FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
ASEPTICALLY FILLED MULTIDOSE INJECTABLE DOSAGE FORMS OF GRANISETRON OR SALT THEREOF
2. APPLICANT (S)
(a) NAME: Wockhardt Ltd.,
(b) NATIONALITY: Indian
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051
3. PREAMBLE TO THE DESCRIPTION
The present invention provides aseptically filled multidose injectable dosage forms of granisetron or salt thereof.
The following specification particularly describes the invention and the manner in
which it is to be performed,
4. DESCRIPTION
The present invention provides aseptically filled multidose injectable dosage forms of granisetron or salt thereof.
Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HTl; 5-HT1A; 5-HTlB/C; 5-HT2; for alphal-, alpha2- or beta-adrenoreceptors; for dopamine-D2; 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 endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-l-methyl-lH-indazole-3-carboxamide. It is marketed in form of its hydrochloride salt as represented by Formula I. 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 prevention and treatment of postoperative nausea and vomiting.
N—CH3

FORMULA I
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US Patent No 4,886,808 provides granisetron or pharmaceutical^ acceptable salts, hydrates and solvates thereof, as being useful as an anti-emetic, particularly in the treatment of cytotoxic agent induced emesis, in, the entire disclosure of which is hereby incorporated by reference. It further provides process for preparation of granisetron.
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.
US Patent No 5,954,320 provides use of granisetron for treatment of Post-Operative Nausea and Vomiting (PONV). It further provides 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. Advantageously, adjuvants such as a local anaesthetic, 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.
US Patent No 6,294,548 provide multiple dose vials containing granisetron and benzyl alcohol as preservative. The specification of the '548 Patent suggests, that the prior 1 mg/ml single dose vial of granisetron hydrochloride has proved undesirable for patients weighing greater than 100 kg as a portion of a second vial will have to be utilized 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 '548 Patent provides numerous advantages of a suitable multidose vial comprising granisetron hydrochloride which are minimizing wasted product, conserving resources, containing costs, making better use of storage space and more cost effective to produce and transport.
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While preparing the multidose vials of granisetron hydrochloride the inventors of the '548 Patent have identified terminal autoclaving as a method for sterilization of the dosage form. It is provided in the specification of the '548 Patent that due to steam sterilization of the filled multidose ampoules or vials, preservative selection was very critical. Benzyl alcohol, m-cresol, methyl paraben, propyl paraben and mixture of methyl and propyl paraben have been studied. It was found that as preservative, only benzyl alcohol was suitable. Other preservatives when dissolved in vehicle along with granisetron and placed into glass vials for autoclaving at about 121°C 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 common practice in pharmaceutical industry to make the product sterile. It involves heating the injectable solution or suspension, to be sterilized, placed in suitable glass vial or ampoule, at 121°C for about 15-20 minutes. However, in many cases it is not advisable due to heat sensitivity of the drug or excipients, incompatibility of excipients with drug at higher temperature and cost involved.
While working on the development of multidose injectable dosage form of granisetron or salt thereof present inventors have embarked upon a simple technique, which eliminates the steam sterilization or autoclaving. It was surprisingly found that aseptic filing of the solution for injectable administration comprising granisetron or salt thereof can impart the same sterility to the injectable dosage form as that obtained with autoclaving. At the same time since aseptic filing of the granisetron solution takes place at lower temperature there is no heat incompatibility issues with preservatives. The aseptically filled injectable dosage forms of granisetron thus offer a choice of preservative without been worried about the compatibility problems.
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The present inventors have also noticed that the buffer is not required to impart stability to injectable dosage form as the formulation developed has no tendency to change pH during shelf-life.
One of the aspects of the present invention provides aseptically filled multidose injectable dosage form comprising granisetron or salt thereof.
In another aspect of the present invention there is provided multidose injectable dosage form comprising granisetron or salt thereof along with a pharmaceutically acceptable preservative said preservative being other than benzyl alcohol.
In yet another aspect of the present invention there is provided a process for preparation of multidose injectable dosage form comprising granisetron or salt thereof wherein the said process comprises of aseptic riling in to the desired container, a solution containing granisetron or salt thereof and pharmaceutically acceptable preservative.
In yet another aspect of the present invention there is provided multidose injectable dosage form comprising granisetron or salt thereof along with a pharmaceutically acceptable preservative wherein the dosage form is characterized by the fact that no buffer is added.
Pharmaceutically acceptable preservative solution is prepared in Water For Injection (WFI) and to it is added buffer such as citric acid to get a pH of about 4 to 6. It was found that addition of buffer such as citric acid is not required. To this solution is added granisetron or salt thereof 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 desired container.
The preservative can be selected from group comprising of alkyl parabens such as methyl and propyl paraben, cresols such as ortho- or meta-cresol and benzyl alcohol. All the
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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 developed as a part of present invention has been tested for the sterility and is found to be sterile after multiple piercing.
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.
Example 1:
Five batches of multi-dose injectable formulations of granisetron hydrochloride were taken. The composition of each batch 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 preparation of the dosage form is provided below: Preservative was dissolved in Water for Injection (WFI) and this solution was mixed with solution of sodium chloride, citric acid (optional) in WFI. To the resultant mixture was added granisetron hydrochloride. 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.
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Table 1

s.No. Composition Batch 1 Batch 2 Batch 3 Batch 4 Kytril®
1. Granisetron Hydrochloride Equivalent to Granisetron 1.0 mg/ml 1.0 mg/ml 1.0 mg/ml 1.0 mg/ml 1.0 mg/ml
2. Sodium Chloride 9.0 mg/ml 9.0 mg/ml 9.0 mg/ml 9.0 mg/ml 9.0 mg/ml
3. Citric Acid (Monohydrate) - - 2.0 mg/ml 2.0 mg/ml 2.0 mg/ml
4. Methyl Paraben 0.18 mg/ml - 0.18 mg/ml - -
5. Propyl Paraben 0.02 mg/ml - 0.02 mg/ml - -
6. m-Cresol - 0.25 mg/ml - 0.25 mg/ml -
7. Benzyl Alcohol 10 mg/ml
Table 2: Stability data. U is up right and I is inverted.

s.No. Parameters Batch 1 Batch 2 Batch 3 Batch 4 Kytril®
Initial 1M/40°C Initial Initial 1M/40°C Initial 1M/400 C 1M/40°C Initial 1M/400 C
1. Appearance and Clarityof Solution Clear Clear Clear Clear Clear Clear Clear Clear Clear Clear
2. pH 5.16 6.31 (U) 6.34 (I) 5.32 4.63 4.38 4.60
3 Related Substance
Impurity A (%) 0.000 0.000 U) 0.000 (I) 0.000 0.000 0.000 U) 0.000 (I) - 0.0 (U) 0.00 (I) 0.00 0.0 (U) 0.0 (I)
Impurity B 0.000 0.000 U) 0.000 (I) 0.000 0.000 0.000 U) 0.000 (I) 0.000 0.0 (U) 0.00 (I) 0.00 0.0 (U) 0.00 (I)
Highest Unknown(%) 0.075 0.000 U) 0.000 (I) 0.073 0.000 0.047 U) 0.046 (I) 0.083 0.048 (U) 0.048 (I) 0.00 0.0 (U) 0.00 (I)
Total Impurities(%) 0.122 0.000 U) 0.000 (I) 0.111 0.000 0.047 U) 0.046 (I) 0.083 0.048 (U) 0.048 (I) 0.000 0.0 (U) 0.00 (I)
4. GranisetronAssay (%) 99.0 99.8 (U) 99.8 (I) 106.0 97.7 99.2 (U)99.3 (I) 100.0 103.4(U) 103.3(1) 97.40 97.8(U)97.2 (I)
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WE CLAIM:
1. An aseptically filled multidose injectable dosage form comprising granisetron or salt thereof.
2. A multi-dose injectable dosage form of claim 1 wherein sterilizing grade 0.2-micron membrane is used for imparting sterility.
3. A multidose injectable dosage form comprising granisetron or salt thereof along with a pharmaceutically acceptable preservative said preservative being other than benzyl alcohol.
4. A multidose injectable dosage form of claim 3 wherein the preservatives are selected from group comprising of methyl paraben, propyl paraben, ortho-cresol, meta-cresol or mixtures thereof.
5. A multidose injectable dosage form of claim 3 further comprising of citric acid as buffer.
6. A multidose injectable dosage form of claim 3 wherein sterilizing grade 0.2-micron membrane is used for imparting sterility.
7. A process for preparation of multidose injectable dosage form comprising granisetron or salt thereof wherein the said process comprises of aseptic filing in to the desired container, a solution containing granisetron or salt thereof and pharmaceutically acceptable preservative.
8. A process of claim 7 wherein sterilizing grade 0.2-micron membrane is used for imparting sterility.
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9. A multidose injectable dosage form comprising granisetron or salt thereof along with a pharmaceutically acceptable preservative wherein the dosage form is characterized by the fact that no buffer is added.
10. A stable multi-dose injectable dosage form comprising granisetron or salt thereof along with a pharmaceutically acceptable preservative said preservative being other than benzyl alcohol.

Dated this 16th day of December 2005.

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For Wockhardt Limited