Claims: , Description:FIELD OF INVENTION
The present invention relates to a stable controlled release injectable formulation containing ondansetron or pharmaceutically acceptable salt, derivative or metabolite thereof which releases ondansetron over at least 2 days’ period, a method for preparing the above formulation, and a method for prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, radiotherapy and post operation.

BACKGROUND OF THE INVENTION
Ondansetron is a selective blocking agent of the serotonin 5-HT3 receptor type and is used for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy, prevention of nausea and vomiting associated with radiotherapy in patients receiving total body irradiation, single high-dose fraction to abdomen, or daily fractions to abdomen and prevention of postoperative nausea and/or vomiting.

Ondansetron is structurally represented as


Ondansetron is administered orally in following doses;
1. Highly emetogenic cancer chemotherapy: single dose of 24mg before the start of single-day highly emetogenic cancer chemotherapy;
2. Moderately emetogenic cancer chemotherapy: 8mg administered 30 minutes before the start of chemotherapy, with a subsequent 8mg dose 8 hours after the first dose, and further administration of 8mg twice a day (12 hours apart) for 1 or 2 days after completion of chemotherapy;
3. Radiation:
a. 8mg administered 1 or 2 hours before each fraction of radiotherapy each day for total body irradiation,
b. 8mg administered 1 to 2 hours before radiotherapy, with subsequent 8mg doses every 8 hours after first dose for 1 to 2 days after completion of radiotherapy for single high-dose fraction radiotherapy to abdomen, and
c. 8mg administered 1 to 2 hours before radiotherapy, with subsequent 8mg doses every 8 hours after the first dose for each day radiotherapy for daily fractioned radiotherapy to the abdomen;
4. Postoperative nausea and vomiting: 16mg administered one hour before induction of anaesthesia.
Intravenously ondansetron is administered at a dose of three 0.15 mg/kg for 3 doses (maximum of 16mg per dose) for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy and at a dose of 4mg for prevention of postoperative nausea and vomiting.
There exists a need to develop a stable controlled release ondansetron injectable formulation has the merit to eliminate the need of frequent dosing.

SUMMARY OF THE INVENTION
It is, therefore, an object of the present invention to provide a controlled release sterile injectable formulation containing ondansetron which provides a uniform and constant rate of release over an extended period of time.
Another aspect of the present invention is to provide a non-irritating parenteral formulation comprising ondansetron which is injected intramuscularly and/or subcutaneously.
Further object of the present invention is to provide an injectable controlled release formulation comprising ondansetron as active ingredient which shows good syringability, injectability, no clogging or blockage of the syringe needles, good drainage, sterility and re-suspendibility.
A major object of the present invention is to provide a controlled release injectable formulation of ondansetron, which is used for prevention of chemotherapy induced nausea and vomiting (CINV) and post-operative nausea and vomiting (PONV), which is able to replace the existing CINV and PONV treatment regimens that requires frequent oral and intravenous dosing daily.
The present invention aims at developing a pharmaceutical composition for intramuscular or subcutaneous administration, in a single or multiple injection sites, comprising ondansetron which is able to prevent, reduce or alleviate acute delayed and anticipatory CINV or PONV symptoms from day 1 (beginning of chemotherapy treatment) up to several days.
The invention further includes sterile injectable controlled release formulations comprising ondansetron as active ingredient in the form of ready to use suspensions.
A further approach of the present invention is to provide a fast, simple and cost-effective process for the preparation of a stable injectable pharmaceutical formulation comprising ondansetron.
The invention further includes sterile injectable suspension comprising (a) ondansetron, and (b) a vehicle for the ondansetron, which upon injection, preferably intramuscularly releases the therapeutic amounts of ondansetron over a period of at least 2 days, preferably three, four. five, six and up to seven days or more.
The mean particle size of ondansetron injectable suspension according to this invention is in the range from about 1 micron to about 30 microns which releases the ondansetron over a period of at least 2 days, preferably three, four. five, six and up to seven days or more, for example up to ten days.

DETAILED DESCRIPTION OF THE INVENTION
For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient ondansetron is considered to be “stable” if said active ingredient degrades slowly or more slowly than it does on its own and/or in known pharmaceutical compositions.
According to the present invention, the controlled release injectable, intramuscular (IM) or subcutaneous (SC) formulation of ondansetron that replaces the single dosing regimen.
Controlled release parenteral drug products according to the present invention may be available as powder for suspension, coarse or colloidal liquid suspensions.
The sterile injectable controlled release formulations of the invention will include ondansetron in an amount within the range from about 10mg/mL to about 200mg/mL, more preferably in the range from about 50mg/mL to about 150mg/mL, even more preferably in the range from about 75mg/mL to about 125mg/mL and most preferably of about 100mg/mL based on the total weight of the formulation.
As indicated, desired mean particle size of the ondansetron is essential in producing an injectable formulation having the desired controlled release properties of the ondansetron. Thus, to produce desired controlled release, the ondansetron should have a mean particle size within the range from about 1 to about 30 microns, preferably from about 1 to about 20 microns, and more preferably for about 1 to about 15 microns.
In one embodiment ondansetron formulation of the invention will preferably be formed from a) ondansetron; b) one or more viscosity increasing agents; c) one or more wetting agents; d) optionally one or more solvents, one or more buffers and one or more pH adjusting agents.
The viscosity increasing agent is present in the range from about 0.01mg/mL to 100mg/mL, more preferably from in the range from about 0.1mg/mL to about 50mg/mL, even more preferably in the range from about 1mg/mL to about 10mg/mL and most preferably of about 5mg/mL based on the total weight of the formulation. Examples of the viscosity enhancing agents for use include, but are not limited to aluminum monostearate, carboxy methylcellulose, desoxycholate sodium, gelatin, glycerol, hydroxyethyl cellulose, hydroxypropylmethylcellulose, polyoxyethylene alkyl ethers, polyoxyethylated fatty acid, polysorbate, polyethylene glycol, polyvinyl pyrrolidone and sodium carboxymethylcellulose. The more preferred viscosity increasing agents are Sodium carboxymethylcellulose or hydroxypropylmethylcellulose.
Wetting agents are present in the range from about 0.01mg/mL to 100mg/mL, more preferably from in the range from about 0.1mg/mL to about 50mg/mL, even more preferably in the range from about 1mg/mL to about 25mg/mL and most preferably of about 10mg/mL based on the total weight of the formulation. Examples of suitable wetting agents for use include one or more of the following but not limited to phospholipids selected from group consisting of egg yolk based phospholipids (egg phosphatidyl choline), soya phosphatidylcholine; diethylene glycol monostearate, diethylene glycol monolaurate, glyceryl monostearate, polyoxyethylene sorbitol beeswax, polyethylene lauryl ether, polyoxyethylene lauryl ether, polyoxyethylene monostearate, polyoxyethylene alkyl phenol, polyethylene sorbitan monooleate, polyethylene sorbitan monolaurate, polyoxyethylene lauryl ether, potassium oleate, poloxamer, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sodium lauryl sulfate, sodium oleate, and triethanolamine oleate.
Solvents preferably used in the present invention are pharmaceutically acceptable alcohols, acetone, acetonitrile, chloroform, dichloromethane or mixtures thereof. Pharmaceutically acceptable alcohols are selected from the group consisting of ethanol, benzyl alcohol, tertiary-butyl alcohol, isopropyl alcohol, and suitable mixtures thereof. Ethanol is the most preferably used solvent.
A buffer may be optionally employed, in a specific amount as to adjust the pH value from about 6 to about 8. Examples of suitable buffers include: sodium phosphate and potassium phosphate. Sodium phosphate is particularly preferred as buffering agent.
The controlled release injectable solution of the present invention may optionally include one or more pH adjusting agents. The pH adjusting agents may be either an acid or a base. Examples of pH adjusting agents include one or mixture of the following: acetic acid, calcium carbonate, hydrochloric acid, magnesium oxide, magnesium hydroxide, potassium hydroxide and sodium hydroxide. Sodium hydroxide and hydrochloric acid are particularly preferred as pH adjusting agents.
Additionally, one or more tonicity adjusting agent may be optionally added. Examples of suitable tonicity adjusting agents include, but are not limited to magnesium sulfate, maltose, mannitol, polyethylene glycol, polylactic acid, polysorbate, potassium chloride, povidone, sodium chloride, sodium cholesteryl sulfate, sodium succinate, sodium sulfate, sorbitol, sucrose and trehalose. Sodium chloride is particularly preferred, when necessary, as tonicity adjusting agent.
The following examples are provided to illustrate the present invention. It is understood, however, that the invention is not limited to the specific conditions or details described in the examples below. The examples should not be construed as limiting the invention as the examples merely provide specific methodology useful in the understanding and practice of the invention and its various aspects. While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modification to the disclosed embodiments can occur to those who are skilled in the art.

Example 1: Ondansetron injectable suspension (100mg Ondansetron/mL) with the particle size of 12.5µm.
Composition:
The following ingredients are used for the preparation of the ondansetron injectable suspension.
S.No Ingredient mg/mL
1. Ondansetron base 100
2. Carboxymethyl cellulose sodium salt 5
3. Poloxamer 10
4. Water for Injection q.s to 1mL

Process for Preparation:
1. In a clean and dried vessel carboxymethyl cellulose sodium salt, poloxamer is weighed and dissolved in water for injection and further filtered 0.2µ sterile filter.
2. To the above contents of step 1 sterilized ondansetron base is added and kept under high shear mixing using inline homogenizer at 8000-15,000 rpm. Mixing is continued for about 10 to 15 minutes to form a coarser suspension.
3. The above coarser suspension is subjected to homogenization to reduce the particle size to form the final ondansetron injectable suspension and volume is made up to 100% with water for injection.
After the homogenization the final ondansetron injectable suspension is evaluated for the particle size distribution by laser scattering particle distribution analyser and the ondansetron has the mean particle size of 12.5µm.

Example 2: Ondansetron injectable suspension (100mg Ondansetron/1mL) with the particle size of 4.25µm.
Composition:
The following ingredients are used for the preparation of the ondansetron injectable suspension.
S.No Ingredient mg/mL
1. Ondansetron base 100
2. Carboxymethyl cellulose sodium salt 5
3. Poloxamer 10
4. Water for Injection q.s to 1mL

Process for Preparation:
1. In a clean and dried vessel carboxymethyl cellulose sodium salt, poloxamer is weighed and dissolved in water for injection and further filtered 0.2µ sterile filter.
2. To the above contents of step 1 sterilized ondansetron base is added and kept under high shear mixing using inline homogenizer at 8000-15,000 rpm. Mixing is continued for about 10 to 15 minutes to form a coarser suspension.
3. The above coarser suspension is subjected to homogenization to reduce the particle size to form the final ondansetron injectable suspension and volume is made up to 100% with water for injection.
After the homogenization the final ondansetron injectable suspension is evaluated for the particle size distribution by laser scattering particle distribution analyser and the ondansetron has the mean particle size of 4.25µm.

Example – 3: Ondansetron injectable suspension (100mg Ondansetron/1mL) with the particle size of 5µm.
Composition:
The following ingredients are used for the preparation of the ondansetron injectable suspension.
S.No Ingredient mg/mL
1. Ondansetron base 100
2. Carboxymethyl cellulose sodium salt 5
3. Lipoid E 80 (Egg Phosphatidylcholine) 10
4. Ethanol 0.1 mL
5. Water for Injection q.s to 1mL

Process for Preparation:
1. In a clean dried vessel Lipoid E 80 is dissolved in Ethanol and filtered 0.2µ sterile filter.
2. In a clean dried vessel carboxymethyl cellulose sodium salt and water for injection was added and further filtered 0.2µ sterile filter.
3. To the above contents of step 2, step1 contents are added and stirred to homogenous dispersion.
4. To the above contents of step 3 sterilized ondansetron base is added and kept under high shear mixing using inline homogenizer at 8000-15,000 rpm. Mixing is continued for about 10 to 15 minutes to form a coarser suspension.
5. The above coarser suspension is subjected to homogenization to reduce the particle size to form the final ondansetron injectable suspension and volume is made up to 100% with water for injection.
After the homogenization the final ondansetron injectable suspension is evaluated for the particle size distribution by laser scattering particle distribution analyser and the ondansetron has the mean particle size of 5 µm.