Influence of Poloxamer on the Dissolution and Stability of Hot-Melt Extrusion-Based Amorphous Solid Dispersions Using Design of Experiments.

The current study aimed to see the effects of poloxamer P407 on the dissolution performance of hydroxypropyl methylcellulose acetate succinate (AquaSolve™ HPMC-AS HG)-based amorphous solid dispersions (ASD). A weakly acidic, poorly water-soluble active pharmaceutical ingredient (API), mefenamic acid (MA), was selected as a model drug. Thermal investigations, including thermogravimetry (TG) and differential scanning calorimetry (DSC), were conducted for raw materials and physical mixtures as a part of the pre-formulation studies and later to characterize the extruded filaments. The API was blended with the polymers using a twin shell V-blender for 10 min and then extruded using an 11-mm twin-screw co-rotating extruder. Scanning electron microscopy (SEM) was used to study the morphology of the extruded filaments. Furthermore, Fourier-transform infrared spectroscopy (FT-IR) was performed to check the intermolecular interactions of the components. Finally, to assess the in vitro drug release of the ASDs, dissolution testing was conducted in phosphate buffer (0.1 M, pH 7.4) and hydrochloric acid-potassium chloride (HCl-KCl) buffer (0.1 M, pH 1.2). The DSC studies confirmed the formation of the ASDs, and the drug content of the extruded filaments was observed to be within an acceptable range. Furthermore, the study concluded that the formulations containing poloxamer P407 exhibited a significant increase in dissolution performance compared to the filaments with only HPMC-AS HG (at pH 7.4). In addition, the optimized formulation, F3, was stable for over 3 months when exposed to accelerated stability studies.

Pharmacobezoar Formation From HPMC-AS-Containing Spray-Dried Formulations in Nonclinical Safety Studies in Rats.

Changing the physical state from crystalline to amorphous is an elegant method to increase the bioavailability of poorly soluble new chemical entity (NCE) drug candidates. Subsequently, we report findings from repeat-dose toxicity studies of an NCE formulated as a spray-dried amorphous solid dispersion (SD-ASD) based on hydroxypropyl methylcellulose acetate succinate (HPMC-AS) in rats. At necropsy, agglomerates of SD-ASD were found in the stomach and small intestine, which in reference to literature were termed pharmacobezoars. We interpreted the pH-dependent insolubility of HPMC-AS in the acidic gastric environment to be a precondition for pharmacobezoar formation. Gastric pharmacobezoars were not associated with clinical signs or alterations of clinical pathology parameters. Pharmacobezoar-correlated histopathological findings were limited to the stomach and consisted of atrophy, erosion, ulcer, and inflammation, predominantly of the nonglandular mucosa. Pharmacobezoars in the small intestines induced obstructive ileus with overt clinical signs which required unscheduled euthanasia, prominent alterations of clinical pathology parameters indicative of hypotonic dehydration, degenerative and inflammatory processes in the gastrointestinal tract, and secondary renal findings. The incidence of pharmacobezoars increased with dose and duration of dosing. Besides the relevance of pharmacobezoars to animal welfare, they limit the non-observed adverse effect level in nonclinical testing programs and conclusively their informative value.

Improvement of the Bioavailability and Anti-hepatic Alveolar Echinococcosis Effect of Albendazole-Isethionate/Hypromellose Acetate Succinate (HPMC-AS) Complex.

Maximizing the pharmacodynamics of albendazole (ABZ), which is used to treat echinococcoses, is essential for the long-term treatment of echinococcosis patients. ABZ is a weak base whose solubility depends on the pH value of the solvent. After it has been orally administered, its solubility drops sharply from when it is in gastric juices (pH 1.4) to when it is in intestinal juices (pH 6.5) and is subsequently absorbed in the ileum and jejunum. This results in low solubility and poor bioavailability of the drug. In this study, we developed an orally administered albendazole-isethionate (ABZ-HES)/hypromellose acetate succinate (HPMC-AS) complex tablet (TABZ-HES-H) with improved solubility and bioavailability. Previous studies demonstrated that ABZ-HES has a higher intrinsic dissolution rate under pH 1.4 than the ABZ free base used in the commercial product Albenda and that HPMC-AS can effectively inhibit ABZ crystallization, which could be due to the hydrophobic interaction between ABZ and HPMC-AS in an aqueous environment. In this study, the dissolution behavior of TABZ-HES-Hin vitro was studied by the two-step pH conversion method. Our results demonstrated that the oral bioavailability of TABZ-HES-H was approximately 2.6 times higher than that of ABZ. More importantly, in the rat model of secondary hepatic alveolar echinococcosis, the anti-hepatic alveolar echinococcosis effect of TABZ-HES-H was 3.4 times higher than that of a commercial product. The improved preparation with salt and polymer has proven to be a feasible method of improving the oral bioavailability and pharmacodynamics of ABZ.

Drug-Polymer Interactions in Acetaminophen/Hydroxypropylmethylcellulose Acetyl Succinate Amorphous Solid Dispersions Revealed by Multidimensional Multinuclear Solid-State NMR Spectroscopy.

The bioavailability of insoluble crystalline active pharmaceutical ingredients (APIs) can be enhanced by formulation as amorphous solid dispersions (ASDs). One of the key factors of ASD stabilization is the formation of drug-polymer interactions at the molecular level. Here, we used a range of multidimensional and multinuclear nuclear magnetic resonance (NMR) experiments to identify these interactions in amorphous acetaminophen (paracetamol)/hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) ASDs at various drug loadings. At low drug loading (<20 wt %), we showed that 1H-13C through-space heteronuclear correlation experiments identify proximity between aromatic protons in acetaminophen with cellulose backbone protons in HPMC-AS. We also show that 14N-1H heteronuclear multiple quantum coherence (HMQC) experiments are a powerful approach in probing spatial interactions in amorphous materials and establish the presence of hydrogen bonds (H-bond) between the amide nitrogen of acetaminophen with the cellulose ring methyl protons in these ASDs. In contrast, at higher drug loading (40 wt %), no acetaminophen/HPMC-AS spatial proximity was identified and domains of recrystallization of amorphous acetaminophen into its crystalline form I, the most thermodynamically stable polymorph, and form II are identified. These results provide atomic scale understanding of the interactions in the acetaminophen/HPMC-AS ASD occurring via H-bond interactions.

Solid state nuclear magnetic resonance studies of hydroxypropylmethylcellulose acetyl succinate polymer, a useful carrier in pharmaceutical solid dispersions.

Hydroxypropylmethylcellulose (HPMC) acetyl succinate (HPMC-AS) is a key polymer used for the enablement of amorphous solid dispersions (ASDs) in oral solid dosage forms. Choice of the appropriate grade within the material is often made empirically by the manufacturer of small-scale formulations, followed by extensive real time stability. A key factor in understanding and predicting the performance of an ASD is related to the presence of hydrogen (or other) bonds between the polymer and active pharmaceutical ingredient (API), which will increase stability over the parameters captured by miscibility and predicted by the Gordon-Taylor equation. Solid state nuclear magnetic resonance (NMR) is particularly well equipped to probe spatial proximities, for example, between polymer and API; however, in the case of HPMC-AS, these interactions have been sometimes difficult to identity as the carbon-13 NMR spectra assignment is yet to be firmly established. Using feedstock, selectively substituted HPMC polymers, and NMR editing experiments, we propose here a comprehensive understanding of the chemical structure of HPMC-AS and a definitive spectral assignment of the 13 C NMR spectra of this polymer. The NMR data also capture the molar ratios of the acetate and succinate moieties present in HPMC-AS of various grades without the need for post treatment required by chromatography methods commonly use in pharmacopoeia. This knowledge will allow the prediction and measurement of interactions between polymers and APIs and therefore a rational choice of polymer grade to enhance the solid state stability of ASDs.

Elucidating spray-dried dispersion dissolution mechanisms with focused beam reflectance measurement: contribution of polymer chemistry and particle properties to performance.

Amorphous spray-dried dispersions (SDDs) are a key enabling technology for oral solid dosage formulations, used to improve dissolution behaviour and clinical exposure of poorly soluble active pharmaceutical ingredients (APIs). Appropriate assessment of amorphous dissolution mechanisms is an ongoing challenge. Here we outline the novel application using focused beam reflectance measurement (FBRM) to analyse particle populations orthogonal to USP 2 dissolution. The relative impact of polymer substitution and particle attributes on 25% BMS-708163/HPMC-AS SDD dissolution was assessed. Dissolution mechanisms for SDDs were categorized into erosion versus disintegration. Beyond an initial mixing period, FBRM particle counts diminish slowly and particles are detectable until the point where API dissolution is complete. There is correlation between FBRM particle count decay rate, representing loss of SDD particles in the dissolution media, and UV dissolution rate, measuring dissolved API. For the SDD formulation examined, the degree of succinoyl substitution for HPMC-AS, SDD particle size and surface area all had an impact on dissolution. These data indicate the SDD displayed an erosion mechanism and that FBRM is capturing a rate-limiting step. From this screening tool, the mechanistic understanding and measured impact of polymer chemistry and particle properties can inform a risk-assessment and control strategy for this compound.

Aggregation of Hydroxypropyl Methylcellulose Acetate Succinate under Its Dissolving pH and the Impact on Drug Supersaturation.

Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) is one of the commonly selected polymers used in amorphous solid dispersions (ASD) with excellent capabilities to maintain aqueous supersaturation of poorly water-soluble drugs and inhibit their crystallization, but the underlying mechanisms remain elusive. In this study, posaconazole was chosen as the model drug to study the supersaturation maintaining and crystallization inhibition capabilities of different types of HPMC-AS under pH 5.5-7.5. We analyzed the HPMC-AS aggregation status in solution using combination of static and dynamic light scattering and observed higher polymer aggregation number when higher grade HPMC-AS or lower pH was used, which correlates well with prolonged drug supersaturation or crystallization inhibition. The amount of HPMC-AS coprecipitated with PSZ, a direct indicator of drug/HPMC-AS affinity, also showed positive correlation with the drug supersaturation and crystallization inhibition in the dissolution process. Therefore, we conclude that the aggregation behavior of HPMC-AS and the drug/HPMC-AS affinity are the key mechanisms that lead to posaconazole supersaturation and crystallization inhibition when HPMC-AS was applied.

Formulation and Evaluation of Kaempferol Loaded Nanoparticles against Experimentally Induced Hepatocellular Carcinoma: In Vitro and In Vivo Studies.

The present study was designed to prepare Kaempferol loaded nanoparticles (KFP-Np) and evaluate hepatoprotective and antioxidant effects in hepatocellular carcinoma models. KFP was encapsulated with hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and Kollicoat MAE 30 DP polymers to prepare nanoparticles (Nps) by quasi-emulsion solvent diffusion technique (QESD). The prepared Nps were evaluated for different pharmaceutical characterization to select the optimum composition for the in vivo assessment. An animal model of cadmium chloride (CdCl2)-induced hepatocellular carcinoma in Male Sprague Dawley rats was used in vivo to test the antioxidant and hepatoprotective capacity of free and encapsulated KFP. The prepared Npsshowed nanometric size, low PDI, high drug load as well as encapsulation with a better drug release profile. There was a significant decrease in the increased serum levels of alanine transaminase (ALT), total bilirubin (TBiL), and aspartate transaminase (AST), and the lipid peroxidation's (MDA) level was attenuated, and levels of markers of the cell antioxidant defence system were restored including Glutathione S-transferase (GST), glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) via oral pre-treatment with KFP-Np (50 mg/kg b.w. (body weight), 6 weeks). KFP-Np significantly declines an mRNA expression of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-α) as well as decreased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein expression. It also upregulated the mRNA expression and protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). While comparing the protective effects of KFP encapsulated in Kollicoat MAE 30 DP and HPMC-AS, Nps was found to be betterthan free KFP. Insummary, result indicate that encapsulation of KFP in NPs provides a potential platform for oxidative stress induce liver injury.

Novel On-Demand 3-Dimensional (3-D) Printed Tablets Using Fill Density as an Effective Release-Controlling Tool.

This research demonstrates the use of fill density as an effective tool for controlling the drug release without changing the formulation composition. The merger of hot-melt extrusion (HME) with fused deposition modeling (FDM)-based 3-dimensional (3-D) printing processes over the last decade has directed pharmaceutical research towards the possibility of printing personalized medication. One key aspect of printing patient-specific dosage forms is controlling the release dynamics based on the patient's needs. The purpose of this research was to understand the impact of fill density and interrelate it with the release of a poorly water-soluble, weakly acidic, active pharmaceutical ingredient (API) from a hydroxypropyl methylcellulose acetate succinate (HPMC-AS) matrix, both mathematically and experimentally. Amorphous solid dispersions (ASDs) of ibuprofen with three grades of AquaSolveTM HPMC-AS (HG, MG, and LG) were developed using an HME process and evaluated using solid-state characterization techniques. Differential scanning calorimetry (DSC), powder X-ray diffraction (pXRD), and polarized light microscopy (PLM) confirmed the amorphous state of the drug in both polymeric filaments and 3D printed tablets. The suitability of the manufactured filaments for FDM processes was investigated using texture analysis (TA) which showed robust mechanical properties of the developed filament compositions. Using FDM, tablets with different fill densities (20-80%) and identical dimensions were printed for each polymer. In vitro pH shift dissolution studies revealed that the fill density has a significant impact (F(11, 24) = 15,271.147, p < 0.0001) and a strong negative correlation (r > -0.99; p < 0.0001) with the release performance, where 20% infill demonstrated the fastest and most complete release, whereas 80% infill depicted a more controlled release. The results obtained from this research can be used to develop a robust formulation strategy to control the drug release from 3D printed dosage forms as a function of fill density.

Mechanistic elucidation of formation of drug-rich amorphous nanodroplets by dissolution of the solid dispersion formulation.

Drug-rich amorphous nanodroplets have great potential to improve intestinal absorption of poorly water-soluble drugs. Spray-dried samples (SPDs) of glibenclamide (GLB) with hypromellose (HPMC) or hypromellose acetate succinate (HPMC-AS, grade AS-LF and AS-HF) were prepared to investigate how GLB-rich amorphous nanodroplets form during the dissolution of solid dispersions. The co-spray drying of AS-LF significantly enhanced GLB dissolution from the SPD, leading to the temporary formation of GLB-rich amorphous nanodroplets. However, the droplets gradually coarsened as AS-LF fails to inhibit coarsening. In contrast, the addition of HPMC to the SPD failed to aid GLB-rich amorphous nanodroplet formation during dissolution. The failure of formation of GLB-rich amorphous nanodroplet was caused by slow GLB dissolution, due to the poor controllability of the GLB dissolution by HPMC. The addition of AS-HF to the SPD produced amorphous GLB particles that contained a large amount of AS-HF during dissolution. Gel-like particles formed instead of GLB-rich amorphous nanodroplets. When the SPD containing AS-LF was dissolved in AS-HF solution, stably-dispersed GLB-rich amorphous nanodroplets were successfully formed owing to rapid GLB dissolution from the SPD containing AS-LF and strong coarsening inhibition by AS-HF. Formulation optimization considering both aqueous dissolution of the solid dispersion and the inhibition of nanodroplet coarsening achieved stably-dispersed drug-rich amorphous nanodroplets.

A high-sensitivity HPLC-ELSD method for HPMC-AS quantification and its application in elucidating the release mechanism of HPMC-AS based amorphous solid dispersions.

Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) is one of the most widely used polymers used in amorphous solid dispersions (ASD) for solubility and bioavailability enhancement of poorly water-soluble drugs. Once released from ASDs, HPMC-AS was often found to be highly effective in maintaining drug supersaturation, and this capability is dependent on the concentration and substitution types of this pH-dependent polymer. Therefore, accurate quantification of different grades of HPMC-AS allows us to better understand the release and supersaturation mechanisms of HPMC-AS based ASDs. Since previously reported analytical methods were unable to quantify HPMC-AS in a complex medium with enough sensitivity, we hereby developed a high-sensitivity HPLC-ELSD (evaporative light scattering detector) method with satisfactory specificity, linearity, accuracy and precision, to quantify HPMC-AS down to 20 µg/mL in dissolution media, with the presence of various commonly used pharmaceutical excipients. With the assistance of this method, we compared the intrinsic dissolution rates (IDR) of both the drug and the polymer of posaconazole ASDs based on different types of HPMC-AS. We observed that: 1) For ASDs that were spray dried and uniformly mixed, drug and polymer released simultaneously into the medium with practically identical IDRs slower than the IDR of pure HPMC-AS; 2) For ASDs that were heterogeneously mixed, IDRs of the drug and polymer were significantly slower or faster than the IDRs of the drug and polymer of the uniform ASDs, respectively. In summary, the high sensitivity HPLC-ELSD method established here can be readily applied to quantify HPMC-AS in various dissolution media, thus helps to reveal the release kinetics and mechanisms of different HPMC-AS based ASDs.

Development and characterization of lipid-polymeric nanoparticles for oral insulin delivery.

INTRODUCTION: The oral route is widely accepted as the most physiological path for exogenous administration of insulin, as it closely mimic the endogenous insulin pathway. Thus, in this work it is proposed an innovative lipid-polymeric nanocarrier to delivery insulin orally. Areas covered: Nanoparticles were produced through a modified solvent emulsification-evaporation method, using ethyl palmitate and hydroxypropylmethylcellulose acetate succinate as matrix. Lipid-polymeric nanoparticles were around 300 nm in size, negatively charged (-20 mV) and associated insulin with efficiency higher than 80%. Differential scanning calorimetry suggested thermal stability of nanoparticles. In vitro release assays under simulated gastrointestinal conditions resulted in 9% and 14% of insulin released at pH 1.2 during 2 h and at pH 6.8 for 6 h, respectively, demonstrating the ability of those nanoparticles to protect insulin against premature degradation. Importantly, nanoparticles were observed to be safe at potential therapeutic concentrations as did not originate cytotoxicity to intestinal epithelial cells. Lastly, the permeability of nanoencapsulated insulin through Caco-2 monolayers and a triple Caco-2/HT29-MTX/Raji B cell model correlated well with slow release kinetics, and fosters the effectiveness of nanoparticles to promote intestinal absorption of peptidic drugs. Expert opinion: Lipid-polymeric nanoparticles were developed to encapsulate and carry insulin through intestine. Overall, nanoparticles provide insulin stability and intestinal permeability.

Polymer⁻Surfactant System Based Amorphous Solid Dispersion: Precipitation Inhibition and Bioavailability Enhancement of Itraconazole.

The rapid release of poorly water-soluble drugs from amorphous solid dispersion (ASD) is often associated with the generation of supersaturated solution, which provides a strong driving force for precipitation and results in reduced absorption. Precipitation inhibitors, such as polymers and surfactants, are usually used to stabilize the supersaturated solution by blocking the way of kinetic or thermodynamic crystal growth. To evaluate the combined effect of polymers and surfactants on maintaining the supersaturated state of itraconazole (ITZ), various surfactants were integrated with enteric polymer hydroxypropyl methylcellulose acetate succinate (HPMC AS) to develop polymer⁻surfactant based solid dispersion. The supersaturation stability was investigated by in vitro supersaturation dissolution test and nucleation induction time measurement. Compared to the ASD prepared with HPMC AS alone, the addition of d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) exhibited a synergistic effect on precipitation inhibition. The results indicated that the TPGS not only significantly reduced the degree of supersaturation which is the driving force for precipitation, but also provided steric hindrance to delay crystal growth by absorbing onto the surface of small particles. Subsequently, the formulations were evaluated in vivo in beagle dogs. Compared with commercial product Sporanox®, the formulation prepared with HPMC AS/TPGS exhibited a 1.8-fold increase in the AUC (0⁻24 h) of ITZ and a 1.43-fold increase of hydroxyitraconazole (OH-ITZ) in the plasma. Similarly, the extent of absorption was increased by more than 40% when compared to the formulation prepared with HPMC AS alone. The results of this study demonstrated that the ASD based on polymer⁻surfactant system could obviously inhibit drug precipitation in vitro and in vivo, which provides a new access for the development of ASD for poorly water-soluble drug.

Evaluation of the Microcentrifuge Dissolution Method as a Tool for Spray-Dried Dispersion.

Although using spray-dried dispersions (SDDs) to improve the bioavailability of poorly water-soluble compounds has become a common practice in supporting the early phases of clinical studies, their performance evaluation, whether in solid dosage forms or alone, still presents significant challenges. A microcentrifuge dissolution method has been reported to quickly assess the dissolution performance of SDDs. While the microcentrifuge dissolution method has been used in the SDD community, there is still a need to understand the mechanisms about the molecular species present in supernatant after centrifugation, the molecular nature of active pharmaceutical ingredients (APIs), as well as the impact of experimental conditions. In this paper, we aim to assess the effect of API and polymer properties on the dissolution behavior of SDDs along with centrifuging parameters, and for this, two poorly water-soluble compounds (indomethacin and ketoconazole) and two commonly used polymers in the pharmaceutical industry (PVP and HPMC-AS) were chosen to prepare SDDs. A typical microcentrifuge dissolution procedure as reported in the publication (Curatolo et al., Pharm Res 26:1419-1431, 2009) was followed. In addition, after separation of the supernatant from precipitation, some of the samples were filtered through filters of various sizes to investigate the particulate nature (particle size) of the supernatant. Furthermore, the centrifuge speed was varied to study sedimentation of API, SDD, or polymer particles. The results indicated that for the SDDs of four drug-polymer pairs, microcentrifuge dissolution exhibited varied behaviors, depending on the polymer and the drug used. The SDDs of indomethacin with either PVP or HPMC-AS showed a reproducible dissolution with minimum variability even after filtration and subjecting to varied centrifugation speed, suggesting that the supernatant behaved solution-like. However, ketoconazole-PVP and ketoconazole-HPMC-AS SDDs displayed a significant variation in concentration as the speed of centrifugation and the pore sizes of filters were altered, indicating that their supernatant was heterogeneous with the presence of particulates. In conclusion, microcentrifuge dissolution method was more suitable for indomethacin-PVP and indomethacin-HPMC-AS systems compared with ketoconazole-PVP and ketoconazole-HPMC-AS. Therefore, the use of microcentrifuge dissolution method depends on both compounds and polymers selected, which should be examined case by case.

Site specific solubility improvement using solid dispersions of HPMC-AS/HPC SSL--mixtures.

Many upcoming drug candidates are pH-dependent poorly soluble weak bases in the pH range of the gastrointestinal tract. This often leads to a high in vivo variability and bioavailability issues. Aiming to overcome these limitations, the design of solid dispersions for site specific dissolution improvement or maintenance of a potent supersaturation over the entire gastro-intestinal pH-range, is proposed to assure a reliable drug therapy. Solid dispersions containing different ratios of Dipyridamole (DPD) or Griseofulvin (GRI) and the enteric polymer hydroxypropylmethylcellulose-acetate succinate (HPMC-AS) and the water soluble low-viscosity hydroxypropylcellulose (HPC-SSL) were prepared by hot melt extrusion (HME). The solid dispersions were evaluated for their solid state, dissolution characteristics applying a three pH-step dissolution method following an acidic to neutral pH transition and stability. The use of HPMC-AS in binary mixtures with DPD and GRI facilitated increased solubility and supersaturation at pH-controlled release of the preserved amorphous state of the dispersed drug, which even inverted the pH-dependent solubility profile of the weakly basic model drug (Dipyridamole). I.e. a potent site specific delivery system was created. With ternary solid dispersions of API, HPMC-AS and HPC-SSL, tailored release profiles with superior supersaturation over the applied pH-range could be obtained. At the same time, binary and ternary mixtures showed favorable stability properties at a temperature difference between glass transition temperature and the applied storage temperature of down to 16°C.

Inhibition mechanism of hydroxypropyl methylcellulose acetate succinate on drug crystallization in gastrointestinal fluid and drug permeability from a supersaturated solution.

The effects of drug-crystallization inhibitor in bile acid/lipid micelles solution on drug permeation was evaluated during the drug crystallization process. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was used as a drug-crystallization inhibitor, which efficiently suppressed dexamethasone (DEX) crystallization in a gastrointestinal fluid model containing sodium taurocholate (NaTC) and egg-phosphatidylcholine (egg-PC). Changes of molecular state of supersaturated DEX during the DEX crystallization process was monitored in real time using proton nuclear magnetic resonance (1H NMR). It revealed that DEX distribution to bulk water and micellar phases formed by NaTC and egg-PC was not changed during the DEX crystallization process even in the presence of HPMC-AS. DEX permeation during DEX crystallization was evaluated using dissolution/permeability system. The combination of crystallization inhibition by HPMC-AS and micellar encapsulation by NaTC and egg-PC led to considerably higher DEX concentrations and improvement of DEX permeation at the beginning of the DEX crystallization process. Crystallization inhibition by HPMC-AS can efficiently work even in the micellar solution, where NaTC/egg-PC micelles encapsulates some DEX. It was concluded that a crystallization inhibitor contributed to improvement of permeation of a poorly water-soluble drug in gastrointestinal fluid.

Supersaturated polymeric micelles for oral cyclosporine A delivery.

Polymeric micelles provide a promising platform for improving oral absorption of poorly soluble drugs. However, improved understanding of how drug retention within the hydrophobic micelle core can reduce drug absorption is required. We designed supersaturated polymeric micelles (Super-PMs) to increase molecularly dissolved drug concentration and gain an insight into the effect of the degree of supersaturation on oral absorption of cyclosporine A (CsA) in rats. The drug release from Super-PMs increased with an increase in initial supersaturation degrees in micelles. The cellular uptake of coumarin-6 was reduced by the retention of drug in polymer micelles. The transport flux of CsA across Caco-2 monolayer was increased with initial supersaturation degrees of 0.81-3.53 (p < 0.05). However, increase in supersaturation to 5.64 actually resulted in decreased CsA transport. The same trend was observed in a rat in vivo absorption study, in which the highest bioavailability of 134.6 ± 24.7% (relative to a commercial product, Sandimmun Neoral®, p<0.01) was achieved when the supersaturation degree was 3.53. These results demonstrated that Super-PMs were a promising drug delivery system for compounds with low aqueous solubility. This study also provided an experimental proof for the hypothesis that moderately supersaturated formulations are valuable alternative to high supersaturation formulations, resulting in optimal in vivo performance, and the degree of supersaturation should be carefully controlled to optimize drug absorption.