enhanced dissolution Dotaz Zobrazit nápovědu
Merala sa rozpustnost kalciového antagonistu nimodipínu vo vode a vo vodných roztokoch β-cyklodextrínu (β-CD, až 0,014 mol/l) a rozpustnejšieho hydroxypropyl-β-cyklodextrínu (HP-β-CD, až 0,05 mol/l) s priememým stupňom substitúcie 0,8. Zvýšenie rozpustnosti bolo priamoúmerné koncentrácii cyklodextrínu, pričom v roztoku β-CD bola rozpustnost nimodipínu až 2,2 mg/100 ml, v roztoku HP-β-CD až 6 mg/100 ml, za daných podmienok po 14 dňoch rozpúšťania. Riedením vodou sa takto solubilizovaný nimodipín nezráža. Zo smerníc lineárnych fázových diagramov rozpustnosti sa vypočítali príslušné asociačné konštanty tvorby inklúznych komplexov (1:1) v roztoku nimodipínu s β-CD (401 mol-1 1) a s HP-p-CD (268 mol-1 1). Kinetika rozpúšťania substancie nimodipínu v roztoku HP-β-CD sledovaná od 3 min. až po 14 dní sa vyznačovala oscilováním medzi presýteným roztokom a rozpúšťacou rovnováhou, pre prípravu stálych roztokov v rozpúšťacej rovnováhe sa preto odporúča merať disolučnú krivku v dlhšom časovom intervale. Rozotieracou metódou sa pripravili veľmi lahko rozpustné tuhé zmesi nimodipínu s HP-β-CD a termickou analýzou sa dokázala tvorba tuhého komplexu 1:1.
The solubility of the calcium antagonist nimodipine was measured in water and in aqueous solutions of both β-cyclodextrin (β-CD, up to 0.014 mol/l) and the more soluble hydroxypropyl-β-cyclodextrin (HP-β-CD, up to 0.05 mol/l) with an average substitution degree of 0.8. The solubility enhancement of nimodipine was proportional to the cyclodextrin concentration, it was up to 2.2 mg/100 ml and 6 mg/100 ml in the respective solutions of β-CD and HP-β-CD, under the studied conditions, after 14 days of nimodipine dissolution. The solubilized nimodipine does not precipitate on diluting the Solutions with water. The association constant of the inclusion complexes (1:1) were evaluated from the slopes of the linear phase solubility diagrams of nimodipine in the respective solutions of β-CD (401 mol-1 1) and HP-β-CD (268 mol-1 1). The kinetics of dissolution of the solid nimodipine in the solution of HP-β-CD was followed from 3 min till 14 days and oscillations between the supersaturation and the equilibrium solution were observed. Long term measurements of the dissolution curve are thus recommended if stable solutions, in terms of the solubility equilibrium, are to be prepared. Easily soluble solid mixtures of nimodipine with HP-β-CD were prepared by the kneading method and the formation of the solid complex 1:1 was demonstrated by the differential thermal analysis.
CONTEXT: The preparation of liquisolid systems (LSS) represents a promising method for enhancing a dissolution rate and bioavailability of poorly soluble drugs. The release of the drug from LSS tablets is affected by many factors, including the disintegration time. OBJECTIVE: The evaluation of differences among LSS containing varying amounts and types of commercially used superdisintegrants (Kollidon® CL-F, Vivasol® and Explotab®). MATERIALS AND METHODS: LSS were prepared by spraying rosuvastatin solution onto Neusilin® US2 and further processing into tablets. Varying amounts of superdisintegrants were used and the differences among LSS were evaluated. The multiple scatter plot method was used to visualize the relationships within the obtained data. RESULTS AND DISCUSSION: All disintegrants do not showed negative effect on the flow properties of powder blends. The type and concentration of superdisintegrant had an impact on the disintegration time and dissolution profiles of tablets. Tablets with Explotab® showed the longest disintegration time and the smallest amount of released drug. Fastest disintegration and dissolution rate were observed in tablets containing Kollidon® CL-F (≥2.5% w/w). Also tablets with Vivasol® (2.5-4.0% w/w) showed fast disintegration and complete drug release. CONCLUSION: Kollidon® CL-F and Vivasol® in concentration ≥2.5% are suitable superdisintegrants for LSS with enhanced release of drug.
- MeSH
- anticholesteremika aplikace a dávkování chemie MeSH
- farmaceutické pomocné látky chemie MeSH
- povidon chemie MeSH
- příprava léků MeSH
- rosuvastatin kalcium aplikace a dávkování chemie MeSH
- rozpustnost MeSH
- silikáty chemie MeSH
- škrob analogy a deriváty chemie MeSH
- sloučeniny hliníku chemie MeSH
- sloučeniny hořčíku chemie MeSH
- tablety chemie MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
V priebehu 14 dní sa sledovali časové závislosti rozpúšťania suspendovanej substancie nimodipínuvo vodných roztokoch a-cyklodextrínu (a-CD), hydroxypropyl-a-cyklodextrínu (HP-a-CD), metyl--b-cyklodextrínu (M-b-CD) a hydroxypropyl-g-cyklodextrínu (HP-g-CD). Koncentrácia príslušnéhocyklodextrínu bola vo všetkých prípadoch 0,05 mol/l. Podľa stanovených disolučných kriviek jez uvedených cyklodextrínov veľmi účinným solubilizérom M-b-CD, za daných podmienok sa v jehovodnom roztoku ináč ťažko rozpustný nimodipín rozpúšťa na nezrážajúci sa nasýtený roztoks koncentráciou 5,15 . 10 -4 mol/l (21,5 mg/100 ml). M-b-CD je takto solubilizačne účinnejší akopredtým študovaný HP-b-CD. Solubilizačná schopnosť HP-a-CD a HP-g-CD je podstatne slabšiaa a-CD z dlhodobého hľadiska takmer nezlepšuje rozpustnosť nimodipínu vo vode. Za prítomnostia-CD, HP-a-CD a HP-g-CD sa však pozoroval opakovaný vznik časovo nestálych presýtenýchroztokov nimodipínu, s prechodne zvýšenou koncentráciou nimodipínu, podobne ako za prítomnostiHP-b-CD. Nakoľko podľa literárnych údajov vznik presýtených roztokov pôsobením cyklodext rínovvýznamne ovplyvňuje biologickú dostupnosť liečiv, môžu byť uvedené cyklodextríny a osobitneprírodný a-CD užitočné pre zvýšenie nízkej dostupnosti nimodipínu z perorálnych tuhých liekovýchforiem.
The dissolution curves of the substance of the calcium antagonist nimodipine in aqueous solutionsof four cyclodextrins were determined at ambient temperature in the course of 14 days. The usedcyclodextrins were a-cyclodextrin (a-CD), hydroxypropyl-a-cyclodextrin (HP-a-CD), methyl-b-cy-clodextrin (M-b-CD, random-methylated), and hydroxypropyl-g-cyclodextrin (HP-g-CD) and theirrespective concentrations were always 0.05 mol/l. According to the measured dissolution curves,M-b-CD in aqueous medium was a highly efficient solubiliser, capable to dissolve otherwisesparingly soluble nimodipine into a time-stable aqueous solution, with the saturated concentrationof nimodipine 5.15x10 -4 mol/l (21.5 mg/100 ml) under the given conditions. M- b-CD thus appearedto be a more efficient solubiliser than the previously studied HP-b-CD. The solubilising power ofHP-a-CD and HP-g-CD was much lower and a-CD practically did not improve long-term solubilityof nimodipine in water. However, in the presence of a-CD, HP-a-CD, and HP-g-CD, respectively,repeated shortterm episodes of formation of supersaturated solutions of nimodipine were observedon the dissolution curves, characterised by peaks of nimodipine concentration. Similar supersatu-ration episodes were previously observed in the presence of HP-b-CD. Since the supersaturationcaused by cyclodextrins reportedly substantially improved the biological availability of some drugs,the above-mentioned cyclodextrins, and especially natural a-CD, could be useful for the enhance-ment of the low availability of nimodipine from solid oral drug preparations.
To enhance dissolution rate of meloxicam (MX), a poorly soluble model drug, a natural polysaccharide excipient chitosan (CH) is employed in this work as a carrier to prepare binary interactive mixtures by either mixing or co-milling techniques. The MX-CH mixtures of three different drug loads were characterized for morphological, granulometric, and thermal properties as well as drug crystallinity. The relative dissolution rate of MX was determined in phosphate buffer of pH 6.8 using the USP-4 apparatus; a significant increase in MX dissolution rate was observed for both mixed and co-milled mixtures comparing to the raw drug. Higher dissolution rate of MX was evidently connected to surface activation by mixing or milling, which was pronounced by the higher specific surface energy as detected by inverse gas chromatography. In addition to the particle size reduction, the carrier effect of the CH was confirmed for co-milling by linear regression between the MX maximum relative dissolution rate and the total surface area of the mixture (R2 = 0.863). No MX amorphization or crystalline structure change were detected. The work of adhesion/cohesion ratio of 0.9 supports the existence of preferential adherence of MX to the coarse particles of CH to form stable interactive mixtures.
- MeSH
- chitosan * MeSH
- meloxikam MeSH
- pomocné látky MeSH
- rozpustnost MeSH
- Publikační typ
- časopisecké články MeSH
Co-milling of a drug with a co-former is an efficient technique to improve the solubility of drugs. Besides the particle size reduction, the co-milling process induces a structural disorder and the creation of amorphous regions. The extent of drug solubility enhancement is dependent on the proper choice of co-milling co-former. The aim of this work was to compare the effects of different co-formers (meglumine and polyvinylpyrrolidone) on the dissolution rates of glass forming (indomethacin) and non-glass forming (mefenamic acid) model drugs. A positive impact of the co-milling on the dissolution behavior was observed in all co-milled mixtures, even if no substantial amorphization was observed. While meglumine exhibited pronounced effects on the dissolution rate of both drugs, the slightest enhancement was observed in mixtures with polyvinylpyrrolidone. The evaluation of specific release rate revealed the surface activation of drug particle is responsible for improving the dissolution rate of both drug types, but for the glass former, this surface activation could be persistent while maintaining a high dissolution rate even until a high fraction of drug is released. Our results, therefore, indicate that adequate co-former choice and consideration of drug glass forming ability are important for a successful co-milling approach to poorly water-soluble drugs.
- MeSH
- indomethacin MeSH
- léčivé přípravky * MeSH
- povidon * MeSH
- příprava léků MeSH
- rozpustnost MeSH
- velikost částic MeSH
- Publikační typ
- časopisecké články MeSH
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
Meloxicam (MLX) is a poorly soluble drug exhibiting strong hydrophobicity. This combination of properties makes dissolution enhancement by particle size reduction ineffective; therefore, combined formulation approaches are required. Various approaches were investigated in this study, including milling, solid dispersions, and self-emulsified lipid formulations. Whereas milling studies of MLX and its co-milling with various polymers have been reported in recent literature, this study is focused on investigating the dissolution kinetics of particulate formulations obtained by co-milling MLX with sodium lauryl sulfate (SLS) in a planetary ball mill with 5-25 wt.% SLS content. The effects of milling time and milling ball size were also investigated. No significant reduction in drug crystallinity was observed under the investigated milling conditions according to XRD data. For the dissolution study, we used an open-loop USP4 dissolution apparatus, and recorded dissolution profiles were fitted according to the Weibull model. The Weibull parameters and a novel criterion-surface utilization factor-were used to evaluate and discuss the drug release from the perspective of drug particle surface changes throughout the dissolution process. The most effective co-milling results were achieved using smaller balls (2 mm), with a co-milling time of up to 15 min SLS content of up to 15 wt.% to increase the dissolution rate by approximately 100 times relative to the physical mixture reference. The results suggest that for hydrophobic drugs, particle performance during dissolution is very sensitive to surface properties and not only to particle size. Co-milling with SLS prepares the surface for faster drug release than that achieved with direct mixing.
- Publikační typ
- časopisecké články MeSH
A nanofibrous membrane carrier for nearly water insoluble drug diosmin was formulated. The aim of this study was to evaluate the drug release and dissolution properties in an aqueous buffer of pH 7.8, and to compare the suitability of the drug carrier with the available drug forms and screen diosmin absorption extent. The membranes were produced from HPC/PVA/PEO-drug water solutions and then evaluated by SEM and DSC measurements. The results showed that diosmin was incorporated within the nanofibers in an amorphous state, and/or as a solid dispersion. The results of in vitro release experiments excerpt a very fast release of the drug, followed by the formation of an over saturated solution and partial precipitation of the drug (a "spring" effect). The enormous increases in dissolution of the drug from a nanofibrous carrier, compared to a micronized and crystalline form, was achieved. The in vivo bioavailability study carried out on rats showed higher initial drug plasma levels and higher AUC values after administration of the nanofibrous drug formulation, compared to the micronized form. The results of the study demonstrated that the improvement of the diosmin in vitro dissolution also brought the enhanced in vivo absorption extent of the drug.
- MeSH
- aplikace orální MeSH
- diosmin aplikace a dávkování krev chemie farmakokinetika MeSH
- intestinální absorpce MeSH
- nanovlákna aplikace a dávkování chemie MeSH
- nosiče léků aplikace a dávkování chemie farmakokinetika MeSH
- potkani Wistar MeSH
- příprava léků metody MeSH
- rozpustnost MeSH
- roztoky MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
One of the conventional methods of alleviating the problem of poor drug solubility is the particle size reduction. The efficiency of this approach depends on successful formulation suppressing the drug agglomeration. The aim of this study was to circumvent the dissolution problems of model hydrophobic meloxicam drug (MLX) by using liquid media of different wetting capacity to comminute and formulate a rapidly dissolving carrier system without the use of surfactants. Micro-suspensions of MLX were prepared by ball milling, using water or n-Heptane as a liquid medium. The suspensions were used as granulation liquids to formulate granulate from microcrystalline cellulose and lactose mixture. The release kinetics from prepared granulates were studied using the USP-4 dissolution apparatus. Micro-suspensions prepared via wet milling in non-water liquid media exhibited a massive improvement of release rate compared with source meloxicam and they outperformed their water-milled counterparts. The release rates from those formulations, despite not comprising any surfactant, were comparable to those obtained by different authors using surfactant stabilized nanosuspension formulations. Thus, they can present an interesting formulation alternative for hydrophobic drugs that are dissolution limited.
The paper brings an overview of most important methods for attaining the purpose, such as solubilization using tensides, cosolvents, chelates, cyclodextrins, pH modifiers, interactive powder mixtures, forming solid dispersions and microgranulates. The review summarizes main advantages and drawbacks of the methods and gives some examples. Although, the most frequently used technology in pharmaceutical industry is currently drug micronization, the above methods offer a well established way of enhancing solubility of drugs in water.
