WO2007069070A2

WO2007069070A2 - Aseptically filled multidose injectable dosage forms of granisetron

Info

Publication number: WO2007069070A2
Application number: PCT/IB2006/003661
Authority: WO
Inventors: Chandrashekar Shahaji Kadam; Bhavesh Vallabhbhai Patel; Girish Kumar Jain
Original assignee: Wockhardt Ltd
Priority date: 2005-12-16
Filing date: 2006-12-18
Publication date: 2007-06-21
Also published as: WO2007069070A3

Abstract

The present invention relates to aseptically filled multidose injectable dosage forms of granisetron or salts thereof, and processes for their preparation.

Description

ASEPTICALLY FILLED MULTIDOSE INJECTABLE DOSAGE FORMS OF

GRANISETRON Field of the Invention

Background of the Invention

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.

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. During chemotherapy-induced vomiting, 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.

In most human studies, granisetron has had little effect on blood pressure, heart rate or ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in other studies.

Chemically, 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.

FORMULA I

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.

As indicated in the Physician's Desk Reference. RTM, 1997 edition, published by Medical Economics Company, Inc. at Montvale, N.J., 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). 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. To enhance the stability, 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.

Further, 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. Of the various 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 121⁰C for about 15 to 60 minutes generated significant degradation products and therefore not compatible with granisetron. It further states that granisetron hydrochloride is stable in solution over the pH range 2 to 7. In preparing ' multidose formulations for stability testing, it was noted that a pH shift effect occasionally occurred. In order to stabilize the pH, a citrate buffer was added to control the pH of the solution to a target pH of 6 with limits of 5 to 7.

Steam sterilization or autoclaving of injectable dosage forms is a common practice in the pharmaceutical industry to make the products sterile. It involves heating the injectable solution or suspension to be sterilized, placed in a suitable glass vial or ampoule at 121⁰C for about 15-20 minutes. However, in many cases autoclaving is not advisable due to heat sensitivity of the drug or excipients, incompatibility of excipients with drug at higher temperatures and the cost involved.

Summary of the Invention

In one general aspect there is provided 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. For example, sterilizing grade membrane may be used for imparting sterility. The dosage form may further include one or more buffers.

In another general aspect there is provided 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. For example, sterilizing grade membrane may be used for imparting sterility. The dosage form may further include one or more buffers.

In another general aspect there is provided a process for the preparation of multidose injectable dosage form. The process 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. For example, the process may further include using a sterilizing grade membrane for imparting sterility. The process may further include adding one or more buffers.

hi another general aspect there is provided 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 details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Detailed Description of the Invention

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 worried about the compatibility problems.

The multidose injectable dosage form can include granisetron and one or more pharmaceutically acceptable preservatives.

The term "granisetron" as used herein includes granisetron or a pharmaceutically acceptable salt thereof.

Hence in one aspect there is provided a process for preparing a multidose injectable dosage form that comprise granisetron or a salt thereof, the process 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.

Pharmaceutically acceptable 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.

All the preservatives were found to have no incompatibility or stability issues when aseptic filling was used as technique for imparting sterility to the injectable dosage form.

Several sterilizing grade membrane filters are available for aseptic filtration of water based pharmaceutical injectable dosage forms such as cellulose acetate, nylon, polyether sulfone (PES), polyvinyl difluoride (PVDF), and the like.

The injectable dosage form thus developed was tested for sterility. The dosage form was found to be sterile after multiple piercing.

In another aspect there is provided 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.

Since the formulation developed has no tendency to undergo a change in pH during shelf-life, a stable multidose injectable dosage form can be prepared without adding any buffer to the formulation.

Therefore in another aspect 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.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Example 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. 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.

Table 1

U*- Upright; P - Inverted.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

CLAIMS;We claim:

1. An aseptically filled multidose injectable dosage form comprising granisetron or a salt thereof, and one or more pharmaceutically acceptable preservatives.

2. The multidose injectable dosage form of claim 1, wherein the preservative comprises one or more of methyl paraben, propyl paraben, ortho-cresol, meta-cresol, benzyl alcohol, sodium benzoate, sodium citrate, benzatkonium chloride, and mixtures thereof.

3. The multidose injectable dosage form of claim 1, further comprising one or more buffers.

4. The multidose injectable dosage form of claim 3, wherein the buffer is citric acid, acetic acid or their corresponding salts.

5. The multi-dose injectable dosage form of claim 1, wherein sterilizing grade 0.2-micron membrane is used for imparting sterility.

6. 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.

7. The multidose injectable dosage form of claim 6, wherein the preservative comprises one or more of methyl paraben, propyl paraben, ortho-cresol, meta-cresol, sodium benzoate, sodium citrate, benzalkonium chloride, and mixtures thereof.

8. The multidose injectable dosage form of claim 6, further comprising one or more buffers.

9. The multidose injectable dosage form of claim 8, wherein the buffer is citric acid, acetic acid or their corresponding salts.

10. The multidose injectable dosage form of claim 6, wherein sterilizing grade 0.2-micron membrane is used for imparting sterility.

11. A process for the preparation of multidose injectable dosage form of granisetron or a salt thereof, the process 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.

12. The process of claim 11, wherein sterilizing grade 0.2-micron membrane is used for imparting sterility.

13. 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.