US 20130195978A1

(19) United States

(12) Patent Application Publication

(43) Pub. Date:

Parthasarashi Reddy et al.

(54)

(75)

DARUNAVIR COMPOSITIONS

(86)

PCT No.:

(21) Appl. No.:

(22)

PCT Filed:

Mar. 14, 2013

Publication Classi?cation

(51)

Int. Cl.

A61K 9/20

(73) Assignee:

Aug. 1, 2013

PCT/IN10/00299

371 (0X1),
(2), (4) Date:

Inventors: Bandi Parthasarashi Reddy,

Andhrapradesh (IN); Podili

Khadgapathi, Andhrapradesh (IN); Goli
Kamalakar Reddy, Andhrapradesh (IN)

(10) Pub. N0.: US 2013/0195978 A1

(52)

(2006.01)

US. Cl.

HETERO RESEARCH

CPC .................................. .. A61K 9/2072 (2013.01)

FOUNDATION, Hyderabad (IN)

USPC .......... .. 424/474; 514/470; 424/400; 428/402

13/696,702

ABSTRACT
(57)
The present invention relates to an oral pharmaceutical com

May 10, 2010

position of amorphous darunavir.

Aug. 1,2013

US 2013/0195978 A1

DARUNAVIR COMPOSITIONS

[0010]

More preferably, the d90 particle siZe of darunavir is

in the range of 190 to 200 pm.

FIELD OF THE INVENTION

[0001]

The present invention relates to an oral pharmaceu

tical composition of amorphous darunavir.

[0011] Preferably, the oral pharmaceutical composition is a

solid oral dosage form.
[0012] More preferably, the solid do sage form is in the form
of tablet.

BACKGROUND OF THE INVENTION

[0013]

The tablet composition is optionally ?lm coated.

[0014] The oral pharmaceutical composition of amorphous

darunavir may be prepared by direct compression, Wet granu

[0002] Darunavir, also knoWn as TMC-l l4 and UIC

94017, is a HIV-l protease inhibitor. It selectively inhibits the

lation or roll compaction.

cleavage of HIV encoded Gag-Pol polyproteins in infected

cells, thereby preventing the formation of mature virus par

amorphous darunavir may be prepared by direct compres

ticles.

sion.

[0015] Preferably oral pharmaceutical composition of

[0003] Darunavir is chemically [(3R,3aS,6aR)-2,3,3a,4,5,

[0016]

6a-Hexahydrofuro[5,4-b]furan-3-yl]N-[(2S,3R)-4-[(4-ami

invention may contain one or more additional excipients.

nophenyl)sulfonyl-(2 -methylpropyl)amino] -3 -hydroxy- l -

These excipients may be selected from diluents, binders,

disintegrants and lubricants.
[0017] Preferably, the diluent is selected from lactose,
sucrose, glucose, mannitol, sorbitol, calcium carbonate,
microcrystalline cellulose, Prosolv, magnesium stearate and

phenylbutan-2-yl]carbamate. Its empirical formula is

C27H37N3O7S, and its molecular Weight is 547.66. Darunavir
has the following structural formula.

The oral pharmaceutical composition of the present

mixtures thereof. More preferably, the diluent is Prosolv.

NH2

[0018]

The preferable binder is selected from L-Hydroxy

propyl cellulose, polyvinyl pyrrolidine, hydroxyl propyl

methyl cellulose, hydroxyl ethyl cellulose and pre-gelati
niZed starch.

[0019]

Preferably, the disintegrant is selected from croscar

mellose sodium, crospovidone, sodium starch glycolate and

loW substituted hydroxyl propyl cellulose.
[0020]

The more preferable disintegrant is selected from

loW substituted hydroxyl propyl cellulose and crospovidone.

[0021]

-2

Preferably, the lubricant is selected from sodium

stearyl fumarate, magnesium stearate, Zinc stearate, calcium

stearate, stearic acid, talc, Glyceryl behenate and colloidal
silicon dioxide.

[0022]

More preferably, the lubricant is selected from mag

nesium stearate, Zinc stearate, calcium stearate and colloidal

silicon dioxide.
O
H

[0023] Prefearbly, the oral pharmaceutical composition

comprises amorphous darunavir, prosolv, crospovidone, col
loidal silicon dioxide and magnesium stearate.
[0024] The Wet granulation process includes Wet granula

[0004] Darunavir is commercially available as tablets con

taining darunavir ethanolate under the trade name

tion of amorphous darunavir With the excipient(s), lubrication

PREZISTA in the United States, Europe and Canada.

[0005] The synthesis of darunavir and the manner in Which

and folloWed by compression.

[0025] The compaction process includes compaction of

it may be used to treat HIV infection are described in Us. Pat.

amorphous darunavir With the excipient(s), lubrication and

Nos. 5,843,946, 6,248,775 and 6,335,460.

[0006]

The present invention relates to an oral pharmaceu

tical composition comprising amorphous darunavir having

d9O particle siZe of about 150 um to about 250 um.
OBJECTIVE OF THE INVENTION

folloWed by compression.
[0026] The direct compression process includes blending
amorphous darunavir With the excipient(s), lubrication and

folloWed by compression.
[0027] The tablet composition is optionally ?lm coated
With opadry II orange.

[0028] The folloWing examples further exemplify the

[0007] Accordingly, the main objective of the invention is
to provide an oral pharmaceutical composition comprising
amorphous darunavir having a d9O particle siZe of about 150

invention and are not intended to limit the scope of the inven

tion.

pm to about 250 um.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

[0029]

[0008] According to the present invention there is provided

an oral pharmaceutical composition comprising amorphous
darunavir having a d9O particle siZe of about 150 pm to 250

Ingredients

pm.

Amorphous da1unavir*

600.00

Prosolv

583.75

[0009]

The preferable d9O particle siZe of darunavir is in the

range of 175 to 225 um.

Quantity/Unit (mg)

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US 2013/0195978 A1

-continued
Ingredients

-continued
Quantity/Unit (mg)

Crospovidone
Puri?ed water
Colloidal silicon dioxide
Magnesium stearate
Film coating

37.50
q.s
25.00
3.75

Opadry II orange

25.00

Total Tablet Weight

1275_OO

*Particle size distribution ofamorphous darunavir: dm-ll um; d50-5O urn d90-l95 urn

[0030] The process of the preparation involve following

steps:

[0031] i). Blending of amorphous darunavir, prosolv,

crospovidone dried if necessary
[0032] ii). Lubricating with colloidal silicon dioxide and
magnesium stearate

[0033] iii). Compressing the lubricated blend of step (ii)

Ingredients

Quantity/Unit (mg)

Colloidal silicon dioxide

Magnesium stearate
Film coating

12.50
3.75

Opadry II orange

25.00

Total Tablet weight

1275.00

*Particle size distribution ofamorphous darunavir: d10-l7 um; d50-65 urn d90-2l3 urn

[0042] The process of the preparation involve following

steps:

[0043] i). Compaction of Darunavir, prosolv, crospovidone

with a suitable sovent.

[0044] ii). Lubricating with colloidal silicon dioxide and

magnesium stearate

[0045] iii). Compressing the lubricated blend of step (ii)

into tablets.

[0046] iv). Coating the compressed tablets with opadry.

into tablets.

Example 4

[0034] iv). Coating the compressed tablets with opadry.

[0047]
Example 2

[0035]

Ingredients

Ingredients

Amorphous darunavir*
Microcrystalline cellulose
Crospovidone

Quantity/Unit (mg)

Amorphous darunavir*

600.00

Prosolv

596.25

Crospovidone

25.00

Puri?ed water

q.s

Colloidal silicon dioxide

Magnesium stearate

25.00
3.75

Total Tablet weight

1275.00

*Particle size distribution ofamorphous darunavir: d10-l5 um; d60-6O urn d90-2l0 urn

[0036]
steps:

Puri?ed water

q.s

Colloidal silicon dioxide

Magnesium stearate

37.00
3.75

Opadry II orange

Total Tablet weight

25.00

The process of the preparation involve following

[0037] i). Granulation of amorphous darunavir, prosolv,

crospovidone with a suitable sovent.

[0038] ii). Lubricating with colloidal silicon dioxide and

magnesium stearate

[0039] iii). Compressing the lubricated blend of step (ii)

into tablets.

[0040] iv). Coating the compressed tablets with opadry.

600.00
571.75
37.50

Film coating

Film coating
Opadry II orange

Quantity/Unit (mg)

25.00

1275 .00

*Particle size distribution ofamorphous darunavir: dl0-8 um; d50-45 um d90-l82 pm

[0048] The process of the preparation involve following

steps:

[0049] i). Blending of amorphous darunavir, microcrystal

line cellulose, crospovidone and dried if necessary
[0050] ii). Lubricating with colloidal silicon dioxide and
magnesium stearate

[0051] iii). Compressing the lubricated blend of step (ii)

into tablets.

[0052] iv). Coating the compressed tablets with opadry.

We claim:

1. An oral pharmaceutical composition comprises amor

phous darunavir having a d9O particle size in the range of
about 150 pm to 250 pm.

2. The oral pharmaceutical composition according to claim

Example 3

1, wherein the d90 particle size is in the range of 175 to 225

um.

[0041]

3. The oral pharmaceutical composition according to claim

1, wherein d9O particle size is in the range of 190 to 200 pm.

Ingredients

Quantity/Unit (mg)

Amorphous darunavir*

600.00

Prosolv

608.75

Crospovidone

25.00

Puri?ed water

q.s

4. The oral pharmaceutical composition according to claim

1, wherein the composition is in the form of tablets.
5. The oral pharmaceutical composition according to claim
4, wherein the tablet is ?lm coated.
6. The oral pharmaceutical composition according to claim
1, wherein the composition may contain one or more addi

tional excipients.

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US 2013/0195978 A1

7. The oral pharmaceutical composition according to claim

6, the excipients are selected from diluents, binders, disinte
grants and lubricants.
8. The oral pharmaceutical composition according to claim
7, Wherein the diluent is selected from lactose, sucrose, glu

cose, mannitol, sorbitol, calcium carbonate, microcrystalline

cellulose, Prosolv, magnesium stearate and mixtures thereof.
9. The oral pharmaceutical composition according to claim
7, Wherein the diluent is Prosolv.

10. The oral pharmaceutical composition according to

claim 7, Wherein the binder is selected from L-Hydroxy pro

pyl cellulose, polyvinyl pyrrolidine, hydroxyl propyl methyl

cellulose, hydroxyl ethyl cellulose and pre-gelatiniZed starch.
11. The oral pharmaceutical composition according to
claim 7, Wherein the disintegrant is selected from cro scarmel

lose sodium, crospovidone, sodium starch glycolate and loW

substituted hydroxyl propyl cellulose.

12. The oral pharmaceutical composition according to

claim 7, Wherein the disintegrant is selected from loW substi

tuted hydroxyl propyl cellulose and crospovidone.

13. The oral pharmaceutical composition according to
claim 7, Wherein the lubricant is selected from sodium stearyl
fumarate, magnesium stearate, Zinc stearate, calcium stear
ate, stearic acid, talc, Glyceryl behenate and colloidal silicon
dioxide.

14. The oral pharmaceutical composition according to

claim 7, Wherein the lubricant is selected from magnesium
stearate, Zinc stearate, calcium stearate and colloidal silicon
dioxide.

15. The oral pharmaceutical composition according to

claim 1, Wherein the tablets of darunavir comprises amor

phous darunavir, colloidal silicon dioxide, crospovidone,

magnesium stearate and prosolv.
*