Field of invention

The present invention relates to the preparation of pharmaceutical compositions comprising pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, having specific polymorph with other relevant excipients in formulation.

Background of the invention

Pimavanserin has active moiety of the tartrate salt with the chemical name of urea, N-[(4- fluorophenyl)methyl]-N-(l-methyl-4-piperidinyl)-N’-{ [4-(2-methylpropoxy)phenyl] methyl}, (2R,3R)-2,3-dihydroxybutanedioate. It has molecular weight of 427.55 g/mol, white or off- white powder.

Pimavanserin has been used for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

Parkinson's disease is a progressive nervous system disorder that affects movement. It is a condition in which parts of the brain become progressively damaged over many years. Parkinson's disease is a brain disorder that leads to shaking, stiffness, and difficulty with walking, balance, and coordination.

In general, parkinson's symptoms may include: involuntary shaking of particular parts of the body, slow movement, stiff and inflexible muscles, impaired posture and balance, loss of automatic movements, speech and writing changes.

In addition, there are non-motor symptoms such as hallucinations and delusions for parkinson's disease. Hallucinations and delusions are two main symptoms of Parkinson’s disease-associated psychosis.

The pimavanserin compound can be in amorphous form, in polymorphic forms, or both. Pimavanserin tartrate can be obtained in many polymorphic forms as described in W02006/037043. For example, the procedure described polymorph C of pimavanserin. Polymorphic Form C has been found to be a thermostabile form of pimavanserin.

According to W02006/037043, pimavanserin tartrate exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 12.0, about 10.7, about 5.86, about 4.84, about 4.70, about 4.57, and about 3.77 , it is called form C of pimavanserin tartrate. According to patent applications, there are different polymorphic forms of pimavanserin such as Form I, form II, form III, form IV, form B, form C, form D, form E, form F and also form A.

Originator of pimavanserin product is Acadia Pharmaceuticals. Acadia has many granted patents and patent applications about form C polymorph of pimavanserin.

According to FDA Guideline of ANDAs: Pharmaceutical Solid Polymorphism, polymorphism has crucial effect to property of pharmaceutical drugs. Polymorphic forms of a drug substance can effect many chemical and physical properties, such as melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These kind of properties can have a potential effect on the ability to manufacturing the drug substance and also the drug product.

Polymorphism effects on drug product stability, dissolution, and bioavailability. After all, polymorphism can affect the quality, safety, and efficacy of the drug product.

In the state of art there are many patents/patent applications which are summarized below.

W02007/133802 relates to tablet composition comprising pimavanserin tartarat prepared by wet granulation.

WO2017/015272 relates to capsule composition comprising pimavanserin tartarat form C.

WO20 19046167 relates to capsule composition comprising pimavanserin prepared by wet granulation.

US2020009122 relates to capsule composition comprising pimavanserin tartarat prepared by wet granulation. Capsule sizes is 3 or 4.

Summary of the invention

The present invention provides a pharmaceutical composition comprising pimavanserin or pharmaceutically acceptable salts or esters thereof, for the the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, wherein process including dry granulation method.

In this invention, a pharmaceutical composition in the form of capsule, comprising: a) pimavanserin or a salt thereof in polymorphic form A, b) at least one filler, c) at least one lubricant, wherein the pharmaceutical product is prepared by dry granulation. Brief description of the figures:

Figure 1 : The chemical formula of pimavanserin

Figure 2: The chemical formula of pimavanserin tartrate

Figure 3: Comparative Dissolution Profiles of Nuplazid 34mg Capsule and Pimavanserin 34mg Capsule (Test Product) pH 1.2 with 0, 1 HCL + 0,1% CTAB .

Figure 4: Comparative Dissolution Profiles of Nuplazid 34mg Capsule and Pimavanserin 34mg Capsule (Test Product) in acetat buffer pH 4.5 with % 0.1 CTAB

Figure 5: Comparative Dissolution Profiles of Nuplazid 34mg Capsule and Pimavanserin 34mg Capsule (Test Product) in phosphate buffer pH 6.8 with 0,1% CTAB.

Figure 6: X-ray powder diffraction pattern of Form A of pimavanserin tartrate

Figure 7: X-ray powder diffraction pattern of Form C of pimavanserin tartrate

Detailed description of the invention

The present invention relates to preperation of pharmaceutical compositions comprising pimavanserin in the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

The present invention provides a pharmaceutical composition comprising pimavanserin or pharmaceutically acceptable salts or esters thereof, for the the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, wherein process including dry granulation method.

Dosage forms of capsule and tablet forms are used commonly for oral administration way. Tablet form has many advantages like cost-effective, lighter and compact, easiest and cheapest to package, can be masked by coating technique and greatest chemical and microbial stability over all oral dosage forms.

Capsule form has many advantages like masking the odor and taste of unpleasant medicines, being simply administered, fewer excipients are required than tablets, easy to swallow with water, easy to handle and take and digesting easily and quickly in the gastrointestinal tract.

A pharmaceutical composition may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients examples can be filler, disintegrant, binder, surfactant, lubricant, solvent, antiadherent, flavor, glidant, preservative, sweetener, suspending/viscosity agent, diluent, colorant and the mixtures thereof.

Ideal pharmaceutical excipient profile should have suitable physical and chemical properties with active ingredient and also other raw materials. These properties can be stable and reproducible, no unwanted interaction with active ingredient, inert property, desired functionality and cost effective.

The present invention relates to the preparation of pharmaceutical compositions comprising pimavanserin or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable carriers or excipients.

The present invention relates to the preparation of pharmaceutical compositions comprising pimavanserin or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable carriers or excipients, comprising a filler and a lubricant.

The present invention relates to the preparation of pharmaceutical compositions comprising pimavanserin or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable carriers or excipients, comprising a filler and a lubricant, wherein process including dry granulation method.

The present invention relates to the preparation of pharmaceutical compositions comprising pimavanserin or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable carriers or excipients, comprising a filler and a lubricant, wherein process including dry granulation method in capsule dosage form.

The present invention relates to pimavanserin has the chemical formula, figure 1;

Figure 1: The chemical formula of pimavanserin

Optionally pimavanserin can be referred to as (N-(4-fluorophenylmethyl)-N-(l- methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy) phenylmethyl)carbamide).

According to this invention, pimavanserin can be used as a tartrate salt, chemical formula, figure 2;

Figure 2: The chemical formula of pimavanserin tartrate Polymorphism is an important characteristic properties for pharmaceutical products especially for solid dosage forms.

Polymorphism can effect the formation and properties of medicine both on active ingredients and excipients, fillers, stabilizers, coatings, drying agents, etc. These properties can be related to usage, efficacy and stability of the pharmaceutical products.

The important factors for preparation of pharmaceutical products are dissolution rate and solubility, and also bioavailability of pharmaceutical product. Dissolution rate and solubility can be influenced by polymorhic forms relevant to the formation of hydrates, solvates, metastable forms and amorphous forms for pharmaceutical products.

The present invention relates to pimavanserin tartrate exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 12.0, about 10.7, about 5.86, about 4.84, about 4.70, about 4.57, and about 3.77 , hereinafter referred to as Form C.

One embodiment for pimavanserin tartrate of Form C exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 12.0, about 10.7, about 7.4, about 6.9, about 6.6, about 6.2, about 5.86, about 5.53, about 5.28, about 5.16, about 4.84, about 4.70, about 4.57, about 4.38, about 4.09, about 3.94, about 3.77, about 3.71, about 3.49, about 3.46, about 3.25, about 3.08, and about 2.93.

One embodiment for pimavanserin tartrate of Form C characterized by having an endotherm with an onset of between 167 and 177 °C as obtained by differential scanning calorimetry (DSC) in accordance with USP <891 > .

One embodiment for pimavanserin tartrate of Form C may be characterized by powder diffraction (pXRD), see Figure 4 of W02006/037043.

According to EP1794126B patent, It was found that crystal form C is the most stable form of all found crystal forms, compared to with other polymorhic forms. Form C has stable properties in chemically. It is easy to formulate for tablets or any other pharmaceutically acceptable dosage form.

According to EP1794126B patent, it is given information about forms A and B are very suitable to pharmaceutical processing for granulation with water or with solvent-water mixtures.

One embodiment for pimavanserin tartrate of Form A exhibits X-ray powder diffraction pattern exhibits the following characteristic peaks expressed in d-values (A): 18.6 (s), 16.7 (vs), 10.2 (s), 8.2 (m), 7.7 (w), 7.4 (w), 6.5 (w), 6.2 (m), 6.1 (vs), 5.86 (w), 5.14 (m), 5.03 (m), 4.78 (m), 4.69 (m), 4.63 (s), 4.49 (s), 4.44 (vs), 4.35 (m), 4.10 (m), 3.96 (s), and 3.66 (m).

According to EP1794126B patent, DSC results is given that the melting point of the dehydrated form A is about 133-135 °C (peak temperature) with an enthalpy of fusion of about 70 J/g. Additionally, crystalline form C absorbs much less water than form A. In this invention, a pharmaceutical composition in the form of capsule, comprising: a) pimavanserin or a salt thereof in polymorphic form A, b) at least one filler, c) at least one lubricant, wherein the pharmaceutical product is prepared by dry granulation.

In this invention, the pharmaceutical composition can be formed using a minimum number of excipients. One of the excipient can be a filler and other excipient can be lubricant except pimavanserin active ingredient.

In this invention, it is obtained pharmaceutical compositions comprising pimavanserin or pharmaceutically acceptable salts or esters thereof, pimavanserin used in polymorphic form A.

In this invention, it is obtained pharmaceutical compositions comprising pimavanserin or pharmaceutically acceptable salts or esters thereof and also an excipient of filler.

In this invention, it is obtained pharmaceutical compositions comprising pimavanserin or pharmaceutically acceptable salts or esters thereof and also an excipient of lubricant.

According to a preferred embodiment of this invention, the pharmaceutical composition can be in the form of capsule or tablet.

In this invention, it includes a dry granulation method for use in preparing capsules, the pharmaceutical composition including pimavanserin tartrate and relevant excipients.

In this invention, it includes a dry granulation method with slugging stage for use in preparing capsules, the pharmaceutical composition including pimavanserin or pharmaceutically acceptable salts or esters thereof and relevant excipients.

Another embodiment disclosed herein includes includes a method of preparing a pharmaceutical capsule including dry granulating pimavanserin tartrate using slugging phase with a lubricant, and a filler.

Microcrystalline Cellulose is one of the most common binding and filling agent used to manufacture solid dose foods and also pharmaceutical industry.

In this invention, it includes microcrystalline cellulose (MCC) as a filler. MCC is chemically inactive and will not react with other ingredient. In general, it is used as a bulking agent, binder, glidant, disintegrant and an auxiliary suspending agent and also filler in pharmaceutical products.

MCC is a good option as an excipient for pressing tablets and also filling empty capsules. One of the main advantages of microcrystalline cellulose is that it helps with flow allowing formulations to move smoothly through capsule filling machinery ensuring consistent capsule weights. Lubricant’s main mission is to keep the ingredients in a capsule from sticking together. It also provide a barrier between the ingredients and the machines that are used for manufacturing. The powder improves the consistency and quality of the medication capsules.

Pharmaceutical lubricants are the agents added to capsule formulations in specific quantity (generally, 0.25%-5.0%, w/w) to improve the powder processing properties of formulations. Magnesium Stearate is a common lubricant and is called “flow agent” in pharmaceutical industry.

A capsule is a dosage form which one or more active pharmaceutical ingredients and excipients are enclosed in a hard or soft soluble shell, generally as gelatin.

In generally, capsules are classified as types of hard gelatin or soft gelatin. It depends on the nature of the capsule shell. Soft-shelled capsules are used for pharmaceutical products that are dissolved or suspended in oil. On the other side, hard-shelled capsules are used for dry and powdered active ingredients and excipients.

In this invention, target properties of capsule dosage forms is below:

■ Easy to handle and take.

■ It can mask the odor and taste of unpleasant medicines and also it can be simply administered.

■ Fewer excipients are required than solid dosage forms such as tablets.

■ The gelatin shell can protect of the drug from light.

■ The shells of capsules have physiologically inert property.

■ Capsules have higher bioavailability than tablet dosage forms.

Dissolution test values for pharmaceutical compositions are one of the essential parameters for process development and solid dosage manufacturing.

Generally, excipients that is used in capsule or tablet dosage form are diluent, binder, disintegrants, lubricant, glidant, colouring agent, flavoring agent, sweetening agent and solvent except active ingredient.

In this invention, manufacturing process generally consisting of three stages: a) Sieving and mixing, b) Slugging, Milling and Blending, c) Capsule filling.

In this invention, excipients of filler and lubricant are very critical. These excipients should be in pharmaceutical composition comprising pimavanserin or pharmaceutically acceptable salts or esters thereof with other excipients.

In this invention, the formulations preferably contain active ingredient, filler, lubricant and if needed other excipients.

In this invention, tablets may also be produced. The tablets may vary in shape and be, for example, round, oval, oblong, cylindrical, clover-shaped or any other suitable shape. The present invention provides a pharmaceutical compositions described herein are highly suitable for effective treatment of neuropsychiatric diseases including psychosis, affective disorders, dementia, neuropathic pain and hypertension.

The present invention provides a pharmaceutical composition for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

Advantages

When the physical and chemical test results of the pharmaceutical composition obtained by using a filler and lubricant are evaluated, it has been observed that it has positive effect on the manufacturing process.

According to literature, crystalline form C is more thermodynamically and chemically stable than form A. Although pimavanserin in polymorhic form C is known to be more stable compared to other polymorphs, we can obtain a pharmaceutical product similar to the reference product by using Form A.

According to dissolution profiles, all the multi media profiles of test product (Form A) is comparatively similar to that of the selected Reference product (Form C) .

Solubility result of test product (Form A) is well in all medias. There was no precipitation in the solutions and also it dissolved quickly without the need for a hot water bath. According to solubility results of reference product was slower than test product (Form A) and dissolved in a 37 °C hot water bath.

The pharmaceutical compositions of the invention are particularly shows comparatively similar properties in the stability and dissolution property, it is useful as a pharmaceutical product preparation technique.

It effects on many specifications during determining and designing manufacturing process for pharmaceutical products.

The pharmaceutical compositions of the invention are particularly suited for the oral administration.

The present invention provides pharmaceutical composition comprising pimavanserin and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation

Capsule dosage form is simple, cost-effective, easy and convenient to use and also suitable for substances having bitter taste and unpleasant odor.

Pharmaceutical composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, filler, disintegrant, binder, surfactant, lubricant, solvent and the mixtures thereof, to facilitate the physical formulation of various dosage forms for oral administration like capsules or tablets.

As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties ofthe compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base.

Suitable disintegrants according to the present invention include, but are not limited to, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose (crosslinked carboxymethylcellulose) sodium, cross-linked polyvinylpyrrolidone, crospovidone (crosslinked povidone, a synthetic cross-linked homopolymer of N-vinyl-2-pyrrolidone), alginic acid, microcrystalline cellulose (such as refined wood pulp derived from alpha cellulose), hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, polacrillin potassium, sodium alginate, sodium starch glycolate, partially hydrolysed starch, sodium carboxymethyl starch, and starch.

Suitable binders according to the present invention include, but are not limited to, hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose, HPMC), HPMC E5, acacia, alginic acid, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone and pregelatinized starch.

Suitable lubricants according to the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearylfumarate, zinc stearate and polyethylene glycol. The preferred lubricant is magnesium stearate.

Suitable fillers according to the present invention include, but are not limited to, dibasic calcium phosphate, kaolin, microcrystalline cellulose, silicated microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, lactose such as example the anhydrous form or the hydrate form such as the monohydrate form, sugars such as dextrose, maltose, saccharose, glucose, fructose or maltodextrine, sugar alcohols such as mannitol, maltitol, sorbitol, xylitol, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate and starch. Fillers which are slightly hygroscopic or non- hygroscopic are preferred, with non-hygroscopic fillers being particularly preferred, in particular when the dosage form is to be used for tropical countries. The preferred filler is microcrystalline cellulose.

Suitable surfactants and wetting agents according to the present invention include, but are not limited to, heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, polyoxyethylene stearate, polyoxyethylen sorbitan monolaurate, benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbates, for example polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80, sorbitan monopalmitate, sodium salts of fatty alcoholsulfates such as sodium lauryl sulfate, sodium dodecylsulfate, sodium salts of sulfosuccinates such as sodium dioctylsulfosuccinate, partially esters of fatty acids with alcohols such as glycerine monostearate, partially esters of fatty acids with sorbitans such as sorbitan monolaurate, partially esters of fatty acids with polyhydroxyethylene sorbitans such as polyethyleneglycol sorbitan monolaurate, - monostearate or -monooleate, ethers of fatty alcohols with polyhydroxyethylene, esters of fatty acids with polyhydroxy ethylene, copolymers of ethylenoxide and propylenoxide (Pluronic®) and ethoxylated triglycerides.

The present invention is described in the following example in more details. This example is not limiting the scope of the present invention and is to be considered under the light of the foregoing detailed description.

Example 1: Pimavanserin 34mg capsule unit formula

The process for the preparation of Pimavanserin 34mg capsule according to the present invention can be carried out according to the following process:

1. Stage 1 Sieving and Mixing

Sieving and mixing: Pimavanserin Tartrate and microcrystalline cellulose.

2. Stage 2 Sieving and Mixing

Sieving: Magnesium Stearate.

3. Stage 3 Slugging, Milling and Blending

Procedure for final mixture.

4. Stage 4 Capsule filling

Capsule filling process

Dissolution Tests

In this invention, dissolution testing has been performed in pH 1.2 (O,1N HCI), acetate buffer pH 4.5, phosphate buffer pH 6.8.

General properties of relevant batches are shown in Table 1.

The results have been compared to the reference product Nuplazid 34mg Capsule and Pharmactive Test Product.

Table 1: Summary of Batches used in In Vitro Dissolution Tests

In this invention, the dissolution test has been performed for Nuplazid 34mg Capsule and Pimavanserin 34mg Capsule (Test Product) pH 1.2 (0,1 HCL). It is shown in Table 2 and Figure 3. Drug release for both the test product and the reference product were found to be satisfactory. Table 2: Summary of Dissolution Results of Pimavanserin 34mg Capsule (Test Product) in Comparison to Nuplazid 34mg Capsule (Reference Product) in pH 1.2 (O,1N HCL).

In this invention, the dissolution test has been performed for Nuplazid 34mg Capsule and Pimavanserin 34mg Capsule (Test Product) in acetate buffer pH 4.5. It is shown in Table 3 and Figure 4. Drug release for both the test product and the reference product were found to be satisfactory.

Table 3: Summary of Dissolution Results of Pimavanserin 34mg Capsule (Test Product) in Comparison to Nuplazid 34mg Capsule (Reference Product) in acetat buffer pH 4.5. In this invention, the dissolution test has been performed for Nuplazid 34mg Capsule and

Pimavanserin 34mg Capsule (Test Product) in phosphate buffer pH 6.8. It is shown in Table 4 and Figure 5. Drug release for both the test product and the reference product were found to be satisfactory.

Table 4: Summary of Dissolution Results of Pimavanserin 34mg Capsule (Test Product) in Comparison to Nuplazid 34mg Capsule (Reference Product) in phosphate buffer pH 6.8.

Overall conclusion for dissolution results:

In-vitro comparative dissolution data and profiles has been demonstrated above in pH 1.2, pH 4.5, pH 6.8. All the multi media profiles were comparatively similar to that of the selected Reference product Nuplazid 34mg Capsule. Solubility Tests

The analytical method is the HPLC method for polymorphs of pimavanserin tartrate solubility study.

Table 5: Summary of pimavanserin tartrate polymorphs The highest of the Ctest given in the results are accepted as Cmax and the table are evaluated according to it.

Table 6: Pimavanserin Tartrate (Form A) Assessment table

ED = Label Value (mg), (34 mg Pimavanserin = 40 mg Pimavanserin Tartrate) VT = Media volume

C = Concentration of label value in media volume (mg/mL) Tablo 7: Pimavanserin Tartrate (Form C) Assessment table

VT = Media volume

C = Concentration of label value in media volume (mg/mL) Overall conclusion for solubility results:

Form A / Pimavanserin: It is very well dissolved in all medias and sink condition is provided in all medias. During solubility, it was dissolved as pellets on the surface and in the solution. There was no precipitation in the solutions. It dissolved quickly without the need for a hot water bath. Form C / Pimavanserin: It is very well dissolved in all medias and sink condition is provided in all medias. While solubility, it became gel-like in the lower part of the solution and dissolved. Dissolution was slower than Form A/Pimavanserin and dissolved in a 37 °C hot water bath. There was no precipitation in the solutions.

The term “w/w %” as used herein, and as conventionally used in the pharmaceutical industry, refers to a percentage by weight compared to the total weight of the composition considered.

A pharmaceutical composition according to the invention is considered "stable", if during a certain period of time 70%, preferably 80% and most preferably 95% of the initial content of pimavanserin, is maintained over said period of time.