FIELD OF INVENTION

The invention relates to oral pharmaceutical compositions comprising adefovir or its pharmaceutically acceptable esters, salts, ethers enantiomers, solvates/ hydrates, and mixtures thereof.

Particularly, the invention relates to oral pharmaceutical composition comprising adefovir, wherein the composition comprises a solid dispersion comprising adefovir, a dispersive agent(s) and optionally other pharmaceutically acceptable excipients, characterized, in that the dispersion is devoid of any sugar alcohol. Further, the invention relates to process for preparing such dispersion of adefovir and oral pharmaceutical composition comprising the same.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Adefovir is a nucleotide reverse transcription enzyme inhibitor invented at the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic by Antonin Holy, and the drug was developed by Gilead Sciences for HIV with the brand name Preveon and it is disclosed in US4808716.

Adefovir dipivoxil is a bis-pivaloyloxymethyl ester of the parent compound 9-[2-(phosphonomethoxy) ethyl] adenine ("Adefovir"), which has antiviral activity in animals and in humans and is disclosed in US5663159.

Adefovir dipivoxil is commercially available under trade name of HEPSERA® as l0mg tablet in the US and Europe.

Adefovir dipivoxil is unstable to moisture and can degrade to several degradation products (Yuan et al., Pharmaceutical Research, Vol. 17, 1098-1103, 2000).
WO/2010/032958 describes preparation of solid dispersion containing adefovir dipivoxil. This patent application describes the use of soluble, high molecular substance and sugar alcohol for the preparation of solid dispersion using a fluidized bed processor or a spray drier.

OBJECTIVES OF THE INVENTION

The invention relates to oral pharmaceutical compositions comprising adefovir or its pharmaceutically acceptable esters, salts, ethers, enantiomers, solvates/ hydrates, and mixtures thereof.

Particularly, the invention provides a solid dispersion comprising adefovir, a dispersive agent(s) and optionally other pharmaceutically acceptable excipients characterized in that the dispersion is devoid of any sugar alcohol.

Further, the invention also provides oral pharmaceutical compositions comprising solid dispersion of adefovir and optionally other pharmaceutically acceptable excipients, characterized in that the solid dispersion is devoid of any sugar alcohol.
In an embodiment, the invention provide processes of preparing solid dispersion comprising adefovir, a dispersive agent(s) and optionally other pharmaceutically acceptable excipients, characterized in that the dispersion is devoid of any sugar alcohol.
In yet another embodiment, the invention also provide processes of preparing oral pharmaceutical compositions comprising solid dispersion of adefovir and optionally other pharmaceutically acceptable excipients, characterized in that the solid dispersion is devoid of any sugar alcohol.

In still another embodiment, the invention provides oral pharmaceutical compositions comprising solid dispersion of adefovir and optionally other pharmaceutically acceptable excipients, wherein the composition demonstrates a similar dissolution profile as that of HEPSERA

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1: Overlaid pXRD of Placebo, Example 4 (at Initial) & Example 4 (at Accelerated Storage Condition [40°C/75% RH])

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to oral pharmaceutical compositions comprising adefovir or their pharmaceutically acceptable esters, salts, ethers, enantiomers, solvates/ hydrates, and mixtures thereof.
Particularly, the invention provides a solid dispersion comprising adefovir, a dispersive agent(s) and optionally other pharmaceutically acceptable excipients characterized in that the dispersion is devoid of any sugar alcohol.

Further, the invention also provides oral pharmaceutical compositions comprising solid dispersion of adefovir and optionally other pharmaceutically acceptable excipients, characterized in that the solid dispersion is devoid of any sugar alcohol.
In an embodiment, the invention provide processes of preparing solid dispersion comprising adefovir, a dispersive agent(s) and optionally other pharmaceutically acceptable excipients, characterized in that the dispersion is devoid of any sugar alcohol.

In yet another embodiment, the invention also provide processes of preparing oral pharmaceutical compositions comprising solid dispersion of adefovir and optionally other pharmaceutically acceptable excipients, characterized in that the solid dispersion is devoid of any sugar alcohol.

Adefovir for the purpose this invention encompasses pharmaceutically acceptable esters, salts, ethers enantiomers, solvates/ hydrates, and mixtures thereof. More preferably, adefovir is selected to be adefovir dipivoxil.

The "dispersive agents" according to the invention can be any pharmaceutically acceptable polymer that once co-processed with adefovir, functions to disperse/ solubilize and inhibit crystallization/ form change of adefovir. The polymer(s) to be combined with adefovir can be crystalline or amorphous. Non-limiting examples of such polymer(s) include cellulosic polymers such as an alkyl celluloses (e.g., methylcellulose, ethyl cellulose, and the like); modified celluloses such as carboxymethylcellulose, hydroxypropyl methyl cellulose, cross-linked sodium carboxymethylcellulose, hydroxyl alkyl cellulose; poloxamers; polysorbates; polyvinylpyrrolidone; cross-linked homopolymer of N-vinyl-2-pyrrolidone; polyvinylpyrrolidone-vinyl acetate copolymer (Plasdone S630™); polysaccharides; a mono or disaccharides; or a combination comprising at least one of the foregoing polymer.
Sugar alcohols which are excluded from the scope of the invention include lactose, glucose, sorbitol, mannitol and isomalt.

Adefovir used in the preparation of the solid dispersion can be either pure crystalline or pure amorphous form. It further includes adefovir in either partially crystalline or partially amorphous form. It also includes adefovir comprising a mixture of both crystalline and amorphous form in any ratio.

Various methods of preparing solid dispersion known in the art can be employed according to the invention, which includes and is not limited to, solvent evaporation, spray-drying; freeze-drying (lyophilization); crash cooling from supercritical fluids, solution enhanced dispersion by supercritical fluids; rapid expansion of supercritical solution; vacuum distillation followed by drying and co-precipitation with suitable excipients.

In one embodiment, the solid dispersion comprising adefovir, dispersive agents(s), and optionally other pharmaceutically acceptable excipients is prepared using a fluid bed processor.

In an other embodiment the solid dispersion comprising adefovir, dispersive agents(s), and optionally other pharmaceutically acceptable excipients is prepared using a rapid mixer granulator.

Organic solvents that may be used for preparing the solid dispersion include those that do not adversely affect the stability of adefovir, and are preferably inert. Organic solvents may be aliphatic alcohols such as methanol, ethanol, n-propanol, and isopropanol; aliphatic ketones such as acetone and methyl ethyl ketone; aliphatic carboxylic esters such as ethyl acetate; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane; aliphatic nitriles such as acetonitrile; chlorinated hydrocarbons such as dichloromethane; aliphatic sulfoxides such as dimethyl sulfoxide; and the like, as well as mixtures comprising at least one of the foregoing organic solvents.

In a further embodiment, the invention provides for pharmaceutical compositions comprising the solid dispersion of adefovir. Such compositions are preferably in the form of oral solid dosage forms. The term "solid dosage" defines a system in a solid state in the form of a tablet, mini-tablet, pellet, powder or granule or a micro-granule comprising a solid dispersion of adefovir along with other suitable pharmaceutical excipients such as fillers, binders, glidants, disintegrants and lubricants.

Binders according to the invention are selected from a group comprising povidone, copovidone, hyroxypropyl methylcellulose, hyroxypropyl cellulose, polyvinyl alcohol, sodium alginate, sodium carboxymethyl cellulose, polydextrose, methacrylic acid copolymers, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate, cellulose acetate phthalate and the like or combinations thereof.

Disintegrants according to the invention are selected from a group comprising starch, sodium starch glycolate, calcium carboxymethlycellulose, croscarmellose sodium, polacrillin potassium, alginic acid, crospovidone, low-substituted hydroxypropyl cellulose and the like or combinations thereof.

Lubricants according to the invention are selected from a group comprising magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and the like or combinations thereof.

Glidants according to the invention are selected from a group comprising talc, colloidal silicon dioxide and the like or combinations thereof.

The pharmaceutical compositions preferably in the form of tablets comprising adefovir dispersion along with other suitable pharmaceutical excipients are prepared involving the steps of:

a) Preparation of granules comprising adefovir dispersion;

b) Granules comprising adefovir dispersion is blended with extra-granular excipients comprising diluents, disintegrants, binders, glidants and lubricants;

c) Compress the lubricated blend of step (b) to get the tablets.
The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

A. Adefovir Dipivoxil Dispersion

Adefovir dipivoxil solid dispersions are prepared by dissolving /dispersing adefovir dipivoxil, dispersive agent(s) in a hydro-alcoholic/ alcoholic solvent followed by drying as disclosed in the Table 1, Table 2 , Table 3 and Table 4.

Table 1

Brief Manufacturing Procedure:

Dissolve adefovir dipivoxil and Plasdone S630™ in acetone. This solution is sprayed over pregelatinized starch using a fluidized bed processor or rapid mixer granulator and dried further, to get the solid dispersion /granules.

Table 2

Brief Manufacturing Procedure:

Dissolve adefovir dipivoxil and Plasdone S630 ™ in acetone. This solution is sprayed over microcrystalline cellulose in a fluidized bed processor or rapid mixer granulator and dried further, to get the solid dispersion /granules.

Table 3

Brief Manufacturing Procedure:

Dissolve adefovir dipivoxil and Plasdone S630™ in acetone. This solution is sprayed and dried in a fluidized bed processor or rapid mixer granulator and dried further, to get the solid dispersion /granules.

Table 4

Brief Manufacturing Procedure:

Dissolve adefovir dipivoxil and Plasdone S630 ™ in acetone. This solution is sprayed over Pregelatinized starch in a fluidized bed processor or rapid mixer granulator and dried further, to get the solid dispersion /granules.

B. Compositions comprising adefovir dipivoxil dispersion

Example 1

Brief Manufacturing Procedure:

a) Dissolve adefovir dipivoxil and Plasdone S630™ in acetone. This solution is sprayed over pregelatinized starch using a fluidized bed processor or rapid mixer granulator and dried further;

b) Dried granules comprising adefovir dipivoxil dispersion from step (a) is blended with microcrystalline cellulose, pregelatinised starch and croscarmellose sodium in a blender for suitable period of time;

c) Blend the granules from step (b) with talc and magnesium stearate in a blender;

d) The blended mass from step (c) was compressed using suitable tooling to form the tablets.

Example 2

Brief Manufacturing Procedure:

a) Dissolve adefovir dipivoxil and Plasdone S630™ in acetone. This solution is sprayed over microcrystalline cellulose in a fluidized bed processor or rapid mixer granulator and dried further;

b) Dried granules comprising adefovir dipivoxil dispersion from step (a) is blended with microcrystalline cellulose, pregelatinised starch and croscarmellose sodium in a blender for suitable period of time;

c) Blend again the above granules in from step (b) with talc and magnesium stearate in a blender;

d) The blended mass in step (c) was compressed using suitable tooling to form the tablets

Example 3
Brief Manufacturing Procedure:
a) Dissolve adefovir dipivoxil and Plasdone S630™ in acetone. This solution is sprayed and dried using a fluidized bed processor or rapid mixer granulator;
b) Dried granules comprising adefovir dipivoxil dispersion from step (a) is blended with microcrystalline cellulose, pregelatinised starch and croscarmellose sodium in a blender for suitable period of time;
c) Blend again the granules from step (b) with talc and magnesium stearate in a blender;
d) The blended mass from step (c) was compressed using suitable tooling to form the tablets.
Example 4

Brief Manufacturing Procedure:
a) Dissolve adefovir dipivoxil and Plasdone S630™ in acetone. This solution is sprayed over Pregelatinized starch in a fluidized bed processor or rapid mixer granulator and dried further;
b) Dried granules comprising adefovir dipivoxil dispersion from step (a) is blended with microcrystalline cellulose, pregelatinised starch and croscarmellose sodium in a blender for suitable period of time;

c) Blend again the above granules in from step (b) with talc and magnesium stearate in a blender;

d) The blended mass in step (c) was compressed using suitable tooling to form the tablets

FORMULATION DATA:

The tablets prepared according to Example-4 of the invention was studied for parameters such as such as assay [potency], drug release [dissolution] both at the initial and under accelerated conditions [40°C/75% RH] for 12 weeks and was compared with that of the marketed product Hepsera®. The results are summarized in Table 5.

Table 5

WE CLAIM:

1. A solid dispersion comprising adefovir, wherein said dispersion is devoid of sugar alcohol.

2. A solid dispersion comprising adefovir, a dispersive agent(s) and optionally other pharmaceutically acceptable excipients, wherein said dispersion is devoid of sugar alcohol.

3. A process for preparing a solid dispersion of adefovir, being devoid of sugar alcohol, wherein said process involves the steps of:

(a) Dissolving/ Dispersing adefovir, a dispersive agent(s) and one or more pharmaceutically acceptable excipients in a solvent to get a solution/ dispersion; and
(b) Drying said solution/ dispersion of step (a) to get the solid dispersion of adefovir.

4. The dispersion according to any of the preceding claims, wherein said dispersing agent(s) is selected from a group consisting of methylcellulose, ethyl cellulose, carboxymethylcellulose, hydroxypropyl methyl cellulose, cross-linked sodium carboxymethylcellulose, hydroxyl alkyl cellulose; poloxamers; polysorbates; polyvinylpyrrolidone; cross-linked homopolymer of N-vinyl-2-pyrrolidone; polyvinylpyrrolidone-vinyl acetate copolymer (Plasdone S630™); polysaccharides; mono or disaccharides; or their combinations thereof.

5. The dispersion according to claim 3, wherein said solvent is selected from a group consisting of, ethanol, n-propanol, isopropanol; acetone, dichloromethane; dimethylsulfoxide; acetonitrile, water or their combinations thereof.

6. The dispersion according to claim 3, wherein said drying is carried out by evaporation under reduced pressure or under heat or vacuum in fluidized bed processor, or by freeze-drying or by spray-drying.

7. A pharmaceutical composition comprising solid dispersion of adefovir and optionally other pharmaceutically acceptable excipients, wherein said solid dispersion is devoid of any sugar alcohol.

8. A process for preparing a tablet comprising solid dispersion of adefovir and at least one pharmaceutically acceptable excipient, wherein said process involves the following steps:

(a) Preparation of granules comprising adefovir dispersion;
(b) Blending said granules of step (a) with extra-granular excipients; and
(c) Compress said blend of step (b) to get the tablets.

9. The excipients according to claim 8, are selected from a group consisting of fillers, binders, disintegrants, lubricants and glidants.

10. The dispersion according to any of the preceding claims, wherein said adefovir is adefovir dipivoxil.