An oral non-aqueous solution of carbimazole

Abstract

An oral non-aqueous solution of carbimazole comprising carbimazole or pharmaceutically acceptable salts thereof in an amount of 1 mg / mL to 10 mg / mL is provided. The solution may further comprise an an

Description

FIELD OF THE INVENTION The present invention relates to an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof. The present invention also provides a process for preparing an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof. The present invention also provides an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof for use as a medicament. BACKGROUND OF THE INVENTION Hyperthyroidism, or overactive thyroid, occurs when the thyroid gland produces more thyroid hormones than the body requires. The thyroid is a small, butterfly-shaped gland located at the front of the neck. These hormones are crucial in regulating the body’s energy usage, impacting nearly every organ, including the heart. When there is an excess of thyroid hormone, many bodily functions accelerate, leading to a variety of symptoms. Hyperthyroidism can result from various medical conditions that impact the thyroid gland. These include: Graves' disease: An autoimmune disorder where the immune system mistakenly attacks the thyroid, causing it to produce excess thyroid hormone. Overactive thyroid nodules: Known as toxic adenoma, toxic multinodular goiter, or plummer disease, this condition occurs when one or more thyroid nodules become overactive and produce too much thyroid hormone. Thyroiditis: Inflammation of the thyroid gland, which can lead to an increase in thyroid hormone production. Symptoms of hyperthyroidism can include rapid heart rate (tachycardia), increased blood pressure, shakiness, like hand tremors, feeling anxious, nervous, and / or irritable, weight loss despite a regular or increased appetite, diarrhoea or more frequent pooping, increased sweating and sensitivity to warm temperatures, hair loss or brittle hair, difficulty sleeping (insomnia), menstrual period changes, like lighter or missed periods, swelling and enlargement of your neck (goiter), and swelling or bulging of your eyes (thyroid eye disease). There are many treatment options for hyperthyroidism. Some medications treat the symptoms of hyperthyroidism, such as heart problems, while others aim to address the production of thyroid hormone. Beta-blockers cannot treat hyperthyroidism, but they can reduce the symptoms until other treatments take effect. However, this may take a few weeks or months. The main medications used for the treatment of an overactive thyroid are known as anti-thyroid drugs. These reduce the production of thyroid hormones. Thiamazole (also called methimazole), propylthiouracil, and carbimazole are the most commonly used anti-thyroid drugs. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents thyroid peroxidase enzyme from iodinating and coupling the tyrosine residues on thyroglobulin, thereby reducing the production of the thyroid hormones T3 and T4 (thyroxine). Carbimazole is available in the market in tablet form only under brand names Neo-Mercazole®, Anti-Thyrox® etc. Patient acceptability is a critical factor in the development of any pharmaceutical formulation. Children and older adults, in particular, differ from other age groups and require special attention when it comes to medication acceptance. This is especially true for solid oral formulations, such as tablets, which can be difficult for paediatric, geriatric, and ICU patients to swallow. In these cases, if a medication is available only in solid form, healthcare professionals may face significant challenges in ensuring the patient can take the medicine effectively. In some hospital practices, extemporaneous liquid formulations are prepared by crushing available tablet formulations and mixing them with a suitable vehicle. A sweetener and other ingredients may also be added to create a liquid suspension, making it easier for patients who have difficulty swallowing tablets. However, this practice is not an ideal solution and requires a skilled technician to execute the process correctly. Additionally, it carries the risk of dosing errors. The powder is typically mixed with water or another reconstitution liquid to create a suspension, and any remaining liquid must be discarded immediately. This can lead to incorrect dosing, wasted medication, or reconstitution mistakes, particularly when non-medical personnel are involved in preparing the suspension. Furthermore, storing excess powder or suspension for future use increases the risk of bacterial contamination or degradation, compromising the medication's safety and effectiveness. Ready-to-use liquid dosage forms offer several benefits, particularly in improving patient compliance. They are especially advantageous for paediatric, geriatric, or patients who have difficulty swallowing tablets. Liquid formulations can also be flavoured to mask the taste of the medication, making them more palatable. Additionally, liquids are often absorbed more quickly after oral administration, leading to a faster onset of action. GB2527555B discloses a liquid composition containing methimazole for use in the treatment and prevention of hyperthyroidism in cats. The liquid composition comprising approximately 0.25 to 1% w / v of methimazole, or a pharmaceutically acceptable salts and solvates thereof. The composition also includes at least 0.4% w / v of a polysaccharide, preferably xanthan gum, and water as the liquid vehicle. This product is marketed by Norbrook Laboratories Limited under the brand name of product is Felanorm® AU2008208151B2 describes a composition designed for transdermal administration in cats, which includes at least one anti-hyperthyroid drug. The drug can be selected from carbimazole, methimazole, or their combinations, or propylthiouracil, methyluracil, benzylthiouracil, or their combinations. The composition is further characterized by the inclusion of a penetration enhancer, which can be chosen from fatty acids, terpenes, pyrrolidones, C2-C8 alcohols, glycol ethers, triglycerides, or combinations of thereof. Additionally, the composition contains at least one carrier, such as propylene glycol, dimethylformamide (DMF), cyclodextrin compounds, polyethylene glycol, or their combinations. US10369135B2 discloses compositions specifically designed for the treatment of hyperthyroidism (hyperthyreosis), particularly in cats. These compositions are formulated for transdermal delivery of the active ingredient, which can be applied, for example, to the cat's ear (auricle or pinna). The formulations contain an active agent such as methimazole (or 2-mercapto-1-methylimidazole) or carbimazole, along with at least one wax, one fatty oil, and optionally, an emulsifier. In some embodiments, a nanocarrier may be used as the emulsifier. CN102091026A discloses external-use anti-thyroid gel consists of a combination of medicinal ingredients is selected from thiamazole, carbimazole, propylthiouracil and methylthiouracil, polymer-based materials, solvents, co-solvents, wetting agents, and antiseptics. Additionally, it may optionally include antioxidants, neutralizers, and penetration enhancers. Mohammed Iqdam Al-Shadeedi et al discloses an orodispersible tablet of carbimazole comprising crospovidone, aspartame, talc, magnesium stearate, and mannitol prepared by using a direct compression technique. Based on existing prior art, it can be concluded that current formulations are primarily available in solid oral and topical dosage forms. The prior art referencing liquid compositions pertains to veterinary use and is typically aqueous or water-based. While orodispersible tablets address some limitations of conventional oral tablets, they come with their drawbacks. These tablets are hygroscopic, requiring storage in dry conditions, and may leave an unpleasant taste or grittiness in the mouth. They also require specialized packaging to ensure product stability and safety, and maintaining dose uniformity remains a key technical challenge. In view of the foregoing, it would be advantageous to develop stable oral liquid formulations of carbimazole for human use, offering improved stability and enhanced patient compliance as an alternative treatment option. Therefore, the inventors in the present invention have arrived at an oral non-aqueous solution of carbimazole with the aim to overcome the problems cited above as described herein. OBJECTIVE OF THE INVENTION The main objective of the present invention is to provide an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof. The other main objective of the present invention is to provide an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof that is stable. Another objective of the present invention is to provide an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof which is safe and effective. Yet another objective of this invention is to provide an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof which is ready-to-use. One other objective of the present invention is to provide an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof which provides patient compliance. Yet another object of the present invention is to provide an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof which is free from water. Yet another object of the present invention is to provide a method for the preparation of an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof, wherein the method provides clear, colorless oily liquid free from visible particulate matter of carbimazole or pharmaceutically acceptable salts thereof. SUMMARY OF THE INVENTION The present invention is all about an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof. The main aspect of the present invention is to provide an oral non-aqueous solution of carbimazole comprising a therapeutically effective amount of carbimazole or pharmaceutically acceptable salts thereof, an antioxidant, a flavouring agent, and a vehicle. Yet another aspect of the present invention is to provide a process for the preparation of an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof. DESCRIPTION OF THE INVENTION Before providing a detailed explanation of the present invention, it is important to clarify that the invention is not confined to the specific examples or process parameters described, as these may vary. Additionally, the terminology used throughout this document is intended solely to describe specific embodiments of the invention and should not be construed as limiting the scope of the invention in any way. The detailed description provided below outlines exemplary embodiments of the invention and is not intended to limit the invention to only those specific forms or implementations. It explains the functions and sequences of steps involved in constructing and / or operating the exemplary embodiments. However, it should be understood that equivalent functions and sequences, which may be achieved through alternative methods, are also within the scope of the invention. As defined herein, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. Although any process and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. As stated in the present invention herein, the singular forms “a,” “an” and “the” specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise. The term “about” is intended to be synonymous with "approximately." As understood by one skilled in the art, the precise range of "about" will vary depending on the specific component of the composition. Generally, the use of "about" allows for values that may differ slightly from the stated values, typically within a range of ± 0.1% to 10%, while still maintaining effectiveness and safety. Therefore, compositions that fall slightly outside the specified ranges are also considered within the scope of the present claims. As used herein, when the terms “comprise(s)” or “comprising” appear in a transitional phrase or within the body of a claim, they are to be interpreted with an open-ended meaning. Specifically, these terms are understood to be synonymous with "having at least" or "including at least." In the context of a process, the term "comprising" indicates that the process includes at least the specified steps, but may also encompass additional steps. In the context of a composition, "comprising" means the composition includes at least the listed components or features, but may also contain other features or components. As stated herein, that follows in a transitional phrase or in the body of a claim, the term “consisting of’ excludes any element, step, or ingredient not specified in the claim or description, “consisting of’ is defined as “closing the claim or description to the inclusion of materials other than those recited except for impurities ordinarily associated therewith”. As stated herein, that it follows in a transitional phrase or in the body of a claim, the term “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. In the application, effective amounts are generally those amounts listed as the ranges or levels of ingredients in the descriptions, which follow hereto. A “therapeutically effective amount” or “effective amount” is the amount of a pharmaceutical agent to achieve a pharmacological effect. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. As used herein, the term “therapeutically effective amount” can be understood to include an amount of carbimazole that is effective in reducing the production of the thyroid hormones T3 and T4 (thyroxine). As used herein, the term “active agent” can be understood to include any substance or formulation or combination of substances or composition of matter, when administered to a human or animal subject, induces a desired pharmacologic and / or physiologic effect by local and / or systemic action. The terms are used interchangeably herein: "active", "drug", “active pharmaceutical ingredient”, and "active ingredient". As used herein, the terms “dose” and “dosage” can be understood to mean a specific amount of active or therapeutic agents for administration. As used herein, the term “excipient” can be understood to include any inert substance combined with an active agent such as carbimazole or pharmaceutically acceptable salts thereof to prepare a convenient dosage form. As per one preferred embodiment, the term "oral solution" as used herein refers to a liquid dosage form that is free from suspended particles and is characterized by being a clear, homogeneous liquid solution. As per one preferred embodiment, the term "non-aqueous solution" as used herein refers to a solution obtained by dissolving a solute in any liquid other than water. As per one preferred embodiment the term “free of water” is defined as the said formulation is completely devoid of water. As per one preferred embodiment, the term “ ready-to-use” used herein is defined as the solution that can administered directly to a patient for a treatment without the steps such as reconstitution or dilution. As stated herein the term “RTU” refers to ready-to-use and can interchangeably use for the “ready-to-use” phrase. As stated herein the term “subject” refers to human only and can interchangeably use for the “patient” phrase. As stated herein the term “Cmax” refers to maximum observed drug concentration in serum. As stated herein the term “AUCo-72h” refers to area under the concentration versus time curve from time zero to 72 hours calculated by the linear trapezoidal method. As stated herein the term “Tmax” refers to time to observed maximum drug concentration in serum. If this value is observed at more than one point, the first point shall be taken as Tmax. As stated herein the term “Kei” refers to apparent first - order terminal elimination rate constant calculated from a semi-log plot of the blood concentration versus time curve, using the method of least square regression. As stated herein the term ti / 2 refers to terminal half-life as determined by quotient 0.693 / Kei [Serum concentration half-life]. As per one preferred embodiment the term “free of thickening agent” and / or “free of wetting agent” is defined as the said formulation is completely devoid of thickening agent and / or wetting agent. As per one preferred embodiment of the present invention provides an oral non-aqueous solution of carbimazole, which is free or void from polysaccharides selected from amphoteric (e.g. carboxy methyl chitosan, N-hydroxy-dicarboxyethyl-chitosan, modified potato starch etc.), anionic (e.g. alginic acid, pectin, xanthan gum, hyaluronic acid, chondroitin sulfate, gum arabic, gum karaya, gum tragacanth, carboxymethyl-chitin, cellulose gum etc.), cationic (e.g. chitosan, cationic guar gum, cationic hydroxy ethyl cellulose (1-JEC) etc.), hydrophobic (e.g. cetyl hydroxy ethyl cellulose, poly-quatemium etc.) and non-ionic (e.g. starch, dextrins, guar gum, cellulose ethers (such as hydroxy ethyl cellulose, methyl cellulose or nitro cellulose) etc.); thickening agent (e.g. acetylated distarch adipate, acetylated distarch phosphate, acetylated oxidized starch, acetylated starch, acid treated starch, agar, alginic acid, alkaline treated starch, aluminum distearate, ammonium alginate, arabinogalactan, bleached starch, calcium alginate, carrageenan, dextrin roasted starch, distarch phosphate, enzyme treated starch, gellan gum, guar gum, gum arabic, glycerol, hydrogenated castor oil, hydroxypropyl cellulose, hydroxypropyl distarch phosphate, hydroxypropyl methylcellulose, hydroxypropyl starch, karaya gum, konjac gum, locust bean gum, methyl ethyl cellulose, methylcellulose, monostarch phosphate, oxidized starch, pectin, phosphated distarch phosphate, potassium alginate, processed eucheuma seaweed, propane-1,2-diol alginate, polyvinylpyrrolidone, odium alginate, starch sodium octenyl succinate, tara gum, tragacanth, triethyl citrate etc.); wetting agents (beta-cyclodextrin, brominated vegetable oil, calcium stearoyl lactylate, choline salts and esters, cross-linked sodium carboxymethylcellulose, dioctyl sodium sulfosuccinate, magnesium stearate, polyglycerol polyricinoleate, polyoxyethylene stearate, polysorbate (i.e. 20, 40, 60, 65, 80), simethicone emulsion, sodium carboxymethylcellulose, sodium stearoyl lactylate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, stearyl tartarate, sucroglycerides, sucrose acetate isobutyrate, superglycerinated hydrogenated rapeseed oil, oxidized soya bean oil etc.); buffers (e.g. citric acid, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, sodium carbonate, sodium dihydrogen phosphate, sodium hydrogen carbonate, sodium hydroxide etc.); preservative (e.g. benzoic acid, diphenyl (biphenyl), borax, boric acid, calcium benzoate, calcium disodium EDTA, calcium formate, calcium propionate, calcium sorbate, dehydroacetic acid, dimethyl dicarbonate, ethyl para-hydroxybenzoate, examethylene tetramine (hexamine), formaldehyde, formic acid, gum guaicum, heptyl p-hydroxybenzoate, lecithin citrate, lysozyme, methylparaben (methyl para-hydroxybenzoate), natamycin (pimaricin), nisin, orthophenyl phenol (2-hydroxybiphenyl), phytic acid, potassium benzoate, potassium propionate, potassium sorbate, propionic acid, propylparaben (propyl para-hydroxybenzoate), sodium benzoate, sodium dehydroacetate, sodium ethyl para-hydroxybenzoate, sodium fonnate, sodium methyl para-hydroxybenzoate, sodium orthophenyl phenol, sodium propionate, sodium propyl parahydroxybenzoate, sodium sorbate, sodium tetraborate, thiabendazole etc.). The main embodiment of the present invention is to provide an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof. Another main embodiment of the present invention is to provide an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof in an amount of about 1 mg / mL to about 10 mg / mL. Another main embodiment of the present invention is to provide an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof in an amount of about 1 mg / mL to about 10 mg / mL. The oral non-aqueous solution may further comprise an antioxidant, flavouring agent and vehicle. Another main embodiment of the present invention is to provide an oral non-aqueous solution of carbimazole comprising a therapeutically effective amount of carbimazole or pharmaceutically acceptable salts thereof, an antioxidant, a flavouring agent, and a vehicle. As per one preferred embodiment of the present invention provides an oral non-aqueous solution of carbimazole comprising a therapeutically effective amount of carbimazole or pharmaceutically acceptable salts thereof for the treatment of hyperthyroidism. As per one preferred embodiment, the amount of carbimazole or pharmaceutically acceptable salts thereof may present in the range from about 0.5 mg / mL to about 500 mg / mL, preferably in the range from about 1 mg / mL to about 200 mg / mL, preferably in the range from about 1 mg / mL to about 150 mg / mL, more preferably in the range from about 1 mg / mL to about 100 mg / mL, more preferably in the range from about 1 mg / mL to about 50 mg / mL, more preferably in the range from about 1 mg / mL to about 40 mg / mL, more preferably in the range from about 1 mg / mL to about 30 mg / mL, most preferably in the range from about 1 mg / mL to about 10 mg / mL, or any other value in between thereof. As per one preferred embodiment, the amount of carbimazole or pharmaceutically acceptable salts thereof may present in an amount of about 2.5 mg / mL. As per one embodiment, the “antioxidant” used in the present invention is defined as a substance that inhibits oxidation, especially one used to counteract the deterioration of the final formulation. As per one embodiment, said antioxidant can be selected from, but not limited to, tocopherol (Vitamin E), methionine, ascorbic acid (Vitamin C), ascorbyl palmitate, butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), potassium metabisulfite, and sodium bisulfite or any combination thereof. As per a preferred embodiment, butylated hydroxy anisole is used as an antioxidant. According to one preferred embodiment, the amount of antioxidant or butylated hydroxy anisole may present in the range from about 0.001 mg / mL to about 10 mg / mL, preferably in the range from about 0.005 mg / mL to about 10 mg / mL, preferably in the range from about 0.01 mg / mL to about 10 mg / mL, more preferably in the range from about 0.01 mg / mL to about 5 mg / mL, more preferably in the range from about 0.05 mg / mL to about 5 mg / mL, more preferably in the range from about 0.05 mg / mL to about 3 mg / mL, more preferably in the range from about 0.08 mg / mL to about 3 mg / mL, most preferably in the range from about 0.08 mg / mL to about 2 mg / mL or any other value in between thereof. As per one preferred embodiment, the amount of antioxidant or butylated hydroxy anisole may present in an amount of about 0.2 mg / mL. As per one embodiment, the “flavouring agent” used in the present invention is defined as a pharmaceutical additive that is added to improve the taste or odour of a pharmaceutical dosage form. As per one embodiment, said flavouring agent can be selected from essential oils including peppermint oil, orange oil, lemon oil, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, orange pear, peach, strawberry, raspberry, cherry, plums pineapple, apricot, frozen peppermint, tutti frutti flavour or any combination thereof. As per a preferred embodiment, peppermint oil is used as a flavouring agent. The peppermint oil is procured from AOS Products Pvt. Ltd, S-33, South side GT Road, Industrial area, Ghaziabad, 201012. U.P. According to one preferred embodiment, the amount of flavouring agent or peppermint oil may present in the range from about 0.01 mg / mL to about 20 mg / mL, preferably in the range from about 0.05 mg / mL to about 20 mg / mL, preferably in the range from about 0.05 mg / mL to about 10 mg / mL, more preferably in the range from about 0.05 mg / mL to about 5 mg / mL, more preferably in the range from about 0.08 mg / mL to about 5 mg / mL, more preferably in the range from about 0.1 mg / mL to about 5 mg / mL, more preferably in the range from about 0.5 mg / mL to about 5 mg / mL, most preferably in the range from about 0.8 mg / mL to about 5 mg / mL or any other value in between thereof. As per one preferred embodiment, the amount of flavouring agent or peppermint oil may present in an amount of about 3 mg / mL. As per one embodiment, the “vehicle” used in the present invention is defined as a carrier or inert medium used as a solvent in which the medicinally active agent is formulated and / or administered. As per one embodiment, said vehicle can be selected from glycols, polyethylene glycol (PEG), propylene glycol, ethyl alcohol, vegetable oils like sesame oil, peanut oil, castor oil, olive oil, cottonseed oil, peanut oil, corn oil, soya bean oil, coconut oil, glycerol, triacetin, a triglyceride, an alkyl triglyceride, a diglyceride, perfluorocarbon, N-methyl- pyrrolidone, dimethylsulfoxide (DMSO), oleic acid, medium chain triglyceride (MCT), glycofurol, lauryl lactate, perfluorocarbon, propylene carbonate, or any combination thereof. As per a preferred embodiment, medium chain triglyceride (MCT) is used as a vehicle. As per one preferred embodiment, the amount of vehicle or medium chain triglyceride (MCT) may present in sufficient quantity to make up the final volume of the formulation. As per one preferred embodiment, the amount of vehicle or medium chain triglyceride (MCT) may present in sufficient quantity to make up 100 % w / v of the formulation. As per one preferred embodiment, the amount of vehicle or medium chain triglyceride (MCT) may present in the range from about 0.5 % w / v to about 100 % w / v or any other value between thereof. In one embodiment, the weight ratio of carbimazole to medium chain triglyceride in the oral non-aqueous solution disclosed herein is about 0.1:100 to about 1:95 and all values in between, including, for example, 0.2:96, 0.2:97, 0.2:98, 0.2:99, 0.2:99.5, 0.25:98, 0.25:99, 0.25:99.5, 1:40, and 1:39.8. In one embodiment, the weight ratio of carbimazole to butylated hydroxy anisole in the oral non-aqueous solution disclosed herein is about 1:0.01 to about 15:1 and all values in between, including, for example, 1:0.04, 1:0.06, 1:0.08, 1:0.1, 1:0.5, 1:1, 2:0.06, 2:0.08, 2:0.1, 2.5:0.2, and 12.5:1. As per another main embodiment of the present invention, the process of preparation of an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof comprises steps: a) Adding vehicle to the manufacturing vessel; b) Adding antioxidant into the vehicle-containing manufacturing vessel of step (a) with continuous stirring; c) Adding carbimazole or pharmaceutically acceptable salts thereof into the solution obtained in step (b) with continuous stirring to get a clear formulation; d) Adding flavouring agent into the solution obtained in step (c) with continuous stirring; e) Adding vehicle into the solution obtained in step (d) to adjust the final volume; f) Mixing the solution of step (e) with continuous stirring; g) Filtering the solution of step (f); h) Filling the final formulation obtained in step (g) in the suitable container. In another main embodiment of the present invention, the addition of carbimazole in a formulation is impacted by both the duration (time) of stirring and / or the applied mechanical energy (speed) of stirring. The inventors have found a method of addition of carbimazole in which a clear, colorless oily liquid free from visible particulate matter can be obtained. In another main embodiment of the present invention, there is provided a process for preparing an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof, wherein the process comprises the steps of: a) Adding medium chain triglyceride (MCT) into a manufacturing vessel using fully clean and dry flux pump; b) Adding a butylated hydroxy anisole, with stirring; c) Before going to the next step, a sodium vapour lamp may be used from this step onwards for the reminder of the manufacturing process; d) Adding carbimazole or a pharmaceutically acceptable salt thereof slowly, with stirring at about 25 Hz - about 35 Hz for about 10 minutes to about 60 minutes; e) Now seal the vessel, apply vacuum, with stirring at about 40 Hz - about 50 Hz for about 260 minutes to about 280 minutes; f) Now recirculate the solution in the vessel using the external homogeniser, with stirring at about 40 Hz - about 50 Hz for about 5 minutes to about 15 minutes. Now turn off the homogeniser and stop the stirring; g) Now seal the vessel, apply vacuum and turn on the stirrer at speed of about 40 Hz - 50 Hz for about 35 minutes to about 55 minutes; h) Add peppermint oil with stirring; i) Add remaining amount of medium chain triglycerides to make up the final volume; j) Stir the suspension; k) Transferring the solution to a filling vessel. 1) Packing the final solution into a container. The container may be a HDPE bottle. In some embodiments, the stirring speed in step (b) is about 30 Hz - about 40 Hz, optionally wherein the stirring speed is about 35 Hz. In some embodiments, the stirring duration in step (b) is about 60 minutes - about 70 minutes; optionally wherein the stirring duration is about 65 minutes. In some embodiments, the stirring speed in step (h) is about 30 Hz - about 40 Hz, optionally wherein the stirring speed is about 35 Hz. In some embodiments, the stirring duration in step (h) is about 20 minutes - about 30 minutes; optionally wherein the stirring duration is about 25 minutes. In some embodiments, the stirring duration in step (j) is about 35 minutes - about 45 minutes; optionally wherein the stirring duration is about 40 minutes. In some embodiments, the butylated hydroxy anisole in step (b) is added at a concentration of about 0.2 mg / mL. In some embodiments, the carbimazole in step (d) is added at a concentration of about 2.5 mg / mL. In some embodiments, the peppermint oil in step (h) is added at a concentration of about 3 mg / mL. In some embodiments, the final volume in step (i) is about 1 mL. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole comprising: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL; optionally an antioxidant, a flavouring agent; and a medium chain triglyceride as a vehicle. An oral non-aqueous solution of carbimazole comprising: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL; an antioxidant in an amount from about 0.08 mg / mL to about 2 mg / mL; and a medium chain triglyceride as a vehicle. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole comprises: carbimazole or pharmaceutically acceptable salts thereof in an amount from about 0.5 mg / mL to about 10 mg / mL; an antioxidant; a flavouring agent; and a vehicle. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole comprises: carbimazole or pharmaceutically acceptable salts thereof in an amount from about 0.5 mg / mL to about 10 mg / mL; an antioxidant in an amount from about 0.01 mg / mL to about 1 mg / mL; a flavouring agent; and a vehicle. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole comprises: carbimazole or pharmaceutically acceptable salts thereof in an amount from about 0.5 mg / mL to about 10 mg / mL; an antioxidant in an amount from about 0.01 mg / mL to about 1 mg / mL; a flavouring agent in an amount from about 1 mg / mL to about 5 mg / mL; and a vehicle. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole comprises: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL, a butylated hydroxy anisole in an amount of about 0.2 mg / mL; a peppermint oil in an amount of about 3 mg / mL; and a medium chain triglyceride as a vehicle. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole consisting of: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL; a butylated hydroxy anisole in an amount of about 0.2 mg / mL; a peppermint oil in an amount of about 3 mg / mL; and a medium chain triglyceride as a vehicle. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole consisting essentially of: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL; a butylated hydroxy anisole in an amount of about 0.2 mg / mL; a peppermint oil in an amount of about 3 mg / mL; and a medium chain triglyceride as a vehicle. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole comprises: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 0.25 % w / v, a butylated hydroxy anisole in an amount of about 0.02 % w / v; a peppermint oil in an amount of about 0.3 % w / v; and a medium chain triglyceride as a vehicle. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole consisting of: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 0.25 % w / v; a butylated hydroxy anisole in an amount of about 0.02 % w / v; a peppermint oil in an amount of about 0.3 % w / v; and a medium chain triglyceride as a vehicle. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole is void of polysaccharides, thickening agents, wetting agents, buffers, preservatives, and water. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole is substantially free of polysaccharides, thickening agents, wetting agents, buffers, preservatives, and water, where the expression “substantially free” refers to a situation where the oral non-aqueous solution has no added ingredient (or the amount of ingredient is about 0%). As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole is ready to use, clear, colorless oily liquid free from visible particulate matter. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole consisting of: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 0.25 % w / v, a butylated hydroxy anisole in an amount of about 0.02 % w / v, a peppermint oil in an amount of about 0.3 % w / v; and a medium chain triglyceride as a vehicle; wherein an oral non-aqueous solution of carbimazole is ready to use, and free or void of polysaccharides, thickening agents, wetting agents, buffers, preservatives, and water. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole comprises: about 0.5 mg / mL to about 500 mg / mL carbimazole or pharmaceutically acceptable salts thereof; about 0.001 mg / mL to about 10 mg / mL an antioxidant; about 0.01 mg / mL to about 20 mg / mL a flavouring agent; and a vehicle. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole comprises: about 1 mg / mL to about 10 mg / mL carbimazole or pharmaceutically acceptable salts thereof; about 0.08 mg / mL to about 2 mg / mL an antioxidant; about 0.8 mg / mL to about 5 mg / mL a flavouring agent; and a vehicle. As per the most preferred embodiment of the present invention, an oral non-aqueous solution of carbimazole comprises: about 2.5 mg / ml carbimazole or pharmaceutically acceptable salts thereof; about 0.2 mg / mL an antioxidant; about 3 mg / mL a flavouring agent; and a vehicle. As per the most preferred embodiment of the present invention, an oral non-aqueous solution of carbimazole comprises: about 2.5 mg / ml carbimazole or pharmaceutically acceptable salts thereof; about 0.2 mg / mL butylated hydroxy anisole; about 3 mg / mL peppermint oil; and a medium chain triglyceride as a vehicle. As per the most preferred embodiment of the present invention, an oral non-aqueous solution of carbimazole comprises: about 2.5 mg / ml carbimazole or pharmaceutically acceptable salts thereof; about 0.2 mg / mL butylated hydroxy anisole; about 3 mg / mL peppermint oil; and medium chain triglyceride as a vehicle; wherein the said oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof is free of water. As per the most preferred embodiment of the present invention, an oral non-aqueous solution of carbimazole comprises: about 2.5 mg / ml carbimazole or pharmaceutically acceptable salts thereof; about 0.2 mg / mL butylated hydroxy anisole; about 3 mg / mL peppermint oil; and medium chain triglyceride as a vehicle; wherein the said oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof is free of thickening agents and / or wetting agents. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof is useful in the treatment of hyperthyroidism by reducing the production of the thyroid hormones T3 and T4 (thyroxine). As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof for use as a medicament for the treatment in adults and children in all conditions where reduction of thyroid function is required. The conditions include hyperthyroidism, preparation for thyroidectomy in hyperthyroidism, and therapy prior to and post radio-iodine treatment. As per one embodiment of the present invention, a dosing regimen for administering carbimazole to the patients in all conditions where reduction of thyroid function is required, wherein the conditions include hyperthyroidism, preparation for thyroidectomy in hyperthyroidism, and therapy prior to and post radio-iodine treatment comprising: (1) administering orally to a patient in need of treatment, a first initial dose (titration dose) in the range from about 15 mg to about 60 mg of carbimazole; and (2) administering orally to a patient in need of treatment, a maintenance dose in the range from about 5 mg to about 15 mg of carbimazole for at least 6 months to 18 months; wherein the carbimazole formulated in a ready to use non-aqueous oral solution formulation. In some embodiments, initial dose may be taken twice a day or thrice a day. In some embodiments, maintenance dose may be taken once a day. As per one embodiment of the present invention, a dosing regimen for administering carbimazole to the patients in all conditions where reduction of thyroid function is required, wherein the conditions include hyperthyroidism, preparation for thyroidectomy in hyperthyroidism, and therapy prior to and post radio-iodine treatment comprising: (1) administering orally to a patient in need of treatment, a first initial dose in the range from about 15 mg to about 60 mg of carbimazole; and (2) administering orally to a patient in need of treatment, a maintenance dose in the range from about 5 mg to about 15 mg of carbimazole for at least 6 months to 18 months; wherein the carbimazole formulated in a ready to use non-aqueous oral solution formulation consisting of: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL; a butylated hydroxy anisole in an amount of about 0.2 mg / mL; a peppermint oil in an amount of about 3 mg / mL; and a medium chain triglyceride as a vehicle. As per one embodiment of the present invention, an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof is stable and provides better patient compliance. According to one embodiment, an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof is stable for at least 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months or more at 40°C ± 2°C / 75% ± 5% RH, 30°C ± 2°C / 65 % ± 5 % RH, and 25°C ± 2°C / 60 % ± 5 % RH. According to one embodiment, an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof is stable when exposed to the illumination of 1.2 million lux hours with a fluorescent lamp and an integrated near ultraviolet energy of not less than 200-watt hours / square meter. According to one embodiment, impurity A (Thiamazole) is less than 2.5 %, total impurities are less than 3.0 % and any unknown impurities are less than 0.3 % after 1 month, 3 months, and 6 months of storage at accelerated condition 40°C ± 2°C / 75% ± 5 % RH. According to one embodiment, impurity A (Thiamazole) is less than 2.5 %, total impurities are less than 3.0 % and any unknown impurities are less than 0.3 % after 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months of storage at intermediate condition 30°C ± 2°C / 65 % ± 5 % RH and / or long-term condition 25°C ± 2 °C / 60 % ± 5 % RH. According to one embodiment, the said oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof, when administered orally as a single dose of 8 mL equivalent to 20 mg of carbimazole (20 mg / 8 mL) solution to a subject (i.e., patient) under fasted conditions provides a mean ± SD of pharmacokinetic profiles as mentioned below: Tmax (hr): 0.81 ± 0.47; Cmax(ng / mL): 286.78 ±73.31; AUCo-t (ng.h / mL): 2286.86 ± 396.95; AUC0 / (ng.h / mL): 2571.64 ± 458.17; and Ti / 2(h): 7.46 ± 1.19. According to one embodiment, the said oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof, when administered orally as a single dose of 8 mL equivalent to 20 mg of carbimazole (20 mg / 8 mL) solution to a subject (i.e., patient) under the fasted condition which provides a geometric least-square means of pharmacokinetic profiles like maximum plasma concentration (Cmax) 278.02 ng / mL; and area under the plasma concentration versus time curve from time 0 to the last measurable concentration time (AUCo-t) 2249.82 ng.h / mL. According to one embodiment, the said oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof, when administered orally as a single dose of 8 mL equivalent to 20 mg of carbimazole (20 mg / 8 mL) solution to a subject has a Test (T) / Reference (R) ratio is 92.08 %, wherein Test (T) is a Cmax value of the dose after administration to a human, and wherein Reference (R) is a Cmax value of a tablet comprising 20 mg carbimazole (NeoMercazole®) after administration to the human. According to one embodiment, the said oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof, when administered orally as a single dose of 8 mL equivalent to 20 mg of carbimazole (20 mg / 8 mL) solution to a subject has a Test (T) / Reference (R) ratio is 100.38 %, wherein Test (T) is an AUCo-t value of the dose after administration to a human, and wherein Reference (R) is an AUCo-t value of a tablet comprising 20 mg carbimazole (NeoMercazole®) after administration to the human. In some embodiment, mean and standard deviation of pharmacokinetic parameters provided herewith for carbimazole’s active metabolite methimazole. In some embodiment, least square mean, geometric least square mean, T / R ratio, 90% confidence intervals, intrasubject variability and power for the log transformed Cmax and AUCo-t provided herewith for carbimazole’s active metabolite methimazole. The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. ADDITIONAL EMBODIMENTS Embodiment 1: An oral non-aqueous solution of carbimazole comprising: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL; optionally an antioxidant, a flavouring agent; and a medium chain triglyceride as a vehicle. Embodiment 2: An oral non-aqueous solution of carbimazole comprising: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL; an antioxidant in an amount from about 0.08 mg / mL to about 2 mg / mL; and a medium chain triglyceride as vehicle. Embodiment 3: An oral non-aqueous solution of carbimazole consisting of: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL; a butylated hydroxy anisole in an amount of about 0.2 mg / mL; a peppermint oil in an amount of about 3 mg / mL; and a medium chain triglyceride as vehicle. Embodiment 4: The oral non-aqueous solution of carbimazole of any one of embodiments 1 to 3, wherein the oral non-aqueous solution of carbimazole is void of polysaccharides, thickening agents, wetting agents, buffers, preservatives, and water. Embodiment 5: The oral non-aqueous solution of carbimazole of any one of embodiments 1 to 3, wherein the oral non-aqueous solution of carbimazole is ready to use, clear, colorless oily liquid free from visible particulate matter. Embodiment 6: The oral non-aqueous solution of carbimazole of any one of embodiments 1 to 3, wherein the oral non-aqueous solution of carbimazole is stable at 30°C ± 2°C / 65 % ± 5 % RH and / or 25°C ±2°C / 60%±5% RH after storage of 24 months. Embodiment 7: The oral non-aqueous solution of carbimazole of any one of embodiments 1 to 3, wherein the oral non-aqueous solution of carbimazole has an impurity A (Thiamazole) content is less than 2.5 %, total impurities content are less than 3.0 %, and any unknown impurities content are less than 0.3 % after storage of 24 months. Embodiment 8: The oral non-aqueous solution of carbimazole of any one of embodiments 1 to 3, wherein the oral non-aqueous solution of carbimazole use as a medicament for the treatment in adult and children in all conditions where reduction of thyroid function is required. Embodiment 9: The oral non-aqueous solution of carbimazole of embodiments 1 and 8, wherein the oral non-aqueous solution of carbimazole use as a medicament in the all conditions including hyperthyroidism, preparation for thyroidectomy in hyperthyroidism, and therapy prior to and post radio-iodine treatment. Embodiment 10: The oral non-aqueous solution of carbimazole of embodiment 1, wherein the oral non-aqueous solution of carbimazole when administered orally as a single dose of 8 mL equivalent to 20 mg of carbimazole solution to a subject under fasted conditions, which provides a pharmacokinetic profile as mentioned below: Tmax (hr): 0.81 ±0.47; Cmax(ng / mL): 286.78 ±73.31; AUCo-t(ng.h / mL): 2286.86 ± 396.95; AUCo-»(ng.h / mL): 2571.64 ± 458.17; and Ti / 2 (h): 7.46 ± 1.19. Embodiment 11: A dosing regimen for administering carbimazole to the patients in all conditions where reduction of thyroid function is required, wherein the conditions include hyperthyroidism, preparation for thyroidectomy in hyperthyroidism, and therapy prior to and post radio-iodine treatment comprising: (1) administering orally to a patient in need of treatment, a first initial dose in the range from about 15 mg to about 60 mg of carbimazole; and (2) administering orally to a patient in need of treatment, a maintenance dose in the range from about 5 mg to about 15 mg of carbimazole for at least 6 months to 18 months; wherein the carbimazole formulated in a ready to use non-aqueous oral solution formulation consisting of: carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL; a butylated hydroxy anisole in an amount of about 0.2 mg / mL; a peppermint oil in an amount of about 3 mg / mL; and a medium chain triglyceride as vehicle. 5 EXAMPLES EXAMPLE 1: PROPOSED FORMULATION OF AN ORAL NON-AQUEOUS SOLUTION OF CARBIMAZOLE WITH SELECTED EXCIPIENTS Sr. No. Ingredients Function Quantity (mg / mL) 1 Carbimazole API 1-10 2 Butylated Hydroxy anisole Antioxidant 0.008-2 3 Peppermint Oil Flavouring Agent 0.8-5 4 Medium Chain Triglyceride Vehicle Q. S. Table 1: Proposed formulation of an oral non-aqueous solution of carbimazole 10 EXAMPLE 2: OPTIMIZATION OF FLAVOURING AGENT CONCENTRATION The trials were conducted to optimize the concentration of flavouring agent and batches were evaluated for physical appearance and essence acceptance. Sr. No. Name of Ingredients Batch No. Fl F2 F3 mg / ml % w / v mg / ml % w / v mg / ml % w / v I Carbimazole 2.5 0.25 2.5 0.25 2.5 0.25 2 Butylated Hydroxy Anisole 0.20 0.02 0.20 0.02 0.20 0.02 3 Peppermint Oil 2.0 0.20 3.0 0.30 4.0 0.40 4 Medium Chain Triglycerides Upto 1ml q. s. Upto 1ml q. s. Upto 1ml q. s. Total 1.00 100.00 1.00 100.00 1.00 100.00 Table 2: Composition of flavour optimization Result: Parameter Carbimazole 2.5 mg / ml Oral solution Fl F2 F3 Appearance Clear, colorless oily liquid free from visible particulate matter Clear, colorless oily liquid free from visible particulate matter Clear, colorless oily liquid free from visible particulate matter 15 Table 3: Results for the physical appearance of flavour optimization batches Batch No. Unacceptable Bad Poor Acceptable Good Excellent Fl - - - Yes - - F2 - - - - Yes - F3 - - - Yes - - Table 4: Result of essence evaluation Following the observations above, the decision was made to set the peppermint oil concentration at 3 mg / ml in the carbimazole 2.5 mg / ml oral solution. EXAMPLE 3: FORMULATION OF AN ORAL NON-AQUEOUS SOLUTION OF CARBIMAZOLE (Bl) Sr. No. Ingredients Quantity (mg / ml) Quantity (% w / v) 1 Carbimazole 2.50 0.25 2 Butylated hydroxy anisole 0.20 0.02 3 Peppermint Oil 3.0 0.30 4 Medium Chain Triglycerides q. s. to 1 ml q. s. to 100 Table 5: Formulation of an oral non-aqueous solution of carbimazole (Bl) Procedure: a) Medium chain triglyceride was added to a vessel; b) Butylated hydroxy anisole was added into a vessel of step (a) and mixed with continuous stirring; c) Carbimazole was added into the solution obtained in step (b) and mixed with continuous stirring to get a clear formulation; d) Peppermint oil was added to the solution obtained in step (c) and mixed with continuous stirring; e) Remaining quantity of medium chain triglyceride was added into the solution obtained in step (d) to adjust the volume; f) The solution of step (e) was mixed with continuous stirring; g) The solution of step (f) was filtered; h) The final formulation obtained in step (g) was stored in a suitable container. EXAMPLE 4: COMPARATIVE STUDY OF FINAL FORMULATION (Bl) WITH REFERENCE PRODUCT The final formulation of an oral non-aqueous solution of carbimazole (Bl) was compared with the reference product, i.e. Neo-Mercazole® 20 mg Tablets. Result: Sr. No. Parameter Neo-Mercazole® 20 mg Tablets Batch Bl 1 Description A pale pink tablet, a shallow biconvex tablet with a white centrally located core, one face plain, with “Neo 20” imprinted on the other. Clear, Colorless, Transparent Solution. 2 Dosage Form Tablet Oral Solution 3 Excipients Lactose monohydrate, Starch maize, Gelatin, Magnesium stearate, Sucrose, Acacia, Talc, Red Iron oxide E172, Microcrystalline cellulose BHA, Peppermint Oil &MCT 4 Viscosity (CP) N.A. 21.96 5 Specific Gravity N.A. 0.944 6 Carbimazole Assay (%) 104.3 96.6 7 BHA Content (%) N.A. 111.2 8 Thiamazole Impurity (%) |0.26 Thiamazole Impurity (%) 10.14 Related Substances Highest Unknown Impurity (%) 0.07 Highest Unknown Impurity (%) ND Total Impurity (%) 0.33 Total Imp (%) 0.14 9 Dissolution Studies Media: 0.1 NHC1; Volume: 500 ml; Speed: 50 RPM, Apparatus: Paddle Time Point % Drug Release % Drug Release 10 23 37 15 55 46 30 87 66 45 88 76 60 91 83 Table 6: Comparative evaluation of final formulation and rel ’erence product EXAMPLE 5: STABILITY STUDY The stability study of the final formulation (Bl) was conducted at different storage conditions: 5 Accelerated: 40 °C± 2 °C / 75 % ± 5 % RH for 1, 3, and 6 months Intermediate: 30 °C± 2 °C / 65 % ± 5 % RH for 3, 6, 9, 12, 18, and 24 months Long term: 25 °C ± 2 °C / 60 % ± 5 % RH for 3, 6, 9, 12, 18, and 24 months Result: Sr. Ha SW ...................'w........... Acceptance a’th -i Bi ? i feVI i W wi mu i Description Cleat tee parfaitee raster vO . £ CO^Site CtWte Campis® C®Spl:® I Specific gravity w-w uW w w 6.W : <, teite 3 ytSCuSBy BeW« l&F So .W 23 (23 4 Ass^WLCM%) &T 82.5% ate WT W $ 1» W# MS 95.3 §3.3 §55 iO 5 NLTBmate W amsst W8 sy §84 §8.1 §6.8 ST 8 Related substance (By HPLC) (in %) Impurity A (Thiamazole j Not more Ihas 2.5% 042 0.15 6.56 0^7 14 < 4 Any unspecified impurity Nat more iters 5.3% BLOO ND 8.35 8.66 8.65 685 Total Impurities Nut more iters 38% (l.tz ¢.(5 0.6- 8.63 1.5 15 Microbial enumeration test Total aerobic microbial count Nat more iters !i2cstenl <13 cfurrriL NA NA NA dOcfuM NA 7 Total yeasts and moulds count Nat more iten fir cfuM. <13 duM NA NA NA dOofuM NA Test for specified micro-organisa Eschwichacoii Should be Eton; in M _____iml _ NA NA NA Absent in M NA'lstat applicable, ND-Not Deeded. BLOQ- Below limit of quantification Table 7: Stability study data of final formulation at accelerated condition 10 ci ProSiuci and i Sir? igh........................;............................... Ci Steif-life ; Ifc- s Test i Acceptance alters Carbittetote Oral Stedten 15 mgM {Ccnteion ifotte i 3« • ; am : w • 1 ill i Si i; {0} I (1} ; to to IZbt mmRHi 1» } w (U) } (1} : to i {0 24M R ii ! 1 fttoptten i 0®r,ally i W&Ml Cafes' Cwltesi w K: CtSSpW i 2 Bpe«fcgnwity : ow oixe : ■w I UM: i w.-NqS : 0y3$ ■' i C:<. > : 3 Vrer csrly to »e H&T - R 23 23 £.3 ; ¢4 : 73 : .0^. Z.l > 1 4 Assay (By HPIC| (Sj; MT ® 5 "i W ; 466 I) % oitte tebetel i saxttSsC' caitssWijis to : $37' M2 i g&j i •S / t < Ml ; 3 i 1 Butylated i MT 3113¾ ana nut (By H16 *e : SCuilSSS aHOBOt to i $7.1 w 37.3 ; 30.1 Mi : ^74 ii Related substance {By HPLC) {in %i Impurity A : MW 1^111^2.5% (Thiamazofe) : 0.-2 0 / 7 i 0.33 0.33 : 0.82 i 0.83 0,34 1.6 ! 25 : 2.5 ; Any unspecified : Mt m than 0.4% impurity : 81OQ SIOQ i 0,05 $05 : 0.19 i 0.10 ata G.25 i 0.2$ i 824 1 Total Impurities ; Si® rare thsr-i 0.47 ■ 0.41 0 / 3 : 0.80 1 1.1 1.- 1.3 i 2.7 : derated enumeration test : Total aerobic : microbial count i <10 NA : <10 i duteL kA : <1$ : cfu^nl : NA MA NA I i itoL i NA Total yeasts and 1 Neiiwste'G1 moulds count । Ml ctoi NA i Mai. NA i <10 : CfuM. : NA MA NA ! <10 : i c!U':mL i NA Test for specified nwcrc-organism I - . -.. r : Shousa be absent o Esctencnra coh : , , ; ml Absent tote NA : Absent i in 1ml NA } in 1mL i NA NA NA NA i ■ 1« 1ml <: NA-Nol sppiicaOie, MXAjt Defected, BLOQ- Below ling of quKfifcBferr i Table 8: Stability study data of final formulation at intermediate condition Hams at Proauctswri 1 CarWiazste Oral Splation Z 5 ingftM (ConSiti&re 25 i 2 •«Si5%RK) Strcnaft Sr. : 5£CCF$C3t^ ■ taiva: i : 6M i 12SS 1 "W"T"'W"T"W?"T"W"" Na j fast 'Acceptsrrae critena >I '» i w • <W • w ; w ; (« { {Q ; ® ; (8} t s Description i O:aa:; ok? >Cymtws: Cumrws; tompiieft • Cxjmpl^s; > i ikiuki tree 1::::1 • sarfeusaw matter f l : i i I . 2- s SpecfBe gravity i uW : uW •: : : : i Q.S8S i -W : 8-SSO I 0.858 3 Vtsccsj'v 39^^ .2$ 1 73 ; .23 ■ 23 : .23 : At zd : / 3 : / 3 •< (Sy UPLCj IJ-Hfestorii ■ • 1 1 I ! i (¾) : $<: : Ml • $8.$ • : §7.5 : Mb : M • : i ::::::( b >Butyfeted : Ml.! a.^0 NM t :;;:::: i BySresyanteNs I MterliufSwfetete i §6.8 : 85.6 : ©ft : 87 2 : 80.8 : STI s $7.3 : : tf’:’.? : : 1 : : : : ! : s Related substance (By HPLC) {m %} lmj>unty A (Thismazoiej ^01^0^2.5% eJ2 G45 | a,s j e2s 63S | 0.39 0.64 1.0 1.1 Any unspecified impurity NdmoratnsnO.3% 3Loa ; SL0Q | j G ,2 0.14 0.21 0.20 0.21 Totat Impurities I Not owe than 3.0® ; 0.1.2 0.10 1 0.15 1 0.16 s SAG • 0.51 | 1.5 1.5 i Microbial enumerafion test i Total aerobic J tp v )— -f : <1Q : <W ! : : Cp 1 : ; <10 ! 7 micrcbiaf count / 3 ; Mi NA ; Mt | NA j NA ; | । NA { te4i ( NA i Tout and ’ 1 : : ^■’i ! cfera i tew’ml NA ; crawl | NA j NA ; *A { NA { | NA | Test for specified micro-organism fsc / j^ichfa co# | Stauldbeobsfimin ■ Abseniin .!A • Absent in • Ma • • Abssnt in i I 1ml ; 1ml ' ’ i 1mL I i ' i 1mL 1 v, i v, i Absent-n: N4 Ma : NA : : NA-Not sppiicabite. ND-hfot Detected BLOQ- Below limit of qisantificaiion. I Table 9: Stability study data of final formulation at long-term condition Based on the stability study data for the final formulation, it was concluded that the product satisfies the acceptance criteria for physical, chemical, and microbial evaluation under all storage conditions. 10 EXAMPLE 6: PHOTO-STABILITY STUDY A photostability study was performed by exposing the stored formulation to the illumination of 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200-watt hours / square meter on the batch Bl. Result: Test parameters Stability Product Specification Batch Bl Exposed drug product Drug product in the primary pack Protected Drug Product Pack Description Clear, Colourless, Transparent Solution Complies Assay of Carbimazole 90.0%-110.0% 94.0 % 97.4 % 98.3 % Content of BHA 80.0% - 120.0% 93.3 % 109.2% 110.8% Thiamazole Impurity NMT 5.0% 0.29 % 0.17% 0.11 % Highest Unknown Impurity NMT 0.2% 0.80% 0.15% ND Total Impurities NMT 6.00% 2.29 % 0.42 % 0.11 % Table 10: Results of photostability study of batch Bl The results showed that the formulation remained unchanged under both open and control 5 conditions. However, a significant increase in impurity levels was observed when the product was directly exposed to light. Therefore, the formulation must be protected from light exposure during manufacturing. EXAMPLE 7: FREEZE-THAW STUDY 10 Freeze-thaw studies were performed at a temperature cycle of -20 °C ± 5 °C for 2 days followed by 4 0°C ± 2°C for 2 days. Result: Parameter Specification Batch Bl Initial F reeze-Thaw (After 3 Cycles) Description Clear, Colorless, Transparent Solution Clear, Colorless, Transparent Solution Clear, Colorless, Transparent Solution Assay of Carbimazole 90.0 % - 110 % 99.5 % 96.7 % Content of BHA 80.0 % - 120 % 112.3 % 112% Specific Gravity 0.95 ±0.1 0.9446 NP Viscosity 15-40 cps 26.88 NP Related Substances (%) Thiamazole (%) 5.0 % 0.11 0.17 Highest Unknown Impurity (%) 0.2 % 0.02 ND Total impurity (%) 6.0 % 0.13 0.17 Table 11: Results of t ie freeze-thaw study The results indicated that the final formulation was found to be stable at freeze-thaw conditions. EXAMPLE 8: COMPARATIVE IMPURITY PROFILE OF THE FINAL FORMULATION AND REFERENCE PRODUCT The impurity profile of the final formulation and reference product was evaluated. Result: Related Substance Limit Reference Product Neo-Mercazole® 20 Batch Bl Carbimazole 2.5 mg / mL mg tablets (Carbimazole) oral solution Thiamazole (Impurity A) NMT 1.0% 0.218% 0.04 % Any unspecified impurity NMT 0.20 % 0.005 % Below LOQ Total impurities NMT 2.0 % 0.223 % 0.04 % NMT: Not More Than; LOQ: Limit of Quantification Table 12: Results for comparative impurity profile Based on the results, impurities profile of batch Bl was found satisfactory and its % less as compare with the reference product. EXAMPLE 9: PHARMACOKINETIC STUDY The study was designed as an open-label, balanced, randomized, single-dose, two-treatment, two-sequence, two-period, crossover oral bioequivalence trial, comparing the test and reference products in healthy, adult male subjects under fasting conditions. General screening of potential volunteers was conducted within 21 days prior to the first dose. Subjects who met the protocol’s inclusion and exclusion criteria were enrolled in the study. The clinical phase of the study lasted a total of 10 days, from check-in for Period I to the final blood sample collection for Period II. Each subject received a single oral dose of either the test or reference product in both Period I and Period II, with an 8-day washout period between the two dosing periods. A total of 24 subjects participated in each period. Following an overnight fast of at least 10 hours, each subject was administered a single oral dose of the test or reference product, as per the study protocol. The primary criteria for bioequivalence evaluation were based on the 90% confidence interval for the ratio of the geometric least squares mean for the log-transformed pharmacokinetic parameters Cmax and AUCo-t of the test to the reference product. For bioequivalence to be established, the ratio for both Cmax and AUCo-t needed to fall within the range of 80.00 % to 125.00 % for the active metabolite of carbimazole, methimazole. Test (T): Carbimazole 2.5 mg / ml oral solution Reference Product (R): Neo-Mercazole® 20 mg tablets (Carbimazole) Result: A. Pharmacokinetic Evaluation: Table 13: Mean and Standard Deviation of pharmacokinetic parameters for carbimazole’s active metabolite methimazole, after administration of test product (T) and reference product (R) (N = 23) B. Statistical Evaluation: i Square Means ntramim [.......................................... iaaits) i i i T i R tn (G™} i (ag-ruGi i — Geometric Least i Square Means L . „ i Ratto i 1 0' Vs R) T | R 273.0.20 § $015)42 $10$ 2240.310 5 2241302 10033 ,wl4, »■» : Jam* ; Rover <. UBtldetKr: . . . , , . „ $4-3? ■ 190.49 i 17.33 । 99-39 97.65- K&19 1 5.44 1 590.0 Table 14: Least Square Mean, Geometric Least Square Mean, Ratio, 90% confidence intervals, intrasubject variability and power for the log transformed Cmax and AUCo-t for 10 carbimazole’s active metabolite methimazole (N = 23) The 90% confidence intervals for the test (T) / reference (R) ratios of the geometric least squares means for the primary pharmacokinetic parameters, Cmax and AUCo-t, were within the bioequivalence range of 80.00% to 125.00% for methimazole, the active metabolite of 15 carbimazole, indicating bioequivalence between the test and reference formulations. EXAMPLE 10: ANTIMICROBIAL EFFECTIVENESS TEST (AET) FOR FINAL FORMULATION (Batch Bl) The antimicrobial effectiveness test was conducted after 24 months to assess the efficacy of the preservative, ensuring it is sufficiently effective to inhibit microbial growth. 5 Result: Initial Observation Day 14 Observation Day 28 Observation Organism Initial Log Value Log reduction at i Bay 14 redufttkm at day 28 compared to day 14 Log redwctkw at Day 28 compared to initial count 6.87 5.87 0 GO NA 8.71 5.71 NA £. eo# ».?9 5.79 o<oo NA C. 8,88 5.38 0,GO 5,83 / 1. 6.78 5.70 0.60 6 79 Orgauism Day 14 Result amt observation £tay 28 Result mid observation EP Requirements Bacteria ! NLT 3 8 fog reduction frpm the initial count at 14 days Niioimom Log reduction 71 Ne increase from the 14 days count at 28 days No increase in microbial pcipulagon Yesstand mold NLT 1.0 log reductiors from the initial count. at 14 days Miriimbm Log reduction 5.70 No increase from this 14 days count at 28 days No increase in microbial papulation MSP Requirements Bacteria NLT ' .0 log reduction from the initial count at 14 days Minimum Log reduction 5,7t No increase from Se 14 days count at 28 days No increase in microbial population i.......................... Yeast and mold No increase from the initial calculated count at 14 days Mi™ mum Log reduction 5,78 No increase from the initial calculated count si 28 days No increase in mlcrcibi al pogoi aw» Table 15: Result of antimicrobial effectiveness test 10 The results indicate that the final formulation meets the antimicrobial effectiveness criteria outlined in both the European and US pharmacopoeias. This confirms that the preservative in the product is adequate to maintain its stability and prevent microbial growth during storage and use. 15 EXAMPLE 11: COMPARATIVE STUDY OF BATCH Bl OF PRESENT INVENTION WITH OILY BASED LIQUID COMPOSITIONS DISCLOSED IN GB2527555A Example as per the present invention Example as per GB2527555A Type of Formulation Oral non-aqueous solution Oil-based liquid composition (O-MET-020) Function Ingredient Batch Bl Ex. 2 Table 2 API Carbim azole 0.25 % w / v Methimazole - 0.5 % Antioxidant Butylated hydroxy anisole 0.02 % w / v - Flavouring agent Peppermint Oil 0.30 % w / v - Vehicle Medium Chain Triglyceride q. s. to 1 ml Caprylic / Capric triglyceride 98 % Wetting agent - - Polysorbate 80 - 0.5 % Thickening agent - - Aluminium di stearate - 0.5 % Thickening agent - - Hydrogenated castor oil - 0.5 % Stability and Impurity All the relevant impurities like impurity A, total impurities, and any unknown impurities are found within the specification after storage of 24 months at Aliquots of the O-MET-020 solution were stored at: i) 25°C and 60% RH, ri) 30°C and 65% RH and iii) 40°C and 75% RH. The stability of the 30°C ± 2°C / 65 % ± 5 % RH and / or 25°C ± 2 °C / 60 % ± 5 % RH. The batch Bl is found stable and possess longer shelflife. aliquots was assayed after 1 year of storage. All aliquots were found to be stable. Not mentioned about any impurity data and also not provided any stability data. Just provided the single statement about stability. Table 16: Comparison of Batch Bl of the present invention with oily based liquid composition disclosed in GB2527555A Table 16 shows that batch Bl of the oral non-aqueous solution of carbimazole is the liquid 5 formulation and does not contain wetting agent and thickening agents like polysorbate 80, aluminium distearate, and hydrogenated castor oil. Despite the absence of these excipients, the formulation remains stable and possess longer shelflife, safe, and effective. Removal of these excipients not only produced an oral non-aqueous solution of carbimazole, which is ready to use and when compared to prior-art disclosures, this formulation was also found to be more 10 stable for 24 months or longer. Importantly, the non-aqueous solution of carbimazole as per present disclosure, was also shown to have less impurities. In conclusion, the formulation of the present invention may be advantageous for the patients having swallowing difficulties such as paediatric or geriatric patients or when the patients are 15 unable to take solid oral dosage forms like tablet.

Claims

1. An oral non-aqueous solution of carbimazole comprising: carbimazole or pharmaceutically acceptable salts thereof in an amount of 1 mg / mL to 10 mg / mL.

2. The oral non-aqueous solution of carbimazole of claim 1, further comprising an antioxidant.

3. The oral non-aqueous solution of carbimazole of claim 2, wherein the antioxidant is selected from the group consisting of tocopherol (Vitamin E), methionine, ascorbic acid (Vitamin C), ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxy toluene, potassium metabisulfite, and sodium bisulfite or any combination thereof.

4. The method of claim 2 or claim 3, wherein the antioxidant is butylated hydroxy anisole.

5. The method of any one of claims 2 to 4, wherein the amount of antioxidant present is in the range from about 0.08 mg / mL to about 2 mg / mL.

6. The oral non-aqueous solution of carbimazole of any preceding claim further comprising a flavouring agent.

7. The oral non-aqueous solution of carbimazole of claim 6, wherein the flavouring agent is selected from the group consisting of essential oils including peppermint oil, orange oil, lemon oil, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, orange pear, peach, strawberry, raspberry, cherry, plums pineapple, apricot, frozen peppermint, tutti frutti flavour or any combination thereof.

8. The oral non-aqueous solution of carbimazole of claim 6 or claim 7, wherein the flavouring agent is peppermint oil.

9. The oral non-aqueous solution of any one of claims 6 to 8, wherein the peppermint oil is present in an amount in the range from about 0.8 mg / mL to about 5 mg / mL.

10. The oral non-aqueous solution of carbimazole of any preceding claim, further comprising a medium chain triglyceride as a vehicle.

11. The oral non-aqueous solution of carbimazole of claim 1, consisting of:carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL;a butylated hydroxy anisole in an amount of about 0.2 mg / mL;a peppermint oil in an amount of about 3 mg / mL; and a medium chain triglyceride as vehicle.

12. The oral non-aqueous solution of carbimazole as claimed in any preceding claims, wherein the oral non-aqueous solution of carbimazole is void of polysaccharides, thickening agents, wetting agents, buffers, preservatives, and water.

13. The oral non-aqueous solution of carbimazole as claimed in any preceding claims, wherein the oral non-aqueous solution of carbimazole is ready to use, clear, colorless oily liquid free from visible particulate matter.

14. The oral non-aqueous solution of carbimazole as claimed in any preceding claims, wherein the oral non-aqueous solution of carbimazole is stable at 30°C ± 2°C / 65 % ± 5 % RH and / or 25°C ± 2 °C / 60 % ± 5 % RH after storage of 24 months.

15. The oral non-aqueous solution of carbimazole as claimed in any preceding claims, wherein the oral non-aqueous solution of carbimazole has an impurity A (Thiamazole) content is less than 2.5 %, total impurities content are less than 3.0 %, and any unknown impurities content are less than 0.3 % after storage of 24 months of storage at intermediate condition 30°C ± 2°C / 65 % ± 5 % RH and / or long-term condition 25°C ± 2 °C / 60 % ± 5 % RH.

16. The oral non-aqueous solution of carbimazole as claimed in any preceding claims for use as a medicament for the treatment in adult and children in all conditions where reduction of thyroid function is required.

17. The oral non-aqueous solution of carbimazole for use of claim 16, wherein the all conditions include hyperthyroidism, preparation for thyroidectomy in hyperthyroidism, and therapy prior to and post radio-iodine treatment.

18. The oral non-aqueous solution of carbimazole as claimed in claim 1, wherein the oral nonaqueous solution of carbimazole when administered orally as a single dose of 8 mLequivalent to 20 mg of carbimazole solution to a patient under fasted conditions, which provides a pharmacokinetic profile as mentioned below:Tmax (hr): 0.81 ±0.47;Cmax(ng / rnL): 286.78 ±73.31;AUCo-t(ng.h / mL): 2286.86 ± 396.95;AUCo-»(ng.h / mL): 2571.64 ± 458.17; andTi / 2 (h): 7.46 ± 1.19.

19. A dosing regimen for administering carbimazole to the patients in all conditions where reduction of thyroid function is required, wherein the conditions include hyperthyroidism, preparation for thyroidectomy in hyperthyroidism, and therapy prior to and post radioiodine treatment comprising:(1) administering orally to a patient in need of treatment, a first initial dose in the range from about 15 mg to about 60 mg of carbimazole; and(2) administering orally to a patient in need of treatment, a maintenance dose in the range from about 5 mg to about 15 mg of carbimazole for at least 6 months to 18 months;wherein the carbimazole formulated in a ready to use non-aqueous oral solution formulation consisting of:carbimazole or pharmaceutically acceptable salts thereof in an amount of about 2.5 mg / mL;a butylated hydroxy anisole in an amount of about 0.2 mg / mL;a peppermint oil in an amount of about 3 mg / mL; and a medium chain triglyceride as vehicle.

20. A process for the preparation of an oral non-aqueous solution of carbimazole or pharmaceutically acceptable salts thereof, the process comprising:a) Adding vehicle to the manufacturing vessel;b) Adding antioxidant into the vehicle-containing manufacturing vessel of step (a) with continuous stirring;c) Adding carbimazole or pharmaceutically acceptable salts thereof into the solution obtained in step (b) with continuous stirring to get a clear formulation;d) Adding flavouring agent into the solution obtained in step (c) with continuous stirring;e) Adding vehicle into the solution obtained in step (d) to adjust the final volume;f) Mixing the solution of step (e) with continuous stirring;g) Filtering the solution of step (f);h) Filling the final formulation obtained in step (g) in the suitable container.T +44(0)30 0300 2000A