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 wet granulation process using non-aqueous solvent or mixture of aqueous and non-aqueous solvent for granulation.

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(l,l-dimethylethyl)-8-hydroxy-4,ll-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 antiretro viral 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/magnesium stearate final mixing and encapsulation.

The pharmaceutical industry employs various methods for compounding pharmaceutical agents in tablet formulations. In particular granulation is one of the most prevalent methods.

Granulation is a process whereby granules are formed from a bulk drug substance with or without excipients to improve the properties of the bulk drug or formulation. Granules are preparations consisting of solid, dry agglomerates of powder particles sufficiently robust to withstand handling.

Wet granulation is distinguished from dry granulation in that a granulating liquid, such as water, organic liquids or mixtures thereof, are used in wet granulation to produce granules. The advantages of wet granulation include improvement of the cohesiveness and compactability of powders, increase in density, good distribution provides uniform content of micronized or finely milled low-dosage drugs, reduction of dust and airborne contamination, and prevention of segregation of components.

The following are the patents/patent publications / publications, which disclose pharmaceutical compositions of atazanavir.

US 7,838,678 novel forms of atazanavir bisulfate are provided which includes Pattern C material and Form E3. This patent discloses atazanavir bisulfate composition comprising atazanavir bisulfate as Form A crystals prepared by wet granulation process using water as granulating solvent, wherein form A is converted to Pattern C material during processing.

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. Hence, the inventors of the present invention have endeavored to develop an oral dosage form comprising atazanavir prepared by wet granulation process using non aqueous solvent or mixture of aqueous and non aqueous solvents for granulation, wherein the dosage form shows comparable in-vitro dissolution profile as compared to marketed dosage form of atazanavir.

Objective of the invention

Accordingly, the main objective of present invention is to provide a bioequivalent oral dosage form comprising atazanavir prepared by wet granulation process using non

aqueous solvent or mixture of aqueous and non aqueous solvents for granulation, in such a way that the dosage form will comply with the reference product in terms of in vivo parameters like Cmax, tmax and AUC and/or in vitro parameters like dissolution, disintegration.

Summary of the invention

The present invention relates to an oral dosage form comprising atazanavir or its pharmaceutically acceptable salts, prepared by wet granulation process using non aqueous solvent or mixture of aqueous and non aqueous solvents for granulation.

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

i) granulating atazanavir and one or more pharmaceutically acceptable excipients
using nonaqueous solvent or a mixture of aqueous and nonaqueous solvent system,

ii) drying the granules and
iii) formulating the dried granules obtained in step (ii) into 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, prepared by wet granulation process using non aqueous solvent or mixture of aqueous and non aqueous solvents for granulation.

The pharmaceutically acceptable salt of atazanavir according to present invention includes, 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.

According to another 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 wet granulation process using non aqueous solvent or mixture of aqueous and non aqueous solvents for granulation.

According to another embodiment, the present invention relates to an oral dosage form comprising atazanavir or its pharmaceutically acceptable salts, prepared by wet granulation process using non aqueous solvent or mixture of aqueous and non aqueous solvents for granulation, wherein the dosage forms is essentially free of silicates.

According to another embodiment, the present invention relates to an oral dosage form comprising atazanavir or its pharmaceutically acceptable salts, prepared by wet granulation process using non aqueous solvent or mixture of aqueous and non aqueous solvents for granulation, wherein the dosage forms is substantially free or free of intragranular lubricant/s.

The nonaqueous solvents according to the present invention may be selected from, but not limited to, isopropyl alcohol, ethanol, methylene chloride, acetone, and the like or mixture thereof.

The aqueous solvents according to the present invention includes, but not limited to, water or the mixture of water with non-aqueous solvents.

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

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, cellulose or cellulose derivatives such as 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 combinations 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 or combinations thereof. 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 or combinations thereof.

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 or combinations thereof.

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 combinations thereof.

The dosage form according to the present invention can be selected from, but not limited to, granules, powder, minitablets, tablet, capsule or sachets for powder for suspension.
The dosage form according to the present invention may be uncoated or coated.

In yet another embodiment of the present invention, the granulation is carried out using nonaqueous solvent or a mixture of aqueous and nonaqueous solvent with or without binder.

In another embodiment, the present invention relates to an oral dosage form comprising
atazanavir or its pharmaceutically acceptable salts prepared by a process, which
comprises the steps of:

i) blending atazanavir; a diluent selected from lactose monohydrate, microcrystalline
cellulose and pregelatinised starch and disintegrant selected from crospovidone,
croscarmellose sodium and starch;

ii) granulating the blend using nonaqueous solvent or a mixture of aqueous and
nonaqueous solvent or a binder solution using non-aqueous solvent or a mixture of
aqueous and nonaqueous solvent,

iii) drying the granules and

iv) formulating the dried granules obtained in step (ii) into solid dosage form.

In another embodiment, the oral 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 10% w/w of disintegrant and optionally about 0.01% to about 5% w/w of lubricant as intragranular excipients.
In another embodiment, the oral 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 10% w/w of disintegrant, about 1% to about 20 % w/w of binder, and optionally about 0.01% to about 5% w/w of lubricant as intragranular excipients.

In another embodiment, the oral 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.

"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.

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

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

i) granulating atazanavir and one or more pharmaceutically acceptable excipients
using nonaqueous solvent or a mixture of aqueous and nonaqueous solvent system,

ii) drying the granules and

iii) formulating the dried granules obtained in step (ii) into solid dosage form.

In a preferred embodiment, the present invention provides an oral dosage form
comprising atazanavir or its pharmaceutically acceptable salts prepared by a process,
which comprises the steps of:

(i) 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 20% w/w of binder,

ii) granulating the blend of step (i) using nonaqueous solvent or a mixture of aqueous
and nonaqueous solvent system,

iii) drying the granules and

iv) blending the dried 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 (iv) 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 another preferred embodiment, the present invention provides an oral dosage form
comprising atazanavir or its pharmaceutically acceptable salts prepared by a process,
which comprises the steps of:

(i) 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, microcrystalline cellulose and pregelatinised starch; and about 1% to
about 10% w/w of disintegrant selected from crospovidone, croscarmellose sodium or
sodium starch glycolate; optionally about 0.1% to about 20% w/w of binder selected
from povidone and pregelatinised starch,

ii) granulating the blend of step (i) using nonaqueous solvent or a mixture of aqueous
and nonaqueous solvent system,

iii) drying the granules and

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.

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 monohydrate and crospovidone were sifted and blended,
ii) the blend of step (i) was granulated using isopropyl alcohol,

iii) the granules obtained in step (ii) were blended with crospovidone and lubricated
with magnesium stearate, and

iv) the lubricated granules of step (iii) were then filled into capsules.

Example 2

The processing steps involved in manufacturing atazanavir capsules given in example 2
are given below:

i) atazanavir, microcrystalline cellulose and crospovidone were sifted and blended,

ii) the blend of step (i) was granulated with povidone in isopropyl alcohol,

iii) the granules obtained in step (ii) were blended with crospovidone and lubricated
with magnesium stearate, and

iv) the lubricated granules of step (iii) were then filled into capsules.

Example 3

The processing steps involved in manufacturing atazanavir capsules given in example 3
are given below:

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

ii) the blend of step (i) was granulated with povidone in isopropyl alcohol,

iii) the granules obtained in step (ii) were blended with crospovidone and lubricated
with magnesium stearate, and

iv) the lubricated granules of step (iii) were then filled into capsules.

Example 4

The process steps involved for manufacturing atazanavir capsules given in example 4
are given below:

i) atazanavir, pregelatinized starch and crospovidone were sifted and blended,

ii) the blend of step (i) was granulated with isopropyl alcohol,

iii) the granules obtained in step (ii) were blended with crospovidone and lubricated
with magnesium stearate,

iv) the lubricated granules of step (iii) were then filled into capsules. Example 5

The process steps involved for manufacturing atazanavir capsules given in example 5
are given below:

i) atazanavir, lactose monohydrate and croscarmelose sodium were sifted and blended,

ii) the blend of step (i) was granulated with isopropyl alcohol,

iii) the granules of step (ii) were blended with croscarmellose sodium and lubricated
with magnesium stearate, and

iv) the granules of step (iii) were then filled into capsules.

Tablets prepared according to Examples 1 - 3 and REYATAZ® capsules were subjected to in-vitro dissolution studies in a USP type II apparatus, at 50 rpm, at a temperature of 37° C ± 0.5° C in 1000mL of 0.025N hydrochloric acid medium. Dissolution profiles of these tablets are provided in Table 1.

Table 1: Dissolution profile of Atazanavir Capsules prepared as per Examples 1-3:

We claim:

1. An oral dosage form comprising atazanavir or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients prepared by wet granulation method using a nonaqueous solvent or a mixture of aqueous and nonaqueous solvent system.

2. The dosage form of claim 1, wherein one or more pharmaceutically acceptable excipients is selected from diluent, binder, disintegrant, glidants, surfactant and lubricant.

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 hydroxypropyl methylcellulose, maize starch, povidone, hydroxypropyl cellulose, pregelatinized starch 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.

7. The dosage form of claim 1, wherein the nonaqueous solvent is selected from isopropyl alcohol, ethanol, methylene chloride, acetone and mixture thereof.

8. An oral dosage form comprising atazanavir or its pharmaceutically acceptable salts prepared by a process, which comprises the steps of:

i) granulating atazanavir and one or more intragranular excipients using nonaqueous
solvent or a mixture of aqueous and nonaqueous solvent system,

ii) drying the granules and

iii) formulating the dried granules obtained in step (ii) into solid dosage form.

9. An oral dosage form comprising atazanavir or its pharmaceutically acceptable salts prepared by a process, which comprises the steps of:

i) blending atazanavir; a diluent selected from lactose monohydrate, microcrystalline
cellulose and pregelatinised starch and disintegrant selected from crospovidone,
croscarmellose sodium and starch;

ii) granulating the blend using nonaqueous solvent or a mixture of aqueous and
nonaqueous solvent or a binder solution using non-aqueous solvent or a mixture of
aqueous and nonaqueous solvent,

iii) drying the granules and

iv) formulating the dried granules obtained in step (ii) into solid dosage form.

10. An oral dosage form comprising atazanavir or its pharmaceutically acceptable salts prepared by a process, which comprises the steps of:

i) 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 20% w/w of binder,

ii) granulating the blend of step (i) using nonaqueous solvent or a mixture of aqueous
and nonaqueous solvent system,

iii) drying the granules and

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.