Evolution of a physiological pH 6.8 bicarbonate buffer system: application to the dissolution testing of enteric coated products.

The use of compendial pH 6.8 phosphate buffer to assess dissolution of enteric coated products gives rise to poor in vitro-in vivo correlations because of the inadequacy of the buffer to resemble small intestinal fluids. A more representative and physiological medium, pH 6.8 bicarbonate buffer, was developed to evaluate the dissolution behaviour of enteric coatings. The bicarbonate system was evolved from pH7.4 Hanks balanced salt solution to produce a pH 6.8 bicarbonate buffer (modified Hanks buffer, mHanks), which resembles the ionic composition and buffer capacity of intestinal milieu. Prednisolone tablets were coated with a range of enteric polymers: hypromellose phthalate (HP-50 and HP-55), cellulose acetate phthalate (CAP), hypromellose acetate succinate (HPMCAS-LF and HPMCAS-MF), methacrylic acid copolymers (EUDRAGIT® L100-55, EUDRAGIT® L30D-55 and EUDRAGIT® L100) and polyvinyl acetate phthalate (PVAP). Dissolution of coated tablets was carried out using USP-II apparatus in 0.1M HCl for 2h followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, the various enteric polymer coated products displayed rapid and comparable dissolution profiles. In pH 6.8 mHanks buffer, drug release was delayed and marked differences were observed between the various coated tablets, which is comparable to the delayed disintegration times reported in the literature for enteric coated products in the human small intestine. In summary, the use of pH 6.8 physiological bicarbonate buffer (mHanks) provides more realistic and discriminative in vitro release assessment of enteric coated formulations compared to compendial phosphate buffer

Implementing the additional strength biowaiver for generics: EMA recommended approaches and challenges for a US-FDA submission

International audienceThis review describes the EMA requirements on biowaivers for additional strengths of immediate release and modified release oral solid dosage forms focused on generic applications and highlights the challenges for a simultaneous EMA and FDA submission. Some specificities of the current EMA guidelines are compared with the current FDA Guidance for Industry, with a special focus on the strength to be investigated in vivo, formulation suitability for biowaiver, and optimizing dissolution studies for additional strength biowaivers. In Europe, the same principles applied for generics may be considered for deriving the biowaivers for innovator products. Several case studies are presented to illustrate the challenges of applying for additional strength biowaivers in EMA and FDA simultaneously

A multivariate investigation into the relationship between pharmaceutical characteristics and patient preferences of bioequivalent ibuprofen tablets

Tatiana R Alonso,1 Adrianna Gagol,1 Maximilian Scherer,1 Antonio Matji,1 Santiago Torrado-Santiago,2 Dolores R Serrano,1 Alfredo Garcia-Arieta,3 Juan J Torrado1 1Pharmaceutics and Food Technology, School of Pharmacy, Complutense University, Madrid, Spain; 2Industrial Pharmacy Institute, Complutense University, Madrid, Spain; 3Service on Pharmacokinetics and Generics, Department of Human Use Medicines, Division of Pharmacology and Clinical Evaluation, Spanish Agency for Medicines and Health Care Products, Madrid, Spain Background: In Spain the price of all ibuprofen 600 mg tablet generic products is the same due to reimbursement existing rules so for the patient there is not any economic incentive to choose a particular one. Bearing in mind that the quality of generic products should be similar, it could be questioned if differences in patient preferences evaluated as sales could be related to differences on their pharmaceutical properties. The aims of this work were to study the variability on the pharmaceutical characteristics of marketed bioequivalent tablet formulations and its impact on patient preferences. Methods: Thirty-six batches corresponding to fourteen different generic products were chosen among the best-selling products of the Spanish market in the years 2011 and 2015 and were compared to the reference product. The effect on patient preferences of six variables was studied through a multivariate analysis. The first two variables were marketing characteristics: 1) years in the market and 2) the number of other generic products marketed by the same manufacturer, which could be related to the size and service provided by the manufacturer. The other four variables studied were pharmaceutical tablet properties: 3) mean weight, 4) hardness, 5) disintegration, and 6) dissolution. A multiple linear regression analysis was performed to identify the effect on sales of the six variables studied. Results: The disintegration time was the most significant (P=0.018) factor affecting the sales of Ibuprofen tablets which may be related to the onset of action. Conclusion: The faster the tablet disintegration, the higher its sales. Two possible explanations are suggested: 1) the most specialized ibuprofen tablet manufacturer considers fast disintegration as a key parameter and/or 2) habitual consumers of ibuprofen can detect small differences on the onset of action among different marketed formulations. In this work, all marketed ibuprofen tablets comply with the pharmacopoeia specifications. Keywords: ibuprofen, sales, disintegration, generic, multiple linear regression analysis, multivariate analysi