DESC:
FIELD OF INVENTION

The invention relates to a modified release pharmaceutical composition of molindone or pharmaceutical acceptable salt thereof. The invention, more particularly, relates to a modified release and stable pharmaceutical composition of molindone or pharmaceutical acceptable salt thereof.

BACKGROUND OF THE INVENTION

Molindone is a dihydroindolone compound with antipsychotic and anti-schizophrenic properties. It exerts its effect by blocking dopamine receptors, probably D2 and D3, in the reticular activating and limbic systems, thereby decreasing dopamine excess in the brain. This leads to a reduction of spontaneous locomotion and aggressiveness, suppression of conditioned response, antagonism of stereotyped behaviour and hyperactivity induced by amphetamines.

Impulsive aggression (IA), irritability, and similar syndromes represent a broad category of behaviors that complicate the management of several disease states, such as attention deficit hyperactivity disorder (ADHD), bipolar disorder, autism, Tourette's syndrome, and post-traumatic stress disorder (PTSD). The study of human aggression focuses on classifying aggressive behavior, which may be treated with either or both behavioral and pharmacological intervention. Interventions such as molindone may be useful in the reduction of or the treatment of impulsive aggression, both by itself and as a secondary treatment where patients are already receiving treatment for the underlying disease or disorder, e.g. attention deficit hyperactivity disorder (ADHD), bipolar disorder, autism, Tourette's syndrome or post-traumatic stress disorder (PTSD).

Molindone is an indole derivative with chemical name 3-ethyl-2-methyl-5-(morpholin-4-ylmethyl)-1, 5, 6, 7-tetrahydroindol-4-one hydrochloride represented by formula I.

Formula I

Molindone compound and its acid addition salts were disclosed in US Patent No. 3,491,093.

Molindone hydrochloride was previously marketed as Moban® by Endo pharmaceuticals for the treatment of schizophrenia in adults. It is an immediate release (IR) tablet formulation with dose strengths of 5 mg, 10 mg, 25 mg, 50 mg, and 100 mg. Limited molindone pharmacokinetic (PK) data is available in the literature. The drug substance has a reported bioavailability of 60% to 70% relative to an intramuscular dose. It is absorbed rapidly following oral administration with a tmax observed between 1 to 1.5 hours. The drug substance is extensively and rapidly metabolized with an oral dose plasma elimination half-life of about 2 hours.

US Application Publication No. 20140135326 discloses a method of treating impulsive aggression (IA) in an ADHD patient with molindone dose of 12 mg, 18 mg, 24 mg or 36 mg.

US Patent No. 4,065,453 disclose immediate release formulation of molindone hydrochloride.

US Patent No. 8,748,472 and 10,149,853 discloses modified release molindone formulation comprising stabilizer selected from the group consisting of acidifying agents and hydrophobizing agents.

Though modified release compositions of molindone have been disclosed in the art, there still exists a need to develop an alternative modified release composition of molindone that exhibits either equivalent or superior stability relative to prior art compositions.

The inventors of the present invention have surprisingly found that a stable modified release formulation of molindone can be formulated by using minimum excipient load.

SUMMARY
The invention is directed to a stable modified release pharmaceutical composition comprising molindone or a pharmaceutically acceptable salt.

In one aspect, the invention provides a stable modified release pharmaceutical composition comprising
a. molindone or pharmaceutically acceptable salts thereof,
b. one or more release controlling compounds, and
c. one or more pharmaceutically acceptable excipients;
wherein said composition is free of acidity inducing agent and lipophilic agents.

In another aspect, the invention provides a stable modified release pharmaceutical composition comprising
a. molindone or pharmaceutically acceptable salts thereof,
b. one or more release controlling compounds selected from the group comprising pH-dependent polymers and non-pH-dependent polymers, and
c. one or more pharmaceutically acceptable excipients;
wherein said composition is free of acidity inducing agent and lipophilic agents.

In a further aspect, the invention provides a stable modified release pharmaceutical composition comprising,
A. an intragranular component comprising
i. molindone or pharmaceutically acceptable salt, and
ii. bulking agent;
B. an extragranular component comprising
i. one or more release controlling compounds selected from the group comprising pH-dependent polymers and non-pH-dependent polymers,
ii. glidant, and
iii. lubricant;
wherein said composition is free of acidity inducing agent and lipophilic agents.

In another aspect, the invention covers a stable modified release pharmaceutical composition comprising
A. an intragranular component comprising
i. molindone hydrochloride, and
ii. lactose;
B. an extragranular component comprising
i. hydroxypropyl methylcellulose,
ii. colloidal silicon dioxide and
iii. sodium stearyl fumarate;
wherein said composition is free of acidity inducing agent and lipophilic agents.

In a further aspect of the present invention, the stable modified release composition comprises less than 2.0% w/w of alkaline condition impurities relative to the total weight of molindone or salts thereof after storage at 25°C and 60% relative humidity or 30°C and 65% relative humidity or 40°C and 75% relative humidity for 3 months.

In an aspect of the present invention, the stable modified release composition of molindone as disclosed hereinabove, is prepared by a process which includes slugging or roller compaction, dry granulation, hot melt granulation, direct compression or double compression.

In further aspect of the present invention, the intragranular component of the stable modified release pharmaceutical composition of molindone as disclosed hereinabove all the aspects does not contain binder.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a stable modified release pharmaceutical composition comprising molindone or pharmaceutically acceptable salts thereof, one or more release controlling compounds and one or more pharmaceutically acceptable excipient and particularly, the composition is free of acidity inducing agent and lipophilic agents.

The inventors of the present invention have surprisingly found that stable and modified release compositions of molindone may be prepared by using lesser excipient load.

As used herein, the term ‘molindone’ refers to molindone as pharmaceutically acceptable salts; derivatives; solvates; isomers or mixtures thereof.

As molindone is a weak base, it exhibits greater solubility in acidic to slightly acidic media than in neutral to slightly alkaline pH. Being a weekly basic drug, molindone is typically included into formulations in the form of a salt, such as chloride, sulfate, phosphate, monohydrogen phosphate, dihydrogen phosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, formate, oxalate, malonate, succinate, fumarate, maleate, citrate, lactate, tartrate, methanesulfonate, mandelate, and the like.

The stable modified release pharmaceutical composition of the present invention may contain from 0.1 mg to 200 mg of molindone, preferably 5 mg to 100 mg, and more preferably 20 mg to 75 mg of the weight of the composition.

The term ‘acidity inducing agents’ as used herein throughout the specification refers to the substances which imparts acidic environment or micro-environment to the drug in composition.

The term ‘lipophilic agents’ as used herein throughout the specification refers to the substances which imparts hydrophobic environment or micro-environment to the drug in composition.

The term ‘free’ as used herein throughout the specification refers to either complete absence of the underlying substance or excipient as well as its presence in amount of less than 10 %, preferably less than 5%, more preferably less than 2% by weight of the drug substance.

The term ‘modified release’ as used herein throughout the specification refers to release of a drug substance which is slower than that of an immediate release formulation. The modified release encompass sustained release, slow release, extended release, delayed release, controlled release, programmed release and pulsed release.

The term ‘pharmaceutically acceptable excipients’ refers to one or more non-active pharmaceutical ingredient substances such as bulking agents, binders, diluents, disintegrants, glidants and lubricants. The modified release pharmaceutical composition of the invention may comprise from about 1 % to about 80 % w/w of fillers or diluents, 1 % to about 50% w/w of binder, about 1 % to about 50% w/w of disintegrants, about 0.1 % to about 10% w/w of glidants, and about 0.1 % to about 10% w/w of lubricants based on total weight of the composition.

The release controlling compounds suitable for the stable modified release composition of the present invention may be selected from pH dependent or non-pH-dependent compounds and polymers.

Suitable non-pH-dependent compounds include polymers such as hydrophilic rate controlling polymers or pH dependent polymers such as enteric polymers. The following are non-limiting examples of such polymers.

Hydrophilic compounds includes, but not limited to, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyethylene oxide, acacia, acrylic acid derivatives (e.g., carbomer homopolymer type A and carbomer homopolymer type B), hydroxyethyl cellulose, carrageenan, tragacanth, xanthan gum, povidone, alginic acid (and salts thereof), poly vinyl alcohol, carboxymethylcellulose, and combinations thereof. The preferred hydrophilic compound is hydroxypropyl methyl cellulose and its various available and commercial grades can be used.

Enteric polymers includes, but not limited to, Eudragit® FS 30 D (poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid)), Eudragit® Land Eudragit® S (poly(methacrylic acid-comethyl methacrylate)), Eudragit® L 100-55 (methacrylic acid-ethyl acrylate copolymer), Eudragit® L 30 D-55 (methacrylic acid-ethyl acrylate copolymer dispersion), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, shellac, zein, and combinations thereof.

Suitable non-pH-dependent compounds includes non-polymeric release rate-controlling agents such as hydrogenated vegetable oils (e.g.), magnesium stearate, stearic acid, glyceryl stearate, glyceryl palmitostearate, stearyl macrogolglycerides, lauryl macrogolglycerides, waxes etc. In an embodiment, the modified release pharmaceutical composition may not contain the non-polymeric release rate-controlling agents.

The release controlling compounds (such as non-pH-dependent polymers, pH-dependent polymers or their combination) may be included in the composition in the amount of from about 5% w/w to 95% w/w, preferably about 20% w/w to 50% w/w, and more preferably about 25 % w/w to 45 % w/w by weight of the composition.

The stable modified release composition of the present invention exhibits stability when stored at different stability conditions (E.g. 25°C and 60% relative humidity or 30°C and 65% relative humidity or 40°C and 75% relative humidity for 3 months). In an embodiment, the composition comprises less than 2.0% w/w of total impurities selected from cyclohexane-1,3-dione (Impurity B), 3-ethyl-2-methyl-1,5,6,7-tetrahydro-4H-indol-4-one/ 3-Ethyl-1,5,6,7-tetrahydro-2-methyl-4- (Impurity C) and 3-ethyl-6,7-dihydro-2-methyl-5-methyleneindol-4(5H)-one oxindole (Impurity D) relative to the total weight of molindone or its salts. In a further embodiment, the composition comprises less than 2.0% w/w, preferably less than 1.0% w/w and more preferably less than 0.5% w/w of alkaline condition impurities (such as Impurity D) relative to the total weight of molindone or its salts.

The amounts of the impurities can be determined by procedures known in the art, e.g., HPLC, NMR, or methods from US Pharmacopeia, or European Pharmacopeia, or a combination of two or more of these methods. The percent impurity is on an area percent basis, typically as quantified preferably by analytical HPLC.

The stable modified release pharmaceutical composition may be developed in a dosage form suitable for oral administration, including but not limited to tablet, capsule, granules, pellets, beads, mini-tablets or capsule filled with granules, pellets or mini-tablets.

In another embodiment the present invention is directed to a stable modified release pharmaceutical composition which comprises
A. an intragranular component comprising
i. molindone or pharmaceutically acceptable salt, and
ii. bulking agent;
B. an extragranular component comprising
i. one or more release controlling compounds selected from the group consisting of pH-dependent polymers and non-pH-dependent polymers,
ii. glidant, and
iii. lubricant;
wherein said composition is free of acidity inducing agents and lipophilic agents.

In an embodiment, the stable modified release composition of the present invention exhibits release of molindone over the period of at least 4 hours, 6 hours, 12 hours, 18 hours or 24 hours when tested in USP type I (Basket) dissolution apparatus at 100 RPM in 900 mL 0.1N HCl medium and is suitable for once daily administration.

It is understood that the stable modified release composition may include one or more excipients in addition to those specifically recited in intragranular and extragranular components.

Examples of bulking agent suitable for use in the modified release pharmaceutical composition of the invention includes, but not limited to lactose anhydrous or lactose monohydrate, (i.e., Supertab 20 21AN, Ludipress, Ludipress LCE, Fast Flo Lactose, Supertose, Pharmatose, Respitose), hypromellose, carbomer, low moisture microcrystalline cellulose (Avicel ® grades PH -103, PH -112, PH-I13, PH-200), colloidal silicon dioxide, dextrates (anhydrous), dextrose (anhydrous), maltol, fructose, guar gum, lactilol (anhydrous), magnesium carbonate, maltitol, maltose, mannitol, polyethylene oxide, sorbitol, sucrose, compressible sugar, confectioner's sugar, xylitol or a mixture thereof. The preferred bulking agent is lactose. The composition of the present invention may comprise bulking agent in the range of 5 % to about 60% w/w, preferably 15 % to about 50% w/w, more preferably 20 % to about 45% w/w by weight of the composition.

Examples of disintegrants suitable for use in the modified release pharmaceutical composition of the invention includes, but not limited to povidone; low-substituted hydroxypropyl cellulose; cross- linked polyvinyl pyrrolidone; carboxymethylcellulose; cross-linked sodium Carboxy methylcellulose; hydroxypropyl starch; sodium starch glycolate; sodium carboxymethyl cellulose; carboxymethyl cellulose calcium; sodium carboxymethyl starch; ion- exchange resins such as polacrilin potassium; microcrystalline cellulose; starches and pregelatinized starch; formalin-casein; clays such as bentonite or veegum; guar gum; cellulose powdered; methyl cellulose; sodium alginate; calcium alginate; chitosan; magnesium aluminum silicate and colloidal silicon dioxide or a mixture of one or more of said disintegrants. The formulation of the invention may comprise disintegrant from about 1 % w/w to about 50% w/w of disintegrant, preferably form about 1 % w/w to about 45 % w/w, more preferably 5 % w/w to about 40 % w/w by weight of the composition.

Examples of glidants suitable for use in the modified release pharmaceutical composition of the invention includes, but not limited to magnesium trisilicate; powdered cellulose; starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silicate; colloidal silicon dioxide and silicon hydrogels or a mixture of one or more of said glidants. The preferred glidant is colloidal silicon di-oxide, preferably its hydrophilic grade (e.g. Aerosil® 200). The composition of the invention may comprise glidant from about 0.1 % to about 10% of glidant, preferably form about 0.5 % to about 10%, more preferably 0.5 % w/w to about 5 % w/w by weight of the composition.

Examples of lubricants suitable for use in the modified release pharmaceutical composition of the invention includes, but not limited to magnesium, aluminum, calcium or zinc stearate; polyethylene glycol; polyvinyl alcohol; potassium benzoate; sodium benzoate; sodium stearyl fumarate; talc; stearyl alcohol; leucine; ethylene oxide polymers; poloxamer; octyldodecanol; sodium stearyl fumarate and sodium lauryl sulfate or a mixture of one or more of said lubricants. The preferred lubricant is sodium stearyl fumarate. The composition of the invention preferably comprise hydrophilic lubricant and its amount may range from about 0.1 % w/w to about 10% w/w, preferably about 0.1 % w/w to about 5% w/w, more preferably about 0.1 % w/w to about 2.0 % w/w by weight of the composition.

In an embodiment, the stable modified release pharmaceutical composition of molindone does not comprise of binder in the intragranular component.

In a further embodiment, the stable modified release pharmaceutical composition comprises about 0.1 % w/w to about 50% w/w of molindone hydrochloride, about 25 % w/w to 45% w/w of release controlling substances, about 0.5 % w/w to about 5% w/w of glidant; about 20 % w/w to about 45 % w/w of bulking agent, about 0.1 % w/w to about 2.0 % w/w of lubricant by weight of the composition.

The stable modified release pharmaceutical compositions described in various embodiments of the invention is preferably formed by various methods known in the art. Such manufacturing processes includes, but not limited to slugging or roller compaction, dry granulation, hot melt granulation, direct compression, double compression, layering. Preferably, the modified release composition is prepared by the dry granulation process. In an embodiment, the dry granulation process involves steps of mixing of the drug and excipients, compacting the mixture under pressure followed by milling, sizing, addition of extragranular excipients and lubrication, and optionally further compression to get a desired solid dosage form.

The stable modified release pharmaceutical composition of molindone may be packaged in a container (e.g. HDPE bottle) or material (metal blisters) suitable for solid dosage forms. In an embodiment the packaging comprises desiccant such as silica gel.

The following examples illustrate the invention and they do not any way limit the scope of the invention. A person skilled in the art would easily modify the process for manufacturing the said pharmaceutical composition or could modify the composition with similar materials and finally a person skilled in the art could modify the method of administering the said composition of this invention.

Example 1: Modified release molindone hydrochloride tablet
Table 1
Sr. No. Ingredients Quantity (% w/w)
Intragranular
1 Molindone hydrochloride 12.46
2 Anhydrous lactose 43.94
Extragranular
3 Hydroxypropyl methylcellulose 41.53
4 Colloidal Silicon dioxide 1.38
5 Magnesium stearate 0.69
Total weight of tablet 100.000

Molindone hydrochloride and anhydrous lactose were sifted together and mixed in a roller compactor to form flakes of desired hardness. Flakes were further milled and sifted to the sized granules. Further, hydroxypropyl methylcellulose and colloidal silicon dioxide were sifted together through suitable screen and mixed with sized granules. Magnesium stearate was mixed with the above mixture and the mixture was compressed into tablets.

Dissolution profile of tablets of Example 1
Table 2
Time (Hours) % drug release
1 20
2 35
3 47
4 58
6 75
8 85
10 91
12 94
14 95
16 94
18 95

Dissolution condition: Media: 0.1N HCl, Volume: 900 mL and Method - USP-I (Basket), 100 RPM.

Stability Data - Degradation products in tablet of Example 1 after storage for 3 months in HDPE Bottle
Table 3
Storage Condition Initial 40°C/75%RH 30°C/65%RH 25°C/60%RH
RS Profile
Impurity C (RRT 2.30) BDL 0.02 0.01 0.01
Impurity D (RRT 2.64) 0.01 0.27 0.06 0.03
Total Impurities 0.11 0.37 0.15 0.12
BDL: Below detection limit

Stability Data - Degradation products in tablet of Example 1 after storage for 3 months in HDPE Bottle and silica gel
Table 4
Storage Condition Initial 40°C/75%RH 30°C/65%RH 25°C/60%RH
RS Profile
Impurity C (RRT 2.30) 0 0.01 0.04 0.01
Impurity D (RRT 2.64) 0.01 0.14 0.03 0.01
Total Impurities 0.11 0.24 0.12 0.10

Example 2: Modified release molindone hydrochloride tablet
Table 5
Sr. No. Ingredients Quantity (% w/w)
Intragranular
1 Molindone hydrochloride 12.46
2 Anhydrous lactose 43.94
Extragranular
3 Hydroxypropyl methylcellulose 41.53
4 Colloidal Silicon dioxide 1.38
5 Sodium stearyl fumarate 0.69
Total weight of tablet 100.000

Molindone HCl and anhydrous lactose were sifted together and mixed in a roller compactor to form flakes of desired hardness. Flakes were further milled and sifted to the sized granules. Further, hydroxypropyl methylcellulose and colloidal silicon dioxide were sifted together through suitable screen and mixed with sized granules. Sodium stearyl fumarate was mixed with the above mixture and the mixture was compressed into tablets.

Dissolution profile of tablets of Example 2
Table 6
Time (Hours) % drug release
1 24
2 37
3 49
4 59
6 73
8 82
10 86
12 89
14 89
16 90
18 90

Dissolution condition: Media: 0.1N HCl, Volume: 900 mL and Method - USP-I (Basket), 100 RPM.

Example 3 to 6: Modified release molindone hydrochloride tablet
Table 7
Example 3 Example 4 Example 5 Example 6
Ingredients % w/w % w/w % w/w % w/w
Intragranular
Molindone HCl 14.063 14.754 14.458 14.229
Lactose 49.609 52.049 51.004 50.198
Extragranular
Hydroxypropyl methylcellulose acetate succinate 33.984 - - -
Hydroxypropyl methylcellulose phthalate - 30.738 - -
Shellac - - 32.129 -
Zein - - 33.202
Colloidal silicon dioxide 0.781 0.820 0.803 0.791
Magnesium stearate or Sodium stearyl fumarate 1.56 1.64 1.61 1.58
Total 100.000 100.000 100.000 100.000

Molindone HCl and lactose were sifted together and mixed in a roller compactor to form flakes of desired hardness. Flakes were further milled and sifted to the sized granules. Further, polymer selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, shellac or zein is mixed with colloidal silicon dioxide and the mixture is sifted through suitable screen and then mixed with sized granules. Sodium stearyl fumarate or sodium stearyl fumarate was mixed with the above mixture and the mixture was compressed into tablets.
,CLAIMS:Claim 1: A stable modified release pharmaceutical composition comprising molindone or a pharmaceutically acceptable salts thereof, one or more release controlling compounds, and one or more pharmaceutically acceptable excipients; wherein said composition is free of acidity inducing and lipophilic agents.

Claim 2: The stable modified release pharmaceutical composition of claim 1, wherein said release controlling compounds selected from the group consisting of pH-dependent polymers, non pH-dependent compounds or polymers.

Claim 3: The stable modified release pharmaceutical composition of claim 2, wherein said pH dependent polymer is selected from the group comprising poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly (methacrylic acid-comethyl methacrylate), methacrylic acid-ethyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer dispersion, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate and cellulose acetate phthalate.

Claim 4: The stable modified release pharmaceutical composition of claim 2, wherein said non pH dependent compounds or polymer are selected from the group comprising hydroxypropyl cellulose, hypromellose (hydroxypropyl methyl cellulose), methyl cellulose, polyethylene oxide, acacia, acrylic acid derivatives (e.g., carbomer homopolymer type A and carbomer homopolymer type B), hydroxyethyl cellulose, carrageenan, tragacanth, xanthan gum, povidone, alginic acid (and salts thereof), polyvinyl alcohol, carboxymethylcellulose, ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, cellulose acetate propionate, hydrogenated vegetable oil, magnesium stearate, stearic acid, glyceryl stearate, glyceryl palmitostearate, stearyl macrogolglycerides, lauryl macrogolglycerides and waxes.

Claim 5: A process of preparing the stable modified release pharmaceutical composition of claim 1, wherein said process does not involve use of water or aqueous solvent mixtures.

Claim 6: The process of claim 5 comprises slugging or roller compaction, dry granulation, hot melt granulation, direct compression or double compression.

Claim 7: A stable modified release pharmaceutical composition comprising
A. an intragranular component comprising
i. molindone or pharmaceutically acceptable salts, and
ii. bulking agent;
B. an extragranular component comprising
i. one or more release controlling compounds selected from the group consisting of pH-dependent polymers and non-pH-dependent polymers,
ii. glidant, and
iii. lubricant;
wherein said composition is free of acidity inducing agents and lipophilic agents.

Claim 8: The stable modified release pharmaceutical composition of claim 7, wherein said bulking agent is lactose, release controlling compounds is hydroxypropyl methylcellulose, glidant is colloidal silicon dioxide and lubricant is sodium stearyl fumarate.