Stable and palatable oral solutions of drotaverine and method of preparation thereof

Abstract

Palatable oral solutions comprising drotaverine or a pharmaceutically acceptable salt thereof, along with methods of making and using the same.

Description

[0001] STABLE AND PALATABLE ORAL SOLUTIONS OF DROTAVERINE AND METHOD OF PREPARATION THEREOF

[0002] FIELD

[0003] The present disclosure relates to oral solutions of Drotaverine or salt thereof with improved taste and stability. The disclosure also relates to methods for preparation of such solutions along with uses thereof.

[0004] BACKGROUND

[0005] Oral route of administration for drugs is preferred in patients for being non-invasive and having low risk of pain, leading to improved compliance. Patient groups such as elderly, children, non-cooperative, nauseated patients, patients on reduced liquid-intake or diets, patients with no immediate access to water, patients suffering from Parkinson’s diseases, Alzheimer's diseases, dysphagia, post-surgical patients facing difficulty to straighten up or patients who are restricted to access water prior to surgery have difficulty swallowing conventional solid oral dosage forms such as tablets, capsules, pellets, etc. In some cases, like motion sickness, sudden episodes of allergic attack or coughing, swallowing conventional tablets becomes difficult. Difficulty in swallowing or dysphagia is seen to afflict nearly 35% of general population. Liquid oral dosage forms offer a practical solution, overcoming the difficulties associated with solid formulations and enhancing patient experience and adherence across diverse populations.

[0006] Drotaverine or salts thereof are potent spasmolytic drugs which act directly on the smooth muscles and are devoid of any anticholinergic side effects. Mode of action and pharmacokinetic parameters of Drotaverine, along with the diseases, disorders, and physiological conditions for which Drotaverine is used are well known. Drotaverine is indicated for relieving pain and spasms in smooth muscles across multiple systems. In the gastrointestinal tract, it alleviates or ameliorates abdominal pain, recurrent abdominal pain, cramps, bloating, and discomfort from conditions like irritable bowel syndrome, gastric ulcers, and colicky pain. For the genitourinary system, it manages dysmenorrhea, ureteric colic, and renal colic due to uterine or urinary tract spasms. In the biliary tract, it treats pain from cholecystolithiasis, cholecystitis, cholangitis, biliary colic, and dyskinesia. Drotaverine is therefore suited for the relief or prevention of smooth muscle spasm of various organs, regardless of their function and innervation, including but not limited to treating at least one symptom of a gastrointestinal, biliary, urological or gynaecological disorders. Dosage forms of Drotaverine known in the field are immediate-release tablets, oral suspensions, and injections administered intramuscularly and / or intravenously. However, the development of an oral solution formulation of drotaverine presents significant challenges.

[0007] Drotaverine is an extremely bitter tasting drug with a lingering aftertaste. Further, in oral solution preparations, drotaverine active is required to be in completely dissolved state, so its strong bitter taste and lingering aftertaste will be immediately perceived by patients unless the formulation is formulated using suitable taste masking. Drotaverine hydrochloride salt form is slightly soluble in water, and because of this low aqueous solubility concerns, there exist a major technical challenge to overcome in order to develop drotaverine oral solution dosage forms. In the currently marketed drotaverine injection preparations, ethanol is added as solubilizer because of the low aqueous solubility of drotaverine salt. The use of ethanol as a solvent is undesirable, especially for patients such as children and the elderly, where prolonged treatment might be necessary. In addition to low aqueous solubility and strong bitter lingering taste issues, drotaverine is also highly susceptible to oxidation and changes in pH, which can lead to chemical instability. Drotaverine active moiety is likely to show higher rates of chemical degradation in solution form compared to currently marketed oral suspension preparations wherein the Drotaverine active is in suspension state.

[0008] Oral administration of bitter drugs with acceptable palatability is a critical issue for healthcare providers. Any pharmaceutical formulation with pleasing taste would therefore be preferred and would translate into better compliance and therapeutic value for the patients. The desire of improved palatability in these products has prompted the development of numerous formulations with improved performance and acceptability.

[0009] Various approaches are available for masking bitter taste of drugs for instance employing ingredients such as flavours, sweeteners, and amino acids; employing techniques such as polymer coating; conventional granulation; ion-exchange resins; spray congealing with lipids; formation of inclusion complexes with cyclodextrins; freeze-drying process; making multiple emulsions; gelatin, gelatinized starch, liposomes, lecithin’s or lecithin-like substances, surfactants, salts, or polymeric membranes.

[0010] The available literature has shown use of one or a combination of different flavouring approaches to mask the bitter taste of drugs. For example, a flavour can be selected that complements the taste of the preparation, or a flavour with a longer intensity and stronger taste than the drug can be used. High levels of sweetening agents are often used to mask bitterness with added sweetness. The taste buds may also be anesthetised by strong flavours such as menthol or mint flavours. These approaches are generally not very effective in masking the taste of a bitter drug, and a flavouring system that works with one drug usually does not work with another drug.

[0011] The available literature in the field provides various approaches for taste masking of liquid preparations. Use of combinations of viscosity modifiers for taste masking is known in the field. For example, the patent document US5616621A provides taste-masked liquid preparations by increasing the viscosity with a combination of polyethylene glycol and sodium carboxymethylcellulose; the patent document US5658919A discloses taste-masking of acetaminophen suspension using a suspending system consisting of xanthan gum and a mixture of cellulosic polymers. The increase in viscosity is assumed to limit contact of the drug with tongue, presumably by slowing down salivary water uptake into the viscous liquid medicament, which can lead to dilution and dissolution of the ingested medication. This approach is only moderately successful in reducing bitterness, especially at high drug loading. While bitterness may be reduced at the onset, a bitter after-taste becomes prominent because thick preparations are more difficult to wash down, thus leaving behind some residual viscous liquid medicament in the mouth after swallowing. This bitter after-taste is more prominent with water intake due to subsequent reduction in viscosity and dilution of the residual liquid medicament leading to subsequent dissolution of the drug in the mouth.

[0012] In the field, it is generally known to mix drug in powder form with various polymeric or wax coating agents or to microencapsulate the particles of the drug so that they may be suspended and prevented from solubilizing in liquid for oral administration in order to make oral liquid formulations more palatable. However, the known techniques are complex and expensive, employ various processing steps and exhibit drug delivery problems.

[0013] Therefore, liquid dosage forms are highly desirable in medical care where the dosage form containing active pharmaceutical ingredients disintegrates rapidly, absorbed faster, has improved patient compliance due to ease of administration, provides flexibility to dosage amount to be administered and provide optimal convenience to the patient.

[0014] In view of highly bitter and lingering after taste, chemical stability concerns of drotaverine as mentioned above, inventors focused on appropriate development strategies to mask the bitter taste and chemical stability of the final preparations.

[0015] Despite of all the efforts made till date, none of the known art has been able to overcome the disadvantages of drotaverine to provide chemically stable palatable oral solutions. Thus, there is an unmet need to develop chemically stable and palatable oral solutions of drotaverine or salt thereof to address one or more of problems in field such as low aqueous solubility, highly bitter and lingering aftertaste, and chemical degradation of drotaverine active moiety in solution form and development of a physically and chemically stable palatable oral aqueous solution without using any alcoholic solvent. Further, such oral solution product should be easily prepared by conventional processes without requiring any special or costly equipment and technology.

[0016] SUMMARY

[0017] The present disclosure provides stable and palatable oral solutions of drotaverine or salt thereof. The present disclosure also provides method of preparation of oral solutions of drotaverine or salt thereof.

[0018] The disclosed oral solutions offer a significant advantage over the currently marketed conventional film coated swallowing tablets especially for geriatric patients who usually face difficulty in swallowing such tablets. The disclosed pharmaceutical formulations are chemically stable throughout the product's shelf-life. Using a novel manufacturing process, the disclosed formulations exhibit improved taste, improved aftertaste, and improved palatability.

[0019] Embodiments of the present disclosure provide stable and palatable oral solutions comprising therapeutically effective amount of drotaverine or a salt thereof of the sorts described below in embodiments and detailed description.

[0020] An embodiment of the disclosure provides a palatable oral solution comprising therapeutically effective amount of drotaverine or a salt thereof, at least one sugar alcohol, at least one polyhydric alcohol, at least one solubilizer, and at least one acidifying agent, wherein at least one sugar alcohol and at least one polyhydric alcohol are present in ratio from about 1 : 1 to 20: 1.

[0021] Another embodiment of the disclosure provides that sugar alcohol and polyhydric alcohol in the oral solution are present in ratio from about 3:1 to 10:1.

[0022] In a further embodiment, the sugar alcohol in the oral solution of the present disclosure comprises one or more of mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, hydrogenated starch hydrolysates (HSH), isomalt or erythritol.

[0023] In still further embodiment, the polyhydric alcohol in the oral solution of the present disclosure comprises one or more of propylene glycol, ethylene glycol or glycerine.

[0024] In another embodiment, the solubilizer in the oral solution of the present disclosure is polyvinylpyrrolidone grade of polymers. In yet another embodiment, the acidifying agent in the oral solution of the present disclosure comprises one or more of citric acid, fumaric acid, lactic acid, maleic acid, malic acid or tartaric acid.

[0025] In a further embodiment, the oral solution of the present disclosure further comprises one or more of pharmaceutically acceptable excipients selected from at least one sweetener, at least one taste-masking agent, at least one antioxidant, at least one viscosity -building agent, at least one flavouring agent, at least one colorant, at least one buffering agent, at least one chelating agent, at least one surfactant, at least one wetting agent, at least one preservative, or at least one solvent.

[0026] In an embodiment, the oral solution of the present disclosure comprises sweetener, wherein the sweetener is natural and / or an artificial sweetener alone or in combination.

[0027] In yet another embodiment, the sweetener in the oral solution of the present disclosure is selected from saccharin sodium, sodium cyclamate, sucrose, glycerol, aspartame, sucralose, acesulfame potassium and dipeptide-based sweeteners.

[0028] In another embodiment, the oral solution of the present disclosure comprises tastemasking agent, wherein the taste-masking agent is selected from menthol, monoammonium glycyrrhizinate (MAG) and sodium chloride.

[0029] In still another embodiment, the oral solution of the present disclosure comprises antioxidant, wherein the antioxidant is selected from butylated hydroxy-anisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid, methionine, alanine and cysteine.

[0030] In yet another embodiment, the oral solution of the present disclosure comprises viscosity -building agent, wherein the viscosity-building agent is selected from xanthan gum, carrageenan, tragacanth, guar gum, pectin, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and carboxymethylcellulose sodium blends.

[0031] In further embodiment, the oral solution of the present disclosure comprises flavouring agent, wherein the flavouring agent is selected from cherry, grape, strawberry, raspberry, mango, orange, melon, banana, citrus, vanilla, peppermint flavor, spearmint flavor, lime flavor, apple flavor, pear flavor, peach flavor, raspberry flavor, plum flavour and pineapple flavour.

[0032] In still further embodiment, the oral solution of the present disclosure comprises a metal chelating agent, wherein the metal chelating agent is selected from salts of ethylenediamine-tetraacetic acid, edetate disodium. In another embodiment, the oral solution of the present disclosure comprises buffering agent, wherein the buffering agent is derived from acetic acid, aconitic acid, citric acid, glutaric acid, lactic acid, malic acid, succinic acid, phosphate acid, or carbonic acid.

[0033] In yet another embodiment, the oral solution of the present disclosure comprises preservative, wherein the preservative is selected from sodium benzoate, potassium sorbate, benzyl alcohol, parabens (p-hydroxybenzoic acids esters), methyl paraben, ethyl paraben, propyl paraben and butyl paraben.

[0034] In still another embodiment, the oral solution of the present disclosure comprises surfactant, wherein the surfactant is selected from phospholipids, natural bile acid surfactant, cationic surfactants, anionic surfactants and non-ionic surfactants.

[0035] In another embodiment, the oral solution of the present disclosure comprises colouring agent, wherein the colouring agent is selected form tartrazine, quinoline yellow, erythrosine, sunset yellow and ponceau 4R and is present in an amount of from about 0.0001 to 2.0% w / v of the solution.

[0036] In a further embodiment pH of the oral solution of the present disclosure ranges between about 1 to 7, preferably between about 2.5 to 6.5.

[0037] In another embodiment, drotaverine or a salt thereof in the oral solution of the present disclosure is present in an amount of about 0.01 to 20.0% w / v of the total solution.

[0038] In yet another embodiment, the sugar alcohol in the oral solution of the present disclosure is present in an amount of about 1.0 to 80.0% w / v, preferably about 10.0 to 60.0% w / v of the total solution.

[0039] In still another embodiment, the polyhydric alcohol in the oral solution of the present disclosure is present in an amount of about 1.0 to 60.0% w / v, preferably about 4.0 to 40.0% w / v of the total solution.

[0040] In an additional embodiment, the acidifying agent in the oral solution of the present disclosure is present in an amount of about 0.001 to 4.0 % w / v of the total solution.

[0041] In an embodiment, the solubilizer in the oral solution of the present disclosure is present in an amount of about 0.01 to about 10.0% w / v, preferably about 0.05 to 8.0% w / v of the total solution.

[0042] In another embodiment, the taste masking agent in the oral solution of the present disclosure is present from about 0.001 to 10% w / v of the solution.

[0043] In still another embodiment, the flavouring agent in the oral solution of the present disclosure is present from about 0.001 to 10% w / v, preferably in an amount of about 0.01 to 5.0% w / v, more preferably about 0.05 to 4.0% w / v of the solution formulations. In yet another embodiment, the antioxidant in the oral solution of the present disclosure is present in an amount of about 0.01 to 4.0% w / v, preferably about 0.02 to 4.0% w / v of the total solution.

[0044] In a further embodiment, the sweetening agent in the oral solution of the present disclosure is present in an amount of about 0.1 to 10.0% w / v, preferably about 0.3 to 8.0% w / v of the total solution.

[0045] In yet another embodiment, the viscosity-building agent in the oral solution of the present disclosure is present in an amount of about 0 to 2% w / v, preferably about 0 to 1.0% w / v of the total solution.

[0046] In another embodiment, the drotaverine salt in the oral solution of the present disclosure is drotaverine hydrochloride.

[0047] In an embodiment the present disclosure provides a stable and palatable oral solution formulation of drotaverine or a salt thereof, wherein said oral solution formulation comprises: a) from about 0.01 to 20.0% w / v of drotaverine or a salt thereof; b) from about 1.0 to 80.0% w / v of at least one sugar alcohol; c) from about 1.0 to 60.0% w / v of at least one polyhydric alcohol; d) from about 0.01 to 10.0% w / v of at least one solubilizer; e) from about 0.01 to 5% w / v of at least one preservative; f) from about 0% w / v to about 2.0% w / v of at least one colorant; g) from about 0.001 to 4.0 % w / v of at least one acidifying agent; h) optionally from about 0% to 4.0% w / v of an antioxidant; and i) optionally from about 0.1 to 10.0% w / v of at least one sweetener.

[0048] In a further embodiment, the stable and palatable oral solution formulation of drotaverine or a salt thereof further comprises about 0 to 2% w / v of a viscosity-building agent, about 0.01 to 5.0% w / v of a flavouring agent and optionally one or more of pharmaceutically acceptable excipients.

[0049] In a still further embodiment, the formulation of the present disclosure comprises about 1 to about 500 mg of drotaverine or salt thereof.

[0050] In another embodiment, the drotaverine salt in the formulation of the present disclosure is drotaverine hydrochloride.

[0051] In an embodiment the present disclosure provides a pharmaceutical formulation in the form of an oral solution comprising per 5 ml of oral solution: i) drotaverine or salt thereof from about 1 mg to about 500 mg; ii) at least one sugar alcohol from about 100 mg to about 5000 mg; iii) at least one polyhydric alcohol from about 100 mg to about 4000 mg; iv) at least one sweetener from about 0.1 mg to 500 mg, v) at least one solubilizer from about 1 mg to 100 mg; vi) at least one acidifying agent from about 0.1 mg to 10 mg; vii) at least one taste masking agent from about 0.01 to 100 mg; viii) optionally one viscosity agent from about 0 mg to 10 mg; ix) optionally one antioxidant agent from about 0 mg to 50 mg; x) at least one preservative from about 0.01 mg to 25 mg; xi) at least one flavouring agent from about 0.5 mg to 100 mg; xii) optionally at least one colorant from about 0 mg to 5 mg.

[0052] In another embodiment the present disclosure provides a method for the treatment and / or amelioration of at least one symptom associated with spastic conditions of smooth muscles in a subject in need thereof, wherein the spastic conditions are selected from the group consisting of gastrointestinal disorders including irritable bowel syndrome, gastric ulcers, and gastrointestinal colicky pain; biliary disorders including cholecystolithiasis, cholecystitis, cholangitis, biliary colic, and biliary dyskinesia; genitourinary disorders including dysmenorrhea, ureteric colic, and renal colic; comprising administering to the subject a therapeutically effective amount of oral solution of the present disclosure comprising drotaverine or a pharmaceutically acceptable salt thereof, thereby relieving or preventing smooth muscle spasms in various organs, irrespective of their function or innervation.

[0053] In a further embodiment the present disclosure provides use of an oral solution formulation for treating at least one symptom of a gastrointestinal, biliary, urological or gynaecological disorder characterized by spastic conditions of smooth muscles in a subject, comprising administering the formulation to the subject.

[0054] In still further embodiment the present disclosure provides an oral solution formulation for use in treatment and / or amelioration of at least one symptom associated with spastic conditions of smooth muscles in a subject in need thereof, wherein the spastic conditions are selected from the group consisting of gastrointestinal disorders including irritable bowel syndrome, gastric ulcers, and gastrointestinal colicky pain; biliary disorders including cholecystolithiasis, cholecystitis, cholangitis, biliary colic, and biliary dyskinesia; genitourinary disorders including dysmenorrhea, ureteric colic, and renal colic; comprising administering to the subject a therapeutically effective amount of oral solution formulation comprising drotaverine or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 35, thereby relieving or preventing smooth muscle spasms in various organs, irrespective of their function or innervation.

[0055] In yet further embodiment the present disclosure provides a method comprising administering a therapeutic oral solution formulation of the present disclosure to a subject, wherein said subject is suffering from at least one symptom associated with spastic conditions of smooth muscles, wherein the spastic conditions are selected from the group consisting of gastrointestinal disorders including irritable bowel syndrome, gastric ulcers, and gastrointestinal colicky pain; biliary disorders including cholecystolithiasis, cholecystitis, cholangitis, biliary colic, and biliary dyskinesia; genitourinary disorders including dysmenorrhea, ureteric colic, and renal colic; comprising administering to the subject a therapeutically effective amount of oral solution formulation of the present disclosure comprising drotaverine or a pharmaceutically acceptable salt thereof, thereby relieving or preventing smooth muscle spasms in various organs, irrespective of their function or innervation.

[0056] In yet another embodiment the present disclosure provides a method for preparation of oral solution formulation of drotaverine or salt thereof comprising: a. heating required quantity of water at about 60°C to obtain heated water; b. adding at least one preservative agent and at least one sweetener to heated water of step a) under stirring for about 10 to 30 minutes to obtain a clear solution; c. cooling down the clear solution obtained in step b) at room temperature to obtain cooled solution; d. adding at least one solubilizer, one or more acidifying agents and optionally one or more antioxidants in the cooled solution of step c) under stirring for about 2 to 10 minutes to obtain a clear solution; e. adding drotaverine or salt thereof in the clear solution of step d) followed by mixing until a clear solution is obtained; f. adding desired quantity at least one sugar alcohol, at least one polyhydric alcohol, and at least one suitable colorant in the solution of step e) under stirring for about 10 minutes to obtain a dispersion mixture; g. dissolving desired quantity of one or more taste-masking agents and one or more flavouring agents by adding to the dispersion mixture obtained of step f) under continuous stirring for about 2 to 20 minutes to obtain oral solution; h. optionally transferring the oral solution of step g) to a suitable container. DETAILED DISCLOSURE

[0057] The terms “solutions”, “compositions” and “formulations” are used interchangeably in the present disclosure.

[0058] The term "taste" is used herein to refer to the sensation of flavor experienced when a subject's tongue comes into contact with a dosage form. The term "aftertaste" is used herein to refer to the sensation of flavor experienced in the mouth after administration of a dosage form. For example, an aftertaste typically lasts well after administration of drotaverine. The term "palatability" is used herein to refer to the physical sensation of a dosage form when it is in a subject's mouth, such as the texture of a dosage form. In some embodiments, the disclosed oral solutions disclosed herein exhibit improved taste, aftertaste, and palatability.

[0059] The terms "stable", “stability” or “stabilized” mean the dosage form is able to maintain a product performance test parameters such as an ingredient amount, a related substance amount, without significant changes from the initial levels.

[0060] The term "significant change" means a change of 5% or more from the initial result. For example, if the initial amount of an ingredient is 98%, then a significant change would be an amount of 93% or less of that ingredient. If the product is stable under accelerated conditions (40 °C / 75% RH) for at least 3 months without significant change, then it can be assigned a shelf life of at least 2 years or 24 months when stored under long term storage conditions.

[0061] Chemical compounds or agents act as “buffering agent” are also capable of modifying pH and therefore also referred as “pH modifiers”. Accordingly, “buffering agent” and “pH modifiers” have been used for same compound or class of compounds and been used interchangeably in the disclosure.

[0062] Some chemical compounds or agents may act as “solubilizers” as well as “stabilizers”. Accordingly, terms “solubilizer” and “stabilizer” have been used for same compound or class of compounds and have been used inter-changeably in the disclosure.

[0063] A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier / excipient” as used in the specification and claims includes both one and more than one such carrier or excipient.

[0064] The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ± 10%, preferably ± 5%, the recited value and the range is included.

[0065] “Treating” or “treatment” of a disease or condition includes:

[0066] (1) preventing the disease or condition, i.e. causing the clinical symptoms of the disease or condition not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease or condition;

[0067] (2) inhibiting the disease or condition, i.e., arresting or reducing the development of the disease or condition or clinical symptoms thereof; or

[0068] (3) relieving the disease or condition, i.e., causing regression of the disease or condition or clinical symptoms thereof.

[0069] A “therapeutically effective amount” means the amount of formulation or composition of the present disclosure that, when administered to a patient for treating a disease or condition, is sufficient to effect such treatment for the disease or condition. The “therapeutically effective amount” will vary depending on the formulation, the disease, the condition and severity of the disease or the condition and age, weight, etc., of the mammal to be treated.

[0070] A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. The pharmaceutically acceptable salt of drotaverine include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2 -hydro xyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydro xynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are nontoxic.

[0071] The preferable pharmaceutically acceptable salt of drotaverine is drotaverine hydrochloride.

[0072] The bitterness of pharmaceutical medicines is a consideration in patient compliance, as the oral administration of bitter drugs can be hampered by their unpleasant taste which leads to non-compliance or patient’s inability to swallow the drug, thereby worsening the diseased condition. The present disclosure is therefore related to stable and palatable oral solutions comprising drotaverine or pharmaceutical salt thereof.

[0073] The present disclosure provides oral formulations of multiple strengths of drotaverine or salt thereof. In some embodiments, these formulations provide flexible dose ranges suitable for different groups of patients. In some embodiments, the present disclosure provides methods for preparing the palatable oral formulations of drotaverine or salt thereof. In some embodiments, the present disclosure provides uses of the oral formulations. The present disclosure, according to some embodiments, aims to provide physically and chemically stable, palatable oral solutions or formulations of drotaverine or salt thereof with non-limiting advantages of accurate dose titration, ease of administration and improved patient compliance. The prepared oral solutions are suitable for administration to all age groups, including but not limited to children, adults, and elderly patients, the intellectually disabled, non-cooperative patients, nauseated patients, patients on reduced liquid-intake or diets, patients with no immediate access to water, patients suffering from Parkinson's diseases, Alzheimer's diseases, dysphagia, post-surgical patients facing difficulty to sit up or patients who are restricted to access water prior to surgery have difficulty swallowing oral dosage forms which in turn results in improved patient compliance and effective treatment.

[0074] The present disclosure, according to some embodiments, also aims to provide pharmaceutical oral solutions preferably without any alcoholic content. Also, the prepared oral solutions have desired physical and chemical stability throughout the shelf life of product at the recommended long term storage conditions.

[0075] The prepared oral solutions are a therapeutic bridge between injectable and tablets when those two dosage forms cannot be administered. Moreover, where injectables are not indicated or administrable, the oral solutions can reduce dissolution time compared to tablets.

[0076] Oral solutions deliver small volumes or low doses of a drug to patients ensuring ease of swallowing, dosing flexibility and accurate dose titration. Addition of a suitable stabilizing agent ensures desired drotaverine solubility and chemical stability in the final product throughout the shelf life of drug product. The developed solutions ensure excellent dose uniformity and accuracy of dosages administered to the patients. The available suspension preparations in the market are highly bitter in taste and also exhibit issues associated with suspension products, such as settling of the drug, requirement for shaking, and inaccurate dosing.

[0077] The chronology of the development of oral solutions of drotaverine or salt thereof of the disclosure is briefly described below.

[0078] In the initial development studies, the inventors evaluated the solubility of drotaverine in various combinations of solvent systems to ensure preparation of clear oral solutions. Initial trials were conducted using combination of solvents propylene glycol, sorbitol liquid, glycerine and water / purified water. The quantity of propylene glycol, which was selected for further analysis, was then varied in different trial batches, not exceeding 1295 mg / 5ml which is maximum level allowed per day as per USFDA (United States Food and Drug Administration) IIG (inactive ingredient guide) database guidelines. The resulting drotaverine solutions were initially clear, but crystal growth was observed in about 1 to 5 months. Varying process parameters, such as different temperature ranges for heating step for dissolving drotaverine were tried. The temperature was varied ranging from about 30°C to 90°C. Even though the resulting drotaverine drug solution did not show any crystal growth even after 4 months of storage at room temperature condition, it turned dark brown in colour, possibly resulting in significant chemical degradation of the active drug.

[0079] In view of this, the inventors felt a need to provide a stable drotaverine oral liquid solution that does not recrystallize and is physically and chemically stable with good shelf life.

[0080] While screening for suitable agents for stabilizing the formulation, the inventors unexpectedly found that stabilized pharmaceutical formulations of drotaverine HC1 liquid solutions can be prepared for oral administration with the appropriate levels of stabilizers or solubilizers, which prevented the reprecipitation issue on storage.

[0081] Among the preferred stabilizer(s), one of the polyvinylpyrrolidone grades are more preferred. As polyvinylpyrrolidone includes both soluble and insoluble grades; soluble grades provide improved stability in the current disclosure.

[0082] Usually, soluble polyvinylpyrrolidone is synthesised by the mechanism of polymerization, wherein the free radical polymerization into the water by using hydrogen peroxide as initiator, the mechanism which terminates the polymerisation reaction makes it probable to produce soluble polyvinylpyrrolidone of about any molecular weight. Povidone or Polyvinylpyrrolidone (PVP) is the synthetic, water-soluble polymer. Povidones family has various applications in oral solutions. The functions of oral formulation encompass fast disintegration, sustain drug release, solubility, bioavailability enhancement.

[0083] The examples of soluble grade Povidone are 12 PF, 17 PF, 25, 30, 90, VA64 (Copovidone). The numbers (12, 17, 25, 30, 90) refer to the K-value, which is an indicator of the polymer's molecular weight and viscosity. "PF" typically indicates a "pharmaceutical grade" product, often with lower levels of impurities. VA64’ is a specific grade of povidone, a copolymer of N-vinylpyrrolidone and vinyl acetate.

[0084] Taste is an important and critical parameter in orally administering solutions, which come in contact with the taste buds. Some drugs have a bitter taste, which is a problem encountered during formulation. Due to the bitter taste of a drug, there is a problem in the treatment of the patients due to their inability or unwillingness to swallow such formulations.

[0085] As drotaverine is bitter in taste with a lingering aftertaste and also a pungent smell, the development of an oral solution became a challenge as the bitter taste of the active moiety is immediately perceived, unless bitterness is suitably masked, to make such a product palatable. Thus, masking of the unpleasant taste characteristics of drug was a bigger challenge for the inventors.

[0086] There are numbers of taste masking technologies available today, which can improve the characteristics of the dosage form and achieve good patient compliance. These technologies and approaches to mask bitter taste include the use of flavourants, sweeteners, coatings, micro-encapsulations, prodrugs, lipoproteins, ion exchange resins, inclusion complex formations, salt formations, granulation, and by multiple emulsions used in the industry for taste masking of bitter drugs. However, most of these available options except use of flavourants and artificial sweeteners cannot be used for formulating oral solutions due to the insoluble nature of the most of these components.

[0087] Thus, challenges in the development of oral solutions of drotaverine were two-fold as the inventors aimed to develop taste-masked solutions with suitable physical and chemical stability throughout the proposed shelf life of the drug product. In view of the abovedescribed challenges, the inventors of the current disclosure felt an urgent need to develop palatable and stable oral solution containing drotaverine or salt thereof to address these problems.

[0088] In some embodiments, the oral solutions of the present disclosure mask the bitter taste of drotaverine or salt thereof. During development of the palatable oral solutions of the present disclosure, various methods and combination approaches were tried to overcome sensory challenge of bitter taste and lingering after taste of the drotaverine. Additionally, in order to, achieve physical stability of oral solutions along with chemical stability of drotaverine active drug in the liquid oral drug product formulation, extensive trials were undertaken, including compatibility studies of selected excipients. The details of the initial batch samples prepared during the development studies are given in Table 1 below.

[0089] Table 1: Details of trial batch samples of drotaverine prepared by various combinations of excipients

[0090] Subsequently, few of these trial batch samples were exposed to ‘accelerated stress study’ conditions (40°C / 75% RH / 1 month) and evaluated for impurity profiling for understanding chemical degradation characteristics of the oral solution formulations. The results are presented in Table 2 below. It was observed that there are unknown impurities of nearly about 0.18 to 0.62% w / w in the exposed batch samples just after 1 month of storage under accelerated stress conditions. Therefore, in order to develop stable oral solutions with acceptable impurity profile, further pre-formulation studies of drotaverine drug characteristics were undertaken to determine some of key physicochemical properties to improve the chemical stability characteristics etc.

[0091] Table 2: Chemical degradation characteristics of oral solution formulations trial batches exposed to accelerated stress studies The results for Trial 7 and 8 at accelerated stress conditions as illustrated in Table 2 were surprising. In view of the fact that drotaverine is susceptible to oxidative and hydrolytic degradation it was assumed that adding an antioxidant would result in a batch sample exhibiting best chemical stability. However, two of the prototypes containing reduced quantities of sorbitol and glycerine with addition of an artificial sweetener (z.e., aspartame and sucralose containing formulation batches Trial 7 and Trial 8) showed better chemical stability with lesser degradation of drotaverine active drug despite the absence of an antioxidant in these trial batches. In addition, Trial 4 and 6 showed precipitation while the Trial 7 and 8 did not show any precipitation after 1 month of storage under accelerated conditions. Without being bound by theory, since Sodium Saccharin is present in both trials (4 and 6), this ingredient could be the possible reason of precipitation. Hence, it was decided to continue further studies to improve the overall physical and chemical stability throughout the target shelf life.

[0092] Based on these results, further studies were conducted, with variations in the compositions with different quantities of ingredients including artificial and natural sweeteners, stabilizers, chelating agents, buffering agents or pH modifier, antioxidants and acidifying agents alone and in combination, in order to, further evaluate the degradation profiles of drotaverine active drug. The results of these trial batches indicate that addition of acidifying agent alone or in combination with minor amounts of antioxidant also further improved the chemical stability of oral solution formulation of drotaverine or salt thereof.

[0093] However, best stable compositions developed as per the present disclosure have suitable levels of artificial sweetener, such as but not limited to, sucralose, aspartame; an acidifying agent, such as but not limited to, citric acid, maleic acid; an antioxidant, such as but not limited to, methionine, sodium metabisulfite; and solubilizer that also functions as a stabilizer, such as but not limited to, one of the polyvinylpyrrolidone grades of polymers as preferred embodiments.

[0094] A suitable antioxidant agent for maintaining the chemical stability of the drotaverine active ingredient includes, but not limited to, butylated hydroxy-anisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid, methionine, alanine and cysteine etc. and mixtures thereof.

[0095] Although, the role of artificial sweeteners such as sucralose or aspartame can be used in some embodiments to mask the bitter and lingering taste of drotaverine, they also surprisingly and unexpectedly improve the chemical stability of drotaverine, for example, sodium saccharin.

[0096] In addition, further trials were executed using sucrose sweetener alone and in combination with aspartame and sucralose and the resulting oral solution compositions showed good physical and chemical stability.

[0097] Even though chemical stability of the oral solutions improved in the developed prototypes, the resulting solutions still exhibited the bitter after-taste of drotaverine. Thus, further trials were undertaken to improve the overall acceptability of the oral solutions, thereby improving palatability leading to improved patient compliance.

[0098] In an oral solution, the bitterness of drug is generally perceived at a faster rate than the oral suspension products of same drug owing to less solubility of the drug in suspension, unless the drug is taste-masked in the solutions. The taste-masking of drug can be achieved by including suitable excipients or additives in appropriate levels in the oral solutions

[0099] In the present disclosure, substantially taste-masked and stable oral solutions containing a pharmaceutically effective amount of drotaverine drug dissolved in an aqueous excipient base are provided wherein said excipient base comprises at least one sugar alcohol and at least one polyhydric alcohol. The oral solutions may contain at least one sugar alcohol and at least one polyhydric alcohol in ratios ranging from about 1 :1 to 20:1, preferably about 3: 1 to 10:1 along with suitable levels of a natural and / or an artificial sweetener alone or in combination.

[0100] The disclosure provides palatable oral solution comprising therapeutically effective amount of drotaverine or a salt thereof, at least one sugar alcohol, at least one polyhydric alcohol, at least one solubilizer, and at least one acidifying agent, wherein at least one sugar alcohol and at least one polyhydric alcohol are present in ratio from about 1 : 1 to 20: 1.

[0101] The pH of the solution of disclosure range between about 1 to 7, preferably between about 2.5 to 6.5.

[0102] The drotaverine or a salt thereof is present in an amount of about 0.01 to 20.0% w / v of the total solution.

[0103] The sugar alcohol and polyhydric alcohol are present in ratio from about 3: 1 to 10:1. The sugar alcohol comprises one or more of mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, hydrogenated starch hydrolysates (HSH), isomalt or erythritol.

[0104] The polyhydric alcohol comprises one or more of propylene glycol, ethylene glycol or glycerine.

[0105] The solubilizer or stabilizer is polyvinylpyrrolidone grades of polymers. The acidifying agent comprises one or more of citric acid, fumaric acid, lactic acid, maleic acid, malic acid or tartaric acid.

[0106] The specified ratios of sugar alcohol and polyhydric alcohol along with a natural and / or artificial sweetener, is beneficial to both, achieving the desired organoleptic properties with sufficient masking of bitterness and reducing chemical degradation of drotaverine.

[0107] Sugar alcohols are safe and can usually be safely included in our diet especially if one is diabetic or prediabetic. The safe recommended intake of sugar alcohol intake is 10-15 grams per day. Suitable sugar alcohol are, but not limited to, mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, hydrogenated starch hydrolysates (HSH), , isomalt, erythritol and the likes.

[0108] Suitable polyhydric alcohol is, but not limited to, propylene glycol, ethylene glycol and / or glycerine.

[0109] The disclosure provides oral solutions further comprises ingredients generally used in the drug industry, herein after referred to as ‘additives’ or ‘pharmaceutically acceptable excipients’ used interchangeably.

[0110] The oral solution further comprises one or more of pharmaceutically acceptable excipients selected from at least one sweetener, at least one taste-masking agent, at least one antioxidant, at least one viscosity-building agent, at least one flavouring agent, at least one colorant, at least one buffering agent, at least one chelating agent, at least one surfactant, at least one wetting agent, at least one preservative or at least one solvent.

[0111] The additives may include, but are not limited to, sweetening agents, flavours, colorants, antioxidants, buffering agents, chelating agents, surfactants, wetting agents, pH modifiers, acidifiers, preservatives, solvents, and mixtures thereof.

[0112] The sweetener is natural and / or an artificial sweetener alone or in combination. The sweetener comprises saccharin sodium, sodium cyclamate, sucrose, glycerol, aspartame, sucralose, acesulfame potassium or dipeptide-based sweeteners.

[0113] The taste-masking agent comprises menthol, Monoammonium glycyrrhizinate (MAG) or sodium chloride.

[0114] The antioxidant agent comprises butylated hydroxy-anisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid, methionine, alanine or cysteine.

[0115] The viscosity -building agent comprises xanthan gum, carrageenan, tragacanth, guar gum, pectin, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose or carboxymethylcellulose sodium blends. The flavouring agent comprises cherry, grape, strawberry, raspberry, mango, orange, melon, banana, citrus, vanilla, peppermint flavor, spearmint flavor, lime flavor, apple flavor, pear flavor, peach flavor, raspberry flavor, plum flavour or pineapple flavour.

[0116] The metal chelating agent is selected from salts of ethylenediamine-tetracetic acid, edetate di sodium.

[0117] The buffering agent is derived from acetic acid, aconitic acid, citric acid, glutaric acid, lactic acid, malic acid, succinic acid, phosphate acid, or carbonic acids.

[0118] The disclosure provides a taste-masked oral solution comprising therapeutically effective amount of at least one bitter-tasting drug. The drug is dissolved in an aqueous tastemasking excipient base comprising at least one sugar alcohol, at least one polyhydric alcohol, at least one solubilizer, at least one acidifying agent, and optionally at least an antioxidant. The taste-masked oral solutions have substantially reduced bitter taste and after-taste.

[0119] In some of the embodiments of the disclosure, the oral solutions comprise about 0.01 to 20.0% w / v of at least one bitter-tasting drug wherein the bitter-tasting drug belongs to a group of medicines called antispasmodic agents, for example drotaverine or salts thereof of the total solution formulation. The oral solutions of the disclosure comprise about 1.0 to 80.0% w / v of sugar alcohol; about 1.0 to 60.0% w / v of a polyhydric alcohol; about 0.01 to about 10.0% w / v of suitable grade of polyvinyl pyrrolidone (PVP) and / or copolyvidone as a solubilzer; about 0.01 to 4.0% w / v of an antioxidant; about 0.001% to 4.0 % w / v of a acidifying agent; about 0.1 to 10.0% w / v of a sweetener; about 0 to 2% w / v of a viscositybuilding agent; and about 0.01 to 5.0% w / v of a flavouring agent of the total solution formulation. The pH of prepared liquid solution formulation is adjusted to between 1 to 7.

[0120] In preferred embodiments of the disclosure, the oral solutions comprise about 0.1 to 10.0% w / v of at least one bitter-tasting drug wherein the bitter-tasting drug belongs to a group of medicines called antispasmodic agents, for example drotaverine or salts thereof of the total solution formulation. The oral solutions of the disclosure comprise about 10.0 to 60.0% w / v of sugar alcohol, about 4.0 to 40.0% w / v of a polyhydric alcohol, about 0.01 to 10.0% w / v of PVP and / or polyvidone as a solubilizer, about 0% to 4.0% w / v of an antioxidant, about 0.001 to 4.0 % w / v of an acidifying agent, about 0.1 to 8.0% w / v of a sweetener, about 0 to 2.0% w / v of a viscosity -building agent, and about 0.01 to 5.0% w / v of a flavoring agent of the total solution formulation. In some embodiments, the pH of prepared liquid solution formulation is adjusted to between 2.5 to 6.5. In another embodiment, the disclosure provides stable aqueous solutions further comprising one or more excipients selected from preservatives, colorants, and taste masking agents.

[0121] Suitable solvents such as, but not limited to, include sugar alcohols, such as sorbitol solution, trihydric alcohols, such as glycerine, in specific ratio along with water as a base has been finalized in the stabilized oral solutions of the disclosure containing drotaverine to dissolve or rapidly disperse different additives used in the solutions. Ethanol and propylene glycol, low molecular weight polyethylene glycols, and mixtures thereof may also be generally employed as solvents. Suitable solubilizers cum stabilizers include, but not limited to, water-soluble PVPs, or polyvidone which can be used either singly or in combination.

[0122] The available PVP can either be water-soluble or water-insoluble. PVP is commercially available from a number of suppliers. The water-soluble PVPs or povidone sold under the trademark KOLLIDON K25, K30, K90 having molecular weights of 28, GOO- 34, 000, 44,000-54,000, and 1,000,000-1,500,000. In some embodiments, the PVP is K25 or K30. Polyvidone is a copolymer of vinyl pyrrolidone and vinyl acetate available from BASF under the tradename KOLLIDON VA 64.

[0123] A suitable acidifying agent maintains the solubility of the drotaverine active ingredient while at the same time improving its stability. Suitable acidifying agents include, but not limited to, tartaric acid, citric acid, fumaric acid, malic acid, maleic acid and mixtures thereof.

[0124] Suitable surfactants comprise phospholipids (e.g., lecithin), natural bile acid surfactant (e.g., sodium taurocholate) cationic surfactants (e.g., myristylgammapicolinium chloride), anionic surfactants (e.g., sorbitan monooleate) and non-ionic surfactants (e.g., polysorbates, pol oxamers, docusate sodium etc.).

[0125] Suitable metal chelating agents are for instance, but not limited to, ethylenediaminetetracetic acid salts (e.g., edetate disodium).

[0126] Suitable examples of buffering agents or pH modifiers include, but not limited to, those derived from acetic, aconitic, citric, glutaric, lactic, malic, succinic, phosphate and carbonic acids, as known in the art. Typically employed is an alkali or alkaline earth salts of one of the afore-mentioned acids. Phosphate and citrate buffers, such as phosphoric acid or a pharmaceutically acceptable salt thereof, or citric acid or a pharmaceutically acceptable salt thereof, are preferred. Sodium phosphate or sodium citrate is the preferred buffering agents or pH modifier, with sodium phosphate being most preferred. Suitable sweetening agents are such as, but not limited to, saccharin sodium, sodium cyclamate, sucrose, glycerol, aspartame, sucralose, acesulfame potassium, dipeptide-based sweeteners and the mixtures thereof. The amount of sweetening agent used may be in the range of about 0.01 to 10% w / v of the solution. The preferred amount of sweetening agent used may be in the range of about 0.1 to 10 % w / v of the solution.

[0127] Suitable viscosity-building agents may be selected from, but not limited to, xanthan gum, carrageenan, tragacanth, guar gum, pectin, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and carboxymethylcellulose sodium blends, and mixtures thereof. The viscosity-building agent provides both texture and mouthfeel to the preparations. The viscosity-building agent must be selected carefully to ensure compatibility with the drug and the other components of the solution.

[0128] Suitable preservatives include, but not limited to, sodium benzoate, potassium sorbate, benzyl alcohol, parabens (p-hydroxybenzoic acids esters) such as methyl paraben, ethyl paraben, propyl paraben, butyl paraben and the likes or mixtures thereof. The quantities of preservatives used may be in the range of about 0.01 to 5% w / v of the solution. The preferred quantities of the preservative used in the solutions may be in the range of about 0.02 to 2% w / v of the solutions.

[0129] The colouring agent or colourants may be incorporated to provide an appealing colour to the taste masked liquid pharmaceutical solution. Suitable colouring agents are well known to those skilled in the art and are those that are deemed safe for human consumption by relevant governmental regulatory bodies and which avoid chemical incompatibilities with other ingredients.

[0130] Suitable colouring agents used in the disclosure include, but not limited to, soluble supra colours, example tartrazine, quinoline yellow, erythrosine, sunset yellow colour, ponceau 4R, and the likes or mixtures thereof. The quantities of colorant used may be in the range of about 0% w / v to about 2.0% w / v of the solutions. The preferred quantities of the colorant used may be in the range of about 0%w / v to 1.0% w / v of the solution.

[0131] The flavouring agents used were of type and amount desired to enhance the palatability of the solution. Flavouring agents that may be used in the present disclosure include, but are not limited to, natural flavours, natural fruit flavours, artificial flavours, artificial fruit flavours, flavour enhancers or mixtures thereof. Natural flavours, artificial flavours or mixtures thereof include, but are not limited to, mint (such as peppermint or spearmint), and menthol. Natural fruit flavours, artificial fruit flavours or mixtures thereof include, but are not limited to, cherry. For example, without limiting the flavour to be incorporated into the solution, the flavouring agent may be selected from cherry, grape, strawberry, raspberry, orange, mango, melon, banana and citrus vanilla. Suitable flavouring agents include peppermint flavor, spearmint flavor, lime flavor, apple flavor, pear flavor, peach flavor, raspberry flavor, plum flavor, pineapple flavor and the like. The amount of flavourants used may be in the range of about 0.001 to 10% w / v of the solution formulations. The preferred amount of the flavourants used may be in the range of about 0.01 to 5% w / v of the solution formulations.

[0132] Suitable taste masking agents are the additives that are used to mask unpleasant flavours in pharmaceutical products. Bitterness, glycerine flavour, and mineral flavour, or metallic flavour in the drug product is masked with a flavour ingredient that gives the endproduct an appealing flavour. The non-limiting examples of the taste-masking agents may include menthol, Monoammonium glycyrrhizinate (MAG), sodium chloride alone or mixture thereof, such as but not limited to bitter masking flavour C20346. The amount of taste masking agent used may be in the range of about 0.001 to 10% w / v of the solution. The taste masking flavours are also available which help to successfully mask the bitter tasting drugs. The preferred amount of the taste masking agent or flavourants used may be in the range of about 0.03 to 5% w / v of the solution.

[0133] The oral solution formulations prepared may comprise 0.05 to 500 mg per 5ml drotaverine or a salt thereof. The oral solution formulations prepared may preferably comprise 2.5 to 100 mg per 5ml drotaverine or a salt thereof.

[0134] The disclosure provides a method comprising administering a therapeutic oral solution formulation of the disclosure to a subject, wherein said subject is suffering from at least one symptom of associated with spastic conditions of smooth muscles, wherein the spastic conditions are selected from the group consisting of gastrointestinal disorders including irritable bowel syndrome, gastric ulcers, and gastrointestinal colicky pain; biliary disorders including cholecystolithiasis, cholecystitis, cholangitis, biliary colic, and biliary dyskinesia; genitourinary disorders including dysmenorrhea, ureteric colic, and renal colic; comprising administering to the subject a therapeutically effective amount of formulation comprising drotaverine or a pharmaceutically acceptable salt thereof of the disclosure thereby relieving or preventing smooth muscle spasms in various organs, irrespective of their function or innervation.

[0135] The disclosure provides a method for the treatment and / or amelioration of at least one symptom associated with spastic conditions of smooth muscles in a subject in need thereof, wherein the spastic conditions are selected from the group consisting of gastrointestinal disorders including irritable bowel syndrome, gastric ulcers, and gastrointestinal colicky pain; biliary disorders including cholecystolithiasis, cholecystitis, cholangitis, biliary colic, and biliary dyskinesia; genitourinary disorders including dysmenorrhea, ureteric colic, and renal colic; comprising administering to the subject a therapeutically effective amount of the formulation comprising drotaverine or a pharmaceutically acceptable salt thereof of the disclosure, thereby relieving or preventing smooth muscle spasms in various organs, irrespective of their function or innervation.

[0136] The disclosure provides oral solution formulation for use in treatment and / or amelioration of at least one symptom associated with spastic conditions of smooth muscles in a subject in need thereof, wherein the spastic conditions are selected from the group consisting of gastrointestinal disorders including irritable bowel syndrome, gastric ulcers, and gastrointestinal colicky pain; biliary disorders including cholecystolithiasis, cholecystitis, cholangitis, biliary colic, and biliary dyskinesia; genitourinary disorders including dysmenorrhea, ureteric colic, and renal colic; comprising administering to the subject a therapeutically effective amount of oral solution formulation comprising drotaverine or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 36, thereby relieving or preventing smooth muscle spasms in various organs, irrespective of their function or innervation.

[0137] The disclosure provides pharmaceutical formulation in the form of an oral solution comprising per 5 ml of oral solution: i) drotaverine or salt thereof from about 1 mg to about 500 mg; ii) at least one sugar alcohol from about 100 mg to about 5000 mg; iii) at least one polyhydric alcohol from about 100 mg to about 4000 mg; iv) at least one sweetener from about 0.1 mg to 500 mg, v) at least one solubilizer from about 1 mg to 100 mg; vi) at least one acidifying agent from about 1 mg to 10 mg; vii) at least one taste masking agent from about 0.01 to 100 mg; viii) optionally one viscosity agent from about 0 mg to 10 mg; ix) at least optionally one antioxidant agent from about 0 mg to 50 mg; x) at least one preservative from about 0.01 mg to 25 mg; xi) at least one flavouring agent from about 0.5 mg to 100 mg; xii) optionally at least one colorant from about 0 mg to 5 mg.

[0138] The oral solution formulations comprising drotaverine or salt thereof can be prepared by a representative process comprising the following non-limiting steps: a) heating required quantity of water to a suitable temperature to obtain heated water; b) adding one or more suitable additives and at least one sweetener to the heated water of step a) under stirring to obtain a clear solution; c) cooling down the clear solution of step b) at room temperature to obtain cooled solution; d) adding at least one solubilizer, one or more acidifying agents and / or one or more antioxidants (if included in the respective formulation)in the cooled solution of step c) under stirring to obtain a clear solution; e) adding drotaverine or salt thereof in the clear solution of step d) followed by mixing until a clear solution is obtained; f) adding a quantity of one or more sugar alcohol and polyhydric alcohol and at least one suitable colorant to the solution obtained in step e) under stirring to obtain a dispersion mixture; g) dissolving desired quantity of one or more taste-masking agents and one or more flavouring agents by adding to the dispersion mixture obtained in step f) under continuous stirring to obtain oral solution; h) optionally transferring the oral solution obtained in step g) to a suitable container.

[0139] The following examples further exemplify the current disclosure and are not intended to limit the scope of the disclosure. It is obvious to those skilled in the art to find out the suitable compositions for oral preparations or other possible dosage forms and substitute the equivalent excipients as described in this specification or with the one known in the industry. As representative suitable oral solutions or formulations consistent with the objects, features and advantages of the present disclosure, the following non-limiting examples are provided.

[0140] Example 1: Method for preparation of oral solution formulation

[0141] The oral solution formulations comprising drotaverine or salt thereof were prepared using the process: a) heating required quantity of water to about 60°C to obtain heated water; b) adding methyl paraben, propyl paraben and at least one sweetener to heated water of step a) under stirring for about 10 to 30 minutes to obtain a clear solution; c) cooling down the clear solution obtained in step b) to room temperature to obtain cooled solution; d) adding povidone grade, one or more acidifying agents and one or more antioxidants (if included in the respective formulation) in the cooled solution of step c) under stirring for about 2 to 10 minutes to obtain a clear solution; e) adding drotaverine hydrochloride in the clear solution obtained of step d) followed by mixing until a clear solution is obtained; f) adding desired quantity of sorbitol, glycerine and at least one suitable colorant in the solution obtained in step e) under stirring for about 10 minutes to obtain a dispersion mixture; g) dissolving desired quantity of one or more taste-masking agents and one or more flavouring agents by adding to the dispersion mixture obtained in step f) under continuous stirring for about 10 minutes to obtain oral solution; h) optionally transferring the oral solution obtained in step g to a suitable container and leaving it for about half an hour to 2 hours.

[0142] The process may optionally comprise a step of making up the volume of the oral solution formulation in the container with required quantity of water followed by mixing for about 5 to 30 minutes.

[0143] The process may also optionally comprise sterilization of the prepared solution formulations prior to or after packaging in suitable containers.

[0144] As representative suitable oral solution formulations consistent with the objects, features and advantages of the present disclosure, the following non-limiting examples are provided.

[0145] Example 2:

[0146] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 3 below.

[0147] Table 3: Solution comprising 20 mg / 5ml of drotaverine

[0148] Example 3:

[0149] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 4 below.

[0150] Table 4: Solution comprising 20 mg / 5ml of drotaverine

[0151] Example 4: A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 5 below.

[0152] Table 5: Solution comprising 20 mg / 5ml of drotaverine

[0153] Example 5:

[0154] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 6 below.

[0155] Table 6: Solution comprising 20 mg / 5ml of drotaverine

[0156] Example 6:

[0157] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 7 below.

[0158] Table 7: Solution comprising 20 mg / 5ml of drotaverine Example 7

[0159] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 8 below. Table 8: Solution comprising 10 mg / 5ml of drotaverine

[0160] Example 8

[0161] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 9 below.

[0162] Table 9: Solution comprising 20 mg / 5ml of drotaverine

[0163] Example 9

[0164] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 10 below.

[0165] Table 10: Solution comprising 20 mg / 5ml of drotaverine

[0166] Example 10

[0167] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 11 below.

[0168] Table 11: Solution comprising 40 mg / 5ml of drotaverine

[0169] Example 11 A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 12 below.

[0170] Table 12: Solution comprising 2.50 mg / 5ml of drotaverine

[0171] Example 12

[0172] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 13 below.

[0173] Table 13: Solution comprising 20 mg / 5ml of drotaverine

[0174] Example 13

[0175] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 14 below.

[0176] Table 14: Solution comprising 10 mg / 5ml of drotaverine Example 14

[0177] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 15 below. Table 15: Solution comprising 10 mg / 5ml of drotaverine

[0178] Example 15 A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 16 below.

[0179] Table 16: Solution comprising 20 mg / 5ml of drotaverine

[0180] Example 16

[0181] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 17 below.

[0182] Table 17: Solution comprising 40 mg / 5ml of drotaverine

[0183] Example 17

[0184] A stable pharmaceutical oral solution formulation containing drotaverine may contain the ingredients as listed in Table 18 below.

[0185] Table 18: Solution comprising 80 mg / 5ml of drotaverine

[0186] Example 18: Stability data The oral solution formulations developed as per the present disclosure demonstrated chemical and physical stability using ICH accelerated stability guidelines (40°C ± 2°C and 75% RH ± 5% RH). The accelerated and long-term stability data of drotaverine oral solution formulations prepared according to Examples 8 and 9 are presented in Table 19 and Table 20, respectively. Table 19: Stability data for drotaverine oral solution of Example 8

[0187] Table 20: Stability data for drotaverine oral solution formulation of Example 9

[0188] RS: Related Substances

[0189] The developed pharmaceutical solutions demonstrate good chemical and physical stability as per currently available accelerated stability data as per ICH guidelines (40°C ± 2°C / 75% RH ± 5% RH and 25°C ± 2°C / 60% RH ± 5% RH as shown in Tables 19 and 20 above.

[0190] The surprising, remarkable, and novel oral solution formulations of drotaverine or salt thereof and methods for preparation thereof as set forth in the present application accurately describe the efficacy and utility of these oral formulations and methods to restore healthy functioning in humans and treat the conditions and disorders in humans as identified and described in this patent application.

[0191] The non-limiting advantages provided by the prepared oral solutions of the disclosure are as follows:

[0192] □ The developed solutions have acceptable palatability with less bitterness and reduced unpleasant after-taste.

[0193] □ The drug is in a fully dissolved state, thus there is reduced chance of under-dosing or over-dosing in comparison to currently marketed oral suspension products.

[0194] □ The bitter taste of drotaverine is masked by use of at least one sugar alcohol along with sweeteners and masking flavours.

[0195] □ The solutions have improved chemical stability throughout the shelf-life of the drug product.

[0196] □ The developed product is physically stable with dose uniformity and accurate dosing characteristics.

[0197] □ Oral solutions of the disclosure are easy to administer, safe, and administer a precise dose to patients with compromised swallowing ability.

[0198] □ The developed oral solutions allow easy and accurate division to smaller doses when dose dependent solutions are unavailable Example 19: Studies for organoleptic, palatability and taste evaluation

[0199] Taste is a subjective perception and may therefore be judged by a pool of people. The formulation scoring most favourable rating is usually considered to be acceptable to a large patient population. Organoleptic properties such as taste, smell, sight, color, appearance and texture along with palatability aspects of the formulations were also studied. A basic experimental set up for testing taste, organoleptic and palatability aspects of oral solution formulation comprise several steps such as selection and preparation of volunteers, application of solution to volunteers followed by evaluation of intensity and quality of taste. The volunteers or subjects rinse their mouths with water to ensure a neutral baseline. Solutions are typically applied to the tongue using a cotton swab, pipette, or by having the subject sip and spit. Subjects or volunteers rate intensity and quality of the taste (e.g., salty, sour, bitter, sweet, or no flavor). The volunteers rate the bitterness of the compounds on the bitterness scale as illustrated in Table 21 and 22 below. Table 21: Scoring system for taste evaluation studies

[0200] Table 22: Scoring data for taste evaluation of Example 8 formulation

[0201] After the completion of taste-test, the volunteers are asked to rinse their mouth with water between samples helps to minimize carryover effects. The volunteers may be asked to repeat steps of application, swirl and spit, rating of bitterness and rinsing many times for different samples or samples with varying concentrations.

[0202] To avoid bias between samples, the volunteers were asked to rinse their oral cavity with water at least five times, and a minimum gap of 10 minutes was maintained between two successive taste evaluations. The volunteers were asked to identify compounds that have a taste similar to drotaverine solution for its bitterness. Based on the feedback of volunteers on the similarity in taste to drotaverine and the individual rankings, the surrogate compound was selected for further screening.

[0203] Although the subject matter has been described herein with reference to certain preferred embodiments thereof, other embodiments are possible. For illustrative purpose, the solution of disclosure comprises drotaverine or salt thereof as the anti-spasmodic agent. However, those skilled in the art would appreciate that scope of the disclosure would extend to solutions comprising other anti-spasmodic agents or bitter tasting drugs known in the field of art.

[0204] It will be obvious to those skilled in the art to make various changes, modifications and alterations to the invention described herein. To the extent that these various changes, modifications and alteration do not depart from scope of the present disclosure, they are intended to be encompassed therein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. In addition, where this application has listed the steps of a method or procedure in a specific order, it may be possible, or even expedient in certain circumstances, to change the order in which some steps are performed, and it is intended that the particular steps of the method or procedure claims set forth herein below not be construed as being order-specific unless such order specificity is expressly stated in the claim.

Claims

We Claim:

1. A palatable oral solution comprising therapeutically effective amount of drotaverine or a salt thereof, at least one sugar alcohol, at least one polyhydric alcohol, at least one solubilizer, and at least one acidifying agent, wherein the at least one sugar alcohol and the at least one polyhydric alcohol are present in a ratio from about 1 :1 to 20: 1.

2. The oral solution as claimed in claim 1, wherein the sugar alcohol and polyhydric alcohol are present in ratio from about 3 :1 to 10:1.

3. The oral solution as claimed in claim 1 or 2, wherein the sugar alcohol comprises one or more of mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, hydrogenated starch hydrolysates (HSH), isomalt, or erythritol.

4. The oral solution as claimed in claims 1 to 3, wherein the polyhydric alcohol comprises one or more of propylene glycol, ethylene glycol, or glycerine.

5. The oral solution as claimed in claims 1 to 4, wherein the solubilizer is a polyvinylpyrrolidone grade of polymer.

6. The oral solution as claimed in claims 1 to 5, wherein the acidifying agent comprises one or more of citric acid, fumaric acid, lactic acid, maleic acid, malic acid, or tartaric acid.

7. The oral solution as claimed in claims 1 to 6, further comprising one or more of pharmaceutically acceptable excipients selected from at least one sweetener, at least one taste-masking agent, at least one antioxidant, at least one viscosity-building agent, at least one flavouring agent, at least one colorant, at least one buffering agent, at least one chelating agent, at least one surfactant, at least one wetting agent, at least one preservative, or at least one solvent.

8. The oral solution as claimed in claims 1 to 7, wherein the oral solution comprises a sweetener, and wherein the sweetener is natural and / or an artificial sweetener alone or in combination.

9. The oral solution as claimed in claim 8, wherein the sweetener comprises saccharin sodium, sodium cyclamate, sucrose, glycerol, aspartame, sucralose, acesulfame potassium, or dipeptide-based sweeteners.

10. The oral solution as claimed in claims 7 to 9, wherein the oral solution comprises a tastemasking agent, and wherein the taste-masking agent comprises menthol,Monoammonium glycyrrhizinate (MAG), or sodium chloride.

11. The oral solution as claimed in claims 7 to 10, wherein the oral solution comprises an antioxidant, and wherein the antioxidant comprises butylated hydroxy-anisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid, methionine, alanine, or cysteine.

12. The oral solution as claimed in claims 7 to 11, wherein the oral solution comprises a viscosity -building agent, and wherein the viscosity-building agent comprises xanthan gum, carrageenan, tragacanth, guar gum, pectin, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, or carboxymethylcellulose sodium blends.

13. The oral solution as claimed in claims 7 to 12, wherein the oral solution comprises a flavouring agent, and wherein the flavouring agent comprises cherry, grape, strawberry, raspberry, mango, orange, melon, banana, citrus, vanilla, peppermint, spearmint, lime, apple, pear, peach, raspberry, plum, or pineapple.

14. The oral solution as claimed in claims 7 to 13, wherein the oral solution comprises a metal chelating agent, and wherein the metal chelating agent comprises a salt of ethylenediamine-tetraacetic acid, optionally edetate disodium.

15. The oral solution as claimed in claim 7 to 14, wherein the oral solution comprises a buffering agent, and wherein the buffering agent is derived from acetic acid, aconitic acid, citric acid, glutaric acid, lactic acid, malic acid, succinic acid, phosphate acid, or carbonic acid.

16. The oral solution as claimed in claims 7 to 15, wherein the oral solution comprises a preservative, and wherein the preservative comprises sodium benzoate, potassiumsorbate, benzyl alcohol, parabens (p-hydroxybenzoic acids esters), methyl paraben, ethyl paraben, propyl paraben, or butyl paraben.

17. The oral solution as claimed in claims 7 to 16, wherein the oral solution comprises a surfactant, and wherein the surfactant comprises a phospholipid, a natural bile acid surfactant, a cationic surfactant, an anionic surfactant, or a non-ionic surfactants.

18. The oral solution as claimed in claims 7 to 17, wherein the oral solution comprises a colouring agent, and wherein the colouring agent comprises tartrazine, quinoline yellow, erythrosine, sunset yellow, or ponceau 4R, and wherein the colouring agent is present in an amount of from about 0.0001 to 2.0% w / v of the solution.

19. The oral solution as claimed in claims 1 to 18, wherein the pH of the solution ranges between about 1 to 7, preferably between about 2.5 to 6.5.

20. The oral solution as claimed in claims 1 to 19, wherein the drotaverine or a salt thereof is present in an amount of about 0.01 to 20.0% w / v of the total solution.

21. The oral solution as claimed in claims 1 to 20, wherein the sugar alcohol is present in an amount of about 1.0 to 80.0% w / v, preferably about 10.0 to 60.0% w / v of the total solution.

22. The oral solution as claimed in claims 1 to 21, wherein the polyhydric alcohol is present in an amount of about 1.0 to 60.0% w / v, preferably about 4.0 to 40.0% w / v of the total solution.

23. The oral solution as claimed in claims 1 to 22, wherein the acidifying agent is present in an amount of about 0.001 to 4.0 % w / v of the total solution.

24. The oral solution as claimed in claims 1 to 23, wherein the solubilizer is present in an amount of about 0.01 to about 10.0% w / v, preferably about 0.05 to 8.0% w / v of the total solution.

25. The oral solution as claimed in claims 7 to 24, wherein the taste masking agent is present from about 0.001 to 10% w / v of the solution.

26. The oral solution as claimed in claims 7 to 25, wherein the flavouring agent is present from about 0.001 to 10% w / v, preferably in an amount of about 0.01 to 5.0% w / v, more preferably about 0.05 to 4.0% w / v of the solution formulations.

27. The oral solution as claimed in claims 7 to 26, wherein the antioxidant is present in an amount of about 0.01 to 4.0% w / v, preferably about 0.02 to 4.0% w / v of the total solution.

28. The oral solution as claimed in claims 7 to 27, wherein the sweetening agent is present in an amount of about 0.1 to 10.0% w / v, preferably about 0.3 to 8.0% w / v of the total solution.

29. The oral solution as claimed in claims 7 to 28, wherein the viscosity-building agent is present in an amount of about 0 to 2% w / v, preferably about 0 to 1.0% w / v of the total solution.

30. The oral formulation as claimed in claims 1 to 29, wherein the drotaverine salt is drotaverine hydrochloride.

31. A stable and palatable oral solution formulation of drotaverine or a salt thereof, wherein said oral solution formulation comprises: a) from about 0.01 to 20.0% w / v of drotaverine or a salt thereof; b) from about 1.0 to 80.0% w / v of at least one sugar alcohol; c) from about 1.0 to 60.0% w / v of at least one polyhydric alcohol; d) from about 0.01 to 10.0% w / v of at least one solubilizer; e) from about 0.01 to 5% w / v of at least one preservative; f) from about 0% w / v to about 2.0% w / v of at least one colorant; g) from about 0.001 to 4.0 % w / v of at least one acidifying agent; h) optionally from about 0 to 4.0% w / v of an antioxidant; and i) optionally from about 0.1 to 10.0% w / v of at least one sweetener.

32. The oral solution formulation as claimed in claim 31, further comprising about 0 to 2% w / v of a viscosity-building agent, about 0.01 to 5.0% w / v of a flavouring agent and optionally one or more of pharmaceutically acceptable excipients.

33. The oral formulation as claimed in claim 31 or 32, wherein the formulation comprises about 1 to about 500 mg of drotaverine or salt thereof.

34. The oral formulation as claimed in claims 31 to 33, wherein the drotaverine salt is drotaverine hydrochloride.

35. A pharmaceutical formulation in the form of an oral solution comprising per 5 ml of oral solution: i) drotaverine or salt thereof from about 1 mg to about 500 mg; ii) at least one sugar alcohol from about 100 mg to about 5000 mg; iii) at least one polyhydric alcohol from about 100 mg to about 4000 mg; iv) at least one sweetener from about 0.1 mg to 500 mg, v) at least one solubilizer from about 1 mg to 100 mg; vi) at least one acidifying agent from about 1 mg to 10 mg; vii)at least one taste masking agent from about 0.01 to 100 mg; viii) optionally one viscosity agent from about 0 mg to 10 mg; ix) optionally one antioxidant agent from about 0 mg to 50 mg; x) at least one preservative from about 0.01 mg to 25 mg; xi) at least one flavouring agent from about 0.5 mg to 100 mg; xii) optionally at least one colorant from about 0 mg to 5 mg.

36. A method for the treatment and / or amelioration of at least one symptom associated with spastic conditions of smooth muscles in a subject in need thereof, wherein the spastic conditions are selected from the group consisting of gastrointestinal disorders including irritable bowel syndrome, gastric ulcers, and gastrointestinal colicky pain; biliary disorders including cholecystolithiasis, cholecystitis, cholangitis, biliary colic, and biliary dyskinesia; genitourinary disorders including dysmenorrhea, ureteric colic, and renal colic; comprising administering to the subject a therapeutically effective amount of oral solution comprising drotaverine or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 35, thereby relieving or preventing smooth muscle spasms in various organs, irrespective of their function or innervation.

37. Use of an oral solution formulation as claimed in any of claims 1 to 35 for treating at least one symptom of a gastrointestinal, biliary, urological or gynaecological disordercharacterized by spastic conditions of smooth muscles in a subject, comprising administering the formulation to the subject.

38. An oral solution formulation as claimed in claims 1 to 35 for use in treatment and / or amelioration of at least one symptom associated with spastic conditions of smooth muscles in a subject in need thereof, wherein the spastic conditions are selected from the group consisting of gastrointestinal disorders including irritable bowel syndrome, gastric ulcers, and gastrointestinal colicky pain; biliary disorders including cholecystolithiasis, cholecystitis, cholangitis, biliary colic, and biliary dyskinesia; genitourinary disorders including dysmenorrhea, ureteric colic, and renal colic; comprising administering to the subject a therapeutically effective amount of oral solution formulation comprising drotaverine or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 35, thereby relieving or preventing smooth muscle spasms in various organs, irrespective of their function or innervation.

39. A method comprising administering a therapeutic oral solution formulation as claimed in any one of claims 1 to 35 to a subject, wherein said subject is suffering from at least one symptom associated with spastic conditions of smooth muscles, wherein the spastic conditions are selected from the group consisting of gastrointestinal disorders including irritable bowel syndrome, gastric ulcers, and gastrointestinal colicky pain; biliary disorders including cholecystolithiasis, cholecystitis, cholangitis, biliary colic, and biliary dyskinesia; genitourinary disorders including dysmenorrhea, ureteric colic, and renal colic; comprising administering to the subject a therapeutically effective amount of oral solution formulation comprising drotaverine or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 35, thereby relieving or preventing smooth muscle spasms in various organs, irrespective of their function or innervation.

40. A method for preparation of oral solution formulation of drotaverine or salt thereof comprising: a. heating required quantity of water at about 60°C to obtain heated water; b. adding at least one suitable additive and at least one sweetener to heated water of step a) under stirring for about 10 to 30 minutes to obtain a clear solution; c. cooling down the clear solution obtained in step b) at room temperature to obtain cooled solution;d. adding at least one solubilizer, one or more acidifying agents and optionally one or more antioxidants in the cooled solution of step c) under stirring for about 2 to 10 minutes to obtain a clear solution; e. adding drotaverine or salt thereof in the clear solution of step d) followed by mixing until a clear solution is obtained; f. adding desired quantity of at least one sugar alcohol, at least one polyhydric alcohol, and at least one suitable colorant in the solution of step e) under stirring for about 10 minutes to obtain a dispersion mixture; g. dissolving desired quantity of one or more taste-masking agents and one or more flavouring agents by adding to the dispersion mixture obtained of step f) under continuous stirring for about 2 to 20 minutes to obtain oral solution; h. optionally transferring the oral solution of step g) to a suitable container.

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