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Unveiling Swelling and Erosion Dynamics: Early Development Screening of Mirabegron Extended Release Tablets in Exosome Proteins for Breast Cancer Diagnosis and Detection: With a Focus on Nanotechnology
Ana S. Sousa, J. Serra, C. Estevens, R. Costa & António J. Ribeiro
doi : 10.1208/s12249-024-02994-5
Volume 25, article number 277, (2024)
Although the development of extended release (ER) matrices has been extensively investigated, understanding the most appropriate mechanism of drug release to achieve the desired release remains a cost- and time-consuming challenge in the early stages of formulation development. This study aimed to investigate the early stage of developing ER hydrophilic matrix tablets containing mirabegron as a model drug, focusing on the effects of polymer type, diluent type, and polymer amount on critical quality attributes (CQAs), namely, tablet swelling and erosion behavior. A full factorial design was employed to explore the interactions of control factors through multivariate regression analysis, emphasizing the application of quality by design (QbD) principles. The swelling and erosion performances of 72 formulations were evaluated. The swelling data were fitted to the Vergnaud model. Finally, in vitro drug release profiles were investigated for four of the formulations studied. The polymer type, diluent type, and polymer amount had distinct effects on the swelling and erosion behavior of the ER matrix tablets. Compared with those with isomalt (G720) or dextrate (DXT), formulations with polyethylene glycol 8000 (P8000) consistently exhibited greater swelling. Additionally, higher molecular weight was correlated with increased swelling within the same polymer type. Hydroxypropylmethylcellulose (HPMC) and polyethylene oxide (PEO)-based formulations showed higher swelling rates, while polyvinyl alcohol (PVA-80) displayed the highest erosion percentage. The findings highlight the significance of incorporating early-stage screening designs to maximize efficiency and optimize time and resource. This approach enables the development of a comprehensive understanding of drug release mechanisms from ER matrix tablets.
Advancements in Exosome Proteins for Breast Cancer Diagnosis and Detection: With a Focus on Nanotechnology
Mohamed J. Saadh, Afrah Majeed Ahmed Al-Rihaymee, Mandeep Kaur, Abhishek Kumar, Ahmed Faisal Mutee, Ghufran Lutfi Ismaeel, Shirin Shomurotova, Mahmood Hasen Shuhata Alubiady, Hamza Fadhel Hamzah, Zainab Abbas Abd Alhassan, Tuqa S. Alazzawi, Khursheed Muzammil & Merwa Alhadrawi
doi : 10.1208/s12249-024-02983-8
Volume 25, article number 276, (2024)
Breast cancer, a leading cause of mortality among women, has been recognized as requiring improved diagnostic methods. Exosome proteins, found in small extracellular vesicles, have emerged as a promising solution, reflecting the state of their cell of origin and playing key roles in cancer progression. This review examines their potential in breast cancer diagnosis, discussing advanced isolation and characterization techniques such as ultracentrifugation and microfluidic-based approaches. Various detection methods—including electrochemical, nano-based, optical, and machine learning platforms—were evaluated for their high sensitivity, specificity, and non-invasive capabilities. Electrochemical methods were used to identify unique protein signatures for rapid, cost-effective diagnosis, while machine learning enhanced the classification of exosome proteins. Nano-based techniques leveraged nanomaterials to detect low-abundance proteins, and optical methods offered real-time, label-free monitoring. Despite their promise, challenges in standardizing protocols and integrating these diagnostics into clinical practice remain. Future directions include technological advancements, personalized medicine, and exploring the therapeutic potential of exosome proteins
The Comparison between Pilot-Grade Spray Dryer and Laboratory-Grade Spray Dryer: Structure, Powder Properties and Application for Direct Compaction
Zhe Li, Wanghai Peng, Fucai Chen, Lin Zhu, Abid Naeem, Weifeng Zhu, Yongmei Guan, Yi Feng, Yanni Wu, Xiao Lin & Liangshan Ming
doi : 10.1208/s12249-024-02991-8
Volume 25, article number 275, (2024)
This study investigates the improvements in direct compaction powder properties achieved through particle design using laboratory and pilot-scale spray dryers. Hydroxypropyl methylcellulose and polyvinylpyrrolidone were used as modifying agent, which have low hygroscopicity and surface tension, good flowability, and excellent compactibility. Ammonium bicarbonate and sodium bicarbonate were used as pore-forming agents, and the composite particles were prepared using laboratory and pilot-scale spray dryers. The results showed that the structure of the composite particles and porous particles can effectively improve the flowability, tabletability, and disintegration behaviour; the composite particles prepared by laboratory-scale spray drying have better tabletability; the composite particles prepared by spray drying at pilot-scale had better flowability. In summary, there are significant differences in the properties of products prepared by different scales of spray drying. It will be beneficial to choose the appropriate equipment and the appropriate experimental design. Consequently, this study may contribute to the development of natural plant tablets
User-Friendliness Evaluation of Handling pMDI with Various Add-on Devices in Asthmatic Patients
Ahmed M. Abdelfattah, Rania M. Sarhan, Yasmin M. Madney, Ahmed F. Mady, Mohamed E. A. Abdelrahim & Hadeer S. Harb
doi : 10.1208/s12249-024-02998-1
Volume 25, article number 274, (2024)
The objective of this study was to assess the use of pMDI alone and pMDI with different spacers in asthmatic patients and to identify any associations between errors in handling the device for the first time and the sessions needed to reach the correct handling method, considering patient demographics and clinical characteristics. A total of 150 Asthmatic patients were crossed over to handle pMDI alone and with add-on inhalable devices (Aerochamber plus, Tips Haler, Able, Dispozable and Aer-8) randomly, without receiving verbal or demonstrative instruction (baseline assessment). The assessment of the inhaler technique was performed using checklists that had been set beforehand. Subsequently, the proper utilization of the inhaler was exhibited, and the patient's inhaler usage was reassessed. The demonstration was repeated until an optimal technique was attained. The number of counselling attempts required to achieve successful management, together with patient demographics and clinical factors, were documented. The mean percentage of total errors at baseline shows that pMDI alone is significantly higher than pMDI attached to add-on devices (53.90?±?9.71, 32.54?±?13.93, 24.53?±?14.93, 21.6?±?14.48, 25.14?±?10.99, 27.47?±?10.28) for pMDI alone, Aerochamber plus, Tips Haler, Able, Dispozable and Aer-8 respectively at p?<?0.01. Able and Tips Haler spacers are significantly lower than other spacers with pMDI and pMDI alone in terms of total sessions needed to attain the complete optimal handling technique at p?<?0.01. Weak and very weak correlations were observed between the percentage of total errors at baseline and the total sessions with education years, Montreal Cognitive Assessment, and age as well as some demographics and clinical variables. Handling pMDI can be challenging however the introduction of spacers simplifies this procedure. Different spacers cannot be treated as a homogeneous group due to variations in handling techniques and ease of use. the Able spacer requires the fewest handling steps of any spacer and has the highest percentage of patients who can use it without assistance.
Advancements in Antiviral Therapy: Favipiravir Sodium in Nasal Formulation
Priti Darne, Shankar Vidhate, Somesh Shintre, Somnath Wagdare, Dhiraj Bhamare, Nisha Mehta, Vishal Rajagopalan & Sriram Padmanabhan
doi : 10.1208/s12249-024-02986-5
Volume 25, article number 273, (2024)
Favipiravir (FPV) is an Active Pharmaceutical Ingredient (API) known to have lower solubility in aqueous solvents. In the current study, efforts were made to generate a crystalline Favipiravir Sodium Salt (NaFPV) for enhanced solubility in aqueous media. The in-house generated NaFPV was characterized by NMR studies and its sodium content was determined by Flame Emission Spectroscopy (FES) as a confirmation of salt formation. Its solubility was determined where-in the solubility of NaFPV in water was about 100 times greater than FVP. FPV and NaFPV nasal spray formulations were prepared and its activity was determined against human coronavirus (hCoV) 229E strain. In the anti-hCoV assay as compared to FPV, NaFPV showed almost threefold higher anti-viral activity than its unmodified counterpart. Accelerated stability and spray pattern characteristics of both the formulations were studied. Interestingly, NaFPV showed higher physical stability during storage at conditions 40?±?2 °C/ 75%?±?5% RH. The nasal spray formulations of both FPV and NaFPV showed ideal plume geometry and spray pattern of acceptable specifications. Due to its improvement in terms of solubility, NaFPV will have higher rate and extent of absorption, and faster onset of the therapeutic effect and may appear to be a feasible alternative to regular favipiravir for use in solid dosage forms.
Long-Circulating and Targeted Liposomes Co-loading Cisplatin and Mifamurtide: Formulation and Delivery in Osteosarcoma Cells
Bo Li, Qianhui Zhao, Hanyu Yang, Xueyuying Wang, Zhijun Zhang, Yanling Gong & Xu Wan
doi : 10.1208/s12249-024-02992-7
Volume 25, article number 272, (2024)
Osteosarcoma (OS) is one of the most common primary bone sarcoma with high malignant degree and poor prognosis, for which there is an urgent need to develop novel therapeutic approaches. Recent research has revealed that mifamurtide significantly improved the outcome of OS patients when combined with adjuvant chemotherapy drugs including cisplatin (DDP). The present study aimed to construct a drug delivery system co-loading DDP and mifamurtide. Long-circulating targeted liposomes co-loading DDP and mifamurtide were constructed with Soy lecithin (SPC), cholesterol (Chol) and 1,2-distearoylglycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)] (DSPE-PEG), modified with MMP14 targeting peptide BCY-B in the surface of liposomes. In addition to characterization, the cellular uptake, endocytosis pathway and inhibition on cell viability, migration, invasion and cell apoptosis of MG-63 cells were explored. The constructed liposomal delivery possessed the basic characteristics of liposomes and showed high affinity to MG-63 cells, resulting in high uptake efficiency in MG-63 cells. The endocytosis might be involved in multiple pathways including caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis, dependently on energy. The constructed long-circulating targeted liposomes co-loading DDP and mifamurtide significantly inhibited the cell viability, migration, invasion and cell apoptosis of MG-63 cells, improving the antitumor effect of DDP and mifamurtide in vitro. The constructed liposomal delivery system is suitable for co-loading DDP and mifamurtide to achieve active tumor targeting, supplying a new strategy for the treatment of OS
Albumin and Polysorbate-80 Coated Sterile Nanosuspensions of Mebendazole for Glioblastoma Therapy
Himaxi Patel, Akanksha Patel, Mukti Vats & Ketan Patel
doi : 10.1208/s12249-024-02978-5
Volume 25, article number 271, (2024)
The scarcity of existing and novel therapies for brain cancer has significantly affected the survival rate of glioblastoma patients. Mebendazole (MBZ), an antiparasitic agent demonstrated promising activity against brain cancer. However, poor solubility, multiple polymorphs, and insufficient permeability through blood–brain barrier (BBB) restricts its therapeutic efficacy through parenteral administration. The current study aimed to develop, optimize, and characterize sterile, injectable nanosuspension of mebendazole using parenterally acceptable stabilizers. Albumin and polysorbate 80 (PS-80) coated MBZ Nanosuspension (NS) was prepared using wet media milling technique. Design of experiment (DoE) approach was used to understand effect of drug loading versus stabilizer concentration. The optimized MBZ NS showed hydrodynamic diameter of 208.36?±?0.24 nm with a poly dispersibility index (PDI) of 0.210?±?0.03 and zeta potential of -20.41?±?0.36 mV. The IC50 value of MBZ NS in U-87 MG and LN-229 cell lines were found to be 0.49?±?0.02 ?M and 0.48?±?0.05 ?M, respectively. Additionally, MBZ NS demonstrated a 2.65-fold decrease in colony-forming efficiency and a 1.16-fold reduction in migration of the bridging area compared to MBZ. In 3D spheroids of the U-87 MG glioma cell line, MBZ NS exhibited a 50% reduction in tumor growth and increased cell apoptosis compared to the control. MBZ NS formulations were sterilized by gamma irradiation and tested as per the USP sterility test. Albumin-PS 80 coated NS is rendered to be useful parenteral delivery of mebendazole for the treatment of brain cancer.
Predicting the Thermodynamic Solubility and Stability of Co-crystals and Eutectics of Febuxostat by using a Thermodynamic Model involving Flory Huggins Interaction Parameter
Moksh Jagia, Arvind K. Bansal & Sarsvatkumar Patel
doi : 10.1208/s12249-024-02979-4
Volume 25, article number 270, (2024)
A method is presented for determining the thermodynamic (equilibrium) solubility of a drug in coformer for the non-covalent derivative (NCD) systems i.e. eutectics/co-crystals. The method is based on a thermodynamic model to calculate the Gibbs energy change ?GCC associated with forming a drug-coformer NCD system. This model includes contributions from heat capacity differences between the mixed and unmixed components, breaking up of the solid drug and coformer lattice structure, and drug ? coformer mixing. Calculation of ?GCC from thermal analysis data is demonstrated, and the equilibrium drug solubility in coformer is represented by minima of plots of ?GCC versus the dissolved drug fraction (f1). Eight (8) coformer molecules, namely, 1-hydroxy 2-naphthoic acid (1H-2NPH), 4-hydroxy benzoic acid (4-HBA), salicylic acid (SLC), 4-amino salicylic acid (4-ASA), 5-nitro isophthalic acid (5N-IPH), pyrazinamide (PZD), isonicotinamide (ISNCT), and picolinamide (PICO) were used for the formation of NCDs of a highly water insoluble drug febuxostat (FXT). The importance of heat capacity and interaction parameter in determining the solubility behavior of drug-coformer in the formed NCDs was discussed. Further, ?GCC for FXT in selected NCDs were plotted as a function of composition and temperature to determine the thermodynamic stability over the range of room temperature to formulation melting. It was concluded that the thermodynamic model can reasonably predict the maximum stable drug loading in a multi-crystalline system at a particular temperature, and serve as a complementary screening tool in determining the best stoichiometric ratio of the drug and coformer in terms of solubility and thermodynamic stability.
The Role of Amphiphilic Compounds in Nasal Nanoparticles
Thinh To Quoc, Krisztina Bíró, Ágota Pet?, Dóra Kósa, Ádám Haimhoffer, István Lekli, Ádám Pallér, István Bak, Alexandra Gyöngyösi, Pálma Fehér, Ildikó Bácskay & Zoltán Ujhelyi
doi : 10.1208/s12249-024-03000-8
Volume 25, article number 269, (2024)
Nasal medications hold significant importance and are widely utilized due to their numerous advantageous properties, offering a compelling route for both local and systemic therapeutic effects. Nowadays, the development of nasal particles under 1 micrometer is in the focus of much scientific research. In our experiments, the use of innovative nanotechnology to increase the effectiveness of the active substance was of paramount importance. Our aim was to create solid nanoparticles that enable targeted and effective delivery of the active ingredient into the body. The innovation of this experimental series lies not only in highlighting the importance of amphiphilic compounds in enhancing penetration, but also in the fact that while most nasally administered formulations are in liquid form, our formulation is solid. Liquid formulations frequently suffer from the disadvantage of possible leakage during administration, which can reduce the bioavailability of the active ingredient. In our experiments we created novel drug delivery systems of finely divided powders, which, thanks to the penetration enhancers, can be successfully administered. These enhancers facilitate the swift disintegration and penetration of the particles through the membrane. This represents a new direction in nasal drug delivery methods. The results of our trials are promising in the development of innovative pharmaceutical products and outline the role of amphiphilic compounds in more efficient utilization and targeted application of active substances. According to our results it can be concluded that this innovative approach not only addresses the common issues associated with liquid nasal formulations but also paves the way for more stable and effective delivery methods. The use of finely divided powders for nasal delivery, enabled by penetration enhancers, represents a major breakthrough in the field, providing a dependable alternative to conventional liquid formulations and ensuring improved therapeutic results.
The Role of Phase Separation and Local Mobility in the Stabilization of a Lyophilized IgG2 Formulation
Ashley Lay-Fortenbery, Ryan E. Holcomb, Charles S. Henry, Mark Cornell Manning & Eric J. Munson
doi : 10.1208/s12249-024-02984-7
Volume 25, article number 268, (2024)
The utility of employing solid-state NMR (SSNMR) to assess parameters governing the stability of a lyophilized IgG2 protein was the focus of the present work. Specifically, the interaction between the sugar stabilizer (sucrose) and protein component was measured using SSNMR and compared to physical and chemical stability data obtained from thermally stressed samples. 1H T1 and 1H T1? relaxation times were measured by SSMNR for 5 different formulation conditions, and the resultant values were used to examine local mobility and phase separation, respectively. From the SSNMR measurements, it was found local mobility decreased as the sucrose to protein weight ratio increased. The decrease in local mobility corresponded to an increase in storage stability (both chemical and physical) of the lyophilized solids up to a critical weight ratio of sucrose to protein. Additionally, 1H T1? measurements obtained on formulations having higher protein to sucrose weight ratios indicated phase separation of the protein and sucrose phases was occurring, at least on a small scale. Along with an increase in local mobility, phase separation in these specific formulations is thought to have played a role in their decreased storage stability in the solid state.
Correction: Croscarmellose Sodium as Pelletization Aid in Extrusion-Spheronization
Finn Siebel & Peter Kleinebudde
doi : 10.1208/s12249-024-02989-2
Volume 25, article number 267, (2024)
Figure 2 of the paper does not show a density distribution (%/µm), but a frequency distribution (%). The correct density distribution is provided below. The interpretation of the data and the text is not affected by this.
Correction: Investigations on the Impacts of Drugs or Excipients with Different Physicochemical and Compaction Properties on the Disintegration Behavior of Kollidon®SR-Based Binary Controlled Release Matrix Tablets
Wasfy M. Obeidat & Shadi F. Gharaibeh
doi : 10.1208/s12249-024-02981-w
Volume 25, article number 266, (2024)
In this article the affiliation details for author Shadi F. Gharaibe were given incorrectly as 1,2. The author holds only a single affiliation: Faculty of Pharmacy, Jerash University, Jerash 26150, Jordan.
The Neoteric Paradigm of Biomolecule-Functionalized Albumin-Based Targeted Cancer Therapeutics
Swati Gunjkar, Ujala Gupta, Rahul Nair, Priti Paul, Mayur Aalhate, Srushti Mahajan, Indrani Maji, Manish K. Chourasia, Santosh Kumar Guru & Pankaj Kumar Singh
doi : 10.1208/s12249-024-02977-6
Volume 25, article number 265, (2024)
Albumin is a nature-derived, versatile protein carrier, that has been explored extensively by researchers for anticancer drug delivery due to its role in enhancing drug stability, solubility, circulation time, targeting capabilities, and overall therapeutic efficacy. Albumin nanoparticles possess inherent biocompatibility, biodegradability, and passive tumor-targeting ability due to the enhanced permeability and retention effect. However, non-specific accumulation of cytotoxic agents in healthy tissues remains a challenge. In this paper, the functionalization of albumin nanoparticles using various biomolecules including antibodies, nucleic acids, proteins and peptides, vitamins, chondroitin sulfate, hyaluronic acid, and lactobionic acid have been discussed which enables specific recognition and binding to cancer cells. Furthermore, we highlight the supremacy of such a targeted approach in tumor-specific drug delivery, minimization of off-target effects, potential improvement in therapeutic efficacy, cellular internalization, reduced side effects, and better clinical outcomes. This review centers on how they have revolutionized the field of biomedical research and tuned into an excellent targeted approach. In conclusion, this review highlights in detail the role of albumin as a nanocarrier for tumor-targeted delivery using biomolecules as ligands.
Vesicular Carriers for Improved Oral Anticoagulation Competence of Rivaroxaban: In Vitro and In Vivo Investigation
Samar H. Faheim, Gamal M. El Maghraby & Amal A. Sultan
doi : 10.1208/s12249-024-02962-z
Volume 25, article number 264, (2024)
Rivaroxaban is an anticoagulant for avoidance and therapy of thromboembolic disorders. Unfortunately, oral bioavailability of rivaroxaban is compromised with dose increments. Accordingly, the aim was to test nano-vesicular lipid systems for improved oral anticoagulation activity of rivaroxaban. Rivaroxaban loaded niosomes, bilosomes and spanlastic formulations were prepared. The prepared systems were assessed in terms of particle size, zeta potential, transition electron microscopic features (TEM), entrapment efficiency, in-vitro drug release, and in-vivo anticoagulation performance in rats. The prepared vesicular systems exposed spherical negatively charged vesicles with mean particle size values between 136.6 nm to 387.9 nm depending on the composition. Rivaroxaban was efficiently entrapped in the vesicular systems with entrapment efficiency values ranging from 92.4% to 94.0%. Rivaroxaban underwent sustained release from the fabricated vesicular systems. The in vivo performance of the tested preparation revealed significant enhancement of the anticoagulation parameters. This was manifested from the prolonged clotting time, and prothrombin time. Moreover, the cut tails of the examined rats receiving the formulated nano-systems exposed a lengthy tail bleeding time compared to those receiving the un-processed rivaroxaban aqueous dispersion. In Conclusion, niosomes, bilosomes and spanlastic nano-dispersions have a potential to overwhelm the oral anticoagulation efficiency of rivaroxaban with spanlastic ranked as best.
Chitosan-Based Nanoformulations: Preclinical Investigations, Theranostic Advancements, and Clinical Trial Prospects for Targeting Diverse Pathologies
Seema Yadav, Abhishek Singh, Narahari N. Palei, Prateek Pathak, Amita Verma & Jagat Pal Yadav
doi : 10.1208/s12249-024-02948-x
Volume 25, article number 263, (2024)
Chitosan, a biocompatible and biodegradable polymer, has attracted significant interest in the development of nanoformulations for targeted drug delivery and therapeutic applications. The versatility of chitosan lies in its modifiable functional groups, which can be tailored to diverse applications. Nanoparticles derived from chitosan and its derivatives typically exhibit a positive surface charge and mucoadhesive properties, enabling them to adhere to negatively charged biological membranes and gradually release therapeutic agents. This comprehensive review investigates the manifold roles of chitosan-based nanocarriers, ranging from preclinical research to theranostic applications and clinical trials, across a spectrum of diseases, including neurological disorders, cardiovascular diseases, cancer, wound healing, gastrointestinal disorders, and pulmonary diseases. The exploration starts with an overview of preclinical studies, emphasizing the potential of chitosan-based nanoformulations in optimizing drug delivery, improving therapeutic outcomes, and mitigating adverse effects in various disease categories. Advancements in theranostic applications of chitosan-based nanoformulations highlight their adaptability to diverse diseases. As these nanoformulations progress toward clinical translation, this review also addresses the regulatory challenges associated with their development and proposes potential solutions.
Magnesium Stearate Fatty Acid Composition, Lubrication Performance and Tablet Properties
Natalia Veronica, Paul Wan Sia Heng & Celine Valeria Liew
doi : 10.1208/s12249-024-02980-x
Volume 25, article number 262, (2024)
Magnesium stearate (MgSt) is a common tablet lubricant. As variations in MgSt properties are known to influence tablet attributes, the impact of MgSt fatty acid composition, particularly the significance of the stearate and palmitate contents, and its effects on tablet properties warrant further investigation. This study investigated the effect of MgSt with different stearate and palmitate contents but comparable physical properties (e.g. particle size, crystallinity, specific surface area and morphology) on lubrication performance and resulting tablet quality attributes, including mechanical strength, disintegratability and drug release. The influence of MgSt concentration and blending duration on the resulting tablet properties was also examined. Tablets produced using the lower stearate content MgSt had slightly higher tensile strength. The effect of MgSt stearate content was more apparent in the disintegration time and drug release, whereby MgSt of lower stearate content resulted in tablets with longer disintegration time and slower drug release. The lower stearate content also resulted in a lower lubrication performance, leading to a lesser reduction in tablet ejection force. As expected, a longer blending time of the tablet formulation blend with MgSt yielded tablets with reduced tensile strength, shorter disintegration time and slower drug release. Tablets with higher MgSt concentration showed a greater reduction in tensile strength, longer disintegration time and faster drug release. The study findings reinforced observations by other researchers and provided a better understanding of the fatty acid composition effects of MgSt on lubrication performance and the resulting tablet properties.
Formononetin-Loaded Self-Microemulsion Drug Delivery Systems for Improved Solubility and Oral Bioavailability: Fabrication, Characterization, In Vitro and In Vivo Evaluation
Zhihui Zou, Yuanyuan Xue, Michael Adu-Frimpong, ChengWei Wang, Zhou Jin, Ying Xu, Jiangnan Yu, Ximing Xu & Yuan Zhu
doi : 10.1208/s12249-024-02975-8
Volume 25, article number 261, (2024)
This study aimed to construct a self-microemulsion drug delivery system (SMEDDS) for Formononetin (FMN) to improve its solubility and bioavailability while combining the nanocrystals (NCs) technology. The SMEDDS prescription composition was optimized with a pseudo-three-phase diagram, followed by a series of in vitro and in vivo evaluations of the selected optimal prescriptions. FMN-NCs loaded SMEDDS showed a homogeneous spherical shape in the Transmission electron microscope and the particle size was measured as (20.65?±?1.42) nm. The in vitro cumulative release rate in each dissolution medium within 30 min was higher than 80%, much higher than that of FMN (6%) and FMN-NCs (40%); Cellular experiments confirm that the formulation has a high safety profile and significantly promotes cellular uptake. The results of pharmacokinetics and intestinal absorption in rats showed that the relative bioavailability of FMN-NCs and FMN-NCs loaded SMEDDS were (154.80?±?3.76)% and (557.73?±?32.88)%, respectively, and both of them significantly increased the rate and extent of absorption of the drug in intestinal segments. FMN-NCs loaded SMEDDS significantly enhanced the solubility and bioavailability of FMN.
Strap-on Buoyant Device to Enhance Gastrointestinal Tract Retention of Felodipine Osmotic Pump Tablets
Qijia Ni, Zeru Li, Libumo Baqing, Tianfu Li, Huipeng Xu, Falan Li, Ningning Peng, Caifen Wang, Jianhua Lu, Zhigang Wang, Kai Wang, Chao Jiang, Li Wu, Ye Yang, Hua Zhou, Yongdong Gu & Jiwen Zhang
doi : 10.1208/s12249-024-02976-7
Volume 25, article number 260, (2024)
Osmotic pump systems require prolonged retention time in the stomach to provide enhanced bioavailability and regulated release, which is quite challenging. This study used a three-dimensional printing (3DP) technique combined with a gastro-retentive floating device (GRFD) to extend the retention of the osmotic pump in the stomach and enhance its bioavailability. The strap-on buoyant device was fabricated by stereolithography 3DP and incorporated a felodipine osmotic pump tablet used in clinical practice, which enabled it to float in the stomach or dissolution media without any floating lag time. The components of the device were affixed using a snap-fix mechanism. GRFD dissolution study revealed a notable in vitro floating capability, lasting over 24 h, with a release profile similarity factor f2?=?65.28 compared to the naked tablet dissolution profile. The pharmacokinetics of felodipine osmotic pump in beagles showed a Cmax of 1.893 ng/mL, which increased to 4.511 ng/mL with GRFD. The delivery of an osmotic pump with GRFD enhanced the AUC0?? of felodipine from 10.20 ng/mL·h to 26.54 ng/mL·h. In conclusion, the strap-on buoyant device has been successfully designed to enhance gastrointestinal tract retention of felodipine osmotic pumps and bioavailability in beagles.
An Overview of Film-Forming Emulsions for Dermal and Transdermal Drug Delivery
Aideé Morales-Becerril, Liliana Aranda-Lara, Keila Isaac-Olive, Alejandra Ramírez-Villalva, Blanca Ocampo-García & Enrique Morales-Avila
doi : 10.1208/s12249-024-02942-3
Volume 25, article number 259, (2024)
Drug delivery through the skin is a widely used therapeutic method for the treatment of local dermatologic conditions. Dermal and transdermal methods of drug delivery offer numerous advantages, but some of the most important aspects of drug absorption through the skin need to be considered. Film-forming systems (FFS) represent a new mode of sustained drug delivery that can be used to replace traditional topical formulations such as creams, ointments, pastes, or patches. They are available in various forms, including solutions, gels, and emulsions, and can be categorised as film-forming gels and film-forming emulsions. Film-forming emulsions (FFE) are designed as oil-in-water (O/W) emulsions that form a film with oil droplets encapsulated in a dry polymer matrix, thus maintaining their dispersed nature. They offer several advantages, including improved solubility, bioavailability and chemical stability of lipophilic drugs. In addition, they could improve the penetration and diffusion of drugs through the skin and enhance their absorption at the target site due to the nature of the components used in the formulation. The aim of this review is to provide an up-to-date compilation of the technologies used in film-forming emulsions to support their development and availability on the market as well as the development of new pharmaceutical forms.
Technological Strategies Applied to Pharmaceutical Systems for Intranasal Administration of Drugs Intended for Neurological Treatments: A Review
Maria Vitoria Gouveia Botan, Jéssica Bassi da Silva & Marcos Luciano Bruschi
doi : 10.1208/s12249-024-02974-9
Volume 25, article number 258, (2024)
The complexity of treating neurological diseases has meant that new strategies have had to be developed to deliver drugs to the brain more efficiently and safely. Intranasal drug delivery is characterized by its ease of administration, safety, and rapid delivery directly from the nose to the brain. Several strategies have been developed to improve the delivery of drugs to the brain via nasal administration. These include the use of mucoadhesive and thermoresponsive polymers and their combination into polymer blends, as well as the use of liposomes, niosomes, and nano- and microemulsions. Therefore, this review focuses on technologies for developing pharmaceutical systems aimed at delivery via the nose to the brain, contributing to new treatments for difficult neurological disorders. Some of the most common and difficult-to-treat neurological conditions, the intranasal route of administration, and the anatomy of the nasal cavity have been discussed, as well as factors that may influence the absorption of drugs administered into the nose. The types of intranasal formulations and the devices that can be used to administer these products are also discussed in this review. Strategies for improving the transport of bioactive agents and increasing bioavailability are highlighted. The technologies discussed in this review can facilitate the development of formulations with improved properties, such as drug release and mucoadhesiveness, which have several advantages for patients requiring complex neurological treatments.
An Adaptive Approach in Polymer-Drug Nanoparticle Engineering using Slanted Electrohydrodynamic Needles and Horizontal Spraying Planes
Amna Ali, Saman Zafar, Manoochehr Rasekh, Tahir Ali Chohan, Francesca Pisapia, Neenu Singh, Omar Qutachi, Muhammad Sohail Arshad & Zeeshan Ahmad
doi : 10.1208/s12249-024-02971-y
Volume 25, article number 257, (2024)
The present study focuses on the adaptive development of a key peripheral component of conventional electrohydrodynamic atomisation (EHDA) systems, namely spraying needles (also referred to as nozzles or spinnerets). Needle geometry and planar alignment are often overlooked. To explore potential impact, curcumin-loaded polylactic-co-glycolic acid (PLGA) and methoxypolyethylene glycol amine (PEG)-based nanoparticles were fabricated. To elucidate these technological aspects, a horizontal electrospraying needle regime was adapted, and three formulations containing different polymeric ratios of PLGA: PEG (50:50, 75:25, and 25:75) were prepared and utilised. Furthermore, processing head tip geometries e.g. blunt (a flat needle exit) or slanted (a 45° inclination angle), were subjected to various flow rates (5 µL-100 µL). Successful engineering of curcumin-loaded polymeric nanoparticles (<?150 nm) was observed. In-silico analysis demonstrated stable properties of curcumin, PEG and PLGA (molecular docking studies) and fluid flow direction towards the Taylor-Cone (also known as the stable jet mode), was shown by the assessment of fluid dynamics simulations in various needle outlets. Curcumin-loaded nanoparticles were characterised using an array of methods including Scanning electron microscopy, Differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, as well as their contact angles, encapsulation efficiencies and finally release patterns. The discrepancy when spraying with blunt and angled needles was evidenced by electron micrographs and deposition patterns. Spraying plumes utilising slanted needles enhanced particle collection efficiency and distribution of resultant atomised structures. In addition to needle design, fine-tuning the applied voltage and flow rate impacted the electrospraying process. The coefficient of variation was calculated as 30.5% and 25.6% for blunt and angled needle outlets, respectively, presenting improved particle uniformity with the employment of angled needle tips (8-G needle at 25 µL). The interplay of processing parameters with the utilisation of a slanted exit at a capillary optimised the spray pattern and formation of desired nanoparticulates. These demonstrate great applicability for controlled deposition and up-scaling processes in the pharmaceutical industry. These advances elaborate on EHDA processes, indicating a more cost-effective and scalable approach for industrial applications, facilitating the generation of a diverse range of particle systems in a controlled and more uniform fashion.
Non-Invasive Techniques of Nose to Brain Delivery Using Nanoparticulate Carriers: Hopes and Hurdles
Mansi Butola & Nidhi Nainwal
doi : 10.1208/s12249-024-02946-z
Volume 25, article number 256, (2024)
Intranasal drug delivery route has emerged as a promising non-invasive method of administering drugs directly to the brain, bypassing the blood–brain barrier (BBB) and blood-cerebrospinal fluid barriers (BCSF). BBB and BCSF prevent many therapeutic molecules from entering the brain. Intranasal drug delivery can transport drugs from the nasal mucosa to the brain, to treat a variety of Central nervous system (CNS) diseases. Intranasal drug delivery provides advantages over invasive drug delivery techniques such as intrathecal or intraparenchymal which can cause infection. Many strategies, including nanocarriers liposomes, solid-lipid NPs, nano-emulsion, nanostructured lipid carriers, dendrimers, exosomes, metal NPs, nano micelles, and quantum dots, are effective in nose-to-brain drug transport. However, the biggest obstacles to the nose-to-brain delivery of drugs include mucociliary clearance, poor drug retention, enzymatic degradation, poor permeability, bioavailability, and naso-mucosal toxicity. The current review aims to compile current approaches for drug delivery to the CNS via the nose, focusing on nanotherapeutics and nasal devices. Along with a brief overview of the related pathways or mechanisms, it also covers the advantages of nasal drug delivery as a potential method of drug administration. It also offers several possibilities to improve drug penetration across the nasal barrier. This article overviews various in-vitro, ex-vivo, and in-vivo techniques to assess drug transport from the nasal epithelium into the brain.
Development of Predictive Statistical Model for Gaining Valuable Insights in Pharmaceutical Product Recalls
Jayshil A. Bhatt, Kenneth R. Morris & Rahul V. Haware
doi : 10.1208/s12249-024-02970-z
Volume 25, article number 255, (2024)
The rapid progress in artificial intelligence (AI) has revolutionized problem-solving across various domains. The global challenge of pharmaceutical product recalls imposes the development of effective tools to control and reduce shortage of pharmaceutical products and help avoid such recalls. This study employs AI, specifically machine learning (MI), to analyze critical factors influencing formulation, manufacturing, and formulation complexity which could offer promising avenue for optimizing drug development processes. Utilizing FDAZilla and SafeRX tools, an open database model was constructed, and predictive statistical models were developed using Multivariate Analysis and the Least Absolute Shrinkage and Selection Operator (LASSO) Approach. The study focuses on key descriptors such as delivery route, dosage form, dose, BCS classification, solid-state and physicochemical properties, release type, half-life, and manufacturing complexity. Through statistical analysis, a data simplification process identifies critical descriptors, assigning risk numbers and computing a cumulative risk number to assess product complexity and recall likelihood. Partial Least Square Regression and the LASSO approach established quantitative relationships between key descriptors and cumulative risk numbers. Results have identified key descriptors; BCS Class I, dose number, release profile, and drug half-life influencing product recall risk. The LASSO model further confirms these identified descriptors with 71% accuracy. In conclusion, the study presents a holistic AI and machine learning approach for evaluating and forecasting pharmaceutical product recalls, underscoring the importance of descriptors, formulation complexity, and manufacturing processes in mitigating risks associated with product quality.
In Situ Forming Hydrogel Reinforced with Antibiotic-Loaded Mesoporous Silica Nanoparticles for the Treatment of Bacterial Keratitis
Mohammad Mohammadi, Shokoufeh Rahmani, Zohre Ebrahimi, Ghazal Nowroozi, Fatemeh Mahmoudi, Mohsen Shahlaei & Sajad Moradi
doi : 10.1208/s12249-024-02969-6
Volume 25, article number 254, (2024)
Bacterial keratitis (BK) is a serious ocular infection that can lead to vision impairment or blindness if not treated promptly. Herein, we report the development of a versatile composite hydrogel consisting of silk fibroin and sodium alginate, reinforced by antibiotic-loaded mesoporous silica nanoparticles (MSNs) for the treatment of BK. The drug delivery system is constructed by incorporating vancomycin- and ceftazidime-loaded MSNs into the hydrogel network. The synthesized MSNs were found to be spherical in shape with an average size of about 95 nm. The loading capacities of both drugs were approximately 45% and 43%, for vancomycin and ceftazidime respectively. Moreover, the formulation exhibited a sustained release profile, with 92% of vancomycin and 90% of ceftazidime released over a 24 h period. The cytocompatibility of the drug carrier was also confirmed by MTT assay results. In addition, we performed molecular dynamics (MD) simulations to better reflect the drug-drug and drug-MSN interactions. The results obtained from RMSD, number of contacts, and MSD analyses perfectly corroborated the experimental findings. In brief, the designed drug-MSN@hydrogel could mark an intriguing new chapter in the treatment of BK.
Understanding of Wetting Mechanism Toward the Sticky Powder and Machine Learning in Predicting Granule Size Distribution Under High Shear Wet Granulation
Yanling Jiang, Kangming Zhou, Huai He, Yu Zhou, Jincao Tang, Tianbing Guan, Shuangkou Chen, Taigang Zhou, Yong Tang, Aiping Wang, Haijun Huang & Chuanyun Dai
doi : 10.1208/s12249-024-02973-w
Volume 25, article number 253, (2024)
The granulation of traditional Chinese medicine (TCM) has attracted widespread attention, there is limited research on the high shear wet granulation (HSWG) and wetting mechanisms of sticky TCM powders, which profoundly impact the granule size distribution (GSD). Here we investigate the wetting mechanism of binders and the influence of various parameters on the GSD of HSWG and establish a GSD prediction model. Permeability and contact angle experiments combined with molecular dynamics (MD) simulations were used to explore the wetting mechanism of hydroalcoholic solutions with TCM powder. Machine learning (ML) was employed to build a GSD prediction model, feature importance explained the influence of features on the predictive performance of the model, and correlation analysis was used to assess the influence of various parameters on GSD. The results show that water increases powder viscosity, forming high-viscosity aggregates, while ethanol primarily acted as a wetting agent. The contact angle of water on the powder bed was the largest and decreased with an increase in ethanol concentration. Extreme Gradient Boosting (XGBoost) outperformed other models in overall prediction accuracy in GSD prediction, the binder had the greatest impact on the predictions and GSD, adjusting the amount and concentration of adhesive can control the adhesion and growth of granules while the impeller speed had the least influence on granulation. The study elucidates the wetting mechanism and provides a GSD prediction model, along with the impact of material properties, formulation, and process parameters obtained, aiding the intelligent manufacturing and formulation development of TMC.
Development of Minodronic Acid-Loaded Dissolving Microneedles for Enhanced Osteoporosis Therapy: Influence of Drug Loading on the Bioavailability of Minodronic Acid
Beibei Yang, Zeshi Jiang, Xiaoqian Feng, Jingxin Yang, Chao Lu, Chuanbin Wu, Xin Pan & Tingting Peng
doi : 10.1208/s12249-024-02963-y
Volume 25, article number 252, (2024)
Osteoporosis is a metabolic bone disorder with impaired bone microstructure and increased bone fractures, seriously affecting the quality of life of patients. Among various bisphosphonates prescribed for managing osteoporosis, minodronic acid (MA) is the most potent inhibitor of bone context resorption. However, oral MA tablet is the only commercialized dosage form that has extremely low bioavailability, severe adverse reactions, and poor patient compliance. To tackle these issues, we developed MA-loaded dissolving microneedles (MA-MNs) with significantly improved bioavailability for osteoporosis therapy. We investigated the influence of drug loading on the physicochemical properties, transdermal permeation behavior, and pharmacokinetics of MA-MNs. The drug loading of MA-MNs exerted almost no effect on their morphology, mechanical property, and skin insertion ability, but it compromised the transdermal permeability and bioavailability of MA-MNs. Compared with oral MA, MA-MNs with the lowest drug loading (224.9 ?g/patch) showed a 9-fold and 25.8-fold increase in peak concentration and bioavailability, respectively. This may be ascribed to the reason that the increased drug loading can generate higher burst release, higher drug residual rate, and drug supersaturation effect in skin tissues, eventually limiting drug absorption into the systemic circulation. Moreover, MA-MNs prolonged the half-life of MA and provided more steady plasma drug concentrations than intravenously injected MA, which helps to reduce dosing frequency and side effects. Therefore, dissolving MNs with optimized drug loading provides a promising alternative for bisphosphonate drug delivery.
Effects of Glass Bead Size on Dissolution Profiles in Flow-through Dissolution Systems (USP 4)
Hiroyuki Yoshida, Keita Teruya, Yasuhiro Abe, Takayuki Furuishi, Kaori Fukuzawa, Etsuo Yonemochi & Ken-ichi Izutsu
doi : 10.1208/s12249-024-02972-x
Volume 25, article number 251, (2024)
The effects of glass bead size in the conical space of flow-through cells on the dissolution profiles were investigated in a USP apparatus 4. Dissolution tests of disintegrating and non-disintegrating tablets in flow-through dissolution systems were performed using semi-high precision glass beads with diameters ranging from 0.5 mm to 1.5 mm. Computational fluid dynamics (CFD) was used to evaluate the effect of shear stress from the dissolution media flow. The use of smaller glass beads in a larger cell resulted in a faster dissolution of the model formulations under certain test conditions. The effect on the dissolution was highly dependent on the size of the beads in the top layer, including those in contact with the tablets. The absence of a bead-size effect on the dissolution of an orodispersible tablet in a small cell can be explained by the floating fragments during the test. CFD analysis showed that smaller bead diameters led to greater shear stress on the tablet, which was correlated with the dissolution rate. Hence, fluid flow through the narrow gaps between the small beads generated strong local flows, causing shear stress. The size of the glass beads used in flow-through cells affects the dissolution rate of tablets by altering the shear stress on the tablets in certain cases (e.g., direct deposition of the formulation on glass beads, large cells, and very low flow rates). Thus, glass bead size must be considered for a robust dissolution test in a flow-through cell system.
Self-Nanoemulsifying/ Self-Assembled Cubic Nanoparticles Lyophilized Tablet: A Novel Biphasic Release Approach to Enhance the Bioavailability of a Lipophilic Drug
Michael M. Farag, Wessam El-Sebaie, Emad B. Basalious & Omaima N. El-Gazayerly
doi : 10.1208/s12249-024-02952-1
Volume 25, article number 250, (2024)
This study aimed to prepare a combined self-nanoemulsifying and self-assembled cubic nanoparticles (SNE/SAC) lyophilized tablet eliciting biphasic release pattern escorted with enhanced bioavailability for drugs hampered with slow dissolution and poor absorption. The antimuscarinic Darifenacin hydrobromide (DRF) was selected as a model drug used to treat overactive bladder-associated nocturia. The DRF-SNE/SAC lyophilized tablet was prepared so that upon reconstitution a mixture of DRF-loaded cubic nanoparticles and nanoemulsion dispersion is obtained. The nanoemulsion portion is responsible for the fast release followed by controlled release of the remaining dose loaded in cubic nanoparticles. A comparative pharmacokinetic study adopting randomized crossover design in male albino rabbits versus marketed product Frequefenacine® tablet was performed. Half of the dose (52.05%?±?4.21%) was rapidly released in the first 4 h followed by sustained release of the remaining drug where (90.16%?±?8.85%) was released in 24 h. The tested system showed 2.45 folds higher % relative bioavailability and 1.57 folds higher Cmax with 1.62 longer residence time relative to reference product. The results endow the ability of the developed DRF-SNE/SAC lyophilized tablet to be considered as a propitious approach for the treatment of overactive bladder-associated nocturia without midnight dose administration.
Demystifying the Potential of Embelin-Loaded Nanoformulations: a Comprehensive Review
Layba Noor, Abdul Hafeez, Md. Azizur Rahman, Km Khushboo Vishwakarma, Archita Kapoor, Nargis Ara & Rabia Aqeel
doi : 10.1208/s12249-024-02968-7
Volume 25, article number 249, (2024)
Phytoconstituent based therapies have the potential to reduce the adverse effects and enhance overall patient compliance for different diseased conditions. Embelin (EMB) is a natural compound extracted from Embelia ribes that has demonstrated high therapeutic potential, particularly as anti-inflammatory and anticancer therapeutic applications. However, its poor water solubility and low oral bioavailability limitations make it challenging to use in biomedical applications. Nanostructure-based novel formulations have shown the potential to improve physicochemical and biological characteristics of active pharmaceutical ingredients obtained from plants. Different nanoformulations that have been utilized to encapsulate/entrap EMB for various therapeutic applications are nanoliposomes, nanostructured lipid carriers, niosomes, polymeric nanoparticles, nanosuspensions, phytosomes, self nanoemulsifying drug delivery system, silver nanoparticles, microparticles, solid lipid nanoparticle, gold nanoparticles and nanomicelles. The common methods reported for the preparation of EMB nanoformulations are thin film hydration, nanoprecipitation, ethanol injection, emulsification followed by sonication. The size of nanoformulations ranged in between 50 and 345 nm. In this review, the mentioned EMB loaded nanocarriers are methodically discussed for size, shape, drug entrapment, zeta potential, in vitro release & permeation and in vivo studies. Potential of EMB with other drugs (dual drug approach) incorporated in nanocarriers are also discussed (physicochemical and preclinical characteristics). Patents related to EMB nanoformulations are also presented which showed the clinical translation of this bioactive for future utilization in different indications.
Paroxetine Loaded Nanostructured Lipid Carriers Based In-situ Gel for Brain Delivery via Nasal Route for Enhanced Anti-Depressant Effect: In Vitro Prospect and In Vivo Efficacy
Kiran Akbar, Masood Ur Rehman, Fawad Ali Shah, Sidra Younas, Jamelah S. Al-Otaibi & Haroon Khan
doi : 10.1208/s12249-024-02954-z
Volume 25, article number 248, (2024)
This study focused on developing a thermosensitive gel with nanostructured lipid carriers (NLCs) loaded with paroxetine (PAR) to enhance the treatment and management of depression via nasal administration. Micro emulsion technique was utilized for the PAR-NLCs preparation. The acetyl alcohol and oleic acid were used in the ratio of 76:24. In the NLCs Tween 40, Span40 and Myrj 52 were used as a surfactant. The NLCs were then added into Poloxamer mixture to get thermosensitive NLCs based gel. Characterization, in vitro and in vivo studies were performed to check the efficiency of formulation in drug delivery. The entrapment efficiency of optimized PAR-NLCs was about 90%. The particle size, zeta potential and PDI were 155?±?1.4 nm, -25.9?±?0.5 mV, and 0.12?±?0.01 respectively. The optimized gel showed a gelling temperature of 31.50?±?0.50°C and a gelling time of 1?±?0.12 s with a pH of 6, suitable for nasal administration. The in vitro release assay of PAR-NLC-gel showed a cumulative release of about 59% in the first 6 h after comparison with PAR-NLCs which showed almost 100%release. In vivo studies included forced swim test and tail suspension tests showed significant potential for treating depression when compared to PAR-NLCs. PAR-NLCs and NLCs based gel enhanced the tissue architecture and suppressed the expression of TNF-? in brain cortex from histological and immunohistochemical analysis. PAR- NLCs gel-based delivery system can prove to be an effective delivery system for brain targeting through nose for the better management of depression.
Systematic Approach in the Development of Chitosan Functionalized Iloperidone Nanoemulsions for Transnasal Delivery, In Vitro and In Vivo Studies
Niserga D. Sawant, Pratima A. Tatke & Namita D. Desa
doi : 10.1208/s12249-024-02964-x
Volume 25, article number 247, (2024)
Iloperidone, a second-generation USFDA approved antipsychotic and BCS class II drug shows poor oral bioavailability of 28%. The present research deals with optimization of transnasal nanoemulsions of Iloperidone using Design Expert (Version 11) and further surface functionalization with chitosan for potentiating nose to brain delivery. Chitosan functionalized transnasal Iloperidone nanoemulsions were developed using oleic acid, charge inducer, Tween 80, Transcutol HP and chitosan using ultrasonication technique and evaluated. Droplet size, polydispersity index and zeta potential of Iloperidone nanoemulsions was found to be 173?±?0.5 nm, 0.413?±?0.2 and???22.5?±?0.1 mV while that of chitosan functionalized Iloperidone nanoemulsions was 146.4?±?0.5 nm, 0.291?±?0.02 and?+?23.6?±?0.3 mV respectively. Ninhydrin assay, TEM and FTIR studies confirmed surface functionalization of Iloperidone nanoemulsion droplets with chitosan. In vitro release of Iloperidone from nanoemulsions and chitosan functionalized nanoemulsions was 90.41?±?2.1% and 72.02?±?0.21% while ex vivo permeation of Iloperidone across goat nasal mucosa was 1270.58?±?0.023 ?g/cm2 and 1096.13?±?0.043 ?g/cm2 respectively at the end of 8 h. Studies in RPMI 2650 nasal and Neuro2A brain cell line lines indicated safety of chitosan functionalized transnasal Iloperidone nanoemulsions. Studies in Wistar rats showed increased cataleptic effects, reduced cognitive impairment and anxiety-related behaviour with greater brain accumulation indicating promising potential of this approach in nose to brain drug delivery.
Effect of Liquid Load Level and Binder Type on the Tabletability of Mesoporous Silica Based Liquisolids
Jan Appelhaus, Kristina E. Steffens & Karl G. Wagner
doi : 10.1208/s12249-024-02958-9
Volume 25, article number 246, (2024)
Mesoporous silica offers an easy way to transform liquids into solids, due to their high loading capacity for liquid or dissolved active ingredients and the resulting enhanced dissolution properties. However, the compression of both unloaded and loaded mesoporous silica bulk material into tablets is challenging, due to poor/non-existing binding capacity. This becomes critical when high drug loads are to be achieved and the fraction of additional excipients in the final tablet formulation needs to be kept at a minimum. Our study aimed to investigate the mechanism of compression and tabletability dependent on the Liquid Load Level of the silica and type of filler/binder in binary tabletting mixtures. To this end, Vivapur® 101, FlowLac® 90, Pearlitol® 200 SD and tricalcium citrate tetrahydrate were selected and mixed with Syloid® XDP 3050 at various Liquid Load Levels. Compaction characteristics were analysed using the StylOne® Classic 105 ML compaction simulator. Additionally, the Overall Liquid Load (OLL) was defined as a new critical quality attribute for liquisolid tablets. The Overall Liquid Load allows straightforward, formulation-relevant comparisons between various fillers/binders, liquid components, and silica types. Results indicate strong binding capacity and high plasticity of the fillers/binders as key components for successful high liquid load silica tablet formulation. A volumetric combination of 30% Vivapur® 101 and 70% 0.75 mL/g loaded Syloid® XDP 3050 proved to be the most effective mixture, achieving an Overall Liquid Load of 36–41% [v/v] and maintaining a tensile strength of 1.5 N/mm2 with various liquid vehicles.
Development of a Single Vial Mass Flow Rate Monitor to Assess Pharmaceutical Freeze Drying Heterogeneity
Tiffany Yu, Richard Marx, Michael Hinds, Nicholas Schott, Emily Gong, Seongkyu Yoon & William Kessler
doi : 10.1208/s12249-024-02961-0
Volume 25, article number 245, (2024)
During pharmaceutical lyophilization processes, inter-vial drying heterogeneity remains a significant obstacle. Due to differences in heat and mass transfer based on vial position within the freeze drier, edge vials freeze differently, are typically warmer and dry faster than center vials. This vial position-dependent heterogeneity within the freeze dryer leads to tradeoffs during process development. During primary drying, process developers must be careful to avoid shelf temperatures that would result in overheating of edge vials causing the product sublimation interface temperature to rise above the critical (collapse) temperature. However, at lower shelf temperatures, center vials require longer to complete primary drying, risking collapse or melt-back due to incomplete drying. Both situations may result in poor product quality affecting drug stability, activity, and reconstitution times. We present a new approach for monitoring vial location-specific water vapor mass flow based on Tunable Diode Laser Absorption Spectroscopy (TDLAS). The single vial monitor enables measurement of the gas flow velocity, water vapor temperature, and gas concentration from the sublimating ice, enabling the calculation of the mass flow rate which can be used in combination with a heat and mass transfer model to determine vial heat transfer coefficients and product resistance to drying. These parameters can in turn be used for robust and rapid process development and control.
