pH-independent Controlled Release Research Articles

Polyelectrolyte-based solid dispersions for enhanced dissolution and pH-Independent controlled release of sildenafil citrate

The aim of this study was to design a novel matrix tablet with enhanced dissolution and pH-independent controlled release of sildenafil citrate (SIL), a drug with pH-dependent solubility, by using solid dispersions (SDs) and polyelectrostatic interactions. SIL-loaded SDs were prepared using various polymeric carriers such as poloxamer 188, poloxamer 407, Soluplus®, polyvinylpyrrolidone (PVP) K 12, and PVP K 17 by the solvent evaporation method. Among these polymers, Soluplus® was found to be the most effective in SDs for enhancing the drug dissolution over 6 h in pH 6.8 intestinal fluid. SIL was well dispersed in Soluplus®-based SDs in an amorphous form. When the Soluplus®-based SDs were added in the tablet containing positively charged chitosan and negatively charged Eudragit® L100, the drug release rate was further modulated in a controlled manner. The charge density of the tablet was higher at pH 6.8 than at pH 1.2 due to the polyelectrostatic interaction between chitosan and Eudragit® L100. This interaction could provide a pH-independent controlled release of SIL. Our study demonstrates that a combinatory approach of Soluplus®-based SDs and polyelectrostatic interactions can improve the dissolution and pH-independent release performance of SIL. This approach could be a promising pharmaceutical strategy to design a matrix tablet of poorly water-soluble drugs for the enhanced bioavailability.

Fabrication, optimization, and in vitro evaluation of docetaxel-loaded nanostructured lipid carriers for improved anticancer activity

Lung cancer is the leading cause of cancer-related deaths in both men and women worldwide. It is the leading cancer killer in both men and women in every Ethnic Group. A major problem associated with chemotherapies against their lung cancer is the lack of selective toxicity, which results in a narrow therapeutic index thereby compromising clinical prognosis. To circumvent these challenges, the present investigation sought to develop a docetaxel-loaded nanostructured lipid carrier system (DTX-NLCS) for the treatment of lung cancer. A 3-factor/3-level Box-Behnken Design was applied to systematically optimize the DTX-NLCS parameters. The amount of drug, emulsifier concentration, and homogenization speed was selected as independent variables, while the particle size and % entrapment efficiency (%EE) were selected as dependent variables. The optimized batch parameters were 29.81 mg drug, 19.97% w/w emulsifier, and 13 200 (rpm) speed of homogenization with a mean particle size of 154.1 ± 3.13 nm and a mean %EE of 86.12 ± 3.48%. The in vitro lipolysis experiments revealed that the optimized DTX-NLCs were stabilized by 10% w/w PEG 4000 mono-stearate and exhibited an anti-lipolytic effect. Furthermore, the in vitro gastrointestinal stability studies (at pH-1.2, pH-4.5, pH-6.8, and pH-7.4) revealed that the optimized developed system could withstand various GI tract media. The in vitro dissolution studies depicted a pH-independent controlled-release consistent with the Weibull model. In vitro cytotoxicity studies using NCI-H460 cell lines further revealed that there was a reduction in IC50 values in the DTX-NLCS treated cells as compared to those treated with the pure drug, indicating an improved efficiency for the developed system.

Development and in vitro evaluation of pH-independent release matrix tablet of weakly acidic drug valsartan using quality by design tools

The main objective of this study was the development of pH-independent controlled release valsartan matrix tablet in Quality by design (QbD) framework. The quality target product profile (QTPP), critical quality attributes (CQAs) and critical material attributes (CMAs) were defined by science and risk-based methodologies. Potential risk factors were identified with Fishbone diagram. Following, CMAs were further investigated with a semi-quantitative risk assessment method, which has been revised with mitigated risks after development and optimization studies. According to defined critical material attributes, which one of them was determined to be the dissolution, formulation optimization study was performed by using a statistical design of experiment. Formulation variables have been identified and fixed first with a ‘One factor at a time (OFAT)’ approach. After OFAT studies, a statistical experimental design was conducted with the most critical material attributes. Statistical design space and mathematical prediction equations have been developed for dissolution and hardness, which is important to predict drug dissolution behavior. In conclusion, a pH-independent release has been achieved for weakly acidic drug valsartan with a deeper understanding of drug product quality, with the science and risk-based approaches of QbD tools.

PH-independent controlled release tablets containing nanonizing valsartan solid dispersions for less variable bioavailability in humans

The aims of this work were to design pH-independent controlled release (CR) tablet containing nanonizing solid dispersion (SD) adsorbed on hydrophilic silica (Aeroperl® 300/30). Valsartan (VAL) was chosen to simultaneously modulate solubility and release rate due to its poor water solubility in low pH condition and short elimination half-life. Based on extensive equilibrium solubility and compatibility studies, poloxamer 407 was selected as a SD carrier. The melted mixtures of drug and poloxamer 407 were adsorbed onto hydrophilic fumed silica (Aeroperl® 300/30). Ternary SD system changed crystalline drug into an amorphous state and had intermolecular hydrogen bonding as confirmed by FT-IR with poloxamer 407. The dissolution rate of SD system was markedly enhanced as compared with pure VAL or commercial Diovan® tablet in simulated gastric fluid (pH 1.2). Interestingly, the particle size of SD system was gradually nanonized for 2 hr, ranging from 600 nm to 150 nm during dissolution process. The SD-loaded CR (SD-CR) tablets using hydroxypropylmethylcellulose (HPMC 4000) showed pH-independent zero-order release and good stability at accelerated conditions for six months. The SD-CR tablet showed minimized inter-subject variation of maximum plasma concentration as compared with commercial Diovan® tablets in healthy human volunteers.

Matrix Tablet Containing Quaternary Inclusion Complex of Domperidone for Treatment of Diabetic Gastroparesis

Abstract: Objective: The present investigation is aimed at development and optimization of a pH independent controlled release matrix tablet containing mannitol based quaternary inclusion complex (QIC) of domperidone (DOM) for the treatment of diabetic gastroparesis. Methods: The tablets were prepared by direct compression and central composite design was used to optimize the amount of sodium alginate (SA) and hydroxypropylmethylcellulose (HPMC) to obtain a final formulation with desired release characteristics. The drug release from the optimized formulation was compared with the tablets containing pure DOM, binary and ternary inclusion complexes. Results and Discussion: The formulations showed a zero order release profile. The design models suggested greater influence of SA on the drug release. The optimized formulation showed minimum burst effect and released 88.65±3.19% DOM at the end of 12 h. The comparative study revealed that the optimized formulation exhibited nearly complete release of DOM. Conclusion: It was concluded that the optimized formulation containing QIC may reduce the dose frequency and improve the bioavailability of DOM. Key words: Quaternary inclusion complex, pH independent controlled release, Domperidone, Central composite design, Diabetic gastroparesis.

Hydroxypropyl-β-Cyclodextrin (HBC) Multicomponent Complexation and pH independent controlled release delivery system to Improved Dissolution and oral Bioavailability of Ondansetron HCI

Abstract: The objective of this study was to develop pH independent controlled release matrix tablets of Ondansetron HCl by using Multi component Complexation technique, Methocel K100M as release retarding materials and HP β-cyclodextrin was selected as release modulators. Ondansetron is weakly basic drug and their salts shows pH-dependent solubility that may show drug release problems at higher pH of small intestine. Incorporation of weakly basic drugs, exhibiting pH dependent solubility, into oral controlled release delivery systems shows pH dependent release profiles. In the present investigation, an attempt was made to pH-solubility dependence of drug and dissolution enhancement was attained by inclusion complex of Ondansetron with HP- β-cyclodextrin at 1:1 (drug: β-CD) molar ratio and then prepared complex hydroxyl propyl methyl cellulose controlled released matrix tablets. The in vitro drug release studies were carried out in pH1.2 buffer for 2 hrs and then in pH 6.8 phosphate buffer up to 24 hrs. The formulated matrix tablet F4 (without complexation) was very slow and drug is not released completely from matrix tablets in 6.8 pH phosphate buffer. The matrix tablets prepared using HP β- cyclodextrin with PVP (F8) showed a superior dissolution rate and good dissolution profile that was comparable to without complexation of Ondansetron HCl. Dissolution results showed pH independent controlled and almost complete release behavior of Ondansetron HCl up to 24 hrs time period. The drug release mechanism of the HPMC matrix tablets was found to be quasi Fickian mechanism. These results suggested that the oral bioavailability of Ondansetron HCl was significantly improved by Multi component Complexation strategies. Key word: Ondansetron HCl, pH independent controlled drug delivery, Hydroxypropyl-β- cyclodextrin, Multi component complexes.

Interaction and release kinetics study of hybrid polymer blend nanoparticles for pH independent controlled release of an anti-viral drug

Incompatible interactions of polymers with active chemical entity offer variable challenges in drug delivery kinetics. This study focuses on development of hybrid polymer blend nanoparticles with amphiphilic (Poly Vinyl Pyrrolidone) and hydrophobic (Ethyl cellulose and Eudragit RSPO) polymers to encapsulate maximum drug without significant incompatibility. Optimized nanoparticles developed using Acyclovir model drug exhibited 80% entrapment with size and surface charge of 100 nm and +26 mV, respectively. Spherical morphology and solid state transition of drug from crystalline to amorphous in nanoparticles was confirmed by SEM and XRD analysis. pH independent in-vitro drug release was observed in four different media with initial burst release followed by sustained release for >12 h. Statistically significant difference (P < 0.05) was observed in percentage of drug release from each formulation in different media. H-bonding and hydrophobic interactions between drug and polymer (FTIR, TG-DTA analysis and Makoid–Banakar Kinetics) and diffusion of drug from matrix nanospheres followed by pore transport were the key factors for effective drug release kinetics. Uptake of nanoparticles by corneal epithelial cells was more prominent within 30 min, however viability of cells was not altered significantly. Release kinetics and interactions studies revealed the suitability of polymer blend nanoparticles for better encapsulation and sustained release of the drug.

Bioadhesive mini-tablets for vaginal drug delivery.

Different non-ionic cellulose ethers (methyl cellulose, MC; hydroxyethyl cellulose, HEC; hydroxypropyl cellulose, HPC; hydroxypropylmethyl cellulose, HPMC) and microcrystalline cellulose (MCC) were investigated as matrix formers for preparation of mini-tablets targeting vaginal drug delivery. Hexyl aminolevulinat hydrochloridum (HAL) was used as a model drug. The mini-tablets were characterized with respect to their mechanical strength, bioadhesion towards cow vaginal tissue in two independent tests (rotating cylinder test, detachment test using texture analyzer), and dissolution rate in two media mimicking the pH levels of fertile, healthy and post-menopausal women (vaginal fluid simulant pH 4.5, phosphate buffer pH 6.8). Mini-tablets with a matrix of either HPMC or HPC were found to possess adequate mechanical strength, superior bioadhesive behavior towards vaginal tissue, and pH independent controlled release of the model drug, suggesting that both systems would be suited for the treatment of women regardless of age, i.e., respective of their vaginal pH levels. Bioadhesive mini-tablets offer a potential for improved residence time in the vaginal cavity targeting contact with mucosal tissue and prolonged release of the drug.

Systematic development of pH-independent controlled release tablets of carvedilol using central composite design and artificial neural networks

The purpose of this study was to apply the optimization method incorporating artificial neural network (ANN) using pH-independent release of weakly basic drug, carvedilol from HPMC-based matrix formulation. Because of weakly basic nature of carvedilol, drug shows pH-dependent solubility. The enteric polymer EUDRAGIT L100 was added formulations to overcome pH-dependent solubility of carvedilol. Effects of the Hydroxypropylmethyl cellulose (HPMC) K4M and EUDRAGIT L100 amount on drug release were investigated. For this purpose 13 kinds of formulations were prepared at three different levels of each variables. The optimization of the formulation was evaluated by using ANN method. Two formulation parameters, the amounts of HPMC K4M and Eudragit L100 at three levels (−1, 0, 1) were selected as independent/input variables. In-vitro dissolution sampling times at twelve different time points were selected as dependent/output variables. By using experimental dissolution results and amount of HPMC K4M and EUDRAGIT L100, percentage of dissolved carvedilol was predicted by ANN. Similarity factor (f2) between predicted and experimentally observed profile was calculated and f2 value was found 76.33. This value showed that there was no difference between predicted and experimentally observed drug release profile. As a result of these experiments, it was found that ANNs can be successfully used to optimize controlled release drug delivery systems.

Influence of micro-environmental pH on the gel layer behavior and release of a basic drug from various hydrophilic matrices

The purpose of this investigation is to understand the influence of gastrointestinal (GI) pH on the gel layer formation and its dynamics for various hydrophilic/swellable matrices, in the process of developing a pH-independent controlled release system for a basic drug, oxybutynin hydrochloride (OXB). Cylindrical matrices (8-mm diameter) without and with fumaric acid, were readily prepared by direct compression. Formulations were evaluated for in vitro drug release, and gel layer dynamics was studied by viscosity measurements and texture profiling analysis. In the in vitro drug release study, OXB, which shows pH-dependent solubility, showed faster release from all the matrices in pH 1.2 medium. Release rates enhanced to a lesser extent with change of medium from pH 6.8 to pH 1.2, for HPMC polymer matrices. Anionic polymer matrices showed drastic differences in the release rates when medium was changed from pH 6.8 to pH 1.2. Addition of fumaric acid to matrices demonstrated pH-independent drug release, which was attributed to the micro-environmental pH manipulation within the hydrated gel layer. Viscosity and texture profiling studies revealed that saturation solubility of drug at swelling front play a major role in the pH-dependent drug release from HPMC matrices, while both saturation solubility and the altered gel consistency as a function of pH are involved with anionic polymer matrices. Presence of fumaric acid in HPMC matrices showed efficient retardation and pH-independent drug release. In conclusion, understanding the influence of GI physiological pH on the gel layer dynamics and manipulating the micro-environmental pH provides efficient and predictable in vivo performance from these swellable cylindrical matrices.

Design of pH-independent controlled release matrix tablets for acidic drugs

The rate and extent of drug release from most controlled release systems are influenced by the pH of the dissolution medium for drugs with pH-dependent solubility. This dependency of drug release on pH may lead to additional inter- and intra-subject variability in drug absorption. In the present study, a pH-independent controlled release matrix system for acidic drugs was designed by incorporating release-modifiers in the formulation. Controlled release matrix tablets were prepared by compression of divalproex sodium, Methocel K4M and Eudragit E 100 or Fujicalin as the release-modifier. For formulations without any release-modifier, the extent and rate of drug release at pH 6.8 was much higher than that at pH 1.0. Formulations containing Eudragit E 100 provided drug release that was essentially independent of pH. This was achieved because Eudragit E 100 significantly increased the drug release in acidic medium and slightly decreased the release rate at higher pH. The increased release in the acidic medium can be attributed to the elevation of the micro-environmental pH in the swollen polymer gel layer. Formulations containing Fujicalin were less effective than those containing Eudragit E 100. This was attributed to the relative inability to elevate the pH and shorter residence time of Fujicalin in the matrix relative to Eudragit E 100.

A new type of a pH-independent controlled release tablet

Abstract The release of weakly basic drug such as papaverine HCl from sustained-release formulations is dependent on the environmental pH in the gastrointestinal fluid. Precipitation of the poorly soluble free base occurs within the formulation in the intestinal fluid. Precipitated drug is no longer capable of release from the formulation. pH-independent release tablet was prepared by compressing the mixture of papaverine HCl, polyvinyl pyrrolidone (PVP) and citric acid followed by coating the lateral site of the tablet with ethylcellulose. The tablet was shaped into a cylindrical type. When the composition ratio of citric acid to drug was more than about 3.5, the tablet showed a pH-independent release. The percentage of drug release was not influenced by the drug content when the composition ratio of the matrix remained constant. Release rate was controlled by a surface area which could release the drug, and the amount of citric acid or PVP-K 30 incorporated into the matrix. Release rate can be altered freely while maintaining the pH-independent release characteristic by combining the different composition matrices. By simulating these results, drug released as a function of time has been calculated, giving results in good agreement with experiments.