IE83304B1 - Pharmaceutical compositions comprising calcitonin - Google Patents
Pharmaceutical compositions comprising calcitoninInfo
- Publication number
- IE83304B1 IE83304B1 IE1992/1278A IE921278A IE83304B1 IE 83304 B1 IE83304 B1 IE 83304B1 IE 1992/1278 A IE1992/1278 A IE 1992/1278A IE 921278 A IE921278 A IE 921278A IE 83304 B1 IE83304 B1 IE 83304B1
- Authority
- IE
- Ireland
- Prior art keywords
- calcitonin
- fibrillated
- concentration
- fragment
- fibril
- Prior art date
Links
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 title claims description 44
- 108060001064 Calcitonin Proteins 0.000 title claims description 39
- 229960004015 Calcitonin Drugs 0.000 title claims description 39
- 102400000113 Calcitonin Human genes 0.000 title claims description 39
- 239000008194 pharmaceutical composition Substances 0.000 title description 3
- 229940045644 Human calcitonin Drugs 0.000 claims description 8
- 101500011263 human Calcitonin Proteins 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000000527 sonication Methods 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 239000006185 dispersion Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 235000000346 sugar Nutrition 0.000 claims description 4
- 230000000996 additive Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- FMPTWBWKJAJGSR-LJNLPFSOSA-N Calcitare Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CS)[C@@H](C)O)C(C)C)C1=CC=CC=C1 FMPTWBWKJAJGSR-LJNLPFSOSA-N 0.000 claims description 2
- 206010006956 Calcium deficiency Diseases 0.000 claims description 2
- VSHJAJRPRRNBEK-LMVCGNDWSA-N Eel calcitonin Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CS)[C@@H](C)O)C(C)C)CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C1=CN=CN1 VSHJAJRPRRNBEK-LMVCGNDWSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 229910020936 NaC Inorganic materials 0.000 claims 1
- 239000003349 gelling agent Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000000499 gel Substances 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 9
- 239000007924 injection Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 206010061592 Cardiac fibrillation Diseases 0.000 description 4
- 230000002600 fibrillogenic Effects 0.000 description 4
- 230000001184 hypocalcaemic Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000002035 prolonged Effects 0.000 description 3
- 229940120657 salmon calcitonin Drugs 0.000 description 3
- 108010068072 salmon calcitonin Proteins 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002522 swelling Effects 0.000 description 2
- 238000005429 turbidity Methods 0.000 description 2
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 1
- 102100001249 ALB Human genes 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 229960000686 Benzalkonium Chloride Drugs 0.000 description 1
- 229960001950 Benzethonium Chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M Benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 210000000988 Bone and Bones Anatomy 0.000 description 1
- 210000001715 Carotid Arteries Anatomy 0.000 description 1
- 229960001884 Chlorhexidine diacetate Drugs 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 210000004907 Glands Anatomy 0.000 description 1
- 206010020583 Hypercalcaemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000003393 Mammary Paget's Disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 108010061543 Neutralizing Antibodies Proteins 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000001685 Postmenopausal Osteoporosis Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 210000001685 Thyroid Gland Anatomy 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N Trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- WDRFFJWBUDTUCA-UHFFFAOYSA-N [amino-[(E)-[amino-(4-chloroanilino)methylidene]amino]methylidene]-[6-[amino-[(E)-[amino-(4-chloroanilino)methylidene]amino]methylidene]azaniumylhexyl]azanium;diacetate Chemical compound CC(O)=O.CC(O)=O.C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 WDRFFJWBUDTUCA-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 235000019688 fish Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000005445 natural product Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-N sodium;5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)NC1=O QGMRQYFBGABWDR-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/23—Calcitonins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
PATENTS ACT, 1992
921278
PHARMACEUTICAL COMPOSITIONS COMPRISING CALCITONIN
NOVARTIS AG
The present invention relates to pharmaceutical compositions comprising calcitonin.
Calcitonin is a 32 amino acid polypeptide hormone secreted by the parafollicular cells of the
thyroid gland in mammals and by the ultimobrachial gland of birds and fish. It is a potent drug
for the treatment of Paget’s disease, some aspects of hypercalcaemia, and for postmenopausal
osteoporosis. Calcitonins of different origins, mainly salmon, pig, eel, and human are currently
used therapeutically.
Human calcitonin, although considered less potent and thus required at higher concentrations or
doses than salmon calcitonin, has the advantage of not generating neutralizing antibodies after
prolonged administration as the salmon calcitonin does (Grauer et al. 1990, J. Bone Min. Res.
,387-391, Levy et al. 1988, J. Clin. Endocrinol. Metab. 67,541-545 and the references therein).
In physiological saline solutions or buffers, human calcitonin is not stable, it precipitates and
forms gels which consist of calcitonin fibrils. Since fibrillated calcitonin does not redissolve in
physiologically compatible solutions, the calcitonin fibrils per se have not been considered for
therapeutic use. Due to the fibril formation phenomenon, which was perceived to be undesirable,
various steps have been adopted to avoid the problem. In particular, the injectable dosage form of
human calcitonin is made up only as and when required by mixing hCT powder and the aqueous
solution immediately prior to injection. This procedure is not required for salmon calcitonin
which is provided in stable solution.
We have now found, surprisingly that calcitonin fibrils per se are biologically active and give a
longer-time dose response than calcitonin in solution.
Accordingly the present invention provides fibrillated calcitonin for use in treating calcium
deficiency diseases.
The calcitonin is preferably human calcitonin (hC1') which may be synthetic or it may be
produced by recombinant DNA technology, it may be salmon, eel or porcine calcitonin.
The term "human calcitonin" is used in a broad sense in the context of this description and is
intended to comprise not only natural human calcitonin as described in Helv. Chim. Acta, Vol 53,
loc. cit., which can also be obtained synthetically, but also pharmaceutically acceptable ‘
derivatives and analogues thereof, e. g. those in which one or more of the amino acid groups
occurring in the natural compounds are replaced or the N- or C-terminal group has been
stmctually modified.
Human calcitonin can exist in the free form or in the form of a pharmaceutically acceptable acid
addition salt. Such salts are known and their activity and compatibility are comparable to those of
the free forms. Typical suitable acid addition salts are the hydrochlorides or acetates.
Calcitonin may be fibrillated by adding water or an aqueous solution to calcitonin powder and
then stirring to dissolve. Suitable aqueous solutions include dilute solutions of NaCl, e. g. 0.9%
NaCl; weak acids, e.g. 0.001% to 0.5% acetic acid; and buffers, e.g. phosphate saline buffer at pH
7.4 or other biologically compatible buffers. The solution may then be incubated at a temperature
from 2°-50°C, preferably at room temperature for the fibrillation reaction to be completed, i.e.
when there are no more changes in the samples turbidity. The incubation time is dependent on
the aqueous medium, the temperature and on the concentration of calcitonin. The concentration
of calcitonin may be from 1 to 200 mg/ml, preferably front 5 to 100 mg/ml. Solutions of higher
concentration fibrillate faster and fibrillation occurs faster at higher temperatures. It has been
found that, for the fibrillation process to be completed, an incubation period of 1 hour is needed
for a 200 mg/ml hCT solution in water.
The fibrillated calcitonin may be used in the gel form. In this form it acts as a depot and can be
administered incra-muscularly, intra-nasally, sub-cutaneously, or orally, e. g. intra-colonically.
The fibrillated gels can be squeezed through injection needles. In this case it is preferred to place
the calcitonin solution in a syringe, sterilise it and then allow it to fibrillate in the syringe, after
which it is ready for use. The solution is preferably placed in the syringe at a low temperature to
delay fibrillation. When in the syringe the temperature can be raised.
If desired the calcitonin fibrils may be fragmented or disrupted by any suitable method such as in
a blender or homogeniser or preferably by ultrasound treatment (sonication). Electron
microscopy analysis of a sonicated hCT fibril suspension shows that it consists of small rods of
about l5nm diameter and 26 to 130 nm in length.
In order to fragment or disrupt the fibrils, a further volume of water or aqueous solution is added
to the fibrils and the resulting mass is subjected, preferably, to sonication using, for example, a tip
sonicator until the fibrils are completely disrupted and no further changes in the sarnple’s
turbidity occurs with further sonication. During the sonication, the temperature is preferably
maintained below 37°C. Constant temperature conditions are preferred, e.g. by surrounding the
sample with ice. The sonication is also preferably carried out under an inert gas atmosphere such
as nitrogen or argon.
- 3 _
The fragmentation is preferably carried out within 24 hours of the end of the incubation.
The resulting product is a dispersion of fragmented fibrils in the water or aqueous solution and
this dispersion forms a further aspect of the present invention.
When used as a gel, the concentration of calcitonin may be from 1 to 200 mg/ml, preferably from
to 100 mg/ml. When used as a dispersion of fragmented fibrils the concentration of calcitonin
may be up to 50 mg/ml.
Preferred ranges for fragmented hCI‘ fibril suspensions are from 3 to 10 mg/ml for nasal or oral
solutions and from 0.5 to 3 mg/ml for injectable solutions.
The compositions of the invention have a prolonged hypocalcemic effect such that in calcitonin
therapy the number of injections required, or doses to be taken can be reduced, compared to those
needed when conventional calcitonin solutions are used.
The compositions of the invention may also contain viscosity—increasing swelling agents and/or
sugars and/or other pharmaceutically acceptable additives. As viscosity-increasing swelling
agents there may be used hydrophilic partially etherified cellulose derivatives, hydrophilic
polyacrylates, polymethacrylates, polyethylene glycols, polyvinyl alcohols or mixtures thereof.
Suitable compounds include methyl cellulose, hydroxypropylmethylcellulose, polyethylene
glycol, dextran, which may have a molecular weight of 20,000 to 80,000, but preferably about
40,000, sugars such as sucrose, fructose, glucose, lactose, mannitol and trehalose, ethanol, serum
albumin, lysozyme and preservatives such as benzalkonium chloride, benzethonium chloride and
chlorhexidine diacetate.
The amount of additives used can vary and may depend on the intended use. For example for
nasal or oral solutions, 0.5 to 10% by weight of additive may be used. In the case of injectable
solutions, sugars, polyethylene glycols or dextran would be used as the additive, usually in
amounts of 0.5 to 10% by weight.
The invention is illustrated in the following examples.
Example 1
ul of 0.001% acetic acid/water is added to 20mg hCT powder and solubilisation is performed
using a vortex mixer for 1-2 min. The resulting solution is allowed to fibrillate forl hour. Over
the hard turbid gel of hCl‘-fibril are added 4 ml of 0.001% acetic acid; then ultrasonication is
“ A ' .1 a .1 LIV!‘ CL..2l.. ..L.-.... cl-g
presence of rods as in Figure la. The original hCl" fibrils are shown in Figure lb. The rods of
sonicated hCl‘ fibrils were, on average, 15 nm in diameter and 26-130 nm long.
Example 2
Following the procedure of Example 1. hCI‘ fibrillated gels are formed from a solution of 20 mg
hCT in 100 ul.01% acetic acid. 10ml water are then added and sonication performed as described
in Example 1 with similar results.
Example 3
The product from Example 2 is diluted with 0.9% aqueous NaCl solution to give a solution
having an hCT concentration of 5 ug/ml. This is injected intravenously into a hypocalcaemic rat
model and compared with a similar injection of a solution of hCI‘ made up in the conventional
manner by dissolving hCI‘ powder. The dosage in each case is 5 pg/kg body weight. The results
are shown in Fig 2. The solution of Example 2 is biologically active and has a longer time dose
response than the conventional solution.
Example 4
hC1" fibrillated gels are formed by placing aqueous hCF solutions: (50 mg/ml hCI‘ in 0.1% acetic
acid or in 0.9% NaCl) in syringes and allowing the hCT to fibrillate in the syringes overnight.
The sub-cutaneous (s.c.) intra-nasal (i.n.) intra-rectum (i.r.), intra-ileum (i.i.) or intra-colonical
(i.c.) injection of hCI‘ fibrillated gel can be done easily since the hardened fibrillated hCI‘ gels
can be squeezed through injection needles. Figures 3a and 3b shows that in the hypocalcaemic rat
model s.c., i.n., i.r., i.i. and i.c. injected hCT fibrillated-gel have a strong and prolonged biological
effect. Fibrils formed in 0.9% NaCl were used for s.c. and i.n. experiments and fibrils formed in
0.1% acetic acid were used for the i.r., i.i. and i.c. experiments.
In the i_n @ experiments in Examples 3 and 4 the following hypocalcaemic rat model is used:-
Female Wistar rats 80-100g body weight are fed a normal diet. hCl" is administered as mentioned
to animals anaesthetised with Hypnorrn then sodium pentabarbitone i.m. Blood samples (250 ul)
are taken from a cannulated carotid artery at each time point. Change in calcium level after the
administration of hCI‘ formulations is measured by a colorimetric method using a Ca measuring
kit (Sigma Chem. Co.). For each time point three to five animals are used
Claims (10)
- . Fibrlllated calcitonin for use in treating calcium deficiency diseases.
- . Fibrillated calcitonin as claimed in claim 1 which is human, salmon, eel or porcine calcitonin.
- . Fibrillated calcitonin as claimed in claim 2, which is human calcitonin.
- . Fibrillated calcitonin as claimed in claim 1, 2 or 3, which comprises calcitonin and water and optionally NaC|, a weak acid or a buffer.
- . Fibrillated calcitonin as claimed in any preceding claim which also comprises a viscosity - increasing gelling agent and/or a sugar and/or other pharmaceutically acceptable additive.
- . Fibrillated calcitonin as claimed in any preceding claim, in which the concentration of calcitonin is from 1 to 200 mg/ml.
- . Fibrillated calcitonin as claimed in claim 6, in which the concentration of calcitonin is from 5 to 100mg/ml.
- . A calcitonin fibril fragment obtainable by fragmenting or disrupting calcitonin fibrils in a blender or homogenizer or by sonication.
- . A calcitonin fibril fragment as claimed in claim 8 in which the fragment is in the form of a rod having an average diameter of about 15 nm and a length of 26 to 130 nm.
- 10. A calcitonin fibril fragment as claimed in claim 8 or 9 in which the concentration of calcitonin is up to 50 mg/ml. A dispersion of a calcitonin fibril fragment in water, optionally containing one or more other compounds as given in claim 4 or 5. Fibrilated calcitonin as claimed in claim 1, substantially as hereinbefore described and exemplified. A dispersion as claimed in claim 11, substantially as hereinbefore described and exemplified. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBUNITEDKINGDOM23/04/19919108634.8 | |||
GB919108634A GB9108634D0 (en) | 1991-04-23 | 1991-04-23 | Pharmaceutical compositions |
Publications (2)
Publication Number | Publication Date |
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IE83304B1 true IE83304B1 (en) | |
IE921278A1 IE921278A1 (en) | 1992-11-04 |
Family
ID=10693744
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE127892A IE921278A1 (en) | 1991-04-23 | 1992-04-22 | Pharmaceutical compositions |
Country Status (19)
Country | Link |
---|---|
US (1) | US5593962A (en) |
EP (1) | EP0510913B1 (en) |
JP (1) | JP3532580B2 (en) |
KR (1) | KR100245534B1 (en) |
AT (1) | ATE194775T1 (en) |
AU (1) | AU653395B2 (en) |
CA (1) | CA2066532C (en) |
CY (1) | CY2246B1 (en) |
DE (1) | DE69231263T2 (en) |
DK (1) | DK0510913T3 (en) |
ES (1) | ES2150418T3 (en) |
GB (1) | GB9108634D0 (en) |
GR (1) | GR3034414T3 (en) |
IE (1) | IE921278A1 (en) |
IL (1) | IL101622A (en) |
MX (1) | MX9201825A (en) |
NZ (1) | NZ242440A (en) |
PT (1) | PT510913E (en) |
ZA (1) | ZA922899B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5595760A (en) * | 1994-09-02 | 1997-01-21 | Delab | Sustained release of peptides from pharmaceutical compositions |
EP1161257A2 (en) | 1999-03-17 | 2001-12-12 | Novartis AG | Pharmaceutical compositions comprising tgf-beta |
CA2399505C (en) | 2000-02-04 | 2012-01-03 | Unigene Laboratories, Inc. | Nasal calcitonin formulations |
ME00509B (en) * | 2002-09-27 | 2011-10-10 | Zentaris Gmbh | Administration form for pharmaceutically active peptides with sustained release and method for the production thereof |
GB0422644D0 (en) * | 2004-10-12 | 2004-11-10 | Novartis Ag | Organic compounds |
GB0511269D0 (en) | 2005-06-02 | 2005-07-13 | Creative Peptides Sweden Ab | Sustained release preparation of pro-insulin C-peptide |
EP2282763B1 (en) * | 2008-04-07 | 2013-12-11 | National Institute Of Immunology | Process for preparing supramolecular calcitonin assemblies (SCA) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61267528A (en) * | 1984-11-26 | 1986-11-27 | Yamanouchi Pharmaceut Co Ltd | Transnasal calcitonin agent containing absorbefacient |
MY102411A (en) * | 1986-12-23 | 1992-06-17 | Ciba Geigy Ag | Nasal solutions |
-
1991
- 1991-04-23 GB GB919108634A patent/GB9108634D0/en active Pending
-
1992
- 1992-04-16 IL IL10162292A patent/IL101622A/en active IP Right Grant
- 1992-04-21 CA CA002066532A patent/CA2066532C/en not_active Expired - Fee Related
- 1992-04-21 PT PT92303554T patent/PT510913E/en unknown
- 1992-04-21 MX MX9201825A patent/MX9201825A/en not_active IP Right Cessation
- 1992-04-21 DE DE69231263T patent/DE69231263T2/en not_active Expired - Fee Related
- 1992-04-21 AT AT92303554T patent/ATE194775T1/en not_active IP Right Cessation
- 1992-04-21 DK DK92303554T patent/DK0510913T3/en active
- 1992-04-21 ES ES92303554T patent/ES2150418T3/en not_active Expired - Lifetime
- 1992-04-21 EP EP92303554A patent/EP0510913B1/en not_active Expired - Lifetime
- 1992-04-22 NZ NZ242440A patent/NZ242440A/en not_active IP Right Cessation
- 1992-04-22 KR KR1019920006719A patent/KR100245534B1/en not_active IP Right Cessation
- 1992-04-22 JP JP12794192A patent/JP3532580B2/en not_active Expired - Fee Related
- 1992-04-22 ZA ZA922899A patent/ZA922899B/en unknown
- 1992-04-22 AU AU15066/92A patent/AU653395B2/en not_active Ceased
- 1992-04-22 IE IE127892A patent/IE921278A1/en not_active IP Right Cessation
-
1993
- 1993-08-04 US US08/102,117 patent/US5593962A/en not_active Expired - Lifetime
-
2000
- 2000-09-15 GR GR20000402102T patent/GR3034414T3/en not_active IP Right Cessation
-
2001
- 2001-11-19 CY CY0100038A patent/CY2246B1/en unknown
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