A Dual-Biotic System for the Concurrent Delivery of Antibiotics and Probiotics: <Emphasis Type="Italic">In Vitro</Emphasis>, <Emphasis Type="Italic">Ex Vivo</Emphasis>, <Emphasis Type="Italic">In Vivo and In Silico</Emphasis> Evaluation and Correlation

Purpose

A delayed release bio-polymeric Dual-Biotic system has been extensively evaluated in this study to overcome the therapeutic issue of probiotic killing due to incorrect administration with the antibiotic.

Methods

In vitro and ex vivo release and characterization studies have been undertaken on the Dual-Biotic system. In vivo analyses utilizing a Large White pig model were also performed with commercial products used as a comparison. Intestinal fluid for probiotic quantification was aspirated using a surgically implanted intestinal cannula with Lactobacillus acidophilus cell counts determined through luminescence and inoculation onto Lactobacilli-specific agar. Plasma amoxicillin concentrations were determined through Ultra-Performance Liquid Chromatography. The reactional profile and crosslinking mechanism of ovalbumin and genipin was elucidated using molecular mechanic energy relationships in a vacuum system by exploring the spatial disposition of different concentrations of genipin with respect to ovalbumin with ovalbumin/genipin ratios of 1:1, 1:5 and 1:10.

Results

In vivo evaluation of the Dual-Biotic system detailed maximum Lactobacillus viability (~455% baseline viability) 6 h after oral administration. Concurrent administration of the commercial products revealed a 75% decrease in bacterial viability when compared to the controls analyzed. A level A in vitro-in vivo correlation was also established with 96.9% predictability of amoxicillin release ascertained. The computational results achieved corroborated well with the experimental findings and physicochemical data.

Conclusions

Evaluation and correlation of the Dual-Biotic system has detailed the success of the formulation for the concurrent delivery of an antibiotic and probiotic.

     

Antioxidant <Emphasis Type="Italic">C</Emphasis>-glycosylflavones of <Emphasis Type="Italic">Drymaria cordata</Emphasis> (Linn.) Willd

A new C-glycosylflavone, drymaritin E (6-C-(3-keto-β-digitoxopyranosyl)-4′-O-(β-d-glucopyranosyl)-7-methoxyl-5,4′-dihydroxylflavone) 1 was isolated from the oily upper phase (SU) of the MeOH extract from aerial parts of Drymaria cordata together with two known compounds (cassiaoccidentalin A 2 and anemonin 3) and an inseparable mixture of two known C-glycosylflavones 5,4′-dihydroxy-7-methoxyflavone-6-C-(2′′-O-α-l-rhamnopyranosyl)-β-d-glucopyranoside 4a and 5,7,3′,4′-tetrahydroxyflavone-6-C-(2′′-O-α-l-rhamnopyranosyl)-β-d-glucopyranoside 4b. The alkaline hydrolysis of 3 led to a new hemisynthetic derivative, sodium anemonate (sodium 2-((1’E) 2′-sodium-carboxylate-vinyl)-5-oxo-cyclohex-1-ene carboxylate) 3a. The chemical structures were determined by spectroscopic methods (¹H NMR, ¹³C NMR, ¹H-¹H COSY, HMBC, HSQC, and NOESY) and mass spectrometry (ESI–MS). C-glycosylflavones had significant free radical-scavenging activities on the radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). However, SU and compounds 3 and 3a exhibited no activity. In particular, compound 1 exhibited a concentration-dependent radical scavenging activity on DPPH with EC₅₀ of 31.43 µg/mL.     

Synthesis and evaluation of <Emphasis Type="Italic">p</Emphasis>-<Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-dialkyl substituted chalcones as anti-cancer agents

Several new N,N-dialkyl substituted chalcones (chalconoids or benzylideneacetophenones) have been synthesized via the condensation of corresponding N,N-dialkylbenzaldehyde with various aryl methyl ketones. All the chalcones have been synthesized from readily available and cheap starting materials under environmentally benign conditions in very high yields without work up and column chromatographic purification. Synthesized compounds have been tested for their biological activity against pathogenic microorganisms such as Escherichia coli, Bacillus subtilis, and Mycobacterium smegmatis. Anti-cancer activity of these compounds has also been tested against multiple myeloma (RPMI-8226) and human mammary adenocarcinoma (MCF-7) cell lines. The most hydrophilic molecules 23 and 24 showed very good anti-cancer activity against MCF-7 cell lines at low micro-molar concentrations. All the compounds have also been evaluated for their activity against Beta-secretase 1 enzyme. One of the synthesized compounds showed Beta-secretase 1 enzyme inhibition activity at micro-molar concentration.     

The Immunosuppressive Activity of Polymeric Micellar Formulation of Cyclosporine A<Emphasis Type="Italic">: In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Studies

We have previously developed micelles of methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) as vehicles for the solubilization and delivery of cyclosporine A (CsA). These micelles were able to reduce the renal uptake and nephrotoxicity of CsA. The purpose of the current study was to test the efficacy of polymeric micellar formulation of CsA (PM-CsA) in suppressing immune responses by either T cells or dendritic cells (DCs). The performance of PM-CsA was compared to that of the commercially available formulation of CsA (Sandimmune®). Our results demonstrate that PM-CsA could exert a potent immunosuppressive effect similar to that of Sandimmune® both in vitro and in vivo. Both formulations inhibited phenotypic maturation of DCs and impaired their allostimulatory capacity. Furthermore, both PM-CsA and Sandimmune® have shown similar dose-dependent inhibition of in vitro T cell proliferative responses. A similar pattern was observed in the in vivo study, where T cells isolated from both PM-CsA-treated and Sandimmune®-treated mice have shown impairment in their proliferative response and IFN-γ production at similar levels. These results highlight the potential of polymeric micelles to serve as efficient vehicles for the delivery of CsA.     

Antimicrobial glycoalkaloids from the tubers of <Emphasis Type="Italic">Stephania succifera</Emphasis>

Three new glycoalkaloids, N-formyl-asimilobine-2-O-β-d-glucoside (1), (?)-1-O-β-d-glucoside-8-oxotetrahydropalmatine (2), and 1-N-monomethylcarbamate-argentinine-3-O-β-d-glucoside (3) were isolated from tubers of Stephania succifera. The structures were established based on spectroscopic analysis, and the antimicrobial activities of the three glycoalkaloids are reported.     

Predicting Pulmonary Pharmacokinetics from <Emphasis Type="Italic">In Vitro</Emphasis> Properties of Dry Powder Inhalers

Purpose

The ability of two semi-mechanistic simulation approaches to predict the systemic pharmacokinetics (PK) of inhaled corticosteroids (ICSs) delivered via dry powder inhalers (DPIs) was assessed for mometasone furoate, budesonide and fluticasone propionate.

Methods

Both approaches derived the total lung doses and the central to peripheral lung deposition ratios from clinically relevant cascade impactor studies, but differed in the way the pulmonary absorption rate was derived. In approach 1, the rate of in vivo drug dissolution/absorption was predicted for the included ICSs from in vitro aerodynamic particle size distribution and in vitro drug solubility estimates measured in an in vivo predictive dissolution medium. Approach 2 derived a first order absorption rate from the mean dissolution time (MDT), determined for the test formulations in an in vitro Transwell^® based dissolution system.

Results

Approach 1 suggested PK profiles which agreed well with the published pharmacokinetic profiles. Similarly, within approach 2, input parameters for the pulmonary absorption rate constant derived from dissolution rate experiments were able to reasonably predict the pharmacokinetic profiles published in literature.

Conclusion

Approach 1 utilizes more complex strategies for predicting the dissolution/absorption process without providing a significant advantage over approach 2 with regard to accuracy of in vivo predictions.

     

Bioactive flavanoids from <Emphasis Type="Italic">Glycosmis arborea</Emphasis>

Background

Glycosmis is a genus of evergreen glabrous shrub and distributed all over India. It possesses various medicinal properties and is used in indigenous medicine for cough, rheumatism, anemia, and jaundice. Glycosmis arborea is a rich source of alkaloids, terpenoids, coumarins, as well as flavonoids.

Results

The chemical investigation of methanol fraction of the leaves of G. arborea led to the isolation of one new flavone C-glycoside along with three known flavanoids, named as 5,7-dihydroxy-2-[4-hydroxy-3-(methoxy methyl) phenyl]-6-C-β-d-glucopyranosyl flavone (4), 5,7,4^′-trihydroxy-3^′-methoxy flavone (1), 5,4^′-dihydroxy-3^′-methoxy-7-O-β-d-glucupyranosyl flavanone (2), and 5,4^′-dihydroxy-3^′-methoxy-7-O-(α-l-rhamnosyl-(1?→6?)-β-d-glucopyranosyl) flavanone (3), respectively. The structures of all compounds were elucidated with the help of nuclear magnetic resonance spectrometry. Pure compounds and fractions were evaluated for pest antifeedant and antimicrobial activity.

Conclusion

Four compounds were isolated from the leaves of G. arborea. Among them, compound 4 showed significant antimicrobial activity.

     

Porcine and Human <Emphasis Type="Italic">In Vivo</Emphasis> Simulations for Doxorubicin-Containing Formulations Used in Locoregional Hepatocellular Carcinoma Treatment

It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles. A porcine semi-physiologically based pharmacokinetic (PBPK) model was scaled to a human physiologically based biopharmaceutical (PBBP) model that was altered to include HCC. DOX in vitro and in vivo release data from LIPDOX or DEBDOX were collected from the literature and combined with these in silico models. The simulated pharmacokinetic profiles were then compared with observed porcine and human HCC patient data. DOX pharmacokinetic profiles of LIPDOX-treated HCC patients were best predicted from release data sets acquired by in vitro methods that did not use a diffusion barrier. For the DEBDOX group, the best predictions were from the in vitro release method with a low ion concentration and a reduced loading dose. The in silico modeling combined with historical release data was effective in predicting in vivo plasma exposure. This can give useful insights into the release method properties necessary for correct in vivo predictions of pharmacokinetic profiles of HCC patients dosed with LIPDOX or DEBDOX.     

<Emphasis Type="Italic">In Vitro</Emphasis>-<Emphasis Type="Italic">In Vivo</Emphasis> Dose Response of Ursolic Acid,Sulforaphane, PEITC,and Curcumin in Cancer Prevention

According to the National Center of Health Statistics, cancer was the culprit of nearly 600,000 deaths in 2016 in the USA. It is by far one of the most heterogeneous diseases to treat. Treatment for metastasized cancers remains a challenge despite modern diagnostics and treatment regimens. For this reason, alternative approaches are needed. Chemoprevention using dietary phytochemicals such as triterpenoids, isothiocyanates, and curcumin in the prevention of initiation and/or progression of cancer poses a promising alternative strategy. However, significant challenges exist in the extrapolation of in vitro cell culture data to in vivo efficacy in animal models and to humans. In this review, the dose at which these phytochemicals elicit a response in vitro and in vivo of a multitude of cellular signaling pathways will be reviewed highlighting Nrf2-mediated antioxidative stress, anti-inflammation, epigenetics, cytoprotection, differentiation, and growth inhibition. The in vitro-in vivo dose response of phytochemicals can vary due, in part, to the cell line/animal model used, the assay system of the biomarker used for the readout, chemical structure of the functional analog of the phytochemical, and the source of compounds used for the treatment study. While the dose response varies across different experimental designs, the chemopreventive efficacy appears to remain and demonstrate the therapeutic potential of triterpenoids, isothiocyanates, and curcumin in cancer prevention and in health in general.     

Three new <Emphasis Type="Italic">C</Emphasis>-glycosyflavones with acetyl substitutions from <Emphasis Type="Italic">Swertia mileensis</Emphasis>

Three new acetylated C-glycosylflavones, 3″,6″-di-O-acetylswertiajaponin (1), 4″,6″-di-O-acetylswertiajaponin (2), and 6″-O-acetylswertiajaponin (3), together with six known compounds were isolated from the whole herb of Swertia mileensis. Their structures were elucidated on extensive NMR experiments and mass spectrometry studies. ¹H and ¹³C NMR data exhibited doublet signals at room temperature. Variable temperature ¹H NMR experiments were carried out to investigate the presence of rotational isomerism of C-glycosylflavones. All compounds showed potential antioxidant activities against apoptosis of H₂O₂-induced human embryo liver L02 cells.     

Two new ursane-type triterpenoid saponins from <Emphasis Type="Italic">Elsholtzia bodinieri</Emphasis>

Two new ursane-type triterpenoid saponins, bodiniosides M (1) and N (2), along with three known saponins, oblonganosides I (3), pseudobuxussaponin B (4) and bodinioside A (5), were isolated from the aerial parts of Elsholtzia bodinieri. The structures of compounds 1 and 2 were characterized by spectroscopic data as well as acid hydrolysis and GC analysis as 3-O-β-d-xylopyranosyl-19α-hydroxy-23-acetoxy-urs-12(13)-en-28-oic acid 28-O-α-l-rhamnopyranosyl-(1-2)-β-d-glucopyranoside and 3-O-β-d-glucopyranosyl-2α,19α-dihydroxy-urs-12(13)-en-28,20β-lactone. Compounds 1 and 5 exhibited potent anti-HCV activities in vitro with a selective index of 6.53 and 4.41, respectively.     

Bioequivalence Methodologies for Topical Drug Products: <Emphasis Type="BoldItalic">In Vitro</Emphasis> and <Emphasis Type="BoldItalic">Ex Vivo</Emphasis> Studies with a Corticosteroid and an Anti-Fungal Drug

Objective

To examine whether in vitro and ex vivo measurements of topical drug product performance correlate with in vivo outcomes, such that more efficient experimental approaches can be reliably and reproducibly used to establish (in)equivalence between formulations for skin application.

Materials and Methods

In vitro drug release through artificial membranes, and drug penetration into porcine skin ex vivo, were compared with published human in vivo studies. Two betamethasone valerate (BMV) formulations, and three marketed econazole nitrate (EN) creams were assessed.

Results

For BMV, the stratum corneum (SC) uptake of drug in 6 h closely matched data observed in vivo in humans, and distinguished between inequivalent formulations. SC uptake of EN from the 3 creams mirrored the in vivo equivalence in man (both clinically and via similar tape-stripping experiments). However, EN clearance from SC ex vivo did not parallel that in vivo, presumably due to the absence of a functioning microcirculation. In vitro release of BMV from the different formulations did not overlap with either ex vivo or in vivo tape-stripping data whereas, for EN, a good correlation was observed. No measurable permeation of either BMV or EN was detected in a 6-h in vitro skin penetration experiment.

Conclusions

In vitro and ex vivo methods for topical bioequivalence determination can show correlation with in vivo outcomes. However, these surrogates have understandable limitations. A “one-size-fits-all” approach for topical bioequivalence evaluation may not always be successful, therefore, and the judicious use of complementary methods may prove a more effective and reliable strategy.

     

Two new phenylpropane glycosides from <Emphasis Type="Italic">Allium tuberosum</Emphasis> Rottler

A phytochemical investigation of Allium tuberosum Rottler afforded two new phenylpropane glycosides, named tuberonoid A (1) and B (2), along with four known flavonoids, kaempferol 3-O-β-sophoroside (3), 3-O-β-d-(2-O-feruloyl)-glucosyl-7,4′-di-O-β-d-glucosylkaempferol (4), 3-O-β-sophorosyl-7-O-β-d-(2-O-feruloyl)glucosyl kaempferol (5), kaempferol 3,4′-di-O-β-d-glucoside (6). The identification and structural elucidation of the new compounds were carried out based on spectral data analyses (¹H and ¹³C NMR, ¹H–¹H COSY, HMQC) and HR-MS.     

Examining the Use of a Mechanistic Model to Generate an <Emphasis Type="Italic">In Vivo</Emphasis>/<Emphasis Type="Italic">In Vitro</Emphasis> Correlation: Journey Through a Thought Process

The attention and interest in establishing in vivo/in vitro correlations (IVIVCs) is grounded in its tremendous utility as a prognostic tool. It can be used to support formulation optimization, predict in vivo drug exposure across a potential patient population, select a biologically relevant in vitro dissolution test condition, and support the use of in vitro dissolution data as a surrogate for in vivo bioequivalence trials. The pharmacological and statistical implications of this correlation are linked to the method by which the IVIVC was determined and to the assumptions and optimization approaches integrated into the estimation procedure. Using previously published data generated in normal healthy volunteers, an IVIVC for metoprolol was established using a mechanistic modeling approach. Within that framework, we explored the consequences of (1) our method of fitting a single Weibull function to the in vivo dissolution, (2) our selection of weighting scheme and optimization approaches, (3) the impact of applying a fixed versus fitted gastric emptying time, and 4) the importance of factoring population variability into our IVIVC estimation and profile reconvolution. We identified those factors found to be critical in terms of their influence on the accuracy of our predicted systemic metoprolol concentration-time profiles. We considered the strengths and weaknesses of our approach and discussed how the results of this study may impact efforts to generate IVIVCs with compounds presenting physicochemical characteristics different from that of metoprolol.     

Phenylacylphenol derivatives with anti-melanogenic activity from <Emphasis Type="Italic">Stewartia pseudocamellia</Emphasis>

Three new phenylacylphenol derivatives, stewartianol (1), deoxystewartianol-4′-O-arabinoglucoside (2), and stewartianol-3-O-glucoside (3), along with nine known compounds, methylesculin (4), fraxoside (5), fraxetin (6), scopletin (7), (+)-dihydromyricetin (8), (+)-taxifolin-7-O-β-d-glucose (9), (+)-taxifolin (10), (+)-dihydrokaempferol-7-O-β-d-glucose (11), and 3-acetyl-ursolic acid (12), were isolated from the twigs of Stewartia pseudocamellia; commonly used as folk medicine in Korea. The structures of the isolated compounds were identified using spectroscopic analysis, including 1D, 2D NMR, MS and compared with published data. The compounds were tested for their anti-melanogenic activity in cultured murine B16 melanoma cells. Stewartianol (1) and stewartianol-3-O-glucoside (3) showed an inhibitory effect significantly on melanogenesis in a concentration-dependent manner.     

Influence of Copolymer Composition on <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Performance of Celecoxib-PVP/VA Amorphous Solid Dispersions

Previous studies suggested that an amorphous solid dispersion with a copolymer consisting of both hydrophobic and hydrophilic monomers could improve the dissolution profile of a poorly water-soluble drug compared to the crystalline form. Therefore, this study investigated the influence of the copolymer composition of polyvinylpyrrolidone/vinyl acetate (PVP/VA) on the non-sink in vitro dissolution behavior and in vivo performance of celecoxib (CCX) amorphous solid dispersions. The study showed that the hydrophilic monomer vinylpyrrolidone (VP) was responsible for the generation of CCX supersaturation whereas the hydrophobic monomer vinyl acetate (VA) was responsible for the stabilization of the supersaturated solution. For CCX, there was an optimal copolymer composition around 50–60% VP content where further replacement of VP monomers with VA monomers did not have any biopharmaceutical advantages. A linear relationship was found between the in vitro AUC_0-4h and in vivo AUC_0-24h for the CCX:PVP/VA systems, indicating that the non-sink in vitro dissolution method applied in this study was useful in predicting the in vivo performance. These results indicated that when formulating a poorly water-soluble drug as an amorphous solid dispersion using a copolymer, the copolymer composition has a significant influence on the dissolution profile and in vivo performance. Thus, the dissolution profile of a drug can theoretically be tailored by changing the monomer ratio of a copolymer with respect to the required in vivo plasma-concentration profile. As this ratio is likely to be drug dependent, determining the optimal ratio between the hydrophilic (dissolution enhancing) and hydrophobic (crystallization inhibiting) monomers for a given drug is imperative.     

In vitro antimicrobial and acetylcholinesterase inhibitory activities of coumarins from <Emphasis Type="Italic">Ferulago</Emphasis><Emphasis Type="Italic">carduchorum</Emphasis>

Ferulago carduchorum (Apiaceae) is an endemic plant of Iran. From the hexane and ethyl acetate extracts of F. carduchorum seven coumarins, one flavonoid and one steroid were isolated using column chromatography with silica gel and Sephadex LH₂₀ as the stationary phases. Antimicrobial activity of the isolated compounds was examined by a broth microdilution method. Acetylcholinesterase (AChE) inhibitory activity of isolated coumarins was also investigated. The isolated compounds were identified as suberosin, suberenol, bergapten, xanthotoxin, isopimpinellin, prantschimgin, β-sitosterol and hesperetin by comparison of their NMR and MS spectral data with those reported in the literature. Evaluation of the minimum inhibitory concentration (MIC) for each compound showed that hesperetin (flavonoid) was the most potent antimicrobial agent against a gram-positive bacterium (Staphylococcus aureus) and among the coumarins, bergapten had the best activity against S. aureus and Candida albicans. All coumarins inhibited AchE enzyme, in which xanthotoxin showed the most inhibitory among them (IC₅₀ = 39.64 µM). Our results indicate that isolated coumarins are effective against the tested bacterial strains and have AchE inhibitory activity suggesting their potential for commercial applications.     

Time Scaling for <Emphasis Type="Italic">In Vitro-In Vivo</Emphasis> Correlation: the Inverse Release Function (IRF) Approach

In vitro-in vivo correlations (IVIVC) are methods used to create a link between biopharmaceutical properties such as dissolution and physiological response such as plasma concentration. Level A IVIVC defines 1:1 relationship between the percent absorbed in vivo and the percent dissolved in vitro. A successful level A IVIVC provides the capacity to predict in vivo behavior based only on in vitro data with application in formulation development and support of biowaivers recognized by regulatory agencies across the world. Level A regression may be complicated due to differences in time scales as well as the lack of coincident times of similar release in vitro and in vivo leading to approximate time-to-time links and subsequent loss of information. Here, a novel method to establish Levy’s plot and to provide time scaling for improved IVIVC predictive capacity is presented. The method is mathematically closed and is an inverse release function (IRF) characterizing the single (or more) phases of dissolution/absorption. It uses the complete set of information available from all time points both in vitro and in vivo. An extended-release formulation development situation is presented with three increasing release rate test products compared in a trial versus a reference product. First, the standard level A regression was made. Prediction errors for internal validation were higher than 10% for C_max. The IRF method was applied to obtain the in vitro times of percentage dissolved equivalent to percentage absorbed. The prediction errors from the IRF level A correlation were nearly negligible.     

A new indole glycoside from the seeds of <Emphasis Type="Italic">Raphanus sativus</Emphasis>

A new indole glycoside, β-d-glucopyranosyl 2-(methylthio)-1H-indole-3-carboxylate, named raphanuside A (1), as well as eight known compounds, β-d-fructofuranosyl-(2 → 1)-(6-O-sinapoyl)-α-d-glucopyranoside (2), (3-O-sinapoyl)-β-d-fructofuranosyl-(2 → 1)-α-d-glucopyranoside (3), (3-O-sinapoyl)-β-d-fructofuranosyl-(2 → 1)-(6-O-sinapoyl)-α-d-glucopyranoside (4), (3,4-O-disinapoyl)-β-d-fructofuranosyl-(2 → 1)-(6-O-sinapoyl)-α-d-glucopyranoside (5), isorhamnetin 3,4′-di-O-β-d-glucoside (6), isorhamnetin 3-O-β-d-glucoside-7-O-α-l-rhamnoside (7), isorhamnetin 3-O-β-d-glucoside (8) and 3'-O-methyl-(?)-epicatechin 7-O-β-d-glucoside (9) were isolated from the seeds of Raphanus sativus. Furthermore, compounds 1–3 and 6–9, were isolated from this plant for the first time. The structures of compounds 1–9 were identified using 1D and 2D NMR, including ¹H–¹H COSY, HSQC, HMBC and NOESY spectroscopic analyses. The inhibitory activity of these isolated compounds against interleukin-6 (IL-6) production in TNF-α stimulated MG-63 cells was also examined.     

Effect of Gastric Fluid Volume on the <Emphasis Type="Italic">In Vitro</Emphasis> Dissolution and <Emphasis Type="Italic">In Vivo</Emphasis> Absorption of BCS Class II Drugs: a Case Study with Nifedipine

Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large inter-patient variability in nifedipine absorption results in variable exposure among different patients. We conducted in vitro dissolution studies to compare nifedipine dissolution from immediate release (IR) capsules with different volumes of dissolution media. Results from dissolution studies were used to design a crossover study in healthy volunteers to evaluate the effect of coadministered water volume with nifedipine 10 mg IR capsules on nifedipine pharmacokinetics, especially absorption (C _max, t _max, and AUC_0-6). Dissolution studies demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution from 10 mg IR cosolvent capsules (73 vs. 17% in 200 and 100 mL simulated gastric fluid, respectively, at 30 min). The pharmacokinetic crossover study in healthy volunteers (N?=?6) did not show a significant effect of the water volume administered with the capsule (50 vs. 250 mL) on C _max, t _max, or AUC_0-6 of orally administered nifedipine IR capsules (10 mg). However, administration of large water volumes resulted in lower variability in nifedipine C _max (47 vs. 70% for 250 and 50 mL, respectively). Administration of large water volumes with nifedipine 10 mg IR cosolvent capsules may reduce inter-individual variability in plasma exposure. Evaluation of similar effects in other BCS Class II drugs is recommended.