TECHNICAL FIELD OF INVENTION

The invention relates to oral pharmaceutical compositions comprising tenofovir. More specifically, it relates to oral formulations comprising multi¬particulate^) of tenofovir and optionally one or more pharmaceutically acceptable excipient(s).

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Tenofovir disoproxil fumarate is a nucleotide analogue reverse transcriptase inhibitor and is indicated for the treatment of HIV-1 and chronic hepatitis B infections in adults and pediatric patients. Tenofovir disoproxil fumarate is chemically designated as 9-[(R)-2[[bis [[(isopropoxycarbonyl) oxy] methoxy] phosphinyl] methoxy] propyl] adenine fumarate (1:1). Its molecular formula is C19H30N5O10P 'C^C^ and its molecular weight is 635.52. Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25 °C. In the U.S., Tenofovir disoproxil fumarate is marketed by Gilead under brand name of Viread® and is available as tablets and as an oral powder. Oral powder is available for oral administration as white, taste-masked, coated granules containing 40 mg of tenofovir disoproxil fumarate per gram of oral powder, which is equivalent to 33 mg of tenofovir disoproxil. The oral powder contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, ethylcellulose, and silicon dioxide. Viread® oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g., applesauce, baby food, yogurt). The entire mixture should be ingested immediately to avoid a bitter taste. Viread® oral powder should not be administered in a liquid, as the powder may float on top of the liquid even after stirring.

Per the available public domain literature, it appears that Viread® oral powder formulation uses the proprietary Aptalis Microcaps® taste-masking technology. Aptalis microencapsulation technology Microcaps® employs versatile and precise coating techniques to encapsulate individual drug particles using solvent and aqueous-based coacervation. PCT Application no. WO2006/055142 discloses a coacervation microencapsulation technology for preparing taste-masked microparticle composition comprising one or more bitter-tasting therapeutic agent(s), which exhibits acceptable taste-masking when placed in the oral cavity and provides rapid-release of the therapeutic agent on entry into the stomach. Said patent application also discloses that, crystals of a bitter active with a desired particle size range of from about 20 um to 500 um, more particularly from about 50 urn to 300 um may be taste-masked directly. Alternatively, microgranules containing milled or micronized drug may be produced by granulating in a high-shear granulator using suitable filler/diluent (if required) with a polymeric binder.

The coacervation microencapsulation technology for preparing taste-masked microparticle comprises the steps of:

(a) preparing drug containing core particle by extrusion-spheronization or by drug layering on an inert particle;

(b) preparing solution of water insoluble polymer using solvent in coacervation tank at 80°C;

(c) adding drug containing core particles in to coacervation tank, followed by adding gastro-soluble pore forming agent in the coacervation tank at product temperature of 58°C ;

(d) allowing solvent in the polymer solution to evaporate in the coacervation tank, thus achieving microencapsulation;

(e) allowing the product temperature of the coacervation tank to reach room temperature and then filtered out microencapsulated drug containing core particles and followed by washing with suitable solvent to reduce residual solvent level.

The above prior art represents an attempt to overcome the bitter taste of the drug, by preparing multi-paniculate formulation using solvent based coacervation method. However, the prior art teaches a cumbersome and costly process, which may not be economical. Thus, there is a need in the art to develop simple and cost effective process for taste masking of bitter drugs. The present inventors surprisingly found that the process used for preparing oral multi-particulate formulation of tenofovir can be simple and cost effective and can also be attributed for taste masking properties.

OBJECTIVES OF THE INVENTION

The invention relates to oral pharmaceutical composition comprising tenofovir. More specifically, it relates to oral multi-particulate formulation comprising tenofovir and optionally one or more pharmaceutically acceptable excipient(s). An objective of the invention, is to prepare oral multi-particulate formulation comprising tenofovir and optionally one or more pharmaceutically acceptable excipient(s) by employing extrusion-spheronization process. Another objective of the invention, is to prepare oral multi-particulate formulation comprising tenofovir and optionally one or more pharmaceutically acceptable excipient(s), wherein said multi-particulate comprises core particles containing tenofovir prepared by employing extrusion-spheronization process and said core particles comprising tenofovir are further coated with ethylcellulose or methacrylic acid copolymers) such as Eudragit® EPO or combinations thereof.

Another objective of the invention, is to prepare oral multi-particulate formulation comprising tenofovir and optionally one or more pharmaceutically acceptable excipient(s), wherein:

(a) said multi-particulate comprises core particles containing tenofovir prepared by employing extrusion-spheronization process and said core particles comprising tenofovir are further coated with ethylcellulose or methacrylic acid copolymer(s) such as Eudragit® EPO or combinations thereof, and

(b) characterized in that said coating layer is devoid of gastro-soluble pore-formers.

Another objective of the invention, is to prepare oral multi-particulate formulation comprising tenofovir and optionally one or more pharmaceutically acceptable excipient(s), wherein said multi-particulate comprises core particles containing tenofovir are prepared by coating inert sphere(s) with tenofovir and coating said tenofovir layered core particles, with ethylcellulose or methacrylic acid copolymer(s) such as Eudragit® EPO or combinations thereof. Yet another objective of the invention, is to prepare oral multi-particulate formulation comprising tenofovir and optionally one or more pharmaceutically acceptable excipient(s), wherein:

(a) said multi-particulate comprises core particles containing tenofovir are prepared by coating inert sphere(s) with tenofovir and coating said tenofovir layered core particles, with ethylcellulose or methacrylic acid copolymer(s) such as Eudragit® EPO or combinations thereof, and

(b) characterized in that said coating layer is devoid of gastro-soluble pore-formers.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to oral pharmaceutical composition comprising tenofovir. More specifically, it relates to oral multi-particulate formulation comprising tenofovir and optionally one or more pharmaceutically acceptable excipient(s). As discussed in the background of the invention, taste masking microencapsulation process of bitter drug containing core particles using aqueous or solvent based coacervation technique requires specialized equipment and is very complicated and time consuming. The present inventors surprisingly found that the process used according to the embodiments of the invention for preparing oral multi-particulate pharmaceutical compositions of tenofovir is simple and cost effective and it is also attributed for taste masking properties.

More particularly, the invention relates to -

An oral multi-particulate formulation comprising tenofovir and one or more pharmaceutically acceptable excipient(s), wherein the multi-particulate comprises of:

(a) a core particle comprising tenofovir or its pharmaceutically acceptable esters or salts;

(b) a coating layer over the core particle, comprising ethyl cellulose; wherein the core particle is prepared by extrusion-spheronization process; and the coating layer over the core particle is devoid of a gastro-soluble pore-former.

An oral multi-particulate formulation comprising tenofovir and one or more pharmaceutically acceptable excipient(s), wherein the multi-particulate comprises of:

(a) a core particle comprising tenofovir or its pharmaceutically acceptable esters or salts;

(b) a coating layer over the core particle, comprising Eudragit® EPO; wherein the core particle is prepared by extrusion-spheronization process; and the coating layer over the core particle is devoid of a gastro-soluble pore-former.

An oral multi-particulate formulation comprising tenofovir and one or more pharmaceutically acceptable excipient(s), wherein the multi-particulate comprises of:
(a) a core particle comprising tenofovir or its pharmaceutically acceptable esters or salts;

(b) a coating layer over the core particle, comprising ethylcellulose and Eudragit® EPO; wherein the core particle is prepared by extrusion-spheronization process; and the coating layer over the core particle is devoid of a gastro-soluble pore-former.

An oral multi-particulate formulation comprising tenofovir and one or more pharmaceutically acceptable excipient(s), wherein the multi-particulate comprises of:

(a) a core particle comprising tenofovir or its pharmaceutically acceptable esters or salts;

(b) a coating layer over the core particle, comprising ethyl cellulose; wherein the core particle is prepared by coating tenofovir or its pharmaceutically acceptable esters or salts over an inert pellet; and the coating layer over the core particle is devoid of a gastro-soluble pore-former.

An oral multi-particulate formulation comprising tenofovir and one or more pharmaceutically acceptable excipient(s), wherein the multi-particulate comprises of:

(a) a core particle comprising tenofovir or its pharmaceutically acceptable esters or salts;

(b) a coating layer over the core particle, comprising Eudragit® EPO; wherein the core particle is prepared by coating tenofovir or its pharmaceutically acceptable esters or salts over an inert pellet; and the coating layer over the core particle is devoid of a gastro-soluble pore-former.

An oral multi-particulate formulation comprising tenofovir and one or more pharmaceutically acceptable excipient(s), wherein the multi-particulate comprises of:

(a) a core particle comprising tenofovir or its pharmaceutically acceptable esters or salts;

(b) a coating layer over the core particle, comprising ethyl cellulose and Eudragit® EPO; wherein the core particle is prepared by coating tenofovir or its pharmaceutically acceptable esters or salts over an inert pellet; and the coating layer over the core particle is devoid of a gastro-soluble pore-former. According to an embodiment of the invention, the process for preparing oral multi-particulate formulation comprising tenofovir and optionally one or more pharmaceutically acceptable excipient(s) comprises the steps of:

1) preparing a binder solution using suitable solvent;

2) sifting and blending tenofovir and diluent(s) to get uniform blend;

3) granulating the blend obtained in step (2) using binder solution obtained in step (1) to get wet mass;

4) passing the wet mass of step (3) through an extruder to get extrudates;

5) spheronization of extrudates obtained in step (4) to get pellets or beads or granules or particles of uniform size;

6) drying the pellets or beads or granules or particles obtained in step (5) using tray dryer or fluid bed dryer;

7) dissolving/dispersing ethylcellulose or methacrylic acid copolymer(s) such as Eudragit® EPO polymer(s) and plasticizer in suitable solvent;

8) coating the dried tenofovir pellets or beads or granules or particles obtained in step (6) using polymer dispersion obtained in step (7) by employing spray coating to get final tenofovir multi-particulate.

According to an embodiment of the invention, the process for preparing oral multi-particulate formulation comprising tenofovir and optionally one or more pharmaceutically acceptable excipient(s) comprises the steps of:

1) preparing a binder solution using suitable solvent;

2) adding tenofovir to the binder solution obtained in step (1) under continuous stirring to get uniform suspension/dispersion;

3) coating inert pellets or beads or granules or particles with tenofovir dispersion obtained in step (2) using spray coating to get tenofovir coated pellets or beads or granules or particles;

4) dissolving/dispersing ethylcellulose or methacrylic acid copolymer(s) such as Eudragit® EPO polymer(s) and plasticizer in suitable solvent;

5) coating the tenofovir coated pellets or beads or granules or particles obtained in step (3) using polymer dispersion obtained in step (4) by employing spray coating to get final tenofovir multi-particulate.

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 tenofovir or its pharmaceutically acceptable salts or esters or derivatives thereof. According to the invention, tenofovir may be present in an amorphous or crystalline form. As used herein, the term, "tenofovir" is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or esters or enantiomers or derivatives or polymorphs or solvates/ hydrates or combination thereof. Preferable esters or salts of tenofovir which can be used according to the invention includes tenofovir disoproxil, tenofovir alafenamide, tenofovir disoproxil fumarate, tenofovir disoproxil maleate, tenofovir alafenamide fumarate or tenofovir alafenamide maleate and other pharmaceutically acceptable esters or salts of tenofovir.

As used herein, the term "multi-particulate(s)" relates to pellet(s) or bead(s) or granule(s) or particle(s) or sphere(s) comprising tenofovir and one or more pharmaceutically acceptable excipient(s) prepared by extrusion-spheronization process and/or coating process. As used herein, the term "pellet(s) or bead(s) or granule(s) or particle(s) or sphere(s) or core particle(s)" relates to a small, solid or densely packed rounded and/or cylindrical compacted mass comprising tenofovir and one or more pharmaceutically acceptable excipient(s) obtained by extrusion-spheronization process and/or coating process. According to an embodiment of the invention, tenofovir multi-particulate may be optionally lubricated and mixed with one or more filler(s) such as lactose, xylitol, sucrose, dextrose, mannitol, microcrystalline cellulose, colloidal silica etc. before filling in to capsules or sachet or multi use HDPE bottle. According to an embodiment of the invention, tenofovir multi-particulate may be further blended with one or more pharmaceutically acceptable excipient(s) and compressed in to tablets.

Extrusion-spheronization is a multiple-step process capable of making uniformly sized spherical or cylindrical particles commonly referred to as pellet(s) or bead(s). Extrusion-spheronization process essentially comprises the steps of:

a) dry mixing of ingredient to get homogenous powder blend;

b) controlled wet massing of the powder blend to produce a wet mass;

c) extrusion of the wet mass to form rod shaped particles of uniform diameter and length;

d) spheronization to round off these rod shaped particles into spherical/cylindrical particles with narrow size distribution;

e) drying to achieve desired final moisture content; and

f) screening to obtain desired size of beads/pellets.

According to an embodiment of the invention, inert pellet(s) or bead(s) or granules(s) or particle(s) or sphere(s) or core particle(s) are made up of from either of the ingredients such as microcrystalline cellulose, starch, lactose, sucrose or combinations thereof. Multi-particulates are coated using aqueous or organic based polymer solution/dispersion. The basic components of a polymer coating system are film forming polymer, plasticizer and solvent; optionally may also contain colorants, anti-tackifying agents etc. Preferably spray coating by employing fluid bed coater is used to achieve uniform coating of the multi-particulates. According to an embodiment of the invention, oral multi-particulate formulation comprising tenofovir and optionally one or more pharmaceutically acceptable excipient(s) are selected from a group comprising diluents, binders, surfactants, wetting agents, glidants and/ or lubricants and coating polymer. Suitable diluents according to the invention include, but are not limited to, mannitol, xylitol, sorbitol, lactose, anhydrous lactose, sucrose, cellulose, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, starch, calcium trisilicate, magnesium trisilicate, cellulose acetate, dextrose, or combinations thereof.

Suitable binders according to the invention include, but are not limited to povidone, copovidone, pregelatinized starch, polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), starch, hydroxyethyl cellulose (HEC), ethylcellulose (EC), chitosan, guar gum, methyl cellulose (MC), carbomer, acacia, sodium alginate, calcium alginate or combinations thereof. Suitable surfactants or wetting agents according to the invention include, but are not limited to, anionic surfactants such as potassium laurate, triethanolamine stearate, sodium lauryl sulfate, cationic surfactants include quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide; nonionic surfactants include glycerol monostearate, cetyl alcohol, cetostearyl alcohol, and. polyoxyethylene glycol sorbitan alkyl esters (polysorbate), sorbitan alkyl esters (span), poloxamer or combinations thereof.

Suitable glidants and/or lubricants according to the invention include, but are not limited to, silicon dioxide, colloidal silicon dioxide, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate, sodium dodecyl sulfate or combinations thereof. According to the invention, coating of multi-particulate(s) comprises one or more excipient(s) selected from a group comprising of one or more coating polymer, plasticizers etc. Suitable coating polymers according to the invention include, but are not limited to, ethylcellulose (EC), polyvinylpyrrolidone (PVP), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate, cellulose phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), methacrylic acid copolymer such as Eudragit® EPO or combinations thereof. Preferably ethylcellulose or Eudragit® EPO or combinations thereof.

Suitable plasticizers according to the invention include, but are not limited to castor oil, polyethylene glycol, propylene glycol, glycerin, triacetin, polysorbates, phthalate esters, dibutyl sebacate, citrate esters, and monoglycerides or combinations thereof. Suitable solvents for preparing solution/dispersion of binder and/or coating polymer according to the invention include purified water, ethanol, dichloromethane (DCM), mixture of isopropyl alcohol (IPA), acetone and methanol or combinations thereof. According to the invention, gastro-soluble pore-former(s) which are devoid from the coating includes lactose, mannitol, xylitol, sorbitol, dextrose, calcium carbonate, calcium phosphate, calcium saccharide, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide and magnesium phosphate. The embodiments of the invention, are described in the following examples, but the examples are illustrative and do not limit the scope of this invention.

EXAMPLE 1

Unit Composition:

Brief Manufacturing Procedure:

1) Dissolve povidone in purified water.

2) Add tenofovir disoproxil fumarate to binder solution obtained in step (1) under continuous stirring to get uniform suspension/dispersion.

3) Spray coat sugar pellets with tenofovir disoproxil fumarate dispersion obtained in step (2) using fluid bed coater to get tenofovir disoproxil fumarate coated pellets.

4) Dissolving/dispersing ethylcellulose, hydroxypropylmethyl cellulose and triethyl citrate in isopropyl alcohol and dichloromethane solvent mixture.

5) Spray coat the tenofovir disoproxil fumarate pellets obtained in step (3) using coating polymer solution/dispersion obtained in step (4) by employing fluid bed coater to get tenofovir pellets.

6) Lubricate the tenofovir disoproxil fumarate pellets obtained in step (5) using magnesium stearate; and fill into multiple use HDPE bottle.

EXAMPLE 2

Unit Composition:

Brief Manufacturing Procedure:

1) Dissolve hydroxypropyl cellulose in purified water.

2) Add tenofovir disoproxil fumarate to binder solution obtained in step (1) under continuous stirring to get uniform suspension/dispersion.

3) Spray coat cellulose pellets with tenofovir disoproxil fumarate dispersion obtained in step (2) using fluid bed coater to get tenofovir disoproxil fumarate coated pellets.

4) Dissolving/dispersing Eudragit® EPO, povidone and dibutyl sebacate in isopropyl alcohol and dichloromethane solvent mixture.

5) Spray coat the tenofovir disoproxil fumarate pellets obtained in step (3) using coating polymer solution/dispersion obtained in step (4) by employing fluid bed coater to get tenofovir disoproxil fumarate pellets.

6) Lubricate the tenofovir disoproxil fumarate pellets obtained in step (5) using magnesium stearate; and fill into sachet.

EXAMPLE 3

Unit Composition:

Brief Manufacturing Procedure:

1) Dissolve hydroxypropylmethyl cellulose in purified water.

2) Add tenofovir disoproxil fumarate to binder solution obtained in step (1) under continuous stirring to get uniform suspension/dispersion.

3) Spray coat sugar pellets with tenofovir disoproxil fumarate dispersion obtained in step (2) using fluid bed coater to get tenofovir disoproxil fumarate coated pellets.

4) Dissolving/dispersing ethylcellulose, Eudragit® EPO, povidone and propylene glycol in isopropyl alcohol and dichloromethane solvent mixture.

5) Spray coat the tenofovir disoproxil fumarate pellets obtained in step (3) using coating polymer solution/dispersion obtained in step (4) by employing fluid bed coater to get tenofovir disoproxil fumarate pellets.

6) Lubricate the tenofovir disoproxil fumarate pellets obtained in step (5) with magnesium stearate;

7) Mix the lubricated pellets obtained in step (6) with mannitol and microcrystalline cellulose, fill into multiple use HDPE bottle.

EXAMPLE 4

Unit Composition:

Brief Manufacturing Procedure:

1) Dissolve povidone in purified water.

2) Sift and blend tenofovir disoproxil fumarate and microcrystalline cellulose to get uniform blend.

3) Granulate the blend obtained in step (2) using binder solution obtained in step (1) to get wet mass.

4) Pass the wet mass of step (3) through extruder to get extrudes.

5) Spheronization of extrudes obtained in step (4) to get pellets of uniform size.

6) Dry the pellets obtained in step (5) using fluid bed dryer.

7) Dissolving/dispersing hydroxypropylmethyl cellulose, Eudragit® EPO and dibutyl sebacate in isopropyl alcohol and dichloromethane solvent mixture.

8) Spray coat the dried tenofovir disoproxil fumarate pellets obtained in step (6) using coating polymer dispersion obtained in step (7) by employing fluid bed coater to get tenofovir disoproxil fumarate pellets.

9) Lubricate the tenofovir disoproxil fumarate pellets obtained in step (8) with magnesium stearate.

10) Mix the lubricated pellets obtained in step (9) with lactose and microcrystalline cellulose before filling into multiple use HDPE bottle.

EXAMPLE 5

Unit Composition:

Brief Manufacturing Procedure:

1) Dissolve hydroxypropyl cellulose in purified water.

2) Sift and blend tenofovir disoproxil fumarate, microcrystalline cellulose and ethylcellulose to get uniform blend.

3) Granulate the blend obtained in step (2) using binder solution obtained in step (1) to get wet mass.

4) Pass the wet mass of step (3) through extruder to get extrudes.

5) Spheronization of extrudes obtained in step (4) to get pellets of uniform size.

6) Dry the pellets obtained in step (5) using fluid bed dryer.

7) Dissolving/dispersing ethylcellulose, Eudragit® EPO, povidone and triethyl citrate in isopropyl alcohol and dichloromethane solvent mixture.

8) Spray coat the dried tenofovir disoproxil fumarate pellets obtained in step (6) using coating polymer dispersion obtained in step (7) by employing fluid bed coater to get tenofovir disoproxil fumarate pellets;

9) Lubricate the tenofovir disoproxil fumarate pellets obtained in step (8) with magnesium stearate.

10) Mix the lubricated pellets obtained in step (9) with mannitol and microcrystalline cellulose before filling into multiple use HDPE bottle.

EXAMPLE 6

Unit Composition:

Brief Manufacturing Procedure:

1) Dissolve hydroxypropylmethyl cellulose in purified water.

2) Sift and blend tenofovir disoproxil fumarate, microcrystalline cellulose and Eudragit® EPO to get uniform blend.

3) Granulate the blend obtained in step (2) using binder solution obtained in step (1) to get wet mass;

4) Pass the wet mass of step (3) through extruder to get extrudes.

5) Spheronization of extrudes obtained in step (4) to get pellets of uniform size.

6) Dry the pellets obtained in step (5) using fluid bed dryer.

7) Dissolving/dispersing hydroxypropylmethyl cellulose, Eudragit® EPO and propylene glycol in isopropyl alcohol and dichloromethane solvent mixture.

8) Spray coat the dried tenofovir disoproxil fumarate pellets obtained in step (6) using coating polymer dispersion obtained in step (7) by employing fluid bed coater to get tenofovir disoproxil fumarate pellets.

9) Lubricate the tenofovir disoproxil fumarate pellets obtained in step (8) with magnesium stearate.

10) Mix the lubricated pellets obtained in step (9) with lactose and microcrystalline cellulose before filling into multiple use HDPE bottle.

WE CLAIM:

1. An oral multi-particulate formulation comprising tenofovir and one or more pharmaceutically acceptable excipient(s), wherein said multi-particulate comprises of:

(a) a core particle comprising tenofovir or its pharmaceutically acceptable esters or salts;

(b) a coating layer over said core particle, comprising ethyl cellulose; wherein said core particle is prepared by extrusion-spheronization process; and said coating layer over the core particle is devoid of a gastro-soluble pore-former.

2. An oral multi-particulate formulation comprising tenofovir and one or more pharmaceutically acceptable excipient(s), wherein said multi-particulate comprises of:

(a) a core particle comprising tenofovir or its pharmaceutically acceptable esters or salts;

(b) a coating layer over said core particle, comprising Eudragit® EPO; wherein said core particle is prepared by extrusion-spheronization process; and said coating layer over the core particle is devoid of a gastro-soluble pore-former.

3. An oral multi-particulate formulation comprising tenofovir and one or more pharmaceutically acceptable excipient(s), wherein said multi-particulate comprises of:

(a) a core particle comprising tenofovir or its pharmaceuticaily acceptable esters or salts;

(b) a coating layer over said core particle, comprising ethyl cellulose and Eudragit®EPO; wherein said core particle is prepared by extrusion-spheronization process; and said coating layer over the core particle is devoid of a gastro-soluble pore-former.

4. An oral multi-particulate formulation comprising tenofovir and one or more pharmaceuticaily acceptable excipient(s), wherein said multi-particulate comprises of:

(a) a core particle comprising tenofovir or its pharmaceuticaily acceptable esters or salts;

(b) a coating layer over said core particle, comprising ethyl cellulose; wherein said core particle is prepared by coating tenofovir or its pharmaceuticaily acceptable esters or salts over an inert pellet; and said coating layer over the core particle is devoid of a gastro-soluble pore-former.

5. An oral multi-particulate formulation comprising tenofovir and one or more pharmaceuticaily acceptable excipient(s), wherein said multi-particulate comprises of:

(a) a core particle comprising tenofovir or its pharmaceuticaily acceptable esters or salts;

(b) a coating layer over said core particle, comprising Eudragit® EPO; wherein said core particle is prepared by coating tenofovir or its pharmaceutically acceptable esters or salts over an inert pellet; and said coating layer over the core particle is devoid of a gastro-soluble pore-former.

6. An oral multi-particulate formulation comprising tenofovir and one or more pharmaceutically acceptable excipient(s), wherein said multi-particulate comprises of:

(a) a core particle comprising tenofovir or its pharmaceutically acceptable esters or salts;

(b) a coating layer over said core particle, comprising ethyl cellulose and Eudragit® EPO; wherein said core particle is prepared by coating tenofovir or its pharmaceutically acceptable esters or salts over an inert pellet; and said coating layer over the core particle is devoid of a gastro-soluble pore-former.

7. The oral multi-particulate formulation comprising tenofovir according to any of the preceding claims, wherein said pharmaceutically acceptable excipient is selected form a group comprising of diluents, binders, surfactants, wetting agents, glidants and/ or lubricants, coating polymer and plasticizer.

8. The oral multi-particulate formulation comprising tenofovir according to claims 4-6, wherein said inert pellet is selected among a group consisting of such as sugar, microcrystalline cellulose, starch, lactose, sucrose or combinations thereof.

9. An oral multi-particulate formulation comprising tenofovir and one or more pharmaceutically acceptable excipient(s) as herein described and exemplified.