A new rapidly absorbed paracetamol tablet containing sodium bicarbonate. II. Dissolution studies and in vitro/in vivo correlation

The objective of this study was to compare the in vitro dissolution profile of a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with that of a conventional paracetamol tablet (P), and to relate these by deconvolution and mapping to in vivo release. The dissolution methods used include the standard procedure described in the USP monograph for paracetamol tablets, employing buffer at pH5.8 or 0.05 M HCl at stirrer speeds between 10 and 50 rpm. The mapping process was developed and implemented in Microsoft Excel® worksheets that iteratively calculated the optimal values of scale and shape factors which linked in vivo time to in vitro time. The in vitro-in vivo correlation (IVIVC) was carried out simultaneously for both formulations to produce common mapping factors. The USP method, using buffer at pH5.8, demonstrated no difference between the two products. However, using an acidic medium the rate of dissolution of P but not of PS decreased with decreasing stirrer speed. A significant correlation (r=0.773; p<.00001) was established between in vivo release and in vitro dissolution using the profiles obtained with 0.05 M HCl and a stirrer speed of 30 rpm. The scale factor for optimal simultaneous IVIVC in the fasting state was 2.54 and the shape factor was 0.16; corresponding values for mapping in the fed state were 3.37 and 0.13 (implying a larger in vitro-in vivo time difference but reduced shape difference in the fed state). The current IVIVC explains, in part, the observed in vivo variability of the two products. The approach to mapping may also be extended to different batches of these products, to predict the impact of any changes of in vitro dissolution on in vivo release and plasma drug concentration-time profiles.

Systems biology approach to study permeability of paracetamol and its solid dispersion

Physiological changes that take place at cellular level are usually reflective of their level of gene expression. Different formulation excipients have an impact on physiological behavior of the exposed cells and in turn affect transporter genes, enterocyte-mediated metabolism and toxicity biomarkers. The aim of this study was to prepare solid dispersion of paracetamol and evaluate genetic changes that occur in Caco-2 cell lines during the permeability of paracetamol alone and paracetamol solid dispersion formulations. Paracetamol-PEG 8000 solid dispersion was prepared by melt fusion method and the formulation was characterised using differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Formulation of solid dispersion resulted in the conversion of crystalline drug into an amorphous form. Permeability studies showed that paracetamol absorption was higher from the solid dispersion formulation. DNA microarrays analysis was carried out in order to investigate the involvement of any efflux/uptake transporters in paracetamol or its solid dispersion permeability. Neither transporter carriers nor efflux proteins were found to be involved in the absorption of paracetamol or its PEG solid dispersion. Gene expression analysis established that paracetamol toxicity was potentially reduced upon formulation into solid dispersion when ATP binding cassette (ABC) and solute carrier transporter (SLC) genes were analyzed.

Spray-dried powders for pulmonary drug delivery

Powders for inhalation are traditionally prepared using a destructive micronization process such as jet milling to reduce the particle size of the drug to 2-5 μm. The resultant particles are typically highly cohesive and display poor aerosolization properties, necessitating the addition of a coarse carrier particle to the micronized drug to improve powder flowability. Spray-drying technology offers an alternative, constructive particle production technique to the traditional destructive approach, which may be particularly useful when processing biotechnology products that could be adversely affected by high-energy micronization processes. Advantages of spray drying include the ability to incorporate a wide range of excipients into the spray-drying feedstock, which could modify the aerosolization and stability characterizations of the resultant powders, as well as modify the drug release and absorption profiles following inhalation. This review discusses some of the reasons why pulmonary drug delivery is becoming an increasingly popular route of administration and describes the various investigations that have been undertaken in the preparation of spray-dried powders for pulmonary drug delivery. © 2007 by Begell House, Inc.

Grewia polysaccharide gum as a pharmaceutical excipient

Grewia gum is obtained from the inner stem bark of the edible plant Grewia mollis Juss (Fam. Tiliaceae) which grows widely in the middle belt region of Nigeria, and is also cultivated. The dried and pulverised inner stem bark is used as a thickening agent in some food delicacies in that region of the country. This ability of the material to increase solution viscosity has generated a lot of interest and is the catalysing momentum for this research. Such materials have been used as stabilizers or suspending agents in cosmetics, foods and liquid medications, and as mucoadhesives and controlled release polymeric matrices in solid dosage forms. The physicochemical characterization of candidate excipients forms an essential step towards establishing suitability for pharmaceutical application. For natural gums, this usually requires isolation of the gum from the storage site by extraction processes. Grewia polysaccharide gum was extracted and dried using techniques such as air-drying, freeze-drying or spray-drying. Component analysis of the gum showed that it contains five neutral sugars: glucose, galactose, rhamnose, arabinose and xylose. The gum contains traces of elements such as zinc, magnesium, calcium and phosphorus. At low substance weight, the gum hydrates in aqueous medium swelling and dispersing to give a highly viscous dispersion with pseudoplasmic flow behaviour. The method by which drying is achieved can have significant effect on some physicochemical properties of the gum. Consequently, the intrinsic viscosity and molecular weight, and parameters of powder flow were shown to differ with the method of drying. The gum has good thermal stability. In comparison with established excipients, grewia gum may be preferable to gum Arabic or sodium carboxymethylcellulose as a suspending agent in ibuprofen suspension formulations. The release retardant property of the gum was superior to guar and Metolose® in ibuprofen matrices. Similarly, carboxy methylcellulose, Methocel®, gum Arabic or Metolose® may not be preferable to grewia gum when controlled release of a soluble drug like cimetidine is indicated. The mucoadhesive performance of the gum compared favourably with excellent mucoadhesives such as hydroxypropyl methylcellulose, carboxymethylcellulose, guar and carbopol 971 P.

The development of a novel in vitro model suitable for the prediction of bioavailability

In vitro studies of drug absorption processes are undertaken to assess drug candidate or formulation suitability, mechanism investigation, and ultimately for the development of predictive models. This study included each of these approaches, with the aim of developing novel in vitro methods for inclusion in a drug absorption model. Two model analgesic drugs, ibuprofen and paracetamol, were selected. The study focused on three main areas, the interaction of the model drugs with co-administered antacids, the elucidation of the mechanisms responsible for the increased absorption rate observed in a novel paracetamol formulation and the development of novel ibuprofen tablet formulations containing alkalising excipients as dissolution promoters.Several novel dissolution methods were developed. A method to study the interaction of drug/excipient mixtures in the powder form was successfully used to select suitable dissolution enhancing exicipents. A method to study intrinsic dissolution rate using paddle apparatus was developed and used to study dissolution mechanisms. Methods to simulate stomach and intestine environments in terms of media composition and volume and drug/antacid doses were developed. Antacid addition greatly increased the dissolution of ibuprofen in the stomach model.Novel methods to measure drug permeability through rat stomach and intestine were developed, using sac methodology. The methods allowed direct comparison of the apparent permeability values obtained. Tissue stability, reproducibility and integrity was observed, with selectivity between paracellular and transcellular markers and hydrophilic and lipophilic compounds within an homologous series of beta-blockers.

The stability of pharmaceutical powders: effect of additives and coating

The decomposition of drugs in the solid state has been studied using aspirin and salsalate as models. The feasibility of using suspension systems for predicting the stability of these drugs in the solid state has been investigated.. It has been found that such systems are inappropriate in defining the effect of excipients on 'the decomposition of the active drug due to chqnges in the degradation pathway. Using a high performance liquid chromatographic method, magnesium stearate was shown to induce the formation of potentlally immunogenic products in aspirin powders. These products which included salicylsalicylic acid .and acetylsalicyclsalicylic acid were not detected in aspirin suspensions which had undergone the same extent of decomposition. By studying the effect of pH and of added excipients on the rate of decomposition of aspirin in suspension systems, it has been shown that excipients such as magnesium stearate containing magnesium oxide, most probably enhance the decomposition of both aspirin and salsalate by alkalinising the aqueous phase. In the solid state, pH effects produced by excipients appear to be relatively unimportant. Evidence is presented to suggest that the critical parameter is a depression in melting point induced by: the added excipient. Microscopical examination in fact showed the formation of clear liquid layers in aspirin samples containing added magnesium stearate but not in control samples. Kinetic equations which take into account both the diffusive barrier presented by the liquid films and the. geometry of the aspirin crystals were developed. Fitting of the .experimental data to these equations showed good agreement. with the postulated theory. Monitorjng of weight issues during the decomposition of aspirin revealed that in the solid systems studied where the bulk of the decomposition product sublimes, it is possible to estimate the extent of degradation from the residual weight, provided the initial weight is known. The corollary is that in such open systems, monitoring of decomposition products is inadequate for assessing the extent of decomposition. In addition to the magnesium stearate-aspirin system, mapyramine maleate-aspirin mixtures were used to model interactive systems. Work carried out in an attempt to stabilise such systems included microencapsulation and film coating. The protection obtained was dependent on the interactive species used. Gelatin for example appeared to stabilise aspirin against the adverse effects of magnesium stearate but increased its decomposition in the presence of mapyramine maleate.

Strategies for local drug delivery targeting the oesophagus

Localised, targeted drug delivery to the oesophagus offers the potential for more effective delivery and reduced drug dosages, coupled with increased patient compliance. This thesis considers bioadhesive liquids, orally retained tablets and films as well as chewable dosage forms as drug delivery systems to target the oesophagus. Miconazole nitrate was used as a model antifungal agent. Chitosan and xanthan gum hydrogels were evaluated as viscous polymer viables with the in vitro retention, drug release and minimum inhibitory concentration values of the formulations measured. Xanthan showed prolonged retention on the oesophageal surface in vitro yet chitosan reduced the MIC value; both polymers offer potential for local targeting to the oesophagus. Cellulose derivatives were investigated within orally retained dosage forms. Both drug and polymer dissolution rates were measured to investigate the drug release mechanism and to develop a formulation with concomitant drug and polymer release to target the oesophagus with solubilised drug within a viscous media. Several in vitro dissolution methods were evaluated to measure drug release from chewable dosage forms with both drug and polymer dissolution quantified to investigate the effects of dissolution apparatus on drug release. The results from this thesis show that a range of drug delivery strategies that can be used to target drug to the oesophagus. The composition of these formulations as well as the methodology used within the development are crucial to best understand the formulation and predict its performance in vivo.

Time scale analysis for fluidized bed melt granulation I: granule-granule and granule-droplet collision rates

Fluidized bed spray granulators (FBMG) are widely used in the process industry for particle size growth; a desirable feature in many products, such as granulated food and medical tablets. In this paper, the first in a series of four discussing the rate of various microscopic events occurring in FBMG, theoretical analysis coupled with CFD simulations have been used to predict granule–granule and droplet–granule collision time scales. The granule–granule collision time scale was derived from principles of kinetic theory of granular flow (KTGF). For the droplet–granule collisions, two limiting models were derived; one is for the case of fast droplet velocity, where the granule velocity is considerable lower than that of the droplet (ballistic model) and another for the case where the droplet is traveling with a velocity similar to the velocity of the granules. The hydrodynamic parameters used in the solution of the above models were obtained from the CFD predictions for a typical spray fluidized bed system. The granule–granule collision rate within an identified spray zone was found to fall approximately within the range of 10-2–10-3 s, while the droplet–granule collision was found to be much faster, however, slowing rapidly (exponentially) when moving away from the spray nozzle tip. Such information, together with the time scale analysis of droplet solidification and spreading, discussed in part II and III of this study, are useful for probability analysis of the various event occurring during a granulation process, which then lead to be better qualitative and, in part IV, quantitative prediction of the aggregation rate.

Solid bridge formation between spray-dried sodium carbonate particles

Moisture migration caking of pharmaceutical excipients in the absence of load is a significant quality and stability issue. This study uses Atomic Force Microscopy (AFM) to examine a solid bridge formed between two 20µm spray-dried sodium carbonate particles. The bridge is grown by repeatedly exposing the system to 70% RH and 30% RH cycles at 25?C. A comparison is made with the idealised bridge model developed by Tanaka (1978) which was previously verified using crystalline systems. The resulting system was found to be more complex and grew in two stages. The first stage consisted of linear growth to 5 cycles, followed by a more gradual expansion and the appearance of crystalline structures.

Fixed-dose single tablet antidiabetic combinations

Combinations of two or more oral agents with different mechanisms of action are often used for the management of hyperglycaemia in type 2 diabetes. While these combinations have customarily been taken as separate tablets, several fixed-dose single tablet combinations are now available. These are based on bioequivalence with the separate tablets, giving similar efficacy to the separate tablets and necessitating the same cautions and contraindications that apply to each active component. Fixed-dose combinations can offer convenience, reduce the pill burden and simplify administration regimens for the patient. They increase patient adherence compared with equivalent combinations of separate tablets, and this is associated with some improvements in glycaemic control. Presently available antidiabetic fixed-dose combinations include metformin combined with a sulphonylurea, thiazolidinedione, dipeptidylpeptidase-4 inhibitor or meglitinide as well as thiazolidinedione-sulphonylurea combinations, each at a range of dosage strengths to facilitate titration. Anticipated future expansion of multiple drug regimens for diabetes management is likely to increase the use of fixed-dose single tablet combinations. © 2009 Blackwell Publishing Ltd.

Anti-obesity fixed-dose combinations

The management of hypertension, dyslipidaemia and hyperglycaemia often requires multiple medications that combine two or more agents with different modes of action to give additive efficacy. In some situations lower doses of two agents with different modes of action can achieve greater efficacy than a high dose of one agent. This is achieved by addressing different pathophysiological features of the disease, whilst at the same time producing fewer side effects than a high dose of one agent. Several examples of this have been described for combinations of blood glucose-lowering therapies in type 2 diabetes. However, the pill burden associated with multiple medications can reduce patient adherence and compromise the potential value of the treatments. To reduce the number of daily doses, single-tablet (‘fixed-dose’) combinations have been introduced to offer greater convenience. There are several ant-diabetic FDCs, mostly combining metformin with another type of glucose-lowering agent. The UK has been less enthusiastic about FDCs than many other parts of the world, and does not have most of these combinations available. One of the concerns expressed about FDCs is a reduced flexibility to select desired doses of the two agents for dose titration. However, in practise the variety of dosage strengths for most FDCs matches the dosages available as separate tablets. Another concern has been the preference to add drugs one at a time to be able to attribute any adverse effects. In most cases the FDC is used when a second drug has been added to a monotherapy that is already a component of the FDC, so it is only the same as adding one agent but without increasing the pill burden.

Investigation of formulation and process of lyophilised orally disintegrating tablet (ODT) using novel amino acid combination

Lyophilised orally disintegrating tablets (ODTs) have achieved a great success in overcoming dysphagia associated with conventional solid dosage forms. However, the extensive use of saccharides within the formulation limits their use in treatment of chronic illnesses. The current study demonstrates the feasibility of using combination of proline and serine to formulate zero sacharide ODTs and investigates the effect of freezing protocol on sublimation rate and tablets characteristics. The results showed that inclusion of proline and serine improved ODT properties when compared to individual counterparts. Additionally, annealing the ODTs facilitated the sublimation process and shortened the disintegration time. © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.

Communicating Cuneiform:The Evolution of a Multimedia Cuneiform Database

Our paper presents the work of the Cuneiform Digital Forensic Project (CDFP), an interdisciplinary project at The University of Birmingham, concerned with the development of a multimedia database to support scholarly research into cuneiform, wedge-shaped writing imprinted onto clay tablets and indeed the earliest real form of writing. We describe the evolutionary design process and dynamic research and developmental cycles associated with the database. Unlike traditional publications, the electronic publication of resources offers the possibility of almost continuous revisions with the integration and support of new media and interfaces. However, if on-line resources are to win the favor and confidence of their respective communities there must be a clear distinction between published and maintainable resources, and, developmental content. Published material should, ideally, be supported via standard web-browser interfaces with fully integrated tools so that users receive a reliable, homogenous and intuitive flow of information and media relevant to their needs. We discuss the inherent dynamics of the design and publication of our on-line resource, starting with the basic design and maintenance aspects of the electronic database, which includes photographic instances of cuneiform signs, and shows how the continuous review process identifies areas for further research and development, for example, the “sign processor” graphical search tool and three-dimensional content, the results of which then feedback into the maintained resource.

What the newspapers say about medication adherence:a content analysis

Background - This study investigates the coverage of adherence to medicine by the UK and US newsprint media. Adherence to medicine is recognised as an important issue facing healthcare professionals and the newsprint media is a key source of health information, however, little is known about newspaper coverage of medication adherence. Methods - A search of the newspaper database Nexis®UK from 2004–2011 was performed. Content analysis of newspaper articles which referenced medication adherence from the twelve highest circulating UK and US daily newspapers and their Sunday equivalents was carried out. A second researcher coded a 15% sample of newspaper articles to establish the inter-rater reliability of coding. Results - Searches of newspaper coverage of medication adherence in the UK and US yielded 181 relevant articles for each country. There was a large increase in the number of scientific articles on medication adherence in PubMed® over the study period, however, this was not reflected in the frequency of newspaper articles published on medication adherence. UK newspaper articles were significantly more likely to report the benefits of adherence (p = 0.005), whereas US newspaper articles were significantly more likely to report adherence issues in the elderly population (p = 0.004) and adherence associated with diseases of the central nervous system (p = 0.046). The most commonly reported barriers to adherence were patient factors e.g. poor memory, beliefs and age, whereas, the most commonly reported facilitators to adherence were medication factors including simplified regimens, shorter treatment duration and combination tablets. HIV/AIDS was the single most frequently cited disease (reported in 20% of newspaper articles). Poor quality reporting of medication adherence was identified in 62% of newspaper articles. Conclusion - Adherence is not well covered in the newspaper media despite a significant presence in the medical literature. The mass media have the potential to help educate and shape the public’s knowledge regarding the importance of medication adherence; this potential is not being realised at present.

Chitosan-modified dry powder formulations for pulmonary gene delivery

Spray-drying is an effective process for preparing micron-dimensioned particles for pulmonary delivery. Previously, we have demonstrated enhanced dispersibility and fine particle fraction of spray-dried nonviral gene delivery formulations using amino acids or absorption enhancers as dispersibility-enhancing excipients. In this study, we investigate the use of the cationic polymer chitosan as a readily available and biocompatible dispersibility enhancer. Lactose-lipid:polycation:pDNA (LPD) powders were prepared by spray-drying and post-mixed with chitosan or spray-dried chitosan. In addition, the water-soluble chitosan derivative, trimethyl chitosan, was added to the lactose-LPD formulation before spray-drying. Spray-dried chitosan particles, displaying an irregular surface morphology and diameter of less than 2 mu m, readily adsorbed to lactose-LPD particles following mixing. In contrast with the smooth spherical surface of lactose-LPD particles, spray-dried trimethyl chitosan-lactose-LPD particles demonstrated increased surface roughness and a unimodal particle size distribution (mean diameter 3.4 mu m), compared with the multimodal distribution for unmodified lactose-LPD powders (mean diameter 23.7 mu m). The emitted dose and in vitro deposition of chitosan-modified powders was significantly greater than that of unmodified powders. Moreover, the inclusion of chitosan mediated an enhanced level of reporter gene expression. In summary, chitosan enhances the dispersibility and in vitro pulmonary deposition performance of spray-dried powders.