FORM 2 THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
CHEWABLE 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.

Field of the Invention:
The present invention provides chewable immediate release drug compositions comprising combination of artemether and lumefantrine. The chewable compositions comprise of flavouring agent, microcrystalline cellulose as diluent and aspartame/ xylitol/mannitol as sweetening agents. The said compositions further comprise other excipients like disintegrants, binders, lubricants, glidants and colouring agents.
The present invention provides chewable anti-malarial compositions comprising of artemether and lumefantrine!
Background of tbe Invention;
Artemether and lumefantrine are well known as anti-malarial 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 Novarris.
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.
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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
-CI

Jt conforms, structurally, to the aryl-amino alcohol group of anti-malarials including quinine, mefloquine and halofantrine.
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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]-l,2-benzodioxepin with the following chemical structure


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. These dosage forms usually lead to perceptible exposure of the active drug ingredient to the taste buds, which is a very serious problem when the drug has an extremely unpleasant or bitter taste. The bitter taste of the drugs, which are orally administered, is disadvantageous in several aspects. Taste is an important parameter governing the compliance. The disagreeable taste of drugs causes difficulties in swallowing or causes patients to avoid their medication thereby resulting in low compliance of patients.
Chewable 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. In addition, with chewable tablets, the act of chewing helps to break up the tablet particles as the tablet disintegrates and may increase the rate of absorption by the digestive tract. Chewable tablets also help to overcome the bitter or un-agreeable taste of the active agent.
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
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medicine either in liquid form or in a chewable 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 a chewable solid form (i.e. tablets) because of added convenience versus carrying a supply of liquid medicine.
Chewable tablets have the advantage of portability and easy access and often provide a faster delivery system compared to regular tablets. Chewing the product gives rise to the potential for administration of active ingredients via the buccal cavity of the mouth. Generally, active ingredients administered in this way enjoy slower metabolic decomposition by the body. In case of chewable tablets there is a need to mask the bitter taste as they are chewed and remain in contact with the taste receptors in the mouth for a longer period of time. The disagreeable taste of the active ingredient which manifests itself during chewing can be overpowered by adding flavoring ingredients to the tablet so that when it is chewed, the taste of the active ingredient is simply overpowered. Moreover, a bitter or metallic taste of a drug can lead to its rejection by patients (children or elder patients). An challenge fox an oral drag like artemether formulation is 'tis extreme bitter taste. Coartem® is administered to infants and small children in a grossly crushed form of the tablet mixed with water which is hampered by its bitter taste. This situation is not ideal because oral clrugs for small children should be well tolerated and have a good palatability. Dafra Pharma has developed a paediatric formulation of the combination artemether/lumefan trine powder for oral suspension. The current standard of care, crushed tablets of Artemether/ Lumefantrine, taste bitter, are not
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easy to administer and are difficult for children to swallow. 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.
Another approach to mask the intensely bitter taste of artemether is that artemether is entrapped in crosslinked chitosan microparticles (Effect ofchitosan crosslinking on bitterness of artemether using response surface methodology - Punit P Shah, Rajashree C Mashru, Arti R Thakkar, Atul C Badhan Center of Relevance and Excellence in NDDS).
However there are no reports on chewable 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 tablet capable of being chewed in the oral cavity. 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 tablet capable of being chewed or disintegrated in the oral cavity. This invention provides formulation of
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artemether and lumefantrine in chewable form which has improved taste and mouth feel.
Another object of the present invention is to provide chewable compositions of artemether and lumefantrine which can deliver a substantial amount of the bitter actives immediately with improved taste by using sweetening agents.
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 tablet capable of being chewed in the oral cavity.
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 chewable 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
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a) blending artemether and lumefantrine with one or more pharmaceutical
excipients; b) compressing into a tablet
Detailed Description of the Invention:
The present invention provides chewable tablet compositions for a combination of artemether and lumefantrine for the treatment of malaria. The said compositions comprise combination of artemether and lumefantrine. Xylitol / aspartame / mannitol are added as sweetening agents along with microcrystalline cellulose (Avicel PHI02) as diluent. The other excipients used to arrive at the final compositions include disintegrants like croscarmellose sodium, buffering agents like citric acid anhydrous, glidants and lubricants like magnesium stearate, talc and colloidal silicon dioxide (Aerosil 200) and flavouring and colouring agents.
According to one embodiment there is provided chewable 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 a chewable dosage form, comprising of artemether and lumefantrine along with other pharmaceutically acceptable excipients.
A preferred embodiment of the present invention is a chewable tablet formulation comprising pharmaceutically active agents (artemether and lumefantrine) along with suitable excipients.
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The present invention further comprises a process of preparing a pharmaceutical product, or pharmaceutical compositions, or a medicament substantially as herein before described.
Artemether and Lumefantrine are added along with Avicel PH 102 are dry mixed for 10 minutes. This is followed by adding sifted Xylitol, Pearlitol, Citric acid, Aspartame, Primogel, Ac-di-sol followed by dry mixing for 10 minutes. Other excipients like Aerosil 200, Magnesium Stearate, Purified Talc, Orange Flavour DC116 PH, Peppermint Flavour DC 117, Sunset yellow lake and again dry mixed for 10 minutes followed by final compression.
Diluents increase the bulk of solid pharmaceutical compositions, and may make a pharmaceutical dosage form containing the compositions easier for the patient and care giver to handle. Diluents used in the compositions include diluents commonly used in solid pharmaceutical compositions. Diluents include, but are not limited to, calcium carbonate, microcrystalline cellulose, calcium phosphate (dibasic or tribasic), calcium sulfate, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, maltose, mannitol, sorbitol, sucrose, starch, pre-gelatinized starch, or talc.
Disintegrants increase the dissolution rate of solid pharmaceutical compositions in the patient's body. Disintegrants used in the compositions include disintegrants commonly used in solid pharmaceutical compositions. Disintegrants include, but are not limited to, alginic acid, croscarmellose sodium, crospovidone, potassium
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polacrilin, sodium starch glycolate, and starch. Preferably, the disintegrant is at least one of croscarmellose sodium or Aci-di-sol.
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, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, sodium lauryl sulfate, or zinc stearate. Preferably, the lubricants are magnesium stearate/ colloidal silicon dioxide.
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 agents are at least one of aspartame or xylitol or mannitol.
Flavoring agents make pharmaceutical compositions more palatable to the patient. Flavoring agents used in the compositions include flavoring agents commonly used in solid pharmaceutical compositions. Flavoring agents used in the compositions include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid,
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fumaric acid, ethyl maltol, tartaric acid, peppermint, artificial or natural fruit flavors.
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.
Glidants improve the flowability of non-compacted solid compositions and improve the accuracy of dosing. Glidants used in the compositions include glidants commonly used in solid pharmaceutical compositions. Glidants used in the compositions include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, starch, talc, or tribasic calcium phosphate. Preferably, the glidant is purified talc.
In one preferred embodiment, the pharmaceutical dosage present in chewable tablet form comprises combination of artemether and lumefantrine, and about 4-8% by weight microcrystalline cellulose, 6-11 % by weight croscarmellose sodium, 5-10 % by weight xylitol, 10-25 % by weight mannitol, 1-5 % by weight aspartame, 5-9 % sodium starch glycolate, 0.6-2 % by weight colloidal silicon dioxide, 0.6-2.5 % by weight magnesium stearate, 0.5-2 % by weight purified talc, 1-4% by weight flavour and 0.4-1 % by weight colouring agent.
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The compositions are in the form of chewabie tablets and can be prepared by direct compression.
The present invention provides process for the preparation of a chewabie tablet consisting of compositions of artemether and lumefantrine.
One process comprises blending artemether and lumefantrine with one or more pharmaceutically acceptable excipients to obtain a blend followed by directly compressing the blend to obtain tablets.
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:
Chewabie tablets of artemether and lumefantrine were prepared using the following excipients in the stated quantities:

Sr.
No. Ingredients Quantity per Tab in mg
1 Artemether 20.00
2 Lumefantrine 120.00
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3 Microcrystalline Cellulose (Avicel PH102) 38.400
4 Croscarmellose Sodium (Ac-di-sol) 50.00
5 Xylitol (Xylisorb-300) 43.500
6 Mannitol (Pearlitol 200 SD) 120.00
7 Citric acid Anhydrous 0.600
8 Aspartame 15.000
9 Sodium starch Glycolate (Primogel) 43.500
10 Colloidal Silicon Dioxide (Aerosil 200) 5.0
11 Magnesium Stearate 9.000
12 Purified Talc 5.000
13 Capsaroma flavour orange DC116 PH 10.00
14 Capsaroma flavour peppermint DC117 15.00
15 Sunset Yellow Lake 5.00
Total Weight 500.0 mg
Procedure:
Artemether and Lumefantrine are added along with Avicel PH 102 are dry mixed for 10 minutes. This is followed by adding sifted Xylitol, Pearlitol, Citric acid, Aspartame, Primogel, Ac-di-sol followed by dry mixing for 10 minutes. Other
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excipients like Aerosil 200, Magnesium Stearate, Purified Talc, Orange Flavour DC116 PH, Peppermint Flavour DC117, Sunset yellow lake and again dry mixed for 10 minutes followed by final compression.
Example 2:
Chewable tablets of artemether and lumefantrine were prepared using the following excipients in the stated quantities:

Sr. No. Ingredients Quantity per Tab in nig
1 Artemether 40.00
2 Lumefantrine 240.00
3 Microcrystalline Cellulose (AvicelPH102) ' 51
4 Croscarmeltose Sodium (Ac-di-sol) 65
5 Xylitol (Xylisorb-300) 62
6 Mannitol (Pearlitol 200 SD) 133
7 Citric acid Anhydrous 5
8 Aspartame 24
9 Sodium starch Glycolate (Primogel) 62
10 Colloidal Silicon Dioxide (Aerosil 200) 10
11 Magnesium Stearate 12
12 Purified Talc 9
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13 Capsaroma flavour orange DC116 PH 14
J4 Capsaroma flavour peppermint DC117 18
15 Sunset Yellow Lake 5
Total Weight 750.0 mg
Procedure; Same as mentioned in Example 1. Example 3;
Chewable tablets of artemether and lumefantrine were prepared using following excipients in the stated quantities:

Sr.
No. Ingredients Quantity per Tab in mg
1 Artemether 80
2 Lumefantrine 480
3 Microcrystalline Cellulose

(Avicel PH102) 49
4 Croscarmellose Sodium (Ac-di-sol) 62.4
5 Xylitol (Xylisorb-300) 60
6 Mannitol (Pearlitol 200 SD) 130
7 Citric acid Anhydrous 0.6
8 Aspartame 22
9 Sodium starch Glycolate (Primogel) 60
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10 Colloidal Silicon Dioxide (Aerosil 200) 8
11 Magnesium Stearate 10
12 Purified Talc 7
13 Capsaroma flavour orange DC116 PH 12
14 Capsaroma flavour peppermint DCI17 15
15 Sunset Yellow Lake 4
Total Weight 1000.0 mg
Procedure: Same as mentioned in Example 1.
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We claim:
1. An oral pharmaceutical chewable tablet composition comprising: a
therapeutically effective amount of artemether and lumefantrine, diluent and
sweetening agents, along with pharmaceutically acceptable excipients.
2. The composition of claim 1, wherein the pharmaceutically acceptable excipients include glidants, disintegrants, binders, flavours, colours and lubricants.
3. The composition according to claim 1, the sweetening agents being xylitol and/or aspartame and/or mannitol, wherein xylitol is present in an amount of about 5-10% w/w of the total weight of the composition, aspartame is present in an amount of about 1-5% w/w of the total weight of the composition, mannitol is present in an amount of about 10-25 % w/w of the total weight of the composition.
4. The composition according to claim 1, wherein the diluent is present in an amount of about 4-8 % w/w of the total weight of the composition, wherein the diluent preferably being microcrystalline cellulose (Avicel PHI 02).
5. The composition of claim 2, wherein the disintegrant is present in an amount of about 6-11 % w/w of the total weight of the composition, wherein the disintegrant preferably being croscarmellose sodium.
6. The composition of claim 2, wherein the lubricant is present in an amount of about 0.6-3% w/w of the total weight of the composition, wherein the lubricant preferably being colloidal silicon dioxide and/or magnesium stearate.
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7. The composition according to claim 2, wherein the glidant is present in an
amount of about 0.5-2 % w/w of the total weight of the composition, wherein the
glidant preferably being purified talc.
8. The composition according to claim 2, wherein the flavouring agent is present in
an amount of about 1-4% w/w of the total weight of the composition and colouring
agent is present in an amount of about 0.4-1 % w/w of the total weight of the
composition.
9. A process for making chewable tablet of artemether and lumefantrine
comprising the steps of: .
a) blending artemether and lumefantrine with one or more pharmaceutical excipients;
b) compressing into a tablet
wherein the compression is preferably direct compression.
10. The pharmaceutical composition of claim 1. wherein the said composition is
used to treat patients of malaria.


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(Dr.Eswaran K Iyer) GM- Intellectual Property For Ajanta P harm a Limited