Title of Invention

"A COMPOSITION FOR REVERSING MALARIA DRUG RESISTANCE"

Abstract

The invention relates to a combination for reversing malarial resistance to a quinoline antimalarial agent, such as cholroquine or mefloquine, comprising a quinoline anti malarial agent and a surfactant, in an admixture with pharmaceutically acceptable carrier, excipient, or diluent. The surfactant is optionally a nonylphenolethoxylate (NPE) surfactant comprising at least 15 ethoxylate units, such as NPE 20-40. Another embodiment of the invention relates to uses of the compositions for reversing malarial resistance and preventing or treating malaria in a patient.

Full Text

BACKGROUND OF THE INVENTION Field of the Invention This invention relates to compositions and methods for preventing or treating Plasmodium falciparum malaria. In particular, this invention relates to surfactant compositions and methods for reversing malarial resistance to quinoline antimalarials. Description of the Prior Art Plasmodium falcipantm malaria is the world's most important parasitic infection accounting for an estimated 300 to 500 million cases and 1.5 to 2.7 million deaths annually [reviewed in Kain. 1998a]. P. falciparum infection accounts for over 90% of the morbidity and mortality associated with malaria. Young children living in malaria-endemic areas and other non-immune individuals are at the greatest risk of developing severe complications such as cerebral malaria leading to death. Despite intensive research, no specific treatments have been identified to prevent or improve the outcome of patients with severe malaria [White. 1998]. Severe and cerebral malaria carries a high fatality rate (>15%) even for young, previously healthy individuals [White 1998]. With escalating drug resistance and the lack of an effective vaccine, there is an urgent need for alternative therapeutic strategies. Malaria associated morbidity and mortality is increasing because of widespread resistance to chloroquine. which is one of the safest and least expensive antimalarials. Chloroquine-resistant P. falcipanim malaria was first recognized over 40 years ago and has since spread to almost all malaria-endemic areas [Su, 1997]. Chloroquine-resistant malaria has extended into the high transmission areas of Africa resulting in a public health crisis since switching to alternative antimalarials. such as mefloquine. artemisinin derivatives, halofantrine or quinine, is economically untenable for many countries in sub-Saharan Africa. Recent reports indicate that escalating mortality due to widespread malaria resistance is now taking place [Marsh, 1998]. . The mechanism of chioroquine-resistance in P. falciparum remains controversial. However, it is frequently compared to multidrug resistance in mammalian cells that is often mediated by P-glycoproteins [Bray, 1998]. Mammalian P-glycoproteins are intrinsic membrane protein drug transporters that actively pump a wide variety of drugs and other xenobiotic compounds out of cells. Although P-glycoproteins can pump many types of chemotherapeutic agents like vinblastine and adriamycin out of cancer cells, the multidrug resistance phenotype of such cells can be modified by a variety of compounds including the immunosuppressant. cyclosporin A and calcium channel blockers such as verapamil. These chemosensitizers. competitively interact with drug-binding sites on P-glycoprotein. thereby interfering with the transport of chemotherapeutic agents out of cells. It is known that drug resistance in P. falciparum can be reversed by calcium channel blockers such as verapamil [Martin. 1987]. The amipsychotics (e.g. chlorpromazine [Basco. 1992]), and histamine (H-l) receptor antagonists (e.g. promethazine [Oduola, 1998], chlorpheniramine [Basco. 1994]) also reverse chioroquine-resistance in P. falciparum in vitro and in malaria animal models [Bray. 1998]. However, these agents are pharmacologically active compounds with multisystem effects that result in a variety of undesirable side effects. Furthermore, these compounds are often more expensive than chloroquine itself and the concentrations required to reverse clinical drug-resistance for some of these agents can be toxic. Accordingly, there is a need for safe, stable and inexpensive compositions and methods which reverse resistance to malarial quinoline. SUMMARY OF THE INVENTION This invention provides safe, stable and inexpensive compositions and methods which reverse resistance to malarial quinoline. The combination of a quinoline and a surfactant offers a treatment for malaria that: 1. is inexpensive for use in developing countries, 2. is comprised of two stable compounds that do not require expensive or unusual storage conditions. 3. provides increased absorption and decreased excretion of the anti-malarial component, and 4. does not require the introduction of other pharmacological agents with undesirable side effects. It is an object of the invention to provide an agent that reverses quinoline resistance in P. falciparum malaria. Quinoline antimalarials include, but are not limited to, the 4 amino-quinolines (chloroquine, mefioquine, quinine, and quinidine) and the 8 amino-quinolines (primaquine and etaquine [WR238605]) According to a first aspect of the invention, a composition for reversing malaria] resistance to quinoline antimalarials is provided. The composition comprises a synthetic, a natural or a hybrid surfactant in an admixture with a pharmaceutically acceptable carrier, excipient, or diluent. Preferably, the surfactant is the synthetic compound nonyiphenolethoxylate ("NPE") having between 10 and 70 ethoxylate units. According to a second aspect of the invention, a composition for the treatment or prevention of malaria is provided. The composition comprises a pharmaceutically effective amount of a quinoline in combination with a surfactant, the surfactant being adapted to reverse malarial resistance to the quinoiine. Preferably, the surfactant is NPE having between 10 and 70 ethoxylate units. According to a third aspect of the invention, a method of treating or preventing malaria is provided. The method comprises administering to a patient in need thereof one or both of the compositions described above. According to a fourth aspect of the invention, a method of treating or preventing malaria is provided. The method comprises the steps of: (a) forming a composition by combining a pharmaceutically effective amount of quinoline with a pharmaceutically effective amount of a surfactant; and (b) administering an effective dose of the composition to a patient infected with or at risk of contracting malaria. Preferably, the surfactant is NPE having between 10 and 70 ethoxylate units. Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS In order that the invention may be more clearly understood, the preferred embodiments thereof will now be described in detail by way of example, wiih reference to the accompanying drawings, in which: Figure 1 shows the general chemical structure of nonylphenolethoxylates (NPEs). Figure 2 shows anti-P. falciparum activity and sensitizing potential of NPEs. NPE solutions with increasing average EO content were tested for ami- P.falciparum activity and the IC^s* of these materials were determined using a non-linear regression analysis. IC50 results are expressed on both a per weight basis (A. top panel) and on a molar concentration basis (B, middle panel). The ability of a 5\iM concentration of NPEs to sensitize P.falcipamm in vitro to chloroquine was determined (C, bottom panel). The degree of chloroquine resistance is calculated as the ICjo value observed in the presence of various NPEs divided by the control (no NPE added) chloroquine IC-io (240 ±60 nM). Values greater than I indicate that the particular NPE is rendering the P.falciparum parasites less sensitive to chloroquine. while values less that 1 indicate that the particular NPE is sensitizing the P. falciparum to chloroquine. Anil-P.falciparum activity and sensitization are representative results obtained from multiple determinations. Results are plotted as mean with the standard error (as calculated by Sigma Plot) indicated with bars. Figure 3 shows the effect of adding increasing amounts of NP30 on the degree of chloroquine resistance of P. falciparum. The degree of chloroquine resistance is calculated as the ICso value observed in the presence of various concentrations of NP30 divided by the control (no NPE added) * ICjp values represent the concentration at which 50% of the parasites present are killed or have their growth inhibited. chloroquine 1C50 (274 ±56 nM). Values greater than 1 indicate that the particular NPE is rendering the P. falciparum parasites less sensitive to chloroquine, while values less that I indicate that the particular NPE is sensitizing the P. falciparum to chloroquine. Non-linear analysis of the data points indicates that a NP30 concentration of approximately lu.M (0.0002% on a weight/volume basis) results in a 50% decrease in the degree of chloroquine resistance of the parasites. DESCRIPTION OF THE PREFERRED EMBODIMENT Although the description refers to nonylphenoiethoxylate or NPE. as a preferred surfactant, such references are not intended to be limiting. It will be understood to those skilled in ihe art that natural surfactants, such as fatty acids, oils, bile acids, cholates. cholesterol esters, phospholipids. and chemically modified forms of these materials, as weil as synthetic surfactants such as the Brij™ series, the Tween™ series, the octylphenol ethoxyiate (OPE) Series, the NPE series and any of the synthetic surfactants such as those listed in "Industrial Surfactants" by Ernest W. Rick. Noyes Publications, Park Ridge, New Jersey. USA (1988) ISBN 0-8155-1173-6 may be used and are within the scope of this invention. As shown in Fig. 1. nonylphenolethoxylates (NPEs) consist of a hydrophobic tail group with a polymeric hydrophilic head portion consisting of repeating units of ethoxyiate. NPEs are synthesized by co-polymerization of ethylene oxide with nonylphenol thereby producing a polydisperse mixture of head group lengths (X values) as described by Robert M. Weinheimer and Pierre T. Varineau in their 1998 book "Nonionic surfactants" Volume 72 of the Surfactant Science Series, edited by Nico M. van Os. published by Marcel Dekker. Inc. (New York) (ISBN 0-8247-9997-6). Nonylphenolethoxylates [Charuk, 1998] (NPEs. figure 1) are synthetic surfactants that are inexpensive enough to used in a variety of household products. They can be used as wetting agents and have been tested as intestinal permeability enhancers to improve oral drug delivery [Swenson. 1994]. Their toxicology has been investigated [Larson. 1963: Finnegan. 1953] as has their absorption, distribution and excretion in humans and rodents [Swenson. 1994; Knaak. 1966]. NPEs are rapidly absorbed orally and topically and are actively excreted into the urine of healthy control subjects by ki'dney P-glycoprotein [Charuk. 1998]. We have determined that the nonylphenol (NP) series of ethoxylate (EO) containing surfactants reversed chloroquine resistance in both established laboratory lines of P. falciparum and patient isolates. Optimal chloroquine resistance reversal for P. falcipantm in vitro was seen for NPEs with approximately 30 ethoxylate units, whereas maximal activity for reversing mammalian P-glycoprotein multidrug resistance occurs with NPEs of 9 ethoxylate units [Loe, 1993]. This finding indicates that NPEs can be directed to interact preferentially with the parasite simply by altering the number of ethoxylate units in the surfactant's structure. Methods P.falcipanim cultures were grown in A+ blood obtained by venipuncture of volunteers. Cultures of the laboratory lines ItG and 3D7 [Dolan. 1993] and the patient isolates were maintained by the method of Trager and Jensen [Trager, 1976] using RPMI 1640 supplemented with 10% human serum and SO^iM hypoxanthine. Patient isolates were obtained from pre-treatment blood samples from patients enrolled in ongoing and ethically approved studies at the Tropical Disease Unit (TDU), University of Toronto [Kain. 1998b; Zhong, 1999]. In vitro drug, susceptibility testing was performed using the WHO In Vitro Micro Test (Mark EQ) [ 1997]. The ICJO values were determined using a non-linear regression analysis of the dose-response curve. NPEs were obtained from Union Carbide and were extensively dried by lyophilizing before being made up as 1% (w/v) stock solutions in water. Results Initial experiments were undertaken to confirm that the parasite lines (e.g. 3D7) used for experimentation were chloroquine sensitive, or to examine the degree of chloroquine resistance present by determining the IC50 for the ItG line. Isolate 1 and Isolate 2 (Table 1). We then proceeded to determine what effect increasing concentrations of surfactant alone had on each P. falciparum isolate in vitro. NPE preparations with a common hydrophobic tail group but with hydrophilic head groups of varying EO chain length were assayed for their direct activity against P. falciparum. On a per weight basis. NPEs with an average EO head length of >10 but 10 had low ICso values (Figure 2B). The IC50 values of these surfactants were significantly lower than the concentrations at which micelles form (>100u.M). The mechanism of action of NPEs is therefore unlikely to be simple disruption of membrane integrity. We then determined if NPEs were capable of reversing chloroquine resistance. Initial experiments indicated that 8 ^M NP15 was able to reverse chloroquine resistance as effectively as 1 pM verapamil in the chloroquine resistant ItG line and two drug resistant patient isolates, one from India and one from Africa (Table 1). To determine if chloroquine sensitization was also dependent on the number of EO units in the head group of the surfactant, the reversal potential of the NPE series was determined using 5 |iM concentrations of each surfactant. We determined that an NPE preparation wiih an average EO head length of 30 was the most effective chloroquine resistance reversal agent (Figure 2C). To determine if both the tail and head groups were required for activity, the effect of the ethoxylate polymer polyethylene glycol (PEG, n-75), which has no tail group, was assayed. PEG was completely ineffective as a chloroquine sensitizing agent (Table 1) indicating that both the head and tail portions of NPE are required for reversal activity. To determine what concentration of NP30 that was necessary to reverse chloroquine resistance to clinically achievable levels (~100nM) the degree of chloroquine resistance was determined for several concentrations of NP30 (figure 3). The degree of chloroquine resistance is calculated as the IC50 value observed in the presence of various concentrations of NP30 divided by the control (no NPE added) chloroquine 1CJO (274 ±56 nM). Values greater than 1 indicate that the particular NPE is rendering the P. faldparum parasites less sensitive to chloroquine, while values less that 1 indicate that the particular NPE is sensitizing the P. faldparum to chloroquine. Non-linear analysis of the data points indicates that a NP30 concentration approximately ^M (0.0002% on a weight/volume basis) results in a 50% decrease in the degree of chloroquine resistance of the parasites. Discussion The future use of NPEs as a malarial chloroquine resistance agents can be rationalized since unlike other reversal agents, they have weak, or no, pharmacological properties. Studies of NPE pharmacokinetics in mammals [Knaak, 1966] demonstrate that they are rapidly excreted. NPEs, particularly those with EO> 10, are less toxic than shorter EO chain length surfactants (EO Treatment or prevention of malaria with a chloroquine/NPE combination provides at least three benefits: 1) NPEs enhance the gastrointestinal uptake of chloroquine [Swenson, 1994]. Varying the length of the head group of NPEs alters the hydrophobe /hydrophile balance of the surfactant, and while longer EO polymers may be less well absorbed, they still facilitate intestinal absorption. 2) NPEs in the absence of a quinoline have antimaiarial activity. Our results indicate that NPEs with longer head groups (those found in preparations with an average ethoxylate unit content of 30 units per nonylphenol group) inhibit the development of P.falciparum in red cells and therefore NPEs on their own function as ami-malarials. 3) While NPEs and chloroquine are antimaiarial agents when used separately, in combination they have additive or synergistic effects that make them a potent anti-malarial combination. Further, since P.falciparum is sensitive to NPEs with head group lengths >15 EOs it is possible to treat or prevent P.falciparum infection with little, or no, effect on mammalian P-glycoprotein function. [Charuk, 1998]. The NPEs used in this study are a subset of the available head/tail group combinations that comprise commercially-available surfactants. Further separation of poly-disperse NPE preparations into compounds with uniform head group lengths may allow us to further define the optimal head length (EO number) that sensitizes chloroquine-resistant P. falciparum. An examination of other types of ethoxylate-containing surfactants will also allow us to determine which tail groups ore most active. We believe that fatty acids, oils, bile acids, cholates. cholesterol esters, phospholipids, and chemically modified forms of these materials (such as Cremophor [Woodcock et al.J, and Solutol H515 [Coon et a!., Buckingham et al.J) as well as synthetic surfactants such as the Brij™ series, the Tween™ series, the OPE Series, the NPE series and any of the synthetic surfactants such as those listed in "Industrial Surfactants" [Ernest W. Flick, Noyes Publications, Park Ridge, New Jersey. USA (1988) ISBN 0-8155-1173-6] are promising malarial drug resistance reversal agents. To design and obtain products that reverse malarial resistance to chloroquine we will systematically test a variety of commercially available surfactants. To assay for reversal activity, human red blood cells parasitized with P. falcipanim will be placed in 96 well cell culture plates. The plate will contain a series of chloroquine concentrations (typically from 5,000 to 5nM) and after 24hrs the viability of the malaria will be determined using an assay that measures the levels of Plasmodium lactate dehydrogenase present [Mackler. 1993]. The data obtained from the enzyme assay will be analyzed using a non-linear curve fitting program (Sigma Plot - Jandel) and an ICso value will be derived. This process is repeated in the presence of putative surfactant sensitizing agents. The ability of a surfactant to sensitize Plasmodium to chloroquine or other quinolines is then expressed as the degree of resistance (ICJO with agent/lC50 without agent, where reversal of resistance gives values 1. no effect values=l) [Oduola. 1998]. Using this assay we will evaluate surfactants with common tail groups, and then determine the effect of varying the head group (poly EO) on the compound's ability to sensitize P. falcipanim to chloroquine and other quinolines. A wide variety of surfactants are commercially available, however they are usually polydisperse mixtures of single tail groups with a range of head group lengths that average to a stated value. These mixtures will be separated into their individual monodisperse constituents to allow us to determine the sensitization potential of individual surfactant species. The in vivo effect of surfactant sensitizing agents will be determined by infecting a cohort of Aotus monkeys with P. falcipanim isolates with known quinoline resistance properties. One group of animals will be treated with a quinoline alone, a second will be treated with a surfactant preparation alone, and a third group will be treated with a quinoHne in combination with a surfactant. The course of the infections will be followed and the efficacy of the quinoline/surfactant combination will be determined. In view of the results described above, products containing natural, synthetic or hybrid surfactants in combination with quinolines. can be selected and designed in the manufacture of pharmaceutical compositions for the treatment or prevention of malaria. The pharmaceutical compositions can be administered to patients by methods known to those skilled in the an, such as oral capsule, aerosol administration, direct lavage and intravenous injection. Dosages to be administered depend on patient needs, on the desired effect and on the chosen route of administration. The pharmaceutical compositions can be prepared by known methods for the preparation of pharmaceutically acceptable compositions which can be administered to patients, and such that an effective quantity of the products are combined in a mixture with a pharmaceutically acceptable vehicle. Suitable vehicles are described, for example in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences. Mack Publishing Company. Easton, PA, USA 1990). On this basis, the pharmaceutical compositions could include one or more active ingredients, in association with one or more pharmaceutically acceptable vehicles, such as carriers, excipients or diluents, and contained in buffered solutions with a suitable pH and isoosmotic with the physiological fluids. The methods of combining suitable products with the vehicles is well known to those skilled in the art. When used for parenteral administration, the pharmaceutical compositions of the present invention may be formulated in a variety of ways. Aqueous solutions having the composition of the present invention may be encapsulated in polymeric beads, liposomes. nanoparticles or other injectable depot formulations known to those of skill in the art. (Examples thereof may be found, for example, in Remington's Pharmaceutical Sciences, 18th Edition. 1990.) Compositions including a liquid pharmaceutically inert carrier such as water may also be considered for both parenleral and oral administration. Other pharmaceutically compatible liquids may also be used. The use of such liquids is well known to those of skill in the art. (Examples thereof may be found, for example, in Remington's Pharmaceutical Sciences. 18th Edition, 1990.) The dose level and schedule of administration may vary depending on the^particular product used, the method of administration, and such factors as the age and condition of the patient. Oral formulations of products may optionally and conveniently be used in compositions containing a pharmaceutically inert carrier, including conventional solid carriers, which are conveniently presented in tablet or capsule form. Formulations for rectal or transdermal use may contain a liquid carrier that may be oily, aqueous, emulsified or contain certain solvents suitable to the mode of administration. Suitable formulations are known to those of skill in the art. (Examples thereof may be found, for example, in Remington's Pharmaceutical Sciences, 18th Edition. 1990.) Having illustrated and described the principles of the invention in a preferred embodiment, it should be appreciated to those skilled in the an that the invention can be modified in arrangement and detail without departure from such principles. All modifications coming within the scope of the following claims are claimed. All publications, patents and patent applications referred to in this application are incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. References: 1. Basco LK, Le Bras J. In vitro activities of chloroquine in combination with chlorpromazine or prochlorperazine against isolates of Plasmodium falciparum. Antimicrob Agents Chemother 1992;36(1):209-13. 2. Basco LK, Le Bras J. In vitro reversal of chloroquine resistance with chlorpheniramine against African isolates of Plasmodium falciparum. Jpn J MedSci Biol 1994;47(l):59-63. 3. Bray PG, Ward SA. A comparison of the phenomenology and genetics of multidrug resistance in cancer cells and quinoline resistance in Plasmodium falciparum. Pharmacol Ther 1998;77(1):1- 28. 4. Bray PG, Mungthin M. Ridley RG. Ward SA. Access to hematin: the basis of chloroquine resistance. Mol Pharmacol \ 998:54( 1): 170-9. 5. Charuk JH, Grey AA, Reithmeier RA. Identification of the synthetic surfactant nonylphenol ethoxylate: a P- glycoprotein substrate in human urine. Am J Physiol 1998 ;274(6):F 1127-39. 6. Dolan SA, Herrfeldt JA, Welkins TE. Restriction polymorphisms and fingerprint patterns from an interspersed repetitive element of Plasmodium falciparum DNA. Mol Biochem Parasitol 1993;61(1): 137-42. 7. Finnegan J, Dienna J. Toxicological observations on certain surface-active agents. Proceedings of the Science Section of the Toilet Goods Association 1953:20:16-19. 8. Kain KC. Keystone JS. Malaria in travellers: Prevention and treatment. InfDis Clinics of North Amer 1998a;2:2.1-18 9. Kain KC, Harrington MA. Tennyson S, Keystone JS. Imported malaria: prospective analysis of problems in diagnosis and management. Clin Infect Dis 1998b;27(l): 142-9. 10. Knaak, J.B., Eldridge, J.M.. and Sullivan, L.J., "Excretion of certain polyethylene glycol ether adducts on nonylphenol by the rat. Toxical. Appl. Pharmacol. 9: 331-340, 1966 11. Larson P, Borzelleca J. Bowman E, Crawford E, Smith J, Hennigar G. Toxicological studies ,» on a preparation of p-tertiary octylphenoxy-polyethyl ethanols (Triton X-405). Toxicology and Applied Pharmacology 1963:5:782-789. 12. Loe DW, Sharom FJ. Interaction of multidrug-resistant Chinese hamster ovary cells with amphiphiles. Br J Cancer 1993;68(2):342-51. 13. Mackler MT, Ries JM, Williams JA, et al. Parasite lactate dehydrogenase as an assay for Plasmodiumfalciparum drug sensitivity. Am J Trap Med Hyg 1993;48(6), 739-41. 14. Marsh K. Malaria disaster in Africa. Lancet 1998;352(9132):924. 15. Milhous W. Kyle D. Introduction to the Modes of Action of and Mechanisms of Resistance to Antimalarials. In: Sherman IW. ed. Malaria: Parasite Biology, Pathogenesis and Protection. Washington, D.C.: ASM Press, 1998: 303-316. 16. Martin S. Oduola A. Milhous W. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 1987:235:899-901. 17. Oduola AM. Sowunmi A. Milhous WK, et al. In vitro and in vivo reversal of chloroquine resistance in Plasmodium falciparum with promethazine. Am J Trap Med Hyg 1998;58(5):625-9. 18. Su X, Kirkman LA, Fujioka H, Wellems TE. Complex polymorphisms in an approximately kDa protein are linked to chloroquine-resistant P. falciparum in Southeast Asia and Africa. Cell 1997;91(5):593-603. 19. Swenson ES. Milisen WB, Curatolo W. Intestinal permeability enhancement: structure-activity and structure- toxicity relationships for nonylphenoxypolyoxyethylene surfactant permeability enhancers. Pharm Res 1994:ll(10):1501-4. 20. Trager W. Jensen J. Human malaria parasites in continuous culture. Science 1976;193:673- 675. 21. White NJ. Not much progress in treatment of cerebral malaria. Lancet 1998; 353(9128):594-5 22. WHO. In vitro micro-test (mark III) for the assessment of the response of Plasmodium falciparum to chloroquine, mefloquine, quinine, amodiaquine, sulfadoxine/pyrimethamine and arteminisinin: World Health Organization, 1997. 23. Zhong KJY. Kain KG. Evaluation of a colorimetric PCR-based assay to diagnose plasmodium falciparum malaria in travelers. J din Microbiol 1999;37(2):339-41. We claim: 1. A composition for reversing malarial resistance to a quinoline antimalarial agent comprising a quinoline antimalarial agent and a nonylphenolethoxylate (NPE) surfactant comprising 20 to 40 ethoxylate units, in an admixture with a pharmaceutical^ acceptable carrier, excipient, or diluent. 2. A composition as claimed in claim 1, wherein the quinoline antimalarial agent comprises a 4-amino quinoline, an 8-amino quinoline, halofantrine or mefloquine. 3. A composition as claimed in claim 1, wherein the NPE surfactant comprises NPE30. 4. A composition as claimed in claim 1, wherein the NPE surfactant on average contains 30 ethoxylate units. 5. A composition as claimed in any of claim 1, comprising an oral composition or a parenteraliy injectable composition. 6. A composition as claimed in claim 2, wherein the 4-amino quinoline comprises chloroquine. 7. A composition as claimed in claim 2, wherein the quinoline antimalarial agent comprises mefloquine. 8. A composition as claimed in any one of claims 1 to 7 whenever used for the purposes of manufacture of a medicament for preventing and/or treating malaria. 9. A process for the preparation of a composition as claimed in claims 1 to 7 which comprises combining a pharmaceutically effective amount of a quinoline antimalarial agent, a pharmaceutically effective amount of a NPE surfactant comprising 20 to 40 ethoxyiate units and a pharmaceutically acceptable carrier, excipient, or diluent.

Documents:

IN-PCT-2002-00624-DEL-Abstract-04-04-2008.pdf

IN-PCT-2002-00624-DEL-Abstract-27-05-2008.pdf

in-pct-2002-00624-del-abstract.pdf

in-pct-2002-00624-del-claims-(02-06-2008).pdf

IN-PCT-2002-00624-DEL-Claims-27-05-2008.pdf

in-pct-2002-00624-del-claims.pdf

in-pct-2002-00624-del-correspondence-others-(02-06-2008).pdf

IN-PCT-2002-00624-DEL-Correspondence-Others-04-04-2008.pdf

IN-PCT-2002-00624-DEL-Correspondence-Others-27-05-2008.pdf

in-pct-2002-00624-del-correspondence-others.pdf

in-pct-2002-00624-del-description (complete)-02-06-2008.pdf

in-pct-2002-00624-del-description (complete)-27-05-2008.pdf

in-pct-2002-00624-del-description (complete).pdf

IN-PCT-2002-00624-DEL-Drawings-04-04-2008.pdf

IN-PCT-2002-00624-DEL-Drawings-27-05-2008.pdf

in-pct-2002-00624-del-drawings.pdf

in-pct-2002-00624-del-form-1-(02-06-2008).pdf

IN-PCT-2002-00624-DEL-Form-1-04-04-2008.pdf

in-pct-2002-00624-del-form-18.pdf

in-pct-2002-00624-del-form-2-(02-06-2008).pdf

IN-PCT-2002-00624-DEL-Form-2-27-05-2008.pdf

in-pct-2002-00624-del-form-3.pdf

in-pct-2002-00624-del-gpa-(02-06-2008).pdf

in-pct-2002-00624-del-gpa.pdf

in-pct-2002-00624-del-pct-210.pdf

in-pct-2002-00624-del-pct-409.pdf

in-pct-2002-00624-del-pct-416.pdf

in-pct-2002-00624-del-petition-137-(02-06-2008).pdf

IN-PCT-2002-624-DEL-Correspondence-Others-(21-03-2011).pdf

IN-PCT-2002-624-DEL-Form-27-(21-03-2011).pdf