Lithium acetate gastrointestinal diffusion system. Part 1: Lithium acetate single-unit gastrointestinal diffusion system: preparation and release rate studies

The gastrointestinal diffusion system (GDS), containing lithium acetate (1), releases the drug by a controlled source of diffusion energy. The unit can possibly be used for all soluble drugs in which solubility is independent from the pH of the gastrointestinal contents as is the case with 1. The one-compartment unit is obtained by tabletting the drug and coating the tablets with a membrane of cellulose acetate to which soluble porofores-gum arabic, sodium chloride, 1-are added. When the pore-creating substance is dissolved out of the coating, there remains a porous film, which controls the rate of release of the drug. The release characteristics depend on membrane composition and mass. The systems reported here provided for zero-order drug delivery in vitro.     

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.     

Sustained release methadone salts and methadone-naloxone mixtures. Part 2: In vitro studies of methadone release

Various tablet formulations, using two methadone salts namely methadone-alpha-naphthalenesulfonate and methadone-o-benzoylbenzoate and a number of methadone-naloxone combinations were prepared. The quantities of methadone released from these tablets in simulated gastric and intestinal fluids were examined using spectrophoto-metric studies. All formulations followed a typical release pattern, indicating a high degree of consistency of the formulations.     

The microsponge delivery system of benzoyl peroxide: preparation, characterization and release studies

Benzoyl peroxide (BPO) is commonly used in topical formulations for the treatment of acne and athletes foot. Skin irritation is a common side effect, and it has been shown that controlled release of BPO from a delivery system to the skin could reduce the side effect while reducing percutaneous absorption. Therefore, the aim of the present study was to produce ethylcellulose microparticles containing BPO which were able to control the release of BPO to the skin. In order to optimize the microparticle formulation, factors affecting the physical properties of microparticles were also investigated. Benzoyl peroxide microparticles were prepared using an emulsion solvent diffusion method by adding an organic internal phase containing benzoyl peroxide, ethyl cellulose and dichloromethane into a stirred aqueous phase containing polyvinyl alcohol. Drug content, particle size analysis and loading yield were determined in the prepared microparticles. BPO microparticles were then incorporated into standard vehicles for release studies. Scanning electron microscopy was used to study the shape and morphology of the microsponges. The micrograph of microsponges showed that they were spherical in shape and contained pores. These pores resulted from the diffusion of solvent from the surface of the microparticles and thus the particles were designated as microsponges. It was shown that the drug:polymer ratio, stirring rate, volume of dispersed phase influenced the particle size and drug release behavior of the formed microsponges and that the presence of emulsifier was essential for microsponge formation. The results showed that, generally, an increase in the ratio of drug:polymer resulted in a reduction in the release rate of BPO from microsponges which was attributed to a decreased internal porosity of the microsponges.     

Streptomycin sulphate microspheres: dissolution rate studies and release kinetics. I

Targeting of drugs by microspheres, nanoparticles and liposomes is intended to increase the selective targeting to specific organs and to reduce their side effects. Streptomycin sulphate, a tuberculostatic antibiotic, is used as the active principle in this study. The aim is to accumulate the loaded microspheres in the lungs. The release of drugs associated with microsphere carriers has been found to be dependent on a number of factors. The aim of the investigation was to study the influence of the extent and nature of cross-linking, the type and the amount of the matrix material on the release characteristics of streptomycin sulphate microspheres. Human serum albumin and gelatin (Type B) were used as two different matrix materials. The crosslinking agents used were 2,3-butanedione and formaldehyde at different concentrations, and variable duration times. The in vitro release of streptomycin sulphate from microspheres is characteristically biphasic, with an initial fast release (the 'burst effect'), followed by a much slower release. Alteration in the characteristics of drug-loaded microspheres result in significant changes in the second (slow) phase of release. The release profiles of the different formulations has been studied and evaluated kinetically.     

非洛地平缓释片的研制及其体外释放研究

目的研制非洛地平缓释片,评价其与原研制剂的体外释放度相似性。方法采用骨架片技术,通过研究骨架材料种类、粘度、用量,稀释剂及制备工艺对释放的影响,研制非洛地平缓释片,通过相似因子法研究其与原研制剂在体外4种不同pH条件下的释放度的差异。结果以HPMC为骨架材料,工艺采用湿法制粒法,乙醇溶液浓度为80%,制粒时间为40s,压片硬度在50～70N时,所得的非洛地平缓释片的释放度与原研制剂最接近。4种不同pH条件下的释放度的相似因子均大于50。结论研制的非洛地平缓释片,其体外释放与原研制剂相似     

Long-term stability characterization of a controlled release gastrointestinal therapeutic system coated with a cellulose acetate pseudolatex

The objective of the present study was to study the long term effects of storage of osmotically controlled gastrointestinal therapeutic system (GITS) in exaggerated conditions of temperature and humidity. Bilayered osmotic tablets were obtained with atenolol, Polyox N80, Carbopol 934P and magnesium stearate in one layer, and Polyox 303, Carbopol 974, sodium chloride and magnesium stearate in the other layer. A customized cellulose acetate (CA) pseudolatex was used to provide semipermeable housing around the tablet and an orifice was drilled into the drug layer to obtain the Atenolol GITS. The GITS were stored at 4 degrees C (refrigeration), 25 degrees C, 37 degrees C, 45 degrees C, 55 degrees C, 37 degrees C/11% RH, 37 degrees C/51% RH, and 37 degrees C/91% RH. Quantitative X-ray diffraction and dissolution studies were performed at regular intervals for one year. Aqueous CA polymeric film formation continued in GITS stored at higher temperature by gradual evaporation of moisture and coalescence of polymer. At lower temperatures atenolol crystallinity increased with time, but at higher temperatures the crystallinity was decreased. At higher humidity, a decrease in crystallinity was observed. A decrease in dissolution rate and extent was observed at higher temperature and higher humidity conditions. Exaggerated temperature and humidity conditions affected the dissolution profile by modifying the CA pseudolatex membrane and crystallinity of atenolol.     

Formulation and analysis of suppositories containing papaverine hydrochloride. Part 2. In vitro membrane diffusion studies]

Rectal suppositories with 0.10 g/2.0 g Papaverine hydrochloride content were made with 12 different vehicles. The membrane diffusion method was used to study the factors influencing the in vitro drug liberation. The Polysorbate 20 and 61 tenside pair, the optimal concentration of which was 5% each, was found to influence diffusion favourably. Neutral oils softening the consistency (Miglyol 812 and Estasan), similarly in 5%, also had a favourable effect on the in vitro diffusion by increasing the spreading properties. As to the lipophil suppository masses with high and low hydroxyl numbers, only the latter could be used favourably. The 6-month-long storage resulted in drug retention in several experimental series. Correlation was found in several cases between the physical parameters of the suppositories and their in vitro drug liberation. Finally, with the help of linear regression calculation and in view of the in vitro relative bioavailability values the optimal vehicle is suggested for the formulation of suppositories containing Papaverine hydrochloride. The triglyceride type Estaram 299 was found to be the most suitable in every respect, either in itself or combined with 5% neutral oil.     

Pharmacological studies with the alpha 2-adrenoceptor antagonist midaglizole. Part III: Smooth muscle, gastrointestinal and miscellaneous systems.

Pharmacological properties of midaglizole (DG-5128, CAS 66529-17-7) on smooth muscle, gastrointestinal and miscellaneous systems were investigated in comparison with those of tolbutamide. 1. Isolated smooth muscle: Midaglizole inhibited the contractile responses of the ileum to nicotine, acetylcholine, serotonin and BaCl2, and especially the response to histamine (guinea pig). Tolbutamide also reduced the contractions. On spontaneous motility of the uterus (estrus, diestrus, pregnant), midaglizole produced an increase in tonus and frequency, and decrease in contractile amplitude (rat). Tolbutamide reduced the motility of the uterus. The contractile response of the vas deferens to norepinephrine was potentiated after midaglizole and tolbutamide (guinea pig). Midaglizole inhibited the contractile response of the trachea to histamine, whereas it had little or no effect on the response to acetylcholine (guinea pig). Tolbutamide reduced the responses to both spasmogens. 2. Gastrointestinal system: Midaglizole induced an increase in gastrointestinal transit (mouse) and potentiated the gastrointestinal motility (dog). Tolbutamide was without any effect on these parameters. Gastric emptying rate, gastric secretion and gastric mucosa were not influenced after midaglizole (rat). Tolbutamide decreased gastric secretion and produced injury of gastric mucosa. 3. Urine volume: Midaglizole and tolbutamide showed a diuretic activity (rat). 4. Anti-inflammatory activity: Midaglizole and tolbutamide inhibited carrageenin-induced paw edema (rat).     

Chitosan/cellulose acetate microspheres preparation and ranitidine release in vitro

New microspheres containing hydrophilic core and hydrophobic coating as a controlled-release system with no toxic reagents were proposed. Water in oil in water (W/O/W) emulsion and solvent evaporation methods were used to make chitosan/ cellulose acetate (CCA) microspheres sized 200 - 400 microm. Ranitidine hydrochloride, as a model drug, was investigated for its release properties in vitro. The loading efficiency and release rate of ranitidine were affected by chitosan concentration and molecular weight. Higher loadings were obtained at lower concentrations in the interval of 1% to 2%. With chitosan at a 2% concentration microspheres could be obtained with more spherical appearance, smaller size, and higher ranitidine loading efficiency microspheres than at other concentrations. Among the different molecular weight chitosan (47, 145, 308, 499, and 1130 KD) microspheres, the high molecular weight chitosan (1130 KD) microspheres had relatively high loading efficiency (10%). Molecular weight and concentration of chitosan as well as the size of microspheres affected the release of ranitidine. Microspheres smaller than 280 microm released the drug faster than did the bigger by about 10%. The optimal condition for the preparation of the microspheres was chitosan concentration 2%, molecular weight 1130 KD. The ranitidine release from the microspheres was 30% during 48 h in phosphate-buffer saline medium.     

Two galactomannans and scleroglucan as matrices for drug delivery: preparation and release studies.

Two galactomannans, Guar gum and Locust bean gum, have been used as matrices for tablets to study the release of model molecules. As a comparison, matrices obtained with another polysaccharide, Scleroglucan, have been tested. Despite the different conformations that the polymers assume in aqueous solution (flexible coils for Guar gum and Locust bean gum; triple helix for Scleroglucan), when prepared as tablets, they show (in distilled water and at 37 degrees C) very similar release profiles of guest molecules (i.e. theophylline, vitamin B12 and myoglobin) of different steric hindrance. Furthermore, the polymers were chemically crosslinked with glutaraldehyde to obtain a network suitable as a matrix for modified drug release. The delivery of the model molecules from the Guar gum and Locust bean gum gels, and from tablets prepared from the freeze-dried hydrogels of the three polymers was evaluated, and a comparison with the tablets prepared with the not-crosslinked polymers was carried out. Experimental data showed how the presence in the matrix of a well-defined network, by introducing a spacer among the macromolecular chains, always increased the rate of delivery of the tested molecules in comparison to the release profiles obtained when no crosslinker was present. Release data from the tablets were analyzed according to a mathematical model able to determine the relative importance of drug dissolution and drug diffusion on the overall release kinetics. Good agreement was found between the simulated and the experimental data.     

Study of the gastrointestinal diffusion system (GDS): influence of acacia gum on mechanical and chemical properties in free cellulose acetate films.

In this work a study of free cellulose acetate films was carried out in the presence and absence of acacia gum at high concentrations (50 and 75%). The mechanical toughness and the aspect were influenced by operatory conditions and by the relative air humidity. The increase of relative humidity from about 0% to 75% decreased the mechanical toughness and the color film changed from a clear to opaque white. The presence of acacia gum decreased the mechanical toughness and the water vapour transmission rate and increased the film water solubility.     

Cellulose acetate/chitosan multimicrospheres preparation and ranitidine hydrochloride release in vitro

A noval cellulose acetate/chitosan multimicrospheres (CACM) was prepared by the method of w/o/w emulsion. The concentration of cellulose acetate (CA) and the ratio of CA/chitosan (CS) had influence on the CACM size, and appearance. Ranitidine hydrochloride loading, and releasing efficiency in vitro were investigated. The optimal condition for preparation of the microspheres was CA concentration at 2% and the ratio of CA/CS at 3/1. The microspheres size was 200-350 μm. The appearance of microspheres was spherical, porous, and nonaggregated. The highest loading efficiency was 21%. The ranitidine release from the CACM was 40% during 48 hr in buffers.     

Bioavailability of ambroxol sustained release preparations. Part I: In vitro dissolution studies

The in vitro dissolution of two ambroxol-HCl containing sustained release preparations (75 mg) and the effect of pH of the dissolution medium on the dissolution rats were investigated. The studies were carried out using the USP XXI paddle method. A new ambroxol HCl sustained release formulation based on a dialyzing membrane for controlled release shows a longer release action as compared to a standard sustained release preparation from commercial source which is based on spheroids constituted by a lipid matrix. The in vitro release rate of the latter product also appears to be more pH dependent.     

Formulation and in vitro investigation of antibacterial vaginal suppositories. Part 2. In vitro membrane diffusion and microbiologic studies]

After the physical parameters had been determined, the in vitro drug liberation from vaginal suppositories containing 100 mg of antibacterial agent (sulphadimine, chloramphenicol, gentamicin-sulphate) was studied by membrane diffusion and microbiological methods. Among the vehicles available in Hungary the hydrophylic Massa macrogoli was found to be the best for this purpose. Among the lipophilic bases the in vitro drug liberation of the French Suppocire NA product was significantly better (p < 0.05) compared to the other lipophilic bases. This vehicle is recommended by the authors for the topical treatment of vaginitis, as these suppositories have the further advantage that they can easily be produced on a magistral, galenical or industrial scale as well. In the first part of the publication the formulation and some important physical parameters of lipophilic and hydrophilic antibacterial suppositories for vaginal use were described. In the present paper the drug liberation ability of the compositions with proper physical parameters was studied. The published results were obtained from measurements performed 1 week after formulation.     

Effect of ethylene-vinyl acetate concentration on ethylcellulose-walled microcapsules: preparation and release kinetics of theophylline microcapsules

The effect of concentration of ethylene-vinyl acetate (EVA) copolymer, used as a coacervation-inducing agent, on the preparation of ethylcellulose microcapsules was studied with theophylline as the core material. The influence of EVA concentration on the micromeritic properties of the microcapsules and their drug release behaviour were investigated. Particle size distribution of the microcapsules obtained was dependent on the amount of EVA copolymer. As the EVA concentration increased the quantity of larger particles was reduced and that of the smaller particles was increased. Thus EVA might be used as a protective colloid to prevent aggregation of the microcapsules. The porosity of the microcapsules decreased with respect to EVA concentration, but the wall thickness of the microcapsules showed a corresponding increase. Zero-order release kinetics, from the resulting microcapsules in the initial dissolution phase was obtained. The apparent zero-order release rate in the initial steady-state decreased with the increase of EVA concentration, but T50 increased. The higher concentration of EVA causing a thick, compact wall lead to an effective prolongation of drug release.     

Suppositories containing cyclodextrin complexes. Part 2: Dissolution and absorption studies

The dissolution and absorption of poorly water-soluble drugs from rectal suppositories can be enhanced by complexing these substances (e.g., essential oils, indomethacin) with beta-cyclodextrin. Preliminary in vivo studies showed, that the application of cyclodextrin complexes to suppositories, the same as to oral applications, resulted in an increased blood level.