IT9021913A1 - CALCITONIN-BASED PHARMACEUTICAL COMPOSITIONS FOR NASAL ADMINISTRATION - Google Patents
CALCITONIN-BASED PHARMACEUTICAL COMPOSITIONS FOR NASAL ADMINISTRATION Download PDFInfo
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- IT9021913A1 IT9021913A1 IT021913A IT2191390A IT9021913A1 IT 9021913 A1 IT9021913 A1 IT 9021913A1 IT 021913 A IT021913 A IT 021913A IT 2191390 A IT2191390 A IT 2191390A IT 9021913 A1 IT9021913 A1 IT 9021913A1
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- pharmaceutical compositions
- compositions according
- salts
- chloride
- nasal administration
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 19
- 102000055006 Calcitonin Human genes 0.000 claims description 9
- 108060001064 Calcitonin Proteins 0.000 claims description 9
- 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 claims description 9
- 229960004015 calcitonin Drugs 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- -1 aliphatic primary amine salts Chemical class 0.000 claims description 4
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 229920000570 polyether Polymers 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 4
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 claims description 3
- GKQHIYSTBXDYNQ-UHFFFAOYSA-M 1-dodecylpyridin-1-ium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+]1=CC=CC=C1 GKQHIYSTBXDYNQ-UHFFFAOYSA-M 0.000 claims description 2
- ZCTSINFCZHUVLI-UHFFFAOYSA-M 4-methyl-1-tetradecylpyridin-1-ium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+]1=CC=C(C)C=C1 ZCTSINFCZHUVLI-UHFFFAOYSA-M 0.000 claims description 2
- 241000972773 Aulopiformes Species 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 229960001950 benzethonium chloride Drugs 0.000 claims description 2
- 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 claims description 2
- 239000007853 buffer solution Substances 0.000 claims description 2
- RLGQACBPNDBWTB-UHFFFAOYSA-N cetyltrimethylammonium ion Chemical class CCCCCCCCCCCCCCCC[N+](C)(C)C RLGQACBPNDBWTB-UHFFFAOYSA-N 0.000 claims description 2
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 2
- TWFQJFPTTMIETC-UHFFFAOYSA-N dodecan-1-amine;hydron;chloride Chemical compound [Cl-].CCCCCCCCCCCC[NH3+] TWFQJFPTTMIETC-UHFFFAOYSA-N 0.000 claims description 2
- VUFOSBDICLTFMS-UHFFFAOYSA-M ethyl-hexadecyl-dimethylazanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)CC VUFOSBDICLTFMS-UHFFFAOYSA-M 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 235000015277 pork Nutrition 0.000 claims description 2
- 235000019515 salmon Nutrition 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- CEYYIKYYFSTQRU-UHFFFAOYSA-M trimethyl(tetradecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)C CEYYIKYYFSTQRU-UHFFFAOYSA-M 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims 1
- 239000000872 buffer Substances 0.000 claims 1
- 239000007975 buffered saline Substances 0.000 claims 1
- 125000002091 cationic group Chemical group 0.000 claims 1
- 239000003093 cationic surfactant Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 230000036765 blood level Effects 0.000 description 2
- 230000001886 ciliary effect Effects 0.000 description 2
- 210000002850 nasal mucosa Anatomy 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IZBZQUREHISXFJ-UHFFFAOYSA-N 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid Chemical compound CC1=C(Cl)C(C(F)(F)F)=NN1CC(O)=O IZBZQUREHISXFJ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
Description
Descrizione dell'invenzione industriale dal titolo: Description of the industrial invention entitled:
Composizioni farmaceutiche per la somministrazione per via nasale a base di calcitonina. Pharmaceutical compositions for nasal administration based on calcitonin.
La presente invenzione si riferisce a formulazioni farmaceutiche contenenti Calcitonina come principio attivo adatte alla somministrazione nasale. The present invention relates to pharmaceutical formulations containing Calcitonin as an active principle suitable for nasal administration.
La calcitonina è un polipeptide, usato in terapia per regolare la concentrazione di Calcio nel sangue e viene normalmente somministrata per via iniettabile. Calcitonin is a polypeptide, used in therapy to regulate the concentration of calcium in the blood and is normally administered by injection.
La somministrazione iniettabile presenta tuttavia diversi inconvenienti quali dolori nella zona dell'iniezione e notevole fastidio al paziente che deve assogettarsi nelle cure prolungate ad iniezioni frequenti. However, injectable administration has various drawbacks such as pain in the injection area and considerable discomfort to the patient who must undergo frequent injections in prolonged treatments.
Per ovviare a questi fastidi si è cercato in questi ultimi anni di trovare un'altra via di somministrazione capace di fornire livelli ematici efficaci di Calcitonina. To overcome these problems, in recent years, efforts have been made to find another route of administration capable of providing effective blood levels of Calcitonin.
Il brevetto Italiano 1172324 descrive formulazioni farmaceutiche adatte per la somministrazione nasale contenenti cloruro di benzalconio eventualmente in combinazione con tensioattivi di tipo non ionico. Italian patent 1172324 describes pharmaceutical formulations suitable for nasal administration containing benzalkonium chloride optionally in combination with non-ionic surfactants.
Da tale brevetto si desume che solamente il benzalconio cloruro risulta molto efficace come antisettico nei confronti di contaminazione da microbi. From this patent it is inferred that only benzalkonium chloride is very effective as an antiseptic against contamination by microbes.
La Richiedente ha ora inaspettatamente trovato che anche altri composti possono essere vantaggiosamente usati per la preparazione di composizioni farmaceutiche adatte per somministrazione nasale. The Applicant has now unexpectedly found that also other compounds can be advantageously used for the preparation of pharmaceutical compositions suitable for nasal administration.
In particolare la Richiedente ha trovato che può essere usato un composto scelto fra le seguenti classi: In particular, the Applicant has found that a compound selected from the following classes can be used:
(a) sali di alchilammonio quaternario, con almeno un gruppo alchilico a catena lunga (a) quaternary alkylammonium salts, with at least one long chain alkyl group
(b) sali di alchilpiridinio, dove il gruppo alchile ha catena lunga (b) alkylpyridinium salts, where the alkyl group has a long chain
(c) sali ammonici quaternari di composti mono o polieterei. (c) quaternary ammonium salts of mono or polyether compounds.
(d) sali di ammina alifatica primaria a catena lunga. (d) long-chain primary aliphatic amine salts.
Tra i composti appartenenti alla classe (a)preferibilmente vengono utilizzati i seguenti composti: sali di esadeciltrimetilammonio con anioni di acidi farmaceuticamente accettabili di tipo organico o inorganico, esadecildimetiletilammonio bromuro, tetradeciltrimetilammonio cloruro. Among the compounds belonging to class (a), the following compounds are preferably used: hexadecyltrimethylammonium salts with pharmaceutically acceptable acid anions of organic or inorganic type, hexadecyldimethylethylammonium bromide, tetradecyltrimethylammonium chloride.
Tra i composti appartenenti alla classe (b) vengono preferibilmente utilizzati nella presente invenzione esadecil piridinio cloruro, dodecilpiridinio cloruro, 4-metil-l-tetradecilpiridinio cloruro. Among the compounds belonging to class (b), hexadecyl pyridinium chloride, dodecylpyridinium chloride, 4-methyl-1-tetradecylpyridinium chloride are preferably used in the present invention.
Tra i composti della classe (c) viene preferibilmente usato nella presente invenzione il benzetonio cloruro. Among the compounds of class (c), benzethonium chloride is preferably used in the present invention.
Tra i composti della classe (d) viene preferibilmente usato dodecilammonio cloruro (dodecilammina cloridrato). Among the compounds of class (d) dodecylammonium chloride (dodecylamine hydrochloride) is preferably used.
Ulteriore oggetto della presente invenzione sono composizioni farmaceutiche adatte per la somministrazione nasale contenenti Calcitonina come principio attivo comprendenti inoltre: A further object of the present invention are pharmaceutical compositions suitable for nasal administration containing Calcitonin as an active ingredient further comprising:
i) un composto scelto tra le seguenti classi i) a compound selected from the following classes
(a) sali di alchilammonio quaternario con almeno un gruppo alchilico a catena lunga, (a) quaternary alkylammonium salts with at least one long-chain alkyl group,
(b) sali di alchilpiridinio, dove il gruppo alchile ha catena lunga (b) alkylpyridinium salts, where the alkyl group has a long chain
(c) sali ammonici quaternari di composti mono o polieterei. (c) quaternary ammonium salts of mono or polyether compounds.
(d) sali di una ammina primaria alifatica a catena lunga ii) un veicolo liquido adatto per la somminstrazione nasale. (d) salts of a long-chain aliphatic primary amine ii) a liquid carrier suitable for nasal administration.
Le calcitonine preferibilmente utilizzate nelle composizioni farmaceutiche secondo la presente invenzione sono preferibilmente le calcitonine di salmone, di anguilla, di maiale, umana, ed i loro N'-derivati tutti commercialmente disponibili. The calcitonins preferably used in the pharmaceutical compositions according to the present invention are preferably the calcitonins of salmon, eel, pork, human, and their N'-derivatives, all commercially available.
I tensioattivi nelle composizioni farmaceutiche oggetto della presente invenzione sono presenti in concentrazioni comprese tra 0.001 e lo 0.1% , preferibilmente tra lo 0.005 e lo 0.01% in peso sul peso totale della composizione farmaceutica. The surfactants in the pharmaceutical compositions object of the present invention are present in concentrations ranging from 0.001 to 0.1%, preferably from 0.005 to 0.01% by weight of the total weight of the pharmaceutical composition.
II veicolo liquido preferibilmente utilizzato nelle composizioni farmaceutiche oggetto della presente invenzione è preferibilmente una soluzione acquosa salina tamponata preferibilmente di fosfati o citrati a pH compreso tra 4 e 5. preferibilmente a pH compreso tra 4.2 e 4.4. The liquid vehicle preferably used in the pharmaceutical compositions object of the present invention is preferably an aqueous saline solution preferably buffered of phosphates or citrates at a pH between 4 and 5. preferably at a pH between 4.2 and 4.4.
Nelle prove cliniche le composizioni secondo l'invenzione non hanno provocato fenomeni irritativi della mucosa nasale ed hanno corrisposto alle norme di stabilità e di tolleranza richieste per una somministrazione per via nasale anche per un impiego con applicatoci che forniscono dosi multiple di principio attivo. Le prove di biodisponibilità hanno fornito livelli ematici superiori di circa il 20-40% rispetto a composizioni di controllo prive di tali composti. In clinical trials the compositions according to the invention did not cause irritative phenomena of the nasal mucosa and corresponded to the stability and tolerance standards required for nasal administration even for use with applicators that supply multiple doses of the active principle. Bioavailability tests provided approximately 20-40% higher blood levels than control compositions free of these compounds.
1 test farmacologici condotti per saggiare in primis l'innocuità dei preparati allo studio nei confronti dell'attività ciliare hanno dimostrato 1' assenza di irritazione della mucosa nasale senza causare riduzione della frequenza dei battiti ciliari. Pharmacological tests conducted to test first of all the harmlessness of the preparations under study against ciliary activity demonstrated the absence of irritation of the nasal mucosa without causing a reduction in the frequency of ciliary beats.
Vengono riportati i seguenti esempi a scopo illustrativo ma non limitativo della presente invenzione. The following examples are reported for illustrative but not limitative purposes of the present invention.
ESEMPIO 1 EXAMPLE 1
Alla soluzione tampone si aggiungono nell'ordine esadecilpiridinio cloruro , sodio cloruro , e la calcitonina. Queste operazioni vengono effettuate sotto azoto per evitare fenomeni di ossidazione del principio attivo . Si agita fino solubilizzazione, mantenendo sempre sotto azoto, si filtra la soluzione su membrana sterilizzante di spessore 0.2 micron. To the buffer solution are added in order hexadecylpyridinium chloride, sodium chloride, and calcitonin. These operations are carried out under nitrogen to avoid oxidation phenomena of the active ingredient. It is stirred until solubilization, always keeping under nitrogen, the solution is filtered on a sterilizing membrane 0.2 micron thick.
ESEMPIO 2 EXAMPLE 2
La preparazione di tale composizione avviene con le stesse modalità descritte nell'esempio 1. The preparation of this composition takes place in the same way as described in example 1.
ESEMPIO 3 EXAMPLE 3
La preparazione di tale composizione avviene con le stesse modalità descritte nell'esempio 1. The preparation of this composition takes place in the same way as described in example 1.
ESEMPIO 4 EXAMPLE 4
La preparazione di tale composizione avviene con le stesse modalità descritte nell'esempio 1. The preparation of this composition takes place in the same way as described in example 1.
Claims (12)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02191390A IT1243989B (en) | 1990-10-30 | 1990-10-30 | Calcitonin-based pharmaceutical compositions for administration by the nasal route |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02191390A IT1243989B (en) | 1990-10-30 | 1990-10-30 | Calcitonin-based pharmaceutical compositions for administration by the nasal route |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IT9021913A0 IT9021913A0 (en) | 1990-10-30 |
| IT9021913A1 true IT9021913A1 (en) | 1992-04-30 |
| IT1243989B IT1243989B (en) | 1994-06-28 |
Family
ID=11188685
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT02191390A IT1243989B (en) | 1990-10-30 | 1990-10-30 | Calcitonin-based pharmaceutical compositions for administration by the nasal route |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1243989B (en) |
-
1990
- 1990-10-30 IT IT02191390A patent/IT1243989B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| IT9021913A0 (en) | 1990-10-30 |
| IT1243989B (en) | 1994-06-28 |
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| Date | Code | Title | Description |
|---|---|---|---|
| 0001 | Granted |