Effect of the molecular weight of poly(epsilon-caprolactone-co-DL-lactide) on toremifene citrate release from copolymer/silica xerogel composites

The purpose of this study was to develop a biodegradable polymeric carrier system for toremifene citrate based on epsilon-caprolactone/DL-lactide copolymers and silica xerogel. The effect of the molecular weight of poly(epsilon-caprolactone-co-DL-lactide) affecting the release rate of toremifene citrate from copolymer/silica xerogel composites was evaluated by in vitro dissolution study. Lower and higher molecular weight copolymers (LMW 60000 g/mol and HMW 300000 g/mol) were used in the devices. Drug release was compared from the (copolymer/drug) matrix device and the (copolymer/drug impregnated silica xerogel) composite device. Hydrolysis of the copolymer devices was evaluated by water absorption, weight loss and change of molecular weight by size exclusion measurements (SEC). Controlled release of toremifene citrate was obtained from both matrix and composite devices and the release rate was most affected by the initial molecular weight of the copolymer. Throughout the study better results were obtained with LMW devices, since drug release was steady for nearly 1 year and no changes in the release rate were observed. The drug release was diffusion controlled from both LMW matrix and composite devices. Incorporation of toremifene citrate into the silica xerogel was found to enhance the drug release rate. The copolymer matrices degraded by random hydrolytic chain scission and, unexpectedly, HMW P(CL/LA) degraded faster than LMW P(CL/LA). The release of toremifene citrate from HMW devices was not complete before the second stage of polymer degradation began.     

Release kinetics of procaine hydrochloride (PrHy) from pH-responsive nanogels: theory and experiments

pH-responsive nanogels consisting of methacrylic acid–ethyl acrylate (MAA–EA) cross-linked with di-allyl phthalate (DAP) were synthesized via emulsion polymerization. Drug release studies were conducted under different pHs, drug loading and concentration gradient difference. The drug loading capacity depended on the cross-link density and MAA–EA molar content, where a lower cross-link density and higher MAA–EA molar content resulted in higher loading capacity. A drug selective electrode was used to directly measure the concentration of procaine hydrochloride (PrHy) released from MAA–EA nanogels. More than 50 data points were acquired, where the mathematical fitting to the Berens and Hopfenberg model allowed the parameters describing the contributions of chain relaxation and diffusion process to be determined. The release rate increased with pH and concentration gradient difference due to a reduction in diffusion barrier and higher concentration gradient driving force, respectively, but it decreased with drug loading as the nanogel could not relax from the compact structure as evident from the contribution of Fickian diffusion, _F, and chain relaxation, _R. A balance between chain relaxation and Fickian diffusion process controlled the release of drugs from these pH-responsive nanogels. Exponential relationships could be established between diffusion coefficient, characteristic relaxation time and various physical parameters, where the drug release kinetics could be predicted in a quantitative manner.     

Pilocarpine release from hydroxypropyl-cellulose-polyvinylpyrrolidone matrices

Characteristics of pilocarpine release from cast plasticized hydroxypropylcellulose (HPC) and HPC-polyvinylpyrrolidone (PVP) matrices were studied using tritiated pilocarpine. Increased concentration of PVP and decreased molecular weight of HPC accelerated release of pilocarpine from the matrices. The aqueous solution penetrated rapidly into the matrices, which swelled rapidly to their equilibrium volumes. With increased molecular weight and concentration of HPC in the matrices, the rate of solvent penetration decreased and swollen volume of the matrix increased. Pilocarpine concentration also decreased in the ungelled cores of the matrices, indicating that the solvent had penetrated these cores. Solvent penetration alone did not control the rate of drug release, because penetration was at least twice as rapid as pilocarpine release. In the matrices without polymer dissolution, the best fits of the release data were obtained with diffusional square-root of time dependence, although relaxation of the polymers caused slight deviations from the Fickian diffusion. Thus the rate-limiting step of pilocarpine release was the diffusion of the drug from the matrix. The decreased rate of pilocarpine release with increased molecular weight and concentration of HPC was due to the decreased rate of drug diffusion from the matrix. Retardation of this diffusion was caused by the increased swelling of the matrix and decreased diffusivity of the drug. High initial concentration of PVP resulted in substantial deformation and attrition of the matrices.     

Development and in vitro evaluation of oral controlled release formulations of celecoxib using optimization techniques

The objective of this study was to develop controlled release matrix embedded formulations of celecoxib (CCX) as candidate drug using hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose (EC), either alone or in combination, using optimization techniques like polynomial method and composite design. This would enable development of controlled release formulations with predictable and better release characteristics in lesser number of trials. Controlled release matrix tablets of CCX were prepared by wet granulation method. The in vitro release rate studies were carried out in USP dissolution apparatus (paddle method) in 900 ml of sodium phosphate buffer (pH 7.4) with 1% v/v tween-80. The in vitro drug release data was suitably transformed and used to develop mathematical models using first order polynomial equation and composite design techniques of optimization. In the formulations prepared using HPMC alone, the release rate decreased as the polymer proportion in the matrix base was increased. Whereas in case of formulations prepared using EC alone, only marginal difference was observed in the release rate upon increasing the polymer proportion. In case of formulations containing combination of HPMC and EC, the release of the drug was found to be dependent on the relative proportions of HPMC and EC used in the tablet matrix. The release of the drug from these formulations was extended up to 21 h indicating they can serve as once daily controlled release formulations for CCX. Mathematical analysis of the release kinetics indicates a near approximate Fickian release character for most of the designed formulations. Mathematical equation developed by transforming the in vitro release data using composite design model showed better correlation between observed and predicted t(50%) (time required for 50% of the drug release) when compared to first order polynomial equation model. The equation thus developed can be used to predict the release characteristics of the drug from matrix embedded formulations depending upon the proportion of HPMC and EC used in the formulation.     

β-methasone-containing biodegradable poly(lactide-co-glycolide) acid microspheres for intraarticular injection: effect of formulation parameters on characteristics and in vitro release

A sustained drug release system based on the injectable poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with β-methasone was prepared for localized treatment of rheumatic arthritis. The microscopy and structure of microspheres were characterized by scanning electron microscope (SEM) and Fourier transform infrared (FTIR). The effects of various formulation parameters on the properties of microspheres and in vitro release pattern of β-methasone were also investigated. The results demonstrated that increase in drug/polymer ratio led to increased particle size as well as drug release rate. Increase in PLGA concentration led to increased particle size, but decreased burst release. The drug encapsulation efficiency increased sharply by increasing polyvinyl alcohol (PVA) concentration in the aqueous phase from 1.5 to 2.0%. β-methasone release rate decreased considerately with decreasing OP (organic phase)/AP (aqueous phase) volume ratio. Stirring rate had significantly influence on the particle size and encapsulation efficiency. Independent of formulation parameters, β-methasone was slowly released from the PLGA microspheres over 11 days. The drug release profile of high drug loaded microspheres agree with Higuchi equation with a release mechanism of diffusion and erosion, that of middle drug loaded microspheres best agreed with Hixcon-Crowell equation and controlled by diffusion and erosion as well. The low drug loaded microspheres well fitted to logarithm normal distribution equation with mechanism of purely Fickian diffusion.     

Psyllium and copolymers of 2-hydroxylethylmethacrylate and acrylamide-based novel devices for the use in colon specific antibiotic drug delivery

In order to utilize the psyllium husk, a medicinally important natural polysaccharide, to develop the hydrogels meant for the drug delivery, we have prepared psyllium 2-hydroxylethylmethacrylate (HEMA) and acrylamide (AAm)-based polymeric networks by using N,N'-methylenebisacrylamide (N,N'-MBAAm) as crosslinker and ammonium persulfate (APS) as initiator. The polymeric networks thus formed [psy-cl-poly(HEMA-co-AAm)] were characterized with FTIR and swelling studies which were carried out as a function of crosslinker concentration, time, pH and [NaCl] of the swelling medium. The swelling kinetics of the hydrogels and in vitro release dynamics of model drug (tetracycline hydrochloride) from these hydrogels has been studied for the evaluation of swelling mechanism and drug release mechanism from the hydrogels. The values of the diffusion exponent 'n' have been obtained 0.5 for both swelling kinetics and drug release dynamics. This value shows that the Fickian type diffusion mechanism has occurred for the swelling of the polymers and for the release of drug from the polymers in different release mediums. The values of the initial diffusion coefficients (10.6 x 10(-4), 13.1 x 10(-4), 14.0 x 10(-4))cm(2)/min, average diffusion coefficients (22.2 x 10(-4), 25.7 x 10(-4), 27.0 x 10(-4))cm(2)/min and late diffusion coefficients (1.68 x 10(-4), 2.15 x 10(-4), 2.28 x 10(-4))cm(2)/min for the release of tetracycline HCl respectively in distilled water, pH 2.2 buffer and pH 7.4 buffer from the drug loaded samples shows that in the initial stages, the rate of release of drug from the hydrogels is slow and rate of diffusion of drug increases with time.     

Moulded cross-linked chitosan matrix systems for controlled drug release

Matrix-type drug delivery systems were prepared by moulding and drying cross-linked chitosan gels in 24-well plates and they were evaluated in terms of their physical properties, drug content, surface morphology and swelling. Furthermore, the in vitro drug release profiles were subjected to kinetic modelling at two different pH values. In general, the moulded matrix systems showed statistically significantly slower drug release compared to immediate release tablets as measured by the mean dissolution time. Drug release from the moulded matrix systems prepared from chitosan cross-linked with tripolyphosphate was pH-dependent as can be seen from the release exponent value (n) of 0.75 at pH 5.8 (anomalous transport, erosion), while the n value was only 0.40 at pH 7.4 (Fickian diffusion). The matrix systems obtained from chitosan cross-linked with sodium lauryl sulphate showed higher swelling but mostly Fickian diffusional release (n?=?0.25 at pH 7.4, n?=?0.41 at pH 5.8).     

小剂量阿司匹林胃漂浮胶囊的制备及其体外释药特征的研究

目的:制备小剂量阿司匹林胃漂浮胶囊并研究其体外释药特征。方法:以阿司匹林为模型药物,以不同粘度和不同用量的羟丙基甲基纤维素(HPMC)和卡波姆为主要辅料制成阿司匹林胃漂浮胶囊,测定其释放度。结果:当HPMC K4M和HPMCK15M的最佳配比为3∶1时,阿司匹林胃漂浮胶囊在0h~10h内体外释药符合表观零级动力学过程,体外释放速度常数Kr=10.3%/h,释放参数n=0.6 173。结论:所制胶囊缓释效果明显,HPMC用量、粘度为影响阿司匹林胃漂浮胶囊释放速率的主要因素,其体外释药特征属于骨架溶蚀与药物扩散协同作用。     

Wet granulation fine particle ethylcellulose tablets: Effect of production variables and mathematical modeling of drug release

In the present study, the applicability of fine particle ethylcellulose (FPEC) to produce matrix tablets by a wet granulation technique was evaluated. The effect of various formulation and process variables, such as FPEC content, hardness of the tablet, and solubility of the drug, on the release of drug from these tablets was examined. Tablets were prepared by wet granulation of drug and FPEC in an appropriate mass ratio. Theophylline, caffeine, and dyphylline were selected as nonionizable model drugs with solubilities from 8.3 to 330 mg/mL at 25°C. Ibuprofen, phenylpropanolamine hydrochloride, and pseudoephedrine hydrochloride were selected as ionizable drugs with solubilities from 0.1 to 2000 mg/mL at 25°C. Drug release studies were conducted in 37°C water with UV detection. As the FPEC content and the hardness of the tablets increased, the release rate of the drug decreased. The drug release rate increased with an increase in the solubility of the drug. Model equations, intended to elucidate the drug release mechanism, were fitted to the release data. Parameters were generated and data presented by SAS software. The Akaike Information Criterion was also considered to ascertain the best-fit equation. Fickian diffusion and polymer relaxation were the release mechanisms for nonionizable and ionizable drugs.     

Dissolution of artemisinin/polymer composite nanoparticles fabricated by evaporative precipitation of nanosuspension

Objectives An evaporative precipitation of nanosuspension (EPN) method was used to fabricate composite particles of a poorly water‐soluble antimalarial drug, artemisinin, with a hydrophilic polymer, polyethylene glycol (PEG), with the aim of enhancing the dissolution rate of artemisinin. We investigated the effect of polymer concentration on the physical, morphological and dissolution properties of the EPN‐prepared artemisinin/PEG composites. Methods The original artemisinin powder, EPN‐prepared artemisinin nanoparticles and artemisinin/PEG composites were characterised by scanning electron microscopy, Fourier‐transform infrared spectroscopy, differential scanning calorimetry (DSC), X‐ray diffraction (XRD), dissolution testing and HPLC. The percentage dissolution efficiency, relative dissolution, time to 75% dissolution and mean dissolution time were calculated. The experimental drug dissolution data were fitted to various mathematical models (Weibull, first‐order, Korsemeyer–Peppas, Hixson–Crowell cube root and Higuchi models) in order to analyse the release mechanism. Key findings The DSC and XRD studies suggest that the crystallinity of the EPN‐prepared artemisinin decreased with increasing polymer concentration. The phase‐solubility studies revealed an A_L‐type curve, indicating a linear increase in drug solubility with PEG concentration. The dissolution rate of the EPN‐prepared artemisinin and artemisinin/PEG composites increased markedly compared with the original artemisinin powder. Conclusions EPN can be used to prepare artemisinin nanoparticles and artemisinin/PEG composite particles that have a significantly enhanced dissolution rate. The mechanism of drug release involved diffusion and erosion.     

Novel hybrid silica xerogels for stabilization and controlled release of drug

PURPOSE: The goal was to show that incorporation of a model drug into a porous solid matrix with small enough pores should lead to composites in which the drug would be in the amorphous rather than in the crystalline state. Due to spatial constraints, the amorphous state was expected to be temporally highly stable. METHODS: As a porous solid matrix silica was selected, while nifedipine served as a model drug. The silica-drug composites were prepared using a sol-gel procedure at conditions which yielded pores in the range 2-3 nm. To tune the properties of composites, two silica precursors were combined: tetraethoxysilane (TEOS) and bis-1,2-(triethoxysilyl)ethane (BTSE). RESULTS: In all composites the amorphous state of nifedipine was proven using several analytical methods. The amorphicity was preserved for at least several months. Drug incorporation into purely TEOS-based silica decreased significantly the release rate. Loosening the structure by addition of BTSE, while preserving the amorphicity, increased the drug dissolution rate. The dissolution behaviour was explained using a combination of the Noyes-Whitney and power law model. CONCLUSION: The observed release patterns could be interesting for therapies requiring a high initial drug concentration in blood plasma, followed by a slower release rate of the remaining drug.     

Drug release kinetics from polymeric films containing propranolol hydrochloride for transdermal use

Polymeric films containing propranolol hydrochloride (PPN) were formulated and evaluated with a view to select a suitable formulation for the development of transdermal drug delivery systems. Films containing different ratios of ethyl cellulose (EC), poly(vinylpyrrolidone) (PVP), and PPN were prepared by mercury substrate method. In vitro drug release and skin permeation studies were conducted using paddle over disk and modified Franz diffusion cell, respectively. The drug release profiles from the polymeric film indicated that the drug content in the film decreased at an apparent first-order rate, whereas the quantity of drug release was proportional to the square root of time. The release rate of PPN increased linearly with increasing drug concentration and PVP fraction in the film, but was found to be independent of film thickness. The increase in release rate may be due to leaching of hydrophilic fraction of the film former, which resulted in the formation of pores. It was also observed that the release of drug from the films followed the diffusion-controlled model at low drug concentration. A burst effect was observed initially, however, at high drug loading level, which may be due to rapid dissolution of the surface drug followed by the diffusion of the drug through the polymer network in the film. The in vitro skin permeation profiles displayed increased flux values with increase of initial drug concentration in the film, and also with the PVP content. From this study, it is concluded that the films composed of EC/PVP/PPN, 9:1:3, 8:2:2, and 8:2:3, should be selected for the development of transdermal drug delivery systems using a suitable adhesive layer and backing membrane for potential therapeutic applications.     

Targeted retentive device for oro-dental infections: formulation and development

Fibers loaded with amoxycillin trihydrate were prepared for oro-dental infections using melt spinning technique. Ethylene vinyl acetate, a biocompatible polymer was used for providing controlled release effect over a period of several days. The fibers were evaluated for in vitro release in alkaline borate buffer pH 8.1 in a biological shaker which was rotated at 50 rpm at 37 degrees C. In situ studies were carried out in continuous flow through apparatus which simulated the conditions of periodontal pocket. Microbiological evaluation was carried out on strains commonly implicated in oro-dental infections namely S. aureus, S. mutans, and Bacteroides cereus. Results of in vitro release studies revealed that the effect was sustained over a period of 6 days and followed Fickian diffusion mechanism. In situ release study samples were well above the minimum inhibitory concentration of the drug. These samples were effective in inhibiting the growth of the above-mentioned strains. The optimized formulation was characterized for general appearance, content uniformity, and SEM. Stability studies carried out on the formulation showed the degradation rate constant value of 2.79 x 10(-4) per day. Retentive fibers were found to be very effective in controlled delivery of amoxycillin, and hence can be feasible alternative to systemic administration.     

Release rates of ketoprofen from poloxamer gels in a membraneless diffusion cell

Release rates of ketoprofen from topical gels consisting of poloxamer 407 were evaluated using a membraneless diffusion cell with isopropyl myristate as the receptor medium. The effects of formulation variables such as polymer content (20-30%), drug (0.2-3.0%) and ethanol (0-20%) concentrations, pH (3.0-6.0), and temperature of the gels (25-45 degrees C) on drug release were studied. Release of ketoprofen from the gel decreased exponentially as the polymer concentration increased. Over the temperature range studied, the drug release rate appeared to correlate with the Arrhenius function. The change of the gel pH from 3 to 6 substantially increased the release rate of ketoprofen. The enhanced drug release in the presence of ethanol is attributed to the decrease in viscosity of the gel. With higher drug loading in the gel, an increase in the release rate, but a reduction of diffusion coefficient of the drug, was observed.     

Multiunit floating drug delivery system of acyclovir: development,characterization and in vitro-in vivo evaluation of spray-dried hollow microspheres

Acyclovir, anti-herpes virus drug, was loaded in hollow microspheres to improve bioavailability and patient compliance by prolonging the residence time in the gastrointestinal tract. The hollow microspheres of acyclovir were prepared by spray-drying method using ethyl cellulose as a drug-controlled release polymer. We found that the selected process parameters of spray-drying method like inlet temperature, outlet temperature, spray flow rate and vacuum pressure can give rise to hollow microspheres with good yields of production, high drug content and buoyancy, narrow size distribution and good encapsulation efficiency. The size of the microspheres prepared from different ratios of acyclovir and ethyl cellulose was 1.1-2.7 μm. When the drug:polymer ratio was increased, the size and percent drug content increased. The hollow microspheres having higher polymer concentrations were less buoyant than those with lower polymer concentrations. The formulation HSF1 showed the highest buoyancy of 94.18 ± 4.4 %. Dissolution profiles indicate that when drug:polymer ratio increased from 1:2 to 1:6, a decrease in release rate was observed. The highest correlation coefficient was obtained in first-order release model as compared to zero-order followed by Higuchi model. From the Higuchi plot it was found that drug release from the microspheres was diffusion type. The ‘n’ values from Korsmeyer-peppas model indicated that all three formulations follow Fickian diffusion controlled release. The AUC values for oral administration of selected formulation and conventional tablet (Zovirax) clearly indicated two- to three-fold improvement in the bioavailability of acyclovir from prepared formulation when compared to conventional commercial tablet.     

Formulation and evaluation of a sustained-release tablets of metformin hydrochloride using hydrophilic synthetic and hydrophobic natural polymers

Metformin hydrochloride has relatively short plasma half-life, low absolute bioavailability. The need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 8-12 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. The overall objective of this study was to develop an oral sustained release metformin hydrochloride tablet by using hydrophilic Eudragit RSPO alone or its combination with hydrophobic natural polymers Gum copal and gum damar as rate controlling factor. The tablets were prepared by wet granulation method. The in vitro dissolution study was carried out using USP 22 apparatus I, paddle method and the data was analysed using zero order, first order, Higuchi, Korsmeyer and Hixson-Crowell equations. The drug release study revealed that Eudragit RSPO alone was unable to sustain the drug release. Combining Eudragit with gum Copal and gum Damar sustained the drug release for more than 12 h. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport. Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.     

Hyaluronic Acid and Graphene Oxide-incorporated Hyaluronic Acid Hydrogels for Electrically Stimulated Release of Anticancer Tamoxifen Citrate

Transdermal drug delivery is the transport of drug across the skin and into the systemic circulation. Patch is a one of transdermal device that is used to attach on skin and contains drug. The drug matrices from hyaluronic acid (HA) and graphene oxide (GO) incorporated HA hydrogel were fabricated for the release of tamoxifen citrate (TMX) as the anticancer drug under applied electrical field. The pristine HA hydrogels as the matrix and GO as the drug encapsulation host were fabricated for transdermal patch by the solution casting using citric acid as the chemical crosslinker. In vitro drug release experiment was investigated by utilizing the modified Franz-diffusion cell under the effects of crosslinking ratio, electric potential, and GO. The TMX release behaviors from the hydrogels were found to be from the three mechanisms: the pure Fickian diffusion; the anomalous or non-Fickian diffusion; and Super case II transport depending on the crosslinking conditions. The TMX diffusion and release amount from the pristine HA hydrogels were increased with smaller crosslinking ratios. With applied electrical potential, the enhanced TMX diffusion and release amount were observed when compared to that without due to the electro-repulsive force. Furthermore, the TMX diffusion from the HA hydrogel with GO as the drug encapsulation host was higher by two orders of magnitude than without GO.     

全因子实验筛选盐酸二甲双胍缓释片处方及其释药机制研究

目的 优化盐酸二甲双胍缓释片的处方并对释药机制进行研究。方法 采用高速湿法制粒制备颗粒,然后压片,硬度控制在80～100N。以相似因子f2为主要评价指标,辅以10小时的累计释放百分率Q10为评价指标,用Design Expert软件进行全因子试验设计及分析,筛选最优处方。获取的最优处方进行释放度试验,进行释放机制研究。结果 最佳处方是盐酸二甲双胍100 g,壳聚糖2.5 g,HPMC（K100M）47.5 g,硬脂酸镁1.5 g,相似因子f2与预测值偏差小于4%。该样品释放数据经拟合,符合一级释放模型,释药机制为Fick＇s扩散。结论 用Design Expert软件进行全因子试验设计及分析,能够有效优化盐酸二甲双胍缓释片处方,其药物释放机制为Fick＇s扩散。     

Development and characterization of mucoadhesive microspheres for nasal delivery of ketorolac

The objective of the present investigation was to prepare mucoadhesive microspheres of ketorolac for nasal administration by means of a solvent evaporation technique using carbopol (CP), polycarbophil (PL) and chitosan (CS) as mucoadhesive polymers. The prepared microspheres were characterized for morphology, swelling behavior, mucoadhesion, interaction studies, drug encapsulation efficiency, in vitro drug release, release kinetics, and ex vivo nasal cilio toxicity studies. The effects of various process variables on the particle size of the microspheres were investigated. Drug encapsulation efficiency and particle size of the microspheres ranged from 52-78% w/w and 14-46 microm respectively. Interaction studies revealed that there were no drug-polymer interactions. The in vitro release profiles showed prolonged-release of the drug. In vitro release data showed a good fit with the Higuchi model, and indicated Fickian diffusion. No severe damage was found to the integrity of nasal mucosa after ex vivo experiments.     

用渗滤理论考察阿司匹林-乙基纤维素骨架片的释药机制和释放动力学

目的　用渗滤理论研究阿司匹林骨架片的释药机制及释放动力学。方法　测定了不同阿司匹林含量骨架片的释放曲线,用模型方程对释放数据进行了拟合。利用渗滤理论,经一系列计算可得到阿司匹林的渗滤阈。结果　阿司匹林含量在30%～60%时,以骨架扩散机制释药,遵从Higuchi模型方程;含量较高时则接近零级动力学释药。阿司匹林渗滤阈为0.235。结论　渗滤理论可清楚地阐明阿司匹林骨架片的释药机制,并得到阿司匹林的渗滤阈,由此可确定具有合适释药速率的阿司匹林的含量范围。