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1.
AAPS PharmSciTech ; 22(5): 184, 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34142250

RESUMO

Hot-melt extrusion has found extensive application as a feasible pharmaceutical technological option over recent years. HME applications include solubility enhancement, taste masking, and sustained drug release. As bioavailability enhancement is a hot topic of today's science, one of the main applications of HME is centered on amorphous solid dispersions. This review describes the most significant aspects of HME technology and its use to prepare solid dispersions as a drug formulation strategy to enhance the solubility of poorly soluble drugs. It also addresses molecular and thermodynamic features critical for the physicochemical properties of these systems, mainly in what concerns miscibility and physical stability. Moreover, the importance of applying the Quality by Design philosophy in drug development is also discussed, as well as process analytical technologies in pharmaceutical HME monitoring, under the current standards of product development and regulatory guidance. Graphical Abstract.


Assuntos
Química Farmacêutica/métodos , Portadores de Fármacos/síntese química , Desenvolvimento de Medicamentos/métodos , Tecnologia de Extrusão por Fusão a Quente/métodos , Disponibilidade Biológica , Composição de Medicamentos/métodos , Composição de Medicamentos/tendências , Tecnologia de Extrusão por Fusão a Quente/tendências , Temperatura Alta , Solubilidade , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/tendências , Termodinâmica
2.
AAPS PharmSciTech ; 22(5): 190, 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34159445

RESUMO

In direct compression of tablets, it is crucial to maintain content uniformity within acceptable margins, especially in formulations with low drug loading. To assure it, complex and multistep mixing processes are utilized in the industry. In this study, we suggest the use of a simple segregation test to evaluate mixing process performance and mixture segregation to produce tablets having satisfying content uniformity while keeping the process as simple and low cost as possible. Eventually, the formulation propensity to segregation can be evaluated using process analytical technology (PAT) to adjust the mixing process parameters to changing source drug properties. In this study, that approach was examined on a model drug with a broad batch-to-batch variability in particle size and shape. Excipients were chosen so that the resulting blend composition mimicked some marketed formulations. For each drug batch, two formulation blends were prepared through different preparation processes (one simple and one complex) and subsequently subjected to segregation tests. From those, segregation coefficients were obtained to compare segregation tendencies and homogeneity robustness between the drug batches and the blend preparation methods. The inter-particulate interactions were substantially influenced by the drug particle morphology and size and resulted in different segregation behavior. Based on these findings, a simple segregation test proved to be a useful tool for determining the suitability of different batches of the model drug to be used in a certain formulation. Moreover, for a particular batch A, the test revealed a potential for mixing process simplification and therefore process intensification and cost reduction.


Assuntos
Composição de Medicamentos/métodos , Excipientes/síntese química , Tamanho da Partícula , Tecnologia Farmacêutica/métodos , Pós , Pressão , Comprimidos
3.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071328

RESUMO

Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.


Assuntos
Enzimas/química , Pró-Fármacos/química , Aciclovir/química , Atenolol/química , Atovaquona/química , Catálise , Química Farmacêutica/métodos , Decitabina/química , Dopamina/química , Concentração de Íons de Hidrogênio , Hidrólise , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Conformação Molecular , Nucleosídeos/química , Fenilefrina/química , Prótons , Teoria Quântica , Software , Tecnologia Farmacêutica/métodos , Temperatura , Ácido Tranexâmico/química
4.
AAPS PharmSciTech ; 22(4): 148, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33954856

RESUMO

A practice-based approach for the scale-up of fluid bed granulation in the context of drug product development is presented and evaluated in this work in the context of clinical drug product manufacturing development. The approach is based on the use of a scale-independent parameter, the evaporation energy to drying capacity ratio (EE/DC), and a process model. The EE/DC ratio is used to quantify, in one scale-independent parameter, the combined effect of the most impacting process parameters and to identify the spray rates to be used at different scales to achieve similar granule moisture rate of change. The process model is used to de-risk scale-up, by allowing the consideration of equipment differences across scales and process dynamics, which are aspects not accounted for by the EE/DC ratio. This approach was tested by scaling up the fluid bed granulation process of two formulations, one placebo and one active, from laboratory to pilot scales. This work showed how it was possible to use a simple scale-up approach coupled with a process model to achieve right first-time scale-up of a fluid bed granulation process and show how a placebo formulation could be used instead of active material, first to define the process at laboratory scale and then to de-risk the scale-up, by identifying scale-dependent differences.


Assuntos
Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Tamanho da Partícula , Tecnologia Farmacêutica/métodos , Dessecação/métodos
5.
AAPS PharmSciTech ; 22(3): 85, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33650023

RESUMO

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.


Assuntos
Composição de Medicamentos/métodos , Naproxeno/administração & dosagem , Naproxeno/síntese química , Tecnologia Farmacêutica/métodos , Administração Oral , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Formas de Dosagem , Liberação Controlada de Fármacos , Excipientes/administração & dosagem , Excipientes/síntese química , Excipientes/farmacocinética , Naproxeno/farmacocinética , Comprimidos
6.
AAPS PharmSciTech ; 22(3): 97, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33694033

RESUMO

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.


Assuntos
Módulo de Elasticidade , Excipientes/síntese química , Modelos Teóricos , Tamanho da Partícula , Tecnologia Farmacêutica/métodos , Composição de Medicamentos/instrumentação , Excipientes/farmacocinética , Análise Multivariada , Pós , Comprimidos , Resistência à Tração
7.
AAPS PharmSciTech ; 22(3): 98, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33709195

RESUMO

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.


Assuntos
Química Farmacêutica/métodos , Ciprofloxacina/síntese química , Tamanho da Partícula , Tecnologia Farmacêutica/métodos , Cristalização/métodos , Dessecação , Composição de Medicamentos/métodos , Pós , Comprimidos
8.
Biomed Res Int ; 2021: 6653967, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33521128

RESUMO

3D printing technology is widely used in the field of implantable medical device in recent decades because of its advantages in high precision, complex structure, and high material utilization. Based on the characteristics of 3D printing technology, this paper reviews the manufacturing process, materials, and some typical products of 3D printing implantable medical devices and analyzes and summarizes the development trend of 3D printed implantable medical devices.


Assuntos
Impressão Tridimensional , Próteses e Implantes , Desenho de Prótese/métodos , Tecnologia Farmacêutica/métodos , Materiais Biocompatíveis , Prótese Vascular , Cerâmica , Humanos , Prótese Articular , Lasers , Ortopedia , Polímeros/química , Stents
9.
AAPS PharmSciTech ; 22(2): 57, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33502633

RESUMO

Recent advances in molded vial manufacturing enabled manufacturers to use a new manufacturing technique to achieve superior homogeneity of the vial wall thickness. This study evaluated the influence of the different manufacturing techniques of molded vials and glass compositions on vial heat transfer in freeze-drying. Additionally, the influence of using empty vials as thermal shielding on thermal characteristics of edge and center vials was investigated. The vial heat transfer coefficient Kv was determined gravimetrically for multiple vial systems. The results showed superior heat transfer characteristics of the novel manufacturing technique as well as differences in heat transfer for the different glass compositions. Empty vials on the outside of the array did not influence center vial Kv values compared to a full array. The direct contact area and vial bottom curvature and their correlation to heat transfer parameters were analyzed across multiple vial systems. A new approach based on light microscopy to describe the vial bottom curvature more accurately was described. The presented results for the contact area allowed for an approximation of the pressure-independent heat transfer parameter KC. The results for the vial bottom curvature showed a great correlation to the pressure-dependent heat transfer parameter KD. Overall, the results highlighted how a thorough geometrical characterization of vials with known heat transfer characteristics could be used to predict thermal characteristics of new vial systems as an alternative to a time-consuming gravimetric Kv determination. Primary drying times were simulated to show the influence of Kv on drying performance.


Assuntos
Embalagem de Medicamentos/métodos , Liofilização/métodos , Tecnologia Farmacêutica/métodos , Vidro/química , Temperatura Alta
10.
AAPS PharmSciTech ; 22(1): 25, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33400033

RESUMO

Continuous manufacturing (CM) is an emerging technology which can improve pharmaceutical manufacturing and reduce drug product quality issues. One challenge that needs to be addressed when adopting CM technology is material traceability through the entire continuous process, which constitutes one key aspect of control strategy. Residence time distribution (RTD) plays an important role in material traceability as it characterizes the material spreading through the process. The propagation of upstream disturbances could be predictively tracked through the entire process by convolution of the disturbance and the RTD. The present study sets up the RTD-based modeling framework in a commonly used process modeling environment, gPROMS, and integrates it with existing modules and built-in tools (e.g., parameter estimation). Concentration calculations based on the convolution integral requires access to historical stream property information, which is not readily available in flowsheet modeling platforms. Thus, a novel approach is taken whereby a partial differential equation is used to propagate and store historical data as the simulation marches forward in time. Other stream properties not modeled by an RTD are determined in auxiliary modules. To illustrate the application of the framework, an integrated RTD-auxiliary model for a continuous direct compression manufacturing line was developed. An excellent agreement was found between the model predictions and experiments. The validated model was subsequently used to assess in-process control strategies for feeder and material traceability through the process. Our simulation results show that the employed modeling approach facilitates risk-based assessment of the continuous line by promoting our understanding on the process.


Assuntos
Tecnologia Farmacêutica/métodos , Simulação por Computador , Composição de Medicamentos
11.
AAPS PharmSciTech ; 22(1): 41, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420526

RESUMO

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.


Assuntos
Salicilamidas/química , Tecnologia Farmacêutica/métodos , Composição de Medicamentos/métodos , Tamanho da Partícula , Comprimidos
12.
AAPS PharmSciTech ; 22(1): 49, 2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33458797

RESUMO

Personalized medicine has the potential to revolutionize the healthcare sector, its goal being to tailor medication to a particular individual by taking into consideration the physiology, drug response, and genetic profile of that individual. There are many technologies emerging to cause this paradigm shift from the conventional "one size fits all" to personalized medicine, the major one being three-dimensional (3D) printing. 3D printing involves the establishment of a three-dimensional object, in a layer upon layer manner using various computer software. 3D printing can be used to construct a wide variety of pharmaceutical dosage forms varying in shape, release profile, and drug combination. The major technological platforms of 3D printing researched on in the pharmaceutical sector include inkjet printing, binder jetting, fused filament fabrication, selective laser sintering, stereolithography, and pressure-assisted microsyringe. A possible future application of this technology could be in a clinical setting, where prescriptions could be dispensed based on individual needs. This manuscript points out the various 3D printing technologies and their applications in research for fabricating pharmaceutical products, along with their pros and cons. It also presents its potential in personalized medicine by individualizing the dose, release profiles, and incorporating multiple drugs in a polypill. An insight on how it tends to various populations is also provided. An approach of how it can be used in a clinical setting is also highlighted. Also, various challenges faced are pointed out, which must be overcome for the success of this technology in personalized medicine.


Assuntos
Medicina de Precisão , Impressão Tridimensional , Sistemas de Liberação de Medicamentos , Humanos , Estereolitografia , Tecnologia Farmacêutica/métodos
13.
AAPS PharmSciTech ; 22(1): 37, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33409925

RESUMO

In 2017, there are 451 million people with diabetes worldwide. These figures were expected to increase to 693 million by 2045. The research and development of hypoglycemic drugs has become a top priority. Among them, sulfonylurea hypoglycemic drugs such as glipizide are commonly used in non-insulin-dependent type II diabetes. In order to adapt to the wide range of hypoglycemic drugs and the different individual needs of patients, this topic used glipizide as a model drug, and prepared glipizide preparations with 3D printing technology. The purpose of this study was to investigate the prescription applicability and control-release behavior of structure and explore the application prospects of 3D printing personalized drug delivery formulations. This article aims to establish a production process for personalized preparations based on 3D printing technology. The process is easy to obtain excipients, universal prescriptions, flexible dosages, exclusive customization, and integrated automation. In this paper, the UV method was used to determine the in vitro release and content analysis method of glipizide; the physical and chemical properties of the glipizide were investigated. The established analysis method was inspected and evaluated, and the experimental results met the methodological requirements. Glipizide controlled-release tablets were prepared by the semisolid extrusion (SSE) method using traditional pharmaceutical excipients combined with 3D printing technology. The formulation composition, in vitro release, and printing process parameters of the preparation were investigated, and the final prescription and process parameters (traveling speed 6.0-7.7 mm/s and extruding speed 0.0060-0.0077 mm/s) were selected through comprehensive analysis. The routine analysis results of the preparation showed that the performance of the preparation meets the requirements. In order for 3D printing technology to play a better role in community medicine and telemedicine, this article further explored the universality of the above prescription and determined the scope of application of prescription drugs and dosages. Glipizide, gliclazide, lornoxicam, puerarin, and theophylline were used as model drugs, and the range of drug loading percentage was investigated. The results showed when the solubility of the drug is 9.45 -8.34 mg/mL, and the drug loading is 3-43%; the release behavior is similar.


Assuntos
Formas de Dosagem , Medicina de Precisão , Impressão Tridimensional , Tecnologia Farmacêutica/métodos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Excipientes/química , Glipizida/química , Glipizida/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Solubilidade , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/uso terapêutico , Comprimidos
14.
Int J Pharm ; 595: 120243, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33484923

RESUMO

Cardiovascular diseases constitute a number of conditions which are the leading cause of death globally. To combat these diseases and improve the quality and duration of life, several cardiac implants have been developed, including stents, vascular grafts and valvular prostheses. The implantation of these vascular prosthesis has associated risks such as infection or blood clot formation. In order to overcome these limitations medicated vascular prosthesis have been previously used. The present paper describes a 3D printing method to develop medicated vascular prosthesis using fused deposition modelling (FDM) technology. For this purpose, rifampicin (RIF) was selected as a model molecule as it can be used to prevent vascular graft prosthesis infection. Thermoplastic polyurethane (TPU) and RIF were combined using hot melt extrusion (HME) to obtain filaments containing RIF concentrations ranging between 0 and 1% (w/w). These materials are capable of providing RIF release for periods ranging between 30 and 80 days. Moreover, TPU-based materials containing RIF were capable of inhibiting the growth of Staphylococcus aureus. This behaviour was observed even for TPU-based materials containing RIF concentrations of 0.1% (w/w). TPU containing 1% (w/w) of RIF showed antimicrobial properties even after 30 days of RIF release. Alternatively, these methods were used to prepare dipyridamole containing TPU filaments. Finally, using a dual extrusion 3D printer vascular grafts containing both drugs were prepared.


Assuntos
Antibacterianos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Poliuretanos/química , Rifampina/farmacocinética , Tecnologia Farmacêutica/métodos , Células Sanguíneas/efeitos dos fármacos , Prótese Vascular/efeitos adversos , Preparações de Ação Retardada/química , Dipiridamol/farmacocinética , Liberação Controlada de Fármacos , Desenho de Equipamento/métodos , Células Endoteliais da Veia Umbilical Humana , Humanos , Inibidores da Agregação Plaquetária/farmacocinética , Poliuretanos/uso terapêutico , Impressão Tridimensional , Infecções Estafilocócicas/etiologia , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Trombose/etiologia , Trombose/prevenção & controle
15.
Int J Pharm ; 595: 120069, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33421586

RESUMO

In pharmaceutical wet granulation, drying is a critical step in terms of energy and material consumption, whereas granule moisture content and size are important process outcomes that determine tabletting performance. The drying process is, however, very complex due to the multitude of interacting mechanisms on different scales. Building robust physical models of this process therefore requires detailed data. Current data collection methods only succeed in measuring the average moisture content of a size fraction of granules, whereas this property rather follows a distribution that, moreover, contains information on the drying patterns. Therefore, a measurement method is devised to simultaneously characterise the moisture content and size of individual pharmaceutical granules. A setup with near-infrared chemical imaging (NIR-CI) is used to capture an image of a number of granules, in which the absorbance spectra are used for deriving the moisture content of the material and the size of the granules is estimated based on the amount of pixels containing pharmaceutical material. The quantification of moisture content based on absorption spectra is performed with two different regression methods, Partial Least Squares regression (PLSR) and Elastic Net Regression (ENR). The method is validated with particle size data for size determination, loss-on-drying (LOD) data of average moisture contents of granule samples and, finally, batch fluid bed experiments in which the results are compared to the most detailed method to date. The individual granule moisture contents confirmed again that granule size is an important factor in the drying process. The measurement method can be used to gain more detailed experimental insight in different fluidisation and particulate processes, which will allow building of robust process models.


Assuntos
Espectroscopia de Luz Próxima ao Infravermelho/instrumentação , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Tecnologia Farmacêutica/instrumentação , Tecnologia Farmacêutica/métodos , Água/análise , Calibragem , Dessecação/métodos , Análise dos Mínimos Quadrados , Modelos Químicos , Tamanho da Partícula , Material Particulado/química , Pós/química , Temperatura
16.
Int J Pharm ; 595: 120229, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33484927

RESUMO

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.


Assuntos
Excipientes/química , Comprimidos/química , Tecnologia Farmacêutica/métodos , Água/química , Algoritmos , Excipientes/análise , Cinética , Reprodutibilidade dos Testes , Análise Espaço-Temporal , Comprimidos/análise , Microtomografia por Raio-X/métodos
17.
Int J Pharm ; 595: 120225, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33486019

RESUMO

Localized delivery to oral mucositis ulcerations requires specialized dosage forms, (e.g. in situ forming gels) delivered to the site in relatively low volumes. However, this is challenging for drugs with low solubility such as Bupivacaine γ-Linoleate (Bup-γL). The objective of this study is to develop an in situ forming gel with enhanced loading of Bup-γL for oral mucositis pain control. Two co-solvents (PEG400 and ethanol) and eight solubilizers (Tween 80, sodium lauryl sulfate, Cremophor® RH40, Cremophor® EL, Kolliphor® HS 15, Soluplus®, PEG 3350 and PEG8000) were screened for their capability to solubilize Bup-γL. Among all tested solubilizers, sodium lauryl sulfate (SLS) showed the highest solubilizing capacity (8.83 ± 0.94 mg/mL). This was considered to be a consequence of the similarity between the structure of SLS and Bup-γL. On the addition of SLS to the in situ forming gels, the drug loading was enhanced from ~6.5 to ~10.5 mg/ml. The formulations were characterized for their gelation temperature, rheological properties, in vitro drug release and short-term storage stability. The gelation temperatures of the in situ forming gel formulations were significantly reduced with enhanced drug loading. The in vitro drug release profiles showed good fit to both the first order and the Higuchi models. Formulations with SLS demonstrated sustained drug release (time to plateau ~7 h) compared with formulations without SLS (time to plateau ~3.5 h). This study offers an effective strategy to enhance drug loading of in situ forming gels. The enhanced drug loading will reduce the dosing volume and as such is expected to reduce any unwanted numbing of the healthy mucosa.


Assuntos
Preparações de Ação Retardada/química , Géis/química , Dor/tratamento farmacológico , Estomatite/tratamento farmacológico , Tecnologia Farmacêutica/métodos , Bupivacaína/análogos & derivados , Bupivacaína/uso terapêutico , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Excipientes/química , Concentração de Íons de Hidrogênio , Reologia , Solubilidade , Solventes/química , Temperatura , Viscosidade
18.
Int J Pharm ; 595: 120197, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33486041

RESUMO

Oral films (OFs) continue to attract attention as drug delivery systems, particularly for pedatric and geriatric needs. However, immiscibility between different polymers limits the full potential of OFs from being explored. One example is pullulan (PUL), a novel biopolymer which often has to be blended with other polymers to reduce cost and alter its mechanical properties. In this study, the state-of-the-art in fabrication techniques, three-dimensional (3D) printing was used to produce hybrid film structures of PUL and hydroxypropyl methylcellulose (HPMC), which were loaded with caffeine as a model drug. 3D printing was used to control the spatial deposition of films. HPMC was found to increase the mean mechanical properties of PUL films, where the tensile strength, elastic modulus and elongation break increased from 8.9 to 14.5 MPa, 1.17 to 1.56 GPa and from 1.48% to 1.77%, respectively. In addition, the spatial orientation of the hybrid films was also explored to determine which orientation could maximize the mechanical properties of the hybrid films. The results revealed that 3D printing could modify the mechanical properties of PUL whilst circumventing the issues associated with immiscibility.


Assuntos
Glucanos/química , Derivados da Hipromelose/química , Impressão Tridimensional , Tecnologia Farmacêutica/métodos , Administração Oral , Formas de Dosagem , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Elasticidade , Pressão , Reologia/métodos , Resistência à Tração , Viscosidade
19.
J Pharm Sci ; 110(2): 615-618, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33212162

RESUMO

It is anticipated that effective vaccines will enable the resumption of social and economic normalcy. Current calls for masking, social distancing and other restrictive measures for the public-good are difficult to enforce and are unstainable. As ~2-4% of the 50 million SARS-CoV2-infected have succumbed to Covid-19, the US department of Health and Human Services has organized a public-private partnership called Operation Warp Speed (OWS) to develop, produce and deliver 300 million doses of safe and effective vaccines with a January 2021 target. While a majority of the 300+ Covid-19 vaccine candidates are in various stages of preclinical and early-stage clinical testing, 6 clinical candidates are supported with over 10 billion USD plus integrated resources under the OWS agenda. This unprecedented approach is investing in the manufacture of product candidates ahead of product approval. It is enabled by new gene and recombinant pharmaceutical platform technologies that are accelerating the clinical study timeline from ~10 to less than 1 year. It is anticipated that one or more of the 6 candidates under the OWS initiative will be safe, effective and provide a sustained immune response to prevent infection and disease progression. This way, social and economic activities could return to normalcy.


Assuntos
Vacinas contra COVID-19/economia , COVID-19/prevenção & controle , Desenvolvimento de Medicamentos/economia , Parcerias Público-Privadas , Tecnologia Farmacêutica/economia , Desenvolvimento de Medicamentos/métodos , Humanos , Parcerias Público-Privadas/economia , Parcerias Público-Privadas/organização & administração , SARS-CoV-2 , Tecnologia Farmacêutica/métodos , Fatores de Tempo
20.
Methods Mol Biol ; 2180: 99-127, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32797409

RESUMO

Freeze-drying is a complex process despite the relatively small number of steps involved, since the freezing, sublimation, desorption, and reconstitution processes all play a part in determining the success or otherwise of the final product qualities, and each stage can impose different stresses on a product. This is particularly the case with many fragile biological samples, which require great care in the selection of formulation additives such as protective agents and other stabilizers. Despite this, the process is widely used, not least because once any such processing stresses can be overcome, the result is typically a significantly more stable product than was the case with the starting material. Indeed, lyophilization may be considered a gentler method than conventional air-drying methods, which tend to apply heat to the product rather than starting by removing heat as is the case here. Additionally, due to the high surface area to volume ratio, freeze-dried materials tend to be drier than their conventionally dried counterparts and also rehydrate more rapidly. This chapter provides an overview of freeze-drying (lyophilization) of biological specimens with particular reference to the importance of formulation development, characterization, and cycle development factors necessary for the commercial exploitation of freeze-dried products, and reviews the recent developments in analytical methods which have come to underpin modern freeze-drying practice.


Assuntos
Criopreservação/métodos , Crioprotetores/farmacologia , Estabilidade de Medicamentos , Liofilização/métodos , Tecnologia Farmacêutica/métodos , Animais , Humanos
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