Description:[0001] FIELD OF INVENTION

[0002] The present invention relates to a controlled release injectable ondansetron formulation comprising ondansetron or pharmaceutically acceptable salt, derivative or metabolite thereof which releases ondansetron over a period of at least 2 days period from the date of administration, 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.

[0003] BACKGROUND OF THE INVENTION

[0004] 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.

[0005] Ondansetron is structurally represented as


[0006] Ondansetron is administered orally in following doses;
1. Highly emetogenic cancer chemotherapy: single dose of 24 mg before the start of single-day highly emetogenic cancer chemotherapy;
2. Moderately emetogenic cancer chemotherapy: 8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8mg dose 8 hours after the first dose, and further administration of 8 mg twice a day (12 hours apart) for 1 or 2 days after completion of chemotherapy;
3. Radiation:
a. 8 mg administered 1 or 2 hours before each fraction of radiotherapy each day for total body irradiation,
b. 8 mg 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. 8 mg administered 1 to 2 hours before radiotherapy, with subsequent 8 mg 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.

[0007] Intravenously ondansetron is administered at a dose of three 0.15 mg/kg for 3 doses (maximum of 16 mg per dose) for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy and at a dose of 4 mg for prevention of postoperative nausea and vomiting.

[0008] There exists a need to develop a controlled release ondansetron injectable formulation has the merit to eliminate the need of frequent dosing.

[0009] OBJECTS OF THE INVENTION

[0010] The first object of the present invention to provide a controlled release injectable formulation containing ondansetron which provides a uniform and constant rate of release over an extended period of time.

[0011] Another object of the present invention is to provide a non-irritating parenteral formulation comprising ondansetron which is injected intramuscularly (IM) and/or subcutaneously (SC).

[0012] Further object of the present invention is to provide a controlled release injectable 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.

[0013] 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.

[0014] The present invention aims at developing a pharmaceutical composition for intramuscular (IM) or subcutaneous (SC) 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.

[0015] The invention further includes sterile injectable controlled release formulations comprising ondansetron as active ingredient in the form of ready to use suspensions.

[0016] 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.

[0017] The invention further includes sterile injectable suspension comprising (a) ondansetron, and (b) a vehicle for the ondansetron, which upon injection, preferably intramuscularly (IM) 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 from the date of administration.

[0018] The particle size (D90) 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 from the date of administration.

[0019] SUMMARY OF THE INVENTION

[0020] The present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns, and
(b) one or more viscosity increasing agents,
wherein said controlled release injectable ondansetron formulation upon administration into a subject releases ondansetron over a period of at least 2 days from the date of administration.

[0021] The present invention further provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns, and
(b) one or more viscosity increasing agents,
wherein said controlled release injectable ondansetron formulation upon administration into a subject releases ondansetron over a period of about 2 days to about 10 days from the date of administration.

[0022] In another embodiment, the present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns, and
(b) one or more viscosity increasing agents,
wherein said controlled release injectable ondansetron formulation upon administration into a subject releases ondansetron over a period of 5 days from the date of administration.

[0023] In a further embodiment, the present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns, and
(b) one or more viscosity increasing agents,
wherein said controlled release injectable ondansetron formulation upon administration into a subject releases ondansetron over a period of 7 days from the date of administration.

[0024] In a still further embodiment, the present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns,
(b) one or more viscosity increasing agents,
(c) one or more wetting agents and
(d) one or more solvents,
wherein said controlled release injectable ondansetron formulation upon administration into a subject release ondansetron over a period of about 2 days to about 10 days from the date of administration.

[0025] In a further embodiment, the present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns,
(b) one or more viscosity agents selected from the group consisting of carboxymethyl cellulose or its sodium salt and hydroxypropyl methylcellulose,
(c) one or more wetting agents selected from group consisting of phosphatidyl choline and poloxamer and
(d) one or more solvents selected from group consisting of ethanol and water.

[0026] In a still further embodiment, the present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns,
(b) carboxymethyl cellulose or its sodium salt,
(c) phosphatidyl choline and
(d) one or more solvents.

[0027] In a further embodiment, the present invention provides a controlled release injection ondansetron formulation comprising
(a) about 1 mg/mL to about 350 mg/mL ondansetron,
(b) about 1 mg/mL to about 50 mg/mL carboxymethyl cellulose or its sodium salt,
(c) about 1 mg/mL to about 50 mg/mL phosphatidyl choline.
(d) one or more solvents selected from group consisting of ethanol and water.

[0028] In another embodiment, the present invention provides a controlled release injection ondansetron formulation comprising
(a) about 100 mg/mL to about 250 mg/mL ondansetron having a particle size (D90) of about 1 to 30 microns,
(b) about 5 mg/mL to about 35 mg/mL carboxymethyl cellulose or its sodium salt,
(c) about 10 mg/mL to about 35 mg/mL phosphatidyl choline.
(d) one or more solvents selected from group consisting of ethanol and water.

[0029] The present invention further provides a controlled release injectable ondansetron formulation consisting of
(a) 100 mg/mL to 250 mg/mL ondansetron,
(b) 5 mg/mL to 35 mg/mL carboxymethyl cellulose or its sodium salt,
(c) 10 mg/mL to 35 mg/mL phosphatidyl choline,
(d) ethanol and
(e) water.

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031] For the purpose of the invention, the controlled release injectable, intramuscular (IM) or subcutaneous (SC) formulation of ondansetron means that replaces the single dosing regimen.

[0032] Controlled release parenteral drug products according to the present invention may be available as powder for suspension, coarse or colloidal liquid suspensions.

[0033] The present invention relates to a controlled release injectable ondansetron formulation comprising ondansetron having a particle size (D90) of about 1 to 30 microns, wherein said controlled release injectable ondansetron formulation upon administration into a subject releases ondansetron over a period of at least 2 days from the date of administration, preferably three, four, five, six and up to seven days or more, for example up to ten days from the date of administration.

The controlled release injectable ondansetron formulations of the invention will include ondansetron in an amount within the range from about 1 mg/mL to about 350 mg/mL, preferably in the range from about 10 mg/mL to about 300 mg/mL, more preferably in the range from about 75 mg/mL to about 250 mg/mL, even more preferably in the range from about greater than 100 mg/mL to about 200 mg/mL, and even most preferably in the range from about 105 mg/mL to about 200 mg/mL.

[0034] As indicated, desired particle size (D90) 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 particle size (D90) within the range from about 1 to about 30 microns.

[0035] 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.

[0036] In another embodiment, the present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns, and
(b) one or more viscosity increasing agents,
wherein said controlled release injectable ondansetron formulation upon administration into a subject releases ondansetron over a period of at least 2 days from the date of administration, preferably three, four, five, six and up to seven days or more, for example up to ten days from the date of administration.

[0037] In a further embodiment, the present invention relates to a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns, and
(b) one or more viscosity increasing agents,
wherein said controlled release injectable ondansetron formulation upon administration into a subject releases ondansetron over a period of at least 2 days from the date of administration.

[0038] The present invention further provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns, and
(b) one or more viscosity increasing agents,
wherein said controlled release injectable ondansetron formulation upon administration into a subject releases ondansetron over a period of about 2 days to about 10 days from the date of administration.

[0039] In another embodiment, the present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns, and
(b) one or more viscosity increasing agents,
wherein said controlled release injectable ondansetron formulation upon administration into a subject releases ondansetron over a period of 5 days from the date of administration.

[0040] In a further embodiment, the present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns, and
(b) one or more viscosity increasing agents,
wherein said controlled release injectable ondansetron formulation upon administration into a subject releases ondansetron over a period of 7 days from the date of administration.

The viscosity increasing agent is present in the range from about 0.01 mg/mL to 100 mg/mL, more preferably from in the range from about 0.1 mg/mL to about 50 mg/mL, more preferably in the range from about 2 mg/mL to about 40 mg/mL, even more preferably in the range from about 2.5 mg/mL to about 35 mg/mL and most preferable in the range of about 5 mg/mL to about 30 mg/mL. Examples of the viscosity increasing agents for use include, but are not limited to aluminium monostearate, carboxymethyl cellulose or its sodium salt, desoxycholate sodium, gelatin, glycerol, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, polyoxyethylene alkyl ethers, polyoxyethylated fatty acid, polysorbate, polyethylene glycol, polyvinyl pyrrolidone and sodium carboxymethylcellulose. The more preferred viscosity increasing agents are carboxymethyl cellulose or its sodium salt, and hydroxypropyl methylcellulose. Carboxymethyl cellulose or its sodium salt is used in the range from about 0.01 mg/mL to 100 mg/mL, more preferably from in the range from about 0.1 mg/mL to about 50 mg/mL, more preferably in the range from about 2 mg/mL to about 40 mg/mL, even more preferably from about 2.5 mg/mL to about 35 mg/mL and most preferably in the range of 5 mg/mL to about 30 mg/mL.

[0041] Wetting agents are present in the range from about 0.01 mg/mL to 100 mg/mL, more preferably from in the range from about 2 mg/mL to about 50 mg/mL, even more preferably in the range from about 2.5 mg/mL to about 35 mg/mL, most preferably in the range from about 2.5 mg/mL to about 35 mg/mL, most preferably of about 10 mg/mL to about 30 mg/mL. 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. Phosphatidyl choline is used in the range from about 0.01 mg/mL to 100 mg/mL, more preferably from in the range from about 0.1 mg/mL to about 50 mg/mL, even more preferably in the range from about 0.5 mg/mL to about 45 mg/mL, most preferably of about 2.5 mg/mL to about 35 mg/mL and even most preferably in the range of about 10 mg/mL to about 30 mg/mL.

[0042] Solvents preferably used in the present invention are pharmaceutically acceptable alcohols, acetone, acetonitrile, chloroform, dichloromethane, water 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 alcoholic solvent. The most preferably used solvents is the mixture of ethanol and water.

[0043] In a still further embodiment, the present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns,
(b) one or more viscosity increasing agents,
(c) one or more wetting agents and
(d) one or more solvents,
wherein said controlled release injectable ondansetron formulation upon administration into a subject release ondansetron over a period of about 2 days to about 10 days from the date of administration.

[0044] In a further embodiment, the present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns,
(b) one or more viscosity agents selected from the group consisting of carboxymethyl cellulose or its sodium salt and hydroxypropyl methylcellulose,
(c) one or more wetting agents selected from group consisting of phosphatidyl choline and poloxamer and
(d) one or more solvents selected from group consisting of ethanol and water.

[0045] In a still further embodiment, the present invention provides a controlled release injectable ondansetron formulation comprising
(a) ondansetron having a particle size (D90) of about 1 to 30 microns,
(b) carboxymethyl cellulose or its sodium salt,
(c) phosphatidyl choline and
(d) one or more solvents.

[0046] In a further embodiment, the present invention provides a controlled release injection ondansetron formulation comprising
(a) about 75 mg/mL to about 250 mg/mL ondansetron,
(b) about 2.5 mg/mL to about 35 mg/mL carboxymethyl cellulose or its sodium salt,
(c) about 2.5 mg/mL to about 35 mg/mL phosphatidyl choline.
(d) one or more solvents selected from group consisting of ethanol and water.

[0047] In another embodiment, the present invention provides a controlled release injection ondansetron formulation comprising
(a) about 100 mg/mL to about 200 mg/mL ondansetron having a particle size (D90) of about 1 to 30 microns,
(b) about 2.5 mg/mL to about 30 mg/mL carboxymethyl cellulose or its sodium salt,
(c) about 2.5 mg/mL to about 30 mg/mL phosphatidyl choline.
(d) one or more solvents selected from group consisting of ethanol and water.

[0048] The present invention further provides a controlled release injectable ondansetron formulation consisting of
(a) 105 mg/mL to 200 mg/mL ondansetron,
(b) 2.5 mg/mL to 30 mg/mL carboxymethyl cellulose or its sodium salt,
(c) 2.5 mg/mL to 30 mg/mL phosphatidyl choline,
(d) ethanol and
(e) water.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.
[0053] Example 1: Ondansetron injectable suspension (100mg Ondansetron/1 mL) with the particle size of 12.5 µm.
[0054] Composition:
[0055] 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

[0056] 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.
4. 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 Particle size (D90) of 12.5µm.
[0057] Example 2: Ondansetron injectable suspension (100mg Ondansetron/1 mL) with the particle size of 4.25 µm.
[0058] Composition:
[0059] 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

[0060] 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.
4. 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 particle size (D90) of 4.25µm.

[0061] Example 3: Ondansetron injectable suspension (100mg Ondansetron/1 mL) with the particle size of 5µm.
[0062] Composition:
[0063] 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 phospholipid with 80% Phosphatidylcholine) 10
4. Ethanol 7.89
5. Water for Injection q.s to 1mL

[0064] 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.
6. 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 particle size (D90) of 5 µm.

[0065] Examples 4 to 6: Ondansetron injectable suspension (100mg Ondansetron/1 mL).
[0066] Composition: An ondansetron injectable (IM Depot) suspension (100 mg/mL, 100 mg/Vial) was prepared as follows.

S.No Ingredient Ex:4
mg/mL Ex:5
mg/mL Ex:6
mg/mL
1. Ondansetron base 100 100 100
2. Carboxymethyl cellulose sodium salt 5 5 5
3. Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5 2.5 5
4. Ethanol dehydrated 2.0 2.0 4.0
5. Water for Injection Q.S to 1 mL Q.S to 1 mL Q.S to 1 mL
Particle size of suspension (D90) 5.19 µm 2.17 µm 4.23 µm

[0067] Process for Preparation:
1. In a clean and dried vessel 60% of batch size of water for injection collected.
2. To step 1, carboxymethyl cellulose sodium salt added and dissolved.
3. Step 2 solution filtered 0.2µ sterile filter.
4. In a clean and dried vessel Lipoid E 80 solubilized in Ethanol to get 500 mg/mL of Lipoid E 80 and filtered 0.2µ sterile filter.
5. To step 3 solution measured quantity of step 4 solution to get 10mg/mL of Lipoid E80 added and stirred to get homogenous dispersion.
6. To step 5 solution Ondansetron added and subjected to high shear mixing 10000 rpm for 10 min.
7. Step 6 suspension subjected to high pressure homogenization 5000 psi for 4 passes to reduce the particles to the desired size.
8. Step 7 suspension volume made up to get 100 mg/mL of Ondansetron using water for injection.

[0068] Examples 7 to 9: Ondansetron injectable suspension (100mg Ondansetron/1 mL).
[0069] Composition: An ondansetron injectable (IM Depot) suspension (100 mg/mL, 100 mg/Vial) was prepared as follows.
S.No Ingredient Ex:7
mg/mL Ex:8
mg/mL Ex:9
mg/mL
1. Ondansetron base 100 100 100
2. Carboxymethyl cellulose sodium salt 5 5 5
3. Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 5 5 5
4. Ethanol dehydrated 4.0 4.0 4.0
5. Water for Injection Q.S to 1 mL Q.S to 1 mL Q.S to 1 mL
Particle size of suspension (D90) 8.72 µm 4.35 µm 4.98 µm
The process for preparation is same as disclosed in the examples 4 to 6.

[0070] Examples 10 to 12: Ondansetron injectable suspension (100mg Ondansetron/1 mL).
[0071] Composition: An ondansetron injectable (IM Depot) suspension (100 mg/mL, 100 mg/Vial) was prepared as follows.
S.No Ingredient Ex:10
mg/mL Ex:11
mg/mL Ex:12
mg/mL
1. Ondansetron base 100 100 100
2. Carboxymethyl cellulose sodium salt 5 5 5
3. Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 5 10 10
4. Ethanol dehydrated 4.0 7.89 7.89
5. Water for Injection Q.S to 1 mL Q.S to 1 mL Q.S to 1 mL
Particle size of suspension (D90) 9.40 µm 12.7 µm 4.53 µm
The process for preparation is same as disclosed in the examples 10 to 12.

[0072] Example 13: Animal PK Data: Fasting Single Dose IM Depot Study in Dogs
[0073] Male Beagle dogs were fasted are divided into six groups as G1, G2, G3, G4, G5 and G6 each consisting of four dogs. Ondansetron injection solution 2 mg/mL available in market (Reference) is administered intravenously (IV) to G1, G2 groups and 100 mg/1mL ondansetron injectable suspension (IM Depot) of example 11 and 12 (test) of the present invention are administered intramuscularly G3, G4, G5 and G6 groups, with the dose, dose volume, drug concentration, sites of injection as listed in Table – 1.
Table – 1
Group Dose formulation Dose
(mg/
dog) Dose Volume
(mL/
dog) Drug
Conc.
(mg/
mL) Site of Injection Route of Administration
G1 Ondansetron Injection
(Marketed) 4 2 2 NA IV
G2 Ondansetron Injection (Marketed) 24 12 2 NA IV
G3 Example 11 Formulation 100 1 100 Two Sites
(0.5 mL Per Site) IM
G4 Example 12 Formulation 100 1 100 Two Sites
(0.5 mL Per Site) IM
G5 Example 11 Formulation 100 1 100 One Site
(biceps femoris muscle) IM
G6 Example 12 Formulation 100 1 100 One Site
(biceps femoris muscle) IM

[0074] Blood samples were collected from each IM route dogs at 0 (pre-dose), 0.5, 1, 2, 4, 8, 16, 24, 36, 48, 72, 96, 120, 144, 168 and 240 h post-dose; for IV route dogs, blood samples were collected at 0 (pre-dose), 0.167, 0.33, 0.5, 0.75, 1, 2, 4, 8, 12 and 24 h post-dose and analysed for ondansetron in plasma and calculated using the noncompartmental analysis tool of the validated Phoenix WinNonlin software (Version 8.0). The summary of plasma pharmacokinetics parameters of ondansetron for G1 and G2 animals is summarized in Table – 2 (Figure 1, 2) and G3, G4, G5 and G6 (Figure 3, 4, 5 and 6) animals is summarized in Table – 3.
Table - 2: Summary of plasma pharmacokinetic parameters of Ondansetron (reference) on intravenous bolus administration

Treatment Group Route/
Dose
(mg/dog) C0
(ng/mL)* AUClast
(ng.h/mL) AUCinf
(ng.h/mL) T1/2
(h) CL
(mL/
min) Vss (L) MRTlast
(h)
Ondansetron G1 IV/4 110
±
27.4 106
±
23.7 107
±
23.4 0.878
±
0.139 644
±
123 40.3
±
8.65 1.12
±
0.217
G2 IV/24 828
±
280 715
±
71.7 716
±
71.5 1.28
±
0.160 563
±
56.1 36.3
±
7.96 1.17
±
0.122

Table – 3: Summary of plasma pharmacokinetic parameters of Ondansetron (test) on intramuscular administration
Treatment Group Route/
Dose
(mg/dog) Cmax
(ng/mL) Tmax
(h) AUClast
(ng.h/mL) AUCinf
(ng.h/mL) T1/2
(h) MRTlast
(h)
Ondansetron G3 IM/100 52.8
±
19.2 4.00 2360
±
479 2610
±
819 64.6
±
36.4 63.2
±
13.4
G4 IM/100 68.4
±
36.1 4.00 2970
±
555 4750
±
1510 203
±
158 79.4
±
23.8
G5 IM/100 56.4
±
13.1 4.00 2410
±
409 2500
±
451 48.3
±
14.1 52.6
±
15.1
G6 IM/100 62.9
±
19.5 4.00 2780
±
527 3200
±
796 87.7
±
31.5 69.3
±
6.94
[0075] The equivalent exposure after intramuscular administration of ondansetron injectable suspension of Example 11 and Example 12 is calculated in Table – 4.

Table – 4: Equivalent exposure after intramuscular administration of Ondansetron injectable suspension of Example 11 and Example 12.

Route Amount
Of Dose
(mg) Groups No. of sites of inj Stat Equivalent exposure between the time durations in mg
0-4 h 4-8 h 8-24 h 24-48 h 48-72 h 72-96 h 96-120 h 120-144 h 144-168 h
IM 100 G3 2 sites Mean 5.3 6.7 16.0 15.1 13.2 9.7 6.7 4.5 3.5
IM 100 G4 2 sites Mean 6.2 8.4 17.9 15.6 13.3 10.6 8.0 6.9 6.4
IM 100 G5 1 site Mean 4.9 7.2 22.8 17.0 12.3 8.3 6.3 4.6 2.7
IM 100 G6 1 site Mean 5.3 6.7 16.0 15.1 13.2 9.7 6.7 4.5 3.5

[0076] From it is evident that the exposure of Ondansetron release from the injectable suspension of Example 11 and 12 is extended till day 7. The exposure is higher on day 1 and continues to reduce through subsequent days and tapered off by day 7. The split AUC for durations 0 h, 4 h, 8 h and 24 h shows equivalent exposure during these durations does not indicate any burst release of the formulation at any time. The exposure of ondansetron is equivalent to between 17.0 mg and 6.3 mg between day 2 and day 5.

[0077] Examples 14 – 22: Ondansetron Injectable Suspensions
[0078] The following Table – 2 discloses the compositions of ondansetron with its observations on stability on the suspension.
Table – 2
Example No Composition Observation on Stability of the Suspension
14 Ondansetron – 100 mg/mL
Sodium Carboxymethyl Cellulose – 9 mg/mL Assay of the Ondansetron in suspension after 3 M stability (40°C/75%RH) was observed to be 82.9%.
15 Ondansetron -200 mg/mL
Sodium Carboxymethyl Cellulose - 9 mg/mL After 3 M Stability at (40°C/75%RH), white solid particles were observed to form a non-homogenous suspension and assay of suspension was 96.7%.
16 Ondansetron – 100 mg/mL
Polyethylene glycol – 50 mg/mL
Polysorbate 80 – 5 mg/mL Assay on the initial samples was found to be 81.5%.
17 Ondansetron -100 mg/mL
Sodium Carboxymethyl cellulose - 5 mg/mL
Poloxamer 188 -10 mg/mL Assay on the initial samples was found to be 87.0%.
18 Ondansetron -100 mg/mL
Sodium Carboxymethyl cellulose -5 mg/mL
Poloxamer 188 - 2 mg/mL Assay on the initial samples was found to be 88.3%.
19 Ondansetron -100 mg/mL
Sodium Carboxymethyl cellulose - 5 mg/mL
Poloxamer 188 -5 mg/mL Physical stability of the suspension is not observed w.r.t to redispersion difficulty after 48 hours at 40°C/75%RH.
20 Ondansetron -100 mg/mL
Sodium Carboxymethyl cellulose -5 mg/mL
Phosphatidyl Choline (Lipoid E80) -2.5 mg/mL
Ethanol - qs After six months of stability (40°C/75%RH) white colored homogenous suspension material settled at the neck of the bottle.
21 Ondansetron -100 mg/mL
Sodium Carboxymethyl cellulose -5 mg/mL
Phosphatidyl Choline (Lipoid E80) - 5 mg/mL
Ethanol – qs After six months of stability (40°C/75%RH) white colored homogenous suspension material settled at the neck of the bottle.
22 Ondansetron -100 mg/mL
Sodium Carboxymethyl cellulose -5 mg/mL
Phosphatidyl Choline (Lipoid E80) - 5 mg/mL
Polysorbate 80 - 0.04 mg/mL
Sodium Chloride – 9 mg/mL During mixing of suspension foam was observed and after 3 months of stability (40°C/75%RH) white colored homogenous suspension material settled at the neck of the bottle.
[0079] Example 23: Ondansetron Injectable Suspension 100 mg/mL
[0080] Composition:
S.No Ingredient mg/mL
1. Ondansetron base 100
2. Carboxymethyl cellulose sodium salt 1.5
3. Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4. Ethanol Dehydrated q. s
5. Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.

Stability of the Suspension (Example 23):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white non-homogeneous suspension 7.40 80 2.83 0.03 0.07
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white non-homogeneous suspension 6.5 75 3.01 0.05 0.1
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white non-homogeneous suspension 6.5 75 3.05 0.05 0.1

[0081] Example 24: Ondansetron Injectable Suspension 100 mg/mL
[0082] Compositon
S.No Ingredient mg/mL
1. Ondansetron base 100
2. Carboxymethyl cellulose sodium salt 1.5
3. Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4. Ethanol Dehydrated q.s
5. Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
 
Stability of the Suspension (Example 24):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white non-homogeneous suspension 7.36 85.0 28.9 0.03 0.08
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white non-homogeneous suspension 7.38 82.0 29.8 0.02 0.09
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white non-homogeneous suspension 7.50 83.2 26.9 0.04 0.11

[0083] Example 25: Ondansetron Injectable Suspension 100 mg/mL
[0084] Composition
S.No Ingredient mg/mL
1. Ondansetron base 100
2. Carboxymethyl cellulose sodium salt 2.5
3. Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4. Ethanol Dehydrated q.s
5. Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
Stability of the Suspension (Example 25):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial
White to off-white homogeneous suspension 7.40 101.6 2.56 0.02 0.06
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.53 100.3 2.65 0.03 0.09
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.59 101.2 2.73 0.02 0.07

[0085] Example 26: Ondansetron Injectable Suspension 100 mg/mL
[0086] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 100
2 Carboxymethyl cellulose sodium salt 2.5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
Stability of the Suspension (Example 26):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial
White to off-white homogeneous suspension 7.38 100.6 28.9 0.02 0.07
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.39 100.0 26.7 0.04 0.09
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.38 100.2 28.8 0.02 0.08

[0087] Example 27: Ondansetron Injectable Suspension 100 mg/mL
[0088] Compositon:
S.No Ingredient mg/mL
1 Ondansetron base 100
2 Carboxymethyl cellulose sodium salt 5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
Stability of the Suspension (Example 27):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.43 100.0 3.03 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.46 100.8 2.98 0.02 0.07
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.37 99.99 2.57 0.03 0.08

[0089] Example 28: Ondansetron Injectable Suspension 100 mg/mL
[0090] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 100
2 Carboxymethyl cellulose sodium salt 5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
Stability of the Suspension (Example 28):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.33 100.1 29.3 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.35 100.0 28.6 0.03 0.07
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.37 100.2 27.96 0.04 0.07

[0091] Example 29: Ondansetron Injectable Suspension 100 mg/mL
[0092] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 100
2 Carboxymethyl cellulose sodium salt 15
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 15
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
Stability of the Suspension (Example 29):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.42 100.7 2.78 0.02 0.07
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.45 100.3 2.79 0.02 0.07
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.45 100.6 2.75 0.02 0.08

[0093] Example 30: Ondansetron Injectable Suspension 100 mg/mL
[0094] Composition
S.No Ingredient mg/mL
1 Ondansetron base 100
2 Carboxymethyl cellulose sodium salt 15
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 15
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
Stability of the Suspension (Example 30):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.38 99.99 28.6 0.03 0.05
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.38 100.0 28.7 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.40 100.0 29.3 0.03 0.08

[0095] Example 31: Ondansetron Injectable Suspension 100 mg/mL
[0096] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 100
2 Carboxymethyl cellulose sodium salt 30
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 30
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
Stability of the Suspension (Example 31):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.39 100.0 3.29 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.45 100.0 3.26 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.45 100.3 3.00 0.03 0.06

[0097] Example 32: Ondansetron Injectable Suspension 100 mg/mL
[0098] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 100
2 Carboxymethyl cellulose sodium salt 30
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 30
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
Stability of the Suspension (Example 32):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.40 100.7 28.9 0.02 0.07
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.41 100.2 27.6 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.40 100.06 28.2 0.02 0.07

[0099] Example 33: Ondansetron Injectable Suspension 100 mg/mL
[0100] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 100
2 Carboxymethyl cellulose sodium salt 35
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 35
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
Stability of the Suspension (Example 33):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off white, highly viscous solution. white particles were sticking on the wall of the glass vial 7.40 98.7 3.07 0.02 0.06
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off white, highly viscous solution. white particles were sticking on the wall of the glass vial 7.41 94.6 2.98 0.03 0.07
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off white, highly viscous solution. white particles were sticking on the wall of the glass vial
7.47 88.9 3.37 0.02 0.08

[0101] Example 34: Ondansetron Injectable Suspension 100 mg/mL
[0102] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 100
2 Carboxymethyl cellulose sodium salt 35
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 35
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
Stability of the Suspension (Example 34):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off white, highly viscous solution. white particles was sticking on the wall of the glass vial 7.46 99.6 29.6 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off white, highly viscous solution. white particles was sticking on the wall of the glass vial 7.50 91.3 28.7 0.03 0.06
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off white, highly viscous solution. white particles were sticking on the wall of the glass vial
7.48 89.6 26.9 0.03 0.07

[0103] Example 35: Ondansetron Injectable Suspension 150 mg/mL
[0104] Composition
S.No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 1.5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4.
Stability of the Suspension (Example 35):

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white non-homogeneous suspension 7.39 88.0 2.36 0.03 0.06
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white non-homogeneous suspension 7.45 86.0 2.96 0.02 0.07
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white non-homogeneous suspension 7.48 83.2 3.02 0.02 0.06

[0105] Example 36: Ondansetron Injectable Suspension 150 mg/mL
[0106] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 1.5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 36)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white non-homogeneous suspension 7.39 95.6 26.8 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white non-homogeneous suspension 7.87 87.0 28.6 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white non-homogeneous suspension 7.69 80.0 27.6 0.03 0.07

[0107] Example 37: Ondansetron Injectable Suspension 150 mg/mL
[0108] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 2.5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 37)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.39 100.02 3.02 0.03 0.06
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.40 100.2 3.05 0.02 0.09
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.48 99.99 2.98 0.04 0.09

[0109] Example 38: Ondansetron Injectable Suspension 150 mg/mL
[0110] Composition:
S. No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 2.5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 38)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.40 101.2 28.5 0.04 0.08
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.35 100.3 27.9 0.03 0.06
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.36 101.1 28.8 0.03 0.06

[0111] Example 39: Ondansetron Injectable Suspension 150 mg/mL
[0112] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 39)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.36 101.3 3.0 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.36 100.0 2.96 0.03 0.06
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.38 100.2 2.99 0.02 0.06

 
[0113] Example 40: Ondansetron Injectable Suspension 150 mg/mL
[0114] Composition:
Composition:
S. No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 5
4 Ethanol Dehydrated q.s to solubilize Lipoid E 80
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 40)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.40 100.9 27.9 0.02 0.06
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.45 100.0 28.9 0.02 0.07
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.38 100.4 29.3 0.02 0.07

[0115] Example 41: Ondansetron Injectable Suspension 150 mg/mL
[0116] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 15
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 15
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 41)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.43 100.0 2.67 0.03 0.07
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.48 100.2 2.69 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.48 100.2 2.89 0.03 0.08

[0117] Example 42: Ondansetron Injectable Suspension 150 mg/mL
[0118] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 15
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 15
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 42)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.43 100.4 29.3 0.04 0.09
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.50 99.99 28.6 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.52 100.2 28.9 0.03 0.08

[0119] Example 43: Ondansetron Injectable Suspension 150 mg/mL
[0120] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 30
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 30
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 43)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.43 101.1 3.98 0.03 0.07
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.36 100.5 3.67 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.40 100.6 3.93 0.02 009

[0121] Example 44: Ondansetron Injection Suspension 150 mg/mL
[0122] Composition:
S.No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 30
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 30
4 Ethanol Dehydrated q. s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 44)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.35 101.6 29.3 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.35 100.2 28.6 0.02 0.07
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.39 100.6 27.9 0.03 0.07

[0123] Example 45: Ondansetron Injectable Suspension 150 mg/mL
[0124] Composition
S.No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 35
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 35
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 45)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off white, highly viscous solution. white particles were sticking on the wall of the glass vial 7.35 99.9 3.00 0.03 0.07
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off white, highly viscous solution. white particles were sticking on the wall of the glass vial 7.38 90.2 2.98 0.03 0.08
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off white, highly viscous solution. white particles were sticking on the wall of the glass vial 7.39 88.8 3.02 0.02 0.07

[0125] Example 46: Ondansetron Injectable Suspension 150 mg/mL
[0126] Composition
S. No Ingredient mg/mL
1 Ondansetron base 150
2 Carboxymethyl cellulose sodium salt 35
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 35
4 Ethanol Dehydrated q.s to solubilize Lipoid E 80
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 46)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off white, highly viscous solution. white particles were sticking on the wall of the glass vial 7.45 99.93 28.7 0.02 0.06
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off white, highly viscous solution. white particles were sticking on the wall of the glass vial 7.43 95.6 27.6 0.02 0.06
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off white, highly viscous solution. white particles were sticking on the wall of the glass vial 7.46 93.2 29.3 0.03 0.08

[0127] Example 47: Ondansetron Injectable Suspension 200 mg/mL
[0128] Composition:
S. No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 1.5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 47)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white non-homogeneous suspension 7.39 89 2.36 0.02 0.05
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white non-homogeneous suspension 7.40 87 2.59 0.02 0.06
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white non-homogeneous suspension 7.41 80.0 2.93 0.03 0.09

[0129] Example 48: Ondansetron Injectable Suspension 200 mg/mL
[0130] Composition
S.No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 1.5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 48)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white non-homogeneous suspension 7.39 95.2 26.7 0.02 0.05
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white non-homogeneous suspension 7.69 92.3 28.6 0.02 0.07
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white non-homogeneous suspension 7.56 90.3 29.2 0.03 0.11

[0131] Example 49: Ondansetron Injectable Suspension 200 mg/mL
[0132] Composition
S.No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 2.5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 49)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.39 100.2 2.98 0.02 0.04
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.40 100.6 3.02 0.02 0.06
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.53 100.5 3.62 0.02 0.08

[0133] Example 50: Ondansetron Injectable Suspension 200 mg/mL
[0134] Composition
S.No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 2.5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 2.5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 50)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.52 100.8 27.9 0.03 0.06
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.43 100.2 25.9 0.02 0.05
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.45 100.3 28.8 0.03 0.06

[0135] Example 51: Ondansetron Injectable Suspension 200 mg/mL
[0136] Composition
S.No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 51)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.43 100.6 3.26 0.02 0.04
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.43 100.3 3.62 0.02 0.07
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.48 100.6 3.54 0.04 0.07

 

[0137] Example 52: Ondansetron Injectable Suspension 200 mg/mL
[0138] Composition
S. No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 5
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 5
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 52)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.33 100.1 28.5 0.02 0.05
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.35 100.0 29.1 0.02 0.05
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.34 100.6 29.0 0.03 0.08

[0139] Example 53: Ondansetron Injectable Suspension 200 mg/mL
[0140] Composition
S. No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 15
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 15
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 53)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.37 100.2 3.6 0.02 0.04
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.37 100.3 3.5 0.02 0.05
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.40 100.4 3.6 0.02 0.06

[0141] Example 54: Ondansetron Injectable Suspension 200 mg/mL
[0142] Composition
S. No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 15
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 15
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 54)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.33 100.1 28.5 0.02 0.05
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.35 100.1 29.6 0.02 0.07
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.35 100.2 28.3 0.03 0.08

[0143] Example 55: Ondansetron Injectable Suspension 200 mg/mL
[0144] Composition
Composition:
S.No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 30
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 30
4 Ethanol Dehydrated q.s to solubilize Lipoid E 80
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 55)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.34 100.0 3.27 0.03 0.07
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.35 100.6 2.98 0.02 0.05
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.37 100.0 3.02 0.03 0.08

[0145] Example 56: Ondansetron Injectable Suspension 200 mg/mL
[0146] Composition
S.No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 30
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 30
4 Ethanol Dehydrated q.s to solubilize Lipoid E 80
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 56)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off-white homogeneous suspension 7.48 99.96 28.9 0.03 0.06
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off-white homogeneous suspension 7.48 100.0 27.8 0.02 0.08
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off-white homogeneous suspension 7.49 100.1 28.3 0.03 0.07

[0147] Example 57: Ondansetron Injectable Suspension 200 mg/mL
[0148] Composition
S.No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 35
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 35
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 57)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off white, highly viscous solution. white particles was sticking on the wall of the glass vial 7.36 90.0 3.10 0.03 0.07
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off white, highly viscous solution. white particles was sticking on the wall of the glass vial 7.56 85.0 3.16 0.03 0.08
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off white, highly viscous solution. white particles was sticking on the wall of the glass vial 7.63 87.0 3.50 0.04 0.09
[0149] Example 58: Ondansetron Injectable Suspension 200 mg/mL
[0150] Composition
S. No Ingredient mg/mL
1 Ondansetron base 200
2 Carboxymethyl cellulose sodium salt 35
3 Lipoid E 80 (Egg phospholipid with 80% Phosphatidylcholine) 35
4 Ethanol Dehydrated q.s
5 Water for Injection q.s to 1mL
The process for preparation is same as disclosed in the examples 4
Stability of the Suspension (Example 58)

Time points Description pH Assay (%) Particle size distribution (µm) Related substances (%)
D90 Single max unknown impurity Total impurities
Initial White to off white, highly viscous solution. white particles was sticking on the wall of the glass vial 7.42 92.0 36.5 0.02 0.06
40+2°C/75 ±5 %RH Inverted,
(1 Month) White to off white, highly viscous solution. white particles was sticking on the wall of the glass vial 7.56 89.0 40.2 0.03 0.12
40+2°C/75 ±5 %RH Inverted,
(3 Month) White to off white, highly viscous solution. white particles was sticking on the wall of the glass vial 7.60 89.0 45.6 0.04 0.013

[0151] Example 59: Pharmacokinetic Study of intramuscular administration of ondansetron injectable suspension 200 mg/mL of Examples 49, 50, 55 and 56 in Male New Zealand Rabbits.
[0152] Male New Zealand Rabbits were divided into four groups as G1, G2, G3 and G4, each consisting of four rabbits and each group was administered intramuscularly with the suspensions of Examples 49, 50, 55 and 56 respectively in fasted state as in the following Table – 3.
Table - 3
Group Composition Dose
(mg/rabbits) Dose Volume
(mL/rabbits)
G1 Example - 49 200 1
G2 Example - 50 200 1
G3 Example - 55 200 1
G4 Example - 56 200 1
1 mL of dose formulation was administered at single IM injection at biceps femoris muscle. All animals were fasted overnight and feed was provided 4 h post dose, Water was provided ad libitum during study.

[0153] Blood samples were collected from each IM route rabbit at 0 (pre-dose), 0.5, 1, 2, 4, 8, 16, 24, 36, 48, 72, 96, 120, 144, 168 and 240 h. At each time 0.250 mL of blood was withdrawn from jugular vein and transferred to labeled tubes coated with K2EDTA as an anticoagulant (200 mM 20 μL/mL of blood). Blood samples were kept on wet ice until plasma collection. Samples were stored below -60 ºC until bioanalysis.
[0154] The plasma samples were analyzed for Ondansetron using a fit-for purpose LC-MS/MS method with a Lower limit of quantification (LLOQ) of 0.100 ng/mL and ULOQ of 200 ng/mL.
[0155] The summary of the plasma pharmacokinetic parameters of the suspension formulation of example 49, 50, 55 and 56 in Male New Zealand Rabbits are in following Table – 4 and in Figure 7.
Table – 4:
Summary of plasma pharmacokinetic parameters of Ondansetron 200 mg/mL on intramuscular administration of Examples 49, 50, 55 and 56
Group Route/
Dose
(mg/rabbit) Cmax
(ng/mL) Tmax
(h) AUClast
(ng.h/mL) MRTlast
(h)
G1 IM/200 110.8
±
19.2 4.00 4760
±
479 81.2
±
13.4
G2 IM/200 80.4
±
36.1 8.00 3470
±
555 68.4
±
23.8
G3 IM/200 123.4
±
13.1 4.00 4310
±
409 88.6
±
15.1
G4 IM/200 92.9
±
19.5 8.00 3780
±
527 72.3
±
6.94
Values are express in Mean ± SD

[0156] Example 60: Pharmacokinetic Study of intramuscular administration of ondansetron injectable suspension 100 mg/mL of Examples 25, 26, 31 and 32 in Male New Zealand Rabbits.
[0157] Male New Zealand Rabbits were divided into four groups as G1, G2, G3 and G4, each consisting of four rabbits and each group was administered intramuscularly with the suspensions of Examples 25, 26, 31 and 32 respectively in fasted state as in the following Table – 5.
Table – 5
Group Composition Dose
(mg/rabbits) Dose Volume
(mL/rabbits)
G1 Example - 25 100 1
G2 Example - 26 100 1
G3 Example - 31 100 1
G4 Example - 32 100 1
1 mL of dose formulation was administered at single IM injection at biceps femoris muscle. All animals were fasted overnight and feed was provided 4 h post dose, Water was provided ad libitum during study.

[0158] Blood samples were collected from each IM route rabbit at 0 (pre-dose), 0.5, 1, 2, 4, 8, 16, 24, 36, 48, 72, 96, 120, 144, 168 and 240 h. At each time 0.250 mL of blood was withdrawn from jugular vein and transferred to labeled tubes coated with K2EDTA as an anticoagulant (200 mM 20 μL/mL of blood). Blood samples were kept on wet ice until plasma collection. Samples were stored below -60 ºC until bioanalysis.
[0159] The plasma samples were analyzed for Ondansetron using a fit-for purpose LC-MS/MS method with a Lower limit of quantification (LLOQ) of 0.100 ng/mL and ULOQ of 200 ng/mL.
[0160] The summary of the plasma pharmacokinetic parameters of the suspension formulation of example 25, 26, 31 and 32 in Male New Zealand Rabbits are in following Table – 6 and in Figure 8.
 
Table – 6
Summary of plasma pharmacokinetic parameters of Ondansetron 100 mg/mL on intramuscular administration of Examples 25, 26, 31 and 32.
Group Route/
Dose
(mg/ rabbits) Cmax
(ng/mL) Tmax
(h) AUClast
(ng.h/mL) MRTlast
(h)
G1 IM/100 70.8
±
19.2 4.00 2960
±
479 79.2
±
13.4
G2 IM/100 58.4
±
36.1 8.00 2570
±
555 63.4
±
23.8
G3 IM/100 65.4
±
13.1 4.00 3210
±
409 80.6
±
15.1
G4 IM/100 52.9
±
19.5 8.00 2680
±
527 69.3
±
6.94

, Claims:1. A controlled release injectable ondansetron formulation comprising
(a) 75 mg/mL to 250 mg/mL ondansetron having a particle size (D90) of about 1 to 30 microns,
(b) 2.5 mg/mL to 35 mg/mL carboxymethyl cellulose or its sodium salt and
(c) 2.5 mg/mL to 35 mg/mL phosphatidyl choline.

2. The controlled release injectable ondansetron formulation as claimed in claim 1 is a suspension.

3. The controlled release injectable ondansetron formulation as claimed in claim 1 containing 100 mg/mL to 200 mg/mL ondansetron.

4. The controlled release injectable ondansetron formulation as claimed in claim 1 containing 5 mg/mL to 30 mg/mL carboxymethyl cellulose or its sodium salt.

5. The controlled release injectable ondansetron formulation as claimed in claim 1 containing 10 mg/mL to 30 mg/mL phosphatidyl choline.

6. The controlled release injectable formulation as claimed in claim 1 further contains a mixture of solvents selected from group consisting of ethanol and water.

7. The controlled release injectable formulation as claimed in claim 1 comprising
(a) 100 mg/mL to 250 mg/mL ondansetron,
(b) 2.5 mg/mL to 30 mg/mL carboxymethyl cellulose or its sodium salt,
(c) 2.5 mg/mL to 30 mg/mL phosphatidyl choline,
(d) ethanol and
(e) water.

8. The controlled release injectable formulation as claimed in claim 1 consisting of
(a) 100 mg/mL to 200 mg/mL ondansetron,
(b) 2.5 mg/mL to 30 mg/mL carboxymethyl cellulose or its sodium salt,
(c) 2.5 mg/mL to 30 mg/mL phosphatidyl choline,
(d) ethanol and
(e) water.

9. The controlled release injectable formulation as claimed in claim 1 consisting of
(a) 105 mg/mL to 200 mg/mL ondansetron,
(b) 2.5 mg/mL to 30 mg/mL carboxymethyl cellulose or its sodium salt,
(c) 2.5 mg/mL to 30 mg/mL phosphatidyl choline,
(d) ethanol and
(e) water.