Hamid A. Merchant

Once-daily tablet formulation and in vitro release evaluation of cefpodoxime using hydroxypropyl methylcellulose: a technical note.

Summary and ConclusionsDecreasing the dose frequency of cefpodoxime proxetil increases patient compliance; patients prefer to take the drug once daily. It also improves the rate of bacterial killing and hastens the cure from the indications, and therefore increases compliance. The hydrophilic matrix of HPMC controlled the cefpodoxime proxetil release effectively for 24 hours; hence, the formulation can be considered as a once-daily sustained-release tablet of cefpodoxime proxetil. The formulation showed acceptable pharmacotechnical properties and assay requirements. In vitro dissolution studies indicated a sustained-release pattern throughout 24 hours of the study that was comparable to the theoretical release profile. Drug release kinetics indicated that drug release was best explained by Higuchi’s equation, as these plots showed the highest linearity (r2=0.9734), but a close relationship was also noted with zero-order kinetics (r2=0.9708). Korsmeyer’s plots indicated ann value of 0.57, which was indicative of an anomalous diffusion mechanism or diffusion coupled with erosion; hence, the drug release was controlled by more than one process. Hixson-Crowell plots indicated a change in surface area and diameter of the tablets with the progressive dissolution of the matrix as a function of time.

Does sex matter? The influence of gender on gastrointestinal physiology and drug delivery

We all respond differently to drugs. Personalised medicine aims to improve efficacy and reduce side effects, and efforts are being made to understand the physiological differences that underlie responses to drugs. Genetics, diet and disease state can be key; however, gender also plays an important role in pharmacokinetics, pharmacodynamics and drug toxicity. Differences in metabolism and clearance of drugs as a consequence of distinct hepatic and renal processes in males and females are now much better understood but little is known about gender differences in the gastrointestinal tract. As the recipient of all orally administered medications, differences at this level can have a major impact on drug delivery and bioavailability; yet these continue to be ignored and insufficiently studied in the context of drug disposition. The aim of this review is to highlight the known gender differences in gut physiology. Clinical case studies are presented, where possible, to illustrate the influence of these differences on drug disposition and gaps in current knowledge are highlighted to encourage further research in this area.

Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug development

Laboratory animals are often used in drug delivery and research. However, basic information about their gastrointestinal pH, fluid volume, and lymphoid tissue is not completely known. We have investigated these post-mortem in healthy guinea pigs, rabbits and pigs, to assess their suitability for pre-clinical studies by comparing the results with reported human literature. The mean gastric pH (fed ad libitum) was 2.9 and 4.4 in guinea pig and pig, respectively. In contrast, a very low pH (1.6) was recorded in the rabbits. The small intestinal pH was found in the range of 6.4-7.4 in the guinea pigs and rabbits, whereas lower pH (6.1-6.7) was recorded in the pig, which may have consequences for ionisable or pH responsive systems when tested in pig. A relatively lower pH than in the small intestine was found in the caecum (6.0-6.4) and colon (6.1-6.6) of the guinea pig, rabbit and the pig. The water content in the gastrointestinal tract of guinea pig, rabbit and pig was 51g, 153g and 1546g, respectively. When normalized to the body weight, the guinea pig, had larger amounts of water compared to the rabbit and the pig (guinea pig>rabbit>pig); in contrast, a reverse order was found when normalized to per unit length of the gut (guinea pig<rabbit<pig). The lymphoid tissue distribution (lymphoid follicles, Peyers patches and long strips) along the length of the gut in these animals is presented; in particular, an abundance of lymphoid tissue was found in pigs stomach, small intestine and caecum, and rabbits appendix. Their ample presence indicated the potential utility of these animal species in oral and colonic vaccination. These differences in the gastrointestinal parameters of the guinea pig, rabbit and pig reiterates the crucial importance of correctly selecting animal models for pre-clinical studies.

Oral modified-release formulations in motion: The relationship between gastrointestinal transit and drug absorption

Oral modified-release dosage forms can be designed with the aim of achieving specific pharmacokinetic profiles, delivering to specific gut localities or reducing the number of drug administrations. Multiple-unit systems, such as pellets, beads or granules, often claim superiority to single-unit modified-release formulations in terms of predictability and reproducibility of behaviour in the gastrointestinal tract. This is an oversimplification and in this review we discuss the effect of the highly variable gastrointestinal transit on the bioperformance of multiple-unit dosage forms, relative to their single-unit counterparts. We examine the sometimes contradictory literature in this area and highlight specific case studies which demonstrate the effect of intestinal transit on dosage form performance and drug absorption.

Physiological bicarbonate buffers: stabilisation and use as dissolution media for modified release systems

Bicarbonate media are reflective of the ionic composition and buffer capacity of small intestinal luminal fluids. Here we investigate methods to stabilise bicarbonate buffers which can be readily applied to USP-II dissolution apparatus. The in vitro drug release behaviour of three enteric coated mesalazine (mesalamine) products is investigated. Asacol 400 mg and Asacol 800 mg (Asacol HD) and the new generation, high dose (1200 mg) delayed and sustained release formulation, Mezavant (Lialda), are compared in pH 7.4 Krebs bicarbonate and phosphate buffers. Bicarbonate stabilisation was achieved by: continuous sparging of the medium with 5% CO(2)(g), application of a layer of liquid paraffin above the medium, or a specially designed in-house seal device that prevents CO(2)(g) loss. Each of the products displayed a delayed onset of drug release in physiological bicarbonate media compared to phosphate buffer. Moreover, Mezavant displayed a zero-order, sustained release profile in phosphate buffer; in bicarbonate media, however, this slow drug release was no longer apparent and a profile similar to that of Asacol 400 mg was observed. These similar release patterns of Asacol 400 mg and Mezavant displayed in bicarbonate media are in agreement with their pharmacokinetic profiles in humans. Bicarbonate media provide a better prediction of the in vivo behaviour of the mesalazine preparations investigated.

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.

Colonic bacterial metabolism of corticosteroids

The aim of this study was to investigate the stability of four corticosteroids in the presence of human colonic bacteria to understand better their luminal behaviour when delivered orally in the treatment of inflammatory bowel disease. The stability of prednisolone, budesonide, beclometasone (17, 21) dipropionate (BDP) and its active metabolite, beclometasone-17-monopropionate (17-BMP), were investigated at three different concentrations following incubation in a mixed faecal inoculum (simulated human colonic fluid) under anaerobic conditions. Prednisolone, at all three concentrations, was completely degraded within 3 h. The degradation of budesonide progressed at a slower rate, with complete degradation occurring within 7h; the degradation of the S epimer of budesonide was faster than the R epimer. BDP degraded completely within 2 h while its active metabolite 17-BMP was comparatively stable. In contrast to the results in the faecal inoculum, all molecules were stable in the simulated colonic fluid in the absence of human faeces (control). This study demonstrates that prednisolone, BDP and budesonide are completely metabolized in simulated human colonic fluid and confirms the role of colonic bacteria in the metabolism of corticosteroids.

Pulsatile drug release from electrospun poly(ethylene oxide)–sodium alginate blend nanofibres

Novel and highly tuneable pulsatile drug delivery systems have been prepared through the electrospinning of a blend of poly(ethylene oxide) (PEO), sodium alginate (SA), and sodium ibuprofen (SI). The resultant fibres contain crystallites of SI embedded in a PEO-SA matrix, and rather than being obtained as flat mats on the collector plate form novel three dimensional structures extending upwards the needle. Fibres were prepared with a range of loadings of SI and SA. It was found that at pH 6.8 (reminiscent of the intestinal tract) the fibres dissolve very rapidly, freeing all the embedded drug within ca. 20 minutes. However, at pH 3 (representative of the stomach pH in the fed state or in older patients) an unusual two stage release mechanism is seen. This comprises a rapid burst release, followed by a period where no further drug is released for ca. 120-150 minutes, and then a final stage of release freeing the remainder of the drug into solution. The amount of release in the initial stage, and the length of time between the first and final drug release stages, can be controlled by adjusting the SI and SA contents of the fibres respectively. This results in highly tunable pulsatile release materials.

Predicting the gastrointestinal behaviour of modified-release products: Utility of a novel dynamic dissolution test apparatus involving the use of bicarbonate buffers

The establishment of physiologically relevant in vitro-in vivo correlations (IV-IVCs) is key for any biorelevant dissolution test. Historically, bicarbonate buffers have produced better correlations than compendial phosphate buffered media, though such tests are usually performed at a constant pH experiment, overlooking the notion that the pH of the luminal fluids is variable and fluctuating. In this work, we have devised a dynamic dissolution test method employing a physiological bicarbonate buffer under pH conditions of the proximal gut in order to assess the dissolution behaviour of various enteric polymer-coated (gastro-resistant) prednisolone tablets. The pH of the media is modulated and controlled by an Auto pH System™ which exploits the physiological equilibria between [H2CO3] and [HCO3(-)], to match it to the aboral change in pH with transit of the dosage form through the proximal small intestine (from pH 5.6 up to 6.8). The lag time values for an accelerated release and standard EUDRAGIT(®) L30D-55 coated formulation (25 min and 60 min, respectively) were close to the previously reported initial tablet disintegration time data obtained in-vivo by γ-scintigraphy (28 min and 66 min, respectively). Dissolution of alternative delayed release coated products was also better discriminated in the dynamic buffer system. These data confirm the dynamic dissolution system provides a robust and reliable platform to predict the in vivo fate of oral products in a laboratory setting.

Age-mediated changes in the gastrointestinal tract

Physiological functions of the two extreme ends of the age spectrum, children (<18 y old) and older adults (aged 65 y and over), differ from healthy young adults. This consequently affects the pharmacokinetic profiles of administered drugs, which, in turn, impacts upon clinical practice and drug therapy. The gastrointestinal milieu acts as a distinct and vital organ regulating the dissolution, absorption and metabolism of orally ingested drugs. Age-mediated alteration in the physiology and function of the gut can reshape the pharmacokinetics of certain drugs. However, our understanding of this topic is limited. This article references the gut physiology of healthy adults to capture the available evidence in the literature on the extent and nature of the changes in childhood and older age. The gut, as an organ, is examined with regards to the effect of age on luminal fluid, microbiota, transit and motility, and the intestinal mucosa. Whilst drastic developmental changes were observed in certain aspects of the gastrointestinal environment, the examination reveals significant gaps in our knowledge in the physiology and function of the developing or ageing gut. The revelation of the unknown paves the way towards a better characterization of the human gastrointestinal tract for optimized drug therapy in children and older adults.