DESC:FIELD OF INVENTION:
The present invention relates to long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients. The present invention also relates to processes for making such a formulation and use of the said formulation for the treatment of Parkinson's disease psychosis.

BACKGROUND:
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 does also experience a 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 1/3rd 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 typical antipsychotics (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.

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.

Pimavanserin is the first USFDA approved drug as NUPLAZID, immediate release film coated oral tablet by Acadia Pharmaceuticals Inc. and is available in strength equivalent to 17mg free base for the treatment of hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease wherein two tablets are taken orally once daily.

WO 2007133802 A2 discloses stable pharmaceutical formulations of pimavanserin and at least one pharmaceutically acceptable excipient.

Thus, some oral dosage forms of pimavanserin have been suggested in prior art. However, during diagnosis, PDP patients often retain insight, but as the disease progresses, insights may be lost. PDP is a poor prognostic indicator and is associated with increased caregiver burden, greater functional decline, higher likelihood of nursing home placement, reduced patient compliance and adherence. Also, one of the intrinsic problems that patients suffering from PDP usually face, when the dosage regimen requires daily administration, is that the patients may forget to take the medications regularly and on-time and thus leading to dissociation of some patients from the treatment, risk of accidental or deliberated overdose, irregular or inconstant treatments and appearance of psychotic crisis. Moreover, this kind of therapy gives rise to high differences in the plasma levels (measured as the difference between Cmax and Cmin) in patients, therefore usually affecting the patient's mood. Further, if a patient misses a dose, the patient should take pimavanserin dose as soon as possible. If the dose was missed by more than 12 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

Thus, considering the chronic nature of the disease and the treatment, there is an unmet need to provide an alternate dosage form with improved pharmaceutical composition, especially with those drugs that allow for continuous effect through a combination of inverse agonist and antagonist activity at serotonin 5-HT2A/2C receptors such as pimavanserin which will ultimately delay or prevent the onset of drug-related motor complications, have long duration of action by achieving continuous targeting of receptors for seven days or more, less frequency of dosage administration and provide optimum release profile of pimavanserin with enhanced bioavailability and thus improving the patient compliance.

Pimavanserin is therefore a good drug candidate for incorporation into sustained delivery devices, where the patients would be treated for long time periods with just one dose and without the need of caregivers to pay attention to a daily medication, and where more homogeneous plasma levels in the patient are desirable. Hence, a drug delivery technology, especially depot preparations which can reduce the total number of such administration and maintain the peak plasma drug levels for longer time would be preferred. Such reductions in frequency of drug dosing in practice may be achieved through the use of injectable depot formulations that are capable of releasing drugs in a slow but predictable manner and consequently improve patient compliance. Depot injections allow careful control of drug usage (as opposed to orally administered drugs) and ensure regular contact between the caregivers team and the patient, where overall treatment efficacy and/or side effects may be identified. Furthermore, it is easy to identify defaulters and prepare interventions. These long acting depot formulation of pimavanserin can have the potential to not only boost the therapeutic benefit in most cases, also reduce any unwanted events, such as reduce the risk of accidental or deliberated overdose and maintain a stable release rate for several weeks, several months or longer so as to avoid the drawbacks of oral administration such as poor bioavailability, high frequency of administration, possible toxicity and inadequate individualizable dosing. The long acting depot formulation of pimavanserin of the present invention can address the problems of fluctuating drug concentration and will provide continuous stimulation of receptors prolonging the duration of action and thus improving patient compliance.

OBJECT OF THE INVENTION:
An object of the present invention is to provide a long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients to ensure patient compliance.

Another object of the present invention is to provide a long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt wherein the particle size of the drug is about 0.5 -100 µm.

Another object of the present invention is to provide a process of preparing a long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a method of treating or reducing parkinson’s disease psychosis by administering a long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.
Another object of the present invention is to provide the use of a long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt for the treatment of Parkinson’s disease psychosis for prolonged time.

SUMMARY OF THE INVENTION:
According to an aspect of the present invention, there is provided a long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

According to second aspect of the present invention, there is provided a long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients to ensure patient compliance.

According to third aspect of the invention, there is provided a long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt wherein the particle size of the drug is about 0.5 -100 µm.

According to fourth aspect of the present invention there is provided a process for preparing a long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

According to fifth aspect of the present invention, there is provided method of treating or reducing parkinson’s disease psychosis by administering long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

According to sixth aspect of the present invention there is provided use of a long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients for the treatment of Parkinson’s disease psychosis for prolonged time.

DETAILED DESCRIPTION OF THE INVENTION:
Treatment of PDP with pimavanserin involves administration of two tablets of 17 mg to be taken orally once daily. For most drugs such as pimavanserin, depending on the dose, it may be possible to reduce such administration frequency from daily to once or twice monthly or even longer (6 months). This will help the patients suffering from delusions, hallucinations associated with parkinson’s disease psychosis providing more patient compliance and avoiding the chances of irregular doses caused due to the nature of disease.

Pimavanserin salt is freely soluble in water and pimavanserin base is practically insoluble in water. Thus, it is a critical aspect of present invention to provide a pharmaceutical formulation which will provide the therapeutic amount of pimavanserin or its pharmaceutically acceptable salt for a long duration of time by controlling the release rate to achieve the desired pharmacologic effect and improved systemic absorption. The inventors of present invention after rigorous experimentation considering the physico-chemical properties of pimavanserin or its pharmaceutically acceptable salt and to achieve the desired pharmacokinetic profile of composition for longer duration of time, provided a pharmaceutical long acting depot formulation comprising pimavanserin or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipients.

As used in the specification and the appended claims, the term "therapeutically effective amount" or "effective amount" is such that when administered, the pharmaceutical formulation results in the desired pharmacologic effect.

The term “reduced initial burst release” as per the present invention means the reduction in release of active ingredient from the dosage form at initial time points. The release of active ingredient in first hour according to the present invention is less than 35% and preferably less than 30%.

The term “parenteral” as used herein refers to routes selected from subcutaneous (SC), intravenous (IV), intramuscular (IM), intradermal (ID), intraperitoneal (IP) and the like.

The term "pharmaceutical depot formulation" includes injection preparations, such as liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions), gels, implants (rods, rings), biodegradable or non-biodegradable microparticles/microspheres in the form of controlled release formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations etc. may also be envisaged under the ambit of the invention.

The term “biodegradable” as used herein refers to a component which erodes or degrades at its surfaces over time due, at least in part, to contact with substances found in the surrounding tissue fluids, or by cellular action.

The term “long acting” as used herein refers to a pharmaceutical depot formulation which provides prolonged, sustained or extended release of the pimavanserin or its pharmaceutically acceptable salt to the general systemic circulation of a subject or to local sites of action in a subject. This term may further refer to a pharmaceutical depot formulation which provides prolonged, sustained, controlled or extended duration of action (pharmacokinetics) of the active substance in a subject.
Pimavanserin, which is also known as N-(1-methylpiperidin-4-yl)-N-(4-fluorophenyl methyl)-N' -( 4-(2-methylpropyloxy)phenylmethyl)carbamide, N-[( 4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N' -[[ 4-(2-ethylpropoxy)phenyl]methyl]urea, 1-( 4-fluorobenzyl)-1-( 1-methylpiperidin-4-yl)-3-[ 4-(2-methylpropoxy)benzyl]urea, or ACP-103 has the structure following structural formula:

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.

In some embodiments, the pharmaceutical depot 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, ß-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, mandelate and the like salts. The present invention provides long acting parenteral pharmaceutical depot compositions comprising a therapeutically effective amount of a pharmaceutically acceptable salt of pimavanserin preferably tartarate salt.
In some embodiments, the dose of pimavanserin ranges from about 10 mg to about 50 mg per day. In an embodiment, the typical recommended monthly dosage regimen ranges from about 200 mg to about 1200 mg.

In an embodiment, the amount of pimavanserin in the formulation of present invention is about 1% to about 50% of the total composition. In preferred embodiment, the amount of pimavanserin in the formulation of present invention is about 5% to about 40% of the total formulation. In an embodiment, the amount of pimavanserin in the formulation of present invention is about 200 -1200 mg Pimavanserin in 1-2.5 mL of formulation.

Preferably, pimavanserin or its acceptable salt from the formulation of present invention may be administered to the subject in need thereof once in every three days, once weekly , once in every two weeks, once a month, twice a month or once every 6 months. In particular, the long acting pharmaceutical depot formulation of the present invention provide a dosing regimen which ranges from once in three days to once every 6 months.

Depending on the duration of action required, each depot or implantable device of the present invention will typically contain pimavanserin or its pharmaceutically acceptable salt, designed to be released over a period ranging from a couple of weeks to a number of months.

In one embodiment, the present invention provides a long acting pharmaceutical depot formulation comprising a therapeutically effective amount of pimavanserin or any other pharmaceutically acceptable salt in a depot form suitable for parenteral administration at a medically acceptable location in a subject in need thereof.

Further, the pharmaceutical long acting depot formulations of present invention provide equal or superior therapeutic efficacy to the commercially available dosage form, with reduced incidence and/or severity of side effects at the local and/or systemic levels.

The present invention provides a pharmaceutical long- acting depot formulations comprising pimavanserin or its pharmaceutically acceptable salt in the form of an aqueous depot suspension injection. According to one embodiment, the pharmaceutical depot formulation is in the form of microspheres, implants, cubosomes, hexosomes, solutions, suspensions, microemulsions, in-situ gelling system and the like, that are suitable for subcutaneous or intramuscular administration of pimavanserin base or its salts. According to another embodiment, the pharmaceutical long acting depot formulation of present invention comprising pimavanserin or its salts can be delivered by biodegradable or non-biodegradable carrier/s.

In some embodiments, the pharmaceutical depot formulations of the present invention include, but are not limited to, suspensions of pimavanserin or a pharmaceutically acceptable salt thereof in water, oil or wax phase; poorly soluble polyelectrolyte complexes of pimavanserin or a pharmaceutically acceptable salt thereof; “in-situ” gel-forming matrices based on the combination of water-miscible solvent with pimavanserin or a pharmaceutically acceptable salt thereof; and biodegradable polymeric microparticles with incorporated pimavanserin or a pharmaceutically acceptable salt thereof.

Microspheres, implants and gels are the forms of biodegradable polymeric devices used in prolonging the release of drugs in the body. Besides biodegradable systems, there are non-biodegradable implants and infusion pumps that can be worn outside the body.

In certain embodiments, the dosage forms include, but are not limited to, biodegradable injectable depot systems comprising biodegradable polymers such as polylactide (PLA), poly(lactic-co-glycolic acid) (PLGA) 75:25, PLGA 50:50, Polycaprolactone (PCL); non-PLGA based injectable depot systems comprising polymers such as Ethylene-vinyl acetate (EVA), Polyurethane, and injectable biodegradable gels or dispersions.

In particular, the pharmaceutical depot compositions of the present invention are in the form of injectable microparticles wherein the pimavanserin or pharmaceutically acceptable salt thereof is entrapped in a biodegradable or non-biodegradable carrier. The microparticulate compositions of the present invention may comprise a water-in oil-in water double emulsion.

In embodiment, the present invention provides parenteral pharmaceutical long acting depot compositions of pimavanserin in an aqueous suspension.

In some embodiments, the size distribution of the pimavanserin or its salt of present invention is in the form of particles and has a d10 of about 0.5micron to about 10.0 micron, d50 of about 1 micron to about 40 microns and d90 of about 20 microns to about 100 microns. In other embodiments, the size distribution of the pimavanserin particles in the formulation has a d10 of about 1 micron to about 5 microns, d50 of about 5 microns to about 30 microns and d90 of about 40 microns to about 80 microns.

The limited solubility of Pimavanserin base or its salt in water coupled with controlled particle size is utilized for the preparation of long acting depot formulation of present invention.

Depending on the dosage form, the pharmaceutical long acting depot formulation of present invention comprises of Pimavanserin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients selected from fluid containing stabilizer, matrix forming agent, viscosity enhancing agent, one or more of a preservative, a buffer, an isotonizing agent, lipids and the combination thereof. Particular ingredients may function as two or more of these agents simultaneously. e.g. behave like a preservative and a buffer, or behave like a buffer and an isotonizing agent.

The fluid containing stabilizer of the present invention also act as wetting agent or suspending agent and ensure complete wetting of the microparticles by the injection vehicle and thus stabilizing the pimavanserin base or its pharmaceutically acceptable salt in the composition. Suitable fluid containing stabilizer for use according to the present invention are polyoxyethylene derivatives of sorbitan esters, e.g. polysorbate 20 and polysorbate 80, lecithin,polyoxyethylene- and polyoxypropylene ethers, sodium deoxycholate Preferred wetting agents include polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), and polysorbate 80 (Tween 80). Other fluid containing stabilizer suitable for use include various polymers, low molecular weight oligomers, natural products, and surfactants, including nonionic and ionic surfactants, such as cetyl pyridinium chloride, gelatin, casein, lecithin (phosphatides), dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol 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 (e.g., the commercially available Tweens® such as e.g., Tween 20® and Tween 80® (ICI Specialty Chemicals)); polyethylene glycols (e.g., Carbowaxs 3350® and 1450®, and Carbopol 934® (Union Carbide)), dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, collodial silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose ti calcium, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L), methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F68® and F108®, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); a charged phospholipid such as dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate (DOSS); Tetronic 1508® (T-1508) (BASF Wyandotte Corporation), dialkylesters of sodium sulfosuccinic acid (e.g., Aerosol OT®, which is a dioctyl ester of sodium sulfosuccinic acid (American Cyanamid)); Duponol P®, which is a sodium lauryl sulfate (DuPont); Tritons X-200®, which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F-1100, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also known as Olin-10G® or Surfactant 10-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL-40® (Croda, Inc.); and SA9OHCO, which is C18H37CH2(CON(CH3))—CH2(CHOH)4(CH2OH)2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl ß-D-glucopyranoside; n-decyl ß-D-maltopyranoside; n-dodecyl ß-D-glucopyranoside; n-dodecyl ß-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-ß-D-glucopyranoside; n-heptyl ß-D-thioglucoside; n-hexyl ß-D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonyl ß-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-ß-D-glucopyranoside; octyl ß-D-thioglucopyranoside; and the like.

Most of these fluid containing stabilizer are known pharmaceutical excipients and 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 Society of Great Britain (The Pharmaceutical Press, 1986), specifically incorporated by reference.

The fluid containing stabilizer are present in the formulation of present invention in an amount within the range from about 0.2 to about 10 % of total formulation, preferably for about 0.5 to about 5 % of the total formulation. Preferably, the amount of fluid containing stabilizer in present invention are from about 0.5 mg to about 30 mg of the total formulation, preferably, about 1mg to about 20mg of total formulation.

The matrix forming agent of present composition is selected from polyethylene glycol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycols, polyoxyethylene and polyoxy-propylene ethers and polyvinylpyrrolidone, with sodium carboxymethyl cellulose and polyvinylpyrrolidone being preferred, although other suitable matrix forming agents may also be used. The preferred matrix forming agent is polyethylene glycol. Suitable liquid crystalline matrix forming agent may be used in present invention such as Glyceryl monoleate, Glycerylmonostearate and the combinations thereof. The matrix forming agent are present in the formulation of present invention in an amount within the range from about 0.2 to about 10 % of total formulation.

The viscosity enhancing agent of present invention that increases the viscosity of the injection vehicle is selected from sorbitol, glycerine, propylene glycol and such other solvents may also be used. The viscosity enhancing agent are present in the formulation of present invention in an amount within the range from about 5 to about 15 % of total formulation.

Suitable “in-situ” gel-forming agents of the present invention convert to gels while preparation of the formulation and thus also act as viscosity enhancing agent are selected from Sucrose acetate isobutyrate, poly N,N-dimethyl acrylamide,poly (methyl vinyl ether), poly (N-vinyl caprolactam), Pluronics, PLGA and PLA. The “in-situ” gel-forming agents are present in the formulation of present invention in an amount within the range from about 40 to about 75 % of total formulation.

The tonicity adjusting agents adjust the tonicity to preclude toxicity problems and improve biocompatibility. The tonicity adjusting agent of present invention may be selected from, but not limited to, 0.9% sodium chloride, 5% dextrose, potassium chloride, mannitol, glycerin although other suitable tonicity adjusting agents may also be used.

Pharmaceutically acceptable preservatives are antimicrobials and anti-oxidants used in the present invention can be selected from the group consisting of benzyl alcohol, benzyl benzoate, methyl paraben, propyl paraben benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, a gallate, a hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-?-piccolinium chloride, phenylmercuric acetate and thimerosal. In particular, methyl paraben and propyl paraben can be used in the range of 0.01 – 0.18% w/v of total formulation, benzyl alcohol can be used in the range of 0.5% to 10% w/v of total formulation.

Suitable buffering agents used in present invention are salt of weak acids and should be used in amount sufficient to render the dispersion neutral to very slightly basic (up to pH 8.5), preferably in the pH range of 7 to 7.5. Particularly preferred is the use of a mixture of disodium hydrogen phosphate (anhydrous) (typically about 0.9% (w/v)) and sodium dihydrogen phosphate monohydrate (typically about 0.6% (w/v)). This buffer also renders the dispersion isotonic and, in addition, less prone to flocculation of the ester suspended therein. The pH may also be adjusted by the addition of suitable acids and bases such as sodium hydroxide, hydrochloric acid, glacial acetic acid and the combination thereof.

Pharmaceutically acceptable isotonizing agents used in present invention are, for example, sodium chloride, dextrose, mannitol, sorbitol, lactose, sodium sulfate. The formulation of present invention conveniently comprise from 1 to 10 % (w/v) isotonizing agent. Preferably, mannitol is used in a concentration from 2 to 7 %, more preferably about 5 %. Most preferably, however, from about 1 to about 3 % (w/v), especially from about 1.5 to about 2 % (w/v) of one or more electrolytes are used to render the suspension isotonic, apparently because ions help to prevent flocculation of the suspended ester. In addition, electrolytes have the further advantage of buffering the aqueous suspension. Particularly preferred is the use of a mixture of disodium hydrogen phosphate (anhydrous) (typically about 0.9 % (w/v)) and sodium dihydrogen phosphate monohydrate (typically about 0.6 % (w/v)) for rendering the solution isotonic, neutral and less prone to flocculation of the suspended ester therein.

Suitable lipids used in the formulation of present invention are callable of forming complex with the pimavanserin or its pharmaceutically acceptable salt such as phosphatidylcholine (PC) or purified egg yolk lecithin, phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidic acid (PA), phosphatidylinositol (PI), sphingomyelin (SPM), and the like, alone or in combination. Saturated phospholipids such as hydrogenated soy PC may also be used. The phospholipids can be synthetic or derived from natural sources such as egg or soy. In the preferred embodiments, the phospholipids dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPC), or combinations thereof.

Suitable vehicle used in present invention are water for injection, mixture of glycerine and water for injection. Other vehicle used in present invention when the desired dosage form is oily solution is vegetable oil selected from Cottonseed oil, Castor oil, Sesame oil, arachis oil, oleic acid, ethyl undecanoate, almond oil, coconut oil, olive oil, soyabean oil, (purified) tri-glycerised, propylene glycol esters, ethyl oleate. linseed oil, sunflower oil, peanut oil, olive oil, wheat-germ oil and similar oils and the combinations thereof.

The pharmacokinetic properties of the formulations according to the present invention further may depend to a limited extent on the physico-chemical properties of the drug, such as the particle size and crystal form.

A particularly desirable feature for an injectable depot composition relates to the ease with which it can be administered. In particular, such an injection should be feasible using a needle as fine as possible in a span of time which is as short as possible. This can be accomplished with the aqueous suspensions of the present invention by keeping the viscosity below about 75 mPa.s, preferably below 60 mPa.s. Aqueous suspensions of such viscosity or lower can both easily be taken up in a syringe (e.g. from a vial), and injected through a fine needle (e.g a 21 G 11/2, 26 G 1, 22 G 2 or 22 G 11/4 needle).

The present invention also provides a process for preparing pharmaceutical long acting depot formulation according to dosage forms, which process comprises admixing a pharmaceutically acceptable solvent/s or excipient/s with pimavanserin or its salts.

In some embodiments, methods used for preparation of the present invention may be selected from high sheer homogenization, Ultrasonication /high speed homogenization, admixture of solvents, solubilizers and actives to prepare suspension, solvent emulsification/evaporation etc. A preferred method is high sheer homogenization. In another embodiment, the method used for particle size reduction of pimavanserin of present invention may be selected from sonication, cryomilling or other processes inducing high shear in the presence of phospholipid or other membrane-forming amphipathic lipid. A preferred method is cryomilling for particle size reduction of pimavanserin.

In some embodiments, the pharmaceutical long-acting depot composition of pimavanserin is supplied in an injection volume of 0.5 ml to 2.5 ml in a prefilled syringe.

A person skilled in the art for preparing formulations according to the present invention will understand that the proportions of components with respect to each other will vary depending on the specific components used. For example, the use of different solubilizers and stabilizers will require some straightforward modifications to the proportions, depending on the compatibility and miscibility of a particular stabilizer in a particular vehicle.

In embodiments, the excipients for the present invention may be selected from but not limited to the range of pharmaceutically acceptable excipients, which are soluble in the aqueous solvent system and which are also compatible with the active ingredient. The excipients selected for the purpose of the present invention should not create any degenerative effect on the active ingredient such as Pimavanserin.

The present invention also provides a method of treating or reducing parkinson’s disease psychosis, comprising the administering pharmaceutical long acting depot formulation ccomprising a therapeutically effective amount of pimavanserin or its pharmaceutically acceptable salt of pimavanserin, preferably pimavanserin tartrate.

The present invention also provides a pharmaceutical long acting depot formulation for use in treating or reducing Parkinson’s disease psychosis by administering pharmaceutical long acting depot composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of pimavanserin, preferably pimavanserin tartrate.

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.

Example 1
Intramuscular (IM) Depot Injection - Sterile aqueous suspension
Sr. No. Ingredients Quantity (mg/ml)
1 Pimavanserin tartrate 200-1000 mg
2 Polysorbate 80 2-15 mg
3 Polyethylene glycol 3350 20-50 mg
4 Sodium Hydroxide pH 3-7
5 Hydrochloric acid/ Citric acid/ Glacial Acetic acid pH 3-7
6 Water for Injection q. s. 1-2.5 mL

* pH is adjusted with sodium hydroxide or hydrochloric acid, or both.

Process:
1. Polyethylene glycol 3350, Polysorbate 80, sodium hydroxide were added and dissolved in some amount of water under stirring.
2. Pimavanserin tartrate was added to the solution obtained in step (1) and volume was made up to final volume with remaining water for injection. pH was maintained with Hydrochloric acid/ Citric acid/ Glacial Acetic acid.
3. The suspension obtained in step (2 ) was sterilized.
4 . The suspension obtained in step ( 3 ) was homogenized and was filled in the appropriate container.

Example 2:
Lipophilic Depot Solutions used for intra muscular administration
Sr. No. Ingredients Quantity
1 Pimavanserin 5%-40%
2 Benzyl benzoate 10%-50%
3 Benzyl alcohol 0.5%-10%
4 Vegetable oil qs 0.5%-1.5%
Process:
1. Benzyl benzoate, benzyl alcohol and vegetable oil were mixed in a beaker.
2. Pimavanserin was added to the above mixture with the aid of heat, if required.

Example 3:
Drug- lipid complex formulation for intramuscular injection
Sr. No. Ingredients Quantity
1 Pimavanserin 200 mg-1200mg
2 Purified egg yolk lecithin 1000mg – 7000mg
3 Polysorbate 80 1mg – 3.65 mg
4 Water 0.5 ml-1.5ml
Process:
1.Purified egg yolk lecithin and Pimavanserin were dissolved in Dichloromethane and a thin drug lipid film was prepared using Rotavac.
2.Polysorbate 80 was dissolved in water to prepare aqueous phase.
3.The above aqueous phase containing the surfactant was added to the drug lipid film and homogenized.

Example 4: Intramuscular (IM) Depot Injection - Microspheres
Sr. No. Ingredients Quantity
1 Pimavanserin 5%-40%
2 PLA/PLGA 60%-95%
3 Polyvinyl alcohol 0.1%-2%
4 Water for injection q. s. 100 ml -1.5 L
Process:
1. Pimavanserin and PLA/PLGA polymer were dissolved in methylene chloride (organic phase).
2. Polyvinyl alcohol and mannitol were dissolved in the required quantity of water for the external phase.
3.The drug phase obtained in step (1) was added to the aqueous phase step of (2) under continuous homogenization to form a primary emulsion, stirred and filtered under vacuum.
4 .The microsphere powder was washed and dried.

Example 5: Implants
Ingredient Quantity
Pimavanserin 5%-40%
*Biodegradable/Non biodegradable polymer 60%-95%
Biodegradable polymers: PLA, PLGA 75:25, PLGA 50:50, PCL.
Non biodegradable polymer: EVA, Polyurethane
Process:
1.The polymer and Pimavanserin were cryomilled.
2.The polymer- Pimavanserin powder mixture was introduced into hot melt extruder.
3.The extrudes were then cut to desired length.

Example 6: Liquid crystalline systems (Cubosomes/Hexosomes)
Ingredient Quantity
Pimavanserin 5%-40%
Glycerylmonoleate/ Glycerylmonostearate 80%-90%
Polysorbate 80 0-5%
Water qs 0.5 ml-1.5ml
Process:
1. Glyceryl monoleate/Glycerylmonostearate and polysorbate 80 were dissolved in water under stirring.
2. Pimavanserin was added to the above mixture.
3.After complete addition of Pimavanserin, the mixture was mixed/ vortexed.

Example 7: In situ gelling system
Ingredient Quantity
Pimavanserin 5%-40%
Sucrose acetate isobutyrate (SAIB) 40%-75%
Ethanol 2%-5%
Glycerin 5%-15%

Process:
1. Sucrose acetate isobutyrate, ethanol and glycerine were mixed in a beaker under stirring.
2. Pimavanserin was added to the above mixture and stirred till a homogenous mixture was formed.
3.The mixture was heated, if required.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to fall within the scope of the invention.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.
,CLAIMS:1. A pharmaceutical long-acting depot composition comprising a therapeutically effective amount of pimavenserin or its pharmaceutically acceptable derivative and one or more pharmaceutically acceptable excipients.

2. The pharmaceutical long-acting depot composition according to claim 1, wherein the amount of pimavenserin in the composition is from about 10mg to about 50 mg.

3. The pharmaceutical long-acting depot composition according to claim 1, wherein the particle size (d90) of pimavenserin in the composition is from about 20 microns to about 100 microns.

4. The pharmaceutical long-acting depot composition according to claim 1, wherein the particle size (d90) of pimavenserin in the composition is from about 40 microns to about 80 microns.

5. The pharmaceutical long acting depot composition according to claim 1, wherein the composition is an aqueous depot injection comprising pimavanserin or its pharmaceutically acceptable derivative and one or more pharmaceutically acceptable excipients.

6. The pharmaceutical long-acting aqueous depot injection according to claim 5, wherein the one or more pharmaceutically acceptable excipients are selected from wetting agent or suspending agent, matrix forming agent, viscosity enhancing agent, preservative, buffering agent, isotonizing agent, injection vehicle, or mixtures thereof.

7. The pharmaceutical long acting depot composition according to claim 1, wherein the composition is a lipid coated aqueous depot injection comprising pimavenserin or its pharmaceutically acceptable derivative and one or more pharmaceutically acceptable excipients.
8. The pharmaceutical long-acting aqueous depot injection according to claim 7 , wherein the one or more pharmaceutically acceptable excipients are selected from lipid carrier, complexing agent, stabilizer, suspending agent, wetting agent, preservative, buffering agent, viscosity enhancing agent, density enhancing agent, injection vehicle, isotonizing agent or mixtures thereof.

9. The long-acting sustained-release depot pharmaceutical composition according to claim 1, wherein the composition is administered subcutaneously or intramuscularly.

10. The long acting sustained release depot pharmaceutical composition according to claim 1, wherein the composition is administered bimonthly or monthly.

11. The long depot sustained release depot pharmaceutical composition according to claim 1, wherein the composition is supplied in an injection volume of 0.5 ml to 2.5 ml in a prefilled syringe.

12. The long acting sustained release depot pharmaceutical composition according to claim 1, wherein the composition is for use in the treatment of Parkinson’s disease.