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THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)

1. TITLE OF THE INVENTION:
"Novel Anti-Malarial Combination and Methods of Formulation"
2. APPLICANT
(a) NAME : IPCA LABORATORIES LIMITED
(b)NATIONALITY : Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS : 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner
in which it is to be performed

Technical Field of the Invention:
The present invention relates to a novel combination of two compounds having antimalarial activity. Specifically, the present invention relates to the combination of two anti-malarial drugs, artesunate and amodiaquine. More specifically, the invention relates to the pharmaceutical composition of the two drugs and the process of preparation of the composition.
Background and Prior Art:
Malaria, transmitted through the bite of an infected mosquito, Anopheles spp. is responsible for one to three million deaths per year. Almost all of these deaths occur in the tropics, mostly among children. Globally, hundreds of millions of people are made ill by malaria each year, imposing profound social and economic burden on populations where the disease is endemic. Before widespread resistance developed, malaria could be treated cheaply and effectively with chloroquine. However, chloroquine-resistant strains of the parasite are now common throughout much of the world, and resistance to other standard drug regimens is increasing. In South and Central Asia resistance to chloroquine has reached unmanageable levels, and resistance to sulfadoxine-pyrimethamine is fast emerging. Therefore there is an urgent need to develop an effective remedy.
Artemisinin and its derivatives, extracted from a herb used in traditional Chinese medicine, have shown important anti-malarial properties. . To date, resistance to artemisinin and its derivatives has not been reported, unlike other anti-malarial drugs. Artemisinin-based drugs including artesunate have been found to be effective against resistant strains of malaria when prescribed alone, but disease relapse commonly occurs. When artemisinin is combined with another effective anti-malarial drug, a shorter course of treatment is rapidly effective and recurrence of the disease is uncommon. Both artesunate and amodiaquine are widely used anti-malarial agents. One option for slowing the spread of resistance and improving treatment outcomes is the use of artemisinin combination therapy. Eventhough combination of Artesunate with amodiaquine could be novel, no such combination has hitherto been attempted due to the chemical incompatibility of the two drugs which causes mutual
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decomposition and leads to stability problems. Therefore it is the objective of the present invention to prepare a stable combination dosage form of these two antimalarial drugs.
EP0362810 discloses an improved antimalarial composition and methods of treating malaria which employ a combination with on the one hand, one of the antimalarial agents, Artemisinine, Dihydroartemisinine, Arteether, Artemether, Artesunate and on the other hand, the antimalarial agent Quinidine alone or with Mefloquine and/or their pharmaceutical^ acceptable salts.
WO9202217 describes a synergistic antimalarial composition which comprises the antimalarial agent benflumetol and also an antimalarial agent from the artemisinine group such as artemether. The composition can be formulated into solid dosage forms such as tablets and is useful for the treatment of drug resistant malaria.
US5219865 relates to oral or subcutaneous combinations of the malaria therapeutics artemisinine, dihydroartemisinine, arteether, artemether, artesunate or other artemisinine derivatives with one or more of the antimalarials chloroquine, 10-0-methylfloxacrine, quinine, mefloquine, amodiaquine, pyrimethamine, sulfadoxine and primaquine. But the examples do not describe artesunate or amodiaquin in a stable combination specifically.
US Patents 5,446,070 and 6,562,363 disclose topical composition comprising of a therapeutically effective amount of a pharmaceutical agent(s), including artesunate and amodiaquine among others. The compositions make use of active agents, polymers and solvents.
US Patent 5,656,286 describes transdermal drug delivery system, comprising of a single drug or their combinations wherein among anti-malarial drugs artesunate and amodiaquine are mentioned.
WO03075927 discloses pharmaceutical combinations of artesunate and mefloquine which have antimalarial activity. This invention is concerned with the effective amounts of said combinations and their use in the treatment of malaria in a 3-day
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course. The combination of the present invention is administered preferably orally, most preferably as tablets.
While the prior art references as discussed above claim synergistic combination of artemisinine derivatives with amodiaquine, none have described the formulation or the process of manufacturing of the combination of artemisinine derivatives such as artesunate with amodiaquine as pharmaceutical dosage forms. Artesunate and amodiaquine are incompatible, wherein severe degradation of the drugs in presence of each other. This poses a challenge to the formulating pharmacist while presenting the combination of the two drugs in a single dosage form. The objective of formulating a single dosage form is improved patient compliance resulting in decreased possibility of recurrence or developing resistance. The novelty and inventiveness of the present invention is in formulating the two anti-malarial drugs, artesunate and amodiaquin in a stable single dosage form for the treatment of malaria, which has not been successfully achieved before or reported in the prior art.
Objective of the invention:
The objective of the invention is to formulate a stable pharmaceutical composition comprising the combination of artesunate and amodiaquine as a single dosage form. More particularly the objective of the invention to present a combination of the two drugs, artesunate and amodiaquine in the form of a stable solid dosage form. Another objective of the invention is to overcome the chemical incompatibility of the two drugs by formulating a tablet-in-tablet dosage form. The formulation can also be presented as other solid dosage forms such as capsule, pills, granules, sachets and such like, in a mutually protected environment such as coated granules. Yet another objective of the invention is to present a process for the manufacturing of the combination of artesunate and amodiaquine in a single dosage form, which contributes to enhanced therapeutic benefits and patient convenience.
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Summary of the invention:
A novel combination for the preparation of an anti-malarial compound comprising of artesunate and amodiaquine and the process thereof is disclosed. This combined preparation relates to artesunate 25mg with amodiaquine 75mg, artesunate 50mg with amodiaquine 150 mg, artesunate l00mg with amodiaquine 300mg and artesunate 200mg with amodiaquine 600mg and pharmaceutically accepateble excipients.
According to the invention the combination composition of artesunate and amodiaquine is preferably used as a solid formulation, for example, in the form of tablets. It can be used in the form of tablet-in-tablet, pills, granules, capsule or sachets.
Detailed description of the Invention:
The present invention relates to a novel combination of pharmaceutically active antimalarial compounds artesunate and amodiaquine, and to the use of the combined preparation in anti-malarial therapy. Accordingly, this invention is concerned with the pharmaceutical composition of this combination and the process involved in the manufacturing of this product.
In the combination product, the dose range of artesunate in the present invention is 25 mg to 200 mg and that of amodiaquine is 75 mg to 600 mg. A preferred combination product according to the present invention would comprise of artesunate and amodiaquine in admixture with commonly known but carefully screened pharmaceutical excipients belonging to the categories of diluents, binders, flavours, preservatives, pH adjusters, alkalising agents, disintegrating agents, film formers, plasticizers, lubricants and/or glidants.
The above typical pharmaceutical excipients are incorporated into the formulation singularly or in combinations to prepare a combination product that is physically and chemically stable over the studied period. The composition may be provided as a shaped composition such as a tablet, in which case the composition typically includes one or more conventional excipients for tablet formulation such as diluents, selected from the group of microcrystalline cellulose, lactose, maize starch, mannitol,
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pregelatinised starch, dibasic calcium phosphate and the like; disintegrants'selected from maize starch, modified starch, croscarmellose sodium and such; binders selected from cellulose derivatives, maize starch and polyvinyl pyrrolidone. Lubricants are selected preferably from the group containing magnesium stearate, talc and colloidal silicon dioxide; coating ingredients include pharmaceutically acceptable polymers, plasticizers like polyethylene glycol, opacifier like titanium dioxide, glidant like talc, colours, and other miscellaneous auxiliaries required for the processing and stability of the product.
Accordingly, the present invention provides a wet granulation method for formulation of tablet, wherein artesunate, in the particle range of 50 \i or less is separately granulated with an admixture of pharmaceutical^ acceptable excipients and compressed into tablets. Then, this artesunate tablet may be film-coated after which it can be compressed so as to form the core of amodiaquine tablets by tablet-in-tablet technology.
The preferred diluent in the artesunate tablet is mannitol and lactose in the range of 2 - 15% on a dry weight basis. The preferred disintegrant is cross carmellose sodium, used intra-granularly and extra granularly in the range of 0.5 - 7% based on the weight of the formulation. The resultant dry mix is granulated with an alcoholic solution containing hydroxypropyl cellulose, as binder in the range of 0.1 - 0.5%, and the solvent is evaporated from the granulate by drying in a fluid bed dryer at approximately 60°C to achieve a specified moisture content, determined by loss on drying. The dried granulation is reduced with a screening mill. The granules are lubricated by blending with remaining part of sodium starch glycollate, colloidal silicon dioxide as glidant, in the range of 0.05-0.6% on a dry weight basis, based on the weight of the formulation, and magnesium stearate as lubricant in the range of 0.1-0.4% on a dry weight basis, based on the weight of the formulation,. This blend was compressed into tablets, to a desired target on a suitable tablet press. The resultant tablets were suitably film-coated in a coating pan with an appropriate non-aqueous/alcoholic hydroxypropyl methylcellulose (HPMC) based film coat. The typical level of film coat applied to the tablets was 3-6% w/w of the core artesunate tablet. The coating solution consisted of hydroxypropylmethylcellulose as the film former in the range of 2-6%, polyethylene glycol 6000 as plasticizer in the range of
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0.1-0.4%, titanium oxide in the range of 0.2-0.8%. as opacifier and talc as glidant in the range of 0.6-1.7%. The coating suspension is formulated in organic solvent system consisting of isopropyl alcohol and methylene chloride.
Amodiaquine is granulated separately by blending with pregelatinized starch as diluent in the range of 5-10% on a dry weight basis, based on the weight of the formulation. This is followed by granulating with starch paste, in the range of 5-20% on a dry weight basis, based on the weight of the formulation. The wet granulate were suitably dried in a fluid bed dryer at approximately 60°C and sized with a screening mill. Lubrication was achieved by blending with magnesium stearate. The combination product is prepared by incorporating the coated tablet of artesunate into the core of amodiaquine granules to form a tablet-in-tablet using a suitable tablet press.
The present invention may be further understood with reference to the following example:
Example 1
The manufacturing process comprises of the steps of:
a) preparation of inner tablet of artesunate where artesunate was separately granulated with an admixture of pharmaceutically acceptable excipients and compressed into tablets; b) artesunate tablet thus prepared were film-coated for protection; c) amodiaquine was separately granulated to form outer tablet; d) atesunate coated tablets was compressed within amodiaquine granules so as to form the core of amodiaquine tablets by tablet-in-tablet technology.
A preferred embodiment of the invention is described herein
Inner Tablet
Film-coated artesunate tablet comprised of the inner tablet of the tablet-in-tablet
combination. The formulation for preparation of 100 mg strength artesunate tablets
had the following composition:
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Table 1
Ingredients Parts by weight of tablet
Artesunate 13.51%
Mannitol 6.89%
Lactose 5.54%
Cross caramellose sodium 0.81 %
Hydroxypropyl cellulose 0.27
Isopropyl alcohol qs
Cross caramellose sodium 0.81 %
Colloidal silicon dioxide 0.13%
Magnesium stearate 0.13%
The active ingredient and the diluents were blended together and passed through relevant sieves. The resultant blend was further granulated in a high shear mixer with the binder solution prepared by dispersing hydroxypropyl cellulose in isopropyl alcohol. After the wet mass was sized through suitable sieves, the solvent was evaporated from granulate by drying at 50-55°C to achieve the desired moisture content of the granules, determined by loss on drying. The dried granules were reduced by sizing through suitable sieves and lubricated, cross caramellose sodium, colloidal silicon dioxide and magnesium stearate were incorporated as lubricants to produce the final compression blend. The resultant lubricated granules were compressed into tablets, to a desired target on a suitable tablet press. Film Coating of artesunate tablet cores
Artesunate tablets prepared were film-coated in a coating pan with an appropriate non-aqueous/alcoholic hydroxypropylmthylcellulose (HPMC) based film coat. The film coat was designed to act as a protective barrier for the core artesunate tablets to shield artesunate from direct exposure to the outer amodiaquine as the two active ingredients are incompatible. The typical level of film coat applied to the tablets was about 5% w/w.
Film coating of artesunate tablet cores made in Example I was performed with the following coating solution:
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Table 2
Ingredients Parts by weight of artesunate tablet
Hydroxypropyl methyl cellulose 2.50%
Talc 1.30%
Titanium dioxide 0.67%
Polyethylene glycol 6000 0.25%
Isopropyl alcohol qs
Methylene chloride qs
Tablets of example 1 were coated with 5% of this solution per tablet weight using a film coating device to obtain the artesunate tablets to be compressed within amodiaquine granules to form the tablet-in-tablet product of the present invention. Outer Tablet
The formulation for preparation of amodiaquine granules had the following
composition:
Table 3

Amodiaquine granules were prepared by blending active ingredient with pregelatinised starch, sizing through appropriate sieves and granulation with maize starch paste in purified water in high shear mixer. The wet mass was sized and dried at 60°C to achieve the desired moisture content of the granules, determined by loss on drying. The dried granules were reduced by sizing through suitable sieves and suitably lubricated.
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Compression of Tablet-in-Tablet
Each tablet-in-tablet comprised of 100 mg of artesunate and 300 mg of amodiaquine of total weight 740 mg and containing 220 mg of inner artesunate coated tablet and 520 mg of outer amodiaquine tablet. The inner artesunate tablets are compressed in a regular tablet press, then film coated. The tablet-in-tablet were produced on a specialized tablet press which operated by a specialized pressing procedure, whereby inner tablets are fed into the tablet-in-tablet press with amodiaquine granules and the press operated again such that a final product is of artesunate tablet inside amodiaquine.
Tablets comprising of 50 mg artesunate with 150 mg amodiaquine, 25 mg artesunate with 75 mg amodiaquine and 200 mg artesunate with 600 mg amodiaquine were similarly prepared.
The artesunate coated tablets and amodiaquine granules can be optionally filled into suitable capsule shells using techniques of partial filling method and tablet-in-capsule method.
Stability study was carried out over a period of 3 months at various stability conditions of 25°C/60% RH, 30°C/60% RH and 40°C/75% RH. All the test results at each time station of 1 month, 2 months and 3 months showed compliance with the pre-determined specifications and were found to be stable for the studied period. Industrial Applicability
This invention intends to provide a pharmaceutical^ acceptable combination for oral use that is a stable preparation of the combination of artesunate and amodiaquine. Namely, the present invention relates to the process for preparation of a stable solid oral pharmaceutical combination of the two sensitive active compounds which are chemically incompatible with each other, therefore prepared as a specialized tablet-in-tablet technology, to protect the two active compounds from each other.
Further aspects of this invention suggest that the pharmaceutical combination of the present invention obtained by the process as claimed possesses an enhanced antimalarial action in drug-resistant cases where artesunate and amodiaquine in
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combination can effectively delay or prevent the resistance, and therefore, the amount of drugs used can be reduced as compared with monotherapy.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.
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We claim:
1. A stable, solid, oral pharmaceutical composition comprising a combination of
two chemically incompatible anti-malarial compounds, artesunate and
amodiaquine with pharmaceutically acceptable excipients, in the form of tablet-
in-tablet, wherein said composition is prepared by the process comprising :
a) preparing of the inner core tablet of artesunate;
b) film coating of the core artesunate tablet;
c) preparing of amodiaquine granules;
d) using a specialized tablet-in-tablet technology, whereby inner artesunate tablets prepared in (a) and (b) are fed into the tablet-in-tablet press with amodiaquine granules prepared in (c) and compressed, such that the final tablet-in-tablet product is artesunate tablet inside amodiaquine tablet.

2. The pharmaceutical composition as claimed in claim 1, wherein artesunate and amodiaquine are present in the weight ratio of 1:3 in the dosage form.
3. The pharmaceutical composition as claimed in claim 1, wherein the amount of artesunate in the composition is 25 mg, 50 mg, 100 mg. or 200 mg.
4. The pharmaceutical composition as claimed in claim 1, wherein the amodiaquine in the composition is 75 mg, 150 mg, 300 mg or 600 mg in respective dosage form.
5. The pharmaceutical composition as claimed in claim 1, wherein artesunate is of particle size 50n or less.
6. The pharmaceutical composition as claimed in claim 1, wherein for the inner core tablet of artesunate, pharmaceutically acceptable diluents, mannitol and lactose are used in the range of 2% to 15% by weight on a dry weight basis, based on the weight of the formulation.
7. The pharmaceutical composition as claimed in claim 1, wherein for the inner core tablet of artesunate, pharmaceutically acceptable disintegrant, cross caramellose sodium is used in the range of 0.5% to 7% by weight on a dry weight basis, based on the weight of the formulation, either intra-granularly or extra-granularly or both.
8. The pharmaceutical composition as claimed in claim 1, wherein for the inner core tablet of artesunate, pharmaceutically acceptable binder, hydroxypropylcellulose
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is used in the range of 0.1-0.5% by weight on a dry weight basis, based on the weight of the formulation.
9. The pharmaceutical composition as claimed in claim 1, wherein for the inner core tablet of artesunate, pharmaceutically acceptable glidants colloidal silicon dioxide and talc are used in the range of 0.05% to 0.6% by weight on a dry weight basis, either alone or in combination based on the weight of the formulation.
10. The pharmaceutical composition as claimed in claim 1, wherein for the inner core tablet of artesunate, pharmaceutically acceptable lubricant magnesium stearate is used in the range of 0.1% to 0.4% by weight on a dry weight basis, based on the weight of the formulation.
11. The pharmaceutical composition as claimed in claim 1, wherein the inner core tablet of artesunate is given a protective film coating in an amount of about 3-6%, by weight of the core artesunate tablet.
12. The pharmaceutical composition as claimed in claim 1 and 11, wherein the film coating of inner artesunate tablet comprises of hydroxypropyl methyl cellulose 2 to 6%; polyethylene glycol 6000 0.1 to 0.4 %; titanium dioxide 0.2 to 0.8%; and talc 0.6 to 1.7% by weight of the inner artesunate tablet.
13. The pharmaceutical composition as claimed in claim 1 and 11, wherein the film coating material for artesunate tablet is applied from an organic solvent based system.
14. The pharmaceutical composition as claimed in claim land 13, wherein the organic coating solvents are isopropyl alcohol and methylene chloride.
15. The pharmaceutical composition as claimed in claim 1, wherein the outer tablet of amodiaquine comprises pharmaceutically acceptable binder, maize starch used in the range of 5 to 20% by weight on a dry weight basis, based on the weight of the formulation.

16. The pharmaceutical composition as claimed in claim 1, wherein for the outer tablet of amodiaquine, granulation is done by wet aqueous granulation means.
17. The pharmaceutical composition as claimed in claim 1, wherein the outer tablet of amodiaquine comprises pharmaceutically acceptable diluent, pregelatinised starch used in the range of 5 to 10% by weight on a dry weight basis, based on the weight of the formulation.
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18. The pharmaceutical composition as claimed in claim 1, wherein for the outer tablet of amodiaquine, pharmaceutically acceptable lubricant magnesium state and talc are used in the range of 0.5 to 1% either alone or in combination by weight on a dry weight basis, based on the weight of the formulation.
19. The pharmaceutical composition as claimed in claim 1, wherein amodiaquine forms the outer tablet and artesunate forms the inner tablet of the tablet-in-tablet product.
20. The pharmaceutical composition as claimed in claim 1, wherein the coated artesunate tablet and amodiaquine granules can be filled into capsules.
21. The pharmaceutical composition as claimed in claim 1, wherein coated granules of artesunate and granules of amodiaquine are filled into sachets of single or multiple dose quantities.
22. A stable, solid, oral pharmaceutical composition comprising of artesunate and amodiaquine tablet-in-tablet and process for preparation of said pharmaceutical composition as substantially described herein with reference to the foregoing example 1.
Dated this 11th day of October 2005

Dr. Gopakumar G. Nair Agent for the Applicant
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Abstract:
The invention discloses a stable, solid, oral pharmaceutical composition comprising a combination of two incompatible anti-malarial compounds, artesunate and amodiaquine with pharmaceutically acceptable excipients, in the form of tablet-in-tablet, and the process thereof.