Formulation of a film-coated dutasteride tablet bioequivalent to a soft gelatin capsule (Avodart®): Effect of γ-cyclodextrin and solubilizers

The aim of this study was to optimize a tablet formulation of dutasteride that is bioequivalent to a commercially available soft gelatin capsule (Avodart^®). The effect of cyclodextrin on enhancing the aqueous solubility of dutasteride was investigated, after which the formulation was further optimized with solubilizing polymer and surfactant. Among the cyclodextrins tested, the highest solubility was observed when dutasteride was complexed with γ-cyclodextrin. Moreover, the addition of polyvinylpyrrolidone and Gelucire/TPGS further enhanced the solubility of dutasteride. Differential scanning calorimetry (DSC) and powder X-ray diffraction (pXRD) studies demonstrated that dutasteride existed in the amorphous form in the complex. Optimized dutasteride complexes were selected after a pharmacokinetic study in rats, and film-coated tablets were prepared by the direct compression method. In vitro dissolution profiles for the tablets of dutasteride complexes were similar to those of the reference. Moreover, pharmacokinetic parameters including the C_max and AUC values after oral administration in beagle dogs were not significantly different from those of the reference with a relative bioavailability of 92.4%. These results suggest the feasibility of developing a tablet formulation of dutasteride using cyclodextrin complex in addition to a solubilizing polymer and surfactant.     

Formulation of 3D Printed Tablet for Rapid Drug Release by Fused Deposition Modeling: Screening Polymers for Drug Release,Drug-Polymer Miscibility and Printability

The primary aim of this study was to identify pharmaceutically acceptable amorphous polymers for producing 3D printed tablets of a model drug, haloperidol, for rapid release by fused deposition modeling. Filaments for 3D printing were prepared by hot melt extrusion at 150°C with 10% and 20% w/w of haloperidol using Kollidon^® VA64, Kollicoat^® IR, Affinsiol^?15 cP, and HPMCAS either individually or as binary blends (Kollidon^® VA64 + Affinisol^? 15 cP, 1:1; Kollidon^® VA64 + HPMCAS, 1:1). Dissolution of crushed extrudates was studied at pH 2 and 6.8, and formulations demonstrating rapid dissolution rates were then analyzed for drug-polymer, polymer-polymer and drug-polymer-polymer miscibility by film casting. Polymer-polymer (1:1) and drug-polymer-polymer (1:5:5 and 2:5:5) mixtures were found to be miscible. Tablets with 100% and 60% infill were printed using MakerBot printer at 210°C, and dissolution tests of tablets were conducted at pH 2 and 6.8. Extruded filaments of Kollidon^® VA64-Affinisol^? 15 cP mixtures were flexible and had optimum mechanical strength for 3D printing. Tablets containing 10% drug with 60% and 100% infill showed complete drug release at pH 2 in 45 and 120 min, respectively. Relatively high dissolution rates were also observed at pH 6.8. The 1:1-mixture of Kollidon^® VA64 and Affinisol^?15 cP was thus identified as a suitable polymer system for 3D printing and rapid drug release.     

The effect of polymer properties on direct compression and drug release from water-insoluble controlled release matrix tablets

The objective of this study was to identify and evaluate key polymer properties affecting direct compression and drug release from water-insoluble matrices. Commonly used polymers, such as Kollidon^® SR, Eudragit^® RS and ethyl cellulose, were characterized, formulated into tablets and compared with regard to their properties in dry and wet state. A similar site percolation threshold of 65% v/v was found for all polymers in dry state. Key parameters influencing polymer compactibility were the surface properties and the glass transition temperature (T_g), affecting polymer elasticity and particle size-dependent binding. The important properties observed in dry state also governed matrix characteristics and therefore drug release in wet state. A low T_g (Kollidon^® SR < Eudragit^® RS) decreased the percolation threshold, particle size effect and tortuosity, but increased permeability and sensitivity to heat/humidity treatment. Hence, lower permeability and higher stability are benefits of a high-T_g polymer (ethyl cellulose). However, release retardation was observed in the same order as matrix integrity (Eudragit^® RS < ethyl cellulose < Kollidon^® SR), as the high permeability was counteracted by PVP in case of Kollidon^® SR. Therefore, the T_g and composition of a polymer need to be considered in polymer design and formulation of controlled-release matrix systems.     

Formulation of highly purified fenugreek gum based silica lipid drug delivery system for simvastatin with enhanced dissolution rate and in vitro characterization

In current study, highly purified fenugreek gum (HPFG) isolated by patented method explored as emulsifier and hydrophilic solid carrier in drug delivery system. Anti-hyperlipidemic drug simvastatin (SIM) was selected as drug model for the study as it is associated with poorly water solubility and low bioavailability problems (<5 %). A suitable HPFG-based silica lipid system composed of SIM (1.5 %), medium chain triglyceride Capmul^® MCM (10 %) as lipid phase, 0.6 % HPFG as emulsifier and HPFG 2.5 %, different grades colloidal silica (7.5 %) (Aerosil^® 300 Pharma, Aerosil^® 380 Pharma and Aeroperl^® 300 Pharma) as hydrophilic solid carriers was developed. The optimized HPFG-based silica lipid systems were characterized for physical characteristics like flow ability, compressibility, redispersiblity, solubility and in vitro drug release using USP apparatus II in pH 6.8 phosphate buffer. The system was also characterized for Fourier transform infrared spectroscopy, powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The developed formulation was found to have excellent flow property, readily redispersiblity, better aqueous solubility and showed 3–4-fold increase in dissolution rate as compared to plain drug and marketed formulation (Simlo^® 10). Transition of crystalline drug to amorphous state was confirmed by DSC, PXRD and SEM studies. Enhanced dissolution rate and solubility possibly attributed to improved wetting, amorphous drug state and facilitated diffusion from lipid-based system. Thus developed HPFG-based silica lipid system provides an alternative means for SIM with enhanced dissolution rate and stability in oral solid dosage form.     

Development of Solid Dispersion by Hot Melt Extrusion Using Mixtures of Polyoxylglycerides With Polymers as Carriers for Increasing Dissolution Rate of a Poorly Soluble Drug Model

Various polyoxylglycerides have been researched extensively in the development of solid dispersions (SDs) for bioavailability enhancement of poorly water-soluble drugs. However, because of their low melting points (40°C-60°C), SDs produced are usually soft and semisolid. The objective of present study was to prepare SDs of a Biopharmaceutical Classification System class II drug, carvedilol, in mixtures of stearoyl polyoxylglycerides (Acconon^® C-50; m.p. ～50°C) with polymers by hot melt extrusion to obtain free-flowing powder upon grinding. Miscibility of carvedilol with Kollidon^® VA64, hydroxypropyl methylcellulose acetate succinate, and Klucel^? EXF was first evaluated by film casting, and Kollidon^® VA64 was selected for further study. SDs containing 5%-20% carvedilol, 0%-20% Acconon^® C-50, and the remaining Kollidon^® VA64 were prepared for hot melt extrusion. SDs were characterized by differential scanning calorimetry and powder X-ray diffraction analysis, and dissolution tests were conducted in 250 mL of pH 6.8 phosphate buffer by filling powders in capsules. Carvedilol was miscible with all polymers tested up to 50% and remained amorphous in SDs. The drug release from formulations containing 20% carvedilol and 0, 5%, 10%, and 20% Acconon^® C-50 were 30%, 30%, 70%, and 90%, respectively, in 60 min. SDs containing carvedilol and Acconon^® C-50, up to 20% each, as well as Kollidon^® VA64, were physically stable after 3 months of storage at 25°C/60% relative humidity.     

Improved dosage form of the combined alendronate and calcitriol (Maxmarvil®) on the absorption of alendronate in Korean postmenopausal women

Alendronate is one of the most potent anti-osteoporotic agents for postmenopausal osteoporosis. However, high doses of alendronate cause esophageal irritation, myalgia, gastrointestinal discomfort and decrease of serum calcium level. Recently, Maxmarvil^® was developed as an enteric-coated tablet containing alendronate (5 mg) and calcitriol (0.5 μg) to minimize these side effects of alendronate. In the present study, we evaluated the pharmacokinetic profile and examined the incidence of unfavorable effects after oral administration of Maxmarvil^® in Korean healthy postmenopausal women without a previous history of fracture. In the in vitro dissolution test, alendronate was not released from Maxmarvil^® in pH 1.2 phosphate buffer solution but released in pH 6.0 and 6.8 phosphate buffer solutions and completely dissolved in 30 min. After oral administration of Maxmarvil^®, three out of 18 (16.7 %) women showed mild adverse effects; two myalgia and one upper gastrointestinal discomfort without heartburn. Most of these complaints disappeared during the study without additional treatment. The peak (U _max) and the average (U _ave) urinary excretion rate of alendronate and the time to reach U _max (T _max) were 2.94 μg/h, 0.901 μg/h and 6.77 h, respectively. The total cumulative urinary excretion of alendronate (Ae_0–24 h) was 21.6 μg (0.432 % of oral alendornate), which was similar to the reported values. Taken together, enteric-coated Maxmarvil^® is less harmful for the esophagus and gastrointestinal mucosa, shows the same pharmacokinetic profile to conventional alendronate (70 mg) and improves the tolerability of medication in clinical practice.     

Enhancement of solubility and dissolution of cilostazol by solid dispersion technique

Cilostazol is practically insoluble in water and thus results in poor bioavailability. Only a few approaches have been reported for improving the bioavailability of cilostazol. Solid dispersion technique via solvent evaporation method was applied to improve the solubility and dissolution of cilostazol. Various polymers, mixture of polymer and surfactant, and mixture of polymers were screened as a carrier for the solid dispersion. Solubility of cilostazol was improved significantly when Eudragit^® L100 was used as a carrier. However, addition of surfactant to Eudragit^® L100 decreased the solubility slightly. Whereas, the mixture of Eudragit^® L100 and Eudragit^® S100 as a carrier system further increased the solubility. Based on the highest solubility obtained among the carriers screened, 1:1 ratio of Eudragit^® L100 and Eudragit^® S100 was selected as a carrier, and drug to carrier ratio was optimized to 1:5. Differential scanning calorimetry and X-ray diffraction studies showed that the characteristic peak of cilostazol disappeared in the solid dispersion, indicating that cilostazol existed in amorphous form in this formulation. Spray drying method was superior to vacuum drying method in terms of dissolution rate. Meanwhile, it was observed that the disintegration rate and the concentration of polymer had some effect on the crystallization of cilostazol in dissolution medium. Tablet formulation containing spray dried solid dispersion showed significant improvement in dissolution as compared to the commercial tablet.     

Human skin in vitro permeation of bentazon and isoproturon formulations with or without protective clothing suit

Skin exposures to chemicals may lead, through percutaneous permeation, to a significant increase in systemic circulation. Skin is the primary route of entry during some occupational activities, especially in agriculture. To reduce skin exposures, the use of personal protective equipment (PPE) is recommended. PPE efficiency is characterized as the time until products permeate through material (lag time, T_lag). Both skin and PPE permeations are assessed using similar in vitro methods; the diffusion cell system. Flow-through diffusion cells were used in this study to assess the permeation of two herbicides, bentazon and isoproturon, as well as four related commercial formulations (Basagran^®, Basamais^®, Arelon^® and Matara^®). Permeation was measured through fresh excised human skin, protective clothing suits (suits) (Microchem^® 3000, AgriSafe Pro^®, Proshield^® and Microgard^® 2000 Plus Green), and a combination of skin and suits. Both herbicides, tested by itself or as an active ingredient in formulations, permeated readily through human skin and tested suits (T_lag < 2 h). High permeation coefficients were obtained regardless of formulations or tested membranes, except for Microchem^® 3000. Short T_lag, were observed even when skin was covered with suits, except for Microchem^® 3000. Kp values tended to decrease when suits covered the skin (except when Arelon^® was applied to skin covered with AgriSafe Pro and Microgard^® 2000), suggesting that T_lag alone is insufficient in characterizing suits. To better estimate human skin permeations, in vitro experiments should not only use human skin but also consider the intended use of the suit, i.e., the active ingredient concentrations and type of formulations, which significantly affect skin permeation.     

Effect of Particle Size and Polymer Loading on Dissolution Behavior of Amorphous Griseofulvin Powder

The effect of particle size on the dissolution behavior of the particles of amorphous solid dispersions (ASDs) of griseofulvin (GF), with 0%-50% Kollidon^® VA 64 as a crystallization inhibitor is investigated. Both the final dissolved GF concentration and the dissolution rate of GF ASDs were found to be inversely proportional to the particle size. The solution concentrations for the smallest (45-75 μm) size group with different polymer loadings were significantly higher than those for the largest (250-355 μm) group regardless of the initial GF amount. Specifically, the dissolution rate of GF ASDs with 50% polymer loading for the finest group was 2.7 times higher than for the largest group under supersaturating conditions. The rates of dissolution and recrystallization were assessed through surface concentration (C_s) and Avrami recrystallization rate kinetics, where the solid-state recrystallization was confirmed using Raman spectroscopy. Outcomes indicated that particle size reduction enhanced ASD drug loading by reducing the amount of polymer necessary as finest size ASDs initially dissolve faster, negating their higher recrystallization rate. Kollidon® VA 64 at 30% loading was sufficient to inhibit the GF recrystallization. Overall, the combination of particle size reduction and recrystallization inhibition is effective for improved dissolution behavior of GF ASDs.     

Chemical properties and toxicity of soils contaminated by mining activity

This research is aimed at assessing the total content and soluble forms of metals (zinc, lead and cadmium) and toxicity of soils subjected to strong human pressure associated with mining of zinc and lead ores. The research area lay in the neighbourhood of the Boles?aw Mine and Metallurgical Plant in Bukowno (Poland). The study obtained total cadmium concentration between 0.29 and 51.91 mg, zinc between 7.90 and 3,614 mg, and that of lead between 28.4 and 6844 mg kg^?1 of soil d.m. The solubility of the heavy metals in 1 mol dm^?3 NH₄NO₃ was 1–49 % for zinc, 5–45 % for cadmium, and <1–10 % for lead. In 1 mol HCl dm^?3, the solubility of the studied metals was much higher and obtained values depending on the collection site, from 45 to 92 % for zinc, from 74 to 99 %, and from 79 to 99 % for lead. The lower solubility of the heavy metals in 1 mol dm^?3 NH₄NO₃ than 1 mol HCl dm^?3 is connected with that, the ammonium nitrate has low extraction power, and it is used in determining the bioavailable (active) form of heavy metals. Toxicity assessment of the soil samples was performed using two tests, Phytotoxkit and Microtox^®. Germination index values were between 22 and 75 % for Sinapis alba, between 28 and 100 % for Lepidium sativum, and between 10 and 28 % for Sorghum saccharatum. Depending on the studied soil sample, Vibrio fischeri luminescence inhibition was 20–96 %. The sensitivity of the test organisms formed the following series: S. saccharatum > S. alba = V. fischeri > L. sativum. Significant positive correlations (p ≤ 0.05) of the total and soluble contents of the metals with luminescence inhibition in V. fischeri and root growth inhibition in S. saccharatum were found. The general trend observed was an increase in metal toxicity measured by the biotest with increasing available metal contents in soils. All the soil samples were classified into toxicity class III, which means that they are toxic and present severe danger. Biotest are a good complement to chemical analyses in the assessment of quality of soils as well as in properly managing them.     

Comparison on physical property,dissolution and disintegration of four launched orally disintegration film (ODF) products for erectile dysfunction

Commercially available orally disintegration films (ODF) for erectile dysfunction were Viagra L^® 50 and 100 mg by Pfizer Pharmaceuticals Korea Ltd., and Mvix S^® 50 and 100 mg by SK Chemicals Co. The comparative studies of physical property, disintegration and dissolution time of four ODFs were carried out to evaluate film formulation. For film physical property, thickness and weight uniformity, tensile strength, dissolving pH, hygroscopicity, morphology, flexibility and polymeric characteristics were investigated. In vitro disintegration studies were implemented by six methods. Conventional disintegration method was carried out using USP disintegration apparatus. One side disintegration method and both side disintegration method were performed by using shaking water bath. Slide frame disintegration method was conducted by contact angle measurement. Mouth disintegration method was performed by using two different mediums. One medium was α-amylase free medium, another was add α-amylase. In vitro dissolution studies were carried out using pH 2.0 HCl and pH 6.8 PBS. The results were validated statistically. Film thickness of Mvix S^® 50 and 100 mg was thinner than that of Viagra L 50 and 100 mg, respectively. Film tensile strength of Mvix S^® 50 mg and 100 mg was much higher than that of Viagra L 50 and 100 mg. However, Viagra L^® 50 and 100 mg were more flexible so that it is easier to carry and store. High hygroscopicity and high porosity in Viagra L^® could contribute to disintegrate film quickly. In six kinds of  disintegration studies, both Viagra L^® 50 and 100 mg showed not only muche faster disintegration time but also much faster dissolution rate.     

Toxicity of hydroxylated polychlorinated biphenyls (HO-PCBs) using the bioluminescent assay Microtox<Superscript>®</Superscript>

Hydroxylated polychlorinated biphenyls (HO-PCBs) are toxic contaminants which are produced in the environment by biological or abiotic oxidation of PCBs. The toxicity of a suite of 23 mono-hydroxylated derivatives of PCBs and 12 parent PCBs was determined using the bacterial bioluminescent assay Microtox^®. All HO-PCBs tested exhibited higher toxicity than the corresponding parent PCB, with effect concentration 50 % (EC₅₀) ranging from 0.07 to 133 mg L^?1. The highest toxicities were recorded with 4-hydroxylated derivatives of di-chlorinated biphenyls (EC₅₀ = 0.07–0.36 mg L^?1) and 2-hydroxylated derivatives of tri-chlorinated biphenyls carrying a chlorine substituent on the phenolic ring (EC₅₀ = 0.34–0.48 mg L^?1). The toxicity of HO-PCBs generally decreased when the degree of chlorination increased. Consistently with this observation, a significant positive correlation was measured between toxicity (measured by EC₅₀) and octanol–water partition coefficient (pK _ow) for the HO-PCBs under study (Pearson’s correlation coefficient, r = 0.74), which may be explained by the lower solubility and bioavailability generally associated with higher hydrophobicity. This study is the first one which assessed the toxicity of a suite of PCBs and HO-PCBs using the bioluminescent assay Microtox^®, showing an inverse correlation between toxicity and hydrophobicity.     

Mechanistic Investigation of Pluronic® Based Nano-crystalline Drug-polymer Solid Dispersions

Purpose

To understand the mechanism of nano-crystalline drug formation in Pluronic® (i.e., poly(ethylene oxide-block-propylene oxide) triblock copolymers) based drug-polymer solid dispersions.

Materials and Methods

Four polymers, Pluronic® F127, F108, F68 and PEG 8000, which have different poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) ratio and chain length, were co-spray dried with BMS-347070, a COX-2 inhibitor, to form 50/50 (w/w) drug-polymer solid dispersions. The solid dispersions were analyzed by powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), and hot-stage microscopy. Average size of drug crystallites in different polymers was calculated by the Scherrer equation based on peak-broadening effect in PXRD. Two other drug compounds, BMS-A and BMS-B, were also spray dried with Pluronic® F127, and the solid dispersions were analyzed by PXRD and mDSC.

Results

The average size of BMS-347070 crystallites in PEG 8000, F127, F108 and F68 polymers was 69, 80, 98 and 136 nm, respectively, and the degree of BMS-347070 crystallinity is the lowest in PEG 8000. Hot-stage microscopy showed that 50/50 drug-polymer dispersions crystallized in a two-step process: a portion of the polymer crystallizes first (Step 1), followed by crystallization of drug and remaining polymer (Step 2). The T _g value of the BMS-347070/Pluronic® dispersions after Step 1 (i.e., T _g1) was measured and/or calculated to be 15–26°C, and that of BMS-347070/PEG 8000 was 60°C. Solid dispersions of BMS-A and BMS-B in Pluronic® F127 have T _g1 of 72 and 3°C, respectively; and PXRD showed BMS-A remained amorphous after ～3 weeks under ambient condition, while BMS-B crystallized in F127 with an average crystallite size of 143 nm.

Conclusions

The size of drug crystallites in the drug-polymer solid dispersions is independent of polymer topology, but is caused kinetically by a combined effect of nucleation rate and crystal growth rate. When drug-Pluronic® solid dispersions crystallize at room temperature, that is close to the T _g1 of the systems, a fast nucleation rate and a relatively slow crystal growth rate of the drug synergistically produced small crystallite size. While the much higher T _g1 value of drug-PEG 8000 led to a slower nucleation rate and an even slower crystal growth rate at room temperature, therefore, small crystallite size and low drug crystallinity were observed. Results from BMS-A/Pluronic® and BMS-B/Pluronic® systems confirmed this kinetic theory.

     

Preparation and characterisation of lornoxicam solid dispersion systems using hot melt extrusion technique

The aim of the research study was to investigate the ability of Soluplus^® and surfactant individually as well as in combination to improve the solubility, subsequently the dissolution profile of lornoxicam (LORX). A laboratory size single screw rotating extruder with temperature and speed control parameters employed during hot melt extrusion (HME) processing of LORX along with polymer-surfactant blends. Soluplus^® used as primary solubilizing agent for preparing solid dispersion (SD). Along with Soluplus^® different concentrations of surfactants such as PEG 400, Lutrol F127, Lutrol F68 were used to solve the permeability issues related to LORX. Encapsulation of LORX particles inside the molten matrix of polymer-excipient blend was confirmed by DSC, XRD and FT-IR. Drug excipient microscopic interaction was further confirmed by scanning electron microscopy (SEM). Depending upon the ratio of the polymer and surfactants used, the solubility of the hot melt extruded LORX was improved and found to be in the range 35–86 μg/ml (actual aqueous solubility of LORX was found to be 0.0083 μg/ml). Dissolution profile of the extruded SD was improved and was found to be in the range of 98–104 % within 20 min (actual dissolution profile of LORX was found to be 8 % at the end of 1 h). SEM and Raman images suggest the formation of amorphous dispersion systems. SD was subjected to stability studies as per ICH guidelines and found to be stable after 6 months when analyzed by HPLC. SD prepared from HME significantly improves the solubility and dissolution profile of LORX—a BCS class II drug.     

A time-released osmotic pump fabricated by compression-coated method: Formulation screen,mechanism research and pharmacokinetic study

In this investigation, time-released monolithic osmotic pump (TMOP) tablets containing diltiazem hydrochloride (DIL) were prepared on the basis of osmotic pumping mechanism. The developed dosage forms were coated by Kollidon^®SR-Polyethylene Glycol (PEG) mixtures via compression-coated technology instead of spray-coating method to form the outer membrane. For more efficient formulation screening, a three-factor five-level central composite design (CCD) was introduced to explore the optimal TMOP formulation during the experiments. The in vitro tests showed that the optimized formulation of DIL-loaded TMOP had a lag time of 4 h and a following 20-h drug release at an approximate zero-order rate. Moreover, the release mechanism was proven based on osmotic pressure and its profile could be well simulated by a dynamic equation. After oral administration by beagle dogs, the comparison of parameters with the TMOP tablets and reference preparations show no significant differences for C_max (111.56 ± 20.42, 128.38 ± 29.46 ng/ml) and AUC_0-48 h (1654.97 ± 283.77, 1625.10 ± 313.58 ng h/ml) but show significant differences for T_max (13.00 ± 1.16, 4.00 ± 0.82 h). These pharmacokinetic parameters were consistent with the dissolution tests that the TMOP tablets had turned out to prolong the lag time of DIL release.     

Localized rosuvastatin via implantable bioerodible sponge and its potential role in augmenting bone healing and regeneration

Objective: Statins proved potential bone healing properties. Rosuvastatin is a synthetic, hydrophilic, potent and highly efficacious statin. In the current work, an attempt was investigated to develop, evaluate various bioerodible composite sponges enclosing rosuvastatin and explore their potential in augmenting bone healing and regeneration.

Method: Twelve lyophilized sponge formulae were prepared adapting a 4¹.3¹ full factorial design. Xanthan gum, polycarbophil, Carbopol® and sodium alginate were investigated as anionic polymers, each at three chitosan:anionic polymer ratios (1:3, 1:1, 3:1). The formula of choice was implanted in fractured rat femora.

Results: Visual and microscopic examination showed flexible homogenous porous structures with considerable bending ability. Polyelectrolyte complex formation was proved by DSC and FT-IR for all chitosan/anionic combinations except with xanthan gum where chitosan probably bound to the drug rather than xanthan gum. Statistical analysis proved that anionic polymer type and chitosan: polymer ratio, as well as, their interactions, exhibited significant effects on the release parameters at p?≤?0.05. The optimum chitosan/anionic polymer complexation ratios were 3:1 for polycarbophil and 1:1 for Carbopol and alginate. The release at these ratios followed Fiction diffusion while other ratios had anomalous diffusion. Imwitor® 900K and HPMC K100M were added as release retarardants for further release optimization. The formula of choice was implanted in fractured rat femora. Histopathological examination revealed advanced stages of healing in treated femora compared to control ones.

Conclusion: Biodegradable sponges for local rosuvastatin delivery proved significantly enhanced wound healing and regeneration properties to fractured bones.     

Properties of theophylline tablets dry powder coated with Eudragit® E PO and Eudragit® L 100-55

The aim of the present study was to investigate the influence of Eudragit^® E PO on the drug release mechanism of Eudragit^® L 100-55 film coatings applied to theophylline tablets by a dry powder coating technique. The process was entirely liquid-free. Calculation of the Flory-Huggins interaction parameter based on solubility parameters suggested immiscibility of the two copolymers. MDSC thermograms were characterized by two glass transitions for the investigated Eudragit^® E PO/Eudragit^® L 100-55 ratios and confirmed incomplete miscibility of the copolymers at processing conditions. FT-IR analysis was employed to study binding interactions of the polymers. Due to the higher affinity of the plasticizer, triethyl citrate, for Eudragit^® E PO compared to Eudragit^® L 100-55, redistribution of the plasticizer was observed during the curing phase of the process. Plasticizer migration also affected the initial phase of drug release from powder-coated theophylline tablets that were stored for four weeks. Drug release from powder-coated tablets was dependent on the polymer blend ratio, coating thickness, and the pH of the dissolution medium. A broad range of pH dependent theophylline release profiles were obtained as a function of the polymer blend ratio. The particle size of the coating powder influenced the microstructure of the film coating.     

Development and characterization of extended release Kollidon SR mini-matrices prepared by hot-melt extrusion

Kollidon^® SR as a drug carrier and two model drugs with two different melting points, ibuprofen and theophylline, were studied by hot-melt extrusion. Powder mixtures containing Kollidon^® SR were extruded using a twin-screw extruder at temperatures 70 and 80 °C for ibuprofen and 80 and 90 °C for theophylline. The glass transition temperature (T_g) and maximum torque were inversely related to ibuprofen concentrations, indicating its plasticizing effect. The results of differential scanning calorimetry (DSC) and X-ray diffraction analysis showed that ibuprofen remained in an amorphous or dissolved state in the extrudates containing drug up to 35%, whereas theophylline was dispersed in the polymer matrix. The increase in amounts of ibuprofen or theophylline in the hot-melt extrudates resulted in the increase in the drug release rates. Theophylline release rate in hot-melt extruded matrices decreased as the extrusion temperature increased. In contrast, a higher processing temperature caused the higher ibuprofen release. This was a clear indication of the plasticizing effect of ibuprofen on Kollidon^® SR and a result from water uptake. Theophylline release rate from hot-melt extrudates decreased with increasing triethyl citrate (TEC) level because of the formation of a denser matrix. By adding of Klucel^® LF as a water-soluble additive to the hot-melt extruded matrices, an increase in ibuprofen and theophylline release rates was obtained.     

Paclitaxel Prodrugs with Sustained Release and High Solubility in Poly(ethylene glycol)-b-poly(ε-caprolactone) Micelle Nanocarriers: Pharmacokinetic Disposition, Tolerability, and Cytotoxicity

Purpose

Develop a Cremophor® and solvent free formulation of paclitaxel using amphiphilic block co-polymer micelles of poly(ethylene glycol)-b-poly(?-caprolactone) (PEG-b-PCL) and characterize their release, solubility, cytotoxicity, tolerability, and disposition.

Methods

Hydrophobic prodrugs of paclitaxel were synthesized via DCC/DMAP or anhydride chemistry to overcome the poor loading (<1% w/w) of paclitaxel in micelles of PEG-b-PCL. Micelles were prepared by a co-solvent extraction technique. A micellar formulation of paclitaxel prodrug (PAX7′C₆) was dosed intravenously to rats (10 mg/kg) and compared to Taxol® (paclitaxel in CrEL:EtOH) and PAX7′C₆ in CrEL:EtOH as controls at the same dose. Pharmacokinetic parameters and tissue distribution were assessed.

Results

Paclitaxel prodrugs had solubilities >5 mg/ml in PEG-b-PCL micelles. Resulting PEG-b-PCL micelles contained 17-22% w/w prodrug and were less than 50 nm in diameter. PEG-b-PCL micelles released paclitaxel prodrugs over several days, t_1/2>3 d. Only the 7′derivative of paclitaxel with the shortest acylchain 7′hexonoate (PAX7′C₆) maintained cytotoxic activity similar to unmodified paclitaxel. PAX7′C₆ micelles demonstrated an increase in area under the curve, half-life, and mean residence time while total clearance and volume of distribution decreased.

Conclusions

Paclitaxel prodrugs in PEG-b-PCL micelle nanocarriers augment the disposition and increase tolerability making further studies on tumor efficacy warranted.     

Physicochemical Characterization of Felodipine-Kollidon VA64 Amorphous Solid Dispersions Prepared by Hot-Melt Extrusion

To improve the dissolution and hence the oral bioavailability, amorphous felodipine (FEL) solid dispersions (SDs) with Kollidon® VA 64 (PVP/VA) were prepared. Hot-melt extrusion was employed with an extruding temperature below the melting point (T_m) of FEL. X-ray powder diffraction (XRPD) and ¹³C CP/MAS nuclear magnetic resonance (NMR) measurements show that the extrudates are amorphous. The intermolecular interaction between FEL and PVP/VA in SDs was investigated by Fourier transform infrared spectroscopy, ¹⁵N CP/MAS NMR, and ¹H high-resolution MAS NMR. Furthermore, a single glass transition temperature (T_g) was detected by differential scanning calorimetry in addition to a single ¹H T₁ or T_1rho relaxation time detected by ¹³C NMR signals. These results confirm that the extru-dates contain FEL dispersed into the polymer matrix at a molecular level with no detectable phase separation. This molecular-scale mixing results in a significantly faster dissolution rate compared with the pure crystalline FEL. Additionally, the molecular-scale mixing prevents the amorphous drug from recrystallizing even after being stored at 40°C/75% Relative Humidity for 2 months.