FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
OMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"Novel synergistic antimalarial pharmaceutical composition"


2. APPLICANT(S):
(a) NAME: IPCA LABORATORIES LIMITED
(b)NATIONALI TY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-4OO 067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of this invention and the manner in which it is to be performed:


TECHNICAL FIELD OF THE INVENTION:
The present invention relates to a pharmaceutical formulation comprising of oral arteether (p arteether (artemotil) or a/β arteether) in a fixed dose combination with other antimalarials including piperaquine, lumefantrine, curcumin useful for treating falciparum malaria, including drug resistant falciparum malaria.
BACKGROUND OF THE INVENTION:
Malaria, the most important parasitic disease of humans, remains a major health and economic burden in most tropical countries. Malaria is a major cause of death equal with HIV/AIDS and tuberculosis. The mortality and morbidity associated with malaria have a crippling effect on the economies of endemic countries. It afflicts more than 500 million people, causing from 1.7 million to 2.5 million deaths each year. {Goodman & Oilman's -The Pharmacological Basis of Therapeutics, 10th Ed., 2001, p. 1069)
According to NAMP, total malaria cases in India in 2000 were 2.02 million, out of which 1.05 million was the total P. falciparum cases. There has been increase in P. falciparum percentage from 26% in 1965 to 50% in 2000. (Current Science, Vol 84, No. 4, 25th Feb, 2003, p. 514)
The main obstacle to malaria control is the emergence of drug resistant strains of Plasmodium falciparum. Emergence of resistance in P. falciparum to antimalarial drugs increases malaria morbidity, mortality and treatment cost. P. falciparum has developed resistance to nearly all antimalarials in current use, although the geographical distribution of resistance to any single antimalarial drug varies greatly.
Chloroquine resistance is a major contributor to the increasing malaria-related morbidity and mortality. Resistance has been seen even with sulfadoxine-pyrimethamine, quinine and mefloquine, though it is not as prevalent as chloroquine resistance.
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Early diagnosis and effective treatment with an appropriate drug form the main component to reduce malaria related mortality. The existing armamentarium of drugs for the treatment and prevention of malaria is limited primarily by resistance. However, most of these drugs still have a place and their life span could be prolonged if better deployed and used, and also by rationally combining them based on pharmacodynamic and pharmacokinetic properties. (Parassitologia 2004 Jun;46(l-2);85-7)
Artemisinin and its derivatives are renowned for their potent antimalarial activity. The clinical efficacy of this group of drugs is characterised by an almost immediate onset and rapid reduction of parasitemia, with complete clearance in most cases within 48 hours. Efficacy is high even in areas with multidrug resistant parasite strains. (Drugs, 52(6), 1996 Dec, p. 819)
At present, artemisinins are the only group of antimalarial drugs to which resistance to P. falciparum has not yet developed in the field. Prospective clinical studies of over 10,000 patients and the use of artemisinin drugs in several million patients, has not shown any serious drug related adverse effects.
p arteether (artemotil) is the p-ethyl ether derivative of artemisinin. It is a blood schizonticide active against all stages of P. falciparum, including the very early ring forms. It is an effective and rapidly acting drug for the treatment of falciparum malaria. No serious or inconvenient side effects have been reported with β arteether (artemotil).
It was chosen by the Steering Committee of the Scientific Working Group on Malaria Chemotherapy of the WHO (CHEMAL) for further development. A longer t1/2 and more lipophilic properties than artemether favouring accumulation in brain tissue and thus the treatment of cerebral malaria were regarded as advantages over the other compounds. (Drugs, 52(6), 1996 Dec, p. 818-820)
In addition, its efficacy, without an increased incidence of toxicity, is well suited for treatment of drug-resistant malaria.
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Other advantages of p arteether (artemotil) are its stability, compared with sodium artesunate; its biochemical breakdown does not give methanol, as does artemether. (Am. J, Trop. Med. Hyg., 75(1), 2006, pp. 139-142)
Arteether is also available as an anomeric mixture of a/β arteether (30:70), which has been developed by CDRI.
EP 0330520 discloses a process of epimerization for conversion of the alpha -epimer of arteether to the beta -epimer (ethyletherartemisininelactol) or preparation of arteether by subjecting the alpha -epimer to an acid catalysed isomerization reaction. It further discloses a pharmaceutical composition comprising arteether can be administered as intramuscular or oral administration when combined with a pharmaceutically-acceptable carriers, medium, diluents or excipients
US 6326023 disclose a formulation comprising .alpha./.beta. arteether and a neutralized refined vegetable oil in respective amounts effective to provide for rectal absorption in treating a multi-drug resistant malarial infection in the patient. It further discloses the formulation is administered to the patient in the form of a rectal formulation, rectal suppository or an oral gelatin capsule.
EP 0464233 discloses a pharmaceutical combination with a synergistic action against malaria, which besides customary auxiliaries and/or vehicles contains Arteether and Quinine or Arteether and Quinine with Mefloquine.
US 6214864 disclose a sterile synergistic formulation useful for the control of wide spectrum of malarial infections, which consists essentially of a pharmaceutically effective amount of dihydroartemisimn and a sterilized neutral refined vegetable oil. Further it disclose the artemisinin derivatives, selected from artemether and arteether and the formulation is administered through intramuscular injection to treat severe complicated/cerebral malaria and multi-drug resistant malaria infections
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WO 2007017646 describes an antimalarial composition comprising artisunate and lumefantrine in a single pharmaceutical dosage unit. WO2008001294 disclose high dose oral pharmaceutical compositions of arteemether with lumefantrine. Delayed release antimalarial composition comprising pharmaceutically effective amounts of antimalarial agent selected from artemisinin group such as alpha or beta arteether or artisunate is disclosed in WO2007036947.
In the above stated prior arts, it has been mentioned about different compositions used for Anti malarial activity. Formulations comprising both.alpha./.beta. arteether for rectal use, synergistic combination of arteether with quinine or arteether with quinine and Mefloquine and a sterile synergistic injection formulation of arternisinin derivatives, selected from artemether and arteether with neutral refined vegetable oil. The injectable routes and rectal routes are painful when administered.
Hence there is a need in the art to develop a novel oral antimalarial formulation comprising arteether (p arteether (artemotil) or a/p arteether) in synergistic combination with other antimalarials selected from the group consisting of piperaquine, curcumin and lumefantrine which offer potential solution for second line therapy with lower recrudescence rate; Quick acting; Synergistic effect; Delayed onset of resistance and Better tolerance.
Therefore, the current invention aims to provide a potential successor in the field of antimalarial, which comprises the composition comprising oral formulation of arteether like p arteether (artemotil) or a/β arteether in combination with other antimalarials selected from the group consisting of piperaquine, lumefantrine and curcumin, which works synergistically against drug resistant falciparum malaria.
In India, many experts have questioned 3-day regimen of arteether. A recrudescence rate of 6-14% has been observed with the use of a/p arteether.
Hence according to recent WHO guidelines, when arteether is given as monotherapy, a 7-
day course is recommended and efforts should be made to ensure adherence. This will
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reduce the recrudescence rate and thus delay the onset of resistance. Therefore, a second line therapy with short course treatment is required to fight synergistically against drug resistant malaria.
The availability of oral arteether (p arteether (artemotil) or a/β arteether) will go in a long way in rationalizing the duration of therapy of arteether, which will serve as follow-up for both parenteral arteether formulations (a/β arteether and β arteether), which are marketed in the country.
Thus the advantages associated with oral formulation of arteether ((3 arteether (artemotil) or ct/p arteether) includes:
Reduce recrudescence rate by enabling 7 day dosage regimen
- Useful to those who cannot tolerate parenteral therapy
- Enable the patients on arteether (both a/p arteether and p arteether (artemotil)) parenteral therapy to switch over to oral therapy
- Useful for uncomplicated malaria
Oral arteether (p arteether (artemotil) or a/p arteether) combinations:
There is a growing interest in using antimalarial combinations containing an artemisinin derivative as first-line treatment. Combination of one of these drugs with a longer half-life partner antimalarial drug allows a reduction in the duration of antimalarial treatment while at the same time enhancing efficacy and reducing the likelihood of resistance development.
The rationale for such artemisinin combination therapies (ACTs) was to provide an inexpensive, short-course treatment regimen with a high cure rate and good tolerability that would reduce transmission and protect against the development of parasite resistance.
The particular features of ACT relate to the unique mode of action of the artemisinin component, which includes the following:
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• rapid and substantial reduction of the parasite biomass,
• rapid parasite clearance,
• rapid resolution of clinical symptoms,
• effective action against multidrug-resistant P. falciparum,
• reduction of gametocyte carriage, which potentially reduces transmission of resistant alleles.
• Possible delay or slowing of spread of resistance to available effective and affordable antimalarial drugs, if included in combination therapy
WHO in its new Malaria guidelines (2006) recommends artemisinin combination therapy (ACT) for uncomplicated falciparum malaria. {World Health Organisation - Guidelines for the treatment of malaria, 2006)
Combination of artemisinin derivative with mefloquine, lumefantrine, amodiaquine and sulphadoxine-pyrimethamine is currently being used. However, there is no combination available of oral formulation of arteether (p arteether (artemotil) or a/β arteether) with other antimalarials as setout herein below.
Piperaquine is a bisquinoline antimalarial drug, which is effective against P. vivax and P. falciparum, including strains of P. falciparum resistant to chloroquine. It has favourable safety and toxicity profile. A number of Chinese research groups documented that it was at least as effective as and better tolerated than chloroquine against falciparum and vivax malaria. Piperaquine's tolerability, effectiveness, pharmacokinetic profile and low cost make it a promising partner drug for use as part of short course artemisinin combination therapy.
Curcumin is the major yellow pigment of turmeric, the common curry powder, derived from the rhizome of the herb Curcuma longa. It has demonstrated antimalarial activity in vitro and in experimental animals. It was found to be potent against both chloroquine-sensitive and -resistant P. falciparum strains.
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Curcumin is tolerated at very high doses, and as much as 8 g/day has been given for 3 months to cancer patients on trial without toxic side effects. (Adv Exp Med Biol 2007;595:471-80) Thus the safety of curcumin is well established.
At present, lumefantrine is available in fixed dose combination with artemether. The combination combines the fast onset of action of artemether (an artemisinin derivative) in terms of parasite clearance with the high cure rate of lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria.
All the above molecules appear to be an ideal antimalarial molecule for use in combination with arteether (β arteether (artemotil) or a/p arteether) as it not only will have synergistic effect with p arteether (artemotil) or a/β arteether but will also overcome the problem of adverse reactions and drug resistance. The combination therapy will be safe and effective for falciparum malaria, including drug resistant falciparum malaria, β arteether (artemotil) or a/β arteether, with its quick onset of action, will rapidly reduce parasite biomass and quickly resolves clinical symptoms, whilst the long-acting activity of antimalarials such as piperaquine, curcumin or lumefantrine is thought to prevent recrudescence thus giving synergy to the combinations of the present invention.. This dual effect also appears to reduce the selective pressure on the parasite to develop resistance.
Thus it is an object of the present invention to provide a formulation comprising of oral beta arteether (artemotil) or a/p arteether) in a fixed dose synergistic combination with other antimalarials including piperaquine, curcumin and lumefantrine for falciparum malaria, including drug resistant falciparum malaria. This fixed dose combination will be an effective alternative for drug resistant falciparum malaria.
SUMMARY OF THE INVENTION
The present invention discloses a pharmaceutical formulation comprising of oral arteether (P arteether (artemotil) or a/β arteether) in a fixed dose combination with other
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antimalarials including piperaquine, curcumin and lumefantrine, which works synergistically against drug resistant falciparum malaria.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The composition of the present invention comprises of oral arteether (p arteether (artemotil) or a/p arteether) formulation in a fixed dose combination with other antimalarials including piperaquine, curcumin, lumefantrine etc which works synergistically against drug resistant falciparum malaria
The said formulation comprises therapeutically effective amount of oral arteether (p arteether (artemotil) or a/β arteether) with other antimalarials such as piperaquine, curcumin, lumefantrine for treatment of falciparum malaria, including drug resistant falciparum malaria.
The advantages associated with arteether (p arteether (artemotil) or a/β arteether) are its efficacy without an increased incidence of toxicity, its stability as compared with sodium artesunate and its biochemical breakdown does not give methanol, as does artemether. Other antimalarials such as piperaquine, curcumin, lumefantrine etc. make a promising partner drug for use as part of short course artemisinin combination therapy. Fixed dose combination of arteether (p arteether (artemotil) or a/β arteether) with these antimalarials will thus be safe and effective combination therapy for falciparum malaria, including drug resistant falciparum malaria. It will reduce the duration of antimalarial treatment while at the same time enhance efficacy and reducing the likelihood of resistance development.
Keeping in view of a better combination therapy with greater pharmacological aspects, the inventor has conducted a comparative, open label pre-clinical (animal) study to
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evaluate the efficacy in terms of potency of β-arteether alone and in combination with antimalarials like piperaquine, lumefantrine and curcumin.
The invention can safely be carried out. Arteether is generally administered in mammal in the range of 0.125 to lOmg/kg for 5 days as a single dose. The anti malarial, piperaquine is normally administered in the range of 500 to 2000mg. However, the inventive composition of the present invention for oral administration comprising arteether (p arteether (artemotil) or a/p arteether) and piperaquine that can be administered in a fixed dosage form for an average adult, wherein oral arteether (β arteether (artemotil) or a/β arteether) may be in the range of 25 to 200mg and piperaquine may be in the range of 50 mg to 2000mg. The fixed dose combination of oral arteether (p arteether (artemotil) or ot/p arteether) with piperaquine can be administered once or twice daily for 3 - 7 days to a patient infected with falciparum malaria.
Similarly, in a preferred oral route, the amount of curcumin for an average adult patient may generally be in the range of 100 mg to 2000mg in a fixed dose combination, wherein oral arteether (P arteether (artemotil) or a/p arteether) may be in the range of 25 mg to 200 mg. The fixed dose combination of oral arteether (P arteether (artemotil) or a/p arteether) with curcumin can be administered once or twice daily for 3 - 7 days. The invention encompasses various formulations of curcumin, including those where bioenhancers or absorption enhancers are incorporated in curcumin to increase absorption of curcumin or nano particles of curcumin
Lumefantrine is normally administered in a mammal along with other antimalarial such as p-artemether in an amount of 720mg to 3000mg as daily dose for 3 to 5 days. However, in combination therapy according to the present invention, lumefantrine can be administered along with oral arteether (p arteether (artemotil) or a/p arteether) in an amount of 50mg to lOOOmg. The fixed dose combination of oral arteether (β arteether (artemotil) or a/p arteether) with lumefantrine can be administered once or twice daily for 3 - 7 days to an infected patient.
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The fixed dose composition of oral arteether (p arteether (artemotil) or a/β arteether) along with other antimalarials selected from piperaquine, curcumin and lumefantrine can be administered in combination with pharmaceutical carriers or diluents orally. For oral use, suitable pharmaceutical carriers include inert diluents or fillers thereby forming oral dosage forms such as tablets, powders, capsules, syrups or suspensions and the like.
For example, tablets containing variety of excipients such as disintegrants such as starch, complex silicates together with binding agents such as poly vinyl pyrrolidone, sucrose, gelatin and acacia. Lubricants such as magnesium silicate, sodium lauryl sulfate and talc are often used in tabletting purposes. Solid compositions of the present invention can also be filled into soft and hard gelatin capsules.
For soft gelatin capsule, the composition may be solubilized in suitable vegetable or edible oil such as sunflower oil, corn oil, peanut oil or any other suitable oil.
The safety, efficacy and synergy of the fixed dose combinations of oral arteether (β arteether (artemotil) or a/β arteether) in combination with other antimalarials such as piperaquine, curcumin, and lumefantrine is clinically established by the following experiments.
In this study we compared the efficacy in terms of potency of p-arteether with or without the other antimalarials like piperaquine and curcumin. We have conducted the experiment on mice (~30g) infected with Plasmodium .berghei (P. berghei) for 48 hr or 72hr and were given 1 or 3 oral doses of different strengths of the corresponding drug sample at different time intervals. It was concluded from the study that the protection given by the combination therapy is more as compared to monotherapy.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Example 1
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Experimental study on fixed dose combination of β arteether with piperaquine
An experimental study was conducted in Indian Institute of Science to demonstrate the efficacy of fixed dose combination of p arteether with piperaquine. In this experiment, mice (~30g) infected with P. berghei for 72hr were given 3 oral doses of p-arteether (1.5mg/mouse) with or without piperaquine (5mg/mouse). 5 animals were used in each group. The combination gave 80% protection to mice against P. berghei as compared to individual drugs, p-arteether and piperaquine, which gave 40% protection individually. Hence the combination was found to have synergistic action against malaria, giving high cure rate.
Table I: B-arteether combination with piperaquine (Experiment -1)
Survival (No. of animals) Treatment
D3 D5 D6 D9 D17/D40
Infected mice (Control) 5 2 0 0 0
AE(3 doses, 1.5mg) 5 5 5 4 2
PQ (3 doses, 5mg) 5 5 4 3 2
AE(1.5mg) + PQ(5mg) 55544
(3 doses)
In this experiment mice (~30g) infected with P.berghei for 72hr were given 3 oral doses of p-arteether (AE, 1.5mg/mouse) with or without piperaquine (PQ, 5mg/mouse) as described below. 5 animals were used in each group. Survival of mice was used as the end point. 10 animals were used in each group. All infected animals in Control group, to which no drug was administered died by the 7th day. 80% of the animals treated with the combination drug survived till Day 40, whereas only 40% of the animals treated with monotherapy survived till Day 40.
Conclusions:-
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AE at 1.5mg/mouse (3 doses) is partially protective (40%). PQ at 5mg/mouse (3 doses) is partially protective (40%). AE + PQ (3 doses) gives 80% protection.
Example 2:
Experimental study on fixed dose combination of p arteether with curcumin
An experimental study was conducted in Indian Institute of Science, Bangalore, to demonstrate the efficacy of fixed dose combination of p arteether with curcumin. In this experiment, mice (~30g) were infected with P.berghei and after 48 or 72hr, the animals received p arteether (oral), 1 or 3 doses, with or without curcumin (oral) as indicated. DMSO was used as the solvent. The animals were given the drugs at 24hr intervals. Survival of mice was used as the end point. 10 animals were used in each group. All infected animals (control) died by the 7th day.
Mice infected with P.berghei were partially protected (40-50%) when given β arteether orally at 1.5mg/mouse in 3 doses at 24hr intervals. A combination of p arteether with 3 oral doses of curcumin gave 90-100% protection, β arteether by itself was able to provide 100% protection when given at 3mg/mouse in 3 oral doses at 24hr interval. However, with combination of curcumin, the dose of β arteether can be reduced to 1.5mg/mouse and still get 100% protection. Hence the combination was found to have synergistic action against malaria, giving high cure rate.
Table II: B - Arteether Combination With Curcumin(Experiment -2)
Infection at the Treatment Survival
start of experiment (No. of doses) Amount / mouse 7d 14d 21 d

1 AE
1 AE + 3C 1 AE
1 AE + 3C 48 hr
3 AE

1.5mg 1.5mg + 5mg 3mg 3mg + 5mg 6
7
10
10 1 3
10 10 0 0 0 0
1.5mg 6 4 2
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3 AE + 3C 1.5mg + 5mg 9 8 8
3 AE 3mg . 10 10 10
3 AE + 3C 3mg + 5mg 10 10 9

1 AE 1.5mg 5 2 0
1 AE + 3C 1.5mg + 5mg 8 3 0
1 AE 3mg 10 10 2
1 AE + 3C 3mg + 5mg 10 10 2
3 AE 1.5mg 10 10 5
3 AE + 3C 1.5mg + 5mg 10 10 10
3 AE 3mg 10 10 10
3 AE + 3C 3mg + 5mg 10 10 10
Mice (~30g) were infected with P.berghei and after 48 or 72hr, the animals received β-arteether (AE, oral), 1 or 3 doses, with or without curcumin (oral) as indicated. DMSO was used as the solvent. The animals were given the drugs at 24hr intervals. Survival of mice was used as the end point. 10 animals were used in each group. All infected animals in the Control group, to whom no drug was administered died by the 7th day. Partial protection (40-50%) were obtained when the drug was given as monotherapy, whereas 90-100% protection was obtained when the drug was given in combination with curcumin.
Conclusions:-
Mice infected with P.berghei were partially protected (40-50%) when given p-arteether orally at 1.5mg/mouse in 3 doses at 24hr intervals. Here, a combination with 3 oral doses of curcumin gave 90-100% protection, p-arteether by itself was able to provide 100% protection when given at 3mg/mouse in 3 oral doses at 24hr interval. The results obtained with mice infected for 48 or 72hr is similar.
The said formulation is for oral administration in the solid dosage form preferably in the form of tablets or capsules.
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The advantages associated with oral arteether (P arteether (artemotil) or a/β arteether) formulations are:
- Reduce recrudescence rate by enabling 7 day dosage regimen
- Useful to those who cannot tolerate parenteral therapy
- Enable the patients on arteether (both a/β arteether and β arteether (artemotil)) parenteral therapy to switch over to oral therapy
- Useful for uncomplicated malaria
The advantages associated with the combination of oral arteether (p arteether (artemotil) or a/β arteether) with other antimalarials are:
• Synergistic action in malaria, hence high cure rates
• Quick acting due to artemisinin component
• Prevents recrudescence due to long acting activity of piperaquine
• Fixed dose co-formulation which improves adherence
• Better tolerated
• Short treatment course of 3 days
• Combination therapy and hence reduces the selective pressure on the parasite to develop resistance
Example 3:
i. Each tablet/capsule contains:
P arteether (artemotil) or a/β arteether 25mg to 200mg
Piperaquine .... 50mg to2000mg
Example 4:
....25mg to 200mg ....100mg to 2000mg
ii. Each tablet/capsule contains:
P arteether (artemotil) or a/β arteether
Curcumin
(various formulations of curcumin, including
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those where bioenhancers or absorption enhancers are incorporated in curcumin to increase absorption of curcumin or nano particles of curcumin)
Example 5
iii. Each tablet/capsule contains:
parteether (artemotil) or a/β arteether 25mg to 200mg
Lumefantrine .... 50mg to lOOOmg
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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I Claim:
1. Novel synergistic pharmaceutical composition comprising oral arteether like p
arteether (artemotil) or a/β arteether in combination with other antimalarials
selected from the group consisting of piperaquine, lumefantrine and curcumin
along with pharmaceutical excipients/carriers useful in treating drug resistant
falciparum malaria.
2. The oral pharmaceutical composition as claimed in claim 1 , wherein the said
pharmaceutical composition is oral, preferably in the form tablets or capsules.
3. The pharmaceutical combination as claimed in claim 1, wherein the other
antimalarial used in fixed dose combination is piperaquine.
4. The oral pharmaceutical composition as claimed in claim 1, wherein the other
antimalarial used in fixed dose combination is curcumin.
5. The oral pharmaceutical composition as claimed in claim 1, wherein the other
antimalarial used in fixed dose combination is lunefantrine.
6. The oral pharmaceutical composition according to any of preceding claim,
wherein oral arteether (P arteether (artemotil) or a/β arteether) is used in the
range from 25mg to 200mg.
7. The oral pharmaceutical composition according to claims 1 and 3, wherein
piperaquine is used in the range from 50mg to 2000mg.
8. The oral pharmaceutical composition according to claims 1 and 4 , wherein curcumin is used in the range from l00mg to 2000mg
9. The oral pharmaceutical composition according to claims 1 and 5 , wherein lumefantrine is used in the range from 50mg to l000mg
10. The oral pharmaceutical composition as claimed in claims 1 to 9 wherein the
pharmaceutically acceptable carrier includes one or more of diluents, binders,
disintegrants, wetting agents, glidants and lubricants..
Dated this 7th day of July, 2008

Dr. Gopakumar G. Nair
Agent for the Applicant
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