Monolithic Osmotic Tablets for Controlled Delivery of Antihypertensive Drug

An oral monolithic osmotically controlled delivery system for nifedipine using asymmetric membrane technology was developed and evaluated. Unlike conventional osmotic systems, which require laser drilling, this system releases the drug in a controlled manner from asymmetric membrane coated core tablets. Asymmetric membrane is formed by dry process with phase inversion technology process using cellulose acetate as the coating material. Higher water influx of this membrane aids in delivery of nifedipine, which is highly water insoluble with low osmotic pressure. The porous structure of the membrane was confirmed by scanning electron microscopy. Influence of different osmotic agents on drug release was evaluated. In vitro release studies showed that as concentration of osmotic agents was increased, the drug release was also enhanced. Drug release from the developed monolithic system was independent of external agitation and pH of dissolution media. Comparative in vitro release data was obtained using different types of coating membranes like controlled porosity membrane and dense coating membrane with mechanically drilled orifice. Osmotic pressure generated in the system was determined using freezing point osmometer. The osmotic pressure developed was found to be linearly proportional to time and concentration of osmotic agent.     

Modified push-pull osmotic system for simultaneous delivery of theophylline and salbutamol: development and in vitro characterization

An oral osmotic system which can deliver theophylline and salbutamol sulphate simultaneously for extended period of time was developed and characterized in a view to reduce the problems associated with the multidrug therapy of asthma. Simple controlled porosity osmotic pump contained both drugs (in freely soluble form) did not provide satisfactory extended release of theophylline. A modified two-layered, push-pull osmotic system was developed by using the basic designs of various oral osmotic pumps, such as controlled porosity osmotic pump (CPOP), elementary osmotic pump (EOP) and push-pull osmotic pump (PPOP). Scanning electron microscopy of cellulose acetate coating membrane after dissolution revealed that 25% (w/w) of sorbitol can be used as an optimized concentration of pore forming agent with 25% (w/w) of plasticizer, which was kept constant. Formulations were initially developed for theophylline and the release was optimized by using two different soluble forms of theophylline with varying amount of hydrophilic polymer mixture in upper layer and polyethylene oxide (expandable hydrogel) in lower layer. Further, the release of salbutamol sulphate was optimized by keeping the drug in upper or lower layer or both layers. In vitro release studies showed satisfactory controlled release profiles of both drugs. The release profiles of both drug statistically compared with respective marketed controlled release formulations. An optimized system was selected to study the effect of concentration of pore forming agent and orifice diameter on the release of both drugs.     

Controlled porosity osmotic pumps of highly aqueous soluble drug containing hydrophilic polymers as release retardants

Controlled porosity osmotic pumps (CPOPs) are devoid of delivery orifice to release core contents and essentially possess pore-forming agent(s) in coating composition. When the pump comes in contact with aqueous media, pore-forming agent(s) generate pores through which core contents are delivered. Diltiazem hydrochloride (DLTZ) is a freely water-soluble drug and the release rates of DLTZ are higher from oral osmotic pumps including CPOPs, in which the drug release is controlled by concentration of pore-forming agents. The effect of appropriate concentration of hydroxypropyl methyl cellulose and sodium carboxy methyl cellulose mixture on the release of DLTZ from CPOPs was studied. In vitro drug release profiles were compared with that of different marketed controlled release formulations and statistically analysed to examine the suitability of CPOP for twice or once daily administration. Dissolution models were applied to drug release data in order to establish the mechanism of drug release and kinetics. Drug release from the CPOPs was effectively modified with the concentration of pore-forming agent in membrane and concentration of hydrophilic polymers in the core. CPOPs showed minimum 65% of consistent DLTZ release at 16 h. Statistical analysis confirmed that with an increase in the amount of hydrophilic polymers release rate decreased. Drug release from the systems follows Hixson-Crowell cube root model and mechanism of release follow non-Fickian diffusion.     

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.     

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.     

Investigation of Release Pattern of a Drug with Low Solubility Through Asymmetric Membrane Capsules

Asymmetric membrane capsules are a type of osmotic drug delivery systems. They are nondisintegrating capsules, which utilize osmotic pressure to drive the drug outwards for controlled delivery. Preceded by systems such as elementary osmotic pump, controlled porosity osmotic pump, single composition osmotic tablet this system has the advantage of simple and easy fabrication as it obviates the necessity of drilling an orifice into the drug delivery system. Moreover; it seems to be a low-cost alternative. The cellulose acetate capsule shell, on coming in contact with the aqueous medium shows in situ pore formation due to leaching of pore formers, which have been incorporated into the shell forming solution. Until date, a number of osmotic agents to the likes of sodium chloride, mannitol has been used to build up osmotic pressure inside the cell. The system is endowed with high water flux, which is a plus point for delivery of poorly soluble drugs like cephalexin in terms of increasing release rates. Studies envisaged in this research include the effect of different concentrations of different pore formers on in vitro drug release as well as the effect of modification of inner contents of the capsule. The system was successful in producing a gradual release of drug for 12 h.     

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.     

长春西汀双层渗透泵控释片的制备及体外释放度考察

目的制备难溶性药物长春西汀单室双层渗透泵控释片,并对其体外释药影响因素进行考察。方法利用正交设计优化了渗透泵处方,根据不同时间累积释放度对药物的释放情况进行了考察。结果渗透泵控释片的最优处方为长春西汀15 mg、HPMC 140 mg、PEO 65 mg、氯化钠14 mg,包衣增质量24 mg。其体外释药特征符合控释制剂的要求。结论本渗透泵片以渗透压差为释药动力,能在14 h内良好的控制长春西汀零级释放。     

An insight to osmotic drug delivery

In a typical therapeutic regimen the drug dose and the dosing interval are optimized to maintain drug concentration within the therapeutic window, thus ensuring efficacy while minimizing toxic effects. For many decades treatment of acute disease or a chronic illness has been mostly accomplished by delivery of drugs to patients using various pharmaceutical dosage forms. The immediate release conventional dosage form does not provide the proper plasma concentration of drug for prolonged period. This results in the development of various controlled drug delivery system. Among which the osmotic drug delivery systems (ODDS) are gaining importance as these systems deliver the drug at specific time as per the path physiological need of the disease, resulting in improved patient therapeutic efficacy and compliance. They work on the principle of osmotic pressure for controlling the delivery of the drug. Osmotic drug delivery systems with their versatility and their highly predictable drug release rates offer various biomedical advantages when given parenterally like reduced dose, targeting of site, avoiding gastrointestinal stability, hepatic bypass of drug molecule and follows zero order kinetics. Osmosis is an aristocratic phenomenon that seizes the attention for its exploitation in zero-order drug delivery systems. The release of the drug is independent of pH and physiological factors of the GIT to a large extent. Optimizing semi-permeable membrane characteristics and osmotic agent can modulate delivery of drug from the system. This review highlights the theoretical concept of drug delivery, history, types of oral osmotic drug delivery systems, factors affecting the drug delivery system, advantages and disadvantages of this delivery system, theoretical aspects, applications, and the marketed status.     

Factors Affecting the Release of Nifedipine from a Swellable Elementary Osmotic Pump

Oral osmotic devices including an elementary osmotic pump (EOP) are efficient systems for the delivery of drugs with high/moderately water-solublility. In this study we designed a new type of EOP for the efficient delivery of poorly water-soluble and practically insoluble drugs. In this system, called swellable elementary osmotic pump (SEOP), drug is released from the delivery orifice in the form of a very fine dispersion of drug in gel which is ready for dissolution and absorption. Factors affecting the release of drug from the SEOP containing a poorly water-soluble drug, nifedipine, were explored extensively. To this end, effect of swelling and wetting agents, orifice size, concentration of osmotic agent, and hydrophobic plasticizer were investigated. Interestingly, in the absence or low concentration of a hydrophobic plasticizer (caster oil), the osmotic devices did not retain their integrity in dissolution media. Caster oil in concentration of > 1% was necessary for tablets to retain their integrity during dissolution process. A zero-order release kinetics for nifedipine was achieved following the effective optimization of the concentrations of swelling agent, osmotic agent, wetting agent, and also size of orifice and membrane thickness in SEOP. The zero-order release lasted for 10 hr at pH 6.8 dissolution medium. The designed SEOP is suggested as an efficient controlled delivery system for oral delivery of a poorly water soluble drug such as nifedipine.     

Factors affecting the release of nifedipine from a swellable elementary osmotic pump

Oral osmotic devices including an elementary osmotic pump (EOP) are efficient systems for the delivery of drugs with high/moderately water-solubility. In this study we designed a new type of EOP for the efficient delivery of poorly water-soluble and practically insoluble drugs. In this system, called swellable elementary osmotic pump (SEOP), drug is released from the delivery orifice in the form of a very fine dispersion of drug in gel which is ready for dissolution and absorption. Factors affecting the release of drug from the SEOP containing a poorly water-soluble drug, nifedipine, were explored extensively. To this end, effect of swelling and wetting agents, orifice size, concentration of osmotic agent, and hydrophobic plasticizer were investigated. Interestingly, in the absence or low concentration of a hydrophobic plasticizer (caster oil), the osmotic devices did not retain their integrity in dissolution media. Caster oil in concentration of > 1% was necessary for tablets to retain their integrity during dissolution process. A zero-order release kinetics for nifedipine was achieved following the effective optimization of the concentrations of swelling agent, osmotic agent, wetting agent, and also size of orifice and membrane thickness in SEOP. The zero-order release lasted for 10 hr at pH 6.8 dissolution medium. The designed SEOP is suggested as an efficient controlled delivery system for oral delivery of a poorly water soluble drug such as nifedipine.     

Development and characterization of transdermal drug delivery systems for diltiazem hydrochloride

Transdermal drug delivery system of diltiazem hydrochloride was developed to obtain a prolonged controlled drug delivery. Both the matrix diffusion controlled (MDC) and membrane permeation controlled (MPC) systems were developed. The matrix diffusion controlled systems used various combinations of hydrophilic and lipophillic polymers, whereas membrane permeation controlled systems were developed using the natural polymer chitosan. The MDC systems were prepared using the cast film method and the MPC systems by an adhesive sealing technique. Both the systems were characterized for in vitro and in vivo performance. The MDC systems were characterized for physicochemical properties such as tensile strength, moisture content, and water vapor transmission. The in vitro release studies showed that the release from the matrix diffusion controlled transdermal drug delivery systems follows a nonfickian pattern and that from the membrane permeation controlled transdermal drug delivery systems follow zero-order kinetics. The release from the matrix systems increased on increasing the hydrophilic polymer concentration, but the release from the membrane systems decrease on cross-linking of the rate controlling membrane and also on addition of citric acid to the chitosan drug reservoir gel. The in vivo studies of the selected systems showed that both systems are capable of achieving the effective plasma concentration for a prolonged period of time. The MPC system achieved effective plasma concentration a little more slowly than the MDC system, but it exhibited a more steady state plasma level for 24 hr.     

Recent advances in asymmetric membrane capsule based osmotic pump: a patent overview

Conventional drug delivery systems have little control over their drug release and almost no control over the effective concentration at the target site. This kind of dosing pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be delivered in a controlled pattern over a long period of time by the process of osmosis. Osmotic devices are the most promising strategy based systems for controlled drug delivery. They are the most reliable controlled drug delivery systems and could be employed as oral drug delivery systems. The present review is concerned with the study of drug release through asymmetric membrane capsule systems. When these systems are exposed to water, low levels of water soluble additive are leached from polymeric material i.e. the semipermeable membrane and the drug releases in a controlled manner over an extended period of time. Drug delivery from this system is not influenced by the different physiological factors within the gut lumen and the release characteristics can be predicted easily from the known properties of the drug and the dosage form. This patent review is useful in the knowledge of asymmetric membrane capsule osmotic pump for its application.     

格列齐特推拉式渗透泵的制备

目的:优化格列齐特推拉式渗透泵的处方,并对影响释放度的各种因素进行考察。方法:以紫外分光光度法对格列齐特推拉式渗透泵的体外释放度曲线进行测定,应用f2因子法为手段,对不同处方中药物释放曲线的相似性进行评价,对处方进行优化。结果:包衣增重、片心硬度及助推层中氯化钠的用量对药物的释放曲线有显著影响,释药孔径大小、转速以及打片时的填料顺序对释放曲线无显著性影响。结论:应用推拉式渗透泵系成功制备了格列齐特渗透泵,控释时间达12 h。     

A novel solubility-modulated granules through porosity osmotic pump for controlled carvedilol delivery

A method for the preparation of porosity osmotic pump granules was obtained by modulating carvedilol solubility with tartaric acid. Controlled porosity of the membrane was accomplished by the use of pore-forming agent in the coating. In this study, carvedilol was chosen as a model drug with an aim to develop a zero-order release system; tartaric acid was used as the solubility promoter; NaCl was used as the osmotic agent; cellulose acetate (CA) was used as the materials of semipermeable membrane; and PEG-400 was used as the pore-forming agent in the semipermeable membrane. The influence of different factors or levels on the in vitro release was studied. In order to simulate the gastrointestinal tract environments, two kinds of pH media (pH 1.5 and 6.8) on drug release were studied in this research, respectively. This porosity osmotic pump was optimized by single factor design experiments, and it was found to deliver carvedilol at a zero-order rate within 12?h and controlled release for 24?h. We drew a conclusion that the solubility-modulated porosity osmotic pump system is simple to prepare and might be used for the preparation of osmotic pump system of other poorly water-soluble drugs with alkaline or acid groups.     

Evaluation of some compression aids in tableting of roller compacted swellable core drug layer

Swellable core technology (SCT) represents a broadly applicable oral osmotic drug delivery platform for the controlled release of drugs. SCT tablets control drug delivery by using osmosis to regulate the influx of water into the tablet's core. The tablet consists of two layers; drug layer and sweller layer, with a semi-permeable membrane coating and delivery port located in the drug layer side of the tablet.     

马钱子碱双层渗透泵控释片的研制及处方优化

目的 制备马钱子碱双层渗透泵控释片,通过正交试验优化处方,并探讨最佳处方的释药机制。方法 以累积释放度及释药曲线是否呈线性作为评价指标,单因素试验考察PEO N750、PEO Coagulant和致孔剂PEG 4000用量以及包衣增重对马钱子碱双层渗透泵控释片体外释药情况的影响。设计正交试验优化马钱子碱双层渗透泵控释片处方,并对最佳处方体外释药行为进行模型拟合。结果 正交试验结果表明,PEO N750用量对马钱子碱双层渗透泵控释片体外释药行为有显著性影响（P<0.05）,最佳处方：PEO N750 175 mg,PEO Coagulant 65 mg,PEG 4000用量为11%,包衣增重7%。马钱子碱双层渗透泵控释片最佳处方在12 h内释药速率恒定,12 h内累积释放度达93.14%。结论 研制的马钱子碱双层渗透泵控释片在12 h内具有明显的零级释放特征,可有效控制马钱子碱缓慢、恒速释放。     

A novel solubility-modulated granules through porosity osmotic pump for controlled carvedilol delivery

A method for the preparation of porosity osmotic pump granules was obtained by modulating carvedilol solubility with tartaric acid. Controlled porosity of the membrane was accomplished by the use of pore-forming agent in the coating. In this study, carvedilol was chosen as a model drug with an aim to develop a zero-order release system; tartaric acid was used as the solubility promoter; NaCl was used as the osmotic agent; cellulose acetate (CA) was used as the materials of semipermeable membrane; and PEG-400 was used as the pore-forming agent in the semipermeable membrane. The influence of different factors or levels on the in vitro release was studied. In order to simulate the gastrointestinal tract environments, two kinds of pH media (pH 1.5 and 6.8) on drug release were studied in this research, respectively. This porosity osmotic pump was optimized by single factor design experiments, and it was found to deliver carvedilol at a zero-order rate within 12?h and controlled release for 24?h. We drew a conclusion that the solubility-modulated porosity osmotic pump system is simple to prepare and might be used for the preparation of osmotic pump system of other poorly water-soluble drugs with alkaline or acid groups.     

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.     

Use of scoring to induce reproducible drug delivery from osmotic pulsatile tablets

An osmotic-controlled pulsatile delivery technology was developed for targeted drug delivery. This novel system consists of a tablet core surrounded by an osmotic coating that has been mechanically compromised in strategic locations to facilitate reliable drug release at a given time point after administration. The tablet core contains a high drug load in addition to several osmotic agents and swellable polymers, and the surrounding mechanically-compromised osmotic coating consists of a semipermeable membrane that has been scored with a razor blade in several key locations. The components in the tablet core attract water into the core, causing it to swell and propagate the scores in the coating along the length of the tablet. After the scores have fully propagated, the coating bursts open, releasing the tablet core’s contents, including the drug, into the surrounding media. The variables that were investigated in this study included the configuration of the scores in the coating, the length of the scores, and the distance between the scores. The delivery system developed in this work is able to generate a reproducible dissolution profile consisting of a specific targeted lag time, between five minutes and two hours, followed by immediate release of the drug from the core. The performance of the system was validated in vitro using the drug salicylic acid. Unlike previously developed osmotic pulsatile delivery systems, the present system is able to accommodate higher drug loading levels, it is easier to manufacture, and has demonstrated more reproducible burst times (i.e. burst time) than several other pulsatile systems.