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Correction to: 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/s12249-021-02158-9
AAPS PharmSciTech volume 22, Article number: 276 (2021)
Preparation and Characterization of pH-Independent Sustained-Release Tablets Containing Hot Melt Extruded Solid Dispersions of Clarithromycin
Qazi Amir Ijaz, Sumera Latif, Qurat-ul-ain Shoaib, Memoona Rashid, Muhammad Sohail Arshad, Amjad Hussain, Nadeem Irfan Bukhari, Sohail Riaz & Nasir Abbas
doi : 10.1208/s12249-021-02115-6
AAPS PharmSciTech volume 22, Article number: 275 (2021)
The limited solubility of clarithromycin (CAM), coupled with low bioavailability and rapid elimination, are major shortcomings, needed to be addressed to achieve optimum therapeutic goals. Therefore, sustained-release (SR) tablets containing solid dispersion (SD) granules of CAM were prepared in this study. Initially, SD granules of CAM were prepared by hot melt extrusion (HME) technique using Kollidon VA64 as a hydrophilic carrier. The saturation solubility of SD showed almost 4.5-fold increase as compared to pure CAM in pH 6.8 medium. In vitro drug dissolution data indicated a substantial increase in the dissolution of SD as compared to that of pure CAM. The thermal stability of drug, carrier, and SD at elevated HME temperatures was evident from the results of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Powder X-ray diffraction (PXRD) data and scanning electron microscope (SEM) images revealed a decrease in the crystallinity and the uniform dispersion of drug, respectively. Moreover, Fourier transformed infrared spectroscopy (FT-IR) data confirmed the formation of hydrogen bond between the carbonyl group of drug and the hydroxyl group of carrier. SD loaded sustained-release (SD-SR) matrix tablets were prepared with hydrophobic polymers (Eudragit RS100 and Eudragit RL100). The pH-independent swelling and permeability of both polymers were responsible for the sustained drug release from SD-SR tablets. Pharmacokinetic (PK) studies suggested a 3.4-fold increase in the relative bioavailability of SD-SR tablets as compared to that of pure CAM.
A Software Tool for Lyophilization Primary Drying Process Development and Scale-up Including Process Heterogeneity, I: Laboratory-Scale Model Testing
Robin Bogner, Emily Gong, William Kessler, Michael Hinds, Arushi Manchanda, Seongkyu Yoon, Huolong Liu, Richard Marx, Jessie Zhao, Puneet Sharma, Akhilesh Bhambhani, Justin Stanbro, Alina Alexeenko & Petr Kazarin
doi : 10.1208/s12249-021-02134-3
AAPS PharmSciTech volume 22, Article number: 274 (2021)
Freeze-drying is a deceptively complex operation requiring sophisticated design of a robust and efficient process that includes understanding and planning for heterogeneity across the batch and shifts in parameters due to vial or lyophilizer changes. A software tool has been designed to assist in process development and scale-up based on a model that includes consideration of the process heterogeneity. Two drug formulations were used to test the ability of the new tool to develop a freeze-drying cycle and correctly predict product temperatures and drying times. Model inputs were determined experimentally, and the primary drying heterogeneous freeze-drying model was used to design drying cycles that provided data to verify the accuracy of model-predicted product temperature and primary drying time. When model inputs were accurate, model-predicted primary drying times were within 0.1 to 15.9% of experimentally measured values, and product temperature accuracy was between 0.2 and 1.2°C for three vial locations, center, inner edge, and outer edge. However, for some drying cycles, differences in vial heat transfer coefficients due to changes in shelf and product temperature as well as altered product resistance due to product temperature-dependent microcollapse increased inaccuracy (up to 28.6% difference in primary drying time and 5.1°C difference in product temperature). This highlights the need for careful determination of experimental conditions used to calculate model inputs. In future efforts, full characterization of location- and shelf temperature-dependentKv as well as location- and product temperature-dependentRp will enhance the accuracy of the predictions by the model within the user-friendly software.
A Practical Discussion on Estimating Shelf Life Through Tolerance Intervals
James Schwenke, Patrick Forenzo, Walter Stroup & Michelle Quinlan
doi : 10.1208/s12249-021-02119-2
AAPS PharmSciTech volume 22, Article number: 273 (2021)
This paper is a companion article to the research originally presented in “Estimating Shelf Life through Tolerance Intervals” (Schwenke et al., 21:290, 2020) published in AAPS PharmSciTech where tolerance intervals are introduced as an alternative methodology for estimating pharmaceutical shelf life. An industry stability shelf life example data set was used to demonstrate the proposed methods. Although using industry data does give relevance to examples demonstrating shelf life estimation, measures of how well the proposed methods accurately and effectively estimate shelf life cannot be obtained because the true shelf life values are not known for example data sets. In this current paper, the results of a computer simulation are reported where the tolerance interval estimates of shelf life are compared to theoretically known true shelf life values. Various factors that affect a tolerance interval estimate of pharmaceutical shelf life are investigated. A critical decision factor is the choice of the proportion of the stability distribution allowed out of specification at expiry to define the pharmaceutical risk. The number of stability batches available for shelf life estimation and the storage time at which the estimate is made are also considered in this simulation study. The industry example data are again used as the basis for the simulation study to give relevance to this research.
Development and Optimization of Microballoons Assisted Floating Tablets of Baclofen
Pradipkumar Wavhule & Padma V. Devarajan
doi : 10.1208/s12249-021-02139-y
AAPS PharmSciTech volume 22, Article number: 272 (2021)
The objective of the present study was to develop microballoons aided gastro-retentive floating tablets of baclofen, a skeletal muscle relaxant with a low elimination half-life of?~?3.5 h. Baclofen floating tablet was prepared to offer convenience by designing a tablet that would float in the stomach for a prolonged period and allow controlled drug release to enable once-a-day administration. Ethylcellulose microballoons (ECMBs) prepared by pseudo emulsion solvent diffusion method were employed as floating aid. The ECMBs were spherical with a size of 446.71 µm and a circularity index of 0.995. Buoyancy of 98.90 percent and good flowability reflected by an angle of repose of 23° suggested the feasibility of preparing floating tablets by direct compression. Directly compressed baclofen floating tablets comprised ECMBs, HPMC-K15M, and hydroxyl ethylcellulose as independent variables in the Box-Behnken design, however, performance characteristics of tablets such as in vitro drug release, floating lag time, and swelling index were selected as the dependent variables. Among the variables, ECMBs played a critical role in ensuring buoyancy. However, HPMC-K15M significantly influenced in vitro drug release. The optimized batch displayed Hickson-Crowell kinetics and exhibited a similar drug release profile as a marketed once-a-day formulation (f2, 91.03). Furthermore, optimized tablets showed a swelling index of?>?300, floating lag time?<?3 s, and total floating time?>?24 h. Microballoons assisted floating tablets exhibited great promise for assured gastric retention of tablets.
Highlighting DEM’s Potential to Gauge Mechanistic Attributes of MUPS Tablet and Capsule Formulations
Shishir Shekhar, Negin Amini, David A. V. Morton, Karen P. Hapgood & Alexander Russell
doi : 10.1208/s12249-021-02120-9
AAPS PharmSciTech volume 22, Article number: 271 (2021)
Simulation of pharmaceutical unit operations by the discrete element method (DEM) has elevated our understanding of the impact of single-particle interactions on themselves, and on the entire tablets/powder. Studies in the past have shown how this knowledge helps to mitigate/solve multiple challenges during conventional formulation and process development/modernization/troubleshooting, with minimal use of active drug material. This communication adds to this— highlighting the tool’s potential for a rapid preliminary assessment of the mechanistic attributes of multiple unit particle system (MUPS) based tablet and capsule drug products.
AddaVax Formulated with PolyI:C as a Potential Adjuvant of MDCK-based Influenza Vaccine Enhances Local, Cellular, and Antibody Protective Immune Response in Mice
Xuanxuan Nian, Jiayou Zhang, Tao Deng, Jing Liu, Zheng Gong, Chuanshuo Lv, Luyao Yao, Junying Li, Shihe Huang & Xiaoming Yang
doi : 10.1208/s12249-021-02145-0
AAPS PharmSciTech volume 22, Article number: 270 (2021)
Poor immune responses to inactivated influenza vaccine can be improved by effective and safe adjuvants to increase antibody titers and cellular protective response. In our study, AddaVax and PolyI:C combined adjuvant (AP adjuvant) were used for influenza vaccine development. After immunizing BALB/c mice and Wistar rats intramuscularly, Split inactivated H3N2 vaccine adjuvanted with AP elicited higher serum hemagglutination-inhibition antibodies and IgG titers. We demonstrated that AP induced a transient innate immune cytokines production at the injection site, induced H3N2 uptake by DCs, increased recruitment of monocytes and DCs in LNs, and promoted H3N2 vaccine migration; AP facilitated vaccines to induce a vigorous adaptive immune response. Besides, AP showed good safety as shown by lymph nodes (LNs) size, spleens index of BALB/c mice, and weight changes and C-reaction protein level of BALB/c mice and Wistar rats after repeated administration of high-dose vaccine with or without adjuvant. These findings indicate that AP is a potential novel adjuvant and can be used as a safe and effective adjuvant for MDCK-based influenza inactivated vaccine to induce cellular and antibody protective response.
Brucine, one of the natural medications obtained from Nux vomica seeds, is used as an anti-inflammatory drug. Several investigations were performed to overcome its drawbacks, which will affect significantly its pharmaceutical formulation. The goal of the current investigation was to design, optimize, and evaluate the anti-inflammatory performance of BRU ethosomal gel. Brucineethosomal formulations were prepared using thin film hydration method and optimized by central composite design approach using three independent variables (lecithin concentration, cholesterol concentration, and ethanol percentage) and three response variables (vesicular size, encapsulation efficiency, and skin permeation). The optimized formulation was examined for its stability and then incorporated into HPMC gel to get BRU ethosomal gel. The obtained BRU-loaded ethosomal gel was evaluated for its physical properties, in vitro release, and ex vivo permeation and skin irritation. Finally, carrageenan-induced rat hind paw edema test was adopted for the anti-inflammatory activity. The developed BRU ethosomal gel exhibited good physical characteristics comparable with the conventional developed BRU gel. In vitro release of BRU from ethosomal gel was effectively extended for 6 h. Permeation of BRU from ethosomes was significantly higher than all formulations (p?<?0.05), since it recorded steady state transdermal flux value 0.548?±?0.03 ?g/cm2 h with enhancement ratio 2.73?±?0.23. Eventually, BRU ethosomal gel exhibited potent anti-inflammatory activity as manifested by a significant decrease in rat hind paw inflammation following 24 h. In conclusion, the study emphasized the prospective of ethosomal gel as a fortunate carrier for intensifying the anti-inflammatory effect of Brucine.
Marwa H. Abdallah, Amr S. Abu Lila, Rahamat Unissa, Heba S. Elsewedy, Hanaa A. Elghamry & Mahmoud S. Soliman
doi : 10.1208/s12249-021-02113-8
AAPS PharmSciTech volume 22, Article number: 269 (2021)
Brucine, one of the natural medications obtained from Nux vomica seeds, is used as an anti-inflammatory drug. Several investigations were performed to overcome its drawbacks, which will affect significantly its pharmaceutical formulation. The goal of the current investigation was to design, optimize, and evaluate the anti-inflammatory performance of BRU ethosomal gel. Brucineethosomal formulations were prepared using thin film hydration method and optimized by central composite design approach using three independent variables (lecithin concentration, cholesterol concentration, and ethanol percentage) and three response variables (vesicular size, encapsulation efficiency, and skin permeation). The optimized formulation was examined for its stability and then incorporated into HPMC gel to get BRU ethosomal gel. The obtained BRU-loaded ethosomal gel was evaluated for its physical properties, in vitro release, and ex vivo permeation and skin irritation. Finally, carrageenan-induced rat hind paw edema test was adopted for the anti-inflammatory activity. The developed BRU ethosomal gel exhibited good physical characteristics comparable with the conventional developed BRU gel. In vitro release of BRU from ethosomal gel was effectively extended for 6 h. Permeation of BRU from ethosomes was significantly higher than all formulations (p?<?0.05), since it recorded steady state transdermal flux value 0.548?±?0.03 ?g/cm2 h with enhancement ratio 2.73?±?0.23. Eventually, BRU ethosomal gel exhibited potent anti-inflammatory activity as manifested by a significant decrease in rat hind paw inflammation following 24 h. In conclusion, the study emphasized the prospective of ethosomal gel as a fortunate carrier for intensifying the anti-inflammatory effect of Brucine.
A Novel Method for Rapid Particle Size Analysis of Ibuprofen Using Near-infrared Spectroscopy
Monika Stojanovska Pecova, Nikola Geskovski, Gjorgji Petrushevski & Petre Makreski
doi : 10.1208/s12249-021-02156-x
AAPS PharmSciTech volume 22, Article number: 268 (2021)
Particle size distribution (PSD) is often considered as critical material attribute for active pharmaceutical ingredients (APIs), and the need for regular evaluation stands as an important quality control parameter in the pharmaceutical industry. Near-infrared (NIR) spectroscopy, used routinely for API identification, was introduced as analytical tool for simultaneous determination of particle size of ibuprofen. The demonstrated potential was highlighted by the development of rapid, robust, and noninvasive method coupled with multivariate data analysis (MVA), which can be easily transferred in QC laboratories for routine analysis. Principal component analysis (PCA) and partial least squares (PLS) regression analyses were performed on a calibration set of 61 ibuprofen samples, which differed in their median particle size Dv(50). The score scatterplots revealed evident clustering of ibuprofen samples according to their particle size, as well as occurrence of a distinctive outlying group of ibuprofen samples originating from one manufacturer. Further testing by means of mid-infrared spectroscopy, X-ray powder diffraction, and particle morphology analysis pinpointed particle morphology being responsible for the observed outlying group. Consequently, PLS class modeling based on particle morphology was introduced, which delivered two separate PLS regression models: one for blade-like ibuprofen crystals and another for irregular plate-like ibuprofen crystals. The former regression model exhibited high correlation coefficients and satisfactory predictive power (R2X?=?0.999, R2Y?=?0.917, Q2?=?0.901), whereas the latter demonstrated lower statistical indicators (R2X?=?0.99, R2Y?=?0.72, Q2?=?0.55). Additionally, the study underlines the importance of particle shape evaluation and sample classification according to particle morphology similarity prior to building NIRS-based regression models for PSD determination.
Design and Characterization of HY-038 Solid Dispersions via Spray Drying Technology: In Vitro and In Vivo Evaluations
Taotao Jiang, Limei Han, Enhao Lu, Wenxiu He, Shilin Du & Xianyi Sha
doi : 10.1208/s12249-021-02135-2
AAPS PharmSciTech volume 22, Article number: 267 (2021)
The aim of this study was to prepare HY-038 solid dispersions (SDs) with single carrier at high drug loading and then forming a tablet to enhance solubility, dissolution, and bioavailability via spray drying technology. At the same time, we hope to develop a more convenient in vitro method to predict the absorption behavior of different formulations in vivo. Different solid dispersions, varying in drug/polymer ratios, were prepared. Infrared spectroscopy, differential scanning calorimetry, scanning electron microscope, and X-ray diffraction were used to perform solid-state characterizations of the pure drug and SDs. Contact angle of water, dissolution in pH?=?6.8 phosphate buffer, and in vivo absorption in dogs were studied. As a result, solid-state characterization demonstrated the transformation of the crystalline HY-038 to an amorphous state in the solid dispersions, and the in vivo exposure followed with the trend of the dissolution curve combined with contact angle. Compared with the prototype formulation, the Cmax and AUC0–? of optimized formulation SD2 (HY-038-HPMCAS 3:1) increased by about 5?~?9 times at the same dose. More importantly, the SD2 formulation showed approximately linear increases in Cmax and AUC0–? as the dose increased from 50 to 100 mg, while the prototype formulation reached absorption saturation at 50 mg. SD2 (HY-038-HPMCAS 3:1) was selected as the best formulation for the downstream development.
Recommended Best Practices for Lyophilization Validation 2021 Part II: Process Qualification and Continued Process Verification
Feroz Jameel, Alina Alexeenko, Akhilesh Bhambhani, Gregory Sacha, Tong Zhu, Serguei Tchessalov, Puneet Sharma, Ehab Moussa, Lavanya Iyer, Sumit Luthra, Jayasree Srinivasan, Ted Tharp, Joseph Azzarella, Petr Kazarin & Mehfouz Jalal
doi : 10.1208/s12249-021-02107-6
AAPS PharmSciTech volume 22, Article number: 266 (2021)
This work describes the lyophilization process validation and consists of two parts. Part one (Part I: Process Design and Modeling) focuses on the process design and is described in the previous paper, while the current paper is devoted to process qualification and continued process verification. The goal of the study is to show the cutting edge of lyophilization validation based on the integrated community-based opinion and the industrial perspective. This study presents best practices for batch size determination and includes the effect of batch size on drying time, process parameters selection strategies, and batch size overage to compensate for losses during production. It also includes sampling strategies to demonstrate batch uniformity as well as the use of statistical models to ensure adequate sampling. Based on the LyoHUB member organizations survey, the best practices in determining the number of PPQ runs are developed including the bracketing approach with minimum and maximum loads. Standard practice around CQA and CPP selection is outlined and shows the advantages of using control charts and run charts for process trending and quality control. The case studies demonstrating the validation strategy for monoclonal antibody and the impact of the loading process on the lyophilization cycle and product quality as well as the special case of lyophilization for dual-chamber cartridge system are chosen to illustrate the process validation. The standard practices in the validation of the lyophilization process, special lyophilization processes, and their impact on the validation strategy are discussed.
Interrelationships Between Coating Uniformity and Efficiency in Pan Coating Processes
Michael Choi, Stuart C. Porter & Axel Meisen
doi : 10.1208/s12249-021-02155-y
AAPS PharmSciTech volume 22, Article number: 265 (2021)
The relationships between coating uniformity and efficiency were explored for tablet coating processes in pan coaters. The factors affecting the size of the spray zone were modeled using one-dimensional deposition analysis of spray droplets. This model was incorporated into the analytical model developed for coating uniformity by Choi et al. (AAPS PharmSciTech 22(7), 2021) that farther elucidated the effects of tablet shape and bed porosity. The results were compared with literature data on coating efficiency. The variables examined included tablet shape and size, coating time, pan speed, atomizing and pattern air flow rates, bed porosity, spray rate, batch size, coating solution concentration, spray gun-to-bed distance, and pan diameter. It is shown that, except for pan diameter and atomizing air flow rate, variables that improve coating efficiency adversely affected coating uniformity and vice versa. Implications of these relationships are discussed to improve formulation, process, and equipment designs.
Budding Multi-matrix Technology—a Retrospective Approach, Deep Insights, and Future Perspectives
Anitha Sriram, Suma Tangirala, Srividya Atmakuri, Sajid Hoque , Sheela Modani, Saurabh Srivastava, Srushti Mahajan, Indrani Maji, Rahul Kumar, Dharmendra Khatri, Jitender Madan & Pankaj Kumar Singh
doi : 10.1208/s12249-021-02133-4
AAPS PharmSciTech volume 22, Article number: 264 (2021)
The human race is consistently striving for achieving good health and eliminate disease-causing factors. For the last few decades, scientists have been endeavoring to invent and innovate technologies that can substitute the conventional dosage forms and enable targeted and prolonged drug release at a particular site. The novel multi-matrix technology is a type of matrix formulation where the formulation is embraced to have a matrix system with multiple number of matrices. The MMX technology embraces with a combination of outer hydrophilic layer and amphiphilic/lipophilic core layer, within which drug is encapsulated followed by enteric coating for extended/targeted release at the required site. In comparison to conventional oral drug delivery systems and other drug delivery systems, multi-matrix (MMX) technology formulations afford many advantages. Additionally, it attributes for targeting strategy aimed at the colon and offers modified prolonged drug release. Thus, it has emerged rapidly as a potential alternative option in targeted oral drug delivery. However, the development of this MMX technology formulations is a exigent task and also has its own set of limitations. Due to its promising advantages and colon targeting strategy over the other colon targeted drug delivery systems, premier global companies are exploiting its potential. This article review deep insights into the formulation procedures, drug delivery mechanism, advantages, limitations, safety and efficacy studies of various marketed drug formulations of MMX technology including regulatory perspectives and future perspectives.
Preformulation Studies to Guide the Production of Medicines by Fused Deposition Modeling 3D Printing
Ludmila A. G. Pinho, Ana Luiza Lima, Livia L. Sa-Barreto, Tais Gratieri, Guilherme M. Gelfuso, Ricardo Neves Marreto & Marcilio Cunha-Filho
doi : 10.1208/s12249-021-02114-7
AAPS PharmSciTech volume 22, Article number: 263 (2021)
Fused deposition modeling (FDM) 3D printing has demonstrated high potential for the production of personalized medicines. However, the heating at high temperatures inherent to this process causes unknown risks to the drug product's stability. The present study aimed to assess the use of a tailored preformulation protocol involving physicochemical assessments, including the rheological profiles of the samples, to guide the development of medicines by FDM 3D printing. For this, polymers commonly used in FDM printing, i.e., high impact polystyrene (HIPS), polylactic acid (PLA), and polyvinyl alcohol (PVA), and their common plasticizers (mineral oil, triethyl citrate, and glycerol, respectively) were evaluated using the thermolabile model drug isoniazid (INH). Samples were analyzed by chemical and physical assays. The results showed that although the drug could produce polymorphs under thermal processing, the polymeric matrix can be a protective element, and no polymorphic transformation was observed. However, incompatibilities between materials might impact their chemical, thermal, and rheological performances. In fact, ternary mixtures of INH, PLA, and TEC showed a major alteration in their viscoelastic behavior besides the chemical changes. On the other hand, the use of plasticizers for HIPS and PVA exhibited positive consequences in drug solubility and rheologic behavior, probably improving sample printability. Thus, the optimization of the FDM 3D printing based on preformulation studies can assist the choice of compatible components and seek suitable processing conditions to obtain pharmaceutical products.
Quick and Simultaneous Analysis of Dissolved Active Pharmaceutical Ingredients and Formulation Excipients from the Dissolution Test Utilizing UHPLC and Charged Aerosol Detector
Mariko Kimoto, Toshiyasu Sakane, Hidemasa Katsumi & Akira Yamamoto
doi : 10.1208/s12249-021-02152-1
AAPS PharmSciTech volume 22, Article number: 262 (2021)
The objective of the study is to develop a quick and simultaneous analysis system for the dissolution of the active pharmaceutical ingredient (API) and the formulation excipient in samples from the dissolution test by UHPLC using the charged aerosol and PDA detectors. The combination of two columns for size-exclusion chromatography (SEC) and the equipment of the charged aerosol detector allowed the quick determination of various water-soluble polymers. Three model sustained-release tablets, each containing a different API of different water solubility (propranolol (soluble), ranitidine (very soluble), and cilostazol (practically insoluble)), were prepared from polyethylene oxide (PEO) matrix to verify the applicability and utility of the analysis system. The dissolution of propranolol was the same as that of PEO, indicating that the diffusion rate of propranolol was consistent with the erosion rate of the PEO and that the dissolution of PRO was based on diffusion. Ranitidine was released faster than PEO, suggesting that ranitidine was diffused through the gel layer of PEO early upon contact with the dissolution medium and before PEO gel erosion. Cilostazol was released slower as compared to PEO, indicating that cilostazol dissolution was based on the polymer’s erosion. These results suggested that the analysis system developed in this study is a precise and valid tool to study the dissolution behavior of both APIs and excipients. Optimization of the SEC column for the appropriate separation of APIs and excipients makes the analysis system more efficient and convenient to study the drug release mechanisms and to design formulations.
Low-Frequency Sonophoresis as an Active Approach to Potentiate the Transdermal Delivery of Agomelatine-Loaded Novasomes: Design, Optimization, and Pharmacokinetic Profiling in Rabbits
Mai Ahmed Tawfik, Magdy Ibrahim Mohamed, Mina Ibrahim Tadros & Sara Nageeb El-Helaly
doi : 10.1208/s12249-021-02147-y
AAPS PharmSciTech volume 22, Article number: 261 (2021)
The first melatonergic antidepressant drug, agomelatine (AGM), is commonly used for controlling major depressive disorders. AGM suffers low (<?5%) oral bioavailability owing to the hepatic metabolism. The current work investigated the potential of low-frequency sonophoresis on enhancing transdermal delivery of AGM-loaded novasomes and, hence, bioavailability of AGM. Drug-loaded novasomes were developed using free fatty acid (stearic acid or oleic acid), surfactant (span 60 or span 80), and cholesterol via thin-film hydration technique. The systems (N1-N16) were assessed for zeta potential (ZP), particle size (PS), encapsulation efficiency (EE%), and drug percent released after 0.5 h (Q0.5 h) and 8 h (Q8h), drug-crystallinity, morphology, and ex vivo drug permeation. Skin pre-treatment with low-frequency ultrasound (LFU) waves, via N13-novasomal gel systems, was optimized to enhance ex vivo drug permeation. Influences of LFU mode (continuous or pulsed), duty cycle (50% or 100%), and application period (10 or 15 min) were optimized. The pharmacokinetics of the optimized system (N13-LFU-C4) was assessed in rabbits. N13 was the best achieved novasomal system with respect to PS (471.6 nm), ZP (??63.6 mv), EE% (60.5%), Q0.5 h (27.8%), Q8h (83.9%), flux (15.5 ?g/cm2/h), and enhancement ratio (6.9). N13-LFU-C4 was the optimized novasomal gel system (desirability; 0.997) which involves skin pre-treatment with LFU in a continuous mode, at 100% duty cycle, for 15 min. Compared to AGM dispersion, the significantly (P?<?0.05) higher flux (26.7 ?g/cm2/h), enhancement ratio (11.9), Cmax (118.23 ng/mL), and relative bioavailability (? 8.6 folds) could elucidate the potential of N13-LFU-C4 system in improving transdermal drug permeability and bioavailability.
Enhancing Biopharmaceutical Attributes of Khellin by Amorphous Binary Solid Dispersions
Sonali S. Bharate
doi : 10.1208/s12249-021-02126-3
AAPS PharmSciTech volume 22, Article number: 260 (2021)
Khellin, a furanochromone isolated from fruits and seeds of Ammi visnaga, is traditionally used in many eastern Mediterranean countries. The plant decoction and the crystalline substance khellin have many pharmacological activities. For instance, it acts as a bronchodilator and also relieves renal colic and urethral stones, etc. However, the low water solubility (~?120 µg/mL) and low bioavailability limit its therapeutic application. Thus, the present research explores the development of its binary and ternary solid dispersion formulations to improve its solubility and dissolution behavior. A 24-well plate miniaturized protocol was established to identify the optimal hydrophilic polymer to prepare its solid dispersions. PEG-4000 was recognized as the favorable hydrophilic carrier in preparation of solid dispersion, SSB17. The formulation displayed?~?five-fold enhancement in the aqueous solubility of khellin. The binary solid dispersion SSB17 was manufactured at a gram scale and evaluated using 1H-NMR, 13C-NMR, FT-IR, p-XRD, SEM, DSC, in vitro dissolution, and predicted pharmacokinetics. The quantitative dissolution data of SSB17 demonstrated?~?2–3-fold improvement in AUC at physiological pH conditions. These conclusions highlight the basis for further preclinical studies on solid dispersions of khellin with improved biopharmaceutical properties.
Cliv-92-Loaded Glycyrrhetinic Acid-Modified Chitosan Nanoparticles for Enhanced Hepatoprotection–Preparation, Characterization, and In Vivo Evaluation
Kuldeep Singh Yadav, Nidhi Srivastava, Vineet Kumar Rai, Ranjana, Sudeep Tandon, Pooja Rani Mina, Debabrata Chanda, Navodayam Kalleti, Srikanta Kumar Rath, Mahendra Pandurang Darokar, P. V. Ajayakumar, Karuna Shanker & Narayan Prasad Yadav
doi : 10.1208/s12249-021-02130-7
AAPS PharmSciTech volume 22, Article number: 259 (2021)
Cliv-92 is a mixture of three structurally similar coumarinolignoids and a proven hepatoprotective agent. Low aqueous solubility and poor bioavailability are notable hindrances for its further use. Therefore, glycyrrhetinic acid-linked chitosan nanoparticles loaded with Cliv-92 were prepared for active targeting to the liver. The nanoparticles were prepared by the ionic gelation method to avoid the use of toxic solvents/rigorous agitation. The method of preparation was optimized using a central composite design with independent variables, namely polymer: drug ratio (3:1, w/w), crosslinker concentration (0.5%), and stirring speed (750 rpm). The optimized nanoparticles had a mean particle size of 185.17 nm, a polydispersity index of 0.41, a zeta potential of 30.93 mV, and a drug loading of 16.30%. The prepared formulation showed sustained release of approximately 63% of loaded Cliv-92 over 72 h. The nanoparticles were freeze-dried for long-term storage and further characterized. The formulation was found to be biocompatible for parenteral delivery. In vivo imaging study showed that optimized nanoparticles were preferentially accumulated in the liver and successfully targeting the liver. The present study successfully demonstrated the improved pharmacokinetic properties (?12% relative bioavailability) and efficacy profile (evidenced by in vivo and histopathological studies) of fabricated Cliv-92 nanoparticles.
Investigation of the Fused Deposition Modeling Additive Manufacturing I: Influence of Process Temperature on the Quality and Crystallinity of the Dosage Forms
Jiaxiang Zhang, Rishi Thakkar, Vineet R. Kulkarni, Yu Zhang, Anqi Lu & Mohammed Maniruzzaman
doi : 10.1208/s12249-021-02094-8
AAPS PharmSciTech volume 22, Article number: 258 (2021)
With the advancements in cutting-edge technologies and rapid development of medical sciences, patient-focused drug development (PFDD) through additive manufacturing (AM) processes is gathering more interest in the pharmaceutical area than ever. Hence, there is an urgent need for researchers to comprehensively understand the influence of three-dimensional design on the development of novel drug delivery systems (DDSs). For this research, fused deposition modeling (FDM) 3D printing was investigated, and phenytoin (PHT) was selected as the model drug. The primary purpose of the current investigation was to understand the influence of AM process on the pharmaceutical products’ quality. A series of comparative studies, including morphology, solid-state analysis, and in vitro drug release studies between additive manufactured filaments (printlets) and extruded filaments, were conducted. The FDM-based AM showed adequate reproducibility by manufacturing printlets with consistent qualities; however, the model slicing orientation significantly affected the print qualities. The texture analysis studies showed that the mechanical properties (breaking behavior) of additive manufactured printlets were varied from the extruded filaments. Additionally, the higher printing temperature also influenced the solid state of the drug where the process assisted in PHT’s amorphization in the printed products, which further affected their mechanical properties and in vitro drug release performances. The current investigation illustrated that the AM process would change the printed objects’ macrostructure over the conventional products, and the printing temperature and slicing will significantly affect the printing process and product qualities.
Amalgamation of Solid Dispersion and Melt Adsorption Technique: Improved In Vitro and In Vivo Performance of Ticagrelor Tablets
Mukesh Yadav, Jayant Sarolia, Bhavin Vyas, Manisha Lalan, Shubhada Mangrulkar & Pranav Shah
doi : 10.1208/s12249-021-02138-z
AAPS PharmSciTech volume 22, Article number: 257 (2021)
Ticagrelor (TG) suffers from low peroral bioabsorption (36%) due to P-gp efflux and poor solubility (10 µg/mL). TG solid dispersion adsorbates (TG-SDAs) were formulated using an amalgamation of solid dispersion and melt adsorption techniques which were simple, economic, scalable, and solvent-free. FTIR indicated no incompatibility between drug and excipients. DSC, XRD, and SEM suggested a reduction in TG crystallinity. Q30min from TG-SUSP and TG-conventional tablets was only 2.30% and 6.59% respectively whereas TG-SDA-based tablets exhibited a significantly higher drug release of 86.47%. Caco-2 permeability studies showed 3.83-fold higher permeability of TG from TG-SDAs. TG-SDA-based tablets exhibited relative bioavailability of 748.53% and 153.43% compared to TG-SUSP and TG-conventional tablets respectively in rats. TG-SDA-based tablets were devoid of any cytotoxicity as indicated by MTT assay and exhibited better antiplatelet activity in rats. Enhanced oral bioavailability of TG-SDAs can be attributed to inhibition of P-gp efflux by PEG 4000, increased wettability, and reduced crystallinity of drug leading to improved drug solubility and dissolution. Improved bioabsorption results in a reduction of dose, cost of therapy as well as dose-related side effects. Thus, SDAs can be considered a promising and scalable approach for the improvement of dissolution rate and solubility of TG. TG-SDAs can be translated to an effective and safe dosage form, whereby its rapid onset of action promotes the prevention of heart attack, stroke, and related ill events in individuals with the acute coronary syndrome. However, scale-up, validation, and clinical-studies are necessary for confirmation of the proof-of-concept.
Development of Self-Microemulsifying Drug Delivery System to Improve Nisoldipine Bioavailability: Cell Line and In Vivo Evaluations
Veenu P. Mundada, Mitali H. Patel, Piyush K. Mundada & Krutika K. Sawant
doi : 10.1208/s12249-021-02109-4
AAPS PharmSciTech volume 22, Article number: 256 (2021)
The authors attempted to fabricate a novel lipid-based formulation of a lipophilic drug, nisoldipine (NISO). As NISO belongs to BCS class 2 drug, it suffers from low bioavailability (5%). Hence, the research was intended to ameliorate oral bioavailability of NISO via intestinal lymphatic transport. The NISO loaded self microemulsifying drug delivery system (SMEDDS) (NISO SMEDDS) was prepared using Peceol, Cremophor EL, and Transcutol HP. The Cremophor EL and Transcutol HP at 1:1 ratio showed maximum microemulsifying area, and average globule size was 16.78?±?0.97 nm with PDI 0.121?±?0.024. Cellular uptake studies (confocal microscopy and flow cytometry) using Caco-2 cells depicted higher fluorescence with coumarin-6 loaded SMEDDS as that of coumarin-6 solution which indicated deeper penetration. Mean fluorescence intensity (MFI) of coumarin-6 loaded SMEDDS was significantly improved (9.92-fold) in contrast to coumarin-6 solution. The NISO SMEDDS showed enhanced permeability (5.02 times) across Caco-2 cells compared to NISO suspension. The bioavailability improvement with NISO SMEEDS was 2.14 times relative to suspension, and lymphatic uptake was involved in oral absorption of NISO SMEDDS.
Correction to: Preparation and Evaluation of Self-emulsifying Drug Delivery System (SEDDS) of Cepharanthine
Pan Gao, Zhujun Jiang, Qiao Luo, Chengqiao Mu, Mengsuo Cui & Xinggang Yang
doi : 10.1208/s12249-021-02161-0
AAPS PharmSciTech volume 22, Article number: 255 (2021)
Effects of Formulation and Manufacturing Process on Drug Release from Solid Self-emulsifying Drug Delivery Systems Prepared by High Shear Mixing
Gustavo Parreira Araújo, Felipe Terra Martins, Stephânia Fleury Taveira, Marcílio Cunha-Filho & Ricardo Neves Marreto
doi : 10.1208/s12249-021-02128-1
AAPS PharmSciTech volume 22, Article number: 254 (2021)
This study sought to investigate the influence of formulation and process factors of the high shear mixing (HSM) on the properties of solid self-emulsifying drug delivery systems (S-SEDDS) containing the model drug carvedilol (CAR). Firstly, liquid SEDDS (L-SEDDS) were prepared by mixing castor oil with different proportions of surfactant (Solutol or Kolliphor RH40) and cosolvent (Transcutol or PEG400). A miscible L-SEDDS with high drug solubility (124.3 mg/g) was selected and gave rise to 10% (m/m) CAR loaded-emulsion with reduced particle size. Then, a factorial experimental design involving five component’s concentration and two process factors was used to study the solidification of the selected L-SEDDS by HSM. CAR content, diffractometric profile, and in vitro dissolution were determined. Morphological and flow analyses were also performed. Porous and spherical particles with mean sizes ranging from 160 to 210 µm were obtained. Particle size was not affected by any formulation factor studied. Powder flowability, in turn, was influenced by L-SEDDS and crospovidone concentration. CAR in vitro dissolution from S-SEDDS was significantly increased compared to the drug as supplied and was equal (pH 1.2) or lower (pH 6.8) than that determined for L-SEDDS. Colloidal silicon dioxide decreased drug dissolution, whereas an increase in water-soluble diluent lactose and L-SEDDS concentration increased CAR dissolution. The proper selection of liquid and solid constituents proved to be crucial to developing an S-SEDDS by HSM. Indeed, the results obtained here using experimental design contribute to the production of S-SEDDS using an industrially viable process.
Fabrication and Evaluation of Transdermal Delivery of Carbamazepine Dissolving Microneedles
Rana Obaidat, Fatima BaniAmer, Shereen M. Assaf & Ahmed Yassin
doi : 10.1208/s12249-021-02136-1
AAPS PharmSciTech volume 22, Article number: 253 (2021)
This project aims to prepare hydrogel microneedle patches (MNs) as a painless method to deliver carbamazepine transdermally. This can be used as a sustained release system that offers the advantages of lower gastrointestinal side effects and avoids the first-pass metabolism of the drug. MNs were composed of two medicated layers, a microneedle layer and a base layer. MNs were fabricated using polyvinyl alcohol with or without polyvinylpyrrolidone Kollidon 30 as a matrix polymer and in the presence of selected solubilizing agent (polyethylene glycol 400, Tween 80, or ?-tocopherol polyethylene glycol). Freezing–thawing cycle was evaluated as one of the processing parameters that may affect the drug release. The MNs were evaluated for their weight variation, base thickness, and content uniformity. The physicochemical compatibility between carbamazepine and the polymers was estimated by Fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and X-ray powder diffraction. Evaluation for the in vitro release studies and ex vivo permeation studies was performed. The prepared MNs were flexible, clear, and uniform in weight, base thickness, and drug content. Physicochemical characterizations showed that carbamazepine was amorphous in most of the MNs. In vitro release and ex vivo permeation studies of carbamazepine were significantly higher for MNs containing a combination of 1:1 w/w of PEG 400 and Tween 80 as solubilizing agents where the release was extended over 96 h, with the release of 85.2% and 59.6% permeation percentage compared to other MNs. A significant effect of the freezing–thawing cycle on the release profile of the drug was observed. The hydrogel MNs are shown to be stable under the studied storage conditions.
Development and Evaluation of Icariin-Loaded PLGA-PEG Nanoparticles for Potentiation the Proapoptotic Activity in Pancreatic Cancer Cells
Nabil A. Alhakamy
doi : 10.1208/s12249-021-02111-w
AAPS PharmSciTech volume 22, Article number: 252 (2021)
Thiolated Chitosan-Centella asiatica Nanocomposite: A Potential Brain Targeting Strategy Through Nasal Route
Hajira Banu Haroon, Dhrubojyoti Mukherjee, Jayaraman Anbu & Banala Venkatesh Teja
doi : 10.1208/s12249-021-02131-6
AAPS PharmSciTech volume 22, Article number: 251 (2021)
The major challenge associated with the treatment of neurological disorders is the inefficiency of drugs to enter the Central Nervous System (CNS). Polymer-drug conjugates are now being tailored to overcome this hindrance associated with conventional drugs. The study aimed at developing polymer hybrid nasal nanocomposite for enhanced delivery of Centella to the CNS. Thiolated chitosan was complexed with Centella to form a composite using EDAC hydrochloride. The composite was characterized by FTIR, XRD, NMR, and MS. Further, this composite was converted into a nanoformulation by the ionic-gelation method, characterized, and subjected to ex vivo permeation studies. Additionally, MTT assay was performed using Human Uumbilical cord Vein Endothelial Cells (HUVECs) mimicking Blood–Brain Barrier (BBB) to establish the safety of nanocomposite. The targeting efficacy was predicted by molecular docking studies against receptors associated with BBB. The FTIR, XRD, NMR, and MS studies confirmed the chemical conjugation of thiolated chitosan with Centella. Nanocomposite characterization through SEM, AFM, and DLS confirmed the size and stability of the developed nanocomposite having a zeta potential of???14.5 mV and PDI of 0.260. The nanocomposite showed no signs of nasal ciliotoxicity and good permeation of 89.44?±?1.75% (mean?±?SD, n?=?3) at 8 h across the nasal mucosa. MTT assay showed that the nanocomposite had lesser toxicity compared to the free drug (IC50 of Centella—269.1 ?g/mL and IC50 of CTC nanocomposite—485.375 ?g/mL). The affinity of polymer to the BBB receptors as proved by docking studies suggests the ability of polymer-based nanocomposite to concentrate in the brain post nasal administration.
Correction to: 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/s12249-021-02129-0
AAPS PharmSciTech volume 22, Article number: 250 (2021)
