Design and evaluation in vitro of controlled release mucoadhesive tablets containing chlorhexidine

This investigation deals with the development of buccal tablets containing chlorhexidine (CHX), a bis-bis-guanide with antimicrobial and antiseptic effects in the oral cavity, and able to adhere to the buccal mucosa to give local controlled release of drug. A mucoadhesive formulation was designed to swell and form a gel adhering to the mucosa and controlling the drug release into the oral cavity.

Some batches of tablets were developed by direct compression, containing different amounts of hydroxypropylmethylcellulose (HPMC) and carbomer; changing the amount ratio of these excipients in formulations, it is possible easily modulate the mucoadhesive effect and release of drug. The in vitro tests were performed using the USP 26/NF paddle apparatus, a specifically developed apparatus, and a modified Franz diffusion cells apparatus. This last method allows a simultaneous study of drug release rate from the tablets and drug permeation through the buccal mucosa.

Similar tests have also been carried out on a commercial product, Corsodyl gel^®, in order to compare the drug release control of gel with respect to that of the mucoadhesive tablet, as a formulation for buccal delivery of CHX. While the commercial formulation does not appear to control the release, the formulation containing 15% w/w methocel behaves the best, ensuring the most rapid and complete release of the drug, together with a negligible absorption of the active agent as required for a local antiseptic action in the oral cavity.     

Preparation and In Vitro Evaluation of Controlled Release Hydrophilic Matrix Tablets of Ketorolac Tromethamine Using Factorial Design

Controlled release matrix tablets of ketorolac tromethamine (KT) were prepared by direct compression technique using cellulose derivatives as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), and carboxymethyl cellulose (CMC) in different concentrations (10–20%). The effect of polymer type and concentration was investigated on drug release by 2³ factorial design. For the quality control of matrix tablets, weight deviation, hardness, friability, diameter–height ratio, content uniformity of KT, and in vitro dissolution technique were performed. UV Spectrophotometric method was used to detection of KT in matrix tablets. This method was validated. Dissolution profiles of the formulations were plotted and evaluated kinetically. An increase in polymer content resulted with a slow release rate of drug as was expected. According to the dissolution results, tablets prepared with HPMC + HEC + CMC (F1 and F8) were found to be the most suitable formulation for KT. About 99.27% KT was released from F8 in 7 h.     

Mucoadhesive and Physicochemical Characterization of Carbopol-Poloxamer Gels Containing Triamcinolone Acetonide

The viscosity and bioadhesive property of Carbopol-Poloxamer gels containing triamcinolone acetonide to mucosa were tested according to various concentrations of Carbopol gels of various pH. The increase in Carbopol concentration caused increased viscosity and bioadhesiveness. The neutralization of pH in various concentrations of Carbopol gels showed the increased viscosity, showing the highest viscosity and highest bioadhesiveness when neutralized to pH 6. A relationship between the viscosity and bioadhesive strength was shown from the neutralized Carbopol gels. The physicochemical interactions between triamcinolone acetonide and polymers were investigated by X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectrophotometry. According to FTIR and XRD studies, the drug did not show any evidence of an interaction with the polymers used and was present in an unchanged state.     

Formulation and Evaluation of Mucoadhesive Tablets Containing Eugenol for the Treatment of Periodontal Diseases

Eugenol is the principle chemical constituent of clove oil and has been used to cure dental problems for ages. Eugenol is an integral part of the dentist's kit due to its analgesic, local anesthetic, anti‐;inflammatory, and antibacterial effects. It is used in the form of a paste or mixture as dental cement, filler, and restorative material. This study reports the development and evaluation of controlled‐release mucoadhesive tablets for gingival application, containing eugenol, which are prepared by taking carbopol 934 P and Hydroxypropyl methylcellulose (HPMC) K4M in the ratio of 1:2, 1:1, and 2:1. Incorporation of eugenol (10 mg) in a mucoadhesive formulation provides controlled release for a period of 8 hours, which is advantageous over conventional use. In vitro mucoadhesion measured as detachment force in grams and the formulations show good correlation in vivo. The release study indicates that increase in carbopol increases the release rate of eugenol from the formulation whereas HPMC retards it. Increased in vitro bioadhesion is related to HPMC content of the formulation. The release kinetics of eugenol in vitro correlates with the in vivo results. This indicates the increased potential of eugenol as antibacterial, local analgesic, and anaesthetic treatment.     

Directly Compressed Mini Matrix Tablets Containing Ibuprofen: Preparation and Evaluation of Sustained Release

ABSTRACT

Directly compressed mini tablets were produced containing either hydroxypropylmethylcellulose (HPMC) or ethylcellulose (EC) as release controlling agent. The dynamics of water uptake and erosion degree of polymer were investigated. By changing the polymer concentration, the ibuprofen release was modified. In identical quantities, EC produced a greater sustaining release effect than HPMC. Different grades of viscosity of HPMC did not modify ibuprofen release. For EC formulations, the contribution of diffusion was predominant in the ibuprofen release process. For HPMC preparations, the drug release approached zero-order during a period of 8 h. For comparative purposes, tablets with 10 mm diameter were produced.     

Effect of Sodium Bicarbonate on the Properties of Metronidazole Floating Matrix Tablets

The effect of sodium bicarbonate (SB) on the swelling behavior and the sustained release of floating systems was studied with varied proportions of this excipient and metronidazole. Two polymers with different hydration characteristics, Methocel K4M and Carbopol 971P NF, were used to formulate the matrices. Under in vitro dissolution conditions, the addition of SB to metronidazole sustained-release tablets modifies the matrix hydration volume, increasing at the beginning, reaching a maximum, and then declining. Pure Carbopol matrices show a rapid hydration with a limited further effect of the SB and metronidazole loads. Methocel show a significant increase of the apparent hydration volume due to SB addition with no further notable change due to metronidazole load. Increasing the metronidazole load reduces the floating time of Carbopol matrices while no effect on Methocel matrices could be observed within 8 hours dissolution. Matrices show increasing release constant values (k) as the metronidazole load increases. Methocel matrices release the drug 10% to 15% faster than Carbopol matrices. SB increases the cumulative amount of drug released from Methocel but not that releasing from Carbopol. These results are attributed to the intrinsic polymer properties, the barrier effect of CO₂ bubbles, and the matrix volume expansion produced after addition of SB.     

Design and Evaluation of a New Gastrointestinal Mucoadhesive Patch System Containing Chitosan-Glutathione

Within this study, a novel gastrointestinal patch system was developed and investigated regarding water-absorbing capacity, adhesive properties, in vitro release, unidirectional release and permeation enhancing effect. Water uptake studies revealed that the weight of patch systems with Ch-GSH increased about 44.5 ± 2.3 mg (127%) after 90 min. This patch system remained even after 180 h on the mucosa and released 49.7 ± 0.7% of FD₄ within 8 h. A 2.5-fold higher transport of FD₄ can be obtained in contrast to control. In conclusion this patch system could be an interesting possibility for the transport through the intestinal mucosa of macromolecules which will normally be degraded in the intestinal tract.     

High-Throughput Evaluation of Non-Swellable Controlled Release Matrix Tablets

Abstract

Drug release from controlled-release (CR) matrix tablets involves the permeation and diffusion of water through the system. In this study, a new methodology is proposed for the measurement of water permeation and simultaneous drug release from the inert, non-swellable CR matrix tablet of diltiazem (DLT) and a correlation is made between these two processes. Cylindrical matrices were readily prepared by direct compression of pellets obtained by extrusion-spheronization. Water transport was studied using tritiated water (HTO) as a permeant in a Franz-diffusion cell and simultaneously drug release was measured. Further, dissolution was performed on USP XXI/XXII dissolution apparatus I using demineralized water. Matrices showed a steady water-uptake up to 6 h and the steady state for HTO permeation lasting from 6-h to 24-h Flux of water permeated and flux of drug released correlated well. Thus, HTO permeation through the matrix tablet and the proposed methodology can be used as a tool and/or surrogate marker for evaluation of controlled release matrix tablets. This methodology can be coined as “high-throughput” in terms of amount of labor and resources required in comparison to that of dissolution.     

Polymersomes Containing a Hydrogel Network for High Stability and Controlled Release

Capillary microfluidic devices are used to prepare monodisperse polymersomes consisting of a hydrogel core and a bilayer membrane of amphiphilic diblock‐copolymers. To make polymersomes, water‐in‐oil‐in‐water double‐emulsion drops are prepared as templates through single‐step emulsification in a capillary microfluidic device. The amphiphile‐laden middle oil phase of the double‐emulsion drop dewets from the surface of the innermost water drop, which contains hydrogel prepolymers; this dewetting leads to the formation of a bilayer membrane. Subsequently, the oil phase completely separates from the innermost water drop, leaving a polymersome. Upon UV illumination of the polymersome, the prepolymers encapsulated within the interior are crosslinked, forming a hydrogel core. The hydrogel network within the polymersomes facilitates sustained release of the encapsulated materials and increases the stability of the polymersomes through the formation of a scaffold to support the bilayer. In addition, this approach provides a facile method to make monodisperse hydrogel particles directly dispersed in water.     

琼脂糖醋酸酯纳米粒子的制备及药物缓释性

通过纳米沉淀法制备了一种粒径均一的琼脂糖醋酸酯纳米粒子,并对影响粒径的相关因素进行了研究。结果表明,纳米粒子分别随着二甲基亚砜(DMSO)与水的比率、姜黄素含量及琼脂糖醋酸酯(AA)的浓度的增加而增大,随转速的增加而下降,异丙醇和聚乙烯醇(PVA)浓度也有一定的影响。同时研究了载体对姜黄素的包载情况及缓释行为。结果显示,无异丙醇组中姜黄素载药率和包封率均比异丙醇组中的高。但两组都表明,随着姜黄素的含量增加,载药粒子的载药率不断增加,包封率不断降低。载药粒子大大延长了姜黄素的缓释时间。获得的琼脂糖醋酸酯纳米粒子可望用于姜黄素的控释。     

In Vitro and In Vivo Evaluation of Two Extended Release Preparations of Combination Metformin and Glipizide

A system that can deliver multi-drugs at a prolonged rate is very important to the treatment of various chronic diseases such as diabetes, asthma, and heart disease. Two controlled-release systems, which exhibited similar release profiles of metformin and glipizide, i.e., elementary osmotic pump tablets (EOP) and bilayer hydrophilic matrix tablet (BT), were designed. The effects of pH and hydrodynamic conditions on drug release from two formulations were investigated. It was found that both drug releases from EOP were not sensitive to dissolution media pH and hydrodynamics change, while the release of glipizide from BT was influenced by the stirring rate. Moreover, in vivo evaluation was performed, relative to the equivalent dose of conventional metformin tablet and glipizide tablet, by a three-crossover study in six Beagle dogs. Cumulative percent input in vivo was compared to in vitro release profiles. The linear correlations of metformin and glipizide between fraction absorbed in vivo and fraction dissolved in vitro were established for EOP—a true zero-order release formula, whereas only nonlinear correlations were obtained for BT. In conclusion, drug release from EOP was both independent of in vitro and in vivo conditions, where the best sustained release effect was achieved, whereas the in vitro dissolution test employed for BT needed to be further optimized to be biorelevant.     

Formulation and Evaluation of Methocel K15M Bioadhesive Matrix Tablets

Methocel K15M is a bioadhesive polymer. Its adhesion and bioadhesion characteristics were evaluated by shear stress measurement and detachment force measurement methods, respectively. The effect of pH on adhesion was studied, and it was found that the maximum adhesion was between pH 5 and pH 6. Adhesion strength at different parts of the sheep intestine was studied; in the duodenal portion of the intestine, the adhesion was maximum. Chlorpheniramine maleate and diclofenac sodium drugs are formulated with Methocel K15M as matrix tablets. In vitro release studies revealed that some of the formulations showed initial first-order behavior followed by zero-order release behavior.     

Development of Nitrendipine Controlled Release Formulations Based on SLN and NLC for Topical Delivery: In Vitro and Ex Vivo Characterization

The aim of the investigation is to develop solid lipid nanoparticles (SLN) and nano-structured lipid carrier (NLC) as carriers for topical delivery of nitrendipine (NDP). NDP-loaded SLN and NLC were prepared by hot homogenization technique followed by sonication, and they were characterized for particle size, zeta potential, entrapment efficiency, stability, and in vitro release profiles. Also the percutaneous permeation of NDPSLN A, NDPSLN B, and NDPNLC were investigated in abdominal rat skin using modified Franz diffusion cells. The steady state flux, permeation coefficient, and lag time of NDP were estimated over 24 h and compared with that of control (NDP solution). The particle size was analyzed by photon correlation spectroscopy (PCS) using Malvern zeta sizer, which shows that the NDPSLN A, NDPSLN B, and NDPNLC were in the range of 124–300 nm during 90 days of storage at room temperature. For all the tested formulations (NDPSLN A, NDPSLN B, and NDPNLC), the entrapment efficiency was higher than 75% after 90 days of storage. The cumulative percentage of drug release at 24 h was found to be 26.21, 30.81, and 37.52 for NDPSLN A, NDPSLN B, and NDPNLC, respectively. The results obtained from in vitro release profiles also indicated the use of these lipid nanoparticles as modified release formulations for lipophilic drug over a period of 24 h. The data obtained from in vitro release from NDPSLN A, NDPSLN B, and NDPNLC were fitted to various kinetic models. High correlation was obtained in Higuchi and Weibull model. The release pattern of drug is analyzed and found to follow Weibull and Higuchi equations. The permeation profiles were obtained for all formulations: NDPSLN A, NDPSLN B, and NDPNLC. Of all the three formulations, NDPNLC provided the greatest enhancement for NDP flux (21.485 ± 2.82 μg/h/cm²), which was fourfold over control (4.881 ± 0.96 μg/h/cm²). The flux obtained with NDPSLN B (16.983 ± 2.91 μg/h/cm²) and NDPNLC (21.485 ± 2.82 μg/h/cm²) meets the required flux (16.85 μg/h/cm²).     

Design and In Vitro Evaluation of Polymeric Formulae of Simvastatin for Local Bone Induction

ABSTRACT

Simvastatin (SVS), a cholesterol-lowering drug, has been shown to stimulate bone formation. This study deals with the design and in vitro evaluation of local delivery systems for simvastatin. They are intended to treat bony defects resulting from periodontitis or to induce osteogenesis around the titanium implants. Granules and gels were formulated using bioerodible/biocompatible polymers, namely hydroxypropylmethyl cellulose (H), sodium carboxymethyl cellulose (C), and chitosan (Ch). The in vitro release profiles and kinetics were evaluated and the swelling and/or erosion was monitored. Differential scanning calorimetry (DSC) and infrared (IR) were used to detect any SVS/polymer interactions that may affect drug release. The results revealed variable extents of controlled drug release from the designed formulae depending on the polymer nature. About 50% cumulative SVS was released from both H granules and gel formulae within 24 h and ～66% and ～88% from C granules and gel, respectively. Ch formulae exhibited ～50% release from granules and ～30% from gel.     

Ketoprofen Suppository Dosage Forms: In Vitro Release and in Vivo Absorption Studies in Rabbits

In vitro release of ketoprofen from suppository bases and in vivo absorption in rabbits were studied. Suppositories containing 50 mg of ketoprofen were prepared using theobroma oil, esterified (c₁₀–c₁₈) fatty acids, and polyethylene glycol 1000 bases. The displacement values of the drug were determined and found to be of the order of theobroma oil > esterified (c₁₀–c₁₈) fatty acids and polyethylene glycol 1000 bases. The suppository hardness data revealed that the theobroma oil base produced relatively brittle suppositories. Using the USP dissolution method, the release of ketoprofen was observed to be greatest from polyethylene glycol 1000 suppositories. With the dialysis technique, the maximum release of drug was obtained from theobroma oil suppository containing polysorbate 40 at a 6% level. Selected suppository formulations were evaluated for rectal absorption studies in rabbits. The in vivo data showed that the optimum drug absorption took place from the polyethylene glycol 1000 base and theobroma oil formulation containing 6% polysorbate 40.     

Preparation and In Vitro Release of Dual-Drug Resinates Containing Equivalent Content Dextromethorphan and Diphenhydramine

ABSTRACT

The dual-drug resinate containing equivalent content of dextromethorphan hydrobromide (DTM) and diphenhydramine hydrochloride (DPH) was developed and characterized. To achieve this specific resinate, a procedure of simultaneous dual-drug loading using loading solutions composed of different proportions of DTM and DPH was performed and a dual-drug loading diagram was constructed to determine the equivalent drug loading solution (ELS) and also the estimated equivalent drug content (EQC). The effects of resin crosslinkage, overall drug concentration of the loading solution, and temperature during drug loading on the values of ELS and EQC were assessed. The increased overall drug concentration from 0.25 to 1.0% w/v elevated the EQC values from 18 to 35% w/w for low crosslinked resins (Dowex 50W × 2 and × 4), and from 18 to 27% w/w for high crosslinked resin (Dowex 50W × 8). It also changed the values of ELS from 0.50 to 0.48 for the low crosslinked resins, and 0.50 to 0.55 for the high crosslinked resin. For the high crosslinked resin, the applied heat from 35 to 65°C further increased the values of EQC from 27 to 32% w/w, and changed the values of ELS in the reverse direction from 0.55 to 0.48. However, the heat did not exert significant effects on the values of EQC and ELS for the low crosslinked resins. Different batches of dual-drug resinates prepared from the determined ELS provided the resultant resinates with equivalent contents of DTM and DPH which were very close to the estimated EQC. The drug release from the resinates was performed in 0.05, 0.1, 0.2, and 0.4 N of KCl solutions. The increased ionic strength generally accelerated the release of both drugs except for 0.4 N KCl solution in which the drug release from the resinates of high crosslinkage was decreased. The congestion on the outward movement of drugs through the high crosslinked matrix might cause the delay of drug release. In conclusion, the release study demonstrated that the dual-drug resinate using a suitable crosslinked resin could be used for extended delivery of two combined drugs with the equivalent therapeutic dose.     

壳聚糖水凝胶的制备及其在药物释放中的应用

水凝胶作为性能良好的载体,在药物的控释、组织工程等领域有着广泛的应用。壳聚糖是一类天然的带正电荷的碱性多糖,由其形成的水凝胶具有较好的生物相容性、生物降解性、抗菌和低细胞毒性,因此,壳聚糖水凝胶有着良好的生物应用前景。本文综述了壳聚糖水凝胶的制备方法(包括物理交联法和化学交联法),在物理交联法部分着重介绍了离子化合物及聚电解质分子与壳聚糖通过离子交联形成水凝胶,以及利用分子链间的疏水作用形成壳聚糖水凝胶的方法;而在化学交联法部分介绍了合成壳聚糖水凝胶的化学手段,包括交联剂、光照辐射和酶的使用。继而概述了壳聚糖水凝胶在药物缓释应用方面的研究进展,包括温度、pH值和电场响应的药物控释体系。最后展望了壳聚糖水凝胶未来的发展前景。     

Multiparticulate Drug Delivery System for the Treatment of Diabetes Mellitus: In Vitro and In Vivo Evaluation

Biodegradable microspheres of poly(?)caprolactone were prepared by solvent evaporation method for controlled release of repaglinide. The prepared microspheres were spherical in shape having smooth surface. The average diameter was in the range of 24 to 31.04 µm. Drug entrapment efficiency of the prepared microspheres was in the range of 68.81% to 79.30%. Differential scanning calorimetry and x-ray diffraction analyses indicated the amorphous dispersion of drug in the microspheres. The drug release was continued up to 24 h depending upon the formulation variables; drug release was slow from the microspheres which were prepared with higher concentration of polymer and as the initial drug loading was increased, the drug release was also increased. A non-Fickian transport was the mechanism of drug release for all the microspheres. The in vivo anti-diabetic activity performed on steptozotocin induced rats indicated that the plain repaglinide has shown maximum percentage of reduction in blood glucose at the end of 3 h and then the percentage of reduction in blood glucose was decreased. While in case of rats treated with PCL5 microspheres, the percentage of reduction in glucose level was slow as compared to plain repaglinide within 3 h, but it was gradually increased to 74.86% at the end of 24 h.     

Physicochemical Characterization and Evaluation of Buccal Adhesive Tablets Containing Omeprazole

The objective of this study was to develop an effective omeprazole buccal adhesive tablet with excellent bioadhesive force and good drug stability in human saliva. The omeprazole buccal adhesive tablets were prepared with various bioadhesive polymers, alkali materials, and croscarmellose sodium. Their physicochemical properties, such as bioadhesive force and drug stability in human saliva, were investigated. The release and bioavailability of omeprazole delivered by the buccal adhesive tablets were studied. As bioadhesive additives for the omeprazole tablet, a mixture of sodium alginate and hydroxypropylmethylcellulose (HPMC) was selected. The omeprazole tablets prepared with bioadhesive polymers alone had bioadhesive forces suitable for a buccal adhesive tablet, but the stability of omeprazole in human saliva was not satisfactory. Among alkali materials, only magnesium oxide could be an alkali stabilizer for omeprazole buccal adhesive tablets due to its strong waterproofing effect. Croscarmellose sodium enhanced the release of omeprazole from the tablets; however, it decreased the bioadhesive forces and stability of omeprazole tablets in human saliva. The tablet composed of omeprazole/sodium alginate/HPMC/magnesium oxide/croscarmellose sodium (20/24/6/50/10 mg) could be attached on the human cheek without disintegration, and it enhanced the stability of omeprazole in human saliva for at least 4 h and gave fast release of omeprazole. The plasma concentration of omeprazole in hamsters increased to a maximum of 370 ng/ml at 45 min after buccal administration and continuously maintained a high level of 146-366 ng/ml until 6 h. The buccal bioavailability of omeprazole in hamsters was 13.7% ± 3.2%. These results demonstrate that the omeprazole buccal adhesive tablet would be useful for delivery of an omeprazole that degrades very rapidly in acidic aqueous medium and undergoes hepatic first-pass metabolism after oral administration.