DESC:“STABLE PHARMACEUTICAL COMPOSITIONS OF HYDROCORTISONE OR COMBINATIONS THEREOF”

FIELD OF THE INVENTION:
The present invention relates to a stable pharmaceutical composition of corticosteroid and optionally other active agent(s). The present invention relates to a stable pharmaceutical composition of hydrocortisone and optionally other active agent(s) having a reduced level of impurities, and a method of maintaining the stability of such pharmaceutical compositions. Further it also relates to process of preparation and treatment thereof.

BACKGROUND OF THE INVENTION:
Millions of people worldwide suffer from various ear disorders and associated conditions such as otitis media, hearing loss, tinnitus, and meniere’s disease. For example, the chronic otitis media or otitis externa affects 3–5% of the U.S. population, with an estimated annual cost of more than $2.98 billion. Potentially lifethreatening infections can spread to surrounding tissues if these diseases are not optimally treated, especially for immunocompromised patients. According to a WHO survey, 250 million people worldwide have moderate to severe hearing loss. The prevalence of hearing loss in the U.S. increases as the population ages and causes serious social and economic burden. Tinnitus, meniere’s disease, and autoimmune inner ear disease are also common disorders that significantly reduce an individual’s quality of life [Xu Liu et al].

Ear infections is an inflammation of the inner, middle or outer ear, often with infection. There are different types of ear infections. Middle ear infection (acute otitis media) is an infection in the middle ear. Another condition that affects the middle ear is called otitis media with effusion. This condition occurs when fluid builds up in the middle ear without causing an infection. Otitis media with effusion does not cause fever, ear pain, or pus build-up in the middle ear. Swimmer’s ear is an infection in the outer ear canal. Swimmer’s ear (also known as otitis externa) is a bacterial infection typically caused by water that stayed in the outer ear canal for a long period of time, providing a moist environment for bacteria to grow. Anyone can get swimmer’s ear, but it is most often seen in children. Swimmer’s ear cannot be spread from one person to another. [cdc.gov/antibiotic-use/ear-infection.html]

Most cases of otitis externa (OE) are caused by superficial bacterial infections and can be treated with over-the-counter analgesics and topical eardrops. Commonly used topical eardrops are acetic acid drops, which change the pH of the ear canal; antibacterial drops, which control bacterial growth; and antifungal preparations. Oral or parenteral antibiotics are reserved for severe cases. Otic antibiotic and steroid combinations have shown to be highly successful in treatment. The corticosteroid ingredient decreases inflammation and can help to ease the pain. These eardrops treat bacterial infection and reduce canal edema. The agents commonly prescribed for treating otitis externa are associated with cure rates between 87% and 97%. In severe cases, oral or intravenous (IV) antibiotic therapy and narcotic analgesics may be required. [Ariel A Waitzman et al]

Hydrocortisone, a corticosteroid, also known as cortisol. Hydrocortisone is an anti-inflammatory hormone. The chemical name of hydrocortisone is 11ß,17a,21-trihydroxy-pregn-4-ene-3,20-dione, and its empirical formula is C21H30O5. The molecular weight of hydrocortisone is 362 g·mol-1. It appears as white to almost white, crystalline and not hygroscopic. It is practically insoluble in water, sparingly soluble in acetone and in alcohol and slightly soluble in methylene chloride.

Neomycin sulfate is the sulfate salt of neomycin B and C, which are produced by the growth of Streptomyces fradiae Waksman (Fam. Streptomycetaceae). It has a potency equivalent of not less than 600 mcg of neomycin standard per mg, calculated on an anhydrous basis.

Polymyxin B sulfate is the sulfate salt of polymyxin B1 and B2, which are produced by the growth of Bacillus polymyxa (Prazmowski) Migula (Fam. Bacillaceae). It has a potency of not less than 6,000 polymyxin B units per mg, calculated on an anhydrous basis.

Fixed-dose combination of hydrocortisone; neomycin sulfate; polymyxin b sulfate was approved as otic solution, for otic administration use under the tradename CORTISPORIN® by Monarch Pharmaceuticals LLC. CORTISPORIN® Was indicated for the treatment of superficial bacterial infections of the external auditory canal caused by organisms susceptible to the action of the antibiotics. CORTISPORIN comprises of hydrocortisone 1%; neomycin sulfate EQ 3.5MG BASE/ML; polymyxin b sulfate 10,000 UNITS/ML) is a sterile. Currently CORTISPORIN® is discontinued in US FDA.

The following local adverse reactions have been reported with topical corticosteroids, especially under occlusive dressings: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, and miliaria. Stinging and burning have been reported when this product has gained access to the middle ear.

Australian AU 502937 B2 patent, disclosed pharmaceutical compositions for topical application to the skin comprising an essentially saturated solution of hydrocortisone in an aqueous propylene glycol solution containing at least 15% but less than 50% by weight of proylene C glycol and having a pH of 4.5 to 5, the proportion of hydrocortisone in the composition being at least 0.08% but not greater than 0.4% by weight of acqueous propylene glycol and from 0.025 to 0.4% based on the total weight of the composition, are very much more effective on topical application than the hydrocortisone-containing compositions which have heretofore been used for that purpose. Further states the proportions of water and propylene glycol in these compositions are very important.

Korean KR 20220130253 A patent publication, disclosed the stable glucocorticoid preparations with low concentrations of preservatives. More specifically, they disclosed high-concentration formulations of aqueous pharmaceutical compositions containing glucocorticoids formulated together with low levels of preservatives for antioxidant activity. Previously formulated at high dose levels, these preservatives have been found to be associated with patient toxicity. Thus, as disclosed herein, the ability to achieve sustained drug stability and purity in the presence of low levels of antioxidants is highly desirable.

Canadian CA 583224 A patent publication, disclosed compositions containing hydrocortisone and neomycin as the essential active ingredients. Further discloses a composition comprising hydrocortisone (or its therapeutically active derivatives) and neomycin (or its therapeutically active derivatives). While it is impossible to assess all of the interactions that exist between these two materials or explain some of the therapeutic results obtained by clinical use of the combination, it is impossible to deny that such interaction does exist and has contributed a great deal to the immediate clinical and commercial success of the composition.

Jens Hansen et al, disclosed studies on the stability of corticosteroids v. the degradation pattern of hydrocortisone in aqueous solution. Further disclosed the degradation pattern of hydrocortisone in aqueous solution was investigated utilizing an HPLC procedure capable of separating and quantitating hydrocortisone and its major degradation products.

Jumpei Saito et al, disclosed stability of hydrocortisone in oral powder form compounded for pediatric patients in japan. Further disclosed in this study, they formulated a 20 mg/g oral hydrocortisone powder by adding lactose monohydrate to crushed and filtered hydrocortisone tablets and assessed the stability and physical properties of this compounded product in polycarbonate amber bottles or coated paper packages laminated with cellophane and polyethylene.

Hydrocortisone impurities [Jumpei Saito et al]
Sr. Impurity Name Impurity Synonym
1 Prednisolone Impurity A
2 Cortisone Impurity B
3 Hydrocortisone Acetate Impurity C
4 6ß-Hydorxy-hydrocortisone Impurity D
5 6-Hydrocortisol Impurity E
6 Reichstein substances S Impurity F
7 Hydrocortisone-21-aldehyde Impurity G
8 7a-Hydroxy- Hydrocortisone Impurity H
9 14a-Hydroxy- Hydrocortisone Impurity I
10 Hydrocortisone Dimer Impurity N

Xu Liu et al, disclosed otic drug delivery systems: formulation principles and recent developments. Further disclosed disorders of the ear severely impact the quality of life of millions of people, but the treatment of these disorders is an on-going but often overlooked challenge particularly in terms of formulation design and product development.

One approach for providing sterile, effective, stable composition of hydrocortisone optionally with other active agent(s). Numerous factors can impact the design of an effective drug delivery system and certain classes of drugs, such as the corticosteroid, are typically considered to be relatively short lasting such that they are most often used only in relatively minor or moderate treatments. Steroids are used to treat many conditions in which the body’s defense system doesn’t work properly and causes tissue damage. Steroids may be the main therapy for certain diseases. There remains a need for stable compositions for the treatment of bacterial infection that are sterile, efficacious, convenient to administer, and that can overcome some of the drawbacks associated with the use of steroids or combination with other active agent(s). The present compositions and methods satisfy these and other needs.

Stable otic compositions comprising stabilizer with other inactive agents to provide stable composition for the usage in humans or animals. Instability can be in the form of reduced assay or elevated impurity and increased level of degradant profile. This type of instability needs to be handled critically, the inventors of the present invention have surprisingly found suitable and robust methods or process to stabilize active agent(s), so that the finished product is stable during the shelf life.

Moreover, there is a lack of critical reviews that have summarized formulation design principles of the various local drug administration methods that guide the development of otic drug products. Specifically, there are numerous challenges to develop an otic drug solution for otic infections.

Despite the above-mentioned prior art stable pharmaceutical composition of hydrocortisone optionally with other active agent(s), there still exists a need for a stable otic pharmaceutical composition of hydrocortisone, which is capable of stabilising the composition.

Accordingly, inventors of the present invention unexpectedly found a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate, propylene glycol and one or more pharmaceutically acceptable excipient(s) having a reduced level of impurities, and a method of maintaining the stability of such pharmaceutical compositions with a novel process of preparation thereof.

OBJECT OF THE INVENTION:
It is object of the present invention to provide a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate, propylene glycol and one or more pharmaceutically acceptable excipient(s) having a reduced level of impurity B and /or impurity F, and a method of maintaining the stability of such pharmaceutical compositions.

It is another object of the present invention to provide a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate is from 0.0001 mg to 0.7 mg, propylene glycol is from 400 mg to 700 mg and one or more pharmaceutically acceptable excipient(s) having a reduced level of impurity B and/or impurity F, and a method of maintaining the stability of such pharmaceutical compositions.

It is another object of the present invention to provide a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate, propylene glycol and one or more pharmaceutically acceptable excipient(s) having a reduced level of impurity B, and a method of maintaining the stability of such pharmaceutical compositions and treatment thereof.

It is yet another object of the present invention to provide a method or process of preparation of a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate, propylene glycol and one or more pharmaceutically acceptable excipient(s).

SUMMARY OF THE INVENTION:
The present invention relates to a stable pharmaceutical composition of corticosteroid and optionally other active agent(s) with one or more pharmaceutically acceptable excipient(s).

The present invention relates to a stable pharmaceutical composition of corticosteroid and optionally one or more antibacterial active agent(s) with one or more pharmaceutically acceptable excipient(s).

The present invention relates to a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with one or more pharmaceutically acceptable excipient(s), having a reduced level of impurities, and a method of maintaining the stability of such pharmaceutical compositions.

The present invention relates to a method of preparation of a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate, propylene glycol and one or more pharmaceutically acceptable excipient(s).

The present invention relates to a stable pharmaceutical composition, comprising: hydrocortisone or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipient(s); wherein the pH of the composition from about 2 to about 4.5; wherein said composition comprises =2% w/w of impurity B.

The present invention relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B.

The present invention relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally one or more active agent(s) or pharmaceutically acceptable salts thereof and
(iii) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B.

The present invention relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally neomycin and/or polymyxin B or pharmaceutically acceptable salts thereof;
(iii) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B.

The present invention relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally neomycin and/or polymyxin B or pharmaceutically acceptable salts thereof;
(iii) cupric sulfate, propylene glycol, glycerin or combination thereof;
(iv) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B.

The present invention relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally neomycin and/or polymyxin B or pharmaceutically acceptable salts thereof;
(iii) cupric sulfate, propylene glycol, glycerin or combination thereof;
(iv) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =0.5% w/w of impurity F.

The present invention relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally neomycin and/or polymyxin B or pharmaceutically acceptable salts thereof;
(iii) cupric sulfate, propylene glycol, glycerin or combination thereof;
(iv) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B and/or =0.5% w/w of impurity F.

The present invention relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally neomycin and/or polymyxin B or pharmaceutically acceptable salts thereof;
(iii) cupric sulfate is from 0.0001 mg to 0.7 mg;
(iv) propylene glycol is from 400 mg to 700 mg;
(v) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B and/or =0.5% w/w of impurity F.

The present invention, provides the stable pharmaceutical composition, method of preparation of stable composition, comprising of below steps:
(i) dissolving cupric sulfate, potassium metabisulfite, optionally one or more active agent(s) in to the water for injection;
(ii) dissolving hydrocortisone, glycerin in to the propylene glycol;
(iii) add step (i) & (ii) content to form solution;
wherein the pH of the composition from about 2 to about 4.5.

The present invention relates to a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate, propylene glycol, glycerin and one or more pharmaceutically acceptable excipient(s) having a reduced level of impurity B, and a method of maintaining the stability of such pharmaceutical compositions and treatment thereof

The present invention relates to a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate used for the treatment of bacterial infections.

DETAILED DESCRIPTION:
The present invention relates to a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate, propylene glycol and one or more pharmaceutically acceptable excipient(s) having a reduced level of impurity B, and a method of maintaining the stability of such pharmaceutical compositions and treatment thereof

Before the present process and methods are described, it is to be understood that this invention is not limited to particular compound(s), composition(s), embodiment(s), Process described, as such may, of course, vary.

Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, the words or terms set forth below have the following definitions:

The term "active pharmaceutical ingredient" or "drug" or “API” or “active agent” refers to a substance that has a physiological effect when ingested or otherwise introduced into the body, in particular or a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well- being. The "active pharmaceutical ingredient" or "drug" or “API” or “active agent” is corticosteroid, antibacterial agent, and the like.

In one embodiment, the corticosteroid is hydrocortisone or pharmaceutically acceptable salts thereof.

Another embodiment related to any one or more of the foregoing embodiments, the antibacterial agent and other active is selected from the group comprising of neomycin, polymyxin B, fluconazole, voriconazole tobramycin, cefoperazone, cefotaxime, cefprozil, erthyromycin, ciprofloxacin, ofloxacin, tetracycline, metronidazole, ornidazole, rifampicin, vancomycin, cycloserine, protionamide, isoniazide, clotrimazole, fluconazole, itraconazole, griseofulvin, ketoconazole, terbinafine, ketoconazole, acyclovir, ganciclovir, levamisole, mebendazole, artemether, artesunate, hydroxychloroquine, mefloquine, metronidazole, furazolidine, artesunate, arteether, artemether etc. and the like.

Another embodiment related to any one or more of the foregoing embodiments, the one or more active agent(s) comprises of neomycin, polymyxin B, ciprofloxacin, acyclovir, bacitracin, chloramphenicol, colistin, thonzonium, tetracycline, pramoxine or pharmaceutically acceptable salts thereof.

By "pharmaceutically acceptable excipient(s)", it is meant any of the components of a pharmaceutical composition other than the active ingredients and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.

The term "pharmaceutically acceptable salts" or “salts thereof” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts, solvate, hydrate, esters and the like thereof. Pharmaceutically-acceptable salt forms of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.

"Carrier" or "vehicle" or "solvent" or “diluent” as used herein refers to pharmacologically inert materials that provide more or less fluid matrix, suitable for otic drug administration. Carriers, vehicles or diluent useful herein include any such materials known in the art, which are nontoxic and do not interact with other components of a pharmaceutical composition or drug delivery system in a deleterious manner. In one embodiment vehicle comprises of water for injection and the like.

Herein, the term “pharmaceutical composition” or “composition” refers to a formulation of a pharmaceutical active which renders the biological activity of the active ingredient therapeutically effective, but which does not include other ingredients which are obviously toxic to a subject to which the formulation are intended to be administered. Further composition according to the invention comprise but are not limited to solid, semisolid, liquid dosage forms. Non limiting examples of the composition of the invention include composition is in the form of liquids, ointments, gels, creams, and foams. Preferably composition in the form of solution. The term “solution” or "drug solution" or "medicament" is used herein as a synonym describing a pharmaceutical formulation containing one or more active pharmaceutical ingredient(s) or a pharmaceutically acceptable salt or solvate thereof and optionally a pharmaceutically acceptable carrier.

In an embodiment of the present invention, relates to a stable pharmaceutical composition supplied as sterile otic solution.

The term “about” or “approximately” means within (±) 10% of a given value or range or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Alternatively, the term “about” means within an acceptable standard error of the mean.

The term "optional" or "optionally" means that the subsequently described element, component or circumstance may or may not be present, so that the description includes instances where the element, component, or circumstance is included and instances where it is not.

The term "stability" or "stable" as used herein includes both physical and chemical stability. Stability parameters include but not limited to potency, stable pH value, less impurities and other physico-chemical parameters.

The term "stabilizer" means a pharmaceutically acceptable excipient that protects the active pharmaceutical ingredient and / or pharmaceutical composition from chemical and / or physical degradation during preparation, storage and use. Stabilizer may comprise, but are not limited to, cupric sulfate, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinyl pyrrolidones, polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture-absorbing polymers, may be in the form of salt(s), ester(s), solvate(s), hydrate(s), anhydrous and/or combinations thereof. In some embodiments, amide analogues of stabilizers are also used. In another embodiment some of these stabilizers are used as solvents/co-solvents (e.g., ethanol) and the like.

The term " Preservative" means a substance which is inhibits microbial growth, has antimicrobial activity, or otherwise inhibits the deterioration of a solution to which it is added. Preservative may comprise, but are not limited to, aluminum acetate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, boric acid, chlorobutanol, isopropyl alcohol, phenethyl alcohol, methylparaben, potassium metabisulfite, propylparaben, thiomersal or a combination thereof and the like.

pH modifier or pH adjusting agent may comprise, but are not limited to, citric acid, sodium citrate, potassium citrate, calcium citrate, hydrochloric acid, nitric acid, sodium hydroxide, potassium hydroxide, triethanolamine, diisopropanolamine, or a combination thereof and the like.

In an embodiment of the present invention, relates to a stable pharmaceutical composition can comprise an amount of one or more pH adjusting agents to adjust pH from about 1 to 6; for example pH from about 2 to about 4.5.

Humectant may comprise, but are not limited to, glycerin, hyaluronic acid, salicylic acid, glycolic acid, lactic acid, sorbitol or a combination thereof and the like.

Solvent may comprise, but are not limited to, polyethylene glycol, propylene glycol, or combination(s) thereof and the like.

The present invention provides a composition that may have low level of impurities. The term “impurity” refers to an undesired substance in a composition. In some embodiments, amount of impurities may be present in an initial composition and/or may be formed upon shelf life of a composition. In some embodiments, impurities may be formed via degradation of one or more components of the composition. Unless indicated otherwise, the percentages of impurities expressed herein are expressed as % w/w of the active agent or composition thereof.

In one embodiment, the impurity is cosrtisone (impurity B). In one embodiment, the amount of the cosrtisone (impurity B) is decreased by at least 0-1% W/W, 1-2% W/W, 2-3%W/W, 3-4%W/W, 0-5%W/W, 0-10%W/W.

In one embodiment, the impurity is reichstein substances S (impurity F). In one embodiment, the amount of the reichstein substances S (impurity F) is decreased by at least 0-1% W/W, 1-2% W/W, 2-3%W/W, 3-4%W/W, 0-5%W/W, 0-10%W/W.

As used herein, the term "Impurity B" & "Impurity F" defines a compound of formula:

In an embodiment of the present invention, relates to a stable pharmaceutical composition of corticosteroid and optionally other active agent(s) with one or more pharmaceutically acceptable excipient(s).

In an embodiment of the present invention, relates to a stable pharmaceutical composition of corticosteroid and optionally one or more antibacterial active agent(s) with one or more pharmaceutically acceptable excipient(s).

In an embodiment of the present invention, relates to a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with one or more pharmaceutically acceptable excipient(s), having a reduced level of impurities, and a method of maintaining the stability of such pharmaceutical compositions.

In an embodiment of the present invention, relates to a method of preparation of a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate, propylene glycol, glycerin and one or more pharmaceutically acceptable excipient(s).

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising: hydrocortisone or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipient(s); wherein the pH of the composition from about 2 to about 4.5; wherein said composition comprises =2% w/w of impurity B.

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B.

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally one or more active agent(s) or pharmaceutically acceptable salts thereof and
(iii) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B.

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally neomycin and/or polymyxin B or pharmaceutically acceptable salts thereof;
(iii) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B.

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally neomycin and/or polymyxin B or pharmaceutically acceptable salts thereof;
(iii) cupric sulfate, propylene glycol, glycerin or combination thereof;
(iv) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B.

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally neomycin and/or polymyxin B or pharmaceutically acceptable salts thereof;
(iii) cupric sulfate, propylene glycol, glycerin or combination thereof;
(iv) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =0.5% w/w of impurity F.

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally neomycin and/or polymyxin B or pharmaceutically acceptable salts thereof;
(iii) cupric sulfate, propylene glycol, glycerin or combination thereof;
(iv) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B and/or =0.5% w/w of impurity F.

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally neomycin and/or polymyxin B or pharmaceutically acceptable salts thereof;
(iii) cupric sulfate is from 0.0001 mg to 0.7 mg;
(iv) propylene glycol is from 400 mg to 700 mg;
(v) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B and/or =0.5% w/w of impurity F.

In an embodiment of the present invention, relates to a stable pharmaceutical composition, method of preparation of stable composition, comprises of below steps:
(i) dissolving cupric sulfate, potassium metabisulfite, optionally one or more active agent(s) in to the water for injection;
(ii) dissolving hydrocortisone, glycerin in to the propylene glycol;
(iii) add step (i) & (ii) content to form solution;
wherein the pH of the composition from about 2 to about 4.5.

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone or pharmaceutically acceptable salts thereof;
(ii) optionally neomycin and/or polymyxin B or pharmaceutically acceptable salts thereof;
(iii) cupric sulfate, propylene glycol, glycerin or combination thereof;
(iv) one or more pharmaceutically acceptable excipient(s);
wherein the pH of the composition from about 2 to about 4.5;
wherein said composition comprises =2% w/w of impurity B;
wherein said composition comprises about 95% hydrocortisone assay in accelerated condition.

In an embodiment of the present invention, relates to a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate, propylene glycol and one or more pharmaceutically acceptable excipient(s) having a reduced level of impurity B, and a method of maintaining the stability of such pharmaceutical compositions and treatment thereof

In an embodiment of the present invention, relates to a stable pharmaceutical composition of a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate used for the treatment of bacterial infections.

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) about 1 mg to about 20 mg hydrocortisone
(ii) about 0.0001 mg to about 0.5 mg cupric sulfate
(iii) about 1 mg to about 1500 mg propylene glycol
(iv) one or more pharmaceutically acceptable excipient(s).

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) about 1 mg to about 20 mg hydrocortisone
(ii) about 1 mg to about 10 mg neomycin sulfate
(iii) about 2000 units to about 20000 units polymyxin B sulfate
(iv) about 0.1 mg to about 10 mg potassium metabisulfite
(v) about 0.0001 mg to about 0.5 mg cupric sulfate
(vi) about 400 mg to about 700 mg propylene glycol
(vii) one or more pharmaceutically acceptable excipient(s).

In another embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) about 1 mg to about 20 mg hydrocortisone
(ii) about 0.0001 mg to about 0.5 mg cupric sulfate
(iii) about 400 mg to about 700 mg propylene glycol
(iv) one or more pharmaceutically acceptable excipient(s).

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone
(ii) cupric sulfate is from 0.0001 mg to 0.7 mg;
(iii) propylene glycol is from 400 mg to 700 mg;
(iv) one or more pharmaceutically acceptable excipient(s).

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone, neomycin sulfate, polymyxin B sulfate
(ii) cupric sulfate is from 0.0001 mg to 0.7 mg;
(iii) propylene glycol is from 400 mg to 700 mg;
(iv) one or more pharmaceutically acceptable excipient(s).

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(i) hydrocortisone, neomycin sulfate, polymyxin B sulfate one or combination thereof;
(ii) stabilizer is less than 0.7 mg;
(iii) solvent is from 400 mg to 700 mg;
(iv) one or more pharmaceutically acceptable excipient(s).

In an embodiment of the present invention, relates to a stable pharmaceutical composition, comprising:
(v) hydrocortisone, neomycin sulfate, polymyxin B sulfate one or combination thereof;
(vi) cupric sulfate is less than 0.7 mg;
(vii) propylene glycol is from 400 mg to 700 mg;
(viii) one or more pharmaceutically acceptable excipient(s).

In yet another embodiment of the present invention, relates to a stable pharmaceutical composition, method of preparation of stable composition, comprises of below steps:
(i) dissolving cupric sulfate, potassium metabisulfite, optionally one or more active agent(s) in to the water for injection;
(ii) dissolving hydrocortisone, glycerin in to the propylene glycol;
(iii) add step (i) & (ii) content to form solution;
wherein the pH of the composition from about 2 to about 4.5.

In one embodiment of the present invention, impurity can be measured using many different methods for a) Organic impurities: FTIR, Preparative Liquid Chromatography (LC), Liquid Chromatography and Ultraviolet Detection (LC/UV), Liquid Chromatography and Mass Spectrometry (LC/MS) [single quadrupole (SQ), quadrupole time-of-flight (Q-TOF), and triple quadrupole (QQQ)], Capillary Electrophoresis (CE), and Supercritical Fluid Chromatography (SFC) b) Inorganic/elemental impurities: Inductively-Coupled Plasma Optical Emission Spectroscopy (ICP-OES) and Inductively-Coupled Plasma Mass Spectrometry (ICP-MS) c) Residual solvents: Gas Chromatography (GC) and Gas Chromatography and Mass Spectrometry (GC/MS) and the other similar methods available in the art.

In another embodiment of the present invention, impurity can be measured using HPLC and the other similar methods available in the art.

In yet another embodiment of the present invention, the stable pharmaceutical composition having a reduced level of impurities.

In an embodiment of the present invention, provides a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate, propylene glycol and one or more pharmaceutically acceptable excipient(s) having a reduced level of impurity B, and a method of maintaining the stability of such pharmaceutical compositions and treatment thereof.

In an embodiment of the present invention, provides a stable sterile solution for otic administration of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate with cupric sulfate, propylene glycol and one or more pharmaceutically acceptable excipient(s) having a reduced level of impurity B, and a method of maintaining the stability of such pharmaceutical compositions and treatment thereof, species including but not limited to Staphylococcus aureus, Escherichia coli, Haemophilus influenzae, Klebsiella-Enterobacter species, Neisseria species, and Pseudomonas aeruginosa.

In an embodiment of the present invention, provides a stable pharmaceutical composition of a stable pharmaceutical composition of hydrocortisone optionally neomycin sulfate and/or polymyxin B sulfate used for the treatment of bacterial infections.
The present invention is further illustrated by reference to the following tables which is for illustrative purpose only and does not limit the scope of the invention in any way.
Table 1: Compositions
Sr Ingredients Comp. I Comp. II
1 Hydrocortisone - 1-20 mg
2 Potassium Metabisulfite 0.1-10 mg 0.1-10 mg
3 Cupric sulfate 0.0001 mg to 0.7 mg 0.0001 mg to 0.7 mg
4 Propylene glycol 400-700 mg 400-700 mg
5 Glycerin 400-700 mg 400-700 mg
6 Hydrochloric acid q.s to pH q.s to pH
7 Sodium Hydroxide q.s to pH q.s to pH
8 Water for Injection q.s to 1 mL q.s to 1 mL

Manufacturing Process:
Step I:
Required quantity of water for injection was collected and bubble the nitrogen till dissolved oxygen (DO) reaches less than 2 ppm. Dispensed quantity of stabilizer was added to the above and stirred to dissolve. Dispensed quantity of preservative was added to the above and stirred to dissolve.
Step II:
Dispensed quantity of solvent was collected in a cleaned and dried vessel. The temperature of the above step was raised to 40-50ºC. Dispensed quantity of hydrocortisone was added to the above and stirred to dissolve. above solution was cooled to room temperature. Dispensed quantity of humectant was added and stirred to dissolve.
Addition of Step I to Step II:
The Step I content to Step II content were transferred and stirred to dissolve. pH to 2.0 - 4.5 of the above bulk solution were adjusted with diluted hydrochloric acid and/or diluted sodium hydroxide solution. The volume was made up to 100 % with nitrogen bubbled water for injection and stirred the contents to form homogeneous solution. Above bulk solution was filtered through sterilizing grade filter. Above filtered solution was filled in LDPE bottles.
Table 2: Compositions
Sr Ingredients Comp. III Comp. IV Comp. V
1 Neomycin
(Neomycin Sulfate) 1-10 mg 1-10 mg 1-10 mg
2 Polymyxin B (Polymyxin B sulfate) 2000-20000 units 2000-20000 units 2000-20000 units
3 Hydrocortisone 1-20 mg 1-20 mg 1-20 mg
4 Potassium Metabisulfite 0.1-10 mg 0.1-10 mg 0.1-10 mg
5 Cupric sulfate - 0.0001 mg to 0.5 mg 0.0001 mg to 0.7 mg
6 Propylene glycol 400-700 mg 400-700 mg 400-700 mg
7 Glycerin 400-700 mg 400-700 mg 400-700 mg
8 Hydrochloric acid q.s to pH q.s to pH q.s to pH
9 Sodium Hydroxide q.s to pH q.s to pH q.s to pH
10 Water for Injection q.s to 1 mL q.s to 1 mL q.s to 1 mL

Manufacturing Process:
Step I:
Required quantity of water for injection was collected and bubble the nitrogen till DO reaches less than 2 ppm. Dispensed quantity of stabilizer was added to the above and stirred to dissolve. Dispensed quantity of preservative was added to the above and stirred to dissolve. Dispensed quantity of neomycin sulfate was added to the above and stirred to dissolve. Dispensed quantity of polymyxin B sulfate was added to the above and stirred to dissolve.
Step II:
Dispensed quantity of solvent was collected in a cleaned and dried vessel. The temperature of the above step was raised to 40-50ºC. Dispensed quantity of hydrocortisone was added to the above and stirred to dissolve. above solution was cooled to room temperature. Dispensed quantity of humectant was added and stirred to dissolve.
Addition of Step I to Step II:
The Step I content to Step II content were transferred and stirred to dissolve. pH to 2.0 - 4.5 of the above bulk solution were adjusted with diluted hydrochloric acid and/or diluted sodium hydroxide solution. The volume was made up to 100 % with nitrogen bubbled water for injection and stirred the contents to form homogeneous solution. Above bulk solution was filtered through sterilizing grade filter. Above filtered solution was filled in LDPE bottles.

Above composition loaded on to stability and monitored for pH, impurity and assay, the details of stability data are mentioned in below table.
Table 3: Stability data of Composition III
Parameters Initial 400c/25RH 400c/25RH 400c/25RH 250c/40RH 400c/25 RH 250c/40
RH
1M 2 M 3M 3M 6M 6M
Assay of
Hydrocortisone 98.7 93.8 91.9 84.9 86.3 73.7 75.6
Hydro
cortisone Impurity B 0.36 % 0.98 % 1.75 % 4.25 % 3.85 % 5.36 % 6.15 %
Impurity F 0.01 % 0.01 % 0.14 % 0.66 % 0.49 % 1.17 % 1.05 %
Total Impurities 0.76 % 1.76 % 3.01% 6.68% 5.59%
8.41 %
8.97 %
Description Clear, colorless solution
pH 2 - 4.5
Table 4: Stability data of Composition IV
Parameters Initial 400c/25
RH 400c/25
RH 400c/25
RH 250c/40
RH 400c/25
RH 250c/40
RH
1M 2 M 3M 3M 6M 6M
Assay of Hydrocortisone 100.0 98.2 94.5 94.8 98.5 89.5 96.0
Hydro
Cortisone Impurity B 0.22 % 0.27 % 0.29 % 0.32 % 0.21 % 0.87 % 0.25 %
Impurity F 0.02 % 0.01 % 0.02 % 0.03 % <0.01 % 0.14 % 0.02 %
Total Impurities 0.62 % 1.13 % 1.35% 1.83% 0.85%
3.39 %
1.17 %
Description Clear, colorless solution
pH 2 - 4.5

Table 5: Stability data of Composition V
Parameters Initial 400c/25RH 400c/25RH 400c/25RH 250c/40RH
1M 2 M 3M 3M
Assay of Hydrocortisone 98.4 91.1 83.3 75.8 74.1
Description Clear, colorless solution
pH 2 - 4.5

Table 6: Stability trend of Impurity B in %:
T0 40ºC/NMT
25% RH-1M 40ºC/NMT
25% RH -2M 40ºC/NMT
25% RH -3M 25ºC/40%
RH-3M 40ºC/NMT 25% RH -6M 25ºC/40%
RH-6M
Without Cupric sulfate
0.36 % 0.98 % 1.75 % 4.25 % 3.85 % 5.36 % 6.15 %
With Cupric sulfate
0.22 % 0.27 % 0.29 % 0.32 % 0.21 % 0.87 % 0.25 %

Table 7: Stability trend of Impurity F in %:
T0 40ºC/NMT
25% RH-1M 40ºC/NMT
25% RH -2M 40ºC/NMT
25% RH -3M 25ºC/40%
RH-3M 40ºC/NMT
25% RH -6M 25ºC/40%
RH-6M
Without Cupric sulfate
0.01 % 0.01 % 0.14 % 0.66 % 0.49 % 1.17 % 1.05 %
With Cupric sulfate
0.02 % 0.01 % 0.02 % 0.03 % <0.01 % 0.14 % 0.02 %

On course of stability, it was observed significant decrease in the impurity level and improves the hydrocortisone assay from the above table(s), its evident that presence of cupric sulfate in the composition inhibits hydrocortisone related impurity level to higher.
Dated this 4th day of July, 2024.

Signature: .
Name: Dr. Hiren Patel
,CLAIMS:WE CLAIM:

1. A stable pharmaceutical composition, comprising: hydrocortisone or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipient(s); wherein the pH of the composition is from about 2 to about 4.5; wherein said composition comprises =2% w/w of impurity B of total impurity after stored at room temperature for 6 months.

2. The stable pharmaceutical composition according to claim 1, wherein one or more pharmaceutically acceptable excipient(s) comprises of preservative, stabilizer, solvent, humectant, pH adjuster, vehicle or mixtures thereof.

3. The stable pharmaceutical composition according to claim 2, wherein the composition comprises of
i. stabilizer is less than 0.7 mg;
ii. solvent is from 400 mg to 700 mg.

4. The stable pharmaceutical composition according to claim 3, wherein the composition comprises of
i. cupric sulfate is less than 0.7 mg;
ii. propylene glycol is from 400 mg to 700 mg.

5. A method of preparation of stable pharmaceutical composition, comprises of below steps:
(i) dissolving cupric sulfate, potassium metabisulfite, optionally one or more active agent(s) in to the water for injection;
(ii) dissolving hydrocortisone, glycerin in to the propylene glycol;
(iii) add step (i) & (ii) contents to form solution;
wherein the pH of the composition from about 2 to about 4.5; wherein said composition comprises =2% w/w of impurity B of total impurity after stored at room temperature for 6 months.

6. The stable pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of solution, suspension, emulsion.

7. The stable pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of solution, the solution is sterile for otic administration.

8. The stable pharmaceutical composition according to any one of the preceding claims, further comprising one or more active ingredient(s) comprises of neomycin, polymyxin B, ciprofloxacin, acyclovir, bacitracin, chloramphenicol, colistin, thonzonium, tetracycline, pramoxine or pharmaceutically acceptable salts thereof.

9. The stable pharmaceutical composition according to any one of the preceding claims, wherein further comprises = 0.5% impurity F of total impurity after stored at room temperature for 6 months.

10. The stable pharmaceutical composition according to any one of the preceding claims, wherein the composition is used for the treatment of bacterial infections.

Dated this 7th day of July, 2023.

Signature: .
Name: Dr. Hiren Patel