FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
LIQUID PHARMACEUTICAL COMPOSITIONS OF NEBIVOLOL
2. APPLICANT(S)
NAME : CADILA PHARMACEUTICALS LIMITED
NATIONALITY: An INDIAN Company

ADDRESS : "Cadila Corporate.Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad - 382210, Gujarat, India . PREAMBLE TO THE DESCRIPTION

COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed

4. DESCRIPTION
(Description starts from next page)

FIELD OF THE INVENTION
The present invention relates to a stable liquid pharmaceutical compositions of nebivolol or its pharmaceutical acceptable salts or derivatives and process for the preparing the same.
BACKGROUND OF THE INVENTION
Nebivolol (2,2'-azanediylbis(1-(6-fluorochroman-2-yl)ethanol) is a β1-adrenoceptor blocking drug, distinguished from other members of its drug class by having additional nitric oxide (NO)-mediated vasodilatory effects. It is used for the treatment and prevention of coronary vascular disorders. Methods for preparation of nebivolol are disclosed in EP 0145067 and EP 0334429 (EP '429 patent). EP '429 patent describes [iminobismethylene] bis β, 4-dihydro-2H-1-benzopyran-2-methanol] derivatives including nebivolol.

Nebivolol is available in market for oral administration in tablet dosage form as BYSTOLIC® tablets and contains nebivolol hydrochloride equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of nebivolol base, but out of all the routes of drug administration, parenteral route gives rapid effect because the drug is directly delivered to systemic circulation. Under acute conditions, it is desired to deliver antihypertensive drug by parenteral route like during sudden hypertension condition or in condition of hypertension in subconscious patient.
Nebivolol and its hydrochloride salt have very low solubility in aqueous medium and nebivolol or Nebivolol hydrochloride crystallizes out or exhibits partial decomposition on prolonged storage. The challenge has been to provide stable liquid dosage form of nebivolol in aqueous medium.
EP patent 0145067 describes that 2, 2'-iminobisethanol derivatives useful for the treatment and/or prevention of disorders of the coronary vascular system and discloses the preparation of oral liquid pharmaceuticals using water, glycols, oils and alcohols. The said patent does not disclose any method to improve the solubility of 2, 2'-iminobisethanol derivatives to prepare clear and stable liquid pharmaceutical composition.
US application 20090030071A1 relates to use of nebivolol for treatment of cardiovascular disease in Mexican Americans and discloses use of water, ethanol, polyols and mixture of thereof for the preparation of parenteral formulation. The said application is silent about solubility improvement of nebivolol or its pharmaceutical acceptable salt to prepare stable pharmaceutical composition.

The effects of d!-nebivolol and its enantiomers on ischemic myocardium in dogs are discussed in research paper of Journal of Cardiovascular Pharmacology, 41(5):766-770, May 2003, Satoh, Kumi et al. The article discloses Dimethyl Sulphoxide (DMSO) is used as vehicle in preparation of Nebivolol injection. The use of DMSO is discouraged in parenteral preparation due to its systemic toxicity.
Hence, there is a need to develop a stable liquid pharmaceutical composition of nebivolol or its' salts or derivatives, in order to resolve the issues of crystallization or precipitation of nebivolol on prolonged storage and deliver nebivolol in soluble form in liquid pharmaceutical composition.
OBJECT OF THE INVENTION
The main object of the invention is to provide a stable liquid pharmaceutical composition comprising nebivolol or its pharmaceutically acceptable salts or derivatives.
Another object of the invention is to provide stable, mono phasic liquid pharmaceutical composition of nebivolol or its pharmaceutical acceptable salts or derivatives.
Another object of the invention is to provide stable, multi phasic liquid pharmaceutical composition of nebivolol or its pharmaceutically acceptable salts or derivatives.
Another object of the invention is to provide a process for preparation of stable liquid compositions of nebivolol or its pharmaceutically acceptable salts or derivatives.
SUMMARY OF THE INVENTION
The present invention relates to a stable liquid pharmaceutical composition comprising nebivolol or its pharmaceutical acceptable salts or derivatives, solubilizer, solvent, co-solvent, surfactant and optionally other pharmaceutically acceptable excipients and process for preparing same.
DETAILED DESCRIPTION OF THE INVENTION
The term "stable" as used herein is related to physical and / or chemical stability. In chemical stability none of the impurity should increase by more than 0.5 % after storage at about 40°C-75% RH for period of at least 3 months. In physical stability, the drug should not be crystallized in the pharmaceutical composition during shelf life or stability conditions or at 2 -8°C for at least three months.
The liquid pharmaceutical composition according to present invention can be administered by. oral and parenteral route. The preferred route of administration of liquid pharmaceutical composition of Nebivolol is by parenteral route.

The term "parenteral" is given its ordinary and customary meaning in the field of pharmaceutical drug routes of administration. According to the Food and Drug Administration's Center for Drug Evaluation and Research Data Standards Manual (CDER Data Element Number C-DRG-00301; Data Element Name: Route of Administration) "parenteral" refers to administration by injection, infusion or implantation. Injection and infusion include administration into a vein (intravenous), into an artery [intraarterial), into a muscle (intramuscular), under the skin (subcutaneous), and into the peritoneum (intraperitoneal). Intrapulmonary (administration within the lungs or its bronchi) and nasal (administration into the nose or by way of the nose) is also contemplated.
The term "monophasic system" as used herein is related to one continuous aqueous or non-aqueous in the dosage form.
The term "multiphasic system" as used herein is related presence of more than one phase in the dosage form like non-aqueous and aqueous phase.
The term "drug" or "active ingredient" or "nebivolol" means Nebivolol and its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, prodrugs. In stable liquid pharmaceutical composition of Nebivolol suitable of intravenous bolus injection in a single unit dosage form higher percentage of aqueous system is preferred, however non aqueous parenteral formulation of Nebivolol can also be made
Accordingly, the invention is to provide a stable parenteral liquid pharmaceutical composition comprising nebivolol or its pharmaceutical acceptable salts or derivatives, solubilizer, solvent, co-solvent, surfactant and optionally other pharmaceutically acceptable excipients, wherein the weight ratio of solubilizer to nebivolol or its pharmaceutically acceptable salt or derivatives is between 5:1 to 20:1.
The amount of nebivolol or its pharmaceutically acceptable salts or derivatives in a stable parenteral liquid pharmaceutical composition is preferably 0.01 -10 mg/ml (0.001-1.0 %), more preferably 0.05-2.5 mg/ml (0.005 -0.25 %), most preferably 0.10-1.0 mg/ml (0.01-0.1%), wherein nebivolol or its pharmaceutically acceptable salts or derivatives is in soluble form.
Solubilizer used in the invention is selected from the group of hydroxypropyl betacyclodextrin, povidone. The preferable solubilizer is hydroxypropyl betacyclodextrin in concentration of 0.1% to 20%, preferably 0.2 to 5%. Nebivolol Hydrochloride has very low solubility in aqueous medium and nebivolol crystallizes out or exhibits partial decomposition on prolonged storage. The different solubilizing agent used in the present invention is to improve the solubility of nebivolol hydrochloride in aqueous media. The solubilizing agent

provides nebivolol hydrochloride in soluble form in liquid pharmaceutical composition and also inhibits the recrystalization or precipitation of nebivolol hydrochloride in liquid pharmaceutical composition on prolonged storage.
Solvent used in the invention is selected from the group of water, alcohol, oils or combination thereof. Co-solvents used in the present invention is selected from the group of monohydric alcohols as well as polyhydric alcohol such as polyethylene glycols, benzyl alcohol, propylene glycols, glycofurol, alcohol, glycerin, polyoxyethylene glycolated castor oils. The preferable co-solvent is propylene glycol ranging from 10-20%. Another preferred co-solvent is glycerin preferably in 2-15% of the total composition, more preferably 5%.
Surfactant used in the invention is selected from the group of sorbitan esters like polysorbate 80, alpha-tocopherol polyethylene glycol succinate, polyethoxylated castor oil . (Cremophor EL®).
The pharmaceutically acceptable excipients are optionally be selected from tonicity-modifiers, antimicrobial preservatives, antioxidants, chelating agent, surfactants, pH modifier and buffers. The pH modifier is selected from the group of organic or inorganic acid such as citric acid, phosphoric acid, hydrochloric acid, sulphuric acid.
The preferred stable liquid pharmaceutical composition of nebivolol comprises of solubilizer in the range of 0.1% - 20%, cosolvent in the range of 2% - 40%, and solvent in the range of 5% - 90% of the weight of the composition.
The more preferred stable liquid pharmaceutical composition of nebivolol comprises of hydroxypropyl betacyclodextrin in an amount of 0.3%, propylene glycol in an amount of 15%, glycerin an amount of 5% and water to make up the required amount of dosage form.
The stable liquid pharmaceutical composition according to invention can be administered by oral, parenteral route. The preferred route of administration of stable liquid pharmaceutical composition of Nebivolol is by parenteral route.
In a stable parenteral liquid pharmaceutical composition of nebivolol or its pharmaceutical^ acceptable salts or derivatives suitable of intravenous bolus injection in a single unit dosage form, higher percentage of aqueous system is preferred; however non aqueous parenteral formulation of nebivolol can also be made.
The aqueous phase generally has an osmolality is of approximately 300 mOsm/kg and may include potassium or sodium chloride, trehalose, sucrose, sorbitol, glycerol, mannitol, polyethylene glycol, propylene glycol, albumin, amino acid and mixtures thereof.

The present invention also provides, process for preparing a stable parenteral liquid
pharmaceutical composition comprising nebivolol or its pharmaceutical acceptable salts or
derivatives, solubilizer, solvent, co-solvent, surfactant comprising the steps of:
i). dissolving Nebivolol in suitable solvent or in mixture of solvent and co-solvent;
ii). adding solubilizer in mixture of step (i); and
iii) adding solvent to the mixture of step-(ii) to make up the required volume.
Accordingly, the present invention provides a stable liquid pharmaceutical composition of nebivolol or its pharmaceutically acceptable salts or derivative, where, nebivolol is in soluble form and process for preparing suitable dosage form for oral and parenteral route .
It will be understood by those of skill in the art that numerous modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the following examples are illustrative only and should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1:-
A parenteral pharmaceutical composition of Nebivolol Hydrochloride was prepared as follows:
110 mg of Nebivolol Hydrochloride was dissolved in 90 ml Water for Injection containing 10 ml of Polysorbate - 80. The pH was adjusted to 5.0 by adding 0.1 N HCI. Total volume of the solution was adjusted up to 100 ml using Water for Injection. Precipitates of Nebivolol Hydrochloride were observed after 72 hrs at 2°C - 8°C storage.
Example 2:-
A parenteral pharmaceutical composition of Nebivolol Hydrochloride (0.5 mg/ml) was prepared as follows:
Table 1: Composition of Example 2

S. No. Ingredients Qty / 500ml
1 Nebivolol Hydrochloride 275 mg
2 Propylene Glycol 50 ml
3 Water for Injection q.s. to 500 ml
4. 0.1 N Hydrochloric acid for pH adjustment q.s.

275 mg of Nebivolol Hydrochloride was dissolved in 50 ml propylene glycol. Water for Injection (450 ml) was added to this solution of propylene glycol. The pH of the solution was adjusted to 4.5 using 0.1 N HCI. Final volume of the solution was made up 500 ml by Water for Injection. The precipitates of Nebivolol Hydrochloride were observed after 7 days at 2 -8°C storage.
Example 3:-
A parenteral pharmaceutical composition of Nebivolol Hydrochloride (2.5 mg/ml) was prepared as follows:
Table 2: Composition of Example 3

s.
No. Ingredients Qty/2000ml
1. Nebivolol Hydrochloride 5.5 gm
2. Propylene glycol 800 ml
3. Ethanol 200 ml
4. Water for injection q.s. to 2000 ml
5. 0.1 N Hydrochloric acid for pH adjustment q.s.
800 ml of propylene glycol was mixed in 200 ml of ethanol. 5.5 gm of Nebivolol Hydrochloride was dissolved in the above propylene glycol-ethanof solution. After getting clear solution, Water for injection (950 ml) was added. The pH of the solution was adjusted to 4.5 using 0.1 N HCI. Final volume of the solution was made up 2000 ml by Water for Injection. The precipitates of Nebivolol Hydrochloride were observed during stability studies and also crystals of Nebivolol Hydrochloride were observed after 72 hrs at 2 - 8°C storage.
Example 4:-
A parenteral pharmaceutical composition of Nebivolol Hydrochloride (1 mg/ml) was prepared as follows:
Table 3: Composition of Example 4

S. No. Ingredients Qty / 500ml
1. Nebivolol Hydrochloride 550 mg
2. Propylene glycol 75 ml
3. Glycerin 25 ml
4. Acetate Buffer solution pH 4.5 q.s. to 500 ml

25 ml of Glycerin was mixed in 75 ml of Propylene glycol. 550 mg of Nebivoiol hydrochloride was dissolved in the above solution. After getting clear solution volume makeup of the above mixture was done by acetate buffer solution pH 4.5 upto 500 ml.This formulation is found to be unstable as crystals of Nebivoiol Hydrochloride were observed on storage at 2 -8°C after 72 hrs.
Example 5;
A parenteral pharmaceutical composition of Nebivoiol Hydrochloride (0.5 mg/ml) was prepared as follows:
Table 4: Composition of Example 5

S. No. Ingredients Qty/100ml
1 Nebivoiol Hydrochloride 55.00 mg
2. Propylene Glycol 15.00 ml
3. Glycerin 5.00 ml
4. Hydroxypropyl Betacyclodextrin 320.00 mg
5. Water for injection q.s. to 100ml
5 ml of Glycerin was mixed in 15 ml of Propylene glycol. 55 mg of Nebivoiol hydrochloride was dissolved in the above solution. 320.00 mg of hydroxypropyl betacyclodextrin is dissolved in 60 ml of water for injection. After getting clear solution volume makeup of the above mixture was done by water for injection upto 100 ml. The formulation was stable for 3 months on refrigerated (2-8°C) condition and no crystallization occurs.
Example 6
A parenteral pharmaceutical composition of Nebivoiol Hydrochloride (0.5 mg/ml) was prepared as follows:
Table 5: Composition of Example 6

S. No. Ingredients Qty/100ml
1 Nebivoiol Hydrochloride 55.00 mg
2. Propylene Glycol 40.00 ml
3. Glycerin 5.00 ml
4. Hydroxypropyl Betacyclodextrin 320.00 mg
5. Water for injection q.s to 100 ml
5 mi of Glycerin was mixed in 40 ml of Propylene glycol. 55 mg of Nebivoiol hydrochloride was dissolved in the above solution. 320 mg of hydroxypropyl betacyclodextrin is dissolved

in 40 ml of water for injection. After getting clear solution volume makeup of the above mixture was done by water for injection upto 100 ml. The formulation was found to be stable.
Example 7
A parenteral pharmaceutical composition of Nebivolol Hydrochloride (2.5 mg/ml) was prepared as follows:
Table 6: Composition of Example 7

S. No. Ingredients Qty/100ml
1 Nebivolol Hydrochloride 275 mg
2. Propylene Glycol 15.00 ml
3. Glycerin 5.00 ml
4. Hydroxypropyl Betacyclodextrin 5.00 gm
5. Water for injection q.s to 100ml
5 ml of Glycerin was mixed in 15 ml of Propylene glycol. 275 mg of Nebivolol hydrochloride was dissolved in the above solution. 5.00 g of hydroxypropyl betacyclodextrin is dissolved in 60 ml of water for injection. After getting clear solution volume makeup of the above mixture was done by water for injection upto 100 ml. The formulation was found to be stable.
Example 8
A parenteral nanoemulsion pharmaceutical composition of Nebivolol Hydrochloride (0.5 mg/gm) was prepared as follows:
Table 7: Composition of Example 8

S.
No. Ingredients Qty / 50 gm
1 Nebivolol Hydrochloride 27.50 mg
2. Cremophor EL 2,50 gm
3. Soyabean Oil 15.00 gm
4. Water for injection 32.50 mi
27.5 mg of Nebivolol hydrochloride was dissolved in 2.5 gm of Cremophor El with gentle heating on water bath. After getting homogenous solution, 32.5 gm of water for injection was added to get clear solution. This solution was added to 15 gm of soyabean oil and subjected to probe sonication for 10 minutes with 5 second pulse and 2 second stops to get milky homogenous solution.

A stable liquid pharmaceutical composition of Nebivolol comprises of solubilizer in the range of 0.1% - 20%, cosolvent in the range of 2% - 40%, and solvent in the range of 5% - 90% of the weight of the composition.
A stable liquid pharmaceutical composition of Nebivolol comprises of hydroxypropyl betacyclodextrin in an amount of 0.3%, propylene glycol in an amount of 15%, glycerin an amount of 5% and water to make up the required amount of dosage form.

We CLAIM
1. A stable liquid pharmaceutical composition comprising nebivolol or its pharmaceutical acceptable salts or derivatives, solubilizer, solvent, co-solvent, surfactant and optionally other pharmaceutically acceptable excipients.
2. The pharmaceutical composition claimed in claim 1, wherein weight ratio of solubilizer to nebivolol or its pharmaceutically acceptable salt or derivatives is between 5:1 to 20:1.
3. The pharmaceutical composition as claimed in claim 1, wherein the amount of nebivolol or its pharmaceutically acceptable salts or derivatives in a stable liquid pharmaceutical composition is 0.01% to 1.0%.
4. The pharmaceutical composition claimed in claim 1, wherein nebivolol or its pharmaceutically acceptable salts or derivatives is in soluble form.
5. The pharmaceutical composition as claimed in claim 1, wherein the solubilizer is selected from the group of hydroxypropyl betacyclodextrin, povidone.
6. The pharmaceutical composition as claimed in claim 1, wherein the solvent is selected from the group of water, alcohol, oils or mixture thereof.
7. The pharmaceutical composition as claimed in claim 1, wherein the Co-solvents is selected from the group of monohydric alcohols, polyhydric alcohol such as polyethylene glycols, benzyl alcohol, propylene glycols, glycofurol, alcohol, glycerin, polyoxyethylene glycolated castor oils or mixture thereof. -
8. The pharmaceutical composition as claimed in claim 1, wherein the surfactant is selected from the group of sorbitan esters like polysorbate 80, alpha-tocopherol polyethylene glycol succinate, polyethoxylated castor oil.
9. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients is selected from the group of tonicity-modifiers, antimicrobial preservatives, antioxidants, chelating agent, surfactants, pH modifier and buffers.
10. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical dosage form is oral dosage form, parenteral dosage form, and preferably parenteral dosage form.
11. A process for preparing the pharmaceutical composition as claimed in claim 1 comprising the steps of
i). dissolving Nebivolol in suitable solvent or in mixture of solvent and co-solvent;
ii).- adding solubilizer in mixture of step (i); and
iii). Adding solvent to the mixture of step-(ii) to make up the required volume.
12. A stable clear liquid pharmaceutical composition comprising nebivolol or its pharmaceutical
acceptable salts or derivatives, solubilizer, solvent, co-solvent, surfactant and optionally
other pharmaceutically acceptable excipients substantially as herein describe with
reference to forgoing examples.