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@#Oral route drug delivery system is still considered as the most convenient and patient friendly drug delivery route. Over the decades, many research has been performed to improve the functionality oral dosage form. Orally disintegrating film (ODF) is a newer oral drug delivery system, which is in the form of a thin film that will disintegrate in the oral cavity within a matter of seconds. The aim of this review paper is to recap ODF, its benefits, formulation contents and manufacturing method. With more research and development work has been conducted on ODF, the dosage form is expected to be manufactured and scaled up to be commercializable products to be sold in the market.
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@#Most drugs taste bitter and irritating, resulting in poor compliance of patients, and the bad odor affects the therapeutic effect. The successful research and development of a drug should not only conform to the five quality characteristics of effectiveness, stability, safety, uniformity and economy, but also the compliance of patients to drugs with bad odor. The development of taste masking techniques is critical for bitter drugs.This review describes the principles, advantages and drawbacks of traditional taste masking techniques, and introduces the mechanism and application of novel taste masking techniques, such as melt granulation, hot melt extrusion, 3D printing, drug complex preparation, and bitter taste inhibitors. The in vitro evaluation methods of drug taste masking effect, such as functional magnetic resonance imaging, in vitro dissolution, and electronic tongue technology, are described. And introduce in vivo evaluation methods, such as animal and human taste, in the field of taste masking effect. A new strategy of BP neural network prediction model for drug taste evaluation is proposed, with a view to providing theoretical reference for the future research on drug taste masking.
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One of the challenges in developing three-dimensional printed medicines is related to their stability due to the manufacturing conditions involving high temperatures.This work proposed a new pro-tocol for preformulation studies simulating thermal processing and aging of the printed medicines,tested regarding their morphology and thermal,crystallographic,and spectroscopic profiles.Gener-ally,despite the strong drug-polymer interactions observed,the chemical stability of the model drugs was preserved under such conditions.In fact,in the metoprolol and Soluplus? composition,the drug's solubilization in the polymer produced a delay in the drug decomposition,suggesting a pro-tective effect of the matrix.Paracetamol and polyvinyl alcohol mixture,in turn,showed unmistakable signs of thermal instability and chemical decomposition,in addition to physical changes.In the presented context,establishing protocols that simulate processing and storage conditions may be decisive for obtaining stable pharmaceutical dosage forms using three-dimensional printing technology.
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In this study, the reverse engineering technology was used to analyze the prescription and process of Doppelherz® Energy DIRECT, based on the composition of the prescription on the official website of the product, the detection method of composition is established according to the pharmacopoeia and literature information, combined with gravimetric analysis to complete prescription analysis. The prescription composition of the reference listed drug was determined to be composed of caffeine, taurine, vitamin B, anhydrous glucose, citric acid, sorbitol, sucralose, magnesium salts of fatty acids, in which the glucose content was 71.4%, the citric acid content was 7.0% and the magnesium salts of fatty acids content was < 5.8%. According to patent inquiry, Raman imaging and other technologies, the preparation process of the marketed preparation has been basically obtained, and the development of the self-made preparation has been completed on this basis. The study was approved by the Ethics Committee of the Academy of Military Medical Sciences. Combined with the results of the taste evaluation experiment and the caffeine dissolution test of the preparation in 1 min, the hot-melt extrusion technology was screened out as the taste-masking technology of the self-made preparation, the parameters of the hot-melt extrusion process were screened by differential scanning calorimetry analysis, and finally a product with good taste and qualified quality was obtained, which provided a reference method for the research and development of related preparations.
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OBJECTIVE: To prepare a ternary supersaturated indomethacin (IND) solid dispersion and investigate its characteristics by screening carrier materials with different functions based on quality by design (QbD) concept. METHODS: Based on dissolution tests, the carriers with solubilization function were selected and the appropriate drug loading ratio of binary solid dispersion was determined. The material as inhibitor of precipitation was chosen using the solvent shift method. The IND ternary supersaturated solid dispersion was prepared by the hot melt extrusion of IND, solubilization material and precipitation inhibitor. The dispersion state of IND was identified by differential scanning calorimetry and powder X-ray diffraction, and its characteristics were explored by the powder wettability test and the stability test. RESULTS: The binary IND solid dispersion with Eudragit EPO could sharply increase IND dissolution rate with a behavior of more than 80%dissolution within 5 min but subsequently followed an obvious concentration decline. Kollidon VA64 had a satisfactory effect of precipitation inhibition for IND supersaturated solution in that the concentration of 0.1% could keep the 50 μg•mL-1 IND solution unchanged within 30 min. The ternary solid dispersion with a mass ratio of 1:2:0.3 (IND:EPO:VA64) could significantly increase the dissolution of IND, eliminating the crystallization and precipitation of the drug in the supersaturated system during the dissolution process and enabling the drug to maintain amorphous form within 3 months. CONCLUSION: Based on the understanding of the functions of different carrier materials and the QbD concept, it could effectively improve the formulation design of solid dispersions. The prepared ternary IND solid dispersions have excellent drug dissolution behavior.
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The aim of this study is to prepare acetaminophen sustained-release tablets by hot melt extrusion 3D printing technology based on the concept of "Quality by Design" (QbD). Firstly, the failure mode and effect analysis (FMEA) was used to determine the critical process parameters (CPPs), then full-factor experimental design was used to analyze the critical quality attributes (CQAs) and to establish the design space. The results showed that the content of plasticizer, the path spacing and the shell numbers are independent variable for the experimental design. The design space was concluded to be plasticizer content: 9%, and the shell number: 3-5, the path spacing: 1.05-1.2 mm. In this study, 3D printing technology was used to prepare acetaminophen sustained-release tablets in accordance with the concept of QbD, which improved the durability of the process and ensured the uniform and controllable quality of the preparation and also provided experimental basis for personalised medicine.
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Objective: To prepare acetaminophen tablets by hot-melt extrusion 3D printing technique. Methods:The acetaminophen tablets were prepared by the direct combination of hot-melt extrusion technology and 3D printing. Soluplus was used as hot-melt matrix and PEG6000 as plasticizer. The physical properties and molecular structure of the materials in the tablets were investigated, and in vitro release of the tablets was studied. Results:The printing of acetaminophen tablets was completed successfully, and the size, internal structure and shape of the tablets could be changed by 3D printing technology. The thermogravimetric analysis showed that all materials could maintain thermal stability at printing temperature. The results of crystal form study showed that all materials solidified in a amorphous form after the hot-melt 3D printing. The IR, Raman, MS and 1 H NMR data showed that the molecular structure of acetaminophen kept unchanged after the 3D printing. The in vitro release studies showed that the release of printed tablets could achieve over 80% within 24 h in the pH 6.8 phosphate buffer medium, by adding the disintegrating agent, kolidon cl-F, and changing the path spacing and shell numbers in the printing process. Conclusion:The acetaminophen tablets could be prepared by the hot-melt extrusion 3D printing technology, and the release of the tablets could be adjusted by the change of printing-related parameters.
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Objective: The aim of present work was to develop a platform technology for the pediatric dosage form to mask the bitter taste of Furosemide (FUR) and prepare a flexible solid oral dosage form. Methods: Excipient compatibility study was carried out by using Fourier-transform infrared spectroscopy (FTIR). Taste masking was done by hot melt extrusion (HME) technology. Eudragit EPO and Soluplus were used as a taste masking and solubilizing polymers respectively. The prepared solid dispersion and tablets were evaluated for their physicochemical parameters such as hardness, friability, disintegration, in vitro drug release. Results: Experimental data revealed that physical integrity, brittleness of granules, conversion of a drug in amorphous form was improved by combining Eudragit EPO with Soluplus. Plasticizer helped to complete HME at 80 °C. Less than 10% drug release in pH 6.8 medium revealed that release would be extremely limited in the saliva and thus avoiding bitterness. Animal study data revealed that bioavailability has been increased by 30%. Differential scanning calorimetry (DSC) and x-ray diffraction (XRD) tests confirmed the existence of molecularly dispersed drug. Fourier-transform infrared spectroscopy (FTIR) confirmed the unchanged functional groups of FUR after HME processing. Conclusion: Proposed platform technology masked the bitter taste and enhanced the bioavailability of FUR in D: P ratio of 1:2.
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@#Abstract The indomethacin-nicotinamide cocrystal was prepared by hot melt extrusion(HME)to improve the dissolution of indomethacin in vitro. The optimum preparation conditions were investigated using temperature and rotate speed as variables. Thermogravimetric analysis(TGA), determination of content and determination of related substances were performed to evaluate the thermal stability of indomethacin during the process. Cocrystal was also prepared by solution crystallization from acetonitrile. The products obtained by the two methods were characterized by differential scanning calorimetry(DSC), Fourier transform infrared(FTIR)and powder X-ray diffraction(PXRD). The solubility and dissolution advantages of cocrystal were evaluated. The results showed that the HME method could successfully prepare the indomethacin-nicotinamide cocrystal at 115 °C and eutectic mixture was formed during the process. The cocrystal significantly improved the solubility and dissolution of indomethacin in deionized water, with pH 5. 5 and pH 6. 8 phosphate buffer. The preparation of poorly soluble drug cocrystal by HME can significantly improve its solubility, providing new idea for the development of poorly soluble drugs and HME technology.
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Hot melt extrusion (HME) is a novel technique to prepare solid dispersions and granules. During the manufacturing process, the drugs and polymers melt and show the complex rheological properties under the heat and forces of shear and extension. Rheology is a potential tool to guide their formulations, manufacturing process and in-line quality control. In this review, we summarized the basic theories of the molten polymer viscoelasticity with temperature and shear rate, and the time-temperature superposition, the widely used rheometries and their applications in the pharmaceutical polymer thermoplasticity, drug solubility and interactions in the molten polymers, manufacturing parameters and the in-line quality control of hot melt extrusion.
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OBJECTIVE: To prepare high carbamazepine (CBZ) loading solid dispersion and investigate its solubilization mechanism and stability. METHODS: The effects of different drug-carrier ratios and preparation METHODS on dissolution were investigated by intrinsic dissolution rate. The existing form of CBZ in the solid dispersion was characterized by differential scanning calorimetry(DSC) and powder X-ray diffraction(PXRD). The micromorphology was observed with scanning electron microscopy and the solubilization mechanism was probed by wettability test and particle size measurement. RESULTS: The solid dispersion prepared by hot-melt extrusion with the drug/carrier ratio of 4∶1 demonstrated the highest dissolution, which was 327 fold that of the untreated drug. CBZ in the solid dispersion was small crystalline which had been transformed from polymorph III to . Wettability of the solid dispersion in hydrochloric acid solution was increased significantly, which could be rapidly dispersed into a nanometer-sized suspension. The solid dispersion was very stable without any changes for more than 6 months under accelerated test conditions. CONCLUSION: The CBZ solid dispersion with 80% drug loading prepared by hot melt extrusion with a hydrophilic polymer, Eudragit EPO, as carrier possesses satisfactory properties such as fast drug dissolution and excellent stability.
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Objective: Hot-melt extrusion technique was applied to prepare magnolol solid dispersions, which can improve the in vitro solubility of magnolol and the in vivo bioavailability in rats. Methods: Four kinds of excipients, such as PS-630, HPC, EPO, and Soluplus, which were compatible with magnolol were used to prepare solid dispersions of different drug loadings by solubility parameter calculation. The prepared solid dispersion was characterized by differential scanning calorimetry (DSC), X-ray diffraction analysis (XRPD) and infrared spectroscopy (IR) using in vitro dissolution as an indicator; UPLC-MS/MS was used to evaluate the pharmacokinetic behavior of rats after oral administration of magnolol solid dispersion. Results: The in vitro dissolution test showed that the solid dispersion prepared by the 1:6 drug loading of PS-630, HPC, and EPO can significantly improve the dissolution of magnolol, and the drug was dispersed in the carrier in an amorphous state. The in vivo bioavailability test showed that the Cmax of magnolol in the solid dispersion prepared by PS-630 and HPC was about five times and 2.3 times that of the monomer, respectively, and the AUC0-t was increased about 37.22% and 70.88%, respectively. There was no increase in the EPO system. Conclusion: Hot melt extrusion technology can be successfully applied to improve the in vitro dissolution and in vivo bioavailability of the poorly soluble drug magnolol.
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@#Aimed at developing new formulation, amorphous solid dispersion of itraconazole was prepared via hot-melt extrusion technology and compared with sporanox for improving its dissolution. According to the solubility parameter and glass transition temperature, Soluplus, Kollidon VA64, HPMCAS and Eudragit EPO were used as carriers. After screening the carriers by modulated temperature-differential scanning calorimetry(MT-DSC), the amorphous solid dispersion was prepared successfully and characterized by MT-DSC, polarized light microscope(PLM), X-ray powder diffraction(XRPD)and Fourier Transform InfraRed(FT-IR). Results suggested that the amorphous form of ITZ solid dispersion and whether the interaction between polymer and ITZ was appeared. Using 30% and 50% drug loading, solid dispersion were tested by in vitro dissolution and kinetic solubility tests. When using Soluplus(3 ∶7)as carrier and extrusion temperature of 170 ℃, dissolution rate of itraconazole was improved significantly compared to Sporanox. In 40 ℃, 75% RH condition, itraconazole in the solid dispersion was amorphous for 30 d with no crystal observed. MT-DSC indicated the molecular level miscibility between Soluplus and amorphous itraconazole was probably the main cause of solubilization. The result from this research help understanding the solublization of amorphous itraconazole and future formulation development.
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Objective Hot-melt extrusion technique was applied to prepare curcumin solid dispersions, which can improve the solubility and dissolution of curcumin. Methods Using curcumin as a model drug and Eudragit E PO (EPO) as a carrier, the solubility parameter method was used to evaluate the miscibilty between the drug and the carrier. Taking the content, crystallinity, and dissolution of curcumin as evaluation indicators, the single-factor test was used to select the barrel temperature, screw speed, and cooling rate in the hot-melt extrusion process. The preparation process was optimized and compared with the solvent method and the fusion method. By means of differential scanning calorimetry, X-ray diffraction, Fourier transform infrared spectroscopy, saturated solubility measurement and in vitro dissolution test, the solid dispersions prepared by the best hot-melt extrusion process were characterized and evaluated. Results The best preparation process were as follow: screw speed 100 r/min, barrel temperature 130—160 ℃, and cooling mode of liquid nitrogen cooling. Under such condition, the drug was dispersed in the carrier in an amorphous state, and a strong molecular interaction occurred between the drugs and the carriers. Conclusion Hot-melt extrusion technique can be applied for the preparation of heat-sensitive curcumin dispersions, which provides a certain experimental reference for the preparation of heat-sensitive drug solid dispersions by hot-melt extrusion.
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Objective To prepare solid dispersions (SD) of Polygonum cuspidatum extract (PCE) with the intention of improving the dissolution rate of its active ingredients in vitro and exploring the applicability of hot melt extrusion in SD of traditional Chinese medicine extract. Methods The SD of PCE were prepared via hot melt extrusion based on Eudragit EPO. The cumulative dissolution of resveratrol and emodin in the extract of PCE was used as an evaluation index, and the single factor experiment was optimized. Then physicochemical properties of the SD prepared by optimized process were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscope (SEM). Results The optimized process was 120 r/min for screw speed, 160 ℃ for barrel temperature and liquid nitrogen cooling. Under the optimized conditions, the dissolution rate of resveratrol and emodin in the extract was significantly improved, and the drug was present in the amorphous state in the carrier. Conclusion Hot melt extrusion can prepare SD of PCE to improve the dissolution rate of resveratrol and emodin, which provided experimental reference and data support for the study ofpreparation of SD of traditional Chinese medicine by hot melt extrusion.
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Three dimensional printing (3D printing) has been known as additive manufacturing technique based on digitally-controlled deposition of materials. Fused deposition modeling (FDM) is one of techniques commonly used in 3D printing, in which materials are soften or melt by heat to create objects during printing. This paper is prepared to review the research and application of 3D printing via FDM in the pharmaceutical sciences, including its advantages and limitations.
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OBJECTIVE: To investigate the effect of copovidone (PVP/VA), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and hydroxypropylmethylcellulose (HPMC) on drug dispersion and in vitro dissolution of solid dispersion by using nifedipine as model drug. METHODS: Nifedipine solid dispersion was prepared by hotmelt extrusion (HME) technology, and the drug dispersion was evaluated by differential scanning calorimetry (DSC) and dissolution test. RESULTS: DSC analysis results showed that nifedipine was amorphous in all HME extruders. Drug release from solid dispersion prepared with HPMCAS reached 100% in 30 min, but was only 75% for PVP/VA solid dispersion. Adding 5% HPMC E5 to PVP/VA extruders before dissolution test could raise the drug release from 75% to 90%. CONCLUSION: HPMCAS or combination of PVP/VA and HPMC E5 are desirable polymers for nifedipine solid dispersion.
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Os sistemas multiparticulados são aqueles nos quais a dose do fármaco está dividida em pequenas unidades funcionais, tendo assim, uma série de vantagens sobre os sistemas monolíticos convencionais. Este trabalho teve por objetivo desenvolver formulações multiparticuladas de uso oral para fármacos anti-hipertensivos que serão utilizados na composição de associações. O material está dividido em seis capítulos, sendo inicialmente apresentada uma revisão da literatura a respeito da caracterização física destas pequenas unidades. Ensaios como análise granulométrica, morfologia, densidade, porosidade, avaliação de resistência mecânica e desintegração são os mais empregados para esta finalidade, possibilitando ao formulador conhecer os fatores de maior impacto relacionados às matérias primas e ao processo de fabricação no comportamento das formulações produzidas. Os demais capítulos seguem com o desenvolvimento dos sistemas multiparticulados, que foram embasados em diferentes delineamentos experimentais, seja pela utilização de planejamento fatorial fracionado ou projeto de mistura. Para o metoprolol, fármaco de alta solubilidade, foram produzidas formulações de liberação controlada, sendo a estratégia dividida em três etapas: (I) Produção de minicomprimidos revestidos, nos quais foram avaliadas diferentes combinações do polímero modulador de liberação; (II) otimização do perfil de liberação do fármaco, com avaliação de misturas das formulações produzidas na primeira etapa; (III) Processo de extrusão a quente, no qual diferentes proporções de fármaco e polímero hidrofóbico foram avaliadas. Para os fármacos hidroclorotiazida e olmesartana medoxomila, ambos de baixa solubilidade, a estratégia adotada foi a incorporação de uma dispersão dos fármacos e agentes solubilizantes em grânulos inertes obtidos por extrusão/revestimento. Adicionalmente, também foram produzidas formulações por extrusão a quente de diferentes proporções destes fármacos em polímero hidrofílico. De acordo com os resultados obtidos, foi possível obter formulações de minicomprimidos e grânulos com perfil de dissolução satisfatório, semelhantes aos apresentados pelos medicamentos adotados como referência. Em relação à extrusão a quente foi possível avaliar a influência do processo e polímeros empregados no perfil de dissolução dos grânulos produzidos
Multiparticulate systems are dosage forms in which dose is divided into small functional units presenting some advantages over monolithic conventional systems. The objective of this work was developing multiparticulate formulations for oral use containing antihypertensive drugs to be used in association. The thesis is divided into six issues, been first presented a literature review about physical characterization of multiparticulate systems. Granulometric analysis, morphology, density, porosity, mechanical strength and disintegration are the most used physical characterization tests, enabling formulator knowing the major impact factors related to raw materials and manufacturing process in the performance of the produced formulations. The other issues present the development of the multiparticulate systems based on different statistical experimental design, as fractional factorial design or mixture project. For metoprolol, a highly soluble drug, controlled release formulations were obtained, and the strategy was divided into three steps: (I) coated minitablets production, where different combinations of the controlled release polymer were analyzed; (II) drug release profile optimization, evaluating formulations mixtures produced in the first step; (III) hot melt extrusion process, where different drug: hydrophobic polymer ratios were evaluated. For hydrochlorothiazide and olmesartan medoxomil, both low soluble drugs, the strategy was incorporating a dispersion containing the drugs and solubilizing agents in inert granules obtained by extrusion/coating processes. Additionally, formulations containing different ratios of these drugs and hydrophilic polymers were produced by hot melt extrusion. According to the results, it was possible to obtain minitablets and granules with good dissolution profile, similar to the reference products. Regarding to hot melt extrusion, it was possible to evaluate the influence of process and polymers used in the dissolution profile of the produced granules
Subject(s)
Pharmaceutical Preparations/administration & dosage , Antihypertensive Agents/adverse effects , Olmesartan Medoxomil/administration & dosage , Hydrochlorothiazide/administration & dosage , Hypertension/complications , Metoprolol/adverse effectsABSTRACT
@#Hot-melt extrusion technology was used to prepare solid dispersion of posaconazole for improving its dissolution. Solubility parameter, glass transition temperature and melting method were utilized to screen polymers. Using KollidonVA64, Soluplus, Eudragit L100 and combined carrier KollidonVA64-Eudragit L100 as polymer carrier, solid dispersion was prepared by hot-melt extrusion technology and characterized by drug dissolution. The formulation and process factor affecting dissolution were studied. The state of posaconazole in solid dispersion was characterized by differential scanning calorimetry and preliminary analysis of the stability was studied by influencing factors experiments. When using KollidonVA64-Eudragit L100(2 ∶8)as the carrier, 10 % triethyl citrate as the plasticizer and extrusion temperature of 150 °C, the dissolution of posaconazole was improved significantly. Drug was molecular or amorphous form in the carrier. Proportion of Eudragit L100 and KollidonVA64, temperature, drug loading and plasticizer influenced dissolution of posaconazole. Solid dispersion was stable for high temperature and strong light but sensitive to high humidity. Solid dispersion using hot-melt extrusion technology can significantly improve the dissolution of posaconazole.
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Hot melt extrusion (HME) is an effective method to make the drugs form amorphous solid dispersions (ASD) inmicrostructure, through which we can improve the dissolution behavior so as to improve the bioavailability ofhydrophobic drugs This review mainly focuses on the. screening of active pharmaceutical ingredients and polymer carriers, feasibility evaluation of the technique, and the control of key parameters of preparation process, summarizes the application of HME to develop drug delivery system.