FIELD OF THE INVENTION

The present invention relates to pharmaceutical formulation comprising aripiprazole as an active agent or a pharmaceutically acceptable salt thereof, at least one acid other than organic acid, optionally along with one or more pharmaceutically acceptable excipient(s). The present invention also provides process of preparing such fonnulations and prophylactic and/or therapeutic methods of using such fonnulations for the treatment of CNS disorders such as schizophrenia, bipolar I disorder, major depressive disorder and autistic and other associated disorders. The fonnulations of the present invention are safe, effective and well-tolerated, and are useful for the management such as prophylaxis, amelioration and/or treatment of CNS disorders in adults and in children.

BACKGROUND OF THE INVENTION

Schizophrenia is a mental disorder characterized by delusions, hallucinations and extensive withdrawal from others. Genetics and early environment, as well as psychological and social processes, appear to be important contributory factors. Schizophrenia can be described in tenns of positive and negative symptoms. Positive symptoms are those that most individuals do not nonnally experience but are present in people with schizophrenia. They can include delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, typically regarded as manifestations of psychosis. Positive symptoms generally respond well to medication.

Negative symptoms are includes the patient population that respond less well to medication. They commonly include flat expressions or little emotion, poverty of speech, inability to experience pleasure, lack of desire to fonn relationships, and lack of motivation. Negative symptoms appear to contribute more to poor quality of life, functional ability, and the burden on others than do positive symptoms. People with greater negative symptoms often have a history of poor adjustment before the onset of illness, and response to medication is often limited.

Onset of schizophrenia typically occurs between the age of 16 and 25 and affects 1 in 100 individuals worldwide. It is more prevalent than Alzheimer's disease, multiple sclerosis, insulin-dependent diabetes and muscular dystrophy. Early diagnosis and treatment can lead to significantly improved recovery and outcome.

Aripiprazole is an antipsychotic agent, used for the treatment of CNS disorders such as schizophrenia, bipolar I disorder, major depressive disorder and autistic and other associated disorders. Aripiprazole is chemically known as 7-[4-[4-(2,3-dichlorophenyl)-lpiperazinyl]butoxy]-3,4-dihydrocarbostyril. Its empirical formula is C23H27CI2N3O2 and its molecular weight is 448.38. Its chemical structure is illustrated with Formula I given below.

Aripiprazole is currently marketed as Abilify® oral solution in the USA by Otsuka. It is available as a clear, colorless to light-yellow solution in a concentration of 1 mg/mL. The inactive ingredients for this solution include disodium edetate, fructose, glycerin, dl-lactic acid, methylparaben, propylene glycol, propylparaben, sodium hydroxide, sucrose and purified water. The oral solution is flavored with natural orange cream and other natural flavours.

US patent 5,006,528 discloses the compound Aripiprazole. US patent 7,053,092 discloses a method of treating a patient suffering from a disorder of the central nervous system associated with 5-HTiA receptor subtype wherein the disorder is depression selected from the group consisting of endogenous depression, major depression, melancholia and treatment resistant depression, which comprises administering to said patient a therapeutically effective amount of aripiprazole.

US patent 6,977,257 discloses an oral solution comprising aripiprazole, a solvent system, taste-enhancing/masking agent(s) and one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid, wherein said solution has a pH from 2.5 to 4.5. As per '257 patent, an oral solution of aripiprazole was prepared using one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid as a part of said composition. The acids disclosed in '257 patent were limited to category of organic acids.

US patent publication 2014/0107130 discloses pharmaceutical formulation suitable for oral administration comprising aripiprazole, glycerin, propylene glycol, a buffer, a sweetener, and a flavouring agent, wherein said pharmaceutical formulation does not comprise a sugar, and wherein said pharmaceutical formulation has a pH of 4.3 or greater. This publication provides stable oral sugar-free solution of aripiprazole that allow its long term storage.

PCT publication WO 2014/060324 Al discloses an oral pharmaceutical solution comprising aripiprazole, hydrochloric acid, glycerin and ethyl alcohol wherein the weight ratio of glycerin to ethyl alcohol is 4:1.

Aripiprazole is mostly administered orally in the form of solid dosage forms. The oral solution dosage form can be a viable alternative for patients who have problems in swallowing the tablet dosage form. It provides assurance of dosage uniformity upon administration to patients and eliminates difficulty of administration. An oral solution can also provide physicians more flexibility in designing dosage regimens for patients. Aripiprazole oral solution is suitable for administration to both pediatric and geriatric patients while also compensating for a good organoleptic properties and remaining suitably stable. The development of a liquid oral formulation is therefore desirable since it offers improved patient compliance.

Aripiprazole also has stability problems when present in oral solutions as a result of environmental and physical conditions. Exposure to air and humidity causes structural degradation and chemical behavior changes in aripiprazole. Thus the stability of the solutions of aripiprazole is not at a desired level and the shelf life thereof is shortened. Additionally, aripiprazole may react with the excipients which are used together in the formulation. This situation leads to impurity in the formulations. Another disadvantage of aripiprazole is that it has a bitter taste. Thus there is a need to increase the water solubility of aripiprazole and its derivatives and to mask the bitter taste of these compounds so that they can be effectively incorporated into the aqueous based formulations.

In addition to above-said disadvantages, oral solutions have the risk of contamination due to bacterial growth since they contain high amounts of water. Hence, there is a need to develop an oral solution of aripiprazole that has reduced risk of contamination.

Thus there is still a need for development of pharmaceutical formulations of aripiprazole with improved stability, enhanced taste and reduced risk of contamination. Accordingly, inventors of the present invention have developed pharmaceutical formulations of aripiprazole or a pharmaceutically acceptable salt thereof, at least one inorganic acid, optionally along with one or more pharmaceutically acceptable excipient(s).

SUMMARY OF THE INVENTION

An aspect of the present invention provides pharmaceutical formulation comprising antipsychotic agent as an active agent or a pharmaceutically acceptable salt thereof, at least one acid other than organic acid, optionally along with one or more pharmaceutically acceptable excipient(s).

Another aspect of the present invention provides pharmaceutical formulation comprising aripiprazole as an active agent or a pharmaceutically acceptable salt thereof, at least one acid other than organic acid, optionally along with one or more other pharmaceutically acceptable excipient(s).

Yet another aspect of the present invention provides pharmaceutical formulation comprising aripiprazole as an active agent, at least one acid other than organic acid, a pharmaceutically suitable solvent system, optionally a chelating agent, and optionally along with one or more other pharmaceutically acceptable excipient(s).

An aspect of the present invention provides pharmaceutical formulation comprising aripiprazole as an active agent, at least one acid other than organic acid, and a pharmaceutically suitable solvent system, optionally a chelating agent, optionally along with one or more other pharmaceutically acceptable excipient(s), and wherein the said formulation has a pH of less than about 5.0.

In an aspect, the present invention provides process for the preparation of pharmaceutical formulations, wherein the process comprises of the following steps:

(i) preparing solution using a pharmaceutically suitable solvent system and at least one acid other than organic acid,

(ii) adding aripiprazole to the material of step (i) under continuous stirring to form a clear solution, and

(iii) optionally adding one or more other pharmaceutically acceptable excipients to the solution of step (ii), to make up the final volume.

Another aspect of the present invention relates to method of using such formulations for the treatment of CNS disorders such as schizophrenia, bipolar I disorder, major depressive disorder and autistic and other associated disorders.

DETAILED DESCRIPTION OF THE INVENTION

The term "particle size" unless indicated otherwise in the specification relates to particles of Aripiprazole free base as well as pharmaceutically acceptable salt, amorphous or crystalline, anhydrous, esters, or isomer or derivative, hydrate, prodrug or solvates thereof. Aripiprazole with specific "particle size" and distribution, or surface area would provide a fast dissolution of the active ingredient, would be easy to prepare and stable while maintaining the beneficial properties with respect to fast solubility and bioavailability, particularly according to the present invention, Aripiprazole having an D90 particle size less than 100 microns, and/ or surface area less than about 5m2/ gm are useful.

The term "therapeutically effective amount" is defined to mean the amount or quantity of the active drug (e.g. aripiprazole), which is sufficient to elicit an appreciable biological response when administered to the patient.

In accordance with the present invention, the term "aripiprazole" unless indicated otherwise in the entire specification refers to aripiprazole in the form of free base or its pharmaceutically acceptable salt, amorphous, crystalline or any isomer or derivative, hydrate or solvate, prodrug or combinations thereof. Preferably aripiprazole is in the form of free base.

The term "excipient" means a pharmacologically inactive component such as solvents, preservatives, antioxidants, flavors, buffers, or the like. The excipients that are useful in preparing a phamiaceutical formulation are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use.

As used in this specification, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, a reference to "a process" includes one or more process, and/ or steps of the type described herein and/ or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

The phrase "substantially pure polymorphic form of aripiprazole", unless otherwise specified is to be understood as a substance free of other polymorphic and/or pseudo-polymorphic forms at amounts detectable with typical analytical methods such as X-ray powder diffraction and/or solid state infrared absorption, i.e. containing less than 10% of other polymorphic and/or pseudo-polymorphic forms.

In an embodiment, the formulation of the present invention is a stable oral formulation wherein the oral formulation is a liquid formulation.

An embodiment of the present invention provides phamiaceutical formulation comprising antipsychotic agent as an active agent or a pharmaceutically acceptable salt thereof, at least one acid other than organic acid, optionally along with one or more pharmaceutically acceptable excipient(s).

Another embodiment of the present invention provides pharmaceutical formulation comprising aripiprazole as an active agent or a pharmaceutically acceptable salt thereof, at least one acid other than organic acid, optionally along with one or more other pharmaceutically acceptable excipient(s).

Yet another embodiment of the present invention provides pharmaceutical formulation comprising aripiprazole as an active agent, at least one acid other than organic acid, a pharmaceutically suitable solvent system, optionally a chelating agent, optionally along with one or more other pharmaceutically acceptable excipient(s).

An embodiment of the present invention provides pharmaceutical formulation comprising aripiprazole as an active agent, at least one acid other than organic acid, and a pharmaceutically suitable solvent system, optionally a chelating agent, optionally along with one or more other pharmaceutically acceptable excipient and wherein the said formulation has a pH of less than about 5.0.

In an embodiment the present invention provides pharmaceutical formulation comprising aripiprazole as an active agent, at least one acid other than organic acid selected from a group comprising hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, orthophosphoric acid and the like, and mixtures thereof; a pharmaceutically suitable solvent system selected from a group comprising water and one or more water miscible solvents and the like, and mixtures thereof; optionally a chelating agent which is ethylenediamine tetraacetic acid (EDTA) or its pharmaceutically acceptable salts, and optionally along with one or more other pharmaceutically acceptable excipient(s), and wherein the said solution has a pH of less than about 5.0.

In another embodiment the present invention provides pharmaceutical formulation comprising aripiprazole as an active agent, at least one acid which is hydrochloric acid, a pharmaceutically suitable solvent system selected from a group comprising water and one or more water miscible solvents and the like, and mixtures thereof, optionally a chelating agent which is ethylenediamine tetraacetic acid (EDTA) or its pharmaceutically acceptable salts, and optionally along with one or more other pharmaceutically acceptable excipient(s), and wherein the said solution has a pH of less than about 5.0.

In an embodiment, the pharmaceutical formulation of the present invention comprises organic acid in an amount of less than about 0.1 mg/ml by weight of the formulation. In a preferred embodiment, the pharmaceutical formulation of the present invention comprises organic acid in an amount of less than about 0.09 mg/ml by weight of the formulation.

In an embodiment, the pharmaceutical formulation of the present invention has a pH of from about 2.0 to about 4.5. According to one embodiment of the present invention the phannaceutically suitable solvent system comprising propylene glycol, glycerin and water may be present in a ratio of 0.10-0.50:0.35-1.75:1.05-5.25 w/w respectively. According to another embodiment of the present invention the phannaceutically suitable solvent system comprising propylene glycol and glycerin may be present in a ratio of 0.10-0.50:0.35-1.75 w/w respectively. According to another embodiment of the present invention the phannaceutically suitable solvent system comprising propylene glycol and water may be present in a ratio of 0.10-0.50:1.05-5.25 w/w respectively. According to another embodiment the phannaceutically suitable solvent system comprising glycerin and water may be present in a ratio of 0.35-1.75:1.05-5.25 w/w respectively.

In an embodiment, a phannaceutically suitable solvent system may further comprise of one or more solubilizing agents, surfactants, antioxidants and buffering agents.

The one or more water-miscible solvents used in the present invention are selected from but not limited to a group comprising glycerin, propylene glycol, low molecular weight polyethylene glycols, sorbitol, ethanol, isopropyl alcohol and the like, and mixtures thereof. Solubilizing agents can be selected from a group comprising but not limited to povidone and cyclodextrins and the like, and mixtures thereof. Surfactants are compounds which are capable of improving the wettability of the drug and/or enhancing the dissolution. The surfactants can be selected from hydrophilic surfactants or lipophilic surfactants, or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and/or zwitterionic surfactants. Surfactants according to the present invention are selected from but not limited to a group comprising polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol (PEG) fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulphate and the like or mixtures thereof. Buffering agents are used to adjust the pH of the formulation. Suitable buffering agents used in the present invention are selected from but not limited to phosphoric acid, sodium hydroxide, sodium phosphate, sodium chloride, disodium hydrogen phosphate, sodium hydrogen carbonate, mono sodium phosphate, monopotassium phosphate, potassium citrate and the like, and mixtures thereof. Formulations of the present invention may include an appropriate amount of antioxidants in a suitable concentration range to prevent oxidation. Suitable antioxidants of the present invention are selected from but not limited to a group comprising sodium metabisulfite, sodium sulfite, sodium bisulfate, sodium thiosulfate, sodium ascorbate, sodium formaldehydesulfoxylate, alkyl gallates like propyl gallate, lauryl gallate, or octyl gallate and the like, and mixtures thereof.

In an embodiment of the present invention, the formulation further comprises one or more excipients selected from preservatives, sweetening agents and flavouring agents. Suitable preservatives used according to the present invention are selected from but not limited to parabens (p-hydroxybenzoic acids esters) such as methylparaben, ethylparaben, propylparaben, butylparaben; sodium benzoate; potassium sorbate; benzyl alcohol; and the like or mixtures thereof. Suitable sweetening agents used according to the present invention are selected from but not limited to sucrose, fructose, saccharin sodium, sodium cyclamate, sorbitol, xylitol, glycerol, aspartame and the like or mixtures thereof. Suitable flavoring agents used according to the present invention are selected from but not limited to peppermint flavor, spearmint flavor, lime flavour, apple flavour, pear flavour, peach flavour, raspberry flavour, plum flavour, pineapple flavour, natural orange cream flavour and other natural flavours and the like or mixtures thereof.

In an embodiment, the present invention provides process for the preparation of pharmaceutical formulations, wherein the process comprises of the following steps:

(i) preparing solution using a pharmaceutically suitable solvent system and at least one acid other than organic acid,

(ii) adding aripiprazole to the material of step (i) under continuous stirring to form a clear solution, and

(iii) optionally adding one or more other pharmaceutically acceptable excipients to the solution of step (ii), to make up the final volume.

In an embodiment, the present invention provides process for the preparation of pharmaceutical formulations, wherein the process comprises of the following steps:

(i) preparing solution using a phannaceutically suitable solvent system and at least one acid other than organic acid,

(ii) adding aripiprazole to the material of step (i) under continuous stirring to form a clear solution, and

(iii) optionally adding a chelating agent which is ethylenediamine tetra acetic acid (EDTA) or its phannaceutically acceptable salts to the material of step (ii) under continuous stirring to form a clear solution, and

(iv) optionally adding one or more other phannaceutically acceptable excipients to the solution of step (ii), to make up the final volume.

The phannaceutical formulations of the present invention may be dispensed in amber colored bottles, amber round medical bottles with dropper top, or bottles with child-resistant closures.

Yet another embodiment of the present invention relates to method of using such fonnulations for the treatment of CNS disorders such as schizophrenia, bipolar I disorder, major depressive disorder, and autistic and/or other associated disorders.

The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention. It is obvious to those skilled in the art to find out the fonnulations for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

EXAMPLE 1

Manufacturing process:

i. Propylene glycol and glycerin were dissolved in a required quantity of purified water under stirring and the pH of the solution was adjusted to a pH of 2.5 with hydrochloric acid, ii. Aripiprazole was added to the solution of step (i) under stirring to form a clear solution, iii. Methyl paraben and propyl paraben were dissolved in required quantity of purified water and added to the solution of step (ii). iv. The pH of solution of step (iii) was adjusted to a pH of 3.2 with sodium hydroxide, v. Sucrose and fructose were dissolved in sufficient quantity of purified water and added to the solution of step (iv) under stirring, vi. Spearmint flavor and remaining quantity of water was added to the solution of step (v) to make up the final volume.

EXAMPLE 2
Manufacturing process: The manufacturing process followed is similar to process of preparation provided for example 1.

EXAMPLE 3

Manufacturing process: The manufacturing process followed is similar to process of preparation provided for example 1.

EXAMPLE 4

Manufacturing process:

i. Propylene glycol and glycerin were dissolved in a required quantity of purified water under stirring and the pH of the solution was adjusted to a pH of 2.5 with hydrochloric acid, ii. Aripiprazole was added to the solution of step (i) under stirring to form a clear solution, iii. Methyl paraben and propyl paraben were dissolved in required quantity of purified water and added to the solution of step (ii). iv. The pH of solution of step (iii) was adjusted to a pH of 3.2 with sodium hydroxide, v. Sucrose and fructose were dissolved in sufficient quantity of purified water and added to the solution of step (iv) under stirring, vi. Disodium EDTA was dissolved in sufficient quantity of purified water and added to the solution of step (v) under stirring, vii. Natural orange flavor and remaining quantity of water was added to the solution of step (vi) to make up the final volume.

EXAMPLES 5 to 8

Manufacturing process: The manufacturing process followed is similar to process of preparation provided for example 4.

EXAMPLES 9 & 10:

Manufacturing process: The manufacturing process followed is similar to process of preparation provided for example 1.

EXAMPLES 11 to 14:

Manufacturing process: The manufacturing process followed is similar to process of preparation provided for example 1.

EXAMPLE 15:

Manufacturing process: The manufacturing process followed is similar to process of preparation provided for example 1.

We claim:

1. A pharmaceutical formulation comprising aripiprazole as an active agent, at least one acid other than organic acid, and a pharmaceutically suitable solvent system, optionally a chelating agent, optionally along with one or more other pharmaceutically acceptable excipient and wherein the said formulation has a pH of less than about 5.0.

2. The pharmaceutical formulation according to claim 1, wherein at least one acid other than organic acid is selected from the group comprising hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, orthophosphoric acid or mixtures thereof, a pharmaceutically suitable solvent system selected from the group comprising water and one or more water miscible solvents or mixtures thereof, a chelating agent which is ethylenediamine tetra acetic acid (EDTA).

3. The pharmaceutical formulation according to claim 2, wherein the one or more water miscible solvents are selected from the group comprising glycerin, propylene glycol, low molecular weight polyethylene glycols, sorbitol, ethanol, isopropyl alcohol or mixtures thereof.

4. The pharmaceutical formulation according to claim 1, wherein the organic acid is in an amount of less than about 0.1 mg/ml by weight of the formulation.

5. The pharmaceutical formulation according to claim 1, wherein the pharmaceutically suitable solvent system comprising propylene glycol and glycerin may be present in a ratio of 0.10-0.50:0.35-1.75 w/w.

6. The pharmaceutical formulation according to claim 1, wherein the pharmaceutically suitable solvent system comprising propylene glycol and water may be present in a ratio of 0.10-0.50:1.05-5.25 w/w respectively.

7. The pharmaceutical formulation according to claim 1, wherein the phamiaceutically suitable solvent system comprising glycerin and water may be present in ratio of 0.35-1.75:1.05-5.25 w/w respectively.

8. The pharmaceutical formulation according to claim 1, wherein the pharmaceutically suitable solvent system may further comprise of one or more solubilizing agents, surfactants, antioxidants and/or buffering agents.

9. The pharmaceutical fonnulation according to claim 1, wherein the fonnulation further comprises one or more excipients selected from preservatives, sweetening agents and flavouring agents.

10. A process for the preparation of phamiaceutical formulation according to claim 1, wherein the process comprises of the following steps:
 
(i) preparing solution using a pharmaceutically suitable solvent system and at least one acid other than organic acid, (ii) adding aripiprazole to the material of step (i) under continuous stirring to form a clear solution, and (iii) optionally adding one or more other phamiaceutically acceptable excipients to the solution of step (ii), to make up the final volume.