Hydroxypropyl Cellulose Gel Research Articles

In Vitro Evaluation of a Hydroxypropyl Cellulose Gel System for Transdermal Delivery of Timolol

In this work, the development of a gel reservoir for a timolol (TM) transdermal iontophoretic delivery system is investigated. TM gel is prepared using hydroxypropyl cellulose (HPC) and the permeability of TM from the gel through an artificial membrane (Polyflux) and pig stratum corneum (SC) is studied. For a constant TM donor concentration, the TM transport across the Polyflux membrane alone decreases when the concentration of the gel increases due to increase of the gel viscosity. For constant gel concentration, however, the TM permeation across the membrane increases when the TM donor concentration increases. In addition, no effect of the electrical current (iontophoresis, current density 0.5 mA cm-2) on the TM permeation is found. For the combination of the Polyflux membrane with pig SC, the TM transport is much lower than for the membrane alone and the SC fully controls the TM delivery. In this case, the application of electrical current enhances the TM delivery 13-15 times in comparison to passive (no current) transport. According to our estimation, the daily TM dose (10-60 mg) can be delivered by an iontophoretic patch with Polyflux membrane area of 6-36 cm2 containing 20% (w/w) HPC gel and 15 mg cm-3 of TM.

Microporous, fast response cellulose ether hydrogel prepared by freeze-drying

A simple and effective method of preparing fast-response gels is developed. The freeze-drying and subsequent rehydration of thermosensitive gels alters the microstructural properties of the gels in a way that leads to rapid shrinking rates. Microporous hydroxypropyl cellulose (HPC) gels were created by this method to investigate the influence of the process on the swelling and shrinking kinetics of the gels in response to temperature changes. Micropores of different size ranges were produced by freezing gels with different amounts of water at −20 °C. Water content was the key factor to control the microporosity and the shrinking rates of gels. After the freezing treatment, an effective diffusion coefficient for shrinking could be determined by fitting Fick's law to the data (5.2 × 10 −4 cm 2/s). This was an increase of two orders of magnitude over that of the untreated, non-porous gel (6.0 × 10 −6 cm 2/s). The magnitude of the shrinking coefficient indicates that the shrinking rate of the microporous gel is probably limited by the convective flow, as unsteady flow through porous media follows the same differential equation as Fick's law, but with much greater transport coefficients, as observed here. Physically, the shrinking rate may be determined by the level of interconnected-cells in a microporous structure present at the beginning of shrinking process because the convection through the interconnected-cells is estimated to be much slower than the polymer network diffusion rate of the struts of micropores (0.1–3.0 μm) as well as heat transfer.

Stimuli responsive gels based on interpenetrating network of hydroxy propylcellulose and poly( N-isopropylacrylamide)

Sequential networks made of hydroxypropylcellulose (HPC) and poly( N-isopropylacrylamide) (PNIPA) were synthesized by adsorption of a solution of NIPA monomer into a dried porous HPC network. NIPA polymerization inside the network allows us to obtain IPN which show, as the neat components, thermosensitive volumetric behavior. The volumetric transition temperatures range between those of HPC and PNIPA gels. Moreover, as the rate of the swelling–deswelling process is quite higher than that of PNIPA irrespective of the composition, the synthesis method appears interesting in modulated thermosensitive behavior and in the application of this kind of IPN.

Ketoprofen: release from, permeation across and rheology of simple gel formulations that simulate increasing dryness

The migration of ketoprofen through a series of simple gels that varied in solvent composition to simulate snapshots of a dynamically drying topical formulation was studied. Firstly, the release rate of ketoprofen was determined from formulations based on Cabosil ® and PEG 400, the proportion of which was varied to mimic progressively dryer states. Secondly, the apparent permeability of ketoprofen across the corresponding blank Cabosil ® gels was determined. Thirdly, the effect of macro viscosity on these data was probed by comparing permeation of ketoprofen across Cabosil ® and hydroxypropyl cellulose (HPC) gels of equal viscosity. Linear release profiles were produced for all formulations suggesting first-order release and the rate of ketoprofen liberated was inversely to the proportion of Cabosil ®, suggesting that the drier the film, the slower the rate of release. At the lowest level of thickener used (5%) the release rate was reduced to 45% of the control. At 25% the release rate was reduced to 24% of the control. The presence of the Cabosil ® had an even more dramatic effect on the apparent permeability of ketoprofen across the gels. At 5% Cabosil ® the apparent steady state flux was reduced to 4% of the control. At 25% the apparent steady state flux was reduced to <1% of the control. Although the 0.5% HPC gel and the 1% Cabosil ® gel possessed identical macro viscosities, the permeation of ketoprofen through the HPC gel was almost double that of the Cabosil ® gel. The data from these experiments demonstrated that migration of active molecules through a gel is significantly affected by the amount of solvent present in, or lost from, the system. It is proposed that increased adsorption of active to the thickener plays a more important role than increased macro viscosity for reduced active release as the formulation becomes increasingly dry. Furthermore, such affects are profoundly influenced by the chemical nature of the thickener.

Influence of menthol and pressure-sensitive adhesives on the in vivo performance of membrane-moderated transdermal therapeutic system of nicardipine hydrochloride in human volunteers

A membrane-moderated transdermal therapeutic system of nicardipine hydrochloride was developed using 2% w/w hydroxypropylcellulose (HPC) gel as a reservoir system containing 5% w/w of menthol as a penetration enhancer. The permeability flux of nicardipine hydrochloride through the ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31 ®, MA-38 ® or TACKWHITE A 4MED ®) on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28% w/w vinyl acetate) or EVA 2825 membrane/skin composite was also studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED ®/skin composite was higher than that coated with MA-31 ® or MA-38 ®. Thus, a new transdermal therapeutic system for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED ®, and 2% w/w HPC gel as reservoir containing 5% w/w of menthol as a penetration enhancer. In vivo studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 26 h with improved bioavailability in comparison with the immediate release capsule dosage form.

Enhanced Percutaneous Permeability of Nicardipine Hydrochloride by Carvone Across the Rat Abdominal Skin

The purpose of this study was to investigate the effect of carvone on the permeation of nicardipine hydrochloride across the excised rat abdominal epidermis from 2% w/w hydroxypropyl cellulose (HPC) gel system. The HPC gel formulations containing nicardipine hydrochloride (1% w/w) and selected concentrations of carvone (0 to 12% w/w) were prepared, and evaluated for drug content, stability of the drug, and in vitro permeation of the drug through excised rat abdominal epidermis. The HPC gel was found to contain 99.98 to 101.6% of nicardipine hydrochloride, and the drug was found to be stable in the HPC gels. The permeation flux of nicardipine hydrochloride across rat epidermis was increased markedly by the addition of carvone to the HPC gels. A maximum flux of nicardipine hydrochloride (243.95.70 ± 1.90 µg/cm2/hr) was observed with an enhancement ratio of 7.9 when carvone was incorporated at a concentration of 12% w/w in the HPC reservoir system. The differential scanning calorimetry and Fourier transform-infrared data indicated that carvone increased the permeability of nicardipine hydrochloride across the rat epidermis by partial extraction of lipids in the stratum corneum. The results suggest that carvone may be useful for enhancing the skin permeability of nicardipine hydrochloride from transdermal therapeutic system containing HPC gel as a reservoir.

Formulation and In Vivo Evaluation of Membrane-Moderated Transdermal Therapeutic Systems of Nicardipine Hydrochloride using Carvone as a Penetration Enhancer

A membrane-moderated transdermal therapeutic system (TTS) of nicardipine hydrochloride was developed using 2%w/w hydroxy propyl cellulose (HPC) gel as a reservoir system containing 8%w/w of carvone as a penetration enhancer. The permeability flux of nicardipine hydrochloride through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38, or TACKWHITE A 4MED) on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28%w/w vinyl acetate) or EVA 2825 membrane/skin composite also was studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new TTS for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED and 2%w/w HPC gel as reservoir containing 8%w/w of carvone as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 23 hr with improved bioavailability in comparison with the immediate-release capsule dosage form.

Influence of limonene on the bioavailability of nicardipine hydrochloride from membrane-moderated transdermal therapeutic systems in human volunteers

The aim of the present study was to develop a membrane-moderated transdermal therapeutic system (TTS) of nicardipine hydrochloride using 2%w/w hydroxy propyl cellulose (HPC) gel as a reservoir system containing 4%w/w of limonene as a penetration enhancer. The permeability flux of nicardipine hydrochloride through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate (VA) content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38 or TACKWHITE A 4MED) on the permeability of nicardipine hydrochloride through EVA membrane 2825 (28% w/w VA) or membrane/skin composite was also studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE 4A MED/skin composite was higher than that coated with MA-31or MA-38. Thus a new TTS for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED and 2%w/w HPC gel as reservoir containing 4%w/w of limonene as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady state plasma concentration of the drug with minimal fluctuations for 20 h with improved bioavailability in comparison with the immediate release capsule dosage form.

Penetration Enhancing Effect of Menthol on the Percutaneous Flux of Nicardipine Hydrochloride Through Excised Rat Epidermis from Hydroxypropyl Cellulose Gels

The aim of the present investigation is to study the penetration enhancing effect of menthol on the percutaneous flux of nicardipine hydrochloride through the excised rat epidermis from 2% w/w hydroxypropyl cellulose (HPC) gel system. The HPC gel formulations containing nicardipine hydrochloride and selected concentrations of menthol (0–12% w/w) were prepared, and evaluated for in vitro permeation of the drug through excised rat abdominal epidermis. The percutaneous flux of nicardipine hydrochloride across rat epidermis was enhanced markedly by the addition of menthol to the HPC gels. A maximum flux of nicardipine hydrochloride (227.70±1.30 μ_rm;g cm−2 hr−1) was observed with an enhancement ratio of 7.12 when menthol was incorporated at a concentration of 8% w/w in a reservoir HPC system. The differential scanning calorimetry and Fourier transform-infrared spectroscopy data indicated that menthol increased the percutaneous flux of nicardipine hydrochloride through the rat skin by partial extraction of lipids in the stratum corneum. The results suggest that menthol may be useful for increasing the skin permeability of nicardipine hydrochloride from transdermal therapeutic system containing HPC gel as a reservoir.

The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities

Four model drugs were selected based on their lipophilicity denoted as log P (nicardipine hydrochloride log P −0.99±0.1, hydrocortisone log P 1.43±0.47, carbamazepine log P 2.67±0.38, and tamoxifen log P 7.87±0.75). The enhancing activities of four terpene enhancers (fenchone log P 2.13±0.30, thymol log P 3.28±0.20, d-limonene log P 4.58±0.23, and nerolidol log P 5.36±0.38) were tested in vitro across full thickness hairless mouse skin with each of the evaluated drugs formulated in hydroxypropyl cellulose gel formulations. The relationships between lipophilicity (log P) of the terpene enhancers and model drugs and efficacy (represented by the enhancement ratio of flux ER flux) of the drugs when coadministered with the enhancers were examined using linear regression. Terpene enhancers had significant effect on the percutaneous permeation of the model drugs. Nerolidol (highest lipophilicity) provided the highest increase in the flux of the evaluated model drugs. The flux of nicardipine hydrochloride increased by approximately 135-fold, hydrocortisone by 33-fold, carbamazepine 8-fold, and tamoxifen 2-fold. The lowest increase in the flux was observed with fenchone. Linear relationships were generated between the ER flux of nicardipine hydrochloride, hydrocortisone, carbamazepine, and tamoxifen and the log P of the terpene enhancers [ r=0.951, ( P=0.049), r=0.977, ( P=0.023), r=0.942, ( P=0.057), and r=0.874, ( P=0.126), respectively]. Furthermore, the four terpene enhancers produced linear relationships, indicating that they were more effective at enhancing the penetration of hydrophilic drugs rather than lipophilic drugs r=−0.824 ( P=0.176) for fenchone, r=−0.891 ( P=0.109) for thymol, r=−0.846 ( P=0.154) for limonene, and r=−0.769 ( P=0.232) for nerolidol.

Self-Association of Hydroxypropylcellulose in Water

The association of hydroxypropylcellulose (HPC) chains above their lower critical solution temperature (LCST, ∼41 °C) leads to metastable nanosphere aggregates instead of precipitation. Laser light scattering (LLS) measurements revealed that the size of the aggregates is dependent not only on temperature and HPC concentration but also on heating history. There existed a narrow temperature range from ∼41 to ∼44 °C in which narrowly distributed metastable nanospheres formed in a few minutes and lasted for a few days without changing their sizes and molar masses. Increasing temperature in this range and increasing HPC concentration resulted in larger and denser nanosphere aggregates. In situ cross-linking of self-associated HPC chains was performed in a LLS sample cuvette at 42 °C using divinyl sulfone as a cross-linker. Formation of HPC gel microspheres was monitored by LLS and demonstrated by allowing the gel microspheres to swell and shrink at temperatures below and above the LCST, respectively.

Microviscosity of hydroxypropylcellulose gels as a basis for prediction of drug diffusion rates

This study investigated the influence of the rheological properties of hydroxypropylcellulose (HPC) gels on the in vitro release of theophylline included in the gel at 0.2 g/l. Experiments were performed with six HPC varieties (mean molecular weight between 5×10 5 and 1.2×10 6, nominal viscosity between 100 and 4000 mPa·s) at concentrations of 0–2% (w/w). Theophylline diffusion coefficients at 37°C ranged from 3.5×10 −7 to 1.1×10 −3 cm 2/min, and were in all cases markedly higher than those predicted on the basis of gel macroviscosity as determined by capillary viscometry. In general, the theophylline diffusion coefficient declined exponentially with HPC concentration; in the case of the lowest-molecular-weight HPC, however, the diffusion coefficient remained constant to HPC concentrations of up to 0.8%, probably because of the high entanglement concentration of the HPC. Gel microviscosities as determined by dynamic light scattering (DLS) with latex microspheres (162 nm diameter) were considerably lower than the macroviscosities determined by capillary viscometry, and similar to microviscosities estimated on the basis of theophylline diffusion. Nevertheless, macroviscosity was correlated with microviscosity, suggesting that it is of value for approximate estimates of rates of diffusion of theophylline from HPC gels.

Rheological Characterization of Hydroxypropylcellulose Gels

The present paper describes the rheological properties of hydroxypropylcellulose (HPC) gels formulated in propylene glycol (PG), water, ethanol, and mixtures of these components. The effects of molecular weight, polymer concentration, and solvent composition on the apparent viscosity and flow characteristics have been studied by continuous shear rheometry. The HPC gels are shear thinning and do not exhibit significant yield or hysteresis in their rheograms. The apparent viscosity increases with increasing molecular weight and concentration of the polymer, as expected. Although not so pronounced at lower concentrations (≤ 1.5%), HPC gels tend to become increasingly non-Newtonian with increasing molecular weight at higher polymer concentrations (3%). A mathematical model has been proposed for the prediction of viscosities of HPC gels. There exists a high degree of dependence on molecular interactions between various solvent molecules in the prediction of mixture viscosities in ternary systems. The effects of solvent composition on the viscoelastic behavior of these gels have also been examined by dynamic mechanical analysis. The HPC gels are highly viscoelastic and exhibit greater degrees of elasticity with increased PG content in ternary solvent mixtures with water and ethanol. The study also suggests that dynamic mechanical analysis could prove to be a useful tool in the determination of zero-shear viscosities, viscosities that are representative of most realistic situations.

Skin disposition of drugs after topical application in hairless rats.

Drug fraction transported from a topical formulation on skin to subcutaneous tissues or muscles is dependent on the physicochemical properties of the entrapped drug. Cutaneous disposition of model drugs, antipyrine (ANP), lidocaine (LC) and piroxicam (PXC) as well as flurbiprofen (FP) was thus evaluated in hairless rats in which an agar gel disc was subcutaneously inserted into the abdominal region as a drug receptor and a drug donor cell was placed above it. Time courses of plasma level and agar gel amount were measured after topical application of 50% ANP, 3% LC, 1% PXC and 1% FP in hydroxypropylcellulose gel. Percutaneous absorption clearance of unionized form, CLab* was proportional to true octanol/water distribution coefficient and the order of FP > PXC > LC > ANP, suggesting that skin permeation of the drug was determined mainly by its distribution from the formulation to the skin barrier. PXC, however, had a relatively low flux compared to the other three drugs, probably due to its high molecular weight and melting point. Migration clearance of unionized form from systemic circulation to the subcutaneous agar gel, CLg* was also influenced by the lipophilicity of drugs. On the other hand, fraction from the formulation to the systemic circulation was in the order of PXC > FP > ANP > LC. This fraction was much higher than the direct migration fraction from the formulation to the subcutaneous agar gel. Factors determining for these fractions are still unclear. A drug having a low lipophilicity and a low protein binding, however, had a tendency to have a great targeting ability to the subcutaneous agar gel. In addition, most of the drug in the agar gel was contributed by the direct flow from formulation, not from the systemic circulation. The present in situ experimental method is a useful tool to evaluate skin disposition of drugs. Detailed understanding of the skin disposition of drugs from several formulations will enable the findings of a good drug and formulation candidates.

Microporous, Responsive Hydroxypropyl Cellulose Gels. 1. Synthesis and Microstructure

An effective technique for the synthesis of microporous gels is developed along with correlations between synthesis conditions and microstructure. Such gels have substantially different properties than their nonporous analogues. Microporous hydroxypropyl cellulose (HPC) gels were prepared by heating aqueous HPC solutions above their lower critical solution temperatures (LCST's) while cross-linking the polymer with divinyl sulfone. The effective porosity of the gel increased from 23 to 76% by decreasing HPC concentration from 22.6 to 9 wt %, as anticipated from the system phase diagram. The pore size range decreased from 0.5−9.0 to 0.05−0.2 μm by increasing reaction time before phase separation from 1.5 to 25 min, demonstrating that cross-linking in the homogeneous state limits the extent of phase separation possible. Gel morphology changed from open-celled to closed-celled by decreasing reaction time in the phase-separated state, which limits cross-linking in the polymer-rich phase.

In vitro/in vivo Difference in Enhanced Skin Permeation of Nicardipine Hydrochloride by the 1-Menthol-Ethanol System

The in vitro/in vivo difference in enhanced skin permeation of nicardipine hydrochloride (NC) by simultaneous use of 1-menthol and ethanol (MEW system, 1-menthol:ethanol:water = 5:40:55) was investigated in hairless rats. First, the cutaneous blood flow clearance (clearance from skin to blood flow) of NC per unit area of skin (CLCB/A), which was comparable to the permeability coefficient across skin (PC), was calculated from intracutaneous and intravenous injection data using the deconvolution method; the value was 1.67 microliters/h/cm2. Two formulations containing NC and the MEW system, solution (SOL) and 15% hydroxypropyl cellulose gel (GEL), were used for in vitro and in vivo permeation experiments. The in vitro PC of NC via excised skin from SOL (23.3 microliters/h/cm2) was significantly higher than CLCB/A, and that from GEL (1.48 microliters/h/cm2) was similar to CLCB/A. Consequently, the steady-state concentration of NC in skin during in vivo application of SOL was 6.6 times higher than corresponding in vitro data. In vivo PCs from SOL and GEL were however significantly lower than CLCB/A. These results may be explained by the findings, using a laser Doppler flowmeter, that cutaneous blood flow was decreased by the application of MEW.

Application of the Solid Dispersion Method to the Controlled Release of Medicine. VIII. Medicine Release and Viscosity of the Hydrogel of a Water-Soluble Polymer in a Three-Component Solid Dispersion System.

Solid dispersions were prepared with a highly water-soluble medicine (oxprenolol hydrochloride (OXP)), water-insoluble ethylcellulose (EC) and four grades of water-soluble hydroxypropylcellulose (HPC) having different molecular weights. The effects of the composition ratio within the range of 5% of HPC and of the viscosity of HPC hydrogels on the release of OXP were studied. The bulk viscosity of HPC hydrogels was evaluated from the relationship between shear rate and shear stress. The microscopic viscosity was evaluated by the spin probe method of the electron spin resonance (ESR) technique.The release rate of OXP decreased with increasing HPC composition ratio and became almost constant at the HPC composition ratio of 3% and more. This result suggests that the release of OXP will occur through its diffusion into the swollen HPC gel phase formed in a solid dispersion at the HPC composition ratio of 3% and more. The bulk viscosity of HPC hydrogels markedly increased with increasing molecular weight of HPC, but there was little noticeable change in release rate and activation energy for the diffusion of OXP. This result can be explained by the fact that the microscopic viscosity was hardly affected by the molecular weight of HPC, suggesting that the resistance to diffusion of OXP into the swollen HPC gel phase in the solid dispersion was almost the same regardless of the moleclar weight of HPC.

Controlling the swelling characteristics of temperature-sensitive cellulose ether hydrogels

Novel temperature-sensitive hydrogels; have been synthesized by chemically crosslinking cellulose ethers; hydroxypropyl cellulose, methyl cellulose and hydroxypropylmethyl celluloses. These gels are highly swollen at low temperatures, gradually deswelling as temperature rises, usually sharply over a limited temperature range. Linear polymer type, crosslink density and ionic content have been varied in order to determine the effects of controllable network parameters on the important properties (degree of swelling, transition temperature and sharpness of transition) of the gels obtained. The transition temperature itself is about that of the observed linear polymer lower critical solution temperature (LCST). Producing gels from increasingly hydrophilic cellulose ethers raises the transition temperature and increases the swelling degree at comparable crosslink densities. However, decreasing crosslinking has little effect on swelling above the transition temperature. In contrast, increasing ionic content increases swelling at all temperatures. The transition temperature is not affected by the degree of crosslinking, but increases with increasing ionic content. The volume transition of the hydroxypropyl cellulose gel is significantly sharper than for the other gels. Crosslinking and ionic content have little effect on transition sharpness. The trends observed with cellulose ether gels are consistent with those observed in gels produced by conventional copolymerization/crosslinking synthesis methods, though some differences are noted.