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 – AN INTRAVENOUS INFUSION OF MAGNESIUM SULPHATE
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 particularly describes the invention and the manner in which it is to be performed.

AN INTRAVENOUS INFUSION OF MAGNESIUM SULPHATE
FIELD OF THE INVENTION
The present invention is all about an intravenous infusion of magnesium sulphate. The present invention also relates to an intravenous infusion of magnesium sulphate comprising magnesium sulphate, atleast two pH adjusting agents and a vehicle. The present invention also relates to an intravenous infusion of magnesium sulphate and process of preparing the same.

BACKGROUND OF THE INVENTION
Magnesium sulfate is a drug used to treat convulsions during pregnancy, nephritis in children, magnesium deficiency, and tetany.

Magnesium sulphate is widely distributed in nature, e.g. it may be found as a geological salt deposit in the form of kieserite (MgS04.H20) or as the heptahydrate salt epsomite (MgS04.7H20), which is also known as Epsom salt. It may also be found in the form of a double salt langbeinite (K2S04.2MgS04) and in brines.

Magnesium sulphate may also be produced by reacting magnesium carbonate or magnesium hydroxide with sulphuric acid.

Used for immediate control of life-threatening convulsions in the treatment of severe toxemias (pre-eclampsia and eclampsia) of pregnancy and in the treatment of acute nephritis in children. Also indicated for replacement therapy in magnesium deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those of hypocalcemia. Also used in uterine tetany as a myometriat relaxant.

Magnesium is the second most plentiful cation of the intracellular fluids. It is essential for the activity of many enzyme systems and plays an important role with regard to neurochemical transmission and muscular excitability. Magnesium sulfate reduces striated muscle contractions and blocks peripheral neuromuscular transmission by reducing acetylcholine release at the myoneural junction. Additionally, Magnesium inhibits Ca2+ influx through dihydropyridine-sensitive, voltage-dependent channels. This accounts for much of its relaxant action on vascular smooth muscle. Magnesium is excreted solely by the kidney at a rate proportional to the serum concentration and glomerular filtration.

Magnesium sulfate is a small colorless crystal used as an anticonvulsant, a cathartic, and an electrolyte replenisher in the treatment of pre-eclampsia and eclampsia. It causes direct inhibition of action potentials in myometrial muscle cells. Excitation and contraction are uncoupled, which decreases the frequency and force of contractions. Magnesium sulfate is gaining popularity as an initial treatment in the management of various dysrhythmias, particularly torsades de pointes, and dyrhythmias secondary to TCA overdose or digitalis toxicity.

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

OBJECTIVE OF THE INVENTION
The main objective of the present invention is an intravenous infusion of magnesium sulphate.

The other main objective of the present invention is an intravenous infusion of magnesium sulphate which is stable.

Another objective of the present invention is to provide an intravenous infusion of magnesium sulphate which is having enhanced effectiveness.

Yet another objective of the present invention is to provide an intravenous infusion of magnesium sulphate which is having improved patient compliance.
Yet another objective of this invention is to provide an intravenous infusion of magnesium sulphate which is having low risk of systemic infection.

Yet another objective of the present invention is to provide an intravenous infusion of magnesium sulphate which is safe and effective.

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an intravenous infusion of magnesium sulphate.

The other main aspect of the present invention is to provide an intravenous infusion comprising magnesium sulphate, at least two pH adjusting agents and a suitable vehicle.

Another aspect of the present invention is to provide an intravenous infusion of magnesium sulphate and process of preparing the same.

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
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

As used herein, the term "formulation" or “composition” unless otherwise defined refers to granules and/or solid oral pharmaceutical dosage forms or solid dispersions, suspension of the invention.
As used herein, whether in a transitional phase or in the body of a claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term “comprising” means that the composition includes at least the recited features or components, but may also include additional features or components.

As used herein, the singular forms “a,” “an” and “the” specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise.

The term “about” is used herein to means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” or “approximately” is used herein to modify a numerical value above and below the stated value by a variance of 20%.

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.

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 an intravenous infusion of magnesium sulphate.

As per one embodiment the infusion is defined as infusion is administered a PICC line, intraosseous (IO), intravenous, porta cath or any other device. Infusion, in this case, administered the medicine directly into the bloodstream. An injection is usually administered continuously while infusion may be continuous or even in spurts. This is done using infusion can as well as be time controlled.

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.

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 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 an intravenous infusion of magnesium sulphate comprising magnesium sulphate, atleast two pH adjusting agents and a suitable vehicle.

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 the present invention, most preferably vehicle is water.

As per one preferred embodiment the pH adjusting agents 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.

As per one embodiment, the pH stabilizing agents to be selected from succinic acid, carbonates, bicarbonates, and hydrogen phosphates, formic acid, sulfuric acid, fumaric acid, sulfamic acid, formic acid, Acetic acid, acetate, sodium hydroxide, dihydrogenphosphate and hydrogenphosphate or combination thereof.

As per preferred embodiment, the present invention contains at least two pH adjusting agent. As per more preferred embodiment, the preferred pH adjusting agent are sodium hydroxide and sulfuric acid.

As per one embodiment the Magnesium sulphate can be present in the composition in an amount from about 0.1 to 500 mg/ml, preferably in the range from about 0.1 to 450 mg/ml, preferably in the range from about 0.1 to 400mg/ml, more preferably in the range from about 0.5 to 350 mg/ml, more preferably in the range from about 0.5 to 300 mg/ml, more preferably in the range from about 0.5 to 250 mg/ml, more preferably in the range from about 1 to 200 mg/ml, more preferably in the range from about 5 to 150 mg/ml, more preferably in the range from about 10 to 120 mg/ml, more preferably in the range from about 15 to 100 mg/ml, more preferably in the range from about 20 to 80 mg/ml, more preferably in the range from about 25 to 80 mg/ml or any other range in between thereof. In a most preferred embodiment the Magnesium sulphate is present in the range from 25 to 75 mg/ml.

As per one embodiment of the present invention, the pH of the pharmaceutical composition is in the range from 3 to 7, more preferably in the range from 3.5 to 6.5.

As per one embodiment of the present invention, the vehicle can be present in the composition in an amount from about 0.1 to 1000 ml, preferably in the range from about 0.1 to 800 ml, preferably in the range from about 0.1 to 700 ml, more preferably in the range from about 1 to 500 ml, more preferably in the range from about 1 to 300 mg/ml or any other range in between thereof. In a most preferred embodiment the vehicle is present in the range from 1 to 200 ml.

As per one embodiment, the present invention relates to pharmaceutical composition of Magnesium sulphate for parenteral administration.
As per one embodiment, the present invention relates to process for preparing an intravenous. Particularly, a process for the preparation of a stable pharmaceutical composition of magnesium sulphate comprising an intravenous infusion of magnesium sulphate.
As per one preferred embodiment procedure, the process of preparing an intravenous infusion of magnesium sulphate comprising the steps:
a) transferring water for injection to S.S jacketed container;
b) dissolving Magnesium Sulphate Heptahydrate under stirring in step (a);
c) checking the pH of step (b) between 3.5 to 6.5;
d) adding Sulfuric acid and or Sodium Hydroxide solution to step (c) to attain required pH.;
e) making up the volume to 100.0 liters with water for injection and;
f) stirring for 15 minutes;
g) filtering the preparation through 2.0 micron nylon prefilter and following by 0.2 micron nylon filter paper;
h) filling the bulk in 100 ml FFS;
i) packing the filled ampoules using current approved packaging specifications.

As per one preferred embodiment the advantages of the present invention is chemically stable pharmaceutical composition of magnesium sulphate which is parenteral formulation and ready to use. Parenteral administration reduces dose frequency as it can provide extended effect with a single injection. Another advantage of the parenteral administration is that the patient acquires 100% bioavailability of the drug rather compared to the oral administration.

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: AN INTRAVENOUS INFUSION OF MAGNESIUM SULPHATE:
Ingredients Quantity/FFS
in g Quantity/Batch
In g Category
Magnesium Sulphate Heptahydrate 4.0g 4.0kg Active
Sodium Hydroxide - 1.0g For pH ajustement
Sulfuric Acid - 1.0g For pH ajustement
Water for Injection - 100.0Ltr Vehicle
Table: 1 Formulation of an intravenous infusion of magnesium sulphate

Procedure:
a) the water for injection was transferred to stainless steel jacketed container;
b) the Magnesium Sulphate Heptahydrate was dissolved under stirring in step (a);
c) the pH of step (b) between 3.5 to 6.5 was checked;
d) the Sulfuric acid and or Sodium Hydroxide solution was added to step (c) attain required pH;
e) the volume to 100.0 liters with water for injection was made up of step (d) and;
f) the step (e) was stirred for 15 minutes;
g) the preparation of step (f) was filtered through 2.0 micron nylon prefilter and following by 0.2 micron nylon filter paper;
h) the bulk of step (g) was filled in ampules;
i) The step (h) was packed using current approved packaging specifications.

EXAMPLE 2: STABILITY STUDY
The stability of the final composition was performed. The stability were carried out at 2 temperatures which is 30°C ± 2°C and 40°C ± 2°C at Initially and after 3 months for formulation batches (P1 to P3)
The following table shows the result:

2.1 Stability study of magnesium sulfate intravenous infusion for formulation P1
Storage Condition 30°C±2°C
75% ± 5% RH 40°C ±2°C
75% ± 5% RH
Test Specification Initial 3 month Initial 3 month

Description A clear colourless solution A clear colourless solution A clear colourless solution A clear colourless solution A clear colourless solution
pH 3.5 to 6.5 5.85 5.80 5.85 5.80
Assay of Magnesium sulfate 90.0% - 110.0% 101.5 % 100.8% 101.5 % 100.8%
Bacterial endotoxins <0.09EU/mg of magnesium sulfate ?0.09EU/mg NA ?0.09EU/mg NA
Particular matter Average particles <6000 per container =10µm and <600 per container =25 µm 13.33 NA 13.33 NA
Sterility Should be sterile Sterile NA Sterile NA

2.2 Stability study of magnesium sulfate intravenous infusion for formulation P2
Storage Condition 30°C±2°C
75% ± 5% RH 40°C ±2°C
75% ± 5% RH
Test Specification Initial 3 month Initial 3 month

Description A clear colourless solution A clear colourless solution A clear colourless solution A clear colourless solution A clear colourless solution
pH 3.5 to 6.5 5.75 5.77 5.75 5.74
Assay of Magnesium sulfate 90.0% - 110.0% 101.2 % 100.1% 101.2 % 100.5%
Bacterial endotoxins <0.09EU/mg of magnesium sulfate ?0.09EU/mg NA ?0.09EU/mg NA
Particular matter Average particles <6000 per container =10µm and <600 per container =25 µm 86.67 NA 86.67 NA
Sterility Should be sterile Sterile NA Sterile NA

2.3 Stability study of magnesium sulfate intravenous infusion for formulation P3
Storage Condition 30°C±2°C
75% ± 5% RH 40°C ±2°C
75% ± 5% RH
Test Specificati
on Initial 3 month Initial 3 month

Description A clear colourless solution A clear colourless solution A clear colourless solution A clear colourless solution A clear colourless solution
pH 3.5 to 6.5 5.73 5.66 5.73 5.68
Assay of Magnesium sulfate 90.0% - 110.0% 101.2 % 101.1% 101.2 % 100.8%
Bacterial endotoxins <0.09EU/mg of magnesium sulfate ?0.09EU/mg NA ?0.09EU/mg NA
Particular matter Average particles <6000 per container =10µm and <600 per container =25 µm 73.33 NA 73.33 NA
Sterility Should be sterile Sterile NA Sterile NA

,CLAIMS:CLAIMS
We claim;

1. An intravenous infusion of magnesium sulphate comprising magnesium sulphate, at least two pH adjusting agents and a suitable vehicle.
2. The intravenous infusion of magnesium sulphate as claimed in claim 1, wherein the vehicle is selected from the 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.
3. The intravenous infusion of magnesium sulphate as claimed in claim 1, wherein the pH adjusting agents are selected from succinic acid, carbonates, bicarbonates, and hydrogen phosphates, formic acid, sulfuric acid, fumaric acid, sulfamic acid, formic acid, Acetic acid, acetate, sodium hydroxide, dihydrogenphosphate and hydrogenphosphate or combination thereof.
4. The intravenous infusion of magnesium sulphate as claimed in claim 1, wherein the
Magnesium sulphate present in the composition is in the range from 25 to 75mg/ml.
5. The intravenous infusion of magnesium sulphate as claimed in claim 1, wherein the vehicle present in the composition is in the range from 1 to 200ml.
6. The intravenous infusion of magnesium sulphate as claimed in claim 1, wherein the pH of the pharmaceutical composition is in the range from 3.5 to 6.5.
7. The intravenous infusion of magnesium sulphate as claimed in claim 1, wherein, the process of preparation of an intravenous infusion of magnesium sulphate comprises the steps of,
a) transferring water for injection to S.S jacketed container;
b) dissolving Magnesium Sulphate Heptahydrate under stirring in step (a);
c) checking the pH of step (b) between 3.5 to 6.5;
d) adding Sulfuric acid and or Sodium Hydroxide solution to step (c) to attain required pH.;
e) making up the volume to 100.0 liters with water for injection and;
f) stirring for 15 minutes;
g) filtering the preparation through 2.0 micron nylon prefilter and following by 0.2 micron nylon filter paper;
h) filling the bulk in 100 ml FFS;
i) packing the filled ampoules using current approved packaging specifications.

Dated this 23rd Dec, 2021