methylcellulose and calcium-phosphate--dibasic--anhydrous

Design of a new dosage form manufactured by laminar extrusion for oral administration of drugs. Different mixtures of materials (microcrystalline cellulose [MCC], hydroxypropyl methylcellulose [HPMC], lactose [LAC], dicalcium phosphate [DCP], coumarin [COU], propranolol hydrochloride [PRO], water [W]) were prepared prior to laminar extrusion. Mono, bi and tri layer extrudates were manufactured and evaluated for extrudability, drying, water uptake and swelling ability and in vitro characterization of the drug release. Good quality extrudates were manufactured with higher HPMC molecular weight and fraction in formulation at an extrusion rate of 400 mm/min and slow drying (forced air stream), otherwise surface roughness, thickness in-homogeneity, bending and shark skin were present in the extrudates. Swelling of extrudates was dependent on HPMC fraction and molecular weight (60% up to 90% weight gain for low and high polymer chains, respectively) and the presence of either MCC or DCP. The release of drug was dependent on its solubility (PRO>COU), the fraction of HPMC (low>high fractions), the type of diluent (DCP>MCC) and number of layers (1>2>3 layers). By designing the number and type of layers, dosage forms with well-defined release-kinetics can be tailored. The study has shown the ability of the technology of extrusion to manufacture a controlled release dosage form in a continuous fashion.

Topics: Administration, Oral; Calcium Phosphates; Cellulose; Coumarins; Delayed-Action Preparations; Dosage Forms; Excipients; Hypromellose Derivatives; Lactose; Methylcellulose; Propranolol; Technology, Pharmaceutical; Water

Swellable core technology (SCT) represents a broadly applicable oral osmotic drug delivery platform for the controlled release of drugs. SCT tablets control drug delivery by using osmosis to regulate the influx of water into the tablet's core. The tablet consists of two layers; drug layer and sweller layer, with a semi-permeable membrane coating and delivery port located in the drug layer side of the tablet. The key component of SCT formulations is polyethylene oxide (PEO), which is typically wet granulated with organic solvents to prevent rapid gel hydration observed during contact with aqueous environments. However, the use of organic solvents has their own environmental and cost considerations which make this form of processing undesirable. To overcome this issue, dry granulation can be employed. However, PEO is a very plastic material and problems may be encountered during the tableting process, when work hardening occurs upon double compression. The addition of compression aids to the drug layer will help to increase the roll force when generating ribbons - reducing fines and segregation potential - while also reducing work hardening effects which impact tablet friability. The five compression aids used in this study were microcrystalline cellulose (MCC), xylitol, di-calcium phosphate (anhydrous), lactose monohydrate and starch. The work undertaken here studies the compression properties of the drug layer blends with different levels of the five compression aids as part of the formulation. Roller compaction properties are also varied to provide granules with differing solid fractions. The results of this study indicate that addition of microcrystalline cellulose in the formulation in levels between 10% and 30% significantly improve the tablet hardness at lower tablet compression forces. Further work is required to investigate the impact on dissolution.

Topics: Calcium Phosphates; Cellulose; Compressive Strength; Drug Compounding; Excipients; Hardness; Hypromellose Derivatives; Lactose; Methylcellulose; Starch; Tablets; Xylitol

Different hydroxypropyl methylcellulose (HPMC)/anhydrous dibasic calcium phosphate (ADCP) matrix tablets have been developed aiming to evaluate the influence of both components ratio in the control release of a water-soluble drug (theophylline). In order to characterise the matrix tablets, swelling, buoyancy and dissolution studies have been carried out in different aqueous media (demineralised water, progressive pH medium, simulated gastric fluid, simulated intestinal fluid and simulated colonic fluid). The HPMC/ADCP ratio has turned out to be the determinant in the matrix behaviour: the HPMC characteristic swelling behaviour was modulated, in some cases, by the ADCP characteristic acidic dissolution. When the HPMC/ADCP ratio was ≥0.69, buoyancy, continuous swelling and low theophylline dissolution rate from the matrices (H1, H2 and H3) were observed in all dissolution media. Consequently, these formulations could be adequate as gastro-retentive drug delivery systems. Additionally, HPMC/ADCP ratio ≤0.11 (H5 and H6) induces a pH-dependent drug release which could be applied to design control drug release enteric formulations (with a suitable enteric coating). Finally, a HPMC/ADCP ratio between 0.11 and 0.69 (H4) yield a gastrointestinal controlled drug release, due to its time-dependent buoyancy (7 h) and a total drug delivery in 17 h in simulated colonic fluid.

Topics: Body Fluids; Calcium Phosphates; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Delivery Systems; Excipients; Gastrointestinal Tract; Hydrogen-Ion Concentration; Hypromellose Derivatives; Methylcellulose; Solubility; Tablets; Theophylline; Water

The dissolution of HPMC matrix tablets containing different amounts of highly soluble (mannitol) or poorly soluble (dicalcium phosphate, DCP) was studied to deduce the parameters critical to release robustness.. The release of HPMC and additives was studied using a modified USP II method at two paddle stirring rates, 50 and 125 rpm, at HPMC content varying from 15% to 100%.. At HPMC contents between 30% and 35% a critical point was identified and found crucial to the release from the HPMC/mannitol tablets. Below this point the matrix rapidly disintegrated in a non robust manner. At higher HPMC contents the mannitol release became increasingly diffusion controlled with maintained matrix integrity. The release robustness was lower for HPMC/DCP than HPMC/mannitol tablets at high HPMC contents, however, lacking critical points. The critical point was interpreted as the percolation threshold for HPMC and differences explained in terms of water transport into the matrix.. The release robustness was lower for formulations with additives of low solubility having an erosion controlled release than for additives with higher solubility and a diffusion controlled release. However, for additives creating a steep osmotic pressure gradient, an HPMC content above the percolation threshold becomes vital for maintaining the release robustness.

Topics: Calcium Phosphates; Diffusion; Excipients; Lactose; Mannitol; Methylcellulose; Porosity; Solubility; Tablets

The objective of the present investigation was to prepare and evaluate an ispaghula husk based directly compressible (DC) adjuvant that can be used as matrixing agent using an agglomeration technique. Addition of hydroxypropyl methylcellulose was found necessary to improve cohesion. Lactose (X1), calcium hydrogen phosphate dihydrate (X2) and Avicel PH101 (X3), used along with ispaghula in preparation of agglomerates, were selected as three independent variables in a simplex lattice design affecting compressional and dissolution characteristics of the drug from the DC adjuvant. The agglomerates were evaluated for their flow properties. Tablets were prepared using 70% agglomerates and 30% acetaminophen, a poorly compressible drug, and were subjected to in vitro drug release study. Amounts of the drug released at the end of 60 min (Y60), 300 min (Y300) and 480 min (Y480) were selected as dependent variables in a simplex lattice design. Batch IH05 that contained lactose and calcium hydrogen phosphate dihydrate in a 1:2 ratio could control the release for 12 hours and thus form the basis for twice a-day-dosing.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Calcium Phosphates; Cellulose; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Compounding; Excipients; Hypromellose Derivatives; Kinetics; Lactose; Methylcellulose; Models, Chemical; Psyllium; Solubility; Tablets; Technology, Pharmaceutical

Calcium phosphate cement (CPC) sets in situ with intimate adaptation to the contours of defect surfaces, and forms an implant having a structure and composition similar to hydroxyapatite, the putative mineral in teeth and bones. The objective of the present study was to develop an injectable CPC using dicalcium phosphate dihydrate (DCPD) with a high solubility for rapid setting. Two agents were incorporated to impart injectability and fast-hardening to the cement: a hardening accelerator (sodium phosphate) and a gelling agent (hydroxypropyl methylcellulose, HPMC). The cement with DCPD was designated as CPC(D), and the conventional cement was referred to as CPC(A). Using water without sodium phosphate, CPC(A) had a setting time of 82 +/- 6 min. In contrast, CPC(D) exhibited rapid setting with a time of 17 +/- 1 min. At 0.2 mol/L sodium phosphate, setting time for CPC(D) was 15 +/- 1 min, significantly faster than 40 +/- 2 min for CPC(A) (Tukey's at 0.95). Sodium phosphate decreased the paste injectability (measured as the paste mass extruded from the syringe divided by the original paste mass inside the syringe). However, the addition of HPMC dramatically increased the paste injectability. For CPC(D), the injectability was increased from 65% +/- 12% without HPMC to 98% +/- 1% with 1% HPMC. Injectability of CPC(A) was also doubled to 99% +/- 1%. The injectable and rapid-setting CPC(D) possessed flexural strength and elastic modulus values overlapping the reported values for sintered porous hydroxyapatite implants and cancellous bone. In summary, the rapid setting and relatively high strength and elastic modulus of CPC(D) should help the graft to quickly attain strength and geometrical integrity within a short period of time postoperatively. Furthermore, the injectability of CPC(D) may have potential for procedures involving defects with limited accessibility or narrow cavities, when there is a need for precise placement of the paste, and when using minimally invasive surgical techniques.

Topics: Biocompatible Materials; Bone Cements; Calcium Phosphates; Humans; Hypromellose Derivatives; Materials Testing; Methylcellulose; Phosphates; Stress, Mechanical; Surface Properties; Time Factors; Water

Synthesis of grafting silane on a hydro soluble cellulose ether (HPMC) was described. In alkaline medium, this derivate is under gel form. With a decrease of the pH, a self-hardening occurs due to the silanol condensation. For potential biomedical use, we described the silated-HPMC synthesis, the gel behavior after steam sterilization and the parameters of the silanol condensation i.e. pH, silane percentage and temperature. Minimum kinetic of the condensation was observed for pH between 5.5 and 6.5. So temperature catalyzed the reaction and the self-hardening speed was increased by silane percentage.

Topics: Animals; Bone Substitutes; Calcium Phosphates; Ceramics; Gels; Hardness; Hydrogen-Ion Concentration; Hypromellose Derivatives; Kinetics; Materials Testing; Methylcellulose; Powders; Rheology; Silanes; Sodium; Spectroscopy, Fourier Transform Infrared; Sterilization; Viscosity

A floating dosage form composed of nicardipine hydrochloride (NH) and hydroxypropylmethylcellulose acetate succinate (enteric polymer) was prepared using a twin-screw extruder. By adjusting the position of the high-pressure screw elements in the immediate vicinity of die outlet, and by controlling the barrel temperature, we were able to prepare a puffed dosage form with very small and uniform pores. It was found that the porosity and pore diameter could be controlled by the varying amount of calcium phosphate dihydrate. In the shaking test, the puffed dosage form was found to have excellent floating ability and mechanical strength in acid solution (JP First Fluid, pH 1.2). The dissolution profile of NH was controlled by the amount of wheat starch. In the dissolution test using JP Second Fluid (pH 6.8), rapid dissolution of NH and loss of buoyancy were observed. It was shown that the puffed dosage form, consisting of enteric polymer prepared using the twin-screw extruder, was very useful as a floating dosage form that was retained for a long period in the stomach.

Topics: Administration, Oral; Calcium Phosphates; Chemistry, Pharmaceutical; Dosage Forms; Kinetics; Methylcellulose; Microscopy, Electron, Scanning; Nicardipine; Vasodilator Agents

The purpose of this study was to check the chemical stability of an injectable bone substitute (IBS) composed of a 50/50 w/w mixture of 2.92% hydroxypropyl methylcellulose (HPMC) solution in deionized water containing biphasic calcium phosphate (BCP) granules (60% hydroxyapatite/40% beta-tricalcium phosphate w/w). After separation of the organic and mineral phases, capillary gas chromatography (GC) was used to study the possible modification of HPMC due to the contact with BCP granules following steam sterilisation and 32 days storage at room temperature. HPMC was extracted from IBS in aqueous medium, and a dialytic method was then used to extract calcium phosphate salts from the HPMC. The percentage of HPMC extracted from BCP was 98.5%+/-0.5%, as measured by UV. GC showed no chemical modifications after steam sterilisation and storage.

Topics: Biocompatible Materials; Calcium Phosphates; Chromatography, Gas; Hydrogen-Ion Concentration; Hypromellose Derivatives; Methylcellulose; Salts; Temperature; Time

The purpose of the study was to develop a new three-dimensional model using force, time and displacement to characterize the densification behavior of tableting materials. Normalized time (x), displacement converted to ln(1/1 - D(rel)) according to Heckel (y) and force presented as pressure (z) were used to plot a graph. A twisted plane was fitted to this three-dimensional plot. This plane was characterized by three parameters d, the slope over time called 'time plasticity', e, the slope over pressure called 'pressure plasticity' and omega, the angle of rotation called 'fast elastic decompression'. These parameters were used to characterize the densification behavior of the well-known materials microcrystalline cellulose, dicalcium phosphate dihydrate, theophylline monohydrate, cellulose acetate and hydroxypropyl methylcellulose at different rho(rel, max). It could be shown that brittle, elastic and plastic compression properties could be very well distinguished and differentiated. Further on, it could be shown whether these properties were due to pressure or time. Thus this model has the prevailing advantage to characterize tableting materials in one step according to time and pressure and it is a useful tool to develop tablet formulations or new excipients.

Topics: Algorithms; Calcium Phosphates; Cellulose; Drug Compounding; Excipients; Hypromellose Derivatives; Methylcellulose; Models, Theoretical; Pressure; Tablets; Theophylline; Time Factors

An injectable composite material based on biphasic calcium phosphate (BCP) and a nonionic cellulose ether has been elaborated for use in percutaneous surgery for spine fusion. This paper reports the characterization results of this material by spectroscopic techniques including X-ray diffraction (XRD), infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) fitted with an energy dispersive X-Ray analysis system and high-resolution transmission electron microscopy (HR-TEM). From FTIR and XPS results, it was observed that the adhesion between the polymer and the ceramic might be insured by oxygen bridging developed through an ionic bonding between calcium ions and (C-O) groups of the polymer. Moreover, XPS showed attraction of Ca2+ ions in the polymer matrix, while the ceramic surface was modified in a HPO4(2-) -rich layer. These results suggest a possible dissolution/precipitation process at the interface ceramic/polymer. HR-TEM observations supported this hypothesis, showing a light contrasted fringe at the surface of the ceramic grains in the composite paste. As well, changes in the XRD spectra could indicate a small decrease in the crystal size of the BCP powder through the contact to polymer solution. In addition, SEM observation showed a decrease of the initial BCP granulometry. Aggregates of 80-200 microm seemed to be mostly dissociated in micrograins. The ceramic grains were coated with and bonded between each other by the polymer matrix, which acted as spacer in between the ceramic grains, creating a macroporous-like material structure.

Topics: Biocompatible Materials; Calcium Phosphates; Ceramics; Chemical Phenomena; Chemistry, Physical; Drug Carriers; Drug Combinations; Electron Probe Microanalysis; Ethers; Hypromellose Derivatives; Injections; Methylcellulose; Microscopy, Electron; Microscopy, Electron, Scanning; Spectroscopy, Fourier Transform Infrared; Sterilization; X-Ray Diffraction

Many different bone substitutes, such as autografts, allografts or synthetic biomaterials have been proposed to restore alveolar bone loss and support efficient placement of dental implants. This experimental study evaluated the osteoconductive properties of an injectable bone substitute (IBS) composed of a polymeric carrier and a calcium phosphate mineral phase, used to fill mandibular and maxillary canine extraction sockets.. The polymer was a cellulose derivative (methyl-hydroxy-propyl-cellulose, MHPC), and the mineral phase consisted of granules of biphasic calcium phosphate (BCP) ceramics 200 to 500 microm in diameter. Mandibular and maxillary premolars extracted from 3 dogs (a total of 60 extraction sites) were immediately treated with the IBS or left unfilled as control sites. Animals were sacrificed 3 months after implantation and all extraction sockets were prepared for histological evaluation.. Qualitative histological studies showed that the IBS was able to support the extensive apposition of well-mineralized newly formed lamellar bone over the entire socket surface and appeared to prevent alveolar ridge bone loss in treated extraction sites. Quantitative evaluation showed that the amount of newly formed bone was significantly higher in mandibular than maxillary extraction sockets for both treated and control sites.. An injectable bone substitute composed of a polymeric carrier and calcium phosphate was effective in enhancing the bone fill of extraction sockets. This approach may prove promising for periodontal lesions. The material expressed osteoconductive capacities, and the biological properties of the mineral phase were conserved.

Topics: Animals; Bone Regeneration; Bone Substitutes; Calcium Phosphates; Ceramics; Dogs; Drug Carriers; Female; Hypromellose Derivatives; Injections; Methylcellulose; Pilot Projects; Statistics, Nonparametric; Tooth Extraction; Tooth Socket

Several sustained-release tablet formulations with acceptable pharmacokinetic properties were found to be unstable because of the effects of lactose. Because the pharmacokinetic properties were acceptable, an attempt was made at developing stable formulations that reproduced the in vitro drug release characteristics of the unstable formulations. Through the use of a statistically designed mixture experiment, alternative formulations were generated and tested for dissolution. The dissolution data collected in the mixture experiment were used to develop a statistical regression model for identifying formulations with dissolution rates equal to those of the unstable formulations. The form of the regression model was based on the Higuchi equation. The data analysis indicated that it is possible to generate dissolution profiles that reproduce those of the original formulations by adjusting the ratios of Methocel K4MCR Premium and Methocel K100MCR Premium and by replacing the detrimental lactose with calcium phosphate dibasic anhydrous.

Topics: Calcium Phosphates; Delayed-Action Preparations; Methylcellulose; Regression Analysis; Solubility; Tablets

The calcium phosphate cement (CPC) used in this study was formed by combining equimolar amounts of tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrous (DCPA). This powder, when mixed with water, sets to a hard cement in about 30 min. However, the water-based CPC paste is not highly cohesive and is vulnerable to washout until hardening occurs. The objectives of this study were to investigate the effects on handling properties, washout resistance, cement hardening behavior, and mechanical properties of adding several gelling agents to CPC paste. Aqueous solutions that contained a mass fraction of 2-4% of hydroxypropyl methylcellulose (HPMC), carboxyl methylcellulose (CMC), chitosan acetate, and chitosan lactate were used as cement liquids. Hardening time was measured by the Gilmore needle test; resistance to washout was evaluated by the disintegration of the cement specimen in water with agitation; and mechanical strength was evaluated by the measurement of diametral tensile strength and compressive strength. Handling properties were greatly improved by the addition of HPMC, CMC, chitosan acetate, and chitosan lactate. Hardening time was retarded by the additions of HPMC and CMC, and mechanical strength was weakened by the addition of either the chitosan lactate or the chitosan acetate.

Topics: Biocompatible Materials; Calcium Phosphates; Carboxymethylcellulose Sodium; Chitin; Chitosan; Dental Cements; Hypromellose Derivatives; Materials Testing; Methylcellulose; X-Ray Diffraction

We report the results obtained by infrared (IR) and X-ray photoelectron spectroscopy (XPS) on the multiphasic composite material formed by the mixture of biphasic calcium phosphate (BCP) and hydroxypropylmethylcellulose (HPMC). This synthetic material, intended for bone substitution, is injectable and allows percutaneous surgery. Core level spectra of carbon, oxygen, calcium, and phosphorus were recorded on separate components before mixing and then compared to those obtained in the final product. Analysis of the spectra shows that formation of calcium carbonate has occurred upon mixing the components in agreement with IR results. An attempt to explain the formation mechanism of the composite is given involving the nature of the constituents on one hand and the possible reactions between the different components on the other.

Topics: Bone Substitutes; Calcium; Calcium Carbonate; Calcium Compounds; Calcium Phosphates; Carbon; Ceramics; Hydrogen-Ion Concentration; Hypromellose Derivatives; Methylcellulose; Oxides; Oxygen; Phosphorus; Polymers; Powders; Spectrophotometry, Infrared