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1.
Nat Commun ; 11(1): 4935, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004797

RESUMO

Gramicidin A (1) is a peptide antibiotic that disrupts the transmembrane ion concentration gradient by forming an ion channel in a lipid bilayer. Although long used clinically, it is limited to topical application because of its strong hemolytic activity and mammalian cytotoxicity, likely arising from the common ion transport mechanism. Here we report an integrated high-throughput strategy for discovering analogues of 1 with altered biological activity profiles. The 4096 analogue structures are designed to maintain the charge-neutral, hydrophobic, and channel forming properties of 1. Synthesis of the analogues, tandem mass spectrometry sequencing, and 3 microscale screenings enable us to identify 10 representative analogues. Re-synthesis and detailed functional evaluations find that all 10 analogues share a similar ion channel function, but have different cytotoxic, hemolytic, and antibacterial activities. Our large-scale structure-activity relationship studies reveal the feasibility of developing analogues of 1 that selectively induce toxicity toward target organisms.


Assuntos
Antibacterianos/farmacologia , Descoberta de Drogas/métodos , Gramicidina/análogos & derivados , Ensaios de Triagem em Larga Escala/métodos , Animais , Antibacterianos/química , Linhagem Celular Tumoral , Química Farmacêutica , Eritrócitos , Estudos de Viabilidade , Bactérias Gram-Positivas/efeitos dos fármacos , Gramicidina/química , Gramicidina/farmacologia , Hemólise/efeitos dos fármacos , Concentração Inibidora 50 , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Coelhos , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem
3.
Molecules ; 25(17)2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32899354

RESUMO

Peptidyl fluoromethyl ketones occupy a pivotal role in the current scenario of synthetic chemistry, thanks to their numerous applications as inhibitors of hydrolytic enzymes. The insertion of one or more fluorine atoms adjacent to a C-terminal ketone moiety greatly modifies the physicochemical properties of the overall substrate, especially by increasing the reactivity of this functionalized carbonyl group toward nucleophiles. The main application of these peptidyl α-fluorinated ketones in medicinal chemistry relies in their ability to strongly and selectively inhibit serine and cysteine proteases. These compounds can be used as probes to study the proteolytic activity of the aforementioned proteases and to elucidate their role in the insurgence and progress on several diseases. Likewise, if the fluorinated methyl ketone moiety is suitably connected to a peptidic backbone, it may confer to the resulting structure an excellent substrate peculiarity and the possibility of being recognized by a specific subclass of human or pathogenic proteases. Therefore, peptidyl fluoromethyl ketones are also currently highly exploited for the target-based design of compounds for the treatment of topical diseases such as various types of cancer and viral infections.


Assuntos
Clorometilcetonas de Aminoácidos/síntese química , Fenilalanina/análogos & derivados , Vírus da SARS/efeitos dos fármacos , Inibidores de Serino Proteinase/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Clorometilcetonas de Aminoácidos/farmacologia , Química Farmacêutica/métodos , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , HIV/efeitos dos fármacos , HIV/enzimologia , Protease de HIV/química , Protease de HIV/metabolismo , Humanos , Cinética , Fenilalanina/síntese química , Fenilalanina/farmacologia , Vírus da SARS/enzimologia , Inibidores de Serino Proteinase/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
4.
Nat Commun ; 11(1): 4371, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873790

RESUMO

Pentacyclic triterpenoids (PTs) constitute one of the biggest families of natural products, many with higher oxidation state at the D/E rings possess a wide spectrum of biological activties but are poorly accessible. Here we report a site-selective C-H hydroxylation at the D/E rings of PTs paving a way toward these important natural products. We find that Schönecker and Baran's Cu-mediated aerobic oxidation can be applied and become site-selective on PT skeletons, as being effected unexpectedly by the chirality of the transient pyridine-imino directing groups. To prove the applicability, starting from the most abundant triterpenoid feedstock oleanane, three representative saponins bearing hydroxyl groups at C16 or C22 are expeditiously synthesized, and barringtogenol C which bears hydroxyl groups at C16, C21, and C22 is synthesized via a sequential hydroxylation as the key steps.


Assuntos
Produtos Biológicos/química , Técnicas de Química Sintética , Triterpenos Pentacíclicos/química , Química Farmacêutica , Hidroxilação , Relação Estrutura-Atividade
5.
Pharm Res ; 37(10): 192, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32914239

RESUMO

PURPOSE: The objective was to characterize hydroxypropyl methylcellulose acetate succinate (HMPCAS) grades L, M, and H to enhance itraconazole (ITZ) release and permeation from spray dried dispersions (SDDs), and to investigate underpinning molecular ITZ-HPMCAS interactions that differentiated grade performance. METHODS: ITZ or its SDDs were subjected to solution stabilization assessment, one-dimensional proton nuclear magnetic resonance (NMR) spectroscopy, saturation transfer difference NMR studies, small volume dissolution, solid state transformation studies, and in vitro dissolution/permeation flux studies. RESULTS: HPMCAS-L was the best performing grade overall and exhibited greatest ITZ supersaturation concentration, small volume dissolution, and in vitro dissolution/permeation flux. Meanwhile, H grade retarded ITZ precipitation to the greatest extent in solution stabilization studies and exhibited greater hydrophobic interaction with ITZ in NMR studies. However, this apparent advantage of H grade through hydrophobic interactions between drug-polymer appeared to limit overall dissolution/permeation performance of SDD. CONCLUSIONS: In vitro SDD studies and drug-polymer interaction studies provided insight into the performance of HPMCAS grades, as well as the relative contributions of various mechanisms that polymer can promote ITZ absorption from SDD.


Assuntos
Itraconazol/química , Metilcelulose/análogos & derivados , Química Farmacêutica , Tecnologia de Fibra Óptica , Cinética , Espectroscopia de Ressonância Magnética , Metilcelulose/química , Solubilidade
6.
Int J Mol Sci ; 21(17)2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32825444

RESUMO

At the moment, there are no U.S. Food and Drug Administration (U.S. FDA)-approved drugs for the treatment of COVID-19, although several antiviral drugs are available for repurposing. Many of these drugs suffer from polymorphic transformations with changes in the drug's safety and efficacy; many are poorly soluble, poorly bioavailable drugs. Current tools to reformulate antiviral APIs into safer and more bioavailable forms include pharmaceutical salts and cocrystals, even though it is difficult to classify solid forms into these regulatory-wise mutually exclusive categories. Pure liquid salt forms of APIs, ionic liquids that incorporate APIs into their structures (API-ILs) present all the advantages that salt forms provide from a pharmaceutical standpoint, without being subject to solid-state matter problems. In this perspective article, the myths and the most voiced concerns holding back implementation of API-ILs are examined, and two case studies of API-ILs antivirals (the amphoteric acyclovir and GSK2838232) are presented in detail, with a focus on drug property improvement. We advocate that the industry should consider the advantages of API-ILs which could be the genesis of disruptive innovation and believe that in order for the industry to grow and develop, the industry should be comfortable with a certain element of risk because progress often only comes from trying something different.


Assuntos
Aciclovir/química , Antivirais/química , Betacoronavirus/efeitos dos fármacos , Butiratos/química , Crisenos/química , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Aciclovir/farmacologia , Antivirais/farmacologia , Disponibilidade Biológica , Butiratos/farmacologia , Química Farmacêutica/métodos , Crisenos/farmacologia , Reposicionamento de Medicamentos/métodos , Humanos , Líquidos Iônicos/química , Pandemias , Solubilidade
7.
An Acad Bras Cienc ; 92(2): e20191445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785428

RESUMO

Sildenafil is a potent selective inhibitor of phosphosdiesterase-5 previously used in erectile dysfunction and subsequently approved in 2005 for pulmonary arterial hypertension treatment. Since oral administration of sildenafil shows pharmacokinetic problems with mean absolute bioavailability of 41%, the goal of this work was to develop a novel sildenafil self-emulsifying drug delivery system (SEDDS) for oral absorption improvement and management of dosage. One pharmaceutical solution and four SEDDS containing sildenafil were successfully obtained and SEDDS formed O/W nanoemulsion with droplet size less than 300 nm. The stability studies evidenced that the SEDDS containing 3.3% w/w of sildenafil yielded the best results. The safety of 2-pyrrolidone/isobutanol in oral formulations was assessed in mice and no lethality was achieved in the placebo groups with LD50 of 490 mg/Kg for SEDDS II-3.3, suggesting it as a safe excipient for humans. Therewithal, in silico studies using PBPK models provided the pharmacokinetic profile of sildenafil SEDDS. Subsequently, in silico evaluation indicated that the sildenafil SEDDS droplet size influenced its bioavailability, enhancing absorption, assuring a good pharmacokinetic profile. These findings suggest that the formulations developed here presented the potential to enhance drug oral absorption with the possibility to control drug dosage as they are liquid pharmaceutical formulations.


Assuntos
Hipertensão Arterial Pulmonar , Animais , Química Farmacêutica , Sistemas de Liberação de Medicamentos , Emulsões , Humanos , Camundongos , Citrato de Sildenafila
8.
Yakugaku Zasshi ; 140(8): 1071-1080, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741865

RESUMO

The purpose of the present study was to establish a novel method to evaluate water penetration rates by combining the local dynamic contact angle and thermographic approach to characterize water conduction properties in orally disintegrating (OD) tablets. The OD tablet tester OD-mate was used to measure the disintegration times of OD tablets. Other formulation characteristics, such as tablet hardness and friability, were evaluated. By examining three formulation characteristics, such as the disintegration time, tablet hardness, and friability, of 33 OD tablets for generic drugs, four characteristic OD tablets containing aripiprazole were selected. To quantitatively evaluate water penetration rates into the tablet interior, we measured the dynamic contact angle after dropping water locally on the tablet surface. Linearity with a high correlation coefficient was observed for each of the initial time-dependent changes in the dynamic contact angle. Water penetration rates into tablets were approximately twice as fast for Pharmaceuticals A and B than for Pharmaceuticals C and D. These rates were consistent with changes observed in tablet thermographic imaging. The relationship between the rapid disintegration of the tablet and its physical strength was discussed based on the internal structure of the tablet by X-ray CT and the additives of each OD tablet. The present results demonstrated that the water penetration rates of OD tablets, as measured by dynamic contact angle, may accurately detect differences in disintegration times in the human oral cavity.


Assuntos
Química Farmacêutica/métodos , Comprimidos , Termografia , Administração Oral , Fenômenos Químicos , Dureza , Solubilidade , Água
9.
Chimia (Aarau) ; 74(7): 549-560, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32778207

RESUMO

This paper summarizes a personal perspective on key learnings from projects the author was involved in over the last 20 years. For example, the discovery of macitentan, the most successful molecule to date from this personal collection, marketed by J&J for the treatment of pulmonary arterial hypertension (PAH). [1] Then the discovery of ACT-462206, a dual orexin receptor antagonist for the treatment of insomnia disorder with a serendipitously short story from the screening hit to the drug [2] followed by the identification of daridorexant, another dual orexin receptor antagonist. Daridorexant successfully passed first pivotal phase 3 clinical trial in April 2020 for the treatment of insomnia disorder [3] ("Good things come to those who wait"). Finally, ACT-451840, an antimalarial drug with a novel mechanism of action, identified in the perfect collaboration between academia and industry. The compound is in phase 2 clinical development. [4] In addition, the importance of the screening compound collection is briefly discussed, as a key asset for drug discovery. The measures Idorsia implemented to obtain valuable hits from high-throughput screening (HTS) campaigns are elaborated. [5] Drug discovery is a multi-disciplinary business with unlimited exciting challenges asking for excessive optimism when tackling them in a playful manner.


Assuntos
Química Farmacêutica , Descoberta de Drogas , Humanos , Distúrbios do Início e da Manutenção do Sono
10.
AAPS PharmSciTech ; 21(5): 182, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32613377

RESUMO

The aim of the present investigation was to formulate self-microemulsifying drug delivery system (SMEDDS) tablets to enhance the oral bioavailability of tizanidine hydrochloride. SMEDDS was prepared by using Capmul G as the oil phase, Tween 20 as the surfactant, and propylene glycol as the co-surfactant. The optimized formulation was characterized by dilution test, % transmittance, thermodynamic stability, dye solubility, assay, globule size, zeta potential, and TEM. A dye solubility test confirmed the formation of o/w microemulsion. Optimized formulation of SMEDDS had a drug content of 98 ± 0.75% (3.2± 0.3 mg) and droplet size of 96.61 ± 2.3 nm. Dilution and centrifugation tests indicated the physical stability of the formulation. The optimized SMEDDS was mixed with Neusilin as adsorbent, microcrystalline cellulose as diluent, and magnesium stearate as flow promoter, and compressed into tablets. The prepared tablets passed the tests of weight variation, hardness, friability, and assay. In vitro dissolution test indicated sustained release of tizanidine hydrochloride from the SMEDDS tablet for a period of 4 h. In vivo pharmacokinetic studies performed on male New Zealand rabbits showed a 4.61-fold increase in bioavailability compared with the marketed formulation. Thus, the developed SMEDDS tablet proved to be capable of enhancing oral bioavailability of tizanidine hydrochloride. Graphical abstract.


Assuntos
Clonidina/análogos & derivados , Emulsões/química , Administração Oral , Animais , Disponibilidade Biológica , Química Farmacêutica , Clonidina/administração & dosagem , Clonidina/química , Clonidina/farmacocinética , Técnicas In Vitro , Masculino , Coelhos , Solubilidade , Comprimidos
11.
Nat Commun ; 11(1): 3628, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686668

RESUMO

Triazolopyridinone derivatives are of high value in both medicinal and material chemistry. However, the chiral or hindered triazolopyridinone derivatives remain an underexplored area of chemical space because they are difficult to prepare via conventional methods. Here we report an electrochemical rearrangement for the efficient synthesis of otherwise inaccessible triazolopyridinones with diverse alkyl carboxylic acids as starting materials. This enables the efficient preparation of more than 60 functionalized triazolopyridinones under mild conditions in a sustainable manner. This method is evaluated for the late stage modification of bioactive natural products, amino acids and pharmaceuticals, and it is further applied to the decagram scale preparation of enantiopure triazolopyridinones. The control experiments support a mechanism involving an oxidative cyclization and 1,2-carbon migration. This facile and scalable rearrangement demonstrates the power of electrochemical synthesis to access otherwise-inaccessible triazolopyridinones and may find wide application in organic, material and medicinal chemistry.


Assuntos
Purinas/síntese química , Química Farmacêutica/métodos , Eletroquímica/métodos , Purinas/análise
12.
AAPS PharmSciTech ; 21(5): 170, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32529303

RESUMO

Felodipine (FLD), a dihydropyridine calcium channel blocker with excellent antihypertensive effect, is poorly soluble and undergoes extensive hepatic metabolism, which lead to poor oral bioavailability (about 15%) and limit its clinic application. The goal of this study was to develop solid lipid nanoparticles (SLNs) loading FLD to improve the oral bioavailability. The FLD loaded solid lipid nanoparticles (FLD-SLNs) were prepared by the effervescent dispersion technique developed by our laboratory, which might have some advantages over traditional methods. The FLD-SLNs showed desired particle characteristics with particle size (198.15 ± 1.82 nm), poly dispersity index (0.26 ± 0.02), zeta-potential (- 25.53 ± 0.60 mV), entrapment efficiency (95.65 ± 0.70%), drug loading (2.33 ± 0.10%), and a spherical appearance. Pharmacokinetic results showed that the FLD-SLNs presented 3.17-fold increase in area under the curve (AUC(0-t)) compared with free FLD after oral administration in beagle dogs, which indicated that SLNs prepared using the effervescent dispersion technique can improve the bioavailability of lipophilic drugs like felodipine by enhancement of absorption and reduction first-pass metabolism.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacocinética , Química Farmacêutica/métodos , Felodipino/farmacocinética , Nanopartículas/metabolismo , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/síntese química , Estudos Cross-Over , Cães , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Felodipino/administração & dosagem , Felodipino/síntese química , Lipídeos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Tamanho da Partícula , Distribuição Aleatória
14.
Yakugaku Zasshi ; 140(6): 773-776, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32475926

RESUMO

The rapid increase in the use of ethical generic pharmaceutical formulations in Japan emphasizes the importance of measures to ensure the quality of pharmaceutical distribution. This short review discusses the contributions of the Japanese Pharmacopoeia (JP) to pharmaceutical quality control. Numerous monographs have defined specifications and tests for multiple active pharmaceutical ingredients and excipients. Standardized methods of performing general tests and reference standards allow efficient, reliable evaluation of pharmaceutical quality during development processes and commercial manufacturing. Some new methods of characterizing the structure and performance of nonbiological complex drugs have been included in recent editions. An introduction to general tests and general information regarding the control of impurities in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines should significantly reduce the safety risks of pharmaceuticals.


Assuntos
Medicamentos Genéricos , Farmacopeias como Assunto , Controle de Qualidade , Química Farmacêutica/métodos , Medicamentos Genéricos/análise , Medicamentos Genéricos/normas , Excipientes/análise , Japão
15.
Yakugaku Zasshi ; 140(6): 777-782, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32475927

RESUMO

Biologics listed in the Japanese Pharmacopoeia (JP) include drugs in which the active pharmaceutical ingredient is a peptide, protein, or polysaccharide. Biologics were previously manufactured by purification from biological sources, however, most recently developed products are manufactured using biotechnology such as genetic recombination and cell culture technologies. The JP provides useful information to ensure the quality of such products in the form of monographs, general test, and general information. A recent topic related to biologics is the adoption of general test 〈6.17〉 "Insoluble Particulate Matter Test for Protein Injections". Test 〈6.17〉 enables the determination of insoluble particulate matter using the light obscuration method with smaller sample volumes and indicates points to consider in handling protein samples. In addition, the draft general information "Basic Concept of Quality Assurance of Biotechnology Products (Biopharmaceuticals)" has been released for public consultation and will be listed in the 18th edition of the JP. In this review, the contents of JP monographs, general chapters, and general information on biologics are introduced, and future perspectives on the role of the JP for ensuring the quality of biologics are discussed.


Assuntos
Produtos Biológicos , Farmacopeias como Assunto , Controle de Qualidade , Produtos Biológicos/análise , Biotecnologia , Química Farmacêutica/métodos , Japão
16.
PLoS One ; 15(6): e0235076, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584876

RESUMO

Due to the complexity and fragility of biological drug products, several challenges exist in their formulation development. Excipients are added to increase product stability, maintain tonicity, and facilitate drug delivery. The potential implications of these additive substances merit clinical consideration. We assessed the safety risk of excipients on the basis of their type and variability through an assessment framework, which quantifies excipient complexity in 230 biological formulations, and identifies excipient-related adverse events through published case reports. A biologic on average contained 4.45 excipients, half of that found in oral medications. The frequency distribution was heavily skewed towards the most commonly occurring excipients: water (40.4%), sodium chloride (38.3%), polysorbate 80 (28.7%), sucrose (24.4%), and mannitol (20.9%), with 44.4% of formulations not listing the concentration of the most commonly occurring inactive ingredients. A literature search revealed only 17 case reports of excipient-related adverse events, suggesting the need for more clarity for clinicians on the safety of chemical additives. These cases included injection site reactions, anaphylaxis, hyperglycemia, and acute renal failure. With the expansion of the biopharmaceutical market, it is important to consider the safety data of biologic excipients, so that therapy can be tailored appropriately for a specific patient.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Anafilaxia/induzido quimicamente , Excipientes/efeitos adversos , Hiperglicemia/induzido quimicamente , Química Farmacêutica , Excipientes/uso terapêutico , Humanos , Manitol/efeitos adversos , Manitol/uso terapêutico , Polissorbatos/efeitos adversos , Polissorbatos/uso terapêutico , Cloreto de Sódio/efeitos adversos , Cloreto de Sódio/uso terapêutico , Sacarose/efeitos adversos , Sacarose/uso terapêutico , Água/efeitos adversos
17.
Nat Commun ; 11(1): 2890, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32513962

RESUMO

Employment of sulfoxides as electrophiles in cross-coupling reactions remains underexplored. Herein we report a transition-metal-free cross-coupling strategy utilizing aryl(heteroaryl) methyl sulfoxides and alcohols to afford alkyl aryl(heteroaryl) ethers. Two drug molecules were successfully prepared using this protocol as a key step, emphasizing its potential utility in medicinal chemistry. A DFT computational study suggests that the reaction proceeds via initial addition of the alkoxide to the sulfoxide. This adduct facilitates further intramolecular addition of the alkoxide to the aromatic ring wherein charge on the aromatic system is stabilized by the nearby potassium cation. Rate-determining fragmentation then delivers methyl sulfenate and the aryl or heteroaryl ether. This study establishes the feasibility of nucleophilic addition to an appended sulfoxide as a means to form a bond to aryl(heteroaryl) systems and this modality is expected to find use with many other electrophiles and nucleophiles leading to new cross-coupling processes.


Assuntos
Álcoois/química , Éteres/química , Hidrocarbonetos Policíclicos Aromáticos/química , Sulfóxidos/química , Elementos de Transição/química , Carbono/química , Catálise , Química Farmacêutica/métodos , Compostos Heterocíclicos/química , Hidrocarbonetos Aromáticos/química , Metais/química , Modelos Químicos , Estrutura Molecular , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Enxofre/química
18.
PLoS One ; 15(6): e0232603, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530964

RESUMO

Drug discovery with phosphorothioate oligonucleotides is an area of intensive research. In this study we have controlled the stereochemistry of the phosphorothioate backbone of LNA oligonucleotides to investigate the differences in safety profile, target mRNA knock down, and cellular uptake in vitro. The study reveals that controlling only four stereocenters in an isomeric phosphorothioate mixture can improve the therapeutic index significantly by improving safety without compromising activity.


Assuntos
Oligonucleotídeos/química , Animais , Sobrevivência Celular , Células Cultivadas , Química Farmacêutica , Células Epiteliais/metabolismo , Hepatócitos/metabolismo , Humanos , Túbulos Renais/metabolismo , Camundongos , Estrutura Molecular , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/toxicidade , Oligonucleotídeos Fosforotioatos/química , RNA Mensageiro/antagonistas & inibidores
19.
AAPS PharmSciTech ; 21(5): 176, 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32572701

RESUMO

This paper presents a rational workflow for developing enabling formulations, such as amorphous solid dispersions, via hot-melt extrusion in less than a year. First, our approach to an integrated product and process development framework is described, including state-of-the-art theoretical concepts, modeling, and experimental characterization described in the literature and developed by us. Next, lab-scale extruder setups are designed (processing conditions and screw design) based on a rational, model-based framework that takes into account the thermal load required, the mixing capabilities, and the thermo-mechanical degradation. The predicted optimal process setup can be validated quickly in the pilot plant. Lastly, a transfer of the process to any GMP-certified manufacturing site can be performed in silico for any extruder based on our validated computational framework. In summary, the proposed workflow massively reduces the risk in product and process development and shortens the drug-to-market time for enabling formulations.


Assuntos
Química Farmacêutica , Temperatura Alta , Composição de Medicamentos , Modelos Químicos , Solubilidade
20.
AAPS PharmSciTech ; 21(5): 161, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488427

RESUMO

Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [µg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [µg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [µg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80-125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations.


Assuntos
Desenvolvimento de Medicamentos , Inibidores de Captação de Serotonina/administração & dosagem , Trazodona/administração & dosagem , Adulto , Área Sob a Curva , Química Farmacêutica , Estudos Cross-Over , Preparações de Ação Retardada/farmacocinética , Feminino , Humanos , Masculino , Inibidores de Captação de Serotonina/farmacocinética , Solubilidade , Equivalência Terapêutica , Trazodona/farmacocinética
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