Oral liquid compositions of pitolisant or a pharmaceutically acceptable thereof

Abstract

The present invention provides pharmaceutical compositions comprising compounds which are selective antagonist or inverse agonist of the histamine H3 receptor, their manufacture and their use for the treatment of excessive daytime sleepiness (EDS) or cataplexy in patients with narcolepsy. Further, the present invention provides an oral liquid composition of Pitolisant or its pharmaceutically acceptable salt thereof and a process of making the same.

Description

[0001] ORAL LIQUID COMPOSITIONS OF PITOLISANT OR A PHARMACEUTICALLY ACCEPTABLE THEREOF RELATED PATENT APPLICATION(S):

[0002] This application claims priority to and benefits from Indian provisional patent application No. 202541004382 filed on January 20, 2025; the disclosure of which is incorporated here by reference.

[0003] FIELD OF INVENTION

[0004] The present invention provides pharmaceutical compositions comprising compounds which are selective antagonist or inverse agonist of the histamine H3 receptor, their manufacture and their use for the treatment of excessive daytime sleepiness (EDS) or cataplexy in patients with narcolepsy. Further, the present invention provides an oral liquid composition of Pitolisant or its pharmaceutically acceptable salt thereof and a process of making the same.

[0005] BACKGROUND OF THE INVENTION

[0006] Narcolepsy, in its broadest sense, describes a collection of chronic neurological disorder characterized by progressive affecting the brain's ability to control sleep-wake cycles and caused by a lack of the brain chemical hypocretin (also known as orexin), which regulates wakefulness. Narcolepsy is categorized in two major types: Type 1 (NT1) and Type 2 (NT2). Narcolepsy type 1 (NT1) is caused by the selective and irreversible loss of hypocretin / orexin (ORX) neurons, by a probable autoimmune process. Patients may also exhibit sleep Paralysis, hypnagogic and hypnopompic hallucinations, and disturbed nocturnal sleep. NT2 shares a symptoms of excessive daytime sleepiness (EDS) and dysregulation of rapid eye movement (REM) sleep, but without cataplexy and loss of ORX neurons. Narcolepsy is associated with impaired cognitive ability, poor quality of life, and risk of work, home, and car accidents.

[0007] Pitolisant hydrochloride is indicated for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy and treatment of excessive daytime sleepiness (EDS) in pediatric patients 6 years of age and older with narcolepsy. Oral administration of pitolisant is upto 35.6 mg once daily, the steady state Cmax and AUC are 73 ng / mL (range: 49.2 to 126 ng / mL) and 812 ng*hr / mL (range: 518 to 1468 ng*hr / mL), respectively. Pitolisant exposure (Cmax and AUC) increases proportionally with dose and steady state is reached by day 7.Pitolisant hydrochloride tablets are for oral administration supplies in bottles of 30 ml and each film-coated tablet contains 5 mg or 20 mg of pitolisant hydrochloride (equivalent to 4.45 mg or 17.8 mg of pitolisant free base, respectively) and the inactive ingredients includes colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The tablets are stored at 20° C to 25°C (68° F to 77°F); and excursions permitted between 15° C to 30° C (59° F to 86° F).

[0008] The recommended dosage range for Pitolisant hydrochloride tablets for the treatment of EDS or cataplexy in adult patients is administered orally once daily in the morning upon wakening.

[0009] Titrate dosage as follows:

[0010] Week 1: Initiate with a dosage of 8.9 mg (two 4.45 mg tablets) once daily Week 2: Increase dosage to 17.8 mg (one 17.8 mg tablet) once daily

[0011] Week 3: May increase to the maximum recommended dosage of 35.6 mg (two 17.8 mg tablets) once daily.

[0012] The recommended starting dosage of Pitolisant hydrochloride tablets for the treatment of EDS in pediatric patients 6 years and older is 4.45 mg administered orally once daily in the morning upon wakening.

[0013] Titrate dosage as follows:

[0014] Week 1: Initiate with a dosage of 4.45 mg (one 4.45 mg tablet) once daily Week 2: Increase dosage to 8.9 mg (two 4.45 mg tablets) once daily

[0015] Week 3: Increase dosage to 17.8 mg (one 17.8 mg tablet) once daily, which is the maximum recommended dosage for patients weighing <40 kg

[0016] Week 4: For patients weighing >40 kg, may increase to the maximum recommended dosage of 35.6 mg (two 17.8 mg tablets) once daily.

[0017] Dose may be adjusted based on tolerability. If a dose is missed, patients should take the next dose the following day in the morning upon wakening. It may take up to 8 weeks for some patients to achieve a clinical response.The chemical name of pitolisant hydrochloride is l-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride. Its empirical formula is C17H26C1NO HC1, and the chemical structure shown below:

[0018]

[0019] Bioprojet US8207197 provided the crystalline l-[3-[3-(4-chlorophenyl) propoxy]propyl] -piperidine monohydrochloride of formula (I) and its pharmaceutically acceptable solvates, including hydrates.

[0020]

[0021] Bioprojet’s US7169928 provided new compounds, the structure of which does not contain an imidazole moiety, which are useful as histamine H3-receptor ligands. US8486947 provided a new method of treatment of Parkinson's disease, obstructive sleep apnea, narcolepsy, dementia with Lewy bodies, vascular dementia with non-imidazole alkylamine of formula (A) that constitute antagonists of the H3-receptors of histamine.

[0022] (A'

[0023]

[0024] Bioprojet’s WO2023180314 provides Pitolisant (3-(4-Chlorophenyl)propyl 3-piperidinopropyl ether) is of formula. Pitolisant for use for treating and / or preventing

[0025]

[0026] severe fatigue (SF), comprising administering in a patient suffering from a disorder associated with SF a dose comprised between 50 mg and 240 mg once a day of pitolisant or one of its pharmaceutically acceptable salts, hydrates, or hydrated salts, or thepolymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereoisomers or enantiomers.

[0027] Several next-generation pitolisant formulations are currently in development, including a gastro-resistant (GR) formulation and a high-dose GR formulation. The GR product is designed to improve gastrointestinal tolerability and simplify dosing by allowing initiation at the therapeutic dose, with a potential FDA approval anticipated around 2026. The high-dose GR formulation is being developed to enhance clinical efficacy through optimized pharmacokinetics and broader symptom control, with a potential FDA approval projected for 2028. Bioprojet’s US2025186353 covers GR formulation comprising: a core that comprises pitolisant monohydrochloride and one or more pharmaceutically acceptable excipients; an anti-moisture barrier that surrounds the core; and an enteric coating that surrounds the core and the anti-moisture barrier. Bioprojet’s US20250120918 covers a combination of a salt of pitolisant with an alkalinizing agent for improving absorption of the active pharmaceutical ingredient.

[0028] Further, there is an unmet need to design a simple oral dosage form which would eliminate the need for dose titration, may improve gastrointestinal tolerability and offer a simple and convenient method of administration for patients of different age groups suffering with narcolepsy.

[0029] SUMMARY OF THE INVENTION

[0030] The objective of the present invention relates to an oral liquid dosage form comprising of selective antagonist or inverse agonist of the histamine H3 receptor and atleast one or more pharmaceutically acceptable excipients.

[0031] The objective of the present invention relates to an oral liquid dosage form comprising of pitolisant or a pharmaceutically acceptable salt thereof and atleast one or more pharmaceutically acceptable excipients.

[0032] The objective of the present invention relates to a process of preparing an oral liquid dosage form comprising of pitolisant or a pharmaceutically acceptable salt thereof and at least one or more pharmaceutically acceptable excipients.Yet another objective of the present invention is to provide a method of treating EDS and cataplexy in adult or pediatric patients with narcolepsy by administering a pharmaceutically effective dose of an oral liquid solution of pitolisant or a pharmaceutically acceptable salt thereof.

[0033] DETAILED DESCRIPTION OF THE INVENTION

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.

[0035] The oral liquid dosage forms according to the present invention comprises a pharmaceutically active ingredient agent or a pharmaceutically acceptable salt thereof and atleast one or more pharmaceutically acceptable excipients or additives selected from the group comprising of solvents, co-solvents, chelating agents, preservatives, buffering agents, pH modifying agents or any combination thereof. The oral liquid dosage forms according to the present invention may further comprise one or more agents selected from the group comprising of antimicrobial preservatives, sweetening agents, flavoring agents, taste masking agents, solubilizing agents or any combination thereof.

[0036] Generally, disclosed herein are pharmaceutical compositions in the form of an oral liquid solution. Particularly, the solution may include a buffering agent and water, in addition to the water-soluble active pharmaceutical ingredient. Additional excipients may also be used. The buffering agent is used to achieve the desired pH, depending on the active pharmaceutical ingredient.

[0037] Because of their liquid character, liquid dosage forms represent an ideal dosage form for patients who have difficulty' swallowing tablets or capsules. This factor is of particular importance in administration of drugs to children and aged patients. The liquid dosage forms disclosed herein are useful for administering to pediatric and aged patients.The term “active pharmaceutical ingredient” (or “API”) denotes the compound or molecule in a pharmaceutical composition that has a particular biological activity. The terms “pharmaceutical composition” or “pharmaceutical formulation” (or “formulation”) or “oral liquid composition” or “oral liquid dosage form” are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.

[0038] The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.

[0039] The term “pharmaceutically acceptable salts” denotes include both acid and base addition salts.

[0040] The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as any excipient but not limited to solvents, co-solvents, chelating agents, antioxidants, buffering agents, pH modifying agents, antimicrobial preservatives, sweetening agents, flavoring agents, taste masking agents, solubilizing agents and any combination thereof.

[0041] The present invention compositions of pitolisant or a pharmaceutically acceptable salt thereof. The present invention compositions comprise pitolisant hydrochloride in crystalline or amorphous form. The crystalline form can be the one which is disclosed under US8207197 patent. The amorphous form can be achieved as such or by a premix or amorphous solid dispersion with any polymer. An amorphous solid dispersion comprising pitolisant hydrochloride and one or more pharmaceutically acceptable excipients which is disclosed under US 11623920 patent. The polymers are selected from a polyvinyl pyrrolidone, a polyvinylpyrrolidone vinyl acetate, a polyvinylacetal diethylaminoacetate, a polyvinyl acetate phthalate, a polyoxyethylene sorbitan fatty acidester, a polyoxyethylene-polyoxypropylene copolymer, a polyoxyethylene stearate, a polyethylene glycol monomethyl ether, colloidal silicon dioxide, a polyethylene glycol, a polyoxylglyceride, a methylcellulose, a methacrylic acid copolymer, a hydroxypropylmethyl cellulose, a hydroxypropyl cellulose, a hydroxypropylmethyl cellulose phthalate, a hydroxypropylmethyl cellulose acetate succinate, a hydroxypropylmethyl cellulose, a hydroxypropyl cellulose SSL, hydroxypropyl cellulose SL, hydroxypropyl cellulose L, hydroxyethyl cellulose, a polyvinyl caprolactampolyvinyl acetate-polyethylene glycol graft copolymer, a polyoxylglyceride, an ethyl cellulose, a D-alpha-tocopheryl polyethylene glycol 1000 succinate, a cellulose acetate phthalate, a carboxymethylethyl cellulose, a cyclodextrin for e.g. Hydroxypropyl Beta Cyclodextrin (HPpCD), a gelatin, a hypromellose phthalate, a sugar, a polyhydric alcohol, a water soluble sugar excipient, a polyethylene oxide, a polyoxyethylene derivative, a polyvinyl alcohol, a propylene glycol derivative, and a combination thereof.

[0042] The expression “amorphous solid dispersion,” as used herein, means that the dispersion comprising the solid dispersion of pitolisant hydrochloride and a polymer having 100% amorphous or at least 98% amorphous or at least 95% amorphous or at least 90% amorphous or at least 85% amorphous or at least 80% amorphous in nature.

[0043] The term “buffer” or “buffer system” denotes a pharmaceutically acceptable excipient or excipient mixture, which stabilizes the pH of a pharmaceutical preparation. Suitable buffers are well known in art and can be found in literature. Pharmaceutically acceptable buffers comprise acetate buffer, citric buffer, phosphate buffer, sodium buffer, maleate buffer, or tartrate buffer, most particularly citrate buffer. Buffer systems of the invention combinations of organic acid and selected salts thereof, e.g., tri-sodium citrate and citric acid anhydride. Alternatively, organic acid (particularly citric acid) can be employed alone as “acidifier” instead of the combination of acid and the corresponding salt. Independently from the buffer used, the pH can be adjusted with an acid, or a base known in the art, e.g., hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid and citric acid, sodium hydroxide and potassium hydroxide.

[0044] The term “antimicrobial preservatives” denotes pharmaceutically acceptable excipients, which prevent the growth of microorganisms.The term “chelating agents” denotes pharmaceutically acceptable excipients, Chelating agents are compounds that can form coordination complexes with metal ions and bind to them through multiple coordination sites. Chelating agents are used in medicine to treat metal toxicity, and chelation therapy involves the administration of chelating agents that bind to metal ions in the body to help eliminate them. Naturally occurring organic chelating agents are citric acid, gluconic acid, 2,3-Di Hydroxy Benzoic Acid etc. and synthetic chelating agents include ethylenediaminetetraacetic acid (EDTA), commercially available both as the free acid and as various salts, for example, disodium EDTA, tetrasodium EDTA, dipotassium EDTA, calcium disodium EDTA, etc., Ethylene diamine -N, N’- disuccinic acid (EDDA) Other commercial chelators are the naturally occurring amino acid L-cysteine, Tannic Acid, and DL-tartaric acid.

[0045] The term “taste masking agents” are added to overcome the bitter or unpleasant taste of active pharmaceutical ingredients / drugs to achieve patient acceptability and compliance. Oral administration of bitter or unpleasant tasting drugs is often the biggest barrier for patient groups, such as pediatrics and geriatrics. It involves adding a combination of sweeteners (sucralose, aspartame) and flavors (orange, mint) to mask the unpleasant taste of low to moderately bitter actives. In complexation, the drug molecule fits into the cavity of a complexing agent i.e., the host molecule, forming a stable complex, complexation decreases the amount of drug particles, which are exposed to taste buds, thereby reducing

[0046] the perception of bitter taste. EDTA is widely used as a complexing agent because of its strong complexing ability with metal cations.

[0047] The term “about” as used herein embodies standard error associated with a physicochemical observable. As used herein, the term “about” means a slight variation of the value specified, for example, within 10% of the value specified. A stated amount for a compositional ingredient that is not preceded by the term “about” does not mean that there is no variance for the stated term, as one of ordinary skill would understand that there may be the possibility of a degree of variability generally associated with experimental error.In one embodiment of the invention, it relates to a pharmaceutical composition comprising pitolisant, or a pharmaceutically acceptable salts thereof and at least one or more pharmaceutically acceptable excipients. The pharmaceutical composition comprising pitolisant, or a pharmaceutically acceptable salts thereof is an oral liquid solution. The compositions of present invention comprise excipients, which are selected from the group consisting of solvents, co-solvents, buffers, chelating agents, antimicrobial preservatives, pH adjusting agents, sweeteners and flavours or combinations thereof.

[0048] The oral liquid compositions according to the present disclosure can comprise a solvent (e.g., liquid carrier). The solvent can include at least one of water, ethyl alcohol, glycerine, propylene glycol, syrup (e.g., sugar or other sweetener based substance, such as, for example, ORA-SWEET™ SF sugar-free flavored syrup), juices (e.g., apple, grape, orange, cranberry, cherry, tomato and the like), other beverages (e.g., tea, coffee, soft drinks, milk and the like), oils (e.g., olive, soybean, corn, mineral, castor and the like), and combinations or mixtures thereof. Certain solvents can be combined to form emulsions for inclusion in the oral liquid compositions. In certain non-limiting embodiments, the solvent comprises a syrup. In some non-limiting embodiments, the solvent comprises water (e.g., purified water).

[0049] In one embodiment, the pitolisant oral liquid dosage form described herein comprises water as a solvent, wherein solvent is present at about 60% w / w, about 70% w / w, about 80% w / w, about 90% w / w and more particularly 95% w / w in the total volume of liquid.

[0050] In one embodiment, the pitolisant oral liquid dosage form described herein comprises water as a solvent and optionally in combination with atleast one co-solvent. For example, the co-solvents may include one or more of polyethylene glycol, propylene glycol, polyethylene alcohol, ethanol, glycerine, propylene glycol esters, glycofural, polyethylene glycol esters, and mixtures thereof.

[0051] In some embodiments, the co-solvent is Propylene glycol. In some embodiments, the Propylene glycol or mixture thereof, wherein co-solvent is present in about 10 mg / ml toabout 100 mg / ml in the oral liquid formulation. In some embodiments, a co-solvent is present in about 1% w / w to about 10% w / w in the oral liquid formulation.

[0052] In one embodiment, the pitolisant liquid dosage form described herein comprises a preservative. Preservatives may be anti-microbial preservatives, which inhibit the growth of bacteria and fungi. Common anti-microbial preservatives include calcium propionate, sodium nitrate, sodium nitrite, sulfites (sulfur dioxide, sodium bisulfite, potassium hydrogen sulfite, etc.), m-cresol, phenol, benzyl alcohol, benzalkonium chloride, chlorobutanol, phenoxyethanol, sodium benzoate, sodium propionate, methylparaben, propylparaben or combinations thereof.

[0053] In some embodiments, the preservative is a paraben. In some embodiments, the paraben or mixture of parabens, wherein each paraben is present in about 0.01 mg / ml to about 1.0 mg / ml in the oral liquid formulation. In some embodiments, a paraben is present in about 0.01% w / w to about 1% w / w in the oral liquid formulation. In preferred embodiments, the pitolisant liquid dosage form described herein does not comprise a preservative. In preferred embodiments, the pitolisant oral liquid solution described herein does not comprise a paraben preservative.

[0054] In one embodiment, the pitolisant liquid dosage form described herein comprises a chelating agent like Disodium EDTA, tetrasodium EDTA, dipotassium EDTA, calcium disodium EDTA, etc., Ethylene diamine -N, N’-disuccinic acid (EDDA). Other commercial chelators are the naturally occurring amino acid L-cysteine, Tannic Acid, and DL-tartaric acid. In some embodiments, the Disodium EDTA or mixture thereof, wherein Disodium EDTA is present in about 0.01 to about 2.0 mg / ml in the oral liquid formulation.

[0055] In one embodiment, the pitolisant liquid dosage form described herein comprises a pH adjustor or a buffering agent. Some examples of such agents include: sodium hydroxide, hydrochloric acid, citrate, acetate, tartrate, and phosphate buffers / buffering agents.

[0056] In one embodiment of the invention, the pharmaceutical composition comprising pitolisant, or a pharmaceutically acceptable salts thereof wherein the composition is an oral liquid in a buffer system at pH between about 4 to about 8.5, preferably betweenabout 4.5 to about 7.5, more preferably between about 5.5 to about 7.5, preferably between about 5.5 to about 7, more preferably between about 6 to about 7. The suitable buffer systems are acetate, citrate and phosphate buffers. The preferrable buffer system is a citrate buffer using combination of Citric acid anhydrous and Tri-sodium citrate.

[0057] In one embodiment of the invention, the pharmaceutical composition further comprises a sweetener and / or flavor to improve palatability. Sweeteners or sweetening agents include any compounds that provide a sweet taste. This includes natural and synthetic sugars, natural and artificial sweeteners, natural extracts and any material that initiates a sweet sensation in a subject.

[0058] In some embodiments, a liquid sweetener is used in the oral liquid formulation described herein. Sugars illustratively include glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltose, hydrogenated isomaltose, lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose, and the like. Other sweeteners illustratively include glycerine, inulin, erythritol, maltol, acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate, saccharin and salts thereof, e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone, sativoside, thaumatin, and the like. Sweeteners can be used in the form of crude or refined products. Sweeteners can be used singly or in combinations of two or more. Suitable concentrations of different sweeteners can be selected based on published information, manufacturers' data sheets and by routine testing. In a particular embodiment of the invention, the sweetener is sucralose.

[0059] In some embodiments, the pitolisant liquid dosage form described herein comprises a flavouring agent or flavorants to enhance the taste or aroma of the formulation in liquid form. Non-limiting examples of suitable natural flavours, some of which can readily be simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon, liquorice, lime, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, wintergreen, etc. Also useful, particularly where the formulationis intended primarily for pediatric use, is tutti-frutti or bubble-gum flavor, a compounded flavouring agent based on fruit flavours. Presently preferred flavoring agents include mixed berry. Flavoring agents can be used singly or in combinations of two or more.

[0060] In one embodiment, Pitolisant is present in about 0.5 mg / ml to about 100 mg / ml in the liquid dosage form. In other embodiment, Pitolisant is present in about concentration from about 0.5 mg / ml to 100 mg / ml, about 1 mg / ml to 50 mg / ml, preferably 10 mg / ml to 40 mg / ml, preferably 10 mg / ml to 30 mg / ml, more preferably 17.8 mg / ml of the liquid dosage form.

[0061] In one embodiment, a method of preparing an oral pitolisant liquid dosage form comprises: (a) dissolving Pitolisant or a pharmaceutically acceptable salt thereof in one or more solvents; (b) adding one or more pharmaceutically acceptable excipients selected from antimicrobial preservatives, buffers, chelating agents, sweeteners, flavouring agents or combination thereof; (c) adjust the pH of solution between about 4 to about 8.5 with pH adjusting agents; (d) packing oral liquid into a primary pack, for e.g. glass or HDPE

[0062] or PET bottle. The dissolving of Pitolisant can be carried out with or without application of heat. Optionally, the heating step can be employed from about 40°C to about 60°C.

[0063] In one embodiment, a method of preparing an oral pitolisant liquid dosage form comprises: (a) dissolving Pitolisant or a pharmaceutically acceptable salt thereof in one or more solvents; (b) adding one or more pharmaceutically acceptable excipients selected from antimicrobial preservatives, buffers, chelating agents, sweeteners, flavouring agents or combination thereof; (c) adjust the pH of solution between about 5.5 to about 7.5 with pH adjusting agents; (d) packing oral liquid into a primary pack, for e.g. glass or HDPE or PET bottle. The dissolving of Pitolisant can be carried out with or without application of heat. Optionally, the heating may be employed from about 40°C to about 60°C.

[0064] In one embodiment of the invention, it relates to a pharmaceutical composition comprising active pharmaceutical ingredient for the treatment, prevention, and / or delaying progression of excessive daytime sleepiness or cataplexy in patients with narcolepsy, which method comprises administering an oral liquid pharmaceuticalcomposition comprising of l-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, or a pharmaceutically acceptable salts thereof as defined above to a subject.

[0065] In one embodiment, present invention provides a method for the treating of excessive daytime sleepiness (EDS) and cataplexy in adult or pediatric patients with narcolepsy, myotonic dystrophy (DM1), idiopathic hypersomnia, prader-willi syndrome by administering a pharmaceutically effective dose of an oral liquid solution of pitolisant or a pharmaceutically acceptable salt.

[0066] The following examples are provided to illustrate the present invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in the following examples:

[0067] Example: 1

[0068] The following is an exemplary method of preparing oral liquid solution of pitolisant hydrochloride - Hydroxypropyl Beta Cyclodextrin (HPpCD) premix or amorphous solid dispersion with preservatives.

[0069] Table No. 1: General composition for oral liquid solution of pitolisant hydrochloride -HPpCD premix or amorphous solid dispersion with preservatives.

[0070]

[0071] AQ.S: Quantity sufficient* 20mg of Pitolisant Hydrochloride -HPpCD premix or amorphous solid dispersion is nothing but amorphous solid dispersion of pitolisant hydrochloride which is equivalent to 5mg of Pitolisant Hydrochloride which is equivalent to 4.45mg of Pitolisant.

[0072] Process of preparation:

[0073] 1. Added the required quantity of purified water (70 ml) in a suitable beaker and placed it on a magnetic stirrer.

[0074] 2. Gradually added Methyl paraben and propyl paraben to the purified water from step 1 while stirring continuously until a clear solution was obtained.

[0075] 3. Added sucralose to the above solution until a clear solution was achieved.

[0076] 4. Pitolisant Hydrochloride-HPpCD premix or amorphous solid dispersion was added to the above solution under stirring.

[0077] 5. Solution was checked and pH adjusted to 6.0-7.0 using 0.5N NaOH solution.

[0078] 6. Added Berry flavor to the solution, under stirring for 5 minutes, and the final volume was made up with purified water.

[0079] 7. Final solution was filled into amber-colored glass bottles.

[0080] Example 2, 3, 4 & 5:

[0081] The following is an exemplary method of preparing oral liquid solution of pitolisant hydrochloride with buffer and without preservatives.

[0082] Table No. 2: General composition for oral liquid solution of pitolisant hydrochloride with buffer and without preservatives.

[0083]

[0084] AQ.S: Quantity sufficientProcess of preparation:

[0085] 1. Added the required quantity of purified water (60 ml) in suitable beaker and placed on a magnetic stirrer.

[0086] 2. Added Citric acid anhydrous and Tri-sodium citrate to the purified water from step 1 while stirring continuously until a clear solution was obtained.

[0087] 3. Added Propylene glycol to the above solution until a clear solution was achieved. 4. Added sucralose & Mixed berry flavor to the above solution until a clear solution was achieved.

[0088] 5. Pitolisant Hydrochloride was added to the above solution from the previous step and stirred until a clear solution was observed. The volume was then made up with purified water.

[0089] 6. Solution was checked and adjusted to pH 6.0-7.0 using 0.5N NaOH solution.

[0090] 7. Final solution was filled into amber-colored glass bottles.

[0091] Example 6:

[0092] The following is an exemplary method of preparing oral liquid solution of pitolisant hydrochloride with buffer, EDTA and without preservative.

[0093] Table No. 3: General composition for oral liquid solution of pitolisant hydrochloride with Buffer, EDTA and without Preservative.

[0094]

[0095] *Q.S: Quantity sufficientProcess of preparation:

[0096] 1. Added the required quantity of purified water (60 ml) in suitable beaker & placed on a magnetic stirrer.

[0097] 2. Added Citric acid anhydrous and Tri-sodium citrate to the purified water from step 1 while stirring continuously until a clear solution was obtained. After mixing, the temperature was lowered.

[0098] 3. Added Propylene glycol to the solution until a clear solution was achieved.

[0099] 4. Added Disodium EDTA to the solution until a clear solution was achieved.

[0100] 5. Added sucralose & Mixed berry flavor to the solution until a clear solution was achieved.

[0101] 6. Pitolisant Hydrochloride was added to the solution from the previous step and stirred until a clear solution was observed. The volume was then made up with purified water.

[0102] 7. Solution was checked and adjusted to pH 6.0-7.0 using 0.5N NaOH solution.

[0103] 8. Final solution was filled into amber-coloured glass bottle.

[0104] Example 7:

[0105] The following is an exemplary method of preparing oral liquid solution of pitolisant hydrochloride with Buffer, EDTA and without Preservative.

[0106] Table No. 4: General composition for oral liquid solution of pitolisant hydrochloride with pitolisant hydrochloride with Buffer, EDTA and without Preservative.

[0107]

[0108] *Q.S: Quantity sufficientProcess of preparation:

[0109] 1. Added the required quantity of purified water (60 ml) in suitable beaker & placed on a magnetic stirrer.

[0110] 2. Added Citric acid anhydrous and Tri-sodium citrate to the purified water from step 1 while stirring continuously until a clear solution was obtained. After mixing, the temperature was lowered.

[0111] 3. Added Propylene glycol to the solution until a clear solution was achieved.

[0112] 4. Added Disodium EDTA to the solution until a clear solution was achieved.

[0113] 5. Added Neotame & Mixed berry flavor to the solution until a clear solution was achieved.

[0114] 6. Pitolisant Hydrochloride was added to the solution from the previous step and stirred until a clear solution was observed. The volume was then made up with purified water.

[0115] 7. Solution was checked and adjusted to pH 6.0-7.0 using 0.5N NaOH solution.

[0116] 8. Final solution was filled into amber-coloured glass bottle.

[0117] Example 7 composition was subjected to stability studies under accelerated conditions (40 °C ± 2 °C / 75% ± 5% RH) and long-term conditions (25 °C ± 2 °C / 60% ± 5% RH). The stability data up to six months indicated that the finished product remains stable and well within the acceptance criteria in the proposed packaging configuration. Additionally, the product meets all specifications through the six month of storage under both accelerated and long-term stability conditions.

[0118] Table No. 5: Several test results are given below:

[0119]

[0120]

[0121] NMT- Not more than; NLT- Not less than; ND- Not detected

[0122] Table No. 6: Preservative efficacy test

[0123]

[0124] NLT - Not less than

[0125] Surprisingly, a reduction of not less than 1.0 log from the initial microbial count was observed at 14 days, with no increase in microbial count at 28 days relative to the 14-day count. In addition, no increase from the initial calculated microbial count was observed at 14 and 28 days.

Claims

We claim:

1. An oral liquid composition comprising of pitolisant or a pharmaceutically acceptable salt thereof and atleast one or more pharmaceutically acceptable excipients.

2. An oral liquid composition according to claim 1, wherein the composition comprising of pitolisant hydrochloride.

3. An oral liquid composition according to claim 2, wherein the pitolisant hydrochloride is a crystalline, amorphous or combinations thereof.

4. An oral liquid composition according to claim 1, wherein concentration of pitolisant is from 1 mg / ml to 50 mg / ml.

5. An oral liquid composition according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group of solvents, co-solvents, buffers, chelating agents, pH adjusting agents, sweeteners, flavours or combinations thereof.

6. An oral liquid composition according to claim 5, wherein the solvent comprises water in an amount of about 90% w / w of the total liquid composition.

7. An oral liquid composition according to claim 5, wherein co-solvents are selected from the group consisting of propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol esters, glycofurol, polyethylene glycol esters and combinations thereof.

8. An oral liquid composition according to claim 5, wherein buffers are selected from the group of citrate, phosphate, acetate and combinations thereof.

9. An oral liquid composition according to claim 5, wherein chelating agents selected from the group consisting of disodium edetate, tetrasodium edetate, dipotassium edetate, calcium disodium edetate, L-cysteine, Tannic Acid, DL-tartaric acid and combinations thereof.

10. An oral liquid composition according to claim 5, wherein the sweeteners are selected from the group of glucose, fructose, sucrose, xylitol, neotame, sucralose, maltitol, isomaltose, hydrogenated isomaltose, lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose and combinations thereof.

11. An oral liquid composition according to claim 5, wherein the flavouring agents are selected from the group of almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon, liquorice, lime, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pineapple, raspberry, rose, spearmint, strawberry and mixed berry.

12. An oral liquid composition according to claim 5, wherein the composition is having a pH of 6.0 to 7.0.

13. An oral liquid composition according to claim 5, wherein the composition is devoid of antimicrobial preservative.

14. A process of making an oral liquid composition comprising of pitolisant or a pharmaceutically acceptable salt thereof and atleast one or more pharmaceutically acceptable excipients comprising of the steps:(a) dissolving Pitolisant or a pharmaceutically acceptable salt thereof or in one or more solvents;(b) dissolving one or more pharmaceutically acceptable excipients selected from buffers, chelating agents, sweeteners, flavouring agents or combination thereof;(c) adjusting pH of solution from about 5.5 to about 7.5; and(d) packing oral solution into a primary pack.

15. An oral liquid composition comprising of pitolisant or a pharmaceutically acceptable salt thereof, citric acid anhydrous, trisodium citrate dihydrate, disodium edetate, propylene glycol and water.

16. An oral liquid composition according to claim 15, wherein the composition comprising neotame and mixed berry flavour.

17. An oral liquid composition according to claim 15, wherein the pitolisant is a premix of Pitolisant HC1 and HPBCD.

18. An oral liquid composition according to claim 15, wherein the concentration of pitolisant is about 17.8 mg / ml.

19. An oral liquid composition according to claim 15, wherein the composition is having a pH about 6.0 to about 7.0.

20. An oral liquid composition according to claim 1 to 18, wherein the composition is used for treatment of excessive daytime sleepiness and cataplexy in adult patients with narcolepsy.

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