Release of hydrocortisone from a cream matrix: dependency of release on suspension concentration and measurement of solubility and diffusivity

The principal object of the present research was to investigate the sensitivity of drug release from a semisolid system to the manner of its preparation and to the concentration of drug placed within it. Established theory indicated that release should be concentration dependent, with the specific dependency determined by whether the drug in the system is fully in solution or is present substantially as suspended matter. To purposefully explore these relatively untested performance expectations, the total amount of drug in the formula was varied from a low concentration of 0.25% to a high concentration of 3%. Conditions were established such that drug release conformed to release from a semi-infinite medium into a receptor sink. At every concentration, release profiles were well reproduced in replicate samples and, where multiple lots of a kind were employed, from lot to identical lot. In all cases square root of time release kinetics were observed. Moreover and without exception, the square root of time release rate from run to run was directly proportional to the square root of the total concentration of hydrocortisone placed in the formulations. The amount released per square root of time per square root of total concentration was nearly identical from run to run irrespective of total concentration. The overall behavior fit theoretical expectations for suspensions having only a small fraction of the drug they contain in solution. That this condition prevailed even at the lowest 0.25% hydrocortisone strength was proven by independently measuring hydrocortisone's solubility (0.02%). Measurement of solubility permitted estimation of the effective diffusivity of the drug through the cream (2 x 10(-7) cm2/s).     

Enhanced Controlled Release of Loratadine From the Ethylene-vinyl Acetate Matrix Containing Plasticizer

An ethylene-vinyl acetate (EVA) matrix containing plasticizer was prepared as a potential controlled release system for loratadine. The EVA matrix containing loratadine was prepared as the transdermal device using casting methods. The solubility of loratadine according to the volume fraction of PEG 400 was determined. The effects of the drug concentration, temperature, and plasticizers on the release of the drug were determined at 37°C using 40% PEG 400 solution as the receptor medium using the modified Keshary-Chien cell. Some types of plasticizers. such as citrates and phthalates, were used to prepare the pores and increase the flexibility of the EVA matrix. The solubility test according to the PEG 400 volume fraction revealed the highest solubility in the 40% PEG 400 solution. The rate of drug released from the EVA matrix increased with increasing temperature and drug loading. There was a linear relationship between the release rate and the square root of the loading dose. The activation energy for drug release from the EVA matrix with a loading dose of 1%, 2%, 3%, 4%, and 5% was estimated to be 6.83, 6.80, 6.77, 6.71, and 6.65 kcal/mol, respectively Among the plasticizers used, diethyl phthalate showed the highest level of loratadine release. In conclusion, an EVA matrix containing plasticizer could be used to enhance the controlled release of loratadine.     

Production of pH-Responsive Microparticles by Spray Drying: Investigation of Experimental Parameter Effects on Morphological and Release Properties

During spray drying, emphasis is placed on process optimisation to generate favourable particle morphological and flow properties. The effect of the initial feed solution composition on the drug release from the prepared microparticles (MPs) is rarely considered. We investigated the effects of solvent composition, feed solution concentration and drug-loading on sodium salicylate, hydrocortisone and triamcinolone release from spray-dried Eudragit L100 MPs. Eudragit L100 is a pH-responsive polymer whose dissolution threshold is pH 6 so dissolution testing of the prepared MPs at pH 5 and 1.2 illustrated non-polymer controlled burst release. Increasing the water content of the initial ethanolic feed solution significantly reduced hydrocortisone burst release at pH 5, as did reducing the feed solution concentration. These findings caution that changes in feed solution concentration or solvent composition not only affect particles' morphological characteristics but can also negatively alter their drug release properties. This work also illustrate that drug-free MPs can have different morphological properties to drug-loaded MPs. Therefore, process optimisation needs to be carried out using drug-loaded systems. Depending on the physicochemical properties of the encapsulated active pharmaceutical ingredient (API), drug-loading can affect the polymer solubility in the initial feed solution with consequent impact on MPs morphological and release properties.     

Controlled Release of Substituted Benzole and Naphthoic Acids Using Carbopol ® Gels: Measurement of Drug Concentration Profiles and Correlation to Release Rate Kinetics

Purpose. The objective of this study is to correlate drug release mechanism with measured drug concentration profiles in gel layers of Carbopol^® matrices containing mesalamine or benzoic acid. Methods. Release rate experiments with Carbopol^® matrices were performed using a rotating disk apparatus. Matrices were frozen and the gel layer in the matrices was sliced using a microtome in a cryostat. Drug concentration profiles were determined by direct measurement of the concentration of the drug in the gel slices. The pH of the slices was measured using microelectrodes, and water content was measured by Karl Fisher titration. Results. The concentration gradient in mesalamine matrices decreased over time and correlated with square root of time release rate kinetics. The concentration profiles of benzoic acid were unchanged over time and correlated with zero order release rate kinetics. Carbopol gel layers were highly hydrated (93–95% water). Gel layers in matrices with mesalamine had a more alkaline microenvironmental pH. This higher pH resulted in increased growth of the thickness of the gel layer and a reduction drug diffusivity in comparison to benzoic acid matrices. Conclusions. The release rate kinetics of mesalamine and benzoic acid correlated to the measured concentration profiles. The shape of the concentration profiles is determined by the rate of growth of the Carbopol^® gel layer and drug diffusivity.     

Controlled Release of a Contraceptive Steroid from Biodegradable and Injectable Gel Formulations: In Vitro Evaluation

Purpose. The purpose of this study was to investigate the effects of formulation factors including varying wax concentration, drug loading and drug particle size, on drug release characteristics from both pure oil and gel formulations prepared with a combination of derivatized vegetable oil (Labrafil 1944 CS) and glyceryl palmitostearate (Precirol ATO 5), using levonorgestrel as a model drug. Methods. The effects of varying drug loadings, different drug particle sizes, and wax (Precirol) concentrations on in-vitro drug release rates were evaluated, and the mechanisms of drug release from the gels were determined. Results. Zero-order drug release rates from the 10% Precirol gel formulations containing 0.25, 0.50 and 2.00% w/v drug loadings were lower than those observed for oil formulations containing identical drug loadings. Higher zero-order release rates were observed from formulations containing smaller drug particles suspended in both oil and gel formulations. The mechanism of drug release from gels containing less than 0.25% w/w drug was diffusion-controlled. Increasing the wax concentrations in the gels from 5% w/w to 20% w/w significantly decreased the diffusivity of the drug through the gel formulations and markedly increased the force required to inject the gels from two different sizes of needles. Conclusions. This study shows how modification of the physicochemical properties of the gel formulations by changing the drug particle size, wax concentration and drug loading, affects drug release characteristics from the system.     

Bead Coating. I. Change in Release Kinetics (and Mechanism) Due to Coating Levels

Beads containing 50% acetaminophen (APAP) and 50% microcrystalline cellulose (Avicel PH 101) were prepared and then coated using an aqueous ethylcellulose based dispersion (Aquacoat) to evaluate the effect of the coating level on drug release. The APAP release was shown to be dependent on levels of the coating and a change in mechanism was suggested. Drug release from incompletely coated beads at low levels of coating can be described with the square root of time model, while drug release from beads with a high level of coating appears to be best described by zero-order release. At low coating levels, the drug release rate constant based on the square root relationship seems to be linear with the coating level. At high coating levels, drug release rate in terms of a zero-order model appears to be proportional to the reciprocal of the coating level.     

Release characteristics of quinupramine from the ethylene-vinyl acetate matrix

An ethylene-vinyl acetate (EVA) matrix containing quinupramine was prepared in an attempt to develop a controlled delivery system for quinupramine. Permeation studies of quinupramine through the EVA copolymer membrane were carried out using a two-chamber diffusion cell. The rate of drug permeation through the EVA membrane was proportional to the PEG 400 volume fraction. The release of quinupramine from the EVA matrix was examined using a modified Franz diffusion cell. A plasticizer was added to prepare the pore structure of the EVA matrix in order to increase the rate of drug release. The effects of PEG 400, membrane thickness, drug concentration, temperature, and plasticizer on drug release rate were investigated. The drug release rate from the EVA matrix increased with increasing PEG 400 volume fraction, temperature and drug loading dose. The activation energy for drug release was 5.91, 5.39, 4.68 and 4.52 kcal/mol for a loading dose of 0.5%, 1%, 1.5%, and 2%, respectively. Among the plasticizers used, diethyl phthalate showed the best results. The release of quinupramine from the EVA matrix follows a diffusion-controlled model, where the quantity released per unit area is proportional to the square root of time. The controlled release of quinupramine was achieved using the EVA polymer including a plasticizer.     

Controlled release of furosemide from the ethylene-vinyl acetate matrix

The ethylene-vinyl acetate (EVA) matrix containing furosemide was prepared by the casting method and the release patterns were observed. The solubility of furosemide was determined as a function of volume fraction of polyethylene glycol 400. The release of drug from the matrix was studied as a function of temperature and drug concentration. Plasticizers such as the citrates and the phthalates were added for preparing the membrane to increase the flexibility of the EVA matrix. The solubility of furosemide was the highest when the concentration of PEG 400 was 40% (v/v). The release rate of drug from the EVA matrix increased with increasing temperature and drug loading doses. A linear relationship was found between the release rate and the square root of the loading dose. The activation energy (Ea), which was measured from the slope of the logP versus 1000/T plots, was 12.33 kcal/mol for the 0.5% loading dose, and 11.58 kcal/mol for the 1.0% loading dose, and 11.00 kcal/mol for the 1.5% loading dose. Among the plasticizers used such as the citrates and the phthalates groups, diethyl phthalate showed the best enhancing effects in drug release. In conclusion, the application of an EVA matrix containing a plasticizer might be useful in the development of a controlled drug delivery system.     

聚酰胺-胺树状大分子作为药物载体的体外增溶、缓释试验

目的:考察以聚酰胺-胺树状大分子(PAMAM)作为喹诺酮类药物载体在增溶、缓释方面的作用。方法:根据文献合成PAMAM,并作结构分析;以巴洛沙星为模型药物,检测不同代数不同浓度的PAMAM对巴洛沙星的增溶作用;同时用不同代数的PAMAM与巴洛沙星复合,检测PAMAM对巴洛沙星体外释放的影响,以及在水及模拟肠液中的释放情况。结果:巴洛沙星在水中溶解度约为1.5g·L-1,完全释药时间约为4h。随着PAMAM代数和浓度的增加巴洛沙星溶解度增加(2～5.25g·L-1),PAMAM与巴洛沙星复合物在水中24h释放80%,在模拟肠液中72h释放73%。结论:PAMAM对巴洛沙星具有增溶、缓释作用,有可能促进其制成具有缓释作用的溶液剂或注射剂。     

Studies on Controlled Release of Hydrophilic Drugs from W/O High Internal Phase Ratio Emulsions

Formation of high internal phase ratio emulsions (HIPREs) has been studied in water/Cremophor WO7/soybean oil and water/Cremophor WO7/liquid paraffin systems. Two hydrophilic model drugs, clindamycin hydrochloride (CH) and theophylline (TP), were incorporated in HIPREs with a water concentration of 90% and an oil/surfactant (O/S) weight ratio of 60:40 and their release was determined in vitro at 25°C. The release of both model drugs from HIPREs was much slower than from aqueous solutions. In aqueous solution the release pattern of both actives was identical. In contrast, a clearly distinct release pattern from HIPREs was observed: The release of CH, which is freely soluble in water, was very slow, regardless of the emulsion system, while the release of TP, which is slightly soluble in water, was faster. By changing the pH of the dispersed phase of HIPREs, which in turn affects solubility, drug release was modulated. An increase in the solubility of TP in the dispersed phase by a factor of roughly 4.5 produced a decrease in the diffusion coefficient of two orders of magnitude. These results show for the first time the key role of drug solubility in the release from W/O-HIPREs. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:701–711, 2010     

Enhanced controlled release of loratadine from the ethylene-vinyl acetate matrix containing plasticizer

An ethylene-vinyl acetate (EVA) matrix containing plasticizer was prepared as a potential controlled release system for loratadine. The EVA matrix containing loratadine was prepared as the transdermal device using casting methods. The solubility of loratadine according to the volume fraction of PEG 400 was determined. The effects of the drug concentration, temperature, and plasticizers on the release of the drug were determined at 37 degrees C using 40% PEG 400 solution as the receptor medium using the modified Keshary-Chien cell. Some types of plasticizers. such as citrates and phthalates, were used to prepare the pores and increase the flexibility of the EVA matrix. The solubility test according to the PEG 400 volume fraction revealed the highest solubility in the 40% PEG 400 solution. The rate of drug released from the EVA matrix increased with increasing temperature and drug loading. There was a linear relationship between the release rate and the square root of the loading dose. The activation energy for drug release from the EVA matrix with a loading dose of 1%, 2%, 3%, 4%, and 5% was estimated to be 6.83, 6.80, 6.77, 6.71, and 6.65 kcal/mol, respectively Among the plasticizers used, diethyl phthalate showed the highest level of loratadine release. In conclusion, an EVA matrix containing plasticizer could be used to enhance the controlled release of loratadine.     

A Comparative Study of Controlled Release Matrix Tablets of Diclofenac Sodium,Ciprofloxacin Hydrochloride,and Theophylline

The need for controlled release formulations for diclofenac sodium, ciprofloxacin, and theophylline is well recognized. In our study, controlled release tablets of the three drugs were formulated by the matrix-embedding technique using ethyl cellulose as retardant. Tablets of all the drugs were of good physical quality with respect to appearance, drug content uniformity, hardness, weight variation, and friability. In vitro release rate studies showed that ethyl cellulose extended the release of the three drugs to 12 hr or more. Release patterns from formulations of the three drugs followed Higuchi's square root kinetics. At pH 6.8, the release rate was higher in all three drugs, probably due to increased solubility of the drugs and/or increased swelling of ethyl cellulose at the higher pH. The formulations were highly stable and possessed reproducible release kinetics across batches.     

Capsules with prolonged action. III. Release of active ingredients from cast films

In the preceding paper we described a gelation process and the development of sustained-release soft gelatin capsules containing codeine or theophylline. Applying this process to indomethacin and nifedipine as active ingredients led to insufficient release rates of the products. To investigate this phenomenon two simple membrane models were used, i.e., a cast drug-free membrane composed of different ratios of polyethylene glycol 400 in a matrix of 5% ethylcellulose, 10% sesame oil, and 57 to 69% citric acid triethyl ester and a cast drug-containing membrane with the same excipients. Codeine and indomethacin were able to penetrate drug-free membranes. The amount of drug diffused through the membrane correlates with the solubility data. Theophylline, which is insoluble in the matrix system, does not penetrate through a drug-free matrix. Nifedipine is enriched within the matrix because of its high partition coefficient into the matrix material, and therefore, little release is observed. From a drug-containing matrix, theophylline and nifedipine were released according to Higuchi's equation [J. Pharm. Sci. 52:1145–1149 (1963)], although the absolute amount of nifedipine released is limited because of its high solubility in the membrane material. For codeine and indomethacin there was no linear relationship between the amount of drug released and the square root of time. These results agree with the findings for capsules obtained from the gelation process.     

Mechanistic Investigation of Drug Release from Asymmetric Membrane Tablets: Effect of Media Gradients (Osmotic Pressure and Concentration), and Potential Coating Failures on <Emphasis Type="BoldItalic">In Vitro</Emphasis> Release

Purpose An asymmetric membrane (AM) tablet was developed for a soluble model compound to study the in vitro drug release mechanisms in challenge conditions, including osmotic gradients, concentration gradients, and under potential coating failure modes. Porous, semipermable membrane integrity may be compromised by a high fat meal or by the presence of a defect in the coating that could cause a safety concern about dose-dumping. Methods The osmotic and diffusional release mechanisms of the AM tablet were independently shut down such that their individual contribution to the overall drug release was measured. Shut off of osmotic and diffusional release was accomplished by performing dissolution studies into receptor solutions with osmotic pressure above the internal core osmotic pressure and into receptor solutions saturated with drug, respectively. The effect of coating failure modes on in vitro drug release from the AM tablet was assessed through a simulated high-fat meal and by intentionally compromising the coating integrity. Results The predominant drug release mechanism for the AM tablet was osmotic and accounted for approximately 90–95% of the total release. Osmotic release was shutoff when the receptor media osmotic pressure exceeded 76 atm. Diffusional release of the soluble drug amounted to 5–10% of the total release mechanism. The observed negative in vitro food effect was attributed to the increased osmotic pressure from the high fat meal when compared to the predicted release rates in sucrose media with the same osmotic pressure. This suppression in drug release rate due to a high fat meal is not anticipated to affect in vivo performance of the dosage form, as the rise in pressure is short-lived. Conclusions Drug release from the AM system studied was determined to be robust to varying and extreme challenge conditions. The conditions investigated included varying pH, agitation rate, media osmotic pressure, media saturated with drug to eliminate the concentration gradient, simulated high fat meal, and intentionally placed film coating defects. Osmotic and diffusional shut off experiments suggest that the mechanism governing drug release is a combination of osmotic and diffusional at approximately 90–95% and 5–10%, respectively. In addition, the coating failure mode studies revealed this formulation and design is not significantly affected by a high fat meal or by an intentionally placed defect in the film coating, and more specifically, did not result in a burst of drug release.     

Release of chlorpheniramine maleate from fatty acid ester matrix disks prepared by melt-extrusion.

Chlorpheniramine maleate was incorporated into disks consisting of glyceryl fatty acid esters, polyethylene glycol fatty acid esters or a combination of the two. A melt-extrusion process was used to prepare the matrix disks containing the drug. The release of the drug into distilled water, pH 1.2 buffer, and pH 7.5 buffer showed the expected square root of time dependence. An increase in the fatty acid ester hydrophilic-lipophilic balance (HLB) from 1 to 14 resulted in a 10-fold increase in the drug release rate from 0.25 +/- 0.01 to 25.84 +/- 1.29 mg cm-2 h-1/2. The maximum release rate was seen from the fatty acid ester with a melting point of 44 degrees C. The pH of the dissolution medium had a small impact on the rate of drug release, but the rate of agitation had no significant influence on the rate of drug release. By blending a fatty acid ester of a high melting point (64 degrees C) and a low HLB value of 2 with esters of lower melting points (33 to 50 degrees C) or higher HLB values (10 to 14), it was possible to modify the release from 10.0 +/- 0.70 to 21.5 +/- 0.57 mg cm-2 h-1/2.     

Drug Release From Hydrocolloid Embeddings with High or Low Susceptibility to Hydrodynamic Stress

Purpose. The subject of the study was the influence of hydrodynamic stress on the drug release from direct compressed hydrocolloid embeddings. Additionally a correlation between the release kinetics and different polymer characterising parameters was attempted. Methods. The drug release was fitted to an expanded Korsmeyer equation to describe the release kinetics. The influence of the stirring rate of the paddle in the USP paddle apparatus on the Mean Dissolution Time (MDT) was expressed as quotient of the MDT's at the stirring rate of 200 and 100 min^–1. Results. If the drug release followed the square root of time kinetics, nearly no effect of the agitation speed on the release rate was observed. To achieve this diffusion controlled drug release the developing gel layer had to be hydrated very well and resistant against erosion (viscosity of at least 4000 mPa · s of the 2% polymer solution and a small expansion of the swelling gel especially at the beginning of the release). The erosion controlled zero order release was generally much affected by the hydrodynamic stress except for some hydrocolloids with incomplete swelling. Thus, it was possible to define a new release mechanism, the polymer particle erosion. The drug release was controlled by the attrition of partially swollen polymer particles and not by the polymer dissolution or drug diffusion. Conclusions. Polymer particle erosion or diffusion control should be the release controlling mechanisms for negligible influence of hydrodynamic stress.     

Release Liner Removal Method For Transdermal Drug Delivery Systems (TDDS)

A release liner removal test is a valuable test for assessing the quality of a transdermal drug delivery system (i.e., TDDS, patch). This test measures the force required to remove the release liner from a patch. The objective of the present study was to establish sample preparation and instrument parameters for measuring release liner removal adhesion for TDDS. Ten TDDS were evaluated (six drugs for a total of 29 lots). Patches which had a ratecontrolling membrane were run as-is, since they could not be cut to a precise width without sacrificing their structural integrity. Patches that were square or rectangular in shape were run as-is, and the width of these patches was determined using a digital caliper. Patches which were not square or rectangular in shape and did not have a rate-controlling membrane were cut to a precise width using a specimen cutter. Double-sided tape was used to adhere the liner side of the transdermal system to a clean stainless steel test panel. A release liner peel adhesion method for TDDS is proposed using a dwell time of approximately 3 min, a peel angle of 90°, and a peel speed of 300 mm/min.     

The Solubility-Modulated Osmotic Pump: In Vitro/in Vivo Release of Diltiazem Hydrochloride

A generalized method was investigated for conversion of controlled-porosity osmotic pump release profiles from first-order to zero-order kinetics using diltiazem · HC1 as a model drug. Diltiazem · HC1 has an aqueous solubility >590 mg/ml (37°C) and was released from controlled-porosity osmotic pump devices with first-order kinetics. This high solubility was markedly reduced (155 mg/ ml; 37°C) in the presence of NaCl (1 M). Based on theory for osmotically actuated drug release, this reduced solubility would be expected to result in a zero-order release profile of >80% of an initial diltiazem · HC1 load. Devices were prepared with cores that contained diltiazem · HC1 and sufficient NaCl granules coated with a microporous cellulose acetate butyrate 381-20 film to maintain a 1 M NaCl concentration within the drug compartment over a 16-hr period. This resulted in release of 75% of the initial diltiazem HC1 load with zero-order kinetics over a 14- to 16-hr period. The in vivo performance of these devices in beagle dogs was analyzed. The in vivo percentage diltiazem absorbed profiles were superimposable with the in vitro release profile. These results suggest that diltiazem release and absorption from the solubility modulated osmotic pump occur throughout the GI tract in a fashion predictable from in vitro dissolution data.     

Release characteristics of polymethacrylate nanospheres containing coumarin-6

Sustained release nanospheres were prepared from the polymethacrylates Eudragit^r` S₁₀₀ and E₁₀₀ containing a water insoluble dye by a salting-out method. Coumarin-6 was used as a model for insoluble analgesics to ascertain uptake and release properties dependent on polymer characteristics and pH. Morphology and particle size were characterized by scanning electron microscopy (SEM). Particles were smooth, spherical and uniform with diameters ranging from 0.6–0.8 μm. Yield was 38% and 86% for E₁₀₀and S₁₀₀, respectively, and encapsulation of coumarin-6 efficiency was 58% and 75%, respectively. Coumarin-6 was stable within the polymer matrix at temperatures from -20$C to 45$C for 4 months. Release was most efficient from S₁₀₀ polymers in phosphate buffer at pH 7.4 and 8.0 reaching a maximum ～ 5 hours prior to samples at pH 7.0 and 9.0. Release was biphasic and concentration as a function of the square root of time produced linear data suggesting a Higuchi type diffusion from a polymer matrix. Release from E₁₀₀ was 65% lower than that from S₁₀₀ and was not solely dependent upon the ionization of polymer but most likely due to a combination of factors including buffer ionization.     

In Vitro Release of Betamethasone Dipropionate from Petrolatum-Based Ointments

ABSTRACT

The purpose of this research was to develop new in vitro methodology for measuring release from petrolatum-based semisolids and to determine whether two ointments, both of which contained betamethasone dipropionate, 0.05%, but with different formulations, could be distinguished by release measurements. Several receptor media were explored to optimize the procedure utilizing Franz-type cells. Analysis was by HPLC. The release slope was 1.5 to 6 times greater from the ointment than the “augmented” ointment (which had greater clinical potency). Release was highest with a receptor consisting of a 5% solution of hexane in acetonitrile. Even so, it was necessary to subject samples of receptor from the augmented ointment to evaporation followed by reconstitution with a smaller volume of mobile phase to bring corticosteroid concentrations up to quantifiable levels. In another series of experiments, the HPLC mobile phase was used as the receptor and a relatively large volume (100 μl) was injected onto the column. With the second approach, measured concentrations were lower but more reproducible. Quantifiable levels of betamethasone dipropionate were obtained for both formulations beginning from the first data point (at 1 hr), with satisfactory linearity of plots of amount released per unit area of membrane versus the square root of time. Using this methodology, it was possible to distinguish the effect of formulation differences in two ointments containing the same drug in the same concentration.