FIELD OF INVENTION

The invention relates to the pharmaceutical field. Specifically, it relates to stable liquid injectable pharmaceutical composition comprising thiotepa and process for preparing the same.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Thiotepa is an ethylenimine type compound, also referred to as tris (1-aziridinyl) phosphine sulfide. It is a polyfunctional alkylating agent used in the chemotherapy of various neoplastic diseases including adenocarcinoma of the breast and ovaries and for the treatment of superficial papillary carcinoma of the urinary bladder.

Thiotepa was introduced into the U.S. under the brand name of "Thiotepa" as a sterile powder for reconstitution containing 15 mg of thiotepa powder, sodium chloride and sodium bicarbonate for intravenous, intracavitary or intravesical administration. "Thiotepa" was discontinued from the market; and currently lyophilized thiotepa injection is available in the market. The Thiotepa injection should be reconstituted with 1.5 mL of sterile water for injection resulting in a drug concentration of approximately 10 mg/mL. When reconstituted with sterile water for injection, the resulting solution has a pH of approximately 5.5 to 7.5. Thiotepa is stable in alkaline medium and unstable in acid medium. When reconstituted with sterile water for injection, solutions of thiotepa should be stored in a refrigerator, protected from light and should be used within 8 hours. Reconstituted solutions further diluted with 0.9% sodium chloride injection should be used immediately.

The thiotepa sterile powder is known to degrade rapidly to a hazy solution upon reconstitution with sterile water for injection. It is theorized that the haze is due to a polymerization reaction which occurs when the thiotepa is exposed to aqueous media. In order to eliminate haze, solutions must be filtered through a 0.22 micron filter (Polysulfone membrane (Gelman's Sterile Aerodisc®, single use) or triton-free mixed ester of cellulose/PVC (Millipore's MILLEX®-GS filter unit)) prior to administration. Reconstituted solutions should be clear. Solutions that remain opaque or precipitate after filtration should not be used.

US Patent No. 5561121 discloses a stable lyophilized composition of the antitumor alkylating agent thiotepa and a method of preparing such a composition via co-lyophilization of the active ingredient with a pharmaceutically acceptable alkalizing agent such as sodium bicarbonate and sodium carbonate.

US Patent No. 3014902 discloses a method of stabilizing thiotepa composition which comprises incorporating 1-5 parts by weight of thiotepa in 99-95 parts by weight of anhydrous polyethylene glycol having an average molecular weight of 200-600.

European Patent Application No. 0419890 discloses preconstituted pharmaceutical compositions comprising thiotepa and a water-free, water-miscible, neutral or basic, oxygen containing pharmaceutically acceptable solvent such as polyethylene glycol. Such compositions remain stable for prolonged periods under refrigerated conditions and are reconstitutable in water or other I.V. diluents to provide injectable dosage forms.

In the above mentioned prior arts, several attempts have been made to stabilize thiotepa composition and to slow-down or prevent the haze formation that occurs in aqueous media.

Thus, there is constant need in the art for preparing stable injectable pharmaceutical composition comprising thiotepa for parental administration.

Surprisingly, the inventors have found that liquid injectable pharmaceutical compositions comprising thiotepa can be formulated, which are stable at room temperature and does not form haze or precipitate when further diluted with sterile water for injection and/or 0.9% sodium chloride injection.

Further the stable liquid injectable pharmaceutical compositions according to the invention do not need to be lyophilized.

The stable liquid injectable pharmaceutical composition according to the invention comprises: thiotepa, PHARMASOLVE™ (N-methyl-2-pyrrolidone), and optionally one or more pharmaceutically acceptable excipients.

Further, the stable liquid injectable pharmaceutical composition, according to the invention comprises thiotepa, ethylenediaminetetraacetic acid (EDTA), sterile water for injection and optionally one or more pharmaceutically acceptable excipients.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to a stable liquid injectable pharmaceutical composition comprising thiotepa and one or more pharmaceutically acceptable excipients. More specifically, it relates to a stable injectable pharmaceutical composition comprising (i) thiotepa, PHARMASOLVE™ (N-methyl-2-pyrrolidone), and optionally one or more pharmaceutically acceptable excipient, or (ii) thiotepa, EDTA, sterile water for injection and optionally one or more pharmaceutically acceptable excipient and process for preparing the same.

An objective of the invention is to prepare stable liquid injectable pharmaceutical composition comprising thiotepa and one or more pharmaceutically acceptable excipients.

An objective of the invention is to prepare stable liquid injectable pharmaceutical composition comprising thiotepa, PHARMASOLVE™ (N-methyl-2-pyrrolidone), and optionally one or more pharmaceutically acceptable excipient, wherein the injectable composition is stable at room temperature and does not form haze or precipitate when further diluted with sterile water for injection or 0.9% sodium chloride injection.

An objective of the invention is to prepare stable liquid injectable pharmaceutical composition comprising thiotepa, sterile water for injection, EDTA and optionally one or more pharmaceutically acceptable excipient, wherein the injectable composition is stable at room temperature and does not form haze or precipitate when further diluted with sterile water for injection or 0.9% sodium chloride injection.

Another objective of the invention relates to the processes for preparing stable liquid injectable pharmaceutical composition comprising (i) thiotepa, PHARMASOLVE™ (N-methyl-2-pyrrolidone), and optionally one or more pharmaceutically acceptable excipient, or (ii) thiotepa, EDTA, sterile water for injection and optionally one or more pharmaceutically acceptable excipient, wherein the injectable composition is stable at room temperature and does not form haze or precipitate when further diluted with sterile water for injection or 0.9% sodium chloride injection.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to a stable liquid injectable pharmaceutical composition comprising thiotepa and one or more pharmaceutically acceptable excipients. More specifically it relates to a stable injectable pharmaceutical composition comprising (i) thiotepa, PHARMASOLVE™ (N-methyl-2-pyrrolidone), and optionally one or more pharmaceutically acceptable excipient, or (ii) thiotepa, EDTA, sterile water for injection and optionally one or more pharmaceutically acceptable excipient and process for preparing the same.

More particularly, the invention relates to

A stable liquid injectable pharmaceutical composition comprising thiotepa, N-methyl-2-pyrrolidone, and optionally one or more pharmaceutically acceptable excipients.

A stable liquid injectable pharmaceutical composition comprising thiotepa, ethylenediaminetetraacetic acid (EDTA), and optionally one or more pharmaceutically acceptable excipients.

A process to prepare stable liquid injectable pharmaceutical composition comprising thiotepa, N-methyl-2-pyrrolidone and optionally one or more pharmaceutically acceptable excipients, wherein said process involves the following steps:

(i) mixing and dissolving thiotepa in N-methyl-2-pyrrolidone under aseptic conditions at 2 to 8°C to get a solution;

(ii) filling said solution obtained in step (i) into vial(s) or ampule(s).

A process to prepare stable liquid injectable pharmaceutical composition comprising thiotepa, ethylenediaminetetraacetic acid (EDTA), sterile water for injection and optionally one or more pharmaceutically acceptable excipient, wherein said process involves the following steps:

(i) mixing and dissolving thiotepa, ethylenediaminetetraacetic acid in sterile water for injection under aseptic condition at 2 to 8°C to get a solution;

(ii) filling said solution obtained in step (i) into vial(s) or ampule(s).

As discussed in the background of the invention it is very difficult to prepare stable liquid injectable composition of thiotepa, due to polymerization reaction which occurs when the thiotepa is exposed to aqueous media.

It is surprisingly found by the inventors that liquid injectable pharmaceutical composition comprising: (i) thiotepa, PHARMASOLVE (N-methyl-2-pyrrolidone), and optionally one or more pharmaceutically acceptable excipient, or (ii) thiotepa, sterile water for injection , EDTA and optionally one or more pharmaceutically acceptable excipient are stable at room temperature and does not form haze or precipitate when further diluted with sterile water for injection or 0.9% sodium chloride injection.

Injectable preparations are sterile liquid preparations for parenteral administration and are administered by injection or by infusion. There are several methods of injection or infusion including intradermal, subcutaneous, intramuscular, intravenous, and intraperitoneal etc.

According to the invention, the stable liquid injectable pharmaceutical composition comprising thiotepa can be administered via intravenous, intracavitary or intravesical route after reconstituting with sterile water for injection or 0.9% sodium chloride injection.

According to the invention, the stable liquid injectable pharmaceutical composition comprising thiotepa should be stored in refrigerator at 2-8°C.

PHARMASOLVE™ - N-methyl-2-pyrrolidone (NMP) is a water-miscible polar aprotic solvent with high interfacial activity is marketed by Ashland Inc. It is used as a drug solubilizer and penetration enhancer in human parenteral and topical dosage forms.

As used herein, the term, "thiotepa" is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or derivatives thereof. According to the invention, thiotepa may be used in an amorphous or crystalline form.

As used herein, the term, "stable" when used in connection with "liquid injectable pharmaceutical composition comprising thiotepa" relates to physical stability of thiotepa injection when reconstituted using sterile water for injection or 0.9% sodium chloride injection with respect to precipitation and/or haze formation.

As used herein, the term, "under aseptic condition" refers to a procedure that is performed under sterile conditions, preferably in a class 100 designated area.

According to the invention, the stable liquid injectable pharmaceutical composition comprising thiotepa further contain one or more pharmaceutically acceptable excipient(s) selected from a group comprising of chelating agent(s), isotonicity agent(s), antioxidant(s), buffer(s), vehicle or solvent etc.
According to the invention, the stable liquid injectable pharmaceutical composition comprising thiotepa may be filled into vial(s) or ampoule(s).

According to the invention, the stable liquid injectable pharmaceutical composition comprising thiotepa is preferably filled in to 2 ml glass vials made up of type 1 glass.

Suitable chelating agent(s) according to the invention include, but are not limited to EDTA (ethylenediaminetetraacetic acid), sodium EDTA, calcium EDTA, disodium EDTA, calcium disodium EDTA, or mixtures thereof. EDTA is a hexadentate ligand and chelating agent, has ability to "sequester" metal ions such as Ca2+ and Fe3+ through its two amines and four carboxylates. EDTA and its salt(s) are most widely used chelating agent(s) for ophthalmic and parental products.

Suitable isotonicity agent(s) according to the invention include, but are not limited to, sodium chloride, glucose, potassium chloride, calcium chloride, mannitol, lactose, dextrose, glycerol, sorbitol, or mixtures thereof.

Suitable antioxidant(s) according to the invention include, but are not limited to ascorbic acid, citric acid, acetylcysteine, thioglycerol, sodium bisulfite, sodium sulfite, thiourea, or mixtures thereof.

Suitable buffer(s) according to the invention include, but are not limited to citric acid, sodium citrate, acetic acid, sodium acetate, sodium lactate, lactic acid, succinic acid, sodium succinate, tartaric acid, sodium tartarate sodium phosphate, potassium phosphate, sodium carbonate, sodium bicarbonate, or mixture thereof.

Suitable vehicle or solvent according to the invention include PHARMASOLVE™ (N-methyl-2-pyrrolidone), polyethylene glycol, ethanol, water or sterile water for injection, preferably PHARMASOLVE™ or water for injection.

In an embodiment of the invention, the stable liquid injectable pharmaceutical composition comprises: thiotepa, PHARMASOLVE™ (N-methyl-2-pyrrolidone), and optionally one or more pharmaceutically acceptable excipients.

In an embodiment of the invention, the stable liquid injectable pharmaceutical composition comprises thiotepa, disodium EDTA, sterile water for injection and optionally one or more pharmaceutically acceptable excipients.

In an embodiment, the process for preparing the stable liquid injectable pharmaceutical composition comprising thiotepa, PHARMASOLVE (N-methyl-2-pyrrolidone), and optionally one or more pharmaceutically acceptable excipients, involves the addition, mixing and dissolving of thiotepa and PHARMASOLVE™ (N-methyl-2-pyrrolidone) together in a requisite container under aseptic conditions at 2-8°C.

In an embodiment, the process for preparing the stable liquid injectable pharmaceutical composition, comprising thiotepa, disodium EDTA, sterile water for injection and optionally one or more pharmaceutically acceptable excipients, involves the addition, mixing and dissolving of thiotepa, disodium EDTA and sterile water for injection together in a requisite container under aseptic conditions at 2-8°C.

Examples and Experiments:

Following examples or experiments are illustrative and do not limit the scope of this invention.

According to the invention effect of various solvents, and chelating agent were studied on thiotepa solution stability which is tabulated in Table 1:

Table 1:

Above formulation were prepared under aseptic condition at 2-8°C by adding, mixing and dissolving thiotepa in respective solvent along with other pharmaceutically acceptable excipient(s) as tabulated in Table 1 and filled into glass vial(s) with rubber stopper(s).

Thiotepa Injection formulations - Physical and Chemical Stability Study:

The formulation A, B, C, D and E prepared as above were stored at various temperatures for 10 days, to study the physical stability of thiotepa solution in terms of color change, precipitation and/or haze formation and the results are compiled in Table 2.

Table 2:

S : Precipitation / Haze observed;
- : No change from initial observed;
CC : Color Change

Further the thiotepa injection formulations A to D were analyzed for chemical stability by analyzing the formation of impurities and related substances (RS) at initial and after 12 weeks at 2-8°C, 25°C/60%RH and 40°C/75%RH, the resultant data are compiled in Table 3.

Table 3:

From the above data, as summarized in Table 2 and 3 respectively, Formulation D comprising thiotepa and PHARMASOLVE™ appears to be the most stable, both physically and chemically.

Thiotepa Injection formulations - Physical Stability Study when reconstituted with 0.9% sodium chloride injection:

Thiotepa injection formulations A to D were diluted further to two different concentrations lmg/mL and 2mg/ml with 0.9% sodium chloride injection and physical stability was evaluated till 24hrs and data are compiled in Table 4.

Table 4:

Thus from above experimental data and analytical results, it is clear that liquid injectable pharmaceutical composition comprising thiotepa, PHARMASOLVE™ (N-methyl-2-pyrrolidone) (Formulation D) is stable and does not form haze or precipitate when further diluted with sterile water for injection or 0.9% sodium chloride injection.

Based on the above experimental data Formulation D comprising thiotepa and PHARMASOLVE™ is selected for full scale stability study as per Example 1 and the resultant data is tabulated in Table 5:
Example 1

Unit Composition:

Brief manufacturing process:

1. Take 200ml PHARMASOLVE™ in a beaker and purge nitrogen gas into it to maintain the temperature of PHARMASOLVE™ to 2-8°C throughout the manufacturing process (Dissolve Oxygen Limit.: NMT 3.0ppm).

2. Add weighed quantity of thiotepa to the step (1) PHARMASOLVE™ with continuous stirring to get the clear solution.

3. Finally make up the volume to 250ml with PHARMASOLVE™ and continue stirring for 30 min to get clear solution.

4. Fill the solution obtained in step (3) into glass vial(s) with rubber stopper(s).
Stability Data:

Table 5:

Thiotepa injection prepared according to Example 1 when further diluted to two different concentrations lmg/mL and 2mg/ml with 0.9% sodium chloride injection does not form haze or precipitate.

WE CLAIM:

1. A stable liquid injectable pharmaceutical composition comprising thiotepa, N-methyl-2-pyrrolidone, and optionally one or more pharmaceutically acceptable excipients.

2. A stable liquid injectable pharmaceutical composition comprising thiotepa, ethylenediaminetetraacetic acid (EDTA), sterile water for injection, and optionally one or more pharmaceutically acceptable excipients.

3. A process to prepare stable liquid injectable pharmaceutical composition comprising thiotepa, N-methyl-2-pyrrolidone and optionally one or more pharmaceutically acceptable excipients, wherein said process involves the following steps:

(i) mixing and dissolving thiotepa in N-methyl-2-pyrrolidone under aseptic conditions at 2 to 8°C to get a solution;
(ii) filling said solution obtained in step (i) into vial(s).

4. A process to prepare stable liquid injectable pharmaceutical composition comprising thiotepa, ethylenediaminetetraacetic acid (EDTA), sterile water for injection and optionally one or more pharmaceutically acceptable excipient, wherein said process involves the following steps:

(i) mixing and dissolving thiotepa, ethylenediaminetetraacetic acid in sterile water for injection under aseptic condition at 2 to 8°C to get a solution;

(ii) filling said solution obtained in step (i) into vial(s).

5. A stable liquid injectable pharmaceutical composition comprising thiotepa,
having the following unit composition:

6. A stable liquid injectable pharmaceutical composition comprising thiotepa, having the following unit composition:

7. A stable liquid injectable pharmaceutical composition comprising thiotepa and N-methyl-2-pyrrolidone and optionally one or more pharmaceutically acceptable excipients as herein described and exemplified.

8. A stable liquid injectable pharmaceutical composition comprising thiotepa, ethylenediaminetetraacetic acid (EDTA), sterile water for injection and optionally one or more pharmaceutically acceptable excipients as herein described and exemplified.