Structured group education programme and accompanying mHealth intervention to promote physical activity in women with a history of gestational diabetes: A randomised controlled trial.

AIMS: Assess effectiveness of a hybrid intervention targeting physical activity in women with prior gestational diabetes. METHODS: Randomised controlled trial with parallel arms. 293 women (35.1 ± 5.1 years; 40% ethnic minority) recruited from two hospitals and randomised to routine care or hybrid lifestyle intervention comprising two group sessions and access to a mobile web app. Primary outcome was a change in objectively measured physical activity at 12 months. Secondary outcomes included self-efficacy for exercise, quality of life and anxiety and depression. Linear regression compared outcome measures between groups. RESULTS: 83% of intervention participants attended at least one group session, of who 66% registered to use the app. There was a non-significant increase in physical activity at 12 months (between-group difference of 0.95 mg [95% CI: -0.46 to 2.37]), equivalent to approximately 500 steps per day. Intervention participants reported higher self-efficacy for exercise (0.54, 95% CI: 0.05 to 1.102; p = 0.029), lower anxiety (-0.91, 95% CI: -1.74 to -0.09; p = 0.031), and higher quality of life (0.05, 95% CI: 0.004 to 0.09; p = 0.032), compared to controls. CONCLUSIONS: The intervention improved confidence in exercise and quality of life. Further research is needed to improve participant engagement with physical activity interventions in multi-ethnic populations with a history of gestational diabetes.

Accessing needle exchange services in disasters for remote areas of Aotearoa New Zealand.

BACKGROUND: Needle Exchange Programme (NEP) mobile outreach services in Aotearoa New Zealand distribute injecting equipment to people who inject drugs (PWID) living in remote regions. In disasters, continued access to such services is imperative for the health and wellbeing of PWID. Disasters can compound existing inequities, particularly in regions characterised by poor or limited infrastructure, smaller populations, and challenging socioeconomic conditions. To gain insight into the barriers that prevent access to NEP harm-reduction services and understand the needs of PWID prior to and during disasters, this study foregrounds the voices of PWID based on the West Coast of the South Island, Aotearoa New Zealand. METHODS: This qualitative study applied an interpretive phenomenological analysis approach, where 14 PWID and one key NEP staff member took part in semi-structured interviews. The interviews provided the opportunity for participants to share their experiences and perspectives about accessing sterile drug-injecting equipment during disasters, including the four-week COVID-19 Level 4 lockdown in March 2020. In total five superordinate and 14 subordinate themes were identified from the interveiws. RESULTS: This study focuses on four of the key themes that impacted accessibility to NEP services: infrastructural hazards and equipment costs; social capital and practical support from peers and key contact networks; social stigma in public locations, including NEP-based pharmacies and emergency centres; and potential solutions to NEP equipment accessibility as frequently suggested by participants. CONCLUSIONS: Access to NEP services is essential during natural hazard and human-generated disasters, as such NEP mobile outreach services and disaster resilience efforts should focus on maintaining service continuity for PWID during adverse times. This study champions a needs-based, stigma free approach to inclusive harm-reduction and emergency management practices for groups with specific needs in a disaster context.

Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery - An update.

Poor water-solubility remains a typical property of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate, and bioavailability of these active ingredients belonging to biopharmaceutical classification system (BCS) II and IV classifications. Since the early 2000s, nanocrystal delivery and amorphous solid dispersions are more established techniques to overcome the limitations of poorly-water soluble drugs in FDA available products. This article provides an updated review of nanocrystal and amorphous solid dispersion techniques primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with marketed product evaluations and a survey of commercially relevant scientific literature.

Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for Poorly Water-Soluble Drug Delivery (Part 2).

The KinetiSol® Dispersing (KSD) technology has enabled the investigation into the use of polyvinyl alcohol (PVAL) as a concentration enhancing polymer for amorphous solid dispersions. Our previous study revealed that the 88% hydrolyzed grade of PVAL was optimal for itraconazole (ITZ) amorphous compositions with regard to solid-state properties, non-sink dissolution performance, and bioavailability enhancement. The current study investigates the influence of molecular weight for the 88% hydrolyzed grades of PVAL on the properties of KSD processed ITZ:PVAL amorphous dispersions. Specifically, molecular weights in the processable range of 4 to 18 mPa · s were evaluated and the 4-88 grade provided the highest AUC dissolution profile. Amorphous dispersions at 10, 20, 30, 40, and 50% ITZ drug loads in PVAL 4-88 were also compared by dissolution performance. Analytical tools of diffusion-ordered spectroscopy and Fourier transform infrared spectroscopy were employed to understand the interaction between drug and polymer. Finally, results from a 30-month stability test of a 30% drug loaded ITZ:PVAL 4-88 composition shows that stable amorphous dispersions can be achieved. Thus, this newly enabled polymer carrier can be considered a viable option for pharmaceutical formulation development for solubility enhancement.

Enabling thermal processing of ritonavir-polyvinyl alcohol amorphous solid dispersions by KinetiSol® Dispersing.

Polyvinyl alcohol has received little attention as a matrix polymer in amorphous solid dispersions (ASDs) due to its thermal and rheological limitations in extrusion processing and limited organic solubility in spray drying applications. Additionally, in extrusion processing, the high temperatures required to process often exclude thermally labile APIs. The purpose of this study was to evaluate the feasibility of processing polyvinyl alcohol amorphous solid dispersions utilizing the model compound ritonavir with KinetiSol® Dispersing (KSD) technology. The effects of KSD rotor speed and ejection temperature on the physicochemical properties of the processed material were evaluated. Powder X-ray diffraction and modulated differential scanning calorimetry were used to confirm amorphous conversion. Liquid chromatography-mass spectroscopy was used to characterize and identify degradation pathways of ritonavir during KSD processing and (13)C nuclear magnetic resonance spectroscopy was used to investigate polymer stability. An optimal range of processing conditions was found that resulted in amorphous product and minimal to no drug and polymer degradation. Drug release of the ASD produced from the optimal processing conditions was evaluated using a non-sink, pH-shift dissolution test. The ability to process amorphous solid dispersions with polyvinyl alcohol as a matrix polymer will enable further investigations of the polymer's performance in amorphous systems for poorly water-soluble compounds.

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions.

Thermal processing technologies continue to gain interest in pharmaceutical manufacturing. However, the types and grades of polymers that can be utilized in common thermal processing technologies, such as hot-melt extrusion (HME), are often limited by thermal or rheological factors. The objectives of the present study were to compare and contrast two thermal processing methods, HME and KinetiSol® Dispersing (KSD), and investigate the influence of polymer type, polymer molecular weight, and drug loading on the ability to produce amorphous solid dispersions (ASDs) containing the model compound griseofulvin (GRIS). Dispersions were analyzed by a variety of imaging, solid-state, thermal, and solution-state techniques. Dispersions were prepared by both HME and KSD using polyvinylpyrrolidone (PVP) K17 or hydroxypropyl methylcellulose (HPMC) E5. Dispersions were only prepared by KSD using higher molecular weight grades of HPMC and PVP, as these could not be extruded under the conditions selected. Powder X-ray diffraction (PXRD) analysis showed that dispersions prepared by HME were amorphous at 10% and 20% drug load; however, it showed significant crystallinity at 40% drug load. PXRD analysis of KSD samples showed all formulations and drug loads to be amorphous with the exception of trace crystallinity seen in PVP K17 and PVP K30 samples at 40% drug load. These results were further supported by other analytical techniques. KSD produced amorphous dispersions at higher drug loads than could be prepared by HME, as well as with higher molecular weight polymers that were not processable by HME, due to its higher rate of shear and torque output.

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1).

Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentration-enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole.

Bioavailability enhancement of a BCS IV compound via an amorphous combination product containing ritonavir.

OBJECTIVES: To evaluate the effect of ritonavir (RTV) co-administration on the bioavailability of an amorphous dispersion of acetyl-11-keto-beta-boswellic acid (AKBA) and to develop a pharmaceutically acceptable AKBA-RTV combination tablet. METHODS: A pharmacokinetic (PK) study in rats was conducted to evaluate the influence of RTV co-administration on the oral bioavailability of an AKBA amorphous dispersion. KinetiSol was utilized to enable production of an improved RTV formulation that facilitated the development of an AKBA-RTV combination tablet. Following in-vitro characterization, the PK performance of the tablets was evaluated in male beagles. KEY FINDINGS: Co-administration of RTV increased oral absorption of AKBA by about fourfold over the AKBA dispersion alone and approximately 24-fold over the pure compound. The improved RTV amorphous dispersion exhibited similar purity and neutral-phase dissolution to Norvir. The AKBA-RTV combination tablets yielded a substantial increase in AKBA's bioavailability in dogs. CONCLUSIONS: Oral absorption of AKBA is substantially limited by intestinal CYP3A activity and poor aqueous solubility. Consequently, AKBA's oral bioavailability is maximized by administration from a supersaturating formulation in conjunction with a CYP3A inhibitor. The AKBA-RTV combination tablet presented herein represents a breakthrough in the oral delivery of the compound facilitating future use as a drug therapy for broad spectrum cancer treatment.

The evaluation of an interactive web-based Pulmonary Rehabilitation programme: protocol for the WEB SPACE for COPD feasibility study.

INTRODUCTION: Pulmonary Rehabilitation (PR) is an evidence-based intervention that has been recommended in guidelines to be available to those who may benefit. However, not all patients with chronic obstructive pulmonary disease (COPD) have access to this service. Healthcare services have shown the need for the provision of PR in other forms to enable patient choice and service capacity. There is an increase in evidence for the use of the internet in the management of long-term conditions to provide education and promote self-management. The aim of this study is to see if an interactive web-based PR programme is a feasible alternative compared with conventional PR. METHODS AND ANALYSIS: This is a feasibility study designed to evaluate the efficacy of providing a web-based PR programme to improve patients exercise capacity, quality of life and promote self-management in patients with moderate to severe COPD compared with conventional PR programmes. Eligible patients will be randomly allocated to receive either the web-based programme or conventional rehabilitation programme for 7 weeks using an internet-based randomisation system. Participants will be recruited from PR assessments, primary care and community rehabilitation programmes. Those randomised to the web-based programme work through the website which contains all the information that the patients receive in the PR classes. They receive weekly phone calls by a professional to help progress through the course on line. The outcome measures will be recruitment rates and eligibility as well as that standard for a PR assessment including measures of exercise capacity, quality of life questionnaires and physical activity. ETHICS AND DISSEMINATION: The research ethics committee for Northampton has provided ethical approval for the conduct of the study. The results of the study will be disseminated through appropriate conference presentations and peer reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN03142263.

Preparation of amorphous solid dispersions by rotary evaporation and KinetiSol Dispersing: approaches to enhance solubility of a poorly water-soluble gum extract.

Acetyl-11-keto-ß-boswellic acid (AKBA), a gum resin extract, possesses poor water-solubility that limits bioavailability and a high melting point making it difficult to successfully process into solid dispersions by fusion methods. The purpose of this study was to investigate solvent and thermal processing techniques for the preparation of amorphous solid dispersions (ASDs) exhibiting enhanced solubility, dissolution rates and bioavailability. Solid dispersions were successfully produced by rotary evaporation (RE) and KinetiSol® Dispersing (KSD). Solid state and chemical characterization revealed that ASD with good potency and purity were produced by both RE and KSD. Results of the RE studies demonstrated that AQOAT®-LF, AQOAT®-MF, Eudragit® L100-55 and Soluplus with the incorporation of dioctyl sulfosuccinate sodium provided substantial solubility enhancement. Non-sink dissolution analysis showed enhanced dissolution properties for KSD-processed solid dispersions in comparison to RE-processed solid dispersions. Variances in release performance were identified when different particle size fractions of KSD samples were analyzed. Selected RE samples varying in particle surface morphologies were placed under storage and exhibited crystalline growth following solid-state stability analysis at 12 months in comparison to stored KSD samples confirming amorphous instability for RE products. In vivo analysis of KSD-processed solid dispersions revealed significantly enhanced AKBA absorption in comparison to the neat, active substance.

Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug delivery.

Poor water-solubility is a common characteristic of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate and bioavailability of these active ingredients belonging to BCS II and IV classifications. Over the last decade, nano-crystal delivery forms and amorphous solid dispersions have become well established in commercially available products and industry literature. This article is a comparative analysis of these two methodologies primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with marketed product evaluations and a survey of commercial relevant scientific literature.

Preparation and characterization of fusion processed solid dispersions containing a viscous thermally labile polymeric carrier.

The primary aim of the present study was to investigate the ability of hydroxypropyl and methoxyl substituted cellulose ethers to stabilize supersaturated concentrations of itraconazole (ITZ), a poorly water-soluble weak base, after an acid-to-neutral pH transition. A secondary aim of the study was to evaluate the effect of fusion processes on polymer stability and molecular weight. Polymer screening studies showed that stabilization of ITZ supersaturation was related to the molecular weight of the polymer and levels of hydroxypropyl and methoxyl substitution. METHOCEL E50LV (E50LV), which is characterized as having a high melt viscosity, was selected for solid dispersion formulation studies. Hot-melt extrusion processing of E50LV based compositions resulted in high torque loads, low material throughput and polymer degradation. KinetiSol Dispersing, a novel fusion based processing technique, was evaluated as a method to prepare the solid dispersions with reduced levels of polymer degradation. An experimental design revealed that polymer molecular weight was sensitive to shearing forces and high temperatures. However, optimal processing conditions resulted in significantly reduced E50LV degradation relative to HME processing. The technique was effectively utilized to prepare homogenous solid solutions of E50LV and ITZ, characterized as having a single glass transition temperature over a wide range of drug loadings. All prepared compositions provided for a high degree of ITZ supersaturation stabilization.

Thermal processing of a poorly water-soluble drug substance exhibiting a high melting point: the utility of KinetiSol® Dispersing.

Poorly water-soluble drug substances that exhibit high melting points are often difficult to successfully process by fusion-based techniques. The purpose of this study was to identify a suitable polymer system for meloxicam (MLX), a high melting point class II BCS compound, and investigate thermal processing techniques for the preparation of chemically stable single phase solid dispersions. Thermal and solution based screening techniques were utilized to screen hydrophilic polymers suitable for immediate release formulations. Results of the screening studies demonstrated that Soluplus(®)(SOL) provided the highest degree of miscibility and solubility enhancement. A hot-melt extrusion feasibility study demonstrated that high temperatures and extended residence times were required in order to render compositions amorphous, causing significant degradation of MLX. A design of experiments (DOE) was conducted on the KinetiSol(®) Dispersing (KSD) process to evaluate the effect of processing conditions on the chemical stability and amorphous character of MLX. The study demonstrated that ejection temperature significantly impacted MLX stability. All samples prepared by KSD were substantially amorphous. Dissolution analysis of the KSD processed solid dispersions showed increased dissolution rates and extent of supersaturation over the marketed generic MLX tablets.

Dissolution enhancement of a drug exhibiting thermal and acidic decomposition characteristics by fusion processing: a comparative study of hot melt extrusion and KinetiSol dispersing.

In this study, hot melt extrusion (HME) and KinetiSol Dispersing (KSD) were utilized to prepare dissolution-enhanced solid dispersions of Roche Research Compound A (ROA), a BCS class II drug. Preformulation characterization studies showed that ROA was chemically unstable at elevated temperatures and acidic pH values. Eudragit L100-55 and AQOAT LF (HPMCAS) were evaluated as carrier polymers. Dispersions were characterized for ROA recovery, crystallinity, homogeneity, and non-sink dissolution. Eudragit L100-55 dispersions prepared by HME required the use of micronized ROA and reduced residence times in order to become substantially amorphous. Compositions containing HPMCAS were also prepared by HME, but an amorphous dispersion could not be obtained. All HME compositions contained ROA-related impurities. KSD was investigated as a method to reduce the decomposition of ROA while rendering compositions amorphous. Substantially amorphous, plasticizer free compositions were processed successfully by KSD with significantly higher ROA recovery values and amorphous character than those achieved by HME. A near-infrared chemical imaging analysis was conducted on the solid dispersions as a measure of homogeneity. A statistical analysis showed similar levels of homogeneity in compositions containing Eudragit L100-55, while differences were observed in those containing HMPCAS. Non-sink dissolution analysis of all compositions showed rapid supersaturation after pH adjustment to approximately two to three times the equilibrium solubility of ROA, which was maintained for at least 24 h. The results of the study demonstrated that KSD is an effective method of forming dissolution-enhanced amorphous solid solutions in cases where HME is not a feasible technique.

Production of advanced solid dispersions for enhanced bioavailability of itraconazole using KinetiSol Dispersing.

OBJECTIVES: To investigate the ability of KinetiSol Dispersing to prepare amorphous solid dispersions of itraconazole using concentration-enhancing polymers. METHODS: Concentration-enhancing nature of several cellulosic polymers (HPMC, hypromellose acetate succinate) was studied using a modified in vitro dissolution test. Solid dispersions were prepared by KinetiSol Dispersing and characterized for solid-state properties using X-ray diffraction and differential scanning calorimetry. Potency and release characteristics were also assessed by high-performance liquid chromatography. Oral bioavailability of lead formulations was also assessed in animal models. RESULTS: Screening studies demonstrated superior concentration-enhancing performance from the hypromellose acetate succinate polymer class. Data showed that stabilization was related to molecular weight and the degree of hydrophobic substitution on the polymer such that HF > MF approximately LF, indicating that stabilization was achieved through a combination of steric hindrance and hydrophobic interaction, supplemented by the amphiphilic nature and ionization state of the polymer. Solid dispersions exhibited amorphous solid-state behavior and provided neutral media supersaturation using a surfactant-free pH change method. Rank-order behavior was such that LF > MF > HF. Addition of Carbopol 974P increased acidic media dissolution, while providing a lower magnitude of supersaturation in neutral media because of swelling of the high viscosity gel. In vivo results for both lead compositions displayed erratic absorption was attributed to the variability of gastrointestinal pH in the animals. CONCLUSIONS: These results showed that production of amorphous solid dispersions containing concentration-enhancing polymers through KinetiSol Dispersing can provide improved oral bioavailability; however, additional formulation techniques must be developed to minimize variability associated with natural variations in subject gastrointestinal physiology.

Applications of KinetiSol dispersing for the production of plasticizer free amorphous solid dispersions.

Thermal manufacturing methods for the production of solid dispersions frequently require the addition of a plasticizer in order to achieve requisite molten material flow properties when processed by unit operations such as hot melt extrusion. KinetiSol Dispersing, a rapid high energy thermal manufacturing process, was investigated for the ability to produce amorphous solid dispersions without the aid of a plasticizer. For this study itraconazole was used as a model active ingredient, while Eudragit L100-55 and Carbomer 974P were used as model solid dispersion carriers. Triethyl citrate (TEC) was used as necessary as a model plasticizer. Compositions prepared by KinetiSol Dispersing and hot melt extrusion were evaluated for solid state properties, supersaturated in vitro dissolution behavior under pH change conditions and accelerated stability performance. Results showed that both manufacturing processes were capable of producing amorphous solid dispersions, however compositions produced by hot melt extrusion required the presence of TEC and yielded a glass transition temperature (T(g)) of approximately 54 degrees C. Plasticized and unplasticized compositions were successfully produced by KinetiSol Dispersing, with plasticizer free solid dispersions exhibiting a T(g) of approximately 101 degrees C. Supersaturated in vitro dissolution testing revealed a significantly higher dissolution rate of plasticized material which was attributed to the pore forming behavior of TEC during the acidic phase of testing. A further contribution to release may also have been provided by the greater diffusivity in the plasticized polymer. X-ray diffraction testing revealed that under accelerated stability conditions, plasticized compositions exhibited partial recrystallization, while plasticizer free materials remained amorphous throughout the 6-month testing period. These results demonstrated that KinetiSol Dispersing could be used for the production of amorphous solid dispersions without the aid of a plasticizer and illustrated the enhanced solid state stability that can be achieved by producing solid dispersions with higher glass transition temperatures.

Fusion production of solid dispersions containing a heat-sensitive active ingredient by hot melt extrusion and Kinetisol dispersing.

Many techniques for the production of solid dispersions rely on elevated temperatures and prolonged material residence times, which can result in decomposition of temperature-sensitive components. In this study, hydrocortisone was used as a model temperature-sensitive active ingredient to study the effect of formulation and processing techniques as well as to characterize the benefits of KinetiSol Dispersing for the production of solid dispersions. Preformulation studies were conducted using differential scanning calorimetry and hot stage microscopy to identify optimum carriers for the production of amorphous solid dispersions. After identification, solid dispersions were prepared by hot melt extrusion and KinetiSol Dispersing, with material characterized by X-ray diffraction, dissolution and potency testing to evaluate physicochemical properties. Results from the preformulation studies showed that vinylacetate:vinylpyrrolidone (PVPVA) copolymer allowed for hydrocortisone dissolution within the carrier at temperatures as low as 160 degrees C, while hydroxypropyl methylcellulose required temperatures upward of 180 degrees C to facilitate solubilization. Low substituted hydroxypropyl cellulose, a high glass transition temperature control, showed that the material was unable to solubilize hydrocortisone. Manufacturing process control studies using hot melt extruded compositions of hydrocortisone and PVPVA showed that increased temperatures and residence times negatively impacted product potency due to decomposition. Using KinetiSol Dispersing to reduce residence time and to facilitate lower temperature processing, it was possible to produce solid dispersions with improved product potency. This study clearly demonstrated the importance of carrier selection to facilitate lower temperature processing, as well as the effect of residence time on product potency. Furthermore, KinetiSol Dispersing provided significant advantages over hot melt extrusion due to the reduced residence times and lower required processing temperatures. This allowed for the production of solid dispersions with enhanced product potency.

Fusion processing of itraconazole solid dispersions by kinetisol dispersing: a comparative study to hot melt extrusion.

KinetiSol Dispersing (KSD) is a novel high energy manufacturing process investigated here for the production of pharmaceutical solid dispersions. Solid dispersions of itraconazole (ITZ) and hypromellose were produced by KSD and compared to identical formulations produced by hot melt extrusion (HME). Materials were characterized for solid state properties by modulated differential scanning calorimetry and X-ray diffraction. Dissolution behavior was studied under supersaturated conditions. Oral bioavailability was determined using a Sprague-Dawley rat model. Results showed that KSD was able to produce amorphous solid dispersions in under 15 s while production by HME required over 300 s. Dispersions produced by KSD exhibited single phase solid state behavior indicated by a single glass transition temperature (T(g)) whereas compositions produced by HME exhibited two T(g)s. Increased dissolution rates for compositions manufactured by KSD were also observed compared to HME processed material. Near complete supersaturation was observed for solid dispersions produced by either manufacturing processes. Oral bioavailability from both processes showed enhanced AUC compared to crystalline ITZ. Based on the results presented from this study, KSD was shown to be a viable manufacturing process for the production of pharmaceutical solid dispersions, providing benefits over conventional techniques including: enhanced mixing for improved homogeneity and reduced processing times.