This application claims priority to Indian patent application no 3263/CHE/2010 filed on Nov 01, 2010 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to stable amorphous dispersion comprising Vorinostat, a dispersing agent and optionally other pharmaceutically acceptable excipients.

The present invention also relates to a process for the preparation of a stable amorphous dispersion comprising Vorinostat, a dispersing agent and optionally other pharmaceutically acceptable excipients.

BACK GROUND OF THE INVENTION

Vorinostat, also called suberoylanilide hydroxamic acid (SAHA) or JV-hydroxy-N'-phenyl- octanediamide, is represented by the structural formula (I).

Vorinostat, marketed under the trade name Zolinza® by Merck, is a histone deacetylase (HDAC) inhibitor, used for the treatment of cutaneous T cell lymphoma (CTCL), a type of skin cancer. It is also used for treating patients having a tumor characterized by proliferation of neoplastic cells, as Vorinostat is thought to be useful for selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells under suitable conditions. Vorinostat is disclosed in US patent No. 5,369,108 as a member of a family compounds that selectively induce terminal differentiation of neoplastic cells. According to the US'108 patent Vorinostat is prepared as per the following scheme:

US patent No. 7,456,219 discloses Vorinostat form I and describes four other polymorphic forms of Vorinostat.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") as well as by content of solvent in the crystalline form, which have been used to distinguish polymorphic forms.

The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid.

Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solutions, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

Vorinostat is known to exist in different crystalline forms. Different polymorphic forms of the same compound may have completely different properties, especially when compared with an amorphous form of the same active. Amorphous materials have properties that can be of advantage in the preparation of pharmaceutical compositions, such as solubility/dissolution rate, and bioavailability. However, the increased reactivity of an amorphous solid, with a consequent high propensity to spontaneously transform to the crystalline state at a certain conditions such as for example relative humidity, force and temperature among others, may negatively affect the physical and chemical stability of the pharmaceutical composition.

Thus there has always been a need to produce pharmaceutical compositions wherein the drug is retained in the amorphous form, either during formulation processing or during the shelf-life of the formulation. Various approaches used for the formulation of an amorphous material include the use of dry granulation techniques for tableting, complexation, drymixing, melt-extrusion, co-precipitation, spray drying, and co-milling, to name a few. Compositions comprising amorphous actives suffer from problems of form conversion either during processing or upon stability.

The development of pharmaceutical compositions comprising the amorphous form of Vorinostat, which do not show change in XRD pattern of the compositions during manufacturing and upon storage, would be a significant improvement in the delivery of the same.

SUMMARY OF THE INVENTION

The present invention relates to a stable amorphous solid mixture of Vorinostat and at least one pharmaceutically acceptable excipient and processes for preparing the same.

One aspect of the present invention provides a stable amorphous dispersion comprising Vorinostat, a dispersing agent and optionally other pharmaceutically acceptable excipients.

Another aspect of the present invention provides a process for the preparation of stable amorphous Vorinostat dispersion; comprising the steps of: a) forming a mixture of Vorinostat, a dispersing agent and a solvent, b) optionally adding pharmaceutically acceptable excipient, and c) removing the solvent to get stable amorphous Vorinostat dispersion.

Yet another aspect of the present invention provides a process for the preparation of stable amorphous Vorinostat dispersion; comprises the steps of: a) forming a mixture of Vorinostat, a dispersing agent and a first solvent, b) optionally adding pharmaceutically acceptable excipient, c) removing the solvent, d) adding a second solvent, and e) isolating stable amorphous Vorinostat dispersion.

Yet another aspect of the present invention provides a process for the preparation of stable amorphous Vorinostat dispersion comprising the steps of: a) forming a mixture of Vorinostat, a dispersing agent and a solvent, b) optionally adding pharmaceutically acceptable excipient, c) adding another dispersing agent, d) removing the solvent, and e) isolating amorphous dispersion.

Yet another aspect of the present invention provides a pharmaceutical composition comprising amorphous Vorinostat dispersion and pharmaceutically acceptable carriers and / or diluents.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a representative X-ray diffraction pattern of stable amorphous Vorinostat

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides stable amorphous dispersion comprising Vorinostat, a dispersing agent and optionally other pharmaceutically acceptable excipients wherein the process comprises forming a mixture of Vorinostat, a dispersing agent and a solvent, removing the solvent from the mixture to result in an amorphous dispersion.

The term "dispersion" as used herein the present invention refers generally to solid dispersion, unless specified otherwise. It may be used interchangeably and
synonymously for "pre-mix" or "admixture" to name a few. It consists of at least two different components, generally a hydrophilic matrix comprising a dispersing agent(s) and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles or in crystalline particles.

The term "stable" according to the present invention refers to the ability of the amorphous Vorinostat dispersion as well as the compositions comprising it, to resist changes against physical, chemical as well as solid-state instability. The term "dispersing agent" according to the present invention can be any pharmaceutically acceptable excipient, which once co-processed with Vorinostat functions to maintain Vorinostat in an amorphous form.

One embodiment of the present invention provides a stable amorphous dispersion comprising Vorinostat, a dispersing agent and optionally other pharmaceutically acceptable excipients.

Another embodiment of the present invention provides a process for the preparation of stable amorphous dispersion comprising Vorinostat comprising the steps of:

a) forming a mixture of Vorinostat, a dispersing agent and a solvent,
b) optionally adding pharmaceutically acceptable excipient, and
c) removing the solvent to get a stable amorphous Vorinostat.

According to the present invention Vorinostat and a dispersing agent are dissolved in a solvent at about 30-40°C to form a clear solution. Optionally pharmaceutically acceptable excipient is added and removed the solvent completely from the mixture to form an amorphous dispersion. The solvent used for dissolution is selected from alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or ketones such as acetone, methylethylketone or methylisobutylketone.

Yet another embodiment of the present invention provides a process for the preparation of stable amorphous Vorinostat dispersion comprising the steps of:

a) forming a mixture of Vorinostat, a dispersing agent and a first solvent,
b) optionally adding pharmaceutically acceptable excipient,
c) removing the solvent,
d) adding a second solvent, and
e) isolating stable amorphous Vorinostat dispersion.

According to the present invention Vorinostat and a dispersing agent are dissolved in a first organic solvent at about 30-40°C to form a clear solution. Optionally pharmaceutically acceptable excipient is added and removed the solvent completely from the mixture. A second organic solvent is added to the mass and stirred for about 15-30 min at 40-60°C. The obtained solid is filtered and suck dried to form an amorphous dispersion.

The solvent used for dissolution is selected from alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or ketones such as acetone, methylethylketone or methylisobutylketone. The second organic solvent used is selected from ethers such as methyltertiary butyl ether, diethyl ether, diisopropyl ether or hydrocarbons such as n-heptane or n-hexane.

Yet another embodiment of the present invention provides a process for the preparation of stable amorphous Vorinostat dispersion comprising the steps of:

a) forming a mixture of Vorinostat, a dispersing agent and a solvent,
b) optionally adding pharmaceutically acceptable excipient,
c) adding another dispersing agent, and
d) removing the solvent to stable amorphous Vorinostat dispersion.

According to the present invention Vorinostat and a dispersing agent are dissolved in a solvent at about 30-40°C to form a clear solution, optionally pharmaceutically acceptable excipient is added. Another dispersing agent is added and the solvent is removed completely from the mixture to form an amorphous dispersion.

The solvent used in the present embodiment for dissolution is selected from alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or ketones such as acetone, methylethylketone or methylisobutylketone.

Dispersing agents used in the present invention are selected from polyvinylpyrrolidine (PVP-K30), hexapropyl methyl cellulose (HPMC), plasdone or microcrystalline cellulose (MCC).

According to the present invention, solvent is removed by techniques such as distillation, filtration, evaporation, lyophilization, agitated thin film drying or spray drying.

Vorinostat and the dispersing agent used in the present invention are in the ratio of 1:3 to 1:10, preferably in the ratio of 1:3 to 1:5. More preferably, stable amorphous dispersion comprising Vorinostat is obtained using 1:5 ratio.

Yet another embodiment of the present invention provides a pharmaceutical composition comprising amorphous Vorinostat dispersion and pharmaceutically acceptable carriers and / or diluents.

Preliminary Stress Stability on Amorphous Vorinostat

0.5g of Vorinostat amorphous dispersion prepared by vorinostat and PVP-K30 in the ratio of 1:3 and 1:5 were subjected to different stress stability conditions in lab and analyzed by PXRD. The results obtained are displayed in Table 1.

Vorinostat amorphous dispersion is seemingly stable under the above mentioned stress conditions.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXPERIMENTAL SECTION

Example 1:

Vorinostat (0.5 g) and polyvinylpyrrolidone K-30 (1.5 g) was dissolved in methanol (30 ml) at 40°C. The resulting clear solution was then distilled out completely under vacuum at 50-60°C. The solid obtained was isolated and identified as amorphous Vorinostat.

Example 2:

Vorinostat (0.5 g) and polyvinylpyrrolidone K-30 (2.5 g) was dissolved in methanol (30 ml) at 40°C. The resulting clear solution was then distilled out completely under vacuum at 50-60°C. The solid obtained was isolated and identified as amorphous Vorinostat.

Example 3:

Vorinostat (0.5 g) and polyvinylpyrrolidone K-30 (1.5 g) was dissolved in methanol (30 ml) at 40°C. The resulting clear solution was then distilled out completely under vacuum at 50-60°C. Methyl tertiary butyl ether (20 ml) was added and the mass was stirred for 15-30 minutes. The product was isolated and suck-dried under reduced pressure at 25-30°C for 30 min. The solid obtained was identified as amorphous Vorinostat.

Example 4;

Vorinostat (0.5 g) and polyvinylpyrrolidone K-30 (2.5 g) was dissolved in methanol (30 ml) at 40°C. The resulting clear solution was then distilled out completely under vacuum at 50-60°C. Methyl tertiary butyl ether (20 ml) was added and the mass was stirred for 15-30 minutes. The product was isolated and suck-dried under reduced pressure at 25-30°C for 30 min. The solid obtained was identified as amorphous Vorinostat.

Example 5:

Vorinostat (0.5 g) and polyvinylpyrrolidone K-30 (1.5 g) was dissolved in methanol (30 ml) at 40°C. The resulting clear solution was then distilled out completely under vacuum at 50-60°C. n-Heptane (20 ml) was added and the mass was stirred for 15-30 minutes. The product was isolated and suck-dried under reduced pressure at 25-30°C for 30 min. The solid obtained was identified as amorphous Vorinostat.

Example 6:

Vorinostat (0.5 g) and polyvinylpyrrolidone K-30 (2.5 g) was dissolved in methanol (30 ml) at 40°C. The resulting clear solution was then distilled out completely under vacuum at 50-60°C. n-Heptane (20 ml) was added and the mass is stirred for 15-30 minutes. The product was isolated and suck-dried under reduced pressure at 25-30°C for 30 min. The solid obtained was identified as amorphous Vorinostat.

Example 7:
Vorinostat (0.5 g) and polyvinylpyrrolidone K-30 (1.0 g) was dissolved in methanol (30 ml) at 40°C. To the clear solution, microcrystalline cellulose (3 g) was added and resulting suspension was then distilled out completely under vacuum at 50-60°C. The solid obtained was identified as amorphous Vorinostat.

WE CLAIM:

1) Stable amorphous Vorinostat.

2) According to claim 1, wherein said stable amorphous vorinostat dispersion comprising; vorinostat and at least one pharmaceutically acceptable excipient.

3) A process for the preparation of stable amorphous Vorinostat, comprising the steps of:

a) forming a mixture of Vorinostat, a dispersing agent and a solvent,
b) optionally adding pharmaceutically acceptable excipient, and
c) removing the solvent to get stable amorphous Vorinostat.

4) A process for the preparation of stable amorphous Vorinostat comprising the
steps of:

a) forming a mixture of Vorinostat, a dispersing agent and a first solvent,
b) optionally adding pharmaceutically acceptable excipient,
c) removing the solvent,
d) adding a second solvent, and
e) isolating stable amorphous Vorinostat dispersion.

5) The process according to claim 4, wherein the first solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, acetone, methylethylketone or methylisobutylketone and the second solvent is selected from ethers such as methyltertiary butyl ether, diethyl ether, diisopropyl ether or hydrocarbons such as n-heptane or n-hexane.

6) A process for the preparation of stable amorphous Vorinostat dispersion which comprises the steps of:

a) forming a mixture of Vorinostat, a dispering agent and a solvent,
b) optionally adding pharmaceutically acceptable excipient,
c) adding another dispersing agent, and
d) removing the solvent to get stable amorphous dispersion .

7) The process according to claims 3, 4 and 6, wherein the dispersing agent is selected from polyvinylpyrrolidine (PVP-K30), hexapropyl methyl cellulose (HPMC), plasdone or microcrystalline cellulose (MCC).

8) The process according to claim 3 and 6, wherein the solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, acetone, methylethylketone or methylisobutylketone.

9) The process according to claim 3, 4 and 6, wherein the solvent is removed by distillation, evaporation, lyophilization, agitated thin film drying or spray drying.

10) A pharmaceutical composition comprising amorphous Vorinostat dispersion and pharmaceutically acceptable carriers and / or diluents.