DESC:FIELD OF THE INVENTION

The present invention relates to a stable non-aqueous injectable pharmaceutical composition of progesterone or its derivatives, wherein the said pharmaceutical composition comprises of benzyl benzoate and polyethylene glycol. Further, the present invention relates to process for the preparation of the said injectable pharmaceutical composition.

BACKGROUND OF THE INVENTION

Progesterone (Pregn-4-ene-3,20-dione) is endogenous steroid molecule, and it is chemically known as (8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one. Its empirical formula is C21H30O2 and the molecular weight is 314.469 g/mol. The chemical structure of Progesterone is shown in formula below:

Progesterone derivative can be synthesized which includes retroprogesterone, 17a-hydroxyprogesterone, 17a-methylprogesterone, and 19-norprogesterone, with a respective example from each group including dydrogesterone, medroxyprogesterone acetate, medrogestone, and promegestone.

Progesterone asserts numerous pharmacological applications. Progesterone is used, for example, in assisted reproduction protocols, in the treatment of threatened miscarriage, amenorrhea and abnormal uterine bleeding. High plasma levels of progesterone must be attained and maintained in order to achieve a therapeutic effect.

It is well known that Progesterone is insoluble in water and its gastrointestinal absorption is slower. Further, progesterone has also high hepatic metabolism which results in lower level of progesterone in plasma. This drawback restricts the oral use of progesterone. Therefore, progesterone is generally administered intra­muscularly.

Commercially available injectable formulations of progesterone utilize oily vehicles like Sesame oil in its composition. Furthermore, it is necessary to administer high doses of progesterone, in the order of 100 mg per day, to obtain adequate plasma level. The undesirable disadvantages which are present when the vehicles used in the prior art were employed with a high dosage level of progesterone, are many. In addition to the said vehicles being incapable of solubilizing any great quantities of the medicaments, it has been found that the compositions heretofore employed produce irritation at the site of injection, when parenterally administered.

U.S. Patent No. 4,727,064 and WO85/02767 disclosed that the water solubility of poorly water-soluble drugs such as progesterone can be increased by the formation of a complex with ß-cyclodextrin ethers, specifically hydroxypropyl-ß-cyclodextrin. Initially, inventor gets clear solution when composition prepared using hydroxypropyl-ß-cyclodextrin. However, it is observed that if this product stored at 2-8°C, then drug precipitates out and particles generates within 15 days and if it is stored at -20°C, then particles generates within 7 days. The problem observed here makes it difficult to formulate and use of injectable formulations described in the known art.

The inventors of present invention have developed a stable non-aqueous injectable pharmaceutical composition of progesterone or its derivatives; wherein the said pharmaceutical composition comprises of benzyl benzoate and polyethylene glycol, which provides irritation free and stable non-aqueous injectable pharmaceutical composition over the period of time.

SUMMARY OF THE INVENTION

The present invention relates to a stable non-aqueous injectable pharmaceutical composition of progesterone or its derivatives; wherein the said pharmaceutical composition comprises of benzyl benzoate and polyethylene glycol, which provides irritation free and stable non-aqueous injectable pharmaceutical composition over the period of time. Further, the present invention relates to process for the preparation of the said pharmaceutical composition and the use of the said pharmaceutical composition in pharmaceutical industry.

OBJECTS OF THE INVENTION

The main object of the present invention is to provide a stable non-aqueous injectable pharmaceutical composition of progesterone or its derivatives, comprising benzyl benzoate and polyethylene glycol.

Another object of the present invention is to provide a stable non-aqueous injectable pharmaceutical composition of progesterone, or its derivatives, comprising benzyl benzoate and polyethylene glycol; wherein the amount of benzyl benzoate is up to 45% v/v in the said stable non-aqueous injectable pharmaceutical composition.

Another object of the present invention is to provide a stable non-aqueous injectable pharmaceutical composition of progesterone, or its derivatives, comprising benzyl benzoate and polyethylene glycol; wherein polyethylene glycol is selected from polyethylene glycol 400 or polyethylene glycol 300 or mixture thereof.

Another object of the present invention is to provide a method for the preparation of a stable non-aqueous injectable pharmaceutical composition of progesterone, or its derivatives, comprising benzyl benzoate and polyethylene glycol.

Another object of the present invention is to provide a method for the preparation of a stable non-aqueous injectable pharmaceutical composition of progesterone, or its derivatives, comprising benzyl benzoate and polyethylene glycol; wherein the method comprises the steps of:
a) Solubilizing progesterone or its derivatives in a benzoyl benzoate to obtain clear solution,
b) Make up the volume of the solution obtained in step a) to 100 % with polyethylene glycol,
c) Optionally filter the solution obtained in step b) through a sterile grade filter, and aseptically filing the filtered solution in to clear sterile vial.

Another object of the present invention is to provide a stable non-aqueous injectable pharmaceutical composition of progesterone, or its derivatives comprising benzyl benzoate and polyethylene glycol; wherein the said injectable pharmaceutical composition is stable for at least 15 days when stored at -20°C.

Another object of the present invention is to provide a stable non-aqueous injectable pharmaceutical composition of progesterone, or its derivatives, comprising benzyl benzoate and polyethylene glycol; wherein the said injectable pharmaceutical composition does not causes irritation at the site of administration.

DETAILED DESCRIPTION

The detailed description and the examples provided herein are exemplary and any modification or variation within the scope of the invention will be apparent to a person skilled in the art. Further, unless otherwise defined, all the technical and scientific terms used herein shall bear the meaning as understood by a person who is ordinarily skilled in the art.

The term “derivatives” refers to as structural analogs or similar compound that can be synthesized from a parent compound by replacement of one atom with another atom or group of atoms. Examples of progesterone derivatives include but not limited to 17a-Hydroxyprogesterone, Medroxyprogesterone, 19-Norprogesterone, 17a-Methylprogesterone and the likes thereof.

The term “Injectable” refers to as pharmaceutical composition administration via parenterally or a route other than through the digestive tract. Examples of injectable includes but not limited to subcutaneous, intramuscular injection, intravenous injection, intraperitoneal injection, intracardiac injection, intraarticular injection intracavernous injection and the likes thereof.

The term “benzyl benzoate” used herein is also called benzoic acid phenylmethyl ester which is a synthetic organic compound with chemical formula C14H12O2. Benzyl benzoate is clear colorless liquid and is used as non-aqueous solvent for the preparation of stable non-aqueous injectable pharmaceutical composition according to the present invention.

Further, the benzyl benzoate has been found to be capable of dissolving great quantities of the medicaments of this invention and the resulting parenterally administrable composition employing this vehicle does not produce undue irritation at the site of administration.

The term “polyethylene glycol” (PEG) used herein is also called poly(oxyethylene) or poly(ethylene oxide) (depending on its molecular weight). Polymerizations of ethylene oxide yields PEG and are commercially available over a wide range of molecular weights from 300 g/mol to 10,000,000 g/mol.

The term “polyethylene glycol 300” (PEG 300) refers as odorless viscous liquid of polyethylene glycol having molecular weight of 285 g/mol to 315 g/mol; more specifically 300 g/mol. PEG 300 is a viscous liquid and is used as a non-aqueous medium for the preparation of stable non-aqueous injectable pharmaceutical composition according to the present invention.

The term “polyethylene glycol 400” (PEG 400) refers as odorless viscous liquid of polyethylene glycol having molecular weight of 380 g/mol to 420 g/mol; more specifically 400 g/mol. PEG 400 is a viscous liquid and is used as a non-aqueous medium for the preparation of stable non-aqueous pharmaceutical composition according to the present invention.

The term “Non-aqueous injectable pharmaceutical composition” refers to as an injectable pharmaceutical composition comprising benzyl benzoate and polyethylene glycol; wherein no water is added during preparation of the composition, and wherein the composition has sufficient stability to allow storage at convenient temperatures 2 – 25 °C. Further, the pharmaceutical composition of progesterone or its derivatives prepared using the said stable non-aqueous injectable pharmaceutical composition is stable even at harsh storage conditions, eg., for at least 15 days, when stored at a temperature of -20 °C.

The pharmaceutical composition disclosed in the examples given herewith is clear colourless solutions, wherein the assay of progesterone complies within the limit prescribed by pharmacopoeia for progesterone injections (i.e. progesterone assay limit of 90-100%).

The injectable pharmaceutical composition of progesterone or its derivatives prepared using the said stable non-aqueous pharmaceutical composition is storage-stable for a reasonable period of time, e.g., the shelf-life of the product which can be as short as one month but is typically six months or longer, preferably at least 18 months or more preferably at least 2 years.

In addition to the above-mentioned ingredients, the stable non-aqueous injectable pharmaceutical composition according to the present invention may also optionally comprise pharmaceutically acceptable ingredients known in the art which include, for example, surfactants (e.g., Polysorbates), organic acids (e.g., citric acid), chelating agents (e.g., EDTA), preservatives (e.g., benzyl alcohol) etc.

In one aspect of the invention, the concentration of benzyl benzoate required to dissolve Progesterone or its derivatives, up to 45%. Preferably, the concentration of benzyl benzoate required to dissolve progesterone, or its derivatives, is 20% v/v to 25% v/v in the said stable non-aqueous injectable pharmaceutical composition.

In another aspect of the invention, PEG 300 or PEG 400 or mixture thereof, is used as a non-aqueous medium up to 100% v/v in the said stable non-aqueous injectable pharmaceutical composition. Preferably, the concentration of PEG 300 or PEG 400 or mixture thereof, required to be act as non-aqueous medium, is up to 90%, more preferably 75% v/v to 80% v/v in the said stable non-aqueous injectable pharmaceutical composition.

Another aspect of the invention is to provide a method for the preparation of a stable non-aqueous injectable pharmaceutical composition of progesterone, or its derivatives comprising benzyl benzoate and polyethylene glycol; wherein the method comprises the steps of:
a) Solubilizing progesterone, or its derivatives in benzoyl benzoate to obtain a clear solution,
b) Make up the volume of the solution obtained in step a) to 100 % with polyethylene glycol,
c) Filtering the solution obtained in step c) through a sterile grade filter, and aseptically filing the filtered solution in to clear sterile vial.

In another aspect of the invention, the stable non-aqueous injectable pharmaceutical composition according to the present invention comprises benzyl benzoate as a non-aqueous solvent. The concentration of progesterone or its derivatives in the said stable non-aqueous injectable pharmaceutical composition would range from about 0.1 mg/mL to about 200 mg/mL. Preferably, the concentration of progesterone, or its derivatives would range from 0.1 mg/ml to 100 mg/ml; more preferably, the concentration of the progesterone, or its derivatives would at least 25 mg/mL.

In another aspect of the invention, stable non-aqueous injectable pharmaceutical composition, using benzyl benzoate in a smaller percentage and PEG 300 or PEG 400 or mixture thereof in higher percentage, resulting in non-aqueous solution product which is stable even at lower temperatures, with no risk of precipitation.

The stable non-aqueous injectable pharmaceutical composition according to the present invention can also be used to prepare stable injectable pharmaceutical composition of drugs other than the said steroid or its derivatives. The non-limiting example includes testosterone, Cholic acid, Dexamethasone, Lanosterole, Medrogestone and ß-sitosterole.

Apart from the steroid drug, the stable non-aqueous injectable pharmaceutical composition according to the present invention can also be used to prepare the stable pharmaceutical compositions for peptide, protein or small molecules drug which precipitates out and generates particles within 15 days when stored at -20°C.

In order to further illustrate the present invention, the following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of present invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the scope of the invention.

Example 1: Stable non-aqueous injectable pharmaceutical composition
Sr. No Ingredients Quantity
1 Progesterone 25 mg/mL
2 Benzyl benzoate up to 45% v/v
3 Polyethylene glycol q.s.

Manufacturing process:
1. Transfer batch quantity of Benzyl benzoate in SS manufacturing vessel.
2. Add & mix Progesterone in the above step and stir for 20 minutes to get clear solution.
3. Make up the volume with Polyethylene glycol and stir for 15 minutes.
4. Filter the solution through 0.2µ hydrophobic polyvinylidenedifluoride (PVDF) membrane filter.
5. Fill the filtered solution into vial, stopper and seal with aluminium flip off seal.
6. Transfer the vials to the packing area for labeling and packaging.

Example 2: Stable non-aqueous injectable pharmaceutical composition
Sr. No Ingredients Quantity
1 Progesterone 25 mg/mL
2 Benzyl benzoate 20% v/v
3 Polyethylene glycol q.s. 1ml

The process for the preparation of pharmaceutical composition as mentioned in example 2 is same as the process mentioned for example 1.

Stability study: Following are the stability data for pharmaceutical composition as mentioned in example 2.

Time period Tests/ Condition
Description Assay (%) pH Unknown Imp Total Imp
Initial A clear colourless solution 99.1 7.00 0.138 0.282
30°C, 75% RH
3 month A clear colourless solution 99.0 6.98 0.111
0.388
30°C, 75% RH
6 month A clear colourless solution 98.0 6.96 0.102 0.397
40°C, 75% RH
3 month A clear colourless solution 98.3 6.95 0.11 0.383
40°C, 75% RH
6 month A clear colourless solution 96.9 6.98 0.104 0.4

The above stability study data comply with the stability testing requirements of injectable pharmaceutical composition.

The pharmaceutical composition disclosed in the examples given herewith is clear colourless solutions, wherein the assay of progesterone complies within the limit prescribed by pharmacopoeia for progesterone injections limit.

Further, the pharmaceutical composition disclosed in the examples given herewith have been found to be clear, free of particles and colourless solutions when observed visually even when stored at 2-25°C and at -20°C for at least 15 days.

All the pharmaceutical compositions and methods disclosed in this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the spirit and scope of the invention. ,CLAIMS:We claim,

1. A stable non-aqueous injectable pharmaceutical composition comprising,
i. Progesterone or its derivatives;
ii. Benzyl benzoate; and
iii. Polyethylene glycol.

2. The pharmaceutical composition as claimed in claim 1, wherein the amount of progesterone or its derivatives in the composition is about 0.1 mg/mL to about 200 mg/mL

3. The pharmaceutical composition as claimed in claim 1, wherein the amount of benzyl benzoate is up to 45% v/v.

4. The pharmaceutical composition as claimed in claim 3, wherein the amount of benzyl benzoate is 20% v/v to 25% v/v.

5. The pharmaceutical composition as claimed in claim 1, wherein polyethylene glycol is selected from the group consisting of polyethylene glycol 400 or polyethylene glycol 300 or mixture thereof.

6. The pharmaceutical composition as claimed in claim 5, wherein the amount of Polyethylene glycol is up to 90%.

7. The pharmaceutical composition as claimed in claim 6, wherein the amount of Polyethylene glycol is 75% v/v to 80% v/v.

8. The pharmaceutical composition as claimed in claim 1, wherein composition is stable for at least 15 days when stored at -20°C.

9. The pharmaceutical composition as claimed in claim 1, wherein composition further optionally comprises of surfactants, organic acids, chelating agents, and preservatives.

10. A method for the preparation of a stable non-aqueous injectable pharmaceutical composition of progesterone, or its derivatives comprising benzyl benzoate and polyethylene glycol; wherein the method comprises the steps of:
a. Solubilizing progesterone, or its derivatives in benzyl benzoate to obtain a clear solution,
b. Make-up the volume of the solution obtained in step a) to 100 % with polyethylene glycol,
c. Filtering the solution obtained in step c) through a sterile grade filter, and aseptically filing the filtered solution in to clear sterile vial.