Lithium acetate gastrointestinal diffusion system. Part 2: Lithium acetate multi-unit gastrointestinal diffusion system: preparation and release rate studies

The method of obtaining the multi-unit gastrointestinal diffusion system (m-GDS), containing lithium acetate, consists in encapsulating the lithium acetate in a form of microballs and thereafter coating the resulting microballs with a porous membrane which controls the diffusion rats of the drug. For the coating, a water-insoluble polymer (cellulose acetate) and two types of polymer-modifying agents (cetyl alcohol and shellac) were used. In this paper in vitro studies of drug release from the unit in relation to the microballs' coating and mass, and exposed surface area of the capsules are presented. Most in vitro systems provide zero-order dry delivery by appropriate selection of manufacturing parameters.     

In vitro study of gastrointestinal diffusion system using disopyramide phosphate

Gastrointestinal Diffusion System (GDS) provides release of a drug by means of a controlled source of diffusion energy. The unit can possibly be used for all soluble agents in which solubility is independent of the pH of the gastrointestinal contents as is the case with disopyramide phosphate. The GDS consists of a soluble tablet-core, surrounded by a cellulose acetate film containing a soluble pore-creating agent. When the pore-creating agent is removed from the coating film, the cellulose acetate membrane which remains is of a porous nature, which controls the diffusion rate of the drug. The release rate of the drug can be varied by changing the composition and mass of the membrane. The resultant system in vitro provides the zero-order drug delivery due to the appropriate selection of manufacturing parameters.     

Diltiazem multi-dose gastrointestinal diffusion system: preparation and release rate studies

The present paper is concerned with a multi-dose gastrointestinal diffusion system, releasing diltiazem through a controlled source of diffusional energy. The method calls for: a) encapsulation of the drug in a microball form, and b) coating of the resulting microballs by a porous membrane which controls the diffusion rate of the drug. The system would be expected to deliver the drug at a declining rate, due to the lower solubility of diltiazem hydrochloride in the intestinal than in the stomach fluid. To maintain a constant drug diffusion rate in the intestinal fluid, a membrane-modifying agent soluble in the intestinal tract (EudragitR L.) was introduced into the cellulose acetate microball coating. In this paper in vitro studies of drug release from the unit in relation to microball coating and coating mass are presented. The system provides a zero-order drug deliver in vitro, as the result of an appropriate selection of manufacturing parameters.     

Mechanism of diffusion of monosubstituted benzoic acids through ethylene-vinyl acetate copolymers.

Ethylene-vinyl acetate (EVAc), a biocompatible copolymer, has been employed as the rate-controlling membrane in several drug delivery systems. To study the mechanism(s) of diffusion of drugs through EVAc membranes, the diffusion, permeability, and partition coefficients of monosubstituted benzoic acids were studied as a function of vinyl acetate content. The diffusion coefficients were found to occupy a narrow range, but the permeability and partition coefficients were found to increase in a nonlinear fashion as a function of vinyl acetate content, indicating that the diffusion process was partition governed. The partitioning data were analyzed on the basis of the partitioning between the vinyl acetate moiety and the aqueous phase, assuming the formation of 1:1 benzoic acid:vinyl acetate complexes. The effects of ionization and the addition of 2-propanol to the diffusion medium were studied. The results suggest that the un-ionized neutral forms of the benzoic acids are responsible for transport across the copolymer. Altering the composition of the medium by addition of 2-propanol increased the donor phase solubility of the acid, the steady-state rate, and the permeability, suggesting that cosolvent modification provides an excellent chemical means to increase release rates.     

Controlled release of triprolidine using ethylene-vinyl acetate membrane and matrix systems.

The studies on the permeability of triprolidine through ethylene-vinyl acetate (EVA) copolymer membrane using two-chamber diffusion cell was carried out to develop the controlled delivery system. To evaluate the effect of drug concentration in reservoir, polyethylene glycol (PEG) 400 was added to saline solution as a solubilizer and a sink condition was maintained in the receptor solution. The permeation rate of drug through EVA membrane was proportional to PEG 400 volume fraction. A linear relationship existed between the permeation rate and the reciprocal of the membrane thickness. Triprolidine-containing matrix was fabricated with EVA copolymer to control the release of the drug. The plasticizers was added for preparing the pore structure of EVA membranes to increase the drug release. The effects of PEG 400, vinyl acetate (VA) contents of EVA, membrane thickness, drug concentration, temperature, and plasticizers, on drug release were studied. The release rate of drug from the EVA matrix increased with PEG 400 volume fraction, increased temperature and drug loading doses. An increased vinyl acetate comonomer content in EVA membrane increased the drug release rate and permeability coefficient. Among the plasticizers used such as alkyl citrates and phthalates, tetra ethyl citrate showed the best enhancing effects showing the enhancement factor of 1.88. The release of triprolidine from the EVA matrix follows a diffusion controlled model, where the quantity released per unit area is proportional to the square root of time. The controlled release of triprolidine could be achieved using the EVA polymer including the plasticizer.     

Release characteristics of quinupramine from the ethylene-vinyl acetate matrix

An ethylene-vinyl acetate (EVA) matrix containing quinupramine was prepared in an attempt to develop a controlled delivery system for quinupramine. Permeation studies of quinupramine through the EVA copolymer membrane were carried out using a two-chamber diffusion cell. The rate of drug permeation through the EVA membrane was proportional to the PEG 400 volume fraction. The release of quinupramine from the EVA matrix was examined using a modified Franz diffusion cell. A plasticizer was added to prepare the pore structure of the EVA matrix in order to increase the rate of drug release. The effects of PEG 400, membrane thickness, drug concentration, temperature, and plasticizer on drug release rate were investigated. The drug release rate from the EVA matrix increased with increasing PEG 400 volume fraction, temperature and drug loading dose. The activation energy for drug release was 5.91, 5.39, 4.68 and 4.52 kcal/mol for a loading dose of 0.5%, 1%, 1.5%, and 2%, respectively. Among the plasticizers used, diethyl phthalate showed the best results. The release of quinupramine from the EVA matrix follows a diffusion-controlled model, where the quantity released per unit area is proportional to the square root of time. The controlled release of quinupramine was achieved using the EVA polymer including a plasticizer.     

Gastrointestinal therapeutic system delivering of a water insoluble drug: isosorbide dinitrate (ISDN)

An oral therapeutic system can only be effective for soluble drugs. If no suitable salt of a drug can be found, then an osmotic agent such as sodium chloride or mannitol has to be used in a modified two-chamber system, or the osmotic dispenser with collapsible supply container. A one-chamber gastrointestinal therapeutic system (GTS) is proposed which is capable of delivering insoluble drug at a relatively constant rate. The unit consists of a tablet containing the insoluble drug and the soluble carrier, surrounded by a rate-controlling membrane with a delivery orifice. If the unit is in contact with fluid, water will pass constantly through the membrane into the tablet, dissolve the carrier which will be pumping out the insoluble drug through the delivery orifice. The effect was studied of variable content and weight of the tablet, size of the delivery orifice and thickness of the membrane on the rate of insoluble drug release from the GTS.     

Exploiting gastrointestinal bacteria to target drugs to the colon: an in vitro study using amylose coated tablets

The bacterial substrate amorphous amylose, in the form of a film coating, provides a means of delivering drugs to the colon. This coating has traditionally been applied to multi-unit systems, in part because of the small size and divided nature of this type of dosage form, which provides a large surface area for enzymatic attack and drug release. The present study was conducted to explore the utility of the coating for colonic targeting of single unit tablet systems. Amylose was combined with the water-insoluble polymer ethylcellulose, which acts as a structuring agent, in different proportions to produce film coatings of various thicknesses for application to mesalazine (mesalamine or 5-aminosalicylic acid)-containing tablets. Drug release from the coated products was assessed under pH dissolution conditions resembling the stomach and small intestine, and also in conditions simulating the colon using a batch culture fermenter inoculated with human faecal bacteria. The rate and extent of drug release was related to the ratio of amylose to ethylcellulose in the film and the thickness of the coating. Increasing the proportion of ethylcellulose in the film and/or the thickness of the coating depressed the rate of drug release in the conditions of the upper gastrointestinal tract. Drug release from the coated products was accelerated in the fermentation environment of the colon. This is attributed to bacterial digestion of the amylose component of the film coat producing pores for drug diffusion. This work indicates that amylose coated tablet formulations are promising vehicles for drug delivery to the colon.     

Captopril gastrointestinal therapeutic system coated with cellulose acetate pseudolatex: evaluation of main effects of several formulation variables

Maintenance of constant drug levels in the body for those drugs that are used in management of hypertension is extremely beneficial. This can be successfully achieved by delivering the antihypertensives as osmotically-controlled drug-delivery system that essentially eliminates the influence of pH on the drug release. The main objective of this study was to evaluate the main effects of the formulation variables on the release of captopril from osmotically-controlled drug-delivery system coated with a custom-made cellulose acetate (CA) pseudolatex reported earlier. A secondary objective was to identify a suitable antioxidant for incorporating in the formulation as the drug undergoes metal-catalyzed oxidative degradation. The drug showed good stability (> or = 90% intact captopril) in solution in the presence of ascorbic acid for a period of 48 h. A seven-factor, 12-run Plackett-Burman screening design was employed to study the main effects of amounts of Polyox(R) N10 and N80, Carbopol(R) 934P and 974P, sodium chloride, orifice size, and % coating weight gain. The response variable was cumulative percent of drug released in 12 h, Y(3), with constraints on lag time Y(1) and time for 50% drug released Y(2)amount of sodium chloride (1.97).     

Controlled release of tetracycline I: In vitro studies with a trilaminate 2-hydroxyethyl methacrylate-methyl methacrylate system.

A membrane-controlled drug delivery device was developed to release tetracycline at zero-order rates. The tetracycline delivery vehicle is a trilaminate disk consisting of core and coating membranes fabricated from a series of 2-hydroxyethyl methacrylate and methyl methacrylate copolymers. Appropriate adjustment of the monomer composition ratio imparts a hydrophobic nature to the copolymer outer coating membrane (relative to the core material), which serves as the rate-limiting membrane in drug diffusion. The trilaminate disks demonstrated a zero-order tetracycline release over 4 months in vitro. The zero-order release rate was a function of the general device geometry, coating membrane thickness, disk surface, area, level of core reservoir drug loading, and membrane coating copolymer composition. Permeability parameters of tetracycline diffusion through a series of 2-hydroxyethyl methacrylate-methyl methacrylate copolymer membranes were determined by a flux-lag time method. Equilibrium hydration values of these membranes also were determined. The ability of trilaminate 2-hydroxyethyl methacrylate-methyl methacrylate devices to release tetracycline at constant rates over a prolonged period offers unique therapeutic and investigational possibilities.     

Use of spray-dried chitosan acetate and ethylcellulose as compression coats for colonic drug delivery: Effect of swelling on triggering in vitro drug release

Spray-dried chitosan acetate (CSA) and ethylcellulose (EC) were used as new compression coats for 5-aminosalicylic acid tablets. Constrained axial or radial swelling of pure CSA and EC/CSA tablets in 0.1 N HCl (stage I), Tris-HCl, pH 6.8 (stage II), and acetate buffer, pH 5.0 (stage III), was investigated. Factors affecting invitro drug release, i.e., % weight ratios of coating polymers, dip speeds of dissolution apparatus or pH of medium or colonic enzyme (β-glucosidase) in stage III, and use of a super disintegrant in core tablets, were evaluated. Swollen CSA gel dissolved at lower pH and became less soluble at higher pH. The mechanism of swelling was Fickian diffusion fitting well into both Higuchi’s and Korsmeyer-Peppas models. EC:CSA, at 87.5:12.5% weight ratio, provided lag time rendering the tablets to reach stage III (simulated colonic fluid of patients), and the drug was released over 90% within 12 h. The system was a dual time- and pH-control due to the insolubility of EC suppressing water diffusion and the swelling of CSA in the stages I and II. The erosion of CSA gel in the stage III induced the disintegration of the coat resulting in rapid drug release. The lower dip speed and higher pH medium delayed the drug release, while a super disintegrant in the cores enhanced the drug release and no enzyme effect was observed.     

Linear drug release from laminated hydroxypropyl cellulose-polyvinyl acetate films.

Release of drug from a single-layer film containing dispersed drug follows a diffusion-controlled matrix model, where the quantity released per unit area is proportional to the square root of time. The kinetics may be made linear with time (zero order) by laminating a second film without drug to the releasing side of the film with dispersed drug. In this manner, the drug layer serves as a reservoir and controls the duration of drug release, while the nondrug layer functions as a rate-controlling membrane. Zero-order drug release was demonstrated in such laminated films using 18-45 percent pentobarbital, methapyrilene, or salicylic acid contained in hydroxypropyl cellulose as the reservoir layer and mixtures of hydroxypropyl cellulose and polyvinyl acetate as the membrane layer. Inverse relationships between the release rate and membrane thickness and between the logarithm of the rate and the percentage of polyvinyl acetate in the membrane layer were observed. Of the three drugs tested, salicylic acid gave the fastest release rates while pentobarbital gave the slowest.     

Drug release properties of polymer coated ion-exchange resin complexes: experimental and theoretical evaluation

Although ion-exchange resins have been used widely as drug delivery systems, their exact release kinetics has not been reported yet. Usually only the rate-limiting step has been taken into account and the rest of the steps have been ignored as instantaneous processes. To investigate the exact release kinetics of polymer-coated drug/ion-exchange resin complexes for sustained drug delivery, the results of new mathematical modeling were compared with experimental results. Drug/resin complexes with a model drug, dextromethorphan, were prepared and used as cores for fluid-bed coating. An aqueous colloidal dispersion of poly(vinyl acetate) was applied for the coating. A comprehensive mathematical model was developed using a mechanistic approach by considering diffusion, swelling, and ion-exchange processes solved by numerical techniques. The rate-limiting factor of the uncoated resin particles was diffusion through the core matrix. Similarly, in the coated particles the rate-limiting factor was diffusion through the coating membrane. The mathematical model has captured the phenomena observed during experimental evaluations and the release dynamics from uncoated and coated (at different coat levels) particles were predicted accurately (maximum RMSE 2.4%). The mathematical model is a useful tool to theoretically evaluate the drug release properties from coated ion-exchange complexes thus can be used for design purposes.     

Enhanced transdermal controlled delivery of glimepiride from the ethylene-vinyl acetate matrix

An ethylene-vinyl acetate (EVA) matrix containing glimepiride was prepared as a potential transdermal drug delivery system. Permeation studies of quinupramine through the EVA copolymer membrane were carried out using a two-chamber diffusion cell. The rate of drug permeation through the EVA membrane was proportional to the PEG 400 volume fraction. The release of glimepiride from the EVA matrix was examined using a modified Franz diffusion cell. A plasticizer was added to prepare the pore structure of the EVA matrix in order to increase the rate of drug release. The effects of PEG 400, drug concentration, temperature, and plasticizer on the drug release rate were investigated. Various types of enhancers were added to an EVA matrix containing 2% glimepiride in an attempt to increase the level of skin permeation of quinupramine through an EVA matrix. The effects of the enhancers on the level of glimepiride permeation through the skin were evaluated using Franz diffusion cells fitted with intact excised rat skin. The rate of drug release from the EVA matrix increased with increasing PEG 400 volume fraction, temperature, and drug loading. The estimated activation energy of drug release was 7.274 kcal/mol for 2% drug loading dose. The release of glimepiride from the EVA matrix followed a diffusion-controlled model, where the quantity released per unit area was proportional to the square root of time. The controlled release of glimepiride was achieved using the EVA polymer including the plasticizer. Among the plasticizers used, such as the alkyl citrates and phthalates groups, diethyl phthalate slightly increased the rate of glimepiride release. Among the various enhancers used, such as the non-ionic surfactants, the glycerides, the propylene glycol derivatives, fatty acids (saturated or unsaturated), and pyrrolidones, linoleic acid showed the highest permeation rate; 3.17-times higher than the control. In conclusion, an EVA matrix containing a permeation enhancer can be used for the transdermal controlled delivery of glimepiride.     

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.     

Oral controlled release optimization of pellets prepared by extrusion-spheronization processing

Controlled release high dosage forms of a typical drug such as Indobufen were prepared as multiple-unit doses by employing extrusion-spheronization processing and subsequently film coating operations. The effects of drug particle size, drug/binder ratio, extruder screen size and preparation reproducibility on the physical properties of the spherical granules were evaluated. Controlled release optimization was obtained on the same granules by coating with polymeric membranes of different thickness consisting of water-soluble and insoluble substances. Film coating was applied from an organic solution using pan coating technique. The drug diffusion is allowed by dissolution of part of the membrane leaving small channels of the polymer coat. Further preparations were conducted to evaluate coatings applied from aqueous dispersion (pseudolatex) using air suspension coating technique. In this system the drug diffusion is governed by the intrinsic pore network of the membrane. The most promising preparations having the desired in vitro release, were metered into hard capsules to obtain the drug unit dosage. Accelerated stability tests were carried out to assess the influence of time and the other storage parameters on the drug release profile.     

Development of pulsatile multiparticulate drug delivery system coated with aqueous dispersion Aquacoat ECD

The objective of this study was to develop and evaluate a pulsatile multiparticulate drug delivery system (DDS), coated with aqueous dispersion Aquacoat ECD. A rupturable pulsatile drug delivery system consists of (i) a drug core; (ii) a swelling layer, comprising a superdisintegrant and a binder; and (iii) an insoluble, water-permeable polymeric coating. Upon water ingress, the swellable layer expands, resulting in the rupturing of outer membrane with subsequent rapid drug release. Regarding the cores, the lag time was shorter, when 10% (w/w) theophylline was layered on sugar cores compared with cores consisting of 100% theophylline. Regarding swelling layer, the release after lag time was fast and complete, when cross-linked carboxymethyl cellulose (AcDiSol) was used as a swelling agent. In contrast, a sustained release was achieved after the lag time, when low-substituted hydroxypropyl cellulose (L-HPC) and sodium starch glycolate (Explotab) were used as swelling agents. The optimal level of AcDiSol to achieve a fast and complete release after the lag time was 26% (w/w) (based on the weight of the coated pellets) for poorly soluble theophylline and 48% (w/w) for highly soluble propranolol HCl. The lag time can be controlled by the coating level of an outer membrane and increased with increasing coating level of the outer membrane. Outer membrane, formed using aqueous dispersion Aquacoat ECD was brittle and ruptured sufficiently to ensure fast drug release, compared to ethylcellulose membrane formed using organic solution. The addition of talc led to increase brittleness of membrane and was very advantageous because of (i) reduced sensitivity of lag time on variations in the coating level and (ii) fast and complete drug release. Drug release starts only after rupturing of outer membrane, which was illustrated by microscopical observation of pellet during release.     

Estimation of 5-fluorouracil-loaded ethylene-vinyl acetate stent coating based on percolation thresholds

The drug percolation thresholds of 5-fluorouracil-loaded ethylene-vinyl acetate stent coatings were estimated to characterize their drug release behavior and mechanical properties. The stent coatings were prepared using 5-fluorouracil (5-FU) as antitumor drug and ethylene-vinyl acetate (EVA) as matrix forming material in different ratios. In vitro release assays were carried out exposing only one side of coating to pH 6.5 PBS. Based on the release profiles, the drug percolation thresholds were estimated as 0.21 of total porosity (corresponding to ca. 32%, w/w of the drug), which is in approximately agreement with the atomic force microscopy (AFM) result. Based on the coating tensible break strength and tear break strength data, the mechanical percolation thresholds of drug were obtained as 39.7+/-0.3 and 37.5+/-1.4% (w/w) of drug content, respectively.     

硫酸沙丁胺醇脉冲控释片的研制

目的:制备硫酸沙丁胺醇双层包衣脉冲片,考察处方及释放条件对体外释药行为的影响,解析其释放机理.方法:混合粉末直接压片,滚转包衣锅法分别包溶胀层和控释衣层.通过测定释放度研究脉冲片的制剂学特征.结果:双层包衣片以脉冲形式释放,释药时滞随控释衣层厚度增加而延长,释药速度减小;渗透压活性物质和溶胀层可提高快速释放期的释药速率.溶出介质pH值和搅拌速度对释药行为无影响.释药机理包括扩散、溶胀和渗透泵机理.结论:调整控释衣膜厚度和组成可获得理想的脉冲释药行为,满足时辰治疗的要求.本给药系统设计可推广应用于水溶性药物的脉冲给药系统研究.     

Dissolution of anecortave acetate in a cylindrical flow cell: re-evaluation of convective diffusion/drug dissolution for sparingly soluble drugs

Steady-state drug release rates were measured from a model cylindrical implant, comprised mainly of the sparingly soluble drug anecortave acetate, suspended as an obstacle in a cylindrical flow cell. Dissolution medium was delivered at a steady, slow flow rate (0.05-0.7 mLs/min) using an HPLC pump, and samples from the outflow were analyzed by direct injection onto an HPLC column. Release rates were determined as a function of flow rate for three different implant orientations--vertical, elevated to the center of the dissolution cell; horizontal, elevated; and horizontal, resting directly upon the flat porous inlet frit. Release rates were ranked as follows: horizontal, floor > horizontal, elevated>vertical, elevated. The steady, laminar flow enabled use of the finite element method (FEM) to simulate the dissolution process using convective diffusion/drug dissolution theory. Simulations predicted the absolute magnitude of the release rate to within < 10% for all situations, and predicted the power law exponent of the dependence of release rate on flow rate with great accuracy. The current method is more general than compendial methods that provide a dissolving surface that is uniformly accessible to the dissolution medium, or a shear rate that is uniform across the entire dissolving surface. The current approach may be utilized to provide estimates of dissolution rates for any geometry and set of hydrodynamic conditions that can be numerically calculated.