Effect of Polymer Architecture and Acidic Group Density on the Degree of Salt Formation in Amorphous Solid Dispersions.

Recent work has shown that an amorphous drug-polymer salt can be highly stable against crystallization under hot and humid storage conditions (e.g., 40 °C/75% RH) and provide fast release and that these advantages depend on the degree of salt formation. Here, we investigate the salt formation between the basic drug lumefantrine (LMF) and several acidic polymers: poly(acrylic acid) (PAA), hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), Eudragit L100, and Eudragit L100-55. Salt formation was performed by "slurry synthesis" where dry components were mixed at room temperature in the presence of a small quantity of an organic solvent, which was subsequently removed. This method achieved more complete salt formation than the conventional methods of hot-melt extrusion and rotary evaporation. The acidic group density of a polymer was determined by nonaqueous titration in the same solvent used for slurry synthesis; the degree of LMF protonation was determined by X-ray photoelectron spectroscopy. The polymers studied show very different abilities to protonate LMF when compared at a common drug loading, following the order PAA > (HPMCP ∼ CAP ∼ L100 ∼ L100-55) > HPMCAS, but the difference largely disappears when the degree of protonation is plotted against the concentration of the available acidic groups for reaction. This indicates that the extent of salt formation is mainly controlled by the acidic group density and is less sensitive to the polymer architecture. Our results are relevant for selecting the optimal polymer to control the degree of ionization in amorphous solid dispersions.

Generality of Enhancing the Dissolution Rates of Free Acid Amorphous Solid Dispersions by the Incorporation of Sodium Hydroxide.

The incorporation of a counterion into an amorphous solid dispersion (ASD) has been proven to be an attractive strategy to improve the drug dissolution rate. In this work, the generality of enhancing the dissolution rates of free acid ASDs by incorporating sodium hydroxide (NaOH) was studied by surface-area-normalized dissolution. A set of diverse drug molecules, two common polymer carriers (copovidone or PVPVA and hydroxypropyl methylcellulose acetate succinate or HPMCAS), and two sample preparation methods (rotary evaporation and spray drying) were investigated. When PVPVA was used as the polymer carrier for the drugs in this study, enhancements of dissolution rates from 7 to 78 times were observed by the incorporation of NaOH into the ASDs at a 1:1 molar ratio with respect to the drug. The drugs having lower amorphous solubilities showed greater enhancement ratios, providing a promising path to improve the drug release performance from their ASDs. Samples generated by rotary evaporation and spray drying demonstrated comparable dissolution rates and enhancements when NaOH was added, establishing a theoretical foundation to bridge the ASD dissolution performance for samples prepared by different solvent-removal processes. In the comparison of polymer carriers, when HPMCAS was applied in the selected system (indomethacin ASD), a dissolution rate enhancement of 2.7 times by the incorporated NaOH was observed, significantly lower than the enhancement of 53 times from the PVPVA-based ASD. This was attributed to the combination of a lower dissolution rate of HPMCAS and the competition for NaOH between IMC and HPMCAS. By studying the generality of enhancing ASD dissolution rates by the incorporation of counterions, this study provides valuable insights into further improving drug release from ASD formulations of poorly water-soluble drugs.

Surfactant-Polymer Complexation and Competition on Drug Nanocrystal Surfaces Control Crystallinity.

Nanosizing drug crystals has emerged as a successful approach to enabling oral bioavailability, as increasing drug crystal surface area improves dissolution kinetics and effective solubility. Recently, bottom-up methods have been developed to directly assemble nanosized crystals by leveraging polymer and surfactant excipients during crystallization to control crystal size, morphology, and structure. However, while significant research has investigated how polymers and other single additives inhibit or promote crystallization in pharmaceutical systems, there is little work studying the mechanistic interactions of multiple excipients on drug crystal structure and the extent of crystallinity, which can influence formulation performance. This study explores how the structure and crystallinity of a model hydrophobic drug crystal, fenofibrate, change as a result of competitive interfacial chemisorption between common nonionic surfactants (polysorbate 80 and sorbitan monooleate) and a surface-active polymer excipient (methylcellulose). Classical molecular dynamics simulations highlight how key intermolecular interactions, including surfactant-polymer complexation and surfactant screening of the crystal surface, modify the resulting crystal structure. In parallel, experiments generating drug nanocrystals in hydrogel thin films validate that drug crystallinity increases with an increasing weight fraction of surfactant. Simulation results reveal a connection between accelerated dynamics in the bulk crystal and the experimentally measured extent of crystallinity. To our knowledge, these are the first simulations that directly characterize structural changes in a drug crystal as a result of excipient surface composition and relate the experimental extent of crystallinity to structural changes in the molecular crystal. Our approach provides a mechanistic understanding of crystallinity in nanocrystallization, which can expand the range of orally deliverable small molecule therapies.

Multiscale structure analysis of a pH-responsive gelatin/hydroxypropyl methylcellulose phthalate blend using small-angle scattering.

HYPOTHESIS: Hydroxypropyl methylcellulose phthalate (HPMCP) is an enteric polymer that has been employed in drug delivery systems to delay the release of the encapsulated active pharmaceutical ingredients through its pH-responsive solubility change. This has been recently demonstrated as an effective means for delaying the drug release from gelatin/HPMCP hydrogels at gastric pH values. However, structural characteristics of HPMCP agglomeration in gelatin/HPMCP hydrogels is not well understood thus limiting further tailoring of their material properties. EXPERIMENTS: We investigated the multiscale structure of a gelatin/HPMCP hydrogel (1:1 by weight) between pH 2 and 6 at 37 °C, i.e. above the upper critical solution transition temperature of gelatin, using small-angle X-ray scattering and contrast-variation small-angle neutron scattering to understand the pH-responsive structure of HPMCP and the cross-correlation between gelatin and HPMCP. FINDINGS: Agglomeration of HPMCP between pH 2 and 4 was evidenced by the formation of mass fractal structures, with a fractal dimension ranging from 1.5 to 2.7, comprising primary particles with a radius of gyration ranging from 70 to 140 Å. Blending with gelatin influenced the fractal structure of HPMCP and the primary particle size. Gelatin and HPMCP exhibited negative cross-correlation in all probed length scales and pH values, which was attributed to volume-exclusion interaction in a double-network-like solution architecture.

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.

Preparation and characterization of water vapor-responsive methylcellulose-polyethylene glycol-400 composite membranes and an indication of freshness of shiitake mushrooms.

Intelligent packaging with freshness indication capability can help consumers purchase fresh food. However, current research primarily focuses on carbon dioxide-sensitive intelligent packaging, with limited research on water vapor-sensitive indication packaging. In this study, the water vapor-sensitive indicator membrane was prepared and used to determine the freshness of mushrooms. The results of this study showed that the water permeability of the indicator membrane decreased from 33.17 % to 21.59 % with the increase of Polyethylene glycol-400(PEG-400) content in methylcellulose(MC) membrane, and the contact angle of the indicator membrane increased from 87 % to 98 % with the addition of PEG-400. The addition of plasticizer PEG-400 increased the hydrophobicity of the indicator film, which could be attributed to the improvement of the molecular arrangement and crystallinity of the indicator film by the addition of PEG-400. After encountering water, the transparency of the indicator membrane changes from completely opaque (white) to transparent. Addition of PEG-400 reduces the rate of change in the transparency of the indicator membrane. The indicator membrane was successfully used to indicate the freshness of mushrooms and effectively reflected the freshness of mushrooms during storage. This technology could be applied to measure the freshness of other foods.

Liquid foam improves potency and safety of gene therapy vectors.

Interest in gene therapy medicines is intensifying as the first wave of gene-correcting drugs is now reaching patient populations. However, efficacy and safety concerns, laborious manufacturing protocols, and the high cost of the therapeutics are still significant barriers in gene therapy. Here we describe liquid foam as a vehicle for gene delivery. We demonstrate that embedding gene therapy vectors (nonviral or viral) in a methylcellulose/xanthan gum-based foam formulation substantially boosts gene transfection efficiencies in situ, compared to liquid-based gene delivery. We further establish that our gene therapy foam is nontoxic and retained at the intended target tissue, thus minimizing both systemic exposure and targeting of irrelevant cell types. The foam can be applied locally or injected to fill body cavities so the vector is uniformly dispersed over a large surface area. Our technology may provide a safe, facile and broadly applicable option in a variety of clinical settings.

Noni (Morinda citrifolia) leaf extract incorporated methylcellulose active films: A sustainable strategy for browning inhibition in apple slice packaging.

Methylcellulose, a prominent polysaccharide prevalent in the food sector, was considered to fabricate the active films with glutaraldehyde as a crosslinker and Noni (Morinda citrifolia) Leaf Extract (NLE) as an active agent. FTIR analysis confirms the intermolecular -OH bonding, and SEM micrograms demonstrate methylcellulose active films' homogeneous, dense morphologic appearance. Due to the crosslinking effect of glutaraldehyde and noni leaf extract, tensile strength (41.83 ± 0.134 MPa) and crystallinity (62.91 %) of methylcellulose films were improved. Methylcellulose active films suppress water and moisture uptake at various relative humidities. The inhibition capability against foodborne pathogens and the excellent antioxidant activity [DPPH (93.191 ± 1.384 %) and ABTS (90.523 ± 1.412 %)] of NLE incorporation suggested that food packed in methylcellulose active films were effective against pathogenic and oxidative attacks. During preservation, to ensure the apple slices' nutritional values, they are covered with physiochemically enhanced methylcellulose active films for up to 120 h. The minimum reduction in vitamin C, reducing sugar content, percentage weight loss, pH, and total phenolic content of apple slices preserved in MGN active films at room temperature suggests it is an affordable and efficient replacement to traditional single-use plastic packaging in the cut fruit industry.

Modified Release 3D-Printed Capsules Containing a Ketoprofen Self-Nanoemulsifying System for Personalized Medical Application.

This study explores the realm of personalized medicine by investigating the utilization of 3D-printed dosage forms, specifically focusing on patient-specific enteric capsules designed for the modified release of ketoprofen, serving as a model drug. The research investigates two distinct scenarios: the modification of drug release from 3D-printed capsules crafted from hydroxypropyl methylcellulose phthalate:polyethylene glycol (HPMCP:PEG) and poly(vinyl alcohol) (PVA), tailored for pH sensitivity and delayed release modes, respectively. Additionally, a novel ketoprofen-loaded self-nanoemulsifying drug delivery system (SNEDDS) based on pomegranate seed oil (PSO) was developed, characterized, and employed as a fill material for the capsules. Through the preparation and characterization of the HPMCP:PEG based filament via the hot-melt extrusion method, the study thoroughly investigated its thermal and mechanical properties. Notably, the in vitro drug release analysis unveiled the intricate interplay between ketoprofen release, polymer type, and capsule thickness. Furthermore, the incorporation of ketoprofen into the SNEDDS exhibited an enhancement in its in vitro cylooxygenase-2 (COX-2) inhibitory activity. These findings collectively underscore the potential of 3D printing in shaping tailored drug delivery systems, thereby contributing significantly to the advancement of personalized medicine.

Effective cryopreservation of human brain tissue and neural organoids.

Human brain tissue models and organoids are vital for studying and modeling human neurological disease. However, the high cost of long-term cultured organoids inhibits their wide-ranging application. It is therefore urgent to develop methods for the cryopreservation of brain tissue and organoids. Here, we establish a method using methylcellulose, ethylene glycol, DMSO, and Y27632 (termed MEDY) for the cryopreservation of cortical organoids without disrupting the neural cytoarchitecture or functional activity. MEDY can be applied to multiple brain-region-specific organoids, including the dorsal/ventral forebrain, spinal cord, optic vesicle brain, and epilepsy patient-derived brain organoids. Additionally, MEDY enables the cryopreservation of human brain tissue samples, and pathological features are retained after thawing. Transcriptomic analysis shows that MEDY can protect synaptic function and inhibit the endoplasmic reticulum-mediated apoptosis pathway. MEDY will enable the large-scale and reliable storage of diverse neural organoids and living brain tissue and will facilitate wide-ranging research, medical applications, and drug screening.

Properties and application of antioxidant and antibacterial composite films based on methylcellulose and spine grape pomace fabricated by thermos-compression molding.

Methylcellulose (MC)/grape pomace (GP) films, plasticized with either glycerol (GLY) or cinnamon essential oil (CEO), were prepared by thermo-compression molding and characterized. Compared to the GLY-plasticized MC50/GP50 films, a considerable increase in TS and YM values of CEO-plasticized films was observed, rising from 9.66 to 30.05 MPa, 762 to 1631 MPa, respectively. Moreover, the water vapor barrier, surface hydrophobic properties, and antioxidant/antibacterial activities of CEO-plasticized films remarkedly improved with increasing CEO content from 5 to 15% w/w. From scanning electron microscopy, phase separation between GP and the MC/GLY mixture were evident for GLY-plasticized MC/GP films. On the other hand, the CEO-plasticized films showed compact morphologies, attributable to the formation of hydrogen bonding and π-π stacking interaction. Preliminary shelf-life study on showed that fresh chicken wrapped with the CEO-plasticized MC/GP films exhibited lower TVB-N, TBARS, and TVC values than the unwrapped control samples, during 7 d storage at 4 °C.

Thermosensitive methyl-cellulose-based injectable hydrogel carrying oxaliplatin for the treatment of peritoneal metastasis in colorectal cancer.

Advanced colorectal cancer (CRC) with peritoneal metastasis (PM) is a highly aggressive malignancy with poor prognosis. Systematic chemotherapy and local treatments are the primary therapeutic approaches. However, systemic chemotherapy is limited by low accumulation of drugs at the tumor site and systemic toxicity. Local treatments include cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). However, CRS faces challenges related to incomplete tumor resection, while HIPEC is restricted by the uneven distribution of drugs and potential complications. Herein, a thermosensitive methyl-cellulose-based injectable hydrogel carrying oxaliplatin (OXA) was synthesized to improve this situation. Specifically, methyl cellulose (MC) coagulated into a hydrogel, and OXA was loaded into the MC hydrogel to construct the OXA-MC hydrogel. We explored the OXA-MC hydrogel for the treatment of PM in CRC. The results demonstrated that the OXA-MC hydrogel had favorable biocompatibility and thermo-sensitivity and could act as a local slow-release drug carrier. Moreover, in a CT-26 tumor-bearing model, it showed a remarkable anti-tumor effect by inhibiting proliferation and promoting apoptosis. Additionally, transcriptome analysis indicated that the OXA-MC hydrogel might be involved in the regulation of the PI3K-AKT signaling pathway. In summary, we successfully prepared the OXA-MC hydrogel and provided a valid approach in the treatment of PM in CRC, which lays a foundation for other PM treatments.

Injectable in situ gelling methylcellulose-based hydrogels for bone tissue regeneration.

Injectable bone substitutes (IBSs) represent a compelling choice for bone tissue regeneration, as they can be exploited to optimally fill complex bone defects in a minimally invasive manner. In this context, in situ gelling methylcellulose (MC) hydrogels may be engineered to be free-flowing injectable solutions at room temperature and gels upon exposure to body temperature. Moreover, incorporating a suitable inorganic phase can further enhance the mechanical properties of MC hydrogels and promote mineralization, thus assisting early cell adhesion to the hydrogel and effectively guiding bone tissue regeneration. In this work, thermo-responsive IBSs were designed selecting MC as the organic matrix and calcium phosphate (CaP) or CaP modified with graphene oxide (CaPGO) as the inorganic component. The resulting biocomposites displayed a transition temperature around body temperature, preserved injectability even after loading with the inorganic components, and exhibited adequate retention on an ex vivo calf femoral bone defect model. The addition of CaP and CaPGO promoted the in vitro mineralization process already 14 days after immersion in simulated body fluid. Interestingly, combined X-ray diffraction and solid state nuclear magnetic resonance characterizations revealed that the formed biomimetic phase was constituted by crystalline hydroxyapatite and amorphous calcium phosphate. In vitro biological characterization revealed the beneficial impact of CaP and CaPGO, indicating their potential in promoting cell adhesion, proliferation and osteogenic differentiation. Remarkably, the addition of GO, which is very attractive for its bioactive properties, did not negatively affect the injectability of the hydrogel nor the mineralization process, but had a positive impact on cell growth and osteogenic differentiation on both pre-differentiated and undifferentiated cells. Overall, the proposed formulations represent potential candidates for use as IBSs for application in bone regeneration both under physiological and pathological conditions.

Evaluating a promising methylcellulose hydrogel for enhanced diabetic foot ulcer therapy through comprehensive preclinical studies.

The present research focuses on formulating and evaluating hydrogels modified with crosslinking agents using methylcellulose to treat diabetic foot ulcers (DFU). Methylcellulose hydrogels are prepared and characterized for their crosslinking capacity through FTIR and degradation studies. The optimized hydrogel is further assessed for viscosity, gel strength, contact angle, in-vitro biodegradation, water-vapor transmission rate, anti-bacterial activity, and in-vivo efficacy. The results demonstrate that the developed hydrogel exhibits promising properties for DFU treatment, including increased wound healing percentage, improved ulcer morphology, reduced levels of proinflammatory cytokines, and enhanced tissue characteristics. These findings suggest that the novel hydrogel composition could serve as a viable alternative to existing dressings for DFU management.

Interplay of Drug-Polymer Interactions and Release Performance for HPMCAS-Based Amorphous Solid Dispersions.

The interplay between drug and polymer chemistry and its impact on drug release from an amorphous solid dispersion (ASD) is a relatively underexplored area. Herein, the release rates of several drugs of diverse chemistry from hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based ASDs were explored using surface area normalized dissolution. The tendency of the drug to form an insoluble complex with HPMCAS was determined through coprecipitation experiments. The role of pH and the extent of drug ionization were probed to evaluate the role of electrostatic interactions in complex formation. Relationships between the extent of complexation and the drug release rate from an ASD were observed, whereby the drugs could be divided into two groups. Drugs with a low extent of insoluble complex formation with HPMCAS tended to be neutral or anionic and showed reasonable release at pH 6.8 even at higher drug loadings. Cationic drugs formed insoluble complexes with HPMCAS and showed poor release when formulated as an ASD. Thus, and somewhat counterintuitively, a weakly basic drug showed a reduced release rate from an ASD at a bulk solution pH where it was ionized, relative to when unionized. The opposite trend was observed in the absence of polymer for the neat amorphous drug. In conclusion, electrostatic interactions between HPMCAS and lipophilic cationic drugs led to insoluble complex formation, which in turn resulted in ASDs with poor release performance.

Understanding Self-Assembly and Molecular Packing in Methylcellulose Aqueous Solutions Using Multiscale Modeling and Simulations.

We present a multiscale molecular dynamics (MD) simulation study on self-assembly in methylcellulose (MC) aqueous solutions. First, using MD simulations with a new coarse-grained (CG) model of MC chains in implicit water, we establish how the MC chains self-assemble to form fibrils and fibrillar networks and elucidate the MC chains' packing within the assembled fibrils. The CG model for MC is extended from a previously developed model for unsubstituted cellulose and captures the directionality of H-bonding interactions between the -OH groups. The choice and placement of the CG beads within each monomer facilitates explicit modeling of the exact degree and position of methoxy substitutions in the monomers along the MC chain. CG MD simulations show that with increasing hydrophobic effect and/or increasing H-bonding strength, the commercial MC chains (with degree of methoxy substitution, DS, ∼1.8) assemble from a random dispersed configuration into fibrils. The assembled fibrils exhibit consistent fibril diameters regardless of the molecular weight and concentration of MC chains, in agreement with past experiments. Most MC chains' axes are aligned with the fibril axis, and some MC chains exhibit twisted conformations in the fibril. To understand the molecular driving force for the twist, we conduct atomistic simulations of MC chains preassembled in fibrils (without any chain twists) in explicit water at 300 and 348 K. These atomistic simulations also show that at DS = 1.8, MC chains adopt twisted conformations, with these twists being more prominent at higher temperatures, likely as a result of shielding of hydrophobic methyl groups from water. For MC chains with varying DS, at 348 K, atomistic simulations show a nonmonotonic effect of DS on water-monomer contacts. For 0.0 < DS < 0.6, the MC monomers have more water contacts than at DS = 0.0 or DS > 0.6, suggesting that with few methoxy substitutions, the MC chains are effectively hydrophilic, letting the water molecules diffuse into the fibril to participate in H-bonds with the MC chains' remaining -OH groups. At DS > 0.6, the MC monomers become increasingly hydrophobic, as seen by decreasing water contacts around each monomer. We conclude based on the atomistic observations that MC chains with lower degrees of substitutions (DS ≤ 0.6) should exhibit solubility in water over broader temperature ranges than DS ∼ 1.8 chains.

Effects of drying method and oil type on edible polyunsaturated oleogels co-structured by hydroxylpropyl methyl cellulose and xanthan gum.

The subtle balance between the interactions of polysaccharide molecules and the interactions of polysaccharide molecules with oil molecules is significantly important for developing polysaccharide-based polyunsaturated oleogels. Here, hydroxylpropyl methyl cellulose and xanthan gum were used to structure edible oleogels via emulsion-template methodology, while the effects of drying methods (hot-air drying (AD) and vacuum-freeze drying (FD)) and oil types (walnut, flaxseed and Moringa seed oil) on the structure, oil binding capacity (OBC), rheological properties, thermal behaviors and stability of oleogels were specially investigated. Compared with AD oleogels, FD oleogels exhibited significantly better OBC, enhanced gelation strength (G' value) and better capacity to holding oil after high temperature processing, which was attributed to the possibly increased oil-polysaccharide interactions. However, the weakened polysaccharide-polysaccharide interactions in FD oleogels failed in providing stronger physical interface or enough rigidity to restrict the migration of oil molecules. Polyunsaturated triacylglycerols in vegetable oils deeply participated in the construction of the network of AD oleogels through weak intermolecular non-covalent interactions, which in turn greatly changed the crystallization and melting behaviors of vegetables oils. In brief, this research may provide useful information for the development of polysaccharide-based polyunsaturated oil oleogels.

Solubility-permeability interplay of a supersaturated lutein delivery system constructed by glycosylated stevioside and hydroxypropyl-methylcellulose.

This study investigated the solubilizing capacity of glycosylated stevioside/hydroxypropyl-methylcellulose (stevia-G-HPMC) complexes with varying mass ratios on lutein. The impact on the steady-state flux and permeability coefficient of intracellular lutein was also explored through the construction of a Caco-2 cellular transport model. The results indicated that the equilibrium solubility of lutein linearly increased with an increase in stevia-G amount. The stability constants of the ternary system surpassed those of the binary system. Molecular dynamics simulation revealed a tight and stable structure in lutein supersaturated complexes. Meanwhile, lutein-stevia-G-HPMC complexes demonstrated superior cumulative penetrations, with the peak Papp (AP â†’ BL) value being (3.24 ± 0.89) × 10-5 cm·s-1. There was a slight decrease in Papp (BL â†’ AP), which improved the forward transport of lutein. Highly soluble lutein in aqueous environments saturated the extracellular transport proteins on the AP side of cell membranes, thereby maintaining the high permeability transport. Notably, the permeability trend of lutein in Caco-2 cells negatively correlated with the equilibrium solubility and matched the single exponential growth model. When the mass ratio of lutein, stevia-G and HPMC was 1:21:5, the solubility-permeability trade-off of lutein was effectively maintained.

Development of Sustained Release System Based on High Water-Absorbable Gel Formation Using Croscarmellose Sodium, Alkaline Excipients and HPMC (ACSH SR System); Novel Application of Croscarmellose Sodium as a Gel Former.

PURPOSE: Croscarmellose sodium, generally used as a superdisintegrant in pharmaceutical formulations, is hydrolyzed to form the gel structure under basic pH conditions. Utilizing this property of croscarmellose sodium, we developed a novel sustained release (SR) system. METHODS: Immediate release (IR) and SR tablets containing croscarmellose sodium, alkaline excipients and/or hydroxypropyl methylcellulose (HPMC) were prepared and examined for wet strength and in vitro drug release behavior. In vivo oral drug absorption was evaluated for IR tablets, HPMC tablets and our novel SR tablets in fasted Beagle dogs. RESULTS: To form the gel structure even under the physiological condition, alkaline excipients were added into the formulation containing croscarmellose sodium. Furthermore, HPMC was used to make the gel structure strong enough against mechanical destructive forces. The novel alkalized croscarmellose sodium-HPMC (ACSH) SR tablet, consisting of croscarmellose sodium, alkaline excipients, and HPMC, successfully sustained the release of acetaminophen, ibuprofen, or nicardipine hydrochloride, compared with the IR tablets. The ACSH SR system provided a better release of acetaminophen than the HPMC tablet without croscarmellose sodium in the release study using a small volume of liquid, suggesting that substantial release and subsequent absorption would be expected in the distal intestinal segments after oral dosing. The in vivo oral absorption study revealed that the ACSH SR system successfully suppressed and prolonged the plasma concentrations of acetaminophen. CONCLUSION: This novel ACSH SR system prepared with croscarmellose sodium, alkaline excipients, and HPMC, would be a promising SR formulation for enabling substantial drug absorption in the distal intestinal segments.

Polymer-inducing chemical degradation of amorphous solid dispersions driven by drug-polymer interactions for physical stabilization.

Intermolecular interactions between active pharmaceutical ingredients (APIs) and carrier polymers are important for the long-term physical stability of amorphous solid dispersions (ASDs). However, the negative impact of intermolecular interactions on chemical stability has rarely been reported. In this study, the relationship between intermolecular interactions and physical and chemical stability was investigated using two ASDs composed of API and hydroxypropyl methylcellulose acetate succinate (HPMCAS) with different stabilities: ASD1 was physically stable but chemically unstable, whereas ASD2 was physically unstable but chemically stable. Ionic-bonding between the pyridine nitrogen in the API and succinyl group in HPMCAS was found in both ASDs. The additional interaction between the succinyl group in HPMCAS and the hydroxyl group in the API was suggested only in ASD1. It was concluded that the additional interaction contributed to the physical stability of ASD1; however, it accelerated the chemical reaction between the succinyl and hydroxyl groups to generate succinyl ester owing to its close proximity. This study shows that the intermolecular interaction between the API and carrier polymer is not always beneficial for chemical stability. Understanding the molecular states of APIs and polymers in ASDs is important for their successful development.