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Role of Permeability on the Biopredictive Dissolution of Amorphous Solid Dispersions
Gayathri Ramachandran & M. S. Sudheesh
doi : 10.1208/s12249-021-02125-4
AAPS PharmSciTech volume 22, Article number: 243 (2021)
An ideal dissolution test for amorphous solid dispersions (ASDs) should reflect physicochemical, physiological, and hydrodynamic conditions which accurately represent in vivo dissolution. However, this is confounded by the evolution of different molecular and colloidal species during dissolution, generating a supersaturated state of the drug. The supersaturated state of a drug is thermodynamically unstable which drives the process of precipitation resulting in a loss of solubility advantage. Maintaining a supersaturated state of the drug with the help of precipitation inhibiting excipients is a key component in the design of ASDs. Therefore, a biopredictive dissolution test is critical for proper risk assessment during the development of an optimal ASD formulation. One of the overlooked components of biopredictive dissolution is the role of drug permeability. The kinetic changes in the phase behavior of a drug during dissolution of ASDs are influenced by drug permeability across a membrane. Conventionally, drug dissolution and permeation are analyzed separately although they occur simultaneously in vivo. The kinetic phase changes occurring during dissolution of ASDs can influence the thermodynamic activity and membrane flux of a drug. The present review evaluates the feasibility, predictability, and practicability of permeability/dissolution for the optimal development and risk assessment of ASD formulations.
Lipopolysaccharide Nanosystems for the Enhancement of Oral Bioavailability
Mumuni Sumaila, Thashree Marimuthu, Pradeep Kumar & Yahya E. Choonara
doi : 10.1208/s12249-021-02124-5
AAPS PharmSciTech volume 22, Article number: 242 (2021)
Nanosystems that incorporate both polymers and lipids have garnered attention as emerging nanotechnology approach for oral drug delivery. These hybrid systems leverage on the combined properties of polymeric and lipid-based nanocarriers while eliminating their inherent limitations. In view of the safety-related benefits of naturally occurring polymers, we have focused on systems incorporating polysaccharides and derivatives into the hybrid structure. The aim of this review is to evaluate existing biopolymers with specific focus on lipopolysaccharide hybrid systems and their advancement toward enhancing oral drug delivery. Furthermore, we shall identify future research areas that require further exploration toward achieving an optimized hybrid system for easy translation into clinical use. In this review, we have appraised formulations that combined polysaccharides/derivatives with lipids in a single nanocarrier system. These formulations were grouped into lipid-core-polysaccharide-shell systems, polysaccharide-core-lipid-shell systems, self-emulsifying lipopolysaccharide hybrid systems, and hybrid lipopolysaccharide matrix systems. In these systems, we highlighted how the polysaccharide phase enhances the oral absorption of encapsulated bioactives with regard to their function and mechanism. The various lipopolysaccharide designs presented in this review demonstrated significant improvement in pharmacokinetics of bioactives. A multitude of studies found lipopolysaccharide hybrid systems as nascent nanoplatforms for the oral delivery of challenging bioactives due to features that favor gastrointestinal absorption and bioavailability improvement. With future research already geared toward product optimization and scaling up processes, as well as detailed pharmacological and toxicology pre-clinical testing, these versatile systems will have remarkable impact in clinical application.
Improvement of Bleached Shellac as Enteric Coating by Composite Formation
Manee Luangtana-anan, Suthep Saengsod & Sontaya Limmatvapirat
doi : 10.1208/s12249-021-02127-2
AAPS PharmSciTech volume 22, Article number: 241 (2021)
The objective of this study was to stabilize the enteric property of bleached shellac by composite formation with ethyl cellulose. The composite film at the ratio of 9:1, 8:2, 7:3, 6:4, and 5:5 was prepared by the film casting method. The physicochemical properties were acid value, insoluble solid, water permeability coefficient, % polarity, mechanical property, FTIR, PXRD, DSC, % solubility in aqueous, and various pH (1.2 and 7.4). All the films were able to protect against the low pH and water. The total solubility at pH 7.4 was reported for the low ratio of ethyl cellulose (9:1 and 8:2). The stability of all films was then investigated for 180 days. The results demonstrated that the ethyl cellulose could stabilize the bleached shellac indicated by the low changes in acid value and insoluble solid. The higher ratio of ethyl cellulose contributed to the lower polymerization during storage. The results were due to the protection of the bleached shellac’s active sites. The entanglement of ethyl cellulose caused interaction difficulties between active groups leading to stabilized bleached shellac. The proper ratio was 7:3 because of high solubility, and low polymerization. The findings demonstrated that the composite film could improve the enteric property of bleached shellac for a long period.
Primaquine Loaded Solid Lipid Nanoparticles (SLN), Nanostructured Lipid Carriers (NLC), and Nanoemulsion (NE): Effect of Lipid Matrix and Surfactant on Drug Entrapment, in vitro Release, and ex vivo Hemolysis
Kai-Wei Wu, Corinne Sweeney, Narendar Dudhipala, Prit Lakhani, Narayan D. Chaurasiya, Babu L. Tekwani & Soumyajit Majumdar
doi : 10.1208/s12249-021-02108-5
AAPS PharmSciTech volume 22, Article number: 240 (2021)
Primaquine (PQ), an 8-aminoquinoline antimalarial drug, has been widely used for the eradication of hypnozoites from the liver and, therefore, recognized as the radical cure of malaria. However, the clinical applications of PQ are restricted to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to severe dose-related hemolytic side effects. Nanoparticle carriers have shown great potential in achieving higher PQ concentrations in the target site, thereby reducing dose-related systemic toxicity caused by non-specific exposure. This work aims to develop, compare, and evaluate three PQ-loaded lipid-based drug carriers including solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and nano-emulsions (NE). The optimized PQ-SLN, PQ-NLC, and PQ-NE had a particle size of 250 nm, a PDI range of 0.1 to 0.3, a zeta potential of???30 mV, and entrapment efficiency of?~?90%. All lipid formulations showed sustained release in both simulated gastric and intestinal fluids over 6 h. Four empirical models — including zero-order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell models — were tested to understand the drug release mechanisms of PQ-SLN, PQ-NLC, and PQ-NE. The model fitness was found to be the highest in the Korsmeyer-Peppas model for all the PQ-loaded lipid formulations (R2: 0.88–0.94). No significant changes were observed in the entrapment efficiency, particle size, and PDI of lipid formulations throughout 1 month of storage at 4 °C and 25 °C. PQ-SLN and PQ-NLC can be further lyophilized with cryoprotectants to improve long-term stability. Finally, the treatment of erythrocytes with PQ-SLN, PQ-NLC, and PQ-NE reduced erythrocyte hemolysis by approximately 4.5-fold compared to the free drug solution.
Piperine-Loaded Glycyrrhizic Acid- and PLGA-Based Nanoparticles Modified with Transferrin for Antitumor
Shuang Li, Jueshuo Guo, Zonghua Tian, Jing Chen, Guojing Gou, Yang Niu, Li Li & Jianhong Yang
doi : 10.1208/s12249-021-02123-6
AAPS PharmSciTech volume 22, Article number: 239 (2021)
The purpose of this study was to enhance the antitumor effect of piperine by constructing the nanoparticles modified with transferrin (Tf-PIP-NPs) and evaluating their efficacy in vitro and in vivo. The Tf-PIP-NPs were prepared by the solvent evaporation method, and their properties were characterized. The effects of Tf-PIP-NPs on cytotoxicity, cell uptake, apoptosis, and mitochondrial membrane potential were evaluated in HepG2 cells, MDA-MB-231 cells, and 4T1 cells. In a 4T1 tumor-bearing mouse model, the antitumor efficacy of Tf-PIP-NPs was assessed in terms of tumor volumes, changes in body weight, HE staining, and immunohistochemical analysis. With a mean particle size of 112.2?±?1.27 nm, the zeta potential of (??28.0?±?1.6 mV) Tf-PIP-NPs were rapidly internalized by tumor cells after 1 h through the transferrin receptor (TfR)-mediated endocytosis pathway, significantly inducing cellular apoptosis and mitochondrial membrane potential loss. Although Tf-PIP-NPs had no significant difference with PIP-NPs in tumor volume inhibition due to the presence of tumor microenvironment, it could significantly upregulate the expression of related pro-apoptotic proteins and induce tumor necrosis. We used the self-assembly properties of glycyrrhizic acid (GL) and polymer-PLGA to encapsulate piperine and modified with the transferrin, which provided a promising approach to improve the antitumor efficacy for anticarcinogen.
Topical Application of Vitamin D3-Loaded Hybrid Nanosystem to Offset Imiquimod-Induced Psoriasis
Sudeep Sudesh Pukale, Anupama Mittal & Deepak Chitkara
doi : 10.1208/s12249-021-02116-5
AAPS PharmSciTech volume 22, Article number: 238 (2021)
Lipid-polymer hybrid nanoparticles display several benefits over either lipid and/or polymer based systems with respect to enhanced drug loading, good colloidal stability, sustained release profile, and high cellular uptake. The present work rivets on development and evaluation of vitamin D3-loaded monolithic lipid-polymer hybrid nanoparticles (VD3/LPHNPs) for their in vivo anti-psoriatic efficacy. These LPHNPs were prepared using a hot homogenization method and exhibited spherical morphology with a lower particle size (123.1 nm) with narrow PDI (0.234) and efficient encapsulation (76.80%). Further, these LPHNPs demonstrated a sustained release profile of VD3 for up to 3 days following a Korsemeyer-Peppas release model. Further, VD3/LPHNPs were formulated into a topical gel containing 0.005% w/w of VD3. Rheological data suggested that the product exhibited non-newtonian flow properties with characteristic shear-thinning and variable thixotropy features that are desirable for topical formulation. The successful formation of gel structure and its long-term stability were confirmed from the oscillatory studies such as amplitude and frequency sweep tests. In vivo efficacy assessment in imiquimod-induced psoriatic mouse model demonstrated enhanced anti-psoriatic activity of VD3 with improved PASI score when delivered as LPHNPs gel as compared to the free VD3 gel that were further supported by histopathology and immunohistochemistry.
Stability Evaluation of Lyotropic Liquid Crystalline Precursor for the Co-delivery of Chlorhexidine and Silver Nanoparticles
Fangqin Fu, Xin Li, Tengyi Zheng, Xiao Xia, Minqun Du, Zhengwei Huang, Ying Huang, Xin Pan & Chuanbin Wu
doi : 10.1208/s12249-021-02102-x
AAPS PharmSciTech volume 22, Article number: 237 (2021)
Sealing the therapeutic agents in the root canal is considered to be an essential step in root canal therapy. The lyotropic liquid crystalline precursor (LLCP) incorporated with chlorhexidine (CHX) and silver nanoparticles (Ag-NPs) has been confirmed as a promising candidate for root canal therapy in the previous study. Importantly, the stability of the LLCP system was a significant determinant for its therapeutic effect and further application. The objective of this study was to comprehensively investigate the stability of the LLCP incorporated with CHX and Ag-NPs. The oil-water partition coefficient of CHX and Ag-NPs was measured. The water absorption and the physical stability of drug-loaded LLCP solution were studied. Stability under high temperature, high humidity, and strong light irradiation was also investigated. The results demonstrated that CHX and Ag-NPs could be entrapped in the water channel of LLCP, indicating the low tendency of drugs leakage. The drug-loaded LLCP was a pseudoplastic fluid and it showed an excellent physical stability with a sedimentation rate of 0.981 and a settling time of 26~28 h. The payload of LLCP was confirmed to weaken the water absorption behavior, which facilitated its transformation to cubic liquid crystal. The stress testing under high temperature, high humidity, and strong light irradiation also manifested that the LLCP was stable when stored under moisture-proof condition. In conclusion, the developed LLCP incorporated with CHX and Ag-NPs was highly stable during storage and qualified for further application.
Investigation on Potential of Chitosan Nanoparticles for Oral Bioavailability Enhancement of Risedronate Sodium
Nikhil Suthar, Jagruti Desai & Hetal Paresh Thakkar
doi : 10.1208/s12249-021-02090-y
AAPS PharmSciTech volume 22, Article number: 236 (2021)
Risedronate sodium (RS) is used in osteoporosis for bone reabsorption. It is a BCS class III drug having poor oral bioavailability (<0.63%) due to low permeability. In the present study, RS-loaded chitosan nanoparticles were developed to increase oral bioavailability and evaluated for various parameters. The DSC study indicated compatibility of RS with excipients in their physical mixture. The nanoparticles were prepared by ionotropic gelation technique and lyophilized. The optimized batch (RS-CNs) was found to have particles of size 268.7 nm and zeta potential of 24.9 mV. The TEM image of RS-CNs revealed discrete spherical particles. Angle of repose of 27.02 indicates good flow property of nanoparticles. FT-IR spectra of RS-CNs showed characteristic peaks of RS indicating compatibility of RS with the excipients. The mucin binding efficiency of RS-CNs was obtained as 63.42%. The in vitro release study of RS indicated controlled delivery from RS-CNs over 22 h. The release mechanism was found to be diffusion- and erosion-controlled release. Ex vivo study using rat intestine revealed faster permeation of 32.78% in 6 h from RS-CNs compared to plain drug solution. In vivo pharmacokinetic study in rats showed increased Cmax (1.8 fold) from RS-CNs compared to marketed formulation. The relative bioavailability of 193% from RS-CNs indicated significant enhancement in bioavailability upon nanoparticle formulation. The RS-CNs were found to be stable at room and refrigerated conditions. In conclusion, developed RS-loaded chitosan nanoparticles seem to be a promising approach to increase oral bioavailability and can avoid upper GI tract side effects.
Solvent-Assisted Hot Melt Extrusion of a Thermally Labile, High Melting Point Compound
C. Lagan, J. E. Huckle, J. M. Katz, B. Khorsand, D. Daurio, G. P. Andrews, J. Chung & F. Alvarez-Nunez
doi : 10.1208/s12249-021-02122-7
AAPS PharmSciTech volume 22, Article number: 235 (2021)
Molecular dispersions are a highly effective method of increasing bioavailability for a poorly soluble active pharmaceutical ingredient (API) and can be prepared on a large scale by hot melt extrusion (HME). Processing thermally labile active pharmaceutical ingredients (APIs) via HME is generally more difficult, with operating temperatures limited to below that of the API melting point. API melting is considered essential to facilitate the formation of a fully homogeneous amorphous system. Processing below the melting point renders the system much more susceptible to residual crystalline content; hence, HME is not suitable for APIs which degrade upon melting. In the following work, meloxicam (MEL) was used as a model API, possessing properties of high melting temperature and thermal lability. In this proof of concept work, a modified HME method, termed solvent-assisted HME, was used to overcome this issue and prepare an amorphous solid dispersion using HME, wherein a solvent was incorporated in the formulation blend during extrusion and removed post-processing. Formulations containing 10%wt meloxicam (MEL) and 90%wt polyvinylpyrrolidone vinyl acetate (PVPVA) copolymer were extruded using a twin-screw extruder at temperatures below the melting point of MEL. Dimethylformamide (DMF) solvent was added directly into the extruder barrel through a liquid addition port, resulting in extrudate products having a higher conversion of API to the amorphous form. The incorporation of solvent allowed a significant reduction in processing temperatures due to its increased mobility, while also driving the conversion of the API to its amorphous form. The solvent was successfully reduced through a secondary drying step using a vacuum oven. This advancement has demonstrated the potential for thermally labile APIs to be processed via HME expanding the applications of this technology.
Accelerated Stability Assessment Program to Predict Long-term Stability of Drugs: Application to Ascorbic Acid and to a Cyclic Hexapeptide
Pauline Legrand, Rabah Gahoual , Pascal Houzé & Sophie Dufa?
doi : 10.1208/s12249-021-02121-8
AAPS PharmSciTech volume 22, Article number: 234 (2021)
During pharmaceutical development, the stability of the product is assessed during long-term study. If any stability issues are discovered at this point of the process, it will result in re-formulation and important loss of time and cost. Therefore, important efforts are made in order to select the most stable product. Nevertheless, predicting the stability of the developed product at early stage of the development is challenging. Accelerated stability assessment program (ASAP), based on modified Arrhenius equation and isoconversion approach, appears as an interesting tool allowing to evaluate stability and shelf-life of pharmaceutical product in a short period of time. Nevertheless, few studies using these approaches are published in the literature, and the majority concern small drug molecules. Here, this approach was applied on a small drug molecule, ascorbic acid (AA), and on a cyclic hexapeptide named cFEE. AA and cFEE have been exposed to various temperatures for a maximum of 3 weeks, and then analyzed by capillary electrophoresis coupled to UV detection (CZE-UV) for AA or LC–MS for cFEE. The level of major degradation products was used to build ASAP models and predict the stability of both compounds. Comparison between predicted and long-term data were found accurate for both compounds undergoing two different degradation pathways (oxidation and hydrolysis), confirming the real interest of accelerated predicting stability approach for consistent determination of long-term stability shelf-life of pharmaceutical products.
Nanotechnology has been utilized in developing novel drug formulations with minimal adverse effects. Nanoparticles in a lower size range with great surface area, increased potency, and easy permeability could be an approach for the treatment of cancer and other diseases. Unlike other nanoparticles, quantum dots have specific functional groups, have charges over their surface, and are extremely small in size (2–10nm), which makes them more permeable through tight junctions. Quantum dots are interesting materials that offer diagnosis and treatment concurrently. Quantum dots are reported to have several applications in pharmaceuticals as well as drug delivery, diagnosis, immunolabeling, and cell labeling tools. However, the existence of heavy metals in quantum dots such as cadmium poses a potential challenge for future medical applications, where quantum dots may be deliberately injected into the body. In this review, we are focusing on various pharmaceutical applications of quantum dots.
Aman Gour, Suman Ramteke & Narendra Kumar Jain
doi : 10.1208/s12249-021-02103-w
AAPS PharmSciTech volume 22, Article number: 233 (2021)
Nanotechnology has been utilized in developing novel drug formulations with minimal adverse effects. Nanoparticles in a lower size range with great surface area, increased potency, and easy permeability could be an approach for the treatment of cancer and other diseases. Unlike other nanoparticles, quantum dots have specific functional groups, have charges over their surface, and are extremely small in size (2–10nm), which makes them more permeable through tight junctions. Quantum dots are interesting materials that offer diagnosis and treatment concurrently. Quantum dots are reported to have several applications in pharmaceuticals as well as drug delivery, diagnosis, immunolabeling, and cell labeling tools. However, the existence of heavy metals in quantum dots such as cadmium poses a potential challenge for future medical applications, where quantum dots may be deliberately injected into the body. In this review, we are focusing on various pharmaceutical applications of quantum dots.
Cyclodextrin Complex Formation with Water-Soluble Drugs: Conclusions from Isothermal Titration Calorimetry and Molecular Modeling
Karim S. Shalaby, Muhammad I. Ismail & Alf Lamprecht
doi : 10.1208/s12249-021-02040-8
AAPS PharmSciTech volume 22, Article number: 232 (2021)
Cyclodextrin (CD) complexes are frequently used for enhancing the solubility or absorption of poorly water-soluble drugs. On the contrary, little is known about their complex formation with water-soluble drugs. Here, we have studied the interaction between 2-hydroxypropyl ?-CD (HP?CD) and three water-soluble drugs, namely naloxone (NX), oxycodone (OC), and tramadol (TR), by isothermal titration calorimetry (ITC) combined with molecular modeling in view of the potential impact on drug release. The results showed that the complex formation of HP?CD with all three drugs occurs spontaneously. The complexes formed with NX and OC were found to be 2NX:1HP?CD and 3OC:2HP?CD, respectively. TR was found to form 2 complexes with HP?CD; of 1:2 and 1:1 complexation ratios. The binding of HP?CD to NX was greater than to OC due to the higher hydrophobicity of the structure of the former. Moreover, the binding affinity of HP?CD to TR was higher than to OC, which indicated the effect of the higher flexibility of the guest in increasing the binding affinity. In vitro drug release experiments from the various complexes revealed a significant impact of the stoichiometry of the complex on the release profiles. Accordingly, the co-administration of cyclodextrins with water-soluble drugs should be closely monitored, as it may result in unintentional complex formation that can potentially impact the drugs’ gastrointestinal absorption.
Formulation of Chitosan-Coated Piperine NLCs: Optimization, In Vitro Characterization, and In Vivo Preclinical Assessment
Ameeduzzafar Zafar, Nabil K. Alruwaili, Syed Sarim Imam, Omar Awad Alsaidan, Khalid Saad Alharbi, Mohd Yasir, Mohammed Elmowafy, Elshaer F. Mohammed & Ziad H. Al-Oanzi
doi : 10.1208/s12249-021-02098-4
AAPS PharmSciTech volume 22, Article number: 231 (2021)
In the present research work, surface-modified nanostructured lipid carriers (NLCs) with chitosan (CH) were prepared to improve the therapeutic efficacy of piperine (PP). NLCs were developed and optimized (CH-PP-NLCs-opt) by design expert software and the selected NLCs surface was coated with chitosan (0.2% w/v). CH-PP-NLCs-opt have shown a particle size of 149.34 ± 4.54 nm and entrapment efficiency of 80.65 ± 1.23%. The results of the solid-state characterization study exhibited that PP enclosed in lipids and present amorphous form. It might be due to the nanoparticle size of NLCs. The drug release study revealed PP-NLCs-opt and CH-PP-NLCs-opt exhibited significant (P < 0.05) difference in PP release (88.87 ± 5.23% and 76.34 ± 4.54%) as compared to pure PP (19.02 ± 2.87%). CH-PP-NLCs-opt exhibited strong bioadhesion than PP-NLCs-opt which has a positive influence the drug permeation and absorption. CH-PP-NLCs-opt showed higher permeation (1083.34 ± 34.15 ?g/ cm2) than pure PP (106.65 ± 15.44 ?g/cm2) and PP-NLCs-opt (732.45 ± 28.56 ?g/ cm2). The significantly enhanced bioavailability of PP was observed from CH-PP-NLCs-opt (3.76- and 1.21-fold) than PP-dispersion and PP-NLCs-opt. The diabetes was induced in rats by a single intraperitoneal administration of streptozotocin (STZ, 40 mg/kg, citrate buffer pH 4.5), and results revealed that PP-NLCs-opt and CH-PP-NLCs-opt reduce the blood glucose level (28.26% and 36.52% respectively) as compared to PP-dispersion (10.87%). It also helps to maintain the altered biochemical parameters. In conclusion, CH-PP-NLC can be a novel oral nanocarrier for the management of diabetes.
Local Treatment of Non-small Cell Lung Cancer with a Spray-Dried Bevacizumab Formulation
Kimberly B. Shepard, David T. Vodak, Philip J. Kuehl, David Revelli, Yue Zhou, Amanda M. Pluntze, Molly S. Adam, Julia C. Oddo, Lauren Switala, Jonathan L. Cape, John M. Baumann & Michael Banks
doi : 10.1208/s12249-021-02095-7
AAPS PharmSciTech volume 22, Article number: 230 (2021)
Local delivery of biotherapeutics to the lung holds great promise for treatment of lung diseases, but development of physically stable, biologically active dry powder formulations of large molecules for inhalation has remained a challenge. Here, spray drying was used to manufacture a dry powder pulmonary formulation of bevacizumab, a monoclonal antibody approved to treat non-small cell lung cancer (NSCLC) by intravenous infusion. By reformulating bevacizumab for local delivery, reduced side effects, lower doses, and improved patient compliance are possible. The formulation had aerosol properties suitable for delivery to the deep lung, as well as good physical stability at ambient temperature for at least 6 months. Bevacizumab’s anti-VEGF bioactivity was not impacted by the manufacturing process. The formulation was efficacious in an in vivo rat model for NSCLC at a 10-fold decrease in dose relative to the intravenous control.
Non-intuitive Behavior of Polymer-Ciprofloxacin Nanoconjugate Suspensions: a Tool for Flexible Oral Drug Delivery
Amos Abioye, Maitham Naqvi, Dillan Pattni & Aderonke Ayinke Adepoju-Bello
doi : 10.1208/s12249-021-02105-8
AAPS PharmSciTech volume 22, Article number: 229 (2021)
Ciprofloxacin (CPX) is prone to spontaneous self-aggregation and formation of supramolecular dimers (????? stacking) due to its complicated surface chemistry which has been associated with its anomalous solubility and instability in aqueous systems particularly near neutral pH. The surface characteristic of ciprofloxacin was modified through non-intuitive counterion interaction between CPX and diethylaminoethyl dextran (DDEX) to form nanoconjugate assembly. The CPX-DDEX nanoconjugate was confirmed by FTIR, SEM, DSC, TGA, and 1H-NMR. The DSC thermograms showed a remarkable 20% reduction in the melting temperature (Tm) of CPX from 268.57±1.11°C to 214.36±1.0211°C and 78% reduction in enthalpy of fusion (?Hf) from 59.84 kJ/mol (180.59 J/g) to 12.90 kJ/mol (38.92 J/g), indicating increased solubility and dissolution efficiency. DDEX polymer alone exhibited pseudoplastic characteristics however with more viscous rather than elastic response, while the CPX-DDEX nanoconjugate suspensions exhibited remarkable elastic behavior with significantly increased storage modulus (G?) thus controlling and extending the release of CPX. The reconstituted freeze-dried CPX-DDEX nanoconjugate suspension was chemically stable throughout the 90-day study both in the refrigerator and at controlled room temperature, while the aqueous suspension of pure CPX without DDEX was only stable for 72 and 24 h, respectively. The dissolution efficiency of the CPX-DDEX nanoconjugate suspensions increased with increasing molar concentration of DDEX to a maximum of 100% at 50 ?M of DDEX followed by a remarkable decrease within the 3-week study. It was apparent that the dissolution efficiency was governed by a critical balance between the CPX solubility and the viscoelastic characteristics of the polymeric nanoassembly. This study demonstrates the potential application of polymer-drug nanoconjugation formulation design to stabilization and flexible delivery of CPX from aqueous suspension systems.
Salts and Polymorph Screens for Bedaquiline
Mercy Okezue, Susan Bogdanowich-Knipp, Daniel Smith, Matthias Zeller, Stephen Byrn, Pamela Smith, Dale K. Purcell & Kari Clase
doi : 10.1208/s12249-021-02106-7
AAPS PharmSciTech volume 22, Article number: 228 (2021)
Bedaquiline is used to treat multi-resistant tuberculosis in adults. The fumarate salt is commercially available and used in the product Sirturo. To provide open access to bedaquiline molecule once the patent on the chemical substance expires, new salts were screened. This work offers additional information on the bedaquiline system, as new salts may present better pharmacokinetic properties. The current studies focus on the attempted isolation of the acetate, benzoate, benzenesulfonate, hydrobromide, succinate, hydrochloride, tartrate, lactate, maleate, malate, and mesylate salts of bedaquiline. Potential salts were screened using a unique combination of conventional screening, and small-scale experiments supplemented by crystallographic analysis and infrared microspectroscopy. Salts were prepared on a larger scale by dissolving 1:1 ratios of the individual salt formers and bedaquiline base (30 mg, 0.055 mmol) in different solvents and allowing the solutions to evaporate or crystallize. X-ray diffraction (XRD) techniques and spectroscopic and thermal analyses were employed to characterize the salts. The benzoate and maleate salts were selected as lead candidates after reviewing preliminary characterization data. To determine the most stable forms for the leads, a polymorph screen was conducted using solvents of various polarities. These salt screens successfully generated five new salts of bedaquiline, namely, benzoate, maleate, hydrochloride, besylate, and mesylate. The existence of these salts was confirmed by powder XRD, proton NMR, and IR spectroscopies. TGA and DSC thermal analysis along with hot-stage optical microscopy were further used to characterize the salts. The polymorph screen conducted on the salts suggested the absence of additional polymorphs at 1 g scale.
Altered Media Flow and Tablet Position as Factors of How Air Bubbles Affect Dissolution of Disintegrating and Non-disintegrating Tablets Using a USP 4 Flow-Through Cell Apparatus
Hiroyuki Yoshida, Keita Teruya, Yasuhiro Abe, Takayuki Furuishi, Kaori Fukuzawa, Etsuo Yonemochi & Ken-ichi Izutsu
doi : 10.1208/s12249-021-02117-4
AAPS PharmSciTech volume 22, Article number: 227 (2021)
This study investigated how air bubbles in media affect tablet dissolution in a flow-through cell system (USP 4) using disintegrating (USP prednisone) and non-disintegrating (USP salicylic acid) tablets. Cell hydrodynamics were studied using particle image velocimetry (PIV) and computational fluid dynamics (CFD). The PIV analysis showed periodic changes in the local flow corresponding to the discharge and suction of the pump cycles. The absence of prior deaeration induced small air bubbles in the media and lower maximum flow during the cycle, explaining the slower dissolution of the USP salicylic acid tablets. Bubbles, occurring during the USP prednisone tablets study, induced the transition of floating disintegrated particles towards the cell outlet, whereas the particles precipitated to form a white layer on the glass beads used in the study with prior deaeration. CFD analysis showed local flow variation in multiple positions of small (ID 12 mm) and large (ID 22.6 mm) cells, explaining the different rates of dissolution of prednisone tablet particles depending on their distribution. These results emphasize the importance of prior deaeration in dissolution studies using a flow-through system. Bubbles in the flow-through cell system affected tablet dissolution by reducing the area in contact with the media (wettability), lowering the maximum instantaneous flow (pressure buffering), and altering the position of disintegrated particles in the cell.
Glucose-Responsive Polyelectrolyte Complexes Based on Dendritic Mesoporous Silica for Oral Insulin Delivery
Tingting Qin, Libiao Yan, Xin Wang, Siqi Lin & Qingbing Zeng
doi : 10.1208/s12249-021-02088-6
AAPS PharmSciTech volume 22, Article number: 226 (2021)
The postprandial glycemic regulation is essential for diabetic patients to reduce the risk of long-term microvascular and macrovascular complications. Herein, we designed a glucose-responsive oral insulin delivery system based on polyelectrolyte complexes (PECs) for controlling the increasing postprandial glucose concentrations. Briefly, alginate-g-3-aminophenylboronic acid (ALG-g-APBA) and chitosan-g-3-fluoro-4-carboxyphenylboronic acid (CS-g-FPBA) were wrapped on mesoporous silica (MSN) to form the negative charged ALG-g-APBA@MSN and the positive charged CS-g-FPBA@MSN nanoparticles, with an optimum insulin loading capacity of 124 mg/g and 295 mg/g, respectively. ALG-g-APBA@MSN was further cross-linked with CS-g-FPBA@MSN to form PECs through electrostatic interaction and borate esters. The dense polyelectrolyte network wrapped on MSN was capable of preventing insulin from diffusion and regulating its release. The in vitro insulin release of PECs demonstrated an obvious glucose response profile in different glucose concentrations (0 mg/mL, 2 mg/mL, 5 mg/mL) and presented a switch “on” and “off” release regulation at hyperglycemic or normal state. The CCK-8 assay showed that none of the MSN, ALG-g-APBA@MSN, CS-g-FPBA@MSN, and PECs possessed cytotoxicity to Caco-2 cells. For in vivo tests, the oral PECs exhibited a significant hypoglycemic effect and maintained in the euglycemic levels up to approximately 12 h on diabetic rats. Overall, the PECs directly triggered by postprandial glucose in the intestine have a good potential to be applied in intelligent insulin delivery by the oral route.
Performance of Multiple-Batch Approaches to Pharmacokinetic Bioequivalence Testing for Orally Inhaled Drug Products with Batch-to-Batch Variability
Elise Burmeister Getz, Kevin J. Carroll, J. David Christopher, Beth Morgan, Scott Haughie, Alessandro Cavecchi, Christopher Wiggenhorn, Hayden Beresford, Helen Strickland & Svetlana Lyapustina
doi : 10.1208/s12249-021-02063-1
AAPS PharmSciTech volume 22, Article number: 225 (2021)
Batch-to-batch pharmacokinetic (PK) variability of orally inhaled drug products has been documented and can render single-batch PK bioequivalence (BE) studies unreliable; results from one batch may not be consistent with a repeated study using a different batch, yet the goal of PK BE is to deliver a product comparison that is interpretable beyond the specific batches used in the study. We characterized four multiple-batch PK BE approaches to improve outcome reliability without increasing the number of clinical study participants. Three approaches include multiple batches directly in the PK BE study with batch identity either excluded from the statistical model (“Superbatch”) or included as a fixed or random effect (“Fixed Batch Effect,” “Random Batch Effect”). A fourth approach uses a bio-predictive in vitro test to screen candidate batches, bringing the median batch of each product into the PK BE study (“Targeted Batch”). Three of these approaches (Fixed Batch Effect, Superbatch, Targeted Batch) continue the single-batch PK BE convention in which uncertainty in the Test/Reference ratio estimate due to batch sampling is omitted from the Test/Reference confidence interval. All three of these approaches provided higher power to correctly identify true bioequivalence than the standard single-batch approach with no increase in clinical burden. False equivalence (type I) error was inflated above the expected 5% level, but multiple batches controlled type I error better than a single batch. The Random Batch Effect approach restored 5% type I error, but had low power for small (e.g., <8) batch sample sizes using standard [0.8000, 1.2500] bioequivalence limits.
Batch Selection via In Vitro/In Vivo Correlation in Pharmacokinetic Bioequivalence Testing
Elise Burmeister Getz, Kevin J. Carroll, Johanna Mielke, Byron Jones & Leslie Z. Benet
doi : 10.1208/s12249-021-02064-0
AAPS PharmSciTech volume 22, Article number: 224 (2021)
Pharmacokinetic differences between manufacturing batches, well established for inhaled drug products, preclude control of patient risk in the customary two-way (single batch) pharmacokinetic bioequivalence crossover design if batches are randomly chosen. European regulators have recommended selecting a “typical” in vitro batch to represent each product in pharmacokinetic bioequivalence testing. We explored the feasibility of this approach to control patient risk (the “false equivalence”, or Type I, error rate). The probability of achieving a Test/Reference 90% confidence interval within (0.80, 1.25) for a true (non-equivalent) value of 1.25 was simulated for a two-way crossover design using the median in vitro batch across a range of number of in vitro batches, in vitro/in vivo correlation (IVIVC) quality (correlation coefficient, r, of zero to one), and within-subject between-batch pharmacokinetic variability. Even under extremely optimistic conditions, e.g., r=0.95 and >100 batches per product screened in vitro, patient risk for typical between-batch variability levels remained at least threefold higher than the 5% regulatory expectation for the significance level (the false equivalence error rate) of the pharmacokinetic bioequivalence test. This elevated error rate in bioequivalence decision-making occurs because of incomplete confidence that the true product average has been identified, and, importantly, omission of this uncertainty from the bioequivalence confidence interval.
Evaluation of the Antitumor Effect and Immune Response of Micelles Modified with a Polysialic Acid-D-?-Tocopheryl Polyethylene Glycol 1000 Succinate Conjugate
Jing Sun, Qingjing Tian, Min Liu, Yuqing Su, Xinrong Liu, Yihui Deng & Yanzhi Song
doi : 10.1208/s12249-021-02047-1
AAPS PharmSciTech volume 22, Article number: 223 (2021)
D-?-Tocopheryl polyethylene glycol 1000 succinate (TPGS) has shown potential applications in cancer therapy owing to its attractive properties, including reversal of multi-drug resistance and synergistic effects with antitumor drugs. However, its associated shortcomings cannot be underestimated, including activation of the body’s immune response and acceleration of blood clearance of polyethylene glycolylated preparations. Polysialic acid (PSA) is a polysaccharide homopolymer, with the dual function of immune camouflage and tumor targeting. PSA and TPGS conjugates (PSA-TPGS) were synthesized to weaken the immune risks of TPGS. We developed PSA-TPGS and TPGS self-assembled mixed micelles and encapsulated the classical antineoplastic, docetaxel. The particle size of docetaxel-loaded mixed micelles was 16.3 ± 2.0 nm, with entrapment efficiency of 99.0 ± 0.9% and drug-loading efficiency of 3.20 ± 0.03%. Antitumor activity studies revealed that the mixed micelles showed better tumor inhibition than Tween 80 and TPGS micelles. Detection of the accelerated blood clearance (ABC) phenomenon demonstrated that insertion of PSA-TPGS into the micelles weakened the ABC phenomenon induced by TPGS. In summary, PSA-TPGS could be a potential nanocarrier to improve antitumor activity and weaken immune responses.
Geniposide-Loaded Liposomes for Brain Targeting: Development, Evaluation, and In Vivo Studies
Jinyan Wan, Yu Long, Songyu Liu, Yulu Zhang, Yan Xiang, Dan Li, Ai Shi, Yu Shuang, Ying Li, Yanan He, Nan Li & Yongmei Guan
doi : 10.1208/s12249-021-02093-9
AAPS PharmSciTech volume 22, Article number: 222 (2021)
Geniposide (GE) possesses excellent neuroprotective effects but with poor brain targeting and short half-life. Liposome was considered to have great potential for brain diseases. Therefore, this research aimed to develop a geniposide liposome (GE-LP) as a brain delivery system for cerebral ischemia reperfusion injury (CIRI) therapy and evaluate its characterization, pharmacokinetics, brain targeting, and neuroprotective effects in vivo. Then, a reverse-phase evaporation method was applied to develop the GE-LP and optimize the formulation. Notably, the GE-LP had suitable size, which was 223.8 nm. Subsequently, the pharmacokinetic behavior of GE solution and GE-LP in mice plasma was investigated, and the brain targeting was also researched. The results showed that GE in plasma of GE-LP displayed three folds longer distribution half-life and a higher bioavailability and brain targeting compared to GE solution. In vivo neuroprotective effects was evaluated through the middle cerebral artery occlusion (MCAO) rat model, and GE-LP exhibited a stronger tendency in preventing the injury of CIRI, which can significantly improve neurological deficits. Overall, this study demonstrates GE-LP as a new formulation with ease of preparation, sustained release, and high brain targeting, which has significant development prospects on CIRI; this is expected to improve the efficacy of GE and reduce the frequency of administration.
Recommended Best Practices for Lyophilization Validation—2021 Part I: Process Design and Modeling
Feroz Jameel, Alina Alexeenko, Akhilesh Bhambhani, Gregory Sacha, Tong Zhu, Serguei Tchessalov, Lokesh Kumar, Puneet Sharma, Ehab Moussa, Lavanya Iyer, Rui Fang, Jayasree Srinivasan, Ted Tharp, Joseph Azzarella, Petr Kazarin & Mehfouz Jalal
doi : 10.1208/s12249-021-02086-8
AAPS PharmSciTech volume 22, Article number: 221 (2021)
This work describes lyophilization process validation and consists of two parts. Part I focuses on the process design and is described in the current paper, while part II is devoted to process qualification and continued process verification. The intent of these articles is to provide readers with recent updates on lyophilization validation in the light of community-based combined opinion on the process and reflect the industrial prospective. In this paper, the design space approach for process design is described in details, and examples from practice are provided. The approach shows the relationship between the process inputs; it is based on first principles and gives a thorough scientific understanding of process and product. The lyophilization process modeling and scale-up are also presented showing the impact of facility, equipment, and vial heat transfer coefficient. The case studies demonstrating the effect of batch sizes, fill volume, and dose strength to show the importance of modeling as well as the effect of controlled nucleation on product resistance are discussed.
Preparation, Characterization, and In Vitro/In Vivo Evaluation of 3-O-?-D-Galactosylated Resveratrol-Loaded Polydopamine Nanoparticles
Beilei Wang, Xiaoxiao Shan, Shujie Lv, Liqiong Zha, Caiyun Zhang, Qiannian Dong & Weidong Chen
doi : 10.1208/s12249-021-02079-7
AAPS PharmSciTech volume 22, Article number: 220 (2021)
3-O-?-D-galactosylated resveratrol (Gal-Res) was synthesized from resveratrol (Res) and 3-O-?-D-galactose (Gal) in our previous study. In order to improve the pH sensitivity and bioavailability of Gal-Res, Gal-Res nanoparticles (Gal-Res NPs) were prepared using polydopamine (PDA) as a drug carrier. The drug loading (DL %) and entrapment efficiency (EE %) of Gal-Res NPs were 46.80% and 88.06%. The average particle size, polydispersity index (PDI), and Zeta potential of Gal-Res NPs were 179.38 ± 2.83 nm, 0.129 ± 0.013, and ? 28.05 ± 0.36 mV, respectively. The transmission electron microscope (TEM) showed that Gal-Res NPs had uniform spherical morphology. Compared with the fast release of raw Gal-Res, the in vitro release of Gal-Res NPs was slow and pH-sensitive. The results of the blood vessel irritation and hemolysis test demonstrated that Gal-Res NPs had good hemocompatibility. The pharmacokinetics study in rats showed that area under the curve of plasma drug concentration time (AUC0?600) and half-life (t1/2) of Gal-Res NPs were enhanced 1.82-fold and 2.19-fold higher than those of raw Gal-Res. The in vivo biodistribution results showed that Gal-Res NPs were more distributed in liver tissue than Gal-Res. Gal-Res NPs with high bioavailability and liver accumulation were hopeful drug delivery systems (DDS) to treat liver diseases.
Digital Image Disintegration Analysis: a Novel Quality Control Method for Fast Disintegrating Tablets
Osamah Malallah, Zara Rashid, Chee Lok Li, Abdulmalik Alqurshi, Mohamed A. Alhanan, Ben Forbes & Paul G. Royall
doi : 10.1208/s12249-021-02080-0
AAPS PharmSciTech volume 22, Article number: 219 (2021)
Measuring tablet disintegration is essential for quality control purposes; however, no established method adequately accounts for the timeframe or small volumes of the medium associated with the dissipation process for fast disintegrating tablets (FDTs) in the mouth. We hypothesised that digital imaging to measure disintegration in a low volume of the medium might discriminate between different types of FTD formulation. A digital image disintegration analysis (DIDA) was designed to measure tablet disintegration in 0.05–0.7 mL of medium. A temperature-controlled black vessel was 3D-printed to match the dimensions of each tablet under investigation. An overhead camera recorded the mean grey value of the tablet as a measure of the percentage of the formulation which remained intact as a function of time. Imodium Instants, Nurofen Meltlets and a developmental freeze-dried pilocarpine formulation were investigated. The imaging approach proved effective in discriminating the disintegration of different tablets (p < 0.05). For example, 10 s after 0.7 mL of a saliva simulant was applied, 2.0 ± 0.3% of the new pilocarpine tablet remained, whereas at the same time point, 22 ± 9% of the Imodium Instants had not undergone disintegration (temperature within the vessel was 37 ± 0.5°C). Nurofen Meltlets were observed to swell and showed a percentage recovery of 120.7 ± 2.4% and 135.0 ± 6.1% when 0.05 mL and 0.7 mL volumes were used, respectively. Thus, the new digital image disintegration analysis, DIDA, reported here effectively evaluated fast disintegrating tablets and has the potential as a quality control method for such formulations.
