Dermal Microdialysis Technique to Evaluate the Trafficking of Surface-Modified Lipid Nanoparticles upon Topical Application

Purpose

To evaluate the skin pharmacokinetics and tissue distribution of cell penetrating peptides (CPP) modified nano-structured lipid carrier (NLC) using an in vivo dermal microdialysis (MD) technique.

Methods

Celecoxib (Cxb) encapsulated NLCs (CXBN), CPP modified CXBN (CXBN-CPP) and Cxb-Solution (CXBS) formulations were prepared and tested for in vitro skin distribution. MD was used to assess pharmacokinetic parameters of Cxb after topical application of Cxb formulations. The effect of pre-treatment with Cxb formulations was evaluated for expression of prostaglandin-E2 (PGE₂) and Interleukin-6 (IL-6) after exposure of xylene using MD. Allergic contact dermatitis (ACD) model was used to confirm in vivo therapeutic response of Cxb formulations.

Results

The cumulative permeation of Cxb in MD dialysate after 24 h for CXBN-CPP was significantly higher (p?2 and IL-6 expression compared to CXBS and CXBN (p?p?Conclusions Surface modification of NLC with CPPs can enhance the skin permeation of Cxb and MD can be used to investigate pharmacokinetics of Cxb nanoparticles in the skin.     

Skin Permeation of Small-Molecule Drugs, Macromolecules, and Nanoparticles Mediated by a Fractional Carbon Dioxide Laser: The Role of Hair Follicles

Purpose

To evaluate skin permeation enhancement mediated by fractional laser for different permeants, including hydroquinone, imiquimod, fluorescein isothiocyanate-labeled dextran (FD), and quantum dots.

Methods

Skin received a single irradiation of a fractional CO₂ laser, using fluence of 2 or 4 mJ with densities of 100?～?400 spots/cm². In vitro and in vivo skin penetration experiments were performed. Fluorescence and confocal microscopies for imaging delivery pathways were used.

Results

The laser enhanced flux of small-molecule drugs 2?～?5-fold compared to intact skin. A laser fluence of 4 mJ with a 400-spot/cm² density promoted FD flux at 20 and 40 kDa from 0 (passive transport) to 0.72 and 0.43 nmol/cm²/h, respectively. Microscopic images demonstrated a significant increase in fluorescence accumulation and penetration depth of macromolecules and nanoparticles after laser exposure. Predominant routes for laser-assisted delivery may be intercellular and follicular transport. CO₂ laser irradiation produced 13-fold enhancement in follicular deposition of imiquimod. Laser-mediated follicular transport could deliver permeants to deeper strata. Skin barrier function as determined by transepidermal water loss completely recovered by 12 h after irradiation, much faster than conventional laser treatment (4 days).

Conclusions

Fractional laser could selectively enhance permeant targeting to follicles such as imiquimod and FD but not hydroquinone, indicating the importance of selecting feasible drugs for laser-assisted follicle delivery.     

In Vitro and In Vivo Characterisation of PEG-Lipid-Based Micellar Complexes of Salmon Calcitonin for Pulmonary Delivery

Purpose

To investigate DSPE-PEG₂₀₀₀-based micellar formulations of salmon calcitonin (sCT) for their ability to improve pulmonary delivery.

Methods

Micelles were characterised by DLS and ³¹P-NMR spectroscopy. Stability against sCT degrading peptidases, trypsin, ??-chymotrypsin and neutrophil elastase as well as their influence on transepithelial absorption was investigated in vitro. In vivo perfomance of sCT micelles was studied in an experimental model of intratracheal aerosolisation into rats.

Results

Micelles with a mean hydrodynamic diameter of 12?nm spontaneously assembled, when a total concentration of 0.02?mM of PEG-lipid and sCT (at 1:1 molar ratio) was exceeded. Nuclear magnetic resonance confirmed the presence of small micellar structures. The micellar formulation showed increased stability against enzymatic digestion. In vitro studies also showed that sCT micelles were able to enhance transepithelial absorption. Data obtained from in vivo experiments provided evidence of significantly (P?AUC _inf and a relative bioavailability of 160?±?55% when compared to plain sCT solution.

Conclusions

The herein described PEG-lipid micelles are promising carriers for enhanced pulmonary delivery of sCT.     

Impact of Different Vehicles for Laser-Assisted Drug Permeation via Skin: Full-Surface versus Fractional Ablation

Purpose

This study aimed to assess impact of different vehicles for laser-assisted skin drug delivery. We also tried to uncover the mechanisms by which different vehicles affect laser-aided skin permeation.

Methods

Full-surface ablative (conventional) and fractional lasers were used to irradiate nude mouse skin. Imiquimod and 5-aminolevulinic acid (ALA) were used as lipophilic and hydrophilic permeants. Vehicles employed included water with 40% polyethylene glycol 400 (PEG 400), propylene glycol (PG), and ethanol. Lipid nanoparticles were also utilized as carriers.

Results

In vitro permeation profiles showed improvement in imiquimod flux with conventional laser (2.5 J/cm²) producing a 12-, 9-, and 5-fold increase when loading imiquimod in 40% PEG400, PG, and ethanol, respectively, as compared with intact skin. Nanoparticulate delivery by laser produced a 6-fold enhancement in permeation. Fractional laser produced less enhancement of imiquimod delivery than conventional laser. Laser exposure increased follicular imiquimod accumulation from 0.80 to 5.81 μg/cm². ALA permeation from aqueous buffer, PEG 400, and PG with conventional laser treatment was 641-, 445-, and 104-fold superior to passive control. In vivo skin deposition of topically applied ALA examined by confocal microscopy indicated the same trend as the in vitro experiment, with aqueous buffer showing the greatest proporphyllin IX signaling. Diffusion of cosolvent molecules into ablated skin and drug partitioning from vehicle to skin are two predominant factors controlling laser-assisted delivery. In contrast to conventional laser, lateral drug diffusion was anticipated for fractional laser.

Conclusions

Our results suggest that different drug delivery vehicles substantially influence drug penetration enhanced by lasers.     

Tumor-Targeted Responsive Nanoparticle-Based Systems for Magnetic Resonance Imaging and Therapy

Purpose

Design and synthesis of a tumor responsive nanoparticle-based system for imaging and treatment of various cancers.

Methods

Manganese oxide nanoparticles (Mn₃O₄ NPs) were synthesized and modified with LHRH targeting peptide or anti-melanoma antibodies (cancer targeting moieties) and a MMP2 cleavable peptide (a possible chemotactic factor). Nanostructured lipid carriers (NLCs) were used to entrap the BRAF inhibitor, vemurafenib, and enhance cytotoxicity of the drug. Size distribution, stability, drug entrapment, cytotoxicity and genotoxicity of synthesized nanoparticles were studied in vitro. Enhancement of MRI signal by nanoparticles and their body distribution were examined in vivo on mouse models of melanoma, ovarian and lung cancers.

Results

Uniform, stable cancer-targeted nanoparticles (PEGylated water-soluble Mn₃O₄ NPs and NLCs) were synthesized. No signs of cyto-,genotoxicity and DNA damage were detected for nanoparticles that do not contain an anticancer drug. Entrapment of vemurafenib into nanoparticles significantly enhanced drug toxicity in cancer cells with targeted V600E mutation. The developed nanoparticles containing LHRH and MMP2 peptides showed preferential accumulation in primary and metastatic tumors increasing the MRI signal in mice with melanoma, lung and ovarian cancers.

Conclusions

The proposed nanoparticle-based systems provide the foundation for building an integrated MRI diagnostic and therapeutic approach for various types of cancer.     

In Vivo Antitumor Activity of a Novel Orally Bioavailable Ifosfamide Nanostructured Lipid Carrier Against Dalton’s Ascitic Lymphoma

Purpose

Ifosfamide is a widely used antineoplastic drug belonging to the alkylating agents. It is difficult to develop a conventional oral dosage form as it degrades in acidic media, with its rate of degradation depending on the pH of the solution. Thereby, ifosfamide is available either as a powder which is reconstituted with diluents for injection or as injectable solution. The present work has attempted to improve oral bioavailability of ifosfamide by incorporating in nanostructured lipid carriers (NLCs). The purpose of this research was to study whether the oral bioavailability of ifosfamide could be improved by administering ifosfamide-loaded NLCs.

Method

Ifosfamide NLCs were developed using chitosan cross-linking with sodium alginate by solvent diffusion technique. Bioavailability studies were conducted in albino rats after oral administration of ifosfamide suspension and NLC. In vivo antitumor activity of ifosfamide nanostructured lipid carrier against Dalton’s ascitic lymphoma (DAL) was also investigated.

Results

The results showed that the relative bioavailability of ifosfamide from NLC was increased by sixfold higher than that of ifosfamide suspension. Administration of ifosfamide NLC significantly decreased the tumor volume and viable cell count. Nonviable cell count was significantly higher in ifosfamide NLC-treated animals when compared with DAL control animals. Further, the median survival time was increased to 35 % on administration of ifosfamide NLC. Ifosfamide NLC significantly decreased biochemical parameters, increased the RBC count and Hb content, and reduced the WBC count as well.

Conclusions

The results of this study show no significant difference in the antitumor efficacy of ifosfamide when administered as injection and nanoformulation. The obtained results are indicative of NLCs as potential carriers for improving the oral bioavailability and acid instability problems. The new nanoformulation would be interchangeable with the standard formulation.     

Nano Composite Emulsion for Sustained Drug Release and Improved Bioavailability

Purpose

To propose a novel composite nanoemulsion formulation that contains no surfactant, but offers great stability and improved oral absorption capabilities.

Methods

The nanoemulsions were prepared by dispersing the oil phase into aqueous solutions containing different amounts of the PMMA/silica composite nanoparticles. The stability was tested under extreme conditions. The structure features of the nanoemulsion droplets were investigated using Electron microscope. The in vitro drug release and in vivo drug absorption profiles after oral administration were investigated using Cyclosporin A as a model drug.

Results

The composite nanoemulsion demonstrated great stability under various disruptive conditions. Electron microscopy studies indicated the existence of internal and surface domains in the nano-droplet structure. In vitro drug release and in vivo uptake characterizations also confirmed the unique interfacial properties of such nanoemulsion structures.

Conclusions

The novel nanoemulsion formulation may have modulated drug release profiles and alternative oral absorption mechanisms, which could offer significant advantages compared to traditional emulsion formulations.     

Investigation of Follicular and Non-follicular Pathways for Polyarginine and Oleic Acid-Modified Nanoparticles

Purpose

To investigate the percutaneous permeation pathways of cell penetrating peptide modified lipid nanoparticles and oleic acid modified polymeric nanoparticles.

Methods

Confocal microscopy was performed on skin cultures (EpiDermFT?) for modified and un-modified nanoparticles. Differential stripping was performed following in vitro skin permeation of Ibuprofen (Ibu) encapsulated nanoparticles to estimate Ibu levels in different skin layers and receiver compartment. The hair follicles (HF) were blocked and in vitro skin permeation of nanoparticles was then compared with unblocked HF. The surface modified nanoparticles were investigated for response on allergic contact dermatitis (ACD).

Results

Surface modified nanoparticles showed a significant higher (p?<?0.05) in fluorescence in EpiDermFT? cultures compared to controls. The HF play less than 5% role in total nanoparticle permeation into the skin. The Ibu levels were significantly high (p?<?0.05) for surface modified nanoparticles compared to controls. The Ibu levels in skin and receiver compartment were not significantly different when HF were open or closed. Modified nanoparticles showed significant improvement in treatment of ACD compared to solution.

Conclusions

Our studies demonstrate that increased skin permeation of surface modified nanoparticles is not only dependent on a follicular pathway but also occur through non-follicular pathway(s).     

Assessment of the Lateral Diffusion and Penetration of Topically Applied Drugs in Humans Using a Novel Concentric Tape Stripping Design

Purpose

To determine the extent of lateral spread and stratum corneum (SC) penetration of caffeine (CAF), hydrocortisone (HC) and ibuprofen (IBU) using a novel concentric tape stripping technique.

Method

Ethanolic solutions of CAF, HC or IBU were applied to the forearm of 8 volunteers. At various time points, 10 successive layers of SC were removed by stripping with tapes perforated into concentric rings and analysed for drug concentration and mass of SC protein. In vitro permeation studies assessed the percutaneous absorption of these compounds across human skin.

Results

CAF and IBU showed significant lateral spreading across the SC while HC formed a drug depot at the site of application. Relative to the applied dose, the in vivo recovery of all compounds from the combined 10 strips at 3?mins ranged between 83.0 and 92.9?% and decreased to between 64.5 and 66.9?% at 3?h. IBU recovery further decreased to 47.7?±?5.6?% at 6?h, correlating with greater in vitro penetration relative to CAF and HC.

Conclusion

Drug concentration decreased with increased lateral distance from the application site. The lower recovery of IBU in the upper tape strip regions compared to CAF and HC may be a consequence of greater penetration into the SC with time.     

Use of In Vitro�CIn Vivo Correlation to Predict the Pharmacokinetics of Several Products Containing a BCS Class 1 Drug in Extended Release Matrices

Purpose

To determine if an IVIVC model can predict PK profiles of varying formulations of a BCS Class 1 drug that is a salt of a weak base.

Method

An IVIVC model (Level A) was created by correlating deconvoluted in vivo absorption data obtained from oral administration of 50?mg, 100?mg, and 200?mg fast and slow extended release formulations with in vitro percent dissolved using residual regression analysis. The model was then used to predict the in vivo profile of five test products that varied in formulation characteristics.

Results

The model passed internal validation for predicted Cmax and AUC. For external validation, in vitro data of five different test formulations was utilized. The model passed external validation for two test formulations that were different but belonging to the same release mechanism as that of the reference formulation. Three formulations failed external validation because they belonged to either a mixed or different release mechanism. The model and results were further confirmed using GatstroPlus? simulation software.

Conclusions

These observations indicate that an IVIVC model for a BCS class I drug may be applicable to varying formulations if the principle of the drug release is similar.     

The role of hair follicles in the percutaneous absorption of caffeine

Aims

The skin and its appendages are our protective shield against the environment and are necessary for the maintenance of homeostasis. Hypotheses concerning the penetration of substances into the skin have assumed diffusion through the lipid domains of the stratum corneum. It is believed that while hair follicles represent a weakness in the shield, they play a subordinate role in the percutaneous penetration processes. Previous investigation of follicular penetration has mostly addressed methodical and technical problems. Our study utilized a selective closure technique of hair follicle orifices in vivo, for the comparison of interfollicular and follicular absorption rates of caffeine in humans.

Methods

Every single hair follicle within a delimited area of skin was blocked with a microdrop of a special varnish-wax-mixture in vivo. Caffeine in solution was topically applied and transcutaneous absorption into the blood was measured by a new surface ionization mass spectrometry (SI/MS) technique, which enabled a clear distinction to be made between interfollicular and follicular penetration of a topically applied substance.

Results

Caffeine (3.75 ng ml⁻¹) was detected in blood samples, 5 min after topical application, when the follicles remained open. When the follicles were blocked, caffeine was detectable after 20 min (2.45 ng ml⁻¹). Highest values (11.75 ng caffeine ml⁻¹) were found 1 h after application when the follicles were open.

Conclusions

Our findings demonstrate that hair follicles are considerable weak spots in our protective sheath against certain hydrophilic drugs and may allow a fast delivery of topically applied substances.

What is already known about this subject

• In recent years, it has been suggested that hair follicles represent important shunt routes into the skin for drugs and chemicals [1–3].
• In vitro studies have shown the importance of skin appendages for skin penetration by hydrophilic compounds [4]. Investigation of follicular penetration in vivo has been difficult due to the absence of appropriate analytical methods or suitable animal model systems.
• Recently, a new method was described that quantifies follicular penetration in vivo by using selective closure of hair follicles [5].
• Caffeine is frequently used in skin penetration experiments as a model for highly water-soluble compounds. Occlusion [6] and skin thickness [7] seem to have little influence on the penetration of caffeine. However, percutaneous absorption rates for caffeine exhibit regional skin differences in humans in vivo[1].

What this study adds

• The results of the present study demonstrate that a fast drug delivery of caffeine occurs through shunt routes. Therefore, hair follicles are considerable weak spots in our protective sheath against penetration into the body by hydrophilic substances.
• We showed that there is a quantitative distinction between follicular penetration and interfollicular diffusion of caffeine in vivo.
• These findings are of importance for the development and optimization of topically applied drugs and cosmetics. In addition, such properties must be considered in the development of skin protection measures.

     

Metal Ions Guided Self-assembly of Therapeutic Proteins for Controllable Release: From Random to Ordered Aggregation

Purpose

To make a comparative study on sustained delivery performance of rhIFN with random amorphous and spherical crystal-like ordered self-assemblies.

Methods

The rhIFN self-assemblies were identified in batch crystallization mode. Physico-chemical characteristics were compared, including morphology, XRD, FTIR, CD, biological potency, the dissolution behaviors in vitro and plasma pharmacokinetics in vivo. Moreover, molecular simulation was performed to better understand their binding site and mode.

Results

Here, we suggest that random amorphous and spherical ordered self-assemblies allow for long action without new molecular entities generation or carriers employed. By manipulating supersaturation, the ordered aggregates were self-organized at high concentration of Zn(II) (>100 mM) in pH 5.5–6.0, which was the first time that spherical semi-crystals of rhIFN can act as a depot source for the sustained delivery of biologically active proteins. The secondary structure and biological potency of rhIFN were unchanged after aggregation. Compared with that of the native rhIFN, both self-assemblies exhibited slower absorption and extended elimination profiles after s.c. administration, which were characterized as 4.75?±?0.82 h and 10.58?±?1.86 h of terminal half-life for random amorphous and spherical ordered self-assemblies, respectively.

Conclusions

The work described here demonstrates the possibility of self-assemblies of biomacromolecules for controllable release application of therapeutic proteins.     

Development of a Bionic System for the Simultaneous Prediction of the Release/Absorption Characteristics of Enteric-Coated Formulations

Purpose

To develop a new bionic system from an existing drug dissolution/absorption simulating system (DDASS) to simultaneously predict the release and absorption of enteric-coated formulations.

Methods

In accordance with the pH-dependent characteristics of enteric-coated formulations, the modified DDASS was designed to effectively imitate the pH change process of the formulations' transfer from stomach to intestine in vivo. Omeprazole enteric-coated tablets were chosen as the model drug to verify the rationality and feasibility of the modified DDASS. The correlations between USP I system release and beagle dog absorption, as well as between modified DDASS elution/permeation and beagle dog absorption, were investigated by linear and nonlinear regression analyses, respectively.

Results

In vitro-in vivo correlation between the modified DDASS elution/permeation method and beagle dog absorption was higher than between the USP I system release and beagle dog absorption in both analytical methods. The ratio of first-order permeation rate constant to first-order release rate constant was consistent with that from modified DDASS.

Conclusions

The modified DDASS provided more information than the USP I system did in the evaluation of enteric-coated formulations. The proposed bionic system model could serve as a new method for improving drug effectiveness.     

Controlling Release of Integral Lipid Nanoparticles Based on Osmotic Pump Technology

Purpose

To achieve controlled release of integral nanoparticles by the osmotic pump strategy using nanostructured lipid carriers (NLCs) as model nanoparticles.

Methods

NLCs was prepared by a hot-homogenization method, transformed into powder by lyophilization, and formulated into osmotic pump tablets (OPTs). Release of integral NLCs was visualized by live imaging after labeling with a water-quenching fluorescent probe. Effects of formulation variables on in vitro release characteristics were evaluated by measuring the model drug fenofibrate. Pharmacokinetics were studied in beagle dogs using the core tablet and a micronized fenofibrate formulation as references.

Results

NLCs are released through the release orifices of the OPTs as integral nanoparticles. Near zero-order kinetics can be achieved by optimizing the influencing variables. After oral administration, decreased C _max and steady drug levels for as long as over 24 h are observed. NLC-OPTs show an oral bioavailability of the model drug fenofibrate similar to that of the core tablets, which is about 1.75 folds that of a fast-release formulation.

Conclusion

Controlled release of integral NLCs is achieved by the osmotic pump strategy.

     

MDR1 and OAT1/OAT3 Mediate the Drug-Drug Interaction between Puerarin and Methotrexate

Purpose

To conduct in vivo and in vitro experiments to investigate puerarin (PUR), an isoflavone C-glyoside, and elucidate its ability to alter methotrexate (MTX) transport and pharmacokinetics.

Methods

In vivo absorption studies, in vitro everted intestinal sac preparation, kidney slices in rats and bi-directional transport assay with mock-/MDCK-MDR1 cells, uptake studies in HEK293-OAT1/3 cells were employed to evaluate the interaction.

Results

In vivo and in vitro MTX absorption in rats were enhanced in combination with PUR. PUR inhibited digoxin efflux transport in MDCK-MDR1 monolayers with an IC₅₀ value of 1.6?±?0.3 μM, suggesting that the first target of drug interaction was MDR1 in the intestine during the absorption process. MTX renal clearance decreased significantly after simultaneous intravenous administration. MTX uptake in rat kidney slices and HEK293-OAT1/3 cells were markedly inhibited by PUR, suggesting that the second target of drug interaction was OATs located in the kidney. Moreover, concomitant administration of PUR reduced renal MTX accumulation and plasma levels of creatinine and BUN.

Conclusions

Co-administration of PUR enhanced MTX exposure by inhibition of intestinal MDR1 and renal OAT1/3. Although the renal damage of MTX was improved by PUR, the high level exposure of MTX should be cautious in the clinical usage.     

In Vivo Evaluation of Doxorubicin-Loaded (PEG)3-PLA Nanopolymersomes (PolyDoxSome) Using DMBA-Induced Mammary Carcinoma Rat Model and Comparison with Marketed LipoDox?

Purpose

To evaluate in vivo doxorubicin-loaded (PEG)₃-PLA nanopolymersomes (PolyDoxSome) using 7,12-dimethyl benz[??]anthracene (DMBA)-induced mammary carcinoma rat model compared to marketed formulation LipoDox?.

Methods

Sprague Dawley female rats with mean tumor volume of about 2?cm³ were used for pharmacokinetics, biodistribution, antitumor efficacy and toxicity studies.

Results

This study demonstrates that PolyDoxSome has higher AUC (569 vs. 4?h*??g/mL), longer plasma circulation half life (21.9 vs. 0.49?h), decreased clearance (10.5 vs. 1579?mL/h/kg) and volume of distribution (137.7 vs. 1091?mL/kg) as compared to free doxorubicin. Tissue distribution profile showed increased doxorubicin concentration in tumor and decreased concentration in heart as compared to free doxorubicin. The toxicity studies as measured from liver function tests, cardiac enzyme assays, hematology test and body weight has demonstrated that it is better tolerated than free doxorubicin. When PolyDoxSome was compared with LipoDox?, it differs in size (171 vs. <100?nm), plasma circulation half life (22 vs. 35?h), C_max (34 vs. 67???g/mL), and AUC (568 vs. 2291?h*??g/mL), however PolyDoxSome was comparable on efficacy and toxicity profile of LipoDox?.

Conclusions

Results suggest that PolyDoxSome has better in vivo profile than free doxorubicin and comparable efficacy and toxicity to LipoDox?.

Utility of Göttingen minipigs for Prediction of Human Pharmacokinetic Profiles After Dermal Drug Application

Purpose

Although Göttingen minipigs have been widely used for the evaluation of skin absorption, the correlation of minipig skin permeability with human skin absorption remains unclear. This study was designed to investigate the prediction of human plasma concentrations after dermal application of drug products using skin permeability data obtained from minipigs.

Methods

First, in vitro skin permeabilities of seven marketed transdermal drug products were evaluated in minipigs, and compared with in vitro human skin permeability data. Next, plasma concentration-time profiles in humans after dermal applications were simulated using the in vitro minipig skin permeability data. Finally, the in vitro-in vivo correlation of minipig skin permeability was assessed.

Results

The in vitro skin permeabilities in minipigs were correlated strongly with in vitro human skin permeability data for the same drug products, indicating the utility of minipig skin as an alternative to human skin for in vitro studies. The steady-state plasma concentration or the maximum concentration of drugs was within 2-fold of the clinical data. Bioavailability was approximately 3-fold lower than in vitro permeated fraction.

Conclusions

Predictions using in vitro skin permeability data in Göttingen minipig skin can reproduce the human pharmacokinetic profile, although the prediction of in vivo skin absorption underestimates human absorption.

     

Biopharmaceutical Modeling of Drug Supersaturation During Lipid-Based Formulation Digestion Considering an Absorption Sink

Purpose

In vitro lipolysis is widely utilized for predicting in vivo performance of oral lipid-based formulations (LBFs). However, evaluation of LBFs in the absence of an absorption sink may have limited in vivo relevance. This study aimed at employing biopharmaceutical modeling to simulate LBF digestion and drug supersaturation in a continuous absorptive environment.

Methods

Three fenofibrate-loaded LBFs were characterized in vitro (dispersion and lipolysis) and drug precipitation was monitored using in-line Raman spectroscopy. In vitro data were combined with pharmacokinetic data derived from an in vivo study in pigs to simulate intestinal LBF transit. This biopharmaceutical model allowed calculation of lipolysis-triggered drug supersaturation while drug and lipolysis products are absorbed from the intestine.

Results

The biopharmaceutical model predicted that, in a continuous absorption environment, fenofibrate supersaturation was considerably lower compared to in vitro lipolysis (non-sink). Hence, the extensive drug precipitation observed in vitro was predicted to be unlikely in vivo. The absorption of lipolysis products increased drug supersaturation, but drug precipitation was unlikely for highly permeable drugs.

Conclusions

Biopharmaceutical modeling is a valuable approach for predicting LBFs performance in vivo. In the absence of in vitro tools simulating absorptive conditions, modeling strategies should be further considered.     

Acid-Responsive Polymeric Nanocarriers for Topical Adapalene Delivery

Purpose

The acne skin is characteristic of a relatively lower pH microenvironment compared to the healthy skin. The aim of this work was to utilize such pH discrepancy as a site-specific trigger for on-demand topical adapalene delivery.

Methods

The anti-acne agent, adapalene, was encapsulated in acid-responsive polymer (Eudragit® EPO) nanocarriers via nanoprecipitation. The nanocarriers were characterized in terms of particle size, surface morphology, drug-carrier interaction, drug release and permeation.

Results

Adapalene experienced a rapid release at pH 4.0 in contrast to that at pH 5.0 and 6.0. The permeation study using silicone membrane revealed a significant higher drug flux from the nanocarrier (6.5?±?0.6 μg.cm^?2.h^?1) in comparison to that (3.9?±?0.4 μg.cm^?2.h^?1) in the control vehicle (Transcutol®). The in vitro pig skin tape stripping study showed that at 24 h post dose-application the nanocarrier delivered the same amount of drug to the stratum corneum as the positive control vehicle did.

Conclusions

The acid-responsive nanocarriers hold promise for efficient adapalene delivery and thus improved acne therapy. Figure

pH liable nanocarriers enhance the adapalene delivery to acne skin.     

Comparison of In Vitro Deposition of Pharmaceutical Aerosols in an Idealized Child Throat with In Vivo Deposition in the Upper Respiratory Tract of Children

Purpose

Deposition of drug emitted from two commercially available inhalers was measured in an in vitro child oral airway model and compared to existing in vivo data to examine the ability of the child model to replicate in vivo deposition.

Methods

In vitro deposition of drug from a QVAR® pressurized metered dose inhaler (pMDI) and Pulmicort® Turbuhaler® dry powder inhaler (DPI) in an Idealized Child Throat (1) and downstream filter was measured using UV spectroscopy and simulated realistic breathing profiles. Potential effects of ambient relative humidity ranging from 10% to 90% on deposition were also considered.

Results

In vitro QVAR pMDI deposition in the idealized mouth-throat at 50% RH (39.2?±?2.3% of delivered dose) compared well (p?>?0.05) with in vivo extrathoracic deposition in asthmatic children age 8 to 14 (45.8?±?12.3%). In vitro Turbuhaler DPI deposition in the idealized mouth-throat at 50% RH (69.0?±?1.5%) matched in vivo extrathoracic deposition (p?>?0.05) in 6 to 16 year old children with cystic fibrosis (70.4?±?21.2%). The effects of ambient humidity were found to be insignificant for Turbuhaler and minor for QVAR.

Conclusions

The Idealized Child Throat successfully mimics in vivo deposition data in school age children for the inhalers tested, and may provide a standard platform for optimizing pediatric treatment with inhaled pharmaceutical aerosols.