Overview of Multicomponent Solid Forms

Multi-drug therapy involves the simultaneous or sequential administration of two or more drugs with similar or different mechanisms of action and is efficient in combating various ailments such as cancer, diabetes, and rheumatoid arthritis. It has emerged advantageous due to larger therapeutic benefits, an increase in patient compliance, lower administrative costs, and reduced number of prescriptions. In the recent past, the clinical success of the Novartis product Entresto (sacubitril, disodium valsartan and water) and Esteve product E-58425 (tramadol and celecoxib) has boosted the development of multi-drug . The present article is hence designed to provide an overview of different multicomponent addicts which provide option of combining the drugs at a supramolecular level (nano-sized level). Key features of multi-drug cocrystal, co-amorphous system and eutectics are described with major emphasis on screening tools, preparation methods, characterization techniques, biopharmaceutical aspects and scale up.

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Abstract P469: Scale-up And Characterization Of Therapeutic Mesenchymal Stromal Cell-derived Extracellular Vesicles

Circulation Research ◽

10.1161/res.129.suppl_1.p469 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Selen Uman ◽

Jason A Burdick

Keyword(s):

Cell Culture ◽

Extracellular Vesicles ◽

Animal Studies ◽

Scale Up ◽

Spinner Flask ◽

Perfusion Bioreactor ◽

Large Animal ◽

Culture Methods ◽

Therapeutic Benefits ◽

Cell Culture Methods

Introduction: Early studies have shown therapeutic benefits of mesenchymal stromal cells (MSCs) in cardioprotection due to their angiogenic, proliferative, anti-apoptotic and anti-inflammatory properties, which are now attributed to secreted factors such as extracellular vesicles (EVs). While MSC-EVs have shown promise in small animals for cardiovascular therapies, large animal studies are required to evaluate the therapeutic benefit of MSC-EVs for clinical translation. One of the biggest challenges for large animal studies is the need to generate clinically-relevant quality and quantity of EVs without batch-to-batch variations that could compromise efficacy. This study aims to explore three different cell culture methods (traditionally-used tissue culture plates (TCP), 3-D printed bioscaffolds in a perfusion system (P), and microcarriers in dynamic spinner flask conditions (M)) to scale-up the production of MSC-EVs across four different biological donors and rigorously investigate EV yield, size, shape, and content. Methods: MSCs were isolated from the iliac crest of four different Yucatan minipigs using heparinized syringes, and cells were expanded to passage four, at which point they were seeded onto the respective cell culture methods. EVs were collected from conditioned medium (CM) via differential ultracentrifugation. EV size, distribution, yield, and protein concentration were studied using Nanoparticle Tracking Analysis (NTA) and microBCA assays. Results: Both perfusion bioreactor and spinner flask systems enabled sustained maintenance of large numbers of cells. Across biological donors and fabrication methods, modes remained within 50-150 nm and were not statistically different. Microcarrier-based spinner flasks and perfusion bioreactor set-ups both improved EV yield, up to 6 times in efficiency. Ongoing research focuses on examining differences in EV content across biological donors using RNA-sequencing and proteomics.

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Nanocrystal Approaches for Poorly Soluble Drugs and their Role in Development of Marketed Formulation

Drug Delivery Letters ◽

10.2174/2210303111666210616115543 ◽

2021 ◽

Vol 11 ◽

Author(s):

Vijay Agarwal ◽

Nitin Kaushik ◽

Pankaj Kumar Sharma

Keyword(s):

Particle Size ◽

Ostwald Ripening ◽

Review Paper ◽

Scale Up ◽

Wet Milling ◽

Particle Size Range ◽

Preparation Methods ◽

Characterization Methods ◽

Poorly Soluble ◽

Pharmaceutical Industries

Objectives: This review paper gives focus on the nanocrystal approaches and their uses in pharmaceutical applications. Also, various preparation methods of the nanocrystal are briefly described in this presented review paper. The paper also describes several factors that are involved in the production of stable drug nanocrystals and provides suggestions for overcoming instability-related issues like aggregation and Ostwald ripening. Finally, the specific opportunities and challenges that are applicable to nanocrystal technology are summarized in this paper. Methods: In this paper, we summarize and discuss the special features of drug nanocrystals that include the enhancement of dissolution velocity, adhesiveness to the surface, and saturation solubility. Nowadays, pharmaceutical industries are using different approaches to prepare the nanocrystal, like bottom-up approach (precipitation), the top-down approach (wet milling, high-pressure homogenization), and some other combinational approaches. Results: Drug nanocrystals can be administered through different routes. Besides this, the various fabrication methods and characterization methods may be used for the development and scale-up production of drug nanocrystals. Conclusion: In this review article, the relevance of drug nanocrystals are presented and illustrated according to their research done by different researchers and finally concluded that marketed formulation related to nanocrystal are gradually in progression. However, some related and developed formulations are under clinical trial. Background: Poor solubility of the drug compounds is a major problem in the pharmaceutical field; therefore, the reduction of particle size may be one of the simplest and efficient processes for enhancing the solubility of such compounds. Drug nanocrystals are the crystals available with some drugs and having a particle size range of 100 to 1000 nm, covered by stabilization.

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Modeling the oxidative consumption of curcumin from controlled released poly(beta-amino ester) microparticles in the presence of a free radical generating system

Regenerative Biomaterials ◽

10.1093/rb/rbz002 ◽

2019 ◽

Vol 6 (4) ◽

pp. 201-210 ◽

Cited By ~ 1

Author(s):

Carolyn T Jordan ◽

J Zach Hilt ◽

Thomas D Dziubla

Keyword(s):

Therapeutic Potential ◽

Clinical Success ◽

Amino Ester ◽

Therapeutic Benefits ◽

Consumption Rates ◽

Rapid Clearance ◽

Drug Modeling ◽

First Time ◽

Kinetics Of ◽

Poor Stability

AbstractDespite the promise of its therapeutic benefits, curcumin as a free molecule has failed to demonstrate significant clinical success. Arguably, its inherently poor stability and rapid clearance is a significant reason for these negative outcomes. The incorporation of curcumin into the backbone of a crosslinked hydrogel that utilizes poly(beta-amino ester) (PBAE) chemistry can provide a tunable protective network with the ability to release at a controlled rate while improving its therapeutic potential. Kinetics of curcumin conjugated PBAE microparticles controlled release delivery system in the presence of oxidative environments was studied for the first time, where consumption rates of active curcumin and release products were obtained. The constituent amount of curcumin present in solution was improved by incorporating the active into the network in comparison to curcumin as a free drug. Modeling curcumin conjugated PBAE microparticles will provide a design platform to improve translation and overall success in delivering a therapeutic agent that matches levels of oxidative stress.

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Manufacturing of Liposomes: A Direct Comparison of Extrusion and Microfluidics Protocols

10.26434/chemrxiv.14604921 ◽

2021 ◽

Author(s):

Mahmoud Tarek Sanad ◽

Claudio Alter ◽

Pascal Detampel ◽

Tomaz Einfalt ◽

Jörg Huwyler

Keyword(s):

Light Scattering ◽

Dynamic Light Scattering ◽

Scale Up ◽

Preparation Methods ◽

Manufacturing Method ◽

Liposomal Formulations ◽

Liposome Preparation ◽

Identical Composition ◽

Manufacturing Methods ◽

Parenteral Drug

Liposomal formulations are frequently used for oral, topical, or parenteral drug administration. However, liposome manufacturing and industrial scale-up remains a challenge, in particular if it comes to the preparation of liposome populations with a homogenous size distribution. Therefore, extrusion through filter membranes with defined pore size is traditionally used during the preparation of small unilamellar liposomes. Microfluidics is considered to be an alternative manufacturing method. Lipids, solvents and excipients are thereby passively mixed using a microfluidics device. While the microfluidic approach is highly scalable, most of the traditional liposome preparation protocols rely on extrusion. It was therefore the aim of the present study to compare liposomal formulations with identical composition, which were prepared using either extrusion or microfluidics protocols. Liposomal formulations produced by both methods were analyzed using dynamic light scattering (DLS) to compare size, polydispersity, and ζ-potential. Our results indicate significant differences between liposomal preparations obtained using the two manufacturing methods. We conclude that the two preparation methods should not be used interchangeably.<br>

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Manufacturing of Liposomes: A Direct Comparison of Extrusion and Microfluidics Protocols

10.26434/chemrxiv.14604921.v1 ◽

2021 ◽

Author(s):

Mahmoud Tarek Sanad ◽

Claudio Alter ◽

Pascal Detampel ◽

Tomaz Einfalt ◽

Jörg Huwyler

Keyword(s):

Light Scattering ◽

Dynamic Light Scattering ◽

Scale Up ◽

Preparation Methods ◽

Manufacturing Method ◽

Liposomal Formulations ◽

Liposome Preparation ◽

Identical Composition ◽

Manufacturing Methods ◽

Parenteral Drug

Liposomal formulations are frequently used for oral, topical, or parenteral drug administration. However, liposome manufacturing and industrial scale-up remains a challenge, in particular if it comes to the preparation of liposome populations with a homogenous size distribution. Therefore, extrusion through filter membranes with defined pore size is traditionally used during the preparation of small unilamellar liposomes. Microfluidics is considered to be an alternative manufacturing method. Lipids, solvents and excipients are thereby passively mixed using a microfluidics device. While the microfluidic approach is highly scalable, most of the traditional liposome preparation protocols rely on extrusion. It was therefore the aim of the present study to compare liposomal formulations with identical composition, which were prepared using either extrusion or microfluidics protocols. Liposomal formulations produced by both methods were analyzed using dynamic light scattering (DLS) to compare size, polydispersity, and ζ-potential. Our results indicate significant differences between liposomal preparations obtained using the two manufacturing methods. We conclude that the two preparation methods should not be used interchangeably.<br>

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A Critical Review of Standardization of Ayurvedic Dosage Form Kwatha - Part - II: Approaches and Outcome

International Journal of Ayurvedic Medicine ◽

10.47552/ijam.v11i3.1552 ◽

2020 ◽

Vol 11 (3) ◽

pp. 378-386

Author(s):

Narendra Bhatt ◽

Manasi Deshpande ◽

Sunetra Chaskar

Keyword(s):

Drug Delivery ◽

Conventional Medicine ◽

Dosage Forms ◽

Raw Material ◽

New Techniques ◽

Preparation Methods ◽

Therapeutic Benefits ◽

Nano Drug Delivery ◽

Liquid Preparation ◽

Manufacturing Technologies

A Kwatha, decoction, is one of the most used classical Ayurvedic dosage forms. It is a liquid preparation to be freshly consumed. For this preparation the raw material, mostly herbs or a group of herbs are extracted in water by boiling them for a specific time span. This is second part of the review paper on Ayurvedic Kwatha - herbal decoction to review and consider various approaches and their outcomes for the standardization. It provides information and reference data for the standardization of decoction across conventional methods and new techniques and explains how this classical process has evolved within new pharmaceutical developments. Many Ayurvedic production units appear to have adapted to newer manufacturing technologies including fermentation techniques. This paper explores the scope for application of newer technologies for the purpose of better standardization and novel product applications. Application of Kwatha's nano-drug delivery systems have a promising potential to enhance operation and resolve issues related to classical dosage forms. In order to tackle further chronic diseases, the incorporation of nano-carriers as NDDS in the conventional medicine system is necessary. This review examines the benefits of the nano-drug delivery system, its properties, its drawbacks, forms of nanoparticles, their preparation methods, and various herbal nano medicines. This review further explores how therapeutic benefits can be improved by reducing toxicity and increasing bioavailability.

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Multicomponent Solid Forms

Multifunctional Nanocarriers for Contemporary Healthcare Applications - Advances in Medical Technologies and Clinical Practice ◽

10.4018/978-1-5225-4781-5.ch010 ◽

2018 ◽

pp. 273-300

Author(s):

Rahul B. Chavan ◽

Balvant Yadav ◽

Anurag Lodagekar ◽

Nalini R. Shastri

Keyword(s):

Pharmaceutical Industry ◽

Scale Up ◽

Aqueous Solubility ◽

Multicomponent Systems ◽

Future Perspectives ◽

Amorphous System ◽

Regulatory Guidelines ◽

Poorly Soluble ◽

Solid Form ◽

Widespread Interest

Multicomponent systems provide the option of combining drugs at the supramolecular level. Among these, co-crystals have gained a widespread interest in pharmaceutical industry as US Food and Drug Administration (FDA) recently introduced new regulatory guidelines regarding this solid form that is anticipated to expand patent portfolios. Apart from co-crystals, other multi-component adducts such as co-amorphous system and eutectics are also a topic of interest for pharmaceutical researchers as they provide therapeutic advantages along with improved the aqueous solubility, dissolution, and bioavailability of poorly soluble drugs. This chapter provides a brief overview of multicomponent solid forms, their preparation methodologies, characterization, evaluation, biopharmaceutical aspects, scale up issues, and regulatory perspectives related to these solid forms. In addition, a section on future perspectives that sheds light on new therapeutic hybrids deploying drug-drug and drug-neutraceuticals combinations with improved pharmaceutical and biopharmaceutical attributes is also included.

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Authors Review on Drug Nanocrystals: A Progress to Targeted Delivery

Current Nanomedicine ◽

10.2174/2468187310666200221103827 ◽

2020 ◽

Vol 10 (3) ◽

pp. 248-270

Author(s):

Manish Kumar ◽

Nithya Shanthi ◽

P.S. Rajnikanth ◽

Arun Kumar Mahato

Keyword(s):

Targeted Delivery ◽

Scale Up ◽

Biological Properties ◽

Third Generation ◽

Preparation Methods ◽

Site Specific ◽

Factors Affecting ◽

Optimization Parameters ◽

Pharmaceutical Industries ◽

Surface Modified

In the last few decades, researchers and pharmaceutical industries have been developing new approaches to overcome the solubility and bioavailability limits observed with poorly soluble drugs. With the advancement of nanotechnology, nanocrystals have emerged as a great potential to overcome these limitations. Nanocrystals owing to its ability to modify the physicochemical and biological properties of the drug have gained widespread attention among the research scientists. This review provides comprehensive detail on the associated advantages, challenges, factors affecting physicochemical properties, and optimization parameters about the stability of nanocrystals. In this review, the evolution of nanocrystals is discussed as first-generation simple nanocrystals, secondgeneration nanocrystals within a carrier, and third-generation surface-modified nanocrystals. It also provides a detailed account of various preparation methods and evaluation of surface-modified nanocrystals. In the proposed "King Design," nanocrystals of the third generation are placed on the top due to their advantage over other nanocarriers like high drug payload, site-specific delivery, improved activity, commercial manufacturing, and easy scale-up. Third generations nanocrystals can provide a novel therapeutic solution for the site-specific, targeted, and efficient delivery for treatment of various acute as well as chronic diseases with high stability and scale-up potential.

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The relevance of skull density ratio in selecting candidates for transcranial MR-guided focused ultrasound

Journal of Neurosurgery ◽

10.3171/2019.2.jns182571 ◽

2020 ◽

Vol 132 (6) ◽

pp. 1785-1791 ◽

Cited By ~ 9

Author(s):

Alexandre Boutet ◽

Dave Gwun ◽

Robert Gramer ◽

Manish Ranjan ◽

Gavin J. B. Elias ◽

...

Keyword(s):

Emergency Department ◽

General Population ◽

Clinical Outcomes ◽

Focused Ultrasound ◽

Clinical Success ◽

Density Ratio ◽

Acoustic Energy ◽

Invasive Treatment ◽

Therapeutic Benefits ◽

Age And Sex

OBJECTIVETranscranial MR-guided focused ultrasound (MRgFUS) is a minimally invasive treatment for movement disorders. Considerable interpatient variability in skull transmission efficiency exists with the current clinical devices, which is thought to be dependent on each patient’s specific skull morphology. Lower skull density ratio (SDR) values are thought to impede acoustic energy transmission across the skull, attenuating or preventing the therapeutic benefits of MRgFUS. Patients with SDR values below 0.4 have traditionally been deemed poor candidates for MRgFUS. Although considerable anecdotal evidence has suggested that SDR is a reliable determinant of procedural and clinical success, relationships between SDR and clinical outcomes have yet to be formally investigated. Moreover, as transcranial MRgFUS is becoming an increasingly widespread procedure, knowledge of SDR distribution in the general population may enable improved preoperative counseling and preparedness.METHODSA total of 98 patients who underwent MRgFUS thalamotomy at the authors’ institutions between 2012 and 2018 were analyzed (cohort 1). The authors retrospectively assessed the relationships between SDR and various clinical outcomes, including tremor improvement and adverse effects, as well as procedural factors such as sonication parameters. An SDR was also prospectively obtained in 163 random emergency department patients who required a head CT scan for various clinical indications (cohort 2). Patients’ age and sex were used to explore relationships with SDR.RESULTSIn the MRgFUS treatment group, 17 patients with a thalamotomy lesion had an SDR below 0.4. Patients with lower SDRs required more sonication energy; however, their low SDR did not influence their clinical outcomes. In the emergency department patient group, about one-third of the patients had a low SDR (< 0.4). SDR did not correlate with age or sex.CONCLUSIONSAlthough lower SDR values correlated with higher energy requirements during MRgFUS thalamotomy, within the range of this study population, the SDR did not appreciably impact or provide the ability to predict the resulting clinical outcomes. Sampling of the general population suggests that age and sex have no relationship with SDR. Other variables, such as local variances in bone density, should also be carefully reviewed to build a comprehensive appraisal of a patient’s suitability for MRgFUS treatment.

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