FIELD OF INVENTION

The invention relates to high drug solid oral dosage form for use in HIV therapy, and process for manufacture of such dosage form. More particularly, the invention relates to a compressed dosage form for use in HIV therapy, comprising effective amount of efavirenz.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Efavirenz and structurally similar reverse transcriptase inhibitors are disclosed in U.S. Patent Nos. 5,519,021, 5,663,169, 5,665,720 and the corresponding PCT International Patent Application WO 95/20389.

Efavirenz, chemically known as (S)-6-chloro-4-(cyclopropylethyl)-l, 4-dihydro-4' (trifluoromethyl)-2H-3,l-benzoxazin-2-one is a non-nucleoside human immunodeficiency virus (HIV) reverse transcriptase inhibitor and is used in HIV therapy. Presently marketed SUSTIVA® tablets contain 600 mg of Efavirenz as the active drug and croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate as the inactive components and the total weight of this marketed composition is around 1200 mg. The tablets are coated with Opadry® Yellow and Opadry® Clear.

U. S. Patent No. 7,060,294 discloses a compressed efavirenz tablet composition. It states that efavirenz concentration can be varied from about 1 to about 75% w/w, by changing the amount of other excipients in the composition, however, there are no actual examples that disclose whether such a tablet with high drug loading was actually made nor does it disclose whether such a tablet if created, would provide efavirenz tablets with desired pharmaceutical properties like compressibility, hardness, friability, disintegration and dissolution profile. Only a single working example for tablet composition is described, where the tablet weight is around 1818 mg, comprising 950 mg of Efavirenz, which equates to around 50% by weight of efavirenz relative to the total dry weight of the tablet.

U. S. Patent Nos. 6,238,695 and 6,555,133 discloses fast dissolving efavirenz compositions. It states that the amount of efavirenz in the wet granulation step can vary from about 25% to about 80% by weight relative to the total dry weight of the materials being granulated in the wet granulation step. Here too only one working example for Efavirenz tablet is described, where the tablet weight is around 600 gm, comprising 300 mg of efavirenz, which equates to around 50% by weight of efavirenz relative to the total dry weight of the tablet.

PCT International Patent Application WO 2006/134610 discloses an efavirenz composition having sodium starch glycolate, polyvinylpyrrolidone k-90 and lactose. It further discloses that the amount of efavirenz in the composition can range from 15 to 65% by weight of the tablet. Two examples for 600 mg Efavirenz are described, where the tablet weight is around 1350 mg and 965 mg, comprising 600 mg of Efavirenz, which equates to around 44.4% and 62% by weight of efavirenz relative to the total dry weight of the tablet.

U. S. Application No. 2009/0088424 discloses compositions for oral dosage forms containing a poorly soluble drug (efavirenz) in an amount of at least 30%) by weight of the pharmaceutical composition. All working examples for 600 mg efavirenz tablets were having tablet weight around 1500 mg, comprising 600 mg of efavirenz, which equates to around 40% by weight of efavirenz relative to the total dry weight of the tablet.

Efavirenz is a fluffy material, with relatively low bulk and tap densities. In addition, efavirenz has undesirable flow characteristics. These properties make it difficult to formulate a large amount of efavirenz into tablet which are smaller in dimension. In a dosage form containing a high dose of active pharmaceutical ingredient (e.g., at least 600 mg), it becomes difficult to make tablets with high percentage of active ingredient and substantially lower amount of excipients in order to achieve smaller tablet size. While many pharmaceutical compositions for oral administration have been proposed, there remains an unmet need for a tablet having high dose efavirenz exhibiting acceptable compressibility, hardness, friability, disintegration, m-vitro dissolution profile, and in-vivo drug release profile.

The invention now provides a compressed solid oral dosage form of efavirenz and process thereof, wherein the dosage form comprises more than 65% by weight relative to the total weight, of efavirenz; preferably more than 75%; and said dosage form exhibits acceptable compressibility, hardness, friability, disintegration, \n-vitro dissolution profile, and bioequivalence [in-vivo] profile similar to that of Sustiva®.

SUMMARY OF THE INVENTION

The invention relates to a compressed, solid oral dosage form comprising effective amount of efavirenz for use in HIV therapy, said dosage form comprises more than 65% of efavirenz relative to the total weight of the dosage form.

The tablets according to the invention contains more than 65% by weight of efavirenz to the total weight of the dosage form and one or more of pharmaceutically acceptable excipient(s), such that the weight ratio of efavirenz: excipient(s) is approximately from 1.0:0.5 to 1.0:0.20

The invention also relates to process of preparing a compressed solid oral dosage form comprising effective amount of efavirenz, wherein said dosage form comprises more than 65% of efavirenz relative to the total weight of the dosage form, preferably more than 70%.

The compressed solid oral dosage forms of efavirenz according to the invention, exhibits acceptable compressibility, hardness, friability, disintegration, in-vitro dissolution profile, and bioequivalence [in-vivo] profile similar to that of Sustiva®.

OBJECT OF THE INVENTION

It is an object of the invention to provide a compressed solid oral dosage form comprising effective amount of efavirenz for use in HIV therapy, wherein said dosage form comprises more than 65% of efavirenz relative to the total weight of the dosage form, preferably more than 70%.

Another object of the present invention is to provide a process of preparing a compressed solid oral dosage form comprising effective amount of efavirenz, wherein said dosage form comprises more than 65% of efavirenz relative to the total weight of the dosage form, preferably more than 70%.

In another object of the present invention is to provide a compressed solid oral dosage form comprising about 70% to about 80% by weight of efavirenz relative to the total weight of the dosage form, providing improved patience compliance and wherein said dosage form provides in-vitro dissolution profile similar to commercially marketed Sustiva® tablets.

In yet another object of the present invention is to provide a compressed tablet comprising effective amount of efavirenz and one or more of pharmaceutically acceptable excipient(s), wherein the weight ratio of efavirenz: excipient(s) is approximately from 1.0:0.5 to 1.0:0.20, preferably form 1.0:0.3 to 1.0:0.25, particularly 1.0:0.26.

DETAILED DESCRIPTION OF THE INVENTION:

Efavirenz is preferably administered in the form of tablets containing 300 mg or 600 mg of the same. In a conventional tablet composition, the tablet contains one or more excipient such as diluents, disintegrants, binders, lubricants etc. Commercially available Sustiva® tablets containing 600 mg of efavirenz have the tablet dimensions of 19.14 x 9.6 x 7.2 mm and contain about 50% w/w of efavirenz. This large tablet size can affect compliance in people with conditions related to impaired swallowing. Hence low weight tablets with high drug loading will tend to have smaller dimension and will be beneficial to pediatric and geriatric patients.

The tablets according to the invention are relatively smaller than the presently marketed Sustiva® tablets, will provide greatly enhance patience compliance. It also includes lesser amount of excipients that provides economic advantage, as well as reduction of processing parameters during large scale manufacturing of tablets of the invention at commercial scale.

The other benefits of smaller tablets with high drug loading tends to have trouble free manufacturing with respect to tablet to tablet, batch to batch and lot to lot uniformity of tablets.

Accordingly, the invention relates to a compressed, solid oral dosage form comprising effective amount of efavirenz for use in HIV therapy, said dosage form comprises more than 65% of efavirenz relative to the total weight of the dosage form, preferably more than 70%.

The invention also relates to compressed tablets comprising effective amount of efavirenz and one or more of pharmaceutically acceptable excipient(s), wherein the weight ratio of efavirenz: excipient(s) is approximately from 1.0:0.5 to 1.0:0.20, preferably form 1.0:0.3 to 1.0:0.25, particularly 1.0:0.26

The invention also relates to process of preparing a compressed solid oral dosage form comprising effective amount of efavirenz, wherein said dosage form comprises at more than 65% by weight of efavirenz relative to the total weight of the dosage form, preferably more than 70%.

It is a characteristic of the tablet according to the invention that it contains a high content of efavirenz given the relatively small amount of excipients. This enables the production of physically small tablets as compared to marketed sustiva tablets. The total amount of excipients in a given unit dosage may be about 35% or less by weight based on the total weight of the tablet, more particularly about 25% or less. Preferably the excipient content is in the range of about 15 to 20%, by weight based on the total weight of the tablet.

The compressed solid oral dosage forms of efavirenz according to the invention, exhibits acceptable compressibility, hardness, friability, disintegration, in-vitro dissolution profile, and bioequivalence [in-vivo] profile similar to that of Sustiva® based on in-vitro/in-vivo correlation.

The solid dosage form according to the invention showing acceptable weight uniformity with weight deviations less than 10 %w/w, less than 1% of friability and 75% or more of efavirenz dissolved/ released within 45 minutes from the dosage form.

As regards the dissolution profile, solid dosage form according to the invention exhibits the following 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

30 to 40% of the efavirenz is released within 10 min;
40 to 50% of the efavirenz is released within 15 min;
45 to 65% of the efavirenz is released within 30 min;
70 to 85% of the efavirenz is released within 45 min;
85 to 98%> of the efavirenz is released within 60 min..

The amount of efavirenz in the dosage form according to the invention is present in an amount from about 300 - 1000 mg, preferably about 600 mg.

The dosage form may further comprise pharmaceutically acceptable additives known in the art. The term 'pharmaceutically acceptable additive' includes 'pharmaceutically acceptable excipient' within its ambit and the singular term includes plural as well. The pharmaceutically acceptable excipients may be one or more of filler/ diluents, binders, disintegrants, lubricants, glidants, coloring agents and flavoring agent. The dosage form may optionally include surfactant.

The compressed solid oral dosage form according to the invention, preferably include tablets.

Fillers/ diluents according to the invention include without any limitation: lactose, kaolin, microcrystalline cellulose, cellulose powder, starches, dibasic calcium phosphate dihydrate, compressible sugars, sucrose, sorbitol, xylitol, fructose, dextrates, dextrin, dextrose, mannitol, maltodextrin and polymethacrylates.

Binders according to the invention include without any limitation: acacia, guar gum, alginic acid, sodium alginate, carbomer, dextrin, gelatin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, povidone, liquid glucose, maltodextrin, magnesium aluminum silicate, polymethacrylates, starch, pregelatinised starch, hydrogenated vegetable oil (type I), and zein. Said binders may be present in an amount from about 1% to about 10% by weight. More preferably, from about 2% to about 5% by weight of the tablet.

Disintegrants according to the invention include without any limitation: alginic acid, cellulose powdered, methylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, L-hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, guar gum, sodium alginate, sodium starch glycolate, microcrystalline cellulose, starches and pre-gelatinized starch, polyvinyl-pyrolidone, polacrilin potassium and magnesium aluminum silicate. Said disintegrant may be present in an amount from about 2% to about 10% by weight. More preferably, from about 4% to about 8% by weight of the tablet.

Surfactants according to the invention include without any limitation both anionic and cationic surfactants, such as benzalkonium chloride, cetylpyridinium chloride, cetrimide, docusate sodium, glyceryl monooleate, sodium lauryl 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.

Lubricants according to the invention include without any limitation: 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 according to the invention can be prepared by the process of wet granulation as well as dry granulation/ and or direct compression. In case of wet granulation, a solvent such as water or non-aqueous solvent can be used. The tablet of the invention can optionally be film coated.

Film coating 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.

The invention also relates to compressed solid oral dosage form comprising a therapeutically effective amount of efavirenz and pharmaceutically acceptable excipients, wherein said tablet exhibits dissolution profile similar to that of Sustiva® tablets.

More particularly, the invention relates to 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 65% to 85% by weight;
b) disintegrant in the range of 4% to about 10% by weight; and
c) one or more pharmaceutically acceptable excipients.
In an embodiment, said tablet contains croscarmellose sodium as the disintegrant.

More particularly, the tablet according to the invention comprises a therapeutically effective amount of efavirenz and pharmaceutically acceptable excipients, comprising efavirenz in the range of 70% to 80% by weight, disintegrant in the range of 5% to about 7% by weight, and other pharmaceutically acceptable excipients, wherein said tablet is bioequivalent to commercially available Sustiva tablet.

The tablet according to the invention comprises 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, nelfinavir, stavudine, tenofovir disoproxyl fumarate, zidovudine & zalcitabine.

The tablet according to the invention is 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 extra-granular excipients and lubricants,

e) compressing blend of step [d] to form tablets.

f) optionally coating the tablet with a coating agent

The tablet according to the invention contains croscarmellose sodium as the preferred disintegrant, microcrystalline cellulose as the preferred filler, hydroxypropyl cellulose as the preferred binder, sodium lauryl sulfate as the preferred surfactant, lactose as the preferred diluent/ compression aid, magnesium stearate as the preferred lubricant. Preferred solvent for use in the wet granulation is purified water. Preferred film coating composition includes: hydroxypropylcellulose, 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.

Example 1-2:

Unit Composition:

Brief 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 .

Example 3:

Unit Composition:

Brief Manufacturing Process:

1. Efavirenz, microcrystalline cellulose, 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 croscaramellose sodium, lactose monohydrate and later lubricated with magnesium stearate and colloidal silicon dioxide.

5. This blend is then compressed in to tablets.

6. These tablets may then be coated with commercially available coating materials like Inztacoat .

Dissolution Studies:

The dissolution test was carried out for tablets prepared according to Example 3 and Sustiva® tablets in USP II apparatus (Paddle) at 50 rpm, containing 1000ml of purified water and 2% w/v sodium lauryl sulfate at 37 ± 0.5 °C. The following release profile for efavirenz is obtained which is shown in Table 1.

Table 1:

Example 4:

Unit Composition:

Brief Manufacturing Process:

1. Efavirenz, microcrystalline cellulose, croscaramellose sodium, Hydroxypropyl cellulose together are granulated using water.

2. The wet mass is dried using fluidized bed drier, tray or similar suitable dryer.

3. The granules are then milled and mixed with croscaramellose sodium, lactose monohydrate and later lubricated with magnesium stearate and colloidal silicon dioxide.

4. This blend is then compressed in to tablets.

5. These tablets may then be coated with commercially available coating materials like Inztacoat®.

Dissolution Studies:

The dissolution test was carried out for tablets prepared according to Example 4 and Sustiva® tablets in USP II apparatus (Paddle) at 50 rpm, containing 1000ml of purified water and 2% w/v sodium lauryl sulfate at 37 ± 0.5 °C. The results shows that more than 85% of the drug is released after 60 minutes

We claim

1. A compressed solid oral dosage form comprising:

a) effective amount of efavirenz; and

b) at least one pharmaceutically acceptable excipient(s);

wherein the weight ratio of efavirenz: excipient(s) is approximately from 1.0:0.4 to 1.0:0.20; and

wherein the total weight of said tablets is less than 900 mg.

2. A compressed solid oral dosage form according to claim 1, the weight ratio of efavirenz: incipient(s) is 1:0.25.

3. A compressed solid oral dosage form according to claim 1, wherein said dosage form exhibits a dissolution profile similar to that of Sustiva® tablets.

4. A compressed solid oral dosage form according to claims 1, wherein said excipient(s) are selected form filler/ diluent, binder, disintegrant, lubricant, glidant and anti-adherent.

5. A compressed solid oral dosage form according to claim 1, wherein said filler/ diluent is selected form sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, microcrystalline cellulose, dibasic calcium phosphate and mannitol.

6. A compressed solid oral dosage form according to claim 1, wherein said binder is selected form potato starch, wheat starch, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose.

7. A compressed solid oral dosage form according to claim 1, wherein said disintegrant is selected form alginic acid, sodium alginate, methylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, L-hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxy propylmethyl cellulose, guar gum, sodium starch glycolate, microcrystalline cellulose, pre-gelatinized starch and polyvinyl-pyrolidone.

8. A process of forming a compressed solid oral dosage form comprising more than 70% by weight of efavirenz, and at least one pharmaceutically acceptable excipient, comprising the steps of:

i) blending the efavirenz and at least one pharmaceutically acceptable excipient to form a mixture;

(ii) wet-granulating said mixture to form granules;

(iii) mixing said granules with pharmaceutically acceptable excipient; and

(iv) compressing said mixture to form a tablet.

Such that the weight ratio of efavirenz: excipient(s) is approximately from 1.0:0.4 to 1.0:0.20; and

wherein the total weight of said tablets is less than 900 mg.

9. A process of forming a compressed solid oral dosage form containing more than 70% by weight of efavirenz, and at least one pharmaceutically acceptable excipient, comprising the steps of:

i) blending the efavirenz and at least one pharmaceutically acceptable excipient to form a mixture;

ii) subjecting said mixture to compression to form a coprimate;

iii) converting said coprimate into a granulate; and,

iv) compressing the granulate to form the compressed solid dosage form.

Such that the weight ratio of efavirenz: excipient(s) is approximately from 1.0:0.4 to 1.0:0.20; and

wherein the total weight of said tablets is less than 900 mg.

10. A compressed tablet comprising:

a) 600 mg of efavirenz; and b) one or more of pharmaceutically acceptable excipient(s);

prepared by dry granulation technique such that the weight ratio of efavirenz:

excipient(s) is around 1.0:0.26; and

wherein the total weight of said compressed tablets is less than 900 mg.