Charles Michael Buchanan

Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: Itraconazole

The aim of the present series of experiments was to improve the solubility and dissolution/precipitation behaviour of a poorly soluble, weakly basic drug, using itraconazole as a case example. Binary inclusion complexes of itraconazole with two commonly used cyclodextrin derivatives and a recently introduced cyclodextrin derivative were prepared. Their solubility and dissolution behaviour was compared with that of the pure drug and the marketed formulation Sporanox®. Ternary complexes were prepared by addition of Soluplus®, a new highly water soluble polymer, during the formation of the itraconazole/cyclodextrin complex. A solid dispersion made of itraconazole and Soluplus® was also studied as a control. Solid state analysis was performed for all formulations and for pure itraconazole using powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicated that with all formulation approaches, the aqueous solubility of itraconazole formed with hydroxypropyl-β-cyclodextrin (HP-β-CD) or hydroxybutenyl-β-cyclodextrin (HBen-β-CD) and Soluplus® proved to be the most favourable formulation approaches. Whereas the marketed formulation and the pure drug showed very poor dissolution, both of these ternary inclusion complexes resulted in fast and extensive release of itraconazole in all test media. Using the results of the dissolution experiments, a newly developed physiologically based pharmacokinetic (PBPK) in silico model was applied to compare the in vivo behaviour of Sporanox® with the predicted performance of the most promising ternary complexes from the in vitro studies. The PBPK modelling predicted that the bioavailability of itraconazole is likely to be increased after oral administration of ternary complex formulations, especially when itraconazole is formulated as a ternary complex comprising HP-β-CD or HBen-β-CD and Soluplus®.

Inhibiting efflux with novel non-ionic surfactants: Rational design based on vitamin E TPGS.

Tocopheryl Polyethylene Glycol Succinate 1000 (TPGS 1000) can inhibit P-glycoprotein (P-gp); TPGS 1000 was not originally designed to inhibit an efflux pump. Recent work from our laboratories demonstrated that TPGS activity has a rational PEG chain length dependency. In other recent work, inhibition mechanism was investigated and appears to be specific to the ATPase providing P-gp energy. Based on these observations, we commenced rational surface-active design. The current work summarizes new materials tested in a validated Caco-2 cell monolayer model; rhodamine 123 (10microM) was used as the P-gp substrate. These results demonstrate that one may logically construct non-ionic surfactants with enhanced propensity to inhibit in vitro efflux. One new surfactant based inhibitor, Tocopheryl Polypropylene Glycol Succinate 1000 (TPPG 1000), approached cyclosporine (CsA) in its in vitro efflux inhibitory potency. Subsequently, TPPG 1000 was tested for its ability to enhance the bioavailability of raloxifene - an established P-gp substrate -in fasted male rats. Animals dosed with raloxifene and TPPG 1000 experienced an increase in raloxifene oral bioavailability versus a control group which received no inhibitor. These preliminary results demonstrate that one may prepare TPGS analogs that possess enhanced inhibitory potency in vitro and in vivo.

The influence of degree of substitution on blend miscibility and biodegradation of cellulose acetate blends

In this account, we report our findings on blends of cellulose acetate having a degree of substitution (DS) of 2.49 (CA2.5) with a cellulose acetate having a DS of 2.06 (CA2.0). This blend system was examined over the composition range of 0–100% CA2.0 employing both solvent casting of films (no plasticizer) and thermal processing (melt-compressed films and injection molding) using poly(ethylene glycol) as a common plasticizer. All thermally processed blends were optically clear and showed no loss in optical quality after storage for several months. Thermal analysis and measurement of physical properties indicate that blends in the middle composition range are partially miscible, while those at the ends of the composition range are miscible. We suggest that the miscibility of these cellulose acetate blends is influenced primarily by the monomer composition of the copolymers. Bench-scale simulated municipal composting confirmed the biodestructability of these blends and indicated that incorporation of a plasticizer accelerated the composting rates of the blends.In vitro aerobic biodegradation testing involving radiochemical labeling conclusively demonstrated that both the lower DS CA2.0 and the plasticizer significantly enhanced the biodegradation of the more highly substituted CA2.5.

Improving glyburide solubility and dissolution by complexation with hydroxybutenyl‐β‐cyclodextrin

Objectives Glyburide, an important drug for type 2 diabetes, has extremely poor aqueous solubility and resulting low bioavailability. This study describes the ability of hydroxybutenyl‐β‐cyclodextrin (HBenBCD) to form complexes with glyburide, with enhanced solubility and dissolution rate in vitro.

Biodegradable Blends of Cellulose Acetate and Starch: Production and Properties

Abstract Blends of cellulose acetate (2.5 degree of substitution) and starch were melt processed and evaluated for mechanical properties, biodegradability during composting, and marine and soil toxicity. Formulations containing, on a weight basis, 57% cellulose acetate (CA), 25% corn starch (St) and 19% propylene glycol (PG) had mechanical properties similar to polystyrene. Increasing plasticizer or starch content lowered tensile strength. Simulated municipal composting of cellulose acetate alone showed losses of 2−3 and 90% dry weight after 30 and 90 days, respectively. CA/St/PG blends in both soil burial and composting experiments indicate that propylene glycol and starch are degraded first. Extended incubations are required to detect losses from cellulose acetate. Marine toxicity tests using polychaete worms and mussels showed no toxicity of cellulose acetate or starch. High doses had an adverse effect due to oxygen depletion in the marine water due to rapid biodegradation of the polymers. Preliminary ...

Synthesis and characterization of water-soluble hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins).

We have examined the synthesis of hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins) and the ability of these cyclodextrin ethers to form guest-host complexes with guest molecules. The hydroxybutenyl cyclodextrin ethers were prepared by a base-catalyzed reaction of 3,4-epoxy-1-butene with the parent cyclodextrins in an aqueous medium. Reaction byproducts were removed by nanofiltration before the hydroxybutenyl cyclodextrins were isolated by co-evaporation of water-EtOH. Hydroxybutenyl cyclodextrins containing no unsubstituted parent cyclodextrin typically have a degree of substitution of 2-4 and a molar substitution of 4-7. These hydroxybutenyl cyclodextrins are randomly substituted, amorphous solids. The hydroxybutenyl cyclodextrin ethers were found to be highly water soluble. Complexes of HBen-beta-CD with glibenclamide and ibuprofen were prepared and isolated. In both cases, the guest content of the complexes was large, and a significant increase in the solubility of the free drug was observed. Dissolution of the complexes in pH 1.4 water was very rapid, and significant increases in the solubility of the free drugs were observed. Significantly, after reaching equilibrium concentration, a decrease in the drug concentration over time was not observed.

Biodegradation of Cellulose Esters: Composting of Cellulose Ester-Diluent Mixtures

Abstract A number of polymers such as polylactic acid (PLA), polycaprolactone (PCL), polyhydroxybutyrate (PHB), Matter-Bi, cellulose acetate (CA) with different degrees of substitution (DS), and cellulose ester–diluent mixtures have been evaluated in a static, bench-scale simulated municipal compost environment. Of the polymers evaluated, cellulose acetate (DS > 2.2), poly(hydroxybutyrate-co-valerate) (PHBV), and PCL exhibited the fastest composting rates, completely disappearing after 14 days. Optically clear resins were prepared from CA (DS = 2.06) and triethylcitrate (TEC) by thermal compounding, and the resins were converted to compression-molded film and injection-molded bars for composting studies. A series of miscible blends consisting of cellulose acetate propionate (CAP) and poly(ethylene glutarate) (PEG) or poly(-tetramethylene glutarate) (PTG) were also prepared and evaluated in composting. In addition to measured weight loss, samples were removed from the compost at different intervals and eva...

Pharmacokinetics of letrozole in male and female rats: influence of complexation with hydroxybutenyl-β-cyclodextrin

Cyclodextrins (CDs) are one of the most successful solutions to the problem of poor drug solubility. In this study, we examined the in‐vitro effects of three CDs on the solubility of letrozole, a breast cancer drug that is practically insoluble in water. The most promising, hydroxybutenyl‐β‐cyclodextrin (HBenβCD), was used for in‐vivo studies in male and female Sprague‐Dawley rats. Letrozole is a drug with dramatic gender‐based differences in pharmacokinetics. For example, the terminal half‐life (t1/2) of letrozole following intravenous administration in male rats was 11.5 ± 1.8 h (n = 3), while in female rats it was 42.3 ± 2.9 h (n = 3). HBenβCD increased the solubility and enhanced the dissolution rate of letrozole. Complexation of letrozole with HBenβCD improved oral absorption in male rats and maximized absorption in female rats. Regardless of gender, the presence of HBenβCD in the formulation increased the in‐vivo rate of absorption. When administered in a capsule formulation with letrozole, HBenβCD resulted in a higher Cmax (61% in male rats, 42% in female), shorter Tmax values (8.4 to 6.3 h in male, 16.4 h to 5.4 h in female) and increased absolute oral bioavailability (46 ± 2 vs 38 ± 3 in male, 101 ± 3 vs 95 ± 2 in female). Thus, solubility limits both rate and extent of letrozole absorption in male rats, but limits only the rate of absorption in female rats.

Composting of miscible cellulose acetate propionate-aliphatic polyester blends

A series of miscible blends consisting of cellulose acetate propionate (CAP) and poly(ethylene glutarate) (PEG) or poly(tetramethylene glutarate) (PTG) were evaluated in a static bench-scale simulated municipal compost environment. Samples were removed from the compost at different intervals, and the weight loss was determined before evaluation by gel permeation chromatography, scanning electron microscopy, and1H NMR. The type of polyester (PEG versus PTG) in the blend made no difference in composting rates. At fixed CAP degree of substitution (DS), when the content of polyester in the blend was increased, the rate of composting and the weight loss due to composting increased. When the CAP was highly substituted, little degradation was observed within 30 days and almost all of the weight loss was ascribed to loss of polyester. Although the polyester was still observed to degrade faster, when the CAP DS was below approximately 2.0, both components are observed to degrade. The data suggests that initial degradation of the polyester is by chemical hydrolysis and the rate of this hydrolysis is very dependent upon the temperature profile of the compost and upon the DS of the CAP.

The relationship between blend miscibility and biodegradation of cellulose acetate and poly(ethylene Succmate) blends

The miscibility of cellulose acetate (CA; degree of substitution = 2.5) and poly(ethylene succinate) (PES) has been investigated using a variety of thermal techniques and by solid-state carbon13 NMR spectroscopy. The blends containing greater than ca. 70% CA were found to be miscible. In the case of blends containing less than ca. 70% CA, a combination of thermal and NMR analyses suggests that these blends are not fully miscible on a 2.5- to 5-nm scale. On the scale which can be probed by dynamic mechanical thermal analysis (15 nm), the low-percentage CA blends exhibit “significant local concentration fluctuations≓. Investigation of the biodegradation of the blend components and of the blends revealed that PES degraded relatively rapidly and that CA degraded slowly. The blends degraded at a rate essentially identical to that of CA. Miscibility (75% CA blend) or crystallization of PES (30% CA blend) had no significant effect. These data suggest that a significant mode of degradation ofPES during composting involves chemical hydrolysis of the polymer followed by biological assimilation of monomers. Degradation of the blends is initiated in the amorphous phase. Because CA is a significant component of the amorphous phase, a small amount of CA significantly impacts the biodegradation rates of the blends.