Properties of tablets containing granulations of ibuprofen and an acrylic copolymer prepared by thermal processes.

The objective of this study was to investigate the properties of tablets containing granulations of ibuprofen (Ibu) and Ammonio Methacrylate Copolymer, Type B (Eudragit RS PO) prepared by hot-melt processing. Tablets were compressed from granules prepared by hot-melt granulation (HMG) or direct compression (DC). For the hot-melt extrusion (HME) process, tablets were prepared by cutting the extrudate, manually. The physicochemical properties of tablets were investigated using thermal analysis, powder X-ray diffraction analysis, tablet hardness, and drug dissolution. The effect of thermal treatment of tablets on the dissolution characteristics of Ibu was also investigated. The results demonstrated that the Ibu lowered the glass transition temperature (Tg) of the Eudragit RS PO and the softened polymer functioned as a thermal binder in the granulation. Ibu was demonstrated to be an effective plasticizer for Eudragit RS PO in the thermal processes. The efficiency of the granulation process increased with increasing levels of Eudragit RS PO in the powder blend. Higher levels of Eudragit RS PO in the tablets prepared by HMG or HME resulted in a decrease in the dissolution rate of the Ibu. An increase in the amount of Ibu in the tablets prepared by HMG or DC led to a decrease in the initial dissolution rate of the Ibu. Following the thermal treatment of the Ibu tablets prepared by HMG, the dissolution rate was significantly decreased due to structural changes in the tablets that resulted from the fusion and coalescence of plasticized polymer particles, causing a reduction in tablet porosity. The Ibu tablets prepared by HME demonstrated minimal changes in their release properties following thermal treatment even at temperatures higher than the Tg of the polymer. HME was shown to be a novel method to prepare matrix tablets and stable dissolution properties were obtained when tablets were stored at 40 degrees C for 30 days.

Release performance of a poorly soluble drug from a novel, Eudragit-based multi-unit erosion matrix.

Mechanisms governing the release of drugs from controlled delivery systems are mainly diffusion, osmosis and erosion. For poorly soluble drugs, the existing mechanisms are limited to osmosis and matrix erosion, that are commonly observed in single unit matrix dosage forms. This study reports formulation and dissolution performance of Eudragit L 100 55 and Eudragit S 100 based multi-unit controlled release system of a poorly soluble thiazole based leukotriene D(4) antagonist, that was obtained by an extrusion/spheronization technique. Effect of triethyl citrate, that was incorporated in the matrix, on the dissolution performance of the drug was also evaluated. In vitro matrix erosion and drug release from the pellets were determined by the use of USP Dissolution Apparatus I, pH 6.8 phosphate buffer, gravimetry and UV spectrophotometry, respectively. Results obtained demonstrated that matrix erosion and drug release occurred simultaneously from the pellets. Pellets eroded with a consequent reduction in size without any change in the pellet geometry for over 12 h. Matrix erosion and drug release followed zero order kinetics. Data obtained strongly suggested a polymer controlled, surface erosion mechanism.

Controlled release of drugs from injectable in situ formed biodegradable PLGA microspheres: effect of various formulation variables.

A novel in situ method for the preparation of injectable biodegradable poly(lactide-co-glycolide) (PLGA) microspheres for the controlled delivery of drugs is described here. A stable dispersion of PLGA microglobules ('premicrospheres' or 'embryonic microspheres') in a vehicle mixture on injection, comes in contact with water from aqueous buffer or physiological fluid, thereby hardening the microglobules into solid matrix type microparticles entrapping the drug (in situ formed microspheres). The drug is then released from these microspheres in a controlled fashion. The effect of the following formulation variables on the characteristics of the novel drug delivery system (NDDS) was investigated: (i) the concentrations of polyethylene glycol 400 (PEG 400), the encapsulated drug, and the hydrophilic excipient (mannitol); and (ii) the types of encapsulated drug (micromolecules and macromolecules such as protein) and vehicles (replacing triacetin and Miglyol 812 by triethyl citrate and soybean oil respectively). Also, the effect of formulation, process, and storage (15 days/4 degrees C) conditions on the physical stability of the encapsulated protein was evaluated. The in vitro drug release was enhanced with decrease in the PEG 400 concentration and increase in the drug and mannitol concentration. The drug release was retarded with increase in the molecular weight of the encapsulated drug. Substitution of triacetin by triethyl citrate and miglyol 812 by soybean oil resulted in variation in the release of the drug from the in situ formed microspheres. A preliminary investigation of the physical stability of the myoglobin revealed that the alpha-helical structure was unaffected by the formulation, process, and the storage conditions.

Comparison of various injectable protein-loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices: in-situ-formed implant versus in-situ-formed microspheres versus isolated microspheres.

The purpose of this research was to prepare various injectable, protein (cytochrome c)-loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices by a novel microencapsulation method and to compare their characteristics. Syringeable mixtures of polymer and protein solidified upon injection when coming in contact with water, and formed a solid matrix-type implant or microspheres (in-situ-formed implant or in-situ-formed microspheres, respectively) with cytochrome c entrapped. These devices exhibited different characteristics in terms of in vitro cytochrome c release profile, percentage cytochrome c encapsulation efficiency, and particle size. The burst effect from these devices exhibited the following trend: in-situ-formed implant > in-situ-formed microspheres > isolated microspheres. The in-situ-formed microspheres were larger in size than the isolated microspheres. Also, the isolated microspheres exhibited the slowest release of cytochrome c, whereas the in-situ-formed implant exhibited the fastest release. The microencapsulation process can produce various drug-loaded injectable biodegradable PLGA devices having different characteristics.

Controlled delivery of drugs from a novel injectable in situ formed biodegradable PLGA microsphere system.

A novel method for in situ preparation of injectable biodegradable microspheres from the copolymer, poly(lactide-co-glycolide) (PLGA), without incorporating unacceptable organic solvents is described. The delivery system is a dispersion of PLGA microglobules ('premicrospheres' or 'embryonic microspheres') in an acceptable vehicle mixture (continuous phase) and whose integrity is maintained by the use of appropriate stabilizers. A solution of PLGA, triacetin, a model protein (cytochrome c), PEG 400, and Tween 80 (oil phase 1) is added dropwise with continuous homogenization to Miglyol 812-Span 80 solution (oil phase 2), thereby inducing phase separation (coacervation) of PLGA and forming PLGA microglobules (containing cytochrome c) dispersed in the continuous phase. This novel drug delivery system (NDDS) is a dispersion and has a viscous consistency, but is sufficiently syringeable. When injected, it comes in contact with water from an aqueous buffer or physiological fluid and, as a result, the microglobules harden to form solid matrix type microparticles entrapping cytochrome c (in situ formed microspheres). Cytochrome c is then released from these microspheres in a controlled fashion. The composition, rationale, and optimization of the NDDS are described here. Various formulation variables such as the PLGA concentration and type and the substitution of the continuous phase by a fresh oil phase 2 influenced the characteristics of this system. A preliminary investigation of the reproducibility and stability of the NDDS, as well as the physical stability of the encapsulated cytochrome c, revealed that these characteristics were not adversely affected.

Effect of formulation and process variables on porosity parameters and release rates from a multi unit erosion matrix of a poorly soluble drug.

The effect of drug loading, water required for granulation and spheronization time on porosity parameters (intrusion-extrusion isotherms, pore size distribution, total pore surface area, mean pore diameter, shape and morphology of pores) and drug release rates from pellets of a poorly soluble drug was investigated. Porosity parameters were determined by mercury intrusion porosimetry. The drug loading was found to have a profound effect on the porosity parameters. Pellets with low drug loading showed increased pore surface area with small mean pore diameters and an increased number of total pores. On the other hand, pellets with high drug loading had decreased pore surface areas with larger mean pore diameters and a reduction in the total number of pores. With high drug loading, the drug release rate decreased. Water required for granulation had a direct effect on the total porosity of the pellets. Spheronization time from 2 to 10 min had a pronounced effect on porosity parameters and release rates. No changes in porosity parameters and release rates were observed from 10 to 20 min of spheronization time. It was shown that each porosity parameter investigated was well correlated with drug release rates and thus it is important to study the effect of porosity parameters in evaluating the in vitro performance of the multi-unit erosion matrix for the controlled release of a poorly soluble drug.

Stability of a hydrophobic drug in presence of hydrous and anhydrous lactose.

The chemical stability of a hydrophobic Leukotriene receptor antagonist drug was investigated in the presence of lactose (both hydrous and anhydrous) under various humidity and temperature conditions. The effect of wet-granulation and direct-mixing on the stability of the drug was also studied. Mixtures of drug:lactose in the ratio 1:25, 1:50 and 1:100 were prepared and analyzed over a 6 week period after storage at 40, 83 and 97% RH (all at 25 degreesC) and 75% RH at 40 degreesC. The mixtures were subjected to LOD, Karl--Fischer titrimetry, HPLC and DSC analysis to evaluate the amount of moisture pickup, percent potency and presence of drug-moisture-lactose interaction. Mixtures containing lactose anhydrous picked up more moisture and exhibited greater drug degradation than those containing lactose hydrous. Also, mixtures stored under high temperature and humidity condition showed greater moisture uptake than those stored at high humidity alone. Lactose anhydrous becomes hydrated on exposure to high humidity/temperature and storage conditions. The transition state of lactose and not its stable state may be responsible for its greater interaction and subsequent degradation of the drug. Therefore, the normal belief that lactose anhydrous, which has less than 0.5% moisture, should provide greater stability as compared to lactose hydrous, needs to be properly evaluated.

Controlled drug delivery by biodegradable poly(ester) devices: different preparative approaches.

There has been extensive research on drug delivery by biodegradable polymeric devices since bioresorbable surgical sutures entered the market two decades ago. Among the different classes of biodegradable polymers, the thermoplastic aliphatic poly(esters) such as poly(lactide) (PLA), poly(glycolide) (PGA), and especially the copolymer of lactide and glycolide referred to as poly(lactide-co-glycolide) (PLGA) have generated tremendous interest because of their excellent biocompatibility, biodegradability, and mechanical strength. They are easy to formulate into various devices for carrying a variety of drug classes such as vaccines, peptides, proteins, and micromolecules. Most importantly, they have been approved by the United States Food and Drug Administration (FDA) for drug delivery. This review presents different preparation techniques of various drug-loaded PLGA devices, with special emphasis on preparing microparticles. Certain issues about other related biodegradable polyesters are discussed.

Mechanical properties of single pellets containing acrylic polymers.

Three aqueous-based acrylic latex dispersions, Eudragit L 30 D, NE 30 D, and RS 30 D, were incorporated as granulating binders into a powder blend of microcrystalline cellulose and anhydrous lactose by wet massing. Spheronized pellets were prepared by extrusion-spheronization and the mechanical properties of single pellets, including the tensile strength at break and the Young's modulus were determined from the stress-strain profiles using a Chatillon TCD-200 tension/compression digital test gauge. The influence of particle size and plasticizer on the mechanical properties of pellets containing Eudragit RS 30 D was investigated. All bead formulations deformed by brittle fracture under a diametral compression force. The mechanical strength was found to be influenced by the adhesive strength between the polymers and the powder particles instead of the cohesive strength of each polymer. The Young's modulus and the tensile strength were also significantly influenced by the type and concentration of polymer, the presence of plasticizer, and the particle size of the beads. The results were related to the properties of the polymers and the fracture mechanisms of the beads. Furthermore, the polymer type and the incorporation of plasticizer influenced the susceptibility of the moistened extruded granules to the shearing forces during the spheronization process, which influenced the surface morphological properties of the pellets.

N-methyl-2-pyrrolidone as a cosolvent: relationship of cosolvent effect with solute polarity and the presence of proton-donating groups on model drug compounds.

N-Methyl-2-pyrrolidone (methylpyrrolidone), a cosolvent which has been used in veterinary medicine and in transdermal delivery devices, was investigated as a cosolvent for model drug compounds of widely varying polarity. These compounds were digoxin, sulfamethoxazole, hydrocortisone acetate, theophylline, phenytoin, and reserpine. Methylpyrrolidone was found to be an extremely efficient cosolvent for low solubility polar drugs such as digoxin or drugs containing multiple proton-donating groups such as phenytoin. The increase in solubility observed in aqueous solutions of digoxin and phenytoin to which 0.2 volume fraction of methylpyrrolidone was added was 500x and 65x, respectively. Significant deviations from log-linear solubilization were observed with digoxin, sulfamethoxazole, phenytoin, and reserpine, indicating significant water-solute-cosolvent interactions.

Biotin uptake and transport across bovine brain microvessel endothelial cell monolayers.

Primary cultures of bovine brain microvessel endothelial cells (BMECs) were used to characterize blood-brain barrier (BBB) uptake and transport of biotin. Both the uptake and the transcellular transport of either radiolabeled or fluorescein-conjugated biotin by confluent monolayers of BMECs were measured. Biotin uptake (Km = 123 microM) and bidirectional transport across BMEC monolayers was a saturable process and could be competed for by unlabeled biotin, biocytin, and biotinmethyl ester. Pantothenic and nonanoic acid were found not to be effective competitors for either biotin uptake or transport. The metabolic inhibitor, 2-deoxyglucose, had only small effects on the saturable apical-to-basolateral transport and apical uptake of biotin by BMECs. In contrast, basolateral-to-apical transport of biotin was substantially attenuated by 2-deoxyglucose pretreatment. Results supported the existence of specific and saturable uptake and efflux carrier systems for biotin in BMEC monolayers. The function of these systems was dependent to some degree on the metabolic status of the BMECs. Our findings confirm the existence of a biotin uptake system at the BBB in vivo and provide the first indication of an efflux system for biotin in BMECs.

Effect of buffer constituents on the determination of therapeutic proteins by capillary electrophoresis.

Capillary electrophoresis has proved to be a versatile method for the determination of proteins, peptides and amino acids in pharmaceutical formulations. For quantification of the capillary electrophoresis data, however, significant errors may result if the analysis is performed using improper separation conditions. The peak area response for protein analytes, which is generally low in conventional UV detection, may also vary dramatically depending on the nature of the buffer used in the separation. This paper describes the effects of various buffer constituents and analytical conditions on the capillary electrophoretic separation and quantification of a humanized monoclonal antibody in bulk form and in a typical therapeutic formulation. For optimum peak area response and reproducibility, protein derivatization with an appropriate chromophore (e.g., fluorescamine) and separation in the presence of a moderate ionic strength buffer containing lithium chloride, tetramethylammonium chloride or trimethylammonium propylsulfonate is recommended. General guidelines for the determination of proteins by capillary electrophoresis and a rationale for the use of internal standards to improve the quantification of data are also discussed.

Nasal delivery of [14C]dextromethorphan hydrochloride in rats: levels in plasma and brain.

Dextromethorphan (DM) is a neuroprotective agent. The mechanism of action is believed to be by N-methyl-D-aspartate receptor blockade. The concentration of DM in the brain is believed to be dose and route dependent. Delivery by the nasal route has received a lot of attention recently, because drug absorption from this route follows intravenous profiles with no first-pass effect. The uptake of DM in the brain from the nasal route was 65.9% compared with the intravenous route, whereas the plasma bioavailability from the nasal route was 78.8%. The nasal route is a viable alternative to the parenteral route for DM administration.

Studies of in vitro skin permeation and retention of a leukotriene antagonist from topical vehicles with a hairless guinea pig model.

A leukotriene antagonist [Ro 23-3544; 6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid; 1] was studied in vitro for its permeation through and retention in hairless guinea pig skin from various topical vehicles. Both the free acid and the sodium salt forms of the drug were used. The vehicles evaluated were polyethylene glycol 400, propylene glycol, dimethyl sulfoxide (DMSO), C12-C15 alcohol lactates, dimethyl isosorbide, butyrolactone, methylpyrrolidone, hexyl laurate, isopropyl myristate, and caprylic/capric triglyceride (Neobee M5). For the salt form of the drug, the highest permeability coefficient and retention were obtained from DMSO and methylpyrrolidone, respectively. For the acid form, however, the highest permeability coefficient and retention were obtained from hexyl laurate and DMSO, respectively. The highest permeation and retention values were not obtained from the same vehicle for either the salt or the acid form of the drug. This observation questions the validity of using permeation (flux) measurements to screen topical drugs and formulations. Although the precise reasons for this lack of correlation between permeation and retention are not known at this time, this study has shown that the solubility parameters of the drug and the vehicles used may play an important role. It seems logical to conduct skin retention studies rather than flux measurements in evaluating drug delivery from dermatological products.

Effect of iontophoresis on in vitro skin permeation of an analogue of growth hormone releasing factor in the hairless guinea pig model.

The shortened analogue of growth hormone releasing factor (GRF) Ro 23-7861 (1) has a molecular weight of 3929 daltons [equivalent to GRF (1-29)] and is more potent than the endogenous GRF (1-44). The in vitro hairless guinea pig model and vertical and horizontal diffusion cell assemblies were used to study the effect of iontophoresis on the permeability to skin of 1. The transport of 1 across the skin was studied by monitoring the rate of its appearance in the receiver compartment with a radioimmunoassay. No permeability of 1 was observed without iontophoresis, whereas with iontophoresis, the permeability of 1 was significant. For example, at a current density of 0.23 mA/cm2 and buffer concentration of 0.05 M, the flux of 1 was 56.8 +/- 8.21 ng/cm2.h. The flux of 1 was independent of the design of the permeation apparatus, the electrodes, the donor and receiver volumes, the type of current (constant or pulsed), and the frequency of the pulsed current. The flux of 1 increased curvilinearly with the increase in salt concentration of the buffer and linearly with the increase in current.