Solid dispersion
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There has been a great interest in solid dispersions since 60's because it is one of the most promising methods to increase the low bioavailability of poorly water soluble drugs. Numerous studies on solid dispersions have been published, showing advantages of these materials. The main benefits of solid dispersions for low soluble drugs lie in the possibility to reduce the particle size, even to molecular level, to enhance wettability and porosity, as well as to change the drug crystalline state, preferably into amorphous state. Despite high research interests, the number of marketed products with solid dispersion is surprisingly low. The aim of this review is to provide basic information for better understanding of solid dispersions. The article contains definitions and characterization of the various system including four generations of solid dispersions, description of preparation methods and mechanisms of drug dissolution.
Autoři popisují cytologický a histologický obraz u případu solidního a papilárního epiteliálního tumoru pankreatu u 341eté ženy. V materiálu získaném tenkojehlovou aspirační cytologií dominovaly pseudopapilárně utvářené fragmenty s jemným fibrovaskulárním stromatem obklopeným jednou či více vrstvami nádorových buněk se světlou cytoplazmou. Přítomny byly též acinární, rozetovité struktury a nádorové buňky volně rozptýlené na pozadí. Nádorové elementy měly drobná, kulatá až oválná jádra s jemným chromatinem a nenápadným jadérkem. Ojediněle byly zastiženy i intranukleární zářezy. Mitózy nebyly přítomny. Histologický šlo o opouzdřený, převážně solidně uspořádaný nádor, ložiskově s tvorbou drobných pseudocyst, pseudopapilárních struktur a granulomů z cizích těles, tvořený drobnými uniformními buňkami se světlou cytoplazmou, prakticky bez mitotické aktivity. Imunohistochemícky nádorové buňky difuzně exprimovaly vimentin, fokálně byla prokázána pozitivita α1-antitrypsinu a CD68. Negativní byl průkaz chromograninu, synaptofyzinu, cytokeratinů, HMB 45, estrogenových a progesteronových receptorů. ^diferenciálně diagnosticky je nutno odlišit zejména mucinózní tumory pankreatu, mikrocystický adenom a pseudocysty, ale též endokrinní nádory pankreatu, karcinom z acinámích buněk, světlobvměčný karcinom ledviny, kôrový adenom nadledvinky či primární extrapulmonální sugar tumor.
Cytologic and histologic features in a case of solid and papillary epithelial neoplasm (SPEN) of the pancreas in a 34-year-old female are presented. In the fine-needle aspiration material, there was a predominance of pseudopapillary fragments with delicate fibrovascular core lined with one or more layers of uniform tumor cells with clear cytoplasm. There were also acinar-Iike or rosette-like structures and dispersed tumor cells. Tumor cells had small, round to oval nuclei, with finely granular chromatin and inconspicuous nucleolus. Rarely, nuclear grooves were present. Mitoses were not seen. Histologically, the encapsulated tumor was predominantly solid, with focal pseudocystic and pseudopapillary areas; foreign body granulomas were focally present. Tumor ceUs were small and uniform with clear cytoplasm. Mitoses were extremely rare. Immunohistochemically, the tumor cells revealed diffuse positivity of vimentin, and focal positivity for α1-antitrypsin and CD68. No immunoreactivity for chromogranin, synaptophysin, cytokeratin, HMB 45, estrogen and progesteron receptors was found. In differential diagnosis, it is important to distinguish SPEN mainly from mucinous tumors of the pancreas, microcystic adenoma and pseudocysts, but also from endocrine tumors of the pancreas, acinic cell carcinoma, renal cell carcinoma, adrenal cortical adenoma and primary extrapulmonary sugar tumor.
Plant mucilages are commonly employed as excipients in pharmaceutical manufacturing. Ocimum basilicum (Lamiaceae family), a source of hydrophilic mucilage referred herein as Ocicum, was evaluated for the solubility enhancer of a model drug, aceclofenac, in solid dispersions prepared using different methods. Polymer was extracted from O. basilicum and solid dispersions of aceclofenac were fabricated with Ocicum or Poloxamer 407 using polymer-to-drug ratios of 1:1, 1:2 and 1:3 utilizing solvent evaporation, lyophilization and melt methods. Ocicum was evaluated for its safety via acute toxicity study including different biochemical and hematological parameters including liver and kidney profiles. Moreover, different characterization studies including melting-point, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and differential thermal analysis (TGA) were used for evaluation of polymer and solid dispersions. Furthermore, solubility and dissolution studies were performed to confirm solubility enhancement. Ocicum was found to be safer, and different characterization studies confirmed the purity of the compounds. In addition, Ocicum exhibited up to 6.27-fold enhanced solubility as compared to pure aceclofenac; similarly, 4.51-fold increased solubility by the synthetic polymer in their respective solid dispersions was shown. Furthermore, Ocicum-based solid dispersions showed substantial improvement in dissolution of aceclofenac. Therefore, it can be concluded from the above-mentioned results that Ocicum might be used as an economical natural oral delivery carrier alternative to the synthetic polymers.
- Publikační typ
- časopisecké články MeSH
PURPOSE: Imaging methods were used as tools to provide an understanding of phenomena that occur during dissolution experiments, and ultimately to select the best ratio of two polymers in a matrix in terms of enhancement of the dissolution rate and prevention of crystallization during dissolution. METHODS: Magnetic resonance imaging, ATR-FTIR spectroscopic imaging and Raman mapping have been used to study the release mechanism of a poorly water soluble drug, aprepitant, from multicomponent amorphous solid dispersions. Solid dispersions were prepared based on the combination of two selected polymers - Soluplus, as a solubilizer, and PVP, as a dissolution enhancer. Formulations were prepared in a ratio of Soluplus:PVP 1:10, 1:5, 1:3, and 1:1, in order to obtain favorable properties of the polymer carrier. RESULTS: The crystallization of aprepitant during dissolution has occurred to a varying degree in the polymer ratios 1:10, 1:5, and 1:3, but the increasing presence of Soluplus in the formulation delayed the onset of crystallization. The Soluplus:PVP 1:1 solid dispersion proved to be the best matrix studied, combining the abilities of both polymers in a synergistic manner. CONCLUSIONS: Aprepitant dissolution rate has been significantly enhanced. This study highlights the benefits of combining imaging methods in order to understand the release process.
- MeSH
- farmaceutická chemie metody MeSH
- krystalizace MeSH
- magnetická rezonanční tomografie metody MeSH
- morfoliny chemie MeSH
- nosiče léků chemie MeSH
- polyethylenglykoly chemie MeSH
- polymery chemie MeSH
- polyvinyly chemie MeSH
- pyrrolidiny chemie MeSH
- rozpustnost MeSH
- spektroskopie infračervená s Fourierovou transformací metody MeSH
- uvolňování léčiv MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Imaging methods were used as tools to provide an understanding of phenomena that occur during dissolution experiments, and ultimately to select the best ratio of two polymers in a matrix in terms of enhancement of the dissolution rate and prevention of crystallization during dissolution. METHODS: Magnetic resonance imaging, ATR-FTIR spectroscopic imaging and Raman mapping have been used to study the release mechanism of a poorly water soluble drug, aprepitant, from multicomponent amorphous solid dispersions. Solid dispersions were prepared based on the combination of two selected polymers - Soluplus, as a solubilizer, and PVP, as a dissolution enhancer. Formulations were prepared in a ratio of Soluplus:PVP 1:10, 1:5, 1:3, and 1:1, in order to obtain favorable properties of the polymer carrier. RESULTS: The crystallization of aprepitant during dissolution has occurred to a varying degree in the polymer ratios 1:10, 1:5, and 1:3, but the increasing presence of Soluplus in the formulation delayed the onset of crystallization. The Soluplus:PVP 1:1 solid dispersion proved to be the best matrix studied, combining the abilities of both polymers in a synergistic manner. CONCLUSIONS: Aprepitant dissolution rate has been significantly enhanced. This study highlights the benefits of combining imaging methods in order to understand the release process.
- MeSH
- aprepitant MeSH
- farmaceutická chemie metody MeSH
- krystalizace MeSH
- magnetická rezonanční tomografie metody MeSH
- morfoliny chemie MeSH
- nosiče léků chemie MeSH
- polyethylenglykoly chemie MeSH
- polymery chemie MeSH
- polyvinyly chemie MeSH
- pyrrolidiny chemie MeSH
- rozpustnost MeSH
- spektroskopie infračervená s Fourierovou transformací metody MeSH
- uvolňování léčiv MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
The aims of this study were to investigate how the release of tadalafil is influenced by two grades of polyvinylpyrrolidone (Kollidon® 12 PF and Kollidon® VA 64) and various methods of preparing solid dispersions (solvent evaporation, spray drying and hot-melt extrusion). Tadalafil is poorly water-soluble and its high melting point makes it very sensitive to the solid dispersion preparation method. Therefore, the objectives were to make a comparative evaluation among different solid dispersions and to assess the effect of the physicochemical nature of solid dispersions on the drug release profile with respect to the erosion-diffusion mechanism. The solid dispersions were evaluated for dissolution profiles, XRD, SEM, FT-IR, DSC, and solubility or stability studies. It was found that tadalafil release was influenced by polymer molecular weight. Therefore, solid dispersions containing Kollidon® 12 PF showed a faster dissolution rate compared to Kollidon® VA 64. Tadalafil was released from solid dispersions containing Kollidon® 12 PF because of the combination of erosion and diffusion mechanisms. The diffusion mechanisms were predominant in the initial phase of the experiment and the slow erosion was dissolution-controlling at the second stage of the dissolution. On the contrary, the tadalafil release rate from solid dispersions containing Kollidon® VA 64 was controlled solely by the erosion mechanism.
- Publikační typ
- časopisecké články MeSH
In this work, novel amorphous solid dispersions based on yeast glucan particles were produced. Yeast glucan particles are hollow and porous, and they are mainly composed of amorphous polysaccharides. We hypothesized that these particles are suitable candidates for the amorphization of drugs with low water solubility. Model drugs ibuprofen and curcumin were successfully encapsulated in glucan particles by spray drying. Different spray-drying parameters were tested to evaluate the influence of atomizing droplet size and initial solid content on encapsulation efficiency. It was shown that higher solid content and, more significantly, larger droplet sizes lead to higher encapsulation efficiencies. The encapsulation efficiency of ibuprofen (10 wt%) into glucan particles was considerably improved from 41.3 ± 0.5% to 64.3 ± 0.2% by increasing initial solid content and droplet size with the two-fluid nozzle. The spray drying process was further optimized by using the ultrasonic nozzle and it was possible to achieve complete encapsulation of ibuprofen and curcumin without any precipitation of the active compound outside of the glucan particles. Overall, it was possible to produce completely amorphous composites with outstanding wettability and dispersion properties, and with significantly faster dissolution rates when compared to the micronized crude drug.
- MeSH
- aerosoly MeSH
- beta-glukany chemie izolace a purifikace MeSH
- ibuprofen chemie MeSH
- kinetika MeSH
- kurkumin chemie MeSH
- nosiče léků * MeSH
- příprava léků MeSH
- rozpustnost MeSH
- Saccharomyces cerevisiae chemie MeSH
- ultrazvuk * MeSH
- uvolňování léčiv MeSH
- velikost částic MeSH
- vysoušení * MeSH
- Publikační typ
- časopisecké články MeSH
Solid dispersions of active pharmaceutical ingredients are of increasing interest due to their versatile use. In the present study polyvinylpyrrolidone (PVP), poly[N-(2-hydroxypropyl)-metacrylamide] (pHPMA), poly(2-ethyl-2-oxazoline) (PEOx), and polyethylene glycol (PEG), each in three Mw, were used to demonstrate structural diversity of solid dispersions. Acetylsalicylic acid (ASA) was used as a model drug. Four distinct types of the solid dispersions of ASA were created using a freeze-drying method: (i) crystalline solid dispersions containing nanocrystalline ASA in a crystalline PEG matrix; (ii) amorphous glass suspensions with large ASA crystallites embedded in amorphous pHPMA; (iii) solid solutions with molecularly dispersed ASA in rigid amorphous PVP; and (iv) nanoheterogeneous solid solutions/suspensions containing nanosized ASA clusters dispersed in a semiflexible matrix of PEOx. The obtained structural data confirmed that the type of solid dispersion can be primarily controlled by the chemical constitutions of the applied polymers, while the molecular weight of the polymers had no detectable impact. The molecular structure of the prepared dispersions was characterized using solid-state NMR, wide-angle X-ray scattering (WAXS), and differential scanning calorimetry (DSC). By applying various (1)H-(13)C and (1)H-(1)H correlation experiments combined with T1((1)H) and T1ρ((1)H) relaxation data, the extent of the molecular mixing was determined over a wide range of distances, from intimate intermolecular contacts (0.1-0.5 nm) up to the phase-separated nanodomains reaching ca. 500 nm. Hydrogen-bond interactions between ASA and polymers were probed by the analysis of (13)C and (15)N CP/MAS NMR spectra combined with the measurements of (1)H-(15)N dipolar profiles. Overall potentialities and limitations of individual experimental techniques were thoroughly evaluated.
For successful formulation of amorphous solid dispersions (ASDs) using hot-melt extrusion, it is imperative to understand the effect that heat and shear rate has on the physicochemical properties of the excipient. In this study, we investigated the influence of hot-melt extrusion parameters on solvent-free binary ASDs of ibuprofen (IBU), a model active pharmaceutical ingredient, in methacrylic acid-ethyl acrylate copolymer type A, 1:1, EUDRAGIT® L100-55 (EUD). To evaluate the impact of barrel temperature, screw speed, and residence time on EUD mass average molar mass and IBU release profile, size-exclusion chromatography and dissolution testing were used, respectively. The optimal conditions were established for IBU loadings less than 40 wt. %. For ASD formulations prepared using the ideal variables, spectral and thermal analyses confirmed that, under dry conditions at a temperature of 25°C, IBU remained amorphous during an 18-month storage period. After 28 months, formulations with active pharmaceutical ingredient content above 30 wt. % started to recrystallize. A temperature-composition phase diagram, constructed using melting point depression and glass-transition temperature measurements of IBU-EUD mixtures, correlated well with the long-term physical stability. The effect that minor-to-moderate polymer degradation within the extrudates has on their long-term physical stability and dissolution characteristics is analyzed and discussed.
