Modelling dosator filling and discharge of powder

Dosators and other dosing mechanisms operating on generally similar principles are very widely used in the pharmaceutical industry for capsule filling, and for dosing products that are delivered to the customer in powder form such as inhalers. This is a trend that is set to increase. However a significant problem for this technology is being able to predict how accurately and reliably, new drug formulations will be dosed from these machines prior to manufacture. This paper presents a review of the literature relating to powder dosators which considers mathematical models for predicting dosator performance, the effects of the dosator geometry and machine settings on the accuracy of the dose weight. An overview of a model based on classical powder mechanics theory that has been developed at The University of Greenwich is presented. The model uses inputs from a range of powder characterisation tests including, wall friction, bulk density, stress ratio and permeability. To validate the model it is anticipated that it will be trialled for a range of powders alongside a single shot dosator test rig.

Characterisation of fluidised bed granulation processes using in situ Raman spectroscopy

Previous work by the authors Walker et al. [2007b. Fluidised bed characterisation using Raman spectroscopy: applications to pharmaceutical processing. Chemical Engineering Science 62, 3832–3838] illustrated that Raman spectroscopy could be used to provide 3-D maps of the concentration and chemical structure of particles in motion in a fluidised bed, within a relatively short (120 s) time window. Moreover, we reported that the technique, as outlined, has the potential to give detailed in-situ information on how the structure and composition of granules/powders within the fluidised bed (dryer or granulator) vary with the position and evolve with time. In this study we extended the original work by shortening the time window of the Raman spectroscopic analysis to 10 s, which has allowed the in-situ real-time characterisation of a fluidised bed granulation process. Here we show an important new use of the technique which allows in-situ measurement of the composition of the material within the fluidised bed in three spatial dimensions and as a function of time. This is achieved by recording Raman spectra using a probe positioned within the fluidised bed on a long-travel x–y–z stage. In these experiments the absolute Raman intensity is used to provide a direct measure of the amount of any given material in the probed volume, i.e. a particle density. Particle density profiles have been calculated over the granulation time and show how the volume of the fluidised bed decreases with an increase mean granule size. The Raman spectroscopy analysis indicated that nucleation/coalescence in this co-melt fluidised hot melt granulation system occurred over a relatively short time frame (t<30 s). The Raman spectroscopic technique demonstrated accurate correlation with independent granulation experiments which provided particle size distribution analysis. The similarity of the data indicates that the Raman spectra accurately represent solids ratios within the bed, and thus the techniques quantitative capabilities for future use in the pharmaceutical industry.

Nucleation and growth in fluidised hot melt granulation

Fluidised hot melt granulation (FHMG) is a novel technology for granulation process in pharmaceutical industry, which has distinct advantages over other commercial techniques. The aim of this research was to investigate granulation and the effect of process parameters that may affect FHMG process. In this work, ballotini beads were used as the model particles and Lutrol (R) F 68 Poloxamer 188 was used as meltable solid binder. In order to determine the granulation and nucleation mechanism in this co-melt FHMG system, several parameters were investigated, such as binder content, particle size of binder and particle size and hydrophobicity of ballotini. These parameters were correlated to granule size distribution, mean granule size and granule shape. Furthermore, these experimental investigations were designed so that the coalescence model could be applied to the co-melt FHMG system. The analysis indicated that the non-inertial regime extends over a relatively short time period of

Advances in biosensor-based analysis for antimicrobial residues in foods

Biosensors are used for a large number of applications within biotechnology, including the pharmaceutical industry and life sciences. Since the production of Biacore surface-plasmon resonance instruments in the early 1990s, there has been steadily growing use of this technology for the detection of food contaminants (e.g., veterinary drugs, mycotoxins, marine toxins, food dyes and processing contaminants). Other biosensing technologies (e.g., electrochemical and piezoelectric) have also been employed for the analysis of small-molecule contaminants. This review concentrates on recent advances made in detection and quantification of antimicrobial compounds with different types of biosensors and on the emergence of multiplexing, which is highly desirable as it increases sample analysis at lower cost and in less time. (C) 2010 Elsevier Ltd. All rights reserved.

Design of potent GlyT1 inhibitors: In vitro and in vivo profiles

Inhibitors of Gly transporter type-1 (GlyT1) for the treatment of schizophrenia have been pursued on the basis of the NMDA receptor (R) hypofunction hypothesis, which stems largely from the observation that NMDAR antagonists induce symptoms that more closely mimic those characteristic of schizophrenia than do other classes of psychotic agents. GlyT1 is responsible for uptake of synaptic Gly, an NMDAR co-agonist amino acid, in neuronal populations throughout the forebrain. GlyT1 inhibition thereby potentiates NMDAR activity by increasing synaptic Gly levels. Correspondingly, a large body of data suggests that GlyT1 inhibitors likely confer more comprehensive symptom alleviation than current antipsychotics. To date, a number of small-molecule GlyT1 inhibitors have been reported by the pharmaceutical industry. Developments in the discovery and characterization of GlyT1 inhibitors are discussed in this review.

Clinical cough II:therapeutic treatments and management of chronic cough

Chronic cough is a common and frequently disruptive symptom which can be difficult to treat with currently available medicines. Asthma/eosinophilic airway disease and gastro-oesophageal reflux disease are most commonly associated with chronic cough but it may also trouble patients with chronic obstructive pulmonary disease, pulmonary fibrosis and lung cancer. Over the last three decades there have been a number of key advances in the clinical approach to cough and a number of international guidelines on the management of cough have been developed. Despite the undoubted benefit of such initiatives, more effective treatments for cough are urgently needed. The precise pathophysiological mechanisms of chronic cough are unknown but central to the process is sensitization (upregulation) of the cough reflex. One well-recognized clinical consequence of this hypersensitive state is bouts of coughing triggered by apparently trivial provocation such as scents and odours and changes in air temperature. The main objective of new treatments for cough would be to identify ways to downregulate this heightened cough reflex but yet preserve its crucial role in protecting the airway. The combined efforts of clinicians, scientists and the pharmaceutical industry offer most hope for such a treatment breakthrough. The aim of this chapter is to provide some rationale for the current treatment recommendations and to offer some reflections on the management of patients with chronic cough.

The shifting engines of medicalization

Social scientists and other analysts have written about medicalization since at least the 1970s. Most of these studies depict the medical profession, interprofessional or organizational contests, or social movements and interest groups as the prime movers toward medicalization. This article contends that changes in medicine in the past two decades are altering the medicalization process. Using several case examples, I argue that three major changes in medical knowledge and organization have engendered an important shift in the engines that drive medicalization: biotechnology (especially the pharmaceutical industry and genetics), consumers, and managed care. Doctors are still gatekeepers for medical treatment, but their role has become more subordinate in the expansion or contraction of medicalization. Medicalization is now more driven by commercial and market interests than by professional claims-makers. The definitional center of medicalization remains constant, but the availability of new pharmaceutical and potential genetic treatments are increasingly drivers for new medical categories. This requires a shift in the sociological focus examining medicalization for the twenty-first century.

Trends in the use of psychotropic medications among adolescents, 1994 to 2001

Objectives: Few psychotropic medications are approved for use among children younger than 18 years. Yet previous studies have shown an increase in the use of psychotropic medications among school-age children and adolescents. Most previous studies examined data only up to 1997; therefore, the results predate any impact of changing federal policies and newly marketed medications. This study examined trends in the prescription of psychotropic medications to adolescents aged 14 to 18 years in office-based care in the United States from 1994 to 2001. Methods: Data from the National Ambulatory Medical Care Survey (NAMCS) were used to determine visit rates and prescribing patterns from 1994 to 2001 for psychotropics that were prescribed in office-based treatment settings to adolescents aged 14 to 18 years. Rates of visits that resulted in a prescription for psychotropic medication were calculated for two-year periods. Analyses were conducted by type of medication, gender, and the prescribing physician's specialty. Results: Rates of visits that resulted in a psychotropic prescription increased from 3.4 percent in 1994-1995 to 8.3 percent in 2000-2001. These trends were evident for males and females. The average annual growth rates for psychotropic prescriptions were much higher after 1999. Trends were also significant across drug classes. By 2001, one out of ten office visits by adolescent males resulted in a prescription for a psychotropic medication. Conclusions: Average annual growth rates for the prescription of psychotropics to adolescents increased from 1994 to 2001, with especially rapid acceleration after 1999. This increase may be associated with changing thresholds of diagnosis and treatment, availability of new medications, and changes in federal regulatory policies concerning promotion of medications by the pharmaceutical industry.

From Lydia Pinkham to Queen Levitra:Direct-to-consumer advertising and medicalisation

The medicalisation of life problems has been occurring for well over a century and has increased over the past 30 years, with the engines of medicalisation shifting to biotechnology, managed care, and consumers. This paper examines one strand of medicalisation during the last century: direct-to-consumer advertising (DTCA) of pharmaceuticals. In particular, it examines the roles that physicians and the Food and Drug Administration (FDA) have played in regulating DTCA in the US. Two advertising exemplars, the late 19 century Lydia E. Pinkham's Vegetable Compound (for 'women's complaints') and contemporary Levitra (for erectile dysfunction) are used to examine the parallels between the patent medicine era and the DTCA era. DTCA re-establishes the direct and independent relationship between drug companies and consumers that existed in the late 19 century, encouraging self-diagnosis and requests for specific drugs. The extravagant claims of Lydia Pinkham's day are constrained by laws, but modern-day advertising is more subtle and sophisticated. DTCA has facilitated the impact of the pharmaceutical industry and consumers in becoming more important forces in medicalisation. © 2008 The Authors.

Human growth hormone and the temptations of biomedical enhancement

It is likely that humans have sought enhancements for themselves or their children for as long as they have recognised that improvements in individuals are a possibility. One genre of self-improvement in modern society can be called 'biomedical enhancements'. These include drugs, surgery and other medical interventions aimed at improving the mind, body or performance. This paper uses the case of human growth hormone (hGH) to examine the social nature of enhancements. Synthetic hGH was developed in 1985 by the pharmaceutical industry and was approved by the FDA for very specific uses, particularly treatment of growth hormone deficiency. However, it has also been promoted for a number of 'off label' uses, most of which can be deemed enhancements. Drugs approved for one treatment pave the way for use as enhancements for other problems. Claims have been made for hGH as a treatment for idiopathic shortness, as an anti-ageing agent and to improve athletic performance. Using the hGH case, we are able to distinguish three faces of biomedical enhancement: normalisation, repair and performance edge. Given deeply ingrained social and individual goals in American society, the temptations of biomedical enhancements provide inducement for individuals and groups to modify their situation. We examine the temptations of enhancement in terms of issues such as unnaturalness, fairness, risk and permanence, and shifting social meanings. In our conclusions, we outline the potentials and pitfalls of biomedical enhancement.

Mutual Solubilities of Ammonium-Based Ionic Liquids with Water and with Water/Methanol Mixture

Over the last two decades, ionic liquids have gained importance as alternative solvents to conventional VOCs in the field of homogeneous catalysis. This success is not only due to their ability to dissolve a large amount of metal catalysts, but it is also due to their potential to enhance yields of enantiopure products. The art of preparation of a specific enantiomer is a highly desired one and searched for in pharmaceutical industry. This work presents a study on solubility in water and in water/methanol mixture of a set of ILs composed of the bis (trifluoromethylsulfonyl) imide anion and of the N-alkyl-triethyl-ammonium cation (abbrev. [NR,222][NTf2]) with the alkyl chain R ranging from 6 to 12 carbons. Mutual solubilities between ILs and water, as well as between ILs and methanol/water mixture were investigated in detail. These solubilities were measured using two well-known and accurate experimental techniques based on a volumetric and a cloud-point methods. Both methods enabled us to measure the Tx diagrams reflecting the mutual solubilities between water (or water/methanol) and selected ILs in the temperature range from 293.15 to 338.15 K. The data were fitted by using the modified Flory-Huggins equation proposed by de Sousa and Rebelo and compared also with the prediction carried out by the Cosmo-RS methodology

Product standardisation as a tool to control prescribing costs a case study of alginate liquid preparations

Introduction Product standardisation involves promoting the prescribing of pre-selected products within a particular category across a healthcare region and is designed to improve patient safety by promoting continuity of medicine use across the primary/secondary care interface, in addition to cost containment without compromising clinical care (i.e. maintaining safety and efficacy). Objectives To examine the impact of product standardisation on the prescribing of compound alginate preparations within primary care in Northern Ireland. Methods Data were obtained on alginate prescribing from the Northern Ireland Central Services Agency (Prescription Pricing Branch), covering a period of 43 months. Two standardisation promotion interventions were carried out at months 18 and 33. In addition to conventional statistical analyses, a simple interrupted time series analysis approach, using graphical interpretation, was used to facilitate interpretation of the data. Results There was a significant increase in the prescribed share of the preferred alginate product in each of the four health boards in Northern Ireland and a decrease in the cost per Defined Daily Dose for alginate liquid preparations overall. Compliance with the standardisation policy was, however, incomplete and was influenced to a marked degree by the activities of the pharmaceutical industry. The overall economic impact of the prescribing changes during the study was small (3.1%). Conclusion The findings suggested that product standardisation significantly influenced the prescribing pattern for compound alginate liquid preparations within primary care across Northern Ireland. © 2012 The Authors. IJPP © 2012 Royal Pharmaceutical Society.

Cationicity-Enhanced Analogues of the Antimicrobial Peptides, AcrAP1 and AcrAP2, from the Venom of the Scorpion, Androctonus crassicauda, Display Potent Growth Modulation Effects on Human Cancer Cell Lines

The non disulphide-bridged peptides (NDBPs) of scorpion venoms are attracting increased interest due to their structural heterogeneity and broad spectrum of biological activities. Here, two novel peptides, named AcrAP1 and AcrAP2, have been identified in the lyophilised venom of the Arabian scorpion, Androctonus crassicauda, through “shotgun” molecular cloning of their biosynthetic precursor-encoding cDNAs. The respective mature peptides, predicted from these cloned cDNAs, were subsequently isolated from the same venom sample using reverse phase HPLC and their identities were confirmed by use of mass spectrometric techniques. Both were found to belong to a family of highly-conserved scorpion venom antimicrobial peptides - a finding confirmed through the biological investigation of synthetic replicates. Analogues of both peptides designed for enhanced cationicity, displayed enhanced potency and spectra of antimicrobial activity but, unlike the native peptides, these also displayed potent growth modulation effects on a range of human cancer cell lines. Thus natural peptide templates from venom peptidomes can provide the basis for rational analogue design to improve both biological potency and spectrum of action. The diversity of such templates from such natural sources undoubtedly provides the pharmaceutical industry with unique lead compounds for drug discovery.

Research in Progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK)

The UK Refractory Asthma Stratification Programme(RASP-UK) will explore novel biomarker stratificationstrategies in severe asthma to improve clinicalmanagement and accelerate development of newtherapies. Prior asthma mechanistic studies have notstratified on inflammatory phenotype and theunderstanding of pathophysiological mechanisms inasthma without Type 2 cytokine inflammation is limited.RASP-UK will objectively assess adherence tocorticosteroids (CS) and examine a novel compositebiomarker strategy to optimise CS dose; this will alsoaddress what proportion of patients with severe asthmahave persistent symptoms without eosinophilic airwaysinflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.

Anti-biofilm activity of ultrashort cinnamic acid peptide derivatives against medical device-related pathogens

The threat of antimicrobial resistance has placed increasing emphasis on the development of innovative approaches to eradicate multidrug-resistant pathogens. Biofilm-forming microorganisms, for example, Staphylococcus epidermidis and Staphylococcus aureus, are responsible for increased incidence of biomaterial infection, extended hospital stays and patient morbidity and mortality. This paper highlights the potential of ultrashort tetra-peptide conjugated to hydrophobic cinnamic acid derivatives. These peptidomimetic molecules demonstrate selective and highly potent activity against resistant biofilm forms of Gram-positive medical device-related pathogens. 3-(4-Hydroxyphenyl)propionic)-Orn-Orn-Trp-Trp-NH2 displays particular promise with minimum biofilm eradication concentration (MBEC) values of 125 µg/ml against methicillin sensitive (ATCC 29213) and resistant (ATCC 43300) S. aureus and activity shown against biofilm forms of Escherichia coli (MBEC: 1000 µg/ml). Kill kinetics confirms complete eradication of established 24-h biofilms at MBEC with 6-h exposure. Reduced cell cytotoxicity, relative to Gram-positive pathogens, was proven via tissue culture (HaCaT) and haemolysis assays (equine erythrocytes).

Existing in nature as part of the immune response, antimicrobial peptides display great promise for exploitation by the pharmaceutical industry in order to increase the library of available therapeutic molecules. Ultrashort variants are particularly promising for translation as clinical therapeutics as they are more cost-effective, easier to synthesise and can be tailored to specific functional requirements based on the primary sequence allowing factors such as spectrum of activity to be varied.