Long acting methadone

Tablets were prepared using pan-coating, congealing, plasticization with organic solvents and direct compression methods. The tablets were evaluated using the official dissolution test, and an analysis of the active ingredient was accomplished by employing gas-liquid chromatography. The formulation and dissolution characteristics of sustained release tablets, employing the matrix concept to regulate drug release, were studied. Particle size distribution of plastic material influenced the release rates from porous inert matrices, and it was found that incomplete drug release occurred from these preparations. Three-layer slowly-eroding sustained release tablets, using a swellable gum (carbomer) were formulated; by adjusting the proportion of the gum quantitative release of the drug was attained. Approximation of linearity for drug release-time relationship was achieved from three-layer slowly-eroding tablets containing different concentrations of drug in the middle and outer layers. Administration of the above tablets, containing 30 mg of methadone, produced analgesia in male albino rats for approximately 60 h, without undesirable effects.     

Evaluation of solubilizers in the drug release testing of hydrophilic matrix extended-release tablets of felodipine

The drug release of felodipine, a water-insoluble drug, was tested by using sodium lauryl sulphate (SLS), polyoxyethylene 20 sorbitan monooleate (Tween) or cetyltrimethylammonium bromide (CTAB) in the test medium as solubilizers. Three slightly different felodipine extended-release (ER) tablets 10 mg based on the gel matrix principle were evaluated under different solubilizer concentrations, agitation intensities and pH. These tablets were also tested in a bioavailability study together with an oral solution. All three solubilizers substantially enhanced the drug solubility and sink conditions were obtained. The choice of solubilizer affected the drug release rate. This is most probably due to physico-chemical interactions between the gel-forming agent and the solubilizers. All in vitro test conditions provided a good correlation (r2 = 0.94-0.97) to in vivo dissolution, as determined by moment analysis. However, a much steeper in vitro/in vivo relationship was obtained for SLS compared to Tween and CTAB reflecting an inferior discrimination between the tablets by use of this anionic solubilizer.     

Clinical evaluation of sodium fluoride chewable tablets in dental caries

Chewable tablets containing low dosage fluoride content were prepared using two varieties of celluloses and their in vitro parameters were evaluated. An eighteen month clinical trial revealed that both these formulations were effective in controlling the caries. However, ethyl cellulose is proved to be superior to methylcellulose as a controlled release matrix material in controlling caries. Thus this study recommends ethylcellulose matrix tablets containing low fluoride content is an efficacious and cost effective drug device in controlling dental caries.     

Drug release from drug-polyanion complex tablets: poly(acrylamido-2-methyl-1-propanesulfonate sodium -co- methyl methacrylate)

A new erodible, anionic carrier for cationic drugs has been synthesized for oral drug delivery systems. The release properties of tablets prepared from this new material, poly(acrylamido-2-methyl-1-propanesulfonate sodium -co- methyl methacrylate) (PAMPSNa/MMA), are discussed. Pseudo-linear release profiles were obtained and the hydrophobicities of both the polymeric carrier and the bound drugs were found to be an important controlling factor in determining the slopes of these release profiles. The effect of the tablet geometry on the shape of the release profiles was also investigated and tablet thickness was demonstrated to be another key parameter controlling both the linearity of the release profiles, as well as the duration of drug release. The release kinetics are strongly dependent on the drug solubility rather than on the type of amine in the drug (i.e. secondary and tertiary amines). The release of drugs from tablets of drug-PAMPSNa/MMA complexes were well described by the dissociation/erosion mechanism.     

Formation of water-insoluble gel in dry-coated tablets for the controlled release of theophylline

Sodium alginate (ALNa) of a natural polysaccharide is known to form a water-insoluble gel when combined with a bivalent metal. In this study, we prepared tablets containing ALNa and calcium gluconate (GLCa) as a bivalent metal, and studied the application of the water-insoluble gel involving the controlled release of a test drug by permeation of water. Dry-coated tablets containing theophylline (TP) as a model drug, ALNa and GLCa were prepared by the dry power compression method. The controlled release of TP was evaluated by the dissolution test according to JP XIII. The release rate was extremely high for the tablets which contained only TP and GLCa. A zero order or sigmoidal release profile was observed for the tablets that contained only TP and ALNa. On the other hand, the lowest dissolution rate and a sigmoidal release profile were observed for the tablet containing TP and GLCa in its core and ALNa in its outer phase. These results suggest that dry-coated tablets containing ALNa and GLCa and prepared by the direct powder compression method would be useful for the controlled release of drugs.     

Thalamo-cortical interactions modeled by weakly connected oscillators: could the brain use FM radio principles?

Effects of drug content and medium pH on the release of papaverine (PAP) from biodegradable poly(l-lactic acid) [P(L)LA] matrix were investigated to reveal the predominant factors affecting the two-stage diffusion-controlled release mechanism. A drug-dissolved cylindrical matrix (rod; 10 mmx1 mm diameter) was prepared by heat compression method. In the case of a PAP content below 10%, pH was found to have a strong effect on the release rate, and drug content was found to have no effect on the release profile. The release profile consisted of two sequential diffusion stages due to P(L)LA transformation from amorphous to the semicrystalline state prior to release. In the first release stage PAP diffused through the swollen matrix. The release accelerated with increasing medium pH due to an increase in water content in the acidic P(L)LA rod. In the second release stage PAP diffused through the water-filled micropores developed as a result of the polymer crystallization. On the assumption that the drug partition between the polymer and the medium in the micropores affects the diffusion and the partition is controlled by pH, we derived a modified diffusion kinetic equation. The observation that the release decelerated with increasing medium pH can be explained by the derived equation as resulting from the increase in the drug partition to the polymer. In the case where the rods contained more than 15% of PAP, the drug precipitated out as crystals during release. Accordingly, these rods showed a slower release.     

Interaction of omeprazole with enteric-coated salicylate tablets

OBJECTIVE: Enteric-coated tablets are designed to resist gastric fluids and to disrupt and dissolve in the alkaline medium of the small intestine. Main objective of the present study was to investigate whether the increase in gastric pH due to omeprazole treatment alters the release rate of a drug from enteric-coated formulation. To this end, we have compared the single dose pharmacokinetics of a single-unit enteric-coated salicylate to that of uncoated acetylsalicylic acid tablets in the presence and absence of omeprazole treatment. METHODS: Study was carried out according to 4 x 4 Latin square design. Eight healthy subjects received either uncoated acetylsalicylic acid tablets or single-unit enteric-coated sodium salicylate tablets alone or following 4 days of treatment with single-dose 20 mg omeprazole, and blood samples were collected for 24 hours. Serum salicylate levels were determined by the modified spectrophotometric method of Brodie et al. [1994]. RESULTS: Salicylate was absorbed rapidly from uncoated tablets but absorption of salicylate from enteric-coated tablets was delayed, as expected. According to our results, omeprazole treatment did not influence the bioavailability from uncoated acetylsalicylic acid tablets but the absorption rate of salicylate from enteric-coated tablets was increased significantly. CONCLUSION: Findings of the present study demonstrate that omeprazole treatment significantly increases the rate of absorption of single-unit enteric-coated medication. Enhanced rate of absorption is most probably due to an early disruption of enteric coating and the intragastric release of the drug secondary to an omeprazole-mediated increase in gastric pH. The results of the present study also corroborate previous findings which have demonstrated highly variable absorption of enteric-coated single units.     

Typical variability in drug dissolution testing: study with USP and FDA calibrator tablets and a marketed drug (glibenclamide) product

To evaluate variability in drug dissolution testing 28 laboratories analyzed USP calibrators, US FDA prednisone tablets and a marketed glibenclamide tablet product. The experiments were conducted using paddle and basket methods at 50 (calibrators) and 75 (glibenclamide) rpm. The media employed were deaerated by equilibrating at 37 degrees C for 24 h and by the USP recommended method. The 95% CI values for percent drug release for the USP calibrator tablets were similar to the reported tolerances for the USP Acceptance Ranges; however, individual results from 15 of 28 laboratories suggest that the apparatus would not comply with the USP Apparatus Suitability Criteria. For FDA prednisone calibrator tablets, percent drug release using equilibrated medium was different (P=0.003) than by the USP recommended method. For the glibenclamide tablet results, a CV of 14-37% was observed, depending upon the sampling time and the type of apparatus employed. The results indicate that failure to meet the USP Dissolution Apparatus Suitability Test may not truly mean that the apparatus is 'out of compliance'. Due to the high variability in dissolution testing, in many cases the impact of formulation or manufacturing changes on drug release characteristics may not be observed, in particular with multi-point profiles.     

Peroral sustained-release film-coated pellets as a means to overcome physicochemical and biological drug-related problems. I. In vitro development and evaluation

In vitro preformulation testing has shown that the solubility and dissolution rate of the model drug compound ucb 11056 are highly pH dependent. Considering this, different sustained-release (SR) oral dosage forms of ucb 11056 were developed aiming to obtain the most constant and complete release of the drug during transit in the gastrointestinal (GI) tract. Classical approaches based on the use of SR formulations such as hydrophilic matrix tablets or pellets coated with one film-forming polymer (Eudragit NE30D or L30D-55) did not fulfill all expectations on the basis of their in vitro evaluation, i.e., the drug release and pattern remained highly dependent on the pH of the dissolution medium. Therefore, taking advantage of the flexibility of release adjustment obtainable from coating of pellets with different kinds of pH-sensitive film layers, a quite satisfactory pH independence of the release characteristics was obtained using formulation blends of neutral and anionic acrylic polymers. For the selected SR pellets batch 15 coated with NE30D/L30D-55 (7:3), the tridimensional topographic representation of the drug release versus time and pH showed that, notwithstanding the pH-dependent aqueous solubility of the drug, the release profiles were relatively homogeneous for any pH value ranging between 1 and 7.     

Complement activation by bacterial surface glycolipids: a study with planar bilayer membranes

Parameters affecting the characteristics of the drug loaded crosslinked sodium alginate matrix films and the release of metoclopramide hydrochloride and cisapride from these matrices were studied. It was shown that the release rate is influenced by the crosslinking technique of the matrix film, crosslinker type and concentration, drug physico-chemical properties especially solubility and the molecular weight, acidity of the release medium, concentration and the loaded quantity of the drug in the matrix. The crosslinking process of the matrix film was shown to be an interfacial phenomenon and the nature of crosslinking depends on the crosslinker type and concentration. This work also showed that crosslinked alginate in a matrix form has limitation in practical use due to the effect of acidic medium on the crosslinking of the matrix film and hence, the rate of drug release.     

Rod and cone function in the Nougaret form of stationary night blindness

The potential of liquisolid systems to improve the dissolution properties of water-insoluble agents was investigated using hydrocortisone as the model medication. The in vitro release patterns of this very slightly water-soluble corticosteroid, formulated in directly compressed tablets and liquisolid compacts, were studied at different dissolution conditions. The new formulation technique of liquisolid compacts was used to convert liquid medications such as solutions or suspensions of hydrocortisone in propylene glycol, a nonvolatile liquid vehicle, into acceptably flowing and compressible powders by blending with selective powder excipients. Several liquisolid tablet formulations were prepared using a new mathematical model to calculate the appropriate quantities of powder and liquid ingredients required to produce acceptably flowing and compressible admixtures. Due to their increased wetting properties and surface of drug available for dissolution, liquisolid compacts demonstrated significantly higher drug release rates than those of conventionally made, directly compressed tablets containing micronized hydrocortisone. The in vitro drug dissolution rates of liquisolid tablets were found to be consistent and independent of the volume of dissolution medium used, in contrast to the plain tablets which exhibited declining drug release patterns with decreasing dissolution volumes. It has been also shown that the fraction of molecularly dispersed drug in the liquid medication of liquisolid systems is directly proportional to their hydrocortisone dissolution rates.     

A designer's polymer as an oral drug carrier (tablet) with pseudo-zero-order release kinetics

A new synthetic polymeric material has been investigated as an oral controlled-release system. The water soluble polymer consists of a non-cross-linked, ionic polymer possessing sulfonate functional groups: poly(sulfopropyl methacrylate potassium-co- methyl methacrylate) (PSPMK/MMA). Drug-resin complexes were obtained by preparing an aqueous solution of the polymer to which propranolol HCl as a model drug was added. Using either dextrose or microcrystalline cellulose as a tablet binder did not cause any problems in fabricating a compact drug-resinate tablet. The release of propranolol HCl from drug-resinate tablets (2.5 mm x 9.0 mm, 10% dextrose) was pseudo-zero-order kinetics from the beginning to the end for over 21 h. This was due to the greater contribution of drug release from the edge of the tablets. However, zero-order release tablets were obtained by increasing the radius to thickness ratio of the tablet to greater than 3.13. A mathematical model describing release kinetics from drug-resinate tablets predicted the effects of drug loading and the physical dimensions of the tablets by a heterogeneous dissociation/erosion-controlled mechanism. As the content of dextrose in the tablets increased, the dissociation/erosion rate constant (K0) increased due to the greater influx of water into the tablets along with counterions. As expected, the release rate was decreased as the stirring rate decreased from 100 to 50 rpm, resulting in the dissociation/erosion rate constant of 2.62-2.04 mg/cm2h, respectively. Therefore, this system has been proven to release drugs independent of the pH of simulated gastric/intestinal fluids (1.2 and 7.5) as well as the compression force of the tablet, which ranged from 1500 to 4400 lbs.     

Relating the phagocytosis of microparticles by alveolar macrophages to surface chemistry: the effect of 1,2-dipalmitoylphosphatidylcholine

This paper describes the preparation of new buccal bilayered devices comprising a drug-containing mucoadhesive layer and a drug-free backing layer, by two different methods. Bilaminated films were produced by a casting/solvent evaporation technique and bilayered tablets were obtained by direct compression. The mucoadhesive layer was composed of a mixture of drug and chitosan, with or without an anionic crosslinking polymer (polycarbophil, sodium alginate, gellan gum), and the backing layer was made of ethylcellulose. The double-layered structure design was expected to provide drug delivery in a unidirectional fashion to the mucosa and avoid loss of drug due to wash-out with saliva. Using nifedipine and propranolol hydrochloride as slightly and highly water-soluble model drugs, respectively, it was demonstrated that these new devices show promising potential for use in controlled delivery of drugs to the oral cavity. The uncrosslinked chitosan-containing devices absorbed a large quantity of water, gelled and then eroded, allowing drug release. The bilaminated films showed a sustained drug release in a phosphate buffer (pH 6.4). Furthermore, tablets that displayed controlled swelling and drug release and adequate adhesivity were produced by in situ crosslinking the chitosan with polycarbophil.     

Cross-linked high amylose starch for controlled release of drugs: recent advances

Cross-linked high amylose starches have been developed as excipients for the formulation of controlled-release solid dosage forms for the oral delivery of drugs. Advantages of this new class of excipients include cost-effectiveness, readily accessible industrial manufacturing technology, high active ingredient core loading and the possibility of achieving a quasi zero-order release for most drugs. In addition to the latter, other features distinguish cross-linked high amylose starches from other excipients used to prepare hydrophilic matrices. Among these are the absence of erosion, the limited swelling and the fact that increasing cross-linking degrees results in increased water uptake rate, drug release rate and equilibrium swelling. Thus the goal of the present study was to gain some insights into the mechanism of drug release control by matrices of cross-linked high amylose starch. Water transport kinetics and dimensional changes were studied in matrices placed in water at 37 degrees C by an image analysis technique. The results show that in the first 5 min, a gel layer is formed at the surface of the tablet, after which the gel front seems to halt its progression toward the center of the tablet. Water continues to diffuse through the front and to invade the core. As a consequence, this latter swells, with a predominance for radial swelling. Equilibrium swelling is reached over 3 days, when the water concentration in the tablet becomes homogeneous and the whole tablet gelifies. Solid-state 13C-NMR were acquired on cross-linked high amylose starch powders, tablets and hydrated tablets with varying cross-linking degrees. They show a predominance of the V-type single helix arrangement of amylose in the dry state irrespective of the cross-linking degree. Upon hydration, the homologues with a low cross-linking degrees show a transition from the V to the B-type double helix arrangement. It is therefore hypothesized that the capacity of amylose to undergo the V to B transition is an important factor in controlling water transport and drug release rate. Finally applications to different drugs are reviewed briefly. They illustrate the versatility of this technology as generic versions of zero order OROS drug (Efidac) and Fickian release conventional matrices (Voltaren SR) were developed and successfully tested in pilot clinical studies to be bioequivalent to the references. These studies further showed that cross-linked high amylose starch matrices have the lowest inter-subject variability among the systems tested and show a total absence of food effect.     

Preparation and evaluation of slow-release pan-coated indomethacin granules

Granules containing indomethacin crystals are coated with Eudragit solutions of different RL/RS ratios using a pan coating technique. The process is reproducible with regard to drug content, inexpensive and the formed granules were directly compressed into tablets. In vitro release of indomethacin from coated granules, tablets and capsules was studied as a function of different ratios of Eudragit RL/RS in the coating solution. The release of the drug was significantly reduced by the coating process in comparison with a formulation made from uncoated granules, prepared using 10 per cent gelatin solution as a binder. Release data were found to follow a diffusion-controlled model.     

Tableting of coated particles. I. Small particle size chitosan as an agent protecting coating membrane from mechanical damage of compression force

Formulation of sustained release tablets containing coated particles whose coating membrane is not damaged during compression was studied and several kinds of chitosan of different particle size were evaluated as protective agents for the membrane. Comparison was made with the dissolution rate of the coated particles. Ethylcellulose or ethylcellulose/hydroxypropylcellulose was chosen as a coating agent. When the coated particles were compressed with the small particle size chitosan (Marine Chito), the coating membrane was not ruptured, and the protective effect was not influenced by the compression pressure. Both the Eudragit RS-coated particles and the tablets manufactured by compressing the coated particles with Marine Chito were orally administered to dogs, and the plasma theophylline levels of the two dosage forms were compared to determine the drug release characteristics in the gastrointestinal tract. It was found that the plasma concentration-time curve of the tablets coincided with that of the coated particles, and the compressed tablet would disintegrate instantly and redisperse into many particles in the body after oral administration.     

Current diagnosis and treatment of leptomeningeal metastasis

A novel colon-specific drug delivery system based on a polysaccharide, guar gum, was evaluated by conducting gamma scintigraphic studies using technetium-99m-DTPA as tracer, in six healthy male human volunteers. Scintigraphs taken at regular intervals have shown that some amount of tracer present on the surface of the tablets was released in stomach and small intestine and the bulk of the tracer present in the tablet mass was delivered to the colon. The colonic arrival time of the tablets was found to be 2 to 4 h. On entering the colon, the tablets were found to be degraded in five out of six volunteers thereby releasing a larger amount of the tracer. The study clearly demonstrates that guar gum, in the form of directly compressed matrix tablets, is a potential carrier for colon-specific drug delivery.     

Description and evaluation of a simplified method to achieve passive fit between cast titanium frameworks and implants

This paper deals with press-coated modified release tablets in which the drug dose is situated in the core or is divided between the core and the coat. The coat contains polymer (sodium alginate or hydroxypropylmethyl cellulose, HPMC) to control drug release. The main objective was to investigate how the pharmacokinetic profile of the model drug could be modified by altering the proportion of the drug between the core and the coat. The effect of the amount of the polymer in the coat was also studied. Bioavailability tests were carried out on healthy volunteers. In the absorption curves of the tablets containing 50%, 67% and 80% of the drug in the core and 180 mg HPMC in the coat a bimodal profile was observed. No bimodal release pattern in the in vitro dissolution studies was found. If the whole dose was incorporated in the core the absorption curve has only one clear t(max) value at about 10 h. Doubling the amount of HPMC in the coat dramatically decreased drug absorption. It was concluded that, if a slightly reduced t(max)-value was required, the viscosity grade of HPMC used should be lowered.     

Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus

Theophylline anhydrate microcapsules with different amounts of MA/MMA copolymer (Eudragit L) were prepared by the solvent evaporation method. Qualitative as well as quantitative investigation of the drug-polymer interaction by Fourier transform infrared (FTIR) spectroscopy with a curve fitting program was undertaken. The release mechanisms of theophylline in pH 1.2 and pH 6.8 media were also studied to elucidate the effect of drug-polymer interaction on the release characteristics of microcapsules. Direct evidence for a hydrogen bonding interaction between theophylline and Eudragit L in microcapsules was obtained. Moreover, the fraction of hydrogen bonded theophylline increased with the increase of Eudragit L. The dissolution of theophylline from microcapsules exhibited an enteric-coated release property. The drug release mechanism was found to fit the Higuchi matrix model in the simulated gastric acid condition, but drug release was much more rapid in the pH 6.8 buffer solution. The drug release rate decreased as the composition of theophylline increased, and it was proportional to the fraction of hydrogen bonded theophylline. These results suggest that the increased fraction of hydrogen bonded theophylline in microencapsulation might improve the mixing and dispersibility of theophylline in the Eudragit L matrix, thus resulting in the increase of the release rate of theophylline from microcapsules.     

The effects of community policies to reduce youth access to tobacco

The aim of this in vitro study was to investigate the effect of troglitazone, a new oral antidiabetic agent, on LDL catabolism. HepG2 cells, which are cells from a well-differentiated cell line of hepatoma cells, were cultured and used to study LDL catabolism. Different concentrations of troglitazone, all within the therapeutic range for humans, were incubated in culture medium with 125I-labeled LDL to measure cell-associated and degraded 125I-LDL. Troglitazone increased cell-associated and degraded 125I-LDL by approximately 30%. We also investigated if this effect occurred through a LDL receptor-mediated pathway or a non-LDL receptor pathway. By using dextran sulfate, a substance known to release bound LDL from its receptor, we found that troglitazone upregulated LDL receptor activity by approximately 35%. In addition, we found that troglitazone increased the expression of the LDL receptor mRNA. The effect of troglitazone was comparable with that of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin, with troglitazone having an upregulatory effect similar to that of fluvastatin. Insulin within human physiological concentrations also increased LDL receptor activity. We found that troglitazone and insulin had an additive effect on LDL catabolism. Also, the effect of troglitazone on LDL catabolism was studied in the presence of cyclosporine, an immunosuppressant drug that reduces LDL catabolism mainly by decreasing LDL receptor activity. The results showed that troglitazone can compensate for the reduced LDL receptor activity induced by cyclosporine, but that cyclosporine had a residual effect on the action of troglitazone. Thus troglitazone enhanced LDL binding, cell association, and degradation by increasing LDL receptor mRNA expression, with a subsequent increase in LDL receptor activity.