DESC:FIELD OF THE INVENTION:
The present invention relates to pharmaceutical parenteral preparation. More particularly the present invention relates to pharmaceutical preparation injection for intravenous application. The present invention further relates to injection comprising brexanolone as an active ingredient. The present injection formulation is stable at refrigerated temperature.

BACKGROUND OF THE INVENTION:
A number of endogenous and synthetic compounds, such as neuroactive steroids and derivatives, can impact central nervous system (CNS) function through multiple mechanism, include but not limited to, positive allosteric modulation of GABAA (? aminobutyric acid type A) receptors that is related to many central nervous system disorders.
Allopregnanolone is one of such neuroactive steroids that have 9 hr half-lives and poor oral bioavailability, and have limited clinical use as oral therapies or parenteral therapy. Brexanolone is a synthetic compound that is chemically identical to endogenous allopregnanolone.
Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone. Brexanolone is a medication used in the treatment of postpartum depression in adult women. It is in the GABA-A modulator class of medications.
Allopregnanolone is 3a-hydroxy-5a-pregnane-20-on, 5a-pregnane-3a-all-20-on, or 3a, 5a-tetrahydroprogesterone (3a, 5a-THP). Synthesized from progesterone in the brain, allopregnanolone becomes a potent positive allosteric modulator of the action of ?-aminobutyric acid (GABA) on GABA-A receptors. Allopregnanolone is similar in effect to other positive allosteric modulators of GABA action on GABA-A receptors, such as benzodiazepines, including, for example, anxiolytic, sedative, and anticonvulsant activity. The structure of allopregnanolone is shown below.

To date the pharmacological management of postpartum depression has been based mainly on the intravenous injection comprising brexanolone.
However storage and stability of these pharmaceutical parenteral injection formulations are associated with stability indication to store these preparations in specific temperature conditions of 2-8°C. Thus to maintain the temperature specific condition at some point become tedious for the patient. Further parenteral injection formulation comprising brexanolone associated with crystallization issue associated with prior art parenteral formulations.
Given the shortcomings associated with current parenteral injection formulation comprising brexanolone, it is highly desirable to have parenteral injection formulation comprising brexanolone that is effective and stable, more particularly with reduced crystallization problem associate on storage of prior art injectable preparation and increased stability on storage at room temperature.
In a preferred embodiment, the composition of the invention has one or more advantages over conventional commercially available brexanolone injection formulations. For example, in certain embodiments, the composition reduces crystallization issue associated on storage as compared to prior art brexanolone injection formulations.
One or more advantages over conventional injectable brexanolone formulations can be shown, including enhancement or improved solubility of the brexanolone.
In a preferred embodiment, the composition of the invention is compatible to the admixture study.

SUMMARY OF THE INVENTION:
The main object of the present invention to provide to a pharmaceutical composition for injectable preparation comprises: a.) Compound A is present in amount of 0.5 to 1%; b.) Compound B is present in amount of 15 to 25%; c.) co solvent are present in amount of 5 to 20%; d.) buffers are present in amount 0.0001 to 0.5% and vehicle is present to make QS.
Another object of the present to provide a process for preparation of pharmaceutical composition for injectable preparation comprises:

i. Take about 50 L water for injection and heat at 80-100 °C, maintain temperature 80-100°C;
ii. add Kleptose under continuous stirring. Stir for 1 hour or till gets a clear solution and cool at 25°C to 30°C;
iii. add Brexanolone and stirr until gets clear solution; add Polyethylene Glycol-400 and Propylene glycol and stir for 30 min.
iv. add citric acid monohydrate and trisodium citrate dehydrate and stir for 30 min;
v. add water and stir for 15 min and filter.
vi. Fill into type I glass vial and rubber stopper it. Seal using aluminum seal and autoclave it to obtain the final product.
In another embodiment of the present invention further provides hydroxy-propyl Beta Cyclodextrin [Kleptose] as a solubilizing agent for the present parenteral injection formulation comprising brexanolone.
In another object of the present invention, brexanolone injection formulations reduces crystallization on storage of the present injection formulation.
In another aspect of the present invention solubility is enhanced or improved in present parenteral injection formulation comprising brexanolone.
The disclosure represents a simplified summary of the invention in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the present invention. It is not intended to identify the key/critical elements of the invention or to delineate the scope of the invention. Its sole purpose is to present some concept of the invention in a simplified form as a prelude to a more detailed description of the invention presented later.
The following description is of exemplary embodiments only and is not intended to limit the scope, applicability or configuration of the invention in any way. Rather, the following description provides a convenient illustration for implementing exemplary embodiments of the invention. Various changes to the described embodiments may be made in the function and arrangement of the elements described without departing from the scope of the invention.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention in detailed provides parenteral injection formulation containing comprising Brexanolone; acting as an active ingredient in present formulation for intravenous application.
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. However, any skilled person will appreciate the extent to which such embodiments could be extrapolated in practice.
The sterile injectable composition of the present invention may be administered via parenteral route and not limited to intravenous (I.V.) route.
The sterile injectable composition of the present invention may provide one or more advantages like, providing a safe composition by solubilizing the drug without usage of providing a stable, clear, aqueous solution suitable for I.V. administration compatible with routinely used I.V. sets and having improved stability, efficacy, and safety profile.
Injectable preparations:
Parenteral articles are preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal, so that the active substances they contain are administered, using gravity or force, directly into a blood vessel, organ, tissue, or lesion. Parenteral articles are prepared scrupulously by methods designed to ensure that they meet Pharmacopeia requirements for sterility, pyrogens, particulate matter, and other contaminants, and, where appropriate, contain inhibitors of the growth of microorganisms. An Injection is a preparation intended for parenteral administration and/or for constituting or diluting a parenteral article prior to administration. Parenteral route of drug administration is most favourable for highly potent and low dose of drug. The various route of administration available among them intravenous route give highest systemic circulation of drug and able to achieve 100% bioavailability of drug.
Injectable preparations possess certain advantages over other dosage forms. Parenteral route is rapid route of administration of the drug molecule in vivo. The parenteral preparations are more useful in case of unconscious patients. Further this route of administration is also beneficial in case of uncooperative patients. Various drug molecules administered orally get inactivated by Gastro- intestinal GIT enzymes. This inactivation can be avoided by administering through parenteral route. Parenteral preparations further avoids the first pass effect. In case of parenteral preparation bioavailability is achieved to 100%.
The following is a detailed description of embodiments of the present disclosure.
The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
Unless the context requires otherwise, throughout the specification which follow,
the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
Reference throughout this specification to “one embodiment” or “an embodiment”
means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
As used in the description herein and throughout the claims that follow, the
meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
In some embodiments, the numbers expressing quantities of ingredients,
properties such as concentration, process conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment.
In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range.
Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
All methods described herein can be performed in suitable order unless otherwise
indicated herein or otherwise clearly contradicted by context. The use of any and all
examples, or exemplary language (e.g. “such as”) provided with respect to certain
embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
The phrase ‘pharmaceutically acceptable’ as used in the invention is meant to refer to those compounds, materials compositions, or other dosage forms that are, within the scope of medical judgment, suitable for use in contact with tissues of human beings and animals and without excessive toxicity, irritation, allergic response, or any other problem or complication.
The term ‘stable’ as used in the present invention relates to both chemical (shelf-life) and physical stability (injectable solution). Improved uniformity results in an improved product because less shaking of the injectable preparation is required before dosing and allows the product to be stored longer (i.e. longer shelf-life) because the drug in the product will not settle and compact.
Generally, disclosed herein are pharmaceutical compositions in the form of an injectable preparation for the intravenous (I.V.) route of administration. Particularly, an injectable preparation includes bulking agents, tonicity adjusting agents, stabilizing agents, antioxidants, chelating agents, buffering agent and water, in addition to the active pharmaceutical ingredient.
Because of their characteristic features, an injectable preparation is an ideal dosage form for patients who have difficulty swallowing tablets or capsules and the active pharmaceutical ingredients having poor absorption by oral route of administration.
The headings and abstract of the invention provided herein are for convenience
only and do not interpret the scope or meaning of the embodiments.
Various terms are used herein. To the extent a term used in a claim is not defined
below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
The present invention further disclosed injectable preparation comprising brexanolone can further include one or more acceptable pharmaceutical excipients. Exemplary of pharmaceutical acceptable excipients includes but not limited to buffering agent, solvents, stabiliser, complexing agent, solubility enhancing agents, diluents, vehicles and any other parenterally acceptable excipients known in the prior art, including mixture thereof.
Buffering agents/ pH modifying agent:
Control of pH is critical to avoid degradation of drug during processing, storage and reconstitution, thereby necessitating addition of buffering agent in the lyophilized formulation. The choice of buffer depends on the pH stability profile of active ingredient as drug needs to be reconstituted and stored for some time before it could be administered to the patient. For this purpose, the pH of maximum stability of drug should be known and maintained.
Selection of a suitable buffer and its concentration is important for sensitive molecules.Commonly used buffers in the parenteral formulations are Acetate, Citrate, Tartrate, Phosphate, Triethanolamine (TRIS).
Suitable pH modifying agents used in the compositions of the present invention include, but are not limited to acids, bases or salt form of one or more, such as sulphuric acid, hydrochloric acid, nitric acid, phosphoric acid, phosphorous acid, carbonic acid, sulfurous acid, nitrous acid, ascorbic acid, propionic acid, lactic acid, citric acid, formic acid, oxalic acid, benzoic acid, acetic acid, tartaric acid, malonic acid, maleic acid, pyruvic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid, salicylic acid, tromethamine, sodium hydroxide, calcium hydroxide, potassium hydroxide and magnesium hydroxide, sodium dihydrogen phosphate and its hydrates, sodium phosphate and its hydrates, disodium hydrogen phosphate and its hydrates, sodium carbonate, sodium hydrogen carbonate, calcium hydrogen carbonate, sodium nitrite, sodium nitrate, magnesium nitrate, calcium nitrite and magnesium nitrite; Tris hydrochloride or combinations thereof. Preferably, the pH modifying agent comprises at least one of tromethamine, citric acid, ascorbic acid, hydrochloric acid, potassium carbonate, potassium bicarbonate and sodium hydroxide, and more preferably mixture of these compounds.
Tonicity adjusting agents
Parenteral formulations should be isotonic with human plasma so as to avoid damage to the tissues. However, not all drugs at their recommended dosage are isotonic with blood, thus requiring the addition of a tonicity adjusting agent to the formulation. The most commonly used tonicity agent is dextrose, while others, such as glycerol and sodium chloride are less commonly used. Other commonly used tonicity adjusting agents are: Glycerine and Mannitol.
The term “antioxidant” refers to the component that may react with oxygen that
might otherwise compromise the composition by producing oxidative impurities in the
composition responsible for unacceptable colour of formulation. Oxygen may
originate from the composition's environment or the composition itself e.g. oxygen
present in headspace of vials. The oxidative impurities comprise one or more of adrenochrome, adrenolutin, and melanins.
The antioxidants are used to prevent/minimize the oxidation reaction of the drug or excipients over the shelf life of the product whereas antimicrobial agents are used to prevent the growth of micro-organisms in the drug product. The most commonly used antioxidants in the sterile formulations are Ascorbic acid, Acetylcysteine, Sulfurous acid salts (bisulfite, metabisulfite), Monothioglyercol etc. The commonly used antimicrobial agents are Phenol, Meta-cresol, Benzyl alcohol, Parabens (methyl, propyl, butyl), Benzalkonium chloride, Chlorobutanol, Thimerosal, Phenylmercuric salts (acetate, borate, nitrate) etc.
The present invention provides for a composition that comprise of at least one
antioxidant that prevent the formation of oxidative degradants in the composition during the period of shelf life.
Antioxidant used in the compositions of the present invention include, but are
not limited to L-Methionine, butyl hydroxyl toluene (BHT), benzotriazol, butyl hydroxyl anisole (BHA), ascorbyl palmitate, disodium calcium ethylene diamine tetra acetate, DL-alpha tocopherol, disodium ethylene di amine tetra acetate, erythorbic acid, dithiothreitol, monothioglycerol, thio glycerol, propyl gallate, erythorbate, sodium thioglycolate, vitamin E and derivatives thereof, a-thioglycerin, and/or salts thereof. More particularly the antioxidant used for the present composition of the injectable preparation is sodium sulphite.
L- Methionine is sulphur-containing amino acids with excellent antioxidant abilities is used hereby in present invention as antioxidant additives to extend shelf-life of preparation and offer beneficial pharmacological effect against cell damage caused by oxidative stress. Further L- Methionine, functions as an antioxidant and as a key component of a biological system for regulation of cellular metabolism. L- Methionine is readily oxidized to methionine sulfoxide by many reactive species. The oxidation of surface exposed methionines thus serves to protect other functionally essential residues from oxidative damage.
Chelating agents:
In addition to the antioxidant and antimicrobial a chelating agent can be defined as a substance whose molecules can form several bonds to a single metal ion. Against the general understanding several single dose preparations contain preservatives due to legacy.
Chelating agents used in the compositions of the present invention include, but are not limited to ethylene diaminetetraacetic acid (EDTA), deferoxannine, desferrioxannine B, dithiocarb sodium, penicillamine, pentetate calcium, a sodium salt of pentetic acid, succimer, trientine, nitrilotriacetic acid, diethylenetriaminepentaacetic acid, trans-diaminocyclohexanetetraacetic acid (DCTA), dihydroethylglycine, bis(anninoethyl) glycolether-N,N,N',N'-tetraacetic acid, iminodiacetic acid, poly(aspartic acid), citric acid, tartaric acid, fumaric acid, succinic acid, glycolic acid, lactic acid, oxalic acid, malic acid, lecithin or any salt thereof, and the like or a combination thereof may be employed. Preferably, the chelating agent is selected from EDTA or Sodium sulphite.
Solubilizing agents:
The agents which help in dissolving or increase the drug solubility into the formulation are known as solubilizing agents, the solubilising agents can be broadly classified into surfactants and co-solvents. The surfactants increase the dissolution by reducing the surface tension of the drug substances whereas, co-solvents are defined as a solvent that in conjunction with another solvent can dissolve a solute.
Few examples of surfactants are Polyoxy ethylene sorbitan monooleate (Tween 80), Sorbitan monooleate Polyoxy ethylene sorbitan monolaurate (Tween 20), Lecithin, Polyoxy ethylene– polyoxy propylene copolymers (Pluronics). Examples of co-solvents are Propylene glycol, Glycerin, Ethanol, Polyethylene glycol (300 and 400), Sorbitol, Dimethyl acetamide and Cremophor EL etc.
Complexing and Dispersing Agents:
Complexation is sometimes used to improve the solubility of drug in the solvent especially water. Cyclodextrins have emerged as very effective additive compounds for solubilizing hydrophobic drugs. In the parenteral dosage form, modified cyclodextrins, such as hydroxypropyl-b-cyclodextrin and sulfobutylether- b –cyclodextrin have been reported to solubilize and stabilize many injectable drugs, including dexamethasone, estradiol, interleukin-2, and other proteins and peptides without apparent compatibility problems.
Tonicity agents
Tonicity agents used in the compositions of the present invention include, but are not limited to sodium chloride, calcium chloride, magnesium chloride, sodium lactate; glucose, fructose, sorbitol, mannitol, galactose, inositol, maltitol, lactose, trehalose, maltose, sucrose, dextran, glycerin, sorbitol, propylene glycol, etc., or a combination thereof. Preferably, the tonicity regulating agent comprises sodium chloride, mannitol or a combination thereof may be employed. The amount of tonicity agent in a given formulation can be selected based on the nature of the tonicity agent and the tonicity of the composition without the tonicity agent.
Stabilising agent:
Stabilizing agent or solubilizer agent for the present invention is selected from and mot limited to L-arginine, Methionine, Asepsis sodium bicarbonate, Butylhydroxyanisol, m-Cresol, Cysteine hydrochloride, Dichlorodifluoromethane, Diethanolamine Diethylene triamine penta acetic acid, Ferric chloride, Highly purified yolk lecithin, Human serum albumin, Hydrolyzed gelatin, Inositol, Lidocaine hydrochloride, D, L-Methionine or combination thereof, tryptophan, leucine, valine, phenylalnine, isoleucine, threonine, L-Lysine, histidine.
Vehicle:
In various embodiments, the aqueous vehicle can be a sterile aqueous vehicle that is normally used as liquid vehicle for injection. Exemplary aqueous vehicle includes, but not limited to, water, saline and aqueous dextrose solution. Preferably, sterile water used for injections can be used as aqueous vehicle in the present disclosure.
Vehicle for the present invention is selected from and not limited to water, Diethylene glycol monoethyl ether, known as Ethyldiglycol or Transcutol, 2- (2-Ethoxyethoxy) ethanol.
Penetration enhancer:
Glycofurol considered aromatic solvent or carrier. It has been reported as an enhancer facilitating the uptake of a biologically active substance through a nasal mucosal membrane of a mammal.
Glycofurol (GF) is a colourless liquid miscible with water, alcohols, such as methanol, ethanol, n-propanol, glycerol and various oils in all proportions. It has been reported to be non-toxic and non-irritating when diluted in water.
Glycofurol is used in pharmaceutical formulation as an excipient and acts to enhance penetration. It is used in parenteral products as a solvent for intravenous as well as intramuscular injection. Moreover, it also has applications in topical and intranasal formulations. At a certain concentration, it is also used in a rectal formulation.
Solvents:
Solvents for the present invention is selected from and not limited to Benzyl benzoate, Castor oil, Cottonseed oil, N, N-dimethylacetamide Ethanol/ethanol dehydrated, Glycerin (glycerol), N-methyl-2-pyrrolidone, Peanut oil, Poppyseed oil, Propylene glycol, Safflower oil, Sesame oil, Soybean oil, Vegetable oil or combination thereof.
Solvents and co-solvents for the present invention is selected from and not limited to Polyethylene Glycol, Polyethylene Glycol 300, Polyethylene Glycol 400, Polyethylene Glycol 600, Polyethylene Glycol 3350, Polyethylene Glycol 4000 or combination thereof.
While the foregoing description discloses various embodiments of the disclosure, other and further embodiments of the invention may be devised without departing from the basic scope of the disclosure. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure.
The present disclosure is further explained in the form of following examples.
However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and
modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.
The sterile injectable composition of the present invention may be administered via parenteral route and not limited to intravenous (I.V.) route.
The sterile injectable composition of the present invention may provide one or more advantages like, providing a safe composition by solubilizing the drug without usage of providing a stable, clear, aqueous solution suitable for I.V. administration compatible with routinely used I.V. sets and having improved stability, efficacy, and safety profile.
Injectable preparations:
Parenteral articles are preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal, so that the active substances they contain are administered, using gravity or force, directly into a blood vessel, organ, tissue, or lesion. Parenteral articles are prepared scrupulously by methods designed to ensure that they meet Pharmacopeia requirements for sterility, pyrogens, particulate matter, and other contaminants, and, where appropriate, contain inhibitors of the growth of microorganisms. An Injection is a preparation intended for parenteral administration and/or for constituting or diluting a parenteral article prior to administration. Parenteral route of drug administration is most favourable for highly potent and low dose of drug. The various route of administration available among them intravenous route give highest systemic circulation of drug and able to achieve 100% bioavailability of drug.
Injectable preparations possess certain advantages over other dosage forms. Parenteral route is rapid route of administration of the drug molecule in vivo. The parenteral preparations are more useful in case of unconscious patients. Further this route of administration is also beneficial in case of uncooperative patients. Various drug molecules administered orally get inactivated by Gastro- intestinal GIT enzymes. This inactivation can be avoided by administering through parenteral route. Parenteral preparations further avoids the first pass effect. In case of parenteral preparation bioavailability is achieved to 100%.
The following is a detailed description of embodiments of the present disclosure.
The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
Unless the context requires otherwise, throughout the specification which follow,
the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
Reference throughout this specification to “one embodiment” or “an embodiment”
means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
While the foregoing description discloses various embodiments of the disclosure, other and further embodiments of the invention may be devised without departing from the basic scope of the disclosure. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
The present invention further relates along with the complexing agent, co-solvents are present which are responsible for API solubility enhancement and to avoid the crystallization. The combination of co-solvents along with the complexing agent helps to improve the stability of the formulation.
The present invention relates to combination of co- solvent and the combination of a solvent and co-solvent in a formulation offers several benefits, particularly in pharmaceutical, cosmetic, and chemical applications. Here are the primary advantages:
1. Improved Solubility of Active Ingredients
Solvent alone may not always dissolve certain compounds, especially if they have low water solubility or are poorly soluble in a single solvent. The use of a co-solvent (a secondary solvent) can significantly enhance the solubility of active ingredients, especially for hydrophobic or lipophilic substances.
A combination of solvents and co-solvents provides a broader range of polarity, allowing better dissolution of a variety of substances.
2. Optimization of Formulation Viscosity
The use of a solvent and co-solvent combination can help in achieving the desired viscosity. The co-solvent can modify the viscosity of the mixture, making it more suitable for its intended application, whether it is for topical creams, injectables, or oral solutions.
3. Increased Stability
Some compounds may degrade or become unstable in a single solvent system. A co-solvent can provide a more stable environment, minimizing degradation due to oxidation, hydrolysis, or other factors.
In pharmaceutical formulations, for example, the right solvent combination can help in maintaining the stability of the active pharmaceutical ingredient (API).
4. Enhanced Permeability and Bioavailability
In drug formulations, especially for oral or topical administration, the use of solvents and co-solvents can improve the permeability of the active compound through biological barriers, such as the skin or intestinal wall, by increasing the solubility and dissolution rate.
This can result in better bioavailability of the active ingredient, improving the effectiveness of the formulation.
5. Control of Release Rate
The solvent and co-solvent combination can control the release rate of the active ingredient. For sustained or controlled-release formulations, the choice of solvents and co-solvents is critical to ensure that the active ingredient is released at a consistent rate over time.
6. Reduced Irritation and Toxicity
Some solvents may cause irritation or toxicity when used alone. The careful selection of a co-solvent can reduce irritation by diluting the active compound, modifying the solvent’s properties, or reducing the overall toxicity of the formulation.
8. Flexibility in Formulation Development
By using a combination of solvents and co-solvents, formulators have greater flexibility to design formulations with specific properties (such as higher concentration, lower toxicity, improved release profile) to meet the requirements of specific applications or regulatory guidelines.
9. Cost Efficiency
In some cases, using a co-solvent may allow the formulator to reduce the amount of more expensive solvents needed in the formulation. The co-solvent may help in reducing the overall cost of production without compromising the formulation's effectiveness.
In conclusion, the combination of a solvent and co-solvent is a powerful approach that allows for fine-tuning of solubility, stability, release rates, and other critical formulation characteristics, enabling the development of more effective, efficient, and safe products.
In a further embodiment of the present invention formulation excipient are selected from and not limited to following categories:
Sr. No. Category Examples
1. Active pharmaceutical ingredient Brexanolone
2. Complexing agent Kleptose (Hydroxypropyl Beta Cyclodextrin)
3. Solvent Polyethylene Glycol 400
4. Co-solvent Propylene Glycol
5. Buffer Citric acid monohydrate
6. Buffer Trisodium citrate dihydrate
7. pH adjusting agent 1N Hydrochloric acid
8. pH adjusting agent 1N Sodium Hydroxide
9. Vehicle Water for injection

The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure.
The present disclosure is further explained in the form of following examples.
However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and
modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.
EXAMPLE 1:
Injection formulation comparing Brexanolone.
Sr. No Ingredients mg/ml % w/v
1. Brexanolone 5.0 0.50
2. Kleptose (Hydroxypropyl Beta Cyclodextrin) 187.5 18.75
3. Polyethylene Glycol 400 100.0 10.00
4. Propylene Glycol 100.0 10.00
5. Citric acid monohydrate 0.265 0.0265
6. Trisodium citrate dihydrate 2.57 0.257
7. Water for injection q. s. to 1 mL -----

Method of preparation Brexanolone injection:
1) Take about 50 L water for injection (WFI) in a SS tank. Heat, maintain temperature 80-100°C
2) Into step no. (1) add weighed quantity of Kleptose under continuous stirring. Stir for 1 hour or till gets a clear solution. Allow to cool at RT. (temperature 25°C to 30°C)
3) Into step no. (2) add weighed quantity of API under continuous stirring. Stir till dissolves completely giving a clear solution.
4) Into step no. (3) add weighed quantity of Polyethylene Glycol-400 stir for 30 min.
5) Into step no. (4) add weighed quantity of Propylene glycol. Stir for 30 minutes.
6) Into step no. (5) add weighed quantity of citric acid monohydrate stir for 30 minutes.
7) Into step no. (5) add weighed quantity of trisodium citrate dihydrate. Stir for 30 minutes.
8) Check and record the pH.
9) Adjust the pH to 6.50 ±0.1. Stir for 15 minutes.
10) Make up the volume, up to the mark using WFI. Stir for 15 minutes.
11) Filter through 0.45µ PVDF followed by 0.22µ PVDF membrane filters.
12) Fill the filtered solution into type I glass vial, rubber stopper and seal it using aluminum seal. Carry out terminal sterilization.

Example of formulation:
Sr. No Ingredients Example 2
% w/v Example 3
% w/v
1. Brexanolone 0.75 1.0
2. Kleptose (Hydroxypropyl Beta Cyclodextrin) 15 25
3. Polyethylene Glycol 400 15 20
4. Propylene Glycol 15 20
5. Potassium Dihydrogen Phosphate 0.50 0.50
6. Dipotassium Hydrogen Phosphate 0.25 0.25
7. Water for injection QS QS

ANALYTICAL STUDY OF INJUCTION FORMULATION:
Analytical study has been conducted for present Injection formulation comprising aforesaid composition. The results are generated for exemplified combinations are provided merely as illustrations of the invention and are not intended to be construed as a limitation thereof.
Analytical data of Example 1:
Condition Description pH Assay RS (%)
(%) Imp A Imp B SMUI Total impurities
Before filtration A clear, colorless solution 6.47 97.1 --- --- --- ---
After filtration A clear, colorless solution 6.47 97.0 ND ND 0.15 0.28
Autoclaved A clear, colorless solution --- 97.9 ND ND 0.20 0.43

Analytical data of Example 2:
Time Condition Description Assay RS (%)
point (%) Imp A Imp B SMUI Total impurities
0 day After filtration A clear, colorless solution 99.4 ND ND 0.26 0.64
1M 2-8°C A clear, colorless solution 95.9 ND ND 0.47 0.77
25°C/60%RH A clear, colorless solution 95.0 ND ND 0.68 1.22

Analytical data of Example 3:
Time Condition Description pH Assay RS (%)
point (%) Imp A Imp B SMUI Total impurities
0 day After filtration A clear, colorless solution 4.63 97.5 ND ND 0.23 0.61
1M 2-8°C A clear, colorless solution 4.08 96.1 ND ND 0.26 0.41
25°C/60%RH A clear, colorless solution 4.26 95.8 ND ND 0.24 0.89

STABILITY STUDY OF INJECTION FORMULATION:
Storage stability study has been conducted for present Injection formulation comprising aforesaid composition. The results are generated for exemplified combinations are provided merely as illustrations of the invention and are not intended to be construed as a limitation thereof.
Table 1: Storage stability Study of the Injection formulation:
Time Condition Description pH Assay RS (%)
point (%) Imp A Imp B SMUI Total impurities
0 day Before filtration A clear, colorless solution 6.47 97.1 --- --- --- ---
After filtration A clear, colorless solution 6.47 97.0 ND ND 0.15 0.28
1M 2-8°C A clear, colorless solution 6.44 101.4 ND ND 0.22 0.37
25°C/60%RH A clear, colorless solution 6.07 98.7 ND ND 0.15 0.27
3M 2-8°C A clear, colorless solution 6.13 97.5 ND ND 0.13 0.24
25°C/60%RH A clear, colorless solution 5.94 97.9 ND ND 0.24 0.34
6M 2-8°C A clear, colorless solution 5.92 100.7 ND ND 0.19 0.44
25°C/60%RH A clear, colorless solution 6.04 102.2 ND ND 0.31 0.68
-- Autoclaved A clear, colorless solution --- 97.9 ND ND 0.20 0.43

,CLAIMS:Claims
I/We Claim,
1. A pharmaceutical composition for injectable preparation comprises:
a. Compound A is present in amount of 0.5 to 1%;
b. Compound B is present in amount of 15 to 25%;
c. solvent are present in amount of 5 to 20%
d. co solvent are present in amount of 5 to 20%;
e. buffers are present in amount 0.0001 to 0.5% and
f. vehicle is present to make QS.

2. The pharmaceutical composition claimed in claim 1, wherein compound A is Brexanolone.

3. The pharmaceutical composition claimed in claim 1, wherein compound B is complexing agent.

4. The pharmaceutical composition claimed in claim 1, wherein compound B is selected from hydroxypropyl-beta-cyclodextrin and sulfobutylether- b –cyclodextrin.

5. The pharmaceutical composition claimed in claim 1, wherein solvent are selected from Benzyl benzoate, Castor oil, Cottonseed oil, N,N-dimethylacetamide Ethanol/ethanol dehydrated, Glycerin (glycerol), N-methyl-2-pyrrolidone, Peanut oil Poppyseed oil, Propylene glycol, Safflower oil, Sesame oil, Soybean oil, Vegetable oil or combination thereof.

6. The pharmaceutical composition claimed in claim 1, wherein co solvent are selected from Polyethylene Glycol, Polyethylene Glycol 300, Polyethylene Glycol 400, Polyethylene Glycol 600, Polyethylene Glycol 3350, Polyethylene Glycol 4000 or combination thereof.

7. The pharmaceutical composition claimed in claim 1, wherein buffers are selected from Citric acid monohydrate, Trisodium citrate dehydrate, Potassium Dihydrogen Phosphate, Dipotassium Hydrogen Phosphate.

8. The pharmaceutical composition claimed in claim 1, wherein vehicle is selected from water, Diethylene glycol monoethyl ether, known as Ethyldiglycol or Transcutol, 2- (2-Ethoxyethoxy) ethanol.

9. A process for preparation of pharmaceutical composition for injectable preparation comprises:

vii. Take about 50 L water for injection and heat at 80-100 °C, maintain temperature 80-100°C;
viii. add Kleptose under continuous stirring. Stir for 1 hour or till gets a clear solution and cool at 25°C to 30°C;
ix. add Brexanolone and stirr until gets clear solution; add Polyethylene Glycol-400 and Propylene glycol and stir for 30 min.
x. add citric acid monohydrate and trisodium citrate dehydrate and stir for 30 min;
xi. add water and stir for 15 min and filter to obtained final product.

10. The process for preparation of pharmaceutical composition claimed in claim wherein filter the solution through 0.45µ PVDF followed by 0.22µ PVDF membrane filters. Fill and seal the filtered solution in glass vial and carry out the terminal sterilization.

Dated this 28th day of January 2022