Controlled Release Solid Dispersion Research Articles

Recent Patents on Solid Dispersions Emphasize Promising Benefits in Solubility Enhancement of Poorly Water-soluble Drugs.

In the development of drug delivery systems, drugs' solubility remains the most challenging constraint. Many newly synthesized chemical compounds are available, but they involve low solubility and poor permeability restrictions. Among various drug delivery systems, the utilization of solid dispersion technologies has become more focused due to their promising benefits. This technology has attracted extensive attention for dissolution rate improvement along with substantial bioavailability enhancement of poorly water-soluble drug candidates. Many approaches have been employed for preparing solid dispersions, such as the melting method, hot melt extrusion, solvent evaporation process, fusion and kneading method, spray drying technique, co-grinding and freeze drying, supercritical fluid technology, etc. Result: A wide variety of hydrophilic and hydrophobic materials are available as carriers, which are employed in the formulation of solid dispersions. Depending on the carrier characteristics, immediate- release solid dispersions and/or controlled-release solid dispersions can be formulated. Multiple hydrophilic materials have been explored for heightening dissolution features with enhanced bioavailability of poorly water-soluble drug molecules. The availability of commercially available products further validates the utility of solid dispersion technology in drug delivery systems. In the current manuscript, an attempt has been made to highlight the comprehensive development techniques, characterization techniques, recent solid dispersion technologies, clinical trial studies, and patented technology, along with studies heightening the dissolution behavior of numerous poorly aqueous soluble drugs. The major stability issues affecting the suitability of solid dispersions are also discussed.

Recent Advances in the Surfactant and Controlled Release Polymer-based Solid Dispersion.

The oral route is the most preferred delivery route for drug administration due to its advantages, such as lower cost, improved patient compliance, no need for trained personnel, and less severity of drug reactions in general. The major problem with new molecules in the drug discovery pipeline is poor solubility and dissolution rate that ultimately results in low oral bioavailability. Numerous techniques are available for solubility and bioavailability (BA) enhancement, but out of all, solid dispersion (SD) is proven to be the most feasible due to fewer issues in manufacturing, processing, storage, and transportation. In the past few years, SD has been extensively applied to reinforce the common issues of insoluble drugs. Currently, many hydrophobic and hydrophilic polymers are used to prepare either immediate release or controlled release SDs. Therefore, the biological behavior of the SDs is contingent upon the use of appropriate polymeric carriers and methods of preparation. The exploration of novel carriers and methodologies in SD technology leads to improved BA and therapeutic effectiveness. Moreover, the clinical applicability of SD-based formulations has been increased with the discovery of novel polymeric carriers. In this review, emphasis is laid down on the present status of recent generations of SDs (i.e., surfactant and controlled release polymer-based SD) and their application in modifying the physical properties of the drug and modulation of pharmacological response in different ailments.

Insoluble Polymers in Solid Dispersions for Improving Bioavailability of Poorly Water-Soluble Drugs.

In recent decades, solid dispersions have been demonstrated as an effective approach for improving the bioavailability of poorly water-soluble drugs, as have solid dispersion techniques that include the application of nanotechnology. Many studies have reported on the ability to change drug crystallinity and molecular interactions to enhance the dissolution rate of solid dispersions using hydrophilic carriers. However, numerous studies have indicated that insoluble carriers are also promising excipients in solid dispersions. In this report, an overview of solid dispersion strategies involving insoluble carriers has been provided. In addition to the role of solubility and dissolution enhancement, the perspectives of the use of these polymers in controlled release solid dispersions have been classified and discussed. Moreover, the compatibility between methods and carriers and between drug and carrier is mentioned. In general, this report on solid dispersions using insoluble carriers could provide a specific approach and/or a selection of these polymers for further formulation development and clinical applications.

A Review on Solid Dispersion and Carriers Used Therein for Solubility Enhancement of Poorly Water Soluble Drugs

A large number of hydrophilic and hydrophobic carriers in pharmaceutical excipients are available today which are used for formulation of solid dispersions. Depending on nature of carriers the immediate release solid dispersions and/or controlled release solid dispersions can be formulated. Initially crystalline carriers were used which are transformed into amorphous solid dispersions with enhanced properties. The carriers used previously were mostly synthetic one. Recent trend towards the use of natural carriers have replaced the use of synthetic carriers. This review is the overview of various synthetic, natural, semisynthetic, modified natural hydrophilic carriers used for formulation of solid dispersions.

Perspectives on Strategies Using Swellable Polymers in Solid Dispersions for Controlled Drug Release.

Poorly water-soluble drugs, which commonly face the issue of poor absorption and low bioavailability, have been under ongoing research of many formulation scientists for the past few decades. Solid dispersion is one of the most effective strategies in concerns for improving bioavailability of poorly water-soluble drugs. Either application of solid dispersions in dissolution enhancement of poorly water-soluble drugs or the use of swellable polymers in controlled drug release has been reported in pharmaceutical designs widely. However, a review of strategies of using swellable polymers in solid dispersion to take a full advantage of these polymers as a current perspective in facilitating drug bioavailability enhancement is still missing. In this review, we aim to provide a summary of techniques used to formulate a swellable polymer in solid dispersion especially a description of a suitable fabrication method in design of a controlled release solid dispersion.

Enhancement of Solubility of Raloxifene HCl by Formulating Immediate and Controlled Release Solid Dispersion

For a practically insoluble drug it is extremely challenging to formulate controlled release tablets due to their low solubility. Since solid dispersion with PVP K30 increased the solubility nearly 4 folds, the effect of three different viscosity grade HPMCs on the in vitro dissolution from controlled release tablets was evaluated at four use levels of 10%, 15%, 30% and 45%. The in vitro dissolution testing in the most challenging medium plain water indicated that the drug release is governed by the type and concentration of the polymer and not by the solubility of the drug. Immediate release tablets of Raloxifene HCl solid dispersions were formulated and compared with those of the plain Raloxifene HCl tablets. In vitro dissolution studies of IR tablets also proved that PVP K30 is the best polymer which showed a maximum release of 81% in 1 hour in water as media. For PVP S630 it was 76% maximum release, when it was 44% for the plain drug.

Electrospun nanofibers as a potential controlled-release solid dispersion system for poorly water-soluble drugs

Electrospinning was introduced as a novel technique for preparing controlled-release (CR) amorphous solid dispersions (SD) and polymeric nanofibers of a poorly water-soluble drug. Piroxicam (PRX) was used as a low-dose poorly-soluble drug and hydroxypropyl methylcellulose (HPMC) as an amorphous-state stabilising carrier polymer in nanofibers. Raman spectroscopy, X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) were used in the physical characterisation of the CR–SD nanofibers. Special attention was paid on the effects of a polymer and solvent system on the solid-state properties and physical stability of nanofibers. The average dry diameter of the electrospun CR–SD nanofibers ranged from 400 to 600nm (SEM). PRX existed in amorphous form in the nanofibers immediately after fabrication and after a short-term (3-month) aging at low temperature (6–8°C/0% RH) and ambient room temperature (22°C/0% RH). At higher temperature and humidity (30°C/85% RH), however, amorphous PRX in the nanofibers tended to slowly recrystallise to PRX form III. The electrospun CR–SD nanofibers exhibited a short lag-time, the absence of initial burst release and zero-order linear CR dissolution kinetics. In conclusion, electrospinning can be used to fabricate supersaturating CR–SD nanofibers of PRX and HPMC, and to stabilise the amorphous state of PRX.

Novel Controlled Release Solid Dispersion for the Delivery of Diclofenac Sodium

This study presents development and evaluation of novel sustained release system of diclofenac sodium (DS) prepared by solid dispersion (SD) technique using Eudragit E 100 (EE 100) and/or Eudragit S 100 (ES 100) as carriers. Compatibility of the drug and its crystalline nature in the SD were examined using Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The drug was relatively stable, amorphous in the SD. The greater amount of EE100 or ES 100 in the SD slowed down the release rates with smaller dissolution efficiency and hence the mean dissolution time was enhanced. Moreover, combined carriers of EE 100-ES 100 exhibited more dissolution retarding effect than any of the carriers. The release of drug followed anomalous transport in artificial intestinal juice (pH 6.8).

Physicochemical Principles of Controlled Release Solid Dispersion Containing a Poorly water-soluble Drug

The aim of this study was to investigate the physicochemical properties of polyethylene oxide (PEO)-based controlled release solid dispersions (CR-SDs) containing aceclofenac, Gelucire 44/14, poloxamer 407 and pH modifier (Na2CO3). The immediate release solid dispersions containing the pH modifier greatly enhanced the drug dissolution rate to approximately 100%, while the CR-SDs with PEO showed controlled release. A bigger droplet size and a higher surface charge for the CR-SDs were observed compared with the immediate release solid dispersions. The pH modifier played an important role in modulating the release rate of the drug through changes in the drug crystallinity and the hydrogen-bonding interaction, as well as the microenvironmental pH. Near-infrared images revealed a modulation of the PEO concentration to preserve the pH modifier within the system for controlled release of the drug. The dissolution process of PEO-based solid dispersions containing a water-insoluble drug was governed by the changing net effect of the microenvironmental pH, the surface charge, the particle size and the release rate of the pH modifier, as well as the function of PEO in controlling drug release.

Design and optimization of diclofenac sodium controlled release solid dispersions by response surface methodology.

A 32 factorial design was employed to produce controlled release solid dispersions of diclofenac sodium in Eudragit RS and RL by coevaporation of their ethanol solution in a flash evaporator. The effect of critical formulation variables namely total polymer pay loads and levels of Eudragit RL on percent drug incorporation (% DI), drug release at the end of 12 hours (Rel12) and drug release at the end of 3 hours (Rel3) were analyzed using response surface methodology. The parameters were evaluated using the F test and mathematical models containing only the significant terms were generated for each parameter using multiple linear regression analysis and analysis of variance. Both the formulation variables studied exerted a significant influence (p < 0.05) on the drug release whereas the total polymer levels emerged as a lone factor significantly influencing the percent drug incorporation. Numerical optimization technique employing desirability approach was used to develop a new formulation by setting constraints on the dependent and independent variables. The experimental values of % DI, Rel12 and Rel3 for the optimized batch were found to be 95.22 ± 1.13%, 74.52 ± 3.16% and 29.37 ± 1.26% respectively which were in close agreement with those predicted by the mathematical models. The Fourier transform infrared spectroscopy, Differential scanning calorimetry and Powder x-ray diffractometry confirmed that the drug was reduced to molecular or microcrystalline form in the hydrophobic polymeric matrices, which could be responsible for the controlled drug release from the solid dispersions. The drug release from the solid dispersions followed first order rate kinetics and was characterized by Higuchian diffusion model.

Preparation and Characterization of Metoprolol Controlled-Release Solid Dispersions

In recent years, great attention has been paid to using solid dispersions to make sustained-release drugs. The objective of this study is to produce sustained-release systems of metoprolol tartrate using solid dispersion techniques and to evaluate their physicochemical characteristics. The solid dispersions were produced by melting and solvent methods, containing 7%, 15%, or 25% of the drug and different ratios of Eudragit RLPO and RSPO in ratios of 0:10, 3:7, 5:5, 7:3, and 10:0. Drug release profiles were determined by USP XXIII rotating paddle method in phosphate buffer solution (pH 6.8). XRD, DSC, IR, and microscopic observations were performed to evaluate the physical characteristics of solid dispersions. Results showed that the drug release from dispersions was at a slower rate than pure drug and physical mixtures. Moreover, the formulations containing greater ratios of Eudragit RSPO showed slower release rates and smaller DE8% but larger mean dissolution time than those containing greater ratios of Eudragit RLPO. Dispersions with particle size of less than 100 μm containing 7% of metoprolol and Eudragit RL:RS 5:5 (solvent method) and those with the ratio of 3:7 (melting method) had similar release pattern to Lopressor® sustained-release tablets by zero-order and Higuchi kinetics, respectively.

INVESTIGATION OF CONTROLLED RELEASE SOLID DISPERSION OF NAPROXEN USING EUDRAGIT RS AND RL POLYMERS

Naproxen was used as a model drug and Eudragit RS and RL were used as inert carriers in an attempt to study the controlled release solid dispersion. Naproxen solid dispersion was prepared using solvent evaporation technique. IR study illustrated Naproxen/Eudragits interaction. Dissolution-rate studies showed that the amounts of Naproxen released were found to be fitted to the Higuchi-Square root of time model. The study proved that the solid dispersions composed of Eudragit RS exhibited slow release rates when compared with those composed of Eudragit RL. By a simple modification in the polymeric ratio of both Eudragit RS and Eudragit RL, the kinetics of release can be modulated. A marked reduction in the magnitude of release rates was observed upon increasing the particle size. It was found that there was a linear relationship between the logarithmic value of release rate constant and the fraction of Eudragit RL in the coevaporate composed of Naproxen/RS/RL. The finding was a confirmatory indication that the release was following Higuchi-diffusion model. The study also proved that the compression forces had no effect on the release rate constant. The incorporation of polyvinylpyrrolidone in the coevaporates containing Eudragit RS improved and increased the release profile of Naproxen.

Development of Diclofenac Sodium Controlled Release Solid Dispersion Powders and Capsules by Freeze Drying Technique Using Ethylcellulose and Chitosan as Carriers

Controlled-release, solid dispersions of diclofenac sodium (DS) were prepared by freeze-drying technique, using ethylcellulose (EC) and chitosan (CS) as single and combined carriers. Factorial design was applied as an experimental design to study the main and interactive effects of EC and CS on drug dissolution from the controlled release solid dispersion. All DS solid dispersions showed slower drug dissolution than did DS powder. The equations of dissolution parameters as functions of EC and CS contents were established through multiple regression. The contour plots of the established equations were constructed. The 10: (2.4 + 0.05) DS:(EC + CS) solid dispersion was prepared and developed into a capsule dosage from, using lactose as diluent. The effect on capsule dissolution of a disintegrant, sodium starch glycolate (Explotab®), in concentrations of 2%, 5%, and 8% was studied. The solid-dispersion capsule containing 5% Explotab was found to provide the most similar dissolution profile to the one obtained with the 10:(2.4 + 0.05) DS:(EC + CS) solid-dispersion powder. The dissolutions of the 10:(2.4 + 0.05) solid-dispersion powder and capsules were closer to a first-order model than to a zero-order or diffusion control model.

Development of Diclofenac Sodium Controlled Release Solid Dispersion Tablet Using Optimization Strategy

Directly compressed diclofenac sodium (DS) controlled release tablets were prepared from spray-dried DS controlled release solid dispersion of optimum dissolution projile. Optimization strategy using a central composite design and multiple regression was used to study the influences of four parameters: compression force, the amounts of spray-dried rice starch (Era-TabR), croscarmellose sodium (Ac-Di-SolR), and magnesium stearate, on tablet physical properties and dissolution. The optimum conditions of those parameters were searched and an optimum DS controlled release tablet formulation was formulated. The dissolution profile of the optimized DS controlled release tablet was similar to that of the DS controlled release solid dispersion. The mechanism of drug release from the optimized DS tablet was found to be diffusion controlled.

Development of Diclofenac Sodium Controlled Release Solid Dispersions by Spray Drying Using Optimization Strategy I. Powder Formulation

AbstractDiclofenac sodium (DS) controlled release solid dispersions were prepared by spray drying using ethylcellulose (EC), methacrylic acid copolymer (Eudragit), chitosan, hydroxypropyl methylcellulose (HPMC), and carbomer as single carriers and EC-chitosan as combined carriers. Among solid dispersions of 3:1 drugsingle carrier, the system containing chitosan exhibited the slowest dissolution followed by the systems containing Eudragit, EC, HPMC, and carbomer, respectively. Combined carriers of EC-chitosan exhibited more dissolution retarding effect than single carrier of EC or chitosan. An Hadamard matrix H[8] was employed to estimate the main effects of four parameters: spray feeding volume and contents of absolute ethanol, EC, and chitosan. Optimization strategy using multiple linear regression and a feasibility computer program was utilized to obtain the optimum quantities of the four parameters that would result in a required DS controlled release solid dispersion. The validation of the optimum DS ...