Alan B. Jones

Sustained Release of Acetaminophen from Heterogeneous Matrix Tablets: Influence of Polymer Ratio, Polymer Loading, and Co-active on Drug Release

The aim of this research was to investigate the effect of pseudoephedrine (PE), polymer ratio, and polymer loading on the release of acetaminophen (APAP) from hydroxypropyl methyl cellulose (HPMC)/polyvinylpyrrolidone (PVP) matrices. Granules formulated with APAP or both APAP and PE, and various blends of HPMC and PVP were compressed into tablets at varying compression forces ranging from 2000 to 6000 Ib. In vitro drug release from the matrix tablets was determined and the results correlated with those of tablet water uptake and erosion studies. Drug release from the formulations containing both APAP and PE was slower than those containing only APAP (P < 0.05, F = 3.10). Drug release from tablets formulated with APAP only showed an initial burst at pH 1.16 or 7.45, and at high total polymer loading (> or = 9.6%). Formulations containing both APAP and PE showed slower drug release at pH 1.16 than at pH 7.45. At pH 1.16, a decline in the percentage of APAP released occurred after 18 hours. This was due to the hydrolysis of APAP to p-aminophenol. The drug dissolution data showed good fit to the Korsmeyer and Peppas model, and the values of the release exponents ranged from 0.20 to 0.62, indicating a complex drug release pattern. Tablet erosion studies indicated that the amount of APAP released was linearly related to the percentage of tablet weight loss. The kinetics of tablet water uptake was consistent with a diffusion and stress relaxation controlled mechanism. Overall, the results of this study indicated that PE, as a co-active in the formulation, modified the matrix, and hence retarded APAP release.

Effect of drug, formulation and process variables on granulation and compaction characteristics of heterogeneous matrices. Part 1: HPMC and HPC systems

Abstract The purpose of this study was to investigate the effects of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) ratios, total polymer loading and the use of pseudoephedrine as a co-active on the physical properties of acetaminophen granulation as well as that of the compressed tablets. The incorporation of pseudoephedrine to the acetaminophen–polymer formulations resulted in a decreased amount of water required for the wet granulation process. Moreover, the particle size of the granules decreased and the tablet hardness increased. Increasing the HPMC-to-HPC ratio increased both the particle size of granules and the tablet hardness. No clear trend in the particle size of granules and the tablet hardness was seen when the total polymer loading was varied at a given HPMC-to-HPC ratio. The tablet disintegration time was not influenced by the presence of pseudoephedrine; however, it decreased for the formulations containing a lower total polymer content. All the matrix systems investigated showed good compressibility. The effect of pseudoephedrine on the physical properties of wet granulated or compressed acetaminophen tablets was attributed to interference in the hydration characteristics of the matrix polymers.

Coca Paste: Chemical Analysis and Smoking Experiments

Several samples of Colombian and a sample of Peruvian coca paste were subjected to chemical analysis to ascertain the complexity of these products. A neutral and acid fraction and a basic fraction were analyzed by gas chromatography/flame ionization detection (GC/FID) and gas chromatography/mass spectrometry (GC/MS). The basic fraction was also analyzed as its trimethylsilyl (TMS) derivative. Several gasoline residue components were identified in the neutral fraction. In addition to cocaine (greater than 60% in all cases), other alkaloids were identified. Lead and manganese analyses were carried out on these samples. While all the samples contained no lead (less than 45 ppm), most of the Colombian samples contained significant amounts of manganese (greater than 5%). Preliminary smoking experiments with a Colombian coca paste sample indicated that it behaves more like free cocaine than like a cocaine sulfate salt.

Development and evaluation of a novel dissolution apparatus for medicated chewing gum products.

A novel dissolution apparatus was developed for medicated chewing gum products. A prototype gum product containing phenylpropa-nolamine hydrochloride (PPA) was used to evaluate the apparatus. The apparatus consists of a conical Teflon base and a rotating, ribbed Teflon plunger suspended in a dissolution vessel. Parameters evaluated were rotation speed, plunger frequency, medium volume, medium type, medium sampling location, number of plunger ribs, and number of gum pieces. Samples were taken over a 20-min period and samples were analyzed by HPLC. Cumulative percentage re-leased-versus-time profiles were obtained for each parameter evaluated. Statistical analysis of the gum product indicated that the only significant differences occurred at the lowest rotation speed and lowest plunger frequencies. A Level A correlation was found between the in vitro release profile for the 20-rpm and 30-cycles/min plunger frequency and the in vivo chew-out study.

Comparison of serum progesterone levels in dogs after administration of progesterone by vaginal tablet and vaginal suppositories

Serum progesterone levels from a vaginal tablet formulation and six different vaginal suppository formulations, each containing 25 mg of progesterone, were evaluated in mongrel dogs. Bioavailabilities relative to an intravenous dose of progesterone were calculated. The vaginal tablet was found to have a significantly higher bioavailability compared with the vaginal suppositories.

Determination of cannabidiol in plasma by electron-capture gas chromatography.

A procedure was developed for the analysis of cannabidiol (CBD) in blood plasma. Tetrahydrocannabidiol was used as an internal standard and was added prior to extraction. The plasma extracts were derivatized with pentafluorobenzyl bromide and the produce purified on a mini-column of Florisil. The pentafluorobenzyl derivatives were then analyzed by gas chromatography on a 5% OV-225 column using an electron-capture detector. A detection limit of 50 ng CBD per ml of plasma was observed. The procedure was used to study the plasma level of CBD after its oral and intravenous administration to monkeys.

Characterization of Drug Release from Liposomal Formulations in Ocular Fluid

The successful application of liposomes in topical ophthalmic drug delivery requires knowledge of vesicle stabilization in the presence of tear fluid. The release of procaine hydrochloride (PCH) from large unilamellar liposomes in the presence of simulated tear fluid was studied in vitro as a function of bilayer lipid content and tear protein composition. Reverse-phase evaporation vesicles were prepared from egg phosphatidylcholine, stearylamine or dicetyl phosphate, and cholesterol. The relationship between lipid composition and encapsulation efficiency, vesicle size, drug leakage upon storage at 4 degrees C, and the release of PCH-loaded liposomes was studied. The encapsulation efficiency was found to be dependent upon the lipid composition used in the liposome preparation. In particular, phosphatidylcholine vesicles containing cholesterol and/or charged lipids had a lower entrapment efficiency than liposomes prepared with phosphatidylcholine alone. However, the drug release rate was reduced significantly by inclusion of cholesterol and/or charged lipids in the liposomes. The release kinetics of the entrapped agent seemed to be a biphasic process and the drug-release in both simulated tear fluid (STF) and pH 7.4 phosphate buffered saline (PBS) solutions followed pseudo first-order kinetics in the early stage of the release profile. The drug-release appeared to be diffusion and/or partition controlled. Drug release from liposomes into STF, pH 7.4 PBS, and five different modified tear formulations was also evaluated. While serum-induced leakage is attributed to high-density lipoprotein-mediated destabilization, it was determined that lactoferrin might be the protein component in tear fluid that has the primary influence on the liposome-entrapped drug release rate. Five local anesthetics, benoxinate, proparacaine, procaine, tetracaine, and benzocaine were entrapped in liposomal vesicles by a reverse-phase evaporation (REV) technique. The release of these structurally similar topical anesthetics entrapped in positively charged liposomes (egg phosphatidylcholine, stearylamine, and cholesterol in a 7:2:1 molar ratio) was evaluated in a simulated tear fluid and pH 7.4 phosphate buffered saline solution. The liposomes appeared to be useful carriers for these drugs to retard their in vitro release in tear fluid and perhaps sustain or control their release in the eye for better therapeutic efficacy. An analysis of the release data demonstrated that for this series of drugs, drug partition coefficient has the largest effect on release rate, with molecular weight exhibiting a smaller effect. Release rate was found to decrease with increased lipophilicity or increased molecular weight.

Effect of Drug, Formulation, and Process Variables on Granulation and Compaction Characteristics of Heterogeneous Matrices: Part II. HPMC and PVP Systems

AbstractA heterogeneous matrix comprising hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) at various ratios was granulated using acetaminophen and pseudoephedrine as model drugs. The effect of drug, polymer ratio, total polymer loading, and volume of the granulating fluid on granule growth, granule size distribution, compaction, and tablet properties of the matrix was studied. Formulations containing both acetaminophen and pseudoephedrine required less water to granulate than those containing only acetaminophen. Moreover, the particle sizes of granules prepared with acetaminophen and pseudoephedrine were smaller than those containing only acetaminophen. Tablet hardness increased and friability decreased considerably in all formulations containing pseudoephedrine. In general, the tablet hardness and tablet disintegration time varied with changes in total polymer loading, fraction of HPMC in the matrix, and composition of the model drug(s). All the matrix systems studied showed good flow...

Percutaneous absorption of bendroflumethiazide from gel and membrane-controlled gel systems: an in vitro and in vivo study

A number of gel formulations were developed for bendroflumethiazide (BFTZ). The gels were composed of BFTZ dissolved in an alcohol–polyol–water medium and mixed with polyacrylic acid. Based on preformulation studies it was determined that a transdermal therapeutic system (TTS) could be constructed with 5% BFTZ, 40% ethanol (EtOH), 20% of a 1:1 mixture of 2-pyrrolidone and N-methyl-2-pyrrolidone (pyrol), 2% polyacrylic acid (PA) and 33% purified water, sandwiched between an aluminum foil backing and a porous polypropylene rate-control membrane. The device was tested, with and without the rate-control membrane, by in vitro diffusion across whole thickness SKH-1 hairless mouse skin and by in vivo percutaneous absorption in New Zealand White rabbits. In vitro results indicate that this device will deliver BFTZ at penetration rates of 0.66 and 0.98 μg/cm2 per h across hairless mouse skin, with and without the rate-control membrane, respectively. In vivo results show that blood levels of 50–300 ng/ml could be reached over a 12-h dosing period. Stability studies on the gel formulation and the TTS indicate that elevated storage temperatures will change the viscosity of the gel matrix and the release of BFTZ from the device.

Inclusion Complexes of Tolnaftate with β-Cyclodextrin and Hydroxypropyl β-Cyclodextrin

AbstractTolnaftate, an antifungal agent, was found to form inclusion complexes with both β-cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrins (HPBCDs) with two different degrees of substitution [HPBCD(A)-8% and HPBCD(B)-3%]. Complex formation in the solution state was studied using phase solubility and spectral shift methods. Solid complexes were prepared by the coprecipitation method. Solubilities and dissolution rates were determined for each solid complex, its corresponding physical mixture, and free drug. The increase in solubility of tolnaftate with added HPBCD was found to be significantly greater than with added β-CD. For both HPBCD(A) and HPBCD(B), over the concentration range 0–0.05 M. 1:1 complexes with stability constants of 1460 ± 139 M-1 and 1860 ± 165 M-1 were observed, respectively. Over the β-CD concentration range 0–0.02 M, a 1:1 complex with a stability constant of 1190 ± 105 M-1 was observed. At higher HPBCD concentrations, the increase in solubility was observed to show a positive d...