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1.
AAPS PharmSciTech ; 20(7): 263, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31338714

RESUMO

Modeling of the lyophilization process, based on the steady-state heat and mass transfer, is a useful tool in understanding and optimizing of the process, developing an operating design space following the quality-by-design principle, and justifying occasional process deviations during routine manufacturing. The steady-state model relies on two critical parameters, namely, the vial heat transfer coefficient, Kv, and the cake resistance, Rp. The classical gravimetric method used to measure Kv is tedious, time- and resource-consuming, and can be challenging and costly for commercial scale dryers. This study proposes a new approach to extract both Kv and Rp directly from an experimental run (e.g., temperature and Pirani profiles). The new methodology is demonstrated using 5% w/v mannitol model system. The values of Kv obtained using this method are comparable to those measured using the classic gravimetric method. Application of the proposed approach to process scale-up and technology transfer is illustrated using a case study. The new approach makes the steady-state model a simple and reliable tool for model parameterization, thus maximizes its capability and is particularly beneficial for transfer products from lab/pilot to commercial manufacturing.


Assuntos
Liofilização/métodos , Transferência de Tecnologia , Tecnologia Farmacêutica/métodos , Temperatura Ambiente
2.
AAPS PharmSciTech ; 20(6): 239, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243640

RESUMO

Polymeric films are safe and effective and can be used for vaginal administration of microbicide drug candidates. Dapivirine (DPV), an investigational and clinically advanced antiretroviral drug, was selected as a model compound for this study. We have previously developed and clinically tested a quick-dissolving DPV film using solvent cast (SC) manufacturing technique. As an alternative to current pharmaceutical film manufacturing techniques, we investigated hot melt extrusion (HME) process in this study because it has several benefits, including its capacity as a continuous manufacturing process, lack of solvents, smaller footprint, and ease of scalability. The goal of this work was to evaluate the feasibility of using HME for DPV vaginal film manufacturing and to develop a robust manufacturing process using HME by evaluating the effect of process parameters on film quality and performance. DPV was successfully incorporated into a vaginal film using HME and maintained acceptable characteristics. Three process parameters (zone temperature, screw speed, and feed rate) had an impact on film quality and performance. Of these, the zone temperature was found to most significantly affect weight, thickness, puncture strength, and dissolution of films. Additionally, film manufacturing using HME was highly reproducible. Finally, the DPV HME film was comparable to films manufactured using SC in terms of physicochemical, biological, and safety characteristics including in vitro drug release, mechanical strength, tissue permeability, compatibility with commensal vaginal Lactobacilli, and in vitro bioactivity. These results demonstrate that HME is an effective, robust, and viable manufacturing method to produce vaginal films.


Assuntos
Preparações Farmacêuticas/química , Pirimidinas/química , Inibidores da Transcriptase Reversa/química , Tecnologia Farmacêutica/métodos , Administração Intravaginal , Liberação Controlada de Fármacos , Feminino , Congelamento , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Temperatura Alta , Humanos , Testes de Sensibilidade Microbiana , Polímeros/química , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacologia
3.
AAPS PharmSciTech ; 20(5): 206, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147791

RESUMO

The multi-stage cascade impactor (CI) is the mainstay method for the determination of the aerodynamic particle size distribution (APSD) of aerosols emitted from orally inhaled products (OIPs). CIs are designed to operate at a constant flow rate throughout the measurement process. However, it is necessary to mimic an inhalation maneuver to disperse the powder into an aerosol when testing passive dry powder inhalers (DPIs), which constitute a significant portion of available products in this inhaler class. Methods in the pharmacopeial compendia intended for product quality assurance initiate sampling by applying a vacuum to the measurement apparatus using a timer-operated solenoid valve located downstream of the CI, resulting in a period when the flow rate through the impactor rapidly increases from zero towards the target flow rate. This article provides recommendations for achieving consistent APSD measurements, including selection of the CI, pre-separator, and flow control equipment, as well as reviewing considerations that relate to the shape of the flow rate-sampling time profile. Evidence from comparisons of different DPIs delivering the same active pharmaceutical ingredients (APIs) is indicative that the compendial method for APSD measurement is insensitive as a predictor of pharmacokinetic outcomes. Although inappropriate for product quality testing, guidance is therefore provided towards adopting a more clinically realistic methodology, including the use of an anatomically appropriate inlet and mimicking patient inhalation at the DPI while operating the CI at constant flow rate. Many of these recommendations are applicable to the testing of other OIP classes.


Assuntos
Aerossóis/normas , Inaladores de Pó Seco/métodos , Desenho de Equipamento/métodos , Tamanho da Partícula , Controle de Qualidade , Administração por Inalação , Aerossóis/administração & dosagem , Aerossóis/química , Inaladores de Pó Seco/instrumentação , Desenho de Equipamento/instrumentação , Humanos , Pós , Fármacos do Sistema Respiratório/administração & dosagem , Fármacos do Sistema Respiratório/química , Fármacos do Sistema Respiratório/normas , Tecnologia Farmacêutica/métodos
4.
AAPS PharmSciTech ; 20(5): 195, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31119403

RESUMO

The main aim of this work was to 3D print metformin HCl-loaded PVA (ML-PVA) tablets by fused deposition modeling. A modified solvent diffusion approach was used to improve drug loading. PVA filaments were placed in metformin HCl solution in ethanol containing low water content (10%(v/v)) to enhance the drug's solubility. The physicochemical properties of ML-PVA filaments were characterized before and after printing. Lastly, ML-PVA filaments were printed into channeled tablet designs to increase their surface area available for dissolution. The loading of metformin HCl onto PVA filament has significantly increased from 0.08 ± 0.02% in metformin HCl solution in absolute ethanol to 1.40 ± 0.02% in ethanol-water (9:1). The IR spectra of PVA filament soaked in ethanol-water depicted higher peak intensity at 1138 cm-1, indicating higher degree of crystallinity. Thermal analysis of the soaked PVA filaments showed higher melting enthalpies yet lower melting temperature (Tm) compared to unprocessed PVA. ML-PVA filaments were successfully printed into round-channeled tablets (10% infill) with higher surface area and area/volume ratios compared with the solid ones. The inclusion of channels in the tablet design modified their printing pattern causing an unexpected increase in their mass. The dissolution profiles of ML-PVA tablets were mainly dependent on their area/mass ratios. Our results show a simple approach to increase metformin HCl loading onto PVA and reveal the significance of tablet design, infill percentage, and printing pattern as they dictate the area, volume, and the mass of the tablet which impact its dissolution rate.


Assuntos
Desenho de Drogas , Hipoglicemiantes/química , Metformina/química , Impressão Tridimensional , Tecnologia Farmacêutica/métodos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Solubilidade , Comprimidos/química , Comprimidos/farmacocinética
5.
Pharm Dev Technol ; 24(6): 775-787, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31023115

RESUMO

This paper addresses the relevance of automated content testing for the rapid automated process development (RAPD). Our previous work demonstrated that RAPD allowed a fast and efficient development of a continuous capsule-filling process. Target was the mean weight and the relative standard deviation of the weight. Likewise important are the content and the content uniformity. However, an implementation demands a certain level of automation. In general, technology is available that can detect active pharmaceutical ingredient (API) inside the capsules but the final application is linked to additional development and investment in machinery. To eliminate doubts regarding the benefits of an automated content check within the RAPD we present an application example. First, an X-ray system was used to detect barium sulfate accurately inside capsules. Second, a process was developed where barium sulfate was filled. The concentration of excipients was modified in the experiments, as well as the setting of the process parameter. The obtained model provided an explicit understanding of the process. Subsequently, the content uniformity model was compared to a model of the capsule weight relative standard deviation, confirming the benefits of an automated content check in the RAPD. Moreover, we presented another example illustrating the advantages of a connected continuous filling process, which permits evaluation of all process steps and their interactions (i.e. evaluation of the entire process).


Assuntos
Sulfato de Bário/análise , Composição de Medicamentos/métodos , Excipientes/química , Gelatina/química , Cápsulas/química , Composição de Medicamentos/economia , Radiografia/economia , Radiografia/métodos , Tecnologia Farmacêutica/economia , Tecnologia Farmacêutica/métodos , Fatores de Tempo , Raios X
6.
Pharmazie ; 74(4): 227-230, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940306

RESUMO

Orodispersible films (ODF) have gained a remarkable success in the market, especially in pediatric and geriatric populations. The time required for an ODF to disintegrate is an essential quality and safety feature, thus an appropriate methodology is crucial. The USP disintegration apparatus is not appropriate for ODFs, as the determination of the end point is challenging and may not predict in-vivo disintegration time. The aim of the present study was to design and evaluate new disintegration protocols as an attempt to select the best approach that would reflect the in-vivo disintegration time in comparison to formerly reported procedures. Novel methods were designed, namely; the frame, the cell, and the agar plate methods, and compared to the previously reported methods; clamp and modified USP disintegration methods. Different ODFs were formulated using various viscosity grades of hydroxypropylmethyl cellulose. The mechanical characteristics of the prepared films were studied using texture analyzer and film folding endurance test. The resultant disintegration time of the films measured by the aforementioned methods were compared and correlated with its in-vivo time. Interestingly, the results obtained through the use of the cell method for the low viscosity polymers did not vary significantly from that of their in-vivo results (p>0.05). Moreover, the disintegration time of all polymeric films determined by the cell method revealed independently on their viscosity the highest correlation with in-vivo disintegration time (R² = 0.999). Such findings indicated the suitability of the cell method in predicting in-vivo disintegration time of low viscosity polymeric films.


Assuntos
Química Farmacêutica/métodos , Excipientes/química , Derivados da Hipromelose/química , Tecnologia Farmacêutica/métodos , Administração Oral , Composição de Medicamentos/métodos , Polímeros/química , Fatores de Tempo , Viscosidade
8.
Int J Pharm ; 563: 184-197, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30930190

RESUMO

Over the recent decade, benefits of continuous manufacturing (CM) of pharmaceutical products have been acknowledged widely. In contrast to batch processes, the product is not physically separated into batches in CM, which creates a few challenges. Product release is done for batches that should have a uniform quality over time, materials need to be tracked along the line, and locations to reject product must be established. To enable these, the residence time distributions (RTDs) of all unit operations must be known. In this paper, three CM tableting lines, each employing a different granulation technique, were investigated. The RTDs of their main unit operations were characterized, utilizing different measurement techniques successfully. All of these RTD measurement techniques could have been performed in any of the lines. The differences were related to the techniques themselves. Overall, external tracer with in-line Near-Infrared detection or color tracer with video recording proved most usable techniques, with few limitations. The RTDs for full lines were calculated by convoluting the unit operation RTDs, which enables material tracking through entire lines. The lines exhibited both truly continuous and quasi-continuous unit operations. Quasi-continuous unit operations divide the material stream into lots that can be utilized for tracking and rejection.


Assuntos
Tecnologia Farmacêutica/métodos , Comprimidos , Fatores de Tempo
9.
Eur J Pharm Sci ; 133: 205-213, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928511

RESUMO

With the rise of nanotherapeutics -and nano based products in general-, there has been an increasing need for better understanding and control of nano-particle (NP) synthesis and formulation processes. Size characteristics are often primary, if not critical, quality attributes of nanodispersions. Process Analytical Technology (PAT) tools for inline size characterization during dispersion processing are therefore highly desired. Traditional methods for NP sizing -based on Dynamic Light Scattering (DLS) - are typically ill-suited for direct inline application: (i) typical dispersion turbidities in process conditions often exceed by far the application limits for DLS (ii) agitation/flow typical for process conditions is incompatible with standard DLS and (iii) direct and convenient inline application requires a non-invasive PAT tool giving measurements on process relevant time scales. In this article we describe a new non-invasive PAT instrument - the NanoFlowSizer (patent pending)- which provides continuous, real-time, inline size and PSD characterization of concentrated and/or flowing nanodispersions in process environments. The instrument employs Fourier Domain low coherence interferometry, yielding path length resolved dynamic light scattering data of nanodispersions. Particle size characteristics can be analyzed from these data while effects of flow and/or multiple scattering are simultaneously characterized and accounted for. As first application examples we describe (i) real-time monitoring of NP size characteristics by remote measurement of mono and bi-disperse suspensions at different turbidities in a stirred beaker (ii) real-time monitoring of NP size characteristics using an online sampling loop with a micro-flow cell and (iii) real-time inline monitoring of size characteristics of a pharmaceutical nanoemulsion during industrial pilot scale nano-emulsification and for a pharmaceutical NP suspension during circulation, at flowrates ranging up to ~l/min.


Assuntos
Nanopartículas/química , Tecnologia Farmacêutica/métodos , Tamanho da Partícula , Poliestirenos/química , Suspensões
10.
Respir Res ; 20(1): 66, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943978

RESUMO

BACKGROUND: Interferon gamma (IFN-γ) is a clinically relevant immunomodulatory cytokine that has demonstrated significant potential in the treatment and management of respiratory diseases such as tuberculosis and pulmonary fibrosis. As with all large biomolecules, clinical translation is dependent on effective delivery to the disease site and delivery of IFN-γ as an aerosol offers a logical means of drug targeting. Effective localization is often hampered by instability and a lack of safe and efficient delivery systems. The present study sought to determine how effectively IFN-γ can be nebulized using two types of vibrating mesh nebulizer, each with differing mesh architectures, and to investigate the comparative efficiency of delivery of therapeutically active IFN-γ to the lungs. METHODS: Nebulization of IFN-γ was carried out using two different Aerogen vibrating mesh technologies with differing mesh architectures. These technologies represent both a standard commercially available mesh type (Aerogen Solo®) and a new iteration mesh (Photo-defined aperture plate (PDAP®). Extensive aerosol studies (aerosol output and droplet analysis, non-invasive and invasive aerosol therapy) were conducted in line with regulatory requirements and characterization of the stability and bioactivity of the IFN-γ post-nebulization was confirmed using SDS-PAGE and stimulation of Human C-X-C motif chemokine 10 (CXCL 10) also known as IFN-γ-induced protein 10KDa (IP 10) expression from THP-1 derived macrophages (THP-1 cells). RESULTS: Aerosol characterization studies indicated that a significant and reproducible dose of aerosolized IFN-γ can be delivered using both vibrating mesh technologies. Nebulization using both devices resulted in an emitted dose of at least 93% (100% dose minus residual volume) for IFN-γ. Characterization of aerosolized IFN-γ indicated that the PDAP was capable of generating droplets with a significantly lower mass median aerodynamic diameter (MMAD) with values of 2.79 ± 0.29 µm and 4.39 ± 0.25 µm for the PDAP and Solo respectively. The volume median diameters (VMD) of aerosolized IFN-γ corroborated this with VMDs of 2.33 ± 0.02 µm for the PDAP and 4.30 ± 0.02 µm for the Solo. SDS-PAGE gels indicated that IFN-γ remains stable after nebulization by both devices and this was confirmed by bioactivity studies using a THP-1 cell model in which an alveolar macrophage response to IFN-γ was determined. IFN-γ nebulized by the PDAP and Solo devices had no significant effect on the key inflammatory biomarker cytokine IP-10 release from this model in comparison to non-nebulized controls. Here we demonstrate that it is possible to combine IFN-γ with vibrating mesh nebulizer devices and facilitate effective aerosolisation with minimal impact on IFN-γ structure or bioactivity. CONCLUSIONS: It is possible to nebulize IFN-γ effectively with vibrating mesh nebulizer devices without compromising its stability. The PDAP allows for generation of IFN-γ aerosols with improved aerodynamic properties thereby increasing its potential efficiency for lower respiratory tract deposition over current technology, whilst maintaining the integrity and bioactivity of IFN-γ. This delivery modality therefore offers a rational means of facilitating the clinical translation of inhaled IFN-γ.


Assuntos
Broncodilatadores/administração & dosagem , Interferon gama/administração & dosagem , Nebulizadores e Vaporizadores , Telas Cirúrgicas , Tecnologia Farmacêutica/instrumentação , Vibração , Administração por Inalação , Aerossóis/administração & dosagem , Aerossóis/química , Broncodilatadores/química , Humanos , Interferon gama/química , Tecnologia Farmacêutica/métodos , Vibração/uso terapêutico
11.
Int J Pharm ; 563: 259-272, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30951859

RESUMO

Data provided by in situ sensors is always affected by some level of impreciseness as well as uncertainty in the measurements due to process operation disturbance or material property variance. In-process data precision and reliability should be considered when implementing active product quality control and real-time process decision making in pharmaceutical continuous manufacturing. Data reconciliation is an important strategy to address such imperfections effectively, and to exploit the data redundancy and data correlation based on process understanding. In this study, a correlation between tablet weight and main compression force in a rotary tablet press was characterized by the classical Kawakita equation. A load cell, situated at the exit of the tablet press chute, was also designed to measure the tablet production rate as well as the tablet weight. A novel data reconciliation strategy was proposed to reconcile the tablet weight measurement subject to the correlation between tablet weight and main compression force, in such, the imperfect tablet weight measurement can be reconciled with the much more precise main compression force measurement. Special features of the Welsch robust estimator to reject the measurement gross errors and the Kawakita model parameter estimation to monitor the material property variance were also discussed. The proposed data reconciliation strategy was first evaluated with process control open-loop and closed-loop experimental data and then integrated into the process control system in a continuous tablet manufacturing line. Specifically, the real-time reconciled tablet weight measurements were independently verified with an at-line Sotax Auto Test 4 tablet weight measurements every five minutes. Promising and reliable performance of the reconciled tablet weight measurement was demonstrated in achieving process automation and quality control of tablet weight in pilot production runs.


Assuntos
Confiabilidade dos Dados , Comprimidos , Tecnologia Farmacêutica/métodos , Automação , Pressão , Controle de Qualidade
12.
Drug Dev Ind Pharm ; 45(6): 999-1008, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30905176

RESUMO

The purpose of this research was to develop a fiber optic (FO) dissolution method for quantification of multiple actives in combination pharmaceutical tablets. FO dissolution allows direct API quantification in the vessel, obviating the need for error-prone facets of traditional dissolution methods. However, FO dissolution is potentially challenged by overlapping UV spectra, matrix effects, UV-active excipients, API interactions with excipients and media, and undissolved components attenuating the UV signal. These obstacles might render FO dissolution method development more complex than LC-end dissolution. The case study in this manuscript has the added complexity of a triple combination product (Midol), where acetaminophen, caffeine, and pyrilamine maleate exhibit similar release kinetics, share largely overlapping UV spectra and span an order of magnitude difference in concentration. Single-wavelength quantification required unique features for the actives of interest, which were not available for the formulation of interest without preprocessing. The methods employed for the quantification of actives were a partial least squares multivariate calibration and a peak area calibration, both using prepared mixtures as reference data. The selected combination tablet demonstrated collinear API release; therefore, individual quantification required a design of experiments for mixture design. The advantages of FO dissolution will be discussed in the context of the formulation under investigation. Additionally, some general guidelines will be suggested for the development of other FO methods.


Assuntos
Liberação Controlada de Fármacos , Tecnologia de Fibra Óptica , Controle de Qualidade , Tecnologia Farmacêutica/métodos , Aspirina/química , Aspirina/farmacocinética , Cafeína/química , Cafeína/farmacocinética , Calibragem , Química Farmacêutica/métodos , Química Farmacêutica/normas , Combinação de Medicamentos , Efedrina/análogos & derivados , Efedrina/química , Efedrina/farmacocinética , Excipientes/química , Guias como Assunto , Análise dos Mínimos Quadrados , Fenacetina/química , Fenacetina/farmacocinética , Solubilidade , Comprimidos , Tecnologia Farmacêutica/normas
13.
Chem Pharm Bull (Tokyo) ; 67(3): 271-276, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828004

RESUMO

The different states of water incorporated in wet granules were studied by a low-field benchtop 1H-NMR time-domain NMR (TD-NMR) instrument. Wet granules consisting different fillers [cornstarch (CS), microcrystalline cellulose (MCC), and D-mannitol (MAN)] with different water contents were prepared using a high-speed granulator, and then their spin-spin relaxation time (T2) was measured using the NMR relaxation technique. The experimental T2 relaxation curves were analyzed by the two-component curve fitting, and then the individual T2 relaxation behaviors of solid and water in wet granules were identified. According to the observed T2 values, it was confirmed that the molecular mobility of water in CS and MCC granules was more restricted than that in the MAN granule. The state of water appeared to be associated with the drying efficiency and moisture absorption capacity of wet granules. Thus, it was confirmed that the state of water significantly affected the wet granulation process and the characteristics of the resultant granules. In the final phase of this study, the effects of binders on the molecular mobility of water in granulation fluids and wet granules were examined. The state of water in granulation fluids was substantially changed by changing the binders. The difference was still detected in wet granules prepared by addition of these fluids to the fillers. In conclusion, TD-NMR can offer valuable knowledge on wet granulation from the viewpoint of molecular mobility of water.


Assuntos
Composição de Medicamentos/métodos , Preparações Farmacêuticas/química , Espectroscopia de Prótons por Ressonância Magnética/métodos , Água/química , Celulose/química , Umidade , Manitol/química , Tecnologia Farmacêutica/métodos , Temperatura Ambiente
14.
Eur J Pharm Biopharm ; 137: 140-147, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30818010

RESUMO

The purpose of this study was to apply the phenomenon of liquid jet breakup to the preparation of sustained-release microspheres. The mechanisms of liquid jet breakup in different jet states were investigated and the single factor method was used to study the effect of each process parameter on the particle size and size distribution of microspheres. Meantime, the prepared microspheres were characterized by morphology, drug loading, encapsulation efficiency and in vitro release. The results indicated that the process of liquid jet breakup could have 5 different states. The laminar flow state dominated when the Reynolds number (Re) was low, and the prepared microspheres had larger particle sizes. When the Re was high, the turbulent state was dominant and the microspheres had smaller particle sizes. And during the transition state from the laminar flow to the turbulence, the microspheres had a wide particle size distribution. Different process parameters could affect the particle size and distribution of microspheres by changing the Re, surface tension coefficient and viscosity. The microspheres prepared by liquid jet breakup were smooth and round with the drug loading of 35% and the encapsulation efficiency of 88%. In addition, when the polymeric carrier materials were different, the microspheres could have various drug release models such as sustained release with a lag phase, sustained release with no lag phase, pulsed release and so on, which could be applied widespread in the future.


Assuntos
Portadores de Fármacos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Risperidona/administração & dosagem , Tecnologia Farmacêutica/métodos , Química Farmacêutica/métodos , Preparações de Ação Retardada , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Microesferas , Tamanho da Partícula , Risperidona/química , Tensão Superficial , Viscosidade
15.
Eur J Pharm Biopharm ; 137: 164-174, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826474

RESUMO

Drying is an important unit operation in the manufacturing of polymer strip films as it affects various film quality attributes. Optimal design and control of convective drying process require models that capture the impact of critical process parameters such as air temperature and velocity on the temporal evolution of film thickness and moisture. Here, a detailed transport model was presented to capture moisture diffusion, heat transfer and moving boundary in convective drying of polymer strip films loaded with griseofulvin (GF), a poorly water-soluble drug. It incorporates a solvent diffusivity model based on free-volume theory. Experimentally, film precursor suspensions were prepared by mixing silica-coated and micronized GF powder with an aqueous solution of hydroxypropyl methylcellulose (HPMC)-glycerin. Films were cast and moisture-time variation during drying was measured. The transport model, whose diffusivity parameters were estimated using drying data at a reference condition, was validated at different drying conditions and wet film thicknesses. It delineates underlying mechanisms of drying kinetics and demarcates a smooth transition from constant-rate to falling-rate period. Overall, our results suggest that the transport model is capable of predicting the temporal evolution of moisture and final film thickness at different drying air velocities and temperatures with reasonable accuracy.


Assuntos
Química Farmacêutica/métodos , Griseofulvina/administração & dosagem , Polímeros/química , Tecnologia Farmacêutica/métodos , Dessecação/métodos , Difusão , Composição de Medicamentos/métodos , Glicerol/química , Griseofulvina/química , Derivados da Hipromelose/química , Dióxido de Silício/química , Solubilidade , Solventes/química , Temperatura Ambiente , Água/química
16.
Eur J Pharm Biopharm ; 137: 196-208, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826475

RESUMO

The problem of many gastroretentive systems is the mechanistic connection of drug release and gastric retention control. This connection could be successfully separated by formulating hollow tubes via hot-melt extrusion and sealing both tube ends, which led to immediately floating devices. The tube wall consisted of metformin crystals embedded in an inert polymer matrix of Eudragit® RS PO and E PO. Very high drug loadings of up to 80% (w/w) were used without generating a 'burst release'. Sustained release profiles from four to more than twelve hours were achieved by varying the polymer proportions without affecting the floatability. Buoyancy was found to mainly depend on the cylinder design, i.e. the outer to inner diameter ratio. This allowed the polymer/metformin composition to be changed without affecting buoyancy, i.e. a separation of floatability and release control was achieved. A prediction model was implemented that allowed for the buoyancy force to be determined with high accuracy by selecting a suitable ratio of outer to inner diameter of the modular tube die. Wall thickness and mass normalized surface area were identified as geometric parameters that mainly influenced the release properties. Conclusively, this study offers a highly flexible and rational manufacturing approach for the development of gastroretentive floating drug delivery systems.


Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos , Metformina/administração & dosagem , Ácidos Polimetacrílicos/química , Cristalização , Preparações de Ação Retardada , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Temperatura Alta , Metformina/química , Tecnologia Farmacêutica/métodos
17.
Eur J Pharm Biopharm ; 137: 148-163, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30836178

RESUMO

This work explores the use of UV imaging in solid dispersion systems. Solid dispersions are one of the common strategies used in improving the dissolution of poorly soluble drugs. Three manufacturing techniques (spray drying (SD), freeze drying (FD) and homogenising (HG)) are investigated. Differential Scanning Calorimetry (DSC) and X-Ray Powder Diffraction (XRPD) was used in characterising the solid dispersions. Advanced imaging was implemented to give an insight into how these solid dispersions performed. The DSC and XRPD results showed that all three methods and the various ratios studied produced amorphous solid dispersions. Ultra-Violet (UV) imaging of the pseudo Intrinsic Dissolution Rate (IDR) deduced only two samples to have superior pseudo IDR values to the IDR of the parent drug indomethacin (INDO). The whole dose imaging of the capsule formulation however showed all the samples (SD, FD and HG) to have superior dissolution to that of INDO which was in contrast to the IDR results. The UV images obtained from the determination of the pseudo IDR also showed a phenomenon the authors are reporting for the first time where increased polymer (Soluplus) content produced "web-like" strands that migrated to the top of the quartz cell which may have been responsible for the low pseudo IDR values. The authors also report for the first time using this UV imaging technique, the tip of a capsule coming off for drug to go into solution. The area under the curve suggested the best five samples dissolution wise to be 1:3 SD > 1:1 HG > 1:1 SD > 1:3 FD > 1:3 HG meaning a ratio of INDO to SOL in these dispersion of up to 1:3 being sufficient to produce significant dissolution increases. The developed interfacial (surface) area ratio (Sdr) highlighted how the surface area of the IDR compacts varied between the batches, in particular highlighting larger surface area gains for the FD and HG compacts. A choice of instrumentation/techniques to use in making solid dispersions may well come down to cost or instrument availability for a formulator as all three techniques were successful in improving the dissolution of indomethacin. This work thus highlights the importance of having both complimentary IDR and whole dosage imaging techniques in giving a better understanding of solid dispersion systems.


Assuntos
Química Farmacêutica/métodos , Indometacina/química , Espectrofotometria Ultravioleta/métodos , Tecnologia Farmacêutica/métodos , Varredura Diferencial de Calorimetria/métodos , Dessecação , Liberação Controlada de Fármacos , Liofilização , Polietilenoglicóis/química , Polímeros/química , Polivinil/química , Solubilidade , Propriedades de Superfície , Difração de Raios X/métodos
18.
Eur J Pharm Biopharm ; 137: 209-217, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30836181

RESUMO

Orodispersible films (ODFs) have a high potential to accelerate the individualized medication. The films can be produced as drug-free templates and subsequently printed with an API (active pharmaceutical ingredient) solution or suspension according to the needs of the patient. While the printing technology already enables a precise dosing of fluids, there is still a high need of suitable, edible templates with elevated loading capacity. The structured orodispersible film templates (SOFTs) developed in this study should overcome this void. The SOFTs are pervaded with pores to realize a high API load into the film structure and possess a closed bottom side to prevent the printed fluids to pass through the film. They consist of a water-soluble cellulose derivative and are produced with the solvent casting method. This study focused on the influence of the formulation of the film casting mass on the film properties, like porosity and disintegration time due to changed pore sizes and numbers. Due to the porous film structure a mass load of up to 6.1 mg cm-2 could be realized already in SOFTs, but, higher loads are feasible. The mechanical film properties could further be improved by additional matrix material in the suspension formulation, also inhibiting particle agglomeration and aggregation during the drying process, and positively influencing the dissolution behavior of the applied nanoparticles. An application of a protection layer on top of the loaded SOFTs improves the handling safety by inhibiting contact to the API and it prevents a removal of the particles from the film surface.


Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos , Nanopartículas , Tecnologia Farmacêutica/métodos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Derivados da Hipromelose/química , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Porosidade , Solubilidade , Solventes/química , Fatores de Tempo
19.
Biotechnol Lett ; 41(4-5): 495-502, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30927135

RESUMO

Mupirocin is an antibiotic from monocarboxylic acid class used as antibacterial agent against methicillin-resistant Staphylococcus aureus (MRSA) and can be obtained as a mixture of four pseudomonic acids by Pseudomonas fluorescens biosynthesis. Nowadays improving antibiotics occupies an important place in the pharmaceutical industry as more and more resistant microorganisms are developing. Mupirocin is used to control the MRSA outbreaks, for infections of soft tissue or skin and for nasal decolonization. Due to its wide use without prescription, the microorganism's resistance to Mupirocin increased from up to 81%, thus becoming imperative its control or improvement. As the biotechnological production of Mupirocin has not been previously reviewed, in the present paper we summarize some consideration on the biochemical process for the production of pseudomonic acids (submerged fermentation and product recovery). Different strains of Pseudomonas, different culture medium and different conditions for the fermentation were analysed related to the antibiotics yield and the product recovery step is analysed in relation to the final purity. However, many challenges have to be overcome in order to obtain pseudomonic acid new versions with better properties related to antibacterial activity.


Assuntos
Antibacterianos/biossíntese , Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Mupirocina/biossíntese , Mupirocina/farmacologia , Pseudomonas fluorescens/metabolismo , Infecções Estafilocócicas/tratamento farmacológico , Portador Sadio/tratamento farmacológico , Portador Sadio/microbiologia , Farmacorresistência Bacteriana , Fermentação , Humanos , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções dos Tecidos Moles/microbiologia , Infecções Estafilocócicas/microbiologia , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Infecções Cutâneas Estafilocócicas/microbiologia , Tecnologia Farmacêutica/métodos
20.
J Pharm Biomed Anal ; 168: 189-200, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30825802

RESUMO

Natural products (NPs) have a long history of clinical use and are rich source of bioactive compounds. The development of tools and techniques for identifying and analyzing NP bioactive compounds to ensure their quality and discover new drugs is thus very important and still in demand. Screening techniques have proven highly useful for screening and analyzing active components in complex mixtures, which rely on cell culture, dialysis, ultrafiltration, chromatographic methods and target molecule immobilization, using biological targets to identify the active compounds. The recent progress in biological screening techniques in the field of natural products is reviewed here. This includes a review on the strategy and application of the screening methods, their detailed description and discussion of their existing limitations of the different models along with prospective in future development of screening techniques.


Assuntos
Produtos Biológicos/farmacologia , Descoberta de Drogas/métodos , Tecnologia Farmacêutica/métodos , Animais , Produtos Biológicos/química , Técnicas de Cultura de Células , Cromatografia/métodos , Humanos , Ultrafiltração/métodos
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