Method of treating muscular dystrophies

Abstract

The present invention provides an oral dosage form for, and a therapeutically effective dose for the management and / or treatment of muscular dystrophy using Sitagliptin or its pharmaceutically acceptable salt, alone or in combination with other therapeutically effective agents.

Description

TITLE OF THE INVENTION: ‘METHOD OF TREATING MUSCULAR DYSTROPHIES’FIELD OF THE INVENTIONThe present invention provides oral dosage forms for the management and / or treatment of muscular dystrophies containing therapeutically effective amount of Sitagliptin or its pharmaceutically acceptable salt, alone or in combination with other therapeutically effective agents.BACKGROUND OF THE INVENTIONMuscular dystrophies, Duchenne / Becker muscular dystrophies, are an X-linked genetic diseases that manifests in young males, and are diagnosed through a genetic test showing deletion / mutation of the dystrophin gene from the X chromosome or by absent or deficient dystrophin protein. The test findings indicate very high muscle enzyme levels, myopathic electroneuromyography results and muscle biopsy with dystrophic appearance. The disease mechanism involves degeneration of muscle cells, with most common complications being respiratory problems, cardiac problems, scoliosis and contractures. Muscular atrophy, especially spinal muscular atrophy, on the other hand, is an autosomal recessive disease that can manifest both in young males and females, with normal or reduced muscle enzymes and muscle biopsy with muscle atrophies. It is diagnosed through a genetic test showing deletion of SMN2 (survival motor neuron) gene from chromosome 5. The disease mechanism involves degeneration of nerve cells in the spinal ventral horn.Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. It is the most common hereditary neuromuscular disease and does not exhibit a predilection for any race or ethnic group. Mutations in the dystrophin gene located on chromosome Xp21 lead to progressive muscle fiber degeneration and weakness. This weakness may present initially with difficulty in ambulation but progressively advances to an extent where affected patients are unable to carry out activities of daily living and movement. Cardiac and orthopedic complications are common, and death usually occurs due to respiratory muscle weakness or cardiomyopathy. Current first-line therapy is centered on treatment with glucocorticoids and physiotherapy to delay disease progression and prevent orthopedic complications.Kar et al (Nirmal C. Kar and Carl M. Pearson. Dipeptidyl Peptidase in Human Muscle Disease. Clinical Chimica Acta, 82 (1978) 185-192) discloses a study on proteolytic enzymes of human muscle, specifically dipeptidyl peptidase enzymes (DPP-I-IV), to understand whether their levels are altered in muscular dystrophies and related neuromuscular disease. However, this reference does not indicate anything about DPP-IV inhibition, and does not indicate use or involvement in any particularmuscle disease. There certainly has been no teaching or suggestion in Kar et al on use of DPP -IV inhibitors in treating or managing muscular dystrophy, or in particular, DMD. Further, other references like Xiang et al (Diabetes, Metabolic Syndrome and Obesity, 2023 : 16, 2433-2446) which discloses use of GLP-1 receptor agonists in improving obesity induced muscle atrophy, and Rajagopal et al (Cureus 15(12): e51352 DOI 10.7759 / cureus.51352) which discloses use of GLP-1 receptor agonists in idiopathic inflammatory myopathy, do not in any way teach or suggest the use of Sitagliptin or its pharmaceutical salts, either alone or in combination with other therapeutic agents, in the management and / or treatment of muscular dystrophy.US10993993 discloses use of DPP -IV inhibitors in maintaining GLP-1 concentration by inhibition of GLP-1 degradation, and consequently having therapeutic effect on muscle atrophy or sarcopenia. While the specification discloses use in muscular dystrophy, the specification of US 10993993 states - “Muscular dystrophy, as used herein, also includes atrophy characterized by muscle degeneration or loss of mass often attributed to aging or various diseases such as polio, severe malnutrition, nerve injuries or other neurogenic disorders.” Clearly then, there is no teaching or suggestion in this reference to use of DPP -IV inhibitors in muscular dystrophy, which is of genetic origin. Further, all studies in this reference are carried out in dexamethasone-induced muscle atrophy mice model, which is neither the model for muscular dystrophies of genetic origin, nor that for age-induced muscle atrophies. Also, while the dose of Sitagliptin used in the study disclosed in US10993993 was 300mg / kg, it provides no indication of its effect in muscular dystrophy or DMD.DPP-IV inhibitors have been disclosed in co-pending application PCT / IN2024 / 050379 (claiming priority of IN 202341026707 dated Apr 11, 2023; incorporated herein by reference) for use in muscular dystrophy. It specifically discloses use of DPP-IV inhibitors selected from a long list comprising of Sitagliptin, melogliptin, linagliptin, vildagliptin, teneligliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, retagliptin, cofrogliptin, fotagliptin, prusogliptin and combination thereof, for upregulating utrophin levels in muscle cells to treat muscular dystrophy. Para

[0007] of this application also states that while use of small molecule drugs has been proposed to enhance the expression of utrophin at transcriptional and translational levels, the long term focus on such an approach remains uncertain. Prior to the co-pending application there has been no suggestion in the art for using DPP-IV inhibitors for upregulating utrophin levels to treat muscular dystrophy, such as Duchenne muscular dystrophy (DMD). In fact, the development program of small molecule drug Ezutromid for upregulation of utrophin was terminated due to its failure to meet endpoints in clinical trials. While the application broadly describes the use of a long list of DPP-IV inhibitors (Example 1), and mouse study with Sitagliptin, it is unclear which of theDPP-IV inhibitors would meet the clinical endpoint in management and / or treatment of muscular dystrophy, and in particular DMD. Further, while Example 2 shows that in vitro upregulation of utrophin by Sitagliptin is better than that by Ezutromid, that data does not provide any expectation about the effective dose of Sitagliptin in the management and / or treatment of DMD, let alone prediction of the therapeutically effective dose. Additionally, while Example 3 of the co-pending application provides details of an in vivo study using D2.mdx mouse model, which establishes the utrophin upregulation and therefore potential of Sitagliptin in treating muscular dystrophy, the specific dose that should be used in humans is not disclosed or taught. The application does not disclose a therapeutically effective dose that has a tolerable adverse event profile. This is especially also important because treatment in DMD begins at an early age in patients, and the paediatric dose of Sitagliptin has not been assessed or approved as yet.US11944621 provides an aqueous liquid oral gliptin composition comprising: 2-4 w / v % of sitagliptin or a pharmaceutically acceptable salt thereof; 0.1-2.0 w / v % of a thickening agent, sweetener, antioxidant, buffer, preservative, surfactant, among other excipients for use in diabetes. This disclosure focusses on taste masking and stability of a solution formulation for use in treating diabetes. Nothing therein discloses use in treating muscular dystrophy, and certainly nothing on specific doses in muscular dystrophy.The present invention now provides oral compositions with a defined dose of sitagliptin or its pharmaceutically acceptable salts for use in the treatment or management of muscular dystrophy.OBJECTIVE OF THE INVENTIONAn object of the present invention is to provide pharmaceutical compositions comprising Sitagliptin or its pharmaceutically acceptable salts, solvates, hydrates and polymorphs, for the treatment or management of muscular dystrophies, including Duchenne muscular dystrophy (DMD).Another object of the present invention is to develop compositions of Sitagliptin or its pharmaceutically acceptable salts, solvates, hydrates and polymorphs, alone or in combination with other agents useful in the treatment or management of DMD.Yet another object of the present invention is to provide multiple dosage forms such as oral tablets, capsules, solutions, ready-to-use suspensions, oral drops, oral gels, reconstitutable powders, granules, gummies, mouth-dissolving thin films, mouth dissolving tablets, jellies, syrups, reconstitution solutions and sprinkles comprising sitagliptin or its pharmaceutically acceptable salts, solvates,hydrates and polymorphs and one or more pharmaceutically acceptable excipients, for better patient compliance.Still another object of the present invention is to provide compositions that are stable when stored at 40°C and 75% relative humidity for at least 6 months.SUMMARY OF THE INVENTIONThe present invention provides an oral pharmaceutical composition for the management and / or treatment of muscular dystrophy comprising sitagliptin or a pharmaceutically acceptable salt, solvate or polymorphic form thereof in an amount ranging from about 2.5mg to about 500mg.The present invention also provides the use of sitagliptin or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition comprising sitagliptin or a pharmaceutically acceptable salt thereof in an amount ranging from about 2.5mg to about 500mg, and a second therapeutic agent, for the management and / or treatment of muscular dystrophy.The composition of the present invention comprising sitagliptin or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent, is useful in improving muscle function, improving muscle strength, reducing inflammation and fibrosis and improvement in serum creatine kinase levels in patients with muscular dystrophy.The composition of the present invention comprising sitagliptin or a pharmaceutically acceptable salt thereof may contain a second therapeutic agent selected from the group comprising corticosteroids, givinostat, gene therapy agents, stem cell therapy agents, RNA-based exon-skipping agents, antisense oligonucleotides, immunomodulatory agents, signal transduction inhibitors, myosin inhibitors, myostatin inhibitors, kinase inhibitors, fibrosis inhibitors, and HD AC inhibitors.BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGSFigure 1 depicts the results of treadmill running exercise to evaluate the disease-related impairment of neuromuscular function in D2-mdx mice and to determine the benefits of a specific treatment using Sitagliptin alone and in combination with Deflazacort.Figure 2 depicts the results of depicts the results of the hanging test in D2-mdx mice treated with Sitagliptin alone and in combination with Deflazacort.Figure 3 depicts the results of grip strength test in D2-mdx mice treated with Sitagliptin alone and in combination with Deflazacort.Figure 4 shows results of creatine kinase analysis in D2-mdx mice treated with Sitagliptin alone and in combination with Deflazacort.Figure 5 depicts mean inflammation score and mean fibrosis score on various heart, diaphragm and skeletal muscle tissues in D2-mdx mice treated with Sitagliptin alone and in combination with Deflazacort.Figure 6 depicts results of hydroxyproline analysis in D2-mdx mice treated with Sitagliptin alone and in combination with Deflazacort.Figure 7 depicts results of CD45 analysis in D2-mdx mice treated with Sitagliptin alone and in combination with Deflazacort.Figure 8 depicts results of Western blot analysis to determine the utrophin levels in D2-mdx mice treated with Sitagliptin alone and in combination with Deflazacort.Figure 9 depicts effect of Sitagliptin on a panel of DMD Mechanism of action related biomarkers.DETAILED DESCRIPTION OF THE INVENTIONUnless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination.Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted.All publications, patent applications, patents, and other references mentioned herein are incorporated by reference herein in their entirety for all purposes.As used herein, “a,” “an,” or “the” can mean one or more than one.Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ±10% of the specified amount.The term “Sitagliptin” has been used interchangeably with “Sitagliptin or its pharmaceutically acceptable salts, solvates, hydrates and polymorphs”, and includes Sitagliptin base as well as all salts, solvates, hydrates and polymorphs listed herein.The term “composition”, “formulation”, “dosage form” have been used interchangeably, and cover pharmaceutical compositions described herein.The present invention provides the therapeutically effective oral dose of Sitagliptin for management and / or treatment of muscular dystrophy in patients.The present invention particularly provides therapeutically effective dose of Sitagliptin in patients 2 years of age and older with DMD, who are either corticosteroid-naive or are already on a stable dose of corticosteroid. Accordingly, the present invention provides an oral pharmaceutical composition for the management and / or treatment of muscular dystrophy comprising: (a) Sitagliptin or a pharmaceutically acceptable salt thereof in an amount ranging from about 2.5mg to about 500mg; and (b) one or more pharmaceutically acceptable excipients selected from fillers, binders, disintegrants, lubricants, preservatives, sweeteners, flavouring agents, suspending agents, emulsifiers, pH modulators, stabilizers, antioxidants, and colorants.The Sitagliptin may be selected from Sitagliptin base and its pharmaceutically acceptable salts. The pharmaceutically acceptable salts of Sitagliptin may be selected from phosphate, hydrochloride, tartarate, orotate, hydrobromide, besylate, tosylate, camphorsulfonate, sulfate, mesylate, benzoate, acetate, succinate, oxalate, mandelate, fumarate, lactate, dodecyl sulfonate, and other salts, as well as their hydrates, solvates and polymorphic forms. In a preferred embodiment of the present invention, the Sitagliptin may be used in the form of Sitagliptin base, Sitagliptin phosphate, Sitagliptin phosphate monohydrate, or Sitagliptin phosphate anhydrous.The oral dose of Sitagliptin or its pharmaceutically acceptable salt that is effective in the treatment and / or management of DMD as per the present invention is in the range of about 0.25mg / kg to about 7.5mg / kg. This dose may be given alone or in combination with a therapeutically effective amount of a second active agent for effective management and treatment of DMD. The compositions of thepresent typically include about 2.5mg to about 500mg of sitagliptin or its pharmaceutically acceptable salt.The compositions of the present invention may contain Sitagliptin or a pharmaceutically acceptable salt thereof, alone or in combination with a second therapeutic agent effective in management of DMD. In an embodiment of the present invention, the agent is selected from the group comprising corticosteroid, givinostat, gene therapy agents, stem cell therapy agents, RNA-based exon-skipping agents, antisense oligonucleotides, immunomodulatory agents, signal transduction inhibitors, myosin inhibitors, myostatin inhibitors, kinase inhibitors, fibrosis inhibitors, sarcoglycan alpha, sarcoglycan beta and HDAC inhibitors. The second agent can directly synergize and / or complement the mechanism of action of Sitagliptin. Such combinations have been discussed herein to be effective in the management and / or treatment of muscular dystrophy, such as DMD. The combination of these agents with Sitagliptin also means that the amount of the agent needed in the combination therapy with Sitagliptin, may be lower than that when used alone.It must be noted that while the prior art does not provide any disclosure on the therapeutically effective dose of Sitagliptin in muscular dystrophy or DMD, and while the co-pending application PCT / IN2024 / 050379 teaches the effect of Sitagliptin in utrophin upregulation, the specific dose or range of doses that can be used in humans, is not known. Further, the treatment of DMD is always initiated and supported with the use of corticosteroids to better manage the symptoms. Corticosteroids are therefore the mainstay of DMD management, and physicians prefer to continue the patient on corticosteroids, despite use of any other agent. Accordingly, the combination of Sitagliptin with corticosteroids is also an aspect of the present invention. However, this also means that the doses of Sitagliptin and corticosteroid need to be titrated well for the effective management of muscular dystrophy, with as low adverse events as possible. The present invention provides the same.Corticosteroids are associated with a number of side effects such as weight gain, hyperglycaemia, insulin resistance, Cushingoid syndrome, short stature, behavioural changes, osteoporosis, bone fractures and the like. It is postulated herein that the combination of Sitagliptin or its pharmaceutically acceptable salt with the corticosteroid helps reduce the amount of corticosteroid that may be used, while also countering certain side effects such as weight gain, hyperglycaemia and insulin resistance, due to the known anti-diabetic effects of Sitagliptin. None of this has been disclosed in the art. Corticosteroids remain the mainstay therapy for DMD, but impose metabolic burdens. Sitagliptin shows emerging anti-inflammatory and myoprotective effects. Finding the effective dose of Sitagliptin, as well as the dose of corticosteroid or the second active agent, that can be used incombination with Sitagliptin, is not a matter of routine selection or identification, and extensive studies are required to find the same.The amount of sitagliptin or its pharmaceutically acceptable salt used in the present invention is such that it is sufficient to provide effective levels in plasma and in relevant tissues, such as muscles, diaphragm, heart and the like, which is essential for the management and / or treatment of muscular dystrophy, including DMD. The use of sitagliptin or its pharmaceutically acceptable salt, alone or in combination with a corticosteroid or another active ingredient, helps provide improvement in muscle growth, muscle strength, muscle function, fibrosis levels, utrophin expression, myogenic factors and inflammation markers, among others. Gene expression data from relevant tissues was found to correlate with the functional improvements thus seen. The oral compositions of the present invention comprising a therapeutically effective amount of sitagliptin, alone or in combination with other active agents may be used in the improvement in average muscle strength score. The oral compositions of the present invention may also be used for the improvement in the average time to loss of ambulation in patients with muscular dystrophy, especially DMD. Further, the compositions of the present invention also provide improvement in glycaemic control, body mass index and steroid-related side effects. The compositions provide a potential reduction in steroid-dose without any loss of efficacy. The compositions are also seen to provide improvement in muscle loss, fibrosis, bone health, as seen via biomarkers and other imaging measures. The compositions were found to especially improve the IL-6, TGF-P and TNF-a levels in patients with muscular dystrophy.In an embodiment of the present invention, the Sitagliptin or its pharmaceutically acceptable salt and the second agent are present in a fixed-dose combination in the same dosage form.In another embodiment of the present invention, the Sitagliptin or its pharmaceutically acceptable salt and the second agent are provided in separate dosage forms that are packaged together for simultaneous or sequential administration.In yet another embodiment of the present invention, the Sitagliptin or its pharmaceutically acceptable salt is present alone as the sole active therapeutic agent.In a preferred embodiment, the corticosteroid is selected from prednisone, prednisolone, deflazacort, and vamorolone. Most preferably, the corticosteroid is deflazacort. In highly preferred embodiments, the Sitagliptin or its pharmaceutically acceptable salt and the corticosteroid are present in amounts such that a synergistic effect is achieved in the management and / or treatment of DMD. In preferredembodiments, the oral compositions contain from about 2.5mg to about 500mg of Sitagliptin or its pharmaceutically acceptable salt, and from about 2mg to about 140mg of deflazacort.In an embodiment of the present invention, the composition may contain one or more pharmaceutically acceptable excipients selected from:(i) one or more fillers selected from the group comprising mannitol, lactose, sorbitol, xylitol, calcium phosphate, maltodextrin, starch and starch derivatives, microcrystalline cellulose, cyclodextrins and mixtures thereof;(ii) one or more binders selected from the group comprising povidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregeletinized starch, poly ethylene glycol, natural gums selected from gum tragacanth, karaya, xanthan, sodium alginate carrageenan, guar gum, tara gum, locust bean gum, pullulan, pectin, carbomer, poloxamers, gellan, cyclodextrins, cellulose acetate phthalate, ethyl cellulose, polyacrylate cross-polymers, poloxamers, Veegum (Mg Al silicate), bentonite and mixtures thereof;(iii) one or more disintegrants selected from the group comprising crospovidone, croscarmellose sodium, sodium starch glycolate, alginic acid, low substituted hydroxypropyl cellulose and mixtures thereof;(iv) one or more lubricants selected from the group comprising sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl behenate, hydrogenated oil, colloidal silica, talc, calcium silicate and kaolin and mixtures thereof;(v) one or more preservatives selected from the group comprising potassium sorbate, sodium benzoate, methyl- & propyl-paraben, benzyl alcohol, sorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, a-tocopherol, ascorbic acid, sodium metabisulfite, propyl gallate and mixtures thereof;(vi) pH modulators selected from the group comprising citric acid, tartaric acid, fumaric acid, tris, sodium citrate, bicarbonates, carbonates, phosphates, tromethamine and mixtures thereof;(vii) one or more suspending agents selected from the group comprising sodium carboxymethylcellulose, xanthan gum, guar gum, tragacanth gum, alginates, carbomers and mixtures thereof;(viii) one or more sweeteners selected from the group comprising sucralose, sodium saccharin, aspartame, acesulfame potassium, neotame, cyclodextrin complexes or a mixture thereof;(ix) one or more flavouring agents selected from the group comprising isomalt, ethyl vanillin, menthol, raspberry, mixed berry, strawberry, black currant, orange, grape, lemon flavour, polacrilin grades and mixtures thereof;(x) one or more solubilisers selected from the group comprising propylene glycol, polyethylene glycol, glycerine, ethanol, triacetin, N-Methyl-2-pyrrolidone, Propylene glycol monocaprylate, sodium lauryl sulfate, polysorbates, poloxamers, lecithin, bile salts and mixtures thereof;(xi) one or more colorants selected from the group comprising iron oxides, titanium, FD&C dyes, natural pigments.The oral compositions of the present invention include oral tablets, capsules, soft gelatin capsules, liquid filled hard gelatin capsules, buccal tablets, sublingual tablets, oral solutions, ready-to-use oral suspensions, oral drops, oral gels, reconstitutable powders, granules, gummies, mouth-dissolving thin films, mouth dissolving tablets, gummies, jellies, syrups, reconstituted solutions, pellets, sprinkles and the like. These compositions allow titration across paediatric age groups, and also provide advantages in patients with swallowing difficulties, thus maximising health care benefits.In one embodiment of the present invention, the therapeutically effective amount of Sitagliptin or its pharmaceutically acceptable salt is formulated into an oral solution. In another embodiment, the oral solution contains Sitagliptin or its pharmaceutically acceptable salt and a therapeutic agent in a fixed dose combination. In preferred embodiments, the oral solution contains Sitagliptin phosphate monohydrate and deflazacort in a fixed dose combination. The amounts or doses of Sitagliptin as well as deflazacort are amenable to dosing by body weight of the patient, such that the prescribed dose can be administered using varying volumes of the oral solution. For example, the oral compositions of the present invention are capable of providing a dose of Sitagliptin or its pharmaceutically acceptable salt in a range of about 0.25mg / kg to about 7.5mg / kg, and a dose of deflazacort in a range of about 0.2mg / kg to about 2mg / kg. The oral solution containing Sitagliptin and / or the second therapeutic agent is packaged in a suitable container to maintain its quality, stability, efficacy and purity. It may be provided with a dosing syringe that is calibrated on the basis of body weight, so as to allow dosing easily and accurately. In one embodiment the oral solution is provided in bottles, while in another it is provided in unit dose cups.In one embodiment, the Sitagliptin or its pharmaceutically acceptable salt is formulated into a suitable oral dosage form and is co-packaged with a suitable oral dosage form of a second agent selected from corticosteroid, givinostat and other agents, such that the required doses of both the active ingredients ±uare provided to the patient, and both the doses can be taken simultaneously or sequentially. The copackaging may be provided with various doses of both the active ingredients so that a fixed dose combination can be administered with ease.In some embodiments the Sitagliptin or its pharmaceutically acceptable salt may be formulated in the form of chewable tablets and chewable medicated compositions, also known as gummies, gummy bears, gum drops, jelly candy, gummi chews, chewable gels, chew gels, soft chews, gummy candy, gummies, jelly fruit candy, confectionery or jellies. These gummies may be formulated using starch, or may be starch-free. The chewable compositions are formulated to effectively mask the bitter taste of Sitagliptin, using various techniques. These compositions can also be prepared free of starch, gelatin and sugar. The dose of Sitagliptin and / or the second therapeutic agent, for example deflazacort, included in the same or separate chewable compositions, can be administered by using one or more units of the chewable tablets or gummies, to meet the required dose. In other embodiments, the Sitagliptin or its pharmaceutically acceptable salt and / or the second therapeutic agent may be formulated in the form of mouth dissolving thin films or orally disintegrating tablets. These can be prepared by conventional methods known in the art, such as by use of polymers and other pharmaceutically acceptable agents to generate wafer-like thin films that dissolve rapidly upon contact with saliva, and release the Sitagliptin and / or the second therapeutic agent contained therein, immediately. The films are sufficiently taste masked to improve patient compliance. Orally disintegrating tablets containing Sitagliptin and / or the second therapeutic agent may be prepared with or without effervescent couples (i.e. acid and salt couples, that release gas upon contact with saliva, thereby causing the tablet to disintegrate, and also help in masking the taste and improving mouthfeel), and generally contain pharmaceutically acceptable agents such as diluents, fillers, disintegrants, super disintegrants, flavoring agents, pH adjusting agents, and the like. The chewable tablets and gummies, as also the mouth dissolving thin films and mouth dissolving tablets can help absorption via the buccal mucosa, thereby by-passing the gut, and providing advantage.The oral compositions of the present invention may also be formulated in the form of sprinkles, i.e. in the form of powder, pellets or granules which are easy to spread on foods or drinks. This is especially useful in children below 5 years of age as it helps in easy administration of the dose. The sprinkles formulation may contain Sitagliptin or its pharmaceutically acceptable salt, alone or in combination with a second therapeutic agent. The sprinkle formulation may be packaged in sachets, packets or sticks that are convenient to carry, and that ensure the quality and stability of the formulation. The sprinkle formulation may be administered by spreading and / or mixing it withconventional items such as yoghurt, apple sauce, fruit preparations, orange juice, mashed potato, puddings, chocolate mousse and the like.The oral compositions of the present invention, when present in the form of oral solutions, suspensions, oral thin films, orally disintegrating tablets or gummies containing Sitagliptin or its pharmaceutically acceptable salt, are suitably formulated to mask the extremely bitter taste of Sitagliptin. Typical taste masking techniques such as use of flavors, complexation technology to ward off bitter taste, coating of Sitagliptin with suitable polymers or a combination thereof may be used. Additionally, other means such as pH adjusting agents, buffers, use of sweeteners may also be used in conjunction, to ensure patient compliance with regard to taste, while ensuring that the shelf life of the oral composition is not compromised in any manner.The formulations are not limited to the above and include true solutions, syrups, nano or microemulsions, structured suspensions, dry powders for extemporaneous reconstitution, direct- compression tablets, orally disintegrating tablets, sublingual tablets, chewable tablets, buccal tablets, mini tablets, bilayer tablets, granules, pellets, sachet powders and the like. The manufacturing process adopted to prepare these formulations include steps that involve solubilization, homogenization (high pressure / high shear), dispersing, suspending, direct compression, wet or dry granulation, roller compaction, melt granulation, spray drying, fluid bed granulation / coating, hot melt extrusion, nano milling, micronizing, film coating, barrier coating and the like.In one embodiment of the present invention, the composition may be an immediate release composition, sustained release composition, controlled release composition, or a combination thereof. The Sitagliptin or its pharmaceutically acceptable salt and / or the second therapeutic agent may also be formulated into modified, sustained or controlled release formulations where one or both of the active ingredients are released in a controlled or sustained manner, such that effective blood levels of the active ingredients are provided over a day, a week or more. Such a controlled release formulation would require once daily, once weekly, respectively, or less frequent administration of the formulation in the management and / or treatment of DMD. The controlled, sustained or modified release of the active ingredients can be achieved by using systems conventional in the art such as matrix systems or reservoir systems, achieved with the help of polymers of the right choice and quantities. Such systems are known in the art and a person of skill in the art would be able to formulate the same.These oral compositions may contain the daily dose of Sitagliptin or its pharmaceutically acceptable salt in single or divided doses which are released immediately or over an extended period of time; orit may contain weekly dose of Sitagliptin that is released in a sustained or controlled manner, over one week; or it may contain a combination of immediate and sustained release doses of Sitagliptin or its pharmaceutically acceptable salt to provide a designed release of the active ingredient. The present invention also provides oral compositions containing a combination of immediate and sustained release doses of Sitagliptin or its pharmaceutically acceptable salt, wherein the composition contains immediate release and sustained or controlled release particles, granules, pellets or mini tablets, in a unit dosage form such as a capsule, or wherein the immediate and sustained release components may be compressed into a single or bilayered tablet. Tablet compositions of the present invention may be film coated.The present invention also provides oral compositions comprising Sitagliptin or its pharmaceutically acceptable salt and a second therapeutic agent in a unit dosage form. The Sitagliptin and the therapeutic agent may be present in the same or different phases of a solid unit dosage form. For example, (1) the Sitagliptin and the therapeutic agent may both be present in the same phase of an immediate release tablet or capsule, (2) the Sitagliptin may be present in one phase and the therapeutic agent may be present in another phase, (3) the Sitagliptin and the therapeutic agent may both be formulated as separate granules or pellets that are mixed and filled into a capsule, or mixed and compacted into a tablet, or (4) mini tablets containing Sitagliptin and therapeutic agent, separately, may be prepared and filled into capsules. The pharmaceutically acceptable excipients used to formulate the compositions of the present invention are chosen carefully, and after extensive compatibility studies, to provide compositions that are stable over their shelf life.The term “shelf life” refers to the amount of time the pharmaceutical composition may be stored without loss of potency and / or performance profile. In some embodiments of the present invention, shelf life refers to the amount of time the pharmaceutical composition may be stored without loss of potency and / or performance for at least 12, 24 or 36 months. The oral compositions of the present invention are stable at room temperature, i.e. the amount of undesirable impurities in the composition, if present, are present in amounts that are low and do not impact the potency and / or performance of the composition. Preferably, the known impurities are below 0.5%w / w of the composition, more preferably, below 0.2%w / w of the composition. The compositions are formulated using suitable excipients so as to meet these requirements.The Sitagliptin or its pharmaceutically acceptable salt used in the oral compositions of the present invention meets the purity requirements under ICH and FDA guidance laid down with respect to single known and unknown impurities, nitrosoamine impurities and total impurities. In a preferred embodiment of the present invention, the Sitagliptin or its pharmaceutically acceptable salt has lessthan 150ppm the of 7-Nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo-[4,3-a]pyrazine (NTTP) impurity. In a preferred embodiment of the present invention the total impurities present in the composition are not more than 1% by weight of the composition. In another embodiment, the sitagliptin acid impurity (Imp A) is present in an amount not more than 0.2% by weight of the composition. In yet another embodiment, the triazecine analogue impurity (Imp B) is present in an amount not more than 0.2% by weight of the composition. In another embodiment, the Phenyl crotonyl Analog impurity (Imp C) is present in an amount not more than 0.2% by weight of the composition. In still another embodiment, the composition contains not more than 0.2% by weight of the composition of styryl acetyl analogue impurity (Imp D). The structures of these impurities are provided in Table A below :Table AIn one embodiment of the present invention, there is provided use of Sitagliptin or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the management and / or treatment of muscular dystrophy. The composition may further comprise an therapeutic agent selected from the group comprising corticosteroid, givinostat, gene therapy agents, stem cell therapy agents, RNA-based exon-skipping agents, antisense oligonucleotides, immunomodulatory agents, signal transduction inhibitors, myosin inhibitors, myostatin inhibitors, kinase inhibitors, fibrosis inhibitors, sarcoglycan alpha, sarcoglycan beta and HD AC inhibitors.In a preferred embodiment the composition contains from about 2.5mg to about 500mg of sitagliptin phosphate and from about 2mg to about 140mg of deflazacort. The composition is in the form of a stable oral solution that can be dosed on the basis of the patient’s body weight. In another embodiment, the composition is in the form of a buccal tablet comprising sitagliptin or its pharmaceutically acceptable salt and deflazacort. In yet another embodiment, the present invention provides a sublingual tablet comprising sitagliptin or its pharmaceutically acceptable salt and deflazacort. Another embodiment provides a stable composition in the form of an oral suspension comprising sitagliptin or its pharmaceutically acceptable salt and deflazacort.In one embodiment the compositions of the present invention are capable of providing a sitagliptin dose ranging in the amount of about 0.25mg / kg to about 7.5mg / kg, and a deflazacort dose ranging in the amount of about 0.2mg / kg to about 2mg / kg. Such compositions provide useful means to dose muscular dystrophy patients by their body weight, which is important in infants and younger children.The combination also helps in lowering the current standard dose of corticosteroids in muscular dystrophy patients because of the synergistic action with sitagliptin, thereby reducing corticosteroid related side effects.In one embodiment the immediate release compositions of the present invention are formulated such that not less than 80% of sitagliptin is released in 30 minutes, and not less than 50% of deflazacort is released in 30 minutes. The compositions include excipients selected so as to meet the dissolution and stability requirements described herein. For example, the pH of the oral solution and suspension compositions is adjusted using suitable pH-adjusting agents and / or buffers, within a range that ensures that the active ingredient(s) included therein remain stable. The compositions may also include antioxidants, stabilizers and / or preservatives to ensure stability.The following examples are provided to illustrate the invention and are not to be construed as limiting the invention in any manner.EXAMPLESEXAMPLE 1: DRUG-EXCIPIENT COMPATIBILITY STUDYExample 1.1- Drug-Excipient Compatibility study for Sitagliptin Oral Solution (200 mg / 5 mL) The purpose of this study was to evaluate the compatibility of Sitagliptin Phosphate with selected pharmaceutical excipients commonly used in oral liquid dosage forms. The study aimed to ensure excipient selection that maintains chemical stability, assay compliance, and minimal degradation during storage.Methodology:Sitagliptin Phosphate and the respective excipients were dissolved in pH 5.0 buffer in different ratios as shown in Table 1. Complete dissolution was confirmed to obtain clear solutions. The solutions were then packed in vials, sealed, and subjected to stability studies by storing at:. 25°C ± 2°C / 60% RH ± 5% RH and. 40°C ± 2°C / 75% RH ± 5% RHSamples were evaluated initially (TO) and after 1 month of storage. The results are included in Tables 1.1a and 1.1b below.Table 1.1a - Storage at 25±2°C / 60 ± 5% RHSitagliptin used in the study above is sitagliptin phosphate; ND - Not DetectedTable 1.1b - Storage at 40 ±2°C / 75 ±5% RHSitagliptin used in the study above is sitagliptin phosphate; ND - Not DetectedSitagliptin (as Sitagliptin Phosphate) was found to be compatible with evaluated excipients in liquid form, i.e., physically and chemically stable, for at least 1 month at 25°C ± 2°C / 60% RH ± 5% RH and 40°C ± 2°C / 75% RH ± 5% RH storage conditions.Example 1.2: Drug-Excipient Compatibility Study for Sitagliptin in Solid Oral Formulations The purpose of this study was to evaluate the compatibility of Sitagliptin phosphate with commonly used pharmaceutical excipients in immediate release formulations, as well as sublingual and buccal tablet dosage forms. The selection of excipients was conducted by compatibility studies with individual excipients previously developed / used in approved oral solid dosage formulations of immediate release, sublingual and buccal tablets. Binary mixtures of Sitagliptin phosphate drug and the excipient were prepared by dry mixing at different drug-to-excipient ratios, as shown in Table 1.2 below. Uniform mixing was visually confirmed. The binary mixtures were placed in open vials and stored 40°± 2°C / 75% ± 5%RH for 1 month.Samples were analyzed initially and after the stability period. The results are included in Table 1.2.Table 1.2 - Storage at 40°C ± 2°C / 75% RH ± 5% RH OpenSitagliptin used in the study above is sitagliptin phosphate; ND - Not DetectedSitagliptin (as Sitagliptin Phosphate) was found to be compatible with evaluated solid excipients as binary mixtures i.e., physically and chemically stable, for at least till 1 month at 40°C ± 2°C / 75% RH ± 5% RH storage condition.EXAMPLE 2: FORMULATIONS OF SITAGLIPTINExample 2.1: Sitagliptin Oral Solution The ingredients for the Sitagliptin oral solution were selected based on drug-excipient compatibility study outcomes of Example 1.Multiple oral solution formulations were prepared, varying the salt form of the drug substance, i.e. Sitagliptin Hydrochloride and Sitagliptin Phosphate, and the drug concentration at 40 mg / mL (equivalent to 200 mg / 5 mL) and 10 mg / mL (equivalent to 50 mg / 5 mL). The formulations are presented in Table 2 below.Table 2The manufacturing of the Sitagliptin oral solution was carried out in two phases. In Phase 1 (active pharmaceutical ingredient or API phase), 50% of the total batch quantity of purified water was charged into a manufacturing vessel, followed by the sequential addition of sodium benzoate, citric acid, trisodium citrate, povidone, disodium EDTA, sorbitol, sodium lauryl sulfate, and sodium saccharin, each mixed for about 5 tol 5 minutes to ensure complete solubilization was achieved before adding the next component. Finally, the Sitagliptin salt (either Sitagliptin hydrochloride or Sitagliptin phosphate) was added and stirred for 20 minutes until a clear solution was obtained.In Phase 2 (adjuvants phase), 30% of the total batch quantity of purified water was taken into a separate container and heated to 50°C, followed by the sequential addition of Tween 80, propyl paraben, and butylated hydroxyanisole, each mixed for about 15-30 minutes until complete solubilization was achieved, after which the solution was cooled to room temperature. Phase 2 was then transferred to the Phase 1 vessel under stirring, with the Phase 2 container rinsed with purified water and transferred to ensure complete transfer of the adjuvants / excipients. The batch volume was adjusted to 100% with the remaining purified water, followed by filtration through a 5 microns polypropylene filter to obtain a clear solution. The clarified solution was filled into amber coloured Type III glass bottles and sealed with polypropylene child-resistant closures.Stability testing of the prepared Sitagliptin oral solutions was conducted under ICH-recommended long-term (25 ± 2°C / 60 ± 5% RH) and accelerated (40 ± 2°C / 75 ± 5% RH) conditions for onemonth, and the formulations were found to remain within the predefined physical, chemical, and microbiological specifications. The results are shown in Tables 3a and 3b.Table 3a - Stability data of Sitagliptin phosphate oral solutionsTable 3b - Stability data of Sitagliptin hydrochloride oral solutionsSitagliptin Solution formulations of various strengths prepared with Sitagliptin Phosphate and Sitagliptin HC1 drug substances were found to be stable at 25°C ± 2°C / 60% RH ± 5% RH and 40°C ± 2°C / 75% RH ± 5% RH conditions for at least 1 month. During this period all physical and chemical properties were noticed to be inline with pre-defined specifications.Example 2.2: Sitagliptin and Deflazacort Oral Suspension FormulationsThe composition of Sitagliptin phosphate and Deflazacort oral suspension was selected based on the outcomes of drug-excipient compatibility studies conducted with individual excipients as described in Example 1.Suspension formulations of Sitagliptin phosphate and Deflazacort were prepared using compositions presented in Table 4.Table 4: Compositions of Sitagliptin phosphate and Deflazacort suspension formulationsThe manufacturing of Sitagliptin phosphate and Deflazacort oral suspension was carried out using three distinct phases - Phase 1 (Suspending Agent Phase), Phase 2 (Sitagliptin API Phase), and Phase 3 (Adjuvant Phase), followed by mixing / homogenization and final dispersion of Deflazacort. For Phase 1, 30% of water required for the batch was taken in a container, and xanthan gum was added with continuous stirring for 2 hours at room temperature. This mixture was then set aside for 12 hours to allow complete hydration of the gum.For Phase 2, 30% of purified water required for the batch was placed in a manufacturing vessel, and sodium benzoate, citric acid, trisodium citrate, povidone, disodium EDTA, sorbitol, sodium lauryl sulfate, and sodium saccharin were added sequentially, with each addition followed by about 5-20minutes of stirring to ensure complete solubilization. Sitagliptin phosphate was then added and mixed for 20 minutes until a clear solution was achieved.For Phase 3, 20% of the water required for the batch was taken into a separate container and heated to 50°C, after which propyl paraben and butylated hydroxy toluene were added sequentially at 20- minute intervals with stirring, until complete solubilization was achieved. The solution was then cooled to room temperature. Phases 1 and 3 were transferred into the Phase 2 vessel under stirring, and all containers were rinsed with purified water to ensure complete transfer. The combined mixture was homogenized for 5 minutes, after which Deflazacort was added and homogenization was continued for three hours at room temperature. The final volume was adjusted to 100% with the remaining purified water, followed by a further 15 minutes of homogenization to ensure uniformity.The finished suspension was filled into amber-coloured type III glass bottles and sealed with polypropylene child-resistant closures. The prepared formulations were subjected to stability studies under ICH-recommended conditions. The stability study results are provided in Table 5 below. Table 5 - Stability data of Sitagliptin and Deflazacort Oral suspension formulationsSitagliptin (as Sitagliptin Phosphate) and Deflazacort suspension formulations of varied strengths evaluated were found to be stable at 2°C to 8°C, 25°C ± 2°C / 60% RH ± 5% RH and 40°C ± 2°C / 75% RH ± 5% RH conditions till 1 month. During this period all physical and chemical properties were noticed to be in line with pre-defined specifications.Example 2.3: Oral Solid Dosage FormulationsThe compositions of Sitagliptin phosphate, and that of combination of Sitagliptin phosphate and Deflazacort were prepared using excipients based on drug-excipient compatibility study outcomes of Example 1.Sublingual and buccal tablets of Sitagliptin phosphate and Sitagliptin phosphate with Deflazacort were prepared according to the compositions in Tables 6-9, using equivalent quantities of Sitagliptin Phosphate. Combination formulations of sublingual and buccal tablets were screened at predefined Sitagliptin / Deflazacort ratios considering drug delivery feasibility and dosage form limitations.All excipients were dispensed as per the manufacturing formula presented. Intragranular and extra- granular materials were sifted separately through a 30# mesh sieve. Sifted intragranular material was transferred to a rapid mixer granulator (RMG) and mixed for 5 minutes at an impeller speed of 150 rpm with the chopper off. Wet granulation was performed by adding the required quantity of purified water over 2 minutes at 150 rpm, followed by kneading for 2 minutes with the chopper on at 750 rpm. The wet granules thus obtained were dried in a fluid bed dryer at an inlet air temperature of 65°C and a product temperature of 40°C, until moisture content was less than 5%. Dried granules were milled in a Quadro Co-mill fitted with a 1 mm grating-type screen. The milled granules were pre-lubricated in a bin blender with pre-sifted extra-granular excipients (excluding lubricants) for 15 minutes at 12 rpm. The sifted lubricants were then added, and lubrication was carried out for 10 minutes at 12 rpm. The lubricated blend was then compressed into tablets using round flat-to-bevelled punches, ensuring target specifications for weight, hardness, thickness, friability, and disintegration time, as per Tables 10-13. The final tablets were packed in opaque HDPE bottles and sealed with polypropylene child-resistant closures.The prepared formulations were subjected to stability studies under ICH-recommended conditions. Stability results are provided in Tables 10-13.Table 6 - Sitagliptin Sublingual tablet formulationsTable 7 - Sitagliptin buccal tablet formulationsTable 8 - Sitagliptin with Deflazacort sublingual tablet formulationsTable 9 - Sitagliptin with Deflazacort buccal tablet formulationsTable 10 - Stability data of Sitagliptin sublingual tablet formulationsSublingual tablets of Sitagliptin (as sitagliptin phosphate) were found to be stable at 40°C ± 2°C / 75% RH ± 5% RH upto 1 month. During this period all physical, chemical and release parameters were found to be in line with pre-defined specifications.Table 11 - Stability data of Sitagliptin buccal tablet formulationsBuccal tablets of Sitagliptin (as sitagliptin phosphate) were found to be stable at 40°C ± 2°C / 75% RH ± 5% RH till 1 month. During this period all physical, chemical and release parameters were found to be in line with pre-defined specifications.Table 12 - Stability data of Sitagliptin with Deflazacort sublingual tablet formulationsSublingual tablets of Sitagliptin (as sitagliptin phosphate) with Deflazacort were found to be stable at 40°C ± 2°C / 75% RH ± 5% RH till 1 month. During this period all physical, chemical and release parameters were found to be in line with pre-defined specifications.Table 13 - Stability data of Sitagliptin with Deflazacort buccal tablet formulationsBuccal tablets of Sitagliptin (as sitagliptin phosphate) with Deflazacort were found to be stable at 40°C ± 2°C / 75% RH ± 5% RH upto 1 month. During this period all physical, chemical and release parameters were found to be in line with pre-defined specifications. Example 3: In vivo efficacy study in D2.mdx mouse model of Duchenne Muscular Dystrophy(PAID)In vivo study was conducted to evaluate the efficacy of Sitagliptin alone and in combination with Deflazacort, in improving functional performance and modulating disease-related biomarkers in the D2.mdx mouse model of Duchenne muscular dystrophy.The study was conducted in mdx background wild-type mice and in D2.mdx mice (D2.B10-DMD mdx / J; Jackson Laboratories, Strain #013141). Sitagliptin and Deflazacort were administered once daily via the oral route for 90 days. For combination groups, Sitagliptin was administered followed by Deflazacort after 1 hour. Control groups (wild type and mdx control) were administered with vehicle only. All treatments were administered orally (PO) once daily (QD) for a duration of 90 days.The study parameters were as follows:Control: Wild type control and D2.MDX controlComparator Molecule: Deflazacort at 5 mg / kg (Human Equivalent Dose (HED) 24 mg)Test Compound (Single Agent) - Sitagliptin• Sitagliptin at 25 mg / kg (Human Equivalent Dose, HED = 122 mg)• Sitagliptin at 50 mg / kg (HED = 244 mg)• Sitagliptin at 100 mg / kg (HED = 488 mg)Test Compound - Combination with Deflazacort• Sitagliptin 25 mg / kg + Deflazacort 5 mg / kg• Sitagliptin 50 mg / kg + Deflazacort 5 mg / kgVehicle Composition• Deflazacort vehicle: 0.1% Tween 80 + 0.5% hydroxypropyl methylcellulose (HPMC), pH 4.0.• Sitagliptin vehicle: 0.1% Tween 80 + 0.5% carboxymethyl cellulose (CMC)Animals were monitored for clinical signs once daily and for mortality and morbidity twice daily (morning and evening). Body weight was recorded once daily for the first 21 days and twice weekly thereafter till day 90. Functional testing and biomarker assessments were performed at baseline (Day 0), Day 28, Day 60, and Day 90.3.1 FUNCTIONAL ASSESMENT TESTSAnimals were trained on three consecutive days in various functional tests before randomization and drug treatment. Animals were subjected to functional tests on Day 0 (Basal), Day 28, Day 60 and at the end of the study, on Day 90. Functional assessment was performed 1 hour after dosing ofSitagliptin or Deflazacort. In the combination groups, functional assessment was performed 1 hour after Deflazacort dosing. Muscle function was assessed based on functional tests such as grip strength test, hanging test and treadmill running in response to drug treatment. The tests were conducted in the animals on two different days by conducting the tests in two batches - 5 animals from each group on one day and the remaining 5 mice on the next day.3.1.1 Treadmill Test:Treadmill running exercise was performed to evaluate the disease-related impairment of neuromuscular function in mdx mice, and to determine the benefits of a specific treatment. For the treadmill test, mice were subjected to a running paradigm to determine the time to exhaustion and the total distance run.Mice were placed on individual lanes of an electrically driven 5-lane treadmill (Pan Lab, Harvard Instruments) and acclimated at 5m / min for 5 minutes on three consecutive days prior to the experiment. The test was conducted on Day 0 (basal), Day 28, Day 60, and Day 90. For logistical consistency, testing was performed in two batches per day (5 mice / group per day).On test days, animals were subjected to a running exercise consisting of speed at 7 cm / sec (4 m / min) for 2 minutes, followed by 20 cm / sec (12 m / min) for 28 minutes. Total running distance and time to exhaustion were recorded for each mouse over the 30-minute test duration.The results of the treadmill test are included in Table 14 below. Figure 1 shows results of the treadmill test, wherein DFZ refers to deflazacort, DFZ-5 refers to deflazacort 5mg and mpk refers to “mg per kg”.Table 14Two-way ANOVA followed by Bonferroni post-test, ***p<0.001 vs mdx controlSignificant improvements in treadmill running distance and exhaustion time were observed in the Sitagliptin treated D2.mdx mice and this effect was comparable with Deflazacort. The combination groups of Sitagliptin at 25 / 50 mg / kg with Deflazacort showed similar maximal efficacy as monotherapy groups in treadmill parameters. The treadmill (total distance travelled and time for exhaustion) performance by sitagliptin, Deflazacort and combination treated groups was consistently equivalent to the wild type control group by Day 60 & 90, which indicates the potential benefits of sitagliptin in muscular dystrophy.3.1.2 Hanging Test:Hanging test was performed to assess the balance, muscle coordination and condition. The test was performed on the principle that the mouse tends to stay hanging on a grid or wire till exhaustion, before falling off. Animals were subjected to hanging test on Day 0 (Basal), Day 28, Day 60 and at the end of the study on Day 90 to measure the strength and functioning. A maximum hanging time of 600 sec was set in place. The hanging test was conducted before and after treadmill exercise.The apparatus consisted of a 2 mm thick metal rod securely fixed to a shelf at a height of 35 cm above bedding. This height was sufficient to encourage suspension while minimizing risk of injury upon falling.For each trial, the mouse was gently held by the tail and allowed to grasp the middle of the rod with its forelimbs only. Upon release of the tail, a timer was started, and the duration until complete release and fall of the mouse was recorded. When a mouse was able to hang for the maximum duration ofthe test (600 sec), it was gently removed from the wire and returned to its cage, and the hanging time was recorded. Each mouse was tested in triplicate, and the average hanging time was calculated.The results are included in Table 15 below. Figure 2 depicts the results of the hanging test, wherein DFZ refers to deflazacort, DFZ-5 refers to deflazacort 5mg and mpk refers to “mg per kg”. Table 15Two-way ANOVA followed by Bonferroni post-test, ***p<0.001, **p<0.01 vs mdx control and ###p<0.001, ##p<0.01, #p<0.05 vs Deflazacort monotherapyHanging time was significantly improved in treated D2.mdx mice and the effect was comparable with Deflazacort. At the higher doses Sitagliptin significantly prolonged the hanging time which was comparable to the wild type control mice. The combination of Sitagliptin with Deflazacort showed superior efficacy over Deflazacort monotherapy at both Day 60 and 90 in the post-treadmill scenario. Sitagliptin treatment led to a significant increase in average hanging time compared to Duchenne muscular dystrophy (DMD) controls, demonstrating improved muscle strength and coordination. Adose-dependent effect was observed, and combination therapy with Deflazacort produced the highest values, indicating a synergistic benefit in functional performance.3.1.3 Grip strength testThe forelimb grip strength test was conducted to evaluate muscle strength in D2.mdx mice. The assessment was based on the instinctive behavior of mice to grasp a grid when suspended by the tail. Testing was performed on Day 0 (baseline), Day 28, Day 60, and Day 90, both before and after the treadmill exercise.A grip strength meter (Orchid Scientific, Model No. : GSM02RS) equipped with a grid attached to a force transducer. The force transducer measured the maximum force applied by the mouse on the grid during the pull. It ensured the setting on peak tension mode for pulling. The unit of force was adjusted in terms of grams of force (gf) and the meter was reset to g (grams) as unit / scale. For each measurement, the mouse was lifted by the tail until the forepaws were aligned with the grid bar, then moved horizontally until the paws made contact. The grip was evaluated for symmetry and tightness. The mouse was gently pulled backward at a constant speed until its grasp was released, and the transducer recorded the peak force. Measurements were discarded if improper grip or hind paw usage was observed. Each mouse underwent three trials, and the average value was calculated. Grip strength was expressed as both absolute gram force (gf) and normalized gram force per gram body weight (gf / g body weight).The results of the grip test are included in Table 16 below. Figure 3 depicts results of grip test, wherein DFZ refers to deflazacort, DFZ-5 refers to deflazacort 5mg and mpk refers to “mg per kg”.Table 16Two-way ANOVA followed by Bonferroni post-test, ***p<0.001, **p<0.01, *p<0.05 vs mdx control and ###p<0.001, ##p<0.01, #p<0.05 vs Deflazacort monotherapyGrip strength was significantly improved in D2.mdx mice treated with Sitagliptin and the effect was comparable with Deflazacort. At the higher doses, Sitagliptin significantly improved muscle strength, which is comparable with the wild type control mice. The combination of Sitagliptin with Deflazacort resulted in a slight improvement in grip strength over the monotherapy groups. Sitagliptin-treated mice showed a statistically significant increase in both absolute and normalized grip strength compared to DMD controls. The effect was dose-dependent, with the combination of Sitagliptin and Deflazacort demonstrating the greatest improvement, indicating enhanced muscle function and synergistic therapeutic benefit.3.2 BIOMARKER ANALYSIS3.2.1 Creatine kinase (CK)Creatine kinase is an enzyme found in skeletal muscle, cardiac muscle, and the brain. It is a sensitive early biomarker of muscle damage. It is used in preclinical studies (e.g., mdx mice) to assess sarcolemmal integrity. In DMD, due to muscle membrane instability, muscle fibers leak CK into the bloodstream. Although it is a non-specific marker of muscle damage, and is not diagnostic of DMD alone, it is extremely useful for screening and monitoring.Animals were randomized into different treatment groups based on body weight and treadmill running performance at the beginning of the in vivo study described in examples above. Animals were treated with test compounds via oral route for 90 days.Creatine kinase (CK) levels were measured as a biomarker of muscle damage in D2.mdx mice. Blood sampling was performed under isoflurane anaesthesia via retro-orbital plexus collection. Sampleswere obtained 10-15 minutes after treadmill exercise on Day 0 (base), Day 28, Day 60, and at the end of the treatment period on Day 90. Blood samples were allowed to clot at room temperature for 30 minutes, then centrifuged at 5000 rpm for 10 minutes to separate serum. Serum samples were stored at -80 °C in deep freezer until analysis.The study results are captured in Table 17 below. Figure 4 depicts the results of creatine kinase analysis, wherein DFZ refers to deflazacort, DFZ-5 refers to deflazacort 5mg and mpk refers to “mg per kg”.Table 17Two-way ANO VA followed by Bonferroni post-test, and ***p<0.001, *p<0.05 vs mdx control and ##p<0.01, #p<0.05 vs Deflazacort monotherapySitagliptin demonstrated significant reduction in serum creatine kinase levels as compared to DMD control mice. Additionally, a synergistic effect was observed in the Sitagliptin and deflazacort combination groups.3.2.2 Tissue samplingAt the end of the CK study of Example 3.2.1, animals were euthanized, skeletal muscles (Gastrocnemius (GA), Tibialis anterior (TA), Extensor Digitorum Longus (EDL)) from right hind limb, diaphragm and heart (cardiac muscle) were isolated and preserved in 10% neutral buffered formalin for histopathology. The tissue samples from the below mentioned groups were submitted for routine histopathology. After fixation, diaphragm was decalcified with 10% EDTA. Two slides were prepared from each sample. One slide was stained with Hematoxylin and Eosin (H&E) and other slide was stained with Masson’s Tri chrome (MT). All thehistopathological evaluations and reading of the slides were carried out as per the coded group numbers and the respective groups were decoded only post-analysis as mentioned in the below Table 18. The animals were given the vehicle or the drug by peroral route, once a day.Table 18The formalin fixed tissues were processed according to an established paraffin embedding protocol. This involved dehydration of tissue by increasing grades of alcohol (70%, 95% and 100%), clearing with xylene and finally infiltration with paraffin. Following the processing, the tissue embedding was carried out with molten paraffin to make the tissue blocks. The labelled tissue blocks were then sectioned serially at 4-6 pm thickness using a microtome and sections were flooded over a tissue flotation bath. The tissue sections were transferred to a slide and allowed to air dry. After drying, one slide per block with the sections was subjected to deparaffinization by using two changes of xylene followed by rehydration with decreasing grade of alcohol (100%, 95% and 70%) and finally in water. The sections were subjected to H&E staining and the excess stain was removed by using running tap water. The tissue sections were then dehydrated and cleared by increasing grades of alcohol (95% and 100%) and xylene, respectively. The second slide was stained with MT stain. Upon completion of dehydration, stained slides were mounted with DPX mounting medium and subjected to evaluation. Each H&E-stained tissue section was evaluated for inflammation, i.e. inflammatory cell infiltrate, and the MT-stained slide was evaluated for fibrosis as per criteria reported by Tinsley JM, (Tinsley JM, et al. (2011) Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse. PLoS ONE 6(5): el 9189. doi: 10.1371 / journal.pone.0019189).Each tissue section was evaluated semi-quantitatively for inflammatory cell infiltration i.e. inflammation and fibrosis using following criteria -All the submitted tissues were evaluated microscopically for inflammatory cell infiltration, muscle fiber degeneration, regeneration, fat / adipose deposition and fibrosis. All the tissues were scored as per scoring criteria mentioned above. Heart muscle sections were evaluated for inflammation and fibrosis considering the ‘left ventricle’ region. The results of mean inflammation are tabulated in Table 19 below, and the mean fibrosis score in Table 20. These are depicted in Figure 5.Table 19Table 20As can be seen in Tables 19 and 20 above, among the animals treated with Sitagliptin at different dose levels of 25, 50 and 100 mg / kg, animals treated with 50 mg / kg, belonging to group 5 showed overall better efficacy than other dose levels. Animals treated with combination of Sitagliptin and Deflazacort at 50 mg / kg + 5 mg / kg belonging to group 8 showed overall better resolution of inflammation and fibrosis when compared to G2 group animals (MDX-Control) and compared to Sitagliptin and Deflazacort dosed alone.3.2.3 HydroxyprolineFollowing blood collection, animals (n=5) were sacrificed using CO2 euthanasia in accordance with standard protocols. Skeletal muscles from the right hind limb, including the Tibialis anterior (TA) muscle, were dissected and divided into two portions: approximately 35% was snap frozen in liquid nitrogen for qPCR analysis, and the remaining 65% was snap frozen for Western blot analysis. Gastrocnemius (GA) and Extensor Digitorum Longus (EDL) muscles were also harvested and snap frozen for subsequent bioanalysis and drug concentration determination. From the left hind limb, the TA muscle was isolated and snap frozen for hydroxyproline content determination via ELISA. Additional muscles (GAS and EDL) were similarly processed and stored at -80 °C.The hydroxyproline content in TA muscle samples was quantified using a hydroxyproline assay kit (ELISA, Sigma, Cat. No. MAK008). Approximately 10 mg of TA muscle tissue was homogenized in 0.1 mL of water, followed by the addition of 0.1 mL concentrated hydrochloric acid (~12 M). Samples were hydrolyzed at 120 °C for 3 hours in pressure-tight polypropylene vials.Following hydrolysis, samples were mixed and centrifuged at 10,000 g for 3 minutes. 20 pL of the supernatant was transferred to a clear 96-well plate and dried by evaporation at 60°C in a hot air oven. The dried samples were treated with 0.1 mL chloramine T / oxidation buffer mixture, andincubated for 5 minutes at room temperature, followed by the addition of 0.1 mL 4-(dimethylamino) benzaldehyde (DMAB) reagent. Samples were incubated for 90 minutes at 60°C, and absorbance was measured at 560 nm using a microplate reader.Separately, Hydroxyproline concentration was determined from a standard curve prepared with known concentrations ranging from 0-1.2pg / well.The results are included in Table 21. Figure 6 shows results of hydroxyproline analysis, wherein DFZ refers to deflazacort, DFZ-5 refers to deflazacort 5mg and mpk refers to “mg per kg”.Table 21The levels of hydroxyproline (a marker for collagen) in tissue samples were higher in D2.mdx mice compared to the wild type control (6.53 vs 4.07 pg / 10 mg of muscle). Animals treated with Deflazacort showed a trend of reduction in hydroxyproline levels compared to D2.mdx control (4.72 vs 6.53 pg / 10 mg of muscle). Animals treated with Sitagliptin at 25 mg / kg showed a significant (P<0.05) reduction in Hydroxyproline levels compared to the D2.mdx control (3.92 vs 6.53 pg / 10 mg of muscle). However, 50 and 100 mg / kg doses of Sitagliptin also showed some reduction of Hydroxyproline (5.56 or 5.77 vs 6.53 pg / 10 mg of muscle) levels with no clear dose response. D2.mdx mice treated with Sitagliptin at 25 mg / kg dose in combination with Deflazacort 5mg / kg showed reduction in tissue hydroxyproline levels compared to the D2.mdx control (4.12 vs 6.53 pg / 10 mg of muscle). Similarly, combination of Sitagliptin at 50 mg / kg with Deflazacort reduced Hydroxyproline levels (4.00 vs 6.53 pg / 10 mg of muscle) compared to control group. In both the combination treatment groups, the hydroxyproline levels were lowered to the wild type mice level.3.2.4 CD45CD45, a pan-leukocyte surface marker expressed on all nucleated hematopoietic cells, is widely studied in Duchenne Muscular Dystrophy (DMD) research for understanding the immune- inflammatory landscape, monitoring disease progression, and evaluating treatment response, especially in preclinical models. In DMD, elevated CD45 levels reflect immune cell infiltration, including T cells, B cells, and macrophages.At the end of the study, animals were euthanized, and Tibialis anterior (TA) muscle from the left hind limb was excised and preserved in 10% neutral buffered formalin for immunohistochemistry analysis. Tissues were trimmed, placed in labelled cassettes, and processed using an automated tissue processor. After processing, tissues were embedded in paraffin, and blocks were prepared using an embedding and cooling station.Tissue sections were incubated overnight at 4°C with CD45 primary antibody (35-Z6; Santa Cruz Biotechnology, sc-1178) at 1 :200 dilution in antibody dilution buffer (1% BSA in 1 *PBS). Subsequently, sections were incubated with HRP-conjugated secondary antibody (PolyExcel PolyHRP) for 1 hour at room temperature, followed by three washes in immuno wash buffer for 3 minutes each.Images were captured using a Leica DM3000LED microscope, and quantitative image analysis was performed with Imaged software to calculate the percentage of stained area.The results are captured in Table 22 below. Figure 7 depicts the results of CD45 analysis. The groups G1-G8 are similar across the studies conducted herein, with respect to the control and treated groups and the doses used.Table 22Sitagliptin significantly reduced CD45-positive staining in TA muscle compared to DMD controls, indicating a decrease in immune cell infiltration. The combination of Sitagliptin with Deflazacort further enhanced this reduction, demonstrating synergistic activity and potential as a promising therapeutic candidate for DMD.3.2.5 UtrophinUtrophin, is a dystrophin-related protein, and has been reported to functionally compensate for dystrophin. It is used as a surrogate marker of functional compensation in muscle biopsies. Its upregulation offers a dystrophin-independent pathway to stabilize muscle fibers, with the advantage of low immunogenicity.At the end of the study, animals were euthanized via CO2 inhalation. Skeletal muscle tissue (Tibialis anterior, TA) from the right hind limb was excised and snap frozen in liquid nitrogen for biomarker analysis by Western blot. Biomarker analysis was done for mouse skeletal samples to detect the expression of Utrophin by Western blot following standard procedure. Utrophin primary antibody (8A4) Santa Cruz (sc-33700) at 1:500 dilution was used.The results are included in Table 23 below. Figure 8 depicts results of Western blot analysis. The groups G1-G8 are similar across the studies conducted herein, with respect to the control and treated groups and the doses used.Table 23Data represented as Mean ± S.E.M.(n= 4-5)Treatment with Sitagliptin demonstrated a dose-dependent trend toward increased utrophin expression in TA muscle relative to DMD controls. The upregulation was more pronounced in the Sitagliptin and Deflazacort combination group, supporting the therapeutic potential of the composition in enhancing muscle fiber stability via utrophin-mediated mechanisms.3.2.6 RNA sequence analysisAt the end of the study, animals were euthanized by CO2 inhalation. Approximately 35% of the Tibialis anterior (TA) muscle was snap frozen in liquid nitrogen for RNAseq analysis. A NanoString mRNA expression assay was conducted using a customized gene panel relevant to the molecular mechanisms of Muscular Dystrophy (MD) with an emphasis on Duchenne Muscular Dystrophy (DMD). The assay involved probing each sample for a panel of genes implicated in MD with an emphasis on DMD pathogenesis and therapeutic response. RNA samples were quantified using the Qubit RNA HS assay kit (Invitrogen, Cat # Q32855) and qualitatively analyzed using the Agilent 2100 Bioanalyzer nano chip (Agilent, Cat # 5067-1511). A total of 250 ng of high-quality RNA was hybridized for 18 hours at 67°C with custom probes A and B along with Tagset-36. The hybridization reaction was performed according to the manufacturer’s protocol (nCounter Gene Expression Panel and Custom Tagset User Manual, MAN- 10086-02). Hybridized RNA samples were processed and scanned using the NanoString nCounter SPRINT platform through a certified service provider. Data analysis included normalization to internal controls and statistical evaluation of gene expression changes.Sitagliptin showed promising effect on a panel of biomarkers related to the mechanism of action of DMD and other muscular dystrophy biomarkers (e.g. LGMD or limb-girdle muscular dystrophy), as seen in Figure 9.

Claims

WE CLAIM:

1. An oral pharmaceutical composition for the management and / or treatment of muscular dystrophy comprising:(a) sitagliptin or a pharmaceutically acceptable salt, solvate or polymorphic form thereof in an amount ranging from about 2.5mg to about 500mg; and(b) one or more pharmaceutically acceptable excipients selected from fillers, binders, disintegrants, lubricants, preservatives, sweeteners, flavouring agents, suspending agents, emulsifiers, pH modulators, stabilizers, antioxidants, and colorants.

2. The composition as claimed in claim 1, wherein the pharmaceutically acceptable salt of sitagliptin is selected from the group comprising phosphate, hydrochloride, tartarate, orotate, hydrobromide, besylate, tosylate, camphorsulfonate, sulfate, mesylate, benzoate, acetate, succinate, oxalate, mandelate, fumarate, lactate and dodecylsulfonate.

3. The composition as claimed in claim 2, wherein the sitagliptin is selected from sitagliptin phosphate monohydrate and sitagliptin phosphate anhydrous.

4. The composition as claimed in claim 2, wherein the sitagliptin is sitagliptin hydrochloride.

5. The composition as claimed in any one of claims 1-4, wherein the composition further comprises a second therapeutic agent.

6. The composition as claimed in claim 5, wherein the second therapeutic agent is selected from the group comprising corticosteroids, givinostat, gene therapy agents, stem cell therapy agents, RNA- based exon-skipping agents, antisense oligonucleotides, immunomodulatory agents, signal transduction inhibitors, myosin inhibitors, myostatin inhibitors, kinase inhibitors, fibrosis inhibitors, and HD AC inhibitors.

7. The composition as claimed in claim 6, wherein the corticosteroid is selected from prednisone, prednisolone, deflazacort and vamorolone.

8. The composition as claimed in claim 7, wherein the corticosteroid is deflazacort.

9. The composition as claimed in claim 8 wherein the deflazacort is used in an amount of about 2mg to about 140mg.

10. The composition as claimed in any one of claims 6-9, wherein the sitagliptin or its pharmaceutically acceptable salt and the second therapeutic agent are present in a fixed-dose combination in a single composition.

11. The composition as claimed in any one of claims 6-9, wherein the sitagliptin or its pharmaceutically acceptable salt and the second therapeutic agent are provided in separate dosage forms for simultaneous or sequential administration.

12. The composition as claimed in any one of claims 1-11, wherein the oral composition is selected from the group comprising oral tablets, capsules, solutions, suspensions, oral drops, oral gels, reconstitutable powders, granules, pellets, gummies, mouth-dissolving thin films, mouth dissolving tablets, gummies, jellies, syrups, reconstituted solutions and sprinkles.

13. The composition as claimed in any one of claims 1-12, wherein the pharmaceutically acceptable excipients are selected from:(xii) one or more fillers selected from the group comprising mannitol, lactose, sorbitol, xylitol, calcium phosphate, maltodextrin, starch and starch derivatives, microcrystalline cellulose, cyclodextrins and mixtures thereof;(xiii) one or more binders selected from the group comprising povidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregeletinized starch, poly ethylene glycol, natural gums selected from gum tragacanth, gum karaya, xanthan gum, sodium alginate, carrageenan, guar gum, locust bean gum, pullulan, pectin, carbomer, poloxamers, polyethylene oxide, gellan, cyclodextrins, cellulose acetate phthalate, ethyl cellulose, polyacrylate cross-polymers, poloxamers, magnesium aluminium silicate, bentonite and mixtures thereof;(xiv) one or more disintegrants selected from the group comprising crospovidone, croscarmellose sodium, sodium starch glycolate, alginic acid, low substituted hydroxypropyl cellulose and mixtures thereof;(xv) one or more lubricants selected from the group comprising sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, colloidal silica, talc, calcium silicate, kaolin and mixtures thereof;(xvi) one or more preservatives selected from the group comprising potassium sorbate, sodium benzoate, methyl paraben, propyl paraben, benzyl alcohol, sorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, a-tocopherol, ascorbic acid, sodium metabisulfite, propyl gallate and mixtures thereof;(xvii) pH modulators selected from the group comprising citric acid, tartaric acid, fumaric acid, triethanolamine, sodium citrate, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium phosphate, tromethamine and mixtures thereof;(xviii) one or more suspending agents selected from the group comprising sodium carboxymethylcellulose, xanthan gum, guar gum, tragacanth gum, sodium alginate, carbomers and mixtures thereof;(xix) one or more sweeteners selected from the group comprising sucralose, sodium saccharin, aspartame, acesulfame potassium, neotame, cyclodextrin complexes and mixtures thereof;(xx) one or more flavouring agents selected from the group comprising isomalt, ethyl vanillin, menthol, raspberry, mixed berry, strawberry, black currant, orange, grape, lemon flavour, potassium polacrilin and mixtures thereof;(xxi) one or more solubilisers selected from the group comprising propylene glycol, polyethylene glycol, glycerine, ethanol, triacetin, N-methyl-2-pyrrolidone, propylene glycol monocaprylate, sodium lauryl sulfate, polysorbates, poloxamers, lecithin, bile salts or a mixture thereof;(xxii) colorants selected from the group comprising iron oxides, titanium, FD&C dyes, and natural pigments.

14. The composition as claimed in any one of claims 1-13, wherein the composition is an immediate release composition, sustained release composition, or a combination thereof.

15. The composition as claimed in claims 1-14, wherein the composition is stable when stored at 40°C and 75% relative humidity for at least 6 months.

16. Use of sitagliptin or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the management and / or treatment of muscular dystrophy wherein the composition comprises sitagliptin or a pharmaceutically acceptable salt thereof in an amount ranging from about 2.5mg to about 500mg and one or more pharmaceutically acceptable excipients.

17. The use as claimed in claims 16, wherein the composition further comprises a second therapeutic agent selected from the group comprising corticosteroids, givinostat, gene therapy agents, stem cell therapy agents, RNA-based exon-skipping agents, antisense oligonucleotides, immunomodulatory agents, signal transduction inhibitors, myosin inhibitors, myostatin inhibitors, kinase inhibitors, fibrosis inhibitors, and HD AC inhibitors.

18. The use as claimed in any one of claims 16-17, wherein the oral composition is selected from the group comprising oral tablets, capsules, solutions, suspensions, oral drops, oral gels, reconstitutable powders, granules, pellets, gummies, mouth-dissolving thin films, mouth dissolving tablets, gummies, jellies, syrups, reconstituted solutions and sprinkles.

19. The use as claimed in any one of claims 16-18, wherein administration of the pharmaceutical composition provides an improvement in muscle function.

20. The use as claimed in any one of claims 16-18, wherein administration of the pharmaceutical composition provides an improvement in muscle strength.

21. The use as claimed in any one of claims 16-18, wherein administration of the pharmaceutical composition provides a reduction in inflammation.

22. The use as claimed in any one of claims 16-18, wherein administration of the pharmaceutical composition provides reduction in fibrosis.

23. The use as claimed in any one of claims 16-18, wherein administration of the pharmaceutical composition provides an improvement in serum creatine kinase levels.

24. The use as claimed in any one of claims 16-18, wherein administration of the pharmaceutical composition provides reduced corticosteroid side effects.

25. A method for treating muscular dystrophy comprising administering to a subject in need thereof a pharmaceutical composition comprising sitagliptin or a pharmaceutically acceptable salt thereof in an amount ranging from about 2.5mg to about 500mg, and one or more pharmaceutically acceptable excipients.

26. The method as claimed in claim 25 wherein the method includes administering a second therapeutic agent selected from the group comprising corticosteroids, givinostat, gene therapy agents, stem cell therapy agents, RNA-based exon-skipping agents, antisense oligonucleotides, immunomodulatory agents, signal transduction inhibitors, myosin inhibitors, myostatin inhibitors, kinase inhibitors, fibrosis inhibitors, sarcoglycan alpha, sarcoglycan beta and HDAC inhibitors27. The method as claimed in claim 26 wherein the sitagliptin or its pharmaceutically acceptable salt and the second therapeutic agent are present in a fixed-dose combination in a single composition.

28. The method as claimed in claim 26 wherein the sitagliptin or its pharmaceutically acceptable salt is administered sequentially or simultaneously with the second therapeutic agent.

29. The method as claimed in claim 26, wherein the corticosteroid is selected from prednisone, prednisolone, deflazacort, and vamorolone.

30. The method as claimed in claim 29, wherein the corticosteroid is deflazacort.

31. The method as claimed in claim 30, wherein the deflazacort is used in an amount of about 2mg to about 140mg.

32. The method as claimed in any one of claims 25-31, wherein the composition is selected from the group comprising oral tablets, capsules, solutions, suspensions, oral drops, oral gels, reconstitutable powders, granules, pellets, gummies, mouth-dissolving thin films, mouth dissolving tablets, gummies, jellies, syrups, reconstituted solutions and sprinkles.

33. The method as claimed in any one of claims 25-31, wherein administration of the pharmaceutical composition provides an improvement in muscle function.

34. The use as claimed in any one of claims 25-31, wherein administration of the pharmaceutical composition provides an improvement in muscle strength.

35. The use as claimed in any one of claims 25-31, wherein administration of the pharmaceutical composition provides a reduction in inflammation.

36. The use as claimed in any one of claims 25-31, wherein administration of the pharmaceutical composition provides reduction in fibrosis.

37. The use as claimed in any one of claims 25-31, wherein administration of the pharmaceutical composition provides an improvement in serum creatine kinase levels.

38. The use as claimed in any one of claims 25-31, wherein administration of the pharmaceutical composition provides reduced corticosteroid side effects.

39. The composition as claimed in claim 1, wherein the composition is stable over a period of at least 12 months.

40. The composition as claimed in claim 39, wherein Imp A, Imp B, Imp C and Imp D are each present in an amount below 0.2%w / w of the composition.

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