Unleashing the healing potential:Exploring next-generation regenerative protein nanoscaffolds for burn wound recovery

Burn injury is a serious public health problem and scientists are continuously aiming to develop promising biomimetic dressings for effective burn wound management.In this study,a greater efficacy in burn wound healing and the associated mechanisms ofα-lactalbumin(ALA)based electrospun nanofibrous scaffolds(ENs)as compared to other regenerative protein scaffolds were established.Bovine serum albumin(BSA),collagen type I(COL),lysozyme(LZM)and ALA were separately blended with poly(ε-caprolactone)(PCL)to fabricate four different composite ENs(LZM/PCL,BSA/PCL,COL/PCL and ALA/PCL ENs).The hydrophilic composite scaffolds exhibited an enhancedwettability and variablemechanical properties.The ALA/PCL ENs demonstrated higher levels of fibroblast proliferation and adhesion than the other composite ENs.As compared to PCL ENs and other composite scaffolds,the ALA/PCL ENs also promoted a better maturity of the regenerative skin tissues and showed a comparable wound healing effect to Collagen sponge^(■)on third-degree burn model.The enhanced wound healing activity of ALA/PCL ENs compared to other ENs could be attributed to their ability to promote serotonin production at wound sites.Collectively,this investigation demonstrated that ALA is a unique protein with a greater potential for burn wound healing as compared to other regenerative proteins when loaded in the nanofibrous scaffolds.

Sustained release donepezil loaded PLGA microspheres for injection:Preparation,in vitro and in vivo study

The purpose of this study was to develop a PLGA microspheres-based donepezil(DP)formulation which was expected to sustain release of DP for one week with high encapsulation efficiency(EE).DP derived from donepezil hydrochloride was encapsulated in PLGA microspheres by the O/W emulsion-solvent evaporation method.The optimized formulation which avoided the crushing of microspheres during the preparation process was characterized in terms of particle size,morphology,drug loading and EE,physical state of DP in the matrix and in vitro and in vivo release behavior.DP microspheres were prepared successfully with average diameter of 30m,drug loading of 15.92±0.31%and EE up to 78.79±2.56%.Scanning electron microscope image showed it has integrated spherical shape with no drug crystal and porous on its surface.Differential scanning calorimetry and X-ray diffraction results suggested DP was in amorphous state or molecularly dispersed in microspheres.The Tg of PLGA was increased with the addition of DP.The release profile in vitro was characterized with slow but continuous release that lasted for about one week and fitted well with first-order model,which suggested the diffusion governing release mechanism.After single-dose administration of DP microspheres via subcutaneous injection in rats,the plasma concentration of DP reached peak concentration at 0.50 d,and then declined gradually,but was still detectable at 15 d.A good correlation between in vitro and in vivo data was obtained.The results suggest the potential use of DP microspheres for treatment of Alzheimer’s disease over long periods.

Co-delivery of resveratrol and docetaxel via polymeric micelles to improve the treatment of drug-resistant tumors

Co-delivery of anti-cancer drugs is promising to improve the efficacy of cancer treatment.This study was aiming to investigate the potential of concurrent delivery of resveratrol(RES)and docetaxel(DTX)via polymeric nanocarriers to treat breast cancer.To this end,methoxyl poly(ethylene glycol)-poly(D,L-lactide)copolymer(mPEG-PDLA)was prepared and characterized using FTIR and 1H NMR,and their molecular weights were determined by GPC.Isobologram analysis and combination index calculation were performed to find the optimal ratio between RES and DTX to against human breast adenocarcinoma cell line(MCF-7 cells).Subsequently,RES and DTX were loaded in the mPEG-PDLA micelles simultaneously,and the morphology,particle size distribution,in vitro release,pharmacokinetic profiles,as well as cytotoxicity to the MCF-7 cells were characterized.IC50 of RES and DTX in MCF-7 cells were determined to be 23.0μg/ml and 10.4μg/ml,respectively,while a lower IC50 of 4.8μg/ml of the combination of RES and DTX was obtained.The combination of RES and DTX at a ratio of 1:1(w/w)generated stronger synergistic effect than other ratios in the MCF-7 cells.RES and DTX loaded mPEG-PDLA micelles exhibited prolonged release profiles,and enhanced cytotoxicity in vitro against MCF-7 cells.The AUC(0→t)of DTX and RES in mPEG-PDLA micelles after i.v.administration to rats were 3.0-fold and 1.6-fold higher than that of i.v.injections of the individual drugs.These findings indicated that the co-delivery of RES and DTX using mPEG-PDLA micelles could have better treatment of tumors.

A donepezil/cyclodextrin complexation orodispersible film: Effect of cyclodextrin on taste-masking based on dynamic process and in vivo drug absorption

The aim of this study was to develop a palatable donepezil(DP) orodispersible film(ODF)to facilitate the swallowing process and investigate the effect of cyclodextrin on tastemasking based on dynamic process and in vivo drug absorption. Complexation of DP with hydroxypropyl-β-cyclodextrin(HP-β-CD) was applied to mask the bitter taste then the prepared complexes were incorporated into ODF using solvent casting method. The tastemasking efficiency was evaluated by e-tongue; meanwhile the pharmacokinetic behavior of DP/HP-β-CD ODF was investigated by in vivo study. Results showed the optimized film was more palatable than donepezil hydrochloride(DH) film and was bioequivalent with DH. The molecular mechanism was revealed by phase solubility study, Fourier-transform infrared spectrometer(FT-IR), Differential scanning calorimeter(DSC), X-ray diffraction(XRD) and molecular modeling. Taste-masking was attributed to the formation of DP/HP-β-CD which was due to moderate interaction between DP and HP-β-CD. The stability of DP/HP-β-CD was decreased because of the acid environment in stomach, which facilitated the absorption of DP. These results extended our understanding about the application of cyclodextrin complexation and provided guidance for the design of ODF especially for drugs with disgusting taste.

Design and evaluation of a novel transdermal patch containing diclofenac and teriflunomide for rheumatoid arthritis therapy

The aim of this study was to design a compound transdermal patch containing diclofenac(DA)and teriflunomide(TEF)for the treatment of rheumatoid arthritis(RA).The various organic amines salts of DA were prepared and their forming was confirmed using DSC and FTIR.The percutaneous permeation of organic amines salt of DA was investigated in vitro using a two-chamber diffusion cell with excised rabbit skin as transdermal barrier.The formulation of the patch was optimized in terms of the concentration of percutaneous permeation enhancer and the loading dose of drugs.The pharmacokinetic behavior of the optimal formulation was studies in rabbits and the anti-inflammatory and analgesic effects of the optimal patch were evaluated with the adjuvant arthritis model in rats and the pain model in mice,respectively.The result showed that skin penetration of diclofenactriethylamine(DA-TEtA)salt was better than other organic amine salts.Based on previous study of our laboratory,teriflunomide-triethylamine(TEF-TEtA)significantly enhanced the skin permeation of TEF.10%of azone(AZ)was the best enhancer for the two drugs.The optimal patch formulation was composed of 2%of TEF-TEtA,6%of DA-TEtA and 10%of AZ.The cumulative permeated amount of DA-TEtA in vitro was comparable with that of the commercial diclofenac-diethylamine(DA-DEtA)patch.The absolute bioavailability of TEFTEtA was 42%,which could achieve the therapeutic drug levels.In animal study,the optimized compound patch containing DA-TEtA and TEF-TEtA displayed significant antiinflammatory and analgesic effect,which indicated the potential of the compound patch.

In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug

This study aims to understand the absorption patterns of three different kinds of inhaled formulations via in silico modeling using budesonide(BUD)as a model drug.The formulations investigated in this study are:(i)commercially available micronized BUD mixed with lactose(BUD-PT),(ii)BUD nanocrystal suspension(BUD-NC),(iii)BUD nanocrystals embedded hyaluronic acid microparticles(BUD-NEM).The deposition patterns of the three inhaled formulations in the rats’lungs were determined in vivo and in silico predicted,which were used as inputs in GastroPlus TM software to predict drug absorption following aerosolization of the tested formulations.BUD pharmacokinetics,estimated based on intravenous data in rats,was used to establish a drug-specific in silico absorption model.The BUD-specific in silico model revealed that drug pulmonary solubility and absorption rate constant were the key factors affecting pulmonary absorption of BUD-NC and BUD-NEM,respectively.In the case of BUD-PT,the in silico model revealed significant gastrointestinal absorption of BUD,which could be overlooked by traditional in vivo experimental observation.This study demonstrated that in vitro-in vivo-in silico approach was able to identify the key factors that influence the absorption of different inhaled formulations,which may facilitate the development of orally inhaled formulations with different drug release/absorption rates.

Evaluating the pharmacokinetics of intrapulmonary administered ciprofloxacin solution for respiratory infections using in vivo and in silico PBPK rat model studies

Respiratory antibiotics have been proven clinically beneficial for the treatment of severe lung infections such as Pseudomonas aeruginosa.Maintaining a high local concentration of inhaled antibiotics for an extended time in the lung is crucial to ensure an adequate antimicrobial efficiency.In this study,we aim to investigate whether an extended exposure of ciprofloxacin(CIP),a model fluoroquinolone drug,in the lung epithelial lining fluid(ELF)could be achieved via a controlled-release formulation strategy.CIP solutions were intratracheally instilled to the rat lungs at 3 different rates,i.e.,T0h(fast),T2h(medium),and T4h(slow),to mimic different release profiles of inhaled CIP formulations in the lung.Subsequently,the concentration-time profiles of CIP in the plasma and the lung ELF were obtained,respectively,to determine topical exposure index(ELF-Plasma AUC Ratio,EPR).The in silico PBPK model,validated based on the in vivo data,was used to identify the key factors that influence the disposition of CIP in the plasma and lungs.The medium and slow rates groups exhibited much higher EPR than that fast instillation group.The ELF AUC of the medium and slow instillation groups were about 200 times higher than their plasma AUC.In contrast,the ELF AUC of the fast instillation group was only about 20 times higher than the plasma AUC.The generated whole-body PBPK rat model,validated by comparison with the in vivo data,revealed that drug pulmonary absorption rate was the key factor that determined pulmonary absorption of CIP.This study suggests that controlled CIP release from inhaled formulations may extend the exposure of CIP in the ELF post pulmonary administration.It also demonstrates that combining the proposed intratracheal installation model and in silico PBPK model is a useful approach to identify the key factors that influence the absorption and disposition of inhaled medicine.

Pharmaceutical strategies to extend pulmonary exposure of inhaled medicines

Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma,chronic obstructive pulmonary diseases and respiratory infections,and systemic diseases such as diabetes.Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit.The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration,but also enhance the clinical benefits to the patients with improved therapeutic outcomes.This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines.It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure,which is followed by recent advances in various strategies to overcome these barriers.Finally,the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized.

Formulation and in vitro characterization of long-acting PLGA injectable microspheres encapsulating a peptide analog of LHRH

The present study aimed to formulate triptorelin acetate(TA)into poly(D,L-lactic-co-glycolic)acid(PLGA)based injectable sustained-release microspheres(TA-PLGA-MS)by usingdouble emulsion solvent extraction/evaporation(DESE)technique and investigate the effects of various material attributes and process parameters on the quality attributes such as size,shape,surface morphology,encapsulation efficiency(EE)and in vitro release behavior of these microspheres.Variable compositions of the outer water phase,type of the organic solvents,volume ratios of inner water phase to oil phase,PLGA concentrations,and the powers for emulsification in the preparation of the microspheres showed an influence on their quality attributes.An optimal formulation(F-2)obtained from this univariate approach possess an excellent EE value of 63.5%±3.4%and an average volumetric particle size of 35.3±1.8μm.This formulation was further accomplished with different solidification rates assisted by variable incubation temperatures,which exhibited an impact on the shape/surface and inner morphology of the microspheres.The resultant microspheres also displayed different in vitro release patterns.The matrices processed with a high incubation temperature conferred the fastest and the most complete drug release profile over the period of 63 days.Thus,the solidification rate could be identified as one of the critical process parameters that affected the quality of the PLGA based injectable microspheres specifically designed for the prolonged delivery of TA.