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1.
ACS Appl Mater Interfaces ; 13(33): 38969-38978, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34399054

RESUMO

Controlling the microstructure of materials by means of phase separation is a versatile tool for optimizing material properties. Phase separation has been exploited to fabricate intricate microstructures in many fields including cell biology, tissue engineering, optics, and electronics. The aim of this study was to use phase separation to tailor the spatial location of drugs and thereby generate release profiles of drug payload over periods ranging from 1 week to months by exploiting different mechanisms: polymer degradation, polymer diluent dissolution, and control of microstructure. To achieve this, we used drop-on-demand inkjet three-dimensional (3D) printing. We predicted the microstructure resulting from phase separation using high-throughput screening combined with a model based on the Flory-Huggins interaction parameter and were able to show that drug release from 3D-printed objects can be predicted from observations based on single drops of mixtures. We demonstrated for the first time that inkjet 3D printing yields controllable phase separation using picoliter droplets of blended photoreactive oligomers/monomers. This new understanding gives us hierarchical compositional control, from droplet to device, allowing release to be "dialled up" without manipulation of device geometry. We exemplify this approach by fabricating a biodegradable, long-term, multiactive drug delivery subdermal implant ("polyimplant") for combination therapy and personalized treatment of coronary heart disease. This is an important advance for implants that need to be delivered by cannula, where the shape is highly constrained and thus the usual geometrical freedoms associated with 3D printing cannot be easily exploited, which brings a hitherto unseen level of understanding to emergent material properties of 3D printing.


Assuntos
Anti-Hipertensivos/química , Doença das Coronárias/tratamento farmacológico , Portadores de Fármacos/química , Excipientes/química , Indóis/química , Polímeros/química , Anti-Hipertensivos/farmacologia , Dioxanos/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Indóis/farmacologia , Metacrilatos/química , Transição de Fase , Poliésteres/química , Impressão Tridimensional , Pirrolidinonas/química , Relação Estrutura-Atividade
2.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200887

RESUMO

Royal jelly is a natural substance produced by worker bees that possesses a variety of biological activities, including antioxidant, anti-inflammatory, antibacterial, and protective. Although fresh royal jelly is kept at low temperatures, to increase its stability, it needs to be incorporated into pharmaceutical formulations, such as in situ gels. The aim of this study was to formulate in situ ocular gels containing Lithuanian royal jelly for topical corneal use in order to increase the retention time of the formulation on the ocular surface and bioavailability. Gels were evaluated for physicochemical characteristics (pH, rheological properties, refractive index) and in vitro drug release measuring the amount of 10-hydroxy-2-decenoic acid (10-HDA). An ocular irritation test and cell viability tests were performed using the SIRC (Statens Seruminstitut Rabbit Cornea) cell culture line. Results indicated that all the in situ gels were within an acceptable pH and refractive index range close to corneal properties. Rheology studies have shown that the gelation temperature varies between 25 and 32 °C, depending on the amount of poloxamers. The release studies have shown that the release of 10-HDA from in situ gels is more sustained than royal jelly suspension. All gel formulations were non-irritant according to the short-time exposure test (STE) using the SIRC cell culture line, and long-term cell viability studies indicated that the formulations used in small concentrations did not induce cell death. Prepared in situ gels containing royal jelly have potential for ocular drug delivery, and they may improve the bioavailability, stability of royal jelly, and formation of non-irritant ocular formulations.


Assuntos
Córnea/efeitos dos fármacos , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Géis/química , Géis/farmacologia , Animais , Abelhas/metabolismo , Disponibilidade Biológica , Produtos Biológicos/química , Produtos Biológicos/farmacocinética , Produtos Biológicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica/métodos , Córnea/metabolismo , Ácidos Decanoicos/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Excipientes/química , Géis/farmacocinética , Poloxâmero/química , Coelhos , Reologia , Temperatura
3.
Proc Natl Acad Sci U S A ; 118(29)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34292870

RESUMO

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2), presents an urgent health crisis. More recently, an increasing number of mutated strains of SARS-CoV-2 have been identified globally. Such mutations, especially those on the spike glycoprotein to render its higher binding affinity to human angiotensin-converting enzyme II (hACE2) receptors, not only resulted in higher transmission of SARS-CoV-2 but also raised serious concerns regarding the efficacies of vaccines against mutated viruses. Since ACE2 is the virus-binding protein on human cells regardless of viral mutations, we design hACE2-containing nanocatchers (NCs) as the competitor with host cells for virus binding to protect cells from SARS-CoV-2 infection. The hACE2-containing NCs, derived from the cellular membrane of genetically engineered cells stably expressing hACE2, exhibited excellent neutralization ability against pseudoviruses of both wild-type SARS-CoV-2 and the D614G variant. To prevent SARS-CoV-2 infections in the lung, the most vulnerable organ for COVID-19, we develop an inhalable formulation by mixing hACE2-containing NCs with mucoadhesive excipient hyaluronic acid, the latter of which could significantly prolong the retention of NCs in the lung after inhalation. Excitingly, inhalation of our formulation could lead to potent pseudovirus inhibition ability in hACE2-expressing mouse model, without imposing any appreciable side effects. Importantly, our inhalable hACE2-containing NCs in the lyophilized formulation would allow long-term storage, facilitating their future clinical use. Thus, this work may provide an alternative tactic to inhibit SARS-CoV-2 infections even with different mutations, exhibiting great potential for treatment of the ongoing COVID-19 epidemic.


Assuntos
COVID-19/prevenção & controle , Nanoestruturas/administração & dosagem , SARS-CoV-2/efeitos dos fármacos , Adesivos/administração & dosagem , Adesivos/química , Adesivos/farmacocinética , Administração por Inalação , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Crioprotetores/química , Armazenamento de Medicamentos , Células Epiteliais/metabolismo , Excipientes/administração & dosagem , Excipientes/química , Excipientes/farmacocinética , Células HEK293 , Humanos , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Ácido Hialurônico/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Nanoestruturas/química , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Ligação Viral/efeitos dos fármacos
4.
AAPS PharmSciTech ; 22(5): 201, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34231193

RESUMO

Particle engineering of excipients, at sub-particulate level using co-processing, can provide high functionality excipients. NanoCrySP technology has been recently explored as a novel approach for the generation of nanocrystalline solid dispersion of poorly soluble drugs, using spray drying process. The purpose of the present study was to generate co-processed mannitol and sorbitol (SD-CSM) using NanoCrySP technology having similar composition to commercial co-processed excipient (Compressol® SM, CP). The characterization of excipients was performed to evaluate their various physicomechanical properties. The sub-micron crystallite size of sorbitol in the matrix of mannitol was determined using the Williamson-Hall equation and Halder-Wagner equation. The reduction in crystallite size of sorbitol and mannitol, lower melting point, and lower heat of fusion of SD-CSM could be responsible for excellent compactibility, better tabletability, and comparable compressibility with respect to CP. This was confirmed by the compressibility-tabletability-compactibility (CTC) profile and Heckel plot analysis. Overall, SD-CSM generated using NanoCrySP technology improved functionalities of excipients over CP and would be useful for direct compression application.


Assuntos
Composição de Medicamentos/métodos , Manitol/química , Nanotecnologia , Sorbitol/química , Força Compressiva , Cristalização , Excipientes/química , Tamanho da Partícula , Porosidade , Comprimidos/química , Resistência à Tração , Molhabilidade
5.
AAPS PharmSciTech ; 22(5): 185, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34143327

RESUMO

Respiratory diseases are among the leading causes of morbidity and mortality worldwide. Innovations in biochemical engineering and understanding of the pathophysiology of respiratory diseases resulted in the development of many therapeutic proteins and peptide drugs with high specificity and potency. Currently, protein and peptide drugs are mostly administered by injections due to their large molecular size, poor oral absorption, and labile physicochemical properties. However, parenteral administration has several limitations such as frequent dosing due to the short half-life of protein and peptide in blood, pain on administration, sterility requirement, and poor patient compliance. Among various noninvasive routes of administrations, the pulmonary route has received a great deal of attention and is a better alternative to deliver protein and peptide drugs for treating respiratory diseases and systemic diseases. Among the various aerosol dosage forms, dry powder inhaler (DPI) systems appear to be promising for inhalation delivery of proteins and peptides due to their improved stability in solid state. This review focuses on the development of DPI formulations of protein and peptide drugs using advanced spray drying. An overview of the challenges in maintaining protein stability during the drying process and stabilizing excipients used in spray drying of proteins and peptide drugs is discussed. Finally, a summary of spray-dried DPI formulations of protein and peptide drugs, their characterization, various DPI devices used to deliver protein and peptide drugs, and current clinical status are discussed.


Assuntos
Peptídeos Catiônicos Antimicrobianos/síntese química , Composição de Medicamentos/métodos , Inaladores de Pó Seco/métodos , Proteínas Recombinantes/síntese química , Secagem por Atomização , Administração por Inalação , Aerossóis/química , Animais , Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Dessecação/métodos , Excipientes/química , Humanos , Isoleucina/administração & dosagem , Isoleucina/síntese química , Manitol/administração & dosagem , Manitol/síntese química , Tamanho da Partícula , Peptídeos , Pós/química , Proteínas Recombinantes/administração & dosagem
6.
Molecules ; 26(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067434

RESUMO

The flexibility of dose and dosage forms makes 3D printing a very interesting tool for personalized medicine, with fused deposition modeling being the most promising and intensively developed method. In our research, we analyzed how various types of disintegrants and drug loading in poly(vinyl alcohol)-based filaments affect their mechanical properties and printability. We also assessed the effect of drug dosage and tablet spatial structure on the dissolution profiles. Given that the development of a method that allows the production of dosage forms with different properties from a single drug-loaded filament is desirable, we developed a method of printing ketoprofen tablets with different dose and dissolution profiles from a single feedstock filament. We optimized the filament preparation by hot-melt extrusion and characterized them. Then, we printed single, bi-, and tri-layer tablets varying with dose, infill density, internal structure, and composition. We analyzed the reproducibility of a spatial structure, phase, and degree of molecular order of ketoprofen in the tablets, and the dissolution profiles. We have printed tablets with immediate- and sustained-release characteristics using one drug-loaded filament, which demonstrates that a single filament can serve as a versatile source for the manufacturing of tablets exhibiting various release characteristics.


Assuntos
Química Farmacêutica/métodos , Cetoprofeno/química , Cetoprofeno/síntese química , Impressão Tridimensional , Comprimidos , Varredura Diferencial de Calorimetria , Preparações de Ação Retardada , Composição de Medicamentos/métodos , Desenho de Fármacos , Liberação Controlada de Fármacos , Elasticidade , Excipientes/química , Álcool de Polivinil , Medicina de Precisão , Reprodutibilidade dos Testes , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Difração de Raios X , Microtomografia por Raio-X
7.
Carbohydr Polym ; 262: 117868, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33838791

RESUMO

In this study, we have investigated the host-guest inclusion complexes between ß-cyclodextrin (ßCD), 2-hydroxypropyl-ß-cyclodextrin (2-HPßCD), and mono-6-tosyl-ß-cyclodextrin (TS-ßCD) excipients and two amino acids, such as L-arginine (L-Arg) and L-lysine (L-Lys). The formation of inclusion complexes was detected, and a comparative study was conducted at different pH, density, and viscosity. A physical mixture, comprising equal amount of amino acids was used to prepare the complex in a solid-state form. The experimental parameters, such as apparent molar volume, limiting apparent molar volume, partial molar volume were analyzed by measuring density at infinite dilution. The other quantities, such as dynamic viscosity, kinematic viscosity, relative viscosity, intrinsic viscosity, spatial viscosity, activation energy were determined for amino acid/ßCD complexes at various mass fractions of ßCDs and different temperatures. Finally, we found moderate (R2 > 0.5) and strong (R2 > 0.7) linear relationships (p-value < 0.0001) between the dynamic viscosity and the temperature: the temperature evaluation promotes the decrease in dynamic viscosity for amnio acid-ßCD (its derivatives) complexes. The results of this study emphasize important properties of analyzed complexes that can be utilized in the development of controlled drug delivery vectors.


Assuntos
Aminoácidos Básicos/química , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina/química , Arginina/química , Ciclodextrinas/química , Excipientes/química , Humanos , Lisina/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Temperatura , Viscosidade
8.
Carbohydr Polym ; 262: 117922, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33838801

RESUMO

Polysaccharide nanocrystals (PNs) are attractive pharmaceutical excipients due to their abundant surface hydroxyl groups, high surface charges, prominent mechanical properties, excellent fluidity, and good swelling properties. In this review, we summarize three kinds of PNs, including cellulose nanocrystals (CNCs), starch nanocrystals (SNCs), and chitin nanocrystals (ChNCs). We introduce the applications of PNs as stabilizers, adsorbents, film-forming materials, gel materials, disintegrants, and ointment matrices. We focus on the advantages of PNs to improve mechanical properties, thermal stability, therapeutic effect, biocompatibility, and release of active pharmaceutical ingredients. We discuss regulatory issues of PNs. We finally propose the challenges and future perspectives of PNs as pharmaceutical excipients.


Assuntos
Excipientes/química , Nanopartículas/química , Polissacarídeos/química , Adsorção , Materiais Biocompatíveis/química , Celulose/química , Celulose/farmacologia , Quitina/química , Quitina/farmacologia , Liberação Controlada de Fármacos , Excipientes/farmacologia , Humanos , Hidrogéis/química , Nanocompostos/química , Polissacarídeos/farmacologia , Solubilidade , Amido/química , Amido/farmacologia
9.
Chem Pharm Bull (Tokyo) ; 69(4): 374-382, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790082

RESUMO

This study examined the selection of small amounts of excipients capable of improving the compactability of ibuprofen, thereby enabling the miniaturization of ibuprofen tablets. Various glidants in amounts of 1% of the total volume were added to dry surface-modified ibuprofen, and the tensile strengths of the resulting tablets were evaluated. The characteristics of the excipients that affected the tensile strengths of the tablets were then extracted using a tensile strength prediction model. We confirmed that the effective angle of the internal friction of the mixed powder, the coating form of the glidant, the packing fraction of the raw material, and the mixed powder affect the tensile strength of the tablet. A smooth particle layer was formed on the surface of the ibuprofen particles when a glidant with a packing fraction of <0.05 was used. In the sample with a smooth particle layer, the angle of the critical state line increased significantly and the tensile strength improved. We inferred that the smoothness of the particle layer allowed the ibuprofen particles to come into close contact with each other. Consequently, the number of junctions increased, and the frictional force between the particles improved, resulting in tablets with improved tensile strengths. In conclusion, the compactability of ibuprofen was improved by adding 1% glidant with a packing fraction of <0.05. The reduction in excipients will allow the creation of smaller tablets, making them easier to swallow. Therefore, the medication adherence of customers will be improved.


Assuntos
Anti-Inflamatórios não Esteroides/química , Excipientes/química , Ibuprofeno/química , Resistência à Tração , Composição de Medicamentos , Propriedades de Superfície , Comprimidos
10.
Chem Pharm Bull (Tokyo) ; 69(4): 400-406, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790084

RESUMO

Oral mucositis is one of the most common adverse effects of radiation and chemotherapy in treatments of cancers. Some clinical guidelines have focused on the prevention and treatment of oral mucositis, and thus, a mouthwash containing drugs is often recommended. In this study, we aimed to evaluate the disappearance time and palatability in the oral cavities of healthy volunteers in foams prepared from different concentrations of the three viscosity grades of methylcellulose (SM-4, -100, -400). In addition, we prepared foam formulations of drugs (benzydamine, dexamethasone, allopurinol and rebamipide) for use as a prevention and treatment of oral mucositis. There was a significant relationship between the foam drainage ratios at 5-15 min and the disappearance time in the oral cavities. The significant relationship of foam densities to the foam disappearance time and overall palatability in a clinical study were observed. Thus, the foam density is considered an important parameter and reflects these clinically important properties. The foam from SM-4 has the longest disappearance time and the best palatability followed by foams from the 4 and 1% SM-4. Drug contents in drug-containing foam formulations which were prepared with 1-4% SM-4 represented 101-112% of the loaded drug contents, and the relative standard deviations of drug contents were <2.2%, which suggests that these formulations had pharmaceutically acceptable properties. This is the first report in regard to foam formulations containing drugs for the prevention and treatment of oral mucositis, and these formulations could be potentially useful for the prevention and treatment of oral mucositis.


Assuntos
Excipientes/química , Metilcelulose/química , Preparações Farmacêuticas/administração & dosagem , Estomatite/tratamento farmacológico , Composição de Medicamentos , Voluntários Saudáveis , Humanos , Viscosidade
11.
Expert Opin Drug Saf ; 20(7): 855-862, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33849366

RESUMO

BACKGROUND: FDA limited N-nitrosodimethylamine (NDMA) - a carcinogenic impurity formed during metformin (MET) tablets manufacturing - level to 96 ng/day; a step which led to recall of MET products. This work aims to investigate the root cause of NDMA formation during MET tablets manufacturing. RESEARCH DESIGN AND METHODS: We focused on three main contributing causes: use of water and heat during intra-granulation, and the nitrite/nitrate quantities in excipients. Thirteen MET tablet formulations (immediate or sustained-release) were manufactured, on batch level. Each batch was manufactured using one excipient and excluding one cause at a time and NDMA level was assayed. RESULTS: NDMA traces were undetectable in MET tablets manufactured using polyvinyl pyrrolidone or hydroxypropyl cellulose SSL, even when water and/or heat were employed during intra-granulation. Levels of NDMA in MET tablets with hydroxypropyl methyl cellulose (HPMC) E5 or carboxymethyl cellulose sodium 4000 were 67.08 ± 2.3 and 66.21 ± 2.5 ng/day, in the presence of water and/or heat. No impact of employing extra-granular PolyoxTM, HPMC E5 or HPMC K15 on NDMA formation, despite the high nitrite and nitrate content in these excipients. CONCLUSIONS: Water, heat, and excipients' nitrite and nitrate levels are the key players, which should collectively exist, to cause NDMA formation during MET tablets manufacturing.


Assuntos
Dimetilnitrosamina/análise , Excipientes/análise , Metformina/análise , Química Farmacêutica/métodos , Preparações de Ação Retardada , Dimetilnitrosamina/química , Composição de Medicamentos/métodos , Contaminação de Medicamentos/prevenção & controle , Excipientes/química , Temperatura Alta , Humanos , Metformina/química , Nitratos/análise , Nitratos/química , Nitritos/análise , Nitritos/química , Comprimidos , Água/química
12.
AAPS PharmSciTech ; 22(3): 122, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33811299

RESUMO

The objective of current research was to develop the models of dissolution prediction of tablets coated with cellulose acetate (CA 320S or CA 398-10) and cellulose acetate phthalate (C-A-P) blends. Independent variables selected were coating percent (X1) and percent of CA 320S or CA 398-10 (X2) in the blend. Dependent variables selected were dissolution in 1 (Y1), 8 (Y2), and 24 h (Y3). Diclofenac sodium core tablets were coated with blend of either CA 320S and C-A-P or CA 398-10 and C-A-P at approximately 5, 7.5, and 10% weight gain. CA 320S and CA 398-10 content in the corresponding blends varied from 33.3-66.7% and 25.0-50.0% relative to C-A-P, respectively. Dissolution was performed in phosphate buffer 6.8 using USP apparatus 2. Coated tablets were also characterized for surface morphology and coating uniformity by near infrared hyperspectroscopy. Y1, Y2, and Y3 were statistically (p < 0.05) affected by X2 in CA 320S/C-A-P and CA 398-10/C-A-P blends coated tablets. On the other hand, X1 had statistically significant (p < 0.05) effect only on the Y3 in CA 320S/C-A-P while Y1 was statistically (p < 0.05) affected by X2 in CA 398-10/C-A-P. Analysis of variance also indicated statistically significant (p < 0.05) effect of the studied variables on the dependent variables for both the blends. The models were verified by independent experiment. Model predicted and empirical values of Y1, Y2, and Y3 were close with maximum residual of 7.0%. In conclusion, dissolution can be modulated by varying composition of blend, polymer type, and coating weight.


Assuntos
Celulose/análogos & derivados , Liberação Controlada de Fármacos , Excipientes/química , Comprimidos com Revestimento Entérico/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Celulose/química , Diclofenaco/administração & dosagem , Modelos Químicos , Solubilidade , Espectrofotometria Infravermelho
13.
Carbohydr Polym ; 264: 118011, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33910715

RESUMO

Veklury™ by Gilead Sciences, Inc., containing antiviral drug, remdesivir (REM) has received emergency authorization in the USA and in Europe for COVID-19 therapy. Here, for the first time, we describe details of the non-covalent, host-guest type interaction between REM and the solubilizing excipient, sulfobutylether-beta-cyclodextrin (SBECD) that results in significant solubility enhancement. Complete amorphousness of the cyclodextrin-enabled REM formulation was demonstrated by X-ray diffraction, thermal analysis, Raman chemical mapping and electron microscopy/energy dispersive spectroscopy. The use of solubilizing carbohydrate resulted in a 300-fold improvement of the aqueous solubility of REM, and enhanced dissolution rate of the drug enabling the preparation of stable infusion solutions for therapy. 2D ROESY NMR spectroscopy provided information on the nature of REM-excipient interaction and indicated the presence of inclusion phenomenon and the electrostatic attraction between anionic SBECD and nitrogen-containing REM in aqueous solution.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Excipientes/química , beta-Ciclodextrinas/química , Monofosfato de Adenosina/química , Alanina/química , Antivirais/química , COVID-19/tratamento farmacológico , Varredura Diferencial de Calorimetria , Liofilização/métodos , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Varredura , Simulação de Acoplamento Molecular , Nanofibras/química , Pós , Solubilidade , Análise Espectral Raman , Difração de Raios X
14.
Molecules ; 26(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807401

RESUMO

The aim of this work is to present an approach to enhance the dissolution of progestin medication, megestrol acetate (also known as MEGACE), for improving the dissolution rate and kinetic solubility by incorporating nano graphene oxide (nGO). An antisolvent precipitation process was investigated for nGO-drug composite preparation, where prepared composites showed crystalline properties that were similar to the pure drug but enhanced aqueous dispersibility and colloidal stability. To validate the efficient release profile of composite, in vitro dissolution testing was carried out using United States Pharmacopeia, USP-42 paddle method, with gastric pH (1.4) and intestinal pH (6.5) solutions to mimic in vivo conditions. Pure MA is practically insoluble (2 µg/mL at 37 °C). With the incorporation of nGO, it was possible to dissolve nearly 100% in the assay. With the incorporation of 1.0% of nGO, the time required to dissolve 50% and 80% of drug, namely T50 and T80, decreased from 138.0 min to 27.0 min, and the drug did not dissolve for 97.0 min in gastric media, respectively. Additionally, studies done in intestinal media have revealed T50 did not dissolve for 92.0 min. This work shows promise in incorporating functionalized nanoparticles into the crystal lattice of poorly soluble drugs to improve dissolution rate.


Assuntos
Excipientes/química , Grafite/química , Acetato de Megestrol , Nanopartículas/química , Disponibilidade Biológica , Química Farmacêutica , Composição de Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Acetato de Megestrol/química , Acetato de Megestrol/farmacocinética , Solubilidade
15.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802960

RESUMO

Risperidone (RSP) is an atypical antipsychotic drug used in treating schizophrenia, behavioral, and psychological symptoms of dementia and irritability associated with autism. The drug substance is practically insoluble in water and exhibits high lipophilicity. It also presents incompatibilities with pharmaceutical excipients such as magnesium stearate, lactose, and cellulose microcrystalline. RSP encapsulation by randomly methylated ß-cyclodextrin (RM-ß-CD) was performed in order to enhance drug solubility and stability and improve its biopharmaceutical profile. The inclusion complex formation was evaluated using thermal methods, powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier transform infrared (UATR-FTIR), UV spectroscopy, and saturation solubility studies. The 1:1 stoichiometry ratio and the apparent stability constant of the inclusion complex were determined by means of the phase solubility method. The compatibility between the supramolecular adduct and pharmaceutical excipients starch, anhydrous lactose, magnesium stearate, and cellulose microcrystalline was studied employing thermoanalytical tools (TG-thermogravimetry/DTG-derivative thermogravimetry/HF-heat flow) and spectroscopic techniques (UATR-FTIR, PXRD). The compatibility study reveals that there are no interactions between the supramolecular adduct with starch, magnesium stearate, and cellulose microcrystalline, while incompatibility with anhydrous lactose is observed even under ambient conditions. The supramolecular adduct of RSP with RM-ß-CD represents a valuable candidate for further research in developing new formulations with enhanced bioavailability and stability, and the results of this study allow a pertinent selection of three excipients that can be incorporated in solid dosage forms.


Assuntos
Composição de Medicamentos/métodos , Excipientes/química , Risperidona/farmacologia , beta-Ciclodextrinas/química , Modelos Moleculares , Simulação de Acoplamento Molecular , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Termogravimetria , Difração de Raios X
16.
Molecules ; 26(7)2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917445

RESUMO

The purpose of the study was to develop a novel, directly compressible, co-processed excipient capable of providing a controlled-release drug system for the pharmaceutical industry. A co-processed powder was formed by adsorption of solid lipid nanoparticles (SLN) as a controlled-release film onto a functional excipient, in this case, dicalcium phosphate dihydrate (DPD), for direct compression (Di-Tab®). The co-processed excipient has advantages: easy to implement; solvent-free; industrial scaling-up; good rheological and compressibility properties; and the capability to form an inert platform. Six different batches of Di-Tab®:SLN weight ratios were prepared (4:0.6, 3:0.6, 2:0.6, 1:0.6, 0.5:0.6, and 0.25:0.6). BCS class III ranitidine hydrochloride was selected as a drug model to evaluate the mixture's controlled-release capabilities. The co-processed excipients were characterized in terms of powder rheology and dissolution rate. The best Di-Tab®:SLN ratio proved to be 2:0.6, as it showed high functionality with good flow and compressibility properties (Carr Index = 16 ± 1, Hausner Index = 1.19 ± 0.04). This ratio could control release for up to 8 h, so it fits the ideal profile calculated based on biopharmaceutical data. The compressed systems obtained using this powder mixture behave as a matrix platform in which Fickian diffusion governs the release. The Higuchi model can explain their behavior.


Assuntos
Preparações de Ação Retardada/farmacologia , Excipientes/química , Lipídeos/química , Nanopartículas/química , Força Compressiva , Liberação Controlada de Fármacos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Pós , Ranitidina/farmacologia , Reologia
17.
Int J Nanomedicine ; 16: 2917-2931, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33911861

RESUMO

Purpose: Ivabradine hydrochloride is selective pacemaker current (If) ion channel inhibitor used in case of chronic heart failure (CHF) with superior efficacy and lower side effects than most ß-blockers. However, the drug suffers from low bioavailability (≈40%) due to extensive first-pass metabolism. Hence, this work aims to formulate nanovesicular platforms to enhance their bioavailability both orally and transdermally. Materials and Methods: A central composite face-centered design was employed to formulate the nanovesicles, both phosphatidylcholine: drug ratio and percentage of pluronic F68 were used as independent variables. The nine developed formulae were characterized in terms of vesicle size (nm), polydispersity index, zeta potential (mV), entrapment efficiency (%). Decreasing vesicle size, increasing negative value of the zeta potential, and increasing entrapment efficiency were the chosen constraints to optimize the engineered nanovesicles. The candidate formula was subjected to further investigation including lyophilization, loading into carbopol gel, in vitro release, imaging with a transmission electron microscope, histopathological examination, in vitro cytotoxicity study and in vivo pharmacokinetics. Results: The optimized nanovesicular formula was composed of lipid: drug ratio of 3.91:1 and 100% pluronic as a stabilizer. It has particle size, zeta potential and entrapment efficiency of 337.6 nm, -40.5 mV and 30.5, respectively. It was then lyophilized in the presence of 5% trehalose as a cryoprotectant, dispersed in 0.5% carbopol to develop the transdermal gel. The two different forms of the candidate formula (lyophilized and gel form) displayed sustained drug release in comparison to drug solution. The histopathological and cytotoxicity studies showed that the optimized formula was safe and highly biocompatible. The pharmacokinetics parameters measured declared a higher Cmax and half-life of both formulae in comparison to market product (Procoralan®) with a 2.54- and 1.85-folds increase in bioavailability, respectively. Conclusion: Hence, the developed nanovesicles can be reported as the first nanoplatforms to be used for simultaneous ivabradine delivery by both oral and topical routes with enhanced oral and transdermal drug delivery. The developed nanoplatforms hence can be further used to formulate other drugs that suffer from low bioavailability due to extensive first-pass metabolism.


Assuntos
Portadores de Fármacos/administração & dosagem , Ivabradina/administração & dosagem , Ivabradina/farmacologia , Nanoestruturas/química , Administração Cutânea , Administração Oral , Animais , Disponibilidade Biológica , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Excipientes/química , Liofilização , Géis/química , Células Hep G2 , Hexoses/química , Humanos , Ivabradina/sangue , Masculino , Nanoestruturas/administração & dosagem , Tamanho da Partícula , Fosfatidilcolinas/química , Poloxâmero/química , Coelhos
18.
Nat Nanotechnol ; 16(6): 725-733, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33767382

RESUMO

Nanoformulations of therapeutic drugs are transforming our ability to effectively deliver and treat a myriad of conditions. Often, however, they are complex to produce and exhibit low drug loading, except for nanoparticles formed via co-assembly of drugs and small molecular dyes, which display drug-loading capacities of up to 95%. There is currently no understanding of which of the millions of small-molecule combinations can result in the formation of these nanoparticles. Here we report the integration of machine learning with high-throughput experimentation to enable the rapid and large-scale identification of such nanoformulations. We identified 100 self-assembling drug nanoparticles from 2.1 million pairings, each including one of 788 candidate drugs and one of 2,686 approved excipients. We further characterized two nanoparticles, sorafenib-glycyrrhizin and terbinafine-taurocholic acid both ex vivo and in vivo. We anticipate that our platform can accelerate the development of safer and more efficacious nanoformulations with high drug-loading capacities for a wide range of therapeutics.


Assuntos
Portadores de Fármacos/química , Ensaios de Triagem em Larga Escala/métodos , Nanopartículas/química , Sorafenibe/farmacologia , Terbinafina/farmacologia , Animais , Candida albicans/efeitos dos fármacos , Simulação por Computador , Portadores de Fármacos/síntese química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Difusão Dinâmica da Luz , Excipientes/química , Feminino , Ácido Glicirrízico/química , Humanos , Aprendizado de Máquina , Camundongos Endogâmicos , Absorção Cutânea , Sorafenibe/química , Sorafenibe/farmacocinética , Ácido Taurocólico/química , Terbinafina/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Expert Opin Ther Pat ; 31(7): 663-686, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33605825

RESUMO

INTRODUCTION: The current availability of dosage forms designed specifically for children is limited, constituting common practice the use of unlicensed or off-labeled medicines and extemporaneous preparations. Swallowing difficulties and taste aversion are the primary reasons for medicine rejection; therefore, enhancing palatability and ease of administration are the most common approaches adopted to overcome these issues. AREAS COVERED: A search of patents was performed for pediatric dosage forms and devices. The review aims to provide an overview on new formulation approaches and technologies adopted to develop pediatric-friendly dosage forms and devices, as well as on the regulatory efforts aiming to support the pediatrics market. EXPERT OPINION: Children deserve medicines of the same efficacy, quality and safety as adults. The present review highlights the momentum developed by pharmaceutical industries in the field of pediatrics, since more than 60 patents have been published in the last 5 years. An increasing interest, especially in mini-tablets, orodispersible, and chewable dosage forms, as well as on excipients and methods, to achieve sufficient taste-masking was identified, recognizing also the need for coordinated research networks and sustainable collaborations across the public and private sectors to provide better medicines for children.


Assuntos
Química Farmacêutica/métodos , Formas de Dosagem , Tecnologia Farmacêutica/métodos , Administração Oral , Criança , Indústria Farmacêutica/métodos , Excipientes/química , Humanos , Patentes como Assunto , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Paladar
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