Kirti Maheshwari

Nanosomal Amphotericin B is an efficacious alternative to Ambisome® for fungal therapy.

Amphotericin B was formulated in lipids (Nanosomal Amphotericin B) without using any detergent or toxic organic solvents during the preparation. Electron microscopy and particle size determination of Nanosomal Amphotericin B showed a homogeneous population of nanosized particles below 100 nm. Hemolysis assay indicated that Nanosomal Amphotericin B causes significantly less lysis of red blood cells than Amphotericin B deoxycholate and was comparable to Ambisome. A maximum daily dose of Nanosomal Amphotericin B at 5 mg/kg in rabbits and 10 mg/kg in mice for 28 days showed no symptoms of toxicity, mortality or significant body weight reduction. Hematological and gross pathological analysis of tissues revealed no abnormalities attributable to the drug treatment. Nanosomal Amphotericin B and Ambisome were injected (iv) at 2 mg/kg consecutively for 5 days into mice infected with Aspergillus fumigatus. The treatment resulted in 90% survival with Nanosomal Amphotericin B and only 30% survival with Ambisome after 10 days of fungal infection. However, all of the 10 control mice which were not treated with Amphotericin B died within 5 days of fungal infection. Nanosomal Amphotericin B is safe, cost effective and provides an alternative option for treatment of fungal disease.

Polyoxyl 60 hydrogenated castor oil free nanosomal formulation of immunosuppressant Tacrolimus: Pharmacokinetics, safety, and tolerability in rodents and humans

OBJECTIVE Develop Nanosomal formulation of Tacrolimus to provide safer alternative treatment for organ transplantation patients. Investigate safety, tolerability and pharmacokinetics of Nanosomal Tacrolimus formulation versus marketed Tacrolimus containing polyoxyl 60 hydrogenated castor oil (HCO-60) that causes side effects. METHODS Nanosomal Tacrolimus was prepared in an aqueous system. The particle size was measured by Particle Sizing Systems and structure morphology was determined by freeze-fracture electron microscopy. Investigational safety studies were conducted in mice and rats. Safety and pharmacokinetics of Nanosomal Tacrolimus were also evaluated in healthy human subjects. RESULTS The morphology of Nanosomal Tacrolimus showed a homogeneous population of nanosized particles with mean particle size of less than 100 nm. A 14 day consecutive administration of Nanosomal Tacrolimus up to 5 and 10mg/kg dose in rats and mice respectively, resulted in no mortality. Nanosomal Tacrolimus in human studies showed that it is safe and the pharmacokinetics profile is similar to the marketed HCO-60 based Tacrolimus. No significant change in peripheral blood lymphocyte percentage was noted in either mice or healthy human male subjects. CONCLUSIONS Nanosomal Tacrolimus is well characterized product which provides a new treatment option. It contains no alcohol or surfactants like HCO-60. Thus, Nanosomal Tacrolimus presents a new and improved therapeutic approach for organ transplant patients compared to the marketed HCO-60 based Tacrolimus product.

Single-dose, Two-way Crossover, Bioequivalence Study of Mycophenolate Mofetil 500 mg Tablet Under Fasting Conditions in Healthy Male Subjects

BACKGROUND Mycophenolate mofetil (MMF) is an immunosuppressant indicated for prophylaxis of acute organ transplant rejection. Generic MMF is less costly than the branded product, but European regulatory authorities require bioequivalence studies for the marketing of generics. OBJECTIVES The aims of the 2 studies reported were to assess the dissolution and bioavailability of a generic (test) and branded (reference) formulation of MMF 500 mg. METHODS An in vitro analytical dissolution profile test was conducted comparing 500 mg MMF test drug with a reference drug. A separate single-dose, randomized, open-label, 2-way crossover study involving fasting, healthy, adult male volunteers was conducted. Two study periods-1 test drug period and 1 reference drug period-were separated by a 14-day washout period. Blood samples were collected for up to 60 hours after drug administration for the determination of MMF and mycophenolic acid (MPA) pharmacokinetics. Concentrations of the analytes were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method; pharmacokinetic parameters were calculated using noncompartmental analysis; C(max), AUC(0-t), and AUC(0-∞) were the primary evaluation criteria. Bioequivalence was assumed if the 90% confidence intervals (CIs) for the test/reference ratios of natural logarithm transformed values (obtained using ANOVA) were between 80% and 125%, per European regulations for bioequivalence. Tolerability was monitored throughout the study. RESULTS The dissolution profiles of the test drug matched those of the reference drug at 4 pH levels. In the bioequivalence study, a total of 126 male subjects were dosed, and 117 subjects completed the study. The 90% CIs for MPA were C(max), 94.13% to 116.46%; AUC(0-t), 98.26% to 102.36%; and AUC(0-∞), 97.85% to 101.99%. These values met with the European regulatory definition of bioequivalence. Reported adverse events were similar in both the test and reference drugs. CONCLUSIONS This single-dose study found that the test and reference MMF 500 mg tablets met the European regulatory criteria for assuming bioequivalence in fasting, healthy, male subjects. Both formulations were well tolerated. (Clinical Trials Registry - India [CTRI]: 2011/03/002211).

A New Topical Formulation of Minoxidil and Finasteride Improves Hair Growthin Men with Androgenetic Alopecia

Objectives: To compare the safety and efficacy of MorrF (combination of Minoxidil [5%]+Finasteride [0.1%] lipid solution) with Minoxidil (5%) solution in adult male patients suffering from Androgenetic Alopecia (AGA). Background: AGA is one of the three most common forms of non-scarring alopecia with approximately 95% of hair loss cases in men and women. Fifty percent of men by age 50 years exhibit some degree of AGA. Currently there are two effective treatments available for the treatment of AGA in men: topical Minoxidil and oral Finasteride. Clinical studies have demonstrated that both Minoxidil and Finasteride have well established therapeutic effect in the management of AGA. Materials and methods: Safety study in rats was carried out for 28 days with topical application of MorrF twice a day for 28 days. Human Pharmacokinetics (PK) and efficacy study was conducted in male patients suffering from Androgenetic Alopecia. PK parameters were determined after 2 weeks of MorrF administration. For efficacy study patients were randomized to receive either MorrF or Minoxidil (5%) alone for 24 weeks. Patients administered 1 mL of the either solution twice day on the effected part of the scalp. Results: Topical treatment of MorrF was found to be well-tolerated in rats and humans. Pharmacokinetics study in human showed the steady state Cmax,ss and exposure (AUC0-τ,ss) for Minoxidil to be 2.7 ng/mL and 19.3 ng.h/mL respectively whereas the steady state maximum Finasteride concentration (Cmax,ss) was 0.6 ng/mL and exposure (AUC0-τ,ss) of Finasteride was found to be 6.3 ng.h/mL. Significantly more patients treated with MorrF showed greater improvement in Investigator score (65% vs. 26%), global photographic assessment (89% vs. 60%) and patient’s self-assessed questionnaire as compared to Minoxidil alone. Conclusion: Topical formulation of MorrF was shown to have clinically significant improvement in terms of hair growth as compared to Minoxidil (5%) alone.

Development of Aqueous Based Formulation of Docetaxel: Safety andPharmacokinetics in Patients with Advanced Solid Tumors

A well characterized Nanosomal Docetaxel Lipid Suspension (NDLS) formulation was developed without using any detergent or toxic organic solvents to avoid hypersensitivity reactions caused by the marketed Taxotere® product. The lyophilized NDLS formulation was easily resuspended in water and found to be physically and chemically stable for 48 hours. Physico-chemical characterization of NDLS confirmed a homogeneous formulation with an average particle size of less than 100 nm. Percent Docetaxel association with lipids in NDLS formulation was found to be greater than 95%. The in-vitro release assay showed a sustained release of 25% Docetaxel after 4 hours and 100% Docetaxel release after 42 hours of incubation. Sub-chronic toxicity in mice and rats showed comparable safety to Taxotere®. However, a pharmacokinetics study in rats revealed greater systemic availability of Docetaxel after administration of NDLS compared to Taxotere®. Further, a comparative safety and pharmacokinetic crossover study at 75 mg/m2 of NDLS and Taxotere® in patients with advanced solid tumor also showed higher exposure of Docetaxel with NDLS formulation than patients treated with Taxotere® formulation.