COMPLETE AFTER PROVISIONAL
FORM-2 LEFT 0N 07.10.2005
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE

(See section 10 and rule 13)
COMBINATION THERAPY FOR TREATMENT OF AIDS
EMCURE PHARMACEUTICALS LTD.,
an Indian Company
of Emcure House, T-184, M.I.D.C, Bhosari, Pune 411 026,
Maharashtra, India,


THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:-


FIELD OF INVENTION
This invention relates to a patient compliant, combination therapy for treatment of AIDS.
This novel presentation can be safely and effectively administered as a first line regimen for HIV infected patients including those who are at the initial stages of nevirapine therapy.
INTRODUCTION
Antiretroviral therapy is the main treatment for Human Immunodeficiency Virus (HTV) or Acquired Immuno-Deficiency Syndrome (AIDS).
Unfortunately, antiretroviral drugs do not result in complete reconstitution of the immune function. Moreover, inhibition of viral replication by these agents is temporary, due to the evolution of resistant strains of virus that can grow in the presence of the antiretroviral agents. Monotherapy with these currently available antiretroviral drugs is hence not recommended.
Therefore, antiretroviral therapy, which typically involves combinations of various antiretroviral drugs, is now the standard of care for people with HIV. It is sometimes called HAART (Highly Active Anti-Retroviral Therapy). Studies clearly show that three-drug combinations of these anti-HIV drugs are much more effective than one drug used alone or two-drug combinations in preventing disease progression and death. Numerous studies of triple drug combinations using either a PI or an NnRTI with two NRTI anti-HlV drugs show that the triple combination could greatly reduce disease progression and deaths in people with AIDS.
Advantages associated with combination therapy over and above antiretroviral monotherapy include:
1. Combination therapy slows disease progression and improves survival.
2. It results in a greater and more sustained virologic and immunologic response.
3. Combination therapy delays development of virus mutations that confer resistance to the drugs being used.
4. Aggressive antiretroviral therapy with at least three drugs during initial treatment preserves immune function and delay disease progression.
In this therapy, a person needs to take at least two and preferably three drugs at the same time. This is because if only one drug is taken, the person might become resistant to the drug within a

1. Fixed Dose Combinations are particularly cautioned against use in patients who are initiating
therapy with nevirapine. Such compositions come with a caution statement that they should not be
administered to patients who have just initiated a therapy with nevirapine. This is because; the
recommended dose of Nevirapine varies depending upon the stage of treatment. Importantly, the
recommended dose of nevirapine, during the initiating phase of the treatment is only one 200 mg
tablet per day. This dosage must not be exceeded under normal circumstances. This is essentially
because, the drug causes a severe rash in the first few weeks of treatment in around 7% of people
who take it and a small proportion develop serious, potentially life threatening liver toxicities.
Hence a lead in period must be followed religiously for the first 14 days of therapy. A lead dose
has been found to lessen the frequency of rash development and other associated side effects.
Following this lead-in dose, a dose escalation (maintenance dose) nevirapine b.d. may be carried out in the absence of any hypersensitivity reaction.
Each tablet of a fixed dose combination of nevirapine + stavudine + lamivudine, to be taken twice daily, contains 200 mg of nevirapine. Hence such a combination is essentially not recommended for patients initiating the three-drug therapy.
2. Overdose of nevirapine in case of unmonitored administration of an FDC.
There is no antidote known, for a nevirapine overdose. Roughly 16% of people starting Nevirapine
get a rash in the form of red blotches, itchy lumps or speckles on the skin. This rash usually
appears after one to four weeks of treatment. In most cases the rash goes away after two to four
weeks on the drug, and thereafter most people experience very few or no side effects. The rash
can be treated in many cases with anti-histamines.
However about 7% of people taking Nevirapine develop a more serious rash which can
occasionally require hospitalisation This rash usually goes away upon discontinuing the drug, but
one patient needed a skin graft.
Starting Nevirapine at a low dose and building up to the standard dose after two weeks seems to
reduce the risk of Nevirapine-related rash.
So it is recommended that people starting this combination should not begin treatment straight
away with triple drug combination, because it contains the full dose of Nevirapine. Instead
treatment should begin with Nevirapine once daily as a separate tablet for first 14 days. After 14
days it can be started as a part of fixed drug combination to be given twice daily.
3. Toxicity management of nevirapine in the fixed dose composition becomes very difficult, more
so because the physicians themselves find it hard to diagnose as to which of the active drug is
causing side effect.

4. Further, in a three in one fixed dose combination, dosage of nevirapine cannot be adjusted as
per requirement and stage of treatment. The patient must therefore switch over to a two-drug
combination or take the three drugs separately. Such regimens are not preferred as they are
difficult to adhere to.
5. Fixed dose combinations offer no solution as far as paediatric administration is concerned.
6. Determination of the differential half-lives of drugs when treatment is interrupted becomes much more difficult and tedious in three-in -one FDCs.
There is a need for presenting to a patient the three drugs in a convenient dosage form and which will make the patient more compliant for repeated dosage .
This invention envisages, the presentation of a co-blister pack in which two or more pills, capsules or tablets are packaged together in one unit of use of a plastic or aluminium blister pack. Co-blister packs help people in taking the pills at the correct time by packaging the drugs together, but the drugs can still be separated. So that in case a patient is exhibiting sensitivity to one drug, it can be substituted with a more patient compliant unit. Dosage flexibility is therefore retained in a co-blister pack.
This invention satisfies the need for such a formulation /presentation which provides Nevirapine tablet as separate dose, along with Stavudine & Lamivudine tablets, in a kit form, so that it is useful from the point of view of patient convenience.
Together, the co-blister packs envisaged in accordance with this invention offer numerable advantages. They facilitate ARV storage and distribution logistics. Also the person taking the pills cannot leave out, forget or sell one of their drugs by not taking some of the pills. This improves the ability of people to take the drugs correctly (known as adherence) and it limits the emergence of resistance.
The solution provided in accordance with this invention are starter packs in which two different fixed dose combinations with or without Nevirapine are presented as the morning and evening pills. A patient compliant combination which while providing a three drug therapy not just limits the concentration of nevirapine present to that of a lead in dose but also offers an easily accessible risk management, particularly of nevirapine, is the need of the hour. Followed by a kit in which all three drugs are presented for use.

OBJECT OF THE INVENTION
The object of the invention is to provide a combination therapy of three anti-retrovirals: stavudine, lamivudine and nevirapine.
Another object of the invention is to provide a co-blister pack of three antiretrovirals: stavudine, lamivudine and nevirapine.
Further, object of the invention is to provide a fixed dose composition of stavudine and lamivudine to be administered in a co-blister pack with nevirapine tablet.
Yet another object of the invention is to provide a combination therapy comprising a fixed dose composition of stavudine and lamivudine, co-packaged with nevirapine composition in a co-blister pack.
In particular, the object of the invention is to provide a more patient compliant combination therapy comprising a fixed dose composition of stavudine and lamivudine, co-packaged with nevirapine composition in a co-blister pack.
The invention will now be described with reference to the accompanying drawings, in which
DESCRIPTION OF THE FIGURES
Figure 1 of Figure 5 is a graph showing the extent of dissolution of active ingredient as a function
of time for a conventional (IR) tablet.
Figure 2 of Figure 5 is a graph showing the comparative dissolution profile of Nevir tablet as
presented in the Kit to Viramune (marketed preparation of nevirapine). Dissolution profile of
Nevir is shown in diamond links and the dissolution profile of a standard Viramune tablet is shown
in box links.
Figure 3 of 5 is a graph showing the Comparative Dissolution of Emduo (Combination of
Stavudine and Lamivudine as per the instant invention) with Zerit (Stavudine) and Epivir
(Lamivudine).
Figure 4 of Figure 5 is a graph showing the Comparative Dissolution of Lamivudine (Emduo) with
Lamivudine (Epivir).
Figure 5 of Figure 5 is a graph showing the Comparative Dissolution of Stavudine (Emduo) with
Stavudine (Zerit) a commercially available tablet.

DETAILED DESCRIPTION
The present invention relates to a combination therapy of three anti-retrovirals: stavudine, lamivudine and nevirapine.
The present invention presents a combination therapy comprising a fixed dose composition of stavudine and lamivudine, co-packaged with nevirapine in a co-blister pack
The Combination therapy in accordance with this invention is useful for the treatment of HIV/AIDS.
Nevirapine + stavudine + lamivudine combination therapy is a well-established and accepted therapy for the treatment of AIDS. However, the therapy comes with an essential caution statement relating to the dosage and administration of nevirapine that Nevirapine is to be administered once daily for the first two weeks followed by twice daily. Therefore, for the first two weeks, one could not administer the triple-regimen as a single FDC.
This invention envisages a kit, which contains two tablets of stavudine 30/40 mg & Lamivudine
150 mg & one tablet of Nevirapine 200 mg, hence the kit fulfills a daily dose. One tablet of
Stavudine & lamivudine, one tablet of Nevirapine to be administered in the morning & one tablet
of stavudine & Lamivudine in the evening.
Each kit contains:
PART A: 2 tablets of Stavudine 30/40 mg & Lamivudine 150 mg tablets
PART B: 1 tablet of Nevirapine 200 mg tablets
The US Pharmacopeia 27 (USP - 2004; Paragraph 1088, Page No. 2514, column 1) has developed a method for dissolution and drug release testing of dosage forms. In case of conventional, immediate release formulations, at least 70% - 80% of the labled content must be dissolved within 30 - 60 minutes of dosage administration. Figure 1 depicts the standard dissolution profile of a conventional dosage form. The Nevirapine composition presented in the kit form shows a predictable release profile as desired for a standard Immediate Release (IR) Formulation (Figure 2).Compositions of the invention containing excipients can be prepared by any known technique of pharmacy. The preparation of the present invention may include appropriate amounts of other pharmaceutically acceptable additives such as diluents or vehicles (e.g., lactose, mannitol, potato starch, wheat starch, rice starch, corn starch, and crystalline cellulose), binders (e.g., pregelatinized

starch, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, and gum arabic), lubricants (e.g., stearic acid, calcium stearate, magnesium stearate, talc, magnesium meta-silicate aluminate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate), disintegrants (e.g., sodium starch glycolate, croscarmellose sodium, crospovidone) fluidizers (e.g., hydrous silica, light anhydrous silicic acid, and dried aluminium hydroxide gel), wetting agent (e.g. sodium lauryl sulphate), colorants (e.g., Lake of Quinoline Yellow, Lake of sunset yellow, yellow iron sesquioxide and iron sesquioxide), surfactants (e.g., sodium lauryl sulfate, sucrose fatty acid ester), coating agents (e.g., zein, hydroxypropyl methylcellulose, and hydroxypropylcellulose), glidant (e.g. colloidal silicon dioxide).
The antiretrovirals composition according to the instant invention is preferably in a blister strip, sufficient for a weekly dose.
The composition as referred above contains the fixed dose tablet composition contains 150 mg of lamivudine and 30/40 mg of stavudine and 200 mg of nevirapine.
The said composition further comprises of excipients such as disintegrant, binder, wetting agent, diluent, glidant and antiadherent. The %ages of excipients as used for combination tablet of stavudine and lamivudine, nevirapine tablet is given below: Table A
Typically ingredients for the combination tablet of stavudine and lamivudine

S.No Excipient Range (%)
1 Disintegrant 0.5 - 10%
2 Binder 1 - 75%
3 Wetting agent Not more than 5%
4 Diluent 5 - 95%.
5 Glidant 0.05-0.5%
6 Antiadherent 0.25 - 5%
Table B
For the tablet of nevirapine

S.No Excipient Range (%)
1 Disintegrant 1 - 8%
2 Wetting agent Not more than 5%
3 Diluent 5-90%
4 Glidant 0.1-10%
5 Antiadherent 0.25 - 5%
6 Binder 5-25%

The invention is described in detail herein below with respect to the following examples, which are provided merely for illustration and are not intended to restrict the scope of the invention in any manner. Any embodiments that may be apparent to a person skilled in the art are deemed to fall within the scope of the present invention. Tables 1-18 provide a summary of release pattern obtained over a period of 60 minutes using the composition of the present invention. These examples also state the best-preferred embodiments of the invention.Example 1
PART A: 2 tablets of Stavudine 30/40 mg & Lamivudine 150 mg tablets
Active ingredient: Stavudine..30/40 mg
Lamivudine.... 150 mg Excipients:
Maize Starch IP 27.38%
Microcrystalline cellulose IP 24.76 %
Pregelatinized starch 1.19%
Sodium starch glycolate 2.38 %
Colloidal silicon dioxide 0.714%
Magnesium stearate 0.714 %
Purified water q.s.
PART B: 1 tablet Nevirapine 200 mg tablets
Active ingredient: nevirapine 200 mg

S.No. Ingredients Qty/tab [mg]
1 Nevirapine IP 200
2 Microcrystalline cellulose IP [Avicel PH 101] 88
3 Lactose IP 40
4 Purified Water IP qs
5 Maize Starch IP 20
6 Colloidal Silicon Dioxide IP 6
7 Sodium Starch Glycollate IP (Primogel) 7
8 Talc IP 3
9 Magnesium Stearate IP 6

Example 2
PART A: 2 tablets of Stavudine 30/40 mg & Lamivudine 150 mg tablets

S.No. Ingredients Qty/tab [mg]
1 Lamivudine 150
2 Stavudine 40
3 Maize Starch 105
4 Avicel pH lOl 104
5 Pregelatinized Starch (Starch 1500)
6 Pregelatinized Starch [Fully pregelatinized starch 78-1551) 5
7 Sodium Starch Glycolate (Primogel) 10
8 Colloidal Silicon Dioxide 3
9 Magnesium Stearate 3
10 Purified water
Tablet weight 420
PART B: 1 tablet Nevirapine 200 mg tablets Same as in Example 1 Dissolution Profile
Table 3

Dissolution Stavudine (Emduo) Lamivudine (Emduo)
5 min 22.44 22.61
10 min 40.74 41.2
20 min 64.83 65.82
30 min 80.16 81.67
45 min 88.01 90.19
60 min 97.14 97.34

Table 4

Dissolution Nevirapine (Nevir)
5 min 84.16
10 min 98.32
20 min 100.15
30 min 102.09
45 min 100.32
60 min 100.55
Example 3 PART A: 2 tablets of Stavudine 30/40 mg & Lamivudine 150 mg tablets

S.No. Ingredients Qty/tab [mg]
1 Lamivudine 150
2 Stavudine 40
3 Maize Starch 90
4 Avicel pH lOl 94
5 Crosscarmellose Sodium 20
6 Sodium Lauryl Sulphate 10
7 Crosscarmellose Sodium 10
8 Colloidal Silicon Dioxide 3
9 Magnesium Stearate 2
10 Purified water qs
Tablet weight 419
PART B: 1 tablet Nevirapine 200 mg tablets Same as in Example 1 Dissolution Profile

Table 5

Table 6

Dissolution Stavudine Lamivudine
5 min 41.46 41.66
lO min 74.95 75.43
20 min 91.63 92.47
30 min 88.96 90
45 min 91.27 92.15
60 min 90.02 92.93

Dissolution Nevirapine (Nevir)
5 min 70.59
10 min 75.99
20 min 80.43
30 min 86.39
45 min 87.82
60 min 91.58
Example 4
PART A: 2 tablets of Stavudine 30/40 mg & Lamivudine 150 mg tablets

S.No. Ingredients Qty/tab [mg]
1 Lamivudine 150
2 Stavudine 40
3 Maize Starch 85
4 Avicel pH lOl 94
5 Crosscarmellose Sodium 20
6 Sodium Lauryl Sulphate 10
7 Crosscarmellose Sodium 10
8 Maize Starch 5
9 Colloidal Silicon Dioxide 3
10 Magnesium Stearate 3
11 Purified water qs
Tablet weight 420

PART B: 1 tablet Nevirapine 200 mg tablets Same as in Example 1 Dissolution Profile
Table 7

Dissolution Stavudine Lamivudine
5 min 38.15 37.24
lO min 68.6 67.81
20 min 88.21 88.28
30 min 89.91 90.11
45 min 90.16 90.7
60 min 89.19 90.04
Table 8

Dissolution Nevirapine [nevir]
5 min 70.59
10 min 75.99
20 min 80.43
30 min 86.39
45 min 87.82
60 min 91.58

Example 5
PART A: 2 tablets of Stavudine 30/40 mg & Lamivudine 150 mg tablets

S.No. Ingredients Qty/tab [mg]
1 Lamivudine 150
2 Stavudine 40
3 Maize Starch 85
4 Avicel pH lOl 94
5 Crosscarmellose Sodium 20
6 Sodium Lauryl Sulphate 10
7 Crosscarmellose Sodium 10
8 Pregelatinized Starch (Starch 1500) 5
9 Colloidal Silicon Dioxide 3
10 Magnesium Stearate 3
11 Purified water qs
Tablet weight 420
PART B: 1 tablet Nevirapine 200 mg tablets Same as in Example 1 Dissolution Profile
Table 9

Dissolution Stavudine Lamivudine
5 min 42.74 42.45
10 min 69.04 69.38
20 min 83.2 83.75
30 min 86.08 86.85
45 min 87.22 88.21
60 min 87.86 89.26

Table 10

Dissolution Nevirapine (Nevir)
5 min 50.32
10 min 54.56
20 min 62.34
30 min 68.74
45 min 75.83
60 min 82.90
Example 6
PART A: 2 tablets of Stavudine 30/40 mg & Lamivudine 150 mg tablets

S.No. Ingredients Qty/tab [mg]
1 Lamivudine 150
2 Stavudine 40
3 Maize Starch 85
4 Avicel pH lOl 94
5 Sodium Lauryl Sulphate 10
6 Maize Starch 5
7 Sodium Starch Glycolate (Primogel) 30
8 Colloidal Silicon Dioxide 3
9 Magnesium Stearate 3
10 Purified water qs
Tablet weight 420
PART B: 1 tablet Nevirapine 200 mg tablets Same as in Example 1 Dissolution Profile

Table 11
Diss olution Stavudine Lamivudine
5 min 33.49 35.93
10 min 56.56 61.65
20 min 78.42 86.48
30 min 82.56 91.25
45 min 83.78 92.83
60 min 83.53 92.9
Table 12

Dissolution Nevirapine (Nevir)
5 min 50.32
10 min 54.56
20 min 62.34
30 min 68.74
45 min 75.83
60 min 82.90
Example 7
PART A: 2 tablets of Stavudine 30/40 mg & Lamivudine 150 mg tablets

S.No. Ingredients Qty/tab [mg]
1 Lamivudine 150
2 Stavudine 40
3 Maize Starch 96.5
4 Avicel pH 101 96.5
5 Crosscarmellose Sodium 3
6 Sodium Lauryl Sulphate 12
7 Crospovidone [Polyplasdone XL 10] 3
8 Crospovidone [Polyplasdone XL 10] 7
9 Crosscarmellose Sodium 7
10 Colloidal Silicon Dioxide 3
11 Magnesium Stearate 2
12 Purified water qs
Tablet weight 420

PART B: 1 tablet Nevirapine 200 mg tablets Same as in Example 1 Dissolution Profile
Table 13

Dissolution Stavudine Lamivudine
5 min 41.19 41.38
lOmin 72.79 73.33
20 min 96.04 97.01
30 min 99.43 100.68
45 min 101.94 103.48
60 min 102.23 104.23
Table 14

Dissolution Nevirapine
5 min 82.65
10 min 97.96
20 min 99.94
30 min 101.05
45 min 101.03
60 min 102.12

Example 8
PART A: 2 tablets of Stavudine 30/40 mg & Lamivudine 150 mg tablets

S.No. Ingredients Qty/tab [mg]
1 2 3 4 5 6 7 8 9 10 Lamivudine Stavudine Maize Starch Avicel pH 101 Crosscarmellose Sodium Sodium Lauryl Sulphate Crosscarmellose Sodium Colloidal Silicon Dioxide Magnesium Stearate Purified water 150 40 86.5 90.5 20 12 15 3 3 qs
Tablet weight 420
PART B: 1 tablet Nevirapine 200 mg tablets Same as in Example 1 Dissolution Profile
Table 15

Dissolution Stavudine Lamivudine
5 min 76.78 80.98
10 min 93.68 99.29
20 min 95.8 101.85
30 min 95.49 101.86
45 min 95.44 102.49
60 min 96.33 103.68

Table 16

Dissolution Nevirapine
5 min 59.39
10 min 80.22
20 min 89.48
30 min 94.97
45 min 98.75
60 min 99.23
Example 9
PART A: 2 tablets of Stavudine 30/40 mg & Lamivudine 150 mg tablets

.No. Ingredients Qty/tab [mg]
Lamivudine IP 150.00
Stavudine IP 30.00
Maize Starch IP 96.000
Microcrystalline cellulose IP 90.50
Sodium Lauryl Sulphate IP 12.000
Croscarmellose Sodium USPNF 20.000
Colour Lake of Quinoline Yellow 0.500
Purified Water IP qs
Croscarmellose Sodium USPNF 15.000
Colloidal Silicon Dioxide IP 3.00
Magnesium Stearate IP 3.00
Tablet weight 420
PART B: 1 tablet Nevirapine 200 mg tablets Same as in Example 1

Comparative profile of Epivir (marketed composition of lamivudine individually) and Zerit (marketed composition stavudine individually) with lamivudine and stavudine as in the combination of this invention showing an equivalent and desired dissolution for an immediate release. (Figure 1)
Table 17

Time Zerit Epivir Emduo Emduo
Minutes Stavudine Lamivudine Stavudine Lamivudine
0 0 0 0 0
5 57.93 79.83 76.68 80.98
10 83.21 88.86 93.68 99.29
20 89.22 91.85 95.8 101.85
30 92.16 94.87 95.49 101.86
45 93.56 95.12 95.44 102.49
60 94.68 96.97 96.33 103.68
Table 18

Time Nevir Viramune
Minutes Nevirapine Nevirapine
0 0 0
5 59.39 68.4
10 80.22 84.9
20 89.48 89.5
30 94.97 90.2
45 98.75 91.2
60 99.23 92.8
The kit in accordance with this invention is presented in a blister strip, so having seven set of tablets of part A and B that it fulfils the weekly dose.

We Claim:
1. A composition of antiretrovirals kit comprising one tablet of a synergistic fixed dose
composition of Part A consisting of two tablet of stavudine and lamivudine in combination, and
Part B being one tablet of Nevirapine.
2. A blister packaging, for the composition of claim 1, wherein the tablets are present in the form of a kit in a co-blister strip, as two tablets of stavudine and lamivudine in combination as Part A and one tablet of Nevirapine in Part B sufficient for a daily dose.
3. A blister packaging, wherein the tablets are present in the form of seven sets as in claim 2, in a blister strip, sufficient for a weekly dose.
4. A blister packaging as claimed in claim 3, wherein the fixed dose tablet composition in part A contains 150 mg of lamivudine and 30/40 mg of stavudine 200 mg of Nevirapine in Part B.
5. A blister packaging as claimed in any one of claims 1 to 4, in which the tablets in addition to the active ingredients in Part A abd B in addition contain disintegrant, binder, wetting agent, diluent, glidant, lubricants, fluidizers, colorants, surfactants, coating agents and antiadherent.
6. A blister packaging having tablet composition in Part A and B substantially as herein described and illustrated with reference to the examples, graphs and figures.
Dated this 7th day of October 2005.
Mohan Dewan of R K Dewan & Co, Applicants' Patent Attorney