DESC:FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1. Title of the invention – STABLE PHARMACEUTICAL COMPOSITION OF CARBETOCIN
2. Applicant(s)
NAME: PRECISE BIO PHARMA PVT. LTD.
NATIONALITY: INDIAN
ADDRESS: E-311 & 312, 3rd Floor, Eastern Business District, Neptune Mall, L.B.S. Road, Bhandup (W), Mumbai-400 078 INDIA

3. PREAMBLE TO THE DESCRIPTION

The following specification describes the invention and the manner in which it is to be performed.

STABLE PHARMACEUTICAL COMPOSITION OF CARBETOCIN

FIELD OF THE INVENTION
The present invention is all about a stable pharmaceutical compositions of Carbetocin. The present invention also relates to a stable pharmaceutical composition of Carbetocin comprising, a therapeutically effective amount of Carbetocin, auxiliary agent, an isotonic agent, pH stabilising agent and a vehicle and process for preparing the same. The present invention also relates to use of stable pharmaceutical composition of Carbetocin for the prevention of uterine atony following delivery of the infant by caesarean section under epidural or spinal anaesthesia.

BACKGROUND OF THE INVENTION
The present invention is all about a stable pharmaceutical compositions of Carbetocin.

Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-income countries and is a significant contributor to severe maternal morbidity and long-term disability.

Carbetocin is a new synthetic analogue of oxytocin. It has a longer half-life than oxytocin. This review examines the current evidence for the use of Carbetocin as an alternative to oxytocin, as a first-line agent in the pharmacological management of the third stage of labour.

Carbetocin is clinically and pharmacologically similar to naturally occurring oxytocin. Carbetocin also binds to the oxytocin receptor of the uterine smooth muscle, causing a rhythmic contraction of the uterus, increasing its frequency and increasing uterine tension on the basis of the original contraction. In non-pregnant conditions, the uterine oxytocin receptor content is very low, increasing during pregnancy and peaking during childbirth. Therefore, Carbetocin has no effect on the non-pregnant uterus, but has an effective uterine contraction effect on the uterus of the pregnancy and the newly produced uterus.

Carbetocin if given through any route, i. e, intravenous or intramuscular, the uterus shrinks rapidly and reaches a clear intensity within 2 minutes. The effect of a single dose of intravenous Carbetocin on the uterus lasts for approximately one hour, thus sufficient to prevent postpartum hemorrhage immediately after production. After the postpartum administration of Carbetocin, the frequency of contraction is longer than the oxytocin. Two randomized, double-blind, Canadian studies comparing Carbetocin and oxytocin in a single intravenous cesarean section and found that there was a tendency to hemorrhage and additional use of oxytocin. It is well tolerated and is as effective and effective as oxytocin.

Carbetocin [(also known as 1 -desamino-1 -monocarba-2-(O-methyl)-tyrosine) oxytocin or 1 -butanoic acid-2-(O-methyl-L-tyrosine)-1 -carbaoxytocin] is a long-acting synthetic oligopeptide analogue of oxytocin, with agonist action. Carbetocin is an unusual peptide: it is small (8 amino acids); possesses no charge, is cyclic, and is highly lipophilic. It is also known that Carbetocin lacks a stable and well-defined tertiary structure. The structure of Carbetocin is shown below;

Carbetocin incorporates the following replacements relative to oxytocin: a) the amino-group of cysteine (position 1) by a hydrogen atom; b) of its disulphide bond by a thioether bond; and c) the hydroxyl group of tyrosine (position 2) by a methyloxyl group. Carbetocin (PABAL®, DURATOCIN®) is currently approved for the prevention of uterine atony following delivery of the infant by Caesarean section under epidural or spinal anaesthesia. The dosages used for this medical indication are relatively small, for instance of the order of 100 micrograms given once.

Initially approved products were available with storage condition to be stored at 2-8 ° C for 24 months. The room temperature stable (RTS) variant of Carbetocin has recently been developed and is now approved in the European Union; this variant differs from the current Carbetocin formulation in its excipients. CARBETOCIN RTS contains 0.1 mg/mL of Carbetocin, 1.19 succinic acid, 47.0 mg/mL mannitol, 1 mg/mL L-methionine, sodium hydroxide 2N to pH 5.45, and water for injection to 1 ml. (Widmer M. et al. (2016) Trials. 17: 143.)

Recently revised formulation product has been launched with improved heat stability and now currently available products have storage condition at room temperature and is heat stable.

Many solutions were tried to make Carbetocin product or composition heat stable as well as with longer shelf life.

Other attempts have been made to make stable high Carbetocin formulations using typical peptide excipients (e.g., surfactants); however, none of the studied excipients prevented Carbetocin aggregation. (Hogstedt U. B. et al. (2018). J Pharm Sci. 107(3):838-847.) Only in the absence of headspace was 15 mM sodium dodecyl sulfate (SDS) capable of preventing shaking induced Carbetocin aggregation.

Further, when aqueous Carbetocin solutions are manufactured, packaged, transported, stored, and handled prior to administration to a patient, they are subject to mechanical and chemical stresses. These types of stresses can be detrimental to various formulations of Carbetocin in solution.

WO2012042371A2 discloses a liquid composition comprising Carbetocin or a pharmaceutically active salt thereof; wherein the pH of the composition is from 5.0 to 6.0 with improved stability.

WO2018113273A1 discloses pharmaceutical composition comprising Carbetocin, comprising (percent by weight): 0.5%-7% of Carbetocin, 1%-10% of a water-soluble matrix material, 0.5%-5% of an amino acid anionic surfactant, 0.1%-5% of a humectant, and the balance of water. The amino acid anionic surfactant in the pharmaceutical composition can effectively eliminate the clinical difference caused by the individual difference, can effectively and stably stimulate uterine contraction, and can maintain the stability of a drug.

WO2019122935A1 discloses an aqueous solution composition of pH in the range 4.0-7.5 comprising: a peptide therapeutic agent; optionally one or more buffers being substances having at least one ionisable group with a pKa in the range 3.0 to 8.5 and which pKa is within 2 pH units of the pH of the composition; and a stabilizer; wherein the peptide therapeutic agent does not contain ionisable groups with pKa in the range 3.0 to 8.5, and wherein the buffers are present in the composition at a total concentration of 0-5 mM.

WO2020061414A1 describes stable aqueous compositions comprising relatively high concentrations of Carbetocin and a solubilizer and/or surface active agent. The disclosed Carbetocin compositions are effective in the treatment of a neurodevelopmental disorder, such as Prder- Willi syndrome. Additionally, the disclosed Carbetocin compositions show improved stability at room temperature and/or under accelerated conditions of stress.

However, still there is a need in the society to have heat stable and chemically stable composition of Carbetocin which can be manufactured easily with less complexity and have longer shelf life even at room temperature.

It has been surprisingly found that the stable pharmaceutical composition of Carbetocin to overcome problems cited in above prior arts can be prepared by composition of Carbetocin with auxiliary agent and vehicle as described herein.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is a stable pharmaceutical compositions of Carbetocin.

The another objective of the present invention is to design and develop a stable pharmaceutical compositions of Carbetocin

Another objective of the present invention is to provide a pharmaceutical composition of Carbetocin, which is ready to use.

Yet another objective of the present invention is to provide a stable pharmaceutical composition of Carbetocin for the prevention of uterine atony following delivery of the infant by caesarean section under epidural or spinal anaesthesia.

Yet another objective of this invention is to provide an alternative dosage form with longer shelf life and heat stability compared to existing composition of Carbetocin.

Yet another objective of the present invention is to provide a stable pharmaceutical composition of Carbetocin which exhibits bio equivalency against marketed formulation.

SUMMARY OF THE INVENTION
The main aspect of the present invention is a stable pharmaceutical compositions of Carbetocin.

In one aspect the present invention provides a stable pharmaceutical composition of Carbetocin comprising, a therapeutically effective amount of Carbetocin, auxiliary agent, an isotonic agent, pH stabilising agent and a vehicle.

In one another aspect the present invention provides a process for the preparation of a stable pharmaceutical composition of Carbetocin comprising the steps of,
a) Maintaining the temperature between 2°C to 8°C temperature and carrying out Nitrogen purging of the 80% volume of water for injection for 30 min.
b) Dissolving the Mannitol, S- Methyl-L-Cysteine & succinic acid in step (a) solution and adjusting the pH at 4.8 with 10% succinic acid.
c) Adding Carbetocin to step (b) and maintaining the temperature range 2°C to 8°C and adjusting the pH to 4.8 with 10% succinic acid.
d) Adjusting the volume of step (c) solution to 100% with water for injection and checking the pH.
e) Filtering aseptically the components of step (f) with 0.2 micron Polyether sulphone.
f) Filling and stoppering the vial with solution of step (e) and adjusting the volume with 1.1 ml/vial with pre- & post- Nitrogen purging.
g) Labelling and sealing the step (f) with defined batch no. & storing below 25?.

The details of one or more aspect of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION
The present invention overcomes the aforesaid drawbacks of the above, and other objects, features and advantages of the present invention will now be described in greater detail. Also, the following description includes various specific details and are to be regarded as merely exemplary. Accordingly, those of ordinary skill in the art will recognize that: without departing from the scope and spirit of the present disclosure and its various embodiments there may be any number of changes and modifications described herein.

Generally, disclosed herein are pharmaceutical composition in the form of stable pharmaceutical composition of Carbetocin comprising therapeutically effective amount of Carbetocin, auxiliary agent, vehicle and optionally one or more inactive excipients.

Stable composition form of the present invention represents an ideal dosage form to get freedom from complex manufacturing procedure and excipients.

The composition of present invention as described herein provide ready to use or ready to dilute solution dosage form.

As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub ranges and combinations of sub ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, et cetera As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, et cetera As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub ranges as discussed above.

As used in this document, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

Nothing in this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtue of prior invention. As used in this document, the term "comprising" means "including, but not limited to."

The following terms shall have, for the purposes of this application, the respective meanings set forth below.

"Optional" or "optionally' means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity.

The present invention discloses a stable pharmaceutical composition of Carbetocin comprising therapeutically effective amount of Carbetocin, auxiliary agent, vehicle and optionally one or more inactive excipients.

As used herein the term “Carbetocin” means Carbetocin in free base or a salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, and a combination thereof. In whole specification, the word “Carbetocin” is to be considered as Carbetocin free base.

As used herein term “formulation” or “composition” or “dosage” conveys the same meaning and can be used interchangeably. As per the present invention pharmaceutical composition for present invention is in the form of liquid.

As per preferred embodiment, the pharmaceutical composition is in the form of liquid composition. As per more preferred embodiment, the pharmaceutical composition is in the form of aqueous liquid composition.
As per preferred embodiment, the pharmaceutical composition is in the form of liquid composition for parenteral administration through Intravenous (IV) or intramuscular (IM) route or any other parenteral route only.

As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used.

By "pharmaceutically acceptable", it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the topical formulation and not deleterious to the recipient thereof.

A 'therapeutically effective amount" or "effective amount" of a composition is a predetermined amount calculated to achieve the desired effect, i.e., to induce a favourable immunological response.

The main embodiment of present invention is about a stable pharmaceutical composition of Carbetocin comprising therapeutically effective amount of Carbetocin, auxiliary agent, vehicle and optionally one or more inactive excipients.

As per one embodiment the Carbetocin can be present in the composition in an amount from about 0.001 to 10 mg/ml, preferably in the range from about 0.001 to about 5 mg/ml, preferably in the range from about 0.001 to about 4 mg/ml, more preferably in the range from about 0.001 to 3 mg/ml, more preferably in the range from about 0.001 to 2 mg/ml, more preferably in the range from about 0.001 to 1 mg/ml, more preferably in the range from about 0.001 to 0.5 mg/ml or any other range in between thereof. In a most preferred embodiment the Carbetocin is present in the range from 0.090 to 0.150 mg/ml.

In an embodiment the auxiliary agent as used herein is the agent that plays a critical role in stabilizing the whole composition. Auxiliary agent can be of any chemical class and structure which can help to stabilize the Carbetocin composition and make it more heat stable with longer shelf life at room temperature.

As per one embodiment, the auxiliary agent can be selected from group consisting of Sodium Meta bisulphite, Glutathione, L-cysteine, S- Methyl-L- cysteine, L-cysteine hydrochloride hydrate, ascorbic acid, ascorbic salt, such as sodium, potassium, or calcium ascorbate, sodium EDTA, monoethanolamine gentisate, sodium formaldehyde sulfoxylate, sodium bisulfite, ascorbyl palmitate, dipalmitate L-ascorbate, sodium L-ascorbate-2-sulfate, glucosamine ascorbate or combination thereof.

As per one preferred embodiment, the auxiliary agent can be selected from Sodium Meta bisulphite, Glutathione, S- Methyl-L- cysteine, L-cysteine or combination thereof.

The auxiliary agent can be present in the composition of present invention in an amount from about 0.01 to 50 mg/ml, preferably in the range from about 0.01 to about 40 mg/ml, preferably in the range from about 0.5 to about 30 mg/ml, more preferably in the range from about 0.5 to 20 mg/ml, more preferably in the range from about 0.5 to 10 mg/ml or any other range in between thereof. In a most preferred embodiment the range is 0.5 to 2 mg/ml.
As per one embodiment of the present invention, the pH of the pharmaceutical composition is in the range from 4 to 5.2, more preferably in the range from 4.6 to 5.

Vehicle for present invention can be used as a base for present invention. Vehicle can be considered as any inert substance, or mixture of substances, added to increase the volume of the composition of present invention in order to make the pharmaceutical composition of the present invention suitable form. It also plays multiple role in term of also act as solubilizer and to facilitate the solubilization and avoid precipitation.

As per one preferred embodiment the vehicle can be selected from water, phosphate buffer, citrate buffer, sorbitol, xylitol, maltitol, lactitol, isomalt, erythritol, lauryl lactate (LL), lauryl alcohol (LA), benzyl alcohol (BA), benzyl benzoate (BB), propylene glycol, polyethyleneglycol, triglycerides (triolein, trilaurin, tricarprin, tricaprylin), ethanol, isopropanol, t-butyl alcohol, cyclohexanol, glycerin or glycerol.

In a preferred embodiment, the vehicle is to be selected from water for injection, propylene glycol, polyethylene glycol, glycerin or glycerol or any combinations thereof.

As per one embodiment the isotonic agents are used to adjust the isotonicity of the stable composition of Carbetocin and may further comprise effective amount of an isotonic agent.

In order to minimize or completely eliminate the risk of cell and tissue damage, the osmolality, i.e., the tonicity of the aqueous dosage forms (if so employed) of the invention which are to be administered parenterally, is preferably adjusted so that they are isotonic or at least approximately isotonic to the physiological osmolality.
As per one preferred embodiment, the isotonic agent is selected from D-mannitol, tartaric acid, fumaric acid, adipic acid, lactose, sodium phosphate dibasic, preferably the isotonic agent is D-mannitol, tartaric acid, fumaric acid, adipic acid, lactose, more preferably the isotonic agent is selected from D-mannitol, tartaric acid, fumaric acid, adipic acid, more preferably the isotonic agent is selected from D-mannitol, tartaric acid, fumaric acid, more preferably the isotonic agent is selected from D-mannitol, tartaric acid, most preferably the isotonic agent is D-mannitol.

As per one preferred embodiment the isotonic agent is in range from 1 to 100 mg/ml, preferably the range is 1mg to 90mg, more preferably the range is 1 to 70 mg/ml, more preferably the range is 1 to 60 mg/ml, more preferably the range is 10 to 50 mg/ml, more preferably the range is 20 to 50 mg/ml, more preferably the range is 30 to 50mg/ml, most preferably the range is 35 to 50 mg/ml, in a most preferred embodiment the range of isotonic agent is 40 to 50mg/ml.

As per one embodiment, the present invention relates to pharmaceutical composition of Carbetocin for parenteral administration.

As per one embodiment, the present invention relates to process for preparing a stable pharmaceutical composition of Carbetocin. Particularly, a process for the preparation of a stable pharmaceutical composition of Carbetocin comprising a therapeutically effective amount of Carbetocin, auxiliary agent, an isotonic agent, pH stabilising agent and a vehicle.

In one embodiment, a stable pharmaceutical composition of Carbetocin is useful for the prevention of uterine atony following delivery of the infant by caesarean section under epidural or spinal anaesthesia.

As per one preferred embodiment the pH stabilizers are providing the stability to the formulation by providing either alkalinity or acidity to the pharmaceutical formulating that ultimately lead to a stable formulation, the pharmaceutical formulation provides a stable pH at which the formulation remains best stable and thus providing the stability to a pharmaceutical formulation the pH stabilizers suitable to be used in the formulation is selected from but not limited to, succinic acid, carbonates, bicarbonates, and hydrogen phosphates, formic acid, fumaric acid, sulfamic acid, formic acid, Acetic acid, acetate, dihydrogenphosphate, hydrogenphosphate, Ammonium ammonia, Bicarbonate, carbonate, sodium hydroxide, Benzoic acid and benzoate. Preferably, the pH stabilising agent is succinic acid. As per one embodiment by stabilising pH it is meant to be in an approximate range of pH 4 to 5, and preferably in the approximate range of pH 2 to 5, most preferably in the approximate range 4 to 5.2. The process results in a stabilized formulation in a pH medium.

As per one preferred embodiment the pH stabilisers suitable to be used in the present invention used in the quantity suitable for providing the desired pH. The concentration of the succinic acid is in range from 1% to 50% w/w, more preferably the concentration range 1% to 30% w/w, most preferably the concentration 5% to 12% w/w, most preferably the concentration of the succinic acid is 10% w/w.

As per one preferred embodiment procedure, the process of preparing a stable pharmaceutical composition of Carbetocin is comprising the steps;
a) Maintaining the temperature between 2°C to 8°C temperature and carrying out Nitrogen purging of the 80% volume of water for injection for 30 min.
b) Dissolving the Mannitol, S- Methyl-L-Cysteine & succinic acid in step (a) solution and adjusting the pH at 4.8 with 10% succinic acid.
c) Adding Carbetocin to step (b) and maintaining the temperature range 2°C to 8°C and adjusting the pH to 4.8 with 10% succinic acid.
d) Adjusting the volume of step (c) solution to 100% with water for injection and checking the pH.
e) Filtering aseptically the components of step (f) with 0.2 micron Polyether sulphone.
f) Filling and stoppering the vial with solution of step (e) and adjusting the volume with 1.1 ml/vial with pre- & post- Nitrogen purging.
g) Labelling and sealing the step (f) with defined batch no. & storing below 25?.

As per one preferred embodiment the stable pharmaceutical composition of Carbetocin comprising, a therapeutically effective amount of Carbetocin, auxiliary agent, an isotonic agent, pH stabilising agent and a vehicle.

As per one preferred embodiment the stable pharmaceutical composition of Carbetocin comprising of 0.001 to 5 mg/ml amount of Carbetocin, 0.01 to 50 mg/ml of auxiliary agent, 1 to 100 mg/ml of an isotonic agent, pH stabilising agent and a vehicle.

As per one preferred embodiment the stable pharmaceutical composition of Carbetocin comprising of 0.001 to 2 mg/ml amount of Carbetocin, 1 to 40 mg/ml of auxiliary agent, 1 to 90 mg/ml of an isotonic agent, pH stabilising agent and a vehicle.

As per one preferred embodiment the stable pharmaceutical composition of Carbetocin comprising of 0.001 to 1 mg/ml amount of Carbetocin, 1 to 20 mg/ml of auxiliary agent, 1 to 80 mg/ml of an isotonic agent, pH stabilising agent and a vehicle.

As per one preferred embodiment the stable pharmaceutical composition of Carbetocin comprising of 0.001 to 0.5 mg/ml amount of Carbetocin, 1 to 10 mg/ml of auxiliary agent, 1 to 60 mg/ml of an isotonic agent, pH stabilising agent and a vehicle.

As per one preferred embodiment the stable pharmaceutical composition of Carbetocin comprising of 0.090 to 0.150 mg/ml amount of Carbetocin, 0.5 to 2 mg/ml of S- Methyl-L- cysteine, 40 to 50 mg/ml of D-Mannitol, Succinic Acid and water for injection.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example 1:
Ingredients Qty. in mg/ ml
Carbetocin 0.1
D-Mannitol 50
L-cysteine hydrochloride hydrate 10
sodium bisulfite 20
Succinic Acid q.s to adjust pH
NaOH q.s to adjust pH
Water for Injection q.s to 1 ml

Procedure:
1. All ingredients were weighed and kept separately.
2. 80% volume of Water for injection were taken and purged with Nitrogen gas for 15 min.
3. D-Mannitol, L-cysteine hydrochloride hydrate and Sodium bisulphite were dissolved in water for injection of step 2.
4. Carbetocin was added in step-3 Solution and pH was adjusted to 4.8 with 1N NaOH or 10% Succinic Acid.
5. Volume was made to 100% with Water for injection.
6. Aseptic filtration was carried out with 0.2 micron Nylon or Polyether sulphone filter.
7. Filling & stoppering of vial was carried out at fill volume of 1.05 ml/Vial with pre- & post- Nitrogen purging.

Example 2:
Ingredients Qty. in mg/ ml
Carbetocin 0.1
D-Mannitol 50
Glutathione (reduced) 10
sodium metabisulfite 18
Succinic Acid q.s to adjust pH
NaOH q.s to adjust pH
Water for Injection q.s to 1 ml

Procedure:
As per Example 1

Example 3:
Ingredients qty. in mg/ ml
Carbetocin 0.1
D-Mannitol 47
Ascorbic Acid 2
Succinic Acid q.s to adjust pH
NaOH q.s to adjust pH
Water for Injection q.s to 1 ml

Procedure:
As per Example 1

Example 4: Stable pharmaceutical composition of Carbetocin
Ingredients Qty. in mg/ ml
Carbetocin 0.105*
D-Mannitol 47
S- Methyl-L- cysteine 1
10% W/V Succinic Acid q.s to adjust pH
Water for Injection q.s to 1000

Procedure:
a) The Nitrogen purging of 80% volume of Water for injection was carried out for 30 min in maintained temperature between 2°C to 8°C temperature.
b) The Mannitol, S- Methyl-L-Cysteine & succinic acid in step (a) were dissolved. The pH was adjusted to pH 4.8 with 10% Succinic Acid
c) Carbetocin was added to step (b) with maintained temperature range 2°C to 8°C and the pH was adjusted to 4.8 with 10% succinic acid.
d) The volume of step (c) was adjusted to 100% with water for injection and pH was checked.
e) The aseptic filtration with 0.2 micron Polyether sulphone filter was carried out of components of step (f).
f) The vial were filled and stoppered with solution of step (g) and with volume of 1.1 ml/vial with pre- & post- Nitrogen purging.
g) The step (h) was labelled and sealed with defined batch no. & store below 25?.

Example 5: Stability study:
The stability of the final compositions was performed in the given conditions and the results obtained after the stability are as summarised below:
Storage Condition Temperature 40°C ± 2°C
RH 75% ± 5% RH
Test Specification Initial 2 month 3 month
Description A clear colourless liquid free from visible particles A clear colourless liquid free from visible particles A clear colourless liquid free from visible particles A clear colourless liquid free from visible particles
pH at 25? 4 to 5.2 4.7 4.79 4.76
Related Substance
Impurity A
at
RRT 0.45 ± 0.02 - Not more than 1.5% Not detected Not detected Not detected
Impurity B at RRT 0.63 ± 0.02 - Not more than 1.5% Not detected Not detected Not detected
Single maximum impurity Not more than 0.5% Not detected Not detected Not detected
Total impurity Not more than 2.0% Not detected Not detected Not detected
Assay (Drug Content)
Carbetocin 100 mcg/ml 90.0% - 110.0% mcg/ml of the stated amount 108.80 % 108.80%
108.00 %
,CLAIMS:CLAIMS

We claim,

1. A stable pharmaceutical composition of Carbetocin comprising, a therapeutically effective amount of Carbetocin, auxiliary agent, an isotonic agent, pH stabilising agent and a vehicle.

2. The stable pharmaceutical composition of Carbetocin as claimed in claim 1, wherein the therapeutically effective amount of Carbetocin is present in range 0.001 to 10 mg/ml.

3. The stable pharmaceutical composition of Carbetocin as claimed in claim 1, wherein the formulation is stable at pH 4 – 5.2.

4. The stable pharmaceutical composition of Carbetocin as claimed in claim 1, the auxiliary agent is selected from Sodium Meta bisulphite, Glutathione, S- Methyl-L- cysteine, L-cysteine or combination thereof, wherein the auxiliary agent is in range from 1 to 100 mg/ml.

5. The stable pharmaceutical composition of Carbetocin as claimed in claim 1, the isotonic agent is selected from D-mannitol, tartaric acid, fumaric acid, adipic acid, lactose, sodium phosphate dibasic, wherein the isotonic agent is in range from 1 to 100 mg/ml.

6. The stable pharmaceutical composition of Carbetocin as claimed in claim 1, wherein the vehicle is selected from water for injection, propylene glycol, polyethylene glycol, glycerin or glycerol or any combinations thereof.

7. The stable pharmaceutical composition of Carbetocin as claimed in claim 1, wherein the pH stabilising agent are selected from succinic acid, carbonates, bicarbonates, and hydrogen phosphates, formic acid, fumaric acid, sulfamic acid, formic acid, Acetic acid, acetate, dihydrogenphosphate, hydrogenphosphate, Ammonium ammonia, Bicarbonate, carbonate, sodium hydroxide, Benzoic acid and benzoate.

8. The stable pharmaceutical composition of Carbetocin as claimed in claim 1, wherein 0.001 to 5 mg/ml amount of Carbetocin, 0.01 to 50 mg/ml of auxiliary agent, 1 to 100mg/ml of an isotonic agent, pH stabilising agent and a vehicle.

9. The stable pharmaceutical composition of Carbetocin as claimed in claim 1, wherein 0.090 to 0.150 mg/ml amount of Carbetocin, 0.5 to 2 mg/ml of S- Methyl-L- cysteine, 40 to 50 mg/ml of D-Mannitol, Succinic Acid and water for injection.

10. The process of preparing a stable pharmaceutical composition of Carbetocin as claimed in claim 1, comprising the steps;
a) Maintaining the temperature between 2°C to 8°C temperature and carrying out Nitrogen purging of the 80% volume of water for injection for 30 min.
b) Dissolving the Mannitol, S- Methyl-L-Cysteine & succinic acid in step (a) solution and adjusting the pH at 4.8 with 10% succinic acid.
c) Adding Carbetocin to step (b) and maintaining the temperature range 2°C to 8°C and adjusting the pH to 4.8 with 10% succinic acid.
d) Adjusting the volume of step (c) solution to 100% with water for injection and checking the pH.
e) Filtering aseptically the components of step (f) with 0.2 micron Polyether sulphone.
f) Filling and stoppering the vial with solution of step (e) and adjusting the volume with 1.1 ml/vial with pre- & post- Nitrogen purging.
g) Labelling and sealing the step (f) with defined batch no. & storing below 25?.

Dated this 03rd March 2021