ITMI940562A1 - PHARMACEUTICAL COMPOSITIONS OF CALCITONIN ADMINISTRABLE BY RECTAL WAY - Google Patents
PHARMACEUTICAL COMPOSITIONS OF CALCITONIN ADMINISTRABLE BY RECTAL WAY Download PDFInfo
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- ITMI940562A1 ITMI940562A1 IT000562A ITMI940562A ITMI940562A1 IT MI940562 A1 ITMI940562 A1 IT MI940562A1 IT 000562 A IT000562 A IT 000562A IT MI940562 A ITMI940562 A IT MI940562A IT MI940562 A1 ITMI940562 A1 IT MI940562A1
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- Italy
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- pharmaceutical compositions
- calcitonin
- compositions according
- contain
- administrable
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 14
- 102000055006 Calcitonin Human genes 0.000 title claims description 11
- 108060001064 Calcitonin Proteins 0.000 title claims description 11
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical group 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 11
- 229960004015 calcitonin Drugs 0.000 title claims description 10
- 229960003964 deoxycholic acid Drugs 0.000 claims description 7
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 7
- 239000000829 suppository Substances 0.000 claims description 7
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 4
- 241000972773 Aulopiformes Species 0.000 claims description 3
- 235000019515 salmon Nutrition 0.000 claims description 3
- 229940037001 sodium edetate Drugs 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 2
- 229940124532 absorption promoter Drugs 0.000 claims 2
- 101000741445 Homo sapiens Calcitonin Proteins 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 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 1
- 108010068072 salmon calcitonin Proteins 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229960002303 citric acid monohydrate Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- -1 118 Chemical class 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Descrizione dell'invenzione industriale avente per titolo: "COMPOSIZIONI FARMACEUTICHE DI CALCITONINA SOMMINISTRABILI PER VIA RETTALE" Description of the industrial invention entitled: "PHARMACEUTICAL COMPOSITIONS OF CALCITONIN ADMINISTRABLE BY RECTAL VIA"
La presente invenzione ha per oggetto ccnposizioni farmaceutiche a base di calcitcnina somministrabili per via rettale. Le oonposizioni in oggetto sono costituite da un liofilizzato contenente calcitcnina, preferibilmente di salmone, glieina, acido citrico mcnoidrato ed edetato bisodico; il liofilizzato viene disperso in una opportuna massa di gliceridi semisìntetici contenente acido desossicolìco o uno dei suoi sali farmaceuticamente accettabili quale promotore dell'assorbimento. The present invention relates to pharmaceutical preparations based on calcitin which can be administered rectally. The compositions in question consist of a lyophilisate containing calcitcine, preferably salmon, glycine, citric acid monohydrate and disodium edetate; the lyophilisate is dispersed in a suitable mass of semi-synthetic glycerides containing deoxycholic acid or one of its pharmaceutically acceptable salts as a promoter of absorption.
La calcitcnina, sia quella di salmone sia quella di altre specie, è un ormone a lunga catena peptidica farmacologicamente attivo nella terapia dell'osteoporosi, del morbo di Paget, dell'ipercalcemia, e agisce inibendo il riassoibinvento osseo fisiologico o patologico. La calcitonina, data la sua natura peptidica, è inutilizzabile per via orale, mentre per via parenterale dà luogo a inecnvenienti a causa delle reazioni dolorose da parte del paziente. Pertanto si sente la necessità di forme di scnrainistrazione alternative. Calcitcnin, both that of salmon and that of other species, is a long-chain peptide hormone pharmacologically active in the therapy of osteoporosis, Paget's disease, hypercalcemia, and acts by inhibiting physiological or pathological bone recovery. Calcitonin, due to its peptide nature, is unusable by the oral route, while parenterally it causes problems due to the painful reactions on the part of the patient. Therefore there is a need for alternative forms of administration.
La richiedente ha sperimentato che è possibile ottenere ccrrposizioni farmaceutiche per sorministrazione rettale contenenti calcitcnina. Una tale via di scnministrazione presenta vantaggi rispetto alla scuministraziane parenterale; in particolare autonomia del paziente da personale medico, ridotti effetti collaterali e nello stesso tenpo livelli di biodisponibilità sufficienti per una terapia clinica efficace. The Applicant has experienced that it is possible to obtain pharmaceutical compositions for rectal administration containing calcitcine. Such an administration route has advantages over parenteral administration; in particular, patient autonomy from medical personnel, reduced side effects and at the same time levels of bioavailability sufficient for effective clinical therapy.
La scriministrazione di farmaci a natura polipeptidica per via rettale è descritta in letteratura. Tra gli altri, si vedano i lavori pubblicati da Nishiata T. et al. J. Pharm. Pharmacol. 1983, 35, 148-151, da Nakanishi K. et al. Chem. Phar. Bull., 1984, 32, 1628-1632, da Nishihata T. et al. J. Pharm. Pharmacol. 1989,£, 799-801. The rectal administration of polypeptide drugs is described in the literature. Among others, see the papers published by Nishiata T. et al. J. Pharm. Pharmacol. 1983, 35, 148-151, from Nakanishi K. et al. Chem. Phar. Bull., 1984, 32, 1628-1632, from Nishihata T. et al. J. Pharm. Pharmacol. 1989, £, 799-801.
La richiedente ha trovato che è possibile ottenere conposizioni farmaceutiche per somministrazione rettale contenenti calcitonina cane sostanza attiva, che corrispendano alle norme di stabilità e di tollerabilità richieste per una tale via di somrminìstrazione. The Applicant has found that it is possible to obtain pharmaceutical compositions for rectal administration containing calcitonin as an active substance, which correspond to the stability and tolerability standards required for such a route of administration.
Uno dei punti critici per questo tipo di formulazioni farmaceutiche è trovare un composto in grado di promuovere l’assorbimento della calcitcnina attraverso la mucosa rettale. Inoltre occorre la presenza nella supposta di un composto sufficientemente tensioattivo da facilitare il rilascio del principio attivo della massa grassa. One of the critical points for this type of pharmaceutical formulations is finding a compound capable of promoting the absorption of calcitcnin through the rectal mucosa. Furthermore, the suppository must contain a sufficiently surfactant compound to facilitate the release of the active ingredient of the fat mass.
Le ricerche condotte dalla richiedente hanno portato ad una formulazione contenente un derivato di sali biliari, il desossicolato di sodio il quale, oltre ad avere, per la sua capacità tensioattiva, le proprietà sopra esposte,ha la proprietà di emulsionare i lipidi delle membrane cellulari. In questo modo si comporta da "carrier” per il principio attivo permettendone il passaggio attraverso tali membrane. Senza un adeguato agente emulsionante, la calcitonina non riuscirebbe ad essere assorbita. The research carried out by the applicant has led to a formulation containing a derivative of bile salts, sodium deoxycholate which, in addition to having, due to its surfactant capacity, the properties described above, has the property of emulsifying the lipids of cell membranes. In this way it acts as a "carrier" for the active principle allowing it to pass through these membranes Without an adequate emulsifying agent, the calcitonin would not be able to be absorbed.
La formulazione dell'invenzione comprende l'utilizzo di edetato bisodico, un chelante di metalli bivalenti, quale stabilizzante. Le prove cliniche eseguite hanno però sorprendentemente dimostrato che la presenza di EDTA nella formulazione favorisce l'assorbimento e quindi l'attività terapeutica del principio attivo. Si può quindi prospettare un'azione dell'ΕDTA quale coadiuvante nella premozione dell'assorbimento del principio attivo,esaltandone la biodisponibilità. The formulation of the invention comprises the use of disodium edetate, a bivalent metal chelator, as a stabilizer. However, the clinical tests performed have surprisingly shown that the presence of EDTA in the formulation favors the absorption and therefore the therapeutic activity of the active ingredient. It is therefore possible to envisage an action of the DTA as an adjuvant in the premozione absorption of the active principle, enhancing its bioavailability.
Costituiscono pertanto oggetto della presente invenzione, formulazioni farmaceutiche per somministrazione rettale contenenti: Therefore, the subject of the present invention are pharmaceutical formulations for rectal administration containing:
a) Una quantità terapeuticamente efficace di calcitonina in un liofilizzato, costituito da una miscela di glieina, acido citrico, edetato sodico,a sua volta disperso in: a) A therapeutically effective amount of calcitonin in a lyophilisate, consisting of a mixture of gliein, citric acid, sodium edetate, in turn dispersed in:
b) Una massa per supposte costituita da gliceridi semisintetici contenenti sodio desossicolato. b) A suppository mass consisting of semisynthetic glycerides containing sodium deoxycholate.
Di seguito seno illustrate le formulazioni farmaceutiche dell'invenzione: The pharmaceutical formulations of the invention are illustrated below:
Formulazione 1 Formulation 1
Si scioglie una quantità pari a 59.460 U.I. di s aleatori ina in 600 mi di una soluzione contenente 61,95 g di glieina, 2,29 g di acido citrico monoidrato, 0,619 g di edetato bisodico. Si porta a voline di 619,5 mi con acqua distillata. Dopo aver filtrato su filtri da 0,22 pm, la soluzione viene distribuita in vassoi di acciaio inox per la liofilizzazione. An amount equal to 59,460 I.U. is dissolved. of random s in 600 ml of a solution containing 61.95 g of gliein, 2.29 g of citric acid monohydrate, 0.619 g of disodium edetate. It is made up to volumes of 619.5 ml with distilled water. After filtering through 0.22 µm filters, the solution is distributed in stainless steel trays for freeze drying.
Il liofilizzato così ottenuto, circa 65 g, viene posto nel fusone. A piccole dosi vengano aggiunti 935 g di massa per supposte contenente 16,2 g di sodio desossicolato. The lyophilisate thus obtained, about 65 g, is placed in the fusone. In small doses 935 g of suppository mass containing 16.2 g of sodium deoxycholate are added.
Quando si è raggiunta una omogeneità soddisfacente, si ripartisce la miscela nelle valve, dosando 1,85 g per supposta. When a satisfactory homogeneity has been achieved, the mixture is divided into the valves, dosing 1.85 g per suppository.
Formulazione 2 Formulation 2
Si ripete il procedimento come descritto nella formulazione 1, usando una quantità di salcatcnina doppia, cioè 118.920 U.I. The procedure is repeated as described in formulation 1, using a double amount of salt, i.e. 118,920 I.U.
Ogni supposta pesa 1,85 g Each suppository weighs 1.85 g
Claims (9)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI940562A IT1269911B (en) | 1994-03-24 | 1994-03-24 | Calcitonin pharmaceutical compositions which can be administered by rectal means |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI940562A IT1269911B (en) | 1994-03-24 | 1994-03-24 | Calcitonin pharmaceutical compositions which can be administered by rectal means |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| ITMI940562A0 ITMI940562A0 (en) | 1994-03-24 |
| ITMI940562A1 true ITMI940562A1 (en) | 1995-09-24 |
| IT1269911B IT1269911B (en) | 1997-04-16 |
Family
ID=11368349
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ITMI940562A IT1269911B (en) | 1994-03-24 | 1994-03-24 | Calcitonin pharmaceutical compositions which can be administered by rectal means |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1269911B (en) |
-
1994
- 1994-03-24 IT ITMI940562A patent/IT1269911B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| IT1269911B (en) | 1997-04-16 |
| ITMI940562A0 (en) | 1994-03-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 0001 | Granted |