Mechanistic explanation of the (up to) 3 release phases of PLGA microparticles: Diprophylline dispersions.

The aim of this study was to better understand the root causes for the (up to) 3 drug release phases observed with poly (lactic-co-glycolic acid) (PLGA) microparticles containing diprophylline particles: The 1st release phase ("burst release"), 2nd release phase (with an "about constant release rate") and 3rd release phase (which is again rapid and leads to complete drug exhaust). The behavior of single microparticles was monitored upon exposure to phosphate buffer pH 7.4, in particular with respect to their drug release and swelling behaviors. Diprophylline-loaded PLGA microparticles were prepared with a solid-in-oil-in-water solvent extraction/evaporation method. Tiny drug crystals were rather homogeneously distributed throughout the polymer matrix after manufacturing. Batches with "small" (63 µm), "medium-sized" (113 µm) and "large" (296 µm) microparticles with a practical drug loading of 5-7% were prepared. Importantly, each microparticle releases the drug "in its own way", depending on the exact distribution of the tiny drug crystals within the system. During the burst release, drug crystals with direct surface access rapidly dissolve. During the 2nd release phase tiny drug crystals (often) located in surface near regions which undergo swelling, are likely released. During the 3rd release phase, the entire microparticle undergoes substantial swelling. This results in high quantities of water present throughout the system, which becomes "gel-like". Consequently, the drug crystals dissolve, and the dissolved drug molecules rather rapidly diffuse through the highly swollen polymer gel.

Hydrophilic thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding.

Hydrophilic aliphatic thermoplastic polyurethane (Tecophilic™ grades) matrices for high drug loaded oral sustained release dosage forms were formulated via hot melt extrusion/injection molding (HME/IM). Drugs with different aqueous solubility (diprophylline, theophylline and acetaminophen) were processed and their influence on the release kinetics was investigated. Moreover, the effect of Tecophilic™ grade, HME/IM process temperature, extrusion speed, drug load, injection pressure and post-injection pressure on in vitro release kinetics was evaluated for all model drugs. (1)H NMR spectroscopy indicated that all grades have different soft segment/hard segment ratios, allowing different water uptake capacities and thus different release kinetics. Processing temperature of the different Tecophilic™ grades was successfully predicted by using SEC and rheology. Tecophilic™ grades SP60D60, SP93A100 and TG2000 had a lower processing temperature than other grades and were further evaluated for the production of IM tablets. During HME/IM drug loads up to 70% (w/w) were achieved. In addition, Raman mapping and (M)DSC results confirmed the homogenous distribution of mainly crystalline API in all polymer matrices. Besides, hydrophilic TPU based formulations allowed complete and sustained release kinetics without using release modifiers. As release kinetics were mainly affected by drug load and the length of the PEO soft segment, this polymer platform offers a versatile formulation strategy to adjust the release rate of drugs with different aqueous solubility.

Thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding.

This study evaluated thermoplastic polyurethanes (TPUR) as matrix excipients for the production of oral solid dosage forms via hot melt extrusion (HME) in combination with injection molding (IM). We demonstrated that TPURs enable the production of solid dispersions - crystalline API in a crystalline carrier - at an extrusion temperature below the drug melting temperature (Tm) with a drug content up to 65% (wt.%). The release of metoprolol tartrate was controlled over 24h, whereas a complete release of diprophylline was only possible in combination with a drug release modifier: polyethylene glycol 4000 (PEG 4000) or Tween 80. No burst release nor a change in tablet size and geometry was detected for any of the formulations after dissolution testing. The total matrix porosity increased gradually upon drug release. Oral administration of TPUR did not affect the GI ecosystem (pH, bacterial count, short chain fatty acids), monitored via the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). The high drug load (65 wt.%) in combination with (in vitro and in vivo) controlled release capacity of the formulations, is noteworthy in the field of formulations produced via HME/IM.

Release characteristics of polyurethane tablets containing dicarboxylic acids as release modifiers - a case study with diprophylline.

The influence of several dicarboxylic acids on the release characteristics of polyurethane tablets with a high drug load was investigated. Mixtures of diprophylline (Dyph) and thermoplastic polyurethane (TPUR) (ratio: 50/50, 65/35 and 75/25 wt.%) were hot-melt extruded and injection molded with the addition of 1, 2.5, 5 and 10% wt.% dicarboxylic acid as release modifier. Incorporating malonic, succinic, maleic and glutaric acid in the TPUR matrices enhanced drug release, proportional to the dicarboxylic acid concentration in the formulation. No correlation was found between the water solubility, melting point, logP and pKa of the acids and their drug release modifying capacity. Succinic and maleic acid had the highest drug release modifying capacity which was linked to more intense molecular interactions with Dyph. A structural fit between the primary and secondary alcohol of Dyph and both carboxylic groups of the acids was at the origin of this enhanced interaction.

Drug release from extruded solid lipid matrices: theoretical predictions and independent experiments.

The aim of this study was to use a mechanistically realistic mathematical model based on Fick's second law to quantitatively predict the release profiles from solid lipid extrudates consisting of a ternary matrix. Diprophylline was studied as a freely water-soluble model drug, glycerol tristearate as a matrix former and polyethylene glycol or crospovidone as a pore former (blend ratio: 50:45:5%w/w/w). The choice of these ratios is based on former studies. Strains with a diameter of 0.6, 1, 1.5, 2.7 and 3.5mm were prepared using a twin-screw extruder at 65 °C and cut into cylinders of varying lengths. Drug release in demineralised water was measured using the USP 32 basket apparatus. Based on SEM pictures of extrudates before and after exposure to the release medium as well as on DSC measurements and visual observations, an analytical solution of Fick's second law of diffusion was identified in order to quantify the resulting diprophylline release kinetics from the systems. Fitting the model to one set of experimentally determined diprophylline release kinetics from PEG containing extrudates allowed determining the apparent diffusion coefficient of this drug (or water) in this lipid matrix. Knowing this value, the impact of the dimensions of the cylinders on drug release could be quantitatively predicted. Importantly, these theoretical predictions could be confirmed by independent experimental results. Thus, diffusion is the dominant mass transport mechanism controlling drug release in this type of advanced drug delivery systems. In contrast, theoretical predictions of the impact of the device dimensions in the case of crospovidone containing extrudates significantly underestimated the real diprophylline release rates. This could be attributed to the disintegration of this type of dosage forms when exceeding a specific minimal device diameter. Thus, mathematical modelling can potentially significantly speed up the development of solid lipid extrudates, but care has to be taken that none of the assumptions the mathematical theory is based on is violated.

Dissolution from solid lipid extrudates containing release modifiers.

The influence of different types of release modifiers on the dissolution from solid lipid extrudates was investigated. Diprophylline was extruded together with 45% tristearin and 5% (w/w) of a release modifier to suitable extrudates. Three groups of release modifiers were defined: Hydrocolloids, disintegrants and pore formers. All of the release modifier-containing extrudates showed a faster release compared to the reference extrudate, which contained 50% (w/w) of each, API and lipid. Increasing the amount of diprophylline in the binary mixture up to 55% (w/w) also increased its release rate. Compared to this new reference, not all of the release modifier-containing extrudates exhibited an increased dissolution rate. Within the group of pore formers, there was a great discrepancy concerning the dissolution rates. Extrudates containing polyethylene glycol (PEG) exhibited a much higher release rate compared with extrudates containing sodium chloride or mannitol. This behaviour was assumed to be based on the extrusion temperature of 65°C at which PEG exists in the molten state. The hypothesis was tested using different PEGs and another solid lipid.

Modeling of drug release from partially coated matrices made of a high viscosity HPMC.

A mathematical model able to describe the release kinetics of two model drugs (Diprophylline and Theophylline) from partially coated hydroxypropylmethylcellulose (HPMC, Methocel) K4M) matrices is presented. As solvent interaction with the system and drug release can only take place in one direction, the physical frame to be modeled turns out simpler. The model was developed starting from the established equation describing drug dissolution and taking into account the resistance to drug release given by the presence of a growing gel barrier around a matrix system. The model fits the release data obtained from both series of hydrophilic matrices containing increasing amounts (from 0.2 to 0.8 mass ratio) of the two xanthine derivatives. Differences were found in drug release rate according to the different solubility of the actives. Interestingly, however, there is no further reduction in the outer gel layer permeability when the polymer mass fraction exceeds a certain value, with both Theophylline and Diprophylline systems. Results confirm the importance of the fraction of the glassy/rubbery interface held by the active substance in defining the release rate from hydrophilic systems.

Application of micellar electrokinetic chromatography to the quality control of a pharmaceutical preparation containing three bronchodilators.

Theophylline(1,3-dimethylxanthine), dyphylline [7-(2,3-dihydroxypropyl)theophylline] and proxyphylline [7-(beta-hydroxypropyl)theophylline] are three bronchodilators administered jointly in a single pharmaceutical preparation used against asthma. A micellar electrokinetic chromatography (MEKC) method for their resolution using a background electrolyte consisting of 20 mM tetraborate at pH 8.5 and 100 mM sodium dodecyl sulfate is proposed. The method was used to determine the three active principles in a pharmaceutical preparation. The small amount of sample required and the expeditiousness of the procedure allow content uniformity to be determined in individual tablets. The values of the validation parameters for the method (viz. selectivity, linearity, accuracy, precision, limit of detection, limit of quantitation and robustness) are reported. A complete factor design (2(3)x2) including pH, the surfactant concentration and the ionic strength of the background electrolyte as factors was used to estimate robustness. Based on the results, the method is robust enough for quantitation purposes.

Dissolution assay of theophylline, diprophylline and proxyphylline from a sustained release dosage form by high performance thin layer chromatography.

The content and dissolution rate of theophylline, diprophylline and proxyphylline from a sustained release formulation were determined by UV in situ densitometry. After separation the chromatographic zones corresponding to the spots of theophylline, diprophylline and proxyphylline on the high performance thin layer chromatographic plates were scanned in reflectance/absorbance mode at 275 nm. Quantification was performed with a second degree polynomial function over the range 40-200 ng for theophylline and 60-300 ng for diprophylline and proxyphylline. Percentages of dissolved theophylline, diprophylline and proxyphylline were monitored over 1, 3 and 6 h. The method was found to be simple, accurate, reliable, time-saving (up to 18 samples can be determined simultaneously) and low-cost.

Dyphylline liposomes for delivery to the skin.

Delivery of dyphylline to the skin using liposomes was investigated. Xanthines are inhibitors of cAMP phosphodiesterase and have been considered for treatment of psoriasis. Dyphylline was chosen because of its solubility in water, which should allow for incorporation of higher concentrations within the liposomes. Liposomes containing dyphylline were prepared by a method using sonication. Transmission electron micrography (TEM) visualization showed small particles ranging from 40 to 100 nm, and particle size distribution determined by light scattering showed the vesicles to have an average diameter of 360 nm. The transdermal delivery of free dyphylline and dyphylline incorporated in unilamellar liposomes was measured from polyethylene glycol (PEG), Carbopol gel, a PEG enhancer base, and water. For comparison, similar experiments were carried out with theophylline as well. When the drugs were incorporated in Carbopol gel, a large difference was seen between their fluxes, with free dyphylline having the highest permeation, followed by liposomal dyphylline, and then theophylline. With the PEG enhancer base, a very high permeation of theophylline was observed relative to dyphylline and liposomal dyphylline. From the PEG base, liposomal dyphylline exhibited the lowest skin permeation flux relative to other bases. Using the PEG base for dyphylline incorporated in liposomes, a high skin partitioning of the drug, along with low transdermal permeation, was measured. These results may indicate that the drug is localized in the skin.

Swelling-activated drug delivery systems.

A previous paper dealt with the preparation of an in vitro programmable zero-order drug delivery system in which the area of the surface exposed to the dissolution medium and the macromolecular relaxation of polymer controlled the release of the drug. In the present study, the preparation of similar delivery systems is described, in which differing drugs and polymers were used to ascertain the mechanism governing the drug-release kinetics. The movement of the interfaces between solvent and system was measured during drug release in systems with varying composition. The results indicate that the synchronization of the movement of swelling and eroding fronts at the solvent-system interface determines the achievement of the linear-release kinetics of such swelling activated systems and that the swelling and dissolution characteristics of the polymer employed for core preparation govern front movement.

Dyphylline prodrugs: plasma hydrolysis and dyphylline release in rabbits.

Ester hydrolysis of prodrugs of dyphylline [7-(2,3-dihydroxypropyl)theophylline] followed first-order kinetics in both human and rabbit plasma. Rate constants were estimated by linear regression analysis of initial conversion rates, determined at different initial prodrug concentrations. Release of dyphylline from different prodrugs was 1.3 to 13 times faster in rabbit plasma than human plasma. However, relative rates of drug release (lability order) followed the same patterns in rabbit and human plasma. Dyphylline concentrations in rabbit plasma were extended slightly following intravenous administration of dyphylline 2',3'-dipivaloate. Oral dosing of the prodrug in rabbits greatly sustained plasma dyphylline concentrations.

Bronchodilator effect of theophylline preparations and aerosol fenoterol in stable asthma.

To compare the acute bronchodilator effect of increasing doses of intravenous theophylline and inhaled beta adrenergic agonists, we administered intravenous theophylline dissolved in ethylenediamine or proxyphylline and diprophylline or placebo in a double blind fashion to nine asthmatics on three different days. At each session, 100 mg theophylline or placebo were given during each of five subsequent periods of 30 minutes' duration and followed by inhalation of 0.4 mg fenoterol. In contrast to placebo, 500 mg theophylline in ethylenediamine or proxyphylline and diprophylline significantly decreased mean specific airway resistance (SRaw in cmH2O.s) from 31.2 to 23.6 or 34.2 to 23.5 at theophylline serum concentrations of 14.4 or 16.6 mg/L, respectively. Fenoterol lowered SRaw to about 40 percent of the respective baseline values independent of theophylline or placebo pretreatment. We conclude that the acute bronchodilator effect of theophylline is weak in comparison to inhaled beta agonists. Furthermore, proxyphylline and diprophylline cause a weak but not significant bronchodilation when compared to ethylenediamine.

[Comparison of the bronchodilator and protective effect of methylxanthines]. / Vergleich der bronchodilatatorischen und protektiven Wirkung von Methylxanthinen.

UNLABELLED: In study I, carried out on 9 asthmatics to investigate whether the bronchodilator and protective effect of intravenous theophylline, dissolved in ethylene diamine (T.E.) or proxyphylline and diprophylline (T.P.D.), showed different dose-effect relationships, 100 mg theophylline with T.E., T.P.D. or NaCl (placebo) were infused 5 times at 30 minute intervals. This was followed by inhalation of 0.4 mg fenoterol. Results showed that the bronchodilator effect of 500 mg theophylline with a serum concentration greater than 15 mg/l was only about 60% of that for fenoterol alone. In study II, 11 patients with exercise-induceable respiratory obstruction received 200 and 351 mg theophylline with T.E., 200 mg with T.P.D. or placebo prior to exercise and cold air inhalation. Here theophylline had a dose-dependent protective effect. With a theophylline serum concentration of 5 mg/l there was already a reduction in exercise asthma by more than 60% in comparison to placebo. At comparable serum concentrations the effect of T.P.D. was better than T.E. in both studies although the difference was not statistically significant. CONCLUSION: Since the bronchodilator effect of methylxanthines is less than the protective effect, the prophylactic use of theophylline should be given more attention.

Theophylline and dyphylline pharmacokinetics in the horse.

The pharmacokinetics of theophylline and dyphylline were determined after IV administration in horses. In a preliminary experiment, the usual human dosage (milligram per kilogram) of each drug was given to 1 horse. Results were used to calculate dosages for a cross-over study, using 6 horses for each drug. Theophylline plasma concentrations decreased triexponentially in 5 of 6 healthy horses after IV infusion of 10 mg of aminophylline/kg of body weight for 16 to 32 minutes. In the 6 horses, total body elimination rate constants were variable, and the half-life of theophylline was 9.7 to 19.3 hours. Clearance was 42.3 to 69.2 ml/hr/kg. The initial distribution phase was rapid (t1/2 approx 3.5 to 4 minutes); a 2nd distribution phase was slower (t1/2 approx 1.5 to 2 hours). Plasma concentrations of theophylline were in the assumed effective range (10 to 20 micrograms/ml) from 15 minutes until 40 minutes after time zero. The mean apparent volume of distribution was 1.02 L/kg. After bolus IV injection of dyphylline (20 mg/kg), pharmacokinetics were best described by a 2-compartment open model in 2 horses and by a 3-compartment open model in 4 horses. In the 6 horses, elimination half-life of dyphylline was 1.9 to 2.9 hours, and clearance was 200 to 320 ml/hr/kg. Plasma concentrations (approx 50 micrograms/ml) were observed at 10 minutes after injection without adverse effects. Concentrations greater than 10 micrograms/ml were observed from time zero to about 1.5 hours after injection. Theophylline induced significant increases in heart rate, but dyphylline did not affect heart rate significantly.(ABSTRACT TRUNCATED AT 250 WORDS)