Swelling studies of gelatin. I: Gelatin without additives

The swelling rate and the equilibrium swelling of gelatin (type B) were studied by casting warm gelatin solutions into films, cutting them into short rectangular strips after gelation, drying them, and measuring the weight gain on immersion in buffer solutions as a function of time. The process variables investigated included concentration of the gelatin casting solutions, the thickness, drying conditions, age and residual moisture content of the film strips, the chemical nature and concentration of the buffers in the swelling solutions, and the temperature of these solutions at a constant pH of 7.0 (1.9 pH units above the isoionic point). The swelling kinetics followed a second-order equation. The initial swelling rate and the equilibrium swelling of the amorphous portion of the gelatin strips (which was somewhat smaller than the total observed swelling) were calculated from a linearized form of the rate equation. Of the factors investigated, the equilibrium swelling was increased most strongly when the temperature of the swelling solution was raised from 20 to 25 degrees C. Strip thickness was the predominant factor governing the rate of swelling, which was inversely proportional to the thickness. Conditions leading to slower drying and longer storage times promoted more extensive crystallization, thereby increasing the density of the gelatin strips and reducing their swelling rate.     

Swelling studies of gelatin. II: Effect of additives

Interactions between gelatin and six cationic, anionic, and nonionic drugs or excipients were investigated through their effects on initial swelling rate and equilibrium swelling of gelatin. Short rectangular strips of Type B gelatin containing the additives were immersed in buffer solutions of pH 7.0 at 20 degrees C. Their weight gain due to uptake of buffer solution and their weight loss due to leaching of the additive and of gelatin were determined as a function of time. During preparation of the strips, methyprylon and dicloxacillin sodium crystallized, while octoxynol 9 separated as small droplets in the gelatin matrix. Up to 7% of gelatin leached into the buffer solution during 96 h of immersion from strips of plain gelatin and strips containing five additives. The sixth additive, cetylpyridinium chloride, tripled the amount of gelatin leached while most of this additive remained in the gelatin strip. The other five additives were largely or completely extracted by the buffer solution. Potassium chloride underwent the fastest leaching, being completely dissolved within the first half hour. Octoxynol 9 was extracted most slowly because the swelling solution formed a viscous liquid crystalline phase inside the gelatin. Swelling followed second-order kinetics. Initial swelling rates and equilibrium swelling were calculated with a linearized function. Cetylpyridinium chloride, dodecylammonium chloride, and methyprylon reduced the initial swelling rate of gelatin while dicloxacillin sodium increased it. Octoxynol 9 and potassium chloride left it unchanged. Cetylpyridinium chloride and dodecylammonium chloride reduced the equilibrium swelling of gelatin substantially. Dicloxacillin sodium and octoxynol 9 increased it substantially, while potassium chloride and methyprylon increased it slightly. The extensive interaction of the cetylpyridinium ion with gelatin may result in reduced bioavailability.     

Temperature Dependence of Non-Fickian Water Transport and Swelling in Glassy Gelatin Matrices

The effect of temperature on the swelling kinetics of glassy gelatin matrices exposed to water was studied. The movement of two distinct and characteristic swelling boundaries was measured directly using an optical microscope. Swelling rate constants associated with these moving boundaries demonstrated Arrhenius behavior over the temperature range of 15 to 40°C. The apparent activation energy for non-Fickian water transport into the gelatin glassy core was determined to be 8.1 kcal/mol, and 3.5 kcal/mol was found for the outer expansion of the swelling gelatin network due to water sorption. These findings are compared with activation energies for other solvent–glassy polymer systems, and possible reasons for the unexpectedly low value for non-Fickian water transport in the glassy gelatin solid are considered.     

Rheological characterization of microcrystalline cellulose and silicified microcrystalline cellulose wet masses using a mixer torque rheometer.

The rheological properties of silicified microcrystalline cellulose (Prosolv 50) were compared with those of standard grades of microcrystalline cellulose (Emcocel 50 and Avicel PH 101). Cellulose samples were analyzed using nitrogen adsorption together with particle size, flowability, density and swelling volume studies. The rheological behaviour of the wet powder masses was studied as a function of mixing time using a mixer torque rheometer (MTR). Silicified microcrystalline cellulose exhibited improved flow characteristics and increased specific surface area compared to standard microcrystalline cellulose grades. Although the silicification process affected the swelling properties and, furthermore, the mixing kinetics of microcrystalline cellulose, the source of the microcrystalline cellulose had a stronger influence than silicification on the liquid requirement at peak torque.     

Modification of Gelatin Beadlets for Zero-Order Sustained Release

A three-phase suspension process was used for the preparation of gelatin beadlets containing succinylsulfathiazole. When the beadlets were hardened with 10% formalin at 5°C for varying periods of time up to 24 hr, the 6-hr hardening time gave the slowest release rate. Drug release rate from gelatin beadlets was slower in simulated gastric fluid (SGF) than in simulated intestinal fluid (SIF) but the sustained effect was too limited to be useful for most applications. When the hardened gelatin beadlets were coated with cellulose acetate butyrate (CAB) by an emulsion–solvent evaporation method, a more pronounced sustained effect and a nearly zero-order release were found in SIF. The effects of the amount of gelatin used, the amount of CAB employed, and the length of hardening time on drug release were investigated. The treatment of gelatin beadlets with formalin reduced the swelling action of gelatin in aqueous medium. A nonzero-order drug release rate was observed when the gelatin swelled sufficiently to rupture the CAB coating. The drug release rate can be adjusted by using different ratios of hardened gelatin beadlets and CAB coating in which the gelatin enhances the release rate and the CAB serves as a barrier.     

Formulation parameters affecting the performance of coated gelatin capsules with pulsatile release profiles

The objective of this study was to develop and evaluate a rupturable pulsatile drug delivery system based on soft gelatin capsules with or without a swelling layer and an external water-insoluble but -permeable polymer coating, which released the drug after a lag time (rupturing of the external polymer coating). The swelling of the gelatin capsule itself was insufficient to rupture the external polymer coating, an additional swelling layer was applied between the capsule and the polymer coating. Croscarmellose sodium (Ac-Di-Sol) was more effective as a swelling agent than low and high molecular weight hydroxypropylmethyl cellulose (HPMC; E5 or K100M). Brittle polymers, such as ethyl cellulose (EC) and cellulose acetate propionate (CAPr), led to a better rupturing and therefore more complete drug release than the flexible polymer coating, Eudragit RS. The lag time of the release system increased with higher polymer coating levels and decreased with the addition of a hydrophilic pore-former, HPMC E5 and also with an increasing amount of the intermediate swelling layer. The water uptake of the capsules was linear until rupture and was higher with CAPr than with EC. Soft gelatin capsule-based systems showed shorter lag times compared to hard gelatin capsules because of the higher hardness/filling state of the soft gelatin capsules. The swelling pressure was therefore more directed to the external polymer coating with the soft gelatin capsules. Typical pulsatile drug release profiles were obtained at lower polymer coating levels, while the release was slower and incomplete at the higher coating levels. CAPr-coated capsules resulted in a more complete release than EC-coated capsules.     

Effect of water-soluble carriers on morphine sulfate release from a silicone polymer.

The influence of gelatin, sodium lauryl sulfate, lactose, and sodium alginate on morphine sulfate diffusion from cylindrical silicone polymer pellets was examined in isotonic pH 7.4 phosphate buffer. These water-soluble carriers caused the pellets to swell in aqueous media. Sodium alginate exerted the greatest influence on drug release. The morphine sulfate diffusion rate from the cylindrical pellets increased as the matrix alginate content increased up to 20%. Water-soluble carrier incorporation into silicone polymeric matrixes permits controlled release of water-soluble drugs that otherwise would be released extremely slowly from the polymer. Drug diffusion from the silicone matrix containing sodium alginate followed second-order kinetics. The release mechanism probably involves the creation of pores or pathways through the matrix secondary to the swelling.     

A comparative study of controlled release matrix tablets of diclofenac sodium, ciprofloxacin hydrochloride, and theophylline

The need for controlled release formulations for diclofenac sodium, ciprofloxacin, and theophylline is well recognized. In our study, controlled release tablets of the three drugs were formulated by the matrix-embedding technique using ethyl cellulose as retardant. Tablets of all the drugs were of good physical quality with respect to appearance, drug content uniformity, hardness, weight variation, and friability. In vitro release rate studies showed that ethyl cellulose extended the release of the three drugs to 12 hr or more. Release patterns from formulations of the three drugs followed Higuchi's square root kinetics. At pH 6.8, the release rate was higher in all three drugs, probably due to increased solubility of the drugs and/or increased swelling of ethyl cellulose at the higher pH. The formulations were highly stable and possessed reproducible release kinetics across batches.     

A Comparative Study of Controlled Release Matrix Tablets of Diclofenac Sodium,Ciprofloxacin Hydrochloride,and Theophylline

The need for controlled release formulations for diclofenac sodium, ciprofloxacin, and theophylline is well recognized. In our study, controlled release tablets of the three drugs were formulated by the matrix-embedding technique using ethyl cellulose as retardant. Tablets of all the drugs were of good physical quality with respect to appearance, drug content uniformity, hardness, weight variation, and friability. In vitro release rate studies showed that ethyl cellulose extended the release of the three drugs to 12 hr or more. Release patterns from formulations of the three drugs followed Higuchi's square root kinetics. At pH 6.8, the release rate was higher in all three drugs, probably due to increased solubility of the drugs and/or increased swelling of ethyl cellulose at the higher pH. The formulations were highly stable and possessed reproducible release kinetics across batches.     

The concentration of the cross-linking agent as a tool for the control of release and swelling properties of gelatin microspheres.

The effect of the concentration of a cross-linking agent (gelatin hardener) on gelatin microspheres was evaluated. A concentration increase of the gelatin hardener (formaldehyde) produced a decrease of drug loading, swelling degree and drug release rate. The cross-linking agent concentration affected also the kinetics of water absorption and drug release. This paper suggests a decreasing significance of the diffusion-type mechanism of drug release as the concentration of the cross-linking agent increased.     

软胶囊崩解迟缓现象机理的初步研究

分别测定甲醛处理后明胶胶片的平衡溶胀量、蛋白质溶出量和氨基酸残基含量,考察常用附加剂对明胶中氨基酸残基含量的影响.结果表明,平衡溶胀量、溶出量和氨基酸残基含量之间呈良好线性关系.软胶囊的崩解迟缓与明胶中氨基酸残基的含量有关,加入丙二醇和山梨醇可使明胶中氨基酸残基含量显著下降,加入甘氨酸和焦亚硫酸钠则含量降低的幅度较小.     

糖类交联明胶微球的制备及其释药特性研究

目的:以生物相容性的糖作交联剂制备明胶药物载体并研究其释药特性。方法:用葡萄糖、葡聚糖、氧化葡萄糖、氧化葡聚糖作交联剂制备明胶盘和微球,测定其溶胀动力学,分别以阿司匹林和牛血清白蛋白为药物模型,紫外分光光度法测定药物包裹率、载药率,并检测明胶微球在模拟体内条件下药物的释放速率。结果:葡萄糖、氧化葡萄糖、葡聚糖、氧化葡聚糖作交联剂制备的凝胶溶胀率分别为204%、246%、166%、233%;4种阿司匹林和牛血清白蛋白明胶微球平均载药率分别为8.73%和4.05%,平均包封率分别为62.55%和31.40%;2h药物释放百分率依次为30%、14%、76%、73%和97.2%、86.6%、60.8%、50.1%。结论:上述4种糖均可以取代化学交联剂制备明胶微球;天然糖交联微球缓释效果优于氧化糖。     

Asymmetric membrane capsules of phenylephrine hydrochloride: an osmotically controlled drug delivery system

The aim of the current study was to develop osmotically controlled release system of freely water soluble drug phenylephrine hydrochloride by use of asymmetric membrane capsules to reduce the dosing frequency and consequently improve the patient compliance. Ethyl cellulose asymmetric membrane capsules were developed by phase inversion process and solubility modulation was accomplished by common ion effect wherein sodium chloride was included in the formulation that also served as an osmogen. The effect of formulation variables namely level of polymer (ethyl cellulose), level of pore former (glycerol) and level of osmogen (sodium chloride) on the in vitro release of the drug was evaluated by 2(3) factorial design. Effects of environmental factors on the release rate of the drug from asymmetric membrane capsules were also evaluated. Membrane characterization by scanning electron microscopy showed an outer dense region with less pores and inner porous region for the prepared asymmetric membrane. The dimensional analysis of asymmetric membrane capsule documented the capsules to be of uniform cap and body size comparable to commercial hard gelatin capsules. In vitro release studies results showed that incorporation of higher amount of osmogen not only increased the osmotic pressure but also controlled the drug release for a period of 12 hr. The drug release was inversely proportional to the level of polymer in asymmetric membrane capsule but directly related to the level of pore former in the membrane. The optimized asymmetric membrane capsule (F5) was able to provide zero order release of phenylephrine hydrochloride independent of agitation rate, intentional defect in the membrane and pH of dissolution medium but was dependent on the osmotic pressure gradient between inside and outside of the delivery system.     

Medical properties of the membrane dressing made of bacterial cellulose

Review of papers devoted to medical properties of membrane dressing made of bacterial cellulose was done. These properties were determined on the basis of studies on application of this membrane to venous leg ulcer healing. Moreover, quantitative method of valuation of wound healing process efficiency which lies in calculating efficiency coefficient was described. Value of this coefficient is directly proportional to ulcer healing speed and indirectly proportional to product of initial surface and healing time.     

Pharmacokinetic model of target-mediated disposition of thrombopoietin

Thrombopoietin, TPO, a 353 amino acid cytokine, is a primary regulator of platelet production that was cloned recently. A target-mediated (platelet receptors) pharmacokinetic model was developed to characterize the disposition of TPO. Receptor-mediated endocytosis was assigned as the major elimination pathway in the model. A nonspecific binding compartment was also incorporated into the model. TPO concentration vs time profiles from a published phase 1 and 2 clinical trial were used to apply this model. Noncompartmental analysis demonstrated that TPO exhibits nonlinear kinetics. The proposed model captured the concentration-time profiles relatively well. The first-order internalization rate constant was estimated as 0.1 h(-1). The endogenous binding capacity was estimated as 164.0 pM. The second-order binding association constant (kon) was 0.055 h(-1).pM(-1) and the first-order dissociation constant (koff) was estimated as 2.5 h(-1), rendering the equilibrium dissociation constant Kd as 45.5 pM. This model may be relevant to other therapeutic agents with receptor-mediated endocytotic disposition.     

Hydrophobic Anionic Gel Beads for Swelling-Controlled Drug Delivery

Using oxprenolol HC1 as a model drug, the effects of pH and buffer concentration on the swelling and drug release properties in cross-linked poly(methyl methacrylate-co-methacrylic acid) (PMMA/ MAA) beads have been investigated. The kinetics of swelling of such hydrophobic anionic gel beads from the dehydrated state appear to be governed primarily by a diffusion– ionization process which becomes more ionization-controlled at higher buffer concentrations. Within the range of ionic compositions studied, the swelling rate increases and the initial swelling/ionization front penetration becomes increasingly linear in time with increasing pH or buffer concentration of the swelling medium. The corresponding swelling bead diameter appears to reach an equilibrium value as soon as the penetrating ionization fronts meet at the center, suggesting a swelling equilibrium in the ionized shell due to rapid mechanical readjustment in the gel phase. At oxprenolol loading levels up to 15%, both the transient drug release and swelling bead diameter exhibit extended quasi-linear regions despite the inherent limitation of decreasing surface area at the penetrating front in the spherical geometry. In addition, both the drug release and the dimensional changes reach completion when the penetrating ionization fronts meet at the center, suggesting a true swelling-controlled drug release behavior.     

Linear drug release from laminated hydroxypropyl cellulose-polyvinyl acetate films.

Release of drug from a single-layer film containing dispersed drug follows a diffusion-controlled matrix model, where the quantity released per unit area is proportional to the square root of time. The kinetics may be made linear with time (zero order) by laminating a second film without drug to the releasing side of the film with dispersed drug. In this manner, the drug layer serves as a reservoir and controls the duration of drug release, while the nondrug layer functions as a rate-controlling membrane. Zero-order drug release was demonstrated in such laminated films using 18-45 percent pentobarbital, methapyrilene, or salicylic acid contained in hydroxypropyl cellulose as the reservoir layer and mixtures of hydroxypropyl cellulose and polyvinyl acetate as the membrane layer. Inverse relationships between the release rate and membrane thickness and between the logarithm of the rate and the percentage of polyvinyl acetate in the membrane layer were observed. Of the three drugs tested, salicylic acid gave the fastest release rates while pentobarbital gave the slowest.     

Probing the Mechanisms of Drug Release from Hydroxypropylmethyl Cellulose Matrices

The transient dynamic swelling and dissolution behavior during drug release from hydroxypropylmethyl cellulose (HPMC) matrices was investigated using fluorescein as a model drug. A new flow-through cell capable of providing a well-defined hydrodynamic condition and a non-destructive mode of operation was designed for this purpose to assess the associated moving front kinetics. The results obtained show a continuous increase in transient gel layer thickness irrespective of the polymer viscosity grade or drug loading. This is attributed to the faster rate of swelling solvent penetration than that of polymer dissolution under the present experimental condition. On the other hand, the observed shrinkage of sample diameter over a longer time period demonstrates that polymer dissolution does indeed occur in HPMC matrices. Further, both the rates of polymer swelling and dissolution as well as the corresponding rate of drug release increase with either higher levels of drug loading or lower viscosity grades of HPMC. For water-soluble drugs, the present results suggest that the effect of HPMC dissolution on drug release is insignificant and the release kinetics are mostly regulated by a swelling-controlled diffusional process, particularly for higher viscosity grades of HPMC.     

Synthesis,Characterization and Evaluation of IPN Hydrogels for Antibiotic Release

We prepared new ternary interpenetrating polymeric networks (IPN) systems containing chitosan, poly(N-vinylpyrrolidone) and poly(acrylamide) polymers. IPNs were synthesized by radical polymerization of acrylamide monomers in presence of glutaraldehyde (G) and N,N′-methylenebisacrylamide as crosslinkers and the other polymers. These IPNs were named as C-P-A. Glutaraldehyde were used in different concentration to control the network porous of IPNs. Spectroscopic and thermal analyses of these cylindrical shaped IPNs were made with fourier transform infrared spectroscopy analysis, thermogravimetric analysis, and thermomechanical analysis. Swelling studies of IPNs were carried out at pH 1.1 and pH 7.4 at 37°C. The swelling and diffusion parameters of IPNs in these solutions were calculated. Amoxicillin as a bioactive species was entrapped to the IPNs during synthesis. In vitro release kinetics of IPNs were investigated. The experimental data of swelling and release studies suggest clearly that the swelling and release process obeys second-order kinetics. The release of the entrapped bioactive species from IPNs depends on the degree of crosslinking of the polymer and pH of the medium at body temperature. We observed that amoxicillin release at pH 1.1 was higher than at pH 7.4. As a result, IPNs-based chitosan with different cross-linker concentration could be promising candidates for formulation in oral gastrointestinal delivery systems.     

莫匹罗星温敏水凝胶的制备和性能研究

目的 制备具有温敏效应的莫匹罗星水凝胶,以达到控释作用。方法 将明胶用马来酸酐改性后得酰化明胶,与热敏材料N-异丙基丙烯酰胺在引发剂和促引发剂的作用下通过自由基聚合的方式制备5种不同配比的水凝胶,然后用干态浸泡法制备1,0.5 mg·mL^-1莫匹罗星溶液浸泡的莫匹罗星温敏水凝胶,并进行表面结构、温敏性、溶胀率、力学性能、载药率、控释率及抑菌性能的研究。结果 本研究制备的莫匹罗星水凝胶具有温敏性,其中酰化明胶与N-异丙基丙烯酰胺比例为1∶1时,表面孔洞结构最致密均匀,25℃时的溶胀率最高,制备的莫匹罗星温敏水凝胶的载药率和释放率以及抑菌率都最高,力学性能随酰化明胶增加而增强;1 mg·mL^-1莫匹罗星溶液制备的水凝胶的载药率和抑菌率高于0.5 mg·mL^-1溶液制备的,释药率则相反,而且水凝胶在2 h左右可达到释药平衡。结论 制备的莫匹罗星水凝胶可达到控释效果,对减少细菌耐药性具有长远的意义。当酰化明胶与N-异丙基丙烯酰胺比例为1∶1时,各个性能相对较好。