Controlled release of nifedipine from gelatin microspheres and microcapsules: in vitro kinetics and pharmacokinetics in man

Abstract

Nifedipine was embedded in a gelatin matrix to develop a prolonged release dosage form. The effects of polymer/drug ratio, size of the beads, cross-linking with formaldehyde and ethylcellulose coating of the gelatin microspheres on the in vitro release rate of the drug were investigated. The data were analysed according to different laws that can govern the release mechanism: first-order, Higuchi square root of time, spherical matrix and zero-order. The in vitro release kinetics of nifedipine from gelatin microspheres were mainly first-order; from formaldehyde hardened gelatin microspheres, complied with the diffusion model for a spherical matrix, and from ethylcellulose-coated gelatin microspheres, obeyed zero-order kinetics. These findings suggest the possibility of modifying the formulation in order to obtain the desired controlled release of the drug for a convenient oral sustained delivery system. The pharmacokinetic parameters of nifedipine, after adminstration of a single oral dose of nifedipine-loaded hardened gelatin microspheres to volunteers, suggest that the preparation can be considered as a sustained release delivery system for nifedipine.     

The kinetics of nifedipine release from porous hydrophilic matrices and the pharmacokinetics in man

Porous hydrophilic tablets of nifedipine were prepared with hydroxypropyl methylcellulose as swellable polymer, as well as with the addition of a solid dispersion of the drug in polyethylene glycol, a water soluble system. The kinetic data conformed with the Higuchi square root equation and first order release for in vitro release from a single planar surface of the tablet, as well as release from the whole tablet. The addition of a soluble fraction to the porous swellable release system increased the nifedipine release rate constant. This shows that the dosage form may be formulated as a drug-polymer system which exhibits constant release at a desired rate. In the bioequivalence study with five volunteers, the pharmacokinetic parameters of a sustained release hydrophilic tablet of nifedipine and of immediate release capsules were determined. Although the bioavailability of the two preparations is similar, the therapeutic effects may differ. The rate of absorption, the maximum concentration levels, the time of the peak and the period of maintenance of the therapeutic serum levels after single oral doses are different after the administration of the two tested formulations. The hydrophilic tablets of nifedipine may be useful as a sustained release formulation for long term treatment of hypertension.     

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.     

Controlled release captopril microcapsules: effect of ethyl cellulose viscosity grade on the in vitro dissolution from microcapsules and tableted microcapsules

Captopril microcapsules were prepared using four different viscosity grades of ethyl cellulose (core: wall ratios 1:1, 1:2 and 1:3) by temperature induced coacervation from cyclohexane. In vitro dissolution studies in 0.1 M hydrochloric acid showed that the drug release was dependent on the core to wall ratio, the viscosity grade of the ethyl cellulose and thus the total viscosity of the coacervation system. Viscosity grade of greater than 100 c.p. was unsuitable for microencapsulation by coacervation method at the concentration used. The surface characteristics of a 1:2 core to wall ratio were studied by scanning electron microscopy. The surface of the microcapsules prepared with 10 c.p. viscosity grade was comparatively more porous with larger size pores than 50 c.p. viscosity grade of ethyl cellulose. However, 300 c.p. viscosity grade showed incomplete wall formation. The microcapsules did not fragment during dissolution, alter in shape or size, or show evidence of enlargement of the surface pores. The tensile strength of tablets prepared at constant pressure from each batch of microcapsules (mean diameter 675 microns) increased as both the core to wall ratios and the viscosity of ethyl cellulose increased. The dissolution rate of the drug from tableted microcapsules was significantly delayed. The in vitro release gave best correlation with first order release kinetics when compared to zero-order and square-root-of-time equations.     

Controlled release captopril microcapsules: effect of non-ionic surfactants on release from ethyl cellulose microcapsules

Captopril microcapsules were prepared with different viscosity grades of ethyl cellulose by temperature induced coacervation from cyclohexane. Both non-ionic surfactants or their combinations and 2 per cent absolute alcohol as cosolvent were added to the coacervation system to ensure complete solvation of the ethyl cellulose and efficient microencapsulation of the drug. The in vitro dissolution was studied in 0.1 N hydrochloric acid. Microcapsules prepared using 2 per cent Tween 80 with ethyl cellulose of 41 c.p. viscosity grade exhibited the most prolonged release with a t70 per cent of 55 min in comparison to 7.75 min for control microcapsules prepared without surfactant. Different kinetic models have been used to explain the release. The best fit with the highest correlation coefficients was the first-order kinetics plot with two straight lines having two different slopes. The initial slope presents the faster release rate than the terminal slope. This fast release would be useful for the initial dose of the prolonged release formulation.     

Controlled release of vancomycin from biodegradable microcapsules

Poly D,L-lactic acid (PLA) and its copolymers with glycolide PLGA 90:10 and 70:30 were polymerized under various conditions to yield polymers in the molecular weight range 12000-40000 daltons, as determined by gel permeation chromatography. Vancomycin hydrochloride was the hydrophilic drug of choice for the treatment of methicillin resistant Staphyloccoccal infections. It was microencapsulated in the synthesized polymers using water-oil-water (w/o/w) double emulsion and solvent evaporation. The influence of microcapsule preparation medium on product properties was investigated. An increase in polymer-to-drug ratio from 1:1 to 3:1 caused an increase in the encapsulation efficiency (i.e. from 44-97% with PLGA). An increase in the emulsifier (PVA) molecular weight from 14-72 kD caused an increase in encapsulation efficiency and microcapsule size. The in vitro release of vancomycin from microcapsules in phosphate buffer saline (pH 7.4) was found to be dependent on molecular weight and copolymer type. The kinetic behaviour was controlled by both diffusion and degradation. Sterilization with 60Co (2.5 Mrad) also affected the degradation rate and release profiles. Degradation of microcapsules could be seen by scanning electron microscopy, by the increase in the release rate from PLA and by the decrease in the Tg values of microcapsules. In vitro bactericidal effects of the microcapsule formulations on S. aureus were determined with a special diffusion cell after the preparations had been sterilized, and were found to have bactericidal effects lasting for 4 days.     

Controlled release of vancomycin from biodegradable microcapsules

Poly D,L-lactic acid (PLA) and its copolymers with glycolide PLGA 90:10 and 70:30 were polymerized under various conditions to yield polymers in the molecular weight range 12000-40000 daltons, as determined by gel permeation chromatography. Vancomycin hydrochloride was the hydrophilic drug of choice for the treatment of methicillin resistant Staphyloccoccal infections. It was microencapsulated in the synthesized polymers using water-oil-water (w/o/w) double emulsion and solvent evaporation. The influence of microcapsule preparation medium on product properties was investigated. An increase in polymer-to-drug ratio from 1:1 to 3:1 caused an increase in the encapsulation efficiency (i.e. from 44-97% with PLGA). An increase in the emulsifier (PVA) molecular weight from 14-72 kD caused an increase in encapsulation efficiency and microcapsule size. The in vitro release of vancomycin from microcapsules in phosphate buffer saline (pH 7.4) was found to be dependent on molecular weight and copolymer type. The kinetic behaviour was controlled by both diffusion and degradation. Sterilization with ⁶⁰Co (2.5 Mrad) also affected the degradation rate and release profiles. Degradation of microcapsules could be seen by scanning electron microscopy, by the increase in the release rate from PLA and by the decrease in the T_g values of microcapsules. In vitro bactericidal effects of the microcapsule formulations on S.aureus were determined with a special diffusion cell after the preparations had been sterilized, and were found to have bactericidal effects lasting for 4 days.     

Controlled release of huperzine A from biodegradable microspheres: In vitro and in vivo studies

This paper describes the effect on Sun Protection Factor (SPF) of the combination of inorganic and organic filters in sunscreen products as determined by an in vitro method. O/W emulsions containing inorganic filters, such as titanium dioxide and zinc oxide, combined with 18 EU-authorized UV-B organic filters were tested. SPF measurements were carried out using a spectrophotometer equipped with an integrating sphere.

This study observed a synergic effect when titanium dioxide was combined with either anisotriazine or octyldimethylPABA. The combination of zinc oxide with 11 UV-B organic filters also exhibited a similar synergy; however, the measured SPF was systematically lower than the protection factor achieved with titanium dioxide.     

壳聚糖-海藻酸钠微囊对干扰素-tau的控释作用

目的用壳聚糖和海藻酸钠为原料,制备干扰素-tau微囊,希望开发成为一种口服干扰素制剂。方法使用注射器手工滴制的方法,在滴加过程中,速度和距离是影响囊形的主要因素。结果壳聚糖-海藻酸钠微囊法应用于干扰素-tau药物的包封,其制备简单快速,干扰素-tau包封率很高,并且具有肠溶缓释作用。结论壳聚糖-海藻酸钠微囊有望用作干扰素-tau或其它肽类药物的口服制剂。     

Comparative assessment of in vitro release kinetics of calcitonin polypeptide from biodegradable microspheres

The objective of our study was to compare the in vitro release kinetics of a sustained-release injectable microsphere formulation of the polypeptide drug, calcitonin (CT), to optimize the characteristics of drug release from poly-(lactide-co-glycolide) (PLGA) copolymer biodegradable microspheres. A modified solvent evaporation and double emulsion technique was used to prepare the microspheres. Release kinetic studies were carried out in silanized tubes and dialysis bags, whereby microspheres were suspended and incubated in phosphate buffered saline, sampled at fixed intervals, and analyzed for drug content using a modified Lowry protein assay procedure. An initial burst was observed whereby about 50% of the total dose of the drug was released from the microspheres within 24 hr and 75% within 3 days. This was followed by a period of slow release over a period of 3 weeks in which another 10-15% of drug was released. Drug release from the dialysis bags was more gradual, and 50% CT was released only after 4 days and 75% after 12 days of release. Scanning electron micrographs revealed spherical particles with channel-like structures and a porous surface after being suspended in an aqueous solution for 5 days. Differential scanning calorimetric studies revealed that CT was present as a mix of amorphous and crystalline forms within the microspheres. Overall, these studies demonstrated that sustained release of CT from PLGA microspheres over a 3-week period is feasible and that release of drug from dialysis bags was more predictable than from tubes.     

肺靶向阿霉素微球的体外释放度测定方法的建立

目的建立肺靶向阿霉素明胶微球(ADM-GMS)体外释放度测定的方法。方法以透析法考察阿霉素明胶微球的体外释放度,采用紫外分光光度法在波长254nm处测定阿霉素明胶微球的体外释药量。结果阿霉素微球体外释药量在1~40mg/L浓度范围内线性关系良好,平均回收率为99.63%,RSD为1.16%。结论该方法简便、快速、准确,可作为阿霉素微球体外释放度的测定方法。     

Controlled release chitosan microspheres of mirtazapine: In vitro and in vivo evaluation

The purpose of the study was to formulate and evaluate controlled release chitosan microspheres of mirtazapine (MTZ) to improve the bioavailability by altering the pharmacokinetic profiles of the drug. Chitosan microspheres were prepared to prolong the release of the drug into the systemic circulation. Microspheres were prepared by a single water in oil (w/o) emulsion technique varying the chitosan/drug ratio, stirring speed and concentration of the crosslinking agent (glutaraldehyde). Drug-polymer compatibility studies were carried out using fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The microspheres were evaluated for encapsulation efficiency, particle size, surface morphology, swelling index, in vitro release, as well as erosion and in vivo studies in rats. The FT-IR and DSC studies revealed no interaction between drug and polymer. The encapsulation efficiency of different formulation varied from 53 ± 1.2% to 78 ± 1.5%. The mean particle size of the optimized formulation F-14 was 106.4 ± 0.5 μm. Surface morphology revealed that chitosan microspheres were discrete and spherical in shape with a porous surface. The release of MTZ from chitosan microspheres was rapid up to 4 h, and then it was continuously and slowly released up to 48 h. Optimized formulation (F-14) was found to be stable under accelerated storage conditions based on International Conference on Harmonisation guidelines. Pharmacokinetic studies revealed that the optimized formulation showed significant increases in systemic exposure (AUC = 177.70 ± 7.39 μg·h/mL), half-life (4.72 ± 0.46 h) and reduced clearance (0.009 ± 0.0001 L/h) compared to pure drug administration. Hence, the present study demonstrates that controlled release formulation of MTZ microspheres using chitosan can improve pharmacokinetic profiles of MTZ.     

Effect of cross-linking on the in vitro release kinetics of doxorubicin from gelatin implants

Doxorubicin is one of the most potent anti-tumor agents used generally in the treatment of bone cancer. Like other cancer chemotharepeutics, it produces undesirable side effects such as cardiotoxicity, which is especially severe when administrated via the conventional intravenous route. In order to minimize the systemic toxicities and to make this drug more suitable for the treatment of bone cancer, an implantable delivery system with cross-linked gelatin as the biodegradable matrix material was developed. This delivery system could possibly improve targeting of the drug as well as sustain the rate of release of the drug to the tumor. Glutaraldehyde was used as a cross-linking agent. Incorporation of glutaraldehyde in the matrix was needed to maintain the mechanical strength of the implant and to sustain the rate of release of the drug from the implant. Besides cross-linking the gelatin matrix, glutaraldehyde was found to cross-link the free amino group of doxorubicin. The effect of cross-linker concentration on the stability of the drug in the implant and on the rate and extent of release were also evaluated. In conclusion, cross-linked gelatin implants were developed for the local delivery of doxorubicin.     

The in vitro evaluation of gelatin coacervate microcapsules

Microcapsules of sulphadiazine have been prepared by the simple gelatin coacervation technique, using sodium sulphate as coacervating agent. The free flowing microcapsular material was hardened with formalin. There is no direct relation between particle size and sulphadiazine concentration nor between different starting gelatin percentages. The effects on size of hardening time, temperature and sampling time are small. In vitro dissolution studies show that first order release characteristics are exhibited by all the hardened materials. Temperature and pH effects indicate the dissolution of the sulphadiazine itself to be the controlling step rather than the rate of diffusion through the microcapsule wall.     

Controlled release of interleukin-2 from chitosan microspheres

Chitosan microspheres were evaluated for sustained-release of recombinant human interleukin-2 (rIL-2) in this study. In addition, the effects of different formulation factors, such as chitosan and protein concentrations, the volume of sodium sulfate solution, addition technique of rIL-2, and presence of glutaraldehyde during the encapsulation process, on microsphere characteristics were investigated. Chitosan microspheres containing rIL-2 were prepared by using the precipitation technique. The average diameter of microspheres was between 1.11-1.59 microm. Recombinant IL-2 encapsulation efficiency in these microspheres was high (75-98%). Formulation factors had no effect on the microsphere size. Recombinant IL-2 had been released from chitosan microspheres over a period of 3 months. The encapsulated rIL-2 remained biologically active and could be completely recovered from the release medium. Briefly, rIL-2 was released from chitosan microspheres in a sustained manner. The efficacy of rIL-2 loaded chitosan microspheres was studied using two model cells, HeLa and L-strain cell lines. Chitosan microspheres were added to the cells at different concentrations, and the amount of rIL-2 was assayed using the ELISA kit. Cell culture studies indicated that microspheres were uptaken by cells, and rIL-2 was released from the microspheres. Cellular uptake of rIL-2-loaded microspheres was dose dependent. It can be said that chitosan microsphere is a suitable carrier for rIL-2 delivery.     

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.     

In vitro drug release from egg albumin microcapsules

The in vitro release of phenacetin from microcapsules prepared using egg albumin as the membrane material was investigated. It was shown by scanning electron microscopy that the albumin microcapsules have nonsmooth surfaces. The amount of phenacetin released is proportional to the square root of time up to 50-70% drug release. Increases in the albumin concentration and 1-vinyl-2-pyrrolidinone polymer content in the aqueous phases used in the microcapsule preparation have an effect on matrix porosity and channel tortuosity in the matrix of albumin microcapsules. The in vitro release rate was found to decrease with increasing albumin concentration and 1-vinyl-2-pyrrolidinone polymer content in the aqueous phases. The in vitro release rate per unit area also decreased with decreasing capsule size.     

Assessment of bioavailability of experimental controlled release microcapsules of nifedipine

Experimental controlled release nifedipine microcapsules composed of ethylcellulose and eudragit RL were explored for the assessment of bioavailability on rabbit. The pharmacokinetic parameters were compared between the formulations and with the pure drug material. A statistically significant difference between the formulations was noticed in the parameters, K, T1/2, AUC (0-->infinity), MRT and bioavailability but not in Vd, Cmax and Tmax and in each case a highly significant difference was observed with reference drug material. Controlled release absorption profiles in vivo were observed from the experimental microcapsules as revealed by the Wagner-Nelson method. The absorption lag time, absorption rate constant, and absorption half life were calculated by using the back projection method of residuals. A good correlation demonstrated between in vivo absorption and in vitro release data for both the products merits specific attention. There was no loss in bioavailability of the experimental ethylcellulose microcapsule (drug content 75.8%), even though nifedipine undergoes extensive first pass metabolism.     

硝苯地平缓释片与普通片在健康人体内药动学的比较

目的比较硝苯地平缓释片与硝苯地平普通片在健康人体内药动学。方法 12名男性健康志愿者平均分为2组,分别单剂量口服硝苯地平缓释片与硝苯地平普通片20 mg,用高效液相色谱法检测硝苯地平的血药浓度,并用DAS 2.1软件进行数据处理。结果硝苯地平缓释片与硝苯地平普通片主要药动学参数ρmax分别为(1 247.8±78.4)μg.L-1和(1 896.7±109.2)μg.L-1,tmax分别为(4.6±0.7)h和(2.6±0.9)h,t1/2分别为(8.6±2.8)h和(4.8±1.5)h,AUC0-∞分别为(5 879.3±176.2)μg.h.L-1和(3 724.9±121.3)μg.h.L-1,AUC0-t分别为(4 427.8±131.7)μg.h.L-1和(2 936.5±75.4)μg.h.L-1。结论硝苯地平缓释片的tmax、t1/2长于普通片,AUC0-t、AUC0-∞高于普通片,而ρmax低于普通片,说明硝苯地平缓释片具有良好的缓释效果。     

Controlled release of levonorgestrel from biodegradable poly(D,L-lactide-co-glycolide) microspheres: in vitro and in vivo studies

Poly(D,L-lactide-co-glycolide) (PLG) biodegradable microspheres containing a contraceptive drug, levonorgestrel (LNG), were prepared using both the solvent evaporation method and a modified solvent extraction-evaporation method. The microspheres prepared with the solvent evaporation process had porous surfaces with low product yields and poor encapsulation efficiencies. On the other hand, the microspheres prepared using the modified solvent extraction-evaporation method were nonporous with encapsulation efficiencies close to 100%. In vitro drug release showed the nonporous microspheres had a lower initial burst and a slightly prolonged duration of release than those porous microspheres. In vivo release kinetics of the low burst microspheres were determined by measuring LNG plasma levels after a single intramuscular injection to female rats. At a LNG dose of 41.1 mg/kg, average plasma LNG levels were 6-10 ng/ml in the first 24 h and subsequently remained above 1 ng/ml until 126 days. The duration above the minimum effective LNG plasma level of 0.2 ng/ml was 168 days. By comparison, a similar dose of LNG microcrystals used as control produced a much higher plasma level of 15-21 ng/ml in the first day followed by a fast and continuous decline of LNG levels with a duration of only about 35 days.