Field of the invention

The technical field of the present invention relates to oral dosage forms of HIV-1 protease inhibitor. More particularly, the present invention relates to oral dosage forms of atazanavir prepared by dry process without using solvents.

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 (S.n-BisCl.l-dimethylethyO-S-hydroxy^,!!-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl) phenyl]methyl]-2,5,6,10,13-pentaazatetra-ecanedioic 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 the granulates, milling, addition of the remaining crospovidone/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 or solid dispersion 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 which does not require the addition of solvents or an additional drying step during granulation. Hence, the inventors of the present invention have endeavored to develop a dosage form comprising atazanavir prepared by dry process without using solvents, such as dry blending and filling of blend or dry granulation, wherein the dosage form shows comparable bioavailability/w-v/fro dissolution as compared to marketed dosage form of atazanavir.

Objective of the invention

Accordingly, the main objective of present invention is to provide bioequivalent dosage form comprising atazanavir prepared by dry process without using solvents, 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/or in vitro parameters like dissolution, disintegration.

Summary of the invention

Accordingly, the present invention provides an oral dosage form comprising atazanavir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients prepared by dry process without using solvents.

Accordingly, the present invention provides an oral dosage form comprising an
effective amount of atazanavir, produced by a process comprising the steps of:

i) dry blending atazanavir or its pharmaceutically acceptable salts and one or more excipients to form a mixture; or dry blending atazanavir or its pharmaceutically acceptable salts and one or more excipients, compressing the resulting blend into a slug or compact, and milling the slug or compact into a free flowing mixture; and

ii) formulating the mixture obtained in step (i) to a solid dosage form.

Detailed description of the invention

In 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 dry process without using solvents.

In another embodiment, the mixture includes powder or granules.

Dry process according to the present invention includes, but not limited to, dry blending, direct compression, dry granulation or the like.

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

In another embodiment, atazanavir is present either in crystalline form A or 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 um preferably 2-50um.

In another embodiment, the present invention provides an oral dosage form comprising
an effective amount of atazanavir, produced by a process comprising the steps of:

i) dry blending atazanavir or its pharmaceutically acceptable salts and one or more
excipients to form a mixture and

ii) formulating the mixture obtained in step (i) to a solid dosage form.

In another embodiment, the present invention provides an oral dosage form comprising
an effective amount of atazanavir, produced by a process comprising the steps of:

i) dry blending atazanavir or its pharmaceutically acceptable salts and one or more
excipients, compressing the resulting blend into a slug or compact, and milling the slug
or compact into a free flowing mixture; and

ii) formulating the mixture obtained in step (i) to a solid dosage form.

Pharmaceutically acceptable excipients according to the present invention includes, but not limited to, diluents, binders, disintegrants, glidants, surfactants and lubricant.

Suitable diluents used according to the present invention are selected from lactose monohydrate, spay dried lactose, anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, pregelatinized starch, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starlac, dihydrated or anhydrous dibasic calcium phosphate and the like or combination 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, cellulose or cellulose derivatives such as microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose or the like; starch or starch derivatives such as maize starch, pregelatinized starch or the like, povidone, sugars, gums, and the like or combination thereof. The amount of diluent may range from about 0.1% 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 an oral dosage form comprising an effective amount of atazanavir, produced by a process comprising the
steps of:

i) dry blending 40% to about 70%w/w of atazanavir or its pharmaceutically acceptable
salts and one or more excipients selected from 5% to about 60% w/w of diluent, 0.5%
to about 15% w/w of disintegrant optionally 0.1% to about 20% w/w of binder and
0.01% to about 5% w/w of lubricant to form a mixture and

ii) formulating the mixture obtained in step (i) to a solid dosage form.

In another preferred embodiment, the present invention provides an oral dosage form comprising an effective amount of atazanavir, produced by a process comprising the steps of:

i) dry blending 40% to about 70%w/w of atazanavir or its pharmaceutically acceptable salts and one or more excipients selected from 5% to about 60% w/w of diluent selected from lactose monohydrate, pregelatinized starch and microcrystalline cellulose; 0.5% to about 15% w/w of disintegrant selected from crospovidone and croscarmellose sodium; optionally 0.1% to about 20% w/w of binder selected from povidone and pregelatinised starch and 0.01% to about 5% w/w of lubricant selected from magnesium stearate and sodium stearyl fumarate to form a mixture and ii) formulating the mixture obtained in step (i) to a solid dosage form.

In another embodiment, the present invention provides an oral dosage form comprising
an effective amount of atazanavir, produced by a process comprising the steps of:

i) dry blending atazanavir or its pharmaceutically acceptable salts and one or more
intragranular excipients to form a mixture and

ii) compressing the resulting blend into a slug or compact,

iii) milling the slug or compact into a free flowing mixture,

iv) formulating the mixture obtained in step (iii) to a solid dosage form with the
addition of one or more extra granular excipients.

In another embodiment, the dosage form comprises about 40% to about 70%w/w of atazanavir, 5% to about 40% w/w of diluent, about 0.5% to about 15% w/w of disintegrant optionally about 0.01% to about 5% w/w of lubricant as intragranular excipients.

In another embodiment, the solid dosage form comprises about 0.5% to about 10% w/w of disintegrant, about 0.01% to about 5% w/w of lubricant and optionally about 10% to about 25% w/w of diluent as extra granular excipients.

In a preferred embodiment, the present invention provides an oral dosage form
comprising an effective amount of atazanavir, produced by a process comprising the
steps of:

i) dry blending about 40% to about 70%w/w of atazanavir or its pharmaceutically
acceptable salts with 5% to about 40% w/w of diluent and about 1% to about 10% w/w
of disintegrant optionally about 0.01% to about 5% w/w of lubricant,

ii) compressing the resulting blend into a slug,

iii) milling the slug into a free flowing granules,

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

(v) lubricating the granules of step (v) with about 0.01% to about 5% w/w of lubricant
and

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

In a preferred embodiment, the present invention provides an oral dosage form
comprising an effective amount of atazanavir, produced by a process comprising the
steps of:

i) dry blending about 40% to about 70%w/w of atazanavir or its pharmaceutically
acceptable salts with 5% to about 40% w/w of diluent and about 1% to about 10% w/w
of disintegrant optionally about 0.1% to about 5% w/w of lubricant,

ii) compacting the resulting blend into a compact using roller compactor,

iii) milling the compacts into granules,

iv) blending the granules of step (iii) with about 1% to about 10% 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 a preferred embodiment, the present invention provides an oral dosage form
comprising an effective amount of atazanavir, produced by a process comprising the
steps of:

i) dry blending about 40% to about 70%w/w of atazanavir or its pharmaceutically
acceptable salts with 5% to about 40% w/w of diluent selected from lactose
monohydrate, pregelatinized starch and microcrystalline cellulose; about 1% to about
10% w/w of disintegrant selected from crospovidone, croscarmellose sodium or sodium
starch glycolate; optionally about 0.01% to about 5% w/w of lubricant selected from
magnesium stearate or sodium stearyl fumarate,

ii) compacting the resulting blend into a compact using roller compactor,

iii) milling the compacts into granules,

iv) blending the granules of step (iii) with about 1% to about 10% w/w of disintegrant
selected from crospovidone, croscarmellose sodium or 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 0.01% to about 5% w/w of lubricant
selected from magnesium stearate or sodium stearyl fumarate and

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

"Slugs" according to the present invention can be prepared by any method known in the art, preferably using tablet punching machine or using roller compactor.

The amount of atazanavir present in the oral dosage form according to the present invention ranges from 25 to 500mg.

In another embodiment, the dosage form includes mini-tablets, tablets, capsules, powder, granules or sachets for powder for suspension. The dosage form may be uncoated or optionally coated.

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 are given below: i) atazanavir, lactose and crospovidone were sifted and blended, ii) lubricated the blend of step (i) with magnesium stearate, and iii) the lubricated blend was then filled in capsules.

Example 2

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

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

ii) magnesium stearate was sifted and added to the blend of step (i),

iii) compacting the blend of step (ii) with roller compactor,

iv) milling the compacts of step (iii) into granules,

v) the milled granules of step (iv) were then blended with crospovidone,

vi) lubricated the blend of step (v) with magnesium stearate, and

vii) the lubricated granules were then filled in capsules.

Example 3

The processing steps involved in manufacturing atazanavir capsules are given below: i) atazanavir, microcrystalline cellulose and crospovidone were sifted and blended, ii) lubricated the blend of step (i) with magnesium stearate, and iii) the lubricated blend was then filled in capsules.

Example 4

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

i) atazanavir, microcrystalline cellulose and croscarmellose sodium were sifted and
blended,

ii) lubricated the blend of step (i) with magnesium stearate, and

iii) the lubricated blend was then filled in capsules.

Example 5

The processing steps involved in manufacturing atazanavir capsules are given below: i) atazanavir, pregelatinised starch and croscarmellose sodium were sifted and blended, ii) lubricated the blend of step (i) with magnesium stearate, and iii) the lubricated blend was then filled in capsules.

Claims;

1. An oral dosage form comprising atazanavir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients prepared by dry process without using solvents.

2. The dosage form according to claim 1, wherein dry process is selected from dry blending, direct compression and dry granulation.

3. The dosage form according to claim 1, wherein one or more pharmaceutically acceptable excipients include a diluent, binder, disintegrant, glidants, surfactant and lubricant or a mixture thereof.

4. The dosage form according to claim 2, wherein the diluent is selected from lactose monohydrate, spray dried lactose, anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, dihydrated or anhydrous dibasic calcium phosphate or combination thereof.

5. The dosage form according to claim 2, wherein the disintegrant is selected from crospovidone, croscarmellose sodium, sodium starch glycolate, starch, carmellose calcium and carmellose sodium or combination thereof.

6. The dosage form according to claim 1, wherein the dry process comprises the steps of:

(a) dry blending atazanavir or its pharmaceutically acceptable salts and one or more excipients to form a mixture; and

(b) formulating the mixture obtained in step (a) to a solid dosage form.

7. The dosage form according to claim 1, wherein the dry process comprises the steps of:

(a) dry blending atazanavir or its pharmaceutically acceptable salts and one or more excipients,

(b) compressing the resulting blend into a slug or compact,

(c) milling the slug or compact into a free flowing mixture; and

(d) formulating the mixture obtained in step (c) to a solid dosage form.

8. An oral dosage form comprising an effective amount of atazanavir, produced by a
process comprising the steps of:

i) dry blending 40% to about 70%w/w of atazanavir or its pharmaceutically acceptable salts and one or more excipients selected from 5% to about 60% w/w of diluent selected from lactose monohydrate, pregelatinized starch and microcrystalline cellulose; 0.5% to about 15% w/w of disintegrant selected from crospovidone and croscarmellose sodium; optionally 0.1% to about 20% w/w of binder selected from povidone and pregelatinised starch and 0.01% to about 5% w/w of lubricant selected from magnesium stearate and sodium stearyl fumarate to form a mixture and ii) formulating the mixture obtained in step (i) to a solid dosage form.

9. An oral dosage form comprising an effective amount of atazanavir, produced by a
process comprising the steps of:

i) dry blending about 40% to about 70%w/w of atazanavir or its pharmaceutically acceptable salts with 5% to about 40% w/w of diluent selected from lactose monohydrate, pregelatinized starch and microcrystalline cellulose; about 1% to about 10% w/w of disintegrant selected from crospovidone, croscarmellose sodium and sodium starch glycolate; optionally about 0.01% to about 5% w/w of lubricant selected from magnesium stearate and sodium stearyl fumarate, ii) compacting the resulting blend into a compact using roller compactor, iii) milling the compacts into granules,

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 0.01% 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.