Title of Invention

A COMBINATION KIT USED IN THE TREATMENT OF MALARIA

Abstract

A combination kit for the treatment of P. vivax malaria comprising: ... a) a predetermined dose of a first anti-malarial agent namely chloroquine; b) a predetermined dose of second anti-malarial agent namely 3-fl[[4-[(6-methoxy-8-quinolinyl)amino] pentyl]-amino]ethylidene]-dihydro-2(3H) furan-one; c) an instruction material containing instructions for administering the two anti-malarial agents during the treatment period, wherein the anti-malarial agents are provided for a period between 5 to 8 days.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION ( See Section 10 ) 1. TITLE OF INVENTION A COMBINATION KIT USED IN THE TREATMENT OF MALARIA GRANTED 30-8-2005 2. NICHOLAS PIRAMAL INDIA LIMITED, a Company incorporated under the Companies Act, 1956, of 100 Centre Point, Dr. Ambedkar Road, Parel, Mumbai - 400012 State of Maharashtra, India, an Indian company COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH, a Society registered under the Societies Registration Act XXI of 1860, of Anusandhan Bhavan, 1, Rafi Marg, New Delhi - 110 001, an Indian Society ORIGINAL 501/MUMNP/2000 The following specification particularly describes the nature of the invention and the manner in which it is to be performed. A Combination Kit Used In The Treatment Of Malaria FIELD OF INVENTION: The present invention relates to a combination kit for use in the treatment of malaria. Particularly, the invention relates to a combination kit comprising anti-malarial agents, 3-[l-[[4-[(6~methoxy- 8- quinolmyl)animo]pentyl]amino]ethylidene]-dihydro-2(3H)furanone and chloroquine. More particularly, the present invention relates to the use of the combination kit containing an anti-malarial agent, 3-[l-[[4-[(6-methoxy-8-qumolinyl)amino]pentyl]amino]ethylidene]-dihydro-2(3H)- furanone and chloroquine against relapsing malaria caused by Plasmodium vivax for better patient compliance. The present invention further relates to a method for the treatment of malaria caused by P. vivax. BACKGROUND OF THE INVENTION: Malaria, caused by a parasitic protozoan called Plasmodium, is one of the most serious and complex tropical parasitic diseases. Generally human malaria is caused by four species of malarial parasites which are Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae. Of these P. falciparum and P. vivax are most widespread and cause most of the mortality and morbidity associated with these types of infections. It is known that the malarial parasites undergo complex life cycle in humans, which is initiated through the bite of an infected female Anopheles mosquito. When the mosquito bites a host, some of the sporozoites are injected into the bloodstream of the host and through the circulation they reach the liver where they multiply and liberate merozoites into the bloodstream which then invade the erythrocytes. In case of infections caused by P. vivax, most of the time the parasites remain dormant in the liver which stage is termed hypnozoites. Hypnozoites are reactivated and reinitiate blood stage parasitemias causing relapse. It has often been observed that people infected with P. vivax do not experience any symptoms for a very long period after their initial illness but become symptomatic after certain period (Korean J. Intern Med, 1999 Jul; 14(2): 86-9). A number of drugs ranging from those of natural origin to synthetic ones have been developed for the treatment of malaria. Quinine and artemisinin are the commonly known drugs of natural origin, which are mostly used for the treatment of malaria. A number of synthetic anti-malarial drugs such as chloroquine, mefloquine, primaquine, halofantrine, amodiaquine, proguanil, maloprim are known in the literature. Of all the synthetic anti-malarial agents chloroquine has been the most widely prescribed drug for the treatment of malaria of all the types, for more than last 60 years. Chloroquine has been the effective treatment so far for the P. vivax malarial infections, however, some strains of P. vivax have shown resistance to this well known drug (Ann. Trop. Med. Parasitol, 1999 Apr; 93(3): 225-230. In recent years drug resistant malaria has become one of the most serious problems in malaria control. Drug resistance necessitates the use of drugs which are more expensive and may have dangerous side effects. To overcome the problems associated with drug resistance, treatments comprising combinations of anti-malarial agents are on the rise. A number of anti¬malarial combinations are already known in the malarial chemotherapy. For example, a combination of amodiaquine and tetracycline, a combination of sulfadoxme and pyrimethamine known as fansidar, are known therapies for the treatment of P. falciparum. Also fansimef, a combination of mefloquine with sulfadoxme and pyrimethamine is used against multidrug resistant strains of P. falciparum. United States Patent No. 5 998 449 describes a method for the treatment of malaria wherein combination of atovaquone and proguanil is used for the treatment of malaria. In US Patent No. 5 834 505, combination of fenozan with another anti-malarial agent selected from artemisinin, sodium artesunate, chloroquine, mefloquine is described for the prophylactic and curative treatment of malaria. All the aforementioned anti-malarial combinations reported heretofore are generally used for the treatment of P. falciparum. None of the standard anti-malarial agents have been found to be favourable for the treatment of P.vivax malaria which is the most relapsing type of malaria. For a very long time chloroquine was used for the treatment of infections caused by P. vivax, however, chloroquine eradicates only the asexual erythrocytic stages of P. vivax and does not eliminate the hypnozoites. Until recently primaquine has been the drug of choice for the treatment of malarial relapse. Generally for the treatment of P. vivax malarial infections a sequential combination treatment regimen comprising of primaquine and chloroquine is used such that primaquine is administered for 14 days following the three days course of chloroquine. However, primaquine is known to cause hemolytic anemia in persons deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD) (Pharmacol Rev. 21: 73-103 (1969); Rev. Cubana Med trop, 1997; 49 (2): 136-8 ). Moreover, methemoglobin toxicity is another predictable dose-related adverse effect associated with primaquine. Needless to say that in the case of sequential combination therapy the patient may not complete the course once the symptoms of malaria are diminished, hence this may increase the chances of relapse. Thus, the chloroquine-primaquine treatment regimen is far from ideal with respect to toxicity of primaquine and also due to longer duration of treatment, it has a further limitation from the standpoint of patient compliance. Another anti-relapse agent namely tafenoquine is disclosed in United States Patent 4 617 394. Though more effective than primaquine, the drug was found to cause methemoglobin toxicity almost three times more than that of primaquine ( Fundam. Appl. Toxicol. 1988, 10(2), 270-275), hence has drawbacks in terms of safety. The compound, 3-[l-[[4-[(6-metho-8-quinolinyl)amino]pentyl]amino]- ethylidene]-dihydro-2(3H)furanone is an analogue of primaquine. was described in Indian Patent Specification No. 158111 as methoxy-8-(4-N-(3'-aceto-4',5'-dihydro-2-furanylamino)-l-methylbutyl-amino)quinoline, the structure of which was revised to that represented by the following formula I. As per the revised structure, the compound is named 3-[l-[[4-[(6-metho-8-quinolinyl)amino]pentyl]amino]ethylidene]-dihydro-2(3H)furanone (hereinafter referred to as compound I). The revised structure is described in WHO Drug Information Vol. 13, No. 4, pg. 268 (1999). The compound of formula (I) has been found to be safer and less toxic than the parent compound primaquine (Am. J. Trop. Med. Hyg, 1989 Dec; 41(6): 635-637). Its anti-relapse activity has been found to be comparable to primaquine. Over the years primaquine was the only drug used for the radical cure of malaria caused by P. vivax. Primaquine is associated with a number of severe adverse effects, therefore there is a need to develop agents which are more effective and/or less toxic than primaquine. The compound I has been found to exhibit anti-relapse activity comparable to Primaquine (Am. J. Trop. Med. Hyg., 41(6): 633-637 (1989)). However, this compound has been shown to cause less methemoglobin formation (Am. J. Trop Hyg., 41(6): 638-642 (1989) ) and also has less effect on anti-oxidant defence en2ymes than primaquine (Biochem Pharmacol. 46(10): 1859-1860 (1993) ). Thus, this primaquine analogue(I) is found to be less toxic as compared to the parent drug, primaquine. Therefore, there is a longfelt need for a more practical, effective, patient compliant and safe remedy for the radical cure of P. vivax malarial infection. The inventors have found that the longfelt need may be fulfilled by providing a treatment regime consisting of regulated use of chloroquine and 3-[l-[[4-[(6-methoxy-8-qumoUnyl)amino]pentyl]amino]ethylidene]-dihydro-2(3H)furanone of formula I over a period of between 5 to 8 days. It has also been found that the treatment regime may be executed most effectively and in a user friendly manner by providing a combination kit which comprises two anti-malarial agents, namely chloroquine and 3-[l-[[4-[(6-methoxy-8-quinolinyl)amino]pentyl]amino]ethylidene]-dihydro-2(3H)furanone and an instruction material containing instructions for the administration of two anti-malarial agents during the period of treatment. Thus the present invention relates to a combination kit for the treatment of P. vivax malaria for a period of between 5 to 8 days which comprises a) a predetermined dose of a first anti-malarial agent namely chloroquine; b) a predetermined dose of second anti-malarial agent namely 3-[l-[[4-[(6-methoxy-8-quinolinyl)amino]pentyl]amino]-ethylidene]-dihydro-2(3H)furanone; c) an instruction manual containing instructions for administering the two anti-malarial agents during the treatment period. The present invention also relates to a method of treatment of malaria caused by P. vivax comprising administering a first anti-malarial agent, chloroquine and a second anti-malarial agent, 3-[l-[[4-[(6-methoxy- 8-quinolinyl)amino]pentyl]amino]ethylidene]-dihydro-2(3H)furanone in predetermined doses and in a predetermined sequence for a period of between 5 to 8 days. DETAILED DESCRIPTION OF THE INVENTION According to a preferred aspect of the invention there is provided a combination kit for the treatment of malaria caused by P. vivax for a period of between 5 to 8 days comprising: 1. individual doses of anti-malarial agent, 3-[l-[[4-[(6-methoxy-8-quinolinyl)aminolpentyl]amino]ethylidene]-dihydro-2(3H)-furanone (I) in the form of capsules and; 2. individual doses of the anti-malarial agent, chloroquine in the form of tablets. 3. instruction material for the administration of the two anti¬malarial drugs. In accordance with a typical embodiment of the invention, there is provided a combination kit for 6 days treatment of malaria caused by P. vivax comprising: a) five tablets containing 500 mg of chloroquine phosphate ( equivalent to 300 mg base). b) five capsules containing 25 mg of 3-[l-[[4-[(6-methoxy-8-quinolmyl)amino]penryl]amino]ethylidene]-dihydro-2(3H)-furanone; c) instruction material having directions to administer treatment in the following manner: (i) to administer three tablets containing 500 mg of chloroquine phosphate ( equivalent to 300 mg base) on day one; (ii) to administer one capsule containing 25 mg of compound I concurrently with a tablet containing 500 mg of chloroquine phosphate (equivalent to 300 mg base) from day two to three; and (iii) to administer one capsule containing 25 mg of compound I from day four to day six. In accordance with a further typical embodiment of the invention, there is provided a method for the treatment of malaria caused by P. vivax for a period of six days comprising: 1. administering three tablets containing 500 mg of chloroquine phosphate ( equivalent to 300 mg base) on day one; 2. administering one capsule containing 25 mg of compound I concurrently with a tablet containing 500 mg of chloroquine phosphate ( equivalent to 300 mg base) from day two to three; and 3. administering one capsule containing 25 mg of compound I from day four to day six. THE KIT The kit used in the present invention may be one or more strips in which the anti-malarial agents are packed individually or in combination. The kit may further comprise an enclosure in the form of a small carton or otherwise. The instruction is in the form of printed instructions provided inside the carton. The instructions may also be printed on the carton and/or on the strip or strips itself. The instructions may be in English and/or in any national or regional language. An illustration of an instruction material for a 6 days treatment regime is shown in Table 1 below, although other forms of instruction materials are not excluded from the scope of the invention. TABLE 1 INSTRUCTION MANUAL FOR 6 DAYS TREATMENT OF MALARIA CAUSED BY Plasmodium Vivax CHLOROQUINE TABLET DAY 1 DAY 2 DAY 3 DAY 4 DAY 5 DAY 6 Start with 2 tablets 1 tablet 1 tablet X X X 1 tablet after 6 hours + + CAPSULE OF COMPOUND OF FORMULA (I) X 1 capsule 1 capsule 1 capsule 1 capsule 1 capsule The radical curative anti-malarial activity and toxicity of the compound I was evaluated and compared with that caused by primaquine. The curative activity of compound I was evaluated against P. cynomolgi (a Plasmodium species which closely resembles the human malarial parasite P. vivax), in rhesus monkeys for seven days and the compound was found to be 100% curative in the dose range of 1.25 mg/kg to 4 mg/kg. The toxicity with respect to methemoglobin formation is very important and it was found that the methemoglobin formation increased 3.2 fold in case of compound I (at 3.75 mg/kg weight for seven days) as against the 10.55 fold increase in case of primaquine (at 3 mg/kg weight for seven days) when tested in beagle dogs. Hence, compound I is safer than the well-known anti-relapse agent, primaquine The invention thus includes the use of this safer anti-relapse agent, compound 1 with chloroquine in the form of a combination kit for the radical cure of P. vivax malaria. According to a typical aspect described above, the total course of treatment wherein compound I is administered concurrently with chloroquine lasts for six days only whereas in the chloroquine-primaquine treatment regimen the total course of the treatment is 17 days. Thus the novel combination therapy of the present invention comprising the use of compound I in combination with chloroquine has distinct advantages in terms of safety and improved patient compliance due to shorter duration of treatment. Thus the use of the combination kit of the present invention containing chloroquine and the compound I becomes a very useful treatment from the standpoint of low toxicity. In addition to this, concurrent administration of the drugs and shorter duration of the treatment may also improve patient compliance. The chloroquine tablets and capsules of compound I may be obtained commercially or prepared by conventional methods. For instance, the capsules containing compound I may be prepared by first mixing appropriate quantities of compound I along with the excipients lactose, colloidal silicon dioxide and magnesium stearate in an octagonal blender to obtain a powdered mixture and further filling hard gelatine capsule shells with the resulting mixture. The capsules are blister packed using approved PVC film and aluminium foil. The dosage of the drugs depends on the need of an individual and the dosages described herein are adult doses. However, this invention is not limited to the dosage of the combination regimen described herein and may be varied according to medical advice. Accordingly the specific dosage described in the typical embodiment is only illustrative and non-limiting combination kits for other dosage forms are also included in the scope of this invention. The term relapse is used herein to indicate that the symptoms of malaria recur. The invention will now be described in further details with respect to the following non-limiting examples: Example 1: Combination kit consisting of chloroquine tablets and capsules of 3-[l-[[4-[(6-methoxy-8-quinolmyl)amino]pentyl]amino]ethylidene]-dihydro-2-(3H)furanone (I) A. Each tablet contains 500 mg of chloroquine phosphate equivalent to 300 mg chloroquine base. The tablet containing chloroquine may be prepared by conventional techniques. B. Each capsule contains 25 mg of 3-[l-[[4-[(6-methoxy-8- quinolmyl)amino]penryl]amino]ethylidene]-dihydro-2(3H)furanone (I). The capsule containing compound I may be prepared according to the following formulation by the procedure as described: Compound I 25 mg Lactose 250 mg Colloidal silicon dioxide 2 mg Magnesium stearate 10 mg Procedure: Compound I (25 mg), lactose (250 mg), colloidal silicon dioxide (2 mg) are separately sifted through an S. S. screen no. 40 fitted on a vibratory sifter and transferred to a octagonal blender and the contents are mixed for 40-45 minutes. Then magnesium stearate (10 mg) is sifted through a S. S. screen no. 40 fitted on a vibratory sifter and transferred to the octagonal blender. The contents are further mixed for 10-15 minutes. The resulting powdered mixture is then filled in size '2' double locking gelatine capsule shells which are further polished using a capsule polishing machine. C. The patients were given the following treatment over a period of six days. Day 1 : Three tablets of chloroquine phosphate 500 mg (equivalent to 300 mg base). Day 2 : One tablet of chloroquine phosphate 500 mg (equivalent to 300 mg base) and one capsule containing 25 mg of compound I. Day 3 : One tablet of chloroquine phosphate 500 mg (equivalent to 300 mg base) and one capsule containing 25 mg of compound I. Day 4 : One capsule containing 25 mg of compound I. Day 5 : One capsule containing 25 mg of compound I. Day 6 : One capsule containing 25 mg of compound I. Example 2 : Combination regimen of chloroquine and 3-[l-[(4-[(6-methoxy-8-qumolmyl)ammo]pentyl]amino]ethylideneJ-dihydro-2(3H)furanone(I) tested against P. cynomolgi in rhesus monkeys. The therapeutic effect of the combination regimen consisting of chloroquine and 3-[l-t[4-[(6-methoxy-8-quinolmyl)amino]pentyl]amino]- ethylidene]-4,5- dihydro-2(3H)furanone (I) was tested against P. cynomolgi on 25 rhesus monkeys. 3-[l-[[4-[(6-methoxy-8-quinolinyl)- armino]pentyl]amino]ethylidene]-dihydro-2(3H)furanone(I) was admini- stered to the monkeys in the dose level of 4.00 mg/kg, 2.50 mg/kg, 2.00 mg/kg and 1.25 mg/kg for seven days. Chloroquine was administered as a companion drug at 5mg /kg (base) dose. Minimum curative dose of compound I was found 1.25 mg/kg in 9 monkeys. Doses higher than 1.25mg/kg i.e. 2.0 mg/kg (base), 2.50 mg/kg (base), 3.00 mg/kg base and 4.00 mg/kg (base) were also found to be curative in 3 monkeys, 4 monkeys, 3 monkeys and 3 monkeys respectively. After stopping the treatment all the monkeys were observed over a period of 100 days and the blood smears remained negative in all the monkeys. Example 3: Toxicity study data: 3-[l-[[4-[(6-methoxy-8-quinolinyl)amino]pentyl]amino]ethylidene]-dihydro-2(3H)furanone (I) was evaluated vis-a-vis primaquine for toxicity related to methemoglobin formation in human. The methemoglobin toxicity of compound I was evaluated vis-a-vis that of primaquine in normal human volunteers. It was found that when the human subjects were administered with 25 mg O.D. of compound I for 7 days the methemoglobin level rose from 2.29 % to 3.02 % and in case of 15 mg O.D. of primaquine for 7 days the methemoglobin level rose from 3.97 % to 16.32 %. It is thus evident from above data that the compound I is safer than primaquine. No monopoly is claimed by this applicant for chloroquine or 3-[l-[[4-[(6-methoxy-8-quinolinyl)amino]pentyl]amino]ethylidene]-dihydro-2(3H)furanone or its combination other than what is disclosed and claimed herein. A combination kit for the treatment of P. vivax malaria comprising: ... a) a predetermined dose of a first anti-malarial agent namely chloroquine; b) a predetermined dose of second anti-malarial agent namely 3-fl[[4-[(6-methoxy-8-quinolinyl)amino] pentyl]-amino]ethylidene]-dihydro-2(3H) furan-one; c) an instruction material containing instructions for administering the two anti-malarial agents during the treatment period, wherein the anti-malarial agents are provided for a period between 5 to 8 days. A combination kit as claimed in claim 1, wherein the anti-malarial agents are provided for 6 days treatment in the following manner: (a) five tablets containing 500 mg of chloroquine phosphate (equivalent to 300 mg base); (b) five capsules containing 25 mg of 3-[l[[4-[(6-methoxy-8-quinolinyl)amino] pentyl]-amino]ethylidene]-dihydro-2(3H) furan-one(I); (c) instruction material for indicating the administration of the two anti¬malarial drugs in the treatment of P. vivax malaria in the following manner: (i) to administer three tablets containing 500 mg of chloroquine phosphate (equivalent to 300 mg base) on day one; (ii) to administer one capsule containing 25 mg of compound I concurrently with a tablet containing 500 mg of chloroquine phosphate (equivalent to 300 mg base) from day two to three; and (iii) to administer one capsule containing 25 mg of compound I from day four to day six. 3. A combination kit as claimed in anyone of the preceding claims, which is in the form of one or more strips in which the anti-malarial agents are packed. 4. A combination kit as claimed in anyone of the preceding claims, which is in the form of a small carton or otherwise, in which the instruction material is in the form of a printed instructions provided inside the carton. 5. A combination kit as claimed in anyone of the claims 1 to 4, which is in the form of a small carton or otherwise, in which the instruction material is in the form of prints on the carton and/or on the strip or strips. Dated this 27th day of May 2000 S. Majumdar Of S. Majumdar&Co. Applicant's Agent

Documents:

501-mum-2000 cancelled pages(30-8-2005).pdf

501-mum-2000 claims(granted)(30-8-2005).pdf

501-mum-2000 correspondence(27-12-2006).pdf

501-mum-2000 correspondence(ipo)(25-4-2007).pdf

501-mum-2000 form 1(23-8-2000).pdf

501-mum-2000 form 1(31-5-2000).pdf

501-mum-2000 form 19(8-9-2003).pdf

501-mum-2000 form 2(granted)(30-8-2005).pdf

501-mum-2000 form 3(31-5-2000).pdf

501-mum-2000 power of attorney(25-9-2000).pdf

501-mum-2000-claims(granted)(30-8-2005).doc

501-MUM-2000-CORRESPONDENCE(4-2-2011).pdf

501-mum-2000-form 2(granted)(30-8-2005).doc