PHARMACEUTICAL FORMULATION FOR USE IN HIV THERAPY
FIELD OF INVENTION
The present invention relates to a pharmaceutical formulation and in particular to pharmaceutical formulations for use in HIV therapy. It also discloses the processes to make the same. The invention has been developed primarily for making a formulation to be used for treatment in HIV therapy and will be described hereinafter with reference to this application. However, it will be appreciated that the invention is not limited to this particular field of use.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ART
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.
Efavirenz, chemically known as (S)-6-chIoro-4-(cyclopropylethyl)-l. 4-dihydro-4' (trifluoromethyl)-2H-3,l-benzoxazin-2-one is a non-nucleoside human immunodeficiency virus (IIIV) reverse transcriptase inhibitor and is used in HIV therapy. Presently marketed SUSTIVA'^ tablet formulation contains 600 mg of Efavirenz as the active drug and croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystaUine cellulose, and sodium lauryl sulfate as the inactive components. The tablets are coated with Opadry" Yellow and Opadry'' Clear.

1
(J. S. patent No. 6,238,695 and 6,555,133 disclose Efavirenz formulations having more than 10% by weight of a disintegrant relative to the total dry weight of the pharmaceutical dosage form. They both disclose the use of sodium starch glycolate as the preferred disintegrant.
U, S. patent No 7,060,294 claims a compressed efavirenz tablet formulation wherein crosscarmellose sodium is used in the range of 1-5%. It explicitly states '...key feature of the formulation is the use of a superdisintegrant and disintegrant intragranularly to achieve a bioequivalent formulation.' Though this patent states that '...efavirenz concentration can be Varied from about 1 to about 75% by changing the concentration of remaining excipients...''. However, there are no actual examples that disclose whether such a tablet was made nor does it disclose whether such a tablet if created, would provide a formulation that has a dissolution profile similar to Sustiva® tablets or provide an equivalent drug release profile as compared to the Sustiva® tablets.
Another document [WO 2006/134610] discloses an Efavirenz composition having the drug and sodium starch glycolate, polyvinylpyrrolidone k-90 and lactose. Sodium starch glycolate, lactose and polyvinylpyrrolidone k-90 used in this composition enhance the dissolution rate in gastrointestinal tract thereby improving the rate and extent of absorption of efavirenz in the bod>-and also improving its therapeutic effect. Here, too there are no actual examples that disclose whether such a formulation has a dissolution profile similar to Sustiva* tablets or provide an equivalent drug release profile as compared to the Sustiva tablets.

While many pharmaceutical compositions for oral administration have been proposed, there still exists a need for a tablet dosage form of efavirenz bioequivalent to the marketed tablet under the trade name Sustiva®.
The present invention is directed to stable solid oral dosage forms of efavirenz which has comparable in-vitro dissolution and bioequivalence [in-vivo\ profile similar to that of Sustiva*.
OBJrCTS OF THR INVENTION
It is an object of the invention in its preferred form to provide a stable, solid oral Efavirenz formulation having comparable in-vitro dissolution and bioequivalence [in-vivo] profile similar to that of Sustiva®. Another aspect of the invention provides a process for making a pharmaceutical tablet disclosed above.
SUMMARY OF THE INVENTION
According lo the invention there is provided a stable, solid oral Efavirenz formulation having comparable in-vitro dissolution and bioequivalence {in-vivo\ profile similar to that of Sustiva .
Also disclosed is a process to make the above mentioned tablet.
DETAILED DESCRIPTION INCLUDING PREFERRED EMBODIMENTS OF THE
INVENTION:
The bioavailability of drugs is directly related to their dissolution in the gastro-intestinal fluids. Absorption of a drug from an oral dosage form such as a tablet or a capsule can be affected by properties of the formulation and its method of manufacture. This is particularly true when the

drug has low solubility in water, has a hydrophobic nature, and/ or is administered in high therapeutic doses, such as Efavirenz. In such cases, dissolution of the drug from thi^ dosage form in the gastrointestinal tract can be the limiting factor that determines the rate and extent of absorption of drug into the body. Changes in the composition and/ or method of manufacture of the dosage form can affect the dissolution rate.
Drug release from a solid dosage form can be enhanced by addition of disintegrant materials. Previous attempts at making efavirenz formulation have used high levels of materials such as sodium starch glycolate as compared to the total weight of the formulation.
By disinlcgrants, we mean substance or a mixture of substances that when added in specific percentage compared to the drug; to the drug formulation facilitate the breakup or disintegration of the tablet contents into smaller particles that dissolve more rapidly, than in the absence of the disintegrant. For a low solubility drug like Efavirenz, disintegrants are added in the present invention to the formulations in range of 6 - 9 %. Representative disintegrants include: alginic acid, cellulose powdered, methylcellulose, carboxymethy I cellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, L- hydroxypropyl cellulose, hydroxypropylmethyl cellulose, guar gum, sodium alginate, sodium starch glycolate. niicrocrvslalline cellulose, starches and pre-gelatinised starch, polyvinyl-pyrolidone. polacrilin potassium and magnesium aluminum silicate.
Fillers/ diluents are substances that increase the bulk of the formulation. Examples of fillers / diluents include: lactose, kaolin, microcrystalline cellulose, sugar spheres, cellulose powder.

starches dibasic calcium phosphate dihydrate, compressible sugars, sucrose, sorbitol, xylilol, fructose, dextrates, dextrin, dextrose, mannitol, maltodextrin and polymethacrylates-
A binder is a material used to bind together two or more other materials in mixtures. Binder can also be included in the present formulation in a concentration between 1 and 10% to complement the drug amount- Examples of binders include: acacia, guar gum, alginic acid, sodium alginate, carbomer, dextrin, gelatin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, povidone, liquid glucose, mahodexlrin, magnesium aluminum silicate, polymethacrylates, starch, pre gelatinised starch, hydrogenated vegetable oil (type I), and zein.
l-,xamples of surfactants comprise anionic and cationic surfactants, such as benzalkonium chloride, cetylpyridinium chloride, cetrimide, docusate sodium, glyceryl monooleate, sodium laiiryl sulfate, lauric acid, sorbitan fatty acid esters (sorbitan monolaurate, sorbitan mono-stearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate), polyoxyethylene sorbitan fatty acid esters, polyoxyethylene cetyl stearyl ether, polyoxyethylene cetyl lauryl ethers and polyhydroxyethylene fatty acid esters.
Hxamples of lubricants include: stearic acid, aluminum-stearate, calcium stearate. magnesium stearate, magnesium silicate, magnesium trisilicate, sodium stearyl fumarate. zinc stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, highly disperse silica (aerosil), hydrogenated castor oil, hydrogenated cotton seed oil, hydrogenated

vegetable oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, and talc.
The tablet of the present invention can be made by wet granulation as well as dry granulation,' direct compression methods. In case of wet granulation, a solvent such as water or ethanol can be used. The tablet of the present invention can optionally be film coated. Film coating suspensions include combinations of one, two or three of the following components: carboxymethylcellulose sodium, carnauba wax, cellulose acetate phthalate, cetyl alcohol, confectioner's sugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, maltodextrin, methyl cellulose, microcrystalline wax, Opadry^ and Opadry®II, polymethacrylates, polyvinyl alcohol, shellac, sucrose, talc, titanium dioxide, and zein.
fhe invention relates to a pharmaceutical tablet comprising a therapeutically effective amount of efa\'ircnz and pharmaceutically acceptable excipients, wherein the tablet exhibits dissolution profile similar to that of Sustiva® formulation.
More particularly, the invention covers a pharmaceutical tablet comprising a therapeutically effective amount of efavirenz and pharmaceutically acceptable excipients exhibiting a dibsolulion profile similar to that of Sustiva® formulation, wherein the tablet comprises:
a) efavirenz in the range of 40% to 60% by weight;
b) disintcgrant in the range of 6% to about 9% by weight; and
c) other pharmaceutically acceptable excipients.

In one embodiment, the pharmaceutical tablet uses croscarmellose sodium as the disintegrant.
More particularly, the tablet of the present invention comprises a therapeutically effective amount of efavirenz and pharmaceutically acceptable excipients, comprising essentially of efavirenz in the range of 40% to 60% by weight, disintegranl in the range of 6% to about 9%, other pharmaceutically acceptable excipients, such that the tablet is bioequivalent to commercially available Sustiva® formulation.
As regards the dissolution profile, the pharmaceutical tablet exhibits the followirig dissolution
profile for efavirenz, when tested in a USP Type II apparatus at 50 rpm and 37° C. in a 2%
sodium lauryl sulphate purified water solution
35 to 45% of the efavirenz is released within 10 min;
50 to 60% of the efavirenz is released within 15 min;
85 to 95% of the efavirenz is released within 45 min;
96 to 98% of the efavirenz is released within 60 min.
The pharmaceutical tablet of the present invention has efavirenz in an amount from about 300 to about 1000 mg, preferably about 600 mg. Additionally, the tablet may also contain effective amount of at least one other anti-HIV active substance selected from abacavir, adefovir, delavirdine, didanosine, emtricitabine, lamivudine, nevirapine, nelfmavir, stavudine, tenofovir disoproxyl fumarate, zidovudine & zalcitabine.

The process for preparation pharmaceutical tablet according lo present invention can also be prepared by following process steps:
a) blending efavirenz with pharmaceutically acceptable diluent, binder, surfactant and
disintegrant,
b) granulating blend of step [a] using a solution of surfactant in water,
c) drying the granules of step [b],
d) blending granules of step [c] with extragranular excipients and lubricants, d} compressing blend of step [d] to form tablets.
e) optionally coat the tablet with a coating agent.
The present invention uses croscarmellose sodium as the preferred disintegrant in the range of 6-9%, based on weight of total weight. The preferred filler is microcrystalline cellulose. The preferred binder is hydroxypropyl cellulose. A preferred surfactant is sodium lauryl sulfate. The preferred diluent/ compression aid is lactose. The preferred lubricant is magnesium stearate. The preferred solvent for use in the wet granulation is purified water. The preferred film coating comprises; hydroxypropyl cellulose, hydroxypropyl methylcellulose, and titanium dioxide; commercially known as Opadry®.
Although the invention has been described with reference to specific examples, it will be appreciated by those skilled in the art that the invention may be embodied in other forms.
The following examples further exemplify the invention and are not intended to limit the scope of the invention.


Manufacturing Process:
1. Efavirenz, Lactose Monohydrate, Croscaramellose sodium, Hydroxypropyl cellulose-L and
half quantity of Sodium Lauryl Sulfate together are granulated using aqueous solution of Sodium
Lauryl Sulfate,
2. The wet mass is dried using fluidized bed drier, tray or similar suitable dryer.
3. The granules are then milled.
4. This blend is then mixed with microcrystalline cellulose and later lubricated with magnesium stearate.

5. This blend is then compressed in to tablets.
6. These tablets may then be coated with commercially available coating materials like Opadry'^

Dissolution Study:
The dissolution test is done using USP II apparatus (Paddle) at 50 RPM, 1000ml of purified water containing 2% w/v Sodium Lauryl Sulfate at 37 ± 0,5 °C.

We claim:
1. A pharmaceutical tablet comprising a therapeutically effective amount of efavirenz and
phannaceutically acceptable excipients, wherein said tablet exhibits a dissolution profile similar to that of Sustiva® formulation.
2. A pharmaceutical tablet comprising a therapeutically effective amount of efavirenz and
pharmaceutically acceptable excipients exhibiting a dissolution profile similar to that of
Sustiva® formulation, wherein said tablet comprises:
a) efavirenz in the range of 40% to 60% by weight;
b) disintegrant in the range of 6% to about 9% by weight; and
c) other pharmaceutically acceptable excipients.
3) A pharmaceutical tablet of claim 2, wherein said disintegrant is croscarmellose sodium.
4) A pharmaceulical tablet comprising a therapeutically effective amount of efavirenz and
pharmaceutically acceptable excipients, comprising essentially of efavirenz in the range of 40%
to 60% by weight, disintegrant in the range of 6% to about 9%, other pharmaceutically
acceptable excipients, such that said tablet is bioequivalent to commercially available Sustiva®
formulation.
5, The pharmaceutical tablet according to claim 2 that exhibits the following dissolution profile
for efavirenz, when tested in a USP Type II apparatus at 50 rpm and 37 ± 0.5° C in a 2% sodium
lauryl sulphate purified water solution
35 to 45% of the efavirenz is released within 10 min;
50 to 60% of the efavirenz is released within 15 min;

85 to 95% of the efavirenz is released within 45 min; 96 to 98% of the efavirenz is released within 60 min.
6. A pharmaceutical tablet according to claim 2, wherein efavirenz is present in an amount from
about 300 to about 1000 mg, preferably about 600 mg,
7. A pharmaceutical tablet according to claim 1, optionally containing effective amount of at
least one other anti-HIV active substance selected from abacavir. adefovir, delavirdine,
didanosine, emtrichabine, lamivudine, nevirapine, nelfinavir, stavudine, tenofovir disoproxyl
fumarate, zidovudine & zalcitabine.
8. A process for preparation pharmaceutical tablet according to claim I, said process comprising
the steps of:
a) blending efavirenz with pharmaceutically acceptable diluent, binder, surfactant and
disinlegrant.
b) granulating blend of step [a] using a solution of surfactant in water,
c) drying said granules,
d} blending granules of step [c] with extragranular excipients and lubricants,
d) compressing blend of step [d] to form tablets.
e) optionally coat said tablet with a coating agent.
9. A process as claimed in claim 9, wherein the disintegrant is croscarmellose sodium.