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1.
AAPS PharmSciTech ; 22(3): 85, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33650023

RESUMEN

In this study, an attempt was made to produce Liqui-Tablets for the first time. This was carried out through the compaction of naproxen Liqui-Pellets. The incentive to convert the novel Liqui-Pellet into Liqui-Tablet was due to the array of inherent advantages of the popular and preferred tablet dosage form. The study showed that naproxen Liqui-Tablet could be successfully produced and the rapid drug release rate (100% drug release ~ 20 min) could be achieved under pH 1.2, where naproxen is insoluble. It was observed that the different pH of the dissolution medium affected the trend of drug release from formulations with varying amounts of liquid vehicle. The order of the fastest drug-releasing formulations was different depending on the pH used. The presence of Neusilin US2 showed considerable enhancement in the drug release rate as well as improving Liqui-Tablet robustness and hardness. Furthermore, images from X-ray micro-tomography displayed a uniform distribution of components in the Liqui-Tablet. The accelerated stability studies showed acceptable stability in terms of dissolution profile.


Asunto(s)
Composición de Medicamentos/métodos , Naproxeno/administración & dosificación , Naproxeno/síntesis química , Tecnología Farmacéutica/métodos , Administración Oral , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacocinética , Formas de Dosificación , Liberación de Fármacos , Excipientes/administración & dosificación , Excipientes/síntesis química , Excipientes/farmacocinética , Naproxeno/farmacocinética , Comprimidos
2.
AAPS PharmSciTech ; 22(3): 97, 2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33694033

RESUMEN

Granule size distribution (GSD) is one of the critical quality attributes in the roller compaction (RC) process. Determination of GSD for newly developed pharmaceutical compounds with unknown ribbon breakage behaviors at the RC milling step requires a quantitative insight into process parameters and ribbon attributes. Despite its pivotal role in mapping the process operating conditions to achieve desired granule size, limited work has been presented in literature with a focus on RC-milling modeling. In this study, a multi-variate mathematical model is presented to simulate the full size-distribution of granulated ribbons as a function of ribbon mechanical properties. Experimental data with a lab-scale oscillating milling apparatus were generated using ribbons made of various powder compositions. Model parameters were determined by fitting it to experimental data sets. Parameters obtained from the first step were correlated to ribbon Young's modulus. The model was validated by predicting GSD of data that were excluded in model development step. Predictive capabilities of the developed model were further explored by simulating GSD profiles of a granulated pharmaceutical excipient obtained at three different conditions of a real-scale Gerteis RC system. While maintaining the milling operating conditions similar to the lab-scale apparatus (i.e., screen size and spacing, and low rotor speed), the proposed modeling approach successfully predicted the GSD of roller compacted MCC powder as the model compound. This model can be alternatively utilized in conjunction with an RC model in order to facilitate the process understanding to obtain granule attributes as part of Quality-by-Design paradigm.


Asunto(s)
Módulo de Elasticidad , Excipientes/síntesis química , Modelos Teóricos , Tamaño de la Partícula , Tecnología Farmacéutica/métodos , Composición de Medicamentos/instrumentación , Excipientes/farmacocinética , Análisis Multivariante , Polvos , Comprimidos , Resistencia a la Tracción
3.
AAPS PharmSciTech ; 22(3): 98, 2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33709195

RESUMEN

The U.S. Food and Drug Administration (FDA) emphasizes drug product development by Quality by Design (QbD). Critical material attributes (CMAs) are a QbD element that has an impact on pharmaceutical operations and product quality. Pharmaceutical drugs often crystallize as needle-shaped (a CMA) particles and affect the process due to poor flowability, low bulk density, and high compressibility, and eventually the product performance. In this study, the product obtained from crystallization was needle-shaped Ciprofloxacin HCl (CIPRO), formed lumps during drying, and compacted during processing through feeders. To delump small amounts of materials and break the needles, multiple available devices (mortar-pestle, Krups grinder) and custom-made grinder were assessed before formulation. The processed CIPRO powder was then used to make tablets in the miniature tablet manufacturing unit developed by the team at MIT. The critical quality attributes (CQA) of the tablets, set by the United States Pharmacopeia (USP), were then assessed for the drug powder processed with each of these devices. Powder properties comparable to commercial CIPRO were obtained when the custom MIT-designed grinder was used, leading to tablets that meet the USP criteria, with comparable dissolution profiles of those for marketed CIPRO tablets. This study demonstrates how needle-shaped crystals have an impact on pharmaceutical operations, even if it is on a miniature scale, and how proper shape and subsequent flow properties can be obtained by processing the particles through the MIT team-designed grinder.


Asunto(s)
Química Farmacéutica/métodos , Ciprofloxacino/síntesis química , Tamaño de la Partícula , Tecnología Farmacéutica/métodos , Cristalización/métodos , Desecación , Composición de Medicamentos/métodos , Polvos , Comprimidos
4.
AAPS PharmSciTech ; 22(3): 99, 2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33709248

RESUMEN

The objective of this work was to investigate the influence of tablet location along the bottom of a USP apparatus II vessel on polymer erosion and drug release of surface-erodible sustained-release tablets using computational simulation methods. Computational fluid dynamics (CFD) methods were performed to simulate the velocity distribution. A mathematical model was developed to describe polymer erosion and tablet deformation according to the mass transfer coefficient. Numerical analysis was used to simulate drug release controlled by drug diffusion and polymer erosion. The results indicated that tablets located at the off-center position deformed faster than the tablets located at the center position. However, tablet location had no profound impact on drug release rate since all drug release profiles were "similar" according to the f2 similarity values which were above 50. Hence, our simulation supported that the USP apparatus II was a reliable and robust device for the dissolution testing of surface-erodible sustained-release tablets.


Asunto(s)
Simulación por Computador , Liberación de Fármacos , Polímeros/química , Polímeros/farmacocinética , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Hidrodinámica , Solubilidad , Comprimidos
5.
Zhongguo Zhong Yao Za Zhi ; 46(6): 1537-1546, 2021 Mar.
Artículo en Chino | MEDLINE | ID: mdl-33787152

RESUMEN

To systematically evaluate the clinical efficacy and safety of Ginkgo Leaf Tablets(GLT) in the treatment of acute cerebral infarction(ACI). Seven databases both at home and abroad were systematically retrieved from their establishment to March 2020. The data of the included studies were extracted after review and screening. The quality of the included studies was assessed with the Cochrane risk bias assessment tool, and then the included studies were put into Meta-analysis by RevMan 5.3 to evaluate the total cli-nical efficiency, neurological function score, blood lipids and incidence of adverse reactions in treatment of ACI by GLT. Finally, the GRADE system was adopted to evaluate the evidence quality of each outcome indicator and form recommendations. Ten studies involving 886 participants were included, all of which were of low quality. Meta-analysis results showed that,(1)in terms of the total clinical efficiency, GLT+Western medicine was superior to Western medicine alone(RR_(NDS)=1.20, 95%CI[1.06, 1.36], P=0.005; RR_(NIHSS)=1.35, 95%CI[1.09, 1.69], P=0.007), and there was no statistical difference between GLT+Xuesaitong Injection+Wes-tern medicine and Xuesaitong Injection+Western medicine(RR=1.16, 95%CI[1.00, 1.35], P=0.05).(2)In terms of improving neurological function score, GLT+Western medicine was superior to Western medicine alone(MD_(NIHSS[moderate(severe)])=-1.55, 95%CI[-2.22,-0.88], P<0.000 01; MD_(NIHSS(severe))=-7.51, 95%CI[-8.00,-7.02], P<0.000 01; MD_(NDS)=-1.36, 95%CI[-2.39,-0.33], P=0.01), and GLT+Danshen Injection+Western medicine was superior to Danshen Injection+Western medicine(MD_(NDS)=-3.09, 95%CI[-3.84,-2.34], P<0.000 01).(3)In terms of regulating blood lipids, GLT+Western medicine was superior to Wes-tern medicine alone(MD_(TC)=-1.40, 95%CI[-2.13,-0.66], P=0.000 2; MD_(TG)=-1.29, 95%CI[-1.86,-0.73], P<0.000 01; MD_(LDL-C)=-1.48, 95%CI[-2.91,-0.04], P=0.04; MD_(HDL-C)=0.07, 95%CI[0.02, 0.12], P=0.009).(4)In terms of incidence of adverse reactions, there was no statistical difference between GLT+Western medicine and Western medicine alone(RR=0.63, 95%CI[0.30, 1.32], P=0.22). The results of the evaluation showed that the evidence level of each outcome indicator was low, and the recommendation was at weak level. In conclusion, GLT+Western medicine could improve the total clinical efficiency, neurological function score, and blood lipid status, with a low incidence of adverse reactions. However, due to the small amount of included stu-dies, low study quality and low level of evidence, it is expected to carry out clinical studies with standardized design and large sample size in the future to further investigate the clinical efficacy and safety of GLT in the treatment of ACI.


Asunto(s)
Infarto Cerebral , Ginkgo biloba , Infarto Cerebral/tratamiento farmacológico , Humanos , Hojas de la Planta , Comprimidos , Resultado del Tratamiento
6.
Int J Nanomedicine ; 16: 905-924, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33603359

RESUMEN

Purpose: The purpose of this proposed research was to investigate a nano-formulation developed using self-nanoemulsifying drug delivery system (SNEDDS) to improve the pharmacodynamic potential of rosuvastatin by assisting its transportation through lymphatic circulation. Methods: The utilized lipids, surfactants, and co-surfactants for SNEDDS were selected on the basis of solubility studies. The SNEDDS formulation was optimized by implementing a D-optimal mixture design, wherein the effect of concentration of Capmul MCM EP (X1), Tween 20 (X2) and Transcutol P (X3) as independent variables was studied on droplet size (Y1), % cumulative drug release (Y2) and self-emulsification time (Y3) as dependent variables. The optimized formulation was evaluated via in vitro parameters and in vivo pharmacodynamic potential in Wistar rats. Results: The D-optimal mixture design and subsequent ANOVA application resulted in the assortment of the optimized SNEDDS formulation that exhibited a droplet size of nano range (14.91nm), in vitro drug release of >90% within 30 minutes, and self-emulsification time of 16 seconds. The in vivo pharmacodynamic study carried out using Wistar rats confirmed the better antihyperlipidemic potential of developed formulation in normalizing the lipidic level of serum in contrast to pure drug and marketed tablets. Conclusion: This research reports the application of D-optimal mixture design for successful and systematic development of rosuvastatin-loaded SNEDDS with distinctly enhanced in vitro and in vivo performance in comparison to marketed formulation. Eventually, improved anti-hyperlipidemic efficacy was envisaged which might be attributed to increased drug solubility and absorption. Overall, this study shows the utility of SNEDDS for improving the dissolution rate and bioavailability of poor aqueous-soluble drugs. The present SNEDDS formulation could be a promising approach and alternative to conventional dosage form.


Asunto(s)
Sistemas de Liberación de Medicamentos , Emulsiones/química , Nanopartículas/química , Rosuvastatina Cálcica/farmacología , Análisis de Varianza , Animales , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Liberación de Fármacos , Estabilidad de Medicamentos , Lípidos/química , Masculino , Nanopartículas/ultraestructura , Tamaño de la Partícula , Transición de Fase , Ratas Wistar , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Tensoactivos/química , Comprimidos , Viscosidad
7.
Drugs Today (Barc) ; 57(1): 5-16, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33594386

RESUMEN

Parkinson's disease is one of the commonest neurodegenerative disorders, particularly in those over 60 years of age. Although the introduction of levodopa was a tremendous advance in its treatment, the condition is a progressive one. It has been found that the longer patients have the condition and are treated with levodopa, the more likely they are to develop OFF episodes in which their ability to do things becomes increasingly limited. The development of a sublingual apomorphine hydrochloride film (APL-130277, Kynmobi) was designed to alleviate this OFF condition by allowing the patients to experience rapid relief of their OFF episodes up to 5 times a day.


Asunto(s)
Apomorfina , Enfermedad de Parkinson , Anciano , Antiparkinsonianos/efectos adversos , Apomorfina/efectos adversos , Humanos , Levodopa , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Comprimidos
8.
AAPS PharmSciTech ; 22(2): 67, 2021 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-33554316

RESUMEN

It is well known that the splitting of tablets can bring serious risks to the health of the treated animals, e.g., the possible adverse reactions caused by overdoses of fenbendazole or aspirin. In this regard, this work aimed to evaluate, for the first time, the splitting behavior of commercial veterinary tablets and identifying the technological aspects that interfere in this process. Tablets were cut in halves using a tablet splitter and were analyzed regarding mass variation, mass loss, friability, and hardness. Microstructural and morphological evaluations were also performed. For most of the tablets, organic flavor additives provided more uniformity and cohesive matrix, which preserved its hardness after the cut and led to subdivision results within acceptable limits for mass measurements and friability. Apart from the microstructure, the most critical technological aspect for a correct splitting performance in such tablets was the presence of a score. Thus, the results presented here allow us to guide the manufacturing of veterinary drug products in order to produce tablets more adapted to the splitting process.


Asunto(s)
Comprimidos/química , Medicina Veterinaria , Animales , Composición de Medicamentos/métodos , Dureza
9.
AAPS PharmSciTech ; 22(2): 68, 2021 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-33564940

RESUMEN

Poor physicomechanical properties and limited aqueous solubility restrict the bioavailability of aceclofenac when given orally. To improve its above properties, aceclofenac (ACE) was cocrystallized with dimethyl urea (DMU) in 1:2 molar ratio by dry and solvent assisted grinding. The cocrystals were characterized by ATR-FTIR, DSC, and PXRD, and their surface morphology was studied by SEM. There was enhancement in intrinsic dissolution rate (IDR) (~eight- and ~fivefold in cocrystals prepared by solvent assisted grinding (SAG) and solid state grinding (SSG), respectively, in 0.1 N HCl, pH 1.2) and similarly (~3.42-fold and ~1.20-fold in phosphate buffer, pH 7.4) as compared to pure drug. Additionally, mechanical properties were assessed by tabletability curves. The tensile strength of ACE was < 1 MPa in contrast to the cocrystal tensile strength (3.5 MPa) which was ~1.98 times higher at 6000 psi. The tablet formulation of cocrystal by direct compression displayed enhanced dissolution profile (~36% in 0.1 N HCl, pH 1.2, and ~100% in phosphate buffer, pH 7.4) in comparison to physical mixture (~ 30% and ~ 80%) and ACE (~18% and ~50%) after 60 min, respectively. Stability studies of cocrystal tablets for 3 months indicated a stable formulation. Pharmacokinetic studies were performed by using rabbit model. The AUC0-∞ (37.87±1.3 µgh/ml) and Cmax (6.94±2.94 µg/ml) of the selected cocrystal C1 prepared by SAG were significantly enhanced (p < 0.05) and were ~3.43 and ~1.63-fold higher than that of ACE. In conclusion, new cocrystal of ACE-DMU was successfully prepared with improved tabletability, in vitro and in vivo properties.


Asunto(s)
Diclofenaco/análogos & derivados , Animales , Cristalización , Diclofenaco/química , Diclofenaco/farmacocinética , Liberación de Fármacos , Estabilidad de Medicamentos , Femenino , Masculino , Conejos , Comprimidos/química , Urea/química
10.
AAPS PharmSciTech ; 22(3): 79, 2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33606113

RESUMEN

Fenofibrate is an effective lipid-lowering drug; however, its poor solubility and high log p (5.2) result in insufficient absorption from the gastrointestinal tract, leading to poor bioavailability. In this study, a one-step continuous twin-screw melt granulation process was investigated to improve the solubility and dissolution of fenofibrate using Gelucire® 48/16 and Neusilin® US2 as the solubilizer and surface adsorbent, respectively. The formulations (granules) were prepared at different ratios of fenofibrate, Gelucire® 48/16, and Neusilin® US2 based on phase-solubility studies and characterized using dissolution, differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy analyses and studies on flow properties. In the phase-solubility studies, a linear relation was observed between Gelucire® 48/16 concentration and the amount of fenofibrate dissolved. In contrast, the dissolution rate of the prepared formulations was independent of the fenofibrate: Gelucire® 48/16 ratio and dependent on the Neusilin® US2 levels in the formulation. Increasing Neusilin® US2 levels decreased the rate of dissolution of the granules but improved the stability of the tablets under storage at accelerated stability conditions. Interestingly, higher Gelucire® 48/16 levels in the granules resulted in tablets with a hard matrix, which slowed disintegration and dissolution. All formulations exhibited improved dissolution compared to pure fenofibrate.


Asunto(s)
Fenofibrato/química , Tecnología Farmacéutica , Composición de Medicamentos , Estabilidad de Medicamentos , Solubilidad , Comprimidos
11.
Int J Nanomedicine ; 16: 591-607, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33531803

RESUMEN

Purpose: The aim of the present study was to develop deflazacort (DFZ) ultra-elastic nanovesicles (UENVs) loaded gel for topical administration to evade gastrointestinal adverse impacts accompanying DFZ oral therapy. Methods: UENVs were elaborated according to D-optimal mixture design employing different edge activators as Span-60, Tween-85 and sodium cholate which were incorporated into the nanovesicles to improve the deformability of vesicles bilayer. DFZ-UENVs were formulated by thin-film hydration technique followed by characterization for different parameters including entrapment efficiency (%EE), particle size, in vitro release and ex vivo permeation studies. The composition of the optimized DFZ-UENV formulation was found to be DFZ (10 mg), Span-60 (30 mg), Tween-85 (30 mg), sodium cholate (3.93 mg), L-α phosphatidylcholine (60 mg) and cholesterol (30 mg). The optimum formulation was incorporated into hydrogel base then characterized in terms of physical parameters, in vitro drug release, ex vivo permeation study and pharmacodynamics evaluation. Finally, pharmacokinetic study in rabbits was performed via transdermal application of UENVs gel in comparison to oral drug. Results: The optimum UENVs formulation exhibited %EE of 74.77±1.33, vesicle diameter of 219.64±2.52 nm, 68.88±1.64% of DFZ released after 12 h and zeta potential of -55.57±1.04 mV. The current work divulged successful augmentation of the bioavailability of DFZ optimum formulation by about 1.37-fold and drug release retardation compared to oral drug tablets besides significant depression of edema, cellular inflammation and capillary congestion in carrageenan-induced rat paw edema model. Conclusion: The transdermal DFZ-UENVs can achieve boosted bioavailability and may be suggested as an auspicious non-invasive alternative platform for oral route.


Asunto(s)
Antiinflamatorios/farmacología , Sistemas de Liberación de Medicamentos , Elasticidad , Nanopartículas/química , Pregnenodionas/farmacología , Administración Cutánea , Administración Oral , Animales , Disponibilidad Biológica , Liberación de Fármacos , Edema/tratamiento farmacológico , Hidrogeles/química , Masculino , Nanopartículas/ultraestructura , Tamaño de la Partícula , Pregnenodionas/farmacocinética , Conejos , Ratas Wistar , Absorción Cutánea/efectos de los fármacos , Electricidad Estática , Comprimidos
12.
Osteoporos Int ; 32(3): 595-606, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33443610

RESUMEN

The use of buffered soluble alendronate 70 mg effervescent tablet, a convenient dosing regimen for bisphosphonate therapy, seems a cost-effective strategy compared with relevant alternative treatments for postmenopausal women with osteoporosis aged 60 years and over in Italy. INTRODUCTION: To assess the cost-effectiveness of buffered soluble alendronate (ALN) 70 mg effervescent tablet compared with relevant alternative treatments for postmenopausal osteoporotic women in Italy. METHODS: A previously validated Markov microsimulation model was adjusted to the Italian healthcare setting to estimate the lifetime costs (expressed in €2019) per quality-adjusted life-years (QALY) of buffered soluble ALN compared with generic ALN, denosumab, zoledronic acid and no treatment. Pooled efficacy data derived from the NICE network meta-analysis were used for bisphosphonate treatments. Two treatment duration scenarios were assessed: 1 year using persistence data derived from an Italian prospective observational study including 144 and 216 postmenopausal osteoporotic women on buffered soluble ALN and oral ALN, respectively, and 3 years. Analyses were conducted for women 60-80 years of age with a bone mineral density T-score ≤ - 3.0 or with existing vertebral fractures. RESULTS: In all simulated populations, buffered soluble ALN was dominant (more QALYs, lower costs) compared to denosumab. The cost per QALY gained of buffered soluble ALN compared to generic ALN and no treatment always falls below €20,000 per QALY gained. In the 1-year treatment scenario, zoledronic acid was associated with more QALY than buffered soluble ALN but the cost per QALY gained of zoledronic acid compared with buffered soluble ALN was always higher than €70,000, while buffered soluble ALN was dominant in the 3-year treatment scenario. CONCLUSION: This study suggests that buffered soluble ALN represents a cost-effective strategy compared with relevant alternative treatments for postmenopausal osteoporosis women in Italy aged 60 years and over.


Asunto(s)
Conservadores de la Densidad Ósea , Osteoporosis Posmenopáusica , Osteoporosis , Anciano , Alendronato , Análisis Costo-Beneficio , Femenino , Humanos , Italia/epidemiología , Persona de Mediana Edad , Estudios Observacionales como Asunto , Osteoporosis Posmenopáusica/tratamiento farmacológico , Posmenopausia , Años de Vida Ajustados por Calidad de Vida , Comprimidos
13.
AAPS PharmSciTech ; 22(1): 40, 2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33417081

RESUMEN

Multiple considerations are essential to address the main challenges of dose flexibility and patient adherence in pediatric drug development, particularly for oncology. Mini-tablets, 2 mm in diameter, were manufactured using a rotary tablet press at a set weight and compression force level. The physical characteristics were consistent for mini-tablets throughout multiple batches. Polymeric amorphous solid dispersion (ASD) was used as a solubility enhancing technique to increase solubility and exposure of lapatinib. The effects of the polymeric excipient and disintegrant on drug release properties were investigated. While having a lower apparent solubility and shorter storage stability, hydroxypropyl methylcellulose E3 (HPMCE3) formulation provided a higher percentage of drug release compared to hydroxypropyl methylcellulose phthalate (HPMCP). The intermolecular interaction within the ASD system plays a role in the level of apparent solubility, physical stability, and concentration of free drug available in an aqueous environment. Juvenile porcine models at two different weight groups (10 and 20 kg) were used to obtain the pharmacokinetic parameters of lapatinib. While the dose-normalized exposure of drug was found to be lower in the pig study, the dose flexibility of mini-tablets enabled a constant dose level to be administered to achieve equivalent plasma concentration-time profiles between the two groups. This linear scaling in the amount of drug in pediatric and adult population has also been observed in human clinical studies.


Asunto(s)
Lapatinib/química , Animales , Niño , Composición de Medicamentos , Desarrollo de Medicamentos , Liberación de Fármacos , Humanos , Lapatinib/farmacocinética , Solubilidad , Porcinos , Comprimidos/química
14.
AAPS PharmSciTech ; 22(1): 41, 2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420526

RESUMEN

After the Food and Drug Association in the USA published guidelines on the enhanced use of process analytical technology (PAT) and continuous manufacturing, many studies regarding PAT and continuous manufacturing have been published. This paper describes a case study involving granulation and coating steps with ethenzamide to investigate interference for PAT model construction and model management. We investigated what factors should be considered and addressed when PAT is implemented for continuous manufacturing and how predictive models should be constructed. The product qualities that were monitored were moisture content and particle size in the granulation step and tablet weight and moisture content in the coating step. We have constructed models for the granulation step and validated the predictive capability of the models against an external dataset. A partial least squares (PLS) model with manual wavelength selection had the best predictive accuracy for loss on drying against the external validation set. We found that the prediction of loss on drying was accurate, but the prediction of particle size was not sufficiently accurate. In the coating step, because of the small amount of data, we performed three-fold cross-validation and y-scrambling 10 times, to select the optimal hyper-parameters and to check if the models were fitted to chance correlations. We confirmed that the coating agent weights, tablet weights, and water content could be accurately predicted based on the mean of the R2 score for cross-validation. Addition of other variables, as well as the absorbance, slightly improved the predictive accuracy.


Asunto(s)
Salicilamidas/química , Tecnología Farmacéutica/métodos , Composición de Medicamentos/métodos , Tamaño de la Partícula , Comprimidos
15.
Int J Pharm ; 595: 120229, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33484927

RESUMEN

Water uptake and swelling of tablets are processes occurring during active pharmaceutical ingredient (API) release. Thereby, disintegration is promoted and the enhanced exposure of API surface area to the release medium facilitates API dissolution. An experimental set-up for the simultaneous and time-resolved determination of water uptake and swelling of tablets has been developed. Water uptake was determined with a balance and swelling was determined with a camera. To validate the gravimetrical analysis, real-time water uptake measurements with inert test specimens were performed. The standard deviation of these measurements was considered to depict precision. A complementary gravimetrical analysis was employed to determine accuracy. For both, precision and accuracy, a maximum deviation of 6% was found. An algorithm for the symmetry-based 3D volume reconstruction was applied to obtain volumes of the tablets from 2D images. X-ray micro computed tomography was used to validate the accuracy and the determined volumes were in good accordance within 6% deviation. A case study with binary formulations of a filler and disintegrants confirmed reproducibility and demonstrated the ability of the method to discriminate formulation characteristics, such as disintegrant type, composition and porosity for water uptake and swelling with the necessary temporal resolution.


Asunto(s)
Excipientes/química , Comprimidos/química , Tecnología Farmacéutica/métodos , Agua/química , Algoritmos , Excipientes/análisis , Cinética , Reproducibilidad de los Resultados , Análisis Espacio-Temporal , Comprimidos/análisis , Microtomografía por Rayos X/métodos
16.
Int J Pharm ; 595: 120274, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33486026

RESUMEN

The mechanical properties of powders determine the ease of manufacture and ultimately the quality of the oral solid dosage forms. Although poor mechanical properties of an active pharmaceutical ingredient (API) can be mitigated by using suitable excipients in a formulation, the effectiveness of that approach is limited for high dose drugs or multidrug tablets. In this context, improving the mechanical properties of the APIs through solid form optimisation is a good strategy to address such a challenge. This work explores the powder and tableting properties of various lamotrigine (LAM) solid forms with the aim to facilitate direct compression by overcoming the poor tabletability of LAM. The two drug-drug crystals of LAM with nicotinamide and valproic acid demonstrate superior flowability and tabletability over LAM. The improved powder properties are rationalised by structure analysis using energy framework, scanning electron microscopy, and Heckel analysis.


Asunto(s)
Composición de Medicamentos/métodos , Lamotrigina/química , Polvos/química , Comprimidos/química , Cristalografía , Excipientes/química , Lamotrigina/análogos & derivados , Microscopía Electrónica de Rastreo , Niacinamida/análogos & derivados , Niacinamida/química , Tamaño de la Partícula , Porosidad , Presión , Reología , Espectrometría Raman , Ácido Valproico/análogos & derivados , Ácido Valproico/química , Difracción de Rayos X
17.
Int J Pharm ; 595: 120257, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33486029

RESUMEN

Main purpose was to evaluate the applicability of a 3D-printer equipped with a hot-melt pneumatic dispenser as a single-step process to prepare tablet dosage forms. Dutasteride, a poorly water-soluble drug, was selected as a model drug. Soluplus®, Kollidon® VA 64, Eudragit® E PO, and hydroxypropyl cellulose (HPC) were premixed as bulking agents prior to printing. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and thermogravimetric analysis (TGA) were utilized to evaluate the physicochemical properties of the 3D-printed tablets. Moreover, different geometries were designed to correlate the surface area/volume (SA/V) of the tablets with respect to their release profiles. As a result, printed dutasteride was confirmed to be in an amorphous state and not recrystallized even after the accelerated storage stability. Out of the four bulking agents, Kollidon® VA 64, enhanced the dissolution of the printed dutasteride, reaching above 80% within 15 min. These results suggest that the hot-melt pneumatic dispenser was efficient in converting the solid state into an amorphous state, which significantly enhanced the dissolution. On the other hand, the tube-shaped 3D-printed tablet exhibited the fastest drug dissolution profile, which had the highest SA/V ratio in comparison to the cube, hemisphere, and pyramid shapes. These results confirm the dependency of the drug dissolution rate not only on its crystallinity but also on the surface area of the 3D-printed tablet. Therefore, a 3D-printer equipped with a hot-melt pneumatic dispenser possesses useful applicability in enhancing drug dissolution, especially for poorly water-soluble drugs, in a single-step process.


Asunto(s)
Composición de Medicamentos/métodos , Tecnología de Extrusión de Fusión en Caliente/métodos , Comprimidos/química , Rastreo Diferencial de Calorimetría , Liberación de Fármacos , Dutasterida/química , Excipientes/química , Polietilenglicoles/química , Polímeros/química , Impresión Tridimensional , Solubilidad , Termogravimetría , Difracción de Rayos X
18.
Nihon Yakurigaku Zasshi ; 156(1): 37-46, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33390479

RESUMEN

Gilteritinib fumarate (Xospata® tablets 40 mg) is a novel, highly selective, oral FMS-like tyrosine kinase 3 (FLT3) inhibitor used for the treatment of patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML), and it was approved in Japan in September 2018. Preclinical studies demonstrated that gilteritinib inhibited FLT3 and showed antiproliferative activity against Ba/F3 cells expressing mutated FLT3. In addition, gilteritinib inhibited tumor growth, induced tumor regression, and prolonged survival in mice xenografted with MV4-11 cells endogenously expressing FLT3-internal tandem duplication. In clinical trials conducted in the United States, Europe, and Japan, plasma concentrations after administration of gilteritinib 20 to 450 mg/day were generally dose proportional, and gilteritinib was well tolerated. Multiple clinical trials, including a global Phase III study, in patients with relapsed or refractory FLT3-mutated AML treated with gilteritinib demonstrated higher response rates of complete remission or complete remission with partial hematologic recovery and longer overall survival compared with patients treated with salvage chemotherapy. Some clinical trials are ongoing in patients with FLT3-mutated AML at various treatment stages, such as induction therapy, maintenance therapy, and treatment after hematopoietic stem cell transplantation. In conclusion, in vitro, in vivo, and clinical data indicate that gilteritinib fumarate is an effective treatment option in adult patients with relapsed or refractory FLT3-mutated AML in Japan.


Asunto(s)
Leucemia Mieloide Aguda , Tirosina Quinasa 3 Similar a fms , Adulto , Compuestos de Anilina , Animales , Humanos , Japón , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Ratones , Mutación , Pirazinas , Comprimidos , Estados Unidos , Tirosina Quinasa 3 Similar a fms/genética
19.
Yakugaku Zasshi ; 141(1): 125-133, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33390439

RESUMEN

The immunosuppressant azathioprine (AZA) is classified as a hazardous drug. AZA contamination during tablet-splitting increases exposure risk. However, there is no study on contamination and exposure during AZA tablet splitting and dispensing. AZA tablet splitting and dispensing methods were classified based on whether tweezers are used during splitting and packaging. In Dispensing Method (1), no tweezers were used in either step. In Dispensing Method (2), no tweezers were used during tablet splitting, but were used during packaging. In Dispensing Method (3), tweezers were used in both steps. After AZA half-tablet split-dispensing, we quantified the adherent AZA removed from the tools, packaging machines, and dispensing counters by three consecutive wipings with water-dampened polypropylene cloths. A large amount of AZA adhered to the gloves used in Dispensing Methods (1) and (2), wherein tablets were placed with gloved hands, compared with Dispensing Method (3), wherein tablets were held with tweezers. Thus, the gloves must be replaced before touching the packaging paper during the final step. After three consecutive wipings, AZA was not detected at most of the sites in the third round. Thus, we recommend that (1) AZA tablet splitting should be performed while wearing gloves, (2) the gloves should be changed before packaging the half tablets, and (3) the tools, packaging machines, and dispensing counters should be wiped twice or thrice with a water-dampened cloth after dispensing.


Asunto(s)
Azatioprina , Composición de Medicamentos/métodos , Contaminación de Medicamentos/prevención & control , Embalaje de Medicamentos/métodos , Inmunosupresores , Exposición Profesional/prevención & control , Azatioprina/efectos adversos , Inmunosupresores/efectos adversos , Comprimidos
20.
Int J Pharm Compd ; 25(1): 82-87, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33503013

RESUMEN

Sildenafil citrate is a phosphodiesterase-5 inhibitor that is approved by the U.S. Food and Drug Administration for the treatment of erectile dysfunction. Rapid-dissolving tablets are relatively novel dosage forms that can be prepared by extemporaneous compounding and potentially provide unique advantages for medications like sildenafil. However, such preparations may present newer stability considerations previously unreported. Therefore, the purpose of this study was to assess the physical and chemical stability of sildenafil 100-mg rapid-dissolving tablets prepared by a commonly practiced molding method, using two different proprietary rapid-dissolving tablet bases (Medi-RDT or RDTPlus) immediately after preparation and over six months of storage at ambient room temperature. To prepare the rapid-dissolving tablets, the powder ingredients were homogeneously mixed, filled, and compressed into a 96-cavity metal mold. The formulation was then heated at 110°C for 10 minutes in the mold, released from the mold, and cooled at room temperature for 15 minutes. The prepared tablets were packaged in amber-colored blister packs with cold-adhesive backing seals and stored at ambient room temperature. At predetermined time points, rapid-dissolving tablets of each formulation were retrieved to perform stability analyses. These analyses included weight variation, breaking force, disintegration, friability, and potency via high-performance liquid chromatography following the United States Pharmacopoeia methods and visual inspection. At time 0 (immediately after preparation), the results of the tests for rapid-dissolving tablets made with Medi-RDT base v. RDT-Plus base were as follows: average tablet weight (649.7 mg v. 753.6 mg); breaking force (24.01 N v. 32.34 N); friability (8.52% v. 7.55%); disintegration time (34 seconds v. 35 seconds); and potency (98.61% v. 101.41%), respectively. Over the six-month storage period, both formulations of rapid-dissolving tablets had no significant changes in visual appearance, tablet weight, breaking force, or disintegration time. High-performance liquid chromatographic-based tablet assays for both formulations were consistently above 95% label claim at each time point, with no chromatographic evidence of degradation. Thus, the studied formulations of compounded sildenafil 100-mg rapid-dissolving tablets prepared using both Medi-RDT or RDT-Plus were found to be physically and chemically stable over six months of storage at ambient room temperature.


Asunto(s)
Inhibidores de Fosfodiesterasa 5 , Citrato de Sildenafil , Composición de Medicamentos , Estabilidad de Medicamentos , Inhibidores de Fosfodiesterasa 5/farmacocinética , Citrato de Sildenafil/farmacocinética , Suspensiones , Comprimidos
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