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Conventional dissolution tests only assess the aqueous release of drugs to ensure quality and performance, without indicating whether absorption occurs through the portal or the lymphatic circulation. To address this issue, this study aimed to develop novel first-generation dissolution models that could investigate the release and uptake of oral lymphotropic drugs and examine relevant formulation issues. Dissolution of three commercial lymphotropic drug products (Terbinafina, Apo-terbinafine, and Lamisil) was done using modified versions of USP Apparatus II and IV. The developed models contained a lymphatic compartment filled with artificial chylomicrons to account for absorption through intestinal lymphatic pathway. The various products exhibited different release profiles into the aqueous media and the lymphatic media across the two tested models. The modified USP IV apparatus demonstrated greater distinction in aqueous release patterns. However, the release pattern into the lymphatic media remained similar in both models. This work represents a progress in meeting the challenges posed by the increasing complexity of pharmaceutical products containing lipophilic drugs or formulations, and has the potential to contribute towards the development of in-vitro bioequivalence standards for formulations targeting intestinal lymphatics.
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Liberação Controlada de Fármacos , Solubilidade , Administração Oral , Química Farmacêutica/métodos , Absorção Intestinal , Modelos BiológicosRESUMO
Topical microemulsion (ME) might provide a novel and advanced transdermal delivery system due to the enhances of drug solubility and permeability across the stratum corneum. Foams are topical delivery systems that have excellent patient compliance, acceptability, and preference. Therefore, this study aimed to investigate a foamable microemulsion as an alternative topical and transdermal dosage form for diclofenac sodium (DS). The physicochemical properties (optical clarity, percentage transmittance, homogeneity, consistency of formulation, particle size, zeta potential, conductivity, viscosity, and morphology, etc.) of the DS-loaded ME were investigated. The foam stability of both drug-free ME and DS-loaded ME was measured. The foam quality was evaluated, and the chemical stability over 90 days was determined. Franz diffusion cells were employed to assess the in vitro drug release of a foamed DS-loaded ME and compared with a commercial topical product. A foamable and stable DS-loaded ME that maintained small particle sizes and constant zeta potential and was transparent and translucent in appearance after 90 days was successfully produced. The foam of the DS-loaded ME was physically more stable compared to the drug-free foam. The foam had an increased drug release rate compared to the commercial product. The foamable DS-loaded ME has a great potential to enhance the transdermal delivery of DS after topical administration. Foamed DS-loaded ME is a promising alternative to the current topical formulation of DS.
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Diclofenaco , Administração Cutânea , Diclofenaco/química , Liberação Controlada de Fármacos , Emulsões/química , Humanos , SolubilidadeRESUMO
Currently, the use of Traditional Chinese Medicine (TCM) for healthy living in daily practice is widely accepted across the world. However, not much attention has been paid to the particular characteristics of TCM "pills", one of the classic dosage forms in TCM. For a better understanding, this review was undertaken to provide a modern pharmaceutical overview of pills. Over many centuries, pills have been developed in different types (honeyed pill, water-honeyed pill, watered pill, pasted pill, waxed pill, concentrated pill, and dripping pill) to achieve varying intended TCM release patterns. It suggests that knowledge relating to the impact of binders and excipients on drug release from TCM pills can be traced back to before dissolution testing was invented. Therefore, although Pills may be considered as an ancient and outdated dosage form compared to current drug delivery systems, they have surprisingly modern pharmaceutical properties that is highlighted in this article. In addition, this review found that the quality control standards for TCM pill are globally substantially different. Hence, greater effort should be taken to establish an internationally harmonized and proper standard to safeguard the quality of this dosage form and to ensure the alignment with TCM use.
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Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicina Tradicional Chinesa/métodos , Liberação Controlada de Fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Excipientes/química , HumanosRESUMO
The aim of this study was to evaluate the enhanced thermal stability and physicochemical properties of fattigated vaccine antigens. High molecular weight influenza hemagglutinin (Heg) was used as a model antigen because of low heat stability requiring cold chamber. Heg was conjugated with long-chain oleic acid (C18) and short-chain 3-decenoic acid (C10) to prepare fattigated Heg. Circular dichroism analysis revealed no significant changes in the three-dimensional structure post-conjugation. In the liquid state, the fattigated Heg was self-assembled into nanoparticles (NPs) due to its amphiphilic nature, with sizes of 136.27 ± 12.78 nm for oleic acid-conjugated Heg (HOC) and 88.73 ± 3.27 nm for 3-decenoic acid-conjugated Heg (HDC). Accelerated thermal stability studies at 60 °C for 7 days demonstrated that fattigated Heg exhibited higher thermal stability than Heg in various liquid or solid states. The longer-chained HOC showed better thermal stability than HDC in the liquid state, attributed to increased hydrophobic interactions during self-assembly. In bio-mimicking liquid states at 37 °C, HOC exhibited higher thermal stability than Heg. Furthermore, solid-state HOC with cryoprotectants (trehalose, mannitol, and Tween® 80) had significantly increased thermal stability due to reduced exposure of protein surface area via nanonization behavior. The current fattigation platform could be a promising strategy for developing thermostable nano vaccines of heat-labile vaccine antigens.
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Estabilidade de Medicamentos , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Nanopartículas , Nanopartículas/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vacinas contra Influenza/química , Vacinas contra Influenza/administração & dosagem , Ácido Oleico/química , Vacinas Conjugadas/química , Ácidos Graxos/química , Temperatura Alta , Tamanho da Partícula , Polissorbatos/química , Interações Hidrofóbicas e Hidrofílicas , Ácidos Graxos Monoinsaturados/química , Antígenos/química , Antígenos/imunologiaRESUMO
Drug absorption via chylomicrons holds significant implications for both pharmacokinetics and pharmacodynamics. However, a mechanistic understanding of predicting in vivo intestinal lymphatic uptake remains largely unexplored. This study aimed to delve into the intestinal lymphatic uptake of drugs, investigating both enhancement and inhibition using various excipients through our previously established in vitro model. It also examined the applicability of the model by assessing the lymphatic uptake enhancement of a lymphotropic formulation with linoleoyl polyoxyl-6 glycerides using the same model. The model successfully differentiated among olive, sesame, and peanut oils in terms of lymphatic uptake. However, it did not distinguish between oils containing long-chain fatty acids and coconut oil. Coconut oil, known for its abundance of medium-chain fatty acids, outperformed other oils. This heightened uptake was attributed to the superior emulsification of this oil in artificial chylomicron media due to its high content of medium-chain fatty acids. Additionally, the enhanced uptake of the tested formulation with linoleoyl polyoxyl-6 glycerides underscored the practical applicability of this model in formulation optimization. Moreover, data suggested that increasing the zeta potential of Intralipid® using sodium lauryl sulfate (SLS) and decreasing it using (+/-) chloroquine led to enhanced and reduced uptake in the in vitro model, respectively. These findings indicate the potential influence of the zeta potential on intestinal lymphatic uptake in this model, though further research is needed to explore the possible translation of this mechanism in vivo.
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This study was tasked with the design of mucoadhesive buccal films (MBFs) containing a peptide drug, leuprolide (LEU), or its diverse nanoparticles (NPs), for enhanced membrane permeability via self-assembled nanonization and deformable behavior. An LEU-oleic acid conjugate (LOC) and its self-assembled NPs (LON) were developed. Additionally, a deformable variant of LON (d-LON) was originally developed by incorporating l-α-phosphatidylcholine into LON as an edge activator. The physicochemical properties of LON and d-LON, encompassing particle size, zeta potential, and deformability index (DI), were evaluated. MBFs containing LEU, LOC, and NPs (LON, d-LON) were prepared using the solvent casting method by varying the ratio of Eudragit RLPO and hydroxypropyl methylcellulose, with propylene glycol used as a plasticizer. The optimization of MBF formulations was based on their physicochemical properties, including in vitro residence time, dissolution, and permeability. The dissolution results demonstrated that the conjugation of oleic acid to LEU exhibited a more sustained LEU release pattern by cleaving the ester bond of the conjugate, as compared to the native LEU, with reduced variability. Moreover, the LOC and its self-assembled NPs (LON, d-LON), equivalent to 1 mg LEU doses in MBF, exhibited an amorphous state and demonstrated better permeability through the nanonization process than LEU alone, regardless of membrane types. The incorporation of lauroyl-L-carnitine into the films as a permeation enhancer synergistically augmented drug permeability. Most importantly, the d-LON-loaded buccal films showed the highest permeability, due to the deformability of NPs. Overall, MBF-containing peptide NPs and permeation enhancers have the potential to replace parenteral LEU administration by improving LEU druggability and patient compliance.
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This study aimed to design mucoadhesive buccal tablets of leuprolide (LEU) and to manufacture and evaluate the properties of buccal tablets containing LEU-oleic acid conjugate (LOC) and self-assembled LEU-oleic acid nanoparticles (LON), which were developed in a previous study. Hydroxypropyl methylcellulose (HPMC 4000) was used as the mucoadhesive polymer, and tablets were prepared by direct compression. The formulations were characterized by weight, content uniformity, thickness, hardness, swelling index, disintegration time, mucoadhesion time, and drug release. The chosen formulation maintained an adhesion time of up to 6.43 h and a disintegration time of 4.10 h. Drug stability in the mucoadhesive tablets was confirmed after 2 h of storage in human mimic saliva (Phosphate buffer solution pH 6.8). Furthermore, the designed LEU formulation and the LOC and LON developed in a previous study were prepared as buccal tablets and compared. In the dissolution and permeation studies, LON-loaded buccal tablets showed the highest permeation rate. This study suggests that mucoadhesive buccal tablets containing self-assembled LON may effectively increase the medication adherence for pediatric and geriatric patients by improving the bioavailability and permeation rate of LEU.
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Ácidos Graxos , Leuprolida , Humanos , Criança , Idoso , Adesividade , Ácido Oleico , Administração Bucal , Comprimidos/química , Mucosa BucalRESUMO
This study aimed to investigate the enhancement of cannabinoid acid solubility and stability through the formation of a cannabinoid acid/cyclodextrin (CD) inclusion complex. Two cannabinoid acids, tetrahydro-cannabinolic acid (THCA) and cannabidiolic acid (CBDA), were selected as a model drug along with five types of CD: α-cyclodextrin (α-CD), ß-cyclodextrin (ß-CD), γ-cyclodextrin (γ-CD), hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and methylated-ß-cyclodextrin (M-ß-CD). Phase solubility studies were conducted using various types of CD to determine the complex stoichiometry. The preparation methods of the CD inclusion complex were optimized by adjusting the loading pH solution and the drying processes (spray-drying, freeze-drying, spray-freeze-drying). The drying process of the cannabinoid acid/M-ß-CD inclusion complex was further optimized through the spray-freeze-drying method. These CD complexes were characterized using solubility determination, differential scanning calorimetry (DSC), field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), and 1H NMR spectroscopy. DSC, XRD, and FE-SEM studies confirmed the non-crystalline state of the cannabinoid acid/CD inclusion complex. The permeation of THCA or CBDA from the M-ß-CD spray-freeze-dried inclusion complex was highly improved compared to those of cannabis ethanolic extracts under simulated physiological conditions. The stability of the cannabinoid acid/M-ß-CD inclusion complex was maintained for 7 days in a simulated physiological condition. Furthermore, the minimum inhibitory concentration of cannabinoid acid/M-ß-CD inclusion complex had superior anti-cancer activity in MCF-7 breast cancer cell lines compared to cannabinoid acid alone. The improved physicochemical and biological performances indicated that these CD inclusion complexes could provide a promising option for loading lipophilic cannabinoids in cannabis-derived drug products.
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Desmopressin acetate (DDAVP), a nonapeptide drug, is easily destroyed by heat in the manufacturing process of orodispersible film (ODF). A new challenging study was conducted to improve thermal stability through glycosylation and hydrogen bonding using carbohydrate gums (agar, arabic gum, carrageenan, xanthan gum) using the solvent casting method. Among gum types, xanthan gum strongly showed dual stabilizing effects of DDAVP via covalent glycosylation and hydrogen bonding, minimizing total impurities and optimizing physicochemical properties of ODF under accelerated conditions for six months. The optimized ODF formulation (O-DDAVP ODF) at a DDAVP and xanthan gum ratio of 1:1.5 had a pharmaceutically equivalent dissolution profile as compared with a commercial 0.2 mg commercial Minirin® tablet in four different media: pH 1.2, pH 4.0, and pH 6.8 buffers and deionized water. Furthermore, O-DDAVP ODF showed in vivo bioequivalence to Minirin® tablets in healthy human volunteers. Glycosylation-oriented stabilization of peptide drug using pharmaceutically active excipients against thermal denaturation could be challenged to design patient-friendly ODF.
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Desamino Arginina Vasopressina , Excipientes , Humanos , Disponibilidade Biológica , Glicosilação , Ligação de Hidrogênio , Comprimidos , Excipientes/química , Solubilidade , Administração OralRESUMO
The lymphatic system plays a crucial role in the absorption of lipophilic drugs, making it an important route for drug delivery. In this study, an in vitro model using Intralipid® was developed to investigate the lymphatic uptake of drugs. The model was validated using cannabidiol, halofantrine, quercetin, and rifampicin. Remarkably, the uptake of these drugs closely mirrored what would transpire in vivo. Furthermore, adding peanut oil to the model system significantly increased the lymphatic uptake of rifampicin, consistent with meals containing fat stimulating lymphatic drug uptake. Conversely, the inclusion of pluronic L-81 was observed to inhibit the lymphatic uptake of rifampicin in the model. This in vitro model emerges as a valuable tool for investigating and predicting drug uptake via the lymphatic system. It marks the first phase in developing a physiologically based predictive tool that can be refined further to enhance the precision of drug interaction predictions with chylomicrons and their subsequent transport via the lymphatic system. Moreover, it can be employed to explore innovative drug formulations and excipients that either enhance or hinder lymphatic drug uptake. The insights gained from this study have significant implications for advancing drug delivery through the lymphatic system.
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Dissolution testing is important in assessing the in vitro drug release performance for oral administration dosage forms. However, currently, a simple and efficient in vitro test to investigate critical factors that may impact the drug release and bioavailability at the development stage of a drug-loaded nanoemulsion (NE) is lacking. Thus, in this study, we developed a new combined biphasic and modified cylinder (BP + MC) method to evaluate the dissolution profile of NEs. Flubendazole (FLZ), a Biopharmaceutical Classification System (BCS) Class II drug, offers a new prospective for drug repositioning for treating lung cancer and cryptococcal meningitis. We compared the drug release profiles of three different FLZ formulations (micronized as a suspension, loaded in NE, and solubilized in oil) by using three different methods (dialysis bag, modified cylinder method, and a new BP + MC method). The results showed potential higher drug release of FLZ from the suspension compared to FLZ-loaded NE at pH 1.2, and higher drug release from FLZ-loaded NE compared to other forms in octanol phase. These results correlate well with the in vivo test performed in mice carried out in our previous works. Furthermore, the partition mechanism of the drug released from the NE is discussed in-depth in this article, as well as the advantage of drug-loaded NEs over other preparations in creating supersaturable conditions. Based on the results, we provide new insights into how dissolution methods for a poorly water-solubility drug can be designed. Therefore, we present this new combined BP + MC method as a potential new discriminative dissolution test for future studies when developing drug-loaded NE and comparing with other dosage forms.
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Solubilidade , Camundongos , Animais , Preparações Farmacêuticas , Estudos Prospectivos , Liberação Controlada de Fármacos , Composição de Medicamentos , Administração OralRESUMO
Background and purpose: Lysosomal-targeted drug delivery can open a new strategy for drug therapy. However, there is currently no universally accepted simulated or artificial lysosomal fluid utilized in the pharmaceutical industry or recognized by the United States Pharmacopeia (USP). Experimental procedure: We prepared a simulated lysosomal fluid (SLYF) and compared its composition to a commercial artificial counterpart. The developed fluid was used to test the dissolution of a commercial product (Robitussin®) of a lysosomotropic drug (dextromethorphan) and to investigate in-vitro lysosomal trapping of two model drugs (dextromethorphan and (+/-) chloroquine). Findings/Results: The laboratory-prepared fluid or SLYF contained the essential components for the lysosomal function in concentrations reflective of the physiological values, unlike the commercial product. Robitussin® passed the acceptance criteria for the dissolution of dextromethorphan in 0.1 N HCl medium (97.7% in less than 45 min) but not in the SLYF or the phosphate buffer media (72.6% and 32.2% within 45 min, respectively). Racemic chloroquine showed higher lysosomal trapping (51.9%) in the in-vitro model than dextromethorphan (28.3%) in a behavior supporting in-vivo findings and based on the molecular descriptors and the lysosomal sequestration potential of both. Conclusion and implication: A standardized lysosomal fluid was reported and developed for in-vitro investigations of lysosomotropic drugs and formulations.
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The objective of this study was to evaluate the effectiveness of organ-on-chip system investigating simultaneous cellular efficacy and real-time reactive oxygen species (ROS) occurrence of anticancer drug-loaded nanoparticles (NPs) using hepatocarcinoma cells (HepG2) chip system under static and hepatomimicking shear stress conditions (5 dyne/cm2). Then, the role of hepatomimetic shear stress exposed to HepG2 and drug solubility were compared. The highly soluble doxorubicin (DOX) and poorly soluble paclitaxel (PTX) were chosen. Fattigated NPs (AONs) were formed via self-assembly of amphiphilic albumin (HSA)-oleic acid conjugate (AOC). Then, drug-loaded AONs (DOX-AON or PTX-AON) were exposed to a serum-free HepG2 medium at 37 °C and 5% carbon dioxide for 24 h using a real-time ROS sensor chip-based microfluidic system. The cellular efficacy and simultaneous ROS occurrence of free drugs and drug-loaded AONs were compared. The cellular efficacy of drug-loaded AONs varied in a dose-dependent manner and were consistently correlated with real-time of ROS occurrence. Drug-loaded AONs increased the intracellular fluorescence intensity and decreased the cellular efficacy compared to free drugs under dynamic conditions. The half-maximal inhibitory concentration (IC50) values of free DOX (13.4 µg/mL) and PTX (54.44 µg/mL) under static conditions decreased to 11.79 and 38.43 µg/mL, respectively, under dynamic conditions. Furthermore, DOX- and PTX-AONs showed highly decreased IC50 values of 5.613 and 21.86 µg/mL, respectively, as compared to free drugs under dynamic conditions. It was evident that cellular efficacy and real-time ROS occurrence were well-correlated and highly dependent on the drug-loaded nanostructure, drug solubility and physiological shear stress.
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Background: Leuprolide (LEU), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH), could exert a direct inhibitory activity on the proliferation of prostate cancer cells. However, the short half-life in blood and the biopharmaceutical problem of LEU limit this anticancer activity. Purpose: To improve its druggability for improving anticancer activity, the amine-group targeted LEU was conjugated with different chain lengths of saturated fatty acids (FAs). Methods: LEU-fatty acid conjugates (LFCs) were synthesized by exploiting N-hydroxysuccinimidyl (NHS) conjugation chemistry. The physicochemical properties and the self-assembled behaviors of the conjugates were extensively investigated. The in vitro anticancer activity of three LFCs was extensively studied in both 2D monolayer and 3D spheroid culture models of a prostate cancer cell line, PC3. Results: Three LFCs could be readily self-assembled into nanoparticles (LFNs) with a small size of around 100 nm, positive charges, and exhibited greater permeability rates compared to the same concentration of LEU, excluding LSN. The chain length of FA in conjugate was positively related to the selectivity index between cancer cells and non-cancerous cell lines. All LFCs showed a superior direct antiproliferative effect on cancer cells in the following order: LSC (98.9%) > LPC (86.7%) > LLC (75.0%) > LEU (8.9%) after repeat daily of the same dose strength of LEU for 4 days. In addition, the 3D spheroid model study indicates that all LFCs with a one-time treatment performed a long-acting inhibitory effect on tumor growth as compared to LEU after 7 days. Conclusion: The conjugation of LEU with different chain lengths of FAs could provide a novel strategy to improve peptide stability and exert an additional superior direct inhibitory effect for the treatment of several hormone-responsive tumor systems using therapeutic peptides.
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Produtos Biológicos , Neoplasias da Próstata , Masculino , Humanos , Leuprolida/farmacologia , Ácidos Graxos , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular TumoralRESUMO
The aim of this study was to design a novel matrix tablet with enhanced dissolution and pH-independent controlled release of sildenafil citrate (SIL), a drug with pH-dependent solubility, by using solid dispersions (SDs) and polyelectrostatic interactions. SIL-loaded SDs were prepared using various polymeric carriers such as poloxamer 188, poloxamer 407, Soluplus®, polyvinylpyrrolidone (PVP) K 12, and PVP K 17 by the solvent evaporation method. Among these polymers, Soluplus® was found to be the most effective in SDs for enhancing the drug dissolution over 6 h in pH 6.8 intestinal fluid. SIL was well dispersed in Soluplus®-based SDs in an amorphous form. When the Soluplus®-based SDs were added in the tablet containing positively charged chitosan and negatively charged Eudragit® L100, the drug release rate was further modulated in a controlled manner. The charge density of the tablet was higher at pH 6.8 than at pH 1.2 due to the polyelectrostatic interaction between chitosan and Eudragit® L100. This interaction could provide a pH-independent controlled release of SIL. Our study demonstrates that a combinatory approach of Soluplus®-based SDs and polyelectrostatic interactions can improve the dissolution and pH-independent release performance of SIL. This approach could be a promising pharmaceutical strategy to design a matrix tablet of poorly water-soluble drugs for the enhanced bioavailability.
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In this study, the electrostatic molecular effect of differently charged surfactants on the solubilization capacity and physicochemical properties of salt-caged nanosuspensions (NSPs) containing poorly water-soluble drug was investigated. Anionic rebamipide (RBM) was chosen as a model drug because of its poor water solubility in low pH condition and ionizable acidic forms. Negatively charged sodium lauryl sulfate (SLS) and positively charged cetyltrimethylammonium bromide (CTAB) were selected as surfactants for the preparation of NSPs or in the dissolution medium. Salt-caged NSPs surrounded by NaCl were prepared by the HCl-NaOH neutralization method in the presence of poloxamer 407. Interestingly, the addition of positively charged CTAB in the preparation process or the dissolution media could interfere with the solubilization capacity of salt-caged NSPs containing a negatively charged drug via intermolecular electrostatic attraction. In the presence of positively charged CTAB, the salt-caged NSP was disordered in structure via electrostatic attractive interaction with partially ionizable anionic RBM resulting in changes in the physicochemical properties of the salt-caged NSP such as low drug content, increased particle size, decreased dissolution rate, and the formation of water-insoluble precipitates with rough and irregular crystals. This inhibitory effect of CTAB on the dissolution rate of pure RBM and the salt-caged NSP in pH 6.8 intestinal fluid was pronounced in a concentration-dependent manner mainly owing to the formation of precipitates, so-called poorly soluble complexes. When the salt-caged NSP (F1) was dissolved in DW containing CTAB, the dissolution rate decreased more significantly, dissolving less than 20% within 2 h. Depending on the surfactant charges, the charge density and the initial potential were varied during the dissolution of NSPs in deionized water (DW). In contrast, the negatively charged SLS did not significantly change the physicochemical properties of the salt-caged NSP. For example, the dissolution rate of the salt-caged NSP containing SLS in DW or pH 1.2 gastric fluid remained over 90% for 2 h. Surfactants for the formulation or dissolution media should be chosen carefully because of their effect on the physicochemical properties and solubilization capacity of salt-caged NSPs containing poorly water-soluble and ionizable drugs via electrostatic molecular interactions.
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Tensoativos , Água , Alanina/análogos & derivados , Cetrimônio , Concentração de Íons de Hidrogênio , Quinolonas , Cloreto de Sódio , Solubilidade , Eletricidade Estática , Tensoativos/química , Água/químicaRESUMO
The objective of this study was to design and evaluate an orodispersible film (ODF) composed of aripiprazole (ARP), prepared using a conventional solvent casting technique, and to fuse a three-dimensional (3D) printing technique with a hot-melt extrusion (HME) filament. Klucel® LF (hydroxypropyl cellulose, HPC) and PE-05JPS® (polyvinyl alcohol, PVA) were used as backbone polymers for 3D printing and solvent casting. HPC-, PVA-, and ARP-loaded filaments were applied for 3D printing using HME. The physicochemical and mechanical properties of the 3D printing filaments and films were optimized based on the composition of the polymers and the processing parameters. The crystalline states of drug and drug-loaded formulations were investigated using differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). The dissolution and disintegration of the 3D-printed films were faster than those of solvent-cast films. HPC-3D printed film was fully disintegrated within 45 ± 3.5 s. The dissolution rate of HPC films reached 80% within 30 min at pH 1.2 and pH 4.0 USP buffer. There was a difference in the dissolution rate of about 5 to 10% compared to PVA films at the same sampling time. The root mean square of the roughness (Rq) values of each sample were evaluated using atomic force microscopy. The higher the Rq value, the rougher the surface, and the larger the surface area, the more salivary fluid penetrated the film, resulting in faster drug release and disintegration. Specifically, The HPC 3D-printed film showed the highest Rq value (102.868 nm) and average surface roughness (85.007 nm). The puncture strength of 3D-printed films had desirable strength with HPC (0.65 ± 0.27 N/mm2) and PVA (0.93 ± 0.15 N/mm2) to prevent deformation compared to those of marketed film products (over 0.34 N/mm2). In conclusion, combining polymer selection and 3D printing technology could innovatively design ODFs composed of ARP to solve the unmet medical needs of psychiatric patients.
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The purpose of this study was to develop a once-daily, bilayer matrix tablet with immediate (IR) and sustained release (SR) layers of poorly water-soluble and absorption site dependent rebamipide (RBM) to substitute three times a day IR tablet. Owing to the pH-dependent poor water solubility of RBM in low pH condition, salt-caged nanosuspensions (NSPs) consisting of RBM and poloxamer 407 (POX 407) or poloxamer 188 (POX 188) were prepared using an acid-base neutralization method to increase the dissolution rate, which was subsequently applied to the immediate-release (IR) layer. Polyethylene oxide (PEO) with different molecular weights (PEO 100,000 and PEO 5,000,000) and hydroxypropyl methylcellulose 4000 (HPMC 4000) were then investigated as SR agents to incorporate into the SR layer with pure RBM via wet granulation method. The dissolution profile of the optimized bilayer tablet having 50% IR and 50% SR layer of 300 mg RBM showed that the IR layer could rapidly disintegrate in pH 1.2 buffer solution within 2 h, reaching 50% of drug release from the tablet, followed by an extended drug release from the SR layer in pH 6.8 buffer over 24 h. An in vivo pharmacokinetic study was carried out in beagle dogs to compare the optimal formulation (300 mg RBM bilayer tablet) and the commercial tablet (Mucosta® 100 mg) as a reference. Unexpectedly, despite enhanced dissolution rate in a controlled manner, a designed bilayer tablet had no dose- and dosage form dependent in vivo bioavailability in beagle dogs as compared with IR 100 mg RBM reference tablet. It was evident that solubility in low pH condition, gastric residence time and absorption site of RBM should be carefully considered for designing specific SR or gastroretentive dosage form to improve therapeutic outcomes.
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Poloxâmero , Água , Alanina/análogos & derivados , Animais , Disponibilidade Biológica , Preparações de Ação Retardada/química , Cães , Quinolonas , Solubilidade , ComprimidosRESUMO
BACKGROUND: Hydrophilic Hydroxypropyl Methylcellulose (HPMC) matrix tablets are the standard role model of the oral controlled-release formulation. Nevertheless, the HPMC kinetics for the mechanistic understanding of drug release and hydrodynamic behaviors are rarely investigated. This study aims to investigate the release behaviors of both HPMC and paracetamol (model drug) from the hydrophilic matrix tablet. METHODS: Two different viscosity grades of HPMC were used (Low viscosity: 6 cps, High viscosity: 4,000 cps). Three different ratios of drug/HPMC (H:38.08%, M:22.85%, and L:15.23% (w/w) of HPMC amounts in total weight) matrix tablets were prepared by wet granulation technique. The release profiles of the drug and HPMC in a matrix tablet were quantitatively analyzed by HPLC and 1H-Nuclear Magnetic Resonance (NMR) spectroscopy. The hydrodynamic changes of HPMC were determined by the gravimetric behaviors such as swelling and erosion rates, gel layer thickness, front movement data,and distributive Near-Infrared (NIR) chemical imaging of HPMC in a matrix tablet during the dissolution process. RESULTS: High viscosity HPMC tablets showed slower release of HPMC than the release rate of drug, suggesting that drug release preceded polymer release.Different hydration phenomenon was qualitatively identified and corresponded to the release profiles. The release behaviors of HPMC and drug in the tablet could be distinguished with the significant difference with fitted dissolution kinetics model (Low viscosity HPMC 6cps; Korsmeyer-Peppas model, High viscosity HPMC 4000cps; Hopfenberg model, Paracetamol; Weibull model) according to the weight of ingredients and types of HPMC. CONCLUSION: The determination of HPMC polymer release correlating with drug release, hydrodynamic behavior, and NIR chemical imaging of HPMC can provide new insights into the drug release- modulating mechanism in the hydrophilic matrix system.
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Acetaminofen , Hidrodinâmica , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Derivados da Hipromelose/química , Cinética , Metilcelulose/química , Polímeros , Solubilidade , Comprimidos , ViscosidadeRESUMO
The aim of this study was to develop a stable microemulsion (ME) for transdermal delivery of tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA). The lipid-based vehicles were selected by screening cannabinoid solubility and the emulsifying ability of surfactants. Pseudo-ternary phase diagrams were constructed by formulation of cannabinoids with Capryol® 90 as oil phase, Tween® 80, Solutol® HS15, Procetyl® AWS, and Cremophor® RH40 as surfactants, ethanol as cosurfactant, and distilled water as the aqueous phase. A significant improvement in transmembrane flux (Jss), permeability coefficient (Kp), and enhancement ratio (ER) was found in one system compared to other formulations. This ME consisted of 1.0% (w/w) of cannabinoids, 5% (w/w) of Capryol® 90, 44% (w/w) Smix (2:1, Procetyl® AWS and Ethanol) and 50.0% (w/w) of distilled water. Additionally, the effects of pH on the permeation of the cannabinoids were investigated. Based on the pH value THCA and CBDA-loaded ME exhibited the highest permeation at pH 5.17 and pH 5.25. After storing the pH-adjusted P2 ME and the optimized P2 ME for 180 days at 4â and 25â, the content of cannabinoids was over 95%. Consequently, the cannabinoid-loaded ME system is a promising option for solubilizing and stabilizing lipophilic drugs like cannabinoids and utilize them for transdermal delivery.