FIELD OF INVENTION

The invention relates to stable pharmaceutical compositions comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s) wherein, the composition is devoid of a stabilizer and further being devoid of a desiccant for use as a packaging aid.

Further, the invention also relates to process of preparing stable pharmaceutical compositions comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s).

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Adefovir dipivoxil is a phosphonomethylether prodrug of adefovir, a synthetic nucleotide analog of adenosine 5'-monophosphate. In-vivo, adefovir dipivoxil is converted to the parent compound, adefovir, and through two phosphorylation reactions to adefovir diphosphate. It is chemically known as 9-[2-[[bis[(pivaloyloxy)methoxy]-phosphinyljmethoxy]ethyl]adenine, having chemical structure as below:

Adefovir diphosphate exhibits activity against the hepatitis B virus (HBV) DNA polymerase. A structural modification of the parent drug has been carried out in order to increase the lipophilicity and to enhance the oral bioavailability of adefovir.

Adefovir dipivoxil is commercially available has Hepsera®, which is a 10 mg tablet, having the following excipients - croscarmellose sodium, lactose monohydrate, magnesium stearate, pregelatinized starch, and talc, wherein said tablet is indicated for the treatment of chronic hepatitis B.

Prior art literatures relating to adefovir dipivoxil pharmaceutical compositions are discussed below.

U.S. Patent No. 6,451,340 disclose compositions comprising crystalline adefovir dipivoxil and process of preparing said compositions using wet granulation method.

U.S. Patent No. 6,635,278 discloses compositions comprising adefovir dipivoxil and an alkaline excipient. Also, this publication discloses commercially available adefovir dipivoxil tablet formulation, which is typically packaged in HDPE bottle with upto 5 g of silica gel as a desiccant to allow storage of adefovir dipivoxil tablets of at least 2 years at room temperature.

U.S. Publication No. 2012/0196834 discloses highly stable compositions comprising orally active nucleotide analogue and inactive polymer, to stabilize the orally active nucleotide analogue against degradation.

U.S. Publication No. 2011/0201575 relates to amorphous adefovir dipivoxil solid dispersion for improved stability, comprising a water-soluble polymer substance and a sugar alcohol.

It is known from the above prior arts that adefovir dipivoxil pharmaceutical composition were found to be unstable and on long term storage lead to the formation of mono-esters impurity which reduced its oral bioavailability. Hence, stabilizers were required to control the formation of degradants during the storage conditions. It is further reported that such formulations require high amount of desiccants to stabilize the formulations.

The currently available marketed brand Hepsera® contains silica gel as a desiccant in the finished dosage form bottle to control the formation of degradants on long term storage.

The prior art U.S. Patent No. 6,635,278 represents an attempt for improving the stability of adefovir compositions, using alkaline excipient, in which the presence of silica gel or activated carbon is reduced or eliminated as a secondary stabilizer in the composition.

Keeping in mind, the sensitive nature of adefovir dipivoxil, still there exist a need for a stable adefovir dipivoxil pharmaceutical composition which contain minimal excipients, involve minimal unit operations and being economical, thereby having satisfactory chemical and physical stability. This can be ideally achieved by formulating a composition without using any alkalizer or desiccants in the composition by using conventional methods.

This necessitated the present inventors to evaluate the excipient(s) attributes which are suitable to obtain satisfactory chemical and physical stability. Hence, inventors performed various experiments using different diluents and processes in order to obtain pharmaceutical compositions having satisfactory physical and chemical stability.

On continuous optimization evaluation, the inventors observed that selection of particular pharmaceutically acceptable excipients and the selection of the process of preparing the composition has varied effects on the composition and were found to be critical for the stability.

The inventors, then surprisingly found that pharmaceutical compositions comprising adefovir dipivoxil or its solvates prepared using only microcrystalline cellulose as diluent and sodium stearyl fumarate as lubricant and employing the simplest direct compression method, were stable both in physical and chemical characteristics on long term storage without involving the use of any stabilizer in the composition and desiccant as packaging aid. Further, the pharmaceutical composition prepared using minimal ingredients without any stabilizer and desiccant as packaging aid by direct compression method is simple, cost effective and easy to manufacture on a commercial scale.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to stable pharmaceutical compositions comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s), wherein the composition is devoid of any stabilizer and further being devoid of a desiccant for use as a packaging aid. Further the invention, also relates to process for preparing a stable pharmaceutical composition comprising adefovir dipivoxil or its solvates with one or more pharmaceutically acceptable excipient(s).

An objective of the invention is to prepare a stable pharmaceutical composition comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s) for oral administration, wherein the composition is devoid of any stabilizer and further being devoid of a desiccant for use as a packaging aid.

Another objective of the invention relates to a process for preparing a stable pharmaceutical composition in the form of oral tablet comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s) using direct compression method wherein the tablet is devoid of any stabilizer and further being devoid of a desiccant for use as a packaging aid.

Yet another objective of the invention relates to stable pharmaceutical tablet comprising adefovir dipivoxil or its solvates, and one or more pharmaceutically acceptable excipient(s), having comparable in-vitro dissolution profile with that of the marketed Hepsera® tablet, wherein the tablets is essentially devoid of any stabilizer and further being devoid of a desiccant for use as a packaging aid.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to a stable pharmaceutical composition comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s) and a process for preparing the same. More particularly, the invention relates to a stable pharmaceutical composition comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s), wherein, the composition is devoid of any stabilizer and further being devoid of a desiccant for use as a packaging aid.

As mentioned in the background of the invention, adefovir dipivoxil is unstable in nature and can undergo degradation, it is very difficult to prepare a stable pharmaceutical composition of adefovir dipivoxil or its solvates without using any stabilizer to reduce the level of impurities formed in the composition.

It was surprisingly found that the pharmaceutical composition comprising adefovir dipivoxil or its solvates prepared using microcrystalline cellulose as diluent and sodium stearyl fumarate as lubricant using direct compression method were stable both in physical and chemical characteristics on long term storage without involving the using of any stabilizer and a desiccant as packaging aid.

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for adefovir dipivoxil or its solvates thereof.

According to the invention, the stable pharmaceutical composition comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s) is devoid of any stabilizer. The preferred stabilizer, which according to the invention is not present in the composition, belongs to the group consisting of calcium carbonate, magnesium carbonate, zinc carbonate, manganese carbonate, aluminum carbonate, ferrous carbonate, cobalt carbonate, magnesium hydroxide, calcium hydroxide, aluminum hydroxide or iron hydroxide.

As used herein, the packaging aid is a desiccant widely used in pharmaceutical preparations to retain the physical or chemical stability of the composition on long term storage. Use of packaging aid like desiccant is selected based on the nature of the active ingredient, inactive ingredients and primary packaging material used in the formulation.

According to the invention, the stable pharmaceutical composition comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s) is devoid of desiccant as packaging aid. The preferred desiccant, which according to the invention is not present in the composition, belongs to the group consisting of natural or synthetic zeolite (molecular sieves 3A, 4A, 5A, 13X), silica gel, silica alumina, activated carbon, activated alumina, clay desiccants, calcium sulfate, calcium chloride, calcium oxide and the mixtures thereof.

According to an embodiment of the invention, the stable adefovir dipivoxil composition may be prepared by any suitable process such as direct compression, or dry granulation. Preferably direct compression is used.

Direct compression is a process in which active ingredient and one or more pharmaceutically acceptable excipient(s) is blended uniformly and compressed into a desired dosage form. Direct compression method provides advantage over other methods of preparing pharmaceutical composition, in terms of having lesser manufacturing steps or unit operations. Since, it requires less number of procedural steps, hence direct compression process has quick processing time and minimal manufacturing costs. Also, unlike wet granulation process, the direct compression process also has the advantage that the active ingredient is not subjected to humidity conditions like addition of solvents and/or non-solvents or to high temperatures, which are known to be detrimental to the stability of the pharmaceutical composition.

According to an embodiment of the invention, it includes the process for preparing a stable pharmaceutical composition comprising adefovir dipivoxil or its solvates with one or more pharmaceutically acceptable excipient(s), wherein the process involve the steps of: i) adding adefovir dipivoxil or its solvate and one or more pharmaceutically acceptable excipient(s) together and optionally screening; ii) optionally blending the material obtained in step no. i); iii) optionally sifting one or more pharmaceutically acceptable excipient(s) and blending with blend obtained in step ii); iv) compressing the blend of step iii) using suitable tooling.

The wording herein below is implied with in the concept of invention as below:

"Adefovir dipivoxil" as used herein refers to adefovir as base and/ or their pharmaceutically acceptable salts, solvates, enantiomers, diastereomers and polymorphs thereof which may be present in crystalline or amorphous forms. More particularly, adefovir dipivoxil formic acid solvate is used. Various crystalline forms and co-crystals of adefovir dipivoxil have been disclosed in prior art literatures. Adefovir dipivoxil formic acid solvate has been described in PCT application number WO 2012/032541, which is being mentioned here with reference to. Said publication also provides novel crystal form of adefovir dipivoxil formic acid solvate.

The term "long term storage" as used herein, refers to pharmaceutical composition of adefovir dipivoxil formic acid solvate having storage or shelf-life for at least 12 weeks to 9 months at different storage conditions like 40±2°C and 75±5% relative humidity or 25±2°C and 60±5% relative humidity.

The term "stable pharmaceutical composition" as used herein, refers to composition comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s) which may be in the form of granules, pellets, mini-tablets, tablets, modified release tablets and capsules filled with granules or pellets. Preferably, the pharmaceutical composition is a tablet.

The term "impurity" as used herein, refers to adefovir dipivoxil formic acid solvate degradation products as formed in the pharmaceutical composition. The term "total impurities" as used herein, refers to the sum of all the degradation products like monoester impurity, carbonyl impurity, adefovir impurity and any other unknown impurities as formed in the pharmaceutical composition, upon storage at various conditions.

As used herein with respect to pharmaceutical composition, unless otherwise defined, the term "stable" means that the amount of the corresponding total impurities within the pharmaceutical composition has not increased by more than 4% by weight from the initial amount of adefovir dipivoxil formic acid solvate after storing at various conditions like 40±2°C and 75±5% relative humidity for 4 weeks to 12 weeks period or 25±2°C and 60±5% relative humidity for 9 months. Preferably, the corresponding content of total impurities has not increased by more than 3% by weight of the initial amount of adefovir dipivoxil formic acid solvate after storing at various conditions like 40±2°C and 75±5% relative humidity for 4 weeks to 12 weeks period or 25±2°C and 60±5% relative humidity for 9 months. More preferably, the corresponding content of total impurities has not increased by more than 2% by weight of the initial amount of adefovir dipivoxil formic acid solvate after storing at various conditions like 40±2°C and 75±5% relative humidity for 4 weeks to 12 weeks period or 25±2°C and 60±5% relative humidity for 9 months.

The pharmaceutical composition of the invention in addition to the active ingredient may optionally contain one or more pharmaceutically acceptable excipient(s) which may include, but are not limited to diluent(s), disintegrant(s), glidant(s), lubricant(s) and the like.

Suitable diluent(s) according to the invention include, but are not limited to lactose, sucrose, dextrose, maize starch, potato starch, rice starch, wheat starch, potato starch, pregelatinized starch, sorbitol, manntiol, microcrystalline cellulose (Avicel® PH 101, Avicel® PH 102, Avicel® PH 112, Avicel® PH 113), silicified microcrystalline cellulose, cellulose derivatives, dicalcium phosphate, dextrates, dextrin, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate or magnesium oxide and the combinations thereof. Preferably, microcrystalline cellulose is used.

Suitable disintegrant(s) according to the invention include, but are not limited to cross-linked polyvinylpyrollidone, cross-linked sodium carboxymethylcellulose (croscarmellose sodium), sodium starch glycolate, maize starch, pregelatinized starch, salts of carboxy methyl cellulose, microcrystalline cellulose, alginic acid, sodium alginate, guar gum, low-substituted hydroxypropyl cellulose and the combinations thereof.

Suitable glidant(s) and lubricant(s) according to the invention include, but are not limited to silica, colloidal silica, magnesium trisilicate, talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate and the combinations thereof. Preferably, sodium stearyl fumarate is used.

The pharmaceutical composition according to an embodiment of the invention may optionally be coated with functional and/ or non-functional coating using film-forming polymer(s).

According to an embodiment of the invention, the process for preparing stable pharmaceutical composition comprising adefovir dipivoxil formic acid solvate and one or more pharmaceutically acceptable excipient(s) involves the following steps:

(i) preparing intragranular mixture of adefovir dipivoxil formic acid solvate with one or more diluent(s), and lubricant;

(ii) the mixture is blended for suitable period of time;

(iii) the prepared blend was dry granulated using roll compactor and the compact were milled through Quadro® comil® to get granules;

(iv) preparing extragranular mixture with diluent, lubricant and suitable other excipients;

(v) the mixture is blended for suitable period of time;

(vi) step (iii) granules are mixed with step (v) extragranular portion;

(vii) mixing the intragranular and extragranular portion together to make the final blend;

(viii) lubricating the above blend obtained in step (vii) and compressing the lubricated blend into tablets using appropriate tooling and;

(ix) optionally coating the tablets.

According to another embodiment of the invention, the process of preparing stable pharmaceutical composition comprising adefovir dipivoxil formic acid solvate, and one or more pharmaceutically acceptable excipient(s) using direct compression method involves the following steps:

(i) sifting adefovir dipivoxil formic acid solvate with diluent using suitable sieve/screen;

(ii) blend the step (i) materials using suitable blender;

(iii) sift lubricant using suitable sieve/screen;

(iv) add the blend obtained in step (ii) into step (iii) and blend for suitable period of time;

(v) compressing the final blend into tablets using appropriate tooling.

According to an embodiment of the invention, the comparative study of commercially available formulation Hepsera® tablet and the composition of the present invention are done after subjecting both the products to accelerated stability testing kept at 40±2°C and 75±5% relative humidity for 4 weeks to 12 weeks period to monitor and analyze the impurity level.

According to an embodiment of the invention, the stability study of adefovir dipivoxil formic acid solvate composition in the form of oral tablet are done after subjecting for long term testing kept at 25±2°C and 60±5% relative humidity for 9 months to analyze the percentage purity, drug release and individual impurity level.

A further embodiment of the invention relates to adefovir dipivoxil formic acid solvate in the form of oral tablet wherein said tablet possess comparable in-vitro dissolution profile with commercially available tablets of Hepsera" tablet, wherein the tablets are essentially devoid of any stabilizer and further being devoid of a desiccant for use as a packaging aid.

According to the invention, the impurities for adefovir dipivoxil formic acid solvate tablets are determined using HPLC procedure using following Chromatographic conditions:

Chromatographic conditions:

Column: YMC ODS-AQ, 250 x 4.6 mm, 5 urn or equivalent

Injection volume: 10 uL

Flow rate: 1.0 mL/ minute

Wavelength: 260 ran

Column oven temperature: 35°C

Sample cooler temperature: 10°C

Needle wash solvent: Mobile phase - B.

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.

Example-1:

Tablets comprising adefovir dipivoxil formic acid solvate prepared using dry granulation method.

Unit Composition:

Brief Manufacturing Process:

1. Adefovir dipivoxil formic acid solvate, microcrystalline cellulose and lactose were sifted together through suitable sieve/screen.

2. Sodium stearyl fumarate was sifted through suitable sieve/screen.

3. Step 2 materials were loaded into blender and blend for suitable period of time.

4. Step 3 material was dry granulated using roller compactor and the compact were milled through Quadro® comil® to get granules.

5. Step 4 materials were mixed with extragranular lactose and croscarmellose sodium and blended for suitable period of time.

6. Extragranular sodium stearyl fumarate was sifted through suitable sieve/screen.

7. Step 6 materials were added into the step 4 materials and mixed for suitable period of time.

8. Step 7 lubricated blends were compressed into tablet using suitable tooling and the tablets were packed in white heavy HDPE bottle with rayon and lg silica gel.

Examples-2:

Tablets comprising adefovir dipivoxil formic acid solvate prepared using direct compression method.

Unit Composition:

Brief Manufacturing Process:
1. Sift adefovir dipivoxil formic acid solvate and dicalcium phosphate together through suitable sieve/screen.
2. Load step 1 materials into blender and blend for suitable period of time.
3. Sift sodium stearyl fumarate through suitable sieve/screen.
4. Add step 3 materials to step 2 blend and blend for suitable period of time.

9. Compress the blend using suitable tooling and the tablets were packed in white heavy HDPE bottle with rayon and lg silica gel.

ExampIe-3:

Tablets comprising adefovir dipivoxil formic acid solvate prepared using direct compression method.
Unit Composition:

Brief Manufacturing Process:

1. Weigh all the ingredients separately.

2. Sift adefovir dipivoxil and microcrystalline cellulose (Part 1) together through suitable sieve/screen.

3. Sift step 2 material and microcrystalline cellulose (Part 2) together through suitable sieve/screen.

4. Sift step 3 material and microcrystalline cellulose (Part 3) together through suitable sieve/screen.

5. Load step 4 materials into blender and blend for suitable period of time.

6. Sift sodium stearyl fumarate through suitable sieve/screen.

7. Add step 6 materials to step 5 blend and blend for suitable period of time.

8. Compress the blend using suitable tooling of 5.5 mm, round shaped, flat-faced with beveled edges and the tablets were packed in white heavy HDPE bottle with rayon.

As discussed earlier, it is known that adefovir dipivoxil is a sensitive molecule for chemical degradation. To overcome the stability problems, inventors on their continuous efforts, undertook various experiment/ trials using different diluents and different manufacturing process in order to arrive at a stable tablet dosage form with satisfactory physical and chemical stability.

The tablets prepared according to the above examples were stored in white heavy HDPE bottle with rayon and subjected to accelerated stability testing which were kept at 40±2°C and 75±5% relative humidity for 4 weeks to 12 weeks period. The tablets were analyzed using HPLC method to identify the impurities. The results are depicted in Table - 1.

The stability data of tablets provided in Table - 1, indicates that the tablets of Example - 1 had 4.291 %w/w of total impurities at the end of 12 weeks study and the tablets of Example - 2 had 6.821 %w/w of total impurities at the end of 4 weeks itself and the reference product Hepsera® 10 mg tablets with silica gel had 4.003% w/w of total impurities at the end of 12 weeks.

But, the tablets of Example - 3 according to the invention which is prepared without using any stabilizer in the composition and without using any desiccant as packaging aid; had decreased level of impurity of 1.727 %w/w after 12 weeks when compared with Example - 1 & 2 of the invention and Hepsera" 10 mg tablets with silica gel.

From the results obtained, the tablets of Example - 3 according to the invention which is prepared without using any stabilizer in the composition and without using any desiccant as packaging aid were selected for further studies.

The tablets of Example - 3 were stored in heavy HDPE bottles in different pack sizes and subjected to long term testing which were kept at 25±2°C and 60±5% relative humidity for 9 months. The percentage purity and drug release was studied; also individual impurities were identified in the tablets using HPLC method. The results are depicted in Table - 2. The results showed that total impurities at the end of 9 months for different pack sizes were 1.410 %w/w and 1.084 %w/w respectively.

The above results obtained indicates that when compared to the Hepsera® 10 mg tablets with silica gel, Example - 3 of the invention, the tablets prepared without using any stabilizer in the composition and without using any desiccant as packaging aid showed improved stability and decreased levels of impurities on long term storage.

Also, the tablets of Example - 3 were prepared using direct compression method using minimal ingredients which is simple, cost effective and easy to manufacture on a commercial scale.

Comparative dissolution data:

Adefovir dipivoxil tablets prepared according to Example - 3 and commercially available tablets of Hepsera® tablet were subjected to in-vitro dissolution profile by using USP type II (paddle) dissolution apparatus using 600ml of 0.01 N HC1 at 50 rpm and the resultant data is compiled in table - 3.

Table-3

The above result shows that tablet of Example - 3 exhibit similar in-vitro drug release with respect to the commercially available tablets of Hepsera® tablet.

WE CLAIM:

1. A stable oral pharmaceutical composition comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s), wherein said composition is devoid of any stabilizer and desiccant as a packaging aid.

2. A direct compression method for preparing stable oral pharmaceutical composition comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s), wherein said composition is devoid of any stabilizer and desiccant as a packaging aid.

3. The stable oral pharmaceutical composition according to any of the claims 1 or 2, characterized in that the total impurities formed are not more than about 2% w/w when stored at 40±2°C and 75±5% relative humidity for a period of up to about 12 weeks.

4. The stable oral pharmaceutical composition according to any of the claims 1 or 2, characterized in that the total impurities formed are not more than about 2% w/w when stored at 25±2°C and 60±5% relative humidity for a period of up to about 9 months.

5. The stable oral pharmaceutical composition according to any of the preceding claims, wherein one or more pharmaceutically acceptable excipient(s) are selected from a group consisting of diluent(s), disintegrant(s), glidant(s), lubricant(s) or their combinations thereof.

6. A process for preparing a stable oral pharmaceutical composition comprising adefovir dipivoxil or its solvates and one or more pharmaceutically acceptable excipient(s), wherein said process involve the steps of:

i) mixing adefovir dipivoxil formic acid solvate and one or more pharmaceutical^ acceptable excipient(s) together and optionally screening;

ii) optionally blending the material obtained in step no. i);

iii) optionally sifting one or more pharmaceutically acceptable excipient(s) and blending with blend obtained in step ii);

iv) compressing the blend of step iii) using suitable tooling.

7. A tablet comprising adefovir dipivoxil formic acid solvate, having the following unit composition. wherein said tablet is devoid of any stabilizer and desiccant as a packaging aid.