Special Issue "Delivery Systems of Peptides and Proteins: Challenges, Status Quo and Future Perspectives".

Peptides and proteins have emerged as more important therapeutic molecules compared to small molecular chemicals due to their high specificity and efficacy and low toxicity [...].

Evaluation of the efficacy and safety of ionic liquids containing ketoconazole in patients with tinea pedis: A randomized controlled clinical trial.

Ionic liquids (ILs) loading ketoconazole (KCZ) have shown better efficacy on rats with tinea pedis than the marketed Daktarin® but clinical studies are still lacking. In this study, we described the clinical translation of ILs containing KCZ (KCZ-ILs) from the lab into the clinic and evaluated the efficacy and safety of KCZ-ILs in patients with tinea pedis. Thirty-six enrolled participants were randomized to receive either KCZ-ILs (KCZ, 4.72 mg/g) or Daktarin® (control group; KCZ, 20 mg/g) topically twice daily, making the lesion be covered with a thin layer of medication. The randomized controlled trial lasted for 8 weeks including 4 weeks of intervention and 4 weeks of follow-up. Primary efficacy outcome was the proportion of treatment success responders, defined as patients achieving negative mycological result and ≥60% relative reduction in total clinical symptom score (TSS) from baseline at week 4. Secondary outcomes mainly for evaluating the relapse of disease included the proportion of treatment success individuals at week 8 and fungal recurrence rate at weeks 2, 3, 4, and 8. After 4 weeks of medication, 47.06% of the KCZ-ILs subjects were treatment successes compared with only 25.00% of those using Daktarin®. Throughout the trial period, KCZ-ILs induced a significantly lower recurrence rate (52.94%) than that of control patients (68.75%). Furthermore, KCZ-ILs were found to be safe and well-tolerated. In conclusion, ILs loading only 1/4 KCZ dose of Daktarin® showed a better efficacy and safety profile in the management of tinea pedis, creating a new opportunity for the treatment of skin diseases caused by fungal infection and is worthy of clinical application.

Establishment of In Vitro Dissolution Based on Similarity with In Vivo Dissolution: A Case Study on Aripiprazole.

In vitro dissolution that predicts the in vivo performance of solid preparations is extremely important in formulation optimization. Fraction absorbed (Fa) has been used to screen in vitro dissolution protocols based on the idea of in vitro-in vivo correlation (IVIVC) but failed to increase the success rate due to the inaccuracy of the Fa. The essence of IVIVC is the correlation between in vitro dissolution and in vivo dissolution. We tried to establish in vitro dissolution protocol via similarity with in vivo dissolution using aripiprazole (APZ) as a model drug. Hybrid APZ crystals (APZ-HCs) were prepared by physically embedding aggregation-caused quenching (ACQ) fluorophores inside the lattice to measure the in vivo dissolution. The process did not change the physicochemical properties and crystallinity of APZ. The fluorophore illuminated APZ crystals but was quenched upon dissolution of APZ-HCs in aqueous media, enabling monitoring intact APZ-HCs in real-time. The good correlation between fluorescent quenching and dissolution of APZ-HCs justified reliable quantification of intact APZ crystals. The residual percentage of fluorescence intensity in rats treated by APZ-HCs was recorded with time, which was converted to in vivo dissolution by the difference from 100%. The in vivo dissolution was validated with the Fa. The in vitro dissolution profile of APZ was set up via a similarity factor larger than 50 in comparison with the in vivo dissolution. The study provides a novel idea and method to establish in vitro dissolution protocol.

Translation of ionic liquids to be enteric nanoparticles for facilitating oral absorption of cyclosporine A.

Ionic liquids (ILs) attract more and more interests in improving drug transport across membrane, including transdermal, nasal, and oral delivery. However, some drawbacks of ILs impede the application in oral drug delivery, such as rapid precipitation of poorly soluble drugs in stomach. This study aimed to employ enteric mesoporous silica nanoparticles (MSNs) to load ILs to overcome the shortcomings faced in oral administration. The choline sorbate ILs (SCILs) were synthesized by choline bicarbonate and sorbic acid and then adsorbed in mesopores of MSNs after dissolving cyclosporin A (CyA). MSNs loading SCILs and CyA were coated by Eudragit® L100 to form enteric nanoparticles. The in vitro release study showed that the CyA and SCILs released only 10% for 2 h in simulated gastric fluids but more than 90% in simulated intestinal fluid. In addition, SCILs and CyA were able to release from MSNs synchronously. After oral administration, enteric MSNs loading SCILs were capable of improving oral absorption of CyA significantly and the oral bioavailability of CyA was similar with that of oral Neoral®. In addition, the oral absorption of enteric MSNs was higher than that of nonenteric MSNs, which showed that enteric coating was necessary to ILs in oral delivery. These findings revealed great potential of translation of ILs to be enteric nanoparticles for facilitating oral absorption of CyA. It is predictable this delivery system is promising to be a platform for delivering poorly water-soluble drugs and even biologics orally.

"Hook&Loop" multivalent interactions based on disk-shaped nanoparticles strengthen active targeting.

How to enhance active targeting efficiency remains a challenge. Multivalent interactions play a crucial role in improving the binding ability between ligands and receptors. It is hypothesized that nanoparticles bearing a flat conformation attain simultaneous formation of multiple ligand-receptor bindings, which could be vividly metaphorized by the "Hook&Loop" rationale. In this study, spherical, rod-shaped and disk-shaped folic acid-modified red blood cell membrane-coated biomimetic mesoporous silica nanoparticles (FRMSNs) were prepared to verify the shape-based multivalent interactions. The fundamental concepts of multivalent interactions have been proved by a series of both in vitro and in vivo evaluations. Physical characterization confirmed the morphology, shape and surface features of FRMSNs. Strengthened binding and internalization of disk-shaped FRMSNs by K562 cells stresses the merits of multivalent interactions. Whereas Bio-TEM visually demonstrates the proposed "plane" contact of disk-shaped particles with cells, quantification further confirmed strengthened "plane" binding affinity with folate binding proteins owing to multivalent interactions. In K562 xenograft mice, doxorubicin-loaded disk-shaped FRMSNs effectively slowed down chronic myeloid leukemia progression. It is concluded that disks favor multivalent interactions which leads to enhanced active targeting efficiency.

Ionic co-aggregates (ICAs) based oral drug delivery: Solubilization and permeability improvement.

Due to the overwhelming percentage of poorly water-soluble drugs, pharmaceutical industry is in urgent need of efficient approaches for solubilization and permeability improvement. Salts consisting of lipophilic fatty acid anions and hydrophilic choline cations are found to be surface active and able to form ionic co-aggregates (ICAs) in water. Choline oleate-based ICAs significantly enhance oral absorption of paclitaxel (PTX) as compared with cremophor EL-based micelles (MCs). Aggregation-caused quenching probes enable tracking of intact ICAs in in vivo transport and cellular interaction. Prolonged intestinal retention of ICAs than MCs implies stronger solubilizing capability in vivo. Ex vivo imaging of major organs and intestinal tracts suggests transepithelial transport of intact ICAs. Cellular studies support the enhanced absorption of PTX and transmembrane transport of intact ICAs. In conclusion, ICAs, consisting of lipophilic ions and hydrophilic counter-ions, are of great potential in delivery of poorly water-soluble drugs by enhancing solubility and permeability.

Ionic Liquids-Based Drug Delivery: a Perspective.

Ionic liquids (ILs) recently draw attention for addressing unmet needs in biomedicines. By converting solids into liquids, ILs are emerging as novel platforms to overcome some critical drawbacks associated with the application of solid or crystalline active pharmaceutical ingredients (APIs). ILs have shown promise in liquidizing or solubilizing APIs, or as green solvents, novel permeation enhancers or active ingredients, alone or synergistically with APIs. Meanwhile, challenges turn up in company with the deepening understanding of ILs as drug delivery carrier systems. This perspective aims to provide a sketchy overview on the status quo with specific attention paid to new problems arising from the utilization of ILs-based technologies in drug delivery.

The in vivo fate of polymeric micelles.

This review aims to provide a systemic analysis of the in vivo, as well as subcellular, fate of polymeric micelles (PMs), starting from the entry of PMs into the body. Few PMs are able to cross the biological barriers intact and reach the circulation. In the blood, PMs demonstrate fairly good stability mainly owing to formation of protein corona despite controversial results reported by different groups. Although the exterior hydrophilic shells render PMs "long-circulating", the biodistribution of PMs into the mononuclear phagocyte systems (MPS) is dominant as compared with non-MPS organs and tissues. Evidence emerges to support that the copolymer poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) is first broken down into pieces of PEG and PLA and then remnants to be eliminated from the body finally. At the cellular level, PMs tend to be internalized via endocytosis due to their particulate nature and disassembled and degraded within the cell. Recent findings on the effect of particle size, surface characteristics and shape are also reviewed. It is envisaged that unraveling the in vivo and subcellular fate sheds light on the performing mechanisms and gears up the clinical translation of PMs.

Ionic Liquids: Emerging Antimicrobial Agents.

Antimicrobial resistance has become a serious threat to global health. New antimicrobials are thus urgently needed. Ionic liquids (ILs), salts consisting of organic cations and anions with melting points less than 100°C, have been recently found to be promising in antimicrobial field as they may disrupt the bacterial wall and membrane and consequently lead to cell leakage and death. Different types of antimicrobial ILs are introduced in the review, including cationic, polymeric, and anionic ILs. Being the main type of the antimicrobial ILs, the review focuses on the structure and the antimicrobial mechanisms of cationic ILs. The quantitative structure-activity relationship (QSAR) models of the cationic ILs are also included. Increase in alkyl chain length and lipophilicity is beneficial to increase the antimicrobial effects of cationic ILs. Polymeric ILs are homopolymers of monomer ILs or copolymers of ILs and other monomers. They have great potential in the field of antibiotics as they provide stronger antimicrobial effects than the sum of the monomer ILs. Anionic ILs are composed of existing anionic antibiotics and organic cations, being capable to enhance the solubility and bioavailability of the original form. Nonetheless, the medical application of antimicrobial ILs is limited by the toxicity. The structural optimization aided by QSAR model and combination with existing antibiotics may provide a solution to this problem and expand the application range of ILs in antimicrobial field.

Novel Pharmaceutical Strategies for Enhancing Skin Penetration of Biomacromolecules.

Skin delivery of biomacromolecules holds great advantages in the systemic and local treatment of multiple diseases. However, the densely packed stratum corneum and the tight junctions between keratinocytes stand as formidable skin barriers against the penetration of most drug molecules. The large molecular weight, high hydrophilicity, and lability nature of biomacromolecules pose further challenges to their skin penetration. Recently, novel penetration enhancers, nano vesicles, and microneedles have emerged as efficient strategies to deliver biomacromolecules deep into the skin to exert their therapeutic action. This paper reviews the potential application and mechanisms of novel skin delivery strategies with emphasis on the pharmaceutical formulations.

The long-circulating effect of pegylated nanoparticles revisited via simultaneous monitoring of both the drug payloads and nanocarriers.

The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin (DOX)-loaded methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration; DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. Hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.

[Imaging study and clinical application of peroneal perforating chimeric tissue flap].

Objective: To explore the feasibility of peroneal perforating chimeric tissue flap in repairing the composite defects of calf and heel based on lower limb angiography, and the clinical effect. Methods: The digital subtraction angiography images of lower limbs of 50 patients met the selection criteria between May 2011 and October 2014 were used as the research object to observe the course of peroneal artery and its perforating vessels. Based on the observation results, between April 2015 and October 2020, the peroneal perforating chimeric tissue flap was designed to repair 7 cases of composite defects of the calf and heel. There were 5 males and 2 females with an average age of 38 years (range, 25-55 years). The causes of injury included traffic accident in 4 cases, falling from height in 2 cases, and machine strangulation in 1 case. There were 5 cases of calf skin defect and tibial defect. The size of skin defect ranged from 5 cm×3 cm to 11 cm×7 cm, and the length of bone defect was 5-8 cm. There were 2 cases of heel skin defect and calcaneal defect. The sizes of skin defects were 5.0 cm×4.0 cm and 7.5 cm×6.5 cm, and the bone defects were 3.0 cm×2.6 cm and 4.0 cm× 3.0 cm. For the calf defect, the size of skin flap ranged from 6 cm×4 cm to 12 cm×8 cm, and the length of the fibula was the same as that of the tibial defect. For the heel defect, the sizes of the skin flaps were 8.5 cm×5.5 cm and 13.0 cm×5.0 cm, and the lengths of the fibulae were 10 cm and 12 cm. Free transplantation was performed in 5 cases and pedicle transplantation in 2 cases. The wound at donor site was repaired with skin grafting or sutured directly. Results: The peroneal artery ran close to the fibula 7.25-8.40 cm below the fibula head and send out 5-7 perforating vessels, with an average of 6.5 vessels. Perforating vessels mainly appeared in four places, which were (9.75±0.91), (13.21±0.74), (18.15±1.22), and (21.40±0.75) cm below the fibular head, with the occurrence rates of 94%, 90%, 96%, and 88%, respectively. Clinical application of 7 cases of peroneal perforating chimeric tissue flap all survived, all wounds healed by first intention. The skin graft at donor site survived and the incision healed by first intention. All patients were followed up 6-36 months, with an average of 12 months. Peroneal perforator chimeric tissue flap had good shape and soft texture. X-ray films showed that the bone graft healed well, and the healing time was 6-11 months (mean, 7 months). No obvious bone resorption was observed during follow-up. Five patients had no pain when walking, and 1 had mild pain with claudication. Postoperative heel ulcers formed in 1 case and healed after wearing custom plantar pressure dispersing shoes. At 6 months after operation, 2 patients were rated as grade Ⅳ and 5 patients as grade Ⅴ according to Holden walking function score. Conclusion: The peroneal perforating vessel distribution is constant and the peroneal perforating chimeric tissue flap is safe and reliable for repairing the composite defects of calf and heel.

Parallel Cross-Leg Free Flap with Posterior Tibial Artery Perforator Pedicle Propeller Cable Bridge Flap for the Treatment of Lower Extremity Wounds: A Case Series Report.

BACKGROUND: A cross-leg flap can be used to treat severely injured lower limbs but associated with complications. Herein, we describe a technique of a parallel cross-leg free flap combined with posterior tibial artery perforator pedicle propeller cable bridge flap for the treatment of lower extremity wounds. METHODS: The artery and veins of the free flap are anastomosed to the contralateral posterior tibial artery and vein, respectively. The vascular pedicle is wrapped with a posterior tibial artery perforator pedicle propeller flap. The legs are allowed to remain in a straight, relaxed position which is maintained with a bandage or Kirschner wire placed at the distal limbs. Pedicle division is performed around 21 days after flap creation, and the posterior artery is re-anastomosed and pedicled flap returned to its original position. RESULTS: From June 2017 to March 2020, 7 patients with lower extremity wounds and tissue loss received reconstruction with this method. The recipient vessels for all flaps were the posterior tibial artery and vein. The average operation time was 5 hours. The average time to ambulation was 4 weeks, and the average follow-up time was 13.7 months. All flaps survived, and limb salvage was successful in all patients. Patients were not uncomfortable with the limbs held in position until pedicle division, and there were no complications. At the final follow-up, the function of all limbs was normal, and the esthetic appearance was acceptable to all patients. CONCLUSIONS: The method described overcomes the disadvantages of traditional cross-leg flaps for the treatment.

Converting Tretinoin into Ionic Liquids for Improving Aqueous Solubility and Permeability across Skin.

PURPOSE: The aim of this study is to convert tretinoin (Tr), an active pharmaceutical ingredient (API), into ionic liquid for improving aqueous solubility and permeability of Tr in transdermal drug delivery applications. METHODS: Three ionic liquids of Tr (TrILs) were synthesized through neutralization reactions, which were characterized to confirm the compositions and ionic interactions. The in vitro drug release studies and skin penetration tests were carried out to assess the performance of formulations containing TrILs. RESULTS: The TrIL formed by choline and Tr at the molar ratio of 2:1 (2[Ch][Tr]), was found to have prominent solubility, stability as well as permeability. In contrast with the insoluble Tr, 2[Ch][Tr] presented as clear and transparent aqueous solution even after diluted to 14%. The aqueous solution of 2[Ch][Tr] demonstrated better permeation effect, of which the solution with 20% of 2[Ch][Tr] showed the optimal delivery efficiency in both epidermis (2.09 ± 0.18‰) and dermis (3.31 ± 0.48‰), realizing the improvement on the permeability of API. Meanwhile, TrILs can be easily fabricated as o/w emulsions as transdermal formulation. The emulsions are also able to improve the skin permeability of Tr, though the enhanced effect is inferior to TrILs solutions. CONCLUSIONS: Ionic liquid technology can be used to improve solubility and permeability of Tr, providing a high potential strategy for the development of topical formulations and the desired transdermal application of drugs.

Oral delivery of proteins and peptides: Challenges, status quo and future perspectives.

Proteins and peptides (PPs) have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy, but fewer side effects. Owing to the poor stability and limited permeability through gastrointestinal (GI) tract and epithelia, the therapeutic PPs are usually administered by parenteral route. Given the big demand for oral administration in clinical use, a variety of researches focused on developing new technologies to overcome GI barriers of PPs, such as enteric coating, enzyme inhibitors, permeation enhancers, nanoparticles, as well as intestinal microdevices. Some new technologies have been developed under clinical trials and even on the market. This review summarizes the history, the physiological barriers and the overcoming approaches, current clinical and preclinical technologies, and future prospects of oral delivery of PPs.

An update on oral drug delivery via intestinal lymphatic transport.

Orally administered drug entities have to survive the harsh gastrointestinal environment, penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation. Whereas the gastrointestinal stability can be well maintained by taking proper measures, hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism. The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway. Intestinal lymphatic transport is emerging as a promising pathway to this end. In this review, we intend to provide an updated overview on the rationale, strategies, factors and applications involved in intestinal lymphatic transport. There are mainly two pathways for peroral lymphatic transport-the chylomicron and the microfold cell pathways. The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.

Ionic liquids as a useful tool for tailoring active pharmaceutical ingredients.

Ionic liquids (ILs) have been widely used in biomedical and pharmaceutical fields as solvents or permeation enhancers. Recently, more and more researchers focused on optimizing the physicochemical properties of active pharmaceutical ingredient (API) by ILs technology. Converting APIs into ILs (API-ILs) has shown great potential for drug delivery by eliminating polymorphism, tailoring solubility, improving thermal stability, increasing dissolution, controlling drug release, modulating the surfactant properties, enhancing permeability of APIs and modulating cytotoxicity on tumor cells. In addition, API-ILs are also used in various formulations as active ingredients, such as solutions, emulsions, even tablets or nanoparticles. This paper aims to review current status of API-ILs, including the rational and design, preparation and characterization, the improvement on the physicochemical characteristics of APIs, the compatibility of API-ILs with various formulations, and the future prospects of API-ILs in biomedical and pharmaceutical fields.

[Application of lateral circumflex femoral artery chimeric flap to repair complex wounds of foot and ankle].

OBJECTIVE: To investigate the effectiveness of lateral circumflex femoral artery chimeric flap transplantation in repair of complex wounds of foot and ankle. METHODS: A retrospective study was conducted to analyze the clinical data of 20 patients with complex wounds of foot and ankle treated with lateral circumflex femoral artery chimeric flap between June 2017 and June 2020. There were 14 males and 6 females with an average age of 42.8 years (range, 21-65 years). Among them, 8 cases had dorsalis pedis tendon defect with or without bone exposure, 4 cases had partial or total Achilles tendon defect without bone exposure, and 8 cases had deep cavity and bone exposure. The wound area ranged from 10 cm×6 cm to 21 cm×11 cm. The time from injury to operation ranged from 6 to 22 days, with an average of 9.4 days. The lateral femoral circumflex artery flap was used in 6 cases with fascia lata flap, 6 cases with rectus femoris aponeurosis flap, and 8 cases with lateral femoral muscle flap. The flap area ranged from 12.0 cm×6.5 cm to 35.0 cm×7.5 cm. All flap donor sites were sutured directly. The survival, appearance, texture, sensation of the flap, and complications of the donor site were observed. The foot and ankle function was evaluated by Kofoed score. RESULTS: All patients were followed up 8-24 months (mean, 14.2 months). On the 3rd day after operation, 1 case had partial necrosis of 1 flap with fascia lata flap and healed after dressing change; 1 case of chimeric muscle flap developed venous crisis at 12 hours after operation; the chimeric flaps survived successfully in the other 18 patients and the wounds were primary healing. The color and texture of the flaps were good, the flaps recovered protective sensation. Only linear scar remained in the donor site of thigh. There was no sensory disturbance around the incision or walking disturbance. The Kofoed score of the foot and ankle function at last follow-up was 75-96, with an average of 89.8. Among them, 15 cases were excellent, 4 cases were good, and 1 case was qualified. The excellent and good rate was 95.0%. CONCLUSION: The application of lateral circumflex femoral artery chimeric flap can accurately and stereoscopically repair the complex wounds of foot and ankle and achieve satisfactory effectiveness.

Gastrointestinal lipolysis and trans-epithelial transport of SMEDDS via oral route.

Self-microemulsifying drug delivery systems (SMEDDSs) have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules. However, information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare. Aggregation-caused quenching (ACQ) fluorescent probes are utilized to visualize the in vivo behaviors of SMEDDSs, because the released probes during lipolysis are quenched upon contacting water. Two SMEDDSs composed of medium chain triglyceride and different ratios of Tween-80 and PEG-400 are set as models, meanwhile Neoral® was used as a control. The SMEDDS droplets reside in the digestive tract for as long as 24 h and obey first order kinetic law of lipolysis. The increased chain length of the triglyceride decreases the lipolysis of the SMEDDSs. Ex vivo imaging of main tissues and histological examination confirm the trans-epithelial transportation of the SMEDDS droplets. Approximately 2%-4% of the given SMEDDSs are transported via the lymph route following epithelial uptake, while liver is the main termination. Caco-2 cell lines confirm the cellular uptake and trans-epithelial transport. In conclusion, a fraction of SMEDDSs can survive the lipolysis in the gastrointestinal tract, permeate across the epithelia, translocate via the lymph, and accumulate mainly in the liver.

In vivo dissolution of poorly water-soluble drugs: Proof of concept based on fluorescence bioimaging.

In vitro‒in vivo correlation (IVIVC) of solid dosage forms should be established basically between in vitro and in vivo dissolution of active pharmaceutical ingredients. Nevertheless, in vivo dissolution profiles have never been accurately portrayed. The current practice of IVIVC has to resort to in vivo absorption fractions (F a). In this proof-of-concept study, in vivo dissolution of a model poorly water-soluble drug fenofibrate (FNB) was investigated by fluorescence bioimaging. FNB crystals were first labeled by near-infrared fluorophores with aggregation-caused quenching properties. The dyes illuminated FNB crystals but quenched immediately and absolutely once been released into aqueous media, enabling accurate monitoring of residual drug crystals. The linearity established between fluorescence and crystal concentration justified reliable quantification of FNB crystals. In vitro dissolution was first measured following pharmacopoeia monograph protocols with well-documented IVIVC. The synchronicity between fluorescence and in vitro dissolution of FNB supported using fluorescence as a measure for determination of dissolution. In vitro dissolution correlated well with in vivo dissolution, acquired by either live or ex vivo imaging. The newly established IVIVC was further validated by correlating both in vitro and in vivo dissolution with F a obtained from pharmacokinetic data.