Sustained-release Solid Dispersion Research Articles

Development and evaluation of a sustained release solid dispersion of cefdinir using a hydrophobic polymeric carrier and aminoclay

Development and evaluation of a sustained release solid dispersion of cefdinir using a hydrophobic polymeric carrier and aminoclay

The preparation and characterization of sustained-release solid dispersion of resveratrol by hot-melt extrusion technology

The preparation and characterization of sustained-release solid dispersion of resveratrol by hot-melt extrusion technology

Comprehensive evaluation of extemporaneous preparation containing ambroxol HCl and salbutamol sulfate: Compatibility, chemometrics, and stability study

Sustained release solid dispersion of Metoclopramide HCL: formulation, evaluation and pharmacokinetic studiesS. L. Neha, Neelam Singh, Mohd Yasir

Sustained-Release Solid Dispersion of High-Melting-Point and Insoluble Resveratrol Prepared through Hot Melt Extrusion to Improve Its Solubility and Bioavailability.

This study aimed to prepare a sustained-release solid dispersion of poorly water-soluble resveratrol (RES) with high melting point in a single hot melt extrusion step. A hydrophobic–hydrophilic polymeric blend (Eudragit RS and PEG6000) was used to control the release of RES. With the dispersive mixing and high shear forces of hot melt extrusion, the thermodynamic properties and dispersion of RES were changed to improve its solubility. The effects of the formulation were investigated through univariate analysis to optimize the preparation of the sustained-release solid dispersion. In vitro and in vivo studies were performed to evaluate the prepared RES/RS/PEG6000 sustained-release solid dispersion. The physical state of the solid dispersion was characterized using differential scanning calorimetry and X-ray diffraction. Surface properties of the dispersion were visualized using scanning electron microscopy, and the chemical interaction between RES and excipients was detected through Fourier-transform infrared spectroscopy. Results suggested that the optimized sustained-release solid dispersion was obtained when the mass ratio of RES-polymeric blend was 1:5, the ratio of PEG6000 was 35%, the barrel temperature was 170 °C, and the screw speed was 80 rpm. In vitro studies demonstrated that the solid dispersion showed a good sustained release effect. The cumulative release of RES reached 82.42% until 12 h and was fit by the Weibull model. In addition, the saturated solubility was 2.28 times higher than that of the bulk RES. In vitro studies demonstrated that the half-life increased from 3.78 to 7.09 h, and the bioavailability improved to 140.38%. The crystalline RES was transformed into the amorphous one, and RES was highly dispersed in the polymeric blend matrix.

Impact of drying on dissolution behavior of carvedilol-loaded sustained release solid dispersion: development and characterization

PurposeThe present study aimed to develop carvedilol (CAR)-loaded (25% w/w) sustained release solid dispersion (SRSD), for enhanced dissolution and to explore the applicability of different industrially accessible drying techniques. MethodsSRSD-CAR containing different ratios of polymers were prepared and physicochemically characterized. Dissolution study was carried out in both sink and supersaturated conditions to identify the possible enhancement in dissolution behavior. ResultsBased on the solubility study, Kolliphor® P188 and Eudragit® RSPO (50:25, % w/w) ratio exhibited the highest solubility among the samples and was chosen as the optimal composition of SRSD-CAR for further characterization. The crystallinity assessments of the optimized formulation indicated amorphization of CAR in the formulation, bring about improved solubility of CAR. The infrared spectroscopic study revealed minor transitions; demonstrating the absence of significant interactions between drug and carrier. Furthermore, the SRSD-CAR exhibited immediate formation of nano particles when dispersed in water. Dissolution study revealed significant improvement in dissolution behavior, with a release of CAR in a gradual manner compared to crystalline CAR. From the dissolution kinetics analysis, the Korsmeyer Peppas model fit the best and diffusion was predominant in release of CAR. The drug release pattern showed insignificant differences between the SRSD-CAR formulations prepared by rotary vacuum drying and freeze drying. ConclusionFrom these experimental findings, SRSD approach might be a favorable dosage option for CAR, offering improved biopharmaceutical properties.

The Preparation of Curcumin Sustained-Release Solid Dispersion by Hot Melt Extrusion—Ⅰ. Optimization of the Formulation

The purpose of this study was to optimize the formulation for developing curcumin sustained-release solid dispersion to increase the solubility of curcumin, delay drug release by hot-melt extrusion, and to explore the possibility of hot-melt extrusion for one-step preparation of insoluble drug sustained-release solid dispersion. The miscibility of curcumin and Eudragit RSPO and Eudragit RLPO were assessed by solubility parameter and melting point depression. Orthogonal test was used to optimize the formulation, based on the results of single-factor experiment, and the final optimal formulation: the ratio of the sustained-release carrier material RS/RL was 1:3, the ratio of drug and carrier was 1:6, and the porogen was used in an amount of 40% of the sustained-release carrier material. The curcumin solid dispersion of the best formulation had been prepared and had a significant sustained-release effect compared to the curcumin and the physical mixture.

The Preparation of Curcumin Sustained-Release Solid Dispersion by Hot-Melt Extrusion—Ⅱ. Optimization of Preparation Process and Evaluation In Vitro and In Vivo

The purpose of this study was to optimize hot-melt extrusion (HME) preparation process and evaluate in vitro and in vivo for developing curcumin (CUR) sustained-release solid dispersion, to explore the possibility of HME for one-step preparation of insoluble drug sustained-release solid dispersion. The effect of 3 process parameters—barrel temperature, screw speed, and cooling rate—was systematically studied. Physical state of CUR sustained-release solid dispersion was characterized by differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy. It was found that CUR–Eudragit RS/RL system exhibited a good miscibility. Curcumin in the solid dispersion existed in an amorphous state and had molecular interactions with carriers. Stability studies showed no apparent difference of physical state of solid dispersion after 6 months. The mechanism of the CUR release in sustained-release solid dispersion was a diffusion and dissolution coexisting action. Pharmacokinetics study showed the relative bioavailability of the CUR in sustained-release solid dispersion to CUR was 223.44%. The CUR sustained-release solid dispersion have been successfully prepared by HME, significantly extending the half-life, ensuring a stable and effective blood concentration, and improving the bioavailability of CUR. In conclusion, HME can be used to prepared sustained-release solid dispersion of a poorly water-soluble drug as a promising method.

Cellulosic and acrylic polymers based composites for controlled drug release

The study focused on the preparation and in vitro characterization of sustained release polymeric systems or solid dispersions for highly water-soluble drugs. Several polymeric composites were fabricated with ethyl cellulose (EC), Eudragit S100 (E-S100) or Eudragit RS100 (E-RS100) in conjunction with hydroxypropyl methylcellulose (HPMC) using 5-fluorouracil (5-FU) as a model drug. The solvent-evaporated composites were evaluated for in vitro release of the drug. In this respect, various mathematical models were applied to assess the release kinetics. Further characterization was accomplished by X-ray diffraction (XRD) analysis, differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Formulations comprising 5-FU/HPMC/(EC, E-S100 or E-RS100) at the weight ratio of 1/1/3 (formulations III, V and VI) significantly reduced the burst effect in vitro as compared to the plain drug powder. In particular, EC provided better sustained release effect compared with E-S100 and E-RS100 (~ 70% versus 85–87% in 8 h). The effect of higher quantity of EC on drug release was tested with a formulation containing 5-FU/HPMC/EC at the weight ratio of 1/1/4 (formulation IV). The drug was present in the amorphous state of all the above formulations. Thus, these formulations, in particular formulation IV, might be promising delivery systems to circumvent the burst effect caused by highly water-soluble drugs.

PHARMACOKINETIC COMPARISON OF MONTELUKAST SODIUM FORMULATIONS AFTER A SINGLE ORAL DOSE IN HEALTHY GUINEA PIGS

Objective: Pharmacokinetic evaluation of montelukast sodium chronomodulated capsules (sustained-release solid dispersion of drug enclosed in pH-sensitive film-coated hard gelatin shell) and marketed tablets has been carried out in this study.
 Methods: A single oral dose of prepared capsules and marketed conventional tablets was administered in healthy male Dunkin-Hartley albino guinea pigs. Blood samples were collected at different time intervals and plasma concentration of drug was determined by reversed-phase high-performance liquid chromatography. Different pharmacokinetic parameters were assessed from plasma drug concentration-time profile by one-compartment model, first-order kinetics.
 Results: Pharmacokinetic parameters such as time to reach maximum concentration, elimination rate constant, elimination half-life, and mean residence time data indicates that drug release from chronomodulated capsules is significantly prolonged with initial release lag time of 3.5–4 h in comparison with marketed conventional tablets. However, maximum drug plasma concentration, area under the concentration-time curve, and apparent volume of distribution values show non-significant difference between capsules and marketed tablets.
 Conclusion: The findings specified that capsules were providing time controlled delivery of drug at a desired rate for prolonged time, which may be helpful for the prevention of episodic attack of asthma in early morning hours.

A single subcutaneous administration of a sustained-release ivermectin suspension eliminates Psoroptes cuniculi infection in a rabbit farm

Background: Psoroptes cuniculi mites are the most common ear parasites infesting breeding female rabbits. The suffering rabbits show cutaneous signs of the infestation in the ears and are prone to secondary infections.Objectives: This trial was conducted to eliminate P. cuniculi in farm rabbits with a sustained-release ivermectin-loaded solid dispersion suspension (IVM-SD) suspension, and studied the stability of the formulation.Animals: There were 986 breeding female Hyplus rabbits naturally infected with P. cuniculi.Methods: All rabbits infected with P. cuniculi were subcutaneously administered with a single dose of IVM-SD suspension at 2 mg/kg body weight. Twenty-seven rabbits with severe infections were observed daily and examined on days 0 and 14 to score the lesions and count mites in crusts.Results: Fourteen days after the treatment no live mites were detected, demonstrating 100% therapeutic efficacy. The mean lesion scores decreased from 4.33 to 0.11 in the left ears and from 4.22 to 0.22 in the right ears. No reinfection occurred within 60 days of treatment.Conclusions: A single subcutaneous administration of the IVM-SD suspension at 2 mg/kg was effective in eliminating P. cuniculi infection in the rabbit farm.

Improving Solubility of the Telmisartan that is Poorly Water Soluble by Wet Granulation and Vitrification Process

Telmisartan (TS) have developed for the treatment of hypertension as the angiotensin II receptor blocker. TS belongs to class II drug in BCS classification and it has good permeability. But, it is poorly water soluble. Biological half-life of TS is 24 hours because it has not good bioavailability (only 42∼58%). The absorption of a drug is often limited by dissolution rate. Drug dissolution is important factor to the therapeutic efficacy of a medicine. Therefore, TS requires alternative methods of drug delivery system to improve solubilization. In this study, we have prepared solid dispersions (SD) of the TS, polyvinylpyrrolidone (PVP) K-30 using rotary evaporation to promote release rate. So, we made sustained release formulation to make that is continually released and reduced the number of administration to patients. We selected the methods which are wet granulation (WG) and vitrification (VT) for sustained release. WG is a common techinique in the pharmaceutical industry that is mixing the powder to make bonds between powder particles using water. VT is techinique that transforms the crystalline particle into amorphous state using cryomilling. We measured the characterization of SD that was performed using various methods to analyze the structure of powder sample. Characterizations of SD were performed to analyze the surface by scanning electron microscopy. The crystallinity and molecular structure are analyzed by Fourier transform infrared spectroscopy, powder X-ray diffractometer. Also, thermal porperties are analyzed by differential scanning calorimeter. In vitro dissolution test assessed by RP-HPLC to analyze dissolution rate of sustained release formulation and solid dispersion. In this results, these indicate that both methods improve solubility and dissolution rate. The drug solubility of processed VT almost greater than the pure drug and WG. And, in Bats, VT 3 has higher dissolution rates than others. So, this results are useful to improve TS in the pharmaceutical industry.

Sustained-release solid dispersion of pelubiprofen using the blended mixture of aminoclay and pH independent polymers: preparation and in vitro/in vivo characterization

The present study aimed to develop the sustained-release oral dosage form of pelubiprofen (PEL) by using the blended mixture of 3-aminopropyl functionalized-magnesium phyllosilicate (aminoclay) and pH-independent polymers. The sustained-release solid dispersion (SRSD) was prepared by the solvent evaporation method and the optimal composition of SRSD was determined as the weight ratio of drug: Eudragit® RL PO: Eudragit® RS PO of 1:1:2 in the presence of 1% of aminoclay (SRSD(F6)). The dissolution profiles of SRSD(F6) were examined at different pHs and in the simulated intestinal fluids. The drug release from SRSD(F6) was limited at pH 1.2 and gradually increased at pH 6.8, resulting in the best fit to Higuchi equation. The sustained drug release from SRSD(F6) was also maintained in simulated intestinal fluid at fasted-state (FaSSIF) and fed-state (FeSSIF). The structural characteristics of SRSD(F6) were examined by using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR), indicating the change of drug crystallinity to an amorphous form. After oral administration in rats, SRSD(F6) exhibited the prolonged drug exposure in plasma. For both PEL and PEL-transOH (active metabolite), once a day dosing of SRSD(F6) achieved oral exposure (AUC) comparable to those from the multiple dosing (3 times a day) of untreated drug. In addition, the in vivo absorption of SRSD(F6) was well-correlated with the in vitro dissolution data, establishing a good level A in vitro/in vivo correlation. These results suggest that SRSD(F6) should be promising for the sustained-release of PEL, thereby reducing the dosing frequency.

Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation

This work aimed to develop a sustained release solid dispersion of ivermectin (IVM-SD) in a lipid matrix (hydrogenated castor oil, HCO) for subcutaneous delivery. Solvent-melting technology was employed to prepare IVM-SDs using HCO. The physicochemical properties of the IVM-SDs were evaluated by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), and Fourier transform infrared spectroscopy (FTIR). The release of IVM from IVM-SDs was evaluated with HPLC in vitro. Pharmacokinetics of IVM was studied in rabbits following a single subcutaneous administration of IVM-SD formulations. The efficacy of IVM-SD against the ear mange mite was evaluated in rabbits. IVM was completely dispersed in HCO in an amorphous state at a drug:carrier ratio lower than 1:3. No chemical interactions between drug and carrier were found besides hydrogen bonding for the amorphous IVM-SDs. The amorphous IVM-SDs formulations exhibited a sustained release of IVM versus physical mixtures (PMs) of IVM and HCO. The drug release decreased as the drug:carrier ratios decreased, and the release kinetics of IVM were controlled via diffusion. Cytotoxicity of IVM-SD to MDCK cells was lower than native IVM. The IVM plasma concentration of SD1:3 remained above 1 ng/mL for 49 d. Higher AUC, MRT, and Tmax values were obtained at a SD1:3 relative to the IVM group. The IVM-SD improved almost 1.1-fold bioavailability of drug compared with IVM in rabbits. IVM-SD could provide longer persistence against rabbit’s ear mites than a commercial IVM injection. This study shows that these solid lipid dispersions are a promising approach for the development of subcutaneous IVM formulations.

Development and characterisation of sustained release solid dispersion oral tablets containing the poorly water soluble drug disulfiram

Administration of drugs via the oral route is the most common and preferred route due to its ease of administration, cost-effectiveness and flexibility in design. However, if the drug being administered has limited aqueous solubility it can result in poor bioavailability. Furthermore, the low pH of the stomach as well as enzymatic activity can result in drugs delivered via the oral route being rapidly metabolised and degraded. Here we demonstrate the development and characterisation of sustained release solid dispersion oral tablets, containing the poorly water-soluble drug disulfiram (DSF). The tablets, which are manufactured from two different polymers (Kolliphor® P 188 and P 237) specifically designed for the manufacture of solid dispersions and two different polymers (Kollidon® SR and HPMC) specifically designed to provide sustained release, can enhance the solubility of DSF, sustain its release, while protecting it from degradation in simulated gastric fluid (SGF). The paper demonstrates that when using the hot melt method at 80°C the DSF loading capacity of the Kolliphor® P 188 and P 237 polymers is approximately 43 and 46% respectively, with the DSF completely in an amorphous state. The addition of 80% Kollidon® SR to the formulation completely protected the DSF in SGF for up to 70min with 16% degradation after 120min, while 75% degradation occurred after 120min with the addition of 80% HPMC. The release rate of DSF can be manipulated by both the loading and type of sustained release polymer used, with HPMC providing for a much faster release rate compared to Kollidon® SR.

Development of a Sustained Release Solid Dispersion Using Swellable Polymer by Melting Method.

This study is to design a sustained release solid dispersion using swellable polymer by melting method. Polyethylene glycol 6000 (PEG 6000) and hydroxypropyl methylcellulose 4000 (HPMC 4000) were used in solid dispersion for not only enhancing drug dissolution rate but also sustaining drug release. HPMC 4000 is a common swellable polymer in matrix sustained release dosage form, but could not be used in preparation of solid dispersion by melting method. However, the current study utilized the swelling capability of HPMC 4000 accompanied by the common carrier PEG 6000 in solid dispersion to accomplish the goal. While PEG 6000 acted as a releasing stimulant carrier and provided an environment to facilitate the swelling of HPMC 4000, this swellable polymer could act as a rate-controlling agent. This greatly assisted the dissolution enhancement by changing the crystalline structure of drug to more amorphous form and creating a molecular interaction. These results suggested that this useful technique can be applied in designing a sustained release solid dispersion with many advantages.

Sustained release solid dispersion of Metoclopramide HCL: formulation, evaluation and pharmacokinetic studies

Development and Characterization of Controlled Release Ketoprofen MicrospheresMarwa H. Abdallah, Omaima A. Sammour, Hanaa A. El-ghamry, Hanan M. El-nahas, Waleed Barakat

Sustained-release formulation of sarpogrelate hydrochloride.

Sarpogrelate HCl (SGL) has been used clinically as an anti-platelet drug for the prevention of thrombus, proliferation of vascular smooth muscle cells and platelet aggregation. This study was to investigate the bioavailability of sustained-release solid dispersion (SR-SD) formulation of SGL to sustain the drug release for up to 24h. The SR-SD formulations with various drug-to-polymer ratios were prepared by hot-melt coating method. Waxy material carriers such as Compritol 888 ATO and stearyl alcohol were added to SGL and different amounts of HPMC K 15 (HPMC) were mixed. Dissolution profile and bioavailability were compared to SGL powder. Compritol 888 ATO showed the controlling effect of the initial release rate of drug from the formulation and the controlling effect was increased for 24h by addition of HPMC. As the amount of HPMC increased, the drug release rate from SR-SD decreased because HPMC formed gel layer in aqueous media. Pharmacokinetic study showed that the AUC and Tmax of SGL in SR-SD formulation increased as compared to the SGL powder. These data suggest that the SR-SD formulation effectively controls the drug release rate for 24h, hoping to be useful for the development of once-a-day formulation of SGL.

Sustained Release Solid Dispersions of Pentoxyfylline: Formulation and Optimization

Objective: The purpose of the study is to formulate and optimize sustained release solid dispersions of pentoxyfylline using a combination of eudragit polymers and ethyl cellulose. Methods: Solid dispersions were formulated by solvent evaporation method.Preliminary batches were formulated using various drug to polymer ratio; with eudragit S100 and L100 (1:1 to 1:5 ratio), and with ethyl cellulose(1:1 to 1:3 ratio) and evaluated for solubility analysis. Based on results of preliminary batches, Box Behnken design was further applied and three factors (X1- concentration of Eudragit S100, X2- concentration of Eudragit L100, X3- concentration of Ethyl Cellulose) were selected with three levels (+1, 0, -1). Multiple linear regression was applied to generate polynomial equations and statistical evaluation. Prepared solid dispersions were investigated for sustained release properties via in vitro dissolution studies. Fourier transform infrared spectroscopic analysis (FTIR), X-ray diffraction analysis (X-RD), Differential scanning calorimetry (DSC) studies were carried out to evaluate drug polymer interactions. Scanning Electron Microscopy (SEM) analysis of optimized solid dispersion was carried out to evaluate surface morphology of the particles. Results: Batch F5 showed maximum sustained release (65.46% in 24 h) characteristics out of all solid dispersions. DSC studies indicated drug integrity when mixed with the polymeric carriers. FTIR and X-RD studies also ruled out any drug polymer interaction. A change in crystalline habit was observed in solid dispersion particles (F5 batch) as seen in SEM micrographs. Polynomial mathematical model generated using multiple regression analysis was found to be statistically significant (p<0.05). Conclusion: Release retarding effect was found to be dependent on polymer concentration. Therefore, an optimized combination may lead to better sustaining effect.

Preparation and evaluation of sustained-release solid dispersions co-loading gastrodin with borneol as an oral brain-targeting enhancer

Borneol is a traditional Chinese medicine that can promote drug absorption from the gastrointestinal tract and distribution to the brain. However, stomach irritation may occur when high doses of borneol are used. In the present work, gastrodin, the main bioactive ingredient of the traditional Chinese drug “Tianma” (Rhizoma Gastrodiae) was used as a model drug to explore reasonable application of borneol. Sustained-release solid dispersions (SRSDs) for co-loading gastrodin and borneol were prepared using ethylcellulose as a sustained release matrix and hydroxy-propyl methylcellulose as a retarder. The dispersion state of drug within the SRSDs was analyzed by using scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffractometry. The results indicated that both gastrodin and borneol were molecularly dispersed in an amorphous form. Assay of in vitro drug release demonstrated that the dissolution profiles of gastrodin and borneol from the SRSDs both fitted the Higuchi model. Subsequently, gastric mucosa irritation and the brain targeting of the SRSDs were evaluated. Compared with the free mixture of gastrodin and borneol, brain targeting of SRSDs was slightly weaker (brain targeting index: 1.83 vs. 2.09), but stomach irritation obviously reduced. Sustained-release technology can be used to reduce stomach irritation caused by borneol while preserving sufficient transport capacity for oral brain-targeting drug delivery.

Studies on sustained release solid dispersion of tripterine carried by HPMC-stearic acid

To prepare the sustained release solid dispersion of tripterine, using HPMC-stearic acid with the intention of improving drug dissolution and controlling drug releases moderate, so that the drug performances lower toxicity. Tripterine sustained release solid dispersions was prepared by the solvent method with different weight ratios of HPMC-stearic acid and tripterine, which were dissolved in 95% ethanol. And in vitro dissolution experiment was conducted. Differential scanning calorimetry, scanning electron microscopy and X-ray powder diffraction can prove the formation of solid dispersions. The ideal tripterine sustained release solid dispersions were prepared under the condition as follows, the weight ratio of tripterine and HPMC-stearic acid was 1: 10, and the release rate of drug can keep moderate and controllable. In vitro cumulative release of tripterine sustained release solid dispersion is up to more than 90% after 8 h, and the tripterine exist as amorphous in the solid dispersion. The sustained release solid dispersion of tripterine, carried by HPMC-stearic acid, can improve the release of tripterine effectively and controls the release rate keep moderate and controllable, and the preparation process is simple, which has potential applications.