polypeptide (PACAP), neuropeptide Y (NPY), peptide YY (PYY) and a gastric inhibitory polypeptide (GIP). Any water-soluble peptide or protein salt may also be used by a person skilled in the art if they consider it appropriate.
The peptide salt used for the invention will preferably be selected from a group comprising salts of somatostatin or its analogues, particularly lanreotide acetate or octreotide acetate, triptorelin salts, particularly triptorelin acetate, salts of calcitonin or its analogues, salts of LH—RH hormone analogues, salts of GH, GHRF, PTH or PTHrp peptide, and analogues of the latter.
The peptide salts which can be used for the invention are preferably pharmaceutically acceptable salts of organic acids, such as those of acetic, lactic, malic, ascorbic, succinic, benzoic, methanesulphonic or toluenesulphonic acids, or pharmaceutically cceptable salts of inorganic acids, such as
Bismuth Frederic
Pellet Marc
Bierman, Muserlian and Lucas
Dodson Shelley A.
Societe de Conseils de Recherches et d'Applications Scienti
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