Technical Field of Invention
The present invention relates to formulations comprising atazanavir and a silicate, and the process of preparation thereof, wherein the silicate is present in the extragranular portion.
Background of the Invention
Atazanavir is an azapeptide protease inhibitor which selectively inhibits the virus-specific processing of viral gag-pol polyproteins in HIV-1 infected cells. It is commercialized in the form of its sulfate salt and is available under the trade name REYATAZ® 100mg, 150mg, 200mg and 300mg capsules from Bristol-Myers Squibb Company, USA. The US Patent 5,849,911 discloses atazanavir and its use in AIDS therapy. The US Patent No. 6,087,383 describes specifically atazanavir sulfate and process of preparation thereof.
Atazanavir is a substrate of the cytochrome P450 3A4 isoenzyme, leading to unfavourable pharmacokinetics of the drug on oral administration. Consequently, co-administration of atazanavir with an agent that inhibits metabolism by cytochrome P450 monooxygenase will improve the pharmacokinetics (i.e., increase half-life, increase the time to peak plasma concentration, increase blood levels) of atazanavir leading to beneficial therapeutic effects. Such pharmacokinetic property-improving action of ritonavir when subjected to coadministration with drugs susceptible to metabolism by cytochrome P450 enzymes has been illustrated vividly in the PCT application WO/1997/001349. Therefore, ritonavir is used as a booster in atazanavir pharmacokinetics as it has shown to significantly increase the pharmacokinetic parameters of atazanavir. It is also recommended that 300mg atazanavir should be taken once daily with ritonavir 100mg once daily and with food for treatment-experienced patients with prior viroiogic failure as per the Physicians Desk Reference. USA.
The art records several documents describing pharmaceutical formulations containing protease inhibitors. The PCT application WO/1995/09614 reports solid pharmaceutical formulation of a HIV protease inhibiting compound which comprises an adsorbate of a mixture of protease inhibitor, adsorbents, an organic solvent and a combination of pharmaceutically acceptable acids. The PCT applications WO/2001/34118 and WO/2001/34119 describe solid dispersion formulations comprising HIV protease inhibitor/s and process for preparation. Further, the PCT application WO/2005/039551 discloses another such solid dispersion formulation which exhibits improved bioavailability. Our
publication IPCOM000168469D also discloses unitary dosage forms containing co-formulated atazanavir and ritonavir.
It is always desirable that a solid dosage form undergoes rapid disintegration in a way that, it releases the active ingredient into the body quickly, which in turn would lead to a rapid onset of therapeutic action. Accordingly, it is necessary to formulate a solid dosage form for oral administration that is adapted to disintegrate quickly in the gastro-intestinal tract. This however has always posed a challenge in front of the formulation scientists, especially when formulating tablets. A tablet dosage form should comprise of excipients that are compatible with the active ingredient. Such excipients should ensure that the active ingredient and excipients bind together as a unit and at the same time not provide a tablet that is too large for patient consumption or cannot be produced according to standard large scale manufacturing processes. Furthermore, such formulations should be sufficiently hard to withstand the rigours of the manufacturing process (for example as encountered during the stage of film coating in a perforated rotating drum and packaging etc) but should have appropriate disintegration characteristics to ensure rapid release of the drug from the formulation and consequently appropriate dissolution characteristics.
While formulating atazanavir tablets, the present inventors found that the use of conventional disintegrants did not satisfy the disintegration characteristics. In fact, it was observed that atazanavir tablets when subjected to in vitro studies, instead of disintegration formed a lump and exhibited extremely poor dissolution. It was surprisingly found that the presence of extragranular silicates lead to appropriate disintegration and consequently superior dissolution properties The European Patent Application Number 1800681 describes use of silicates in solid pharmaceutical composition comprising ritonavir and atazanavir. Silicate compounds are used in such formulations in the intragranular portion, as a compound which enables gastrointestinal fluid to penetrate that composition. However, in the course of research, unlike the teachings of the prior art, the present inventors found that use of intragranular silicate in atazanavir formulations also did not yield desirable results with respect to disintegration and consequently dissolution. However, when silicates were used in the extragranular portion, the resulting formulations exhibited effective disintegration and consequently appropriate release characteristics.
In the present case, formulations comprising of atazanavir, silicates and other
pharmaceutically acceptable excipients are described, wherein the silicate is present in the extragranular portion
Summary of the Invention
In one general aspect, it relates to a pharmaceutical formulation which comprises of
(a) atazanavir in the intragranular portion:
(b) a silicate in the extragranular portion; and
(c) one or more of pharmaceutically acceptable excipient(s).
In another general aspect, it relates to a pharmaceutical formulation which comprises of
(a) atazanavir in the intragranular portion:
(b) a silicate in the extragranular portion; and
(c). one or more of pharmaceutically acceptable excipient(s); wherein the said silicate is calcium silicate.
In another general aspect, it relates to a pharmaceutical formulation which comprises of
(a) atazanavir in the intragranular portion;
(b) a silicate in the extragranular portion; and
(c) one or more of pharmaceutically acceptable excipient(s); wherein the said formulation further comprises of ritonavir.
In another general aspect, it relates to a pharmaceutical formulation which comprises of
(a) atazanavir in the intragranular portion
(b) a silicate in the extragranular portion; and
(c) one or more of pharmaceutically acceptable excipient(s):
wherein the said formuiation is further co-processed with a composition comprising of ritonavir into a unit dosage form.
In another general aspect, it relates to a process of preparation of a pharmaceutical formulation which comprises of
(a) atazanavir in the intragranular portion.
(b) a silicate in the extragranular portion; and
(c) one or more of pharmaceutically acceptable excipient(s); wherein the process comprises of the following steps:
(i) atazanavir is blended with one or more of pharmaceutical^ acceptable
excipient(s), in a suitable mixer; (ii) the blend of step (i) is granulated with a granulating fluid; (iii) the granules of step (ii) are dried and sized; and (iv) the sized granules of step (iii) are mixed with a silicate; (v) the blend of step (iv) is mixed with one or more of pharmaceutically acceptable
excipient(s).
In an embodiment of above aspect, the pharmaceutical formulation so obtained is filled into capsules or compressed into tablets.
In another general aspect, it relates to a pharmaceutical formulation which comprises of
(a) atazanavir in the intragranular portion
(b) a silicate in the extragranular portion; and
(c) one or more of pharmaceutically acceptable excipient(s);
wherein the said formulation releases at least about 50% of atazanavir in 5 minutes when subjected to in vitro dissolution in a USP type II apparatus, at 50rpm, at a temperature of 37°C±0.5°C in 1000mL of 0.025N hydrochloric acid.
Detailed Description of the Invention
The term "pharmaceutical formulation" as described herein, encompasses without limitation intimate or non-intimate blend, tablets, minitablets or capsules.
Atazanavir as described herein include pharmaceutically acceptable salts, solvates, enantiomers, diastereomers and polymorphs thereof. In one embodiment, the preferred salt form of atazanavir is atazanavir sulphate.
Atazanavir and/or ritonavir present in the said pharmaceutical formulation is in amounts suitable to elicit a particular biological or medicinal or clinical response being sought by the person skilled in the art. The amount may be a "therapeutically effective amount"; i.e., atazanavir or ritonavir in amounts that result in the alleviation of the symptoms of the disease or condition being treated by the drug. The amount may be a "prophylactically effective amount"; i.e., atazanavir or ritonavir in amounts that result in prophylaxis of the symptoms of the disease or condition being prevented by the drug. The amount also
refers to an amount that would provide enhanced therapeutic activity of another drug that is co-administered with it, in a way that if the later drug was administered alone, would not have achieved the desired response (e.g., unsatisfactory pharmacokinetic values for the drug and/or an unsatisfactory drug circulation level resulting in little or no efficacy).
The amount of atazanavir in the pharmaceutical formulation may be in the range from about 100 to about 1000mg and the amount of ritonavir may be in the range from about 10 to about 500mg. In one embodiment, the amount of atazanavir is 300mg.
The term "silicate" includes without limitation silicic acid, alkali metal silicates such as sodium silicate and potassium silicate; alkaline earth metal silicates such as magnesium silicate and calcium silicate; silicic acid-aluminium complex compounds such as silicic acid-alumina; aluminium-magnesium complex compounds such as magnesium aluminosilicate and magnesium aluminometasilicate; or mixtures thereof. In one embodiment, the silicate is calcium silicate, like those available from J. M. Huber Corporation, under the trade name Hubersorb®. The amount of the silicate present may range from about 1% (w/w) to about 20% (w/w), preferably from about 1% (w/w) to about 10% (w/w) by weight of the pharmaceutical formulation.
The term "pharmaceutically acceptable excipients" as recited herein includes conventional pharmaceutical additives known in the art, such as diluent(s), binder(s), disintegrant(s), superdisintegrant(s), lubricants(s), granulating solvent(s), glidants(s) or combinations
thereof
Diluents may be selected depending upon the compatibility with the active ingredient, and may be exemplified as, but are not limited to, saccharides like lactose, dextrose, sucrose, fructose, maltose; sugars like mannitol, erythritol, sorbitol, xylitol and lactitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; starch and pregelatinized starch, dicalcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate, kaolin and the like. In one embodiment, lactose is the diluent. Lactose may be lactose monohydrate, anhydrous lactose or spray-dried lactose.
Binders that may be used include, but are not limited to, starch derivatives like corn starch and pregelatinized starch; cellulose ethers such as carboxymethyl cellulose,
methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; carboxy vinyl polymers like carbomers; acrylates such as Eudragits; polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer; xanthan gum, guar gum and other such materials routinely used in the art of pharmaceutical manufacturing.
Disintegrants and superdisintegrants may be selected from the group consisting of alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, guar gum, magnesium aluminium silicate, sodium starch glycolate, , corn starch, potato starch, pregelatinized starch, low-substituted hydroxypropylcellulose, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, and methacrylic acid divinylbenzene copolymer salts.
Lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, powdered stearic acid, magnesium oieate, calcium palmitate, potassium laureate, sodium suberate, vegetable oil, mineral oil and the like. Glidants may be selected from talc, colloidal silicon dioxide, corn starch and the like.
Suitable granulating solvents may be used include without limitation, water, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone and the like
The pharmaceutical formulation, as referred to herein may further be co-processed with another composition comprising of ritonavir. The said composition of ritonavir may be, without limitation in the form of a solid dispersion, granules, an intimate or a non-intimate blend with pharmaceutically acceptable excipients, minitablets, microparticles, beads or pellets.
The pharmaceutical formulation as described herein, along with a composition comprising ritonavir may be further processed to a unit dosage form. The term "unit dosage form" as used herein encompasses standard pharmaceutical solid dosage forms and may be in the form of coated or uncoated tablets, multilayer tablets, capsules, pills, and the like. The pharmaceutical formulation may be compressed to a mono- or bi- or multi-layer tablet or may be filled into capsules of suitable size, using appropriate tooling.
The pharmaceutical formulation, as described herein may be processed using conventional techniques known in the art, viz. dry and wet granulation.
In one embodiment, a pharmaceutical formulation comprises
(a) atazanavir in the intragranular portion;
(b) a silicate in the extragranular portion; and
(c) pharmaceutically acceptable excipients comprising of diluent(s), binder(s), disitengrant(s), lubricant(s) and glidant(s).
In one embodiment, a pharmaceutical formulation comprises
(a) atazanavir in the intragranular portion;
(b) calcium silicate in the extragranular portion; and
(c) pharmaceutically acceptable excipients comprising of diluent(s), binder(s), disitengrant(s), lubricant(s) and glidant(s)
In one embodiment, a pharmaceutical formulation comprises
(a) atazanavir in the intragranular portion;
(b) a silicate in the extragranular portion; and
(c) pharmaceutically acceptable excipients comprising of diluent(s), binder(s), disitengrant(s), lubricant(s) and glidant(s),
wherein the said formulation is further processed into a tablet, or filled into a capsule.
In one embodiment, a pharmaceutical formulation comprises
(a) atazanavir in the intragranular portion;
(b) calcium silicate in the extragranular portion; and
(c) pharmaceutically acceptable excipients comprising of diluent(s), binder(s), disitengrant(s), lubricant(s) and glidant(s),
wherein the said formulation is further processed into a tablet or filled into a capsule.
In one embodiment, a pharmaceutical formulation comprises
(a) atazanavir in the intragranular portion;
(b) a silicate in the extragranular portion; and
(c) pharmaceutically acceptable excipients comprising of diluent(s), binder(s), disitengrant(s), lubricant(s) and glidant(s),
wherein said formulation further comprises of ritonavir
In one embodiment, a pharmaceutical formulation comprises
(a) atazanavir in the intragranular portion;
(b) calcium silicate in the extragranular portion; and
(c) pharmaceutically acceptable excipients comprising of diluent(s), binder(s), disitengrant(s), lubricant(s) and glidant(s),
wherein said formulation further comprises of ritonavir
In one embodiment, a pharmaceutical formulation is prepared by
a) blending atazanavir with pharmaceutically acceptable excipient(s) comprising of diluent(s), binder(s), and disintegrant(s) in a suitable mixer;
b) the blend of step (a) is granulated with a granulating fluid;
c) the granules of step (b) are dried and sized; and
d) the sized granules of step (c) are mixed with a silicate; and
e) the blend of step (d) is mixed with pharmaceutically acceptable excipient(s) comprising of diluent(s), binder(s), disintegrant(s), lubricant(s), and glidant(s).
In one embodiment, a pharmaceutical formulation is prepared by
a) blending atazanavir with pharmaceutically acceptable excipient(s) comprising of diluent(s), binder(s), and disintegrant(s) in a suitable mixer;
b) the blend of step (a) is granulated with a granulating fluid;
c) the granules of step (b) are dried and sized; and
d) the sized granules of step (c) are mixed with calcium silicate; and
e) the blend of step (d) is mixed with pharmaceutically acceptable excipient(s) comprising of diluent(s), binder(s), disintegrant(s), lubricant(s), and glidant(s)
In the above embodiments, the pharmaceutical formulation so obtained may be filled into capsules or compressed into tablets
In one embodiment, the tablets so prepared are further coated using conventional coating techniques known in the art.
From the above it is apparent that various modifications and combinations of the formulations detailed in the text may be made without departing from the spirit and scope of the invention. The invention as described herein may be illustrated by the following examples but is not to be construed to be limiting by them.
Examples 1-6:

(Table Removed)
Procedure:
Example 1
Atazanavir was blended with lactose, crosslinked polyvinylpyrrolidone and granulated using an aqueous solution in rapid mixer granulator. The granules so obtained were dried and subjected to sizing. The sized granules thus obtained were blended with calcium
silicate, polyvinylpyrrolidone and Lake of Quinolene Yellow. The blend so formed was further blended with magnesium stearate and compressed into tablets.
Example 2
Atazanavir was blended with lactose, crosslinked polyvinylpyrrolidone, calcium silicate and granulated using an aqueous solution in rapid mixer granulator. The granules so obtained were dried and subjected to sizing. The sized granules thus obtained were blended with crosslinked polyvinylpyrrolidone. The blend so formed was further blended with magnesium stearate and compressed into tablets.
Example 3
Atazanavir was blended with lactose, crosslinked polyvinylpyrrolidone and granulated using an aqueous solution in rapid mixer granulator. The granules so obtained were dried and subjected to sizing. The sized granules thus obtained were blended with calcium silicate, polyvinylpyrrolidone and Lake of Quinolene Yellow The blend so formed was further blended with magnesium stearate and compressed into tablets.
Example 4
Atazanavir was blended with lactose, crosslinked polyvinylpyrrolidone and granulated using an aqueous solution in rapid mixer granulator. The granules so obtained were dried and subjected to sizing. The sized granules thus obtained were blended with calcium silicate, polyvinylpyrrolidone, microcrystalline cellulose and Lake of Quinolene Yellow. The blend so formed was further blended with magnesium stearate and compressed into tablets
Example 5
Atazanavir was blended with lactose, crosslinked polyvinylpyrrolidone and granulated using an aqueous solution in rapid mixer granulator. The granules so obtained were dried and subjected to sizing. The sized granules thus obtained were blended with polyvinylpyrrolidone and Lake of Quinolene Yellow. The blend so formed was further blended with magnesium stearate and compressed into tablets.
Example 6
Atazanavir was blended with lactose, crosslinked polyvinylpyrrolidone and granulated using an aqueous solution in rapid mixer granulator. The granules so obtained were dried and subjected to sizing. The sized granules thus obtained were blended with crosslinked polyvinylpyrrolidone and Lake of Quinolene Yellow. The blend so formed was further blended with magnesium stearate and compressed into tablets.
Tablets in Examples 1-6 and REYATAZ® Capsules (From Bristol Myers Squibb, Batch Number 7C3015A) were subjected to in vitro dissolution studies in a USP type II apparatus, at 50rpm, at a temperature of 37°C±0.5°C in 1000mL of 0.025N hydrochloric acid medium. Aliquot of sample was withdrawn at predetermined time intervals and replaced with an equal amount of fresh media. Samples were processed and analysed suitably Dissolution profiles of these tablets are provided in Table 1
Table 1: In vitro release pattern of atazanavir from REYATAZ® capsules (From Bristol Myers Squibb, Batch Number 7C3015A) and tablets prepared as per compositions in Examples 1-6 in USP II apparatus in 1000ml_ of 0.025N hydrochloric acid medium at 50 rpm at a temperature of 37°C±0.5°C.
Time PercenI of atazanavir released from compositions in
(Table Removed)
The atazanavir tablets in examples 1, 3 and 4 were prepared as per the present invention and comprise of calcium silicate in the extragranular portion. All the said three formulations exhibited at least about 50% of drug release in 5 minutes. In contrast, the tablet in example 2, which comprised of calcium silicate in the intragranular portion or tablets in examples 5 and 6, which did not have calcium silicate exhibited poor drug release in 5 minutes. Similarly, REYATAZ® capsules exhibited less than 50% of drug release in 5 minutes

WE CLAIM:
1 A pharmaceutical formulation which comprises of
(a) atazanavir in the intragranular portion;
(b) a silicate in the extragranular portion; and
(c) one or more of pharmaceutically acceptable excipient(s).

2. The pharmaceutical formulation according to claim 1, wherein the said silicate is calcium silicate
3. The pharmaceutical formulation according to claim 1, wherein the said silicate is present in an amount from about 1 % (w/w) to about 20% (w/w) by weight of the said formulation.
4. The pharmaceutical formulation according to claim 1,wherein the said formulation releases at least about 50% of atazanavir in 5 minutes when subjected to in vitro dissolution in a USP type II apparatus, at 50rpm, at a temperature of 37°C±0.5°C in 1000mL of 0.025N hydrochloric acid.
5. The pharmaceutical formulation according to claim 1, wherein the said pharmaceutically acceptable excipient(s) is selected from a group consisting of diluent(s), binder(s), disintegrant(s), lubricant(s) and glidant(s) as herein described.
6. The pharmaceutical formulation according to claim 1, wherein the said formulation further comprises of ritonavir.
7. A process of preparation of the pharmaceutical formulation according to claim 1, wherein the process comprises of the following steps:

(a) atazanavir is blended with one or more of pharmaceutically acceptable excipient(s), in a suitable mixer;
(b) the blend of step (a) is granulated with a granulating fluid;
(c) the granules of step (b) are dried and sized;
(d) the sized granules of step (c) are mixed with a silicate; and
(e) blend of step (d) is mixed with one or more of pharmaceutically acceptable excipient(s).
8. The process for the preparation of the pharmaceutical formulation according to claim
7, wherein the process further comprises of compressing the said formulation into a
tablet.
9. The process for the preparation of the pharmaceutical formulation according to claim 7, wherein the process further comprises of filling the said formulation into a capsule.
10. A pharmaceutical formulation which comprises of atazanavir in the intragranular portion, a silicate in the extragranular portion, and one or more of pharmaceutically acceptable excipient(s) and the process of preparation thereof, substantially as described and illustrated by examples herein.