TREA

PHARMACEUTICAL COMPOSITIONS OF 5-HT6 RECEPTOR ANTAGONIST

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Information

  • Patent Application
  • 20210346374
  • Publication Number
    20210346374
  • Date Filed
    July 16, 2021
    3 years ago
  • Date Published
    November 11, 2021
    3 years ago
Information
Abstract
The present invention relates to an immediate release (IR) pharmaceutical composition comprising 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or pharmaceutically acceptable salt (s) and one or more pharmaceutically acceptable excipients. The present invention also relates to methods of preparation of said pharmaceutical compositions.
Description
FIELD OF INVENTION

The present invention relates to immediate release (IR) pharmaceutical compositions comprising 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt (s) thereof as an active ingredient and one or more pharmaceutically acceptable excipients and to methods of preparation of said compositions.


BACKGROUND OF INVENTION

Alzheimer's disease (AD) is the most common cause of dementia worldwide. The exponential rise in the number of cases of AD in the past and the future projection over the next few decades is anticipated to result in great pressure on the social and health-care systems of developed and developing economies alike. AD also imposes tremendous emotional and financial burden to the patient's family and community.


The compound of the present invention is a pure 5-hydroxytryptamine 6 receptor (5-HT6R) antagonist with high affinity and very high selectivity over closely related serotonin receptor subtypes and improves learning and memory in animals. The 5-HT6R antagonist, 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt (s) thereof is described in U.S. Pat. No. 7,875,605 which is incorporated by reference.


1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate (herein after referred to as Compound 1), which has chemical structure,




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is a promising pharmaceutical active agent intended for the symptomatic treatment of Alzheimer's disease and other disorders of memory and cognition like Attention deficient hyperactivity, Parkinson's disease, schizophrenia, lewy body dementia, vascular dementia or frontotemporal dementia. The process for preparing compound 1 on a larger scale is described in WO2015083179A1.


There is a need to develop a suitable dosage form of the compound 1 to treat the patients with AD and other disorders of memory and cognition like Attention deficient hyperactivity, Parkinson's disease, schizophrenia, lewy body dementia, vascular dementia or frontotemporal dementia. In our present invention, we developed IR pharmaceutical compositions of compound 1 having (1) excellent properties of tablet formation, (2) excellent wetting, disintegration, rapid and complete drug release properties, (3) good purity profile and (4) stable formulation for the treatment of AD and other disorders of memory and cognition like Attention deficient hyperactivity, Parkinson's disease, schizophrenia, lewy body dementia, vascular dementia or frontotemporal dementia.


SUMMARY OF INVENTION

In one aspect, the present invention relates to immediate release pharmaceutical composition comprising 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.


In another aspect, the present invention relates to immediate release pharmaceutical composition comprising 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate and one or more pharmaceutically acceptable excipients.


In another aspect, the present invention relates to immediate release pharmaceutical composition comprising 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate, wherein the pharmaceutical composition comprises binder, diluent, lubricant, glidant, and disintegrant.


In another aspect, the present invention relates to immediate release pharmaceutical composition comprising,

    • a) 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof;
    • b) diluent;
    • c) lubricant; and
    • d) glidant.


In another aspect, the present invention relates to immediate release pharmaceutical composition comprising,

    • a) 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof;
    • b) diluent;
    • c) lubricant;
    • d) glidant; and
    • e) disintegrant.


In yet another aspect, the present invention relates to immediate release pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof, wherein said composition comprises on a total of 100% by weight:

    • (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 36% to about 97% diluent;
    • (c) from about 0.5% to about 2% lubricant;
    • (d) from about 0.5% to about 1% glidant;
    • (e) 0% to about 10% binder; and
    • (f) 0% to about 5% disintegrant.


In yet another aspect, the present invention relates to immediate release pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate, wherein said composition comprises on a total of 100% by weight:

    • (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 36% to about 97% diluent;
    • (c) from about 0.5% to about 2% lubricant;
    • (d) from about 0.5% to about 1% glidant;
    • (e) 0% to about 10% binder; and
    • (f) 0% to about 5% disintegrant.


In yet another aspect, the present invention relates to immediate release pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate, wherein said composition comprises on a total of 100% by weight:

    • (a) from about 2% to about 3% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) about 95% to about 97% diluent;
    • (c) about 1% lubricant; and
    • (d) about 0.5% glidant.


In yet another aspect, the present invention relates to immediate release pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate, wherein said composition comprises on a total of 100% by weight:

    • (a) from about 11% to about 38% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 61% to about 87% of diluent;
    • (c) from about 1% to about 2% lubricant; and
    • (d) about 0.5% glidant.


In yet another aspect, the present invention relates to immediate release pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate, wherein said composition comprises on a total of 100% by weight:

    • (a) from about 48% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) about 38% to about 48% diluent;
    • (c) about 1% lubricant; and
    • (d) about 0.5% glidant.


In yet another aspect, the present invention relates to immediate release pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate, wherein said composition comprises on a total of 100% by weight:

    • (a) from about 12% to about 18% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 78% to about 86% diluent;
    • (c) about 1% lubricant;
    • (d) about 0.5% glidant; and
    • (e) about 2% disintegrant.


In yet another aspect, the present invention relates to immediate release pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate, wherein said composition comprises on a total of 100% by weight:

    • (a) from about 24% to about 38% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 61% to about 72% diluent;
    • (c) from about 1% to about 1.25% lubricant;
    • (d) about 0.5% glidant; and
    • (e) from about 0.5 to about 2% disintegrant.


In yet another aspect, the present invention relates to immediate release pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate, wherein said composition comprises on a total of 100% by weight:

    • (a) from about 36% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 36% to about 62% diluent;
    • (c) from about 0.5% to about 1% lubricant;
    • (d) about 0.5% glidant; and
    • (e) about 2% disintegrant.


In yet another aspect, the present invention relates to immediate release pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate, wherein said composition comprises on a total of 100% by weight:

    • (a) from about 11% to about 38% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 61% to about 72% diluent;
    • (c) about 1% lubricant;
    • (d) from about 2% to about 10% binder;
    • (e) about 0.5% glidant; and
    • (f) from about 2% to about 5% disintegrant.


In yet another aspect, the present invention also relates to methods of preparation of immediate release pharmaceutical compositions.


In yet another aspect the present invention relates to an immediate release tablet, wherein said tablet comprises on a total of 100% by weight:

    • (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 36% to about 97% diluent;
    • (c) 0% to about 10% binder;
    • (d) from about 0.5% to about 2% lubricant;
    • (e) from about 0.5% to about 1% glidant; and
    • (f) 0% to about 5% disintegrant.


In yet another aspect, the present invention relates to immediate release tablet, wherein said tablet comprises on a total of 100% by weight:

    • (a) from about 2% to about 3% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) about 95% to about 97% diluent;
    • (c) about 1% lubricant; and
    • (d) about 0.5% glidant.


In yet another aspect, the present invention relates to immediate release tablet, wherein said tablet comprises on a total of 100% by weight:

    • (a) from about 11% to about 38% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 61% to about 87% diluent;
    • (c) from about 1% to about 2% lubricant; and
    • (d) about 0.5% glidant.


In yet another aspect, the present invention relates to immediate release tablet, wherein said tablet comprises on a total of 100% by weight:

    • (a) from about 48% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) about 38% to about 48% diluent;
    • (c) about 1% lubricant; and
    • (d) about 0.5% glidant.


In yet another aspect, the present invention relates to immediate release tablet, wherein said tablet comprises on a total of 100% by weight:

    • (a) from about 12% to about 18% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 78% to about 86% diluent;
    • (c) about 1% lubricant;
    • (d) about 0.5% glidant; and
    • (e) about 2% disintegrant.


In yet another aspect, the present invention relates to immediate release tablet, wherein tablet comprises on a total of 100% by weight:

    • (a) from about 24% to about 38% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 61% to about 72% diluent;
    • (c) from about 1% to about 1.25% lubricant;
    • (d) about 0.5% glidant; and
    • (e) from about 0.5% to about 2% disintegrant.


In yet another aspect, the present invention relates to immediate release tablet, wherein said tablet comprises on a total of 100% by weight:

    • (a) from about 36% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 36% to about 62% diluent;
    • (c) from about 0.5% to about 1% lubricant;
    • (d) about 0.5% glidant; and
    • (e) about 2% disintegrant.


In yet another aspect, the present invention relates to immediate release tablet, wherein said tablet comprises on a total of 100% by weight:

    • (a) from about 11% to about 38% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 61% to about 72% diluent;
    • (c) about 1% lubricant;
    • (d) from about 2% to about 10% binder;
    • (e) about 0.5% glidant; and
    • (f) from about 2% to about 5% disintegrant.


In yet another aspect, the present invention relates to the immediate release pharmaceutical composition of dose ranges from about 5 mg to about 200 mg.


In yet another aspect, the present invention relates to the immediate release pharmaceutical composition, wherein the total weight of the immediate release tablet is from about 100 mg to about 600 mg.


In yet another aspect, the present invention relates to the immediate release pharmaceutical composition, wherein the immediate release pharmaceutical composition comprises,

    • i) less than 0.5% of chloro impurity;
    • ii) less than 0.5% of unknown impurity;
    • iii) less than 1% of total impurity.


In yet another aspect, the present invention relates to the immediate release pharmaceutical composition, wherein the purity of the 1-[(2-bromophenyl)sulfonyl]-5-m ethoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate is about 99.3%.


In yet another aspect, the present invention relates to the immediate release pharmaceutical composition, wherein the 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate is released about 85% to about 100% within 30 minutes.







DETAILED DESCRIPTION OF INVENTION

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:


The term, “pharmaceutically acceptable excipients” as used herein refers to diluents, disintegrants, binders, lubricants, glidants, polymers, coating agents, solvents, co-solvents, preservatives, wetting agents, thickening agents, antifoaming agents, sweetening agents, flavouring agents, antioxidants, colorants, solubulizers, plasticizer 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 “binder” employed in a composition of the present invention is capable for holding the ingredients together and forming the granules with required mechanical strength. Example of binders includes without limitation, polyvinylpyrrolidone (povidone (PVPK30)), polyethlylene glycol (PEG), saccharides, gelatins, pregelatinized starches, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC) and cellulose ethers.


The “diluent” employed in a composition of the present invention is capable for providing bulkiness to obtain a desired immediate release pharmaceutical composition. Preferred diluents are 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 isomalt (galenIQ-721).


The “disintegrant” employed in a composition of the present invention is capable of facilitating the breakup of an immediate release pharmaceutical composition prepared from the composition when placed in contact with an aqueous medium. Preferred disintegrants are alginic acid or sodium alginate; cellulose or cellulose derivatives such as carboxymethylcellulose sodium, croscarmellose sodium, powdered cellulose or croscarmellose; 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 1-ethenyl-2-pyrrolidinone); sodium starch glycolate or starch.


The “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 are fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, magnesium stearate, 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 “glidant” employed in a composition of the present invention is capable for increase in flow, those selected from the group consisting of colloidal silicon dioxide (Aerosil), higher fatty acids, the metal salts, talc, and the like or the mixtures thereof.


The “coloring agent” (or “colorant”) employed in a composition of the present invention may be one or more compounds which impart a desired color to the composition. Addition of a coloring agent may be used, for example, so that tablets of different potencies may be easily distinguished. Example of coloring agent includes but not limited to beta-carotene, indigo carmine, sunset yellow FCF, tartrazine, brilliant blue FCF, titanium dioxide, quinoline yellow, allura red AC, quinizarine green SS and iron oxides, which are accepted universally.


The “active ingredient” defined in this invention is 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate.


The term “about” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. 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, “pharmaceutically acceptable salt” as used herein refers to salts of the active ingredient and are prepared by reaction with the appropriate acid or acid derivative, depending on the particular substituents found on the compounds described herein. The pharmaceutically acceptable salt includes but not limited to dimesylate monohydrate salt, dihydrochloride salt, oxalate salt, tartrate salt and the like. Preferably, the pharmaceutically acceptable salt is dimesylate monohydrate salt and dihydrochloride salt. More preferably, the pharmaceutically acceptable salt is dimesylate monohydrate salt.


The term, “patient” as used herein refers to an animal. Preferably the term “patient” refers to mammal. The term mammal includes animals such as mice, rats, dogs, rabbits, pigs, monkeys, horses and human. More preferably the patient is human.


The term “impurity” as used herein refers to any component of a drug substance that is not the chemical entity defined as the drug substance and in addition, for a drug product, any component that is not a formulation ingredient.


The term, “immediate release composition” refers to a composition of an active ingredient which disintegrates rapidly and releases greater than 85% at 30 minutes.


The immediate release pharmaceutical compositions of the present invention can be used for treatment or prevention of Alzheimer's disease and other disorders of memory and cognition like Attention deficient hyperactivity, Parkinson's disease, schizophrenia, lewy body dementia, vascular dementia or frontotemporal dementia. The immediate release pharmaceutical composition of the instant invention can be administered orally, in an effective amount, to a mammalian (especially human) subject to treat or prevent the aforementioned disorders.


The effective dosage of the immediate release pharmaceutical composition comprising 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate is about 5 mg to about 200 mg. The immediate release pharmaceutical composition can be administered 1 to 3 times per day, based on condition of the patients. The total weight of immediate release pharmaceutical composition of the present invention is from about 100 mg to 600 mg.


The compound 1 belongs to class I as per BCS classification based on our experimental results and hence particle size of the compound 1 does not effect in the treatment of the patient.


In one embodiment the present invention relates to the immediate release pharmaceutical composition comprising:


















Range
Preferred Range



Ingredient
(% w/w)
(% w/w)









Compound 1
 2-60
10-50



(Active ingredient)



Diluent
36-97
40-90



Binder
 0-10
3-5



Disintegrant
0-5
2-4



Lubricant
0.5-2 
0.5-1 



Glidant
0.5-1 
0.5-1 










In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprises about 2% to about 3% by weight of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprises about 10% to about 40% by weight of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprises about 20% to about 40% by weight of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprises about 30% to about 50% by weight of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprises about 30% to about 60% by weight of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprising about 40% to about 80% by weight of diluent.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprising about 70% to about 90% by weight of diluent.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprising about 20% to about 40% by weight of diluent.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition in the form of tablet or capsule.


In yet another embodiment, the present invention relates to an immediate release tablet, wherein the tablet comprises,

    • (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 36% to about 97% microcrystalline cellulose;
    • (c) from about 0.5% to about 2% magnesium stearate; and
    • (d) from about 0.5% to about 1% colloidal silicon dioxide.


In yet another embodiment, the present invention relates to an immediate release tablet, wherein the tablet comprises,

    • (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 36% to about 97% microcrystalline cellulose;
    • (c) from about 0.5% to about 2% magnesium stearate;
    • (d) from about 0.5% to about 1% colloidal silicon dioxide; and
    • (e) from about 0.5% to about 5% crospovidone.


In yet another embodiment, the present invention relates to an immediate release tablet, wherein the tablet comprises,

    • (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 36% to about 97% microcrystalline cellulose;
    • (c) from about 0.5% to about 2% magnesium stearate;
    • (d) from about 0.5% to about 1% colloidal silicon dioxide;
    • (e) 0% to about 10% povidone; and
    • (f) 0% to about 5% crospovidone.


In yet another embodiment, the present invention relates to an immediate release tablet, wherein the tablet comprises,

    • (a) from about 20% to about 50% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
    • (b) from about 40% to about 75% microcrystalline cellulose;
    • (c) from about 0.5% to about 2% magnesium stearate;
    • (d) from about 0.5% to about 1% colloidal silicon dioxide; and
    • (f) from about 0.5% to about 2% crospovidone.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprises about 40% to about 80% by weight of microcrystalline cellulose.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprises about 70% to about 90% by weight of microcrystalline cellulose.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprises about 20% to about 40% by weight of microcrystalline cellulose.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprises from 0.5% to about 2% by weight of crospovidone.


In yet another embodiment, the present invention relates to the immediate release pharmaceutical composition comprises about 4% by weight of povidone.


In other aspect, the present invention relates to the use of the immediate release pharmaceutical composition comprising 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients for the treatment of Alzheimer's disease, memory and cognition disorders selected from Attention deficient hyperactivity disorder, Parkinson's disease, schizophrenia, lewy body dementia, vascular dementia or frontotemporal dementia.


In yet another aspect, the instant invention relates to the method of treatment of Alzheimer's disease, memory and cognition disorders selected from Attention deficient hyperactivity disorder, Parkinson's disease, schizophrenia, lewy body dementia, vascular dementia or frontotemporal dementia comprising administering to a patient a therapeutically effective amount of the immediate release pharmaceutical composition comprising 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.


Methods of Preparation of Immediate Release Pharmaceutical Composition

In another aspect, the instant invention relates to the process for the preparation of the immediate release pharmaceutical composition comprising 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof.


The preparation of the immediate release pharmaceutical composition includes two methods, a) direct compression method and b) wet granulation method.


In one embodiment, the preparation of the immediate release pharmaceutical composition using direct compression method comprises the following steps:

  • a) weighing the active ingredient and diluent and sieving through sieve number 40;
  • b) mixing the sieved active ingredient and diluent;
  • c) weighing the lubricant, glidant, disintegrant and sieving through sieve number 40;
  • d) adding the mixture obtained in step (c) into step (b) and blending the mixture for 5-20 minutes to form homogenous mixture; and
  • e) compressing the lubricated blend to obtain the required dosage form.


The above obtained dosage forms can be optionally coated with polymers, solvents and coloring agents by methods known in the art.


In another embodiment, the preparation of the immediate release pharmaceutical composition using wet granulation method comprises the following steps:

  • a) weighing the active ingredient, diluent and disintegrant;
  • b) sieving the weighed materials through sieve number 40;
  • c) blending the sieved active ingredient, diluent and disintegrant for 10 minutes in an octagonal blender;
  • d) weighing the binder and dissolve in required quantity of purified water;
  • e) transferring the active ingredient, diluent and disintegrant into RMG;
  • f) adding binder solution dropwise to RMG to form cohesive mass;
  • g) drying the blend in a tray drier at 50° C.;
  • h) passing the blend through #18 mesh to form granules;
  • i) weighing the lubricant and glidant and pass through sieve number 40;
  • j) adding the mixture obtained in step (h) to step (i) and blend for 10 minutes in an octagonal blender; and
  • k) compressing the lubricated blend to obtain the required dosage form.


The above obtained dosage forms can be optionally coated with polymers, solvents and coloring agents by methods known in the art.


Abbreviations

AUC Area under the curve


Cmax Maximum plasma concentration


HDPE High density polyethylene


HPMC Hydroxypropyl methylcellulose


HPLC High performance liquid chromatography


kg Kilogram

LC-MS/MS Liquid chromatography/Tandem mass spectrometry


mg Milligram
mL Milliliter
ng Nanogram
N Normality

rpm Rotation per minute


RMG Rapid mixer granulator


Tmax Time of maximum plasma concentration


T1/2 Half-life
° C. Degree Celsius

% W/W Percent weight/weight


UV Ultra violet


EXAMPLES

The following Examples are provided to illustrate preferred embodiments of the invention and are not intended to limit the scope of the present invention.


Example 1: Pharmaceutical Composition of Compound 1 IR Tablets

By using range of ingredients (% w/w) in below mentioned table and procedures explained in above mentioned preparation methods, the IR tablets of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate are prepared.
















Ingredient
Range (% w/w)









Compound 1
 2-60



Binder
0-5



Diluent
36-97



Disintegrant
0-4



Lubricant
0.5-2 



Glidant
0.5-1 










Example 2
Preparation of IR Tablet Using Direct Compression Method:
Composition of 5 mg Dose IR Tablet:

















Ingredient
% w/w
mg/tablet




















Compound 1
2.47
7.41#



Microcrystalline cellulose
96.03
288.09



(Avicel PH 102)



Magnesium stearate
1
3



Colloidal silicon dioxide
0.5
1.5



(Aerosil ®)





Total
100
300








#equivalent to 5 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound).






Method of Preparing IR Tablet:

All the ingredients were accurately weighed (Compound 1 of 2.47%, Avicel PH 102 of 96.03%) and sieved using sieve number 40. The sieved compound 1 and Avicel PH 102 were blended for 10 minutes in an octagonal blender. The mixture obtained was added to magnesium stearate (1%) and aerosil (0.5%) and blended for 10 minutes in an octagonal blender. The lubricated blend was compressed using 9 mm round concave punches and dies on rotary compression machine to obtain 300 mg tablet.


The examples 3 to 46 were prepared by following the method of preparation of example 2 by using appropriate amount of active ingredient, diluent, disintegrant, lubricant, and glidant.


Examples 3 to 11
Compositions of 25 mg Dose IR Tablets:
















Example 3
Example 4











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
12.34
37.02#
14.81
37.02#


Microcrystalline
86.16
258.48
83.69
209.23


cellulose (Avicel


PH 102)


Magnesium stearate
1
3
1
2.5


Colloidal silicon
0.5
1.5
0.5
1.25


dioxide (Aerosil ®)






Total
100
300
100
250






#equivalent to 25 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)




















Example 5
Example 6











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
37.03
37.03#
12.42
37.26#


Microcrystalline
61.47
61.47
84.08
252.24


cellulose (Avicel


PH 102)


Magnesium stearate
1
1
1
3


Colloidal silicon
0.5
0.5
0.5
1.5


dioxide (Aerosil ®)


Crospovidone
—
—
2
6


Total
100
100
100
300






#equivalent to 25 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)




















Example 7
Example 8











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
16.93
37.25#
16.93
37.25#


Microcrystalline
79.57
175.05
81.57
179.45


cellulose (Avicel


PH 102)


Magnesium stearate
1
2.2
1
2.2


Colloidal silicon
0.5
1.1
0.5
1.1


dioxide (AerosiH)


Crospovidone
2
4.4
—
—


Total
100
220
100
220






#equivalent to 25 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)




















Example 9
Example 10











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
16.93
37.25#
16.93
37.25#


Microcrystalline
—
—
81.57
179.45


cellulose (Avicel


PH 102)


Dibasic calcium
81.57
179.45
—
—


phosphate dihydrate


Magnesium stearate
1
2.2
1
2.2


Colloidal silicon
0.5
1.1
0.5
1.1


dioxide (Aerosil ®)






Total
100
220
100
220






#equivalent to 25 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)




















Example 11












Ingredient
(% w/w)
mg/tablet















Compound 1
16.93
37.25#



Starch (Starlac)
81.57
179.45



Magnesium stearate
1
2.2



Colloidal silicon dioxide
0.5
1.1



(Aerosil ®)





Total
100
220








#equivalent to 25 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)






Examples 12 to 33
Compositions of 50 mg Dose IR Tablets:
















Example 12
Example 13











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
29.62
74.05#
29.62
74.05#


Microcrystalline
66.63
166.58
—
—


cellulose (Avicel


PH 102)


Isomalt
—
—
68.88
172.2


Magnesium stearate
1.25
3.12
1
2.5


Colloidal silicon
0.5
1.25
0.5
1.25


dioxide (Aerosil ®)


Crospovidone
2
5
—
—


Total
100
250
100
250






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)




















Example 14
Example 15











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
29.62
74.05#
28.8
72#  


Starch (Starlac)
68.88
172.2
—
—


Microcrystalline
—
—
69.45
173.63 


cellulose (Avicel


PH 113)


Magnesium stearate
1
2.5
1.25
3.12


Colloidal silicon
0.5
1.25
0.5
1.25


dioxide (Aerosil ®)






Total
100
250
100
250   






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)




















Example 16
Example 17











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
28.8
72#  
29.62
74.05#


Microcrystalline
69.45
173.63 
—
—


cellulose (Avicel


PH 102)


Lactose Monohydrate
—
—
68.63
171.58


Magnesium stearate
1.25
3.12
1.25
3.12


Colloidal silicon
0.5
1.25
0.5
1.25


dioxide (Aerosil ®)






Total
100
250   
100
250






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)




















Example 18
Example 19











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
29.62
74.05#
28.8
72#  


Starch (Starcap 1500)
68.63
171.58
—
—


Microcrystalline
—
—
69.45
173.63 


cellulose (Avicel


PH 101)


Magnesium stearate
1.25
3.12
1.25
3.12


Colloidal silicon
0.5
1.25
0.5
1.25


dioxide (Aerosil ®)






Total
100
250
100
250   






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)




















Example 20
Example 21











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
29.62
74.05#
29.62
74.05#


Dextrose Monohydrate
68.88
172.2
—
—


Mannitol
—
—
68.88
172.2


Magnesium stearate
1
2.5
1
2.5


Colloidal silicon
0.5
1.25
0.5
1.25


dioxide (Aerosil ®)






Total
100
250
100
250






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)




















Example 22
Example 23











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
37.03
74.06#
29.62
74.05#


Microcrystalline
61.47
122.94
—
—


cellulose (Avicel


PH 102)


Dicalcium phosphate
—
—
68.63
171.58


dihydrate


Magnesium stearate
1
2
1.25
3.12


Colloidal silicon
0.5
1
0.5
1.25


dioxide (Aerosil ®)






Total
100
200
100
250






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)




















Example 24
Example 25











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
29.62
74.05#
29.62
74.05#


Microcrystalline
68.63
171.58
—
—


cellulose (Avicel


PH 101)


Lactose Monohydrate
—
—
66.63
166.58


Magnesium stearate
1.25
3.12
1.25
3.12


Colloidal silicon
0.5
1.25
0.5
1.25


dioxide (Aerosil ®)


Crospovidone
—
—
2
5


Total
100
250
100
250






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)




















Example 26
Example 27











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
29.62
74.05#
29.62
74.05#


Starch
—
—
66.63
166.58


(Starcap 1500)


Dicalcium phosphate
66.63
166.58
—
—


dihydrate


Magnesium stearate
1.25
3.12
1.25
3.12


Colloidal silicon
0.5
1.25
0.5
1.25


dioxide (Aerosil ®)


Crospovidone
2
5
2
5


Total
100
250
100
250






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)



















Example 28
Example 29











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
29.62
74.05#
29.62
74.05#


Lactose Monohydrate
66.63
166.58
—
—


Microcrystalline
—
—
66.63
166.58


cellulose (Avicel






101)






Magnesium stearate
1.25
3.12
1.25
3.12


Colloidal silicon
0.5
1.25
0.5
1.25


dioxide (Aerosil ®)






Crospovidone
2
5
2
5


Total
100
250
100
250






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)



















Example 30
Example 31











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
24.83
74.5#
33.86
74.5#


Microcrystalline
71.67
215
62.64
137.8


cellulose (Avicel






PH 102)






Magnesium stearate
1
3
1
2.2


Colloidal silicon
0.5
1.5
0.5
1.1


dioxide (Aerosil ®)






Crospovidone
2
6
2
4.4


Total
100
300
100
220






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free ase compound)



















Example 32
Example 33











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
12.35
74.1#
49.67
74.51#


Microcrystalline
84.15
504.9
49.83
70.24


cellulose (Avicel






PH 102)






Magnesium stearate
1
6
1
1.5


Colloidal silicon
0.5
3
0.5
0.75


dioxide (Aerosil ®)






Crospovidone
2
12
2
3


Total
100
600
100
150






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)






Example 34 to 37
Composition of 75 mg Dose IR Tablets:















Example 34
Example 35











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
37.25
111.75#
50.79
111.74#


Microcrystalline
59.25
177.75
45.71
100.56


cellulose (Avicel






PH 102)






Magnesium stearate
1
3
1
2.2


Colloidal silicon
0.5
1.5
0.5
1.1


dioxide (Aerosil ®)






Crospovidone
2
6
2
4.4


Total
100
300
100
220






#equivalent to 75 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)



















Example 36
Example 37











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
50.8
111.76#
50.8
111.76#


Microcrystalline
47.7
104.94
—
—


cellulose (Avicel






PH 102)






Starch (Starlac)
—
—
47.7
104.98


Magnesium stearate
1
2.2
1
2.2


Colloidal silicon
0.5
1.1
0.5
1.1


dioxide (Aerosil ®)






Total
100
220
100
220






#equivalent to 75 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)






Examples 38 to 44
Composition of 100 mg Dose IR Tablets:















Example 38
Example 39











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
49.36
148.08#
49.37
148.11#


Microcrystalline
49.14
147.42
49.13
147.39


cellulose (Avicel






PH 102)






Magnesium stearate
1
3
1
3


Colloidal silicon
0.5
1.5
0.5
1.5


dioxide (Aerosil ®)






Total
100
300
100
300






#equivalent to 100 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)



















Example 40
Example 41











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
59.24
148.1#
37.03
148.12#


Microcrystalline
39.26
98.15
61.47
245.88


cellulose (Avicel






PH 102)






Magnesium stearate
1
2.5
1
4


Colloidal silicon
0.5
1.25
0.5
2


dioxide (Aerosil ®)






Total
100
250
100
400






#equivalent to 100 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)



















Example 42
Example 43











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
49.67
149.01#
59.6
149#  


Microcrystalline
47.33
141.99
36.9
92.25


cellulose (Avicel






PH 102)






Magnesium stearate
0.5
1.5
1
2.5


Colloidal silicon
0.5
1.5
0.5
 1.25


dioxide (Aerosil ®)






Crospovidone
2
6
2
5  


Total
100
300
100
250   






#equivalent to 100 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)



















Example 44












Ingredient
(% w/w)
mg/tablet














Compound 1
24.7
148.2#



Microcrystalline
71.8
430.8



cellulose (Avicel





PH 102)





Magnesium stearate
1
6



Colloidal silicon
0.5
3



dioxide (Aerosil ®)





Crospovidone
2
12



Total
100
600






#equivalent to 100 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)






Examples 45 to 46
Composition of 150 mg and 200 mg Dose IR Tablets:















Example 45
Example 46











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
49.67
223.52*
49.67
 298.02#


Microcrystalline
46.83
210.73
46.83
 280.98


cellulose (Avicel






PH 102)






Magnesium stearate
1
4.5
1
6


Colloidal silicon
0.5
2.25
0.5
3


dioxide (Aerosil ®)






Crospovidone
2
9
2
12 


Total
100
450
100
600 





*equivalent to 150 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)



#equivalent to 200 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)






Example 47
Preparation of IR Tablet Using Wet Granulation Method
Composition of 50 mg IR Tablet:
















Ingredient
% w/w
mg/tablet



















Compound 1
24.67
74#



Microcrystalline cellulose
66.83
200.5 



(Avicel PH 102)





Povidone
4.0
12 



Crospovidone
3.0
9



Magnesium stearate
1.0
3



Colloidal silicon dioxide
0.5
  1.5



(Aerosil ®)





Total
100
300 






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)






Method of Preparing IR Tablet:

All the ingredients were accurately weighed (Compound 1 of 24.67%, Avicel PH 102 of 66.83% and crospovidone of 3%) and sieved using sieve number 40. The sieved compound 1, Avicel PH 102 and crospovidone were blended for 10 minutes in an octagonal blender. The mixture obtained was transferred into RMG and added povidone binder solution (povidone (4%) was dissolved in purified water) dropwise to RMG to form cohesive mass. The blend obtained was dried in a tray drier at 50° C. Dried blend was passed through #18 mesh to form granules. The granules obtained were mixed with magnesium stearate and aerosil and the mixture was blended for 10 minutes in an octagonal blender. The lubricated blend was compressed using 9 mm round concave punches and dies on rotary compression machine to obtain 300 mg tablet.


Examples 48 to 49

The following examples are prepared by following the method of preparation of example 47.


Composition of 50 mg IR Tablets:















Example 48
Example 49











Ingredient
(% w/w)
mg/tablet
(% w/w)
mg/tablet














Compound 1
24.67
 74#
24.67
 74#


Microcrystalline
65.83
 197.5
64.83
 194.5


cellulose






(Avicel PH 102)






Povidone
4.0
12
—
—


(PVP K30)






HPMC
—
—
5.0
15


Sodium starch
4.0
12
—
—


glycolate






Croscarmellose
—
—
4.0
12


sodium






Magnesium stearate
1
 3
1
 3


Aerosil
0.5
  1.5
0.5
  1.5


Total
100
300 
100
300 






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free Base compound)






Example 50 to 51

The examples 50 to 51 were prepared by following the method of preparation of example 2 by using appropriate amount of active ingredient, diluent, disintegrant, lubricant, and glidant.


Composition of 50 mg and 100 mg IR Tablets:















Example 50












Ingredients
(% w/w)
mg/tablet














Compound 1
24
72#  



Microcrystalline cellulose
74
222   



(Avicel PH 102)





Magnesium stearate
1
3  



Colloidal silicon dioxide
0.5
1.5



(Aerosil ®)





Crospovidone
0.5
1.5



Total
100
300   






#equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)



















Example 51












Ingredients
(% w/w)
mg/tablet














Compound 1
48
144# 



Microcrystalline cellulose
48.5
145.5 



(Avicel PH 102)





Magnesium stearate
1
3



Colloidal silicon dioxide
0.5
  1.5



(Aerosil ®)





Crospovidone
2
6



Total
100
300 






#equivalent to 100 mg of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole (free base compound)






Example 52
Dissolution Studies of IR Tablets

The dissolution studies were conducted for the immediate release tablets of the instant invention to demonstrate the % release of active ingredient at different time intervals.


Protocol:

Dissolution was carried out in accordance with the United States pharmacopeia general procedures using dissolution apparatus II (paddle method). The IR tablet was placed in 900 mL of simulated gastric fluid (pH 1.2), 0.1N hydrochloric acid or water at 37° C. with a paddle speed of 50 rpm/100 rpm and measuring the amount of active ingredient dissolved (especially, using UV at 255 nm or using HPLC, wavelength 220 nm) at 15 and 30 minutes.


Results:

The dissolution studies data of the IR tablets are tabulated below.

















Time
% of Active


S. No
Examples
(minutes)
ingredient release


















1
Example 2
15
97




30
97


2
Example 3
15
108




30
105


3
Example 4
15
85




30
97


4
Example 6
15
103




30
106


5
Example 7
15
103




30
103


6
Example 10
15
100




30
100


7
Example 11
15
102




30
102


8
Example 12
15
102




30
101


9
Example 13
15
98




30
98


10
Example 14
15
100




30
99


11
Example 15
15
102




30
107


12
Example 15
15
107




30
106


13
Example 17
15
101




30
103


14
Example 18
15
99




30
99


15
Example 20
15
98




30
97


16
Example 21
15
104




30
103


17
Example 22
15
102




30
106


18
Example 25
15
104




30
104


19
Example 27
15
98




30
100


20
Example 28
15
102




30
101


21
Example 32
15
98




30
96


22
Example 33
15
98




30
102


23
Example 35
15
101




30
101


24
Example 36
15
100




30
100


25
Example 37
15
106




30
108


26
Example 41
15
82




30
94


27
Example 42
15
105




30
105


28
Example 44
15
101




30
99


29
Example 45
15
98




30
96


30
Example 46
15
99




30
99


31
Example 47
15
99




30
99


32
Example 48
15
100




30
100


33
Example 49
15
101




30
101









Example 53
Stability Study of IR Tablets

The stability study was conducted to assess the stability of the immediate release tablets and the impurity profile of the instant invention under different storage conditions.


The stability studies were carried out at ambient temperature (25±2° C./65±5% RH), accelerated storage (40±2° C./75±5% RH), and 60° C. oven for 6 months.


Protocol:

The immediate release tablets are packed in HDPE bottles with polyethylene liners with desiccant for a period of 6 months at different storage conditions. The samples were analyzed for purity using HPLC.


Results:
Dissolution:

The dissolution data of examples for different time points at accelerated storage conditions are tabulated below.















% of Active ingredient release















Time
Day
1
3
6


S. No
Examples
(minutes)
1
month
months
months
















1
Example 13
30
106
106
90
104


2
Example 15
30
91
99
89
97


3
Example 16
30
98
99
103
102


4
Example 17
30
99
100
103
99


5
Example 32
30
96
99
100
102


6
Example 33
30
102
101
100
99


7
Example 44
30
99
99
99
99


8
Example 50
30
102
101
99
100


9
Example 51
30
101
100
100
102









The dissolution data of examples 50 and 51 for different time points at ambient storage conditions are tabulated below.















% of Active ingredient release




(in 30 minutes)












Storage time
Example 50
Example 51














Initial
102
101










1
month
100
99


3
months
100
100


6
months
103
101


9
months
102
103


12
months
102
102


18
months
100
100


24
months
102
97


36
months
100
101


44
months
101
101


48
months
102
101


60
months
101
103









Conclusion:

We observed no significant variation in dissolution of the IR tablets after storing for 6 months at accelerated storage conditions (i.e, temperature 40±2° C. at 75±5% relative humidity (RH)).


Further no significant variation was observed in dissolution of the IR tablets after storing for 60 months at ambient storage conditions.


Purity:

The purity of IR tablet on day 1 is tabulated below.






















Purity of

Maximum
Other






active
Chloro
unknown
unknown
Total



Example
Dose
ingredient
impurity
impurity
impurities
impurities


S. No
number
(mg)
(%)
(%)
(%)
(%)
(%)






















1
13
75
99.64
0.19
0.06
0.11
0.36


2
15
75
99.66
0.19
0.06
0.09
0.34


3
17
75
99.64
0.20
0.06
0.10
0.36









The purity of IR tablets under different storage conditions at the end of 6 months is tabulated below.


























Maximum









Chloro
unknown
Other
Total



Example
Dose
Storage
Purity
impurity
impurity
impurities
impurities


S. No
number
(mg)
conditions
(%)
(%)
(%)
(%)
(%)























1
13
75
60° C.
99.38
0.21
0.09
0.32
0.62





Oven


2
13
75
40° C./
99.63
0.19
0.06
0.12
0.37





75% RH


3
15
75
40° C./
99.64
0.19
0.06
0.11
0.36





75% RH


4
17
75
60° C.
99.37
0.20
0.08
0.35
0.63





Oven


5
17
75
40° C./
99.62
0.20
0.06
0.12
0.38





75% RH










The purity of IR tablets under accelerated conditions (40° C./75% RH) for 6 months is tabulated below.





















1
2
3
6


Examples
Test
Initial
month
months
months
months





















Example 50
Chloro impurity (%)
0.19
0.18
0.19
0.19
0.17



Maximum Unknown
0.03
0.03
0.03
0.02
0.03



impurity (%)








Total impurities (%)
0.22
0.21
0.22
0.21
0.2


Example 51
Chloro impurity (%)
0.19
0.19
0.19
0.19
0.17



Maximum Unknown
0.03
0.03
0.02
0.03
0.03



impurity (%)








Total impurities (%)
0.22
0.22
0.21
0.22
0.2










The purity of IR tablets under ambient conditions for 60 months is tabulated below.















Examples










Example 50
Example 51















Maximum


Maximum




Chloro
Unknown
Total
Chloro
Unknown
Total



impurity
impurity
impurities
impurity
impurity
impurities













Test
(%)
(%)
(%)
(%)
(%)
(%)
















Initial
0.19
0.03
0.22
0.19
0.02
0.21














1
month
0.18
0.02
0.2
0.19
0.03
0.22


3
months
0.19
0.03
0.22
0.19
0.03
0.22


6
months
0.17
0.03
0.2
0.17
0.03
0.2


9
months
0.16
0.03
0.21
0.16
0.03
0.21


12
months
0.21
0.04
0.28
0.22
0.04
0.29


18
months
0.21
0.03
0.24
0.21
0.03
0.26


24
months
0.19
0.03
0.24
0.19
0.03
0.26


36
months
0.2
0.04
0.27
0.2
0.04
0.28


44
months
0.21
0.04
0.28
0.21
0.04
0.29


48
months
0.21
0.04
0.27
0.21
0.04
0.29


60
months
0.19
0.05
0.27
0.2
0.04
0.28









Conclusion:

We observed no significant variation in purity of the active ingredient under different storage conditions. As evident from the above stability data the active ingredient in immediate release tablets of instant invention is stable at least six months under accelerated storage condition.


It was also observed that the active ingredient in immediate release tablets of the instant invention is stable for at least 60 months under ambient storage condition.


Example 54
In-Vivo Pharmacokinetic Study of IR Tablets

The dog pharmacokinetic study is conducted to confirm the dissolution data of Compound 1.


Experimental Procedure of Dog Pharmacokinetic Study

Male beagle dogs (10±2 kg) were used as experimental animals. Each dog was housed in individual cages. Animals were fasted over night before oral dosing (p.o) and food pellets were allowed 2 hours post dosing. Two beagle dogs (˜11 mg/kg) were dosed orally with IR tablets prepared by pharmaceutical compositions disclosed in Example 42.


At each time point, blood (0.5 mL) was collected through cephalic vein. Collected blood was transferred into a labeled eppendroff tube containing 10 μL of heparin as anticoagulant. Typically blood samples were collected at following time points: Pre dose, 0.25, 0.5, 1, 1.5, 2, 3, 5, 7, 12, 24, 30 and 48 hours post dose (n=2). Blood was centrifuged at 4000 rpm for 10 minutes. Plasma was separated and stored at −20° C. until analysis. The concentrations of active ingredient were quantified in plasma by validated LC-MS/MS method using suitable extraction technique. The active ingredient was quantified in the calibration range around 0.2-200 ng/mL.


Pharmacokinetic parameters Cmax, Tmax, AUC0-t and T1/2 were calculated by using standard non-compartmental model Phoenix WinNonlin 6.2 version Software package.


The results of this study are tabulated below.


















Strain/
Dose
Dosage
Cmax
Tmax
AUC0-t
T1/2


Gender
(mg/kg)
form
(ng/mL)
(hours)
(ng · hour/mL)
(hours)







Beagle dog
~11
Tablet
60 ± 16
1.25 ± 0.35
251 ± 27
5.97 ± 0.40








Claims
  • 1. An immediate release pharmaceutical composition comprising, a) 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof;b) diluent; wherein said diluent is selected from microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate, lactose, lactose hydrate, lactose anhydrate, mannitol, starch or isomalt;c) lubricant; andd) glidant.
  • 2. An immediate release pharmaceutical composition comprising, a) 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof;b) diluent; wherein said diluent is selected from microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate, lactose, lactose hydrate, lactose anhydrate, mannitol, starch or isomalt;c) lubricant;d) glidant; ande) disintegrant.
  • 3. The immediate release pharmaceutical composition as claimed in claim 1, wherein the composition on a total of 100% by weight comprising, (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof;(b) from about 36% to about 97% diluent;(c) from about 0.5% to about 2% lubricant; and(d) from about 0.5% to about 1% glidant.
  • 4. The immediate release pharmaceutical composition as claimed in claim 1, wherein the composition on a total of 100% by weight comprising, (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;(b) from about 36% to about 97% diluent;(c) from about 0.5% to about 2% lubricant; and(d) from about 0.5% to about 1% glidant.
  • 5. The immediate release pharmaceutical composition as claimed in claim 2, wherein the composition on a total of 100% by weight comprising, (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof;(b) from about 36% to about 97% diluent;(c) from about 0.5% to about 2% lubricant;(d) from about 0.5% to about 1% glidant; and(e) from about 0.5% to about 5% disintegrant.
  • 6. The immediate release pharmaceutical composition as claimed in claim 2, wherein the composition on a total of 100% by weight comprising, (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;(b) from about 36% to about 97% diluent;(c) from about 0.5% to about 2% lubricant;(d) from about 0.5% to about 1% glidant; and(e) from about 0.5% to about 5% disintegrant.
  • 7. The immediate release pharmaceutical composition as claimed in claim 2, wherein the disintegrant is selected from crospovidone, sodium starch glycolate or croscarmellose sodium.
  • 8. The immediate release pharmaceutical composition as claimed in claim 2 further comprises binder, wherein the binder is povidone or hydroxypropyl methylcellulose.
  • 9. The immediate release pharmaceutical composition as claimed in claim 1, wherein said lubricant is magnesium stearate; and glidant is colloidal silicon dioxide.
  • 10. The immediate release pharmaceutical composition as claimed in claim 2, wherein said lubricant is magnesium stearate; and glidant is colloidal silicon dioxide.
  • 11. The immediate release pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of tablet or capsule.
  • 12. The immediate release pharmaceutical composition as claimed in claim 2, wherein the composition is in the form of tablet or capsule.
  • 13. The immediate release pharmaceutical composition as claimed in claim 1, wherein the dosage of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof is about 5 mg to about 200 mg.
  • 14. The immediate release pharmaceutical composition as claimed in claim 2, wherein the dosage of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof is about 5 mg to about 200 mg.
  • 15. The immediate release pharmaceutical composition as claimed in claim 11, wherein the tablet on a total of 100% by weight comprising, (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;(b) from about 36% to about 97% microcrystalline cellulose;(c) from about 0.5% to about 2% magnesium stearate; and(d) from about 0.5% to about 1% colloidal silicon dioxide.
  • 16. The immediate release pharmaceutical composition as claimed in claim 12, wherein the tablet on a total of 100% by weight comprising, (a) from about 2% to about 60% 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;(b) from about 36% to about 97% microcrystalline cellulose;(c) from about 0.5% to about 2% magnesium stearate;(d) from about 0.5% to about 1% colloidal silicon dioxide; and(e) from about 0.5% to about 4% crospovidone.
  • 17. The immediate release pharmaceutical composition as claimed in claim 15, wherein the dosage of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate is about 5 mg to about 200 mg.
  • 18. The immediate release pharmaceutical composition as claimed in claim 15, wherein the total weight of immediate release tablet is from about 100 mg to 600 mg.
  • 19. The immediate release pharmaceutical composition as claimed in claim 16, wherein the dosage of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate is about 5 mg to about 200 mg.
  • 20. The immediate release pharmaceutical composition as claimed in claim 16, wherein the total weight of immediate release tablet is from about 100 mg to 600 mg.
Priority Claims (1)
Number Date Country Kind
201641033741 Oct 2016 IN national
CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application to U.S. application Ser. No. 16/337,685, filed Mar. 28, 2019, the national state completion application of PCT Application No. PCT/IB2017/056009, filed Sep. 29, 2017, and claims priority from India Application No. 201641033741, filed Oct. 3, 2016. Each of these applications is incorporated by reference in their entirety.

Continuation in Parts (1)
Number Date Country
Parent 16337685 Mar 2019 US
Child 17378434 US