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Biomedical subjects

R Fassihi

Publications and source records attributed to R Fassihi.

At least 19 recordsLinked to original sources
PubMed2000

In situ electrolyte interactions in a disk-compressed configuration system for up-curving and constant drug delivery.

A new approach in drug delivery system design for meeting the needs that are associated with certain circadian variations is presented. The system is comprised of a pure compressed drug disk, which is encased by a polymeric coat using hydroxypropylmethylcellulose or polyethylene oxide. Within the polymeric coat, a physiologically acceptable binary electrolyte combination such as sodium deoxycholate and adipic acid is disposed. Through this process and upon exposure to dissolution media, ionic interactions occur and a texturally variable matrix is manifested in the form of peripheral stiffening' with self-correcting boundaries as demonstrated by texture analysis studies. The peripheral boundaries erode and progressively shift toward the disk-core, thus constantly reducing the diffusional pathlength with the resultant up-curving kinetics. Utilizing these mechanisms, a lag time is induced and drug is delivered over a 24-h period in one of two ways namely, in an up-curving or constant manner for drug models theophylline and diltiazem hydrochloride with water solubilities of 0.85% and > 50% at 25 degrees C, respectively. It appears that for both sparingly and highly soluble drugs, sum of the dissolution/diffusion rates, dynamics of diffusional pathlength and system erosion rate control the release process. The heterogeneous nature of changes in coat thickness, stiffening dynamics and erosion rate in relation to disk geometry is discussed. The developed technology has potential to provide release patterns, compatible with specific chronophysiological conditions, and overcome the absorption-limited capacity of the distal gastrointestinal tract

Diltiazem↗
PubMed2000

A novel approach for constant rate delivery of highly soluble bioactives from a simple monolithic system.

A novel monolithic drug delivery system for highly water-soluble bioactive agents to follow pH-independent zero-order kinetics is described. The system utilizes a hydrophilic gel-based swellable polymeric material (polyethylene oxide), a model drug (metoprolol tartrate, 100% water soluble at 25 degrees C) and different electrolytes, such as sodium carbonate and/or pentasodium tripolyphosphate. Based on the induction of in situ intra-gel chemical reactions between different ionic species, drug and polymer, a heterogeneous structure manifested as 'peripheral boundary stiffening,' is accomplished. The consequence of these interactions essentially include the development of gradient-controlled matrix swelling as elucidated through textural profiling, which may contribute to inhibition of drug solubility and its outward diffusion. Analysis of textural profiles and photomicroscopy distinctly provides information on the disposition of peripheral boundary densification for the electrolyte-containing matrices. Electrolytic conductivity measurements performed with the simultaneous analysis of matrix swelling showed that sodium carbonate forms a highly reactive matrix within the first 3 h of medium penetration. On the other hand, larger molecules such as pentasodium tripolyphosphate maintain a constant conductivity level, which may be related to its lower solubility and diffusion in comparison to sodium carbonate. Based on model fitting and statistical analysis, it is shown that drug release kinetics were adequately described by M(t)/M(infinity)=k(0)t, with zero-order release rate constant k(0) of 0.054 h(-1). This novel approach in formulation development could potentially be used for constant rate delivery of highly soluble bioactive agents over an extended period for specific biopharmaceutical needs.

Calcium Carbonate↗
PubMed2000

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.

Adhesiveness↗
PubMed1999

In vitro release modulation from crosslinked pellets for site-specific drug delivery to the gastrointestinal tract. I. Comparison of pH-responsive drug release and associated kinetics.

Multiple unit dosage forms for oral delivery of bioactive agents offer many advantages over single unit products (e.g., site-specific delivery, predictable gastrointestinal transit time and less localized adverse effects). In view of such benefits, this paper investigates the crosslinking of sodium alginate, low methoxylated pectin and their novel binary mixture with calcium ions through ionotropic gelation to pelletize the model drug, diclofenac sodium, using "environmentally benign" solvents and processing techniques. Crosslinked pellets of the above polymers in 2% (w/v) aqueous calcium chloride solution were prepared and evaluated for their structural and release behavior. The average size of the different pellets was 1.3 mm and drug entrapment capacity was optimized by reducing the calcium chloride solution pH to 1.6. Three types of pellet formulations were subjected to dissolution studies using the USP 23 Apparatus 2 and 3 over a pH range simulating the human gastrointestinal tract. Negligible drug release occurred in pH 1-4. However, rate of drug release in pH 6.6 ranged from rapid to slow (i. e., 100% drug release in 4 to 10 h, respectively) but always in a controlled manner. Weight change/erosion studies and swelling measurements were used to provide experimental correlation of kinetic model analysis for each of the three pellet systems. From model fitting studies and statistical treatment, the modified Hopfenberg equation {Mt/M infinity =1-[1-k1(t-tL,min)]n} best described the release kinetics for calcium-pectinate pellets. The model assumes heterogeneous erosion with kinetic constant k1=k0/C0r0, in which k0 is the erosion rate constant, C0 is the uniform initial concentration of drug in the matrix, r0 is the initial radius and tL, min is the lag time. The n values of 1, 2 and 3 apply to a slab, cylinder and sphere, respectively. In addition, the exponential models, namely the Power Law (Mt/M infinity =k1tn) and its derivative containing the lag time [Mt/M infinity =k1(t-tL,min)n], employed in the statistical treatment of data provided n values of approximately 0.8-1 in the case of the calcium-alginate and calcium-alginate-pectinate release kinetics. It is concluded that the proper selection of rate-controlling polymers and their interactive potential for crosslinking is important, and will determine the overall size and shape of pellets, the duration and pattern of dissolution profiles, pH sensitivity, drug loading capacity and mechanism of drug release.

Administration, Oral↗
PubMed1999

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.

Administration, Oral↗
PubMed1999

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.

Algorithms↗
PubMed1999

Electrolyte-induced compositional heterogeneity: a novel approach for rate-controlled oral drug delivery.

In this work a new approach for in situ interactions between drug and electrolyte(s) is devised to control the release of highly water soluble drugs from oral hydrophilic monolithic systems. The model drug diltiazem hydrochloride (water solubility in excess of 50% at 25 degrees C), in conjunction with specific electrolytes, was principally employed in the design of swellable tablet formulations comprised of hydrophilic polymers such as hydroxypropylmethlcellulose (HPMC) or poly(ethylene oxide) (PEO). Electrolytes such as sodium bicarbonate or pentasodium tripolyphosphate were used to modulate intragel pH dynamics, swelling kinetics, and gel properties. Through in situ ionic interactions (an intragel matrix system composed of different chemical species that promote competition for water of hydration), a compositionally heterogeneous structure referred to as a "metamorphic scaffold" was established. It is shown that this latter structure results in the inhibition of drug dissolution, induction of a differential swelling rate, and attainment of "matrix stiffening" and axially provides a uniform gel layer. Presence of such phases in matrix structure and its influence on swelling dynamics enabled control of diltiazem hydrochloride release in a zero-order manner in different pH environments over a 24-h period. From kinetic analysis using the power law expressions [M(t)/M(infinity) = k(1)t(n), M(t)/M(infinity) = k(1)t(n) + k(2)t(2)(n)] and Hopfenberg model [M(t)/M(infinity) = 1 - (1 - k(1)t)(n)], it became apparent that the dynamics of matrix relaxation and controlled erosion were major factors involved in the release mechanism, while the composite rate constant k(1) (in Hopfenberg model) decreased by approximately 2-fold in the presence of electrolyte(s). These findings indicated that the dynamics of swelling and gel formation in the presence of ionizable species within hydrophilic matrices provide an attractive alternative for zero-order drug delivery from a simple monolithic system.

Administration, Oral↗
PubMed1999

An investigation into the erosion behaviour of a high drug-load (85%) particulate system designed for an extended-release matrix tablet. Analysis of erosion kinetics in conjunction with variations in lubrication, porosity and compaction rate.

The effects of the amounts of lubricants (magnesium stearate 0-5% and talc 0-3%) and changes in compaction rate and tablet porosity on the mechanism of drug release from high drug-load controlled-release theophylline tablets have been examined. Drug release was satisfactorily described by a surface-erosion model that takes into account the geometry of the tablet, differential radial and axial erosion rates, and the initial burst effect (r2 > 0.99 for all formulations). The axial and radial erosion rate constants were inversely proportional to the amount of magnesium stearate in the formulation (P < 0.0001). The most dramatic reductions in erosion rate occurred between 0 and 1% magnesium stearate content. For magnesium stearate concentrations > or =2.5% the ratio of radial to axial erosion rate constants was essentially constant at 3 (approx.); however, for formulations with magnesium stearate < or =1% the ratio tended toward unity. Reducing matrix porosity over the range 26 to 14% resulted in reduced erosion rates. However, a threshold of 17% (approx.) porosity was identified below which further reductions in porosity resulted in only incremental changes in release rates. The rate of erosion and drug release was insensitive to changes in machine speed over the range 20 to 100 rev min(-1). For highly loaded matrix tablets containing sparingly soluble drugs, such as theophylline, magnesium stearate at appropriate levels can modulate the erosion rate constants and act as an effective release-controlling excipient. Drug-release profiles are predictable and relatively robust in terms of changes in compaction rate and applied force routinely encountered in large-scale tablet manufacturing.

Chemistry, Pharmaceutical↗
PubMed1998

Evaluation and comparison of dissolution data derived from different modified release dosage forms: an alternative method.

Dissolution testing is an essential requirement for the development, establishment of in vitro dissolution and in vivo performance (IVIVR), registration and quality control of solid oral dosage forms. The objective of the present study was to investigate the effect of delivery system positioning in accordance with the USP 23-recommended dissolution methods and the proposed modification on drug release from controlled release systems having different operating release mechanisms, namely, swellable floatable, swellable sticking and osmotic pump. The delivery systems were evaluated by placing each dosage form either in the dissolution vessel in accordance with the USP 23 methods or over/below a designed ring/mesh device for achieving full surface exposure to the dissolution medium for sticking or floatable systems respectively. Results indicate that the overall release profiles from the sticking and floatable systems of theophylline are sensitive to their positioning in the dissolution vessel (P<0.05). Furthermore, release of diltiazem hydrochloride from the sticking system also demonstrated sensitivity (P<0.05). In contrast, the floatable dosage form of this latter drug with the application of a helical wire sinker, or when it was placed below the ring/mesh assembly, or by allowing the dosage form to float, did not show sensitivity (P>0.05) for the overall release behavior. This was attributed to the greater solubility of diltiazem hydrochloride (50% solubility in water at 25 degreesC) in comparison to theophylline which is a sparingly soluble drug (0.85% solubility in water at 25 degreesC). Drug release from the osmotic pump appeared to be identical under the given experimental conditions (P>0.05). Statistical analysis of data was performed by comparing the t50%, t70%, t90%; mean dissolution times (MDT50%, MDT70%, MDT90%); the "difference factor, f1" and "similarity factor, f2". It is concluded that the results derived from the application of the "similarity factor, f2" are superior to the individual time points (e.g. tx%) and MDTx% values in differentiating between overall release patterns or the border line release profile differences. It also became apparent that in the case of the swellable sticking systems full surface exposure to the dissolution medium results in greater release rate. For the osmotic pump the required osmotic pressure threshold necessary for constant rate drug delivery appears to have reached independent of the hydrodynamic conditions. A successful and more accurate evaluation of dissolution data can be derived when full surface exposure is considered and this can be accomplished by dissolution method modification with the aid of the designed ring/mesh assembly.

Algorithms↗
PubMed1997

Application of a binary polymer system in drug release rate modulation. 1. Characterization of release mechanism.

A new binary polymer matrix tablet for oral administration was developed. The system will deliver drug at variable rates according to zero-order kinetics for total drug content and is manufactured by direct compression technology. Highly methoxylated pectin and hydroxypropyl methylcellulose (HPMC) at different ratios were used as major formulation components, and prednisolone was used as the drug model. The results indicate that by increasing pectin:HPMC ratios, release rates are increased, but zero-order kinetics prevail throughout the dissolution period (e.g., 3-22 h). Different pectin:HPMC ratios provide a range of viscosities that modulates drug release and results in rapid hydration/gelation in both axial and radial directions, as evidenced by photomicrographic pictures. This hydration-gelation contributes to the development of swelling/erosion boundaries and consequently to constant drug release. Combination of these particular polymers facilitates rapid formation of necessary boundaries (i.e., gel layer and solid core boundaries) to control overall mass transfer processes. The drug fraction released (Mt/M infinity), release kinetics, and mechanism of release were analyzed by applying the simple power law expression Mt/M infinity = kt(n), where k is a kinetic constant and the exponent n is indicative of the release mechanism. The calculated n values for pectin:HPMC ratios of 4:5, 3:6, and 2:7 were >0.95, which is indicative of a Case II transport mechanism (polymer relaxation/dissolution). The achievement of total zero-order kinetics is due to the predictable swelling/erosion and final polymer chain deaggregation and dissolution that is regulated by the gelling characteristics of polymers in the formulation.

Delayed-Action Preparations↗
PubMed1997

Application of binary polymer system in drug release rate modulation. 2. Influence of formulation variables and hydrodynamic conditions on release kinetics.

The significance of factors such as drug solubility, polymer molecular weight, drug loading dose, compression force, and hydrodynamic conditions on drug release from a swellable hydrophilic delivery system was investigated. Hydroxypropyl methylcellulose (HPMC) and pectin were major polymeric constituents of the delivery system. Nifedipine, prednisolone, theophylline anhydrous, and diltiazem hydrochloride with solubilities of < 0.001%, <0.1%, <1%, and >50%, respectively, were used as drug models. Results show that changes in pectin:HPMC ratios, HPMC molecular weight, and hydrodynamic conditions exert notable influences on release rate and release duration from the designed system. In the case of prednisolone, drug loading up to 30% (w/w) of the matrix composition (pectin:HPMC K4M; 3:6) had no effect on zero-order release kinetics, and the delivery system was insensitive to changes in compression force (2000 to 5000 lb). For nifedipine, theophylline, and diltiazem, determination of mean dissolution time (MDT) for 50 and 80% drug release provided accurate information on release behavior. The dominating effect of matrix composition over variations in drug solubilities in controlling drug release from the delivery system was evident from similarities in dissolution profiles. It is further shown that hydrodynamic stress and intensity of fluid flow causes greater attrition at the swollen periphery and is responsible for dramatic increases in release rates. This latter observation confirms that the mechanism of drug release from this swellable system is erosion dependent. Influence of polymer molecular weight and drug solubility on release kinetics and the potential of the delivery system is discussed.

Delayed-Action Preparations↗
PubMed1997

Mechanistic evaluation of binary effects of magnesium stearate and talc as dissolution retardants at 85% drug loading in an experimental extended-release formulation.

The feasibility of producing extended-release matrix tablets with high drug loadings (80-90% w/w) containing a binary combination of magnesium stearate (MS) and talc (T) at different levels as major dissolution retardants was investigated. Matrix tablets were prepared from a granulation containing theophylline, starch, hydroxypropylcellulose, and varying amounts of MS and T. Using a 32 factorial design, the effect of MS and T levels on the physical properties and drug release characteristics of the tablets was evaluated. Response surface analysis showed that the binary combination of MS and T at levels >3% adversely affected both tensile strength and friability. A parabolic relationship was observed for the increase in time required for the release of 50% of the theophylline (t50%) with increased MS levels. Moreover, as the proportion of MS and T was increased, the release profiles became more linear. A combination of 3% MS and T provided both near zero-order release kinetics as well as a coherent matrix structure. Based on model fitting, a release mechanism combining diffusion and matrix erosion/dissolution is proposed. It may be concluded that in the development of controlled-release systems, the binary combination of MS and T at levels exceeding those conventionally used for lubrication can be employed as an inexpensive, low bulk dissolution retardant for formulations with high drug loading.

Chemical Phenomena↗
PubMed1997

A new ternary polymeric matrix system for controlled drug delivery of highly soluble drugs: I. Diltiazem hydrochloride.

PURPOSE: 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 HCl 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 HCl 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.

Delayed-Action Preparations↗
PubMed1996

Zero-order release kinetics from a self-correcting floatable asymmetric configuration drug delivery system.

A new approach based on the three-layer matrix technology to control drug release for oral administration is presented. Polyethylene oxide polymers of various molecular weight together with theophylline as drug model and other excipients have been directly compressed into a three-layer asymmetric floatable system. The core layer contains the active drug while external layers with different thickness, composition, and erosion rates are designed to delay the hydration of the middle layer, restrict the early drug diffusion only through cylindrical side surfaces of the tablet, and provide controlled drug release. Results show that during a 16 h dissolution study drug is completely released following the zero-order kinetics with no burst effect. The release rate remains around 0.1 mg min-1 throughout the dissolution study. The release kinetics is independent of changes in pH and compression force but dependent on layer thickness and formulation components. It appears that the operating release mechanism is based on the existence of a balance between the velocities of advancing glassy/rubbery front and erosion at the swollen polymer/dissolution front.

Administration, Oral↗
PubMed1996

Characterization of compressibility and compactibility of poly(ethylene oxide) polymers for modified release application by compaction simulator.

Poly(ethylene oxide) polymers (PEO) appear to have great potential for controlled release applications. These polymers are hydrophilic with good water solubility, low toxicity, and high swelling capacity. As part of formulation optimization for a large-scale solid dosage form production, physicomechanical characterization of PEO was undertaken using a compaction simulator. Heckel plots for all PEOs were constructed, and yield pressures (Py) at different punch velocities were calculated from the linear portion of the plots. Low Py values, increase of Py with increasing punch speed, upward curvature of the plot, and strain rate sensitivity values indicate that the densification process and consolidation mechanism for PEOs of various molecular weights (0.2 x 10(6) to 7 x 10(6)) are identical and follow plastic deformation. PEOs have a high degree of crystallinity (57-85%) and show significant axial recovery (15-25%) upon decompression and ejection. The low Py values (58-78 MPa) and low mean compaction pressures demonstrate that volume reduction (compressibility) under pressure is excellent. However, due to viscoelastic behavior and large axial expansion, tablets of relatively low tensile strength are produced. These observations suggest the need to blend PEO with highly compactible excipients in order to produce tables on a high-speed production press.

Molecular Weight↗