High-viscosity Hydroxypropylmethylcellulose Research Articles

Surface Modification of Silk Fabric by Polysaccharide Derivatives towards High-Quality Printing Performance Using Bio-Based Gardenia Blue Ink.

Ink-jet-printed silk, a premium textile material, was achieved by utilizing a bio-based gardenia blue dye. However, the sharpness of the printing pattern is difficult to control due to the limited water-retention capacity of silk. To address this issue, three polysaccharide derivatives, namely, sodium alginate (SA), low-viscosity hydroxypropyl methyl cellulose (HPMC-I), and high-viscosity hydroxypropyl methyl cellulose (HPMC-II), were employed as thickeners to modify the silk by the dipping-padding method. Firstly, the preparation of the gardenia blue ink and the rheology assessment of the thickener solution were conducted. Furthermore, the impacts of different thickeners on the micro-morphology, element composition, and hydrophilicity of the silk, along with the wetting behavior of the ink on the silk, were analyzed comparatively in order to identify an appropriate thickener for preserving pattern outlines. Lastly, the color features, color fastness, and wearing characteristics of the printed silk were discussed to evaluate the overall printing quality. Research results showed that the optimized ink formulation, comprising 12% gardenia blue, 21% alcohols, and 5.5% surfactant, met the requirements for ink-jet printing (with a viscosity of 4.48 mPa·s, a surface tension of 34.12 mN/m, and a particle size of 153 nm). The HPMC-II solution exhibited prominent shear-thinning behavior, high elasticity, and thixotropy, facilitating the achievement of an even modification effect. The treatment of the silk with HPMC-II resulted in the most notable decrease in hydrophilicity. This can be attributed to the presence of filled gaps and a dense film on the fibers' surface after the HPMC-II treatment, as observed by scanning electron microscopy. Additionally, X-ray photoelectron spectroscopy analysis confirmed that the HPMC-II treatment introduced the highest content of hydrophobic groups on the fiber surface. The reduced hydrophilicity inhibited the excessive diffusion and penetration of gardenia blue ink, contributing to a distinct printing image and enhanced apparent color depth. Moreover, the printed silk demonstrated qualified color fastness to rubbing and soaping (exceeding grade four), a soft handle feeling, an ignorable strength loss (below 5%), and a favorable air/moisture penetrability. In general, the surface modification with the HPMC-II treatment has been proven as an effective strategy for upgrading the image quality of bio-based dye-printed silk.

Multivariate Analysis and Computational Predictability of Modified Release Formulation of Chirally Pure Metoprolol Succinate

This study employs computational techniques to predict the performance of a modified-release matrix formulation of chirally pure S (-) Metoprolol Succinate, using a Quality by Design (QbD) approach. The research defines the Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQAs) of the S (-) Metoprolol Succinate matrix formulation. To assess risks, an Ishikawa diagram and Failure Mode Effect Analysis (FMEA) following ICH Q8 guidelines were conducted. The formulation screening process utilized Plackett–Burman design, followed by optimization through Box–Behnken design. The modified-release formulation was developed using high shear granulation, incorporating a combination of high and low viscosity Hydroxypropyl Methylcellulose (HPMC) polymers along with other excipients. The impact of polymer composition and stearic acid on the release profile of S (-) Metoprolol Succinate was investigated, revealing their significant influence on the drug delivery system's desired effect. Specifically, the variables X1: HPMC K4M and X2: HPMC K100M were identified as key factors affecting drug release (Y1). Statistical analysis (ANOVA) confirmed the significance of the selected model, with predicted outcomes aligning well with observed results, comparable to the reference product Seleken® XL range. Both drug content and release performance were found to be similar to the innovator formulation. In summary, this investigation underscores the potential of employing a QbD approach with a combination of low and high viscosity HPMC polymers to achieve precise single-dose delivery of S (-) Metoprolol Succinate.

Cellulase as an “active” excipient in prolonged-release HPMC matrices: A novel strategy towards zero-order release kinetics

Hydrophilic matrices are of utmost interest for oral prolonged release of drugs. However, they show decreasing release rate over time, mainly due to lengthening of the diffusional pathway across the gel formed upon glass-rubber transition of the polymer. Therefore, achievement of zero-order release kinetics, which could reflect in constant drug plasma levels, is still an open issue. With the aim of improving the release performance of hydroxypropyl methylcellulose (HPMC) systems, the use of cellulolytic enzymes was proposed to aid erosion of the swollen matrix, thereby counteracting the release rate decrease particularly toward the end of the process. The effectiveness of this strategy was evaluated by studying the mass loss and drug tracer release from tableted matrices consisting of high-viscosity HPMC (Methocel® K4M), Acetaminophen and increasing amounts (0.5–10% on HPMC) of a cellulolytic product (Sternzym® C13030). A faster erosion and progressive shift to linearity of the overall release profiles were observed as a function of the enzyme concentration. Release was markedly linear from matrices containing 5 and 10% Sternzym® C13030. In partially coated matrices with these cellulase concentrations, such results were in agreement with data of erosion and swelling front movement, which exhibited early and long-lasting synchronization.

Formulation of Sustained Release Hydrophilic Matrix Tablets of Tolcapone with the Application of Sedem Diagram: Influence of Tolcapone's Particle Size on Sustained Release.

Hydrophilic matrix tablets are a type of sustained release dosage form characterized by distributing a drug in a matrix that is usually polymeric. Tolcapone is a drug that inhibits the enzyme catechol-O-methyl transferase. In recent years, it has been shown that tolcapone is a potent inhibitor of the amyloid aggregation process of the transthyretin protein, and acts by stabilizing the structure of the protein, reducing the progression of familial amyloid polyneuropathy. The main objective of this study was to obtain a sustained release tablet of tolcapone for oral administration with a preferred dosage regimen of 1 administration every 12 or 24 h and manufactured, preferably, by direct compression. The SeDeM Diagram method has been used for the formulation development of hydrophilic matrix tablets. Given the characteristics of tolcapone, the excipient selected for the formation of the polymeric matrix was a high viscosity hydroxypropylmethylcellulose (Methocel® K100M CR). A decrease in the particle size of tolcapone resulted in a slower dissolution release of the formulation when the concentration of the polymer Methocel® K100M CR was below 29%. These surprising and novel results have given rise to patent number WO/2018/019997.

Design of multi-particulate "Dome matrix" with sustained-release melatonin and delayed-release caffeine for jet lag treatment.

Multi-particulate Dome matrix with sustained-release melatonin and delayed-release caffeine was designed to restore jet lag sleep-wake cycle. The polymeric pellets were produced using extrusion-spheronization technique and fluid-bed coated when applicable. The compact and Dome module were produced by compressing pellets with cushioning agent. Dome matrix was assembly of modules with pre-determined compact formulation and drug release characteristics. The physicochemical and in vivo pharmacokinetics of delivery systems were examined. Melatonin loaded alginate/chitosan-less matrix exhibited full drug release within 8h gastrointestinal transit with low viscosity hydroxypropymethylcellulose as cushioning agent. The cushioning agent reduced burst drug release and omission of alginate-chitosan enabled full drug release. Delayed-release alginate-chitosan caffeine matrix was not attainable through polymer coating due to premature coat detachment. Admixing of cushioning agent high viscosity hydroxypropylmethylcellulose and high viscosity ethylcellulose (9:1wt ratio) with coat-free caffeine loaded particulates introduced delayed-release response via hydroxypropylmethylcellulose swelled in early dissolution phase and ethylcellulose sustained matrix hydrophobicity at prolonged phase. The caffeine was released substantially in colonic fluid in response to matrix polymers being degraded by rat colonic content. Dome matrix with dual drug release kinetics and modulated pharmacokinetics is produced to introduce melatonin-induced sleep phase then caffeine-stimulated wake phase.

Erodible coatings based on HPMC and cellulase for oral time-controlled release of drugs.

Oral drug delivery systems for time-controlled release, intended for chronotherapy or colon targeting, are often in the form of coated dosage forms provided with swellable/soluble hydrophilic polymer coatings. These are responsible for programmable lag phases prior to release, due to their progressive hydration in the biological fluids. When based on high-viscosity polymers and/or manufactured by press-coating, the performance of functional hydroxypropyl methylcellulose (HPMC) layers was not fully satisfactory. Particularly, it encompassed an initial phase of slow release because of outward diffusion of the drug through a persistent gel barrier surrounding the core. To promote erosion of such a barrier, the use of a cellulolytic product (Sternzym® C13030) was here explored. For this purpose, the mass loss behavior of tableted matrices based on various HPMC grades, containing increasing percentages of Sternzym® C13030, was preliminarily studied, highlighting a clear and concentration-dependent effect of the enzyme especially with high-viscosity polymers. Subsequently, Sternzym® C13030-containing systems, wherein the cellulolytic product was either incorporated into a high-viscosity HPMC coating or formed a separate underlying layer, were manufactured. Evaluated for release, such systems gave rise to more reproducible profiles, with shortened lag phases and reduced diffusional release, as compared to the reference formulation devoid of enzyme.

Tablets of paliperidone using compression-coated technology for controlled ascending release

The aim of this work was to prepare ascending release compression-coated (CC) tablets with paliperidone (PAL) using a simple manufacturing technique and short manufacturing process. The release behavior and mechanisms in vitro of the final tablets was investigated and evaluated. The PAL CC tablets were comprised of a core layer of high viscosity hydroxypropyl cellulose (HPC-H) and a coating layer of high viscosity hydroxypropyl methylcellulose (HPMC-K100M). Several factors such as materials and core tablet compositions were studied for their influence in the formulation procedure. The drug release mechanism was studied using gravimetric analysis. The data could be fitted to the Peppas model. The ascending drug release results were expressed in terms of the slope of the release curve at different time points. Results showed that the formulation could achieve a good ascending drug release when the weight ratio of PAL was 5:1 (core:layer). The fraction of HPC and HPMC was 33 %, and the combination of Eudragit RL-PO was 10%. The ascending release mechanism was due to solvent penetration into the PAL CC tablets, and subsequent drug dissolution from the gelatinous HPC and HPMC matrix erosion. The release mechanism was therefore a combination of diffusion and erosion. This work demonstrated that the compression-coated tablets could achieve controlled ascending release over 24 h for the oral administration systems.

Hydroxypropyl methylcellulose, a viscous soluble fiber, reduces insulin resistance and decreases fatty liver in Zucker Diabetic Fatty rats

BackgroundDiets producing a high glycemic response result in exaggerated insulin secretion which induces hepatic lipogenesis, contributing to development of insulin resistance and fatty liver. Viscous dietary fibers blunt the postprandial rise in blood glucose, however their effect on type 2 diabetes and obesity are not entirely known. This study examined the effect of chronic consumption of the viscous, non-fermentable dietary fiber, hydroxypropyl methylcellulose (HPMC), on glucose control, insulin resistance and liver lipids in an obese diabetic rat model.MethodsThree groups of Zucker Diabetic Fatty (ZDF) rats were fed diets containing either 5% non-viscous cellulose (control), low viscosity HPMC (LV-HPMC) or high viscosity HPMC (HV- HPMC) for six weeks. Zucker lean littermates consuming cellulose served as a negative control. Markers of glucose control, including oral glucose tolerance test, glycated hemoglobin and urinary glucose, were measured as well as adiposity and the accumulation of liver lipids.ResultsThe HPMC diets increased the viscosity of the small intestinal contents and reduced the postprandial rise in blood glucose. The food efficiency ratio was greater with HPMC feeding compared to the obese control and urinary excretion of glucose and ketone bodies was reduced. The two HPMC groups had lower glycated hemoglobin and kidney weights and a reduced area under the curve during a glucose tolerance test, indicating improved glucose control. Epididymal fat pad weight as percent of body weight was reduced in the HV-HPMC group compared to the obese control group. The HV-HPMC group also had lower concentrations of liver lipid and cholesterol and reduced liver weight. However, HV-HPMC feeding did not affect hepatic gene expression of SREBP-1c or FAS. Muscle concentration of acylcarnitines, a lipid intermediate in fatty acid β-oxidation, was not different between the HPMC groups and obese control, suggesting no change in muscle fatty acid oxidation by HPMC.ConclusionsConsumption of the viscous non-fermentable fiber HPMC decreased diabetic wasting, improved glucose control and reduced insulin resistance and fatty liver in a model of obesity with diabetes.

Development and comparative evaluation of in vitro, in vivo properties of novel controlled release compositions of paroxetine hydrochloride hemihydrate as against Geomatrix™ platform technology

The objective of this study is to develop, in vitro and in vivo evaluation of novel approaches for controlled release of paroxetine hydrochloride hemihydrate (PHH) in comparison to patented formulation PAXIL CR® tablets of GlaxoSmithKline (Geomatrix™ technology). In one of the approaches, hydrophilic core matrix tablets containing 85% of the dose were prepared and further coated with methacrylic acid copolymer to delay the release. An immediate release coating of 15% was given as top coat. The tablets were further optionally coated using ethyl cellulose. In the second approach, hydrophobic matrix core tablets containing metharylic acid copolymer were prepared. In the third approach, PHH was granulated with enteric polymer and further hydrophobic matrix core tablets were prepared. The effect of polymer concentration, level of enteric coating on drug release was evaluated by in vitro dissolution study by varying dissolution apparatus and the rotation speeds. It was found that increase in concentration of high viscosity hydroxypropylmethylcellulose (HPMC) resulted in reduction of the release rate. The drug release was observed to be dependent on the level of enteric coating and ethyl cellulose coating, being slower at increased coating. The release mechanism of PHH followed zero-order shifting to dissolution dependent by the increase of HPMC content. The formulation was stable without change in drug release rate. In vivo study in human volunteers confirmed the similarity between test and innovator formulations. In conclusion, HPMC-based matrix tablets, which were further coated using methacrylic acid copolymer, were found to be suitable for the formulation of single layer-controlled release PHH.

Ultra high viscosity hydroxypropylmethylcellulose blunts postprandial glucose after a breakfast meal

The effects of two water soluble dietary fibers, ultra-high-viscosity hydroxypropylmethylcellulose (UHV-HPMC, non-fermentable) and psyllium fiber (fermentable), on postprandial glucose and second meal effects in 13 healthy adults were studied. In a single blind crossover design, subjects were given standardized pre-measured breakfast and lunch meals with either 4 g of the fiber supplements or a placebo. Blood glucose was measured with a continuous blood glucose monitoring system (DexCom Seven Plus, San Diego, CA). Subjects consuming UHV-HPMC had significantly (P < 0.05) lower blood glucose area under the curve (AUC) two hours after breakfast then those receiving a placebo. Albeit not significant (P = 0.07), subjects consuming psyllium tended to have lower glucose levels than the placebo group. Peak glucose concentration following breakfast was significantly (P < 0.01) less with both UHV-HPMC and psyllium when compared to the placebo. The glucose lowering effect of these dietary fiber supplements appeared to be greater in those subjects who habitually consumed little dietary fiber. There were no significant differences in AUC or peak glucose concentration between treatments following the second meal (lunch) suggesting no residual effect from the fiber supplements.

Development of amitriptyline buccoadhesive tablets for management of pain in dental procedures

Administration of lidocaine and nonsteroidal anti-inflammatory drugs (NSAIDs) as a routine procedure for relief of dental pains by and large is restricted due to some side effects. Amitriptyline (AM) has long been known to exert analgesic activity as a result of blocking the Na+ channels. The objective of the present investigation was to prepare suitable buccoadhesive tablets using cellulose derivatives in order to obtain new formulations containing AM to provide local analgesic action. The tablets were evaluated in terms of physical characteristics, mucoadhesion performance, drug release, and in vivo assessment of analgesic efficiency. Tablets containing higher amounts of high-viscosity hydroxypropylmethyl cellulose (HPMC-K4M) significantly demonstrated enhanced adhesive performances. On the other hand, presence of sodium carboxymethyl cellulose (NaCMC) in formulations including HPMC of lower-viscosity grade (HPMC-E5LV) provided further adhesiveness by increase in viscosity. Rate of drug release from HPMC-E5LV tablets was significantly higher than the HPMC-K4M tablets. Kinetically, patterns of AM release from the tablets fitted best to Higuchi model. Moreover, in a randomized double-blind trial, analgesic efficiency of the prepared bioadhesive tablets was revealed to be satisfactory. It is suggested that applying the topical AM mucoadhesive tablet containing the low amount of drug is a safe and promising alternative to relief the pain in the buccal region.

Viscous dietary fibers reduce visceral adiposity, lower oxidative stress and improve glucose control in ZDF rats

Viscous dietary fibers have been shown to blunt the postprandial rise in blood glucose. Previous studies in this lab have suggested that viscous dietary fibers decrease adiposity in rats with little or no change in body weight. The aim of this study was to examine the effect of consumption of viscous dietary fibers, hydroxypropyl methylcellulose (HPMC) and β‐glucans (Sustagrain), in an obese diabetic rat model. Zucker Diabetic Fatty (ZDF) rats and their lean counterparts (n=12) were fed diets containing either 5% non‐viscous cellulose, low viscosity (LV) HPMC, high viscosity (HV) HPMC or 40% Sustagrain flour. After 6 weeks of feeding, the HV HPMC group had a reduced percentage epididymal fat pad weight (visceral fat) compared to the other ZDF groups, but no differences in percentage inguinal (subcutaneous) fat pad weights were found. Fasting plasma leptin did not differ among the ZDF groups. Rats fed HPMC and Sustagrain had lower percent glycated hemoglobin and kidney weights than the cellulose group, indicating improved glycemic control. Urinary 8‐isoprostane concentrations in the ZDF cellulose, LV HPMC and Sustagrain groups were significantly higher than the lean group, but HV HPMC and lean groups did not differ. These results indicate that consumption of viscous dietary fiber can lower visceral adiposity and oxidative stress and improve diabetic control in ZDF rats. (Supported by the MN Agric Exp Station)Grant Funding Source: MN Agric Exp Station/CHE Administative Fund

Glycemic response of mashed potato containing high-viscocity hydroxypropylmethylcellulose

Potatoes generally have one of the highest glycemic index values of any food. Relatively small differences in the glycemic response (GR) of regularly consumed starch foods have shown beneficial effects on health. Lowering the GR of a potato-based meal has potentially wide-reaching health benefits. High-viscosity hydroxypropylmethylcellulose (HV-HPMC) is a modified cellulose dietary fiber extensively used in the food industry. We hypothesized that the GR of a high-glycemic index product such as mashed potato would be lower with the addition of HV-HPMC. In a nonblind, randomized, repeat-measure, crossover controlled trial, 15 healthy adults consumed portions of mashed potato with different doses (0%, 1%, 2%, and 4%) of a specially selected and optimized HV-HPMC and a reference food (glucose) on separate occasions. Five subjects were excluded from the final analysis due to noncompliance with study procedures. Capillary blood glucose was measured in fasted subjects and at 15, 30, 45, 60, 90, and 120 minutes after starting to eat. For each sample, the incremental area under the blood glucose response curve was calculated and the GR determined. There was a significant lowering effect of HV-HPMC on GR (P < .001) of mashed potato. Glycemic responses for all mashed potato samples with the HV-HPMC were significantly lower than the standard mashed potato: 1% level (P < .05), 2% level (P < .05), and 4% level (P < .05). However, there was no significant effect of the HV-HPMC dose on GR. We conclude that addition of select HV-HPMC to mashed potato blunts GR.

Dose–Response Characteristics of High-Viscosity Hydroxypropylmethylcellulose in Subjects at Risk for the Development of Type 2 Diabetes Mellitus

Hydroxypropylmethylcellulose (HPMC) is a modified cellulose fiber that creates a viscous solution in the gastrointestinal tract. The present study examined the dose-response characteristics of high-viscosity (HV)-HPMC consumption on postprandial glucose and insulin levels in men and women at increased risk for type 2 diabetes mellitus. Subjects were a subset of participants in two trials with elevated peak postprandial glucose [>or=7.8 mmol/L (>or=140 mg/dL)] and body mass index (BMI) >or=27 kg/m(2). Subjects (n = 39) consumed breakfast meals containing 75 g of carbohydrate, each of which contained 1, 2, 4, or 8 g of HV-HPMC or a cellulose control in a randomized, double-blind manner. Each subject completed tests with control and two HV-HPMC doses. Peak glucose concentration was lower than control (all P < 0.01) following 2 g (10%), 4 g (18%), and 8 g (20%) of HV-HPMC. Peak insulin was also reduced (P < 0.01) following 2 g (32%), 4 g (35%), and 8 g (46%) of HV-HPMC doses versus control. Incremental areas for glucose from 0 to 120 min were reduced by 8-40% versus control but only reached significance for the 4-g and 8-g conditions, whereas incremental areas under the insulin curves were reduced by 14-53% (P < 0.01 for 2, 4, and 8 g of HV-HPMC). Among subjects at risk for type 2 diabetes mellitus, 1.0-8.0 g of HV-HPMC blunted postprandial glucose and insulin responses in a dose-dependent manner. Additional research is warranted to assess whether chronic consumption might retard the development or progression of glucose intolerance.

Controlled poorly soluble drug release from solid self-microemulsifying formulations with high viscosity hydroxypropylmethylcellulose

The objective of this work was the development of a controlled release system based on self-microemulsifying mixture aimed for oral delivery of poorly water-soluble drugs. HPMC-based particle formulations were prepared by spray drying containing a model drug (nimodipine) of low water solubility and hydroxypropylmethylcellulose (HPMC) of high viscosity. One type of formulations contained nimodipine mixed with HPMC and the other type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system (SMES) consisting of ethyl oleate, Cremophor ® RH 40 and Labrasol ®. Based on investigation by transmission electron microscopy (TEM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction, differences were found in the particle structure between both types of formulations. In vitro release was performed and characterized by the power law. Nimodipine release from both types of formulations showed a controlled release profile and the two power law parameters, n and K, correlated to the viscosity of HPMC. The parameters were also influenced by the presence of SMES. For the controlled release solid SMES, oil droplets containing dissolved nimodipine diffused out of HPMC matrices following exposure to aqueous media. Thus, it is possible to control the in vitro release of poorly soluble drugs from solid oral dosage forms containing SMES.

Glucose tolerance modifies the effects of high‐viscosity hydroxypropylmethylcellulose on postprandial glucose and insulin excursions

High-viscosity hydroxypropylmethylcellulose (HV-HPMC) is a dietary fiber that forms a viscous gel in the gastrointestinal tract after consumption. The aim of the present analysis was to evaluate th...

High-Viscosity Hydroxypropylmethylcellulose Blunts Postprandial Glucose and Insulin Responses

High-viscosity hydroxypropylmethylcellulose (HV-HPMC) is a modified cellulose fiber that produces a viscous gel in the gastrointestinal tract. Clinical trials demonstrate that consumption of HV-HPMC significantly lowers cholesterol, but limited information has been available on the influence of HV-HPMC on postprandial insulin and glucose responses. The objective of this investigation was to assess the influence of HV-HPMC on postprandial glucose and insulin responses in overweight and obese men and women. Participants were 31 overweight or obese men and women without diabetes who underwent three breakfast meal tests in random order, separated by > or = 72 h. Test meals containing 75 g carbohydrate plus 4 or 8 g HV-HPMC or control meals containing 8 g cellulose were delivered in a double-blind fashion. Peak glucose was significantly lower (P < 0.001) after both HV-HPMC-containing meals (7.4 mmol/l [4 g] and 7.4 mmol/l [8 g]) compared with the control meal (8.6 mmol/l). Peak insulin concentrations and the incremental areas for glucose and insulin from 0 to 120 min were also significantly reduced after both HV-HPMC doses versus control (all P < 0.01). These findings indicate that HV-HPMC consumption reduces postprandial glucose and insulin excursions, which may favorably alter risks for diabetes and cardiovascular disease.

RAT PHARMACOKINETICS AND PHARMACODYNAMICS OF A SUSTAINED RELEASE FORMULATION OF THE GABAA α5-SELECTIVE COMPOUND L-655,708

The pharmacokinetic and pharmacodynamic (i.e., receptor occupancy) properties of L-655,708, a compound with selectivity for alpha5-over alpha1-, alpha2-, and alpha3-containing GABA(A) receptors, were examined in rats with the aim of developing a formulation that would give sustained (up to 6 h) and selective occupancy of alpha5-containing GABA(A) receptors suitable for behavioral studies. Standard rat pharmacokinetic analyses showed that L-655,708 has a relatively short half-life with kinetics in the brain mirroring those in the plasma. In vivo binding experiments showed that plasma concentrations of around 100 ng/ml gave relatively selective in vivo occupancy of rat brain alpha5-versus alpha1-, alpha2-, and alpha3-containing GABA(A) receptors. Therefore, this plasma concentration was chosen as a target to achieve relatively selective occupancy of alpha5-containing receptors using s.c. implantations of L-655,708 (0.4, 1.5, or 2.0 mg) formulated into tablets of various size (20 or 60 mg) containing different amounts of L-655,708 and combinations of low and high viscosity hydroxypropyl methylcellulose (LV- and HV-HPMC). The optimum formulation, 1.5 mg of L-655,708 compressed into a 60-mg tablet with 100% HV-HPMC, resulted in relatively constant plasma concentrations being maintained for at least 6 h with very little difference between C(max) concentrations (125-150 ng/ml) and plateau concentrations (100-125 ng/ml). In vivo binding experiments confirmed the selective occupancy of rat brain alpha5-over alpha1-, alpha2-, and alpha3-containing GABA(A) receptors.

The Role of Excipients in the Control of Dehydroepiandrosterone Inclusion Complex Delivery

AimThe aim of this study was to develop systems containing dehydroepiandrosterone (DHEA), in the form of an inclusion complex with α-cyclodestrin (c-DHEA), which are able to change the release profile of the hormone according to time and excipient composition.MethodTwenty-five formulations were prepared containing DHEA (prasterone) in the chemical form of an inclusion complex with α-cyclodextrin (57.3% w/w). The drug was mixed with three different excipient systems: the first ‘fast’ one was a mixture of two disintegrants (microcrystalline cellulose and sodium carboxymethyl starch at prefixed 4.15 weight ratio); the second ‘gelling’ excipient contained two gel-forming agents (high viscosity hydroxypropyl methylcellulose and cross-linked polyvinyl pyrrolidone) at three weight ratios: 0.31, 1.00, and 2.45; and the third type of ‘binary’ mixture was prepared by combining ‘fast’ and ‘gelling’ systems at three weight ratios: 1:2, 1:1, and 2:1. Tablets were prepared by direct compression or after wet granulation of these formulations.Results’Fast’ tablets induced a rapid release of the drug while ‘gelling’ tablets were found to modify the release, according to composition. A profile, characterized by an initial phase of rapid drug release, followed by a period of slower release is achieved with series 1:1 tablets. Series 1:2 tablets provide linear release of the drug; while an undifferentiated profile was found for series 2:1 tablets.ConclusionDifferent release mechanisms and the control of drug release were obtained by using DHEA in its inclusion complex and varying the weight ratios of the excipients.

Controlled drug delivery from swellable hydroxypropylmethylcellulose matrices: model-based analysis of observed radial front movements

This work is related to the on-going development of mathematical models describing transient drug delivery from hydroxypropylmethylcellulose (HPMC) matrices. Recently, experimental data providing a detailed mapping of radial swelling, diffusion, and erosion front movements in a high-viscosity HPMC matrix were published [J. Controlled Release 70 (2001) 383]. Using these and other data for verification of simulations, a detailed mathematical model, taking into account water-induced swelling, drug dissolution, and external and internal mass transport resistances of dissolved drug, has been developed. In contrast to earlier models, explicit equations for the rate of movement of the swelling, diffusion and erosion fronts, with the relevant physical properties of drug and HPMC matrix contained in the equations, were derived. Simulations have been compared to transient experimental data for three drugs of very different water solubility and a good agreement was found, taking into account the uncertainty of key input parameters. Furthermore, the model predicts the presence of the drug particle translocation phenomenon observed experimentally. However, continued swelling of the matrix, subsequent to the disappearance of the swelling front, could not be described by the present model. The front-tracking approach illustrated is of relevance in the development of detailed and accurate models of drug delivery from swellable cylindrical matrices involving both axial and radial diffusion.