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A sensitive and selective LC-MS/MS method was developed and validated for the quantitation of a novel Gα i 2 inhibitor, GT-14, in rat plasma using a SCIEX 6500+ triple QUAD LC-MS system equipped with an ExionLC UHPLC unit. GT-14 (m/z 265.2 → 134.1) and griseofulvin (Internal Standard, IS) (m/z 353.1 → 285.1) were detected in a positive mode by electrospray ionization (ESI) using multiple reaction monitoring (MRM). The assay was linear in the concentration range of 0.78-1000 ng/mL in rat plasma. Both accuracy and precision values were within the acceptance criteria of ±15 %, as established by FDA guidance. The matrix effect was negligible from plasma, with signal percentages of 98.5-106.9 %. The mean recovery was 104.5 %, indicating complete extraction of GT-14 from plasma. GT-14 was found to be stable under different experimental conditions. The validated method was successfully applied to evaluate plasma protein binding and in vivo pharmacokinetics of GT-14 in rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Production of submicron particles (0.1-1 μm) has been identified by the pharmaceutical industry as a key technology to enhance the bioavailability of poorly water-soluble drugs. However, nanosuspensions derived from commonly applied wet milling suffer from long-term stability issues, making further downstream processing necessary. In previous works, the formulation as a long-term stable solid crystalline suspension (SCS) was introduced, for which the crystalline drug is ground in a (molten) hydrophilic carrier matrix. The model formulation of the antimycotic Griseofulvin and the sugar alcohol Xylitol was reused for comparative purposes. Due to process limitations regarding the degree of comminution, the present work demonstrates the application of fine grinding in the framework of SCS manufacturing. A custom-built mill with annular gap geometry successfully yielded particles in the targeted submicron range. A process optimization study lead to improved energy utilization during grinding, which reduced the necessary grinding time and, thereby, the thermal exposition of the drug. Investigation of solid-state properties of the SCS, via differential scanning calorimetry and x-ray powder diffraction, showed no alteration even for extended grinding times. In dissolution experiments, the melt-milled SCS outperformed its predecessors, although mostly agglomerates were found by SEM imaging in the solidified product. In conclusion, melt milling is a valuable tool to overcome low aqueous solubility., (Copyright © 2020. Published by Elsevier B.V.)

Griseofulvin is a commonly used antifungal agent which is administered per oral (p.o.). The oral administration route, however, shows rather low bioavailability. The aim of this study was to improve the bioavailability and to evaluate and interpret the pharmacokinetic profiles after subcutaneous (s.c.) administration of crystalline griseofulvin nano- and microsuspensions. Both formulations were injected at 5 and 500 µmol/kg to rats. For the lower concentration, the profiles were similar after s.c. injection but extended as compared to p.o. administration. For the higher concentration, injection of microsuspension resulted in a maintained plateau whereas the nanosuspension resulted in an obvious peak exposure followed by extended elimination. Both suspensions showed improved exposure with dose. The differences in peak exposures between nano- and microparticles, at the high dose, were mainly ascribed to differences in dissolution rate, experimentally determined in vitro, using spectroscopic methods. The extended appearance in the circulation may depend on the physicochemical properties of the compound and the physiological conditions at the injection site. The bioavailability was improved for both formulations compared with an orally administered nanosuspension, suggesting the s.c. route to be a preferred administration option for compounds with low oral bioavailability regarding both overall exposure and extended efficacy.

The objective of the study was to evaluate the pharmacokinetic profile after different subcutaneous (s.c.) administrations of nano- and microparticle suspensions of griseofulvin to mice. The solubility of the compound was determined as approximately 40 µM, at 37 °C, independent of particle size, stabilizer mixtures investigated and solvent used for measurement. The present in vivo studies demonstrated non-linear absorption kinetics (in peak concentration, C max ) for griseofulvin up to 50 mg/kg after s.c. administration of nanocrystals and microsuspensions but linear increase in area under the curve (AUC) at all occasions investigated. C max was higher for smaller particles administered. Both investigated suspensions, at 10 and 50 mg/kg, showed significantly sustained plasma profiles compared to i.v. and p.o. administration. Administering 10 and 50 mg/kg of griseofulvin nanocrystals as 10 mL/kg, instead of 2.5 mL/kg, improved C max but AUC was unchanged. The present study showed that the bioavailability of griseofulvin, administered as nano- and microparticles, increased significantly after s.c. administration (60-100%) compared with p.o. dosing (17%). The drug is currently orally administered and clearly exposed to a significant first pass metabolism, i.e. an ideal candidate for an alternative administration route, like s.c. injection., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Thylakoid-rich spinach extract is being used as dietary weight-loss supplements in Japan. A recent rat study has suggested that intake of thylakoid-rich spinach extract with dietary oil inhibits dietary fat absorption via binding to bile acids, which promotes excretion of bile acids in feces. While, we confirmed that a serving size of thylakoid-rich spinach extract contains a large amount of calcium (130 mg/5 g). Therefore, using rats, we evaluated whether one-time ingestion of thylakoid-rich spinach extract affects the gastrointestinal absorption of water-insoluble drugs, such as griseofulvin (GF) and indomethacin (IM), or ciprofloxacin (CPFX) that chelate with polyvalent metal cations. Pretreatment of the rats with thylakoid-rich spinach extract (100 or 300 mg/kg) for 15 min prior to oral administration of GF (50 mg/kg) or IM (10 mg/kg) did not significantly alter the pharmacokinetic properties of either drug. Meanwhile, co-administration of thylakoid-rich spinach extract (500 mg/kg) and CPFX (20 mg/kg) significantly reduced the peak plasma concentration and the area under the plasma concentration-time curve of CPFX to 25 and 40%, respectively in rats. In vitro studies demonstrated that when a mixture of thylakoid-rich spinach extract and CPFX was centrifuged, there was a significant reduction in the supernatant concentration of CPFX relative to the control. When the experiment was repeated in the presence of ethylenediaminetetraacetic acid, the concentration of CPFX was unchanged. These results suggest that the intake of thylakoid-rich spinach extract may reduce the absorption of drugs that form a chelate with polyvalent metal cations, such as CPFX.

Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low μM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2'-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

This work investigates whether the solubility of poorly soluble compounds can be improved by using mesoporous magnesium carbonate (MMC) as the drug delivery system. A solvent evaporation method was used to load structurally diverse model drugs (celecoxib, cinnarizine and griseofulvin) into the pores of MMC. The drug-loaded carrier system was then characterized in terms of porosity, crystallinity, and release profiles by a variety of experimental techniques, including X-ray diffraction, nitrogen adsorption analysis, differential scanning calorimetry, infrared spectroscopy, UV absorption spectroscopy, and thermogravimetric analysis. All three drugs were in a non-crystalline state after loading into the pores of MMC. The concentrations of the drugs in solution over time (a measure of the release rates from loaded MMC) were higher than the corresponding concentrations (dissolution rates) of equal amounts of the crystalline drugs. The release rates were five (celecoxib), three (cinnarizine) and two times (griseofulvin) higher than the dissolution rates of their crystalline counterparts. Supersaturation release profiles were also observed; the areas under the concentration-time curves (0-240min) were 25- (celecoxib), 5- (cinnarizine) and 2-fold (griseofulvin) greater than those of the crystalline drugs. Hence, MMC shows promise as a general drug delivery vehicle for increasing the bioavailability of compounds with dissolution rate- or solubility-limited absorption., (Copyright © 2016. Published by Elsevier B.V.)

The aim of this study is to assess pullulan as a novel steric stabilizer during the wet-stirred media milling (WSMM) of griseofulvin, a model poorly water-soluble drug, and as a film-former in the preparation of strip films via casting-drying the wet-milled drug suspensions for dissolution and bioavailability enhancement. To this end, pullulan films, with xanthan gum (XG) as thickening agent and glycerin as plasticizer, were loaded with griseofulvin nanoparticles prepared by WSMM using pullulan in combination with sodium dodecyl sulfate (SDS) as an ionic stabilizer. The effects of drug loading and milling time on the particle size and suspension stability were investigated, as well as XG concentration and casting thickness on film properties and dissolution rate. The nanosuspensions prepared with pullulan-SDS combination were relatively stable over 7 days; hence, this combination was used for the film preparation. All pullulan-based strip films exhibited excellent content uniformity (most <3% RSD) despite containing only 0.3-1.3 mg drug, which was ensured by the use of precursor suspensions with >5000 cP viscosity. USP IV dissolution tests revealed fast/immediate drug release (t80 < 30 min) from films <120 μm thick. Thinner films, films with lower XG loading, or smaller drug particles led to faster drug dissolution, while drug loading had no discernible effect. Overall, these results suggest that pullulan may serve as an acceptable stabilizer for media milling in combination with surfactant as well as a fast-dissolving film former for the fast release of poorly water-soluble drug nanoparticles.

Like other GLP-1 receptor agonists used for treatment of type 2 diabetes, liraglutide delays gastric emptying. In this clinical absorption study, the primary objective was to investigate the effect of liraglutide (at steady state) on the rate and/or extent of gastrointestinal (GI) absorption of concomitantly orally taken drugs from three classes of the Biopharmaceutics Classification System (BCS). To provide a general prediction on liraglutide drug-drug absorption interaction, single-dose pharmacokinetics of drugs representing BCS classes II (low solubility-high permeability; atorvastatin 40 mg and griseofulvin 500 mg), III (high solubility-low permeability; lisinopril 20 mg), and IV (low solubility-low permeability; digoxin 1 mg) were studied in healthy subjects at steady state of liraglutide 1.8 mg, or placebo, in a two-period crossover design. With liraglutide, the oral drugs atorvastatin, lisinopril, and digoxin showed delayed tmax (by ≤2 h) and did not meet the criterion for bioequivalence for Cmax (reduced Cmax by 27-38%); griseofulvin had similar tmax and 37% increased Cmax. Although the prespecified bioequivalence criterion was not met by all drugs, the overall plasma exposure (AUC) of griseofulvin, atorvastatin, lisinopril, and digoxin only exhibited minor changes and was not considered to be of clinical relevance.

The oral bioavailability of a poorly water-soluble drug is often inadequate for the desired therapeutic effect. The bioavailability can be improved by enhancing the physicochemical properties of the drug (e.g., dissolution rate, permeation across the gastrointestinal tract). Other approach include shielding the drug from the gastric metabolism and targeted drug release to obtain optimal drug absorption. In this study, a poorly water-soluble model drug, griseofulvin, was encapsulated as disordered solid dispersions into Eudragit L 100-55 enteric polymer micromatrix particles, which were produced by electrospraying. Similar micromatrix particles were also produced with griseofulvin-loaded thermally oxidized mesoporous silicon (TOPSi) nanoparticles dispersed to the polymer micromatrices. The in vitro drug dissolution at pH 1.2 and 6.8, and permeation at pH 7.4 across Caco-2/HT29 cell monolayers from the micromatrix particles, were investigated. The micromatrix particles were found to be gastro-resistant, while at pH 6.8 the griseofulvin was released very rapidly in a fast-dissolving form. Compared to free griseofulvin, the permeability of encapsulated griseofulvin across the intestinal cell monolayers was greatly improved, particularly for the TOPSi-doped micromatrix particles. The griseofulvin solid dispersions were stable during storage for 6 months at accelerated conditions. Overall, the method developed here could prove to be a useful oral drug delivery solution for improving the bioavailability of poorly water-soluble or otherwise problematic drugs.

In this study, we reported the application of Povacoat®, a hydrophilic polyvinylalcohol copolymer, as a dispersion stabilizer of nanoparticles of poorly water-soluble compounds. In addition, the influence of aggregation of the nanoparticles on their solubility and oral absorption was studied. Griseofulvin (GF) was used as a model compound with poor water solubility and was milled to nanoparticles by wet bead milling. The dispersion stability of GF milled with Povacoat® or the generally used polymers (polyvinylalcohol, hydroxypropylcellulose SSL, and polyvinylpyrrolidone K30) was compared. Milled GF suspended in Povacoat® aqueous solution with D-mannitol, added to improve the disintegration rate of freeze-dried GF, exhibited high dispersion stability without aggregation (D90 = ca. 0.220 μm), whereas milled GF suspended in aqueous solutions of the other polymers aggregated (D90 > 5 μm). Milled GF with Povacoat® showed improved aqueous solubility and bioavailability compared with the other polymers. The aggregation of nanoparticles had significant impact on the solubility and bioavailability of GF. Povacoat® also prevented the aggregation of the various milled poorly water-soluble compounds (hydrochlorothiazide and tolbutamide, etc.) more effectively than the other polymers. These results showed that Povacoat® could have wide applicability to the development of nanoformulations of poorly water-soluble compounds., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

After the great commercial success of sub-3 µm superficially porous particles, vendors are now also starting to commercialize 5 µm superficially porous particles, as an alternative to their fully porous counterparts which are routinely used in pharmaceutical analysis. In this study, the performance of 5 µm superficially porous particles was compared to that of fully porous 5 µm particles in terms of efficiency, separation performance and loadability on a conventional HPLC instrument. Van Deemter and kinetic plots were first used to evaluate the efficiency and performance of both particle types using alkylphenones as a test mixture. The van Deemter and kinetic plots showed that the superficially porous particles provide a superior kinetic performance compared to the fully porous particles over the entire relevant range of separation conditions, when both support types were evaluated at the same operating pressure. The same observations were made both for isocratic and gradient analysis. The superior performance was further demonstrated for the separation of a pharmaceutical compound (griseofulvin) and its impurities, where a gain in analysis time of around 2 could be obtained using the superficially porous particles. Finally, both particle types were evaluated in terms of loadability by plotting the resolution of the active pharmaceutical ingredient and its closest impurity as a function of the signal-to-noise ratio obtained for the smallest impurity. It was demonstrated that the superficially porous particles show better separation performance for griseofulvin and its impurities without significantly compromising sensitivity due to loadability issues in comparison with their fully porous counterparts. Moreover these columns can be used on conventional equipment without modifications to obtain a significant improvement in analysis time., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: This study aimed to develop a novel approach for predicting the oral absorption of low-solubility drugs by considering regional differences in solubility and permeability within the gastrointestinal (GI) tract., Methods: Simulated GI fluids were prepared to reflect rat in vivo bile acid and phospholipid concentrations in the upper and lower small intestine. The saturated solubility and permeability of griseofulvin (GF) and albendazole (AZ), a drug with low aqueous solubility, were measured using these simulated fluids, and fraction absorbed (Fa) at time t after oral administration was calculated., Results: The saturated solubility of GF and AZ, a drug with low aqueous solubility, differed considerably between the simulated GI fluids. Large regional differences in drugs concentration were also observed following oral administration in vivo. The predicted Fa values using solubility and permeability data of the simulated GI fluid were found to correspond closely to the in vivo data., Conclusion: These results indicated the importance of evaluating regional differences in drug solubility and permeability in order to predict oral absorption of low-solubility drugs accurately. The new methodology developed in the present study could be useful for new oral drug development.

Drug polymer-based amorphous solid dispersions (ASD) are widely used in the pharmaceutical industry to improve bioavailability for poorly water-soluble compounds. Spray-drying is the most common process involved in the manufacturing of ASD material. However, spray-drying involves a high investment of material quantity and time. Lower investment manufacturing processes such as fast evaporation and freeze-drying (lyophilization) have been developed to manufacture ASD at the bench level. The general belief is that the overall performance of ASD material is thermodynamically driven and should be independent of the manufacturing process. However, no formal comparison has been made to assess the in vivo performance of material generated by different processes. This study compares the in vitro and in vivo properties of ASD material generated by fast evaporation, lyophilization, and spray-drying methods using griseofulvin as a model compound and hydroxypropyl methylcellulose acetate succinate as the polymer matrix. Our data suggest that despite minor differences in the formulation release properties and stability of the ASD materials, the overall exposure is comparable between the three manufacturing processes under the conditions examined. These results suggest that fast evaporation and lyophilization may be suitable to generate ASD material for oral evaluation. However, caution should be exercised since the general applicability of the present findings will need to be further evaluated.

Griseofulvin-loaded solid lipid nanoparticles (SLNs) were prepared by hot microemulsion technique and optimized for type and concentration of lipid and surfactant. The optimized SLN composition was characterized in terms of particle shape and size, drug entrapment efficiency, pH, stability, spreadability, ex-vivo skin permeation, dermatokinetics, skin sensitivity, in vitro antifungal assay and in vivo antifungal activity against Microsporum canis using guinea pig model for dermatophytosis. The cumulative amount of drug permeated through excised mice skin from SLNs was more than 5-folds as compared to permeation from conventional cream base. Fluorescent microscopy revealed presence of nanoparticles in the skin layers suggesting the penetration of nanoparticles into the skin owing to their nano-size and thence a controlled drug release. A complete mycological and clinical cure was observed in M. canis infected guinea pigs after twice daily application of SLN gel containing griseofulvin for 8 days. Also, the formulation was observed to be non-sensitizing, histopathologically safe, and SLN gel was stable at 5 +/- 3 degrees C, 25 +/- 2 degrees C and 40 +/- 2 degrees C for a period of six months. It can be concluded from our study that SLNs provide a good skin permeation effect and may be a promising carrier for topical delivery of griseofulvin.

It is well known that large differences exist in the bioavailability of orally administered drugs between species. Dissolution is the first step in the oral absorption of solid drugs. In this study, we measured the in vivo luminal concentrations of griseofulvin (GF) and albendazole (AZ), Biopharmaceutics Classification System (BCS) class II drugs, and the GF fraction absorbed (Fa) in rats. Then, we compared the GF Fa in rat with that in other species reported previously to evaluate differences in drug dissolution and oral absorption. The Fa of GF has been reported to decrease from 80% to 40% with an increase in the oral dose in dogs and humans, because the rate-limiting step for absorption shifts from dissolution to solubility. However, such non-linearity was not observed in rats that were administered doses in the same ranges as those in humans, and the Fa values in rats were higher than those in dogs or humans. The in vivo luminal concentration of GF after oral administration in rats was much higher than the saturated solubility of GF in fasted-state simulated dog (FaSSIF(dog)) or human intestinal fluid (FaSSIF(human)). Furthermore, oral administration of AZ showed similar tendencies of interspecies differences in dissolution and oral absorption.

Purpose: To introduce guidelines in selecting the particle size distribution (n(0), cm(-1)) that will guarantee optimal oral absorption for drugs with low solubility., Methods: Unlike other multi-compartmental models the gastrointestinal tract is modeled as a continuous tube with spatially varying properties. The transport through the intestinal lumen is described using the dispersion model. The model accounts for the dissolution of poly-dispersed powders., Results: The model was used to examine the sensitivity of the absorption on permeability (P) and water solubility (C(s)) following administration in different log-normal powders. The absorption exhibits inverse sigmoidal dependence on the mean particle size (r(m), µm) regardless of the administrated dose or drug properties. Thus, there is an optimal r(m) that maximizes the benefit-cost ratio of the formulation; finer particles do not improve the absorption while coarser particles decrease it. Using the model we find that the optimal r(m) depends mainly on the drug C(s) and on the geometrical standard deviation (gSTD)., Conclusions: The results of this work provide the formulator with guidelines to select both r(m) and gSTD that guarantee optimal absorption.

Purpose: To investigate the use of nano self-assemblies formed by polyallylamine (PAA) modified with 5 or 10% mole fluorenylmethoxy carbonyl (Fmoc(5)/(10)), dimethylamino-1-naphthalenesulfonyl (Dansyl(5)/(10)) and 5% mole cholesteryl group (Ch(5)) for oral hydrophobic drug delivery., Methods: Propofol, griseofulvin and prednisolone were loaded into amphiphilic PAAs. Particle size and morphology of drug-loaded self-assemblies were determined using photon correlation spectroscopy and transmission electron microscopy. Solubilising capacity, in vitro drug release and formulation stability were analysed by HPLC, and in vitro biocompatibility studies (haemolysis and cytotoxicity) were carried out on bovine erythrocytes and Caco-2 cells, respectively. Dansyl(10) and Ch(5) griseofulvin formulations were administered intra-gastrically to rats, and drug plasma levels were analysed by HPLC., Results: Drug-encapsulated self-assemblies typically have hydrodynamic size of 300-400 nm. Dansyl(10) exhibited universal drug solubiliser property and had significantly improved prednisolone, griseofulvin and propofol solubility by 145, 557 and 224-fold, respectively. Fmoc polymers resulted in modest drug solubility improvement. These polymers were non-haemolytic, did not enhance cytotoxicity compared to unmodified PAA, and demonstrated significant increase in griseofulvin plasma concentration compared to griseofulvin in water after oral administration., Conclusions: Ch(5) and Dansyl(10) showed promising potential as nano-carriers for oral hydrophobic drug delivery.

As 95% of all prescriptions are for orally administered drugs, the issue of oral absorption is central to the development of pharmaceuticals. Oral absorption is limited by a high molecular weight (>500 Da), a high log P value (>2.0) and low gastrointestinal permeability. We have designed a triple action nanomedicine from a chitosan amphiphile: quaternary ammonium palmitoyl glycol chitosan (GCPQ), which significantly enhances the oral absorption of hydrophobic drugs (e.g., griseofulvin and cyclosporin A) and, to a lesser extent, the absorption of hydrophilic drugs (e.g., ranitidine). The griseofulvin and cyclosporin A C(max) was increased 6- and 5-fold respectively with this new nanomedicine. Hydrophobic drug absorption is facilitated by the nanomedicine: (a) increasing the dissolution rate of hydrophobic molecules, (b) adhering to and penetrating the mucus layer and thus enabling intimate contact between the drug and the gastrointestinal epithelium absorptive cells, and (c) enhancing the transcellular transport of hydrophobic compounds. Although the C(max) of ranitidine was enhanced by 80% with the nanomedicine, there was no appreciable opening of tight junctions by the polymer particles.

The powder flow and tableting properties of novel silicified microcrystalline cellulose II (SMCCII) were evaluated and compared with current silicified cellulosic I excipients such as ProSolv(®) SMCC50 and ProSolv(®) SMCC90. This excipient was prepared by coprocessing cellulose II and silicon dioxide (SiO(2)) at a 95:5 ratio by spray drying. The novel SMCCII yielded more benefits in terms of functionality as compared with the parent cellulose II material. SMCCII had higher bulk and tap densities, better powder packing ability, reduced porosity, increased surface area, and increased flowability. This silicified excipient had the highest brittleness behavior as given by the Heckel, Leuenberger and brittle fracture index analyses. The mechanical properties of SMCCII, such as toughness and Young's modulus were comparable to those of commercial products. SMCCII was the least sensitive material to magnesium stearate, and blending time or reprocessing did not affect its compactibility. It also provided for the fastest compact disintegration and release of griseofulvin. This new material has the potential for use as a direct compression excipient., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Development of oral dosage forms containing poorly water-soluble drugs is a major challenge in the pharmaceutical industry. This paper describes the use of coaxial electrospray deposition as a promising formulation technology for oral delivery of poorly water-soluble drugs. The technology produced core-shell particles composed of griseofulvin and poly(methacrylic acid-co-methyl methacrylate) (Eudragit L-100), with a diameter of around 1 μm. The drug phase was in an amorphous state when the griseofulvin core was coated with the Eudragit L-100 shell. The in vitro dissolution and in vivo oral absorption studies revealed that the core-shell formulation significantly improved dissolution and absorption behaviors, presumably because of a reduction in particle size, improvement in dispersity, and amorphization. Results demonstrated that coaxial electrospray deposition possesses great potential as novel formulation technology for enhancing oral absorption of poorly water-soluble drugs.

Poly[2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate]s (PMBs) are water-soluble solid copolymers of 2-methacryloyloxyethyl phosphorylcholine (MPC) and n-butyl methacrylate with a molecular weight of 30,000 (PMB50T) or 100,000 (PMB100T). Here, we characterized the solubilizing properties of PMBs using miconazole (MCZ), vidarabine (Ara-A) and griseofulvin (GRF), which are class 2, 3 and 4 compounds, respectively, in the Biopharmaceutics Classification System (BCS). Moreover, we evaluated the enhancement of gastric absorption of GRF dissolved in PMB solutions and the toxicity of PMBs in rats. PMB50T solution dramatically increased the solubility of GRF and MCZ compared with Ara-A, and these drugs became more soluble as the concentration of PMB50T was increased. The solubility of GRF in 10% PMB solutions was higher than with any other tested aqueous solubilizer. When a solution of GRF (20 mg/10 mL/kg) in 10% PMB was orally administered to rats, GRF absorption was greatly increased compared with that following administration of a suspension in water or Gelucire. After repeated oral administration of PMBs once daily for 14 successive days, no organ lesions or changes in biochemical parameters were observed. Thus, the polymers are expected to be useful and safe solubilizers and oral absorption enhancers for poorly soluble lipophilic drugs.

Micelles formed in the GI tract by bile acid and lecithin play an important role in oral absorption of poorly soluble drugs. In this situation, the drug molecules are present in equilibrium between the free and micellar states. In this study, the relationship between the free drug concentration and the membrane permeability of poorly soluble drugs was examined. Permeability across a Caco-2 monolayer and a dialysis membrane were measured in a side-by-side chamber system. The concentrations of sodium taurocholate (NaTC) and lecithin were varied to allow measurement of membrane permeability at different concentrations of free drugs. For troglitazone, hexylparaben, and heptylparaben, an increase in the NaTC and lecithin concentrations caused the permeability across the Caco-2 monolayer to decrease slightly, whereas the permeability across the dialysis membrane decreased markedly. In contrast, the changes in permeability of griseofulvin with an increased micelle concentration were similar for the Caco-2 monolayer and the dialysis membrane. Assuming that the permeability for the dialysis membrane reflects the free drug concentration in the medium, these results suggest that troglitazone and alkylparabens, but not griseofulvin, can partition directly from micelles to Caco-2 monolayers. This mechanism may contribute to oral absorption of drugs that are poorly soluble in water., (2009 Wiley-Liss, Inc. and the American Pharmacists Association)

The effect of Wellsolve, a new solubilizing agent, on the function of intestinal membrane barrier and transporters including P-glycoprotein (P-gp) and peptide transporter (PEPT1) was examined by an in vitro diffusion chamber and an in situ closed loop method. The model drugs used in this study were 5(6)-carboxyfluorescein (CF), rhodamine123 (a P-glycoprotein substrate), cephalexin (a typical substrate for PEPT1) and griseofulvin (a BCS Class II drug). Intestinal absorption of CF was not affected by the addition of 1-10% (v/v) Wellsolve, while 20% (v/v) Wellsolve significantly enhanced its intestinal absorption by the in situ absorption study. Therefore, this finding suggested that high concentration of Wellsolve might alter the intestinal barrier function. The mucosal to serosal (absorptive) and serosal to mucosal (secretory) transport of rhodamine123 was significantly inhibited in the presence of 5.0-20% (v/v) of Wellsolve, suggesting that Wellsolve might not affect the function of P-gp in the intestine. The intestinal transport of cephalexin was not affected in the presence of Wellsolve, suggesting that this solubilizing agent might not change the function of PEPT1 in the intestine. In the toxicity studies, we found that 1-10% (v/v) Wellsolve did not change the release of lactate hydrogenase (LDH) and protein from the intestinal membranes. Furthermore, intestinal absorption of griseofulvin in the presence of 10% (v/v) Wellsolve significantly increased as compared with the control. In summary, Wellsolve at lower concentrations might be a potent and safe solubilizing agent for improving the solubility and absorption of poorly water-soluble drugs including griseofulvin.

The present investigation aims to establish efficacious screening strategy to clarify the phototoxic potential of pharmaceutical substances and its possible pathways by characterizing both photobiochemical properties and pharmacokinetic profiles. Photochemical behavior of griseofulvin, as model compounds, was evaluated by reactive oxygen species (ROS) assay, and the photogenotoxic potential was also assessed by DNA binding assay, DNA photocleavage assay, and atomic force microscopy. Pharmacokinetic (PK) study was also carried out after dermal and oral administration of griseofulvin in rats. ROS assay suggested the phototoxic potential of griseofulvin via type II photochemical pathways, and the photogenotoxic risk of griseofulvin was also proposed as evidenced by high affinity toward DNA and potent DNA photocleaving activity. PK profiling and in vivo phototoxicity testing demonstrated that a highly concentrated griseofulvin in the skin might cause phototoxic skin reactions in rats, whereas oral administration of griseofulvin in single dosing regimen (20mg/kg) resulted in 10(3)-fold less skin deposition than phototoxic skin concentration of griseofulvin. Upon these findings, the phototoxic potential of griseofulvin might not be severe at least in a single oral dosing regimen, whereas it might be phototoxic in dermal administration. The combination use of photobiochemical and pharmacokinetic data would be valuable to provide reliable prediction on phototoxic risk and possible toxic pathways of new drug entities in the early stage of drug discovery.

Peanut oil and Tween 80 blends devoid of any cosurfactant were employed in the formulation of different batches of liquid self-microemulsifying drug delivery systems (LSMEDDS) and their suitability as vehicles for the delivery of a typical lipophilic drug-griseofulvin-was investigated. The LSMEDDS were evaluated using the following parameters: phase separation, globule size, viscosity, solubility of griseofulvin, and partition coefficient. The release profile of griseofulvin from the optimized LSMEDDS was evaluated in citrate/phosphate buffer solutions of pH 2.0, pH 6.5, and pH 7.4. The results obtained indicated that there was significantly higher (alpha

The aim of the present report was to develop nonionic surfactant vesicles (niosomes) to improve poor and variable oral bioavailability of griseofulvin. Niosomes were prepared by using different nonionic surfactants span 20, span 40, and span 60. The lipid mixture consisted of surfactant, cholesterol, and dicetyl phosphate in the molar ratio of 125:25:1.5, 100:50:1.5, and 75:75:1.5, respectively. The niosomal formulations were prepared by thin film method and ether injection method. The influence of different formulation variables such as surfactant type, surfactant concentration, and cholesterol concentration was optimized for size distribution and entrapment efficiency for both methods. Result indicated that the niosomes prepared by thin film method with span 60 provided higher entrapment efficiency. The niosomal formulation exhibited significantly retarded in vitro release as compared with free drug. The in vivo study revealed that the niosomal dispersion significantly improved the oral bioavailability of griseofulvin in albino rats after a single oral dose. The maximum concentration (Cmax) achieved in case of niosomal formulation was approximately double (2.98 microg/ml) as compared to free drug (1.54 microg/ml). Plasma drug profile also suggested that the developed niosomal system also has the potential of maintaining therapeutic level of griseofulvin for a longer period of time as compared to free griseofulvin. The niosomal formulation showed significant increase in area under the curve0-24 (AUC; 41.56 microg/ml h) as compared to free griseofulvin (22.36 microg/ml h) reflecting sustained release characteristics. In conclusion, the niosomal formulation could be one of the promising delivery system for griseofulvin with improved oral bioavailability and prolonged drug release profiles.

The effect of oil-in-water submicron emulsion (SE) droplet surface charge on absolute bioavailability of a poorly water-soluble drug (griseofulvin, as model drug) after oral administration was studied in conscious rat. Positively, negatively, and neutrally charged SE were designed and characterized (size, polydispersity index, zeta potential, and pH). Three emulsion formulations, whose compositions included 40% oil phase and differed only in the nature of the emulsifying agent, were retained. Only the positively charged SE showed a higher area under the plasma concentration-time curve (AUC(0 --> infinity)) in comparison with the tablet and with the other SE.

The oral bioavailability of griseofulvin (GF) formulated as a fast disintegrating lyophilized dry emulsion (LDE) tablet was studied and compared to the commercially available immediate release (IR) tablet, as a reference, in both the fasted and fed states in nine healthy volunteers after a single oral dose (125 mg) in a crossover design. Furthermore the LDE tablets were ingested with and without water under both the fasted and fed states. In the fasted state, the rate of absorption was found to be significantly faster from LDE tablets, in the presence and absence of water, as shown by a higher C(max) (more than two times higher, p=0.0001) and a shorter t(max) (by more than 3h, p=0.0001) compared to IR tablets. The extent of absorption, expressed as AUC, from LDE tablets in the presence and absence of water was 65% and 77% larger and statistically significantly different relative to the mean AUC from IR tablets (p=0.006). In the fed state, C(max) from LDE tablets ingested with and without water was found to be about 30% and 50% higher, respectively, than the immediate release tablets. A shorter t(max) was also shown whether LDE tablets were ingested with or without water in the fed state as compared to immediate release tablets. The mean AUC from LDE tablets under fed conditions in the presence of water was about 21% larger and was not statistically significantly different from AUC from immediate release tablets (p=0.517). When ingested without water, AUC from LDE tablets was about 43% larger and statistically significantly different relative to AUC from IR tablets (p=0.033). The mean AUC from the LDE tablet ingested with water under fed conditions relative to AUC from LDE tablet ingested without water was not statistically significantly different (p=0.454). Results show that the food effect of the high fat meal is very pronounced in case of the immediate release tablets, Fulvin, than in case of LDE tablets whether given with or without water.

Purpose: Nonlinear oral absorption due to poor solubility often impedes drug development. The purpose of this study was to elucidate the rate-limiting process in oral absorption of Biopharmaceutical Classification System (BCS) class II (low solubility-high permeability) drugs in order to predict nonlinear absorption of dose caused by solubility-limited absorption., Methods: Oral absorption of danazol, griseofulvin, and aprepitant was predicted from a miniscale dissolution test and a physiologically-based model. The effect of particle size reduction and dose increase on absorption was investigated in vitro and in vivo to clarify the rate-limiting steps of dissolution-rate-limited and solubility-limited absorption., Results: The rate-limiting steps of oral absorption were simulated and increase in the dissolution rate and administration dose showed a shift from dissolution rate-limited to solubility-limited absorption. In the study in dogs, particle size reduction improved the oral absorption of large particle drugs but had little effect on small particle drugs. Dose nonlinearity was observed with small particles at a high dose. Our model quantitatively predicted results observed in vivo, including but not exclusively, dissolution-rate-limited and solubility-limited absorption., Conclusion: The present study provides a powerful tool to predict dose nonlinearity and will aid in the success of BCS class II drug development.

Mean plasma concentration-time profile of griseofulvin, a BCS class II drug, orally administered as powders into rats, was predicted based on GITA model. However, it was very difficult to predict the individual plasma profile because of large inter-individual difference. As the absorption of griseofulvin would be rate-limited by the dissolution process, we tried to analyze the in vivo dissolution kinetics of griseofulvin by focusing on gastric emptying and intestinal transit as physiological factors influencing the in vivo dissolution kinetics. After oral administration of griseofulvin, theophylline and sulfasalazine into rats, gastric emptying and intestinal transit were simultaneously estimated by analyzing the absorption kinetics of theophylline and observing the appearance of sulfapyridine in plasma, respectively. Gastric emptying kinetics was not significantly correlated with absorption or dissolution behavior of griseofulvin. On the other hand, the cecum-arriving time reflecting the intestinal transit was significantly correlated with both AUC and total dissolved amount of griseofulvin. T(max) of griseofulvin also increased with the increase of cecum-arriving time. These results clearly indicate that the longer residence time could lead to the higher dissolution and absorption of griseofulvin and that the variance of intestinal transit could be responsible for the inter-individual difference of the in vivo absorption behavior.

To enhance the dissolution and oral absorption of poorly water-soluble griseofulvin (GF), self-emulsifying drug delivery system (SEDDS) composed of oil, surfactant and cosurfactant for oral administration of griseofulvin was formulated, and its physicochemical properties and pharmacokinetic parameters were evaluated. The solubility of griseofulvin was further improved by the addition of hydrochloric acid. Droplet size of griseofulvin emulsion was kept constant both in simulated gastric fluid without pepsin and simulated intestinal fluid throughout 12 weeks incubation period. Griseofulvin in the SEDDS rapidly dissolved in different dissolution media. This was not the case for the commercial GRIS-PEG tablets. In different fed diet groups, AUC 0-->24 h, Cp max, and T max of griseofulvin after oral administration of SEDDS in rats were comparable to those after oral dose of GRIS-PEG tablet. Although, in fed lipidic diet group, the mean AUC and Cp max after oral administration of GRIS-PEG in rats were 1.28 and 1.15 fold higher, respectively, compared with those of SEDDS, these have not shown to be significantly different. These results demonstrate that the SEDDS of griseofulvin composed of Capmul GMO-50, Poloxamer and Myvacet 9-45 greatly enhanced the dissolution of griseofulvin (without ultramicronisation). However, food intake effect on the bioavailability of griseofulvin has remained. Thus, this system may provide a useful dosage form for oral water-insoluble drugs which have problems in their dissolution.

Development of a fast-disintegrating lyophilized dry emulsion (LDE) tablet that enhanced the in vitro dissolution and in vivo absorption of griseofulvin (GF) is presented. The LDE tablets were prepared by freeze-drying o/w emulsions of GF, a drug for which bioavailability is known to be enhanced by fat co-administration. Oil-in-water emulsions were prepared using a gelatin solution (2%, w/v) as the water phase and medium chain triglycerides (Miglyol) or sesame oil as the oil phase. In addition, different emulsifiers were evaluated. The influence of formulation parameters on the disintegration and in vitro dissolution of GF from LDE tablets along with other tablet characteristics were investigated. A significant influence of the emulsifier type on the tablet disintegration time was seen (p<0.01). Results obtained from dissolution studies showed that LDE tablets of GF improved the dissolution rate of the drug compared to the plain drug. The extent of absorption of GF from a selected LDE tablet formulation as compared to an immediate release conventional tablet as reference after single oral dose (125mg) administration was determined in four healthy subjects using a randomized crossover design. In this study, the rate of absorption of GF from LDE tablet was faster than that from the reference tablet and had significantly higher (p=0.02) peak plasma concentration (more than three times higher) and shortened time to C(max) by 4h (p=0.014). The extent of absorption expressed by AUC was 85% larger as compared to the commercial tablet. Stability results, after 6 months storage of LDE tablets at 25 degrees C and 60% relative humidity, showed a slight increase in disintegration time and residual moisture content, while results from dissolution studies showed slightly slower initial drug release.

(1) We evaluated the involvement of brain mitochondrial and microsomal cytochrome P-450 in the metabolization of known porphyrinogenic agents, with the aim of improving the knowledge on the mechanism leading to porphyric neuropathy. We also compared the response in brain, liver and kidney. To this end, we determined mitochondrial and microsomal cytochrome P-450 levels and the activity of NADPH cytochrome P-450 reductase. (2) Animals were treated with known porphyrinogenic drugs such as volatile anaesthetics, allylisopropylacetamide, veronal, griseofulvin and ethanol or were starved during 24 h. Cytochrome P-450 levels and NADPH cytochrome P-450 reductase activity were measured in mitochondrial and microsomal fractions from the different tissues. (3) Some of the porphyrinogenic agents studied altered mitochondrial cytochrome P-450 brain but not microsomal cytochrome P-450. Oral griseofulvin induced an increase in mitochondrial cytochrome P-450 levels, while chronic Isoflurane produced a reduction on its levels, without alterations on microsomal cytochrome P-450. Allylisopropylacetamide diminished both mitochondrial and microsomal cytochrome P-450 brain levels; a similar pattern was detected in liver. Mitochondria cytochrome P-450 liver levels were only diminished after chronic Isoflurane administration. In kidney only mitochondrial cytochrome P-450 levels were modified by veronal; while in microsomes, only acute anaesthesia with Enflurane diminished cytochrome P-450 content. (4) Taking into account that delta-aminolevulinic acid would be responsible for porphyric neuropathy, we investigated the effect of acute and chronic delta-aminolevulinic acid administration. Acute delta-aminolevulinic acid administration reduced brain and liver cytochrome P-450 levels in both fractions; chronic delta-aminolevulinic acid administration diminished only liver mitochondrial cytochrome P-450. (5) Brain NADPH cytochrome P-450 reductase activity in animals receiving allylisopropylacetamide, dietary griseofulvin and delta-aminolevulinic acid showed a similar profile as that for total cytochrome P-450 levels. The same response was observed for the hepatic enzyme. (6) Results here reported revealed differential tissue responses against the xenobiotics assayed and give evidence on the participation of extrahepatic tissues in porphyrinogenic drug metabolization. These studies have demonstrated the presence of the integral Phase I drug metabolizing system in the brain, thus, total cytochrome P-450 and associated monooxygenases in brain microsomes and mitochondria would be taken into account when considering the xenobiotic metabolizing capability of this organ.

The purpose of this study was to investigate the impact of different lipid based formulations of lipophilic drugs on in vitro solubilization and intestinal ex vivo permeability processes. Thereafter, to evaluate the ability of these in vitro and ex vivo results to predict the corresponding in vivo oral bioavailability data. The dissolution of dexamethasone and griseofulvin in long (LCT), medium (MCT) and short (SCT) chain triglyceride formulations was tested in a dynamic in vitro lipolysis model. Following the completion of the lipolysis, the permeability through the gut wall was tested in an ex vivo side-by-side diffusion chamber model. The absolute oral bioavailability of the drugs from the tested formulations was investigated in rats. The dynamic in vitro lipolysis experiments indicated an equivalent performance of the different formulations for dexamethasone, and a performance rank order of MCT>LCT>SCT>H(2)O for griseofulvin. In the subsequent ex vivo permeability studies, the SCT formulation caused enhanced permeation with doubled permeability coefficient for both drugs. The in vivo bioavailability of both drugs correlated well with the in vitro data, i.e., LCT=MCT=SCT for dexamethasone and MCT>LCT>SCT>H(2)O for griseofulvin, despite the significant augmented intestinal permeability produced by the SCT formulation. In conclusion, the in vitro lipolysis model was found to be useful in the intelligent optimization of oral lipid formulations for lipophilic drugs, even in the case where the intestinal permeability is enhanced by the formulation. The SCT vehicle showed to be a potential permeability enhancer; however, for class 2 compounds, the permeability does not correlate with in vivo bioavailability.

A simple, sensitive and rapid liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has been developed and validated to quantify griseofulvin in human plasma using propranolol hydrochloride as internal standard (IS). Samples were prepared using solid phase extraction and analysed without drying and reconstitution. The analytes were chromatographed on Hypersil, hypurity C18 reverse phase column under isocratic conditions using 0.05% formic acid in water:acetonitrile (30:70, v/v) as the mobile phase. Total chromatographic run time was 3.0 min. Quantitation was done on a triple quadrupole mass analyzer API-3000, equipped with turbo ion spray interface and operating in multiple reaction monitoring (MRM) mode to detect parent-->product ion transition for analyte and IS. The method was validated for sensitivity, matrix effect, accuracy and precision, linearity, recovery and stability studies. Linearity in plasma was observed over the concentration range 20-3000 ng/mL for griseofulvin. Lower limit of quantification (LLOQ) achieved was 20 ng/mL with precision (CV) less than 10% using 5 microL injection volume. The absolute recovery of analyte (87.36%) and IS (98.91%) from spiked plasma samples was consistent and reproducible. Inter-batch and intra-batch coefficients of variation across four validation runs (LLOQ, LQC, MQC and HQC) was less than 7.5%. The accuracy determined at these levels was within +/-4.2% in terms of relative error. The method was applied to a pilot bioequivalence study of 500 mg griseofulvin tablet in six healthy human subjects under fed condition.

A novel generic ultra performance liquid chromatography-tandem mass spectrometric (UPLC/MS/MS) method for the high throughput quantification of samples generated during permeability assessment (PAMPA) has been developed and validated. The novel UPLC/MS/MS methodology consists of two stages. Firstly, running a 1.5min isocratic method, compound-specific multiple reaction monitoring (MRM) methods were automatically prepared. In a second stage, samples were analyzed by a 1.5min generic gradient UPLC method on a BEH C18 column (50mmx2.1mm). Compounds were detected with a Waters Micromass Quattro Premier mass spectrometer operating in positive electrospray ionization using the compound-specific MRM methods. The linearity for the validation compounds (caffeine, propranolol, ampicillin, atenolol, griseofulvin and carbamazepine) typically ranges from 3.05nM to 12,500nM and the limits of detection for all generically developed methods are in the range between 0.61nM and 12nM in an aqueous buffer. The novel generic methodology was successfully introduced within early Drug Discovery and resulted in a four-fold increase of throughput as well as a significant increase in sensitivity compared to other in-house generic LC/MS methods.

Oral dosage forms are the preferred means of delivering drugs for systemic absorption. However, development problems occur for drugs with poor water solubility and/or gastrointestinal permeability. It is generally believed that the in-vivo bioavailability of poorly water-soluble drugs from Class II of the Biopharmaceutics Classification System can be improved by increasing the dissolution rate. We have attempted to increase the in-vivo oral bioavailability of a model Class II drug (griseofulvin) by preparing rapidly-dissolving particles. The solvent-diffusion method was used to prepare particles with hydrophilic surfactants (Brij 76/Tween 80 surfactant blend) and in-vivo studies were conducted in rats. The griseofulvin particles produced were bipyramidal in habit with a particle size of 2.18 +/- 0.12 microm; they contained crystalline drug and a relatively large proportion (12% w/w) of hydrophilic surfactant. The latter and the small particle size ensured rapid particle dispersion and dissolution in-vitro. Thus, within 30 min of the in-vitro dissolution test, the bipyramidal particles had released approximately 70% of drug compared with approximately 10% from the starting material (particle size 12.61 +/- 1.11 microm). However, the rapid and increased drug dissolution in-vitro was not translated to rapid and enhanced absorption in-vivo, and the oral bioavailability of the model drug was found to be the same from the control and from the bipyramidal particles. The poor in-vivo performance of the bipyramidal particles showed that although the dissolution rate of a Class II drug is thought to be a good indicator of its in-vivo bioavailability, this is not always the case.

Chitosan is widely used as a dietary weight-loss supplement in Japan. In the present study, we examined the effect of chitosan on the gastrointestinal absorption profiles of the water-insoluble drugs, indomethacin and griseofulvin, and the water-soluble drugs, acetaminophen and cephalexin, after oral administration in rats. Rats received oral administration of chitosan (5 mg/kg or 25 mg/kg) dissolved in 5% acetic acid or vehicle 15 min before oral administration of each drug. Chitosan at a dose of 25 mg/kg, but not 5 mg/kg, significantly decreased the plasma concentrations of indomethacin and griseofulvin after administration as a suspension with a significant delay of the time to reach maximum concentration compared to the corresponding control values (vehicle-pretreated rats). However, pretreatment of chitosan (25 mg/kg) did not change the pharmacokinetics of indomethacin administered as a solution. Further, the same dose of chitosan had no effect on the pharmacokinetics of acetaminophen. The gastrointestinal absorption profile of an amino-beta-lactam antibiotic, cephalexin, which is actively absorbed via carrier-mediated transport system, was also unchanged. The present findings at least suggest the possibility that chitosan at high dose reduces the gastrointestinal absorption of water-insoluble drugs such as indomethacin and griseofulvin, but not water-soluble drugs, by diminishing the surfactant-like effect of bile acids.

The slow dissolution rate exhibited by poorly water-soluble drugs is a major challenge in the drug development process. Following oral administration, drugs with slow dissolution rates generally show erratic and incomplete absorption which may lead to therapeutic failure. The aim of this study was to improve the dissolution rate and subsequently the oral absorption and bioavailability of a model poorly water-soluble drug. Microparticles containing the model drug (griseofulvin) were produced by spray drying the drug in the absence/presence of a hydrophilic surfactant. Poloxamer 407 was chosen as the hydrophilic surfactant to improve the particle wetting and hence the dissolution rate. The spray dried particles were characterized and in vitro dissolution studies and in vivo absorption studies were carried out. The results obtained showed that the dissolution rate and absolute oral bioavailability of the spray dried griseofulvin/Poloxamer 407 particles were significantly increased compared to the control. Although spray drying griseofulvin alone increased the drug's in vitro dissolution rate, no significant improvement was seen in the absolute oral bioavailability when compared to the control. Therefore, it is believed that the better wetting characteristics conferred by the hydrophilic surfactant was responsible for the enhanced dissolution rate and absolute oral bioavailability of the model drug.

The aim of this work is to evaluate the feasibility of hydrophilic silica aerogels as drug carriers and to investigate the influence of the aerogels properties on the release rate of poorly water-soluble drugs. Hydrophilic silica aerogels of different densities were loaded with two model drugs, ketoprofen and griseofulvin, by adsorption from their solution in supercritical CO2. It is demonstrated that up to 30 wt% of ketoprofen and 5.4 wt% of griseofulvin can be deposited on hydrophilic aerogels through physical adsorption. The obtained drug-aerogel formulations were characterized by IR- and UV-spectroscopy, X-ray diffraction and scanning electron microscopy. Release kinetics of both drugs were studied in vitro. The release rate of ketoprofen from the drug-aerogel formulation is much faster than that of the corresponding crystalline drugs. The release rate of ketoprofen increases in 500% and that of griseofulvin in 450%, respectively. The reasons for the release enhancement are the enlarged specific surface area of drugs by adsorption on aerogels compared to their crystalline form and the immediate collapse of aerogel network in aqueous media. The dissolution rate of poorly water soluble drugs can be significantly enhanced by adsorption on highly porous hydrophilic silica aerogels.

We have compared the distribution of fluconazole (FLC) with that of itraconazole (ITC) and griseofulvin (GRF) in the abdominal skin tissues after a single oral dose was administered to guinea pigs. The FLC concentrations in the stratum corneum reached a peak at 2 h after administration and were similar to those of ITC and higher than those of GRF in spite of the administration of a lower dose. GRF was eliminated from the stratum corneum faster than FLC and ITC. The FLC concentrations were also remarkably higher than those of ITC and GRF in the epidermis-cutis but lower in the subcutaneous fatty tissue. The distribution characteristics of each drug result from differences in their physicochemical properties. Following the administration of multiple doses, the FLC concentrations in the stratum corneum were highest in the abdominal skin tissues; those at 24 h after each administration increased gradually and were maintained at a level more than 10 times higher than that of the plasma concentrations. The FLC concentrations in the planta pedis stratum corneum and in the nail showed good dose proportionality and obvious accumulation and were 60 and 40 times as high as that in plasma on day 14. The extent of binding of FLC to human corneous keratin in vitro was about 10%, which is lower than those of ITC (94 to 97%) and GRF (36 to 38%). FLC, unlike ITC, therefore, is presumed to exist in the stratum corneum at high concentrations in an active nonbinding form. These excellent intracutaneous pharmacokinetic properties of FLC probably account in large part for the in vivo efficacy of FLC.

Griseofulvin is a metabolic product of Penicillium spp. It was the first available oral agent for the treatment of dermatophytoses and has now been used for more than forty years. Griseofulvin is fongistatic, the exact mechanism in witch it inhibits the growth of dermatophytes is doubtful. Several ways are invoked: inhibition of fungal cell mitosis and nuclear acid synthesis, probable interference with the function of microtubules. Griseofulvin is poorly absorbed from the gastrointestinal tract. Absorption is enhanced by administration with fatty meal. Peak plasma occurs four hours after oral administration. Griseofulvin is detected in the outer layer of the stratum corneum soon after it is ingested, it is diffused from the extracellular fluid and sweat. There is no information regarding the mechanism by witch the drug is delivered to nails and hair. Deposition in the newly formed cells could be the major factor. Griseofulvin has also anti-inflammatory properties and some direct vasodilatory effects when it is used in high doses. It is metabolised by the liver microsomial enzyme system and excreted in the urine. The half-life is 9 to 21 hours. Griseofulvine has been used in the therapy of dermatophyte onychomycosis, treatment periods from 6 to 18 months were necessary with disappointing results and numerous relapses. Newer oral antifungal agents are now preferred especially in toenail infections. For many authors griseofulvin is still the treatment of choice of tinea capitis. Doses are 15-20 mg/kg/d for 6 to 8 weeks in children with the microsized form. Clinical response rates have been reported between 80 and 90 p. 100 in controlled studies. Griseofulvin is well-tolerated particulary in children. More frequent side effects are minor: headaches, gastrointestinal reactions and cutaneous eruptions. The major drug interactions has been noted with phenobarbital, anticoagulants and oral contraceptives.

We attempted to prepare a new griseofulvin formulation for topical application using N-methyl-2-pyrrolidone (NMP). Griseofulvin dissolves poorly in both water and oil, but dissolves in NMP to a concentration of about 100 mg/ml. A soybean oil-water emulsion with soybean lecithin and NMP as emulsifier and co-solvent, respectively, was prepared using a Microfluidizer, a high-pressure homogenizer. The size of the droplets in emulsion was about 200 nm, and the emulsion was stable for over 3 months. The skin permeation of griseofulvin through Yucatan micropig skin was studied in vitro using vertical type cells under donor phase open conditions. The permeation of griseofulvin from the NMP-water mixture (0-40%) into the skin tended to increase with increasing NMP concentration, although this finding was not statistically significant. Permeation from emulsion (oil phase, 20%; NMP 10-40%) was significantly higher than that from the water-NMP mixture. Permeation from the oil-NMP mixture was highest among the formulations investigated, and permeation from emulsion under donor phase closed conditions was significantly lower than that under open conditions. We believe that the evaporation of water from the emulsion after application to the skin was an important factor in skin permeation enhancement. When the emulsion containing 3% l-menthol was applied, a sufficient skin concentration (47 microg/cm3 in dermis) was obtained.

Purpose: To develop an integrated absorption model for estimating the fraction of dose absorbed and determining the causes of poor oral drug absorption., Methods: Both analytical and numerical methods were used to estimate the fraction of dose absorbed., Results: An integrated absorption model was developed by considering transit flow, dissolution, and permeation processes, simultaneously. A framework was proposed to determine permeability-, dissolution-, and solubility-limited absorption. Digoxin, griseofulvin, and panadiplon were employed to illustrate the applications of the integrated model in identifying the causes of poor absorption and guiding formulation development., Conclusions: The integrated absorption model was successfully applied to digoxin, griseofulvin, and panadiplon to estimate the fraction dose absorbed and to roughly determine the causes of poor oral drug absorption.

The release profiles of acidic and neutral drugs from poly(L-lactic acid) [P(L)LA] matrices were investigated to reveal their release mechanism. Cylindrical matrices (rods; 10 mmx1 mm diameter) were prepared by the heat compression method. The acidic and neutral drugs investigated were dissolved in the P(L)LA rods. It was found that the release profiles consisted of two sequential stages. At the first release stage, P(L)LA remained in an amorphous state and the drugs diffused through the hydrated matrices. At the second release stage, P(L)LA transformed to a semicrystalline state and the drugs diffused through water-filled micropores developed by polymer crystallization. In addition, the drugs were also found to precipitate out as crystals in the rods, resulting in a transformation of the rods into drug-dispersed matrices. On the basis of these findings, we derived a modified diffusion equation for the drug release at the second stage. This equation showed good fits to the release profiles of these drugs. Furthermore, the availability of the derived equation was supported by the acceleration in the fractional drug release rate noted both with decreases in the drug content in the rod and increases in the pH of the medium.

Two studies on the pharmacokinetics of fluconazole in skin and nails are reported here. In 1 study, 12 healthy volunteers received fluconazole 50 mg once daily for 12 days and 11 healthy volunteers received fluconazole 150 mg once weekly for 2 weeks. Fluconazole assays were performed on samples of serum, stratum corneum, dermis-epidermis, and eccrine sweat. In a second study, 36 patients with toenail onychomycosis received either fluconazole 150 mg once weekly or griseofulvin 1000 mg once daily for 12 months. Fluconazole assays were performed on nail clippings and serum samples from the patients receiving fluconazole. Tissue concentrations of fluconazole regularly exceeded plasma concentrations in these studies. In the skin study, the highest concentrations were achieved in stratum corneum, with accumulation occurring up to the end of dosing. Subjects who received 50 mg once daily had higher levels of fluconazole in stratum corneum, sweat, and epidermis-dermis than those subjects who received 150 mg once weekly. In the toenail study, fluconazole concentrations increased for the first 6 months, reaching levels much higher than serum concentrations (P < .001), with no significant difference between healthy and diseased nails.

Griseofulvin is a poorly soluble antifungal antibiotic drug, the solubility of which can be enhanced by complexation with beta-cyclodextrin. The inclusion complex was prepared by coprecipitation method in various molar ratios of 1:1, 2:1, 3:1, and 1:2 of the drug and beta-cyclodextrin, respectively. The inclusion complex was characterized and evaluated by UV-VIS spectral studies and FTIR. The in vitro drug release studies indicated that the 1:2 molar ratio complex form of the drug significantly increased the dissolution rate when compared to the free form. The acute toxicity studies clearly indicated that the beta-cyclodextrin complex was nontoxic and the safety range was close to other Griseofulvin formulations. The in vivo study of the beta-cyclodextrin was carried out in both animals and human beings by administering in four different rabbits and volunteers, respectively. Pellets made with Griseofulvin-beta-cyclodextrin complex also showed a significant increase in the dissolution of the drug, revealing that beta-cyclodextrin plays an important role in the solubilization of Griseofulvin.

For poorly soluble drugs, the digestive absorption depends on their rate of dissolution. Decreasing the particle size of these drugs improves their rate of dissolution. Fine grinding mills are use to micronize powders: either jar mills or fluid energy mills. Theses processes were applied to griseofulvin, progesterone, spironolactone and diosmin. For each drug, micronization improved their digestive absorption, and consequently their bioavailability and clinical efficacy.