Abstract

1.Title of the innovation: Novel process of manufacture antimalarial Atovaquone nanoformulation and evaluation for antimalarial efficacy in a novel ACT.

2.Background:Atovaquone is poorly soluble and hence it shows 23% bioavailability as suspension and in case of tablet it is 5 to 10%. Dose for atovaquone is high (1000mg daily) and hence needs to be reduced.Meprone suspension of GSK is a nanosuspension with particle size distribution of 100 to3000 nm  (Patent US006018080A, 2000).Borhade et. al., 2013 compared in vivo antimalarial activity of atovaquone with Malarone. The antimalarial suppressive activity was satisfactory with 1/8th and 1/16th dose of Atovaquone (25 and 12.5 mg/kg in mice) by the formulated Atovaquone Nanosuspension. The drawback being use of organic solvent with only 1% concentration of drug and problem of instability in liquid form.Aditya et al., 2017, reported   1/128th dose of Atovaquone nanoparticles to be effective in exhibiting antimalarial activity and 1/32th dose as curative dose. The electrospraying technology was used which is not a feasible option for large scale manufacturing Artemisinin-based combination therapies (ACTs) are recommended for the treatment of acuteuncomplicated falciparum malaria in many malaria-endemic countries. Despite the emergence of artemisinin resistance, few alternative non-ACTs, including atovaquone-proguanil, are currently available.Atovaquone-proguanil was characterized by a slow blood schizonticidal action and resulted in early treatment failure in a few patients. Artesunate-atovaquone-proguanil was a highly effective alternative treatment.1The Center for Disease Control and Prevention (CDC) suggests 4 equal doses of artesunate(2.4mg/kg each by IV) over a 3-day period followed by oral treatment with atovaquone-  proguanil, doxycycline, clindamycin or mefloquine to avoid emergence of resistance.

 In the current study, nanosized Atovaquone with proguanil and artesunate as a fixed dose combination is beinginvestigated for its improved pharmacokinetics as well as its effectiveness in treating malaria.Nanosuspensionformulation will improve the chance of therapeutic success and reduce resistance to the drugs and improve the bioavailability of poorly soluble Atovaquone. It has thepotential to reduce the dose in suppressive therapy at atleast 1/80th the dose and atleast upto1/20th the therapeutic dose in clinical simulation studies in micewhich could be safely used in pregnancy and other conditions where otherwise the drug may prove tobe toxic at the normal dose  level.

 

3. Product Description:Novel anti-malarial drug combination of Atovaquone, Proguanil and Artesunate to reducethe dose of atovaquone, improve bioavailability and reduce the resistance to therapy.

4. Technology:Simple pH based precipitation method in presence of surfactant and stabilizers followed byfurther size reduction to particle size less than 200 nm using probe sonicator or microfluidizer.On alarge scale the same technology as used in recrystallization of drug during synthesisbut inpresence of surfactant and stabilizer can be used. Also top down equipment for particle size reduction offers feasibility of large scale production.

5. Stage of Development: 4 day suppressive antimalarial efficacy in murine malaria model has been proven at 1/80th dose for atovaquone nanoformulation alone. Also clinical simulation study of Atovaquone nanosuspension in ACT is underway to prove its curative potential inACT in Plasmodium berghei  infected mice. Freeze drying will be carried out for converting itinto solid dosage form. Freeze dried product will be then formulated as a dry syrup which can bereconstituted before admin