WO2007069070A2 - Formes pharmaceutiques injectables multidoses remplies de maniere aseptique de granisetron - Google Patents

Formes pharmaceutiques injectables multidoses remplies de maniere aseptique de granisetron Download PDF

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Publication number
WO2007069070A2
WO2007069070A2 PCT/IB2006/003661 IB2006003661W WO2007069070A2 WO 2007069070 A2 WO2007069070 A2 WO 2007069070A2 IB 2006003661 W IB2006003661 W IB 2006003661W WO 2007069070 A2 WO2007069070 A2 WO 2007069070A2
Authority
WO
WIPO (PCT)
Prior art keywords
multidose
dosage form
granisetron
injectable dosage
salt
Prior art date
Application number
PCT/IB2006/003661
Other languages
English (en)
Other versions
WO2007069070A3 (fr
Inventor
Chandrashekar Shahaji Kadam
Bhavesh Vallabhbhai Patel
Girish Kumar Jain
Original Assignee
Wockhardt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wockhardt Ltd filed Critical Wockhardt Ltd
Publication of WO2007069070A2 publication Critical patent/WO2007069070A2/fr
Publication of WO2007069070A3 publication Critical patent/WO2007069070A3/fr

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole

Definitions

  • the present invention relates to aseptically filled multidose injectable dosage forms of granisetron or salts thereof, and processes for their preparation.
  • Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HTlB/C; 5-HT2; for alphal-, alpha2- or beta-adrenoreceptors; for dopamine-t ) 2; or for histamine-Hl; benzodiazepine; picrotoxin or opioid receptors.
  • 5-HT3 5-hydroxytryptamine3
  • Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema.
  • mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent discharge and may induce vomiting.
  • Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.
  • granisetron is enc?o-N-(9-methyl-9-azabicyclo [3.3.1] non-3 -yl)-l -methyl- IH- indazole-3-carboxamide. It is marketed in the form of its hydrochloride salt as represented by Formula I and commercially available under the trade name KYTRIL®. It is indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. It is also indicated for the prevention and treatment of postoperative nausea and vomiting.
  • U.S. Patent No. 4,886,808 discloses granisetron or pharmaceutically acceptable salts, hydrates and solvates thereof, as being useful as an anti-emetic, particularly in the treatment of cytotoxic agent induced emesis.
  • an injectable dosage form of granisetron hydrochloride is commercially available in a 1 ml single use vial containing an aqueous solution comprising 1.12 mg of granisetron hydrochloride equivalent to granisetron 1 mg.
  • the recommended dosage for granisetron hydrochloride is 10 mcg/kg infused intravenously over 5 minutes, beginning within 30 minutes before initiation of chemotherapy.
  • U.S. Patent No. 5,954,320 discloses the use of granisetron for the treatment of Post-Operative Nausea and Vomiting (PONV).
  • PONV Post-Operative Nausea and Vomiting
  • the patent also discloses single dose parenteral dosage forms prepared by dissolving granisetron in a vehicle and filter sterilizing before filling into a suitable vial or ampoule and sealing.
  • the adjuvants such as local anesthetics, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • U.S. Patent No. 6,294,548 discloses multiple dose vials containing granisetron and benzyl alcohol as preservative.
  • the patent also suggests that the prior 1 mg/ml single dose vial of granisetron hydrochloride has proven undesirable for patients weighing greater than 100 kg as a portion of a second vial will have to be utilized to administer the recommended dose of 10 mcg/kg and the remaining medication discarded. Further, product wastage will occur when administering to lighter patients who do not require the full 1 ml dose.
  • the patent discloses numerous advantages of a suitable multidose vial comprising granisetron hydrochloride which include: minimizing wasted product, conserving resources, containing costs, making better use of storage space and more cost effective to produce and transport.
  • the patent identifies terminal autoclaving as a method for sterilization of the dosage form for preparing the multidose vials of granisetron hydrochloride.
  • the selection of preservatives has been considered to be critical for steam sterilization of the filled multidose ampoules or vials.
  • preservatives such as benzyl alcohol, m-cresol, methyl paraben, propyl paraben and mixture of methyl and propyl paraben, only benzyl alcohol was found to be suitable.
  • Other preservatives when dissolved in vehicle along with granisetron and placed into glass vials for autoclaving at about 121 0 C for about 15 to 60 minutes generated significant degradation products and therefore not compatible with granisetron.
  • aseptically filled multidose injectable dosage form that includes granisetron or a salt thereof and one or more pharmaceutically acceptable preservatives.
  • Embodiments of the multidose injectable dosage form include one or more of the following features.
  • sterilizing grade membrane may be used for imparting sterility.
  • the dosage form may further include one or more buffers.
  • a multidose injectable dosage form that includes granisetron or a salt thereof and one or more pharmaceutically acceptable preservatives, wherein the preservative is other than benzyl alcohol.
  • Embodiments of the multidose injectable dosage form include one or more of the following features.
  • sterilizing grade membrane may be used for imparting sterility.
  • the dosage form may further include one or more buffers.
  • a process for the preparation of multidose injectable dosage form includes a step of aseptic filing in to a desired container, a solution containing granisetron or a salt thereof and one or more pharmaceutically acceptable preservatives.
  • Embodiments of the process may include one or more of the following features.
  • the process may further include using a sterilizing grade membrane for imparting sterility.
  • the process may further include adding one or more buffers.
  • a multidose injectable dosage form that includes granisetron or a salt thereof and one or more pharmaceutically acceptable preservatives, wherein the dosage form is free of any buffer.
  • the inventors have recognized that there is an unmet and unrecognized need for a simpler multidose injectable dosage form of granisetron or salts thereof, hi particular, the inventors have now discovered that multidose injectable dosage forms of granisetron or a salt thereof can be effectively prepared without using steam sterilization or autoclaving for imparting sterility. It was surprisingly found that aseptic filing of the solution for injectable administration that includes granisetron or a salt thereof can impart the same sterility to the injectable dosage form as that obtained with autoclaving. Since aseptic filling of the granisetron solution takes place at a lower temperature, there is no heat incompatibility issue with preservatives. The aseptically filled injectable dosage forms of granisetron thus offer a choice of preservatives without being concerned about the compatibility problems.
  • the multidose injectable dosage form can include granisetron and one or more pharmaceutically acceptable preservatives.
  • granisetron as used herein includes granisetron or a pharmaceutically acceptable salt thereof.
  • a process for preparing a multidose injectable dosage form that comprise granisetron or a salt thereof comprising a step of aseptic filling into a desired container, a solution containing granisetron or a salt thereof and one or more pharmaceutically acceptable preservatives.
  • the multidose injectable dosage forms as described herein may include one or more buffers.
  • the buffer systems suitable for the multidose injectable dosage forms of the present invention are those which maintain the pH of the dosage form in the range of about 4 to about 6.
  • Suitable buffers may include citric acid or its corresponding salts and acetic acid or its salts.
  • preservative solution is prepared in "Water For Injection (WFI)" and a buffer such as citric acid is added to get a pH of about 4 to 6. To this solution, granisetron or a salt thereof is added, and the resultant solution is adjusted for tonicity. It is then passed through 0.2-micron membrane filter. The so formed sterile granisetron injection is then filled aseptically in a desired container.
  • the preservatives can be selected from the group that includes alkyl parabens such as methyl and propyl paraben, cresols such as ortho- or meta-cresol, benzyl alcohol, sodium benzoate, sodium citrate and benzalkonium chloride as well as other pharmaceutically acceptable preservatives.
  • the injectable dosage form thus developed was tested for sterility.
  • the dosage form was found to be sterile after multiple piercing.
  • a multidose injectable dosage form comprising granisetron or a salt thereof and one or more pharmaceutically acceptable preservatives, wherein the preservative is other than benzyl alcohol.
  • a stable multidose injectable dosage form can be prepared without adding any buffer to the formulation.
  • the present invention provides a multidose injectable dosage form comprising granisetron or a salt thereof and one or more pharmaceutically acceptable preservatives, wherein the dosage form is free of any buffer.
  • composition of the four batches of multi-dose injectable formulations of granisetron hydrochloride is provided in Table 1 and the analytical data of initial and one-month stability (both up-right and inverted) is provided in Table 2.
  • Table 1 The composition of the four batches of multi-dose injectable formulations of granisetron hydrochloride is provided in Table 1 and the analytical data of initial and one-month stability (both up-right and inverted) is provided in Table 2.
  • Table 2 The general procedure used for the preparation of the dosage form is provided below:
  • the preservative was dissolved in "Water for Injection” (WFI) and this solution was mixed with a solution of sodium chloride, and citric acid in WFI. To the resultant mixture, granisetron hydrochloride was added. The pH and osmolality of this solution was measured and adjusted, if required and volume was made using WFI. The solution was allowed to pass through 0.2-micron membrane filter and the sterile solution so obtained was aseptically filled in the desired depyrogenated multi-dose containers. The containers are plugged aseptically with sterile stoppers and sealed.
  • WFI Water for Injection

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des formes pharmaceutiques injectables multidoses remplies de manière aseptique de granisétron ou de sels de celui-ci, et des procédés pour leur préparation.
PCT/IB2006/003661 2005-12-16 2006-12-18 Formes pharmaceutiques injectables multidoses remplies de maniere aseptique de granisetron WO2007069070A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1587MU2005 2005-12-16
IN1587/MUM/05 2005-12-16

Publications (2)

Publication Number Publication Date
WO2007069070A2 true WO2007069070A2 (fr) 2007-06-21
WO2007069070A3 WO2007069070A3 (fr) 2009-04-16

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Family Applications (1)

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Country Status (1)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8835453B2 (en) 2008-12-11 2014-09-16 Development Center For Biotechnology Sustained release implant for granisetron

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060211982A1 (en) * 2002-12-20 2006-09-21 Steven Prestrelski Intracutaneous injection
US20070015808A1 (en) * 2005-07-13 2007-01-18 Baxter International Inc. Pharmaceutical formulations of endo-N-(9-methyl-9-azabicyclo[3,3. 1]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060211982A1 (en) * 2002-12-20 2006-09-21 Steven Prestrelski Intracutaneous injection
US20070015808A1 (en) * 2005-07-13 2007-01-18 Baxter International Inc. Pharmaceutical formulations of endo-N-(9-methyl-9-azabicyclo[3,3. 1]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8835453B2 (en) 2008-12-11 2014-09-16 Development Center For Biotechnology Sustained release implant for granisetron

Also Published As

Publication number Publication date
WO2007069070A3 (fr) 2009-04-16

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