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:
"Delayed Release Anti-Malarial Composition"
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 delayed release anti-malarial pharmaceutical compositions. More particularly, the invention relates to delayed release formulations comprising the artemisinin derivative, b-arteether, which is formulated such that the compositions are suitable for drug release in the gastrointestinal tract and is of use to a patient in need of treatment related thereto.
Background and prior art:
With the emergence of widespread chloroquine resistance and a world-wide scarcity of quinine, a search for newer antimalarial drugs has become imperative. Artemisinin derivatives appear to be the most promising new antimalarial agents. Arteether is safe and therapeutically as effective as quinine for the treatment of cerebral malaria and because of its ease of administration, it appears to be a promising alternative drug for the treatment of severe, complicated and multi-drug resistant malaria in areas of quinine resistance and in rural zones where monitoring facilities are usually absent. P-arteether, a third generation ethyl ether derivative of dihydroartemisinin, a drug introduced in India for the first time by Central Institute of Medicinal and Aromatic Plants (CEVLAP), Lucknow, recommended by World Health Organization (WHO), has undergone extensive preclinical, animal, toxicological studies as well as clinical studies on Indian subjects for drug regulatory purposes. Arteether shows rapid schizonticidal action with quicker clearance rate, short fever clearance time with no side effects and low recrudescence rate. Arteether has advantages over artemether, it is more lipophilic and can accumulate easily in brain tissues, which is advantageous in cerebral malaria patients. The b anomer of arteether, a crystalline solid, is the predominant anomer upon synthesis and is easy to separate from the a anomer, which is a liquid, so that there is the potential for large-scale production. Finally, because of this and because arteether was manufactured jointly by WHO and other partners, it costs less than artemether and cost is a critical factor in determining use of antimalarial drugs.
Artemisinin and its derivative arteether are a class of antimalarial compounds derived from Artemisia annua. Various processes adequately describing the methods of preparation of arteether are reported by Jain et al (Jain D. C, Bhakuni R. S, Saxena S,
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kumar, S and Vishwakarma, R. A. ref: U.S. Pat. No. 6,346,631, G.B.2360517 and German no 10014669); Bhakuni et al, (Bhakuni, R. S.; Jain D. C and Sharma R. P. Indian. J. Chemistry, 34B, 529-30,1995) and Bhakuni et al, (Bhakuni, Singh R; Tewari A, Singh T, Khanuja S) ref: U.S. Pat. No. 6,750,356.
U.S. patent no. 6,326,023 describes the process for formulation of alpha/beta, arteether and a neutralized refined vegetable oil which is administered by rectal route.
U.S. patent no. 6,423,741 discloses antimalarial combinations and composition regarding process of formulation comprising of alpha arteether in combination with other drugs. These compositions are useful for the treatment of drug-resistant cases.
U.S. 5,446,070 and 6,562,363 disclose compositions for topical application comprising of therapeutically effective amounts of pharmaceutical agents such as arteether.
U.S. patent no. 6127405 describes the compositions and formulations related to alpha arteether alone or in combinations. These are known for their anti-bacterial and antifungal action in drug resistant cases.
U.S. patent 5219865 discloses combinations of the synergistic therapeutic actions of subcurative doses of malaria therapeutics, artemisinine and its derivatives, dihydroartemisinine and arteether in combination with subcurative doses of chloroquine, 10-0-methylfloxacrine, mefloquine or pyrimethamine against chloroquine-sensitive Plasmodium berghei infection in mice.
EP0464233 describes compositions of antimalarial combinations of arteether with quinine alone or with quinine and mefloquine, besides customary auxiliaries and/or vehicles. This can be in a form suitable for parenteral administration, or even in a form suitable for oral administration where these semi-solid compositions may also be employed as fillers in soft and hard gelatin capsules.
WO9202217 discloses benflumetol combinations with artemisinine or its derivatives such as artemether where a synergistic antimalarial composition, methods of treating
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malaria by administering that composition, and a process for the preparation of that synergistic antimalarial composition are described. The combined preparations are exemplified for enteral (suppositories) , parenteral or oral (tablets, hard gelatine and soft capsules) dosage forms according to conventional formulation methods.
A related application has been filed by us, Indian application no.: 763/MUM/2005 disclosing combination of artesunate with amodiaquine in solid oral dosage form, which is fully incorporated herein by reference.
In the present invention, a novel, stable pharmaceutical composition of delayed release, enteric coated form of P-arteether tablets is exemplified in detail, which has hitherto not been seen in the teachings of the prior art. The rationale for attempting enteric coating of P-arteether tablets is that, P-arteether decomposes to dihydroartemisinin in simulated stomach conditions, which subsequently rearranges to a new compound with significantly reduced anti-malarial activity, thus rendering P-arteether unstable and ineffective in the stomach. Therefore, P-arteether tablets, when subjected to enteric coating to protect from acid degradation in the stomach region, and to safely deliver it to the intestinal region where the active substance could be more effectively released and absorbed, adds increased and assured therapeutic benefit to the patient.
Objectives of the invention:
The main objective of the present invention is to provide a delayed release formulation of P-arteether in the form of enteric coated tablets, such that the drug is protected from acid decomposition by gastric fluid in stomach and facilitated for release in the gastrointestinal tract.
A further objective of this invention is to provide a process for preparation of stable pharmaceutical formulation of P-arteether in the form of enteric coated tablets.
Another object of the present invention is to provide a process for preparation of an improved, safe, less expensive pharmaceutical composition, in particular for the treatment of uncomplicated malarial infections as well as for the control of multi-drug
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resistant malaria and emerging treatment for severe, complicated cerebral malarial infections.
Summary of the Invention:
The present invention discloses a novel antimalarial formulation comprising artemisinin derivative suitable for oral administration, and is formulated into a solid, delayed release, enteric-coated composition.
Further, the present invention is directed to a delayed release dosage form for oral administration comprising of therapeutically effective amount of P-arteether; and, protected with a delayed release enteric coating designated to afford suitable protection to the active substance known for its decomposition in the acidic environment of the stomach.
Also, the present invention is directed to a simplified, economical, time saving method of manufacturing for stable, enteric coated oral dosage form of P-arteether, more particularly tablets of P-arteether.
Detailed Description of the Invention:
The pharmaceutically active agents used in the present invention are therapeutic agents for the treatment of cerebral malaria and severe, complicated, multi-drug resistant malaria. They are artemisinin compounds which may be first generation, second generation and/or third generation compounds including a- and P-arteether, artemether, artesunate and combinations thereof. The preferred active ingredient is P-arteether. Typically the amount of active ingredient may vary from about 12.5 mg to about 200 mg. The preferred dosage of active ingredient according to the present invention is between 25 mg and 150 mg and most preferably between 50 mg and 100 mg. The preferred dosage form is enteric coated tablets for the delayed release of P-arteether.
The tabletting process usually includes the steps of: (a) Formulation of the cores; (b) Coating the cores. The preparation of the core tablets can be done following wet granulation, dry granulation or direct compression. In the current invention, p-arteether core tablets are prepared by a process of direct compression. Direct
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compression is a ecomomical, time saving process for manufacturing core tablets, since it avoids the steps of granulation and drying. Core tablets manufactured by the process of direct compression usually include excipients such as fillers, preferably of direct compression grade, disintegrants, lubricants, glidants, anti-adherents, surfactants, colours, flavours, taste masking agents and such like. In the present invention, core tablet contains excipients such as microcrystalline cellulose and lactose as fillers/diluents to aid in direct compression tabletting process. Microcrystalline cellulose is usually used in the range of 45-50% by weight of the tablet and lactose in the range of 12-15%) by weight of the tablet, wherein 16-22% of microcrystalline cellulose and 8-14% of lactose are direct compression tabletting aids. Other excipients include disintegrants selected from sodium starch glycollate, cross carmellose sodium, micro-crystalline cellulose, crospovidone and such like, either alone or in combination, usually in the range of 1-10%) by weight of the tablet. The tablet core further includes glidants, lubricants or anti-adherents selected from colloidal anhydrous silica, magnesium stearate and talc in the range of 1.1-2.0%, 0.9-1.5% and 0.3-0.7%) by weight of the tablet respectively, either alone or in combinations thereof. The tablet also contains surface active agent such as sodium lauryl sulphate in the range of 1.5-1.9% by weight of the tablet.
In the second part of the processing of the P-arteether tablets, the core tablets are coated with an enteric coating to produce delayed-release p-arteether tablets. Optionally, a seal coating is applied to the tablets before the enteric coating is provided. The enteric coated P arteether tablets are further coated with a film-coating. The enteric coating material is selected from the group consisting of ethyl cellulose, acrylic polymers, methacrylic polymers and hydrophobic polymers such as hypromellose phthalate. The enteric coating material is coated in an amount of from about 10 to about 30 percent by weight of the total oral dosage form and the total enteric coating comprises 15%) by weight of the oral dosage form. The enteric coating formula further comprises dibutyl phthalate in the range of 1 to 2%>; titanium dioxide in the range of 0.3 to 0.7%) and talc in the range of 0.3 to 0.7% of the oral dosage form. The film coating on the enteric coated tablets is in an amount of about 2 percent by weight of the total oral dosage form. The film coating comprises of hydroxypropyl methyl cellulose in the range of 2 to 6%; polyethylene glycol 6000 in the range of 0.1 to 0.3 %>; titanium dioxide in the range of 0.3 to 0.6%; talc in the range of 0.8 to 1.5%
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and red ferric oxide in the range of 0.05 to 0.1% of the film coated tablet. The solvents for enteric coating and film coating comprises organic solvents such as isopropyl alcohol and methylene chloride and combinations thereof.
The delayed release, enteric coated tablets of P-arteether is manufactured by the process comprising:
Dry mixing of the active agent, diluents and disintegrants in suitable equipment till uniform mixing is complete to form a blend; (if required, the ingredients are milled and sieved before dry mixing); mixing suitable tabletting lubricants with the blend to form a lubricated blend; directly compressing said lubricated blend into core tablets; enteric coating of core tablets with enteric coating agents applied from organic solvent based system and film coating of the enteric coated tablets with organic solvent based system.
The delayed release enteric coated tablet of the invention were tested for dissolution in the following conditions:
USP Type 2 apparatus at 100 rpm in 900 ml of 0.1 HC1 for 1 hour, and subsequently in USP Type 2 apparatus at 100 rpm in 900 ml of pH 7.2 phosphate buffer 1 hour. Drug release after 1 hour in 0.1 N HC1: 0 to 10%; Drug release after 1 hour in pH 7.2 phosphate buffer: not less than 95%.
The dissolution pattern of the enteric coated tablet showed that the tablets released less than 10% of the drug in one hour in 0.1N HCL and more than 95% in pH 7.2 phosphate buffer. The enteric coated tablets as formulated in the present invention thus provided a time lag of one hour before releasing the drug, and released the drug by the end of the next one hour in phosphate buffer.
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The following examples illustrate the present invention: Example 1 Tabletting
The formulation for direct compression had the following composition for the core:
Ingredients Preferred embodiment
(Parts by weight)

P-arteether: 28.33 %
Microcrystalline cellulose: 47.45 %
Lactose: 13.16%
Sodium starch glycollate: 3.42 %
Crospovidone: 1.32%
Purified talc: 0.53 %
Colloidal anhydrous silica: 1.56%
Sodium lauryl sulfate: 1.84%
Magnesium stearate: 1.05%
The core is manufactured by the following process:
(a) Blending, milling and sieving p-arteether, microcrystalline cellulose, lactose, sodium starch glycollate, crospovidone, talc, colloidal anhydrous silica, sodium lauryl sulfate and magnesium stearate;
(b) tabletting the blend of step (a) by direct compression means into tablets containing 50 mg and 100 mg of P-arteether.
100 mg strength tablets 50 mg strength tablets
Tabletting tools: 10.0 mm 8.0 mm
Target Weight: 380 mg 190 mg
Target Hardness: 80-100N 80-100N
LOD of granules: less than 3% less than 3%
(c) An enteric coating is applied to core tablets with a weight gain of about 15% as
follows:
P-arteether tablet cores
(of 100 mg strength as prepared above)
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Ingredients Preferred embodiment
(Parts by weight)
Hypromellose phthalate: 13.08%
Dibutyl phthalate: 1.31%
Titanium dioxide: 0.54 %
Purified talc: 0.54 %
Isopropyl alcohol: q.s.
Methylene chloride: q.s.
The solid coating materials were dissolved/suspended in isopropyl alcohol and methylene chloride, dibutyl phthalate was added and this solution was coated onto the 6-arteether tablet cores using a perforated pan. (d) Film Coat
A film coat was applied to the enteric coated tablets as follows:
Enteric coated tablets
(of 100 mg strength as prepared above)
Preferred embodiment (Parts by weight)

Hydroxypropyl methyl cellulose: 2.6 %
Purified talc: 1.1 %
Titanium dioxide: 0.48 %
Polyethylene glycol: 0.2 %
Iron oxide Red: 0.08 %
Isopropyl alcohol: q.s.
Methylene chloride: q.s.
The solid coating materials were dissolved/suspended in isopropyl alcohol and methylene chloride. The film coat was applied onto the enteric coated P-arteether tablets with a weight gain of about 2% using a perforated pan coater. The formula for 50 mg strength tablets is linear and dose-weight proportional, therefore they are similarly prepared.
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Example 2
Dissolutions tests on tablets so produced were carried out in a paddle apparatus (USP Type II) and the pH of the dissolution medium was raised by changing from 0.1N HC1 for 1 hour to pH 7.2 phosphate buffer for next 1 hour in order to better simulate the GI tract. Core tablets were coated with enteric coating material (15%) and film coating (2%) of example 1. The dissolution data for these coated tablets is presented below in
Table 1. Table 1

Time % Arteether Dissolution
0.1NHC1 pH 7.2 phosphate buffer
1 hour 0.00% -
2 hours - 104.16%
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 station (1 month, 2 months, 3 months) showed compliance with the predetermined specifications and were found to be stable for the studied period.
Having now fully described the invention, it will be understood by those of skill in the art that the invention may be performed within a wide and equivalent range of conditions, parameters and the like, without affecting the spirit or scope of the invention or any embodiment thereof.
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We claim:
1. A pharmaceutical composition comprising of antimalarial agent in delayed release oral dosage form, designed such that said antimalarial agent is protected in the stomach region and released in the intestinal tract.
2. The pharmaceutical composition according to claim 1, wherein said antimalarial agent is the parent compound artemisinin, or semi-synthetic derivatives thereof selected from dihydroartemisinin, artemether, alpha/beta arteether and artesunate.
3. The pharmaceutical composition according to claim 1 and claim 2, wherein said anti-malarial artemesinin derivative is b-arteether.
4. The pharmaceutical composition according to claim 1, wherein said delayed release pharmaceutical composition is in the form of enteric coated tablets.
5. The pharmaceutical composition according to claims 1 to 4, wherein the concentration of P-arteether is in the range of 12.5 mg to 200 mg per tablet.
6. The pharmaceutical composition according to claim 5, wherein said p-arteether is 50 mg or 100 mg per tablet.
7. The pharmaceutical composition according to claim 1 comprising of : P-arteether 25 to 30%; Microcrystalline cellulose 45 to 50%; Lactose 12 to 15%, Sodium starch glycollate 2 to 4%; Crospovidone 1 to 2.5%; Talc 0.4 to 0.6%, Colloidal anhydrous silica 1.4 to 1.7%; Sodium lauryl sulfate 1.5 to 1.9% and magnesium stearate 0.9 to 1.5% by weight of the oral dosage form are mixed to form a blend.
8. The pharmaceutical composition according to claim 1, wherein the process of preparing said tablets is a direct compression process.

9. The direct compression tabletting process according to claim 8, wherein said process is carried out with direct compression tabletting aids selected from directly compressible lactose and microcrystalline cellulose, added to the blend prior to tabletting.
10. The direct compression process according to claim 9, wherein said lactose comprises 8 to 14% and said microcrystalline cellulose comprises 16 to 22% by weight of the oral dosage form.
11. The pharmaceutical composition according to claim 1 and claim 8, wherein said composition comprises disintegrant selected from microcrystalline cellulose,
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cross carmellose sodium, crospovidone and sodium starch glycolate either alone or in combination.
12. The pharmaceutical composition according to claim 11, wherein said sodium starch glycolate is used in the range of 1 to 10% by weight on a dry weight basis, based on the weight of the formulation.
13. The pharmaceutical composition according to claim 1 and claim 8, wherein said composition comprises glidant selected from colloidal silicon dioxide in the range of 1.1 to 2.0% and talc in the range of 0.3 to 0.7% either alone or in combination.
14. The pharmaceutical composition according to claim 1 and claim 8, wherein said composition comprises magnesium stearate' in the range of 0.9-1.5% as lubricant.
15. The pharmaceutical composition according to claim 1 and claim 4, wherein said enteric coated tablet comprises enteric coating material selected from the group consisting of acrylic polymers, methacrylic polymers and hydrophobic polymers.
16. The enteric coating material according to claim 15, wherein said enteric coating material is the hydrophobic polymer, hypromellose phthalate.
17. The enteric coating material according to claim 15 and claim 16, wherein said enteric coating material is present in an amount of from 10 to 30 percent by weight of the total oral dosage form, preferably 15 percent by weight of the total oral dosage form.

18. The pharmaceutical composition according to claims 1 to 18, wherein said enteric coating comprises of : hypromellose phthalate 12 to 14 %; dibutyl phthalate 1 to 2%; titanium dioxide 0.3 to 0.7% and talc 0.3 to 0.7% by weight of the oral dosage form.
19. The pharmaceutical composition according to claim 1 to claim 18, wherein said enteric coated tablets are further film coated in an amount of about 2 percent by weight of the total oral dosage form.
20. A pharmaceutical composition according to claims 1 to 20, wherein said film coating comprises of hydroxypropyl methyl cellulose 2 to 6%; polyethylene glycol 6000 0.1 to 0.3 %; titanium dioxide 0.3 to 0.6%; talc 0.8 to 1.5% and red ferric oxide 0.05 to 0.1% by weight of the film coated tablet.
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21. The pharmaceutical composition according to claim 1 to claim 21, wherein said enteric coating and said film coating is applied from an organic solvent based system comprising isopropyl alcohol and methylene chloride.
22. The delayed release enteric coated tablet as defined in claim 1 and claim 4, wherein said delayed release enteric coated tablet exhibits the following dissolution profile when tested in a USP Type 2 apparatus at 100 rpm in 900 ml of 0.1 HC1 for 1 hour and subsequently in a USP Type 2 apparatus at 100 rpm in 900 ml of pH 7.2 phosphate buffer for 1 hour:
Drug release after 1 hour in 0.1 N HC1: 0 to 10%;
Drug release after 1 hour in pH 7.2 phosphate buffer: not less than 95%.
23. The pharmaceutical composition according to claim 1 to 24 wherein a method of
treating malaria comprises administering a stable delayed release oral dosage
form for oral administration of p-arteether, manufactured by the steps
comprising:
(a) Dry mixing of the active agent, diluents and disintegrants in suitable equipment till uniform mixing is complete to form a blend; (if required, the ingredients are milled and sieved before dry mixing);
(b) mixing suitable tabletting lubricants with the blend of step (a) to form a lubricated blend;
(c) directly compressing said lubricated blend of step (b) into core tablets;

(d) enteric coating of core tablets of step ( c) with enteric coating agents applied from organic solvent based system and
(e) film coating of enteric coated tablets of step (d) with organic solvent based system.
Dated this 29th day of September 2005

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Abstract:
This invention discloses a novel, stable delayed release antimalarial composition of a pharmaceutical^ effective amount of antimalarial agent from the artemisinin group such as p-arteether. Since the antimalarial agent is unstable in stomach, the dosage form is designed such that the active ingredient is released and absorbed in the gastrointestinal tract. The invention encompasses the composition in the form of delayed release, enteric coated tablet dosage form.. The invention also provides a process to prepare said tablets comprising a process of direct compression for preparing the core tablets, which are then enteric coated with suitable polymer coating material in organic solvent based system. These enteric coated are further film coated. The enteric coating is useful to protect the sensitive active ingredient against acid decomposition by the gastric fluid and delay release of the active ingredient for local delivery at the intestine. Such enteric coated tablets are useful for the treatment of drug resistant malaria.
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