Novel design of osmotic chitosan capsules characterized by asymmetric membrane structure for in situ formation of delivery orifice

In this study, chitosan capsules with asymmetric membrane to induce osmotic effects and in situ formation of the delivery orifice were optimally prepared and characterized. Chitosan capsules were formed on stainless steel mold pins by dipping the pins into a chitosan solution followed by forming asymmetric structure by dipping into a quenching solution containing tripolyphosphate (TPP) to cause an ionic cross-linking reaction between the outer layer of chitosan and TPP. Factors influencing the properties of the capsule membrane, such as the molecular weight of chitosan, the dipping solution and dipping time, and the quenching solution and time, were optimized to successfully produce osmotic chitosan capsules with asymmetric membrane using chitosans that possessed different viscosities. In situ formation of a delivery orifice on the asymmetric membrane of the chitosan capsule was proven by the observation of a jet stream of chlorophyll being released from the capsule. Drugs with different solubility were selected, and a linear correlation between drug solubility and the initial drug release rate calculated from the slope of the drug release profile was used to verify that the delivery orifices that were in situ formed on the asymmetric membrane of the chitosan capsules induced by osmotic effect was responsible for the drug release. Water permeability across the optimally produced asymmetric membrane of the capsule from chitosan of 500 cps (300-700 cps) quenched with TPP for 30 min (C500/TPP30) was determined to be 1.40 x 10(-6)cm(2)h(-1)atm(-1) at 37.0+/-0.5 degrees C. The encapsulation of poorly water-soluble drugs, felodipine (FE) and nifedipine (NF), in such an asymmetric chitosan capsule was capable of creating a sufficient osmotic effect to activate the release of the drug with the addition of SLS and HPMC. The multiple regression equations of maximal release percent at 24h for FE and NF confirmed that both sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) positively influenced this response factor, and the effect of SLS was greater than that of HPMC.     

In situ-formed asymmetric membrane capsule for osmotic release of poorly water-soluble drug

A non-disintegrating, in situ-formed, asymmetric membrane, polymeric capsular system, offering improved osmotic effect, was used to deliver poorly water-soluble drug in a controlled manner. The poorly water-soluble drug ketoprofen was selected as a model drug to demonstrate how controlled release characteristics can be manipulated by design of in situ-formed polymeric capsule with an asymmetric membrane and core formulations. In situ-formed, asymmetric membrane capsule was made by dry method via precipitation of asymmetric membrane on the walls of hard gelatin capsule. Resulting asymmetric membrane composed of a dense outer region with fewer pores and a lighter inner porous region. The present study evaluates the influence of variables based on two-factor composite design, namely, ethylcellulose and osmogen (sodium chloride), apart from studying effect of varying osmotic pressures of dissolution medium and level of pore-former concentration (glycerol) on drug release. Statistical significance was tested at P < 0.05. Results showed the best formulation (F-5) to closely corresponded to extra design checkpoint formulation by a similarity (f2) value of 95.41 and capsules made with 15% w/v EC, 50 mg sodium chloride, 8% w/v glycerol and 30 mg citric acid (F-11), to achieve therapeutic concentration within first hour of dissolution not observed with any other formulations used in the study. Drug release followed Fickinan diffusion and was independent of pH but dependent on the osmotic pressure of the dissolution medium.     

Osmotically regulated asymmetric capsular system for sustained delivery of indomethacin

The aim of the current study was to develop a sustained release asymmetric membrane capsular system for oral delivery of indomethacin. The capsule membrane was prepared using fabricated glass mold pins by phase inversion technique. Cellulose acetate was used as the semi permeable membrane. The capsule contains pore-forming water-soluble additives, which after coming in contact with aqueous medium, dissolves, resulting in an in situ formation of a micro porous structure. The effect of different formulation variables, like, ratio of drug to osmogen, solubilizing agent and level of pore former, stirring rate on the in vitro release was studied. Scanning electron microscopy of the membrane confirmed its porous, dense asymmetric nature. It was found that drug release rate increased with the increase in amount of osmogen and solubilizer, and independent of stirring rate. Indomethacin release was, directly proportional to the level of pore former, in the membrane. In the present investigation, efforts have been made to increase the release of poorly water soluble drug by means of porosity osmotic pump.     

盐酸维拉帕米不溶性微孔膜缓释胶囊的制备和体外释药试验

目的制备盐酸维拉帕米不溶性微孔膜胶囊剂并研究其体外释药行为。方法以乙酸纤维素（CA）为囊膜材料,聚乙二醇400为增塑剂,蘸胶法制备囊壳,并从致孔剂种类、比例、不同释放条件和内容物配方等因素考察盐酸维拉帕米的释药行为,通过扫描电镜对释药后囊壳结构进行观察。结果选用泊洛沙姆为致孔剂,增加其用量能使药物释放加快;囊内添加柠檬酸,能使药物释放更平稳。结论维拉帕米不溶性微孔膜缓释胶囊在体外能得到缓释效果,通过胶囊内微环境的控制,可以得到平稳的体外释药速度。     

Controlled porosity osmotic pump for the delivery of flurbiprofen

Controlled porosity osmotic pump contains water-soluble additives in the coating membrane, which in contact with aqueous environment dissolves and results in formation of micro porous membrane. The resulting membrane is substantially permeable to both water and dissolved drug. The drug release from this type of system is independent of pH and follows zero order kinetics. In the present investigation, effort has been made to study release mechanism of drug having low water solubility by means of controlled porosity osmotic pump. The capsule membrane was prepared by phase inversion technique. The phase inversion was carried by dipping the stainless steel mould in a 15% solution of cellulose acetate containing varying amounts of pore-forming agent, glycerol (50% to 70% w/w), followed by quenching in an aqueous solution (10% w/v glycerol), which resulted in the formation of the asymmetric membrane. The delivery orifices so formed were confirmed by release of an encapsulated dye from the capsule and scanning electron microscope (SEM). The drug selected for this study, Flurbiprofen, has low water solubility and hence is unable to create osmotic pressure to cause drug release. To enhance the solubility and its osmotic pressure, this study was conducted with a solubility enhancer sodium lauryl sulfate (SLS). The quantity of SLS was predetermined by conducting a solubility study of flurbiprofen with SLS. Release rate studies revealed that less than 10% of drug was released from the system without SLS, while about 75% release was observed from systems containing SLS. The release rate increased as the concentration of pore forming agent increased.     

In Situ Phase-Transited Asymmetric Membrane Capsules: A Means for Achieving Delayed and Osmotic Release for pH Solubility-Dependant Drugs

In the present study, an in situ nondisintegrating polymeric capsular system in achieving delayed as well as improved osmotic flow for the model drug cefadroxil was developed. In situ formed asymmetric membrane capsule was prepared by precipitation of the asymmetric membrane (AM) on the walls of conventional hard gelatin capsules in fabricated glass holders via a dry phase inversion process. The effect of different formulation variables were studied based on a 2(3) factorial design as one variable changed from one level to another, namely, the level of osmogen, ethylcellulose, and pore former, apart from studying the effect of varying osmotic pressure and agitation intensity on drug release. Scanning electron microscopy showed an outer, dense, non-porous region and an inner, lighter, porous region for the prepared AM inside, and a gelatin layer outside. Statistical testing (Dunnett multiple comparison test) was applied for in vitro drug release (n = 6) at P < 0.05. The best formulation in the design closely corresponded to the extra design checkpoint formulation by a similarity (f(2)) value of 96.18. The drug release was independent of the agitation intensity but dependent on the osmotic pressure of the dissolution media. The release kinetics followed the Higuchi model, and the mechanism of release was Fickian diffusion. LAY ABSTRACT: The asymmetric membrane capsule (AMC) is a unique drug delivery system that looks like a conventional hard gelatin capsule but has significant advantages over it. In the present study, a system was made that had an outer disintegrating hard gelatin capsule and an inner nondisintegrating polymeric capsular system for delivering a model drug cefadroxil. The inner nondisintegrating polymeric capsular system was the AMC, which was prepared by precipitation of the asymmetric membrane (AM) on the walls of conventional hard gelatin capsules in fabricated glass holders via a dry phase inversion process. The effect of different formulation variables that might affect the drug release were studied based on a 2(3) factorial design. The formulation variables were level of osmogen, ethylcellulose, and pore former. The effect of varying osmotic pressure and agitation intensity on drug release was also studied. Scanning electron microscopy showed an outer, dense, nonporous region and an inner, lighter, porous region for the prepared AM inside, and a gelatin layer outside. Statistical testing was applied for in vitro drug release. Results showed the drug release to be independent of the agitation intensity but dependent on the osmotic pressure of the dissolution media. The release kinetics followed the Higuchi model, and the mechanism of release was Fickian diffusion.     

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.     

Asymmetric membrane in membrane capsules: A means for achieving delayed and osmotic flow of cefadroxil

In the present study, both disintegrating and non-disintegrating polymeric capsular system in achieving delayed as well as improved osmotic flow for the model drug cefadroxil was developed. Asymmetric membrane in membrane capsule (AMMC) was prepared on a glass mold pin via phase inversion process in two steps. Step 1 included formation of a non-disintegrating, asymmetric membrane capsule (AMC) and step 2 involved formation of a pH sensitive, disintegrating, asymmetric membrane (AM) formed over the non-disintegrating membrane. The effects of different formulation variables were studied namely, level of osmogen, membrane thickness, and level of pore former. Effects of varying osmotic pressure, agitational intensity and intentional defect in the inner membrane on drug release were also studied. Membrane characterization by scanning electron microscopy showed dense regions with less pores on the outer surface of the disintegrating membrane and porous regions on the inner surface of the non-disintegrating asymmetric membrane. In vitro release studies for all the prepared formulations were done (n=6). The drug release was independent of pH, agitational intensity and intentional defect on the membrane but dependent on the osmotic pressure of the dissolution medium. The release kinetics followed the zero order and the mechanism of release was Fickian diffusion.     

Osmotically regulated flow of flurbiprofen through in situ formed asymmetric membrane capsule

An in situ formed non-disintegrating controlled release asymmetric membrane capsular system, offering improved osmotic effect, was used to deliver poorly water soluble drug flurbiprofen (model drug) to demonstrate how controlled release characteristics could be manipulated by design of polymeric capsule with an asymmetric membrane. In situ formed asymmetric membrane capsule was made by dry method via precipitation of asymmetric membrane on the walls of hard gelatin capsule. Effect of different formulation variables were studied based on 2(3) factorial design, namely, level of osmogen, ethylcellulose and pore former apart from studying the effect of varying osmotic pressure on drug release. Scanning Electron Microscopy showed an outer dense non porous region and an inner lighter porous region for the prepared asymmetric membrane inside and a gelatin layer outside. Statistical test (Dunnett Multiple Comparison Test) was applied for in vitro drug release at P>0.05. The best formulation closely corresponded to the extra design checkpoint formulation by a similarity (f(2)) value of 96.88. The drug release was independent of pH but dependent on the osmotic pressure of the dissolution medium. The release kinetics followed Higuchi model and mechanism of release was Fickian diffusion.     

Drug release behavior of polymeric matrix filled in capsule

A single unit sustainable drug release system was developed using hydroxypropyl methylcellulose (HPMC)-based matrices filled in capsule as the drug delivery device. Release behavior of propranolol HCl from these capsules was investigated and least square fitting was performed for the dissolution data with the different mathematical expressions. Effect of diluent, polymer, pH and hydrodynamic force on the drug release from the developed systems was investigated. The utilization of HPMC as a matrix former extended the drug release longer than 8 h. HPMC viscosity grades affected the drug release, that is, increasing the amount of fillers such as lactose and dibasic calcium phosphate enhanced the drug release rate of HPMC matrices. The hydrodynamic force, type and amount of incorporated polymer apparently influenced the drug release. The physiochemical properties of polymers and interaction between HPMC and other polymers were important factors for prolongation of the drug release. The release mechanism from HPMC-based matrices in capsules was the non-Fickian transport in which the sustainable drug release of HPMC capsules could be achieved by the addition of polymeric matrix.     

Osmotically regulated two-compartment asymmetric membrane capsules for simultaneous controlled release of anti-hypertensive drugs

In the present study, asymmetric membrane capsules (AMCs) with two compartments were successfully developed for simultaneous delivery of two poorly water-soluble drugs, Atenolol and Amlodipine Besylate, by using solubility modulation approach. Scanning electron microscopy (SEM) before dissolution showed presence of outer dense region and inner porous region for the prepared asymmetric membrane and the pore size increased after dissolution for both outer and inner layer. Diffuse reflectance spectroscopy (DRS) showed no incompatibility between the drug(s) and the excipients used in the study. The developed system was able to control the release of ATN and AMB by increasing the solubility through buffering agents of different strengths (0.25N to 1.0N). As the level of buffering agent was increased, the solubility of drugs also increased inside the asymmetric membrane capsule. The developed system was independent of the agitation intensity of the dissolution fluid but was dependent on the polymer diffusibility and osmotic pressure of the media, which clearly stated that osmotic pumping was the primary mechanism of drug(s) release from AMCs. The results of in-vitro demonstration of effect of membrane thickness on dissolution fluid entering AMCs showed that as the membrane thickness increased the volume of dissolution fluid entering into AMC decreased. The release kinetic studies of different formulations of AMCs showed that formulation code six, which consists of the highest amount of osmotic agents and optimum amount of buffering agents, was the best formulation, and it followed zero order release kinetics (r(2)=0.9990 for ATN and r(2)=0.9988 for AMB).     

Asymmetric Membrane Osmotic Capsules for Terbutaline Sulphate

The aim of the present study was to design an asymmetric membrane capsule, an osmotic pump-based drug delivery system of ethyl cellulose for controlled release of terbutaline sulphate. asymmetric membrane capsules contains pore-forming water soluble additive, sorbitol in different concentrations in the capsule shell membrane, which after coming in contact with water, dissolves, resulting in an in situ formation of a microporous structure. The terbutaline sulphate is a β-adrenoreceptor agonist widely used in the treatment of asthma. The oral dosage regimen of terbutaline sulphate is 5 mg twice or thrice daily, the plasma half-life is approximate 3-4 h and it produces GI irritation with extensive first pass metabolism. Hence, terbutaline sulphate was chosen as a model drug with an aim to develop controlled release system. Different formulations of ethyl cellulose were prepared by phase inversion technique using different concentrations of sorbitol as pore forming agent. It was found that the thickness of the prepared asymmetric membrane capsules was increased with increase in concentration of ethyl cellulose and pore forming agent, i.e. sorbitol. The dye release study in water and 10% sodium chloride solution indicates that, the asymmetric membrane capsules follow osmotic principle to release content. The pores formed due to sorbitol were confirmed by microscopic observation of transverse section of capsule membrane. Data of in vitro release study of terbutaline sulphate from asymmetric membrane capsules indicated that, the capsules prepared with 10% and 12.5% of ethyl cellulose and 25% of sorbitol released as much as 97.44% and 76.27% in 12 h, respectively with zero order release rate. Hence asymmetric membrane capsule of 10% ethyl cellulose and 25% of sorbitol is considered as optimum for controlled oral delivery of terbutaline sulphate.     

Fatty acid and water-soluble polymer-based controlled release drug delivery system

Sustained release capsule formulations based on three components, drug, water-soluble polymer, and water-insoluble fatty acid, were developed. Theophylline, acetaminophen, and glipizide, representing a wide spectrum of aqueous solubility, were used as model drugs. Povidone and hydroxypropyl cellulose were selected as water-soluble polymers. Stearic acid and lauric acid were selected as water-insoluble fatty acids. Fatty acid, polymer, and drug mixture was filled into size #0 gelatin capsules and heated for 2 h at 50 °C. The drug particles were trapped into molten fatty acid and released at a controlled rate through pores created by the water-soluble polymer when capsules were exposed to an aqueous dissolution medium. Manipulation of the formulation components enabled release rates of glipizide and theophylline capsules to be similar to commercial Glucotrol XL tablets and Theo-24 capsules, respectively. The capsules also exhibited satisfactory dissolution stability after exposure to 30 °C/60% relative humidity (RH) in open Petri dishes and to 40 °C/75% RH in closed high-density polyethylene bottles. A computational fluid dynamic-based model was developed to quantitatively describe the drug transport in the capsule matrix and the drug release process. The simulation results showed a diffusion-controlled release mechanism from these capsules.     

Preparation of a novel floating ring capsule-type dosage form for stomach specific delivery

Study objectives were to develop a unique floating ring capsule dosage form which combines gastric soluble and insoluble portions, and to evaluate its suitability for stomach specific drug delivery. New floating ring capsules were developed using different polymers and were compared for various parameters. The formulation with HPMC and sodium CMC has better floating properties. The effects of polymers concentration on drug release were studies by in vitro release studies. The interaction studies of combined drug with polymers were determined using FT-IR spectroscopy. The entrapped air within the gel barrier and lower densities of HPMC and sodium CMC resulted in better floating behavior. Steady slow gel formations showed prolonged drug release. The in vitro release rates were generally found to be faster with low concentration of carbopol showing release within 2 h, while formulations containing high amount of HPMC showed release in 8 h. In particular, the higher concentration of HPMC formulation shows the best drug release performance. A very low change in peak shift was observed only with sodium alginate formulations. Further, FT-IR measurements confirmed the absence of any chemical interactions. Results indicate that new floating ring capsule is a promise dosage form for stomach specific delivery.     

Effect of fill weight, capsule shell, and sinker design on the dissolution behavior of capsule formulations of a weak acid drug candidate BMS-309403

Two strengths of BMS-309403 capsules were developed from a common stock granulation. Dissolution testing of the capsules was conducted utilizing the USP apparatus 2 (paddle) with a neutral pH dissolution medium. Unexpectedly, the lower-strength capsules exhibited slower dissolution than the higher-strength capsules filled with the same stock granulation. Higher variability was also observed for the lower-strength capsules. This was found to be mainly caused by a low fill weight in a relatively large size hard gelatin capsule shell. Instead of bursting open, some gelatin capsule shells softened and collapsed onto the granulation, which delayed the release of the active drug. The problem was aggravated by the use of coil sinkers which hindered the medium flow around the capsules. Switching from the gelatin capsule shells to the HPMC (hydroxypropyl methylcellulose) shells reversed the dissolution rate ranking between the two capsule strengths. However, both dissolved at a slower rate initially than the gelatin capsules due to the inherent dissolution rate of the HPMC shells at pH 6.8. Notably, the HPMC shells did not occlude the granulation as observed with the gelatin shells. The study demonstrated that the dissolution of capsule formulations in neutral pH media was significantly affected by the fill weight, sinker design, and capsule shell type. Careful selection of these parameters is essential to objectively evaluate the in vitro drug release.     

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。     

麻黄复配胶软胶囊的制备及其稳定性研究

目的:探讨提高麻黄软胶囊稳定性的方法.方法:明胶与羟丙基甲基纤维素(HPMC)复配作为软胶囊的囊壳材料,减少明胶交联反应.采用中心复合试验设计,优选复配胶的处方和工艺,测定复配胶的凝胶性质,并进行复配胶软胶囊的稳定性考察.结果:复配胶处方确定为明胶(冻力180 g)、明胶(冻力240 g)、HPMC、甘油、水用量比为49∶26∶25∶30∶200,复配软胶囊胶凝时间5.72 min,崩解时限4.6 min,加速90 d的崩解时限11.2 min,加速90 d的累积溶出百分率86.6％.结论:明胶-HPMC复配可以提高麻黄软胶囊的稳定性.     

Effect of Fill Weight,Capsule Shell,and Sinker Design on the Dissolution Behavior of Capsule Formulations of a Weak Acid Drug Candidate BMS‐309403

Two strengths of BMS‐309403 capsules were developed from a common stock granulation. Dissolution testing of the capsules was conducted utilizing the USP apparatus 2 (paddle) with a neutral pH dissolution medium. Unexpectedly, the lower‐strength capsules exhibited slower dissolution than the higher‐strength capsules filled with the same stock granulation. Higher variability was also observed for the lower‐strength capsules. This was found to be mainly caused by a low fill weight in a relatively large size hard gelatin capsule shell. Instead of bursting open, some gelatin capsule shells softened and collapsed onto the granulation, which delayed the release of the active drug. The problem was aggravated by the use of coil sinkers which hindered the medium flow around the capsules. Switching from the gelatin capsule shells to the HPMC (hydroxypropyl methylcellulose) shells reversed the dissolution rate ranking between the two capsule strengths. However, both dissolved at a slower rate initially than the gelatin capsules due to the inherent dissolution rate of the HPMC shells at pH 6.8. Notably, the HPMC shells did not occlude the granulation as observed with the gelatin shells. The study demonstrated that the dissolution of capsule formulations in neutral pH media was significantly affected by the fill weight, sinker design, and capsule shell type. Careful selection of these parameters is essential to objectively evaluate the in vitro drug release.     

Formulation and development of hydrodynamically balanced system for metformin: in vitro and in vivo evaluation.

The objective of the present study was to develop a hydrodynamically balanced system of metformin as a single unit floating capsule. Various grades of low-density polymers were used for the formulation of this system. They were prepared by physical blending of metformin and the polymers in varying ratios. The formulation was optimized on the basis of in vitro buoyancy and in vitro release in simulated fed state gastric fluid (citrate phosphate buffer pH 3.0). Effect of various release modifiers was studied to ensure the delivery of drug from the HBS capsules over a prolonged period. Capsules prepared with HPMC K4M and ethyl cellulose gave the best in vitro percentage release and were taken as the optimized formulation. By fitting the data into zero order, first order and Higuchi model it was concluded that the release followed zero order release, as the correlation coefficient (R(2) value) was higher for zero order release. It was concluded from R(2) values for Higuchi model that drug release followed fickian diffusion mechanism. In vivo studies were carried out in rabbits to assess the buoyancy, as well as the pharmacokinetic parameters of the formulation using gamma scintigraphy. The formulation remained buoyant during 5h of study in rabbits. The comparative pharmacokinetic study was performed by administration of the optimized HBS capsules and immediate release capsules, both with radiolabeled metformin, using gamma counter. There was an increase in AUC in optimized HBS capsules of metformin when compared with immediate release formulation.     

尼莫地平柱塞型脉冲释药胶囊的制备

目的:制备尼莫地平柱塞型脉冲释药胶囊。方法:采用灌注法制备非渗透性囊体,以HPMC K15M为缓释骨架材料制备柱塞片,以PEG 6000和PEG 4000为基质制备尼莫地平滴丸,用柱塞片将滴丸密封于非渗透性囊体内制备尼莫地平柱塞型脉冲释药胶囊。结果:溶剂为丙酮/二氯甲烷/乙酸乙酯(2:0.7:0.3),醋酸纤维素溶液浓度为10.5%,柱塞片缓释骨架材料HPMC K15M和乳糖比例为1:10,制得的尼莫地平柱塞型脉冲释药胶囊体外呈明显的脉冲释放,释药时滞为4~5 h。结论:通过调节柱塞片中HPMC K15M和乳糖比例可调节脉冲胶囊的释药时滞,将尼莫地平制成滴丸可满足脉冲胶囊时滞后快速释药的要求。