FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATIION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
“COMBINATION THERAPY FOR TREATMENT OF AIDS”
2. APPLICANT (S)
(a) NAME : EMCURE PHARMACEUTICALS LTD.
(b) NATIONALITY : India
(c) ADDRESS : R&D Centre T-184, MIDC, Bhosari, Pune - 411 046,
Maharashtra, India,

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FIELD OF THE INVENTION
The invention relates to a pharmaceutical composition of reverse transcriptase inhibitors comprising of lamivudine, stavudine and nevirapine for treating viral infections, especially human immunodeficiency virus (HIV) infections.
BACKGROUND OF THE INVENTION
Human immunodeficiency virus (HIV), a retrovirus, is the etiological agent of a complex disease that leads to progressive destruction of the immune system (acquired immune deficiency syndrome or AIDS) and degeneration of the central and peripheral nervous system.
A common feature of retrovirus replication is the extensive post-translation processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and functions. Inhibition of this processing prevents the production of the normally infectious virus. The genetic inactivation of the HIV encoded protease results in the production of immature, non-infectious virus particles. Inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV [(Nature 313, 277 (1985); Science, 231,1567 (1986)].
One substantial and persistent problem in treatment of AIDS has been the ability of the HIV virus to develop resistance to the individual therapeutic agents employed to treat the disease. Thus a need remains for an efficacious and long lasting therapy for AIDS, which lowers HIV viral levels of patients to undetectable levels and raises CD4 cell counts for prolonged periods of time without the development of resistance.
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Many antiretroviral drugs are known in the literature and re commercially available. These can be classified under three broad categories
1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
2) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
3) Protease Inhibitors (Pis)
Some of these drugs are zidovudine, lamivudine, stavudine and abacavir (NRTIs), nevirapine (NNRTIs) and indinavir, ritonavir, saquinavir (Pis).
Out of these, lamivudine (also known as 3TC) is chemically known as (2R-cis)-4-amino-l-[2- (hydroxymethyl)-l, 3-oxatholan-5-yl]-2-(lH)-pyrimidone. This drug has proven anti viral activity against human immunodeficiency virus (HIV) and other viruses such as hepatitis B. Its utilization against HIV has been described in WO 91/17159 and EP 0382526. Pharmaceutical combination of lamivudine with other reverse transcriptase inhibitors, in particular zidovudine is described in WO 92/20344, WO 98/18477 and WO 99/55372. Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite (L-TP). The principal mode of action of L-TP is inhibition of HIV reverse transcription via viral DNA chain termination. L-TP also inhibits the RNA-and DNA-dependent DNA polymerase activities of reverse transcriptase (RI).
Lamivudine oral absorption is rapid, with a mean absolute bioavailability of 82-87%. Food has no significant effect on systemic exposure to Lamivudine. Plasma protein binding is <36%. Intracellularly, Lamivudine is phosphorylated to its active 5'- triphosphate metabolite (L-TP), which has an intracellular half-life of 10.5 — 15.5 hours. Hepatic metabolism is a minor route of elimination for Lamivudine; most of an oral dose of Lamivudine (70-71%) is excreted unchanged in the urine. The only known metabolite of lamivudine in humans is the trans-
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sulfoxide metabolite, which accounts for less than 5% of a dose appearing in the urine. The mean elimination half-life after a single dose of lamivudine ranges 5-7 hours.
Stavudine, chemically known as (3'deoxythymidin-2'-ene-(3'deoxy-2', 3'-didehydrothymidine) is a synthetic anti-retro viral drug exhibiting activity against HIV virus. The activity of stavudine is inhibited when used in combination with zidovudine, since zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Further the combination of stavudine and didanosine develop a fatal condition of pancreatitis, therefore this combination should be used with caution in pregnant women.
Stavudine, a nucleoside analogue of thymidine, inhibits the replication of HIV. It is phosphorylated by cellular kinases to the active metabolite Stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV reverse transcriptase by two mechanisms: firstly by competing with the natural substrate deoxythymidine triphosphate and secondly by its incorporation into viral DNA causing a termination of DNA chain elongation because Stavudine lacks the essential 3'-OH group. Stavudine triphosphate inhibits cellular DNA polymerase beta and gamma, and markedly reduces the synthesis of mitochondrial DNA.
Stavudine is rapidly absorbed with an oral bioavailability of 77 to 86%. It may be taken with food or on an empty stomach. It reaches a Cmax of approximately 1.4 μ g/ml (6.2 μ moles/1) after a single oral dose of 70mg after 0.5 - 1.5 hrs. Approximately 40% of the drug is excreted unchanged in the urine in 6 - 24 hours. Protein binding of stavudine is negligible. It is phosphorylated intracellularly to stavudine triphosphate, the active substance for HIV-reverse transcriptase inhibition. In case of normal renal function, the half-life of the drug in adults ranges from 1-1.6 hours. In subjects with impaired renal function
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(Creatinine Clearance <25mL/min [<0.42 ml/sec]) the half-life is approximately 4.8 hours. Approximately 50% of the administered dose undergoes non-renal elimination. Although the exact metabolic fate is unknown, Stavudine may be cleaved to thymine, and the subsequent degradation and/or utilization of thymine may account for the unrecovered Stavudine.
Nevirapine chemically known as ll-cyclopropyl-5,ll-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e][l,4] diazepin-6-one is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1, exhibiting its therapeutic action by binding directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependant DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine, unlike stavudine does not compete with template or nucleoside triphosphates.
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site.
Nevirapine is readily absorbed after oral administration. Bioavailability is greater than 90%. It reaches a Cmax of 2 \i g/ml after 4 hours following a single 200mg dose. Nevirapine may be administered with or without food. The volume of distribution of Nevirapine is 1.2 1/kg. It is highly lipophillic and widely distributed. The drug readily crosses the placenta and is excreted in breast milk. It is approximately 60% protein bound. Metabolism of Nevirapine to hydroxylated metabolites occurs primarily via the cytochrome P450 (CYP) 3A family of hepatic enzymes. Its half-life is approximately 45 hours after single dose, and 25 to 30 hours following multiple dosing with 200 to 400 mg per day. About 91% the drug is eliminated in urine, with > 80% of that made up of
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glucuronide conjugates of hydroxylated metabolites. Less than 5% of the recovered dose consists of the parent drug.
Currently, these drugs are administered as a combination, wherein one is administered after the other. One of the problems with such a therapy is that if one of the drugs is not available or is not taken by the patient, there is an increased chance of resistance being developed by the HIV. As has been discussed earlier, antivirals cannot be combined abruptly. This is because as combination, they tend to counteract with each other resulting in loss of the beneficial effects of the combination therapy.
Hence, to maximize the benefits of antiretroviral therapy it would be ideal to have a rational combination of these drugs.
However, yet a combination of these drugs for the preparation of a dispersible tablet formulation has not been possible. Hence, a need is felt for a formulation, which is not just effective in curing the disease with a recommended three-drug regimen, but also ameliorates the drawbacks associated with the marketed and available preparations.
OBJECT OF THE INVENTION
The object of the invention is to provide a combination therapy of three anti-retrovirals: stavudine, lamivudine and nevirapine in the desirable dosage form.
Another object of the invention is to provide a dispersible tablet of three antiretrovirals: stavudine, lamivudine and nevirapine.
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Further, object of the invention is to provide a fixed dose composition of stavudine, lamivudine and nevirapine in the form of a dispersible tablet.
Still further object of the invention is to provide a dispersible tablet of three antiretrovirals: stavudine, lamivudine and nevirapine for pediatric usage.
Yet another object of the invention is to provide a dispersible tablet of three antiretrovirals: stavudine, lamivudine and nevirapine for geriatric usage.
Also, the object of the invention is to provide a process for the preparation of a fixed dose composition of stavudine, lamivudine and nevirapine.
In particular, the object of the invention is to provide a fixed dose tablet composition of three antiretrovirals that can be administered to children, adults or elderly people with equal ease.
DESCRIPTION OF THE INVENTION
Accordingly, to obviate the problem of the prior art, the inventors have developed a novel dispersible tablet formulation. The product of the instant invention is an easily administrable dispersible tablet formulation for the treatment of AIDS having pediatric, geriatric and adult usage.
The present invention provides a dispersible tablet, which is a combination of one Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) i.e. nevirapine and/or its pharmaceutically acceptable derivatives, salts, hydrates, solvates thereof, and two Nucleoside Reverse Transcriptase Inhibitors (NRTIs), lamivudine, and stavudine and their pharmaceutically acceptable derivatives, salts, hydrates, solvates thereof.
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The dispersable tablet of the invention comprises approximately 60-80 mg (preferably 70 mg) of nevirapine, 30-50 mg (preferably 40 mg) of lamivudine and 5-15 mg (preferably 10 mg) of stavudine. The said drugs stavudine, lamivudine and nevirapine may be taken in any other appropriate amount as well while maintaining their ratio as 1:4:7.
This pharmaceutical combination therapy as provided by the present invention provides enhanced effectiveness in treating AIDS and substantially precludes the development of resistance to the individual therapeutic agents employed. In fact, the ingredients when combined do not counteract with each and instead provide enhanced beneficial effects to the patient.
The pharmaceutical composition as per the present invention is in the form of a dispersible tablet of the above three active ingredients along with pharmaceutically acceptable excipients. The formulation according to the present invention is directed towards oral administration for pediatric use, since there are many formulations, which are administered in solid dosage form.
The triple combination as compared to other formulations has the following
advantages:
i) low dosage of each pharmaceutical ingredient, ensuring minimal side
effects of the drug,
ii) each ingredient taking care of the therapeutic deficiency of the other
pharmaceutical ingredient,
iii) slowing disease progression and improving survival,
iv) a greater and more sustained virologic and immunologic response,
v) delay in development of virus mutations that confer resistance to the
drugs being used,
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vi) preservation of immune function and delay in disease progression and
vii) They can be easily administered to elderly patients, preferably to those who are at a greater risk of oesophageal injury.
viii) They can be administered to patients, who have difficulty in swallowing or those who are bed ridden.
ix) They are easily administrable to patients who have discomfort and are feeling nauseatic.
x) After swallowing, conventional solid tablets or capsules are transported to the stomach where they dissolve gradually. The passage takes variably long in different people, depending on anatomical and physiological factors. In case of a longer passage time, solid dosage forms can dissolve partially and this can cause irritation of mucous membranes. With a dissolved dispersible tablet, the ingredients are evenly distributed in the solution, so that high, localized concentrations cannot occur.
xi) Dispersible tablets being foil-packed can easily be carried in pocket or bag.
xii) As against syrups and suspensions, dispersible tablets are easier to distribute and store, less costly to produce, and are easier to handle and to keep track of the number of days given.
xiii) Dispersible tablets offer a large dosage of active ingredient incorporated in an easy to swallow liquid.
xiv) They offer an increased absorption rate of the active ingredients.
xv) Dispersible tablets, offer the advantages of suspensions without the problems of instability, measurement inaccuracy, difficulty in swallowing, or size limitation.
xvi) Dispersible tablets are possibly dissolved in a glass of water, soda, or fruit juice - and after a short period of time a palatable solution is ready for drinking. This is a great advantage over having to dissolve granules or powders. Granules and instant powders must be measured first and then stirred in the glass several times to obtain a uniform solution. With
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dispersible tablets, the dose is standardized and the liquid quantity is
variable allowing for the taste to be adjusted according to individual
preference,
xvii) From a marketing point of view, tablets can be set apart from syrups and
uniquely positioned as a treatment,
xviii) As against liquid dosage forms, dispersible dosage forms are a unit dose
form and they offer the greatest capabilities of all oral dosage forms for
the greatest dose precision and the least content variability,
xix) Further, they are better suited to large-scale production than any other
oral dosage forms,
xx) Product identification is potentially the simplest and cheapest requiring
no additional processing steps when employing an embossed or
monogrammed punch face,
xxi) Tablets in general have the best-combined properties of chemical,
mechanical and microbiologic stability of all oral dosage forms.
It is usually not easy to combine the drugs that are administered singly since they could be counteractions between the drugs or the efficacy as a combination may be far less than expected. When lamivudine, stavudine and nevirapine were combined surprisingly, the ingredients do not counteract with each other and instead provide enhanced beneficial and therapeutic effects to the patient. Further, the composition prepared is synergistic in that the ingredients potentiate the activity of one another and eventually provide beneficial therapeutic effects to the patient.
The present invention, in particular, provides the pharmaceutical composition with fixed dose combination of NRTIs viz. stavudine and lamivudine, and NNRTIs viz. nevirapine with suitable excipients.
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Excipients employed in pharmaceutical compositions of the present invention can be solids, semi-solids, liquids or combinations thereof. These include surfactant(s), preservative(s), disintegrant(s), lubricant(s), effervescent(s), glidant(s), antiadherent(s), diluent(s) and binder(s). Other than these, colorants, flavors and sweeteners, which are known in the pharmaceutical art, are also be used in pharmaceutical compositions of the present invention.
Suitable diluent(s) illustratively include, but are not limited to, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate. Lactose is the most commonly used carbohydrate in compressed tablets. Spray - dried lactose may be used to improve flowability. Starches, including directly compressible starch, starch 1500 and hydrolysed starches may also be used as filler as per the invention. Sugars such as sucrose, mannitol, sorbitol, xylitol, dextrose and dextrose monohydrate can be employed as diluents. Further, dibasic calcium phosphate dihydrate, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, granular calcium lactate trihydrate, dextrates, inositol, hydrolyzed cereal solids, amylose, celluloses including microcrystalline cellulose, food grade sources of alpha-and amorphous cellulose powdered cellulose, hydroxypropylcellulose (HPC) and hydroxypropyl methylcellulose (HPMC), calcium carbonate, glycine, bentonite, block co-polymers, polyvinylpyrrolidone can also be employed.
The preferable carrier or diluent is selected from the group comprising lactose, mannitol, dibasic sodium phosphate, starch including maize starch, perlitol SP 200, perlitol SD 200, alphacel pH 101 and microcrystalline cellulose (particularly Avicel PH microcrystalline cellulose such as Avicel PH 101), either individually or in combination, are preferred diluents. Lactose, especially lactose monohydrate, is more preferred. Such diluents constitute in total about 20 % to
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about 90 % of the total weight of the composition. The carrier, carriers, diluent, or diluents selected preferably exhibit suitable flow properties and compressibility.
Pharmaceutical compositions of the invention optionally comprise one or more pharmaceutically acceptable binding agents and granulating fluids as excipients, particularly for tablet formulations. Such binding agents and adhesives binders are added to hold a tablet together after it has been compressed. Without binders, tablets would break down into their component powders during packaging, shipping, and routine handling. Many of the binding agents are polymers comprising amide, ester, ether, alcohol or ketone groups and, as such, are preferably included in pharmaceutical compositions of the present invention. Suitable binding agents and adhesives include, but are not limited to, either individually or in combination acacia, tragacanth, sucrose, gelatin, glucose, starches, celluloses, alginic acid and salts of alginic acid; magnesium aluminium silicate, PEG, guar gum, polysaccharide acids, bentonites, polyvinyl pyrrolidones, polymethacrylates, HPMC, hydroxypropylcellulose and ethylcellulose. Polymeric binding agents can have varying molecular weight, degrees of crosslinking, and grades of polymer. Polymeric binding agents can also be copolymers, such as block co-polymers that contain mixtures of ethylene oxide and propylene oxide units. Variation in these units' ratios in a given polymer affects properties and performance. Examples of block co-polymers with varying compositions of block units are Poloxamer 188 and Poloxamer 237. Such binding agents and/or adhesives constitute in total about 1 % to about 20 % of the total weight of the pharmaceutical composition.
Pharmaceutical compositions of the invention optionally comprise one or more pharmaceutically acceptable antifrictional agents (including soluble lubricants, insoluble lubricants, anti-adherents and/or glidants) as excipients. Lubricants are required during manufacture to ensure that the tableting powder (i.e. the raw
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ingredient blend) does not stick to the pressing equipment. Lubricants improve the flow of powder mixes through the presses, and they help finished tablets release from the equipment with a minimum of friction and breakage. Suitable lubricants include, but are not limited to, either individually or in combination, glyceryl triacetate, adipic acid, d,l- leucine, glyceryl triacetate, magnesium lauryl sulfate, PEG 400, 6000 and 8000, polyoxyethylene monostearate, sodium benzoate, sodium lauryl sulfate, sucrose monolaurate, stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate, polytetrafluoroethylene, paraffins, colloidal silica (cab-o-sil), talc, waxes, magnesium trisilicate, magnesium carbonate, calcium silicate. Such lubricants constitute in total about 0.1 % to about 10% of the total weight of the pharmaceutical composition.
Pharmaceutical compositions of the invention optionally comprise one or more pharmaceutically acceptable effervescent agent. The same may be by way of example and without limitation an effervescent couple including acid and carbonate base wherein the acid is selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, acid citrates, succinic acid and mixtures thereof and the carbonate base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium carbonate, sodium glycocarbonate, carboxylysine and mixtures thereof. Preferred effervescent agent as used in the instant invention is sodium bicarbonate. Such agent(s) constitute in total about 0.50 % to 50 % of the total weight of the composition.
Glidant is used in tablet and capsule formulations to promote flowability of the granulation. Such compounds include, by way of example and without limitation, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon dioxide (cab-o-sil), silicon hydrogel and other materials known
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to one of ordinary skill in the art. Such glidant(s) constitute in total about 0.1 % to 2% of the total weight of the composition.
Antiadherents are agents, which prevent the sticking of tablet formulation ingredients to punches and dies in a tableting machine during production. Such compounds include, by way of example and without limitation, magnesium stearate, talc, calcium stearate, PEG, hydrogenated vegetable oil, mineral oil, stearic acid and other materials known to one of ordinary skill in the art. Such antiadherent(s) constitute in total about 0.1 % to 1% of the total weight of the composition
Surfactants are amphiphilic molecules, which have an ability to modify the interface between various phases. Common surfactants known in the art and which can be used as per the invention include, soaps, sulfates, sulfonates, sodium stearate, sodium lauryl sulfate, cetyltrimethylammonium bromide, lecithin, N-dodecyl-N,N- dimethylglycine, N-Alkyl polyoxyethylene, polyoxyl 40 stearate, sorbitan esters of fatty acid, polyoxyethylene hydrogenated castor oil, polysorbate, glyceryl monostearate, and sodium monododecyl sulfate. Such surfactants constitute in total about 0.5% to 2% of the total weight of the composition.
Disintegrant is a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles, which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre-gelatinized and modified starches thereof, croscarmellose sodium, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g., Avicel), carboxymethylcellulose calcium, cellulose polyacrilin potassium (e.g., Amberlite), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth;
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crospovidone and other materials known to one of ordinary skill in the art. Such disintegrant constitute in total about 2 % to 8 % of the total weight of the composition.
Preservatives commonly used in the preparation of pharmaceutical composition include chlorocresol, chlorobutanol, benzoates, phenylmercuric nitrate, sodium benzoate, sorbic acid, the methyl and propyl esters of p-hydroxybenzoic acid (parabens). Addition of preservatives ensures physical and chemical integrity of the system and defence against microbial growth. Such preservatives constitute in total about 0.01 % to 0.2 % of the total weight of the composition.
Flavours or sweetening agents are often used in pharmaceutical compositions. Depending on the type of flavour or sweetener used, they comprise only a small percentage of the overall formulation. A flavouring component is a "functional" excipient so it is important to ensure that it is distributed as evenly as possible in the final blend to yield a product with uniform organoleptic attributes. Suitable flavorings include, for example, liquid and powdered, water soluble natural, Mixed Fruit, Tulsi Vanila Special and nature-identical flavorings. Particularly preferred are liquid flavorings, particularly raspberry, strawberry and honey. Suitable flavouring agent constitute in 0.5% to 4% of the total weight of the composition. Suitable sweeteners include, for example, saccharin sodium, sucrose, mannitol, aspartame, sodium-saccharin, cyclamate, acesulfame potassium and taumatin. Such sweeteners constitute in total about 1% to 40% of the total weight of the composition.
The process for preparation of Emtri dispersible is described as under.
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Procedure A
Step I. Sifting
Sieve all dry mix ingredients including nevirapine, stavudine, diluent,
disintegrant and surfactant through sieve of appropriate mesh size such as
24#, 30#, # 40 or 60#.
Step II. Preparation of a blend
A blend of all the sifted excipients along with active ingredient(s) is
prepared.
Step III. Wet Granulation
Blended mass was wet granulated with suitable solvent such as purified
water taken alone or in combination with ingredients selected from group
comprising of sodium saccharin, sucrose, methyl paraben and/ or propyl
paraben. Step IV. Drying
Step (III) wet mass is dried at temperature at about 50-70°C.
Step V. Sizing
Step (IV) Dried granules are passed through a mesh of an appropriate size
for example # No. 20 - # No. 30. Step VI. Lubrication
Step (V) granules are lubricated with # No. 40 passed stavudine,
disintegrant, preservative, sweetener, flavour and lubricants. Step VII. Compression
Step (VI) lubricated granules are compressed into tablets.
Using the procedure disclosed herein, dispersible tablets of various strengths could be prepared, particularly by making slight variations in the general ratio of 10: 40: 70, as discussed above. Hence, any embodiments that may be apparent to a person skilled in the art are deemed to fall within the scope of the present invention.
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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.
Example 1
Table -1

S.No. Ingredient Qty./tablet (mg)
1 Nevirapine 70
2. Lamivudine 40
3 Stavudine 10
4 Avicel pH 101 150.135
5 Mannitol 15
6 Maize Starch 100
7 Sodium Starch Glycollate 30
8 Sodium saccharin 2.5
9 Croscarmellose sodium 10
10 Colloidal Silicon Dioxide 2
11 Sodium Bicarbonate 40
12 Flavour 10
13 Colloidal silicon dioxide 5
14 Croscarmellose sodium 10
15 Magnesium stearate 3
Total 500
Procedure for formulation: As per procedure A
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Example 2
Table - 2

S. No. Ingredient Qty./ tablet (mg)
1 Nevirapine 70
2. Lamivudine 40
3 Stavudine 10
4 Alphacel (101) 147.135
5 Crosscarmellose Sodium 30
6 Maize Starch 120
7 Sodium Bicarbonate 60
8 Colloidal silicon dioxide 5
9 Flavour 10
10 Magnesium stearate 3
11 Sodium Saccharin 2.5
Total 500
Procedure for formulation: Tablets are formulated as per procedure A.
Example 3
Table - 3
S. No. Ingredient Qty./tablet (mg)
1 Nevirapine 70
2. Lamivudine 40
3 Stavudine 10
4 Maize starch 61
5 Alphacel pH 101 139.135
6 DCP (dihydrate) 162
7 Sodium Starch Glycollate 35

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8 Sodium saccharin 2.5
9 Colloidal Silicon Dioxide 5
10 Flavour 10
11 Sodium Bicarbonate 10
12 Magnesium stearate 3
Total 550
Procedure for formulation: As per procedure A.
Example 4
Table - 4

S.No. Ingredient Qty. / tablet (mg)
1 Nevirapine 70
2. Lamivudine 40
3 Stavudine 10
4 Maize Starch 48
5 Avicel pH 101 141.5
6 DCP (dihydrate) 162
7 Sodium Starch Glycollate (Primogel) 35
8 Cab- o -sil 5
9 Mixed fruit flavour 10
10 Sodium bicarbonate 10
11 Aspartame 10
12 Talc 2
13 SLS 4
14 Methyl Paraben 2
15 Propyl paraben 0.5
Total 550
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Procedure for formulation: As per procedure A.
Example 5
Table - 5

S.No. Ingredient Qty./tablet (mg)
1 Nevirapine 70
2. Lamivudine 40
3 Stavudine 10
4 Maize starch 51
5 Alphacel pH 101 114.135
6 DCP 157
7 Sodium Starch Glycollate 35
8 Colloidal Silicon Dioxide 5
9 Flavour 10
10 Magnesium stearate 3
11 Sodium saccharin 2.5
Total 500
Procedure for formulation: As per procedure A
The following example have been provided to show that pharmaceutical composition prepared by a different process as used in the preferred embodiments will not achieve the desired profile, thus emphasizing the technique used in developing the dispersible tablet formulation, is very critical and is in accordance with this invention.
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Example 6
Table - 6

S.No. Ingredient Qty. / tablet (mg)
1 Nevirapine 70
2. Lamivudine 40
3 Stavudine 10
4 Avicel pH 102 90
5 Sodium bicarbonate 87.135
6 Sodium Starch Glycollate (Primogel) 35
7 Colloidal silicon dioxide 2.5
8 Sucrose 100
9 Magnesium stearate 3
10 Flavour 10
Total 450
Procedure for formulation:
Step I. Sifting
Sieve nevirapine, lamivudine and stavudine through sieve of appropriate mesh size such as # 40, 30#, 60# sieve. Sift all other excipients except lubricant appropriately through # 40 sieve, #60 and 80 #. Sift sweetener through sieve such as # 30, 24#, 40# sieve.
Step II. Preparation of a blend
A blend of all the sifted excipients except lubricant is prepared
Step III. Mixing of magnesium stearate
Blended mass was mixed with lubricant Step IV. Compression
Step (III) lubricated granules are compressed into tablets.
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Instead of using the steps of the process of the invention, a dry compression was tried out without resorting to granulation. Tablets so formed were not dispersible in nature. Moreover severe problems of capping and sticking were faced at the time of formulation. Hence, desired effect was not achieved.
This shows that without the precise application of the precise combination and the technique provided and disclosed in the specification, the invention cannot be worked out by one skilled in the art. The invention is therefore, not a mere admixture of known ingredients to obtain a predictable profile.
Example 7

S. No. Ingredient Qty. / tablet (mg)
1 Nevirapine 70
2. Lamivudine 40
3 Stavudine 10
4 Sucrose 100
5 Magnesium stearate 3
6 Sodium Starch Glycollate (Primojel) 25
7 Mixed fruit flavour 10
8 Sodium bicarbonate 87.135
9 Avicel pH 102 90
10 Colloidal Silicon Dioxide 2.5
Total 450
This is a dry mix lot. Tablets so formed were not dispersible in nature. Disintegration time of these tablets was 4 to 5 minutes. This formulation was not found to be pharmaceutically acceptable.
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Example 8

S.No. Ingredient Qty./ tablet (mg)
1 Nevirapine 70
2. Lamivudine 40
3 Stavudine 10
4 Mannitol 119.365
5 Magnesium stearate 3
6 Sodium Starch Glycollate (Primojel) 25
7 Mixed fruit flavour 6
8 Sodium bicarbonate 20
9 Aspartame 2
10 Colloidal Silicon Dioxide 2
Total 300
This is a wet mix lot. Tablets so formed were not dispersible m nature. Disintegration time of these tablets was 4 to 5 minutes. This formulation was not
Found to be pharmaceutically acceptable
Example 9: Preparation of Kit
For preparation of a kit, three separate dispersible tablets ot lamivudine, stavudine and nevirapine were prepared. The said tablets were packed together in a box with separators. A manual of instruction was included instructing the patient to mix the three tablets in liquid before consumption.
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WE CLAIM:
1. A dispersible tablet formulation comprising
(a) therapeutically effective amount of stavudine, pharmaceutical derivatives, salts, hydrates, solvates,
(b) therapeutically effective amount of lamivudine, pharmaceutical derivatives ,salts, hydrates, solvates,
(c) therapeutically effective amount of nevirapine, pharmaceutical derivatives, salts, hydrates, solvates and
(d) suitable excipients.

2. A pharmaceutical dispersible tablet formulation as claimed in claim 1, wherein the ratio of stavudine : Lamivudine : Nevirapine is 10 : 40 : 70 or suitable for the various age groups.
3. A pharmaceutical dispersible tablet formulation as claimed in claim 1 and 2, wherein the quantity of stavudine is equivalent to 10 mg of stavudine.
4. A pharmaceutical dispersible tablet formulation as claimed in claim 1 and 2, wherein the quantity of lamivudine is equivalent to 40 mg of lamivudine.
5. A pharmaceutical dispersible tablet formulation as claimed in claim 1 and 2, wherein the quantity of nevirapine is equivalent to 70 mg of nevirapine.
6. A pharmaceutical composition as claimed in claim 1, wherein the excipients include a diluent selected from the group comprising of lactose, mannitol, dibasic sodium phosphate, starch including maize starch, perlitol SP 200, perlitol SD 200, powdered cellulose and microcrystalline cellulose (particularly Alphacel pH 101, Avicel PH microcrystalline cellulose such as Avicel PH 101), either individually or in combination.
7. A pharmaceutical composition as claimed in claim 6, wherein the quantity of diluent ranges from about 20 % to about 90 %.
8. A pharmaceutical composition as claimed in claim 1, wherein the excipients include a surfactant selected from the group comprising of
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soaps, sulfates, sulfonates, sodium stearate, sodium lauryl sulfate, cetyltrimethylammonium , bromide, lecithin, N-dodecyl-N,N-dimethylglycine, N-Alkyl polyoxyethylene, polyoxyl 40 stearate, sorbitan esters of fatty acid, polyoxyethylene hydrogenated castor oil, polysorbate, glyceryl monostearate, and sodium monododecyl sulfate
9. A pharmaceutical composition as claimed in claim 6, wherein the quantity of surfactant ranges from about 0.5% to about 2%.
10. A pharmaceutical composition as claimed in claim 1, wherein the excipients include a disintegrant selected from amongst the group comprising of starches such as corn starch, potato starch, pre-gelatinized and modified starches thereof, croscarmellose sodium, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. Avicel), carboxymethylcellulose calcium, cellulose polyacrilin potassium (e.g., Amberlite), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth and crospovidone
11. A pharmaceutical composition as claimed in claim 8, wherein the quantity of disintegrant agent ranges from about 2% to about 8%.
12. A pharmaceutical composition as claimed in claim 1, wherein the excipients include a glidant selected from amongst the group comprising of colloidal silica (cab-o-sil), cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel.
13. A pharmaceutical composition as claimed in claim 8, wherein the quantity of glidant agent ranges from about 0.1% to about 2.0%.
14. A pharmaceutical composition as claimed in claim 1, wherein the excipients include a preservative selected from the group comprising of chlorocresol, chlorobutanol, benzoates, phenylmercuric nitrate, sodium benzoate, sorbic acid, the methyl and propyl esters of p-hydroxybenzoic acid (parabens).
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15. A pharmaceutical composition as claimed in claim 10, wherein the quantity of preservative ranges from about 0.01% to about 0.2%.
16. A pharmaceutical composition as claimed in claim 1, wherein the lubricant is selected from the group comprising of glyceryl triacetate, adipic acid, d,l- leucine, glyceryl triacetate, magnesium lauryl sulfate, PEG 400, 6000 and 8000, polyoxyethylene monostearate, sodium benzoate, sodium lauryl sulfate, sucrose monolaurate, stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate, polytetrafluoroethylene, paraffins, colloidal silica (cab-o-sil) , talc, waxes, magnesium trisilicate, magnesium carbonate, calcium silicate.
17. A pharmaceutical composition as claimed in claim 10, wherein the quantity of lubricant ranges from about 0.1% to about 10%.
18. A pharmaceutical composition as claimed in claim 1, wherein the excipients include an effervescent agent selected from the group comprising of effervescent couple including acid and carbonate base wherein the acid is selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, acid citrates, succinic acid and mixtures thereof and the carbonate base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium carbonate, sodium glycocarbonate, carboxylysine and mixtures there of.
19. A pharmaceutical composition as claimed in claim 10, wherein the quantity of effervescent agent ranges from about 0.5% to about 50%.
20. A pharmaceutical composition as claimed in claim 1, wherein the excipients include sweeteners ranging from about 1% to about 40%
21. A pharmaceutical composition as claimed in claim 1, wherein the excipients include flavouring agent ranging from about 0.5% to 4%.
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22. A process for the preparation of dispersible tablet formulation of
stavudine, lamivudine, nevirapine consisting of the process steps of;
(a) sifting all dry mix ingredients through sieve of appropriate mesh size such as 24#, 30#, 40# or 60#,
(b) blending the sifted excipients,
(c) granulating the blended mass with suitable solvent such as purified water alone or in combination with ingredients selected from group comprising of sodium saccharin, sucrose, and methyl paraben and/ or propyl paraben,
(d) drying the granules obtained in (c) at about 50-70°C,
(e) sizing the dried granules to a size between mesh # No. 20 # to No. 30 #,
(f) lubricating the said granules with stavudine, disintegrant, preservative, sweetener, flavour and lubricants.
(g) compressing the sized lubricated granules to form a tablet.

23. A liquid comprising the dispersible composition as claimed in claim 1.
24. A kit for preparation of a composition as claimed in claim 1, comprising:
- 60-80 mg of nevirapine,
- 30-50 mg of lamivudine,
- 5-15 mg of stavudine, and
- a manual of instructions.
25. A composition substantially as herein described and illustrated with examples.
26. A process for the preparation of composition substantially as herein described and illustrated with examples.
Dated this 6th day of January, 2006.

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