High Molecular Weight Hydroxypropyl Methylcellulose Research Articles

Gastroretentive fibrous dosage forms for prolonged delivery of sparingly-soluble tyrosine kinase inhibitors. Part 1: Dosage form design, and models of expansion, post-expansion mechanical strength, and drug release

At present, the efficacy and safety of many sparingly-soluble tyrosine kinase inhibitors (TKIs) delivered by the prevalent oral dosage forms are compromised by excessive fluctuations in the drug concentration in blood. To mitigate this limitation, in this four-part study gastroretentive fibrous dosage forms that deliver drug into the gastric fluid (and into the blood) at a controlled rate for prolonged time are presented. The dosage form comprises a cross-ply structure of expandable, water-absorbing, high-molecular-weight hydroxypropyl methylcellulose (HPMC)-based fibers coated with a strengthening, enteric excipient. The intervening spaces between the coated fibers are solid annuli of drug particles, and low-molecular-weight HPMC and enteric excipients. The central regions of the annuli are open channels. In this part, models are developed for dosage form expansion, post-expansion mechanical strength, and drug release. The models suggest that upon immersing in a dissolution fluid, the fluid percolates the open channels, diffuses into the annuli and the coated fibers, and the dosage form expands. The expansion rate is inversely proportional, and the post-expansion mechanical strength proportional to the thickness of the strengthening coating. Drug particles are released from the annuli as the surrounding excipient dissolves. The drug release rate is proportional to the concentration of low-molecular-weight HPMC at the annulus/dissolution fluid interface. The dosage forms can be readily designed for expansion in a few hours, formation of a high-strength viscoelastic mass, and drug release at a constant rate over a day.

WITHDRAWN: Gastroretentive fibrous dosage forms for prolonged delivery of sparingly-soluble tyrosine kinase inhibitors. Part 1: Dosage form design, and models of expansion, post-expansion mechanical strength, and drug release

At present, the efficacy and safety of many sparingly soluble tyrosine kinase inhibitors (TKIs) are compromised due to the drug's pH-dependent solubility, and the associated excessive fluctuations in the drug concentration in blood. To mitigate this limitation, in this four-part study gastroretentive fibrous dosage forms that deliver drug into the low-pH gastric fluid (and into the blood) for prolonged time are presented. The dosage form comprises a cross-ply fibrous structure of water-absorbing, high-molecular-weight hydroxypropyl methylcellulose (HPMC) fibers coated with a strengthening, enteric excipient. The intervening spaces between the coated fibers are solid annuli that contain drug particles, low-molecular-weight HPMC, and an enteric excipient. There are open channels in the central regions of the annuli. In this first part, models are developed for in vitro dosage form expansion, post-expansion mechanical strength, and drug release. The models suggest that the expansion rate and the post-expansion mechanical strength can be varied by changing the thickness of the enteric coating over the fibers. The drug particles in the annulus are released as the surrounding excipient erodes. The drug release rate is proportional to the concentration of low-molecular-weight HPMC at the interface between the annulus and the dissolution fluid in the channels. The dosage forms can be readily tailored for expansion in a few hours, formation of a high-strength viscoelastic mass, and drug release at a constant rate over a day.

Mechanical strength and gastric residence time of expandable fibrous dosage forms

Expandable, gastroretentive dosage forms are promising for precise control of drug concentration in blood. So far, however, short gastric residence times and safety considerations have limited their use. To mitigate such limitations, in this work expandable fibrous dosage forms were investigated for mechanical strength and gastric residence time in dogs. The fiber formulation comprised ibuprofen drug; water-absorbing, high-molecular-weight hydroxypropyl methylcellulose (HPMC) excipient; fiber-strengthening, enteric methacrylic acid-ethyl acrylate excipient; and barium sulfate, a gastrointestinal contrast agent. The fibers were coated either with a hydrophilic sugar, or with a strengthening enteric excipient. Upon administration to a dog, in the stomach the dosage form with sugar-coated fibers expanded to 1.7 times its initial radius in 50–100 minutes, and disintegrated after 4.8 hours. The dosage form with the enteric-excipient-coated fibers, by contrast, expanded to 1.6 times the initial radius in 5 hours, and fractured after 31 hours due to cyclic loads applied by the contracting stomach walls. The fragments passed into the small intestine where they dissolved in less than 2–3 hours. Diametral compression tests and dynamic fatigue failure models show that the substantial increase in gastric residence time is due to strengthening of the fibers by the enteric-excipient coating. Because the enteric excipient is a rubbery semi-solid in the acidic gastric fluid and dissolves in the pH-neutral intestinal fluids, safety concerns should be minimal. Thus, expandable fibrous dosage forms can be readily designed for prolonged, safe gastric retention.

Expandable, dual-excipient fibrous dosage forms for prolonged delivery of sparingly-soluble drugs

In this work, expandable fibrous dosage forms containing water-absorbing and fiber-strengthening excipients are investigated for prolonged delivery of sparingly-soluble drugs. The formulation comprised: sparingly-soluble ibuprofen drug; water-absorbing, high-molecular-weight hydroxypropyl methylcellulose (HPMC) excipient; and strengthening methacrylic acid-ethyl acrylate excipient. Upon immersion in a dissolution fluid, the single fibers and all the dosage forms (fiber volume fractions, φ = 0.16, 0.39, and 0.56) expanded roughly at the same rate. The size of the dosage forms doubled in fifteen minutes, and they were converted into a highly viscous gel. The gel was stabilized by the strengthening excipient for over two days. Eighty percent of the drug was released from single fibers in less than an hour, and in thirty-eight hours from the dosage form with φ = 0.56. Theoretical models suggest that if φ is small, drug release is limited by the diffusion of drug molecules through the thin fibers, which is fast. If φ is large, however, drug release is limited by the diffusion of drug molecules through the thick, monolithic dosage form gel, which is slow. Between these extremes, the drug release time increases exponentially with φ.

Expandable fibrous dosage forms for prolonged drug delivery

Many drug therapies could be greatly improved by dosage forms that reside in the stomach for prolonged time and release the drug slowly. In this work, therefore, slow-release fibrous dosage forms that expand rapidly in the gastric fluid to prevent their passage into the intestines are investigated. The dosage forms consisted of acetaminophen drug and a high-molecular-weight hydroxypropyl methyl cellulose (HPMC) excipient. Upon immersion in a dissolution fluid, they transitioned to viscous, and expanded in proportion to the square-root of time and the reciprocal of fiber radius. The normalized axial expansion was up to 100 percent by fifteen minutes, fast enough to convert a swallowable, 10-mm diameter disk into a gastroretentive, 20-mm diameter viscous gel. The drug was released slowly, eighty percent in 2–8.4 hours. Theoretical models show that the fibrous dosage forms expand rapidly due to the fast diffusion of dissolution fluid into the thin fibers. The fibers then coalesce into a uniform viscous gel, and the diffusion length increases from the radius of the thin fibers to the half-thickness of the gelated dosage form. Consequently, drug diffusion out is slow, and the twin requirements, fast expansion and prolonged drug release, are simultaneously satisfied.

Development of Itraconazole Tablets Containing Viscous KinetiSol Solid Dispersions: In Vitro and In Vivo Analysis in Dogs.

The formulation factors relevant to developing immediate and controlled release dosage forms containing poorly soluble drugs dispersed in amorphous systems are poorly understood. While the utility of amorphous solid dispersions is becoming apparent in the pharmaceutical marketplace, literature reports tend to concentrate on the development of solid dispersion particulates, which then must be formulated into a tablet. Amorphous solid dispersions of itraconazole in high molecular weight hydroxypropyl methylcellulose were prepared by KinetiSol® Dispersing and tablets were formulated to immediately disintegrate or control the release of itraconazole. Formulated tablets were evaluated by two non-sink dissolution methodologies and the dosage form properties that controlled the gelling tendency of the dispersion carrier, hydroxypropyl methylcellulose, were investigated. Selected formulations were evaluated in an exploratory beagle dog pharmacokinetic study; the results of which indicate potential for a prolonged absorption phase relative to the commercially extruded control.

Effect of temperature on the wetting behavior of hydroxypropyl methylcellulose in a twin-screw granulator

Temperature has rarely been examined in twin-screw wet granulation despite the obvious capabilities of the extruder for operating at elevated temperatures. The present work investigates the wetting behavior of a mixture of powders with different sorption characteristics at various temperatures to explain the unique granulation behavior witnessed with high molecular weight hydroxypropyl methylcellulose in a twin-screw extruder. The work studies the twin-screw granulation of a controlled release formulation at three different temperatures, namely 30°C, 55°C and 80°C and attempts to interpret the granular properties of collected samples relative to characterized moisture sorption isotherms measured for the individual ingredients as well as the mixtures. A result of higher temperature processing was reduced coarse particles and a final product with more spherical granules. Increasing temperature was found to reduce water absorption capacity among the ingredients, especially hydroxypropyl methyl cellulose and microcrystalline cellulose, leaving more of the added water for particle bridging. The gel layer of hydroxypropyl methyl cellulose particles was diminished by the higher temperatures which did not appear to impact the strength of the particle bridges formed. Inclusion of a more hydrophobic ingredient like acetaminophen complicates the distribution of water in a granule.

Tailoring the mucoadhesive and sustained release characteristics of mesalamine loaded formulations for local treatment of distal forms of ulcerative colitis

Direct delivery of sustained therapeutic levels of mesalamine (MS) via rectal systems to manage distal forms of ulcerative colitis was studied. The High molecular weight hydroxypropyl methylcellulose (HPMC K4M) polymer was combined with hydrophilic surfactants to control polymer hydration process allowing optimization of the mucoadhesive and controlled drug release properties for the rectal systems. Physical mixtures and granules of MS and HPMC K4M were prepared and in vitro characterized using scanning electron microscope, differential scanning calorimetry and X-ray diffraction techniques. Rectal formulations were prepared utilizing MS-HPMC K4M mixtures in different polyethylene glycol (PEG) combination bases. The developed rectal formulations were investigated for physical, mucoadhesion, in-vitro drug release and swelling characteristics. Results revealed acceptable physical characteristics of the prepared formulations with good content uniformity and minimum weight variation. Sustained release patterns of MS form HPMC K4M based formulations were observed. Formulations prepared using high proportions of the polymer or PEG 400 showed higher extent of mucoadhesion, swelling and greatly extended drug release time. Efficacy of an optimized formulation was assessed using the acetic acid induced colitis model in rats and compared to a reference polymer-free formulation of the drug. Clinical evaluation included bleeding from rectum, consistency of animal stool and colon/body weight ratio. Furthermore, histopathological analysis was carried out to evaluate the degree of inflammation and mucosal damage. Overall results showed a significant enhancement in the clinical pictures and colon histopathology of animals treated by the sustained release mucoadhesive formulation compared to the reference polymer free formulation and the non-treated colitis group.

The influence of hydroxypropyl methylcellulose (HPMC) molecular weight, concentration and effect of food on in vivo erosion behavior of HPMC matrix tablets

Four different hydrophilic matrix formulations based on hydroxypropyl methylcellulose (HPMC) were investigated for erosion properties in vivo. Three formulations contained a fixed amount of HPMC (40%) with varying proportions of two HPMC grades with different molecular weights (Methocel K100LV and K4M), and a fourth formulation contained a lower amount of the HPMC of lower molecular weight (20%). The effect of food on the in vivo erosion behavior was investigated on two formulations containing different contents of the same HPMC grade. The in vivo erosion behavior and gastrointestinal transit were investigated using magnetic marker monitoring (MMM). The in vitro and in vivo erosion–time profiles show that the erosion was strongly dependent on the composition of the formulation. The formulations containing a larger proportion of high molecular weight HPMC or higher content of HPMC exhibit relatively slower erosion rate and vice versa. In vivo erosion rates were significantly higher under postprandial administration as compared to fasted state administration. No rapid disintegration of any of the formulations (i.e. formulation failure that can potentially cause dose dumping) was observed.

<i>In Vitro</i> and <i>In Vivo</i> Evaluation of Diclofenac Sodium Gel Prepared with Cellulose Ether and Carbopol 934P

Purpose: To develop diclofenac sodium gel using high molecular weight hydroxypropyl methylcellulose (HPMC) and Carbopol 934P for topical and systemic delivery.Methods: Diclofenac sodium gel was prepared with HPMC K100M and Carbopol 934P as gelling agents. The formulations were examined for pH, spreadability, consistency, viscosity, homogeneity, drug content and stability. In vitro drug release was evaluated using Franz diffusion cell. Carrageenaninduced rat paw oedema model was used for the evaluation of the anti-inflammatory activity of the gels. A commercial diclofenac sodium gel product was used as the reference drug.Results: Formulations containing glycerin as permeation enhancer gave drug release patterns comparable to that of the reference product. The drug content of F2, F5 and F9 was 99.81, 99.75 and 99.96 %, respectively. Accelerated stability results showed no significant variation in the appearance and drug release after storage for 3 months.Conclusion: Diclofenac sodium gel containing HPMC K100M and Carbopol 934P exhibited pronounced anti-inflammatory activity and could be further developed for topical and systemic delivery..Keywords: Diclofenac sodium, Anti-inflammatory, Hydroxypropyl methylcellulose, Carbopol, Drug release, Glycerin

Extended release of high molecular weight hydroxypropyl methylcellulose from molecularly imprinted, extended wear silicone hydrogel contact lenses

Symptoms of contact lenses induced dry eye (CLIDE) are typically treated through application of macromolecular re-wetting agents via eye drops. Therapeutic soft contact lenses can be formulated to alleviate CLIDE symptoms by slowly releasing comfort agent from the lens. In this paper, we present an extended wear silicone hydrogel contact lens with extended, controllable release of 120 kDa hydroxypropyl methylcellulose (HPMC) using a molecular imprinting strategy. A commercial silicone hydrogel lens was tailored to release approximately 1000 μg of HPMC over a period of up to 60 days in a constant manner at a rate of 16 μg/day under physiological flowrates, releasing over the entire range of continuous wear. Release rates could be significantly varied by the imprinting effect and functional monomer to template ratio (M/T) with M/T values 0, 0.2, 2.8, 3.4 corresponding to HPMC release durations of 10, 13, 23, and 53 days, respectively. Lenses had high optical quality and adequate mechanical properties for contact lens use. This work highlights the potential of imprinting in the design and engineering of silicone hydrogel lenses to release macromolecules for the duration of wear, which may lead to decreased CLIDE symptoms and more comfortable contact lenses.

Formulation and evaluation of pectin-hydroxypropyl methylcellulose coated curcumin pellets for colon delivery

High molecular weight hydroxypropyl methylcellulose (HPMC) and biodegradable pectin were used for coating the pellets containing curcumin, to be released in the colon. The prepared pellets were freeflowing. in vitro release of curcumin remained intact up to pH 3.0, disintegrated at pH 7.2, and released up to 12 hours. The ideal batch (1:3) showed minimum release at pH 1.2 and maximum release at pH 6.8, and an increased amount of curcumin in the blood stream(1.287 μg/ml) was achieved when compared with pure curcumin (0.5 μg/ml). The drug release was retarded by the high concentrationand greater thickness of the coating of HPMC on the pellets. Release kinetics of the preparation shows a non-Fickian or anamolous diffusion or matrix erosion.

Molecular and functional modification of hydroxypropylmethylcellulose by high-intensity ultrasound

The application of high-intensity ultrasound (HIUS) to modify biopolymers is increasingly been studied. Because of cavitation, HIUS can modify the structure of some proteins and polysaccharides. The objective of this study was to evaluate the effect of high-intensity ultrasound on the particle size of hydroxypropylmethylcellulose (HPMC) with different molecular weights by dynamic light scattering and to assess the impact on some relevant functional properties. Solutions of different commercial HPMC of the same type and degree of substitution, but differing in molecular weight were prepared at 0.01–7 %wt concentration and submitted to HIUS. The size distributions and Z average ( Zav) of particles, before the treatment, immediately after HIUS treatment and up to 3 days after treatment, were measured by dynamic laser light scattering as well as the cloud point, gelation temperature, thermal transitions (the last by differential scanning calorimetry), apparent viscosity and water mobility by NMR. Ultrasound treatment of HPMC induced the formation of concentration-dependent transient clusters. The performance of HPMC on 10:90 oil-in-water emulsions was not modified by ultrasound as well as the gelation parameters characterizing the gel regime (gelation temperature, thermal transitions by DSC). However, the cloud point decreased by 8–9 °C. Changes in viscosity and water mobility were observed for high molecular weight HPMC revealing structural modifications that were not apparent for the low molecular weight HPMC.

Compression and compaction properties of plasticised high molecular weight hydroxypropylmethylcellulose (HPMC) as a hydrophilic matrix carrier

The compression and compaction properties of plasticised high molecular weight USP2208 HPMC were investigated with the aim of improving tablet formation in HPMC matrices. Experiments were conducted on binary polymer–plasticiser mixtures containing 17 wt.% plasticiser, and on a model hydrophilic matrix formulation. A selection of common plasticisers, propylene glycol (PG) glycerol (GLY), dibutyl sebacate (DBS) and triacetin (TRI), were chosen to provide a range of plasticisation efficiencies. T g values of binary mixtures determined by Dynamic Mechanical Thermal Analysis (DMTA) were in rank order PG > GLY > DBS > TRI > unplasticised HPMC. Mean yield pressure, strain rate sensitivity (SRS) and plastic compaction energy were measured during the compression process, and matrix properties were monitored by tensile strength and axial expansion post-compression. Compression of HPMC:PG binary mixtures resulted in a marked reduction in mean yield pressure and a significant increase in SRS, suggesting a classical plasticisation of HPMC analogous to that produced by water. The effect of PG was also reflected in matrix properties. At compression pressures below 70 MPa, compacts had greater tensile strength than those from native polymer, and over the range 35 and 70 MPa, lower plastic compaction values showed that less energy was required to produce the compacts. Axial expansion was also reduced. Above 70 MPa tensile strength was limited to 3 MPa. These results suggest a useful improvement of HPMC compaction and matrix properties by PG plasticisation, with lowering of T g resulting in improved deformation and internal bonding. These effects were also detectable in the model formulation containing a minimal polymer content for an HPMC matrix. Other plasticisers were largely ineffective, matrix strength was poor and axial expansion high. The hydrophobic plasticisers (DBS, TRI) reduced yield pressure substantially, but were poor plasticisers and showed compaction mechanisms that could be attributed to phase separation. The effect of different plasticisers suggests that the deformation characteristics of this HPMC in the solid state is dominated by hydroxyl mediated bonding, rather than by hydrophobic interactions between methoxyl-rich regions.

Formulation parameters affecting the performance of coated gelatin capsules with pulsatile release profiles

The objective of this study was to develop and evaluate a rupturable pulsatile drug delivery system based on soft gelatin capsules with or without a swelling layer and an external water-insoluble but -permeable polymer coating, which released the drug after a lag time (rupturing of the external polymer coating). The swelling of the gelatin capsule itself was insufficient to rupture the external polymer coating, an additional swelling layer was applied between the capsule and the polymer coating. Croscarmellose sodium (Ac-Di-Sol) was more effective as a swelling agent than low and high molecular weight hydroxypropylmethyl cellulose (HPMC; E5 or K100M). Brittle polymers, such as ethyl cellulose (EC) and cellulose acetate propionate (CAPr), led to a better rupturing and therefore more complete drug release than the flexible polymer coating, Eudragit RS. The lag time of the release system increased with higher polymer coating levels and decreased with the addition of a hydrophilic pore-former, HPMC E5 and also with an increasing amount of the intermediate swelling layer. The water uptake of the capsules was linear until rupture and was higher with CAPr than with EC. Soft gelatin capsule-based systems showed shorter lag times compared to hard gelatin capsules because of the higher hardness/filling state of the soft gelatin capsules. The swelling pressure was therefore more directed to the external polymer coating with the soft gelatin capsules. Typical pulsatile drug release profiles were obtained at lower polymer coating levels, while the release was slower and incomplete at the higher coating levels. CAPr-coated capsules resulted in a more complete release than EC-coated capsules.

Viscous fingering in polymer solutions

Characteristics of viscous fingering patterns in polymer solutions were investigated by radially pushing air in a radial Hele-Shaw cell containing hydroxypropyl methyl cellulose (HPMC) solutions. Low and high molecular weight HPMC samples were used. An increase in molecular weight easily yielded chain entanglements, which led to a strong shear thinning and an increase in elasticity. For the low molecular weight HPMC solutions, only the dense-branching patterns were observed over the entire injection pressure range. When isopropyl alcohol was added into the HPMC solutions, leading to less elasticity, the pattern was tip-splitting one, which is observed for Newtonian fluids. On the other hand, for the high molecular weight HPMC solutions, the resulting patterns showed a systematic change from dense-branching to skewering patterns through tip-splitting patterns as the injection pressure increased. The measured tip velocity was compared with the modified Darcy's law, but the coincidence is poor. The velocity corrected by the displaced area ratio provided a good linear relation.

Viscous fingering patterns in polymer solutions

Characteristics of viscous fingering patterns in polymer solutions were investigated by radially pushing air in a radial Hele-Shaw cell containing hydroxypropyl methyl cellulose (HPMC) solutions. Low and high molecular weight HPMC samples were used. An increase in molecular weight easily yielded chain entanglements, which led to a strong shear thinning and an increase in elasticity. For the low molecular weight HPMC solutions, only the dense-branching patterns were observed over the entire injection pressure range. On the other hand, for the high molecular weight HPMC solutions, the resulting patterns showed a systematic change from dense-branching to skewering patterns through splitting patterns as the injection pressure increased. The characteristic quantities of pattern growth, such as the finger width and tip velocity, were evaluated. Darcy's law was compared with the measured tip velocity. HPMC solutions provided a linear relation between the measured tip velocity and the ratio of the injection pressure to effective viscosity at a shear rate imposed to HPMC solutions.

Ability of two comestible formulations of hydroxypropylmethylcellulose to lower serum cholesterol concentrations

High molecular weight hydroxypropylmethylcellulose (HPMC) is a water-soluble cellulosic ether that has recently been shown to reduce serum cholesterol levels when administered as a diet Jell-O ® formulation. For long term therapy, it would be desirable to formulate HPMC into a palatable, portable formulation. In this study, the ability of HPMC to lower cholesterol levels was compared between cookie and diet Jell-O ® formulations. A randomized, double-blind cross-over placebo controlled study was conducted at the General Clinical Research Centre within the University of Michigan Medical Centre. Twelve healthy, mildly hypercholesterolemic individuals participated in the three one-week phases: HPMC in a cookie formulation. HPMC in a diet Jell-O ® formulation and a placebo formulation. Dietary intake was reproduced exactly in each phase. Total cholesterol levels were reduced by 14±8% ( P<0.05) after one week of administration of HPMC in the cookie formulation and 19±7% ( P<0.05) using the diet Jell-O ® formulation, compared to placebo. LDL cholesterol levels were reduced by 19±13% ( P<0.05) and 26±6% ( P<0.05), respectively. In vitro and canine experiments suggested that the tendency to smaller reductions in total and LDL cholesterol levels achieved with the cookie formulation were associated with the slower development of viscosity in solution. Notwithstanding the slightly less impressive clinical results, the cookie formulation offers a palatable, portable and effective alternative to the diet Jell-O ® formulation of HPMC.

Dow food additive lowers cholesterol levels

A cellulose derivative developed by Dow Chemical as a food additive has been shown to be a cholesterol-lowering agent with potential advantages over existing agents. In most cases the compound lowers cholesterol levels to a greater extent than do current drugs. In addition, it does not appear to have any of the toxic side effects found in some existing cholesterol-lowering medications. The development could be of major importance because high cholesterol levels are a key risk factor for heart disease. The cholesterol-lowering compound is a high molecular weight hydroxypropyl-methylcellulose (HPMC). HPMC is an inexpensive substance made from natural cellulose that is extracted from wood pulp and then derivatized. Some HPMC products are currently marketed as food additives to thicken cheesecakes, puddings, and other food products. They are also used in pharmaceutical applications as tablet coatings, controlled-release agents, and granulation binders. HPMC's effectiveness at lowering cholesterol levels was f...

Rheological properties of silica suspensions in aqueous cellulose derivative solutions

The rheology of the silica suspensions in aqueous solutions of hydroxypropylmethylcellulose (HPMC) was investigated as a function of silica content, HPMC concentration, and HPMC molecular weight. Some silica suspensions showed rheopexy behavior after the silica suspensions were subjected to preshearing at the highest shear rate. All silica suspensions showed non-Newtonian flow. For most silica suspensions there were some frequency ranges where the G″ value exceeds the G′ value. On the other hand, for the silica suspensions with the highest silica contents in the solution of high molecular weight HPMC the G′ values were larger than the G″ values in the entire frequency range.