Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index, excipient interactions, as well as dissolution and BE and bioavailability studies were taken into consideration. Solubility and permeability studies indicate that amoxicillin doses up to 875 mg belong to BCS class I, whereas 1000 mg belongs to BCS class II and doses of more than 1000 mg belong to BCS class IV. Considering all aspects, the biowaiver procedure can be recommended for solid oral products of amoxicillin trihydrate immediate-release preparations containing amoxicillin as the single active pharmaceutical ingredient at dose strengths of 875 mg or less, provided (a) only the excipients listed in this monograph are used, and only in their usual amounts, (b) the biowaiver study is performed according to the World Health Organization-, U.S. Food and Drug Administration-, or European Medicines Agency-recommended method using the innovator as the comparator, and (c) results comply with criteria for "very rapidly dissolving" or "similarly rapidly dissolving." Products containing other excipients and those containing more than 875 mg amoxicillin per unit should be subjected to an in vivo BE study.

Background:No pricing formula has been implemented from November 2002 to date in Sri Lanka. Therefore, we initiated a study in 2003 to determine the prices, availability and affordability of medicines in the private sector of Sri Lanka in the absence of a price control.Materials and Methods:The World Health Organization/Health Action International methodology was used. The study was conducted in retail pharmacies (Rajya Osu Sala) of State Pharmaceuticals Corporation (semigovernment) and privately owned retail pharmacies (n = 15) in 2003, 2006 and 2009 in a geographical area. Essential medicines (n = 28) were studied and, for each medicine, innovator, most sold generic and cheapest generic were monitored. The medicine’s median price was compared with the international reference prices (IRP) to obtain the median price ratio. The daily wage of the lowest-paid government worker was used to calculate affordability.Results:Innovators were five to six-times the IRP at privately owned pharmacies and four to seven-times at the Rajya Osu Sala. The prices of generics were ≤1 the IRP during 6 years in privately owned and Rajya Osu Sala pharmacies. Cheapest generics were high in availability (>80%) throughout the study period. Innovators cost more than a day’s wage of the lowest-paid government worker; in contrast, generics were always less than one day’s wage. There seems to be no difference in affordability between privately owned or semigovernment pharmacies.Conclusion:In Sri Lanka, generic medicines have effective pricing and are available and affordable. No drastic changes in prices of medicine in the private sector were observed over the 6 years despite removal of price control.

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Aims The parasite, Leishmania donovani is responsible for lethal visceral leishmaniasis (VL) in humans. There is a need to investigate novel medicines as antileishmanial drugs, as medication currently introduced for leishmaniasis may cause resistance, serious side-effects, chemical instability and high cost. Therefore, this computational study was designed to explore potential phytochemical inhibitors against Leishmania donovani squalene synthase (LdSQS) enzyme, a drug target. Main methods Multiple sequence alignment was carried to detect conserved regions across squalene synthases from different Leishmania spp. Their evolutionary relationships were studied by generating phylogenetic tree. Homology modeling method was used to build a three dimensional model of the protein. The validated model was explored by docking simulation with the phytochemicals of interest to identify the most potent inhibitors. Two reported inhibitors were used as references in the virtual screening. The top hit compounds (binding energy less than -9 kcal/mol) were further subjected to intermolecular interaction analysis, pharmacophore modeling, pharmacokinetic and toxicity prediction. Key findings Seven phytochemicals displayed binding energies less than -9 kcal/mol hence demonstrating ability to be strongly bound to the active site of LdSQS to inhibit the enzymatic activity. Ancistrotanzanine B demonstrated the lowest binding affinity of -9.83 kcal/mol superior to reported inhibitors in literature. Conserved two aspartate rich regions and two signatory motifs were found in the L. donovani squalene synthase by multiple sequence alignment. In addition, study of pharmacophore modeling confirmed that top hit phytochemicals and the reported inhibitor (E5700) share common chemical features for their biochemical interaction with LdSQS. Among seven phytochemicals, 3-O-methyldiplacol showed admissible physicochemical, pharmacokinetic and toxicity predictions compared to the reported inhibitors. All seven phytochemicals satisfied in silico prediction criteria for oral bioavailability. Significance Based on the current study, these hits can be further structurally optimized and validated under laboratory conditions to develop antileishmanial drugs.

Bioequivalence studies are the usually accepted method to determine the therapeutic equivalence of two drug products. Because in-vivo bioequivalence studies are time consuming and expensive to conduct, major regulatory authorities have introduced biowaivers for some selected medicines belonging to BCS class 1 and III drugs. Comparative dissolution tests are used in biowaiver procedure to waiver the bioequivalence requirement. We performed this study to see whether two brands of paracetamol tablets are bioequivalent using the in-vitro methodology. In the first stage of this research study, British Pharmacopeia 2012 quality tests were performed on the two selected paracetamol tablet products to determine whether they are pharmaceutically equivalent. In the second stage in-vitro equivalence of the two products was determined using the biowaiver testing procedure given by the World Health Organization. Dissolution profiles were generated at pH values, 1.2, 4.5 and 6.8. Results were compared through two model independent methods, difference factor (f 1) and similarity factor (f 2). The two paracetamol tablet products tested, complied with all the quality requirements of the British Pharmacopeia 2012. For the two products, the difference factor (f 1) was below the 15 and similarity factor (f 2) was above the 50 in all dissolution test conditions. These results confirm that the two products are pharmaceutically equivalent. The test product is also bioequivalent to the reference product in-vitro, and therefore they can be interchangeable during clinical use. This study shows that in-vivo bioequivalence testing can be waived using the in-vitro method, for some pharmaceutical products such as paracetamol tablets.