Sustained release of alcohol: subcutaneous silastic implants in mice.

A sustained-release device for use in ethanol dependence studies in mice is described. The Silastic device, dubbed SERT (sustained ethanol release tube), holds 0.35 milliliter of 95 percent ethanol (by volume) and is implanted under the skin of the back where it releases ethanol for up to 12 hours, with no observable tissue damage. The device may be adaptable to the release of other volatile liquids or drugs, in other animals.

Solid state interactions between the proton pump inhibitor omeprazole and various enteric coating polymers.

The influence of the acidic film formers Eudragit L 100, HPMCAS-HF, HP-55, and shellac on the stability of the acid-labile proton pump inhibitor omeprazole in solid drug-polymer blends at accelerated storage conditions (40 degrees C/75% RH) was determined by fourier transform infrared spectroscopy (FTIR), modulated temperature differential scanning calorimetry (MTDSC), and high performance liquid chromatography (HPLC). As expected, acidic polymers caused a degradation of omeprazole which was manifested by discolorations and increasing amounts of degradation products. However, MTDSC curves and FTIR spectra did not show additional peaks resulting from the omeprazole degradation products. These methods appeared to be not sensitive enough to separate analytically the drug and polymer signals from those of the decomposition products. With HPLC a sufficient quantification of the degradation products was possible. HP-55 caused the highest degree of omeprazole degradation, followed by shellac, HPMCAS-HF, and Eudragit L 100. No correlation with the microenvironmental pH values generated by the acidic polymers at the applied storage conditions was found. The melting process and the dissolution of acidic impurities were figured out as possible reasons for the more pronounced decomposition of the drug in presence of HP-55 and shellac.

Physical-mechanical, moisture absorption and bioadhesive properties of hydroxypropylcellulose hot-melt extruded films.

The objective of this study was to investigate the moisture absorption, physical-mechanical and bioadhesive properties of hot-melt extruded hydroxypropylcellulose (HPC) films containing polymer additives. These additives included polyethylene glycol (PEG) 5%, polycarbophil 5%, carbomer 5%, Eudragit E-100 5%, and sodium starch glycolate (SSG) 5%. Relative humidity (RH) and temperature parameters of the films studied included 25 degree C at 0, 50, 80 and 100% RH, and 40 degrees C at 0 and 100% RH, stored for 2 weeks. Tensile strength and percent elongation were determined on an Instron according to the ASTM standards. The bioadhesive properties of the HPC/PEG 3350 5% film and the polycarbophil 5% containing films, with and without PEG, were investigated in vivo on the human epidermis. Although all films studied exhibited an increase in percent water content as the percent RH increased, the SSG containing film exhibited an almost three-fold increase in percent water content compared to that of the HPC/PEG film. The temperature storage condition of 40 degrees C/100% RH (versus 25 degrees C/100% RH) increased the percent water content of the SSG containing film. Percent elongation was highest for films containing polycarbophil 5% (without PEG). In addition, the HPC film containing polycarbophil 5% exhibited a greater force of adhesion and elongation at adhesive failure in vivo, and a lower modulus of adhesion when compared to the HPC/PEG film. A novel approach to determine bioadhesion of films to the human epidermis is presented.

Bioadhesive properties of hydroxypropylcellulose topical films produced by hot-melt extrusion.

The objective of this study was to investigate the in vivo bioadhesive properties of hydroxypropylcellulose (HPC) films containing seven polymer additives on the epidermis of 12 human subjects, including two ethnic sub-groups. HPC films containing polyethylene glycol (PEG 3350) alone, Vitamin E TPGS (TPGS) 5%, sodium starch glycolate 5%, Eudragit E-100 5%, carbomer 974P and 971P 5%, and polycarbophil 5%, all with and without plasticizer, were prepared by hot-melt extrusion utilizing a Randcastle Microtruder (Model #RCP-0750). Bioadhesion testing was performed using a Chatillon digital force gauge DFGS50 attached to a Chatillon TCD-200 motorized test stand to determine force of adhesion (FA), elongation at adhesive failure (EAF), and modulus of adhesion (MA) for the 12 films tested. In vivo, the TPGS-incorporated film exhibited a two-fold increase in FA when compared to the control film containing the PEG 3350 5%. The carbomer 971P and polycarbophil containing films were determined to have the highest FA and EAF, and the lowest MA of all films tested. The film containing carbomer 971P had a higher FA than the film containing 974P. In addition, films in one ethnic sub-group exhibited higher FA and EAF than the other. Force--deflection profiles obtained from these experiments indicate that the force of adhesion, elongation at adhesive failure and modulus of adhesion are a function of the polymer additive in the HPC extruded films. The incorporation of carbomer 971P and a polycarbophil into HPC films increased bioadhesion significantly when compared to the film containing HPC and PEG 3350. Differences in FA and EAF were discovered between two ethnic sub-groups tested.

Adhesion of polymeric films to pharmaceutical solids.

The two major forces influencing polymer adhesion include the strength of the interfacial bonds between the polymeric film and the surface of the solid and the internal stresses within the film coating. While good adhesion between the polymer and the substrate is desirable for pharmaceutical products, the small size of the dosage form and the non-uniform surface roughness have created difficulties in assessing polymer adhesion. In this review, the experimental devices and procedures used to quantitate polymer adhesion are addressed. The affects of the physical and chemical properties of the substrate, including surface roughness and tablet hydrophobicity, on adhesion of a polymer to either tablets or capsules are discussed. The influence of the plasticizers, pigments, and solvents in film coating formulations on polymer adhesion, and the effects of aging of the coated solids on adhesion of polymers to tablets and capsules are also discussed.

Influence of relative humidity on the mechanical and drug release properties of theophylline pellets coated with an acrylic polymer containing methylparaben as a non-traditional plasticizer.

The purpose of this study was to investigate the influence of relative humidity (RH) on the mechanical and dissolution properties of theophylline pellets coated with Eudragit((R)) RS 30 D/RL 30 D containing methylparaben (MP) as a non-traditional plasticizer. The coated beads were stored at 23 degrees C and at different relative humidities (0, 29, 51, 75 and 84% RH). The effect of storage conditions on the rate of drug release from coated beads was determined in pH 7.4 phosphate buffer solution. The mechanical properties, including tensile strength and Young's modulus, of individual beads were determined by a diametral compression method with a Chatillon((R)) tension/compression apparatus. The morphology of the intact and fractured beads was investigated using scanning electron microscopy (SEM). The moisture content of the polymeric films was determined using a Karl Fischer coulometric moisture analyzer. The results from the mechanical studies demonstrated that an increase in the relative humidity resulted in a decrease in the tensile strength and Young's modulus of the coated beads. SEM photographs showed that coated beads stored at 0% RH exhibited brittle fracture failure. The coated beads stored at 84% RH showed ductile behavior, which was attributed to the hydroplasticization effect on the acrylic polymer due to the uptake of moisture. The moisture content in the films was also shown to influence the rate of drug release from Eudragit((R)) RS 30 D/RL 30 D coated beads containing MP as the plasticizer. The change in release profiles could be minimized when the relative humidity was reduced to zero. The dissolution rate of theophylline from the coated beads decreased when stored at high relative humidities. This trend was reversed when the coated beads that were stored at 84% RH for 5 weeks, were then equilibrated at 0% RH.

Influence of processing on the stability and release properties of biodegradable microspheres containing thioridazine hydrochloride.

Biodegradable microspheres of poly(DL-lactic-co-glycolic acid) (PLGA) containing thioridazine HCl were produced by four emulsion-solvent evaporation methods including an O/W emulsion method, an O/O emulsion method, a W/O/W multiple emulsion method, and a W/O/O/O multiple emulsion method. Gel permeation chromatography was used to determine the molecular weight of the polymer before and after processing. Resultant microspheres were either incubated in an oven at 40 degrees C, or stored in a desiccated chamber at 20 degrees C. Change in the molecular weight of the polymer was monitored as a function of time. Premature degradation of the polymer was evident in microspheres produced by the O/W conventional solvent evaporation method. Thioridazine HCl catalyzed hydrolysis of PLGA was evident in normalized molecular weight distribution plots of the O/W microspheres. The in vitro release of thioridazine HCl from multiphase microspheres produced by potentiometric dispersion was compared with the release of drug from conventional microspheres prepared from the same polymer. Release of thioridazine HCl from multiphase microspheres of the W/O/O/O type occurred by diffusion during initial stages of drug release.

Properties of lipophilic matrix tablets containing phenylpropanolamine hydrochloride prepared by hot-melt extrusion.

The objective of the present study was to investigate the influence of formulation factors on the physical properties of hot-melt extruded granules and compressed tablets containing wax as a thermal binder/retarding agent, and to compare the properties of granules and tablets with those prepared by a high-shear melt granulation (MG) method. Powder blends containing phenylpropanolamine hydrochloride, Precirol and various excipients were extruded in a single-screw extruder at open-end discharge conditions. The extrudates were then passed through a 14-mesh screen to form granules. The extrusion conditions and the optimum amount of wax to function as the thermal binder were dependent on the properties of the filler excipients. At the same wax level, drug release from tablets decreased in the order of using microcrystalline cellulose (MCC), lactose and Emcompress as the filler excipient. The observed differences in the dissolution properties of the tablets were due to the differences in the solubility, swellability and density of the filler excipients. Replacing Precirol with Sterotex K, a higher melting point wax, resulted in slightly increased dissolution rates, when the extrusion was performed at the same temperature conditions. Hot-melt extruded granules were observed to be less spherical than high-shear melt granules and showed lower values of bulk/tap densities. However, tablets containing MCC or lactose granules prepared by hot-melt extrusion (HME) exhibited higher hardness values. Slower drug release rates were found for tablets containing MCC by HME compared with MG. Analysis of the hot-melt extruded granules showed better drug content uniformity among granules of different size ranges compared with high-shear melt granules, resulting in a more reproducible drug release from the corresponding tablets.

Aqueous ethyl cellulose dispersion containing plasticizers of different water solubility and hydroxypropyl methyl-cellulose as coating material for diffusion pellets II: properties of sprayed films.

This study investigates the properties of sprayed films prepared from aqueous ethyl cellulose dispersions (ECD) containing hydroxypropyl methylcellulose (HPMC) and plasticizers of different water solubility in order to clarify the drug release mechanisms of pellets coated with the respective material. It is of special interest to measure the migration of the water soluble components as well as the physical properties of the swollen ethyl cellulose film. Swelling experiments with sprayed films in 0.1 N-HCl at 37 degrees C show that fairly water soluble plasticizers and the pore forming agent (HPMC) migrated rapidly and almost completely out of the films. The water insoluble plasticizers remain predominantly in the film and the migration rate of HPMC is reduced in a release medium of high ionic strength. The glass transition temperature (T(g)) and the softening temperature (T(s)) of these films after swelling are dependent on the water solubility of the plasticizer. The T(g) of ECD films plasticized with triethyl citrate is above the swelling temperature of 37 degrees C after migration of the plasticizer, transforming the polymer in the glassy state. In contrast, dibutyl phthalate-containing ECD films demonstrate a T(g) below the swelling temperature, leaving the polymer in the rubbery state. The mechanical properties of dry and wet films are studied as a function of the state of curing of the films and of the swelling temperature. On contact with water, a pronounced shrinkage of ECD/HPMC films plasticized with water insoluble plasticizers is observed. All these results are used to explain the different drug release mechanisms of the coated pellets and to enable the prediction and optimization of drug release-rates from coated pellets.

Sustained-release applications of montmorillonite interaction with amphetamine sulfate.

Urinary recovery studies showed that montmorillonite significantly affects the initial therapeutic levels of amphetamine sulfate. The combination of a 1:20 drug-montmorillonite complex with pure drug in a 1:1 ratio, based on amphetamine content, resulted in recovery profiles resembling those obtained from prolonged-release dosage forms. The 1:20 complex, pure drug, and combination formulations showed comparable bioavailability after 48 hr.

Stabilizing effect of inorganic phosphate salts on antibiotic-steroid ophthalmic preparations.

Drocinonide phosphate potassium forms an insoluble complex with neomycin sulfate in aqueous solution. Dibasic sodium phosphate can be employed in an ophthalmic formulation to prevent the formation of this precipitate without affecting the stability of the steroid or the bioactivity of the antibiotic. Other phosphate steroid salts behaved in a like manner.

Influence of monovalent and divalent electrolytes on sorption of neomycin sulfate to attapulgite and montmorillonite clays.

Langmuir isotherms for the adsorption of neomycin sulfate to clays such as attapulgite, bentonite, and magnesium aluminum silicate were constructed. Monovalent and divalent cations were investigated for their influence on the formation of neomycin-clay adsorbates and the resulting equilibrium concentration in a neomycin solution. Divalent magnesium ions were more effective in displacing the antibiotic from each clay than were monovalent sodium ions. Ions present in the GI fluid might increase the bioavailability of neomycin from such neomycin-clay adsorbates.

Compaction properties of microcrystalline cellulose and sodium sulfathiazole in combination with talc or magnesium stearate.

The dynamic indentation hardness, tensile strength, bonding index, and brittle fracture index were employed to investigate the compaction properties of a plastic excipient, microcrystalline cellulose, and a brittle drug, sodium sulfathiazole, in combination with different levels of either magnesium stearate or talc. These parameters were also used to quantitate properties of various combinations of microcrystalline cellulose and sodium sulfathiazole in order to illustrate the effects of combining a plastic excipient and a brittle drug. It was shown that the tensile strength, indentation hardness, bonding index, and brittle fracture index for compacts composed of microcrystalline cellulose in combination with either talc or magnesium stearate generally decreased as the amount of talc or magnesium stearate was increased over the concentration range of 0 to 9%. Similar results were observed for admixtures of sodium sulfathiazole in combination with either talc or magnesium stearate. It was also demonstrated that the tensile strength, indentation hardness, and bonding index increased, and the brittle fracture index decreased, as the percent of microcrystalline cellulose was increased in a binary mixture of sodium sulfathiazole and microcrystalline cellulose.

In vitro adsorption of various pharmaceutical to montmorillonite.

Dissolution and dialysis studies showed that cationic drugs and certain nonionic drugs bind strongly to montmorillonite clay. The quantity of drug bound by one unit of clay varied considerably. Anionic drugs were weakly bound, and less bioavailabilty problems would be anticipated with these medicinals. The mechanism of binding of cationic drugs to montmorillonite was proposed as a two-step process: a cation-exchange reaction followed by strong surface chemisorption.

Crystallinity and dissolution rate of tolbutamide solid dispersions prepared by the melt method.

The influence of cooling rate of solid dispersions prepared by the melt method was studied by X-ray diffraction and scanning electron microscopy. Tolbutamide was the model drug investigated, and the carriers included urea and polyethylene glycol 6000. Slow-cooled urea dispersions of tolbutamide demonstrated a complete lack of crystallinity, suggesting the formation of an amorphous material. The rapidly cooled dispersion showed peaks for urea and an absence of drug in the X-ray pattern, suggesting that a true molecular dispersion was formed. The X-ray patterns of rapid- and slow-cooled dispersions of tolbutamide and polyethylene glycol 6000 demonstrated that a physical mixture of drug and carrier resulted from both methods of dispersion preparation.

Influences of matrixes on nylon-encapsulated pharmaceuticals.

The preparation and properties of nylon microcapsules containing three different matrixes (formalized gelatin, calcium alginate, and calcium sulfate) are described. Microcapsules containing each matrix were dense and free flowing and could be made of very small diameter by controlling the stirring speed during nylon formation. The preparation of microcapsules containing calcium alginate employed freeze-drying procedures. Lyophilization was not necessary with the formalized gelatin and calcium sulfate systems. Various representative drugs (anionic, cationic, nonionic, quaternary, and amphoteric compounds) were used in the formulation studies. The effects of pH, matrix, and encapsulated species on retention of drug in the microcapsules are described. In addition, the surface morphology of the microcapsules was examined using scanning electron microscopy.

Effect of water-soluble carriers on morphine sulfate release from a silicone polymer.

The influence of gelatin, sodium lauryl sulfate, lactose, and sodium alginate on morphine sulfate diffusion from cylindrical silicone polymer pellets was examined in isotonic pH 7.4 phosphate buffer. These water-soluble carriers caused the pellets to swell in aqueous media. Sodium alginate exerted the greatest influence on drug release. The morphine sulfate diffusion rate from the cylindrical pellets increased as the matrix alginate content increased up to 20%. Water-soluble carrier incorporation into silicone polymeric matrixes permits controlled release of water-soluble drugs that otherwise would be released extremely slowly from the polymer. Drug diffusion from the silicone matrix containing sodium alginate followed second-order kinetics. The release mechanism probably involves the creation of pores or pathways through the matrix secondary to the swelling.

Polydimethylsiloxane pellets for sustained delivery of morphine in mice.

A new dosage form was designed whereby a polymeric silicone elastomer provided sustained delivery of morphine to mice over 11 days. These pellets, which can be made easily and inexpensively with a standard tablet mold, gradually released morphine sulfate into the implanted mice. Maximal morphine-induced physical dependence, measured by jumping during naloxone-induced withdrawal, was observed 3--5 days after implantation. At this time, slightly less than 50% of the morphine sulfate had been released. Drug release continued through Day 11 and was accompanied by a physical dependence of decreased magnitude compared to that observed on Day 3 or 5.

Relationship of film properties to drug release from monolithic films containing adjuvants.

The rate of drug release from a polymeric matrix system was influenced by the physical and chemical properties of the monolithic films. The model drugs, salicylic acid and chlorpheniramine maleate, and two poly(methyl methacrylate) copolymers of different permeabilities (Eudragit RL and Eudragit RS), with and without additional adjuvants, were used to form monolithic matrix films for controlled drug release. Adjuvants, including polyethylene glycols (PEG 400 and PEG 8000) and poly(vinylpyrrolidones) (PVP-K15 and PVP-K90), were incorporated into films of Eudragit RL PM and Eudragit RS PM. The moisture permeation constant, glass transition temperature (Tg), tensile strength, and drug release profiles were determined for each acrylic resin slab to correlate the physicochemical and physicomechanical film properties to observed drug release. Faster rates of drug diffusion were observed with the addition of PEG 400 to the films, because of its plasticizing effect and the resultant increased moisture permeability of the matrix. An exception existed with the Eudragit RL PM film containing salicylic acid where drug-polymer interactions inhibited drug diffusion. The small changes in moisture permeability, Tg, and tensile strength observed with incorporation of the PVPs had an insignificant influence on the dissolution results for salicylic acid from Eudragit RS PM films. Increases in the tensile strength and Tg after addition of PVP to the Eudragit RS PM matrix support the observed decreased rate of diffusion for chlorpheniramine maleate. The pores formed by migration of the hydrophilic adjuvants from the films altered the diffusion kinetics of the matrix, compared with that of the nonporous polymer, when only the antihistamine was present.

Physical and chemical factors influencing the release of drugs from acrylic resin films.

An investigation was conducted to evaluate the factors influencing the release of salicylic acid and chlorpheniramine maleate from polymethacrylate amino-ester copolymer films (Eudragits RL PM and RS PM). Differential scanning calorimetry was performed on the films to study the solubility of drug in the polymer and to determine the effect of added drug on the thermal properties of the film. Incorporation of drug into the polymers decreased the glass transition temperature of the polymers. Dissolution of drug from monolithic slabs was followed as a function of temperature, drug concentration in the films, and ionic strength of the release media. In addition, adsorption studies were conducted with each drug:polymer combination to help explain release results and further characterize the drug:polymer interactions that occurred. The rate of drug release increased with increasing temperature. Adsorption of salicylic acid by the polymers was believed to influence the drug release profiles observed for different drug loadings and ionic strengths. Eudragit RL was found to adsorb salicylic acid to a greater extent than the Eudragit RS. Chlorpheniramine maleate was not found to be adsorbed by either polymer.