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1.
Ann Pharm Fr ; 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38942078

RESUMO

OBJECTIVES: Edaravone (EDR) is an effective neuroprotective agent in various neurological diseases; however, its use is restricted due to poor oral absorption. Bile salts are known for improving solubility and inhibiting drug crystallization in supersaturated conditions of the gastrointestinal tract (GIT). In our previous work, we prepared coamorphous dispersion (COAM) of EDR with sodium taurocholate (NaTC) using spray drying. The optimized EDR COAM exhibited superior in vitro performance compared to plain EDR. EDR is well absorbed in fasted-over-fed conditions. METHODS: The present work, we conducted a pharmacokinetic study for EDR and EDR COAM in fasted and fed conditions to check effect of food on its oral absorption. The LC-MS/MS-based method was developed and validated to determine the amount of EDR in plasma. RESULTS: The results suggested that EDR COAM did not show a significant difference in Cmax (p=0.3544) and AUC (p=0.1696) of fasted and fed states. On the other hand, plain EDR showed 2-fold and 3-fold reduced Cmax (p<0.0001) and AUC (p=0.0094) in the fed condition, respectively. The Cmax and AUC of EDR COAM were improved in fasted (AUC:2.56-fold) and fed states (AUC: 5.74-fold) than plain EDR, suggesting better oral absorption of COAM than crystalline EDR without having the effect of food. CONCLUSIONS: The unique structural attributes of NaTC had the potential to inhibit the recrystallization of EDR in GIT, while concurrently reducing the impact of food on the oral absorption of EDR.

2.
Chem Phys Lipids ; 253: 105302, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37031754

RESUMO

In the present study, we aimed to design the spray-dried coamorphous dispersion (COAM) of a neuroprotective agent-edaravone (EDR) with bile salts to improve oral bioavailability. After the initial screening of different bile salts, EDR-sodium taurocholate (NaTC) COAM showed 4-fold solubility than a pure drug in 1-7 pH range. In silico studies to select coformer for COAM revealed a narrow energy gap, easy charge transfer and high chemical reactivity between EDR and NaTC. The optimized EDR-NaTC COAM in a 1:1 molar ratio was characterized for solid state characterizations and in vitro release study. Hydrogen bond formation between the pyrazolone ring of EDR and the -OH group of the phenanthrene ring of NaTC was observed in the ATR-FTIR spectra of COAM. The DSC and XRPD data indicated the formation of an amorphous halo, whereas SEM photographs demonstrated porous, spherical particles of COAM. The pH-independent in vitro drug release of COAM was observed in 0.1 N HCl, pH 4.5 and 6.8 buffers which was 3-fold higher than EDR. The COAM was stable for 6 months at accelerated condition without showing a change in drug content or devitrification (Initial: 98.002 ± 0.942 %; Accelerated condition: 97.016 ± 1.110 %). Although coamorphous form and hydrogen bonding between EDR-NaTC dispersion were primarily responsible for improved dissolution, NaTC, an exceptional surfactant, has also contributed to it. Moreover, its exclusive structural characteristics could prevent the recrystallization of the drug in supersaturated conditions of the GIT and also minimize the effect of food on oral absorption of EDR which will be studied in animals in the second part of this work.


Assuntos
Ácidos e Sais Biliares , Animais , Edaravone , Fenômenos Químicos , Solubilidade , Liberação Controlada de Fármacos
3.
Drug Deliv Transl Res ; 13(2): 419-432, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35994158

RESUMO

Osteoporosis is a bone disorder characterised by low bone mineral density, reduced bone strength, increased bone fragility, and impaired mineralisation of bones causing an increased risk of bone fracture. Several therapies are available for treating osteoporosis which include bisphosphonates, anti-resorptive agents, oestrogen modulators, etc. These therapies primarily focus on decreasing bone resorption and do not assist in bone regeneration or offering permanent curative solutions. Additionally, these therapies are associated with severe adverse events like thromboembolism, increased risk of stroke, and hypocalcaemia. To overcome these limitations, bone regenerative pathways and approaches are now considered to manage osteoporosis. The bone regenerative pathways involved in bone regeneration include wingless-related integration site/ß-catenin signalling pathway, notch signalling pathway, calcium signalling, etc. The various regenerative approaches which possess potential to heal and replace the bone defect site include scaffolds, cements, cell therapy, and other alternative medicines. The review focuses on describing the challenges and opportunities in bone regeneration for osteoporosis.


Assuntos
Conservadores da Densidade Óssea , Osteoporose , Humanos , Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Regeneração Óssea , Difosfonatos/uso terapêutico
4.
AAPS PharmSciTech ; 24(1): 27, 2022 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-36577896

RESUMO

The current study aimed to improve the processability and oral bioavailability of itraconazole (ITZ) via spherical agglomeration. ITZ-spherical agglomerates (ITZ-SA) and ITZ-poloxamer 407-spherical agglomerates (ITZ-PLX-SA) were optimized using Box-Behnken design. Here, the drug release was affected by polymer concentration and stirring speed, whereas particle size was altered by stirring speed, polymer concentration, and amount of bridging liquid. Heckel and Kawakita studies showed a reduction in mean yield pressure and remarkably lowered 1/b value than ITZ, indicating better compactibility and flowability of ITZ-PLX-SA. Physicochemical interactions were not observed during the process, as indicated by ATR-FTIR, DSC, and XRPD. The significant improvement in % drug release of ITZ-PLX-SA was attributed to better wettability and the presence of polymer than ITZ-SA and ITZ. The pharmacokinetic study in rats indicated fivefold enhanced Cmax and twofold improved AUC for ITZ-PLX-SA than plain drug. Thus, spherical agglomeration could improve overall processability and pharmacokinetic profile of ITZ.


Assuntos
Itraconazol , Poloxâmero , Ratos , Animais , Itraconazol/farmacocinética , Disponibilidade Biológica , Polímeros , Liberação Controlada de Fármacos , Tamanho da Partícula , Antifúngicos/farmacocinética
5.
Drug Discov Today ; 27(12): 103371, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36174965

RESUMO

Biotechnology-based therapeutics include a wide range of products, such as recombinant hormones, stem cells, therapeutic enzymes, monoclonal antibodies, genes, vaccines, among others. The administration of these macromolecules has been studied via various routes. The nasal route is one of the promising routes of administration for biotechnology products owing to its easy delivery, the rich vascularity of the nasal mucosa, high absorption and targeted action. Several preclinical studies have been reported for nasal delivery of these products and many are at the clinical stage. This review focuses on biotechnology-based therapeutics administered via the intranasal route for treating various diseases.


Assuntos
Sistemas de Liberação de Medicamentos , Vacinas , Administração Intranasal , Mucosa Nasal , Biotecnologia
6.
Comput Biol Med ; 140: 105084, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34891093

RESUMO

The outbreak of a new coronavirus (SARS-CoV-2) was first identified in Wuhan, People's Republic of China, in 2019, which has led to a severe, life-threatening form of pneumonia (COVID-19). Research scientists all around the world have been trying to find small molecule drugs to treat COVID-19. In the present study, a conserved macrodomain, ADP Ribose phosphatase (ADRP), of a critical non-structural protein (Nsp3) in all coronaviruses was probed using large-scale Molecular Dynamics (MD) simulations to identify novel inhibitors. In our virtual screening workflow, the recently-solved X-ray complex structure, 6W6Y, with a substrate-mimics was used to screen 17 million ZINC15 compounds using drug property filters and Glide docking scores. The top twenty output compounds each underwent 200 ns MD simulations (i.e. 20 × 200 ns) to validate their individual stability as potential inhibitors. Eight out of the twenty compounds showed stable binding modes in the MD simulations, as well as favorable drug properties from our predctions. Therefore, our computational data suggest that the resulting top eight out of twenty compounds could potentially be novel inhibitors to ADRP of SARS-CoV-2.

7.
Eur J Pharmacol ; 913: 174638, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34801531

RESUMO

Cerebral stroke, commonly caused due to hindrance in blood flow, is broadly classified into two categories-ischemic and haemorrhagic strokes. The onset of stroke triggers multiple mechanisms causing inflammation, generation of free radicals and protein damage leading to apoptosis of neuronal cells. The current therapies available for cerebral strokes involve use of complex surgical treatments and tissue plasminogen activator which increases the risk of internal bleeding, brain edema and cerebral damage, thereby restricting their use in clinical setting. The alarming need to develop safe, effective, target specific systems which, promote neuronal growth and reduce cerebral inflammation can be accomplished with use of biotechnological approaches. The article gives an insight to biotechnology-based advancements for tissue plasminogen activators, cell penetrating peptides, growth factors, ribonucleic acid systems and monoclonal antibodies for cerebral stroke. We also emphasis on challenges and future perspective of biotechnology-based therapeutics for better management of stroke.


Assuntos
Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Biotecnologia/tendências , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Peptídeos Penetradores de Células/farmacologia , Peptídeos Penetradores de Células/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Acidente Vascular Cerebral/patologia
8.
J Mass Spectrom ; 56(11): e4789, 2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34716637

RESUMO

This research aims to develop and validate a bioanalytical method for simultaneous estimation of an antidiabetic combination using LC-MS/MS in rat plasma. Nateglinide and metformin hydrochloride are commonly used combination for clinical management of Type 2 diabetes. Hence, simultaneous determination in plasma is essential for the rapid analysis of samples from the pharmacokinetic studies. Statistical optimization was carried out for liquid chromatography (LC) parameters and mass spectroscopic (MS) parameters by design of experiment (DoE) (Design Expert Version 11, Stat Ease Inc., USA) approach. A 33 full factorial design was used for optimization of LC parameters; %methanol, %formic acid, and flow rate were selected as independent variables, whereas peak area and tailing factor were considered as dependent variables for both drugs. Box-Behnken design was used to optimize MS parameters including drying gas flow rate, nebulizing gas flow rate, DL temperature, heat block temperature, and positive voltage as independent factors, and responses selected were [M + H]+ intensity of nateglinide and metformin hydrochloride. The [M + H]+ intensity of the optimized method for nateglinide and metformin hydrochloride were 2,462,838 and 11,873,826, respectively. The model was found significant for optimizing LC and MS parameters with p < 0.05 for both nateglinide and metformin hydrochloride. The optimized method was validated as per the ICH-M10 guideline, which was accurate, precise, and selective. The method was cost-effective and capable of quantitating concentrations in picogram levels for nateglinide and metformin hydrochloride simultaneously.

9.
Mater Sci Eng C Mater Biol Appl ; 113: 110996, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32487405

RESUMO

Nanodiamonds (NDs), recent member of carbon nanomaterial, are nano-scale carbon allotropes having versatile surface chemistry. NDs are commonly synthesized by detonation and followed by purification, surface modification and surface functionalization. Surface functionalization of NDs enhances safety, bio-compatibility and lowers toxicity. It involves initial surface homogenization followed by attachment of ligand on NDs which increases hydrophobicity, reduces surface charge and improves surface chemistry. Generally, surface functionalization is carried out by covalent and non-covalent attachment and in biomedical applications various functional groups, biomolecules, or polymers can be attached to NDs. This review is focused on surface functionalization methods for NDs and their biomedical applications. Surface functionalization is beneficial to improve physicochemical properties of NDs which may be further utilized in diagnosis and targeted drug delivery.


Assuntos
Nanodiamantes/química , Nanomedicina , Adsorção , Antineoplásicos/química , Antineoplásicos/metabolismo , Materiais Biocompatíveis/química , Portadores de Fármacos/química , Humanos , Nanodiamantes/toxicidade , Polímeros/química , Propriedades de Superfície
10.
Curr Pharm Des ; 26(32): 3973-3984, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329681

RESUMO

BACKGROUND: Glioma is one of the most commonly observed tumours, representing about 75% of brain tumours in the adult population. Generally, glioma treatment includes surgical resection followed by radiotherapy and chemotherapy. The current chemotherapy for glioma involves the use of temozolomide, doxorubicin, monoclonal antibodies, etc. however, the clinical outcomes in patients are not satisfactory. Primarily, the blood-brain barrier hinders these drugs from reaching the target leading to the recurrence of glioma post-surgery. In addition, these drugs are not target-specific and affect the healthy cells of the body. Therefore, glioma-targeted drug delivery is essential to reduce the rate of recurrence and treat the condition with more reliable alternatives. METHODS: A literature search was conducted to understand glioma pathophysiology, its current therapeutic approaches for targeted delivery using databases like Pub Med, Web of Science, Scopus, and Google Scholar, etc. Results: This review gives an insight to challenges associated with current treatments, factors influencing drug delivery in glioma, and recent advancements in targeted drug delivery. CONCLUSION: The promising results could be seen with nanotechnology-based approaches, like polymeric, lipidbased, and hybrid nanoparticles in the treatment of glioma. Biotechnological developments, such as carrier peptides and gene therapy, are future prospects in glioma therapy. Therefore, these targeted delivery systems will be beneficial in clinical practices for glioma treatment.


Assuntos
Neoplasias Encefálicas , Glioma , Nanopartículas , Barreira Hematoencefálica , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia
11.
Pharm Dev Technol ; 25(3): 376-384, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31842656

RESUMO

Ethambutol hydrochloride (ETB), high dose anti-tubercular drug exhibits poor micromeritics and compressibility. The current study aimed to enhance flow, compressibility and packing characteristics, thereby improving processability of ETB by spherical agglomeration. Quasi emulsion solvent diffusion method was used for agglomeration process in which saturated aqueous ETB solution was prepared and the crystallization was carried out subsequently at different ratios of acetone and ethyl acetate which act as anti-solvent. Further the process was optimised statistically using 32 factorial design keeping 'speed of stirring' and 'ratio acetone and ethyl acetate' as independent variables and particle size as dependent variable. Optimised batch of ethambutol hydrochloride spherical agglomerates (ETB-SA) was characterised for sieve analysis, solid state characteristics and Kawakita analysis. The uniformity of ETB-SA was observed with SEM while XRPD studies revealed reduction in crystallinity for ETB-SA. DSC and FTIR indicated no polymeric or chemical alteration during crystallization process. The flow properties of ETB-SA were found superior and its Kawakita parameters indicated improved packability and flowability compared to ETB. ETB has high solubility in water therefore was no significant difference was observed in in vitro dissolution of ETB and ETB-SA. Thus spherical agglomeration, a revered particle engineering technique, continues to be a salient approach for enhancing processability of high-dose drugs like ETB.


Assuntos
Antituberculosos/administração & dosagem , Química Farmacêutica/métodos , Etambutol/administração & dosagem , Solventes/química , Antituberculosos/química , Cristalização , Emulsões , Etambutol/química , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Solubilidade , Tecnologia Farmacêutica , Difração de Raios X
12.
Drug Deliv Transl Res ; 9(6): 1067-1081, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31144214

RESUMO

Cyclosporine has been established as a gold standard for its immunosuppressant action. Apart from this, the molecule is boon in treating broad spectrum of diseases like rheumatoid arthritis, psoriasis, and dry eye syndrome. The broad spectrum of cyclosporine demands efficient delivery systems by several routes. Neoral® and Sandimmune® are currently available formulations for oral route, whereas Restasis® is used for ocular delivery of cyclosporine. The available formulations serve the purpose only to a limited extent due to constraints like high molecular weight, low solubility, low permeability, bitter taste, and narrow therapeutic index of cyclosporine. Therefore, several novel formulations like microemulsion, self-emulsifying systems, nanoparticles, and microspheres were developed to overcome these constraints, exploring different routes like oral, ocular, and topical for cyclosporine. Additionally, iontophoresis and ultrasound-mediated delivery has also been studied to improve its poor permeability in topical delivery, whereas biodegradable implants were reported to increase the retention time in cornea and prolonged the release of cyclosporine by ocular route. Although these recent advances in cyclosporine delivery look promising, its clinical translation require in depth studies to deliver safe, efficacious, and stable formulation of cyclosporine. This review focuses on challenges of cyclosporine delivery and the recent advancements for overcoming the constraints.


Assuntos
Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Administração Oftálmica , Administração Oral , Animais , Ciclosporina/farmacocinética , Sistemas de Liberação de Medicamentos , Humanos , Imunossupressores/farmacocinética
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