FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
EFFERVESCENT ANTIMALARIAL COMPOSITIONS

2. APPLICANT (S):
(a) NAME: AJANTA PHARMA LIMITED.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Ajanta House, Charkop, Kandivali (West),
Mumbai - 400 067.
The following specification particularly describes the invention and the manner in which it is to be performed.

5 SEP 2008

Field of the Invention:
The present invention provides effervescent drug compositions comprising combination of artemether and lumefantrine. The effervescent compositions comprise of effervescent agents and other excipients like surfactants, binders, lubricants, and colouring agents.
The present invention provides effervescent anti-malarial compositions comprising of artemether and lumefantrine.
Background of the Invention:
Artemether and lumefantrine are we]] known as anti-malaria] drugs and a fixed dose anti-malarial combination is commercially available in the form of a tablet containing 20mg artemether and 120mg lumefantrine (20+120mg tablet). It is sold under the name of Coartem® / Riamet® by Novartis.
Malaria is caused by a protozoal parasite called Plasmodium, which is carried by mosquitoes. During a bite from an infected mosquito, the parasite passes into the body. Once inside, it lives and reproduces, resulting in the disease known as malaria. Artemether and lumefantrine both work by interfering with the ability of the malaria parasites to convert haem into haemozoin. This causes levels of the toxic haem to rise, which kills the blood stages of the malaria parasites and stops the infection from continuing.
2

Lumefantrine is a racemic fluorene derivative with the chemical name 2-dibutylamino-l-[2,7-dichloro-9-(4-chlorobenylidene)-9H-fluoren-4-yl]-ethanol and with following chemical structure

It conforms, structurally, to the aryl-amino alcohol group of anti-malarials including quinine, mefloquine and halofantrine.
Artemether is a methyl-ether derivative of dihydroartemisinin derived from artemisinin (Qinghaosu), chemically described as (3R, 5aS, 6R, 8aS, 9R, 10S, 12R, 12aR)- Decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12 H-pyrano[4,3-j]-I,2- benzodioxepin with the following chemical structure

3

Pharmaceuticals intended for oral administration are provided in solid form as tablets, capsules, pills, or granules. Tablets are swallowed whole, chewed in the mouth, or dissolved in the oral cavity. However, patients at the extremes of age, such as children and the elderly, often experience difficulty in swallowing solid oral dosages forms. For these patients the drugs are mostly provided in liquid dosage forms such as solutions, emulsions and suspensions.
The value of effervescent tablets has been recognized for many years as a very effective dosage form that permits the active ingredient(s) to be quickly utilized by the patient's body. Effervescent tablets are often employed in the administration of pharmaceuticals where it is impractical to provide a tablet for swallowing whole, for instance with paediatric patients. This is of particular value where rapid availability of the active ingredients is desired. On the other hand, the need for solid pharmaceutical forms capable of making the medicament available within a short time from the administration is particularly felt even for those patients who do not have any swallowing problems.
Children, older persons, and many other persons have trouble swallowing whole tablets and even capsules. Therefore, in cases where the dosage to be administered cannot be made into a very small tablet or capsule, it is desirable to provide the medicine either in liquid form or in a effervescent solid form, in addition to the tablet or capsule that is designed to be swallowed whole. Even where the medicine ' can be formulated as a liquid, it is desirable also to be able to provide an effervescent tablet because of added convenience versus carrying a supply of
4

liquid medicine. Effervescent tablets are more easily transported than liquid medication because no water is added until it's ready to use. Effervescent tablets have major advantage that the drug product is already in solution at the time it is consumed. Thus, the absorption is faster and more complete. Drugs delivered using effervescent technology have predictable and reproducible pharmacokinetic profiles that are much more consistent than tablets or capsules.
Effervescence is achieved by including an acid, for example, citric acid and/or tartaric acid, and an effervescing alkali, for example sodium bicarbonate, potassium bicarbonate and/or calcium carbonate, in the formula. In the presence of traces of water, these ingredients react, forming bubbles of carbon dioxide and liberating more water that further promotes the reaction. Depending on the nature of the active ingredient(s), which may be either soluble in water or are converted to the sodium salt(s) which are then dissolved, all ingredients of effervescent sub¬lingual tablets are typically dissolved before ingestion. Effervescent tablets dissolve in water resulting in active ingredient already dissolved or dispersed in water is in a highly bio-available form.
Effervescent tablet removes the need of masking agent to overcome the bitter taste of artemether. Carbon dioxide released during effervescence helps to mask the bitter taste without the need to add sweetening agents.
Coartem® is administered to infants and small children in a grossly crushed form of the tablet mixed with water. Dafra Pharma has developed a paediatric
5

formulation of the combination artemether/lumefantrine powder for oral suspension. There are developed tablets (Novartis - The American Society of Tropical Medicine and Hygiene 56th Annual Meeting) of artemether/lumefantrine that are rapidly dispersible in water and have a cherry flavor and are suitable for infants and children.
However there are no reports on effervescent tablets which contain a combination of artemether and lumefantrine for the treatment of malaria.
The present invention relates to compositions of artemether and lumefantrine in the form of effervescent tablet. The present invention relates to pharmaceutical compositions comprising such combination; processes for their preparation; and methods of using such compositions for the treatment of patients suffering from malaria.
Object of the Invention:
The major object of the present invention is to provide pharmaceutical compositions of artemether and lumefantrine in the form of effervescent tablet. This invention provides formulation of artemether and lumefantrine as an effervescent tablet that dissolves in water.
Another object of the present invention is to provide effervescent compositions of artemether and lumefantrine which can deliver a substantial amount of the actives immediately when dissolved in water.
6

Yet another major object of the present invention is to provide a process for the preparation of pharmaceutical compositions comprising artemether and lumefantrine for the treatment of malaria.
Summary of the Invention:
One aspect of the present invention is to provide compositions comprising of artemether and lumefantrine in the form of effervescent tablet capable of dissolving in water.
In above said compositions artemether may be present in a dosage range of 20-80 mg and lumefantrine is present in a dosage range of 120-480 mg. The pharmaceutical compositions of the present invention are formulated as effervescent tablets.
Another aspect of the invention is to provide a process for the preparation of pharmaceutical compositions comprising artemether and lumefantrine in a single dosage unit comprising the steps of
a) granulating lumefantrine with surfactants
b) granulating buffering agents with moisture barrier agents to avoid pre-moisture contact of the actives
c) granulating carbonates avoids pre-moistening
d) Lubricating with artemether/Iubricants/col ours/flavours and final compression of the tablet.
7

Detailed Description of the Invention:
The present invention provides effervescent tablet compositions for a combination of artemether and lumefantrine for the treatment of malaria. The said compositions comprise combination of artemether and lumefantrine. The other excipients used to arrive at the final compositions include surfactants life Polysorbate 80, sodium lauryl sulfate, binders like hypromellose, povidone, buffering agents like citric acid anhydrous, moisture barrier agent like simethicone, lubricants like colloidal silicon dioxide (Aerosil 200), purified talc and flavouring and colouring agents.
According to one embodiment there is provided effervescent pharmaceutical compositions of artemether and lumefantrine comprising artemether in an amount of from 20 mg to 80 mg, lumefantrine in an amount of from 120 mg to 480 mg, and one or more pharmaceutically acceptable excipients.
Suitably a formulation according to the present invention provides an effervescent dosage form, comprising of artemether and lumefantrine along with other pharmaceutically acceptable excipients.
In one embodiment, the effervescent composition of the present invention is capable of being inserted into a liquid. The effervescent composition includes at least one compound and is capable of effervescence in the presence of moisture.
In yet another embodiment, a method for making an effervescent composition comprises the steps of providing a composition comprising at least one compound, the composition capable of effervescence in the presence of moisture, wherein the
8

composition substantially avoids effervescence by the composition until the composition contacts a liquid.
The term "effervescent," as defined herein, means any product capable of forming bubbles in liquid environments and may also be considered any product capable of liberating carbon dioxide in or out of liquid environments. Likewise, "effervescence" means forming bubbles in liquid environments or liberating carbon dioxide in or out of liquid environments.
Examples of acids suitable for use in these illustrative embodiments include, but are not limited to, tartaric acid, citric acid, fumaric acid, adipic acid, malic acid, oxalic acid, or sulfamic acid, either alone or in combination. Typically, the effervescent of these embodiments is prepared from citric acid or a combination of citric acid and tartaric acid. Use of citric acid alone may cause difficulties during the manufacturing process. For example, use of citric acid alone may result in a sticky mixture that is difficult to granulate.
Examples of salts suitable for use in illustrative embodiments include, but are not limited to, the alkali metal salts. Sodium carbonate, calcium carbonate, magnesium carbonate, ammonium carbonate, potassium carbonate, sodium bicarbonate, and calcium bicarbonate may all be employed.
The present invention further comprises a process of preparing a pharmaceutical product, or pharmaceutical compositions, or a medicament substantially as herein before described.
9

Lumefantrine is granulated along with Polysorbate 80 and hypromellose. Second step of granulation includes citric acid, tartaric acid, simethicone and isopropyl alcohol. The third step of granulation includes sodium bicarbonate, sodium carbonate, povidone and isopropyl alcohol. The final step includes lubrication with Artemether, aspartame, sodium lauryl sulphate, colloidal silicon dioxide (Aerosil 200), purified talc, sodium benzoate and addition of orange flour DC 116 PH and sunset yellow lake and final compression of the tablet.
Surfactants are essential components and help to reduce the surface tension of water by adsorbing at the liquid-gas interface. They are compounds that have hydrophobic and hydrophilic portions that act to reduce the surface tension of the aqueous solutions they are dissolved in. Useful surfactants can include anionic, nonionic, amphoteric, and cationic surfactants, and blends thereof. Preferably, the surfactants used are sodium lauryl sulphate/Polysorbate 80.
Binders hold the ingredients together so that they can form a tablet. Povidone also known as polyvinyl pyrrolidone (PVP) is one of the most commonly used pharmaceutical binders.
Lubricants are added to pharmaceutical compositions for ease in processing, to prevent adhesion to the equipment used during processing. Lubricants used in the compositions include lubricants commonly used in solid pharmaceutical compositions. Lubricants used in the compositions include, but are not limited to, calcium stearate, colloidal silicon dioxide (Aerosil 200), glyceryl behenate,
10

magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, sodium lauryl sulfate, or zinc stearate. Preferably, the lubricants are purified talc/ colloidal silicon dioxide (Aerosil 200).
Sweetening agents are used to sweeten pharmaceutical compositions. Sweetening agents used in the compositions include sweetening agents commonly used in solid pharmaceutical compositions. Sweetening agents include, but are not limited to, aspartame, dextrates, dextrose, fructose, mannitol, saccharin, sorbitol, sucralose, sucrose, sugar, or syrup. Preferably, the sweetening agent is aspartame.
Flevoring agents make pharmaceutical compositions more paJatabJe to the patient Flavoring agents commonly used in pharmaceutical compositions include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, tartaric acid, peppermint, artificial or natural fruit flavors. Flavoring agents used in the compositions include, but are not limited to, orange flavour DC 116 PH.
Coloring agents improve the appearance of pharmaceutical compositions and/or facilitate patient identification of the compositions. Coloring agents used in the compositions include coloring agents commonly used in solid pharmaceutical compositions. Coloring agents used in the composition include, but are not limited to, caramel, ferric oxides (red, yellow, or black), or natural or synthetic organic colors and lakes.
11

In one preferred embodiment, the pharmaceutical dosage present in effervescent tablet form comprises combination of artemether and lumefantrine, and about 0.3-0.6% by weight Polysorbate 80, 0.10-0.3 % by weight hypromellose, 10-12 % by weight citric acid, 20-30 % by weight tartaric acid, 0.3-0.6 % by weight simethicone, 30-40 % sodium bicarbonate, 4-8 % by weight sodium carbonate, 1-2 % by weight povidone, 2-4 % by weight aspartame, 0.5-1.5% by weight sodium lauryl sulphate and 0.1-0.6 % by weight colloidal silicon dioxide (Aerosil 200), 0.1-0.3 % by weight purified talc, 0.3-0.7 % by weight sodium benzoate, 1-3 % by weight sunset yellow, 0.1-0.3% by weight orange flavour.
The present invention provides process for the preparation of an effervescent tablet consisting of compositions of artemether and lumefantrine.
The present invention will now be illustrated with reference to the following examples, which does not limit the scope of the invention in any way. Further different strengths of the formulation may be achieved by proportionately using a dose weight scale-up or scale-down formula. The concentration of the excipients may also be varied or modified to achieve the desired dissolution profile by a skilled artisan.
Example 1:
Effervescent tablets of artemether and lumefantrine were prepared using the following excipients in the stated quantities:
12

S.No. Ingredients Quantity per Tablet in mg % w/w
Granulation I
1. Lumefantrine 480 12.37
2. Polysorbate 80 20 0.51
3. Hypromellose (HPMC-5 CP) 10 0.25
4. Purified water q.s —
Granulation II
5. Citric acid (anhy.) 450 11.59
6. Tartaric acid 900 23.19
7. Simethicone 20 0.51
8. Isopropyl Alcohol q.s —
Granulation III
9. Sodium bicarbonate 1400 36.08
10. Sodium carbonate 175 4.51
11. Povidone 50 1.28
12. Isopropyl Alcohol q.s —
Lubrication
13. Artemether 80 2.06
14. Aspartame 90 2.31
15. Sodium Lauryl Sulphate 40 1.03
16. Colloidal silicon dioxide (Aerosil 200) 20 0.51
17. Purified Talc 10 0.25
18. Sodium benzoate 25 0.64
19. Orange flavour DC116 PH 100 0.25
20. Sunset yellow lake 10 2.57
Total weight 3880 mg
Procedure:
Lumefantrine is granulated along with Polysorbate 80 and hypromellose. Second step of granulation includes citric acid, tartaric acid, simethicone and isopropyl alcohol. The third step of granulation includes sodium bicarbonate, sodium carbonate, povidone and isopropyl alcohol. The final step includes lubrication with Artemether, aspartame, sodium lauryl sulphate, aerosil, purified talc, sodium benzoate and addition of orange flour DC 116 PH and sunset yellow lake and final compression of the tablet.
13

Example 2:
Effervescent tablets of artemether and lumefantrine were prepared using the
following excipients in the stated quantities:

S.No. Ingredients Quantity per Tablet in nig %w/w
Granulation I
1. Lumefantrine 240 8.33
2. Polysorbate 80 15 0.52
3. Hypromellose (HPMC-5 CP) 5 0.17
4. Purified water q.s —
Granulation II
5. Citric acid (anhy.) 350 12.15
6. Tartaric acid 800 27.77
7. Simethicone 15 0.52
8. Isopropyl Alcohol q.s —
Granulation III
9. Sodium bicarbonate 1000 34.72
10. Sodium carbonate 155 5.38
11. Povidone 45 1.56
12. Isopropyl Alcohol q.s —
Lubrication
13. Artemether 40 1.38
14. Aspartame 75 2.60
15. Sodium Lauryl Sulphate 28 0.97
16. Colloidal silicon dioxide (Aerosil 200) 9 0.31
17. Purified Talc 7 0.24
18. Sodium benzoate 14 0.48
19. Orange flavour DC116 PH 78 0.13
20. Sunset yellow lake 4 2.70
Total weight 2880 mg
Procedure: Same as mentioned in Example 1.
Example 3:
Effervescent tablets of artemether and lumefantrine were prepared using the following excipients in the stated quantities:
14

S.No. Ingredients Quantity per Tablet in mg %w/w
Granulation I
I. Lumefantrine 120 6.38
2. Polysorbate 80 9 0.47
3. Hypromellose (HPMC-5 CP) 3 0.15
4. Purified water q.s —
Granulation II
5. Citric acid (anhy.) 190 10.10
6. Tartaric acid 550 29.25
7. Simethicone 9 0.47
8. Isopropyl Alcohol q.s —
Granulation III
9. Sodium bicarbonate 700 37.23
10. Sodium carbonate 124 6.59
11. Povidone 24 1.27
12. Isopropyl Alcohol q.s —
Lubrication
13. Artemether 20
14. Aspartame 42 2.23
15. Sodium Lauryl Sulphate 14 0.74
16. Colloidal silicon dioxide (Aerosil 200) 5 0.26
17. Purified Talc 4 0.21
18. Sodium benzoate 10 0.53
19. Orange flavour DC 116 PH 54 0.10
20. Sunset yellow lake 2 2.87
Total weight 1880 mg f
Procedure: Same as mentioned in Example 1.
15

We claim:
1. An oral pharmaceutical effervescent tablet composition comprising: a
therapeutically effective amount of artemether and lumefantrine.
2. The composition according to claim 1, further comprises of effervescent agents, buffering agents, surfactants, along with pharmaceutically acceptable excipients.
3. The composition of claim 2, wherein the pharmaceutically acceptable excipients include moisture barrier agents, binders, flavours, sweeteners, colours and lubricants.
4. The composition according to claim 2, the effervescent agents being sodium carbonate and/or sodium bicarbonate, wherein sodium carbonate is present in an amount of about 4-8% w/w of the total weight of the composition, sodium bicarbonate is present in an amount of about 30-40% w/w of the total weight of the composition.
5. The composition according to claim 2, the buffering agents being citric acid and/or tartaric acid, wherein citric acid is present in an amount of about 10-12 % w/w of the total weight of the composition, tartaric acid is present in an amount of about 20-30% w/w of the total weight of the composition.
6. The composition according to claim 2, the surfactants being Polysorbate 80 and/or sodium lauryl sulphate and/or sodium benzoate, wherein Polysorbate 80 is
16

present in an amount of about 0.3-0.6% w/w of the total weight of the composition, sodium lauryl sulphate is present in an amount of about 0.5-1.5 % w/w of the total weight of the composition and sodium benzoate is present in an amount of about 0.3-0.7 % w/w of the total weight of the composition.
7. The composition according to claim 3, the moisture barrier agent preferably being simethicone in an amount of about 0.3-0.6 % w/w of the total weight of the composition, and the binders preferably being hypromellose, povidone and/or isopropyl alcohol present in an amount of about 0.1-2 % w/w of the total weight of the composition.
8. The composition of claim 3, the lubricants preferably being colloidal silicone dioxide and/or purified talc present in an amount of about 0.1-1.5% w/w of the total weight of the composition, the flavouring agent is present in an amount of about 0.1-0.3% w/w of the total weight of the composition, colouring agent is present in an amount of about 1-3 % w/w of the total weight of the composition and sweetening agent is present on an amount of about 2-4% w/w of the total weight of the composition.
9. A process for making effervescent tablet of artemether and lumefantrine comprising the steps of:

a) granulating lumefantrine with surfactants
b) granulating buffering agents with moisture barrier agents to avoid pre-moisture contact of the actives
17

c) granulating carbonates avoids pre-moistening
d) Lubricating with artemether/lubricants/colours/flavours and final compression of the tablet.
10. The pharmaceutical composition of claim 1, wherein the said composition is used to treat malaria.

(Dr.Eswaran K Iyer) GM- Intellectual Property For Ajanta P liar ma Limited
18