Oral formulation of pimavanserin

Abstract

The invention relates to stable oral formulations of pimavanserin or its pharmaceutically acceptable salts, provided in the form of ready-to-use liquids, powders for reconstitution, orally dispersible tablets, and kits containing pre-measured powder and a liquid vehicle for reconstitution. These formulations are stable for longer periods and are palatable, thereby improving patient compliance and adherence in the treatment of psychosis associated with Parkinson's disease.

Description

ORAL FORMULATION OF PIMA VANSERINFIELD OF THE INVENTION

[0001] The present invention relates to the oral formulation comprising Pimavanserin or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients. In particular, the present invention also relates to liquid pharmaceutical compositions of Pimavanserin or its pharmaceutically acceptable salts or derivatives thereof for the treatment of Parkinson's disease psychosis.BACKGROUND OF THE INVENTION

[0002] Parkinson's disease or PD is a progressive debilitating degenerative disorder of central nervous system (CNS) mainly affecting the motor system caused by death of the dopaminergic neurons in the basal ganglia. PD has been traditionally defined based on motor features, including resting tremor, bradykinesia, rigidity, and disturbances of balance and posture, but patients do also experience some numerous non-motor symptoms that are highly prevalent and often have a greater impact on patient disability and quality of life. These non-motor symptoms include psychosis and behavioral disturbances, pain, sensory complaints, depression, and dementia. Among these, perhaps the most significant with respect to morbidity and quality of life, and the most difficult to treat, is psychosis. Psychotic symptoms occur in 20% to 40% of patients with PD in advanced stages of the disease. The hallmark symptoms of PDP are delusions and hallucinations that typically increase in frequency and severity over time. The most common symptom of PDP is visual hallucinations, occurring in up to I / 3rd of patients with PD. Hallucinatory symptoms tend to last for a few seconds to a few minutes, and the frequency may vary. In more severe cases, the symptoms may occur several times a day. Delusions are less common, occur in about 5% - 10% of PD patients, and are generally characterized as paranoid or jealous. On PD progression, patients need increasing assistance with medications, bathing, dressing, walking and other daily activities. Till date, atypical and typicalantipsychotics (for example clozapine & quetiapine) are being used to manage these symptoms. Treating PDP has been extremely challenging as the antipsychotics with dopamine blocking properties may worsen parkinsonian motor features and have been associated with rise in morbidity and mortality among elderly patients with dementia.

[0003] In comparison with other antipsychotics, Pimavanserin has a remarkably lack of interaction with dopamine receptors and its treatment effects were not associated with exacerbation of motor disability, sedation, or other safety challenges. The unique pharmacologic profile of Pimavanserin as a selective inverse agonist and antagonist at serotonin 5-HT2A / 2C receptors allows for the treatment of psychosis without worsening the motor symptoms of Parkinson’s disease. Pimavanserin can produce antipsychotic benefit in Parkinson' s disease psychosis without unnecessary receptor activity that compromises safety and tolerability.

[0004] Pimavanserin is an atypical antipsychotic. FDA approved NUPLAZID contains Pimavanserin tartrate salt with the chemical name, urea, N-[(4-fluorophenyl)methyl]- N-(l-methyl-4-piperidinyl)-N'-[[4-(2-methylpropoxy) phenyl]methyl]-,(2R,3R)-2,3- dihydroxybutanedioate (2:1). NUPLAZID is marketed by Acadia Pharmaceuticals in oral tablet and oral capsule dosage forms. NUPLAZID Tablet is available in two strengths viz. 17 mg and lOmg Pimavanserin. NUPLAZID capsule is available in one strength of 34mg Pimavanserin. Pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. The recommended dose is 34 mg, taken orally once daily, without titration. The following structure of Pimavanserin.

[0005] W02007 / 133802 patent application disclosed a stable pharmaceutical composition comprising Pimavanserin and at least one pharmaceutically acceptable excipient selected from the group consisting of a sugar, a starch, a cellulose preparation, silicon dioxide aerosol, gelatin, calcium phosphate dibasic, sodium lauryl sulfate, magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, and polyvinylpyrrolidone, and combinations thereof.

[0006] US2022 / 0323429 Al patent application disclosed a method of treating a disorder in a patient in need of Pimavanserin, the method comprising administering to the patient about 2 mg to about 80 mg of Pimavanserin via, e.g., an enteral feeding tube, once daily, wherein Pimavanserin is dissolved in, mixed with, or sparkled onto, e.g., about 5 mL to about 150 mL of, a liquid vehicle or soft food vehicle at ambient or cold temperature before the administration. Further, US2022 / 0323429 Al patent application disclosed Pimavanserin is stable in the liquid vehicle for at least 24 hours and altering the original solid dosage (Example: tablet or capsule) form may affect the absorption, stability and delivery of the drug and can lead to significant changes in pharmacological effect.

[0007] US2022 / 0323429 Al also discloses a method of treating a disorder in a patient in need of Pimavanserin, the method comprising administering to the patient about 2 mg to about 80 mg of Pimavanserin once daily, wherein the administration comprises the steps ofa) opening a pharmaceutically acceptable capsule comprising Pimavanserin; b) mixing the contents of the capsule with about 5 mL to about 150 mL (e.g., about 5 mL to about 60 mL) of a liquid vehicle or sprinkling the contents of the capsule onto about 5 mL to about 150 mL of a soft food vehicle at ambient or cold temperature; andc) delivering to the patient, optionally via an enteral feeding tube the contents of the capsule with the liquid vehicle to the patient, or orally delivering the contents of the capsule with the soft food vehicle to the patient.

[0008] US2022 / 0323429 Al also discloses a method of treating a disorder in a patient in need of Pimavanserin, the method comprising administering to the patient about 2 mg to about 80 mg of Pimavanserin once daily, wherein the administration comprises the steps of:a) crushing a pharmaceutically acceptable tablet comprising Pimavanserin; b) mixing the crushed tablet with about 5 mL to about 150 mL of a liquid vehicle or sprinkling the crushed tablet onto about 5 mL to about 150 mL of a soft food vehicle at ambient or cold temperature; andc) delivering to the patient, optionally via an enteral feeding tube, the crushed tablet with the liquid vehicle to the patient, or orally delivering the crushed tablet with the soft food vehicle to the patient.

[0009] The prescribing information of NUPLAZID capsules mentions “NUPLAZID capsules can be taken whole or opened and the entire contents sprinkled over a tablespoon (15 mL) of applesauce, yogurt, pudding, or a liquid nutritional supplement. Consume the drug / food mixture immediately without chewing; do not store for future use.”

[0010] Swallowing difficulties can arise from either psychological aversion, which can occur at any age, or from dysphagia, which is a physical impairment in theswallowing process. Dysphagia can be acute, for example, in patients with a sore throat or those with an exacerbation of gas tro -esophageal reflux disease, or chronic disease, for example, in patients who have experienced a stroke, patients with Parkinson’s disease or Huntingdon’s chorea, or those with muscular dystrophy.

[0011] Dysphagia in Parkinson’s disease is associated with increased morbidity and mortality. Some form of swallowing difficulty is believed to be found in between 70 and 90 per cent of the elderly. This can result from a reduction in the production of saliva and weakening of the muscles involved in swallowing. For instance, it has been reported that up to 80% or more of Parkinson's disease patients experience difficulty swallowing solid dosage forms configured for oral administration (Pflug C et al., Dysphagia 2018, 33:41-50; Kalf J G et al., Parkinsonism Relat. Disord. 2012, 18:311-5).

[0012] The research publication by Oxford University Press on behalf of the British Geriatrics Society (Hard to swallow: dysphagia in Parkinson’s disease; by Nick Miller; Age and Ageing 2006; 35: 614-618) disclosed that swallowing dysfunction occurs from the earliest stages of Parkinson’s disease (PD), even in asymptomatic cases. Changes range from drooling (despite indications of decreased salivary production in PD); food residues in the oral sulci long after meals; poor bolus formation; slowed oral transit; repeated tongue pumping for retropulsion of the bolus; delayed triggering of the pharyngeal swallow reflex; reduced diameter but prolonged opening of the upper esophageal sphincter; to vallecular stasis, residue in the piriform sinuses with risk of aspiration and true aspiration.

[0013] Pimavanserin is presently marketed only in solid dosage forms i.e. immediate release tablets and capsules for oral administration. However, solid dosage forms are not suitable for some patients who have difficulty in swallowing. Further, solid dosage forms may not be convenient, when chronic therapy is needed. Therefore,there exists a clear need in the art for oral liquid compositions of Pimavanserin. To date, no stable liquid compositions of Pimavanserin are known. The only FDA approved Pimavanserin products are solid dosage forms i.e. tablets / capsules. In view of this, ready to use liquid compositions, and dosage forms for reconstitution (like powder, granules, orodispersible tablets) of Pimavanserin are desirable over presently available solid dosage forms, as they would offer better patient compliance, convenience and flexible dosing regimen.

[0014] However, a prime concern with any liquid formulation is the stability of the Pimavanserin, both short term and over the time. Inventors of the present application have for the first time developed formulations for oral administration such as liquid preparations, ready for reconstitution oral dosage forms (powder, granules and orodispersible tablets) providing ease of administration to dysphagiac patients by overcoming administration difficulties of the marketed dosage forms. The compositions are stable both during manufacturing and shelf life.

[0015] In addition to above, currently available solid dosage forms are difficult to administer particularly for dysphagia patient. For example, the prescribing information of NUPLAZID capsules mentions “NUPLAZID capsules can be opened and the entire contents sprinkled over a tablespoon (15 mL) of food vehicle before the administration. The opening of capsule is many a times difficult particularly in Parkinson’s disease patients. In view of this, ready to use oral dosage form such as liquid preparations, and oral dosage forms for reconstitution (powder, granules, orally dispersible tablet) are desirable over presently available solid dosage forms, as they would offer better patient compliance, convenience and flexible dosing regimen.

[0016] Therefore, there is an unmet need to provide an alternate dosage form of Pimavanserin which is stable and has improved patient compliance particularly withrespect to the ease of dosage administration and avoidance of frequent reconstitution required currently at every dosing.SUMMARY OF THE INVENTION

[0017] Provided herein are pharmaceutical compositions comprising Pimavanserin, or a pharmaceutically acceptable salt thereof.

[0018] According to an aspect of the present invention, there is provided an oral liquid composition of Pimavanserin, or a pharmaceutically acceptable salt thereof.

[0019] In another aspect of the present invention, there is provided oral liquid composition of Pimavanserin, or a pharmaceutically acceptable salt thereof wherein the composition is stable for at least 7 days, at least 15 days, at least 1 month, at least 2 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months or at least 15 months and more. The preparation of these dosage forms can be accomplished using standard methods recognized by professionals in the field of pharmaceutical science.

[0020] In another aspect of the present invention, there is provided method of treating Parkinson’s disease with an oral liquid composition of Pimavanserin, or a pharmaceutically acceptable salt thereof.

[0021] In another aspect of the present invention, there is provided a ready for reconstitution (powder, granule or orodispersible tablet) composition of Pimavanserin, or a pharmaceutically acceptable salt thereof wherein these oral dosage forms are reconstituted with suitable vehicle to form a solution, a suspension or an emulsion.

[0022] In another aspect of the present invention, there is provided a powder composition of Pimavanserin, or a pharmaceutically acceptable salt thereof wherein a powder is reconstituted with suitable vehicle to form a solution, a suspension or an emulsion and the composition is stable for at least 48 hours, at least 4 days, at least 6 days, at least 8 days or at least 10 days or more. The preparation of these dosage forms can be accomplished using standard methods recognized by professionals in the field of pharmaceutical science.

[0023] In another aspect of the present invention, there is provided method of treating Parkinson’s disease with a powder composition of Pimavanserin, or a pharmaceutically acceptable salt thereof wherein a powder is reconstituted with suitable vehicle to form a solution, a suspension or an emulsion.

[0024] In another aspect of the present invention, there is provided orally dispersible composition of Pimavanserin, or a pharmaceutically acceptable salt thereof.

[0025] In another aspect of the present invention, there is provided an orally dispersible composition of Pimavanserin, or a pharmaceutically acceptable salt thereof wherein an orally dispersible composition is stable for at least 7 days, 15 days, at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months or at least 15 months or more. The preparation of the dosage form can be accomplished using standard methods recognized by professionals in the field of pharmaceutical science.

[0026] In another aspect of the present invention, there is provided method of treating Parkinson’s disease with an orally dispersible composition of Pimavanserin, or a pharmaceutically acceptable salt thereof.

[0027] In another aspect of the present invention, the present disclosure is based, inter alia, on liquid formulations for preparing a Pimavanserin, or a pharmaceutically acceptable salt thereof Powder for Oral Liquid Kit. The oral liquid kits of the present disclosure contain bottled active pharmaceutical ingredient (API: Pimavanserin) and pre-measured diluent, which can be reconstituted to form an oral Pimavanserin liquid in the form of solution or suspension. These kits containing the Pimavanserin are stable (e.g., at ambient temperature or refrigerated conditions, e.g., 2-8° C.). The API and the diluent of the present disclosure have long-term stability (e.g., up to 24 months). Once reconstituted, the suspension stability can be, for example, up to or greater than 30 days. The liquid formulations (e.g., reconstituted solutions or suspensions) are homogenous and stable for at least 60 days at ambient temperature or refrigerated temperature.DETAILED DESCRIPTION

[0028] Throughout the disclosure, singular forms such as “a,” “an,” and “the” are often used for convenience. However, it should be understood that the singular forms are intended to include the plural, except when context or an explicit statement indicates that the singular alone is intended. It should also be understood that all patents, publications, journal articles, and the like that are mentioned in this Application are incorporated by reference in their entirety and for all purposes.

[0029] Open terms such as “include,” “including,” “contain,” “containing” and the like mean “comprising”.

[0030] The term “treatment” or “treating” refers to administering a therapy in an amount, manner, or mode effective to improve a condition, symptom, or parameter associated with a disorder.

[0031] The term “Administering” or “administration” means providing a drug to a patient in a manner that is pharmacologically useful.

[0032] The term “or” can be conjunctive or disjunctive.

[0033] The term “% by weight” is based on the weight of the total composition.

[0034] As used herein, “pharmaceutical composition” refers to a composition of one or more active pharmaceutical ingredient(s) alone, or administered with other chemical components, such as polymers (pH-dependent and pH independent), pH adjusting agents, stabilizers, solubilizers, buffering agent, anti-oxidants, pH dependent polymers, surfactant etc.

[0035] The term “ready for reconstitution” refers to a process wherein liquid is used to reconstitute, suspend, disperse, emulsify or dissolve medications in powder or solid form, allowing for their administration.

[0036] The term “orally dispersible tablet” refers to an uncoated or film-coated tablets intended to be dispersed in water or any other vehicle before administration giving a homogeneous dispersion.

[0037] Pimavanserin, which is also known as N-(l-methylpiperidin-4-yl)-N- (4fluorophenyl methyl)-N' -( 4-(2-methylpropyloxy)phenylmethyl)carbamide, N-[( 4-fhrorophenyl)methyl]-N-( l-methyl-4-piperidinyl)-N' 4- (2ethylpropoxy)phenyl]methyl]urea, l-( 4-fluorobenzyl)-l-( l-methylpiperidin-4yl)- 3-[ 4-(2-methylpropoxy)benzyl]urea, or ACP-103 has the structure following structural formula:

[0038] The term "Pimavanserin" is used in broad sense to include not only "Pimavanserin" per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable derivatives, pharmaceutically acceptable hydrate, pharmaceutically acceptable polymorphs, pharmaceutically acceptable isomer, pharmaceutically acceptable tautomer, pharmaceutically acceptable anhydrate, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.

[0039] In some embodiments, the pharmaceutical compositions may comprise any other pharmaceutically acceptable salt of Pimavanserin including, but not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, nitrate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, tocopheryl succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4- dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, B-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, mandelate and the like salts. The present invention provides pharmaceutical compositions comprising atherapeutically effective amount of a pharmaceutically acceptable salt of Pimavanserin preferably tartarate salt having following structural formula.

[0040] As used herein, an “excipient” refers to an inactive ingredient that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, solubilization, binding ability, lubrication, disintegrating ability, taste masking, organoleptic additives, etc., to the composition.

[0041] ‘ ‘Ambient temperature” refers to the temperature of the surrounding environment in which a device, system, or component operates. It represents the naturally occurring air temperature external to the apparatus, measured without influence from heat generated by the device itself or from artificial heating or cooling sources. Unless otherwise specified, ambient temperature is considered to be within the range of 20 °C to 30 °C, which corresponds to standard room-temperature environmental conditions.

[0042] “Refrigerated temperature” refers to a controlled low-temperature environment maintained below standard ambient conditions to preserve materials, components, or systems. Unless otherwise specified, refrigerated temperature is considered to be within the range of 2 °C to 8 °C, which aligns with commonly accepted industrial and laboratory refrigeration standards.

[0043] ‘ ‘Multi-dose” refers to the two or more individual unit doses of pimavanserin.

[0044] As used herein, the term “stable” or “stability” as used herein refers to a pharmaceutical composition that retains chemical stability and comply with the standard stability criteria given in USP / EP compendia.

[0045] "Therapeutically effective amount" or "effective amount" is such that when administered, the pharmaceutical formulation results in the desired pharmacologic effect.

[0046] The term “about” includes the indicated amount ±10%.

[0047] As used herein, the term “non-aqueous” refers to compositions containing substantially no water, i.e. less than 1% by volume. In a particular embodiment, the non-aqueous liquid compositions of the present invention contain no water.

[0048] The Pimavanserin or its pharmaceutically acceptable salts thereof may be in micronized form. Suitable micronization techniques such as dry milling, wet milling, air jet milling, sieving, homogenizing using a homogenizer such as rotor-stator and / or high pressure homogenizer such as a microfluidizer can be used for micronization of Pimavanserin or its pharmaceutically acceptable salts thereof. Alternately, the Pimavanserin or its pharmaceutically acceptable salts thereof may be in unmicronized form.A. Oral liquid composition

[0049] A first embodiment of the present invention provides an oral liquid composition comprising Pimavanserin or its pharmaceutically acceptable salts.

[0050] A second embodiment of the present invention provides an oral liquid composition comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the composition comprises Pimavanserin or its pharmaceutically acceptable salts in an equivalent concentration of Pimavanserin from about 0.001 % w / v to about 40% w / v of the composition. Particularly, the composition comprises Pimavanserin or its pharmaceutically acceptable salts in a concentration from about 0.0067% w / v to about 34% w / v of the composition.

[0051] A third embodiment of the present invention provides an oral liquid composition comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the composition is a stable composition. Particularly, the composition is stable for more than 48 hours, at least 1 week, at least 15 days, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 15 months. More particularly, the composition is stable for at least one month or more, to the extent necessary for the sale and use of the composition.

[0052] A fourth embodiment of the present invention provides an oral liquid composition comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the composition has a pH range from about 2 to about 10.

[0053] According to another embodiment of the above aspects, the composition is a taste-masked composition

[0054] According to another embodiment of the above aspects, the composition is administered through an enteral feeding tube, nasogastric tube, orogastric tube, nasoenteric tube, or oroenteric tube.

[0055] A fifth embodiment of the present invention provides an oral liquid composition comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the composition is a ready-to-use liquid composition.

[0056] According to another embodiment, the ready-to- use liquid composition comprises a solution, a suspension, a syrup, a concentrate, an elixir or an emulsion.

[0057] A sixth embodiment of the present invention provides an oral liquid composition comprising Pimavanserin or its pharmaceutically acceptable salts, wherein a composition is aqueous solution formulation.

[0058] A seventh embodiment of the present invention provides an aqueous solution composition of Pimavanserin or its pharmaceutically acceptable salts, wherein an aqueous solution composition is stable for at least 48 hours, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 15 months.

[0059] An eighth embodiment of the present invention provides an oral liquid composition comprising Pimavanserin or its pharmaceutically acceptable salts, wherein a composition is non-aqueous solution formulation.

[0060] A ninth embodiment of the present invention provides a non-aqueous solution composition of Pimavanserin or its pharmaceutically acceptable salts, wherein a nonaqueous solution composition is stable for at least 48 hours, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 15 months.

[0061] A tenth embodiment of the present invention provides an oral liquid composition comprising Pimavanserin or its pharmaceutically acceptable salts, wherein a composition is a solution, a suspension or an emulsion, wherein acomposition comprises mixture of aqueous and non-aqueous vehicles (example, hydroalcoholic system).

[0062] An eleventh embodiment of the present invention provides an oral liquid composition comprising Pimavanserin or its pharmaceutically acceptable salts, wherein a composition is a solution, a suspension or an emulsion, wherein a composition comprises mixture of aqueous and non-aqueous vehicles (example, hydroalcoholic system), wherein a composition is stable for at least 48 hours, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 15 months.

[0063] A twelfth embodiment of the present invention provides an oral liquid composition comprising Pimavanserin or its pharmaceutically acceptable salts, wherein a composition is a suspension formulation.

[0064] A thirteenth embodiment of the present invention provides a suspension formulation of Pimavanserin or its pharmaceutically acceptable salts, wherein a suspension formulation is stable for at least 48 hours, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 15 months.

[0065] A fourteenth embodiment of the present invention provides an oral liquid composition comprising Pimavanserin or its pharmaceutically acceptable salts, wherein a composition is emulsion formulation.

[0066] A fifteenth embodiment of the present invention provides an emulsion formulation of Pimavanserin or its pharmaceutically acceptable salts, wherein an emulsion formulation is stable for at least 48 hours, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 15 months.

[0067] The oral liquid pharmaceutical solution of this invention comprises one or more pharmaceutically acceptable excipient which is selected from the group comprising liquid or semisolid vehicle, surfactants, co-surfactant, solubilizer, stabilizers, pH dependent and independent polymers, ion-exchange resins, adsorbents, steric stabilizer, osmogents, binder, viscosity modifiers, emulsifier, chelating agents, suspending agents, wetting agents, co-solvents, solvents, plasticizer, anti-tacking agent, antioxidants, opacifiers, preservatives, buffering agents, flavoring agents, Flow regulator or glidant, lubricant, Disintegrants, taste masking additives, sweeteners and diluents.

[0068] Liquid vehicles suitable for the Pimavanserin or its pharmaceutically acceptable salts described herein are selected for a particular oral liquid composition (e.g., solution, suspension, emulsion etc.) as well as other properties such as clarity, viscosity, compatibility with excipients, chemical inertness, palatability, odor, and color. Exemplary liquid vehicles include water, ethyl alcohol, glycerin, propylene glycol, PEGs, syrup (e.g., sugar or other sweetener based, e.g., Ora-Sweet® SF sugar-free flavored syrup), juices (e.g., apple, 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 liquid vehicles, e.g., oil and water, can be combined together to form emulsions. In some embodiments, water or non-aqueous vehicle or mixture thereof (example, hydroalcholic system) is used as a vehicle for a Pimavanserin or its pharmaceutically acceptable salts oral aqueous solution. In other embodiments, alcoholic, PG, glycerol, vegetable oils (corn, cottonseed, olive, peanut, and sesame seed oils) or mineral oil, medium chain triglycerides and long chain triglycerides or their mixture thereof are used as a vehicle for a Pimavanserin or its pharmaceutically acceptable salts non-aqueous oral solution. The composition of the present invention may contain about 5% wt% to about 95 wt% liquid vehicle.

[0069] Appropriate solvents, co-solvents, solubilizers, or vehicles that may be utilized in the liquid compositions of the embodiments include, but are not limited to, dichloromethane, acetonitrile, ethyl acetate, acetone, propylene carbonate, water, glycerin, glycerol, coconut fatty acid diethanolamide, medium and long-chain fatty acids or glycerides, monoglycerides, diglycerides, triglycerides, structured triglycerides, soybean oil, peanut oil, corn oil, corn oil monoglycerides, corn oil diglycerides, corn oil triglycerides, polyethylene glycol, caprylocaproylmacroglycerides, caproyl 90, propylene glycol, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene, castor oil derivatives, castor oil, cottonseed oil, olive oil, safflower oil, peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid, methanol, ethanol, isopropyl alcohol, butanol, methyl isobutyl ketone, methyl ethyl ketone, and similar substances, as well as any combinations thereof.

[0070] Surfactant of the present invention may also act as wetting agent or suspending agent and ensure complete wetting of the microparticles or nanoparticles by the vehicle and thus stabilizing the Pimavanserin or its pharmaceutically acceptable salt in the composition. Preferred surface modifiers include nonionic, cationic, zwitterionic and anionic surfactants. Suitable surfactant includes, but are not limited to, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, tocophersolan (Vitamin E TPGS) glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (polysorbate 20, polysorbate 80 and like);, e.g., the commercially available TWEENS™ (For example, Tween 80), Polyoxamers, Sorbitan (Span) esters, polyethylene glycols, polyoxyethylene stearates, Glyceryl Monocaprylocaprate (IMWITOR® 988), colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium,carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phtalate, noncrystalline cellulose, magnesium aluminate silicate, triethanolamine, polyvinyl alcohol (PVA), poloxamers, tyloxapol and polyvinylpyrrolidone (Povidone).. Preferably, the composition of the present invention may contain about 0 wt% to about 40 wt% of surfactant. In preferred embodiment, the composition of the present invention contains about 0.5% wt% to about 20 wt% of surfactants.

[0071] The co-surfactant is selected from the group consisting of propylene glycol monocaprylate, type II (Capryol 90), Propylene glycol monolaurate, type II (Lauroglycol 90), Glyceryl Monocaprylocaprate (IMWITOR® 988), polyglyceryl-3 dioleate (Plurol Oleique). The names used herein are in accordance the nomenclature of US Pharmacopeia. Preferable co-surfactants are propylene glycol monocaprylate, type II (Capryol 90) or polyglyceryl-3 dioleate (Plurol Oleique). The composition of the present invention may contain about 0 wt% to about 25wt% of co-surfactants.

[0072] Suitable examples of pH-dependent polymers are selected from the group comprising acrylic copolymers such as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit® L 100 and Eudragit® S 100, methacrylic acid and ethyl acrylate copolymers, e.g., Eudragit® L 100-55 and Eudragit® L 30 D-55, dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymers e.g., Eudragit® E 100, Eudragit® E PO, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymer; cellulose acetate phthalate; cellulose acetate succinates; hydroxyalkyl cellulose phthalates such as hydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetate succinates such as hydroxypropylmethyl cellulose acetate succinate; vinyl acetate phthalates; vinyl acetate succinate; cellulose acetate trimelliate; polyvinyl derivatives such as polyvinyl acetate phthalate, polyvinyl alcoholphthalate, polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate; zein; shellac; and mixtures thereof. The composition of the present invention may contain about 0.5 wt% to about 50 wt% of pH-dependent polymers.

[0073] Suitable examples of pH-independent polymers are selected from the group comprising Hydroxyethylcellulose (HEC), Polyvinylpyrolidone (PVP) and high molecular weight cellulose polymers such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC). Further non limiting examples of pH- independent insoluble polymers include ethylcellulose polymers and ethyl acrylate methyl methacrylate copolymer (such as Eudragit® NE30D).

[0074] Suitable examples of ion-exchange resin are selected from the group comprising weak anionic and cationic ion exchange resin (polystyrene DVB, sodium polystyrene, methacrylic acid DVB, heavy metal silicates, Sephadex anion exchange resin, zeolites, etc. The composition of the present invention may contain about 0.5 wt% to about 30 wt% of ion-exchange resins.

[0075] Suitable examples of adsorbents are selected from the group comprising silica gel, talc, starch, bentonite, silicates (eg. magnesium aluminium silicate, Aluminium metasilicate) and kaolin. The composition of the present invention may contain about 0.5 wt% to about 20 wt% of adsorbents.

[0076] For the purpose of present invention, the term "stabilizer" used herein may include, but are not limited to Carboxymethylcellulose and its derivatives, polysorbates, polyvinyl alcohol, hydroxypropyl methylcellulose, propylene glycol, sodium oleate and / or polyoxyethylenated sorbitan laurate, Tweens (For example, Tween 80), poloxamers, blockcopolymers, Sodium lauryl sulfate (SES) and the like or mixture thereof. The stabilizers may be present in an amount of 0.1 to 30% by weight.

[0077] Suitable examples of steric stabilizers include, but are not limited to, cellulose derivatives, poloxamers (which may also act as polymeric surfactants), polysorbates, povidones, and mixtures thereof. The composition of the present invention may contain about 0.5wt% to about 50wt% of steric stabilizer

[0078] Suitable antioxidants may include but not limited to butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, alphatocopherol, propyl gallate, gentisic acid sodium ascorbate, sodium bisulfite, sodium metabisulfite, monothioglycero, cysteine, thioglycolate sodium, acetone sodium bisulfite, ascorbate (sodium / acid), bisulfite sodium, cystein / cysteinate HCI, dithionite sodium (Na hydrosulfite, Na sulfoxylate), gentisic acid, gentisic acid ethanolamine, glutamate monosodium, formaldehyde sulfoxylate sodium, metabisulfite potassium, metabisulfite sodium, monothioglycerol (thioglycerol), propyl gallate, sulfite sodium, tocopherol alpha, thioglycolate sodium, EDTA in calcium and sodium compounds or the mixtures thereof. The composition of the present invention may contain about 0.2 wt% to about 20 wt% of antioxidants.

[0079] The term “solubilizer” as used herein refers to solubility enhancer Solubilizer or solubility enhancer and may be used interchangeably. Suitable solubilizer or solubility enhancers include water-soluble organic solvents such as polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin; anionic surfactant such as sodium lauryl sulfate, docusate sodium and the like; non-ionic surfactants such as Cremophore ELP, Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, sorbitan monooleate, poloxamer, poloxamer 188, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, Softigen 767, and mono- and di-fatty acid esters such as polyethylene glycol PEG 300, PEG 400,PEG 1750, or PEG 4000, cyclodextrin, Captisol and the like. The composition of the present invention may contain about 0.5 wt% to about 75wt% of solubilizer.

[0080] The term “sweetener” as used herein refers to a substance providing sweet taste and has taste similar to a sugar to make the product more palatable. This includes natural and synthetic sugars, natural and artificial sweeteners, natural extracts, and any material that initiates a sweet sensation in a subject. In some implementation, a solid / powder sweetener is used in the oral liquid formulation and a liquid sweetener is used in the oral liquid formulation described herein. The amount of sweetener may vary depending on the sweetener used and may range from about 0.5wt% to about 70 wt%. Sweeteners or sugars illustratively include glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, isomaltulose, lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose, and the like. Other sweeteners illustratively include glycerin, inulin, erythritol, 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, stevioside, thaumatin, and the like. Sweeteners can be used in the form of crude or refined products such as hydrogenated starch hydrosylates, maltitol syrup, high fructose corn syrup, and as branded proprietary blend products. Sweeteners can be used singly or combinations of two or more. Suitable concentrations of different sweeteners can be selected based on published information, manufacturers' data sheets, and by routine testing.

[0081] The term “flavoring agent” as used herein refers to a substance that provides enhanced the taste or aroma to the formulation. Non-limiting examples of suitable natural flavors, some of which can be readily simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, banana, blackberry, blackcurrant, blueberry, caramel, cherry, chocolate, cinnamon, cranberry, grape, lemon, lime, orange, peppermint, pineapple, raspberry, spearmint, strawberry,vanilla, etc. Also useful, particularly where the composition is intended primarily for pediatric use is tutti-frutti or bubble gum flavor, a compounded flavoring agent based on fruit flavors. Presently, preferred flavoring agents include bubblegum, strawberry, cherry, grape, orange, peppermint, and vanilla. In some implementation, the resultant liquid form from the Pimavanserin or its pharmaceutically acceptable salts hydrochloride powder or granules described herein comprises a grape (specifically, white grape) flavoring agent. Flavoring agents may be used singly or in combinations of two or more. The composition of the present invention may contain about 0.1 wt% to about 10 wt% of flavoring agent.

[0082] The term “taste masking additive” refers to the sweeteners, essential oils and flavoring agent as described above.

[0083] The term “binder” or “thickener” as used herein refers to substance that impart viscosity or weight to the formulation. Exemplary binders / thickeners include dextrin, cellulose derivatives (hydroxypropyl cellulose, ethylcellulose, hydroxyethyl cellulose, methylcellulose, polyvinylpyrrolidone (povidone or PVP K-90), hypromellose, and the like) starches, gelatin, pectin, polyethylene oxide, microcrystalline cellulose, sodium carboxymethylcellulose and certain gums (xanthan gum, locust bean gum, etc). The composition of the present invention may contain about 0.5 wt% to about 25wt% of thickener.

[0084] The term “preservative” as used herein refers to a compound that provides antimicrobial effect to the formulation, preservative is used in an amount sufficient to provide antimicrobial effectiveness to the Pimavanserin or its pharmaceutically acceptable salts oral liquid formulation described herein. Preservatives include antimicrobials, anti-oxidants, and agents that enhance sterility. Suitable preservatives include ascorbic acid, ascorbyl palmitate, benzyl alcohol butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), erythorbic acid, fumaric acid, malic acid,propyl gallate, sodium ascorbate, sodium benzoate, sodium bisulfate, sodium metabisulfite, sodium sulfite, methyl paraben, propylparaben, benzoic acid, potassium sorbate, and vanillin. In some implementation, the Pimavanserin or its pharmaceutically acceptable salts described herein, when compounded into a liquid form, or in multiple dosage form comprises a preservative. The composition of the present invention may contain about 0.000 lwt% to about 15 wt% of preservative.

[0085] The term “buffer” or “buffering agent” or “pH modifier” as used herein refers to a substance or compound used to maintain the pH of the formulation. Buffering agents maintain the pH when Pimavanserin or its pharmaceutically acceptable salts compounded into a liquid form or the liquid solution or suspension. Examples of suitable buffering agents include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate precipitate, a mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of acid salt and an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include citric acid, sodium citrate, sodium tartrate, tartaric acid, sodium acetate, Lactic acid, sodium lactate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, sodium hydroxide, trisodium phosphate or sodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. Some buffering agents also impart effervescent qualities when Pimavanserin or its pharmaceutically acceptable salts is compounded into a liquid. In some implementation, the Pimavanserin or its pharmaceutically acceptable salts described herein, when compounded into a liquid form, comprises a buffering agent.

[0086] The term “Alkalizing agents” as used herein refers to a substance or compound used to increase the pH of the formulation. Examples of suitable alkalizing agent is sodium bicarbonate.

[0087] The term “coloring agent” or “colorants” as used herein refers to a substance added to identity and / or for aesthetic purposes. Suitable coloring agents approved by the U.S. Food and Drug Administration (FDA) include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Yellow No. 10, caramel, ferric oxide and mixtures thereof. The composition of the present invention may contain about 0.00 lwt% to about 5wt% of coloring agent.

[0088] The term “glidant” as used herein refers to substances that improve flowability of a powder. Suitable glidants include, but are not limited to, calcium phosphate tribasic, calcium silicate, cellulose (powdered), colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc, and the like. The composition of the present invention may contain about 0.1wt% to about 5wt% of glidant.

[0089] As used herein, the term “osmogents”, refers to all pharmaceutically acceptable inert water-soluble compounds that can imbibe or dissolve in water and / or aqueous biological fluids. Suitable examples of osmogents or pharmaceutically acceptable inert water-soluble compounds are selected from the group comprising carbohydrates such as xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, dextrose and raffinose; water-soluble salts of inorganic acids such as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithiumdihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodium phosphate tribasic; water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; water-soluble amino acids such as glycine, leucine, alanine, methionine; urea or its derivatives; propylene glycol; glycerin; polyethylene oxide, xanthan gum, hydroxypropylmethyl cellulose; and mixtures thereof. Particularly, the osmogents used in the present invention are xylitol, mannitol, glucose, lactose, sucrose, and sodium chloride. Particularly, the osmogents used in the present invention are xylitol, mannitol, glucose, lactose, sucrose, and sodium chloride. The composition of the present invention may contain about lwt% to about 30wt% of osmogent.

[0090] Suitable suspending agents are selected from the group comprising cellulose derivatives such as co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts / derivatives, and microcrystalline cellulose; carbomers; gums such as locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and mannitol; colloidal silica; and mixtures thereof. The coprocessed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium have been marketed under the trade names Avicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel® CL-611. The composition of the present invention may contain about 0.5wt% to about 50wt% of suspending agent.

[0091] Suitable wetting agents are selected from the group comprising anionic, cationic, nonionic, or zwitterionic surfactants, and combinations thereof. Suitableexamples of wetting agents are sodium lauryl sulphate; cetrimide; polyethylene glycols; polyoxyethylene -poly block copolymers such as poloxamers; poly glycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid esters such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid ester such as polyoxyethylene monostearate; polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; and mixtures thereof. The composition of the present invention may contain about 0.5 wt% to about 50 wt% of wetting agent.

[0092] Suitable chelating agents are selected from the group comprising ethylenediamine tetraacetic acid (EDTA) and its salts, such as, for example, sodium editate, dipotassium ethylenediamine tetraacetate, calcium disodium ethylenediamine tetraacetate, tetrasodium ethylenediamine tetranetate, and mixtures thereof. The composition of the present invention may contain about 0. lwt% to about 10wt% of chelating agent.

[0093] Suitable binders are selected from the group comprising polyvinyl pyrrolidone, starch, pregelatinized starch, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, gums, acrylate polymers, and mixtures thereof. The composition of the present invention may contain about 0.2 wt% to about 30 wt% of binder.

[0094] Suitable glidant are selected from the group comprising Colloidal silicone dioxide, e.g. Aerosil 200, Talc.

[0095] Suitable disintegrant selected from Maize starch, Crospovidone, Croscarmellose sodium, Sodium carboxymethylstarch e.g. Primojel, pregelatinized starch, e.g. Starch 1500 (Sta RX), calcium silicate.

[0096] Suitable lubricants are selected from the group comprising Hydrogenated e.g. ricinoleic, castor oil, e.g. Cutina, magnesium stearate, calcium stearate, zinc stearate, mineral oil, silicone fluid, sodium lauryl sulfate, L-leucine, sodium stearyl fumarate.

[0097] Suitable viscosity modifiers are selected from the group comprising chitosan, acacia, alginic acid bentonite, carbomers, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethyl cellulose, glycerin, gelatin guar gum, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, any other suitable cellulose-based component, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, starch, sodium starch glycolate, starch tragacanth, xanthan gum, and mixtures thereof. The composition of the present invention may contain about 0.2wt% to about 30wt% of viscosity modifiers.

[0098] Suitable emulsifiers include, but are not limited to natural emulsifier, an anionic emulsifier or a nonionic emulsifier. These include, but are not limited to, sodium dodecyl sulfate, Glyceryl Monocaprylocaprate (IMWITOR® 988), sodium octadecyl sulfate, sorbitol anhydrate, Tween (For example, Tween 80), and mixtures thereof. The composition of the present invention may contain about 0.1 wt% to about 30 wt% of emulsifier.

[0099] Suitable plasticizers are selected from the group comprising triethyl citrate, dibutylsebacate, triacetin, acetylated triacetin, tributyl citrate, glyceryl tributyrate, diacetylated monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, andmixtures thereof. The composition of the present invention may contain about 0 wt% to about 20wt% of plasticizers.

[0100] Suitable opacifiers are selected from the group comprising titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and mixtures thereof. The composition of the present invention may contain about 0.1wt% to about 5wt% of opacifier.

[0101] Suitable anti-tacking agents are selected from the group comprising talc, magnesium stearate, calcium stearate, stearic acid, silica, glyceryl monostearate, and mixtures thereof. The composition of the present invention may contain about 0.05 wt% to about 10 wt% of anti-tacking agent.

[0102] Most of these excipients are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986. The surfactants are commercially available and / or can be prepared by techniques known in the art. Two or more surfactants can be used in combination.

[0103] The viscosity of the suspension composition of the present invention ranges from about 1 cps to about 2000 cps. The viscosity of the suspension base of the present invention is measured by using a Brookfield Viscometer having a #2 spindle rotating at 5 rpm at 25° C.

[0104] The pharmaceutical liquid compositions of present application has viscosity ranges from about about 1 cps to about 200cps.

[0105] The pharmaceutical liquid compositions of present application is stable for more than 48 hours at ambient or refrigerated temperature.

[0106] In some embodiments, the pharmaceutical liquid compositions of present application liquid has pH ranging from 5-8.

[0107] The pharmaceutical liquid compositions of present application may be filled into any suitable pharmaceutically acceptable containers. For example, the pharmaceutically acceptable container may be selected from group consisting of bottles and syringes. The bottle can be made of any material convenient with the storage and the use requirements comprising polymers, metal and glass and so on. It is of importance that the bottle material does not interfere with the components of the liquid formulation as disclosed herein. In an embodiment of the disclosure, the pharmaceutically acceptable container is made of glass or Polyethylene Terephthalate (PET). In order to protect the active ingredients from light-induced degradation, a preferred embodiment comprises amber glass bottle.

[0108] In an embodiment, the pharmaceutically acceptable container may be a bottle, wherein the bottle was selected from group consisting of a glass bottle and a plastic bottle. Examples of glass bottle include, but are not limited to Type I, II and III borosilicate glass bottles. In an embodiment, the pharmaceutically acceptable container was a glass bottle, wherein the glass bottle may be amber color glass bottle or clear glass bottle. Examples of plastic bottles include, but are not limited to, high- density polyethylene (HDPE), polyethylene terephthalate (PET) and polypropylene (PP) bottles. In an embodiment, the pharmaceutically acceptable container is a plastic bottle, wherein the plastic bottle may be amber color, white opaque or translucent plastic bottle. In another embodiment, the HDPE bottles will be available in 30, 60, 75, 100, 150, 200, 250 & 500 ml fill volumes.

[0109] The bottle volume is, for example, about 75ml, about 100ml, about 150 mL to about 200 mL, with a formulation volume of about 75-150 ml. An ambercolored bottle has a light transmission of, for example, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% at any wavelength between 290 nm and 450 nm.

[0110] One aspect relates to a bottled product comprising a formulation described herein. In one aspect, the bottled product comprises an amber glass bottle (see DMF No. 14003) with a pharmaceutically acceptable closure (such as a 28 mm Polypropylene TE-CRC cap with EPE liner, see DMF No. 18371).

[0111] Another aspect relates to a container comprising written material and a bottle comprising any one of the formulations disclosed herein. The written material includes, among other things, a description of the formulation and indications for use of the formulation, as summarized below.

[0112] In an embodiment, the pharmaceutical composition of present application is packed in a kit comprising bottle with child resistant cap, dosing syringe adapter and graduated measuring cap or cup.

[0113] In an embodiment, the pharmaceutical composition of present application is packed in single compliant packaging.

[0114] In an embodiment, the pharmaceutical composition of present application is packed in a kit comprising bottle with child resistant cap, dosing syringe and adapter wherein an adaptor has markings for dose adjustment.

[0115] In yet another embodiment, the composition of present invention is immediate release, sustained release, delayed release, controlled release or modified release composition.

[0116] Also provided herein are processes for preparing a Pimavanserin or its pharmaceutically acceptable salts oral liquid formulation. In one aspect, the process comprises the steps.B. Powder composition for reconstitution

[0117] In another embodiment of the present invention provides a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts.

[0118] In yet another embodiment of the present invention provides a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the composition comprises Pimavanserin or its pharmaceutically acceptable salts in an equivalent concentration of Pimavanserin from about 0.001% w / v to about 40 % w / v of the composition. Particularly, the composition comprises Pimavanserin or its pharmaceutically acceptable salts in a concentration from about 0.0067% w / w to about 3.4% w / w of the composition.

[0119] In yet another embodiment of the present invention provides a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the powder is reconstituted into an oral liquid that is stable for at least 48 hours, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 15 months or at least 18 months. More particularly, the composition is stable for at least one month or more, to the extent necessary for the sale and use of the composition.

[0120] In yet another embodiment of the present invention provides a powder composition for reconstitution comprising Pimavanserin or its pharmaceuticallyacceptable salts, wherein the powder is reconstituted into an oral liquid that is stable to the extent that doesn’t require frequent reconstitution.

[0121] In yet another embodiment, a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the powder is reconstituted to form a solution, a suspension, a syrup, a concentrate, an elixir or an emulsion.

[0122] In yet another embodiment, the composition of the present invention can be a liquid composition wherein the liquid is reconstituted to form a solution, a suspension, a syrup, a concentrate, an elixir or an emulsion.

[0123] In yet another embodiment, a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the powder is reconstituted to form a solution that is stable for at least 48 hours, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 15 months or at least 18 months.

[0124] In yet another embodiment, a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the powder is reconstituted to form a suspension that is stable for at least 48 hours, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 15 months or at least 18 months.

[0125] In yet another embodiment, a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the powder is reconstituted to form an emulsion that is stable for at least 48 hours, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 15 months or at least 18 months.

[0126] In yet another embodiment, a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the powder is in the form of dry powder, granules, pellets, slurry or paste.

[0127] The reconstituted liquid compositions of present application has viscosity ranges from about about 1 cps to about 200cps.

[0128] According to another embodiment of the above aspects, the reconstituted liquid compositions is administered through an enteral feeding tube, nasogastric tube, orogastric tube, nasoenteric tube, or oroenteric tube.

[0129] In yet another embodiment, a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the composition is immediate release, sustained release, delayed release, controlled release or modified release composition.

[0130] In yet another embodiment, a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the composition is packaged in a bottle, stick pack or sachets.

[0131] The powder composition for reconstitution of the present invention comprises one or more pharmaceutically acceptable excipient which is selected from the group comprising liquid or semisolid vehicle, surfactants, co-surfactant, solubilizer, stabilizers, pH dependent and independent polymers, ion-exchange resins, adsorbents, steric stabilizer, osmogents, binder, viscosity modifiers, emulsifier, chelating agents, suspending agents, wetting agents, co-solvents, solvents, plasticizer, anti-tacking agent, antioxidants, opacifiers, preservatives,buffering agents, flavoring agents, Flow regulator or glidant, lubricant, Disintegrants, taste masking additives, sweeteners and diluents as described above.

[0132] Also provided herein are processes for preparing a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts. In one aspect, the process comprises the steps

[0133] In some embodiments, the a powder composition for reconstitution comprising Pimavanserin or its pharmaceutically acceptable salts and diluent is provided in a container, for example, a bottle, vial, bag, beaker, syringe, or the like and a liquid vehicle is provided in a separate container.

[0134] Also disclosed herein are processes for preparing a Pimavanserin oral liquid composition in the form of a solution or suspension. In one aspect, the process comprises:(i) providing a powder comprising Pimavanserin (API) and a diluent in a container;(ii) providing a liquid vehicle for reconstitution in a separate container; (iii) adding the entire liquid vehicle to the container holding the API-diluent mixture;(iv) shaking the mixture for a predetermined period; and (v) optionally instructing the patient to shake the bottle well before each use.

[0135] In some embodiments, the powder composition comprising Pimavanserin or a pharmaceutically acceptable salt thereof is provided in a container, and a liquid vehicle along with a diluent is provided in a separate container.

[0136] In other embodiments, the process for preparing a Pimavanserin oral liquid composition comprises:(i) providing a powder comprising Pimavanserin in a container; (ii) providing a liquid vehicle and diluent in a separate container; (iii) adding the entire liquid-diluent mixture to the container holding the API; (iv) shaking the mixture for a predetermined period; and (v) optionally instructing the patient to shake the bottle well before each use.

[0137] In some embodiments, the shaking time is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 seconds. In other embodiments, the shaking time is 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 minutes. In some embodiments, the shaking time ranges from 1 to 10 minutes, or any sub-range thereof.

[0138] Upon shaking the bottle containing the final product, the Pimavanserin powder particles are dispersed throughout the liquid form to provide a homogenous solution for consistent, accurate dosing for the patient. In some embodiments, the liquid form is a suspension.

[0139] Mixing methods encompass any type of mixing that result in a homogenous liquid formulation. In some embodiments, a quantity of API powder is added to a liquid vehicle and then mixed by stirring, shaking, swirling, agitation, inversion, or a combination thereof. In certain instances, a liquid vehicle is added to a quantity of API powder in a container (e.g., a bottle, vial, bag, beaker, syringe, or the like). The container is then mixed by stirring, shaking, swirling, agitation, inversion, or a combination thereof. In certain instances, a fractional volume of the liquid vehicle (e.g., one-half, one-third, one-fourth volume, etc.) is added to an API powder, mixed by stirring, shaking, swirling, agitation, inversion, or a combination thereof; and, the subsequent liquid fraction(s) is added and mixed.

[0140] In some embodiments, the diluent of the present disclosure comprises a powder mixture of a surfactant, a viscosity building / suspending agent, a buffering agent, a sweetener, a flavoring agent, a coloring agent or a preservative.

[0141] In some embodiments, the diluent comprises one or more of the Sorbitol, Neotame, Xanthan Gum, Colloidal silicon dioxide, Peppermint flavor, Sodium bicarbonate and Potassium sorbate.

[0142] Upon reconstitution, the liquid formulations of the invention have, for example, 30-day stability at refrigerated storage conditions or ambient temperature. The liquid formulations of the invention have improved palatability compared to commercially available formulations, and when compared to previously described oral formulations or reconstituted formulations. The liquid formulations of the invention have improved homogeneity when compared to commercially available liquid formulations. The liquid formulations of the invention have optimized viscosity to reduce agglomeration and adherence of the product to the container.

[0143] The formulations of the present invention does not require frequent reconstitution. In another aspect of the present invention, there is provided a multi-dose reconstitutable oral liquid composition comprising:a) a powder composition containing:Pimavanserin or a pharmaceutically acceptable salt thereof (e.g., Pimavanserin tartrate);A diluent selected from sorbitol, neotame, xanthan gum, colloidal silicon dioxide, sodium bicarbonate, potassium sorbate, flavoring agent, thickener, stabilizer, sweetener, preservative or combinations thereof; and wherein the powder composition is present in a bulk amount sufficient to provide multiple (e.g., 10-50) oral doses upon reconstitution.b) a predetermined volume of liquid vehicle.

[0144] In some embodiments, the contents of a and b are provided in a separate container and are combined at the time of use to produce a homogeneous solution or suspension of Pimavanserin suitable for multiple dosing.

[0145] In some embodiments, the total volume after reconstitution is at least 50 mL, at least 75 mL, at least 100 mL, at least 120 mL, or at least 150 mL, and provides multiple doses, each accurately withdrawn using a dosing syringe.

[0146] In some embodiments, the total volume after reconstitution is 121 mL, 105 mL or 80mL.

[0147] In some embodiments, the reconstituted liquid exhibits stability for at least 60 days, permitting storage without repeated reconstitution.

[0148] In some embodiments, the reconstituted liquid is stable for more than 48 hours at ambient or refrigerated temperature, permitting storage without repeated reconstitution.

[0149] In some embodiments, the reconstituted liquid has pH ranging from 5- 8.

[0150] In certain embodiments, a multidose reconstitutable Pimavanserin oral liquid composition is provided, formulated to deliver 30 oral doses after reconstitution.

[0151] In certain embodiments, the individual dose to be administered is 1.5 mL, 3.5 mL or 2.7 mL of the reconstituted composition.C. Orally dispersible tablet

[0152] In another embodiment of the present invention provides an orally dispersible tablet comprising Pimavanserin or its pharmaceutically acceptable salts.

[0153] In yet another embodiment of the present invention provides an orally dispersible tablet comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the composition comprises Pimavanserin or its pharmaceutically acceptable salts in an equivalent concentration of Pimavanserin from about 0.001 % w / v to about 40 % w / v of the composition. Particularly, the composition comprises Pimavanserin or its pharmaceutically acceptable salts in a concentration from about 0.0067% w / w to about 34% w / w of the composition.

[0154] In yet another embodiment of the present invention provides an orally dispersible tablet comprising Pimavanserin or its pharmaceutically acceptable salts, wherein an orally dispersible tablet is stable for at least 48 hours, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 15 months or at least 18 months. More particularly, the composition is stable for at least one month or more, to the extent necessary for the sale and use of the composition.

[0155] In yet another embodiment of the present invention provides an orally dispersible tablet comprising Pimavanserin or its pharmaceutically acceptable salts, wherein an orally dispersible tablet is capable of dispersible with a small amount of fluid, having a rapid disintegration time, and being maintained stably in a tablet form.

[0156] In yet another embodiment, an orally dispersible tablet comprising Pimavanserin or its pharmaceutically acceptable salts, wherein the composition isimmediate release, sustained release, delayed release, controlled release or modified release composition.

[0157] The orally dispersible tablet of the present invention comprises one or more pharmaceutically acceptable excipient which is selected from the group comprising liquid or semisolid vehicle, surfactants, co-surfactant, solubilizer, stabilizers, pH dependent and independent polymers, ion-exchange resins, adsorbents, steric stabilizer, osmogents, binder, viscosity modifiers, emulsifier, chelating agents, suspending agents, wetting agents, co-solvents, solvents, plasticizer, anti-tacking agent, antioxidants, opacifiers, preservatives, buffering agents, flavoring agents, Flow regulator or glidant, lubricant, Disintegrants, taste masking additives, sweeteners and diluents as described above.

[0158] Also provided herein are processes for preparing an orally dispersible tablet comprising Pimavanserin or its pharmaceutically acceptable salts. In one aspect, the process comprises the steps

[0159] According to the present invention, it has become possible to provide an orally dispersible tablet that is capable of dispersible with a small amount of water, having a rapid disintegration time, and being maintained stably in a tablet form, which could not be achieved by conventional procedures.

[0160] There is no particular limitation to the tableting method for an orally dispersible tablet provided according to the present invention, as long as the tablet exerts the effects of the invention. Examples of the tableting method that can be used in the present invention include a direct compression method, a dry indirect compression method, and a wet indirect compression method.

[0161] An orally dispersible tablet provided by the present invention is shaped using, for example, a single-punch tableting machine, a rotary tableting press, or the like. Although there is no particular limitation to the shape of solid formulations according to the present invention, the tablet may be round, caplet, doughnut, oblong, and the like, may be multilayered, cored, and the like, and can be further coated with a coating agent. Optionally, the tablet may be provided with distinguishing characters, symbols, or marks, and may be provided with a dividing line so that the tablet can be divided.

[0162] Although there is no particular limitation, the orally dispersible tablet according to the present disclosure may have a tablet hardness of about 15 to 70 N, about 20 to 60 N, or about 30 to 60 N. Moreover, the orally dispersible tablet according to the present disclosure preferably has a disintegration time of 70 seconds or less, and more preferably 65 seconds or less, 60 seconds or less, 55 seconds or less, 50 seconds or less, 45 seconds or less, 40 seconds or less, 35 seconds or less, 30 seconds or less, 25 seconds or less, or 20 seconds or less.

[0163] The tablet hardness is a value obtained by measuring the hardness in the diametrical direction of the tablet with a tablet hardness tester (e.g., MultiTest 50 (Pharmatron)). The disintegration time is a value obtained by measurement by the test (temperature setting: 37° C.±2.0° C., test liquid: water) for immediate-release preparations (plain tablets) described in 6.09 Disintegration Test of the General Tests, Processes and Apparatus section of the Japanese Pharmacopoeia, Seventeenth Edition. For example, a disintegration Lester NT-200 (Toyama Sangyo Co., Ltd.) can be used for this measurement.

[0164] In another embodiment, the pharmaceutical compositions of the present invention are stable when stored under storage conditions. The term “storage conditions” as used herein without limitation include typical storage conditions suchas 2° C.-8° C., 30° C.±2° C. / 65±5% RH, 25° C.±2° C. / 60±5% RH, and accelerated conditions such as 40° C. ±2° C. / 75±5% RH.EXEMPLARY EMBODIMENTS:

[0165] The exemplary embodiments described herein are provided to illustrate the principles of the invention and its practical applications. These embodiments are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Various modifications, substitutions, and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.1. An oral liquid pharmaceutical composition comprising:(a) pimavanserin or a pharmaceutically acceptable salt thereof;(b) a liquid vehicle; and(c) one or more pharmaceutically acceptable excipients;wherein the composition is stable for more than 48 hours at ambient or refrigerated temperature.2. The oral liquid pharmaceutical composition of aspect 1, wherein the composition is selected from an aqueous solution, a non-aqueous solution, a suspension, a syrup, a concentrate, an elixir, or an emulsion.3. The oral liquid pharmaceutical composition of aspect 1, wherein the one or more pharmaceutically acceptable excipients are selected from surfactants, co-surfactants, solubilizers, stabilizers, pH-dependent polymers, pH-independent polymers, ion-exchange resins, adsorbents, osmogents, buffering agents, emulsifiers, suspending agents, wetting agents, chelating agents, preservatives,antioxidants, sweeteners, flavoring agents, viscosity modifiers, plasticizers, opacifiers, and anti-tacking agents.4. The oral liquid pharmaceutical composition of aspect 3, wherein the buffering agent is selected from citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium bicarbonate, or combinations thereof.5. The oral liquid pharmaceutical composition of claim 3, wherein the preservative is selected from methyl paraben, propyl paraben, sodium benzoate, potassium sorbate, sodium metabisulfite, sodium bisulfite, benzyl alcohol, ascorbic acid, or combinations thereof.6. The oral liquid pharmaceutical composition of aspect 3, wherein the sweetener is selected from sucrose, glucose, fructose, xylitol, sorbitol, mannitol, maltitol, isomaltulose, lactitol, erythritol, sucralose, acesulfame potassium, aspartame, neotame, saccharin, stevia extract, or combinations thereof.7. The oral liquid pharmaceutical composition of aspect 3, wherein the flavoring agent is selected from peppermint, orange, banana, strawberry, cherry, grape, vanilla, or combinations thereof.8. The oral liquid pharmaceutical composition of aspect 3, wherein the suspending or viscosity-modifying agent is selected from xanthan gum, sodium carboxymethyl cellulose, microcrystalline cellulose, carbomers, pectin, guar gum, or combinations thereof.9. The oral liquid pharmaceutical composition of aspect 3, wherein the chelating agent is sodium editate.10. The oral liquid pharmaceutical composition of aspect 1, wherein the liquid vehicle comprises one or more of water, alcohol, glycerin, propylene glycol, polyethylene glycol, vegetable oil, medium chain triglycerides, long chain triglycerides, or combinations thereof.11. The oral liquid pharmaceutical composition of aspect 1, wherein the composition comprises a hydroalcoholic system comprising ethanol in an amount of about 5 wt% to about 80 wt%.12. A powder formulation suitable for reconstitution with a pharmaceutically acceptable vehicle, comprising: (a) pimavanserin or a pharmaceutically acceptable salt thereof; and (b) optionally, at least one pharmaceutically acceptable excipient;wherein, upon mixing with the pharmaceutically acceptable vehicle, the powder forms a reconstituted oral liquid that is stable for more than 48 hours under ambient or refrigerated conditions.13. The powder formulation of aspect 12, wherein the pharmaceutically acceptable excipient is selected from diluents, surfactants, co-surfactants, solubilizers, stabilizers, pH-dependent polymers, pH-independent polymers, ion-exchange resins, adsorbents, osmogents, emulsifiers, suspending agents, wetting agents, buffering agents, chelating agents, preservatives, antioxidants, sweeteners, flavoring agents, viscosity modifiers, plasticizers, opacifiers, and anti-tacking agents or combinations thereof.14. The powder formulation of aspect 13, wherein the sweetener is selected from sucrose, glucose, fructose, xylitol, sorbitol, mannitol, maltitol, isomaltulose, lactitol, erythritol, sucralose, acesulfame potassium, aspartame, neotame, saccharin, stevia extract, or combinations thereof.15. The powder formulation of aspect 13, wherein the preservative is selected from methyl paraben, propyl paraben, sodium benzoate, potassium sorbate, sodium metabisulfite, sodium bisulfite, benzyl alcohol, ascorbic acid, or combinations thereof.16. The powder formulation of aspect 14, wherein the sweetener is neotame and is present in an amount from about 0.01% to about 5% w / w.17. The powder formulation of aspect 15, wherein the preservative is potassium sorbate and is present in an amount from about 0.1% to about 10% w / w.18. The powder formulation of aspect 13, wherein the diluent is selected from sorbitol, mannitol, lactose, microcrystalline cellulose, or combinations thereof.19. The powder formulation of aspect 13, wherein the suspending agent is selected from xanthan gum, sodium carboxymethyl cellulose, microcrystalline cellulose, carbomers, pectin, guar gum, or combinations thereof.20. The powder formulation of aspect 13, wherein the viscosity-modifying agent is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carbomers, sodium carboxymethyl cellulose, or xanthan gum.21. The powder formulation of aspect 13, wherein the buffering agent is selected from citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium bicarbonate, or combinations thereof.22. The powder formulation of aspect 13, wherein the flavoring agent is selected from peppermint, orange, banana, strawberry, cherry, grape, vanilla, or combinations thereof.23. The powder formulation of aspect 12, wherein the pharmaceutically acceptable vehicle is selected from purified water, aqueous vehicles, alcohol, non-aqueous vehicles, or mixtures thereof.24. The powder formulation of aspect 12, wherein the powder is reconstituted with an aqueous vehicle to form a solution, suspension, or emulsion.25. The powder formulation of aspect 12, wherein the powder is in the form of a dry powder, granules, pellets, slurry, or paste.26. The powder formulation as claimed in aspect 12, wherein the reconstituted oral liquid is prepared by a process comprising: (i) providing the powder formulation in a container; (ii) adding a predetermined volume of a pharmaceutically acceptable liquid vehicle to the container; and (iii) shaking or mixing the container for a predetermined period to obtain a homogeneous oral liquid suitable for multi-dose administration.27. The powder formulation of aspect 12, wherein the powder is packaged together with a predetermined volume of liquid vehicle in a multi-dose reconstitution kit.28. The powder formulation of aspect 12, wherein the reconstituted oral liquid provides 1.5mL, 2.7 mL or 3.5 mL per dose corresponding to a unit dose of 34 mg pimavanserin.29. The powder formulation of aspect 12, wherein the reconstituted oral liquid is suitable for multi-dose storage.30. The powder formulation of aspect 12, wherein the pimavanserin is present as pimavanserin tartrate.31. A kit for preparing a reconstituted oral liquid formulation, comprising:(a) a first container holding a powder formulation suitable for reconstitution with a pharmaceutically acceptable vehicle, the powder formulation comprising:(i) pimavanserin or a pharmaceutically acceptable salt thereof; and (ii) optionally, at least one pharmaceutically acceptable excipient;(b) a second container holding a pre-measured pharmaceutically acceptable vehicle for reconstitution;wherein, upon mixing the powder formulation with the pharmaceutically acceptable vehicle, a reconstituted oral liquid is formed that is stable for more than 48 hours under ambient or refrigerated conditions.32. The kit according to aspect 31, wherein at least one pharmaceutically acceptable excipient is selected from diluents, surfactants, co-surfactants, solubilizers, stabilizers, pH-dependent polymers, pH-independent polymers, ion-exchange resins, adsorbents, osmogents, emulsifiers, suspending agents, wetting agents, chelating agents, preservatives, antioxidants, sweeteners, flavoring agents, viscosity modifiers, plasticizers, opacifiers, and anti-tacking agents or combinations thereof.33. The kit according to aspect 31, wherein the powder formulation comprises one or more excipients selected from sorbitol, neotame, xanthan gum, colloidal silicon dioxide, peppermint flavor, sodium bicarbonate, potassium sorbate,microcrystalline cellulose, sodium carboxymethyl cellulose, mannitol, sodium stearyl fumarate, or combinations thereof.34. The kit according to aspect 31 , wherein the pharmaceutically acceptable vehicle is selected from purified water, aqueous vehicles, alcohol, non-aqueous vehicles, or mixtures thereof.35. The kit according to aspect 31, wherein the powder is reconstituted with an aqueous vehicle to form a solution, suspension, or emulsion.36. The kit according to aspect 31, wherein the reconstituted oral liquid provides 1.5mL, 2.7 mL or 3.5 mL per dose corresponding to a unit dose of 34 mg pimavanserin.37. The kit according to aspect 31, wherein the kit further comprises a child-resistant cap, adapter, dosing syringe and graduated measuring cap or cup.38. The kit of aspect 31, wherein the reconstituted oral liquid is suitable for multi-dose storage.39. The kit according to any of the preceding aspects, wherein the reconstituted oral liquid is used for treating psychosis associated with Parkinson’s disease in a human subject.40. The kit according to aspect 39, wherein the psychosis comprises hallucinations and delusions associated with Parkinson’s disease.41. The kit according to aspect 31 , wherein the pimavanserin is present as pimavanserin tartrate.42. A powder composition for reconstitution into an oral liquid, the composition comprising:a) pimavanserin tartrate;b) at least one sweetener;c) at least one preservative; andd) optionally, one or more pharmaceutically acceptable excipients selected from diluents, stabilizers, suspending agents, viscosity-modifying agents, buffering agents, flavoring agents, coloring agents, surfactants, solubilizers, glidants, lubricants, disintegrants, or combinations thereof.43. The powder composition of aspect 42, wherein the sweetener is selected from sucrose, glucose, fructose, xylitol, sorbitol, mannitol, maltitol, isomaltulose, lactitol, erythritol, sucralose, acesulfame potassium, aspartame, neotame, saccharin, stevia extract, or combinations thereof.44. The powder composition of aspect 42, wherein the preservative is selected from methyl paraben, propyl paraben, sodium benzoate, potassium sorbate, sodium metabisulfite, sodium bisulfite, benzyl alcohol, ascorbic acid, or combinations thereof.45. The powder composition of aspect 43, wherein the sweetener is neotame and is present in an amount from about 0.01% to about 5% w / w.46. The powder composition of aspect 44, wherein the preservative is potassium sorbate and is present in an amount from about 0.01% to about 10% w / w.47. The powder composition of aspect 42, wherein the at least one pharmaceutically acceptable excipient comprises a diluent selected from sorbitol, mannitol, lactose, microcrystalline cellulose, or combinations thereof.48. The powder composition of aspect 42, wherein the at least one pharmaceutically acceptable excipient comprises a suspending agent selected from xanthan gum, sodium carboxymethyl cellulose, microcrystalline cellulose, carbomers, pectin, guar gum, or combinations thereof.49. The powder composition of aspect 42, wherein the at least one pharmaceutically acceptable excipient comprises a viscosity-modifying agent selected from hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carbomers, or xanthan gum.50. The powder composition of aspect 42, wherein the at least one pharmaceutically acceptable excipient comprises a buffering agent selected from citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium bicarbonate, or combinations thereof.51. The powder composition of aspect 42, wherein the at least one pharmaceutically acceptable excipient comprises a flavoring agent selected from peppermint, orange, banana, strawberry, cherry, grape, vanilla, or combinations thereof.52. The powder composition of aspect 42, wherein the powder composition is reconstitutable into a solution, suspension, or emulsion.53. The powder composition of aspect 42, wherein pimavanserin tartrate is present in an amount from about 2% to about 15% w / w.The powder composition according to aspect 42, wherein the powder is present in a bulk quantity sufficient to provide 30 individual unit doses of pimavanserin upon reconstitution.The powder composition according to aspect 42, wherein the reconstituted oral liquid is stable for more than 48 hours under ambient or refrigerated conditions.An orally dispersible tablet comprising:a) pimavanserin or a pharmaceutically acceptable salt thereof;b) at least one sweetener;c) at least one disintegrant; andd) one or more pharmaceutically acceptable excipients selected from diluents, binders, lubricants, glidants, stabilizers, viscosity-modifying agents, buffering agents, surfactants, flavoring agents, or coloring agents;wherein the tablet rapidly disperses in the presence of a small amount of fluid to form a homogeneous dispersion suitable for oral administration.The orally dispersible tablet of aspect 56, wherein the pharmaceutically acceptable salt of Pimavanserin is Pimavanserin tartrate.The orally dispersible tablet of aspect 56, wherein the at least one sweetener is selected from sucrose, xylitol, mannitol, sorbitol, maltitol, sucralose, acesulfame potassium, aspartame, neotame, stevia extract, or combinations thereof.The orally dispersible tablet of aspect 56, wherein the disintegrant is selected from sodium starch glycolate, crospovidone, croscarmellose sodium, pregelatinized starch, or combinations thereof.60. The orally dispersible tablet of aspect 56, wherein the diluent is selected from microcrystalline cellulose, mannitol, lactose, or combinations thereof.61. The orally dispersible tablet of aspect 56, wherein the binder is selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, or starches.62. The orally dispersible tablet of aspect 56, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, or glyceryl behenate.63. The orally dispersible tablet of aspect 56, wherein the glidant is colloidal silicon dioxide.64. The orally dispersible tablet of aspect 56, wherein the viscosity-modifying agent is selected from hydroxypropyl methylcellulose, xanthan gum, carbomers, or hydroxyethyl cellulose.65. The orally dispersible tablet of aspect 56, further comprising a flavoring agent selected from peppermint, orange, strawberry, banana, cherry, grape, vanilla, or combinations thereof.66. The orally dispersible tablet of aspect 56, wherein the tablet has a disintegration time of 30 seconds or less.EXAMPLES:

[0166] The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.• General assay procedure:

[0167] Analytical methods for the determination of Pimavanserin tartrate and its degradation products using high performance liquid chromatography (HPLC) is provided. The assay employs Pimavanserin tartrate reference standard and utilizes HPLC systems equipped with UV detectors. The chromatographic separation is achieved using a column maintained at 30°C with a flow rate of 1.5 mL / min, injection volume of 5 pL, detection wavelength of 230 nm, and a run time of 15 minutes. The mobile phase comprises buffer preparation, acetonitrile, and triethylamine in ratios of 700:300:2 (Phase A) and 300:700:2 (Phase B), adjusted to pH 2.50 ± 0.02 with diluted orthophosphoric acid. Diluent is prepared as a 500:500 v / v mixture of water and acetonitrile, sonicated for degassing, and used for blank, standard, and sample preparations. Standard solutions are prepared by dissolving 39 mg of Pimavanserin tartrate (equivalent to 34 mg Pimavanserin) in diluent to yield a concentration of 680 g / mL. Sample solutions and blend powders equivalent to 34 mg Pimavanserin are similarly prepared, sonicated at controlled temperature (20-25°C), equilibrated to room temperature, diluted to volume, and filtered through 0.45 pm nylon filters.

[0168] The degradation product analysis employs Pimavanserin tartrate standard and HPLC equipped with UV detection at 210 nm. Chromatographic separation is performed using an column maintained at 45°C. The buffer preparation consists of 1.36 g potassium dihydrogen orthophosphate and 2.0 g 1 -octane sulphonic acid sodium salt dissolved in 1000 mL milli-Q water, adjusted to pH 3.00 ± 0.02 with diluted orthophosphoric acid. Mobile phase A comprises 100% buffer, while mobilephase B consists of acetonitrile, methanol, and water in the ratio 50:40: 10 v / v. Diluent is prepared as a 500:500 v / v mixture of water and acetonitrile and used for blank, standard, placebo, and sample preparations. Standard solutions are prepared by dissolving 23 mg Pimavanserin tartrate (equivalent to 20 mg Pimavanserin) in diluent, followed by serial dilution to yield a final concentration of 2 pg / mL. Placebo and sample preparations equivalent to 34 mg Pimavanserin or placebo powder are dissolved in diluent, sonicated at controlled temperature (20-25 °C), equilibrated to room temperature, diluted to volume, and filtered through filters.• Formulation details:A. Oral liquid compositionExample 1: Aqueous Solution CompositionExample 2: Oral Liquid FormulationExample 3: Oral Liquid FormulationExample 4: Oral Liquid FormulationExample 5: Oral Liquid FormulationExample 6: Oral Liquid FormulationExample 7: Oral Liquid FormulationExample 8: Oral Liquid FormulationExample 9: Oral Liquid FormulationExample 10: Oral Liquid suspensionExample 11: Oral Liquid Formulation- SuspensionExample 12: Oral Liquid Formulation- SuspensionExample 13: Oral Liquid Formulation- EmulsionExample 14: Oral liquid formulation (Non-aqueous)Example 15: Oral liquid formulation (Non-aqueous)• Stability study: Degradation Products for Pima vanserin Oral liquid formulation (Non-aqueous)Example 16: Oral liquid formulation (Non-aqueous)Stability study: Degradation Products for Pima vanserin Oral liquid formulation (Non-aqueous)Example 17: Oral liquid formulation (Non-aqueous)• Stability study: Degradation Products for Pima vanserin Oral liquid formulation (Non-aqueous)The formulations exhibit significantly reduced degradation, maintain assay integrity, and keep total impurities within acceptable limits, even under stressed storage conditions.B. Powder for reconstitution composition:Example 18: Oral powder for suspensionExample 19: Oral powder for solutionExample 20: Oral Powder for SuspensionExample 21: Oral emulsion for reconstitutionExample 22: Powder for reconstitution for oral liquida) Powder composition:b) Liquid vehicle:c) Reconstitution and unit dose administration• To be reconstituted with Liquid vehicle and individual unit dose of 34mg Pimavanserin.Example 23: Powder for reconstitution for oral liquida) Powder composition:b) Liquid vehicle:c) Reconstitution and unit dose administration• To be reconstituted with Liquid vehicle and individual unit dose contain 34mg Pimavanserin.Example 24: Powder for reconstitution for oral liquida) Powder composition:b) Liquid vehicle:c) Reconstitution and unit dose administrationTo be reconstituted with Liquid vehicle and individual unit dose contain 34mg Pimavanserin.Example 25: Powder for reconstitution for oral liquidBrief Procedure:1) Sift sorbitol through suitable sieve. Mix it with Simethicone emulsion, colloidal silicon dioxide and Pimavanserin Tartrate using geometric mixing and Sift all materials through suitable sieve.2) Mix together potassium sorbate, Neotame, Xanthan gum, and peppermint flavor. Mix it with step 1 and sift through suitable sieve. Mix the blend in bin-blender.3) Fill the final blend into glass bottles.4) Reconstitute the filled powder with sufficient quantity of water.• Stability Study: In Use Degradation Product DataExample 26: Powder for reconstitution for oral liquidBrief Procedure:1) Sift sorbitol through suitable sieve. Mix it with Simethicone emulsion, colloidal silicon dioxide and Pimavanserin Tartrate using geometric mixing and Sift all materials through suitable sieve.2) Mix together potassium sorbate, Neotame, Xanthan gum, and peppermint flavor. Mix it with step 1 and sift through suitable sieve. Mix the blend in bin-blender.3) Fill the final blend into glass bottles.4) Reconstitute the filled powder with sufficient quantity of water.• Stability Study: In Use Degradation Product DataExample 27: Powder for reconstitution for oral liquidBrief Procedure:1) Mix Pearlitol 100 SD, Sucralose, and Lemon Flavour and sift through suitable sieve.2) Mix Pimavanserin Tartrate with step 1 material and sift through suitable sieve.3) Fill the blend in glass bottle.4) Reconstitute the filled powder with sufficient quantity of water.• Stability Study: Degradation Product DataExample 28: Powder for reconstitution for oral liquidBrief Procedure:Example 29: Powder for reconstitution for oral liquidBrief Procedure:1 ) Mix Sorbitol, Sucralose, and Lemon Flavour and sift through # 30 S.S sieve.2) Mix Pimavanserin Tartrate with step 1 and sift through #30 S.S sieve ensuring uniform blending.3) Fill the blend in glass bottle and seal it.4) Reconstitute the filled powder with sufficient quantity of water.• Stability Study: Degradation Product DataExample 30: Powder for reconstitution for oral liquid• Stability Study: Degradation Product Data for Pima vanserin Powder for Oral liquid Formulation (Stored in Amber colored glass bottle)• Stability Study: In Use Degradation Product DataExample 31: Powder for reconstitution for oral liquida) Powder composition:a) Liquid vehicle:b) Reconstitution and unit dose administrationTo be reconstituted with Liquid vehicle and individual unit dose of 34mg Pimavanserin.Example 32: Powder for reconstitution for oral liquidb) Powder composition:d) Reconstitution and unit dose administrationTo be reconstituted with Liquid vehicle and individual unit dose of 34mg Pimavanserin.Example 33: Powder for reconstitution for oral liquidBrief procedure:1) Dissolve Pimavanserin tartrate in sufficient quantity of water and add sodium bicarbonate to it until above pH 7 is achieved. Keep it overnight to achieve complete precipitation.2) Keep the precipitate for drying in vacuum tray dryer to get LOD less than 3%3) Mix all the excipients with above dried precipitate and reconstitute it with 50 ml purified water4) The pH is 7.14Example 34: Powder for reconstitution for oral liquidBrief procedure:1) Dissolve Pimavanserin tartrate in sufficient quantity of water and add sodium bicarbonate to it until above pH 7 is achieved. Keep it overnight to achieve complete precipitation.2) Keep the precipitate for drying in vacuum tray dryer to get LOD less than 3%3) Mix all the excipients with above dried precipitate and reconstitute it with 50 ml purified water4) The pH is 7.23.Accordingly, the above stability data establish that pimavanserin Powder for reconstitution for oral liquid exhibit markedly enhanced chemical stability and display significantly reduced degradation, improved assay retention, and robust performance across long-term and accelerated conditions.C. Oral dispersible tabletExample 35: Orally dispersible Tablet formulationExample 36: Naso-gastric tube compatibility Study Data:Assay data for reconstituted oral liquid formulation of passed through Nasogastric Tube.The nasogastric (NG) tube compatibility assessment conducted using the reconstituted oral liquid formulation containing a 34-mg unit dose of pimavanserin demonstrates thatthe formulation maintains assay integrity following passage through an 8 Fr feeding tube.The assay result obtained (101.2%) remains well within the established acceptance criteria of 90.0% to 110.0%, confirming that no significant loss of drug substance occurs due to adsorption, retention, or interaction with the tube material.These findings indicate that the reconstituted formulation is compatible with standard nasogastric administration pathways, and that the drug product retains its potency following transit through commonly used feeding tube systems.The data further support that the formulation does not undergo measurable degradation or binding to the tubing surface, ensuring accurate dose delivery in patients requiring enteral administration.Example 37: study to assess the palatability and swallowability of pimavanserin when mixed with liquid vehicle in adultsStudies are conducted on 12 adult subjects to evaluate the palatability of pimavanserin when mixed with liquid vehicle. Out of 12 adult subjects, 11 found the formulation to be extremely pleasant and one adult subjects found moderately pleasant. The vehicle was water. Therefore, the formulations were found to be palatable. The details summarized in below table:& &

Claims

CLAIMS:

1. An oral liquid pharmaceutical composition comprising:(a) pimavanserin or a pharmaceutically acceptable salt thereof;(b) a liquid vehicle; and(c) one or more pharmaceutically acceptable excipients;wherein the composition is stable for more than 48 hours at ambient or refrigerated temperature.

2. The oral liquid pharmaceutical composition of claim 1, wherein the composition is selected from an aqueous solution, a non-aqueous solution, a suspension, a syrup, a concentrate, an elixir, or an emulsion.

3. The oral liquid pharmaceutical composition of claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from surfactants, co-surfactants, solubilizers, stabilizers, pH-dependent polymers, pH-independent polymers, ion-exchange resins, adsorbents, osmogents, buffering agents, pH modifiers, alkalizing agents, emulsifiers, suspending agents, wetting agents, chelating agents, preservatives, antioxidants, sweeteners, flavoring agents, colorants, solvents, co-solvents, viscosity modifiers, plasticizers, opacifiers, and anti-tacking agents.

4. The composition of claim 1, wherein the excipients comprise one or more of: (a) buffering agents and pH modifiers selected from citric acid, sodium citrate, tartaric acid, sodium tartrate, or sodium bicarbonate, sodium hydroxide.(b) preservatives selected from methyl paraben, propyl paraben, sodium benzoate, potassium sorbate, sodium metabisulfite, sodium bisulfite, benzyl alcohol, or ascorbic acid;(c) sweeteners selected from sucrose, glucose, sorbitol, xylitol, mannitol, maltitol, sucralose, acesulfame potassium, aspartame, neotame, saccharin, or stevia extract; and(d) flavoring agents selected from peppermint, orange, banana, bubblegum, strawberry, cherry, grape, or vanilla.

5. The oral liquid pharmaceutical composition of claim 1, wherein the composition comprises a hydroalcoholic system comprising ethanol in an amount of about 5 wt% to about 80 wt%.

6. A powder formulation suitable for reconstitution with a pharmaceutically acceptable vehicle, comprising:(a) pimavanserin or a pharmaceutically acceptable salt thereof; and(b) optionally, at least one pharmaceutically acceptable excipient; wherein, upon mixing with the pharmaceutically acceptable vehicle, the powder forms a reconstituted oral liquid that is stable for more than 48 hours under ambient or refrigerated conditions.

7. The powder formulation of claim 6, wherein the pharmaceutically acceptable excipient is selected from diluents, surfactants, co-surfactants, solubilizers, stabilizers, pH-dependent polymers, pH-independent polymers, ion-exchange resins, adsorbents, osmogents, emulsifiers, suspending agents, wetting agents, buffering agents, pH modifiers, chelating agents, preservatives, antioxidants, sweeteners, flavoring agents, viscosity modifiers, plasticizers, opacifiers, colorants and anti-tacking agents or combinations thereof.

8. The powder formulation of claim 6, wherein the excipients comprise one or more of:(a) sweeteners selected from sucrose, glucose, fructose, xylitol, sorbitol, mannitol, maltitol, isomaltulose, lactitol, erythritol, sucralose, acesulfame potassium, aspartame, neotame, saccharin, stevia extract, or combinations thereof;(b) preservatives selected from methyl paraben, propyl paraben, sodium benzoate, potassium sorbate, sodium metabisulfite, sodium bisulfite, benzylalcohol, or ascorbic acid;(c) diluents selected from sorbitol, mannitol, lactose, microcrystalline cellulose, or combinations thereof; and(d) suspending or viscosity-modifying agents selected from xanthan gum, sodium carboxymethyl cellulose, microcrystalline cellulose, carbomers, pectin, guar gum, hydroxypropyl cellulose, hydroxyethyl cellulose, or hydroxypropyl methylcellulose.

9. The powder formulation as claimed in claim 6, wherein the reconstituted oral liquid is prepared by a process comprising:(i) providing the powder formulation in a container;(ii) adding a predetermined volume of a pharmaceutically acceptable liquid vehicle to the container; and(iii) shaking or mixing the container for a predetermined period to obtain a homogeneous oral liquid suitable for multi-dose administration.

10. The powder formulation of claim 6, wherein the reconstituted oral liquid provides 1.5 ml. 2.7 mL or 3.5 mL per dose corresponding to a unit dose of 34 mg pimavanserin.

11. The powder formulation of claim 6, wherein the pimavanserin is present as pimavanserin tartrate.

12. A kit for preparing a reconstituted oral liquid formulation, comprising:(a) a first container holding a powder formulation suitable for reconstitution with a pharmaceutically acceptable vehicle, the powder formulation comprising: (i) pimavanserin or a pharmaceutically acceptable salt thereof; and (ii) optionally, at least one pharmaceutically acceptable excipient;(b) a second container holding a pre-measured pharmaceutically acceptable vehicle for reconstitution;wherein, upon mixing the powder formulation with the pharmaceutically acceptable vehicle, a reconstituted oral liquid is formed that is stable for more than 48 hours under ambient or refrigerated conditions.

13. The kit according to claim 12, wherein at least one pharmaceutically acceptable excipient is selected from diluents, surfactants, co-surfactants, solubilizers, stabilizers, pH-dependent polymers, pH-independent polymers, ion-exchange resins, adsorbents, osmogents, emulsifiers, suspending agents, wetting agents, pH modifiers, chelating agents, preservatives, antioxidants, sweeteners, flavoring agents, viscosity modifiers, plasticizers, opacifiers, and anti-tacking agents or combinations thereof.

14. The kit according to claim 12, wherein the powder formulation comprises one or more excipients selected from sorbitol, neotame, xanthan gum, colloidal silicon dioxide, peppermint flavor, sodium bicarbonate, potassium sorbate, microcrystalline cellulose, sodium carboxymethyl cellulose, mannitol, sodium stearyl fumarate, or combinations thereof.

15. The kit according to claim 12, wherein the kit further comprises a child-resistant cap, adapter, dosing syringe and graduated measuring cap or cup.

16. A powder composition for reconstitution into an oral liquid, the composition comprising:a) pimavanserin or a pharmaceutically acceptable salt thereof;b) at least one sweetener; andc) optionally, one or more pharmaceutically acceptable excipients selected from diluents, stabilizers, suspending agents, viscosity-modifying agents, buffering agents, pH modifier, flavoring agents, coloring agents, surfactants, solubilizers, glidants, lubricants, disintegrants, or combinations thereof.

17. The powder composition of claim 16, wherein the sweetener is selected from sucrose, glucose, fructose, xylitol, sorbitol, mannitol, maltitol, isomaltulose, lactitol, erythritol, sucralose, acesulfame potassium, aspartame, neotame, saccharin, stevia extract, or combinations thereof.

18. The powder composition of claim 16, wherein the preservative is selected from methyl paraben, propyl paraben, sodium benzoate, potassium sorbate, sodium metabisulfite, sodium bisulfite, benzyl alcohol, ascorbic acid, or combinations thereof.

19. The powder composition of claim 16, wherein the at least one pharmaceutically acceptable excipient comprises one or more of:(a) diluents selected from sorbitol, mannitol, lactose, microcrystalline cellulose, or combinations thereof;(b) suspending agents selected from xanthan gum, sodium carboxymethyl cellulose, microcrystalline cellulose, carbomers, pectin, guar gum, or combinations thereof;(c) viscosity-modifying agents selected from hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carbomers, or xanthan gum; and(d) buffering agents, pH modifiers selected from citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium bicarbonate, Lactic acid, sodium lactate or combinations thereof.

20. The powder composition according to claim 16, wherein the powder is present in a bulk quantity sufficient to provide two or more individual unit doses of pimavanserin upon reconstitution.

21. The powder composition according to claim 16, wherein the powder is present in a bulk quantity sufficient to provide 30 individual unit doses of pimavanserin upon reconstitution.

22. The powder composition according to claim 16, wherein the reconstituted oral liquid is stable for more than 48 hours under ambient or refrigerated conditions.

23. An orally dispersible tablet comprising:a) pimavanserin or a pharmaceutically acceptable salt thereof;b) at least one sweetener;c) at least one disintegrant; andd) one or more pharmaceutically acceptable excipients selected from diluents, binders, lubricants, glidants, stabilizers, viscosity-modifying agents, buffering agents, surfactants, flavoring agents, or coloring agents;wherein the tablet rapidly disperses in the presence of a small amount of fluid to form a homogeneous dispersion suitable for oral administration.

24. The orally dispersible tablet of claim 23, wherein the pharmaceutically acceptable salt of Pimavanserin is Pimavanserin tartrate.

25. The orally dispersible tablet of claim 23, wherein the at least one pharmaceutically acceptable excipient comprises one or more of:(a) sweeteners selected from sucrose, xylitol, mannitol, sorbitol, maltitol, sucralose, acesulfame potassium, aspartame, neotame, stevia extract, or combinations thereof;(b) disintegrants selected from sodium starch glycolate, crospovidone, croscarmellose sodium, pregelatinized starch, or combinations thereof;(c) diluents selected from microcrystalline cellulose, mannitol, lactose, or combinations thereof;(d) binders selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, or starches;(e) lubricants selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, or glyceryl behenate;(f) glidants comprising colloidal silicon dioxide;(g) viscosity-modifying agents selected from hydroxypropyl methylcellulose,xanthan gum, carbomers, or hydroxyethyl cellulose; and(h) flavoring agents selected from peppermint, orange, bubblegum, strawberry, banana, cherry, grape, vanilla, or combinations thereof.

26. The orally dispersible tablet of claim 23, wherein the tablet has a disintegration time of 30 seconds or less.

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