IT9021264A1 - PHARMACEUTICAL COMPOSITIONS FOR INTRANASAL CALCITONIN ADMINISTRATION - Google Patents
PHARMACEUTICAL COMPOSITIONS FOR INTRANASAL CALCITONIN ADMINISTRATION Download PDFInfo
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- IT9021264A1 IT9021264A1 IT021264A IT2126490A IT9021264A1 IT 9021264 A1 IT9021264 A1 IT 9021264A1 IT 021264 A IT021264 A IT 021264A IT 2126490 A IT2126490 A IT 2126490A IT 9021264 A1 IT9021264 A1 IT 9021264A1
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- Prior art keywords
- calcitonin
- pharmaceutical compositions
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- 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 17
- 102000055006 Calcitonin Human genes 0.000 title claims description 14
- 108060001064 Calcitonin Proteins 0.000 title claims description 14
- 229960004015 calcitonin Drugs 0.000 title claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 108010068072 salmon calcitonin Proteins 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 3
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000002663 nebulization Methods 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 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 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 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 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 241001465754 Metazoa Species 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
- 239000004743 Polypropylene Substances 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 230000030991 negative regulation of bone resorption Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- -1 polypropylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Description
"COMPOSIZIONI FARMACEUTICHE PER LA SOMMINISTRAZIONE INTRA-NASALE DI CALCITONINA" "PHARMACEUTICAL COMPOSITIONS FOR THE INTRA-NASAL ADMINISTRATION OF CALCITONIN"
La presente invenzione ha per oggetto composizioni farmaceutiche atte alla somministrazione di dosi singole unitarie di calcitonina per via nasale. The present invention relates to pharmaceutical compositions suitable for administering single unit doses of calcitonin by the nasal route.
Le calcitonine sono da tempo largamente impiegate per il trattamento di osteoporosi, ipercalcernia e morbo di Paget. Calcitonins have long been widely used for the treatment of osteoporosis, hypercalcernia and Paget's disease.
La calcitonina regola il metabolismo del calcio inibendo il riassorbimento osseo fisiologico e patologico. Calcitonin regulates calcium metabolism by inhibiting physiological and pathological bone resorption.
La calcitonina riduce la mobilizzazione del calcio osseo in tutti gli stadi di aumentato ricambio minerale ed esplica un'azione ipocalcemizzante. Calcitonin reduces the mobilization of bone calcium in all stages of increased mineral turnover and has a hypocalcemizing action.
Ha inoltre un effetto inibitorio sulla fase essudativa precoce del processo infiammatorio cui si accompagna anche un'azione antalgica. E' stato anche dimostrato un effetto inibitorio sulla secrezione gastrica e pancreatica esogena. L'inibizione del riassorbimento osseo porta ad una diminuita escrezione urinaria di idrossiprolina che, insieme con la riduzione dei tassi sierici elevati e patologici di fosfatasi alcalina e la normalizzazione del bilancio del calcio, comporta un'azione favorente la ricostruzione del collagene e del tessuto osseo. It also has an inhibitory effect on the early exudative phase of the inflammatory process which is also accompanied by an analgesic action. An inhibitory effect on exogenous gastric and pancreatic secretion has also been demonstrated. The inhibition of bone resorption leads to a decreased urinary excretion of hydroxyproline which, together with the reduction of elevated and pathological serum levels of alkaline phosphatase and the normalization of the calcium balance, leads to an action favoring the reconstruction of collagen and bone tissue .
Come dimostrato dalla sperimentazione sull'animale e dalle ricerche cliniche nell'uomo, la calcitonina di salmone è risultata la più attiva tra le diverse varietà finora conosciute. As demonstrated by experimentation on animals and clinical research in humans, salmon calcitonin was found to be the most active of the various varieties known so far.
La via di somministrazione intranasale di caleitcnine ha recentemente suscitato grande interesse in quanto consente di ovviare ai problemi posti dalla somministrazione parenterale, notoriamente dolorosa e accettata con difficoltà dai pazienti. The intranasal route of administration of kaleitcnine has recently aroused great interest as it allows to overcome the problems posed by parenteral administration, notoriously painful and accepted with difficulty by patients.
Formulazioni adatte alla somministrazione intranasale seno descritte ad esaipio in GB-2127689, EP-A-115627, EP-A-183527, EP-A-277462, EP-A-327756. Formulations suitable for intranasal sinus administration described ad hexipium in GB-2127689, EP-A-115627, EP-A-183527, EP-A-277462, EP-A-327756.
Le formulazioni note lasciano comunque irrisolti i problemi connessi alle modalità di somministrazione che seno generalmente basate sull'impiego di nebulizzatori o erogatori multidose, poco adatti al dosaggio preciso, riproducibile e igienico di principi attivi di natura polipeptidica quali le calcitonine. The known formulations, however, leave unresolved the problems connected with the methods of administration which are generally based on the use of nebulizers or multidose dispensers, not very suitable for the precise, reproducible and hygienic dosage of polypeptide active ingredients such as calcitonins.
La presente invenzione propone forme di dosaggio unitarie di calcitonine che presentano, rispetto alle forme finora note e già entrate nella pratica terapeutica, i seguenti vantaggi: The present invention proposes unit dosage forms of calcitonins which have, with respect to the forms so far known and already entered into therapeutic practice, the following advantages:
- Maggiore praticità d'impiego, con elevata "compìiance" da parte del paziente che non è costretto a operazioni preliminari di pressurizzazione o assemblaggio e a conseguenti possibilità di errori. - Greater practicality of use, with high "compliance" on the part of the patient who is not forced to carry out preliminary pressurization or assembly operations and consequent possibility of errors.
- Assenza di rischi di sovradosaggio, critici nel caso di principi attivi dotati di elevata potenza farmacologica quali appunto gli ormoni caleitcninici. - Absence of overdose risks, critical in the case of active ingredients with high pharmacological power such as kaleitcninic hormones.
- Costanza di erogazione del dosaggio di calcitaiina. - Constancy of delivery of the dosage of calcitaiin.
- Assenza di rischi di contaminazione batterica, presenti invece con le forme multidose destinate a ripetuti contatti con la mucosa nasale e a ripetute esposizioni all'ambiente domiciliare. - Absence of risks of bacterial contamination, present instead with the multidose forms intended for repeated contact with the nasal mucosa and repeated exposure to the home environment.
Le composizioni dell'invenzione comprendono: The compositions of the invention include:
a) un contenitore per una soluzione acquosa di una dose unitaria di calcitanina; a) a container for an aqueous solution of a unit dose of calcitanin;
b) un dispositivo erogatore solidale e cooperante con il contenitore a), in grado di nebulizzare la soluzione acquosa di calcitonina al memento dell'uso; b) a dispensing device integral with and cooperating with the container a), capable of nebulising the aqueous solution of calcitonin at the time of use;
c) mezzi di copertura e protezione del dispositivo erogatore b). c) means of covering and protecting the dispensing device b).
Le dimensioni del contenitore a) e dell'erogatore b) seno scelte in modo da garantire la nebulizzazione di un volume di soluzione tipicamente conpreso tra 50 e 150 nel, contenenti da 25 a 400 unità di calcitonina. The dimensions of the container a) and of the dispenser b) are chosen so as to guarantee the nebulization of a volume of solution typically comprised between 50 and 150 ml, containing from 25 to 400 units of calcitonin.
Le soluzioni acquose di calcitonina inpiegàbili in accordo all'invenzione sono quelle convenzionali contenenti ad esempio agenti tamponanti o regolatori di pH, tensioattivi, agenti preservanti, eventuali promotori di assorbimento e simili. The aqueous solutions of calcitonin which cannot be used according to the invention are conventional ones containing for example buffering agents or pH regulators, surfactants, preserving agents, possible absorption promoters and the like.
E' preferita una soluzione acquosa contenente da circa 1000 a circa 3000 U.I. di calcitonina/ml e da circa 0,05 a circa 0,2 mg/ml di un composto armonico quaternario quale benzalconio cloruro, oltre ad eventuali agenti tamponanti. An aqueous solution containing from about 1000 to about 3000 IU is preferred. of calcitonin / ml and from about 0.05 to about 0.2 mg / ml of a quaternary harmonic compound such as benzalkonium chloride, in addition to any buffering agents.
Esertpi di dispositivi erogatori b) seno descritti in EP-A-0218840. Examples of dispensing devices b) are described in EP-A-0218840.
Secondo una forma preferita di realizzazione, il rapporto funzionale tra contenitore a) ed erogatore b) è tale da permettere la nebulizzazione della soluzione per pressione del contenitore a) centro un'estremità dell'erogatore b) all'interno del quale sono ricavati canali capillari attraverso cui la soluzione è forzata a passare al momento della pressione sul contenitore a) che dovrà essere ovviamente montato a tenuta sull'estremità dell'erogatore b) con possibilità di essere spostato da una posizione iniziale di riposo ad una posizione di pressurizzazione del liquido. Con tale tipo di dispositivo è possibile raggiungere deviazioni standard nella costanza di dosaggio inferiori a circa il 2,5% contro il 5% delle pompe convenzionali multiuso. According to a preferred embodiment, the functional relationship between container a) and dispenser b) is such as to allow nebulization of the solution by pressure of the container a) center one end of the dispenser b) inside which capillary channels are formed through which the solution is forced to pass at the moment of pressure on the container a) which must obviously be mounted hermetically on the end of the dispenser b) with the possibility of being moved from an initial rest position to a liquid pressurization position. With this type of device it is possible to reach standard deviations in dosing constancy lower than about 2.5% against 5% of conventional multipurpose pumps.
Tutti i tipi di calcitonine possono essere vantaggiosamente sommi— nistrati in accordo con la presente invenzione: calcitonina di salmone , di anguilla, calcitonina da DNA ricambinate, calcitonine semisintetiche. All types of calcitonins can be advantageously administered in accordance with the present invention: calcitonin from salmon, eel, calcitonin from DNA reciprocated, semisynthetic calcitonins.
E' particolarmente preferito l'uso della calcitonina di salmone. Il seguente esempio illustra ulteriormente l'invenzione. The use of salmon calcitonin is particularly preferred. The following example further illustrates the invention.
ESEMPIO EXAMPLE
Flaconcini erogatori monodose da 100 U.I. Single-dose dispenser vials of 100 I.U.
Composizione: Composition:
Un flaconcino erogatore monodose eroga 70 itici contenenti; A single-dose dispenser vial dispenses 70 itics containing;
- Principio attivo - Active principle
Calcitonina sintetica di salmone 100 U.I. Synthetic salmon calcitonin 100 I.U.
- Etcapienti - Etcapienti
Sodio citrato diidrato 0,87 mg; acido citrico monoidrato 0,85 mg; sodio edetato 0,07 mg; benzalconio cloruro 0,0084 mg; acqua per pre parazioni iniettabili q.b. a 70 racl. Sodium citrate dihydrate 0.87 mg; citric acid monohydrate 0.85 mg; sodium edetate 0.07 mg; benzalkonium chloride 0.0084 mg; water for injectable preparations to taste to 70 racl.
Il flaconcino erogatore monodose è costituito da un contenitore di vetro del volume totale di 280 mcl e da una pompa erogatrice Pfeiffer 0115-1-0001 in polipropilene. The single-dose dispenser vial consists of a glass container with a total volume of 280 mcl and a Pfeiffer 0115-1-0001 polypropylene dispensing pump.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02126490A IT1244601B (en) | 1990-08-10 | 1990-08-10 | Pharmaceutical compositions for the intranasal administration of calcitonin. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02126490A IT1244601B (en) | 1990-08-10 | 1990-08-10 | Pharmaceutical compositions for the intranasal administration of calcitonin. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IT9021264A0 IT9021264A0 (en) | 1990-08-10 |
| IT9021264A1 true IT9021264A1 (en) | 1992-02-10 |
| IT1244601B IT1244601B (en) | 1994-08-08 |
Family
ID=11179231
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT02126490A IT1244601B (en) | 1990-08-10 | 1990-08-10 | Pharmaceutical compositions for the intranasal administration of calcitonin. |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1244601B (en) |
-
1990
- 1990-08-10 IT IT02126490A patent/IT1244601B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| IT9021264A0 (en) | 1990-08-10 |
| IT1244601B (en) | 1994-08-08 |
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| TA | Fee payment date (situation as of event date), data collected since 19931001 |
Effective date: 19970828 |