Development and evaluation of extended release formulations of isosorbide mononitrate based on osmotic technology

Extended release formulations of isosorbide mononitrate (IMN), based on osmotic technology, were developed. Target release profile was selected and different variables were optimized to achieve the same. Formulation variables like type (PVP, PEG-4000, and HPMC) and level of pore former (0-55%, w/w of polymer), percent weight gain were found to affect the drug release from the developed formulations. Drug release was inversely proportional to the membrane weight but directly related to the initial level of pore former in the membrane. Burst strength of the exhausted shells was inversely proportional to the level of pore former, but directly affected by the membrane weight. Satisfactory burst strength (more than 320 g) was obtained when PVP was used as pore former (up to 55%, w/w of polymer) at the membrane weight of 7.5% and more. The release from the developed formulations was independent of pH and agitational intensity, but dependent on the osmotic pressure of the release media. Results of SEM studies showed the formation of pores in the membrane from where the drug release occurred. The formulations were found to be stable after 3 months of accelerated stability studies. Prediction of steady-state levels showed the plasma concentrations of IMN to be within the desired range.     

Chitosan-based controlled porosity osmotic pump for colon-specific delivery system: screening of formulation variables and in vitro investigation

A microbially triggered colon-targeted osmotic pump (MTCT-OP) has been studied. The gelable property at acid condition and colon-specific biodegradation of chitosan were used to: (1) produce the osmotic pressure, (2) form the drug suspension and (3) form the in situ delivery pores for colon-specific drug release, respectively. The scanning electron microscopy (SEM) study and the calculation of membrane permeability were applied to elucidate the mechanism of MTCT-OP. The effects of different formulation variables, including the level of pH-regulating excipient (citric acid) and the amount of chitosan in the core, the weight gain of semipermeable membrane and enteric-coating membrane, and the level of pore former (chitosan) in the semipermeable membrane, have been studied. Results of SEM showed that the in situ delivery pores could be formed in predetermined time after coming into contact with dissolution medium, and the number of pore was dependent on the initial level of pore former in the membrane. The amount of budesonide release was directly proportional to the initial level of pore former, but inversely related to the weight of semipermeable membrane. The effects of variations in the level of citric acid and chitosan in the core formulation on drug release were studied. The different levels of enteric-coating membrane could prevent cellulose acetate membrane (containing chitosan as pore former) from forming pore or rupture before contact with simulated colonic fluid, but had no effect on the drug release. Budesonide release from the developed formulation was inversely proportional to the osmotic pressure of the release medium, confirming that osmotic pumping was the major mechanism of drug release. These results showed that MTCT-OP based on osmotic technology and microbially triggered mechanism had a high potential for colon-specific drug delivery.     

Push-pull osmotic pump for zero order delivery of lithium carbonate: development and in vitro characterization

Lithium carbonate, a drug with narrow therapeutic index, needs therapeutic drug monitoring and dose adjustment to maintain lithium level within the therapeutic window. Conventional formulations of lithium carbonate exhibit immediate drug release causing swing/fluctuations in the plasma concentration of lithium, consequently leading to unfavorable side-effects and make dose adjustment difficult. The push-pull osmotic pump has been developed for zero order delivery of lithium carbonate for a period of 24 h. The effect of various formulation variables on bilayer core tablet and its semi permeable coating along with orifice diameter have been investigated and optimized for desired drug release profile. Drug release was found to be inversely proportional to the membrane thickness but directly related to the amount of pore formers in the semipermeable membrane. Images from a scanning electron microscope confirmed the presence of pores in the semipermeable membrane which facilitated the required water penetration. No distortion or change in orifice shape was noticed prior to and after the dissolution study. Drug release from the developed formulation was found to be independent of pH, agitation intensity and agitation mode but depended on osmotic pressure of dissolution media.     

Development and evaluation of oral osmotic pump of butorphanol tartrate

Abstract

Butorphanol is potent analgesic useful in pain management. However, because of high first-pass metabolism butorphanol is not available in market as oral dosage form. Drugs that undergo extensive first-pass metabolism can be delivered orally if protected in the stomach, and proximal small intestine. An oral controlled porosity osmotic pump (CPOP) was designed to deliver butorphanol tartrate that can maintain therapeutic blood concentration up to 24?h. The target release profile for extended release formulation was calculated by Wagner Nelson de-convolution using published immediate release blood concentration data for oral route. Composition of the core and coating were optimized using USFDA approved ingredients by evaluation of the drug release. Drug release from the developed system was inversely proportional to the weight gain and directly related to the level of pore former. Scanning electron microscopy (SEM) confirmed the formation of pores in the coating membrane on contact with water which lead to drug to release. Kinetic models were applied to drug release data to establish the drug release mechanism. The developed osmotic system effectively delivers selected drug at a predetermined rate for extended period.     

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.     

Gastroretentive drug delivery system of Ranitidine hydrochloride based on osmotic technology: development and evaluation

Gastroretentive drug delivery systems (GRDDS) of Ranitidine hydrochloride (RHC) has been designed based on the osmotic technology, with the floating and swelling features in order to prolong the gastric retention time. The developed system consisted of osmotic core (containing drug, osmotic agent and hydrophilic polymers), coated with semipermeable membrane (SPM) which is then further coated with compression coating of gelling agent (HPMC K4M) containing gas generating agent (citric acid). All the developed formulations were evaluated for floating lag time, duration of floating, drug content and in-vitro drug release profile. Formulation variables like levels of hydrophilic polymer (0-18.26%w/w), type of plasticizer (PEG-400, Dibutyl phthalate), coat thickness of SPM (60-100 microm), were found to affect the drug release from the developed formulations. Drug release was directly proportional to hydrophilic nature of plasticizer but inversely proportional to the levels of hydrophilic polymer and coat thickness of SPM. Drug release from developed formulations was independent of level of gas generating agent in compression coat, pH and agitation intensities of release media but dependent on osmotic pressure of the release media. All the developed formulation showed floating lag time of less than 2 min (desired) and were floated for more than 12 hr. Floating lag time was inversely related to level of citric acid in compression coat and directly related to the density of the developed formulations. The manufacturing procedure was found to be reproducible and formulations were stable after 3 months accelerated stability study. Prediction of steady state levels showed the plasma concentrations of RHC to be within desired range.     

茶碱的时辰给药系统及其在犬体内的药物动力学

目的 制备一种体外具有"慢速-快速"双相释药特征的茶碱时辰给药系统以用于哮喘的夜间治疗,并考察其在犬体内的药动学.方法 分别以磷酸钠和氯化钠为内外层渗透推动剂,制备双层片片芯,以CA-PEG400-DEP(54.5:36.4:9.1,)为包衣膜组成给药系统.考察包衣膜厚度对茶碱释放的影响,及经口送服后时辰给药系统和缓释片在犬体内的药动学.结果 时辰给药系统包衣增重不影响其双相释药特征,系统体外的累积释放量随包衣的增重而减小.犬体内药动学研究表明较之缓释片,时辰给药系统的Tmax延长,Cmax减小.包衣增重影响时辰给药系统的生物利用度,每片包衣增重19、9 mg时,其相对生物利用度约为50%,每片包衣增重6 mg时,其相对生物利用度约为100%.结论 成功制备了双相释药特征的茶碱时辰给药系统.较之缓释片,可提前至晚9:30服药在清晨达峰浓度,且达峰后可长时间维持较高的血药浓度.     

星点设计-效应面法优化单硝酸异山梨酯微孔渗透泵片处方

目的:应用星点设计-效应面法优化单硝酸异山梨酯微孔渗透泵片处方.方法:以渗透压活性物质用量、致孔剂用量、包衣增重量为影响片剂释放的主要因素,2、4、7、9、12 h的药物累积释药量为效应值,应用Design Expert进行处方优化,并对优化处方进行验证.结果:成功找到了最优释药区域;优化处方呈零级释放特性.结论:通过星点设计-效应面法成功建立了处方优化模型,实现了单硝酸异山梨酯微孔渗透泵片的处方筛选.     

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.     

Microporous bilayer osmotic tablet for colon-specific delivery

Microporous bilayer osmotic tablet bearing dicyclomine hydrochloride and diclofenac potassium was developed using a new oral drug delivery system for colon targeting. The tablets were coated with microporous semipermeable membrane and enteric polymer using conventional pan-coating process. The developed microporous bilayer osmotic pump tablet (OPT) did not require laser drilling to form the drug delivery orifice. The colon-specific biodegradation of pectin could form in situ delivery pores for drug release. The effect of formulation variables like inclusion of osmogen, amount of HPMC and NaCMC in core, amount of pore former in semipermeable membrane was studied. Scanning electron microscopic photographs showed formation of in situ delivery pores after predetermined time of coming in contact with dissolution medium. The number of pores was dependent on the amount of the pore former in the semipermeable membrane. In vitro dissolution results indicated that system showed acid-resistant, timed release and was able to deliver drug at an approximate zero order up to 24 h. The developed tablets could be effectively used for colon-specific drug delivery to treat IBS.     

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.     

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.     

Formulation and evaluation of extended release asymmetric membrane capsules of atenolol

The objective of this study was to demonstrate that the asymmetric membrane capsule can be used to deliver a poorly water soluble drug with a pH dependent solubility such as atenolol for extended periods of time by modulating solubility with organic acid. In osmotic systems, the release rate of an excipient relative to the release rate of the drug is an important factor that determines the duration of drug release. Consequently, for maintaining the desired pH over the entire period of drug dissolution a suitable thickening and suspending agent can be incorporated. By optimizing the concentration of thickening agent, it is possible to extend the availability of pH modifier in the core to provide an osmotic driving force or solubilization over the entire delivery period, so that the desired profile can be achieved for an active agent that has lower solubility characteristics. Finally, it was observed that the release rate of atenolol was influenced by the concentration of citric acid, mannitol and hydroxypropyl methylcellulose (HPMC). Results of scanning electron microscopy studies showed the formation of pores in the membrane from where the drug release occurred. The optimal formulation was found to be able to deliver atenolol at the rate of approximate zero-order up to 24 h, independent of pH of release media and agitation rate.     

Osmotically controlled oral delivery of ciprofloxacin through asymmetric membrane capsules

Asymmetric membrane capsules (AMCs) are based on the concept of osmotic pressure but are much simpler to manufacture. Further, they can be suitably optimized by varying the parameters like concentration of pore former, polymer, osmotic agents and solubility enhancers to cater the specific needs of a particular formulation. The main objective of the present work was to exploit the concept of AMCs for the controlled delivery of poorly soluble anti-infective drugs. Ciprofloxacin was chosen as the model drug. Nine AMCs (F1-F9) with varying concentrations of cellulose acetate [CA] (polymer-12% w/v, 16% w/v and 20% w/v) and glycerol (pore former- 50% w/w, 60% w/w and 70% w/w of polymer) were prepared. AMCs F1-F3 were discarded because of poor rigidity. 18 formulations (F4A-F9C) were prepared with the remaining 6 AMCs by varying concentrations of mannitol in the core (osmogen-15% w/w, 25% w/w and 50 % w/w of drug). F6C prepared with 16% CA, 70% glycerol and 50% mannitol gave highest release (57.93 +/- 0.93 %) after 12 h. Scanning electron microscopy revealed asymmetric structure of the membrane and osmotic release (zero order) through pores formed in situ was confirmed. Three concentrations of tartaric acid were used in F6C (T1-5%, T2-15%, T3-20%) for further optimization. T3 gave maximum release after 12 h (82.21 +/- 0.71%) and was selected as final optimized formulation. The study concluded that AMCs containing a suitable osmogen and a solublizer, can successfully deliver poorly soluble anti-infective drugs in a controlled manner.     

Novel osmotic pump tablet using core of drug-resin complexes for time-controlled delivery system

A novel elementary osmotic pump tablet was developed. The system uses the core of drug-resin complexes (DRCs) loaded with propranolol hydrochloride (PNH) for time-controlled delivery. In traditional osmotic pump tablets (OPTs), the lag time was always minimized. However, in the DRCs osmotic pump tablet (DRCOPT), the lag time was increased to achieve the time-controlled delivery. The quantity of osmotic agent in the core and channeling agent in the coating solution as well as weight gain were confirmed to be essential for the release behavior. A spherical symmetric design was applied to the optimization of the DRCOPT. The optimal formulation mainly consisted of DRC 100 mg, polyethyleneoxide (N80) 182 mg, and NaCl 30 mg. The ratio of cellulose acetate (CA)/polyethylene glycol 4000 was 15:3 (w/w) in coating solution, and the weight gain was 8%. The release behavior of the optimal DRCOPT was evaluated in media with different pH, rotation speeds, and ionic strength. It was found to generate a 2-h lag time, to deliver PNH at a rate of zero order from 2 h to 14 h in the medium of NaCl 0.15 mol/l, and the cumulative release at 24 h was 94%. Drug relee was independent of pH and rotation speed, but was proportional to ionic strength. In summary, the lag time could be used in therapeutic regimens with the characteristics of chronotherapy because of the lag time and provides a new concept for the development of osmotic pumps.     

布地奈德固体分散体增溶型渗透泵片的研制及其释药机制

制备布地奈德固体分散体增溶型单层渗透泵片（以下简称布地奈德渗透泵片）,并进行其释药机制研究。方法：用超临界流体技术制备的布地奈德-聚氧乙烯N750固体分散体作为含药片芯,以提高难溶性药物的溶解度;通过单因素实验优化片芯处方和包衣膜处方,制备布地奈德渗透泵片;设计实验考察包衣膜内外渗透压差对制剂稳态释药速率的影响,阐述其释药机制。结果：药物溶解度、促渗透剂种类和用量、增塑剂用量均对布地奈德渗透泵片的体外释药行为有影响,优化处方的体外释药方程为：Q=7.6077t＋0.7764,r=0.9997;其释药行为主要受包衣膜内外溶液渗透压控制,扩散释药仅占整个药物释放的30.39％。结论：渗透泵机制在布地奈德渗透泵片释药过程中占主导地位,体外释药符合零级动力学过程。     

Preparation of monolithic osmotic tablet of quercetin loaded by solid dispersion

The objective of this study was to prepare monolithic osmotic tablet of quercetin for controlled drug release. Quercetin-PVP solid dispersion was prepared to enhance its solubility and dissolution rate. Solid dispersion, suspending agents, osmotic agents and other conventional excipients were used as tablet core composition and cellulose acetate (CA) with plasticizer as release controlling membrane. Different formulation variables, the amounts of PEO (polyethylene oxide), NaCl, plasticizer, and coating weight gain were optimized to gain the optimum formulation. The mechanism of drug release from monolithic osmotic tablet was also discussed. The optimal monolithic osmotic pump tablet could deliver quercetin at the rate of approximate zero-order up to 12 h, and the cumulative release was 90.74%. The developed monolithic osmotic system for quercetin loaded by solid dispersion was found to be a promising approach for controlled release of poorly-water soluble drug candidates.     

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).     

Osmotic pellet system comprising osmotic core and in-process amorphized drug in polymer-surfactant layer for controlled delivery of poorly water-soluble drug

The aim of the present investigation was to develop controlled porosity osmotic system for poorly water-soluble drug based on drug in polymer-surfactant layer technology. A poorly water-soluble drug, glipizide (GZ), was selected as the model drug. The technology involved core of the pellets containing osmotic agent coated with drug dispersed in polymer and surfactant layer, finally coated with release-retardant layer with pore former. The optimized drug-layer-coated pellets were evaluated for solubility of GZ at different pH conditions and characterized for amorphous nature of the drug by differential scanning calorimetry and X-ray powder diffractometry. The optimized release-retardant layer pellets were evaluated for in vitro drug release at different pH, hydrodynamic, and osmolality conditions. The optimized drug layer showed improvement in solubility (10 times in pH 1.2, 11 times in pH 4.5, and 21 times in pH 6.8), whereas pellets coated with cellulose acetate (15.0%, w/w, weight gain) with pore former triethyl citrate (10.0%, w/w, of polymer) demonstrated zero-order drug release for 24 h at different pH conditions; moreover, retardation of drug release was observed with increment of osmolality. This system could be a platform technology for controlled delivery of poorly water-soluble drugs.     

硝苯地平推拉式渗透泵片体外释放影响因素的研究

目的：本实验的目的是以难溶性药物硝苯地平为模型药物来研究推拉式渗透泵片剂中药物层和推动层的配方中聚合物聚氧乙烯的用量、氯化钠的用量、控释层包衣增重以及药物层和推动层的比例对药物释放的影响。方法：采用推拉式渗透泵设计,分别考察聚氧乙烯-N80在药物层中的不同用量、聚氧乙烯Coagulant在推动层中的不同用量以及氯化钠在推动层中不同用量的7个配方,7个配方片芯同时采用欧巴代CA包衣进行半透膜控释包衣,因片重大小不同,无法同时得到相同的包衣增重,所以结合实际包衣增重的数据,采用统计分析软件对包衣片在不同时间的药物释放数据进行建模分析。结果：统计结果表明欧巴代CA的包衣增重对药物释放有显著影响（P〈0.05）,随着包衣增重的增加,药物的释放变慢。聚氧乙烯N-80在药物层中的用量对药物释放也有显著影响（P〈0.05）,随着聚氧乙烯N-80在药物层中用量的增加,药物的释放变慢。而聚氧乙烯Coagulant和氯化钠在推动层的用量变化,在配方考察的比例范围内对药物的释放的影响不显著。对20小时的药物释放分析结果表明,药物层与推动层的比例对药物的后期释放有显著影响（P〈0.05）。药物层与推动层的比例越高,药物后期释放得越慢。