ITMI20111876A1 - PREPARATION OF PALONOSETRON IN PHARMACEUTICAL PACKAGING - Google Patents
PREPARATION OF PALONOSETRON IN PHARMACEUTICAL PACKAGING Download PDFInfo
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- ITMI20111876A1 ITMI20111876A1 IT001876A ITMI20111876A ITMI20111876A1 IT MI20111876 A1 ITMI20111876 A1 IT MI20111876A1 IT 001876 A IT001876 A IT 001876A IT MI20111876 A ITMI20111876 A IT MI20111876A IT MI20111876 A1 ITMI20111876 A1 IT MI20111876A1
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- palonosetron
- aqueous solution
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- CPZBLNMUGSZIPR-NVXWUHKLSA-N palonosetron Chemical compound C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 CPZBLNMUGSZIPR-NVXWUHKLSA-N 0.000 title claims description 33
- 229960002131 palonosetron Drugs 0.000 title claims description 28
- 238000002360 preparation method Methods 0.000 title claims description 12
- 238000009512 pharmaceutical packaging Methods 0.000 title description 2
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 11
- 229920001577 copolymer Polymers 0.000 claims description 10
- 239000004033 plastic Substances 0.000 claims description 10
- 150000001925 cycloalkenes Chemical class 0.000 claims description 9
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 7
- 239000003381 stabilizer Substances 0.000 claims description 7
- 239000002738 chelating agent Substances 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- 206010047700 Vomiting Diseases 0.000 claims description 5
- 238000002512 chemotherapy Methods 0.000 claims description 5
- 238000004806 packaging method and process Methods 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 238000007911 parenteral administration Methods 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 239000008135 aqueous vehicle Substances 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 229940014175 aloxi Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229920000089 Cyclic olefin copolymer Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000000095 emetic effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 230000008646 thermal stress Effects 0.000 description 2
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229920005557 bromobutyl Polymers 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000007539 photo-oxidation reaction Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229940121356 serotonin receptor antagonist Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 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
- 239000007787 solid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B32—LAYERED PRODUCTS
- B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
- B32B27/00—Layered products comprising a layer of synthetic resin
- B32B27/32—Layered products comprising a layer of synthetic resin comprising polyolefins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4747—Quinolines; Isoquinolines spiro-condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:
“PREPARAZIONE DI PALONOSETRON IN CONFEZIONAMENTO FARMACEUTICO” "PREPARATION OF PALONOSETRON IN PHARMACEUTICAL PACKAGING"
La presente invenzione riguarda preparazioni di palonosetron in confezionamento idoneo all’uso in ambito farmaceutico. Più precisamente l’invenzione riguarda un prodotto farmaceutico consistente in un contenitore di materiale plastico contenente una soluzione acquosa di palonosetron idonea alla somministrazione orale, perorale o parenterale. The present invention relates to preparations of palonosetron in packaging suitable for use in the pharmaceutical field. More precisely, the invention relates to a pharmaceutical product consisting of a container of plastic material containing an aqueous solution of palonosetron suitable for oral, peroral or parenteral administration.
Background dell’invenzione Background of the invention
Il palonosetron è un antagonista del recettore della serotonina di tipo 3 ed è utilizzato per la prevenzione e/o il trattamento dell’emesi indotta da chemioterapia. La specialità medicinale di riferimento (Aloxi) consiste in flaconi di vetro contenenti una soluzione iniettabile di palonosetron. Oltre alla molecola di principio attivo, la soluzione contiene mannitolo, EDTA, sodio citrato, acido citrico, sodio idrossido e acido cloridrico. La confezione del prodotto di riferimento reca le seguenti indicazioni terapeutiche: Palonosetron is a type 3 serotonin receptor antagonist and is used for the prevention and / or treatment of chemotherapy-induced emesis. The reference medicinal product (Aloxi) consists of glass bottles containing an injectable solution of palonosetron. In addition to the active ingredient molecule, the solution contains mannitol, EDTA, sodium citrate, citric acid, sodium hydroxide and hydrochloric acid. The packaging of the reference product bears the following therapeutic indications:
- prevenzione di nausea acuta e vomito associate a cicli iniziali o ripetuti di chemioterapia del cancro moderatamente e altamente emetogenica; - prevention of acute nausea and vomiting associated with initial or repeated courses of moderately and highly emetogenic cancer chemotherapy;
- prevenzione di vomito e nausea ritardati associati a cicli iniziali o ripetuti di chemioterapia del cancro moderatamente emetogenica. - prevention of delayed vomiting and nausea associated with initial or repeated courses of moderately emetogenic cancer chemotherapy.
La molecola del palonosetron contiene due centri chirali e viene sintetizzata come enantiomero (S,S). Allo stato solido può assumere una forma cristallina (forma I e II) o amorfa ed è solubile in acqua. Studi di solubilità effettuati con la forma II hanno dimostrato che in un mezzo acquoso la molecola si converte rapidamente nella forma polimorfa I, che è solubile in acqua. The palonosetron molecule contains two chiral centers and is synthesized as an (S, S) enantiomer. In the solid state it can take a crystalline form (forms I and II) or amorphous and is soluble in water. Solubility studies performed with form II have shown that in an aqueous medium the molecule quickly converts to the polymorphic form I, which is soluble in water.
Studi di stabilità in condizioni forzate indicano che la principale via di degradazione del palonosetron in soluzione acquosa è l’ossidazione, che aumenta con la concentrazione della sostanza attiva. Sono state fatte anche prove di stabilità in condizioni accelerate e a lungo termine, di durata pari a 6 mesi e 2 anni, rispettivamente. L’esame della fotostabilità non ha rivelato cambiamenti significativi nei parametri di stabilità. Stability studies under forced conditions indicate that the main path of degradation of palonosetron in aqueous solution is oxidation, which increases with the concentration of the active substance. Stability tests were also carried out under accelerated and long-term conditions, lasting 6 months and 2 years, respectively. The examination of photostability did not reveal significant changes in the stability parameters.
Essendo il principio attivo sensibile all’ossidazione, ed essendo quest’ ultima facilitata dai gas contenuti nella sommità del flacone e dalle specie cationiche in soluzione, lo spazio sovrastante la soluzione nei flaconi viene riempito con azoto e alla soluzione viene aggiunto il chelante/stabilizzante EDTA. Since the active principle is sensitive to oxidation, and the latter being facilitated by the gases contained in the top of the bottle and by the cationic species in solution, the space above the solution in the bottles is filled with nitrogen and the chelator / stabilizer EDTA is added to the solution. .
Allo scopo di stabilizzare la formulazione di palonosetron, il brevetto europeo EP1601359 (Helsinn Healthcare) propone di aggiustare il pH della soluzione a valori compresi tra 4,0 e 6,0 e di aggiungere un agente chelante, in particolare EDTA. La domanda US2010/0048607 (Chandrashekhar K. et al) propone invece la liofilizzazione della soluzione di palonosetron, da ricostituirsi prima dell’uso. In order to stabilize the palonosetron formulation, the European patent EP1601359 (Helsinn Healthcare) proposes to adjust the pH of the solution to values between 4.0 and 6.0 and to add a chelating agent, in particular EDTA. Application US2010 / 0048607 (Chandrashekhar K. et al) instead proposes the lyophilization of the palonosetron solution, to be reconstituted before use.
Descrizione dell’invenzione Description of the invention
Si è ora trovato che la soluzione acquosa di palonosetron, se conservata in opportuni contenitori, rimane stabile nel tempo in misura uguale o addirittura superiore al prodotto di riferimento (Aloxi). In particolare, si è trovato che contenitori di materiale plastico a base di polimeri o copolimeri di cicloolefine sono in grado di garantire la desiderata stabilità alla soluzione acquosa di palonosetron. Inoltre, tali contenitori presentano l’ulteriore vantaggio di prevenire possibili infortuni al personale medico e paramedico dovuti all’accidentale rottura del flacone di vetro durante la manipolazione. It has now been found that the aqueous solution of palonosetron, if stored in suitable containers, remains stable over time to an equal or even greater extent than the reference product (Aloxi). In particular, it has been found that containers of plastic material based on polymers or copolymers of cycloolefins are able to guarantee the desired stability to the aqueous solution of palonosetron. In addition, these containers have the additional advantage of preventing possible injuries to medical and paramedical personnel due to the accidental breakage of the glass bottle during handling.
Pertanto, oggetto dell’invenzione è una preparazione farmaceutica di palonosetron in confezionamento, preferibilmente pronto all’uso, consistente in un contenitore di materiale plastico a base di polimeri o copolimeri di cicloolefine contenente una soluzione acquosa di palonosetron idonea alla somministrazione orale, perorale o parenterale. Therefore, the object of the invention is a pharmaceutical preparation of palonosetron in packaging, preferably ready to use, consisting of a container of plastic material based on polymers or copolymers of cycloolefins containing an aqueous solution of palonosetron suitable for oral, peroral or parenteral administration. .
Esempi di contenitori secondo l’invenzione includono flaconi, siringhe e fiale. In una particolare realizzazione dell’invenzione, detti contenitori sono flaconi. Examples of containers according to the invention include bottles, syringes and vials. In a particular embodiment of the invention, said containers are bottles.
I polimeri e copolimeri di cicloolefine utilizzabili secondo l’invenzione sono noti possedere peculiari caratteristiche di bassa permeabilità al vapore acqueo, elevata trasparenza e resistenza chimica e meccanica. The cycloolefin polymers and copolymers usable according to the invention are known to possess peculiar characteristics of low permeability to water vapor, high transparency and chemical and mechanical resistance.
Le cicloolefine possiedono una trasmissione di vapore acqueo pari a 0,071 g-mil/100 inch<2>-24h-atm, con temperatura di 23°C e umidità relativa dell’ 85%. Il materiale offre anche buona bio-compatibilità ed è conforme alle specifiche USP in Classe VI. Può essere sterilizzato e resiste all’idrolisi e all’attacco di numerose sostanze chimiche, compresi acidi e basi (Polimerica, 07 Gennaio 2004). Cycloolefins have a water vapor transmission of 0.071 g-mil / 100 inch <2> -24h-atm, with a temperature of 23 ° C and relative humidity of 85%. The material also offers good bio-compatibility and complies with USP Class VI specifications. It can be sterilized and resists hydrolysis and the attack of numerous chemicals, including acids and bases (Polimerica, 07 January 2004).
II materiale plastico a base di (co)polimeri di cicloolefine soddisfa i requisiti indicati dalle farmacopee europea e americana per la conservazione di preparazioni parenterali e viene comunemente impiegato per la produzione di contenitori per uso farmaceutico, e in particolare per la produzione di flaconi contenenti soluzioni acquose iniettabili - si citano ad esempio i prodotti Zometa® ed Aclasta® di Novartis. Tali contenitori COC o COP sono commercializzati da diversi fornitori, ad esempio da West Pharmaceuticals con il marchio CZ® (COP) e Schott con il marchio TopPac® (COC). The plastic material based on cycloolefin (co) polymers meets the requirements indicated by the European and American pharmacopoeias for the preservation of parenteral preparations and is commonly used for the production of containers for pharmaceutical use, and in particular for the production of bottles containing solutions. aqueous injectable - for example, Novartis' Zometa® and Aclasta® products. Such COC or COP containers are marketed by various suppliers, for example by West Pharmaceuticals under the brand CZ® (COP) and Schott under the brand TopPac® (COC).
I contenitori ad uso farmaceutico realizzati con materiale plastico a base di (co)polimeri di cicloolefine, rispetto ai contenitori realizzati in vetro, si distinguono per la superiore leggerezza, l’assenza di Alluminio e Calcio, nonché per una maggiore resistenza e versatilità produttiva. Containers for pharmaceutical use made with plastic material based on cycloolefin (co) polymers, compared to containers made of glass, are distinguished by their superior lightness, the absence of aluminum and calcium, as well as greater resistance and production versatility.
II flacone può assumere diverse forme e generalmente sarà dimensionato in modo da contenere da 1 a 10 mi di soluzione di palonosetron e un volume sovrastante pari a non meno del 10% della soluzione, che sarà convenientemente riempito di gas inerte, preferibilmente azoto. Inoltre, il flacone sarà provvisto di un sistema di chiusura consistente in un tappo in gomma cloro- o bromo-butilica con ghiera, munito di eventuale ed opportuno sigillo antieffrazione (cosiddetto “flip-off”). The bottle can take different shapes and will generally be sized so as to contain from 1 to 10 ml of palonosetron solution and an overlying volume equal to not less than 10% of the solution, which will be conveniently filled with inert gas, preferably nitrogen. Furthermore, the bottle will be equipped with a closure system consisting of a chloro- or bromo-butyl rubber stopper with ring nut, equipped with any appropriate anti-burglary seal (so-called “flip-off”).
La soluzione acquosa di palonosetron secondo l’invenzione può contenere, oltre alla molecola di principio attivo - in quantità preferibilmente compresa tra 0.1 e 1 mg - e al veicolo acquoso, agenti stabilizzanti, in particolare chelanti, tamponi, regolatori di isotonicità e di pH, e altre sostanze farmaceuticamente accettabili per gli usi previsti. The aqueous solution of palonosetron according to the invention may contain, in addition to the molecule of active ingredient - in a quantity preferably between 0.1 and 1 mg - and the aqueous vehicle, stabilizing agents, in particular chelators, buffers, isotonicity and pH regulators, and other pharmaceutically acceptable substances for their intended uses.
Nelle prove di stabilità effettuate in condizioni di stress termico ed ossidativo (luce ossigeno), la soluzione di palonosetron conservata in flaconi di materiale plastico COC e COP è risultata più stabile rispetto al prodotto di riferimento (Aloxi®), conservato in flaconi di vetro. Inoltre, si è sorprendentemente trovato che la stabilità è mantenuta anche in assenza dell’agente stabilizzante EDTA. In the stability tests carried out in conditions of thermal and oxidative stress (light oxygen), the palonosetron solution stored in COC and COP plastic bottles was more stable than the reference product (Aloxi®), stored in glass bottles. Furthermore, it was surprisingly found that stability is maintained even in the absence of the stabilizing agent EDTA.
Pertanto, un altro aspetto dell’invenzione riguarda una preparazione farmaceutica di palonosetron in confezionamento, preferibilmente pronto all’uso, consistente in un flacone di materiale plastico a base di polimeri o copolimeri di cicloolefine contenente una soluzione acquosa di palonosetron idonea alla somministrazione orale, perorale o parenterale e priva di agente stabilizzante, in particolare di agenti chelanti quale EDTA. Therefore, another aspect of the invention relates to a pharmaceutical preparation of palonosetron in packaging, preferably ready to use, consisting of a bottle of plastic material based on polymers or copolymers of cycloolefins containing an aqueous solution of palonosetron suitable for oral, peroral administration. or parenteral and free of stabilizing agent, in particular of chelating agents such as EDTA.
Un ulteriore aspetto dell’invenzione riguarda l’uso di una soluzione acquosa di palonosetron, conservata in contenitori di materiale plastico a base di polimeri e copolimeri di cicloolefine, come qui descritti, per la preparazione di un medicamento idoneo alla somministrazione orale, perorale o parenterale per la prevenzione e/o il trattamento di nausea e vomito associati alla chemioterapia antitumorale. A further aspect of the invention relates to the use of an aqueous solution of palonosetron, preserved in containers of plastic material based on polymers and copolymers of cycloolefins, as described here, for the preparation of a medicament suitable for oral, peroral or parenteral administration. for the prevention and / or treatment of nausea and vomiting associated with anticancer chemotherapy.
L’esempio che segue e le Figure accluse illustrano l’invenzione in maggior dettaglio. The following example and the accompanying Figures illustrate the invention in greater detail.
Descrizione delle Figure Description of the Figures
Fig. 1 : Effetto del solo calore (14 gg a 70°C) sulle formulazioni contenenti palonosetron; Fig. 1: Effect of heat alone (14 days at 70 ° C) on formulations containing palonosetron;
Fig. 2 : Effetto del calore (14 gg a 70°C) e di successiva esposizione a luce ossigeno (7 gg) sulle formulazioni contenenti palonosetron. Fig. 2: Effect of heat (14 days at 70 ° C) and subsequent exposure to oxygen light (7 days) on formulations containing palonosetron.
Esempio Example
Due composizioni corrispondenti alla composizione Aloxi, rispettivamente con e senza EDTA, sono state preparate seguendo la formula riportata nella tabella 1 in reattore con gorgogliamento di azoto: Two compositions corresponding to the Aloxi composition, respectively with and without EDTA, were prepared following the formula reported in table 1 in a reactor with nitrogen bubbling:
Tabella 1 Table 1
Successivamente le soluzioni “N” ed “E” sono state confezionate sotto flusso laminare di azoto e sigillate stringendo con tappi di alluminio i fermi di gomma dei flaconi costituiti da due diversi materiali cicloolefinici, volume nominale 5 mi. In particolare, sono stati usati i polimeri e copolimeri cicloolefinici COP e COC. Subsequently the solutions "N" and "E" were packaged under a laminar flow of nitrogen and sealed by tightening the rubber stoppers of the bottles made of two different cycloolefinic materials, nominal volume 5 ml with aluminum caps. In particular, the cycloolefin polymers and copolymers COP and COC were used.
Le 4 formulazioni sono quindi state sottoposte a sterilizzazione con vapore a 121°C/1 atm per 20 minuti. The 4 formulations were then subjected to steam sterilization at 121 ° C / 1 atm for 20 minutes.
Le analisi HPLC condotte al momento della preparazione hanno confermato l’assenza di perdita di Palonosetron dopo lo stadio finale di sterilizzazione. The HPLC analyzes conducted at the time of preparation confirmed the absence of Palonosetron loss after the final sterilization stage.
Successivamente sono iniziate le prove di stabilità rispetto ad Aloxi in diverse condizioni: Subsequently, the stability tests began with respect to Aloxi in different conditions:
1) Stress termico 1) Thermal stress
Eseguita analisi HPLC. HPLC analysis performed.
Le condizioni di maggiore stress erano 70°C per 14 giorni. In queste condizioni si sono ottenuti i seguenti risultati: The most stressful conditions were 70 ° C for 14 days. Under these conditions the following results were obtained:
Tabella 2 Table 2
* il saggio iniziale per ciascuna composizione è stato normalizzato al valore 100%. ;Seguito da: ;2) Stabilità alla fotoossidazione ;;; ;; Stress combinati sui campioni di COC sottoposti a maggiore stress e conservati 14 giorni a 70°C e successivamente esposti a luce ed ossigeno per ulteriori 7 giorni. ;I risultati dell’analisi HPLC delle soluzioni contenute nei flaconi sono riassunti nella seguente Tabella 3: ;Tabella 3 ;;; ;; * il saggio iniziale per ciascuna composizione è stato normalizzato al valore 100%. * the initial assay for each composition was normalized to 100%. ; Followed by:; 2) Photooxidation stability ;;; ;; Combined stress on COC samples subjected to greater stress and stored 14 days at 70 ° C and subsequently exposed to light and oxygen for a further 7 days. ; The results of the HPLC analysis of the solutions contained in the bottles are summarized in the following Table 3:; Table 3 ;;; ;; * the initial assay for each composition was normalized to 100%.
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| US20100048607A1 (en) * | 2008-08-25 | 2010-02-25 | Chandrashekhar Kocherlakota | Formulations comprising palonosetron |
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Non-Patent Citations (2)
| Title |
|---|
| "High-quality, Break-resistant Container Closure Systems", DAIKYIO CRYSTAL ZENITH VIALS, 28 February 2011 (2011-02-28), pages 1 - 2, XP055023241, Retrieved from the Internet <URL:http://www.westpharma.com/en/products/Documents/Crystal Zenith Vial Solutions.pdf> [retrieved on 20120328] * |
| "SCHOTT TopPac - Superior performance made of polymer", SCHOTT PHARMACEUTICAL SYSTEMS, 30 April 2009 (2009-04-30), pages 1 - 6, XP055023248, Retrieved from the Internet <URL:http://www.adelphi-hp.com/assets/files/SCHOTT/TopPac.pdf> [retrieved on 20120328] * |
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