Matrix Controlled Release Research Articles

Formulation and Physicochemical Characterization of Buccal Mucoadhesive Films Containing Alfuzocin Hydrochloride

The buccal region of oral cavity is a interesting target for the drug of choice administration. To increase prevent first pass metabolism and bioavailability, Alfuzocin Hydrochloride is embedded in buccal film for a sustained release over a period of 8 hours. The purpose of this study was to develop formulations and systematically evaluate in vitro performances of buccoadhesive films of Alfuzocin hydrochloride using the polymers HPMC K100M, Sodium Alginate and Chitosan. The films were provided with a backing layer of Eudragit RS100 so as to get an unidirectional release pattern. The films were evaluated for their physical characteristics like weight, thickness, content uniformity, folding endurance, bioadhesive strength, surface pH, in vitro drug release, ex vivo buccal permeation and XRD studies. The films, which were prepared by the solvent casting method, were smooth and elegant in appearance; uniform in thickness, weight, and drug content; and showed good folding endurance. The mechanical properties reveal that the formulations were found to be strong but not brittle. The in vitro release data were fit to different equations and kinetic models viz. zero order, first order, higuchi’s plot and peppas plot. The best mucoadhesive performance and matrix controlled release was exhibited by the formulation A7 (2% HPMC K100 M and 2% Chitosan). The correlation coefficient value (r) indicates, the kinetic of drug release was zero order. Stability study of optimized films was done and it was found that both drug and buccal films were stable. It can be concluded that the present buccal formulation can be an ideal system to improve the bioavailability of the drug by avoiding hepatic first-pass metabolism.

Paramylon and synthesis of its ionic derivatives: Applications as pharmaceutical tablet disintegrants and as colloid flocculants

Paramylon, a high molecular weight polysaccharide, is a linear and unbranched (1 → 3)-β-d-glucan. Despite its numerous biological benefits, the poor aqueous solubility of crystalline paramylon is a drawback that has hampered some of its applications. In an effort to make this biomaterial amenable to practical uses, cationic and anionic paramylon derivatives were obtained. The degrees of substitution of both products were determined. The products were characterized by FT-IR spectrocopy, ESI mass spectrometry, 1H, 13C and 1H-13C NMR and SEM microscopy. These techniques confirmed the success of the substitution reactions. 1H NMR analysis was used to develop alternative methods for an approximate estimation of the degree of substitution. 1H-13C HSQC NMR spectra were assigned for both derivatives. New applications of native, cationic and anionic paramylon were found. Native paramylon showed similar performance as pharmaceutical tablet disintegrant than sodium croscarmellose. Cationic paramylon behavior as colloid flocculant was comparable with commercial cationic polyacrylamides. The anionic derivative could eventually be used in the formulation of matrix controlled release systems or as a suspending agent.

Prolonged drug release properties for orodispersible films by combining hot-melt extrusion and solvent casting methods

Orodispersible films (ODFs) are an advantageous dosage form to accomplish patient convenience and compliance in oral drug delivery. They provide a number of special application features, such as the ease of administration without water and suitability for patients with swallowing problems. However, this promising dosage form has been limited to immediate release formulations so far. The aim of this study was to develop a thin film produced by solvent casting, which is rapidly disintegrating when placed in the mouth, but which provides prolonged drug release characteristics by incorporating drug-loaded matrix particles (MPs). MPs were produced by hot-melt extrusion and subsequent milling, using theophylline anhydrous as model drug and Eudragit® RS as matrix-forming agent enabling prolonged drug release. ODFs were manufactured using hypromellose as film former. Dissolution studies were performed to investigate the kinetics and the duration of drug release. Additionally, disintegration time was determined using the PharmaTest® disintegration tester equipped with a specific sample holder for ODFs. All produced ODFs containing theophylline-loaded MPs show fast disintegration while the drug release was prolonged. The degree of release prolongation increases with increasing sizes of incorporated MPs. Matrix-controlled release kinetics were found for ODFs containing MPs with at least 315 µm in size.In summary, the production of fast disintegrating ODFs with prolonged release properties was feasible. Furthermore, freely adjustable dissolution profiles could be realized for ODFs by incorporating MPs of various particle sizes.

DESIGN AND EVALUATION OF BUCCAL PATCHES CONTAINING COMBINATION OF HYDROCHLOROTHIAZIDE AND ATENOLOL

Objective: Buccal patch is a non-dissolving thin matrix modified release dosage form which was developed to administer into the unconscious and less co-operative patients.Methods: The mucoadhesive buccal patches of hydrochlorothiazide (HCZ) and atenolol (ATN) were prepared by solvent casting technique using various concentrations of sodium alginate, hydroxyl propyl methyl cellulose, carbopol 934P and sodium carboxy methyl cellulose polymer and polyvinyl alcohol as a backing layer. The formulated patches were evaluated for their physicochemical parameters like thickness, weight variation, surface pH, content uniformity, folding endurance, swelling percentage studies and tensile strength, in vitro and ex vivo drug permeation. Results: The infra-red (IR) spectra showed no interaction between drug and polymer. Physicochemical characteristics of all the samples were found to be satisfactory and well within the range. Swelling of the films were increased with the increasing content of the polymers and it was found that swelling front erosion was comparably slower in the formulations with the carbopol 934 and HPMC. This is probably due to their marked viscous properties and therefore formulation provided sustained release of the drug. The percentage drug content of all the formulations were found to be in the range of 97-99 %. Among the patches, FC (Carbopol 934 and HPMC) patches were considered satisfactory for maintaining the in vitro residence in the oral cavity for almost 8h. Formulations FD (with CP and NaCMC) and FC showed high tensile strength and % E/B which is an indication of the strength and elasticity of the patch. The films were exhibited sustained release for more than 6 h which was confirmed by the in vitro release data and kinetic data reveals the combination of diffusion and erosion mechanism. The best mucoadhesive performance and matrix controlled release was exhibited by the formulation FC.Conclusion: The formulation of HCZ and ATN mucoadhesive buccal patch was found to be satisfactory and reasonable.

DEVELOPMENT AND CHARACTERIZATION OF MUCOADHESIVE BUCCAL PATCH OF TIMOLOL MALEATE

The oral transmucosal Timolol maleate delivery bypasses liver and avoids presystemic elimination in the gastro intestinal tract andliver which enhance the bioavailability as well decreases the adverse effect. Objective: The present investigation highlights the formulation andevaluation of mucoadhesive buccal patch of Timolol maleate because Timolol maleate has biphasic solubility hence relatively permeated throughbuccal mucosa, which is well supplied with both vascular and lymphatic drainage. Material and Method: The mucoadhesive buccal patches ofTimolol maleate were prepared by solvent casting technique using polymers like Hydroxypropylmethyl cellulose-15cps and Polyvinylpyrrolidone. The formulated films were evaluated for their physiochemical parameters like surface pH, percentage moisture absorption, swellingpercentage, thickness, folding endurance and drug content. In vitro permeation and in vitro release studies were performed with pH 6.8 phosphatebuffer solution. Result and Discussion: The patches exhibited controlled release for more than 12 h. The in vitro release data were fit to differentequations and kinetic models to explain release profiles. The kinetic models used were zero order, first order higuchi’s and peppa’s. The bestmucoadhesive performance and matrix controlled release was exhibited by the formulation CK2 (3 % HPMC and 1 % PVP). Conclusion: Goodresults were obtained both in physico chemical characteristics and in vitro studies in formulation CK2. Hence the formulations of Timololmaleate bioadhesive buccal patch is a promising one as the controlled drug delivery with improved bioavailability.

Biomedical segmented polyurethanes based on polyethylene glycol, poly(ε-caprolactone-co-D,L-lactide), and diurethane diisocyanates with uniform hard segment: Synthesis and properties

ABSTRACTIn the study, a new approach for synthesizing biomedical segmented polyurethanes (SPUs) based on polyethylene glycol (PEG, Mn = 800), poly(ε-caprolactone-co-D,L-lactide) (PCLA) and aliphatic diurethane diisocyanates with a long uniform hard segment was developed. By the chain extension of a mixture of PEG diol and PCLA diol with diurethane diisocyanates based on inexpensive 1,6-hexanediisocyanate, three SPUs (SPU-I, SPU-II, and SPU-III) with different contents of hydrophilic segments (PEG) and hard segments were obtained. The chemical structures of diurethane diisocyanates, PCLA and SPUs were confirmed by 1H NMR, 13C NMR, FT-IR, HR-TOF-MS, and GPC. The SPU films exhibited similar thermostability, indicating that the hard segment content marginally affects on the thermostability. From the results of differential scanning calorimetry, two glass transition temperatures were observed, suggesting the microphase separation of soft and hard segments. The SPU films exhibited satisfactory mechanical properties with ultimate stress of 17.4–22.3 MPa and strain at break of 890–1060%, and the initial modulus increased with the increasing content of hard segments. In vitro degradation studies indicated that the time of SPU films to become fragments was 22–33 days, and the degradation rate increased with the increasing content of hydrophilic segments in SPU. Hence, the degradation time of SPU films could be controlled by adjusting the PEG content in SPU, which made them good candidates for further biomedical applications. Studies of in vitro drug release were conducted using vitamin B1 as model drugs. Drug-loaded films exhibited a high initial release rate and matrix-controlled release for more than two weeks, thereby demonstrating a promising material for a long-acting controlled release system. Cytotoxicity test of film extracts and cell attachment on the film surface were conducted using L929 mouse fibroblasts, and the results indicated that the SPU films possess excellent cytocompatibility and cell adhesive ability.

Formulation and development of orodispersible sustained release tablet of domperidone

Commercially available domperidone orodispersible tablets (ODT) are intended for immediate release of the drug, but none of them have been formulated for sustained action. The aim of the present research work was to develop and evaluate orodispersible sustained release tablet (ODT-SR) of domperidone, which has the convenience of ODT and benefits of controlled release product combined in one. The technology comprised of developing sustained release microspheres (MS) of domperidone, followed by direct compression of MS along with suitable excipients to yield ODT-SR which rapidly disperses within 30 seconds and yet the dispersed MS maintain their integrity to have a sustained drug release. The particle size of the MS was optimized to be less than 200 μm to avoid the grittiness in the mouth. The DSC thermograms of MS showed the absence of drug-polymer interaction within the microparticles, while SEM confirmed their spherical shape and porous nature. Angle of repose, compressibility and Hausner’s ratio of the blend for compression showed good flowability and high percent compressibility. The optimized ODT-SR showed disintegration time of 21 seconds and matrix controlled drug release for 9 h. In-vivo pharmacokinetic studies in Wistar rats showed that the ODT-SR had a prolonged MRT of 11.16 h as compared 3.86 h of conventional tablet. The developed technology is easily scalable and holds potential for commercial exploitation.

Higuchi's equation and beyond: Overview of the formulation and application of a generalized model of drug release from polymeric matrices

An account is presented of modeling and experimental work, which complements, in many useful ways, the excellent coverage, afforded by a recent dedicated issue edited by Siepmann and Peppas (Int. J. Pharm. 2011, 418(1)), of the theoretical background and many ramifications, as well as practical applications, of the Higuchi equation. The main notable feature of the said modeling work is formulation and successful practical application, of an ab initio generalized approach, based on solving the fundamental transport equations applicable to the operation of typical matrix-controlled release (MCR) devices. This approach (i) reduces to the Higuchi equation under the pertinent restrictive conditions but can duly handle most of its more complex ramifications and (ii) can be parameterized (by the use of appropriate data from the literature or from independent experiments) to adapt itself to the physics of the particular matrix-solvent-solute system under consideration; as demonstrated here with examples from our laboratory or from the literature. A distinctive feature of the experimental work is the extensive use of simpler "model" MCR systems, chosen so as to promote better understanding of the effect of various physicochemical parameters and mechanisms on drug MCR rate and kinetics. A concept of MCR device efficiency is also discussed.

Drug Release from Poly(dimethylsiloxane)-Based Matrices: Observed and Predicted Stabilization of the Release Rate by Three-Layer Devices

Realistic mathematical modeling can greatly facilitate the optimum design of matrix-controlled release (MCR) devices. Here, we present a practical example of a relevant methodology, based on a previously developed model for symmetrical, three-layer MCR devices. The experimental system is based on PDMS matrices incorporating 10% of poly(ethylene glycol) and loaded with theophylline. The matrices were either single-layer devices uniformly loaded with theophylline or symmetrical three-layer devices with a uniformly loaded inner layer and theophylline-free outer layers. The theophylline loads, and the geometrical characteristics of the multilayer matrices, were chosen according to general guidelines for improved uniformity of rate, previously formulated by model calculations. As anticipated, these devices were found to effectively stabilize the rate of release, as compared to the corresponding single-layer system. The main kinetic characteristics of the experimental systems were then successfully reproduced t...

An advanced model for composite planar three-layer matrix-controlled release devices. Part II. Devices with non-uniform material properties and a practical example

In this series of papers, a new model has been presented for symmetrical, planar, three-layer (ABA) matrix-controlled release (MCR) devices, wherein all the advanced features of a previous monolithic MCR model have been incorporated. An extensive parametric study was performed to explore the possibilities afforded by the ABA configuration to alleviate, or even practically eliminate the undesirable features of initially very high, and subsequently continuously declining, release rates which normally characterize diffusion-limited monolithic devices. ABA matrices with uniform material properties (UMP) and layers A and B carrying different solute loads were examined in Part I. The results presented here refer to the more general case, where A and B may also represent non-uniformity in sorption and transport properties (non-UMP ABA devices). It is shown that judicious choice of two different polymeric materials for layers A and B may further improve the favorable results previously obtained for ABA–UMP matrices to the point where demands of very narrow limits for dose rate uniformity in conjunction with very high efficiency, can be met. The applicability and utility of the ABA, non-UMP model was demonstrated in a real experimental situation concerning surface-modified PVA matrices. Parameterization of the model on the basis of the experimental information provided and on literature data, resulted in successful interpretation of the effect of two different degrees of surface crosslinking on the relative rates of water uptake and proxyphylline release.

An advanced model for composite planar three-layer matrix-controlled release devices: Part I. Devices of uniform material properties and non-uniform solute load

A general model capable of simulating the operation of a polymer-based, solvent-activated, symmetrical three-layer (ABA), or equivalently two-layer (AB with the B surface blocked), matrix-controlled release (MCR) device, is presented and used for a parametric investigation of predicted release kinetics covering a much wider range of conditions than previously studied. The model can account adequately for (i) polymer–solvent–solute sorption and transport interactions, including solvent-induced osmotic effects, (ii) fast or slow (Fickian) solvent penetration relative to solute release and (iii) embedded solute loads exceeding the limit of solubility in the fully swollen matrix. The results obtained for the case of identical A and B layers differing only in solute load are reported here. They reveal important possibilities of markedly alleviating the main problems of non-uniformity of dose rate and initial “burst effect”, which normally characterize the operation of single-layer (monolithic) MCR devices, by use of properly designed ABA systems of the aforementioned type. The comparative analysis of MCR performance data has been put on a firm theoretical basis by the introduction of (i) the concept of efficiency of an MCR system and (ii) examination of the evolution of the fractional solute rate as a function of the fractional amount released rather than as a function of time.

A model for the prediction of the performance of multilayered polymeric matrix-controlled release devices

Simple, matrix controlled release (MCR)devices (usually designed in the form of slabs)consist of a swellable polymer matrix incorporat-ing a drug or another bioactive agent, and are acti-vated by the ingress of water when placed in anaqueous environment. Their structural simplicityand ensuing low cost of manufacture account fortheir wide use. Nevertheless, MCR devices arecommonly characterised by a continuous declineof dose rate, which constitutes a substantial draw-back for most practical applications. One designstrategy to overcome this problem is the develop-ment of multilayered devices [1], consisting of lay-ers with different properties (i.e. permeability,thickness, initial loading of the bioactive sub-stance, or combinations of the above). In this work, our previous model, simulatingthe functioning of single-layer, MCR systems[2,3], is used as a basis for the development ofa model applicable to multilayered devices.Generic parametric studies were then performed,in order to obtain insight on the role of the mainmodel parameters that must be considered in thedesign of practical devices, especially withregard to the achievement of nearly constantrelease rate.

Application of the Gaussian mixture model to drug dissolution profiles prediction

In this paper, the radial basis function-based Gaussian mixture model (GMM) is applied to model and predict drug dissolution profiles in a time-series approach. The Parzen-window method is embedded into the GMM for determining whether the network predictions are derived from interpolation or extrapolation of the training data. A benchmark study on time-series prediction is first used to evaluate and compare the GMM performance with those from other models. The GMM is then used to predict dissolution profiles of a matrix-controlled release theophylline pellet preparation. Performance of the GMM is assessed using the difference and similarity factors, as recommended by the United States Food and Drug Administration for dissolution profile comparison. In addition, bootstrapping is employed to estimate the confidence intervals of the network predictions. The experimental results are analyzed and compared, and implications of the GMM for pharmaceutical product formulation tasks are discussed.

Melt Granulation and Heat Treatment for Wax Matrix-Controlled Drug Release

The purpose of this study was to evaluate sustained drug release after melt granulation and heat treatment. Theophylline (anhydrous) and phenylpropanolamine hydrochloride (PPA) were used as model drugs. Compritol® 888 ATO (Glyceryl Behenate NF) was incorporated as the wax matrix material. Formulations with drug:wax in 3:1 and 1:1 ratios were evaluated. Tablets were made by dry blending or melt granulation; some of the tablets were heat treated at 80°C for 30 min. Tablets with or without heat treatment were tested for drug release using in vitro drug dissolution. The results showed that melt granulation gave slower drug release than dry blending. Heat treatment further retarded drug release for both dry blending and melt granulation. The drug release rates for theophylline were slower than for PPA at the same wax level and processing method. The drug release profiles were linear using a square root of time scale. In conclusion, melt granulation and heat treatment slowed drug release for the wax matrix-controlled release tablets. Heat treatment of the tablets made by melt granulation further retarded drug release. Heat treatment redistributed the wax, forming a new matrix system with higher tortuosity. The application of melt granulation or heat treatment can successfully retard drug release.

Influence of Physiological Variables on the In Vitro Drug-Release Behavior of a Polysaccharide Matrix Controlled-Release System

Hydrophilic matrix systems are popular and versatile controlled release systems. Amongst polysaccharide derivatives used to produce such systems, there are a range of cellulose ethers, e.g., hydrox...

Application of a Recurrent Neural Network to Prediction of Drug Dissolution Profiles

in-vitro dissolution profiles of matrix controlled release theophylline pellet preparation, leading to the potential use of an intelligent learning system in the development of pharmaceutical products with desired drug release characteristics. A total of six different formulations containing various matrix ratios of substance to control the release rate of theophylline were used for experimentation. By using the leave-one-out cross-validation approach, the dissolution profiles of all the matrix ratios were consumed for training, except for one set that was taken as a reference profile, with which the network predicted profiles were compared. Performance of the network was assessed using the similarity factor, f2, a criterion for dissolution profile comparison recommended by the United States Food and Drug Administration. Simulation results indicated that the Elman network was capable of predicting dissolution profiles that were similar to the reference profiles with an error of less than 8%. In addition, the Bootstrap method was used to estimate the confidence intervals of the f2values. The results revealed the potential of a neural-network-based intelligent system in solving non-linear time-series prediction problems in pharmaceutical product development.

Use of artificial neural networks to predict drug dissolution profiles and evaluation of network performance using similarity factor.

To use artificial neural networks for predicting dissolution profiles of matrix-controlled release theophylline pellet preparation, and to evaluate the network performance by comparing the predicted dissolution profiles with those obtained from physical experiments using similarity factor. The Multi-Layered Perceptron (MLP) neural network was used to predict the dissolution profiles of theophylline pellets containing different ratios of microcrystalline cellulose (MCC) and glyceryl monostearate (GMS). The concepts of leave-one-out as well as a time-point by time-point estimation basis were used to predict the rate of drug release for each matrix ratio. All the data were used for training, except for one set which was selected to compare with the predicted output. The closeness between the predicted and the reference dissolution profiles was investigated using similarity factor (f2). The f2 values were all above 60, indicating that the predicted dissolution profiles were closely similar to the dissolution profiles obtained from physical experiments. The MLP network could be used as a model for predicting the dissolution profiles of matrix-controlled release theophylline pellet preparation in product development.

Physico-chemical properties of a rifampicin-releasing polydimethyl-siloxane shunt

Infection of implanted polymeric devices is a major problem in modern medicine. Silicone shunts were modified in order to prevent microbial colonization by incorporating rifampicin. The release mechanism and the altered properties of the silicone were studied. Release rates of rifampicin out of the polymeric shunt material were measured in vitro for up to 60 d. For high velocity of rifampicin in the polymeric matrix and long-lasting controlled release rates, high compatibility of polymer and drug was required. Compatibility and therefore miscibility of drug and polymer were estimated by reduced solubility and cohesion energy densities (Hansen parameter, solubility parameter δ). Mechanical properties of the polymer were influenced by incorporation of small drug amounts, characterized by stress-strain curves. Differential scanning calorimetry (DSC) measurements suggested thermodynamically controlled interaction of the macromolecules with the incorporated substance. The physicochemical state of the drug in the internal phase and the surface of the polymer was studied by scanning electron micrography (SEM), showing homogeneous molecular dispersion of the drug in the polymeric material as well as crystalline structures on the surface.

Development and characterization of tetracycline-poly(lactide/glycolide) films for the treatment of periodontitis

Local delivery of antibiotics has been shown to be effective in reducing periodontopathic micro-organisms. The objective of this research was to develop a biodegradable, poly( d, l-lactide/glycolide), 85:15, (PLGA) film that was capable of delivering therapeutic concentrations of tetracycline HCl for a duration of two weeks into the intra-crevicular fluid within the inflamed periodontal pocket. Films (10 × 2 × 0.5 mm) containing varying amounts (10 to 25% w/w) of tetracycline HCl were prepared by film casting a dispersion of the drug in a solution of PLGA dissolved in methylene chloride. Differential dissolution studies were performed in buffer, pH 7.3, at 37°C. Both the rate and percent of drug released increased as drug loading and dissolution media pH increased. However, complete release of drug from the films was not obtained as 83.1 ± 7.0 μg of tetracycline HCl per mg of PLGA was retained for all drug loadings. Linear relationships obtained for graphs of the percent released versus both the square root of time ( r 2 ≥ 0.96) and drug loading ( r 2 ≥ 0.99) indicated a matrix-controlled release from a porous, granular, monolithic system. Preliminary results from a clinical study with 8 periodontal, maintenance patients indicate that films containing 25% w/w tetracycline HCl were effective in decreasing the bacterial count in the intra-crevicular fluid and demonstrated a significant ( p ⩽ 0.01) microbial inhibition for two weeks over the control placebo film. The decrease in tetracycline HCl concentration in the gingival fluid was approximated by a first order relationship with the tetracycline HCl disappearance rate constant of 0.19 days −1.

Acacia-gelatin microencapsulated liposomes: preparation, stability, and release of acetylsalicylic acid.

Liposomes of dipalmitoylphosphatidylcholine (DPPC) containing acetylsalicylic acid (ASA) have been microencapsulated by acacia-gelatin using the complex coacervation technique as a potential oral drug delivery system. The encapsulation efficiency of ASA was unaltered by the microencapsulation process. The stability of the microencapsulated liposomes in sodium cholate solutions at pH 5.6 was much greater than the corresponding liposomes. The optimum composition and conditions for stability and ASA release were 3.0% acacia-gelatin and a 1- to 2-hr formaldehyde hardening time. Approximately 25% ASA was released in the first 6 hr from microencapsulated liposomes at 23 degrees C and the kinetics followed matrix-controlled release (Q varies; is directly proportional to t1/2). At 37 degrees C, this increased to 75% released in 30 min followed by a slow constant release, likely due to lowering of the phase transition temperature of DPPC by the acacia-gelatin to near 37 degrees C. At both temperatures, the release from control liposomes was even more rapid. Hardening times of 4 hr and an acacia-gelatin concentration of 5% resulted in a lower stability of liposomes and a faster release of ASA. It is concluded that under appropriate conditions the microencapsulation of liposomes by acacia-gelatin may increase their potential as an oral drug delivery system.