Field of the invention

The technical field of the present invention relates to oral solid dosage forms of HIV-1 protease inhibitor. More particularly, the present invention relates to oral dosage forms of atazanavir prepared by melt granulation process.

Background of the invention

Atazanavir, as disclosed in US 5,849,911 is an azapeptide HIV-1 protease inhibitor, used for the treatment of HIV-1 infection in combination with other antiretroviral agents.

Chemically it is (35,85,95,125)-3,12-bis( 1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl) phenyl]methyl]-2,5,6,10,13-pentaazatetraecanedioic acid dimethyl ester, sulfate (1:1) and is slightly soluble in water (4-5 mg/ml, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3°C. It is commercially marketed as 100, 150, 200 and 300 mg capsules under the trade name Reyataz® by Bristol Myers Squibb. Reyataz® capsules contain atazanavir sulfate as active ingredient and inactive ingredients include lactose, crospovidone and magnesium stearate. Reyataz® capsules must be taken with food and the dosage depends on the history of patient and the use of other co-administered drugs. The capsules are to be taken once daily in combination with other antiretroviral drugs.

As disclosed in EMEA, the commercial process produces exclusively a non-solvated, highly crystalline form designed as form A. Atazanavir is not hygroscopic up to 75% relative humidity (RH), but undergoes solid-state modifications to a predominantly amorphous form in aqueous suspension and when exposed to 95% RH.

It is further disclosed that a wet granulation formulation has been chosen based on rapid and complete in-vitro dissolution profiles obtained. During granulation, the dissolution rate of the finished product is further improved by transformation of atazanavir sulphate crystalline form A into a predominantly amorphous form. The amount of water for granulation being a critical parameter for complete conversion of the crystalline form.

The method of manufacture involves mixing of the active substance with lactose monohydrate and crospovidone, low shear wet granulation, drying, milling, addition of the remaining crospovidone and magnesium stearate final mixing and encapsulation.

US 2010/0183715 discloses granule comprising atazanavir sulfate and an intragranular lubricant, said granule having an interior section and an exterior surface and wherein at least a portion of the intragranular lubricant is present in the interior section of the granule. This patent publication further discloses the preparation of atazanavir formulations by wet granulation process using water.

WO 2010/070611 discloses composition comprising an intragranular portion comprising atazanavir and an extragranular portion comprising a silicate. This patent publication further discloses the preparation of atazanavir formulations by wet granulation process using water.

Keizo et al., (Biological & pharmaceutical bulletin (2007), 30(4), 733-8) discloses solid dispersion system for improving the solubility and bioavailability of poorly water soluble drugs such as atazanavir using sodium lauryl sulfate and Gelucire as a carrier by solvent evaporation method.

IPCOM000157245D discloses amorphous form of atazanavir.

The above prior art references discloses formulations of atazanavir prepared by wet granulation process using water to improve the dissolution rate of the finished product by transformation of atazanavir sulphate crystalline form A into a predominantly amorphous form. Atazanavir being the new class of drug under azapeptide inhibitor of HIV-1 protease used for the treatment of HIV-1 infection, there is a need for the development of improved formulations of atazanavir. Hence, the inventors of the present invention have endeavored to develop a bioequivalent dosage form comprising atazanavir with enhanced/comparable solubility and dissolution by melt granulation process.

Objective of the invention

Accordingly, the main objective of present invention is to provide bioequivalent oral dosage form comprising atazanavir prepared by melt granulation process, in such a way that the dosage form will comply with the reference product in terms of in vivo parameters like Cmax, W and AUC and in vitro parameters like dissolution, disintegration.

Summary of the invention

The present invention relates to an oral dosage form comprising atazanavir or its pharmaceutical^ acceptable salts and one or more pharmaceutical^ acceptable excipients prepared by melt granulation process.

The present invention further relates to a process for the preparation of a stable dosage
form comprising atazanavir or its pharmaceutically acceptable salts comprising the steps
of:

(i) blending atazanavir with one or more intra granular excipients,

(ii) granulating the blend of step (i) using molten binder,

(iii) screening the granules of step (ii),

(iv) formulating the granules of step (iii) to a solid dosage form.

Detailed description of the invention

According to an embodiment, the present invention relates to an oral dosage form comprising atazanavir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients prepared by melt granulation process.

Melt granulation involves the addition of molten binder to the powder mixture or vice versa. Another technique in melt granulation includes hot melt extrusion wherein the mixture comprising drug and carrier are passed through different temperature zones. This process carries several advantages over conventional methods such as the process does not require the use of solvents. The dissolution rate and bioavailability of the drug can be improved by forming a solid dispersion or solid solution.

Melt granulation can be performed in shear mixers such as low or high shear mixers/granulators optionally equipped with heating/cooling jackets or in fluid bed granulators. Granulation can be achieved by spraying of melted binder optionally admixed with other additives on to active agent.

The pharmaceutically acceptable salts of atazanavir according to present invention includes, but not limited to, sulfate, phosphate.

In another embodiment, atazanavir is present either in crystalline Form A, Form C or amorphous form.

In another embodiment, the mean particle size of atazanavir used in the present invention is in the range of about 1 to 100 urn preferably 2-50um.

In another embodiment, the present invention provides a process for the preparation of
an oral dosage form comprising atazanavir or its pharmaceutically acceptable salts
comprising the steps of:

(i) blending atazanavir with one or more intra granular excipients,

(ii) granulating the blend of step (i) using molten binder,

(iii) screening the granules of step (ii),

(iv) formulating the granules of step (iii) to a solid dosage form with the addition of one
or more extragranular excipients.

In another embodiment of the present invention, the intra and extra granular excipients include diluent, binder, disintegrant, glidants, surfactant and lubricant.

In another embodiment, the dosage form comprises about 40% to about 70%w/w of atazanavir, 5% to about 60% w/w of diluent, about 0.5% to about 10% w/w of disintegrant as intragranular excipients.

In another embodiment, the solid dosage form comprises about 0.5% to about 10% w/w of disintegrant, about 0.1% to about 5% w/w of lubricant and optionally about 10% to about 25% w/w of diluent as extra granular excipients.

Suitable diluents according to the present invention are selected from, but not limited to, lactose monohydrate, spay dried lactose, anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, modified starches, pregelatinised starch, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, dihydrated or anhydrous dibasic calcium phosphate, starlac and the like, combinations or co-processed mixtures thereof. The amount of diluent may range from about 5% to 60% by weight.
Suitable binders according to the present invention are selected from, but not limited to, compounds having melting point below 130°C, preferably below 100°C selected from the group of polyethleneglycols with molecular weights of 1500 to 20000 such as PEG 4000, PEG 6000; poloxamers with molecular weights in the range 5000 to 20000 such as Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407 commercially available as Lutrol® or Pluronic® types; Cs- Cis fatty acid esters of polyoxylglicerides of Gelucire® type; Cs-Cis fatty acid esters of polyethylene glycol; sugars or sugar esters such as sucrose stearate, sucrose palmitate or sucrose laurate or glyceryl behenate and the like. The amount of binder may range from about 0.5% to 20% by weight.

Suitable disintegrants used according to the present invention are selected from, but not limited to, crospovidone, croscarmellose sodium, sodium starch glycolate, low substituted, hydroxypropyl cellulose, starch or modified starches, microcrystalline cellulose, carmellose calcium, carmellose sodium alginates, resins, gums, and the like.

The amount of disintegrant may range from about 0.5% to 15% by weight.

Suitable glidants according to the present invention include, but not limited to, calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, talc, colloidal silicon dioxide, starch and the like.

Suitable lubricants according to the present invention include, but not limited to, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, vegetable oils, stearic acid, fumaric acid, glyceryl behenate and the like.

Suitable surfactants according to the present invention may be selected from anionic, cationic or non-ionic surfactants including, but not limited to sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), phospholipids, cremophor-40, polyoxyethylene stearates (Macrogol-stearate), polysorbates and the like or mixtures thereof.

In a preferred embodiment, the present invention provides a stable dosage form comprising 40% to about 70%w/w of atazanavir or its pharmaceutical^ acceptable salts, 5% to about 60% w/w of diluent, 0.5% to about 10% w/w of molten binder, 0.5% to about 15% w/w of disintegrant and 0.1% to about 5% w/w of lubricant prepared by melt granulation process.

In a preferred embodiment, the present invention provides an oral dosage form comprising 40% to about 70%w/w of atazanavir or its pharmaceutically acceptable salts, 5% to about 60% w/w of diluent selected from lactose monohydrate, microcrystalline cellulose; 0.5% to about 20% w/w of molten binder selected from gelucire, polyethylene glycol, 0.5% to about 15% w/w of disintegrant selected from crospovidone, croscarmellose sodium or sodium starch glycolate and 0.1% to about 5% w/w of lubricant selected from magnesium stearate or sodium stearyl fumarate prepared by melt granulation process.

In another preferred embodiment, the present invention provides a method for the
preparation of an oral dosage form comprising atazanavir or its pharmaceutically
acceptable salts comprising the steps of:

(i) belnding about 40% to about 70%w/w of atazanavir with 5% to about 60% w/w of
diluent and about 1% to about 10% w/w of disintegrant,

(ii) granulating the blend of step (i) using about 1% to about 20% w/w of molten binder,

(iii) screening the granules of step (ii),

(iv) blending the granules of step (iii) with about 1% to about 15% w/w of disintegrant,
and optionally about 10% to about 25% w/w of diluent

(v) lubricating the granules of step (v) with about 0.1% to about 5% w/w of lubricant and

(vi) formulating the granules of step (v) to a solid dosage form.

In another preferred embodiment, the present invention provides a method for the
preparation of an oral dosage form comprising atazanavir or its pharmaceutically
acceptable salts comprising the steps of:

(i) belnding about 40% to about 70%w/w of atazanavir with 5% to about 40% w/w of
diluent selected from lactose monohydrate, microcrystalline cellulose and about 1% to
about 10% w/w of disintegrant selected from crospovidone, croscarmellose sodium or
sodium starch glycolate;

(ii) granulating the blend of step (i) using about 1% to about 20% w/w of molten binder
selected from gelucire, polyethylene glycol;

(iii) screening the granules of step (ii),

(iv) blending the granules of step (iii) with about 1% to about 10% w/w of disintegrant
selected from crospovidone, croscarmellose sodium and sodium starch glycolate; and
optionally about 10% to about 25% w/w of diluent selected from lactose monohydrate,
microcrystalline cellulose;

(v) lubricating the granules of step (v) with about 0.1% to about 5% w/w of lubricant
selected from magnesium stearate and sodium stearyl fumarate; and

(vi) formulating the granules of step (v) to a solid dosage form.

In another embodiment, the dosage form includes tablets, capsules, granules, powder, beads, minitablets, pellets or like. The dosage form according to the present invention may be uncoated or optionally coated.

"Percentage w/w or percent by weight" according to the present invention is calculated based on the total weight of the dosage form such as capsule fill weight or tablet weight.

In yet another embodiment, the present invention also provides method of treating HIV-1 infection by administering solid dosage forms of the present invention in combination with other antiretroviral agents.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1

The processing steps involved in manufacturing atazanavir capsules given in example 1
are given below:

i) atazanavir, lactose and crospovidone were sifted and blended,

ii) the blend of step (i) was granulated using molten gelucire,

iii) the granules of step (ii) were dried and milled,

iv) the milled granules of step (iii) was then blended with crospovidone,

v) lubricated the granules of step (iv) with magnesium stearate and

vi) the lubricated granules were then filled in capsules.

Example 2

The processing steps involved in manufacturing atazanavir capsules given in example 1 are given below:


i) atazanavir, Microcrystalline Cellulose and crospovidone were sifted and blended, ii) the blend of step (i) was granulated using molten gelucire,

iii) the granules of step (ii) were dried and milled,

iv) the milled granules of step (iii) was then blended with crospovidone,

v) lubricated the granules of step (iv) with magnesium stearate and

vi) the lubricated granules were then filled in capsules.

Example 3

The processing steps involved in manufacturing atazanavir capsules given in example 1 are given below:

i) atazanavir, Microcrystalline Cellulose and Croscarmelose Sodium were sifted and
blended,

ii) the blend of step (i) was granulated using molten gelucire,

iii) the granules of step (ii) were dried and milled,

iv) the milled granules of step (iii) was then blended with Croscarmelose Sodium,

v) lubricated the granules of step (iv) with magnesium stearate and

vi) the lubricated granules were then filled in capsules.

We Claim:

1. An oral dosage form comprising atazanavir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients prepared by melt granulation process.

2. The dosage form of claim 1 wherein one or more pharmaceutically acceptable excipients are selected from diluent, binder, glidant, disintegrant, surfactant and lubricants.

3. The dosage form of claim 2, wherein the diluent is selected from lactose monohydrate, starch, pregelatinised starch, microcrystalline cellulose and combinations thereof.

4. The dosage form of claim 2, wherein the binder is selected from gelucire, polyethylene glycol, sugars, poloxamers and combinations thereof.

5. The dosage form of claim 2, wherein the disintegrant is selected from crospovidone, croscarmellose sodium, sodium starch glycolate, starch and combination thereof.

6. An oral pharmaceutical composition as claimed in claim 7 wherein the binder used according to the present invention is Gelucire.

7. An oral dosage form comprising 40% to about 70%w/w of atazanavir or its
pharmaceutically acceptable salts; 5% to about 60% w/w of diluent selected from lactose
monohydrate, microcrystalline cellulose; 0.5% to about 20% w/w of molten binder
selected from gelucire, polyethylene glycol; 0.5% to about 15% w/w of disintegrant
selected from crospovidone, croscarmellose sodium and sodium starch glycolate and
0.1% to about 5% w/w of lubricant selected from magnesium stearate and sodium stearyl
fumarate prepared by melt granulation process.

8. A method for the preparation of an oral dosage form according to claim 1 comprising
the steps of:

(i) blending atazanavir with one or more intra granular excipients,

(ii) granulating the blend of step (i) using molten binder,

(iii) screening the granules of step (ii),

(iv) formulating the granules of step (iii) to a solid dosage form with the addition of one
or more extragranular excipients.

9. A method for the preparation of an oral dosage form comprising atazanavir or its
pharmaceutically acceptable salts comprising the steps of:

(i) blending about 40% to about 70%w/w of atazanavir with 5% to about 40% w/w of
diluent selected from lactose monohydrate, microcrystalline cellulose and about 1% to
about 10% w/w of disintegrant selected from crospovidone, croscarmellose sodium and
sodium starch glycolate;

(ii) granulating the blend of step (i) using about 1% to about 20% w/w of molten binder
selected from gelucire, polyethylene glycol;

(iii) screening the granules of step (ii),

(iv) blending the granules of step (iii) with about 1% to about 10% w/w of disintegrant
selected from crospovidone, croscarmellose sodium and sodium starch glycolate; and
optionally about 10% to about 25% w/w of diluent selected from lactose monohydrate,
microcrystalline cellulose;

(v) lubricating the granules of step (v) with about 0.1% to about 5% w/w of lubricant
selected from magnesium stearate and sodium stearyl fumarate; and

(vi) formulating the granules of step (v) to a solid dosage form.