Protein release from gelatin matrices

Gelatin is a denatured, biodegradable protein obtained by acid and alkaline processing of collagen. This processing affects the electrical nature of collagen, yielding gelatin with different isoelectric points (IEPs). When mixed with positively or negatively charged gelatin, an oppositely charged protein will ionically interact to form a polyion complex. This review article describes protein release from charged gelatin matrices on the basis of this polyion complexation. The biodegradable hydrogel matrices are prepared by chemical crosslinking of acidic or basic gelatin and are enzymatically degraded in the body with time. The degradation is controllable by changing the extent of crosslinking, which, in turn, produces hydrogels with different water contents. The time course of protein release is in good accordance with the rate of hydrogel degradation. It is very likely that the protein drug complexed with gelatin hydrogel is released as a result of its biodegradation. This gelatin hydrogel system releases the protein drug under maintenance of biological activity. This article will focus on experimental data that sustained release of growth factor from the gelatin hydrogels is very effective in exerting the biological functions of the growth factor.     

Synthesis of a macromolecular camptothecin conjugate with dual phase drug release

A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t(1/2) = 2.2 +/- 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t(1/2) = 2.1 +/- 0.2 h, while the conjugate half-life was 14.2 +/- 1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.     

Examination of self-crosslinked gelatin as a hydrogel for controlled release.

A gelatin matrix crosslinked by extensive dehydration was examined for use in controlled drug delivery in this preliminary investigation. Crosslinking is necessary to prevent gelatin dissolution and immediate drug release at body temperature. Treatment at 105 degrees C and reduced pressure induced crosslinking in discs prepared from Type B gelatin. Crosslinking was evaluated by determining changes in gelatin solubility at 37 degrees C in a USP paddle dissolution apparatus. The crosslinking treatment was reproducible and resulted in 90% of the original gelatin mass remaining after 12 h in water and in phosphate buffer solutions of pH 3 and 6.4. The treated gelatin discs remained intact for greater than 24 h at pH 6.4. Chlorpromazine.HCl (CPZ) was incorporated as a model drug by soaking the treated gelatin discs in an aqueous solution of the drug. Release of CPZ at 37 degrees C in the dissolution apparatus was fitted to an empirical equation. A coefficient of this equation was used as the initial release rate for comparison between different release profiles. The roles of drug solubility, matrix swelling and erosion, and potential drug-matrix interactions were examined by conducting release studies at pH values of 3, 4, 6.4, and 7.4. The insoluble, un-ionized form of the drug had the slowest release rate. The soluble, ionized form under conditions of maximum swelling and a possible drug-matrix repulsive interaction had the fastest release rate. General electrostatic drug-matrix interactions were noted which could influence the drug release rate depending on conditions of the study. The times for 50% release of CPZ ranged from 1.8 to 11.3 h.     

Diffusional release of a solute from a spherical reservoir into a finite external volume

An exact solution has been obtained for the release kinetics of a solute from a spherical reservoir with the burst effect initial condition into a finite external volume. The exact solution is derived based on the time Laplace transform method. The results presented here indicate that as the external fluid volume increases, the cumulative release at any time and the releasable amount of the solute at infinite time increase. In addition, for a given external volume, as the polymeric coat thickness increases the fractional release at any time decreases. Experimentally, cumulative release profiles of theophylline microspheres coated with ethylene vinyl acetate copolymer into different external volumes agreed with the mathematical predictions.     

Mechanisms of solute release from porous hydrophilic polymers

Porous hydrophilic discs were prepared from two grades of poly(vinyl alcohol) of varying degree of hydrolysis. The influence of the molecular size of the tracer used (potassium chloride, phenylpropanolamine hydrochloride and bovine serum albumin), that of the addition of a second water-soluble polymer poly(N-vinyl-2-pyrrolidone) and poly(ethylene glycol)) and the effect of the tracer/excipient ratio on the release profile were examined. Finally the role of the dynamic swelling and the dissolution of the polymer matrix on the release mechanism are discussed.     

含有奥硝唑纳米囊泡的改性明胶膜释药性能的研究

目的:研制含有载药纳米囊泡的明胶缓释膜,对比普通载药膜表征其释药性能。方法:结合超声波法和逆向蒸发法,制备了载药纳米囊泡,并通过共混的方法进一步得到了含有奥硝唑纳米囊泡的改性明胶膜(简称载药纳米囊泡膜)。通过透射电镜观察分析了载药纳米囊泡的形态以及稳定性,通过紫外分光光度法分别测试了载药纳米囊泡的包封率、载药量以及载药纳米囊泡、载药膜和载药纳米囊泡膜的累积释药曲线。结果:载药纳米囊泡粒径在50～150nm之间,能长期稳定地存在于膜材料中,载药量和包封率分别为0．18mg·mg~(-1)和32．15%。普通载药膜在11h左右达到释药平衡,而载药纳米囊泡膜释药平衡时间达到了22h左右。结论:载药纳米囊泡膜同时具有载药膜和载药纳米囊泡的药物释放性能,明显改善了载药膜的药物缓释性和突释现象,扩展了载药膜和载药囊泡的应用范围。     

Drug release from non-disintegrating hydrophilic matrices: sodium salicylate as a model drug

Tablets containing different concentrations of sodium salicylate in a (hydroxyethyl)methylcellulose matrix swelled without disintegration or attrition. The release rate of the drug from the whole tablet was shown to conform with a model diffusional equation for two-sided release from a slab maintaining a constant surface-volume ratio on swelling, and the rate constant was linearly dependent on the drug dosage, as predicted by this equation, when the polymer concentration was kept constant. With varying polymer concentration, correction of the rate constants for their dependence on drug content of the matrix yielded constants dependent on the polymer concentration only. Such rate constants observed a semi-logarithmic relation to polymer content and extrapolated to give reasonable diffusion coefficient values for hypothetical low and high polymer content matrices. The temperature coefficient yielded a high value (9.15 kcal . mol^?1) for the activation energy of the diffusion process, consistent with the energy barrie in a polymer matrix. Such treatment of rate constants and component concentration variables offers a valuable method of correlating formulation and release parameters in non-disintegrating hydrophilic matrices.     

Stabilization of hard gelatin capsule shells filled with polyethylene glycol matrices

The purpose of this study was to evaluate the effects of various stabilizers on the dissolution stability of liquid-filled capsule dosage forms containing a potent drug dissolved in polyethylene glycols. A systematic dissolution slowdown was observed in gelatin capsule formulations without a stabilizer and was exaggerated under stress storage conditions. This slowdown is attributed to cross-linking of the gelatin shells. Addition of butylated hydroxyanisole (BHA) delayed the onset of gelatin cross-linking, and a combination of BHA with water added to this formulation effectively prevented product dissolution slowdown. For similar formulations filled into hypromellose capsule shells, no dissolution slowdown was observed, even in the absence of stabilizers.     

Consideration of drug load on the swelling kinetics of glassy gelatin matrices

The effect of drug load on water transport into glassy gelatin beads and on the dynamic swelling behavior of the hydrated gel was studied through microscopic measurements of moving boundaries. Isoniazid was found to alter the glassy structure of gelatin, resulting in an increase in water penetration rates with a lowering of the apparent activation energy for water front movement. Differential scanning calorimetry studies revealed a decrease in the glass transition temperature with drug load, further indicating plasticization of the gelatin glass. The presence of drug also accelerated the outer swelling gelatin front, but, in contrast to the water front, the apparent activation energy for matrix expansion rose substantially with higher drug loads for temperatures greater than 20 degrees C. This observation may be rationalized as an increasing osmotic stress on the matrix induced by greater loading with hydrophilic drug. The osmotic stress, in turn, forces the gelatin matrix to expand outward, resulting in a higher apparent activation energy (Eact). Furthermore, the enhanced expansion was especially pronounced at higher temperatures where physical bonds, which are associated with gel structure and needed to resist swelling, are presumably weaker and fewer in number.     

On the release of drug from hard gelatin capsules

The effect of particle size and packing on the in vitro release of a water-insoluble hydrophobic drug from hard gelatin capsules has been related to the liquid permeability of powder beds of similar porosities. Drug release and permeability decrease with a decrease in particle size and porosity of the powder bed. A simple moist granulation process transforms a non-permeable powder bed, which allows low drug release, into one with high permeability and high drug release.     

Controlled release of DSBP from genipin-crosslinked gelatin thin films

Controlled release of a marker drug, 4,4'-bis(2-sulfostyryl) biphenyl (DSBP) from genipin crosslinked gelatin thin films, with application to drug delivery by transdermal patches is studied in this paper. A simple method for fabrication of nano-thin films, using basic lab equipment is introduced. This method consists of two steps: dipping of the substrate in a deposition solution, followed by centrifugation of the substrate. Also, swelling and drug release from thin films is modeled, using the Fick's second law of diffusion. The effect of genipin concentration on release of DSBP molecules from thin films is investigated, experimentally and numerically. The results show that controlled release of DSBP from the genipin-crosslinked gelatin thin films is achieved, using various concentrations of genipin in gelatin.     

Modulation of buspirone HCl release from hypromellose matrices using chitosan succinate: Implications for pH-independent release

Chitosan succinate (CS) was synthesized through the acylation of chitosan with succinic anhydride. The interaction of CS with buspirone HCl (BUSP) was evaluated using dialysis experiments and shown to result in complex with a stability constant of 2.26 mM and a capacity of 0.0362 μmol BUSP/mg CS.The extent of complexation upon dry and wet mixing of CS and BUSP was determined quantitatively using differential scanning calorimetry. The extent of the interaction was highest in wet mixtures and was found to be dependent on the pH of the granulation liquid.CS was incorporated in BUSP-containing hypromellose (HPMC) tablets using dry mixing and wet granulation with BUSP. Tablet dissolution was tested in 0.1 N HCl and phosphate buffer, pH 6.8. According to f₂ and mean dissolution time results, the similarity of profiles increased as CS content increased with the highest f₂ value observed when CS was wet granulated with BUSP.Dissolution was also tested in deionized water and 5% NaCl; where increased ionic strength resulted in faster dissolution suggesting an ion exchange involvement in drug release.CS was proved effective in modulating BUSP release from HPMC matrices for pH-independent release through ionic complex formation.     

Biodegradation and drug release studies of BSA loaded gelatin microspheres

Certain variations in the process parameters (emulsification time, surfactant concentration) were performed in order to prepare BSA-loaded gelatin microspheres with high loading efficacy and particle size ranging from 1 to 10 microm using a procedure originally employed by Tabata and Ikada. The mathematical modelling of drug release in the presence of collagenase showed a biphasic release pattern, where the rate constant for the initial time release confirmed the influence of the particle size and/or enzymatic degradation rate on drug release rate.     

胸腺肽明胶微球的制备和体外释药的特性

目的:为提高胸腺肽的生物利用度,增强疗效,制备胸腺肽的明胶微球.方法:用乳化交联法制备胸腺肽明胶微球,正交设计法筛选其最佳制备工艺,Lowry法测定药物的含量,计算微球的载药量、包封率及体外释药量.结果:微球粒径范围为1.0～30.2 μm,平均粒径为14.64 μm,平均载药量为20.20%(w/w),平均包封率为80.82%,其体外释药符合Higuchi方程,稳定性考察实验结果表明其稳定性较好.结论:本法制备的胸腺肽明胶微球粒径分布集中,粒径大小符合设计要求,体外释药有明显的缓释作用,具有良好应用前景.     

Modeling of drug release from bioerodible polymer matrices

Models for drug release from bioerodible polymer matrices are proposed in this article. We consider that drug is released continually by diffusion that is influenced by polymer chain degradation, and polymer matrix erosion starts and enhances the drug release at a certain time. The models give excellent reproduction of drug release profiles within the whole release period, and the parameters can be correlated to various factors such as γ-irradiation dose, copolymer composition, and initial drug loading, this correlation indicates that the new models can be used to predict the effects of various factors on drug release profiles based on limited experimental data.