Characterization of ethyl cellulose polymer.

Ethyl cellulose (EC) polymer was characterized for its property before considering the interactions with the plasicizer. Ethocel Std.10 FP Premium from Dow chemical company USA was tested for its solubility, morphology and thermal properties. Seven percentage of EC solution in ethanol was found to be the right viscosity used to prepare the film. The EC polymer and EC film without any plasticizers showed almost identical thermal behavior, but in X-ray diffraction showed different arrangements of crystallites and amorphous region. Dynamic mechanical analysis of film showed that without a plasticizer, EC film was not flexible and had very low elongation with high applied force. The aim of the work was to avoid using the commercially available EC dispersions Surelease® and Aquacoat®; both already have additives on it. Instead, Ethocel EC polymer (powder) was characterized in our laboratory in order to find out the properties of polymer before considering the interactions of the polymer with various plasticizers.

Evaluation of in vitro percutaneous absorption of olanzapine and fluoxetine HCl: enhancement properties of olanzapine.

The diffusion characteristics of fluoxetine HCl (FLX HCl) and olanzapine (OLZ) alone and in combination with each other were studied to determine their in vitro permeation behavior across a series of gelling agents through a cellulose membrane and human cadaver skin. Klucel 0.5% was selected as the optimal formulation to study their diffusion through human cadaver skin. The release profiles of drugs acting alone and in combinations were identical in the case of the cellulose membrane. However, with human cadaver skin, the permeation of FLX HCl in combination with OLZ drastically increased (732 µg) compared with the release of FLX HCl alone (43.7 µg), while the release of OLZ remained the same whether alone or in combination with FLX HCl (183.7 µg). The results indicate that OLZ enhances the diffusion of FLX HCl through the cadaver skin. Follow-up studies with OLZ were conducted to further investigate this phenomenon and have shown that OLZ enhancement properties are skin reversible as well as concentration dependent. Also, a variety of experiments with different hydrophilic and lipophilic molecules were conducted, and it was found that OLZ enhances the permeation of hydrophilic compounds, while it has no influence on lipophilic compounds. Finally, a number of compounds structurally related to OLZ were investigated as enhancers, and it was determined that piperazine ring attached to the tricyclic system of OLZ is essential for enhancement of FLX HCl (1,837 µg).

Effect of vehicle systems, pH and enhancers on the permeation of highly lipophilic aripiprazole from Carbopol 971P gel systems across human cadaver skin.

The objective of this study was to investigate the effect of vehicle systems, pH and enhancers on the permeation of a highly lipophilic basic drug aripiprazole (ARPZ) through human cadaver skin. Solubility of ARPZ in single, binary, tertiary, and quaternary vehicle systems of N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), water, ethanol and isopropyl myristate (IPM) was studied. Gel formulations of 5% ARPZ were developed with 0.5% Carbopol 971P in quaternary vehicle systems consisting of NMP, DMSO, water and ethanol or IPM at optimum ratio of 40/40/5/15. The effect of pH of the gel formulations and fatty acids with different chain lengths on the permeation was studied. The flux of ARPZ from gel formulation with IPM and ethanol was comparable. A four fold increase in APRZ flux was observed when the pH of the gel systems was lowered from pH 8.2 to pH 6 or pH 7. For fatty acids, the order of flux is lauric acid > myristic acid > caprylic acid > oleic acid. In all the cases, in vitro permeation rate of ARPZ through human cadaver skin followed zero order kinetics. This study demonstrated that ARPZ in tertiary vehicle system of NMP/DMSO/water/IPM at ratio of 40/40/5/15 and gel system of Carbopol 971P with pH 7 is a promising candidate for transdermal delivery.

Effects of process parameters on solid self-microemulsifying particles in a laboratory scale fluid bed.

The purpose of this study was to select the critical process parameters of the fluid bed processes impacting the quality attribute of a solid self-microemulsifying (SME) system of albendazole (ABZ). A fractional factorial design (2(4-1)) with four parameters (spray rate, inlet air temperature, inlet air flow, and atomization air pressure) was created by MINITAB software. Batches were manufactured in a laboratory top-spray fluid bed at 625-g scale. Loss on drying (LOD) samples were taken throughout each batch to build the entire moisture profiles. All dried granulation were sieved using mesh 20 and analyzed for particle size distribution (PSD), morphology, density, and flow. It was found that as spray rate increased, sauter-mean diameter (D(s)) also increased. The effect of inlet air temperature on the peak moisture which is directly related to the mean particle size was found to be significant. There were two-way interactions between studied process parameters. The main effects of inlet air flow rate and atomization air pressure could not be found as the data were inconclusive. The partial least square (PLS) regression model was found significant (P < 0.01) and predictive for optimization. This study established a design space for the parameters for solid SME manufacturing process.

Evaluating the efficacy of a group of nontraditional plasticizers on the glass transition temperature of ethyl cellulose polymer.

OBJECTIVE: The aim of this study was to investigate the efficiency of a homologous series of esters of dicarboxylic acid on ethyl cellulose polymer in terms of their glass transition temperatures (T(g)). METHODS: Ethyl cellulose polymer was plasticized with succinates (C-2), glutarates (C-5), adipates (C-6), pimelates (C-7), suberates (C-8), and sebacates (C-10) at different concentration levels. The film formation and physical state of plasticizers within the polymer were investigated and incompatibility of plasticizers was determined by nonhomogeneous system. RESULTS: A decrease in T(g) of the plasticized polymer was used as an indicator of plasticizing efficiency. Experimental T(g) values were correlated with the theoretical ones predicted by Gordon-Taylor equation. Most of the experimental T(g) values did not fit with the predicted ones. For all plasticizers (except succinates) the measured T(g) was lower than calculated indicating negative deviation from the ideal behavior. Anti-plasticization was obtained with lower plasticizers concentration. Fourier transform infrared spectroscopy was used to determine the interactions between the polymer and plasticizers on T(g) values in predicting the efficiency. CONCLUSIONS: The correlation between experimental and calculated T(g) values verifies that physiochemical properties are the primary factors influencing the plasticization efficiency. However, further studies are needed to establish the plasticization efficiency.

The effect of permeation enhancers on the viscosity and the release profile of transdermal hydroxypropyl methylcellulose gel formulations containing diltiazem HCl.

BACKGROUND AND METHOD: The objective of this study was to characterize the release of Diltiazem HCl (DTM HCl) from hydroxypropyl methylcellulose gels containing the following permeation enhancers at a 0.5% (w/w): sodium lauryl sulfate, dimethyl sulfoxide (DMSO), polysorbate 80, propylene glycol, N-methylpyrrolidone (NMP), fatty acids (oleic acid, caprylic acid, and myristic acid), and isopropyl myristate (IPM). The enhancers' effects on the gel's viscosity were also investigated. RESULTS: The novel findings of this study were the following: (i) polysorbate 80 was used for the first time as an enhancer with a hydrophilic compound in a hydrophilic carrier and it rendered the highest permeation flux (57.1 +/- 0.9 microg/cm(2)/h) compared with the rest of the enhancers, (ii) myristic acid (a 14-carbon-chain fatty acid) rendered the highest permeation flux (18.4 +/- 0.49 microg/cm(2)/h) among all fatty acids because of a decrease in the gel's viscosity, (iii) NMP (46.5 +/- 0.7 microg/cm(2)/h) and IPM (15.3 +/- 0.41 microg/cm(2)/h) increased the permeation flux from the second day onward. Both enhancers increased the gel's viscosity, (iv) sodium lauryl sulfate decreased the viscosity of the gel and the drug's permeation flux (8.1 +/- 0.21 microg/cm(2)/h) because of its binding with the drug, (v) propylene glycol decreased the permeation flux (10.2 +/- 0.32 microg/cm(2)/h) by increasing the gel viscosity, and (vi) DMSO increased the permeation flux (13.8 +/- 0.4 microg/cm(2)/h) without altering the viscosity. CONCLUSION: These findings indicate that to formulate DTM HCl into a hydroxypropyl methylcellulose gel the enhancers of choice should be polysorbate 80, myristic acid, DMSO, NMP, and IPM or combinations thereof.

Permeation study of five formulations of alpha-tocopherol acetate through human cadaver skin.

Alpha-tocopherol (AT) is the vitamin E homologue with the highest in vivo biological activity. AT protects against the carcinogenic and mutagenic activity of ionizing radiation and chemical agents, and possibly against UV-induced cutaneous damage. For stability consideration, alpha-tocopherol is usually used as its prodrug ester, alpha-tocopherol acetate (ATA), which once absorbed into the skin is hydrolyzed to alpha-tocopherol, the active form. The objective of this research was to characterize in vitro the permeation properties of ATA from various solutions and gel formulations. Permeation studies were conducted using modified Franz diffusion cells and human cadaver skin as the membrane. Specifically, 5% (w/w) alpha-tocopherol acetate was formulated in the following vehicles: ethanol, isopropyl myristate, light mineral oil, 1% Klucel gel in ethanol, and 3% Klucel gel in ethanol (w/w). The receiver temperature was 37 degrees C. Samples from the receiver were collected at 2, 4, 6, 8, 12, 24, 30, 36, and 48 hours and analyzed by HPLC for concentrations of alpha-tocopherol acetate and alpha-tocopherol. The permeabilities of ATA through human cadaver skin were 1.0x10(-4), 1.1x10(-2), 1.4x10(-4), 2.1x10(-4), and 4.7x10(-4) cm/h for the ethanol solution, isopropyl myristate solution, light mineral oil solution, 1% Klucel gel, and 3% Klucel gel, respectively. The results show that the formulation had relatively minor effects on the permeability coefficients of ATA through cadaver skin in all cases except for the isopropyl myristate solution.

Faster determination of membrane permeabilities without using the lag time method.

A new method of data analysis is presented that allows the determination of membrane permeabilities. The method is applicable to data obtained from a common experimental setup, in which drug dissolved in an inert donor gel diffuses through a membrane, initially void of drug, into a receiver for which sink conditions are maintained. The equations developed can also be used to predict the release of drug from these systems. Fick's Laws are solved, and the early time behavior of the mathematical solution is used to develop the analysis methods. Limitations of the model and their relations to experimental design are determined, and the method of application to experimental data is presented. The method is tested numerically using simulated data generated by a 1-d finite difference program that was used to numerically solve Fick's Laws, and also applied to in vitro human cadaver skin transdermal data for the drugs doxepin, imipramine and amitriptyline. It is concluded that this method can be applied to determine membrane permeabilities and diffusion coefficients with accuracy comparable to other experimental setups, such as lag time experiments and steady state experiments, but requiring experiments that can be significantly shorter.

An improved in vitro method for measuring skin permeability that controls excess hydration of skin using modified Franz diffusion cells.

When liquid donors/receivers are used for in vitro skin permeation studies, excess hydration can change skin properties compared to in vivo conditions. A novel in vitro method of determining the permeability of drugs through skin was developed that avoids exposing the membrane to dilute donor/receiver solutions. The drug is dissolved in an unstirred donor gel, and diffuses through a membrane into an unstirred gel receiver that can potentially be adjusted to mimic physiological conditions. Pulsatile microdialysis (PMD) was used to sample local concentrations in the receiver medium, and a model was developed to allow the determination of permeability. For Doxepin HCl, permeabilities through artificial membranes and human cadaver skin were determined using the new and previously reported methods. For artificial membranes that minimally hydrate, the new method gave consistent but slightly lower permeability values. For human cadaver skin, the permeability determined using the new method was 1/6 that of the fully hydrated skin. Limitations of the model, their relations to experimental design and data analysis were evaluated. It was concluded that this method can be applied to characterize membrane permeabilities using experiments that may avoid membrane breakdown and more closely mimic physiological conditions.

Development and oral bioavailability assessment of a supersaturated self-microemulsifying drug delivery system (SMEDDS) of albendazole.

OBJECTIVES: Albendazole's (ABZ) poor aqueous solubility is a major determinant of its variable therapeutic response (20-50%). The purpose of this study was to develop and optimize the composition of a self-microemulsifying drug delivery system (SMEDDS) of ABZ and assess its oral pharmacokinetics in rabbits. METHODS: A D-optimal mixture design of experiments was used to select the levels of constraints of the formulation variables. The predicted composition was optimized using four responses: dispersion performance, droplet sizes, dissolution efficiency (DE) and time for 85% drug release (t(85%)). KEY FINDINGS: The optimal composition of the ABZ-SMEDDS formulation, with approximately 5 mg/g drug loading of ABZ, was predicted to be Cremophor EL (30% w/w), Tween 80 (15% w/w), Capmul PG-8 (10% w/w) and acidified PEG 400 (45% w/w). An increase of 63% in the relative bioavailability compared with the commercial suspension was obtained with ABZ-SMEDDS as measured by albendazole sulfoxide (ABZSO) plasma levels. The area under the curve (AUC(0-->24h)) and the peak plasma concentration (C(max)) of ABZ-SMEDDS was higher than those obtained with the commercial suspension by 56% and 52%, respectively. CONCLUSIONS: This study demonstrates a strategy for the development of a supersaturated SMEDDS formulation of a drug with low aqueous solubility.

In vitro evaluation of the release of albuterol sulfate from polymer gels: effect of fatty acids on drug transport across biological membranes.

In this investigation, the diffusion of the beta 2 agonist albuterol sulfate (ABS) across several membranes (cellulose, hairless mouse skin, human cadaver skin) from polymer gels was studied, and the effects of several fatty acids on drug permeation through skin were evaluated. The results were then used to predict whether transdermal delivery would be appropriate for ABS. All in vitro release studies were carried out at 37 degrees C using modified Franz diffusion cells. In preliminary studies, ABS release through cellulose membranes was studied from two polymeric gels, Klucel (hydroxypropylcellulose) and Methocel (hydroxypropylmethylcellulose). Three polymer concentrations were used for each gel (0.5%, 1.0%, and 1.5%). From these experiments, Klucel 0.5% was selected as the optimal formulation to study ABS diffusion across hairless mouse skin. Experiments were conducted to evaluate the effects of capric acid, lauric acid, and myristic acid as penetration enhancers. The results suggested that lauric acid preferentially enhanced ABS diffusion compared to the other fatty acids studied, and follow-up studies were done to evaluate the release through human cadaver skin from a donor containing 2% ABS and lauric acid in 0.5% Klucel. These experiments showed that a 2:1 (lauric acid:ABS) molar ratio gave the best ABS release rates. The release rate across human cadaver skin declined slowly over 24 hr, and an average flux over 24 hr of approximately 0.09 mg/hr cm2 was measured. Using this value as a steady-state flux, extrapolations predicted that transdermal delivery can be used to maintain therapeutic ABS plasma levels (6-14 ng/mL) for extended periods. The results of this research suggest that ABS is a good candidate for transdermal drug delivery.

Characterization of pentamidine excretion in the isolated perfused rat kidney.

OBJECTIVE: To study the renal excretion and kidney accumulation of pentamidine, a potentially nephrotoxic compound, in the isolated perfused rat kidney (IPK). MATERIALS AND METHODS: IPK experiments (3-4 per treatment group) were conducted using male Sprague-Dawley rats (250-350 g). Dose proportionality studies were carried out over a pentamidine dosing range of 80-4000 microg, designed to target initial perfusate concentrations from 1 to 50 microg/mL. Separate interaction experiments were conducted between pentamidine (800 microg) and tetraethylammonium (dose 8000 microg) or dideoxyinosine (dose 80 microg). Inulin was used as a glomerular filtration rate (GFR) marker. Control (drug-naive) perfusions were also carried out. Pentamidine was analysed in perfusate, kidney and urine samples by HPLC. Inulin was measured by a colorimetric method. RESULTS: Pentamidine CLR (1.1 +/- 0.6 to 0.05 +/- 0.03 mL/min) and excretion ratio (3.6 +/- 1.5 to 0.56 +/- 0.15) significantly decreased over the range of doses studied. Significant reductions in viability parameters (GFR, Na reabsorption) were noted in kidneys perfused with high dose pentamidine (4000 microg). Tetraethylammonium co-administration reduced pentamidine renal excretion, resulting in significantly greater kidney accumulation of pentamidine and reduced kidney function. Dideoxyinosine administration had minimal effects on pentamidine disposition. CONCLUSIONS: Pentamidine renal transport involves a combination of mechanisms (filtration, secretion and passive reabsorption). Dose proportionality studies demonstrated non-linear excretion of pentamidine. Inhibition of pentamidine renal clearance by tetraethylammonium was consistent with decreased luminal transport. The detrimental effects of pentamidine on kidney function were the result of significant kidney accumulation of drug. The potential exists for drug-drug interactions between pentamidine and organic cations, increasing the risk of drug-induced nephrotoxicity.