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1.
Curr Drug Discov Technol ; 21(1): e101023222025, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38629170

RESUMO

Recently, it has been observed that newly developed drugs are lipophilic and have low aqueous solubility issues, which results in a lower dissolution rate and bioavailability of the drugs. To overcome these issues, the liquisolid technique, an innovative and advanced approach, comes into play. This technique involves the conversion of the drug into liquid form by dissolving it in non-volatile solvent and then converting the liquid medication into dry, free-flowing, and compressible form by the addition of carrier and coating material. It offers advantages like low cost of production, easy method of preparation, and compactable with thermo labile and hygroscopic drugs. It has been widely applied for BCS II drugs to enhance dissolution profile. Improving bioavailability, providing sustained release, minimizing pH influence on drug dissolution, and improving drug photostability are some of the other promising applications of this technology. This review article presents an overview of the liquisolid technique and its applications in formulation development.


Assuntos
Biofarmácia , Química Farmacêutica , Química Farmacêutica/métodos , Solubilidade , Liberação Controlada de Fármacos , Água , Comprimidos
2.
Chem Pharm Bull (Tokyo) ; 72(4): 374-380, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38599850

RESUMO

Tablets are the most commonly used dosage form in the pharmaceutical industry, and their properties such as disintegration, dissolution, and portability are influenced by their strength. However, in industry, the mixing fraction of powders to obtain a tablet compact with sufficient strength is determined based on empirical rules. Therefore, a method for predicting tablet strength based on the properties of a single material is required. The objective of this study was to quantitatively evaluate the relationship between the compression properties and tablet strength of powder mixtures. The compression properties of the powder mixtures with different plasticities were evaluated based on the force-displacement curves obtained from the powder compression tests. Heckel and compression energy analyses were performed to evaluate compression properties. During the compression energy analysis, the ratio of plastic deformation energy to elastic deformation energy (Ep/Ee) was assumed to be the plastic deformability of the powder. The quantitative relationship between the compression properties and tensile strength of the tablets was investigated. Based on the obtained relationship and the compression properties of a single material, a prediction equation was put forward for the compression properties of the powder mixture. Subsequently, a correlation equation for tablet strength was proposed by combining the values of K and Ep/Ee obtained from the Heckel and compression energy analyses, respectively. Finally, by substituting the compression properties of the single material and the mass fraction of the plastic material into the proposed equation, the tablet strength of the powder mixture with different plastic deformabilities was predicted.


Assuntos
Química Farmacêutica , Química Farmacêutica/métodos , Pós , Resistência à Tração , Comprimidos , Pressão , Composição de Medicamentos
3.
J Med Chem ; 67(7): 5168-5184, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38549449

RESUMO

Molecules with N-oxide functionalities are omnipresent in nature and play an important role in Medicinal Chemistry. They are synthetic or biosynthetic intermediates, prodrugs, drugs, or polymers for applications in drug development and surface engineering. Typically, the N-oxide group is critical for biomedical applications of these molecules. It may provide water solubility or decrease membrane permeability or immunogenicity. In other cases, the N-oxide has a special redox reactivity which is important for drug targeting and/or cytotoxicity. Many of the underlying mechanisms have only recently been discovered, and the number of applications of N-oxides in the healthcare field is rapidly growing. This Perspective article gives a short summary of the properties of N-oxides and their synthesis. It also provides a discussion of current applications of N-oxides in the biomedical field and explains the basic molecular mechanisms responsible for their biological activity.


Assuntos
Química Farmacêutica , Óxidos , Óxidos/química , Polímeros/química
4.
J Chem Inf Model ; 64(6): 1966-1974, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38437714

RESUMO

Chemical diversity is challenging to describe objectively. Despite this, various notions of chemical diversity are used throughout the medicinal chemistry optimization process in drug discovery. In this work, we show the usefulness of considering exploited vectors during different phases of the drug design process to provide a quantitative and objective description of chemical diversity. We have developed a concise and fast approach to enumerate and analyze the exploited vector patterns (EVPs) of molecular compound series, which can then be used in archetypal compound selection tasks, from hit matter identification to hit expansion and lead optimization. We first show that EVPs can be used to assess the progressibility of compounds in a fragment library design exercise. By considering EVPs, we then show how a set of compounds can be prioritized for hit expansion using EVP-based, customizable diversity sampling approaches, reducing the time taken and mitigating human biases. We also show that EVPs are a useful tool to analyze SAR data, offering the chance to uncover correlations between different vectors without predetermining the molecular scaffold structures. The codes used to perform these tasks are presented as easy-to-use Jupyter notebooks, which can be readily adapted for further related tasks.


Assuntos
Quimioinformática , Descoberta de Drogas , Humanos , Desenho de Fármacos , Estrutura Molecular , Química Farmacêutica
5.
Int J Pharm ; 655: 123993, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38484862

RESUMO

Amoxicillin, doxycycline, and clindamycin are among the commonly used antibiotics to treat bacterial infections. However, dosage forms of antibiotics for pediatric patients may not be as readily available as the formulations for adult patients. As such, it is anticipated that during a public health emergency, special instruction may need to be provided on home preparation and administration procedures to dose pediatric patients using available stockpiles of oral tablet and capsule dosage forms. Mixing crushed tablets or capsule contents with soft- or liquid- foods is one of the most common home preparation procedures. To gain knowledge for safe and effective use of prepared drug product instead of the intended intact dosage form, the impact of manipulation of the dosage form was studied. Capsule opening, capsule content assay and uniformity, dissolution, homogeneity, and stability studies of drug mixed with various liquid and soft foods were carried out using intact capsules of amoxicillin, doxycycline, and clindamycin. Higher recovery of capsule contents was achieved when using hands or knives to open capsules compared to using scissors. The capsules of all three antibiotic products contained the labeled amount of active pharmaceutical ingredients (API). The peanut butter-drug mixtures failed both United States Pharmacopeia (USP) assay and dissolution criteria because the peanut butter significantly affected the solubility of the drugs, and hence it was omitted from further study. All drug-food mixtures of the three antibiotic products and 15 selected foods exhibited fast dissolution (e.g., >80 % in 60 min) in the tested medium, except for the amoxicillin-chocolate pudding mixture. Three household containers (cups, plates, and bowls) and four mixing times (0.5 min, 1 min, 2 min, and 5 min) were found to be suitable for preparation of homogeneous mixtures of the antibiotics and foods. For practical purposes, 1 to 2 min mixing time is sufficient to produce homogeneous mixtures. The results of this study provided product quality data on the interactions between the antibiotics and the foods and can potentially support future development of home preparation instructions of antibiotics for pediatric patients or patients with swallowing difficulties.


Assuntos
Antibacterianos , Preferências Alimentares , Adulto , Humanos , Criança , Clindamicina , Doxiciclina , Química Farmacêutica/métodos , Comprimidos , Amoxicilina , Solubilidade , Cápsulas
6.
Drug Res (Stuttg) ; 74(4): 180-186, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38508227

RESUMO

Four natural sweeteners (sucrose, xylitol, fructose, and isomalt) were selected to examine the influence of their qualities and amounts on the characteristics of orodispersible films. Sodium carboxymethylcellulose (2% w/w) was utilized as the film-forming polymer and 1% w/w glycerol as a plasticizer. Films were produced through the solvent casting method, rendering them suitable for convenient application in community or hospital pharmacy settings. The physicochemical and optical properties of the films were analyzed, and Fourier-transform infrared analysis was carried out. All films exhibited acceptable disintegration time, uniformity of mass, thickness, and optical characteristics, with significant dependence (p<0.05) on both sweetener type and quantity. Disintegration time varied based on the employed method, as well as the characteristics and amount of sweetener. Additionally, all films maintained pH values within the oral cavity range, suggesting no potential irritancy upon administration. Fourier-transform infrared analysis confirmed the formation of the film and demonstrated compatibility between its components.


Assuntos
Química Farmacêutica , Edulcorantes , Química Farmacêutica/métodos , Solubilidade , Administração Oral , Solventes/química , Excipientes/química
7.
Int J Pharm ; 655: 124001, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38492896

RESUMO

Monitoring the particle size distribution (PSD) is crucial for controlling product quality during fluidized bed granulation. This paper proposed a rapid analytical method that quantifies the D10, D50, and D90 values using a Convolutional Block Attention Module-Convolutional Neural Network (CBAM-CNN) framework tailored for deep learning with near-infrared (NIR) spectroscopy. This innovative framework, which fuses CBAM with CNN, excels at extracting intricate features while prioritizing crucial ones, thereby facilitating the creation of a robust multi-output regression model. To expand the training dataset, we incorporated the C-Mixup algorithm, ensuring that the deep learning model was trained comprehensively. Additionally, the Bayesian optimization algorithm was introduced to optimize the hyperparameters, improving the prediction performance of the deep learning model. Compared with the commonly used Partial Least Squares (PLS), Support Vector Machine (SVM), and Artificial Neural Network (ANN) models, the CBAM-CNN model yielded higher prediction accuracy. Furthermore, the CBAM-CNN model avoided spectral preprocessing, preserved the spectral information to the maximum extent, and returned multiple predicted values at one time without degrading the prediction accuracy. Therefore, the CBAM-CNN model showed better prediction performance and modeling convenience for analyzing PSD values in fluidized bed granulation.


Assuntos
Química Farmacêutica , Espectroscopia de Luz Próxima ao Infravermelho , Química Farmacêutica/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Tamanho da Partícula , Teorema de Bayes , Redes Neurais de Computação
8.
Int J Pharm ; 655: 124014, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38513817

RESUMO

Despite extensive research in spray drying of biopharmaceuticals, identifying the optimal formulation composition and process conditions to minimize the various stresses a biopharmaceutical undergoes during this drying process. The current study extends previous research on investigating how spray drying processing and solution composition can affect the stability of monoclonal antibodies (mAbs) in reconstituted solutions for subcutaneous injections. The decoupling process stresses on a model mAb (mAb-A) compared to the effect of coupled spray-drying stresses revealed that excipients and protein concentration had a more pronounced effect on stabilizing mAb-A against shear and thermal/dehydration stresses than spray drying operating conditions. These results prompted the continuation of the study, with the aim to investigate in greater depth the effect of mAb-A concentration in the formulation designated to spray-drying and then the effect of type and the concentration of individual excipients (sugars, amino acids and surfactants). The outcomes of this investigation suggest that a general increase in the concentration of excipients, particularly surfactants, correlates with a reduction in aggregation and turbidity observed in the reconstituted spray-dried mAb-A powders. These results, contribute to the identification of a suitable composition for a spray-dried mAb-A powder that ensures robust stability of the protein in reconstituted solutions intended for subcutaneous injection. This valuable insight has important implications for advancing the development of pharmaceutical formulations with enhanced stability and efficacy.


Assuntos
Química Farmacêutica , Excipientes , Excipientes/química , Química Farmacêutica/métodos , Secagem por Atomização , Anticorpos Monoclonais/química , Injeções Subcutâneas , Tensoativos , Pós/química , Liofilização
9.
Int J Pharm ; 655: 123925, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38518870

RESUMO

Spray drying is increasingly being applied to process biopharmaceuticals, particularly monoclonal antibodies (mAbs). However, due to their protein nature, mAbs are susceptible to degradation when subjected to various stresses during a drying process. Despite extensive research in this domain, identifying the appropriate formulation composition and spray drying conditions remains a complex challenge, requiring further studies to enhance the understanding on how process and formulation parameters impact mAb stability in reconstituted solutions. This research aims to explore spray drying as technique for producing pharmaceutical mAbs-based powders intended for reconstitution and subcutaneous injection. In the initial phase of this study, using a model mAb (mAb-A), the influence of dissociated and coupled process stresses on protein stability after solution reconstitution was investigated. The findings revealed a detrimental interplay of mechanical, interfacial, and thermal/dehydration stresses on mAb-A stability, notably characterized by an increase in protein aggregation. Subsequently, in a second phase, the study delved into the impact of spray drying processing conditions, the level of excipients, and protein concentration on mAb-A aggregation in reconstituted solutions. The obtained results highlighted the critical role of formulation composition as a parameter deserving further study, specifically concerning the selection of type and concentration of stabilizers to be added in the liquid mAb-A solution to be dried.


Assuntos
Química Farmacêutica , Secagem por Atomização , Química Farmacêutica/métodos , Anticorpos Monoclonais , Dessecação/métodos , Injeções Subcutâneas , Pós , Liofilização
12.
J Med Chem ; 67(6): 4251-4258, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38456628

RESUMO

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.


Assuntos
Química Farmacêutica , Poder Psicológico , Humanos , Feminino
13.
J Med Chem ; 67(6): 4322-4345, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38457829

RESUMO

Photochemistry has emerged as a transformative force in organic chemistry, significantly expanding the chemical space accessible for medicinal chemistry. Light-induced reactions enable the efficient synthesis of intricate organic structures and have found applications throughout the different stages of the drug discovery and development processes. Moreover, photochemical techniques provide innovative solutions in chemical biology, allowing precise spatiotemporal drug activation and targeted delivery. In this Perspective, we highlight the already numerous remarkable applications and the even more promising future of photochemistry in medicinal chemistry and chemical biology.


Assuntos
Química Farmacêutica , Descoberta de Drogas , Fotoquímica , Química Farmacêutica/métodos , Descoberta de Drogas/métodos , Biologia
14.
Drug Dev Res ; 85(1): e22154, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38349259

RESUMO

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have significantly impacted the HIV-1 wild-type due to their high specificity and superior potency. As well as different combinations of NNRTIs have been used on clinically approved combining highly active antiretroviral therapy (HAART) to resist the growth of HIV-1 and decrease the mortality rate of HIV/AIDS. Although the feeble strength against the drug-resistant mutant strains and the long-term damaging effects have been reducing the effectiveness of HAART, it could be a crucial challenge to develop novel Anti-HIV leads with a vital mode of action and the least side effects. The extensive chemical reactivity and the diverse chemotherapeutic applications of the 1,3,5-triazine have provided a wide scope of research in medicinal chemistry via a structural modification. In this review, we focused on the Anti-HIV profile of the tri-substituted s-triazine derivatives with structure-based features and also discussed the active mode of action to evaluate the significant findings. The tri-substituted 1,3,5-triazine derivatives have been found more promising to inhibit the growth of the drug-sensitive and drug-resistant variants of HIV-1, especially HIV-1 wild-type, HIV-1 K103N/Y181C, and HIV-1 Tyr181Cys. It has been observed that these derivatives have interacted with the enzyme protein residues via a significant π $\pi $ - π $\pi $ interaction and hydrogen bonding to resist the proliferation of the viral genomes. Further, the SAR and the active binding modes are critically described and highlight the role of structural variations with functional groups along with the binding affinity of targeted enzymes, which may be beneficial for rational drug discovery to develop highly dynamic Anti-HIV agents.


Assuntos
HIV-1 , Triazinas , Triazinas/farmacologia , Triazinas/uso terapêutico , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Química Farmacêutica , Descoberta de Drogas
15.
Eur J Pharm Biopharm ; 196: 114201, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38309538

RESUMO

Cocrystal engineering, which involves the self-assembly of two or more components into a solid-state supramolecular structure through non-covalent interactions, has emerged as a promising approach to tailor the physicochemical properties of active pharmaceutical ingredient (API). Efficient coformer screening for cocrystal remains a challenge. Herein, a prediction strategy based on machine learning algorithms was employed to predict cocrystal formation and seven reliable models with accuracy over 0.890 were successfully constructed. Imatinib was selected as the model drug and the models established were applied to screen 31 potential coformers. Experimental verification results indicated RF-8 is the optimal model among seven models with an accuracy of 0.839. When the seven models were combined for coformer screening of Imatinib, the combinational model achieved an accuracy of 0.903, and eight new solid forms were observed and characterized. Benefiting from intermolecular interactions, the obtained multicomponent crystals displayed enhanced physicochemical properties. Dissolution and solubility experiments showed the prepared multicomponent crystals had higher cumulative dissolution rate and remarkably improved the solubility of imatinib, and IM-MC exhibited comparable solubility to Imatinib mesylate α form. Stability test and cytotoxicity results showed that multicomponent crystals exhibited excellent stability and the drug-drug cocrystal IM-5F exhibited higher cytotoxicity than pure API.


Assuntos
Química Farmacêutica , Mesilato de Imatinib , Cristalização , Química Farmacêutica/métodos , Solubilidade
16.
J Chem Inf Model ; 64(4): 1245-1250, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38311838

RESUMO

Central ring systems are the most important part of bioactive molecules. They determine molecule shape, keep substituents in their proper positions, and also influence global molecular properties. In the present study, a database of 4 million medicinal chemistry-relevant ring systems has been created, not by crude random enumeration but by applying a set of rules derived by analyzing rings present in bioactive molecules. The aromatic properties and tautomer stability of generated rings have also been considered to ensure that the rings in the database are stable and chemically reasonable. 99.2% of these rings are novel and not included in molecules in the ChEMBL or PubChem databases. This large database of ring systems has been created with the goal to provide support for bioisosteric design and scaffold hopping as well as to be used in generative chemistry applications. The complete set of created rings is available for download in the SMILES format from https://peter-ertl.com/molecular/data/.


Assuntos
Química Farmacêutica , Bases de Dados Factuais
17.
Molecules ; 29(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38338433

RESUMO

Natural bioactive compounds are valuable resources for drug discovery due to their diverse and unique structures. However, these compounds often lack optimal drug-like properties. Therefore, structural optimization is a crucial step in the drug development process. By employing medicinal chemistry principles, targeted molecular operations can be applied to natural products while considering their size and complexity. Various strategies, including structural fragmentation, elimination of redundant atoms or groups, and exploration of structure-activity relationships, are utilized. Furthermore, improvements in physicochemical properties, chemical and metabolic stability, biophysical properties, and pharmacokinetic properties are sought after. This article provides a concise analysis of the process of modifying a few marketed drugs as illustrative examples.


Assuntos
Produtos Biológicos , Desenho de Fármacos , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Química Farmacêutica , Descoberta de Drogas , Relação Estrutura-Atividade
19.
Eur J Pharm Biopharm ; 197: 114220, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38360119

RESUMO

Over the last 10 years there is an increasing need for the design of personalised medicines at the point of care (PoC) that meet the specific needs of individual patients. A plethora of technologies has been introduced for making affordable personalised pharmaceutical products, which however, do not address manufacturing and regulatory challenges. Here we introduce a novel ultra-compact tablet press which was used for the design and compression of rosuvastatin-aspirin and amiloride-lysonipril bilayer tablets respectively. By applying precision dosing, it was feasible to manufacture tablets of different dose strengths and control features such as hardness, friability and disintegration times. The compaction of on-demand personalised multidrug pills that meet quality standards could revolutionised the treatment of patients at the point of care.


Assuntos
Química Farmacêutica , Sistemas Automatizados de Assistência Junto ao Leito , Humanos , Comprimidos , Tecnologia Farmacêutica , Fenômenos Físicos , Composição de Medicamentos
20.
Molecules ; 29(4)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38398566

RESUMO

Pain is associated with many health problems and a reduced quality of life and has been a common reason for seeking medical attention. Several therapeutics are available on the market, although side effects, physical dependence, and abuse limit their use. As the process of pain transmission and modulation is regulated by different peripheral and central mechanisms and neurotransmitters, medicinal chemistry continues to study novel ligands and innovative approaches. Among them, natural products are known to be a rich source of lead compounds for drug discovery due to their chemical structural variety and different analgesic mechanisms. Numerous studies suggested that some chemicals from medicinal plants could be alternative options for pain relief and management. Previously, we conducted a literature search aimed at identifying natural products interacting either directly or indirectly with opioid receptors. In this review, instead, we have made an excursus including active ingredients derived from plants whose mechanism of action appears from the literature to be other than the modulation of the opioid system. These substances could, either by themselves or through synthetic and/or semi-synthetic derivatives, be investigated in order to improve their pharmacokinetic characteristics and could represent a valid alternative to the opioid approach to pain therapy. They could also be the basis for the study of new mechanisms of action in the approach to this complex and disabling pathology.


Assuntos
Produtos Biológicos , Plantas Medicinais , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Química Farmacêutica , Qualidade de Vida , Dor/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Desenho de Fármacos , Produtos Biológicos/uso terapêutico
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