Reza Fassihi

Gastroretentive Delivery Systems: A Mini Review

Various attempts have been made to develop gastroretentive delivery systems. For example, floating, swelling, mucoadhesive, and high‐density systems have been developed to increase gastric retention time of the dosage forms. It is known that differences in gastric physiology, such as, gastric pH, and motility exhibit both intra‐as well as inter‐subject variability demonstrating significant impact on gastric retention time and drug delivery behavior. Nevertheless, some floating devices have shown promising results. In this paper, the gastric physiology and the reported intragastric delivery systems have briefly been presented.

A new intragastric delivery system for the treatment of Helicobacter pylori associated gastric ulcer: in vitro evaluation.

A new strategy is proposed for the triple drug treatment (tetracycline, metronidazole and bismuth salt) of Helicobacter pylori associated peptic ulcers. The design of the delivery system was based on the swellable asymmetric triple layer tablet approach, with floating feature in order to prolong the gastric retention time of the delivery system. Hydroxypropylmethylcellulose and poly(ethylene oxide) were the major rate-controlling polymeric excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple-layer matrix for controlled delivery, while bismuth salt could be included in one of the outer layers for instant release. The concentration of tetracycline and metronidazole released over time was determined simultaneously on a gradient high-performance liquid chromatography system. Results demonstrated that sustained delivery of tetracycline and metronidazole over 6-8 h can be easily achieved while the tablet remained afloat. The floating aspect was envisaged to extend the gastric retention time of the designed system to maintain effective localized concentration of tetracycline and metronidazole. Additionally, the developed HPLC method for the concurrent determination of tetracycline and metronidazole was proved to be rapid and accurate. The developed delivery system has potential to increase the efficacy of the therapy and improve patient compliance.

Role of surfactant and pH on dissolution properties of fenofibrate and glipizide--a technical note.

Summary and ConclusionsDepending on the dose size and solubility characteristics of low solubility drugs, a meaningful and discriminatory power of dissolution rate testing can be demonstrated. Saturation solubility of fenofibrate and glipizide in different media were determined. Solubility of fenofibrate increased directly with SLS concentration. For a 54-mg fenofibrate tablet, SLS at 0.025 M level is required for a discriminative dissolution test, while for 160-mg tablet, dissolution condition and levels of SLS should be optimized; higher concentrations may be effective (ie, 0.052 M, ∼1.5%). A pH 6.8 phosphate buffer medium is appropriate for glipizide 10-mg tablet dissolution study, when formulation ingredients include excipients with surface activity (eg, HPMC).

Guar-based monolithic matrix systems: effect of ionizable and non-ionizable substances and excipients on gel dynamics and release kinetics*

The effect of ionic and non-ionic excipients and additives as modulators of swelling and erosion kinetics and verapamil HCl release from guar-based matrix tablets was investigated. Tablet dissolution, erosion and water uptake studies were carried out using a modified USP 23 Apparatus 2 method. The kinetics of gel strength and texture development were studied by textural analysis. Near linear drug release over 24 h was obtained from formulations containing water soluble, ionizable sodium chloride and glycine. The contribution of Fickian release to overall drug release was lowest for these formulations and was correlated with greater gel strength and lower water uptake in the early time period. For soluble sugars (lactose and sucrose) the Fickian contribution to overall drug release was large and associated with pronounced curvilinear profiles. Water uptake was greatest for these additives (450% in 6 h). The lowest water uptake and negligible matrix erosion was observed for microcrystalline cellulose. Release from this formulation was predominantly Fickian. It was found that the physico-chemical nature of added excipients significantly influences the release kinetics from guar-based formulations. Ionic, water soluble materials (sodium chloride, glycine) reduce initial hydration of the matrix and thus have the ability to limit the initial rapid diffusion of drug and to sustain near linear release over 24 h.

In vitro release modulation from crosslinked pellets for site-specific drug delivery to the gastrointestinal tract: II. Physicochemical characterization of calcium–alginate, calcium–pectinate and calcium–alginate–pectinate pellets

Pellets of calcium-alginate, calcium-pectinate and calcium-alginate-pectinate were produced via crosslinking in an aqueous medium for site-specific drug delivery in the gastrointestinal tract. A comparative study of their physicochemical characteristics by means of texture analysis, modulated temperature differential scanning calorimetry (MTDSC), scanning electron microscopy and swelling dynamics under different pH conditions was undertaken. It was found that the incorporation of low methoxylated pectin (i.e., degree of methoxylation approximately 35%) together with alginate appears to influence the degree of crosslinking and subsequently the physical, mechanical and resilience behavior. In general, texture analysis of various pellets indicated that both strength and resilience profiles were in the order of calcium-alginate>/=calcium-alginate-pectinate>calcium-pectinate. Calcium-alginate pellets were found to be viscoelastic, while calcium-pectinate was highly brittle. Through the application of MTDSC, depolymerization transitions, reversing and non-reversing heat flow were determined and interpreted for each formulation. Scanning electron microscopy and micro-thermal analysis revealed distinct morphological differences in each case. The influence of and nature of crosslinking, and textural properties of such pellets on drug release rate modulation is discussed.

Gastroretentive Delivery Systems: Hollow Beads

The objective of this study was to develop a floatable multiparticulate system with potential for intragastric sustained drug delivery. Cross‐linked beads were made by using calcium and low methoxylated pectin (LMP), which is an anionic polysaccharide, and calcium, LMP, and sodium alginate. Beads were dried separately in an air convection type oven at 40°C for 6 hours and in a freeze dryer to evaluate the changes in bead characteristics due to process variability. Riboflavin (B‐2), tetracycline (TCN), and Methotrexate (MTX) were used as model drugs for encapsulation. Ionic and nonionic excipients were added to study their effects on the release profiles of the beads. The presence of noncross linking agents in low amounts (less than 2%) did not significantly interfere with release kinetics. For an amphoteric drug like TCN, which has pH dependent solubility, three different pHs (1.5, 5.0, and 8.0) of cross‐linking media were used to evaluate the effects of pH on the drug entrapment capacity of the beads. As anticipated, highest entrapment was possible when cross‐linking media pH coincided with least drug solubility. Evaluation of the drying process demonstrated that the freeze‐dried beads remained buoyant over 12 hours in United States Pharmacopeia (USP) hydrochloride buffer at pH 1.5, whereas the air‐dried beads remained submerged throughout the release study. Confocal laser microscopy revealed the presence of air‐filled hollow spaces inside the freeze dried beads, which was responsible for the flotation property of the beads. However, the release kinetics from freeze dried beads was independent of hydrodynamic conditions. Calcium‐pectinate‐alginate beads released their contents at much faster rates than did calcium‐pectinate beads (100% in 10 hours vs. 50% in 10 hours). It appears that the nature of cross‐linking, drying method, drug solubility, and production approach are all important and provide the opportunity and potential for development of a gastroretentive drug delivery system.

A New Ternary Polymeric Matrix System for Controlled Drug Delivery of Highly Soluble Drugs: I. Diltiazem Hydrochloride

AbstractPurpose. The purpose of this study was to develop a new ternary polymeric matrix system that is easy to manufacture and that delivers a highly soluble drug over long periods of time. Methods. Pectin, hydroxypropylmethylcellulose (HPMC), and diltiazem HC1 granulated with gelatin at optimized ratios were blended at different loading doses and directly compressed. Swelling behavior, dissolution profiles and the effect of hydrodynamic stress on release kinetics were evaluated. Results. Diltiazem release kinetics from the ternary polymeric system was dependent on the different swelling behavior of the polymers and varied with the drug loading dose and hydrodynamic conditions. Drug release followed either non-Fickian or Case II transport kinetics. The relative influence of diffusion and relaxational/dissolution effects on release profiles for different drug loadings was calculated by a nonlinear regression approach. Photographs taken during swelling show that the anisotropic nature of the gel structure, drug loading dose, swelling capacity of polymers used, and the design of delivery system all play important roles in controlling the drug release and dissolution/ erosion processes. Conclusions. Zero-order delivery of diltiazem HC1 from a simple tablet matrix was achieved. The ternary polymeric system developed in this study is suitable for controlled release of highly soluble drugs. It offers a number of advantages over existing systems, including ease of manufacturing and of release modulation, as well as reproducibility of release profiles under well defined hydrodynamic conditions. Our delivery system has the potential to fully release its drug content in a controlled manner over a long time period and to dissolve completely.

Examination of drug solubility, polymer types, hydrodynamics and loading dose on drug release behavior from a triple-layer asymmetric configuration delivery system

Abstract The significance of factors such as drug solubility, polymer molecular weight, drug loading and hydrodynamic conditions on drug release from a swellable triple layer asymmetric configuration delivery system is investigated. Poly(ethylene oxide) (PEO) of various molecular weights and hydroxypropylmethyl cellulose (HPMC) were major polymeric constituents of the delivery system. Theophylline, propranolol hydrochloride and diltiazem hydrochloride with water solubilities of 50%, respectively, were used as drug models. The triple-layer delivery system was produced by compressing particulate systems on a laboratory Carver press with a 10-mm diameter punch and die. Results show that due to the geometry, system design and maintenance of constant surface area linear release kinetics are achievable. Increase in drug solubility expedites drug release rate and shortens duration of release; while increase in polymer molecular weight results in reduction of release rate and prolongation of release period. Drug loading does not seem to affect the release behavior significantly even though a freely water-soluble drug such as diltiazem hydrochloride was employed. In addition, with an increase in stirring rate there was a corresponding increase in release rate, while linearity of release profile remained unaltered. Results further indicate that, as long as surface area is controlled, front synchronization is not a prerequisite for achieving zero-order release kinetics. Moreover, from a pharmaceutical perspective, the complex behavior of release mechanisms for different drugs in relation to matrix erosion, polymer swelling capacity and system design is explained.

Polymer particle erosion controlling drug release. II. Swelling investigations to clarify the release mechanism

The aim of the study was a comprehensive swelling investigation of hydrocolloid tablets with drug release by diffusion, erosion and polymer particle erosion, respectively, in order to reveal differences in the swelling behaviour responsible for the diverging drug release mechanisms. Four different methods were applied to study swelling of the tablets: determination of the expansion factor, texture analysis, visual swelling observation of dye containing tablets sandwiched between plexiglas discs and photomicroscopy. Altogether they allowed the investigation of dimensional changes, swelling velocity, thickness, appearance and strength of the gel layer and front movements. However, none of the methods included a determination of all these factors. A combination of the different techniques proved to be helpful to provide information necessary for a broad understanding of the complex phenomenon of swelling. Intensive swelling was observed for matrices with diffusion controlled release (e.g. MHPC 100000), while erosion controlled systems (e.g. Pharmacoat 606) were characterized by limited swelling and fast polymer erosion. In the case of tablets exhibiting polymer particle erosion (e.g. MHEC 10000 B) the importance of the amount of insoluble fibres was confirmed. Insoluble fibres were clearly visible in the swelling zone of these tablets. They impeded the swelling, weakened the gel layer and caused attrition of polymer material, thus only a thin gel layer was formed. Synchronization of the movement of swelling and erosion fronts occurred during the swelling of tablets with a high content of insoluble fibres. The freely soluble drug proxyphylline was found to promote swelling while the poorly soluble acetophenetidin hindered the hydration of the tablet. Furthermore, the swelling study confirmed the low robustness to hydrodynamic stress of tablets with erosion control compared to tables with polymer particle erosion.

Evaluation of floating and sticking extended release delivery systems: an unconventional dissolution test.

The extent to which hydrophilic matrix tablets with a propensity to stick to the dissolution apparatus and/or float are susceptible to variations in hydrodynamic conditions during dissolution testing was investigated. Furthermore the usefulness of simple alternatives to the current compendial tests is examined. Swellable hydrocolloid (guar) matrix tablets containing verapamil HCl were evaluated using USP dissolution apparatus I and II. Two additional configurations where an additional single ring and mesh device or a double mesh device was located below the paddle in the dissolution vessel were also evaluated. Tablets were placed on top of the single mesh device or in the compartment formed by the two mesh surfaces of the double mesh device. In all cases near linear (n>/=0.82) release profiles were observed. When using apparatus I it was observed that the highly swellable tablets were fully constricted by the basket within 5-7 h. This prevented further independent movement and unimpeded swelling and coincided with a departure from linear release and increased variability (S.D.</=9.5%). Under standard apparatus II conditions two out of three tablets adhered to the bottom of the dissolution vessel for the duration of the experiment. Consequently their release profiles differed markedly from those obtained under apparatus I conditions (similarity factor, f(2)=30.5) with the release rate being approximately half of that obtained under apparatus I conditions. Adhesion to the dissolution vessel was also observed when paddle speed was doubled to 100 rpm, thus again resulting in large variability (S.D.</=34%). Whilst the averaged single and double mesh configuration profiles were similar to the apparatus I profile (f(2)=57.36 and 61.38, respectively), large variability (S.D.</=11%) occurred with the single mesh configuration due to floating and random adhesion of tablets to the paddle or sampling tubes. Almost superimposable profiles were obtained for the individual tablets (S.D.<3%) when the tablets were located in the compartment formed by the double mesh device. Use of a double mesh device may therefore provide an alternative to current compendial dissolution methods when the reliable determination of the true release kinetics of floating and sticking delivery systems is desired.