Cocrystal Prediction of Nifedipine Based on the Graph Neural Network and Molecular Electrostatic Potential Surface.

Nifedipine (NIF) is a dihydropyridine calcium channel blocker primarily used to treat conditions such as hypertension and angina. However, its low solubility and low bioavailability limit its effectiveness in clinical practice. Here, we developed a cocrystal prediction model based on Graph Neural Networks (CocrystalGNN) for the screening of cocrystals with NIF. And scoring 50 coformers using CocrystalGNN. To validate the reliability of the model, we used another prediction method, Molecular Electrostatic Potential Surface (MEPS), to verify the prediction results. Subsequently, we performed a second validation using experiments. The results indicate that our model achieved high performance. Ultimately, cocrystals of NIF were successfully obtained and all cocrystals exhibited better solubility and dissolution characteristics compared to the parent drug. This study lays a solid foundation for combining virtual prediction with experimental screening to discover novel water-insoluble drug cocrystals.

Simultaneous Water Sorption and Crystallization in ASDs 2: Modeling Long-Term Stabilities.

The physical stability of amorphous solid dispersions (ASDs) is a major topic in the formulation research of oral dosage forms. To minimize the effort of investigating the long-term stability using cost- and time-consuming experiments, we developed a thermodynamic and kinetic modeling framework to predict and understand the crystallization kinetics of ASDs during long-term storage below the glass transition. Since crystallization of the active phrarmaceutical ingredients (APIs) in ASDs largely depends on the amount of water absorbed by the ASDs, water-sorption kinetics and API-crystallization kinetics were considered simultaneously. The developed modeling approach allows prediction of the time evolution of viscosity, supersaturation, and crystallinity as a function of drug load, relative humidity, and temperature. It was applied and evaluated against two-year-lasting crystallization experiments of ASDs containing nifedipine and copovidone or HPMCAS measured in part I of this work. We could show that the proposed modeling approach is able to describe the interplay between water sorption and API crystallization and to predict long-term stabilities of ASDs just based on short-term measurements. Most importantly, it enables explaining and understanding the reasons for different and sometimes even unexpected crystallization behaviors of ASDs.

A new three-dimensional (3D) molecularly imprinted polymer fluoroprobe based on green-red dual-emission signals of carbon quantum dots and self-polymerization of dopamine (CDs@PDA-MIPs) for sensitive detection of nifedipine.

Nifedipine (NIF), as one of the dihydropyridine calcium channel blockers, is widely used in the treatment of hypertension. However, misuse or ingestion of NIF can result in serious health issues such as myocardial infarction, arrhythmia, stroke, and even death. It is essential to design a reliable and sensitive detection method to monitor NIF. In this work, an innovative molecularly imprinted polymer dual-emission fluorescent sensor (CDs@PDA-MIPs) strategy was successfully designed for sensitive detection of NIF. The fluorescent intensity of the probe decreased with increasing NIF concentration, showing a satisfactory linear relationship within the range 1.0 × 10-6 M ~ 5.0 × 10-3 M. The LOD of NIF was 9.38 × 10-7 M (S/N = 3) in fluorescence detection. The application of the CDs@PDA-MIPs in actual samples such as urine and Qiangli Dingxuan tablets has been verified, with recovery ranging from 97.8 to 102.8% for NIF. Therefore, the fluorescent probe demonstrates great potential as a sensing system for detecting NIF.

Fabrication, evaluation, and enhanced penetration of vinyl and cellulose-engineered transdermal patch of nifedipine using essential oil as penetration enhancer.

The aim of this study was to develop and evaluate the transdermal patch formulations of nifedipine. The patch formulations containing nifedipine were prepared and optimized with different ratios of vinyl and cellulose-derived polymers, drug contents, and permeation enhancers. Among the various formulations, the patch formulation containing a 1:5 ratio of ethyl cellulose and polyvinyl pyrrolidone was selected for ex vivo pharmacokinetic study based on in vitro permeation studies using stratum corneum of the pig's skin. The cumulative percentage release after the transdermal administration of the optimized patch formulation was 71.43%, and the plasma concentration of nifedipine was maintained for 16 hrs. The physicochemical evaluation study including flatness, thickness, moisture content and uptake, drug content in vitro release, and ex vivo permeation indicated satisfactory results. The formulation batch with clove oil as a penetration enhancer has shown better ex vivo permeation as compared to the formulations without enhancers and another synthetic enhancer. These results suggest that the optimized patch formulation Q3 could be further developed for clinical applications, providing the therapeutic plasma level of nifedipine over an extended period. Hence analyzing the results of the evaluation tests, in vitro and ex vivo data on the preparation and optimization of nifedipine-loaded transdermal patch, it can be concluded that the formulation shows its feasibility as an effective transdermal delivery system for nifedipine.

Use of physiologically-based pharmacokinetic modeling to understand the effect of omeprazole administration on the pharmacokinetics of oral extended-release nifedipine.

Proton pump inhibitors (PPIs) can affect the release of drugs from their dosage forms in vivo by elevating the gastric pH. Our recent clinical study has demonstrated that drug-drug interactions (DDIs) exist between a PPI, omeprazole, and nifedipine extended-release formulations, where systemic exposure of nifedipine was increased in subjects after multiple-dose pretreatment of omeprazole. However, the mechanism of the observed DDIs between omeprazole and nifedipine has not been well-understood, as the DDI may also be mediated through CYP3A4 enzyme inhibition in addition to the elevated gastric pH caused by omeprazole. This study used physiologically-based pharmacokinetic (PBPK) modeling and simulations to investigate the underlying mechanism of these complex DDIs. A formulation exhibiting differences in in vitro dissolution across physiological pH range and another formulation where pH does not impact dissolution appreciably (e.g., an osmotic pump) were chosen to characterize the potential impact of pH. The PBPK models incorporated two-stage in vitro release profiles via US Pharmacopeia 2 apparatus. PBPK simulations suggest that the elevated gastric pH following multiple-dose administration of omeprazole has a minimal effect on nifedipine pharmacokinetics (PKs), whereas CYP3A4-mediated DDI is likely the main driver to the observed change of nifedipine PKs in the presence of omeprazole. Compared to the osmotic formulation, the slightly increased exposure of nifedipine can be accounted for by the enhanced drug release in the pH-dependent formulation. The reported model-based approach may be useful in DDI risk assessments, product formulation designs, and bioequivalence evaluations.

Crystallization of Amorphous Nifedipine Under Isothermal Conditions: Inter-laboratory Reproducibility and Investigation of the Factors Affecting Reproducibility.

High inter-laboratory reproducibility is required for conducting collaborative experiments among several laboratories. The primary aim of our evaluation of the physical stability of amorphous drugs, conducted in co-operation with eight laboratories, was to establish a protocol for isothermal storage tests to obtain data of the same quality from all the participating laboratories. Sharing a protocol that contained the same level of detail as the experimental section of general papers was insufficient for high inter-laboratory reproducibility. We investigated the causes of variations in the data from the various laboratories and restricted the protocol step-by-step to achieve high inter-laboratory reproducibility. The various experimentalists had very different levels of awareness regarding how to control the temperature of a sample as the samples were transferred into and out of thermostatic chambers. Specific instructions on how to conduct this operation, such as regarding the time required for the transfer and thermal protection of the container during the transfer, helped to reduce variation. Improved inter-laboratory reproducibility revealed that the physical stabilities of amorphous drugs differed when samples were prepared in differently shaped aluminum pans designed for various differential scanning calorimeters.

Implications of Drug-Polymer Interactions on Time-Temperature-Transformation: A Tool to Assess the Crystallization Propensity in Amorphous Solid Dispersions.

The critical cooling rate (CRcrit) to prevent drug crystallization during the preparation of nifedipine amorphous solid dispersions (ASDs) was determined through the time-temperature-transformation (TTT) diagram. ASDs were prepared with polyvinylpyrrolidone, hydroxypropylmethyl cellulose acetate succinate, and poly(acrylic acid). ASDs were subjected to isothermal crystallization over a wide temperature range, and the time and temperature dependence of nifedipine crystallization onset time (tC) was determined by differential scanning calorimetry (DSC) and synchrotron X-ray diffractometry. TTT diagrams were generated for ASDs, which provided the CRcrit for the dispersions prepared with each polymer. The observed differences in CRcrit could be explained in terms of differences in the strength of interactions. Stronger drug-polymer interactions led to longer tC and decreased CRcrit. The effect of polymer concentrations (4-20% w/w) was also influenced by the strength of the interaction. The CRcrit of amorphous NIF was ∼17.5 °C/min. Addition of 20% w/w polymer resulted in a CRcrit of ∼0.05, 0.2, and 11 °C/min for the dispersions prepared with PVP, HPMCAS, and PAA, respectively.

Polyvinylpyrrolidone as co-inhibitor of crystallization of nifedipine in paper tablets.

Techniques to maintain drugs amorphous that would otherwise crystallize is an extensively studied approach to enhance the dissolution characteristics of poorly soluble drugs. However, their performance is limited by the low physical stability of the amorphous phase which can lead to recrystallization which in turn results in decreased solubility and bioavailability of the drug. In this work, the crystallinity of nifedipine loaded into a cellulose-based paper matrix, so called smartFilms, was determined by terahertz time-domain spectroscopy. By adding polyvinylpyrrolidone as an extra carrier, the capability of smartFilms to transfer nifedipine into its amorphous state improved. Moreover, the performance of the formulation to inhibit recrystallization of the amorphous drug over a period of six months increased. For formulations containing up to 10 w% drug loading and additional polyvinylpyrrolidone (nifedipine/polyvinylpyrrolidone: 4:1 mass ratio), nifedipine was found to be completely amorphous after six months of storage.

Real-time in situ X-ray micro-computed tomography study of the effect of impurities on the crystallization of amorphous nifedipine.

Controlling the physical stability of noncrystalline active pharmaceutical ingredients remains a major challenge in the development of amorphous formulations such as amorphous solid-dispersion (ASD) formulations. To establish new evaluation and formulation strategies, the spatial distribution of the crystal phase in bulk amorphous nifedipine (NFD) was investigated as a model. The crystallization of amorphous NFD and the effect of a deliberately added impurity were investigated using powder X-ray diffraction (PXRD), differential scanning calorimetry and real-time in situ X-ray micro-computed tomography (X-ray CT). The stability data of amorphous samples, i.e., NFD and a mixture of NFD with an oxidative degradation product of NFD, impurity A (Imp A), at a weight ratio of 90:10, presented as percent amorphous remaining, suggests that Imp A accelerates the bulk crystal growth of NFD. Real-time in situ X-ray CT results showed surface-enhanced crystal growth and cavity formation in solid NFD samples. Moreover, the crystals were heterogeneous in density. These results suggest that Imp A affects the physical stability of the amorphous NFD. X-ray CT equipped with a heating unit can aid in-situ evaluation and assessment of physicochemical properties and physical stability of amorphous samples and formulations.

Visualization of Food Polyphenols.

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is commonly used in food and pharmacological sciences to visualize localization of drugs and food compounds and their metabolites in plant, animal, and human tissues. The localization of compounds obtained by MALDI-MSI images provides useful information for elucidating their physiological and pharmacological properties. Food polyphenols, naturally occurring in tea, coffee, fruits and vegetables, have health benefits owing to their preventative effects against conditions such as cancer, diabetes, and cardiovascular diseases. In order to elucidate the pharmacological properties of polyphenols, their absorption, distribution, metabolism and excretion must be investigated. However, application of MALDI-MS imaging for polyphenols is challenging due to lack of an appropriate matrix reagent to visualize polyphenols in targeted biological tissue. The present work highlights the development of MALDI-MSI for visualization of food polyphenols. Nifedipine, which produces a nitrosophenyl pyridine derivative under laser irradiation, could be a new matrix for MS detection of polyphenols. The combination of nifedipine and phytic acid (a metal-chelating agent) successfully achieved MS visualization of polyphenols in biological tissue. The inhibitor-aided MALDI-MSI has been applied for elucidation of intestinal absorption routes and metabolic behaviors of polyphenols. The MALDI-MSI technique shows great potential for visualizing absorption, distribution and metabolism processes of food polyphenols.

Co-amorphous systems using epigallocatechin-3-gallate as a co-former: Stability, in vitro dissolution, in vivo bioavailability and underlying molecular mechanisms.

Co-amorphous strategy has been extensively investigated to improve the dissolution of hydrophobic drugs. Here, epigallocatechin-3-gallate (EGCG) was exploited as a co-former in co-amorphous systems based on its unique structure including phenyl rings, phenolic hydroxyl groups and the galloyl moiety. Two model BCS class II drugs, simvastatin (SIM) and nifedipine (NIF), were selected to be co-amorphized with EGCG. All drug-EGCG systems at three molar ratios became amorphous by the means of spray drying and showed high physically stable either under dry condition and 75 % RH at 40 °C or under dry conditions at 25 °C. The optimal feed molar ratios of both EGCG based co-amorphous systems fabricated were determined to be three, under which the significant increases were obtained in the maximum apparent concentrations of 4.90-fold for SIM at 1 h and 106.03-fold for NIF at 0.25 h compared to crystalline drugs by non-sink dissolution studies. The underlying molecular mechanisms of two co-amorphous systems formation were involved in molecular miscibility, hydrogen bonds and π-π stacking interactions unraveled by means of DSC, FTIR and molecular dynamics simulations. More to the point, oral pharmacokinetic studies in rats demonstrated that co-amorphous SIM-EGCG and NIF-EGCG systems at 1:3 have a significant increase in Cmax of 1.81- and 5.69-fold, and AUC 0-24h of 1.62- and 4.57-fold compared with those of corresponding crystalline drugs, respectively. In conclusion, EGCG is proved to be a promising co-former in co-amorphous systems.

Surfactants Accelerate Crystallization of Amorphous Nifedipine by Similar Enhancement of Nucleation and Growth Independent of Hydrophilic-Lipophilic Balance.

Amorphous formulations, increasingly employed to deliver poorly soluble drugs, generally contain surfactants to improve wetting and dissolution. These surfactants are often liquids and can potentially increase the mobility of the drug and reduce its stability, but little is known about this effect. Here we investigate the effect of four common nonionic surfactants (Tween 80, Span 80, Triton X-100, and Poloxamer 407) on the crystallization of amorphous nifedipine (NIF). We find that the surfactants significantly enhance the rates of crystal nucleation and growth even at low concentrations, by up to 2 orders of magnitude at 10 wt %. The surfactants tested show similar enhancement effects independent of their structural details and hydrophilic-lipophilic balance (HLB), suggesting that surfactant adsorption at solid/liquid interfaces does not play a major role in crystal nucleation and growth. Importantly, the surfactants accelerate crystal nucleation and growth by a similar factor. This result mirrors the previous finding that a polymer dopant in a molecular glass-former causes similar slowdown of nucleation and growth. These results indicate that nucleation and growth in a deeply supercooled liquid are both mobility-limited, and a dopant mainly functions as a mobility modifier (enhancer or suppressor depending on the dopant). The common surfactants tested are all mobility enhancers and destabilize the amorphous drug, and this negative effect must be managed using stabilizers such as polymers. The effect of surfactants on nucleation can be predicted from the effect on crystal growth and the crystallization kinetics of the pure system, using the same principle previously established for drug-polymer systems. We show how the independently measured nucleation and growth rates enable predictions of the overall crystallization rates.

Polymorphic selectivity in crystal nucleation.

Crystal nucleation rates have been measured in the supercooled melts of two richly polymorphic glass-forming liquids: ROY and nifedipine (NIF). ROY or 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile is known for its crystals of red, orange, and yellow colors and many polymorphs of solved structures (12). Of the many polymorphs, ON (orange needles) nucleates the fastest with the runner up (Y04) trailing by a factor of 103 when compared under the same mobility-limited condition, while the other unobserved polymorphs are slower yet by at least 5 orders of magnitude. Similarly, of the six polymorphs of NIF, γ' nucleates the fastest, ß' is slower by a factor of 10, and the rest are slower yet by at least 5 decades. In both systems, the faster-nucleating polymorphs are not built from the lowest-energy conformers, while they tend to have higher energies and lower densities and thus greater similarity to the liquid phase by these measures. The temperature ranges of this study covered the glass transition temperature Tg of each system, and we find no evidence that the nucleation rate is sensitive to the passage of Tg. At the lowest temperatures investigated, the rates of nucleation and growth are proportional to each other, indicating that a similar kinetic barrier controls both processes. The classical nucleation theory provides an accurate description of the observed nucleation rates if the crystal growth rate is used to describe the kinetic barrier for nucleation. The quantitative rates of both nucleation and growth for the competing polymorphs enable prediction of the overall rate of crystallization and its polymorphic outcome.

Selective Laser Sintering of a Photosensitive Drug: Impact of Processing and Formulation Parameters on Degradation, Solid State, and Quality of 3D-Printed Dosage Forms.

This research study utilized a light-sensitive drug, nifedipine (NFD), to understand the impact of processing parameters and formulation composition on drug degradation, crystallinity, and quality attributes (dimensions, hardness, disintegration time) of selective laser sintering (SLS)-based three-dimensional (3D)-printed dosage forms. Visible lasers with a wavelength around 455 nm are one of the laser sources used for selective laser sintering (SLS) processes, and some drugs such as nifedipine tend to absorb radiation at varying intensities around this wavelength. This phenomenon may lead to chemical degradation and solid-state transformation, which was assessed for nifedipine in formulations with varying amounts of vinyl pyrrolidone-vinyl acetate copolymer (Kollidon VA 64) and potassium aluminum silicate-based pearlescent pigment (Candurin) processed under different SLS conditions in the presented work. After preliminary screening, Candurin, surface temperature (ST), and laser speed (LS) were identified as the significant independent variables. Further, using the identified independent variables, a 17-run, randomized, Box-Behnken design was developed to understand the correlation trends and quantify the impact on degradation (%), crystallinity, and quality attributes (dimensions, hardness, disintegration time) employing qualitative and quantitative analytical tools. The design of experiments (DoEs) and statistical analysis observed that LS and Candurin (wt %) had a strong negative correlation on drug degradation, hardness, and weight, whereas ST had a strong positive correlation with drug degradation, amorphous conversion, and hardness of the 3D-printed dosage form. From this study, it can be concluded that formulation and processing parameters have a critical impact on stability and performance; hence, these parameters should be evaluated and optimized before exposing light-sensitive drugs to the SLS processes.

Chrono modulated multiple unit particulate systems (MUPS) via a continuous hot melt double extrusion technique: Investigation of the formulation and process suitability.

The current study is aimed at the development of chrono modulated multiple unit particulate systems (MUPS) of nifedipine (ND) by a continuous double extrusion process. ND, a poorly soluble drug was formulated into an amorphous solid dispersion (ASD) to improve its solubility. Further, the ASD was converted into MUPS to control the drug release through a combination of pulsatile and sustained release portions. In the preparation of the ASD, the polymer HPMCAS LG was employed at different concentrations. MUPS were formulated by using Eudragit® FS100, Eudragit® RSPO, Klucel™ HF and lipids Precirol® ATO 5, Geleol™, Compritol® ATO5. The differential scanning calorimetry and powder X-ray diffraction studies of MUPS revealed the amorphous nature of ND. Scanning electron microscopy (SEM) studies depicted the surface morphology of the ASD and the gradual change in the surface of the coated MUPS during in-vitro release studies. The in-vitro drug release profiles of ASD indicated significant improvement (p < 0.05) of solubility of ND and MUPS demonstrated a combination of pulsatile and zero-order controlled release up to 12 h. Accelerated stability studies for MUPS at 40 °C/75% RH revealed the formulations were stable. These findings suggest hot melt double extrusion as a potential alternative for conventional techniques to produce MUPS.

Computational drug repositioning for ischemic stroke: neuroprotective drug discovery.

Background: A comprehensive approach to drug repositioning will be required to overcome translational hurdles and identify more neuroprotective drugs. Results & methods: Gene Set Enrichment Analysis was applied to identify related pathways and enriched genes. Candidate genes were optimized using ToppGene, ToppGenet and pBRIT. From the perspective of the local structures, gene-domain-substructure-drug relationships were constructed. Using the MCODE algorithm and K-means clustering, 31 functional subnetworks were obtained, and 252 drugs with proposed neuroprotective function were identified. Using computational analysis, 72 substructures with different scores were found to correspond to neuroprotective functions. The protective effects of benidipine and barnidipine were confirmed in vitro. Conclusion: The authors' research has great potential to discover more neuroprotective drugs and obtain more information regarding mechanisms of action and functional substructures.

Isothermal Crystallization and Time-Temperature Transformation of Amorphous Nifedipine: A Case of Polymorphism Formation and Conversion.

Crystallization of active pharmaceutical ingredients (APIs) from the supercooled liquid state is an important issue in determining the stability of amorphous pharmaceutical dispersions. In the present study, the isothermal crystallization from the supercooled liquid state of the pharmaceutical compound nifedipine was investigated by both rheological and differential scanning calorimetry (DSC) measurements, and the crystallization kinetics was fitted to the Johnson-Mehl-Avrami (JMA) equation. Both the crystallization induction time and completion time from the two methods were used to construct the time-temperature-transformation (TTT) diagram for nifedipine. A model based on a modification of classical homogeneous nucleation and crystal growth theory was employed to fit the induction and completion time curves. Both DSC and rheological methods give similar results for the crystallization kinetics of the nifedipine. From the crystallization kinetics modeling, the solid-liquid interfacial surface tension σSL of nifedipine was estimated and the value was found to be consistent with prior results obtained from melting point depression measurements as a function of crystal size. Evidence is shown that for temperatures below 110 °C, at the early stage of nucleation, NIF first nucleates into the metastable ß'-form and later converts into the stable α-form during the isothermal crystallization. We are also able to report the heat of fusion of the γ'-NIF based on the calorimetric experiments.

pH-Sensitive Glycyrrhizin Based Vesicles for Nifedipine Delivery.

Glycyrrhizic acid, or glycyrrhizin (GA), a major active component of licorice root, has been widely used in traditional Chinese and Japanese medicine since ancient times. However, only in the last decades has a novel and unusual property of the GA been discovered to form water-soluble, supramolecular complexes with a variety of lipophilic drugs. These complexes show significant advantages over other known delivery systems, in particular, due to strong pH sensitivity, the properties of GA self-associates. In the present study, a supramolecular complex formation of the hypotensive and antiarrhythmic drug nifedipine with GA has been studied at different pH values, corresponding to the different degrees of GA dissociation, including a fully dissociated state of GA. Both NMR experiments and molecular dynamics simulations demonstrate the existence of the nifedipine complex with GA at all dissociation states of GA. However, optical absorption experiments show the decrease of complex stability and solubility at pH > 6 when the GA molecule is fully deprotonated. It means the higher release rate of the drug in a neutral and basic environment compared with acid media. These results could form the basis of follow-up studies of GA self-associates as pH-controlled drug delivery systems.

Molecular Mobility and Crystal Growth in Amorphous Binary Drug Delivery Systems: Effects of Low-Concentration Poly(Ethylene Oxide).

Polymer additives have been widely reported to affect the crystallization of amorphous drugs, while the underlying mechanism is poorly understood. The present study aims to investigate the relationship between the crystal growth and the molecular mobility of amorphous nifedipine (NIF) in the presence and absence of low-concentration poly(ethylene oxide) (PEO). The addition of 3% w/w PEO yields approximately a 5-fold increase in the crystal growth rate of NIF in the glassy matrix and a 10-fold increase in the supercooled liquid. Broadband dielectric spectroscopy is performed to investigate the molecular mobility of amorphous pure NIF system and NIF doped with low-concentration PEO. With 3% w/w PEO, the structural relaxation time τα of amorphous NIF significantly decreases, indicating an increase in the global molecular mobility. However, the increase of the molecular mobility is insufficient to explain the 5- to 10-fold increase of the crystal growth rate at the same τα scale. Moreover, we compare the accelerating effect of PEO in NIF-PEO systems to other PEO-doped systems. The accelerating effect of low-concentration PEO on the crystal growth of amorphous drugs is found to be independent of the Flory-Huggins interaction, Tg of the drug, or the increase of the global molecular mobility. These findings suggest that an in-depth understanding regarding the effects of polymer additives on the crystallization of drugs should consider the localized mobility of the host molecules near the crystal-liquid interface.

Dissolution of amorphous nifedipine from micelle-forming carboxymethylcellulose derivatives.

We show that a novel amphiphilic graft copolymer combining the biodegradability and biocompatibility of oxidized carboxymethylcellulose (CMC) with that of hydrophilic poly(ethylene glycol) (PEG), and hydrophobic dodecylamine (DDA), improves the solubility and dissolution performance of nifedipine (NIF), considered as a model hydrophobic drug. The hydrophobic components of the graft copolymer have the multiple effect of favouring micelle formation and loading. At the same time, the interaction between the hydrophobic core and NIF has the secondary effect to suppress drug crystallization, favouring its dissolution, and to increase photostability. Oxidized CMC-g-PEG-DDA micelles reached values of drug concentration, loading capacity and encapsulation efficiency as high as 340 µg mL-1, 6.4 % and 34.1 %, respectively. Loaded micelles showed a good stability with a limited release profile at pH 1.2, whereas at pH 7.4 the swollen cores enable much higher and progressive release, that reaches 3.4 and 6.6 % after 3 and 5 h, respectively, corresponding to very competitive concentration of 34 and 66 µg mL-1.