Effectiveness of 2 Osteopathic Treatment Approaches on Pain, Pressure-Pain Threshold, and Disease Severity in Patients with Fibromyalgia: A Randomized Controlled Trial.

OBJECTIVE: To assess the effectiveness of osteopathic intervention (OI) and general osteopathic treatment (GOT) in individuals with fibromyalgia syndrome (FMS). METHODS: The trial was designed as a randomized controlled trial with 2 osteopathic interventions and 1 untreated control group. The patients in the two osteopathic groups received 10 osteopathic treatments (OI or GOT) within a time period of 12 weeks. The control group did not receive any osteopathic treatment. The primary outcome was the average pain intensity (API) assessed by visual analog scale (VAS). Secondary outcomes were the pressure-pain threshold rated by means of a tender point score, and disease severity, assessed by the Fibromyalgia Impact Questionnaire (FIQ). RESULTS: 50 patients were randomized. The primary outcome parameter API decreased from 7.2 to 4.7 in the OI group, from 6.3 to 4.3 in the GOT group, and increased slightly in the control group from 6.2 to 6.6. There were significant differences for the change in API between the OI group and the control group (VAS: 2.9, 95% confidence interval (CI) = 1.12-4.52), and between the GOT group and the control group (VAS: 2.4, 95% CI = 0.65-4.11), but no significant differences between the OI group and the GOT group. There were no significant differences for the secondary outcome parameters between the groups. CONCLUSION: A series of osteopathic treatments might be beneficial for patients suffering from FMS.

A quality by design approach to understand formulation and process variability in pharmaceutical melt extrusion processes.

OBJECTIVES: In this study, the principles of quality by design (QbD) have been uniquely applied to a pharmaceutical melt extrusion process for an immediate release formulation with a low melting model drug, ibuprofen. METHODS: Two qualitative risk assessment tools - Fishbone diagram and failure mode effect analysis - were utilized to strategically narrow down the most influential parameters. Selected variables were further assessed using a Plackett-Burman screening study, which was upgraded to a response surface design consisting of the critical factors to study the interactions between the study variables. In process torque, glass transition temperature (Tg ) of the extrudates, assay, dissolution and phase change were measured as responses to evaluate the critical quality attributes (CQAs) of the extrudates. The effect of each study variable on the measured responses was analysed using multiple regression for the screening design and partial least squares for the optimization design. KEY FINDINGS: Experimental limits for formulation and process parameters to attain optimum processing have been outlined. A design space plot describing the domain of experimental variables within which the CQAs remained unchanged was developed. CONCLUSIONS: A comprehensive approach for melt extrusion product development based on the QbD methodology has been demonstrated. Drug loading concentrations between 40- 48%w/w and extrusion temperature in the range of 90-130°C were found to be the most optimum.

Molecular indicators of surface and bulk instability of hot melt extruded amorphous solid dispersions.

PURPOSE: To identify molecular indicators of bulk and surface instabilities of amorphous dispersions prepared by hot melt extrusion. METHODS: Four model drugs with different physicochemical properties were formulated with EUDRAGIT(®) E PO using hot melt extrusion. Samples were aged under a range of conditions for up to 6 months and characterized using SEM, ATR-FTIR, PXRD and MTDSC. The effects of a range of thermodynamic, kinetic and molecular parameters, including glass transition temperature, molecular mobility, the crystallization tendency of the amorphous drug and drug-polymer miscibility, on the bulk and surface stabilities of the solid dispersions were evaluated. RESULTS: For all drug-containing systems, a higher degree of instability was observed at the surface of the material in comparison to the bulk. Stressed humidity showed a more profound effect on the dispersions in comparison to stress temperature, reducing both their surface and bulk stabilities. For supersaturated systems the order of the bulk and surface instabilities of the samples was found following the same order of the molecular mobilities of the amorphous model drugs. This was attributed to the presence of phase separation of amorphous drug-rich domains in the supersaturated extrudates. CONCLUSIONS: The stability of the amorphous drug-rich domains appears to be governed by the physical stabilities of the amorphous drugs. The more commonly used indicators such as Tg, fragility of the amorphous drug and the theoretically predicted drug-polymer solubility showed less influence on the bulk and surface stabilities of the extrudates in comparison to the molecular mobility of the amorphous drug.

The effect of processing on the surface physical stability of amorphous solid dispersions.

The focus of this study was to investigate the effect of processing on the surface crystallization of amorphous molecular dispersions and gain insight into the mechanisms underpinning this effect. The model systems, amorphous molecular dispersions of felodipine-EUDRAGIT® E PO, were processed both using spin coating (an ultra-fast solvent evaporation based method) and hot melt extrusion (HME) (a melting based method). Amorphous solid dispersions with drug loadings of 10-90% (w/w) were obtained by both processing methods. Samples were stored under 75% RH/room temperatures for up to 10months. Surface crystallization was observed shortly after preparation for the HME samples with high drug loadings (50-90%). Surface crystallization was characterized by powder X-ray diffraction (PXRD), ATR-FTIR spectroscopy and imaging techniques (SEM, AFM and localized thermal analysis). Spin coated molecular dispersions showed significantly higher surface physical stability than hot melt extruded samples. For both systems, the progress of the surface crystal growth followed zero order kinetics on aging. Drug enrichment at the surfaces of HME samples on aging was observed, which may contribute to surface crystallization of amorphous molecular dispersions. In conclusion it was found the amorphous molecular dispersions prepared by spin coating had a significantly higher surface physical stability than the corresponding HME samples, which may be attributed to the increased process-related apparent drug-polymer solubility and reduced molecular mobility due to the quenching effect caused by the rapid solvent evaporation in spin coating.

Molecular implications of drug-polymer solubility in understanding the destabilization of solid dispersions by milling.

The solubility of drugs in polymer matrixes has been recognized as one of the key factors governing the physical stability of solid dispersions. This study has explored the implications of drug solubility on the destabilization that occurs on milling, which is often used as an additional process for hot melt extruded (HME) solid dispersions. The theoretical drug solubility in the polymer was first predicted using various theoretical and experimental approaches. The destabilization effects of high-energy mechanical milling on the solid dispersions with drug loadings below and above the predicted solubility were then investigated using a range of thermal, microscopic, and spectroscopic techniques. Four model drug-polymer combinations were studied. The HME formulations with drug loading below the predicted solid solubility (undersaturated and true molecular dispersion) showed good stability against milling. In contrast, milling destabilized supersaturated HME dispersions via increasing molecular mobility and creating phase-separated, amorphous, drug-rich domains. However, these additional amorphous drug-rich domains created by milling show good stability under ambient conditions, though crystallization can be accelerated by additional heating. These results highlighted that the processing method used to prepare the solid dispersions may play a role in facilitating the stabilization of amorphous drug in supersaturated solid dispersions. The degree of supersaturation of the drug in the polymer showed significant impact on the destabilization behavior of milling on solid dispersions. An improved understanding of the destabilization behavior of solid dispersions upon milling can provide new insights into the processing related apparent solubility of drugs in polymers.

Poly(meth)acrylate-based coatings.

Poly(meth)acrylate coatings for pharmaceutical applications were introduced in 1955 with the launch of EUDRAGIT(®) L and EUDRAGIT(®) S, two types of anionic polymers. Since then, by introducing various monomers into their polymer chains and thus altering their properties, diverse forms with specific characteristics have become available. Today, poly(meth)acrylates function in different parts of the gastrointestinal tract and/or release the drug in a time-controlled manner. This article reviews the properties of various poly(meth)acrylates and discusses formulation issues as well as application possibilities.

Microstructure of an immiscible polymer blend and its stabilization effect on amorphous solid dispersions.

This study proposes use of the phase separation of immiscible polymer blends as a formulation approach to improve the stabilization and solubilization of amorphous molecular dispersions of poorly soluble drugs. This approach uses the phase separation and different drug solubilization properties of the two immiscible polymers in the blend to optimize drug loading and stabilization. The model system tested in this study is a EUDRAGIT E PO-PVP-VA 50/50 (w/w) blend loaded with felodipine via hot melt extrusion. The phase separation behavior of the polymer blend and drug loaded polymer blend formulations were characterized using a range of thermal (MTDSC), spectroscopic (ATR-FTIR), and imaging (AFM and thermal transition mapping) techniques. The polymer blend formulations demonstrated superior performance in drug release as well as stabilization against stressed temperature, stressed humidity, and mechanical milling in comparison to the drug-polymer binary systems. This is attributed to the configuration of the phase separated microstructure of the polymer blend formulations where the hydrophilic polymer domains host high concentrations of molecularly dispersed drug which are protected from moisture induced recrystallization on aging by the hydrophobic polymer domains. Additionally drug incorporation as a molecular dispersion in different polymer phases reduces the drug recrystallization tendency on aging under high temperatures and during milling.

Physician assistant student exposure to the long-term care setting by working with a consultant pharmacist.

PURPOSE: Physician assistant (PA) students need exposure to a wide range of clinical settings including long-term care (LTC); however, finding consistent educational LTC opportunities is difficult. This article describes a unique, replicable, educational opportunity for PA students to get exposure to the LTC setting by working with a consultant pharmacist. METHODS: Pairs of students spent 4 hours with the pharmacist, reviewing and copresenting two to three patient charts. Students completed a questionnaire that asked them to describe what they had learned. RESULTS: Students indicated they had an increased appreciation of having strong knowledge of medication prescribing and monitoring and avoiding polypharmacy, as well as disease prevention, the importance of interprofessional care, and preventing medication errors. CONCLUSION: Although LTC settings vary, consultant pharmacists may provide a reliable gateway to the LTC setting for PA students. Gains in skills were not directly measured; however, students reported an increased appreciation for aspects of geriatric care related to all six of the competencies outlined in Competencies for the Physician Assistant Profession.

Evaluation of predictive models for stable solid solution formation.

The objective of this study was to evaluate predictive models for stable solid solution formation and to find a quick and successful approach for miscibility screenings. The results show that the interpretation of the chemical structure and the crystallinity by X-ray powder diffraction measurements as well as the determination of melting point depressions and melting enthalpies are beneficial tools to predict the miscibility of drugs and carriers. A combined approach of prediction tools is highly appropriate, as no single technique may yield all the required information. Nevertheless, the evaluation of the melting behavior via differential scanning calorimetry has the highest impact.

Mechanism of drug release from polymethacrylate-based extrudates and milled strands prepared by hot-melt extrusion.

The aim of the study was the formulation of solid dispersions of the poorly water-soluble drug celecoxib and a polymethacrylate carrier by hot-melt extrusion. The objectives were to elucidate the mechanism of drug release from obtained extrudates and milled strands addicted to the solid-state properties of the solid dispersions and to examine and eliminate stability problems occurring under storage, exposure of mechanical stress, and in vitro dissolution. Transparent extrudates containing up to 60% drug could be prepared with a temperature setting below the melting point of celecoxib. XRPD and DSC measurements indicated the formation of a glassy solid solution, where the drug is molecularly dispersed in the carrier. The amorphous state of the glassy solid solution could be maintained during the exposure of mechanical stress in a milling process, and was stable under storage for at least 6 months. Solid-state properties and SEM images of extrudates after dissolution indicated a carrier-controlled dissolution, whereby the drug is molecularly dispersed within the concentrated carrier layer. The glassy solid solution showed a 58-fold supersaturation in 0.1 N HCl within the first 10 min, which was followed by a recrystallization process. Recrystallization could be inhibited by an external addition of HPMC.