DESC:Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
The term " Lumateperone " as used herein includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof, the term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
The term, "pharmaceutically acceptable excipients" as used herein refers to diluents, disintegrants, binders, lubricants, glidants, coating agents, solvents, co-solvents, preservatives, wetting agents, thickening agents, antifoaming agents, sweetening agents, flavouring agents, antioxidants, solubilizers, plasticizers or dispersing agents and the like. The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.

The term "diluent" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. The diluents of instant invention includes, but are not limited to inorganic phosphates such as dibasic calcium phosphate, calcium sulphate or dicalcium phosphate dihydrate; sugars such as lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose, erythritol, lactilol, xylitol, sorbitol, mannitol or malitol; cellulose or cellulose derivatives such as microcrystalline cellulose; Avicel, Avicel PH 101, Avicel PH 102 or Avicel PH 103, maize starch, Starcap-1500, Starlac and galenIQ-721.

The term "Sugar alcohol" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. A sugar alcohol is a polyalcohol resulting from the reduction of the carbonyl group in a monosaccharide to a hydroxyl group. Non-limiting examples of sugar alcohols include isomalt, mannitol, sorbitol, xylitol, lactitol, maltitol, inositol, erythritol, hydrogenated starch hydrolysates and mixtures thereof.

The term "binder" employed in a composition of the present invention is capable for holding the ingredients together and forming the granules with required mechanical strength. The binders of instant invention include, but are not limited to, polyvinylpyrrolidone (povidone), polyethlylene glycol (PEG), saccharides, gelatins, pregelatinized starches, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC) and cellulose ethers.

The term "Lubricant" employed in a composition of the present invention is capable of preventing the ingredients from clumping together and from sticking to the apparatus on which it is formed, for example, preventing adherence to the face of the upper punch (picking) or lower punch (sticking) of a compression machine. Preferred lubricants of instant invention includes, but are not limited to fatty acids or fatty acid derivatives such as calcium stearate, magnesium stearate, glyceryl monostearate, glyceryl palmitostearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid or hydrogenated vegetable oil; polyalkylene glycols such as polyethylene glycol (PEG) or sodium benzoate and the like.

The term " Glidant" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. The Glidant of instant invention includes, but are not limited to inorganic phosphates such as talc, dibasic calcium phosphate, Colloidal Silicon dioxide (fumed silica), hydrophilic silica, Sodium Carboxymethyl starch calcium sulphate or dicalcium phosphate dihydrate; sugars such as lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose, erythritol, lactilol, xylitol, sorbitol, mannitol or malitol; cellulose or cellulose derivatives such as microcrystalline cellulose; Avicel, Avicel PH 101, Avicel PH 102 or Avicel PH 103, maize starch, Starcap-1500, Starlac and galenIQ-721.

The term "Disintegrant" employed in a composition of the present invention is capable of facilitating the breakup of a pharmaceutical composition prepared from the composition when placed in contact with an aqueous medium. The disintegrants of instant invention includes, but are not limited to alginic acid or sodium alginate; cellulose or cellulose derivatives such as carboxymethylcellulose sodium, Sodium Carboxymethyl starch, croscarmellose sodium, powdered cellulose, croscarmellose sodium; iron exchange resin such as amberlite, gums such as agar, locust bean, karaya, pectin and tragacanth, crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone, i.e., cross-linked l-ethenyl-2-pyrrolidinone); Pregelatinized starch, sodium starch glycolate or starch.

The term "composition" or "pharmaceutical composition" or “dosage form” as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.

The term "stable" as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.

The term "about" as used herein refers to a defined range of the value by + 10 %. For example, about 2 % means 1.8 % to 2.2 %, about 5 % means 4.5 % to 5.5 %, about 10 % means 9 % to 11 % and about 40 % means 36 % to 44 %.

The term "oral dosage forms" includes all conventional oral solid dosage forms like a tablet, capsule, Oral disintegrating films or tablets, syrups, suspension, granules, pill, caplet, pellets, powder or sachet, or any other orally ingestible dosage form comprising Lumateperone or its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The terms “prevent” and “preventing” as used herein refers the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The term “particles” refers to individual drug substance particles whether the particles exist singly or are agglomerated. Thus, a composition comprising particulate Lumateperone may contain agglomerates that are well beyond the size limit of about 500 µm specified herein. However, if the mean size of the primary drug substance particles (i.e., Lumateperone) comprising the agglomerate are less than about 500 µm individually, then the agglomerate itself is considered to satisfy the particle size constraints defined herein and the composition is within the scope of the invention.

The “Lumateperone particles” refers to particles of Lumateperone that do not include an added excipient. Lumateperone particles are different than “particles containing Lumateperone”, which are particles that contain Lumateperone and at least one added excipient. Lumateperone particles of the disclosure exclude a polymeric, wax or protein excipient and are not embedded, contained, enclosed or encapsulated within a solid excipient. Lumateperone particles of the disclosure may, however, contain impurities and byproducts typically found during preparation of Lumateperone. Even so, Lumateperone particles comprise at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% Lumateperone, or a pharmaceutically acceptable salt thereof, meaning the Lumateperone particles consist of or consist essentially of substantially pure Lumateperone or pharmaceutically acceptable salt thereof.

According to embodiment, the present invention relates to a stable pharmaceutical compositions comprising Lumateperone or pharmaceutically acceptable salt thereof in crystalline form and one or more pharmaceutical acceptable excipients.

According to embodiment, the present invention relates to a stable pharmaceutical compositions comprising Lumateperone or pharmaceutically acceptable salt thereof in amorphous form and one or more pharmaceutical acceptable excipients.

According to embodiment, the present invention relates to a stable pharmaceutical compositions comprising Lumateperone or pharmaceutically acceptable salt thereof having particle size (D90) less than 200µm, and one or more pharmaceutical acceptable excipients.

According to embodiment, present invention to provide a particle size distribution of the Lumateperone may have from D10 = 10 µm, D50 = 200 µm and D90 = 400µm, wherein the 10th volume percentile particle size (D10) is less than about 50 µm, the 50th volume percentile particle size (D50) is less than about 200 µm, or the 90th volume percentile particle size (D90) is less than about 400 µm, or any combination thereof.

According to embodiment, present invention to provide a particle size distribution of the Lumateperone may have particle size (D90) is less than 500 µm, preferably less than 200 µm, and more preferably less than100 µm are combination thereof.

According to embodiment, present invention to provide a particle size distribution of the Lumateperone may have particle size (D90) is less than 100 µm, preferably less than 50 µm, and more preferably less than 10 µm are combination thereof.

In one embodiment, the present invention relates to a pharmaceutical capsule dosage form composition comprising Lumateperone or pharmaceutically acceptable salt thereof having D90 less than 500µm and one or more pharmaceutically acceptable excipients wherein the composition comprising sugar alcohol at least 60%.

In one embodiment, the present invention relates to a pharmaceutical capsule dosage form composition comprising Lumateperone or pharmaceutically acceptable salt thereof having D90 less than 200µm and one or more pharmaceutically acceptable excipients.
In certain exemplary embodiments, the pharmaceutical composition comprises, Lumateperone or its pharmaceutically acceptable salt thereof, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids.

In one embodiment, the present invention relates to a stable pharmaceutical compositions comprising Lumateperone or pharmaceutically acceptable salt thereof, and one or more pharmaceutical acceptable excipients; wherein Lumateperone or pharmaceutically acceptable salt thereof is crystalline form or amorphous form.

In another embodiment, the oral pharmaceutical composition is in the form of tablet or Syrups or Suspension comprising Lumateperone or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

According embodiment, the present invention relates to oral stable composition of Lumateperone, wherein said composition comprises on a total of 100 % by weight: comprising from about 1-20% of Lumateperone or its pharmaceutical salt thereof in crystalline or amorphous form;
(1) At least 1 % to 60 % one or more Sugar Alcohol
(2) from about 1% to about 30 % Diluent or filler other than sugar Alcohol
(3) from about 10 % to about 15 % one or more Disintegrants;
(4) from about 1.5 % to about 10 % one or more Glidants;
(5) from about 0.25 % to about 5 % one or more Lubricants;

According embodiment, the present invention relates to oral capsule composition of Lumateperone, wherein said composition comprises on a total of 100 % by weight: comprising from about 31 % to about 60 % of Lumateperone or its pharmaceutical salt thereof in crystalline or amorphous form;

(1) at least 1 % to 60% of Mannitol;
(2) at least 1% to 30 % Lactose
(3) Contain 10 % to about 15 % of croscarmellose sodium;
(4) Contain 1.5 % to about 10 % of talc;
(5) Contain 0.2 % to about 5.0 % of magnesium stearate; and
(6) optionally one or more pharmaceutical acceptable excipients;

According embodiment, Lumateperone or pharmaceutically acceptable salt thereof has a particle size distribution with the D90 is less than 500 µm, preferably less than 300 µm, more preferably less than 200 µm.

Particle size analysis can be carried out via different methods. Non-limiting examples of the methods include, but are not limited to, sieve technique, wet dispersion method with laser diffraction analysis, dry dispersion method with laser diffraction analysis, or a combination thereof. Particle size analysis is not limited to the methods described herein and can be carried out using any method known to one skilled in the art. In one embodiment, particle size analysis can be performed via a sieve technique. In another embodiment, particle size analysis can be performed using a wet dispersion method (e.g., water as the dispersing agent, and analysis by laser diffraction using, e.g., Sympatec equipment). In yet another embodiment, particle size analysis can be performed using a dry dispersion method and analyzed by laser diffraction using, e.g., Sympatec equipment.

According embodiment of the present invention relates to the process of preparation of an oral stable composition of Lumateperone having reduced particle size, which is prepared by blending Lumateperone and mannitol together. Adding a disintegrant (e.g., croscarmellose sodium), or a glidant (e.g., talc), or a lubricant (e.g., magnesium stearate), or a combination thereof). The above composition is blended for 20-25 minutes. The above mixture is encapsulating the resulting material, e.g., into hard-walled capsules and optionally applying one or more coatings to the capsule.

According embodiment of the present invention relates to the process of preparation of an oral stable composition of Lumateperone having reduced particle size, which is prepared by mixing mannitol, disintegrant (e.g., croscarmellose sodium), or a glidant (e.g., talc), or a lubricant (e.g., magnesium stearate), or a combination thereof). The above mixture is granulated by adding granulation fluid (consisting of binder and solvent) and obtained granules are lubricated. The above composition is blended for 20- 25 minutes. The lubricated granules are then filled into capsules or sachets or punched in to suitable size tablets and coated with a suitable film coating.

The pharmaceutical compositions as mentioned above can be prepared by using any suitable method known in the art such as direct compression, dry or wet granulation (aqueous/non-aqueous or combination), extrusion spheronization, melt extrusion, melt granulation, coating over inert spheres, spray coating, spray drying and solvent evaporation.

According embodiment of the present invention relates to the process of preparation of an oral stable composition of Lumateperone, which is prepared by using dry granulation method.

According embodiment of the present invention relates to the process of preparation of an oral stable composition of Lumateperone, which is prepared by using wet granulation method.

According embodiment of the present invention relates to the process of preparation of an oral stable composition of Lumateperone, which is prepared by direct compression method.

According embodiment, the present invention composition relates to the oral stable pharmaceutical composition comprising Lumateperone or its pharmaceutical salt thereof having better stability, good purity profile, dissolution profile and better bioavailability.

In an embodiment, the Lumateperone can be administered from about 5 mg/day to about 100 mg/day.
In an embodiment, the Lumateperone Tosylate pharmaceutical composition comprising 60 mg of Lumateperone Tosylate and pharmaceutically acceptable excipients, wherein the composition is devoid of sugar alcohol and the amount of Lumateperone Tosylate is equivalent to 42 mg of Lumateperone base.

In an embodiment, the Lumateperone Tosylate pharmaceutical composition comprising 30 mg of Lumateperone Tosylate and pharmaceutically acceptable excipients, wherein the composition is devoid of sugar alcohol and the amount of Lumateperone Tosylate is equivalent to 21 mg of Lumateperone base.

In an embodiment, the Lumateperone Tosylate pharmaceutical composition comprising 15 mg of Lumateperone Tosylate and pharmaceutically acceptable excipients, wherein the composition is devoid of sugar alcohol and the amount of Lumateperone Tosylate is equivalent to 10.5 mg of Lumateperone base.

The pharmaceutical composition is meant for once daily, twice daily or thrice daily administration.

According embodiment, the present invention relates to the oral stable composition comprising Lumateperone or its pharmaceutical salt thereof, having dissolution more than 90% within 45 minutes.

According embodiment, the present invention relates to the oral stable composition comprising Lumateperone or its pharmaceutical salt thereof, having dissolution more than 98% within 30 minutes.

According embodiment, the present invention relates to the pharmaceutical composition comprising Lumateperone or its pharmaceutical salt thereof for the treatment central nervous system disorders.

According embodiment, the present invention relates to the pharmaceutical composition comprising Lumateperone or its pharmaceutical salt thereof for the treatment of Schizophrenia.

According embodiment, the present invention relates to the pharmaceutical composition comprising Lumateperone or its pharmaceutical salt thereof for the treatment of Depressive episodes associated with bipolar I or II disorder as monotherapy and as adjunctive therapy with lithium or valproate.

According embodiment, the present invention relates to the pharmaceutical composition comprising Lumateperone or its pharmaceutical salt thereof for the treatment of sleep disorders.

According embodiment, the present invention relates to the pharmaceutical composition comprising Lumateperone or its pharmaceutical salt thereof for the treatment of behavioral disorders associated with dementia.

In another embodiment, the present invention relates to a pharmaceutical stable dosage form composition comprising immediate release capsule.

In another embodiment, the present invention relates to a pharmaceutical stable dosage form composition comprising immediate release tablet.

Example:
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
S.no Ingredients Category Quantity in Mg
Ex 1 Ex 2 Ex 3
1 Lumateperone Tosylate API 60 60 60
2 Mannitol Diluent 180 120 60
3 Lactose Diluent 24 93 177.9
4. Croscarmellose sodium Disintegrant 30 24 1.5
5. Talc Glidant 3 1.5 0.3
6. Magnesium stearate Lubricant 3 1.5 0.3
Total 300 300 300

MANUFACTURING PROCESS:
i. Co-sift the Lumateperone mono-tosylate, crystalline or amorphous form, with a portion of lactose; blending the resulting mixture
ii. Co-sift the remaining amount of lactose, Mannitol, Sodium starch glycolate, Silicon dioxide and Calcium stearate;
iii. Blending the resulting mixture for specific period of time
iv. Encapsulate the resulting mixture into a gelatin capsule or punched into tablets with suitable tooling;

Example 2:
S.No Ingredients Category Quantity in Mg/Capsule
Example 1 Example 2 Example 3
1 Lumateperone Tosylate API 60 60 60
2 Mannitol Diluent 180 120 60
3 Lactose Diluent 9 87 171.9
4. Povidone Binder 15 06 06
5. Sodium starch glycolate Disintegrant 30 24 1.5
6. Colloidal Silicon dioxide Glidant 3 1.5 0.3
7. Calcium stearate Lubricant 3 1.5 0.3
Total 300 300 300

MANUFACTURING PROCESS:
i. Co-sift the Lumateperone mono-Tosylate, crystalline or amorphous form, with a portion of lactose; blending the resulting mixture
ii. Binder solution is prepared by adding Povidone to required amount of water and stirred well till povidone is mixed well
iii. Add the binder solution to the above blended mixture and granulated with Rapid mixer granulator till the desired size of granules are obtained
iv. The above granules are dried to specific moisture content.
v. Co-sift the remaining lactose, Mannitol, Sodium starch glycolate, Silicon dioxide blend to the mixer of step iv
vi. Sift calcium stearate and add to the mixture of step v and mix well
vii. Encapsulate the resulting mixture into a gelatin capsule or punched into tablets with suitable tooling;
,CLAIMS:1) A pharmaceutical composition comprising Lumateperone or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients, where in the composition contain sugar alcohol at least 60% from the total weight of the composition.

2) The pharmaceutical composition as claimed in claim 1, where in the composition comprising Lumateperone or pharmaceutically acceptable salt thereof and one or more pharmaceutical excipients are diluent, disintegrant, glidant and lubricant.

3) The pharmaceutical composition as claimed in claim 1, where in the composition comprising Lumateperone or pharmaceutically acceptable salt thereof and
(1) at least 60% of Mannitol;
(2) at least 30 % Lactose
(3) 10% to 15% of croscarmellose sodium;
(4) 1.5% to 10% of talc;
(5) 0.2% to 5.0% of magnesium stearate; and
(6) optionally one or more pharmaceutical acceptable excipients;

4) The pharmaceutical composition as claimed in claim 1, where in the sugar alcohols is used in the formulation is mannitol or one or more pharmaceutically acceptable excipients.

5) The process for a pharmaceutical composition as claimed in claim 1, wherein the composition is prepared by granulation technique or direct compression.

6) The pharmaceutical composition as claimed in claim 1, where in the stable pharmaceutical compositions comprising Lumateperone or pharmaceutically acceptable salt having particle size (D90) less than 200µm.
7) A process for the preparation of the pharmaceutical composition as claimed in claim 1, which is prepared by blending Lumateperone and mannitol together, adding a disintegrant, glidant, lubricant or a combination thereof, blend the above composition, optionally filled in to capsule or punched into tablets with suitable punches.

8) The pharmaceutical composition as claimed in claim 1, where in the composition is used for the treatment of Schizophrenia in adults and Depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults.