Oral Controlled Drug Delivery Systems Research Articles

Formulation and optimization of sustained release tablets of venlafaxine resinates using response surface methodology

The aim of the current study was to design sustained release matrix tablets of venlafaxine hydrochloride using ion exchange resin with the incorporation of hydrophilic and hydrophobic polymer combinations. Venlafaxine HCl was loaded onto Indion 244 by batch method and then resinate were wet granulated with ethyl cellulose and blended with hydroxypropylmethylcellulose and compressed. A central composite design for 2 factors at 3 levels each was employed to systematically optimize drug release profile at 2 h and at 18 h. Hydroxypropylmethylcellulose and ethylcellulose were taken as the independent variables. Response surface plots and contour plots were drawn, and optimum formulations were selected by feasibility and grid searches. Resinate shows inadequate sustained release profile. Compressed matrices exhibited the anomalous release mechanism, as the value of release rate exponent (n) varied between 08109 and 08719, resulting in regulated and complete release until 20 h. Validation of optimization study, performed using five confirmatory runs, indicated very high degree of prognostic ability of response surface methodology, with mean percentage error as 1.152±1.88%. Regulated drug release study indicates that the hydrophilic and hydrophobic matrix tablets of venlafaxine resinate prepared using hydroxypropylmethylcellulose and ethylcellulose, can successfully be employed as a once-a-day oral controlled release drug delivery system.

Rheological Characterization and Drug Release Studies of Gum Exudates of Terminalia catappa Linn

The present study was undertaken to evaluate the gum exudates of Terminalia catappa Linn. (TC gum) as a release retarding excipient in oral controlled drug delivery system. The rheological properties of TC gum were studied and different formulation techniques were used to evaluate the comparative drug release characteristics. The viscosity was found to be dependent on concentration and pH. Temperature up to 60 degrees C did not show significant effect on viscosity. The rheological kinetics evaluated by power law, revealed the shear thinning behavior of the TC gum dispersion in water. Matrix tablets of TC gum were prepared with the model drug dextromethorphan hydrobromide (DH) by direct compression, wet granulation and solid dispersion techniques. The dissolution profiles of the matrix tablets were compared with the pure drug containing capsules using the USP Basket apparatus with 500 ml phosphate buffer of pH 6.8 as a dissolution medium. The drug release from the compressed tablets containing TC gum was comparatively sustained than pure drug containing capsules. Even though all the formulation techniques showed reduction of dissolution rate, aqueous wet granulation showed the maximum sustained release of more than 8 h. The release kinetics estimated by the power law revealed that the drug release mechanism involved in the dextromethorphan matrix is anomalous transport as indicated by the release exponent n values. Thus the study confirmed that the TC gum might be used in the controlled drug delivery system as a release-retarding polymer.

Comparative evaluation of interpolyelectrolyte complexes of chitosan with Eudragit ® L100 and Eudragit ® L100-55 as potential carriers for oral controlled drug delivery

With a view to the application in oral controlled drug delivery systems, the formation of interpolyelectrolyte complexes (IPEC) between chitosan (CS) and Eudragit ® L100 (L100) or Eudragit ® L100-55 (L100-55) was investigated at pH 6.0, using elementary analysis. The interaction or binding ratio of a unit molecule of CS with Eudragit ® L copolymers depends on the molecular weight of CS, and changes from 1:0.85 to 1:1.22 (1.17 < φ < 0.82) for L100 and from 1:1.69 to 1:1.26 (0.60 < φ < 0.79) for L100-55, respectively. Based on the results of FT-IR, the structure of the IPECs can change substantially as a function of pH (from 5.8 till 7.4). Swelling behavior of physical mixtures (PM) is definitely different, and potential interactions between the two polyelectrolytes were not observed. The release of the model drug diclofenac sodium (DS) was significantly delayed from tablets made up of the IPEC and can be modified by two ways: choosing Eudragit ® L copolymer types and/or changing the molecular weight of CS in the IPECs composition.

Polymers for Mucoadhesive Drug Delivery System: A Current Status

To overcome the relatively short gastrointestinal (GI) time and improve localization for oral controlled or sustained release drug delivery systems, bioadhesive polymers that adhere to the mucin/epithelial surface are effective and lead to significant improvement in oral drug delivery. Improvements are also expected for other mucus-covered sites of drug administration. Bioadhesive polymers find application in the eye, nose, and vaginal cavity as well as in the GI tract, including the buccal cavity and rectum. This article lays emphasis mainly on mucoadhesive polymers, their properties, and their applications in buccal, ocular, nasal, and vaginal drug delivery systems with its evaluation methods.

Synthesis of a new mPEG-dexamethasone conjugate and preliminary bioavailability studies in rabbits

Poly(ethylene glycol) esters have been proposed as a potential oral-controlled drug delivery system for dexamethasone (DXM). The drug was covalently attached to monomethoxypolyethylene glycol amine (mPEG-NH 2 ) (Mw = 10,000 Da) using a succinate linker. A new PEG-based prodrug system was designed using ester derivatives. The drug-polymer conjugate (mPEG-DXM) was freely water soluble at room temperature. First of all, the adduct hydrolytic stability was assessed at physiological pH. Then, the bioavailability was evaluated by orally administering the mPEG-DXM conjugate in rabbits and comparing to that obtained by the intravenous route. The area under the concentration-time curve (AUC) of PEGylated drug was twice as large as that of the parent drug after oral administration. In conclusion, PEGylated DXM was useful for maintaining the DXM concentration in the blood after oral administration.

Design and evaluation of matrix-based controlled release tablets of diclofenac sodium and chondroitin sulphate.

The purpose of the present study was to develop and characterize an oral controlled release drug delivery system for concomitant administration of diclofenac sodium (DS) and chondroitin sulfate (CS). A hydrophilic matrix-based tablet using different concentrations of hydroxypropylmethylcellulose (HPMC) was developed using wet granulation technique to contain 100 mg of DS and 400 mg of CS. Formulations prepared were evaluated for the release of DS and CS over a period of 9 hours in pH 6.8 phosphate buffer using United States Pharmacopeia (USP) type II dissolution apparatus. Along with usual physical properties, the dynamics of water uptake and erosion degree of tablet were also investigated. The in vitro drug release study revealed that HPMC K100CR at a concentration of 40% of the dosage form weight was able to control the simultaneous release of both DS and CS for 9 hours. The release of DS matched with the marketed CR tablet of DS with similarity factor (f(2)) above 50. Water uptake and erosion study of tablets indicated that swelling followed by erosion could be the mechanism of drug release. The in vitro release data of CS and DS followed Korsmeyer-Peppas and zero-order kinetics, respectively. In conclusion, the in vitro release profile and the mathematical models indicate that release of CS and DS can be effectively controlled from a single tablet using HPMC matrix system.

Comparative evaluation of various structures in polymer controlled drug delivery systems and the effect of their morphology and characteristics on drug release

Oral controlled drug delivery systems have become an essential part of the development of new medicines. In this investigation, several controlled release drug delivery systems with various structures were designed and evaluated. The materials used in their preparation were mainly hydropolymers that play a dominant role as drug carriers. Polymer selection is determined by the intended use and the desired release profile. The design of the devices was based on a matrix tablet, which is used as a core tablet for the preparation of all other systems such as multilayer systems, core in cup systems and hybrid systems. The findings of the study indicate that all systems exhibit controlled release characteristics. Furthermore, the structure of the device appears to significantly affect its behavior, i.e., the drug release and its release rate. Increasing the covered area of the core tablet results in a decrease of drug release since the cover hindrances the contact of the liquid with the core surface and modifies its dissolution and consequently its release. The hybrid systems exhibited pulsatile release, a feature offering significant advantages for certain therapies. Furthermore, the materials used considerably influence the behavior and function of the system. These effects may be attributed to the nature and the properties of the materials employed. Release mechanisms are also affected considerably by these factors.

Characteristics of interpolyelectrolyte complexes of Eudragit E100 with Eudragit L100

With a view to the application in oral controlled drug delivery systems, the formation of interpolyelectrolyte complexes (IPEC) between Eudragit E100 (EE) and Eudragit L100 (EL) was investigated, using turbidimetry, solution viscosity measurements and elementary analysis. The structure of the synthesized IPEC was investigated by using FT-IR spectroscopy. The binding ratio of a unit molecule of EL with EE was found to be approximately 1:1 in pH 6.0. Based on the results of elementary analysis, and FT-IR, the binding ratio of each component in the solid complexes was very close to that observed in turbidity and viscosity measurements and indicate that the synthesized products can be considered as IPEC. Due to the structure of the IPEC, two maxima were observed in the swelling behaviour as a function of pH. The release of the model drug ibuprofen was significantly retarded from tablets made up of the IPEC.

Factors Affecting Mechanism and Kinetics of Drug Release from Matrix-Based Oral Controlled Drug Delivery Systems

Matrix technologies have often proven popular among the oral controlled drug delivery technologies because of their simplicity, ease in manufacturing, high level of reproducibility, stability of the raw materials and dosage form, and ease of scale-up and process validation. Technological advancements in the area of matrix formulation have made controlled-release product development much easier than before, and improved upon the feasibility of delivering a wide variety of drugs with different physicochemical and biopharmaceutical properties. This is reflected by the large number of patents filed each year and by the commercial success of a number of novel drug delivery systems based on matrix technologies.Matrix-based delivery technologies have steadily matured from delivering drugs by first-order or square-root-of-time release kinetics to much more complex and customized release patterns. In order to achieve linear or zero-order release, various strategies that seek to manipulate tablet geometry, polymer variables, and formulation aspects have been applied. Various drug, polymer, and formulation-related factors, which influence the in situ formation of a polymeric gel layer/drug depletion zone and its characteristics as a function of time, determine the drug release from matrix systems.Various mathematical models, ranging from simple empirical or semi-empirical (Higuchi equation, Power law) to more complex mechanistic theories that consider diffusion, swelling, and dissolution processes simultaneously, have been developed to describe the mass transport processes involved in matrix-based drug release. Careful selection of an appropriate model for drug release provides insight to the underlying mass transport mechanisms and helps in predicting the effect of the device design parameters on the resulting drug-release rate. Thus, a basic understanding of release kinetics and appropriate mechanisms of drug release from matrix system and their inter-relationships may minimize the number of trials in final optimization, thereby improving formulation development processes.

A three-layer guar gum matrix tablet for oral controlled delivery of highly soluble metoprolol tartrate

The objective of the study is to design oral controlled drug delivery systems for highly water-soluble drugs using guar gum as a carrier in the form of a three-layer matrix tablet. Metoprolol tartrate was chosen as a model drug because of its high water solubility. Matrix tablets containing either 30 (M1), 40 (M2) or 50% (M3) of guar gum were prepared by wet granulation technique using starch paste as a binder. Three-layer matrix tablets of metoprolol tartrate were prepared by compressing on both sides of guar gum matrix tablet granules of metoprolol tartrate M1, M2 or M3 with either 50 (TL1M1, TL1M2 or TL1M3) or 75 mg (TL2M1, TL2M2 or TL2M3) of guar gum granules as release retardant layers. Both the matrix and three-layer matrix tablets were evaluated for hardness, thickness, drug content uniformity, and subjected to in vitro drug release studies. The amount of metoprolol tartrate released from the matrix and three-layer matrix tablets at different time intervals was estimated by using a HPLC method. Matrix tablets of metoprolol tartrate were unable to provide the required drug release rate. However, the three-layer guar gum matrix tablets (TL2M3) provided the required release rate on par with the theoretical release rate for metoprolol tartrate formulations meant for twice daily administration. The three-layer guar gum matrix tablet (TL2M3) showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 °C/75% RH for 6 months. The FT-IR study did not show any possibility of metoprolol tartrate/guar gum interaction with the formulation excipients used in the study. The results indicated that guar gum, in the form of three-layer matrix tablets, is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs such as metoprolol tartrate.

Three-layer guar gum matrix tablet formulations for oral controlled delivery of highly soluble trimetazidine dihydrochloride

The present study is carried out to design oral controlled drug delivery systems for highly water-soluble drugs using guar gum as a carrier in the form of three-layer matrix tablets. Trimetazidine dihydrochloride was chosen as a model drug because of its high water solubility. Matrix tablet granules containing 30% (M1), 40% (M2) or 50% (M3) of guar gum were prepared by the wet granulation technique using starch paste as a binder. Three-layer matrix tablets of trimetazidine dihydrochloride were prepared by compressing on either side of guar gum matrix tablet granules of trimetazidine dihydrochloride M1, M2 or M3 with 200 mg of guar gum granules containing either 65% of guar gum (T1M1, T1M2 or T1M3), 75% of guar gum (T2M1, T2M2 or T2M3) or 85% of guar gum (T3M1, T3M2 or T3M3) as release retardant layers. The three-layer matrix tablets were evaluated for hardness, thickness, drug content uniformity, and were subjected to in vitro drug release studies. The amount of trimetazidine dihydrochloride released from the matrix and three-layer matrix tablets at different time intervals was estimated using a HPLC method. The three-layer guar gum matrix tablet (T3M3) provided the required release rate on par with the theoretical release rate for guar gum formulations meant for twice daily administration. The three-layer guar gum matrix tablet (T3M3) showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 °C/RH 75% for 6 months. The DSC study did not show any possibility of interaction between trimetazidine dihydrochloride and guar gum/other formulation excipients used in the study. The results indicated that guar gum, in the form of three-layer matrix tablets, is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs such as trimetazidine dihydrochloride.

An easy producible new oral hydrocolloid drug delivery system with a late burst in the release profile

One of the main drawbacks of hydrocolloid matrices as oral controlled drug delivery systems is the often observed decreasing rate of drug release at the end of the release process. This study describes a new pH-controlled hydrocolloid drug delivery system consisting of a neutral cellulose ether as basis polymer and enteric coating materials as additives. The new dosage form is able to accelerate the drug release at a predetermined pH. In a typical example, methylhydroxy ethylcellulose, MHEC 10000 B, was used as the basis polymer and hydroxypropyl methylcellulose acetate succinate, HPMCAS HF, as release modifier. The new delivery system is characterized by its homogenous structure and easy production by direct compression of the components. The acceleration is well reproducible. Furthermore the new formulation shows high stability against hydrodynamic stress and tolerates ionic strengths up to 0.25 without any significant changes in the release profile. As mechanism of the final burst at pH values >5.7, enforced erosion of the gel layer surrounding the tablet core, could be identified.

Poly(methylglyoxylate), a biodegradable polymeric material for new drug delivery systems

A biodegradable hydrophobic matrix, poly(methylglyoxylate) and a water-soluble drug, metoprolol, were used to prepare solid dispersions in order to obtain an oral controlled drug delivery system. Preliminary thermal and chemical studies of the polymer revealed sufficient properties to undergo the preparation of solid dispersions as well as satisfactory behaviour in acidic or alkaline medium. Consequently, a first series of co-melts and co-precipitates containing various drug concentrations (75, 50, 35 and 25%, w/w) were prepared with a granulometry varying between 250 and 100 μm. DSC studies showed a better dispersion of the drug in the matrix for co-precipitates than for co-melts. In vitro dissolution kinetic studies showed an important burst effect during the first 30 min. Then a very slow release of the drug was observed during the last 7.5 h. A second series of co-precipitates with lower drug content (25, 15 and 5%, w/w) and lower granulometry (up to 100 μm) was tested. Finally, a dissolution profile similar to those of a commercial Seloken 200 LP tablet formulation was obtained, for a 15% (w/w) drug concentration in the polymer matrix and for a solid dispersion prepared by solvent method.

Poly(palmitoyl- l-hydroxyproline ester) microspheres as potential oral controlled drug delivery system

A new type of carrier using poly(palmitoyl- l-hydroxyproline ester) (PPH) [IUPAC name: poly((1-palmitoyl-4,2-pyrrolidinediyl)carbonyloxy)], a poly(amino acid) is described. The polymer is synthesized by conventional method and the microspheres were prepared by solvent evaporation technique for application in drug delivery system. Microspheres with different sizes were prepared by varying certain formulation and technological parameters and their distributive stabilities under physiological conditions were studied. The microspheres were characterized by DSC, optical and laser particle size analysis. A model drug, rifampicin (antituberculosis drug) was entrapped in the microspheres and the in vitro release studies were performed in pH 7.4 and pH 1.5 buffer media. The pH value seemed to have some influence on the dissolution rate of the rifampicin-containing microspheres. Dissolution experiments using rifampicin indicated the possibility of using PPH microspheres with other hydrophobic drugs.

Drug Delivery Systems 5A. Oral Drug Delivery

The two main advantages of controlled drug delivery systems are: maintenance of therapeutically optimum drug concentrations in the plasma through zero-order release without significant fluctuations; and elimination of the need for frequent single dose administrations. The oral and other therapeutic systems in human use have validated the concept that controlled continuous drug release can minimize the daily dose of a drug required to maintain the required therapeutic effect, while minimizing unwanted pharmacological effects. By minimizing patient intervention, a design feature of therapeutic systems, compliance is automatically enhanced. Oral drug delivery systems, in particular, have required innovation in materials science to provide materials biocompatible during prolonged contact with body tissues, bioengineering to develop drug delivery modules, and clinical pharmacology for elucidation of drug action under conditions of continuous controlled drug administration. Recent work in advanced oral delivery has been primarily focused on liposome technology and the concept that substances that are normally destroyed by the stomach can be protected long enough before they could be absorbed downstream. For cost and patient convenience, oral delivery certainly would be an attractive method. The nature of biologic substances, however, with their unique technical problems, will probably limit greatly those that can be delivered orally. Besides, where delivery rate control is critical, oral delivery, even when possible, would probably be insufficiently precise. Oral delivery would also limit the substance to bloodstream delivery to the disease site. Even so, oral controlled drug delivery systems will likely find primary usefulness in specific carefully controlled therapies and prophylactic situations with due regard for drug interactions. This system represents a potentially very significant therapeutic modality. These delivery systems will find usefulness primarily in certain well-defined and well-controllable areas with due regard for individual patient variations. The purpose of the present article is to review oral controlled-release drug delivery systems, with particular emphasis on the practical aspects of testing and fabricating these systems and the underlying mechanisms by which control over drug release rate is accomplished.

Oral controlled drug delivery systems based on microporous polymers

Microporous polypropylene (PP) powder shows excellent properties for tabletting. Oral controlled release delivery systems were made by simply blending with drug and compressing to make both matrix and coated tablets. To prevent wetting problems and food interactions, sodium lauryl sulphate (SLS) was adsorbed prior to tabletting on the surface of the microporous PP. In order to reveal possible dosage form-food interactions a new and simple food interaction model (slight modification of the USP XX paddle method) is proposed to standardize both in vitro and in vivo testing procedures. The PP coated oxprenolol tablets show no food interactions when tested in vitro in the food simulation mixture. The same liquid food was used in the in vivo study. The PP coated oxprenolol tablets were given to six male volunteers with and without the food. The absorption profiles, which were calculated by numerical deconvolution, showed hardly any food interactions in vivo. The absolute bioavailability at 12 hours was 38±19% on an empty stomach and 37±20 for the food experiment. The developed coated tablets are able to control the release of oxprenolol at least 12 hours both with and without concomitant food intake. Their bioavailability is comparable to different OROS formulations of oxprenolol controlled release systems based on microporous PP are not only highly effective ones but also low cost formulation products.

Dried Molasses as a Direct Compression Matrix for Oral Controlled Release Drug Delivery II: Release Mechanism and Characteristics of Theophylline from a Molasses-Hpmc Matrix

Investigation was conducted to evaluate dried molasses as a direct compression matrix for oral controlled release drug delivery system based on its tendency to form a gel-like layer around an inner...