Comparison of the liquisolid technique and co-milling for loading of a poorly soluble drug in inorganic porous excipients.

Drug loading into mesoporous carriers may help to improve the dissolution of poorly aqueous-soluble drugs. However, both preparation method and carrier properties influence loading efficiency and drug release. Accordingly, this study aimed to compare two preparation methods: formulation into liquisolid systems (LSS) and co-milling for their efficiency in loading the poorly soluble model drug cyclosporine A (CyA) into mesoporous magnesium aluminometasilicate Neusilin® US2 (NEU) or functionalized calcium carbonate (FCC). Scanning electron microscopy was used to visualize the morphology of the samples and evaluate the changes that occurred during the drug loading process. The solid-state characteristics and physical stability of the formulations, prepared at different drug concentrations, were determined using X-ray powder diffraction. In vitro release of the drug was evaluated in biorelevant media simulating intestinal fluid. The obtained results revealed improved drug release profiles of the formulations when compared to the milled (amorphous) CyA alone. The dissolution of CyA from LSS was faster in comparison to the co-milled formulations. Higher drug release was achieved from NEU than FCC formulations presumably due to the higher pore volume and larger surface area of NEU.

Study of Disordered Mesoporous Silica Regarding Intrinsic Compound Affinity to the Carrier and Drug-Accessible Surface Area.

There is increasing research interest in using mesoporous silica for the delivery of poorly water-soluble drugs that are stabilized in a noncrystalline form. Most research has been done on ordered silica, whereas far fewer studies have been published on using nonordered mesoporous silica, and little is known about intrinsic drug affinity to the silica surface. The present mechanistic study uses inverse gas chromatography (IGC) to analyze the surface energies of three different commercially available disordered mesoporous silica grades in the gas phase. Using the more drug-like probe molecule octane instead of nitrogen, the concept of a "drug-accessible surface area" is hereby introduced, and the effect on drug monolayer capacity is addressed. In addition, enthalpic interactions of molecules with the silica surface were calculated based on molecular mechanics, and entropic energy contributions of volatiles were estimated considering molecular flexibility. These free energy contributions were used in a regression model, giving a successful comparison with experimental desorption energies from IGC. It is proposed that a simplified model for drugs based only on the enthalpic interactions can provide an affinity ranking to the silica surface. Following this preformulation research on mesoporous silica, future studies may harness the presented concepts to guide formulation scientists.

Mechanistic study of dissolution enhancement by interactive mixtures of chitosan with meloxicam as model.

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.

Comparison of Flow and Compression Properties of Four Lactose-Based Co-Processed Excipients: Cellactose® 80, CombiLac®, MicroceLac® 100, and StarLac®.

The utilization of co-processed excipients (CPEs) represents a novel approach to the preparation of orally disintegrating tablets by direct compression. Flow, consolidation, and compression properties of four lactose-based CPEs-Cellactose® 80, CombiLac®, MicroceLac® 100, and StarLac®-were investigated using different methods, including granulometry, powder rheometry, and tablet compaction under three pressures. Due to the similar composition and the same preparation technique (spray drying), the properties of CPEs and their compacts were generally comparable. The most pronounced differences were observed in flowability, undissolved fraction after 3 min and 24 h, energy of plastic deformation (E2), ejection force, consolidation behavior, and compact friability. Cellactose® 80 exhibited the most pronounced consolidation behavior, the lowest values of ejection force, and high friability of compacts. CombiLac® showed excellent flow properties but insufficient friability, except for compacts prepared at the highest compression pressure (182 MPa). MicroceLac® 100 displayed the poorest flow properties, lower ejection forces, and the best mechanical resistance of compacts. StarLac® showed excellent flow properties, the lowest amounts of undissolved fraction, the highest ejection force values, and the worst compact mechanical resistance. The obtained results revealed that higher compression pressures need to be used or further excipients have to be added to all tested materials in order to improve the friability and tensile strength of formed tablets, except for MicroceLac® 100.

The importance of the coating material type and amount in the preparation of liquisolid systems based on magnesium aluminometasilicate carrier.

Albeit the preparation of liquisolid systems represents an innovative approach to enhance the dissolution of poorly soluble drugs, their broader utilization is still limited mainly due to the problematic conversion of the liquid into freely flowing and readily compressible powder. Accordingly, the presented study aims to determine the optimal carrier/coating material ratio (R value) for formulations based on magnesium aluminometasilicate (NUS2) loaded with polyethylene glycol 400. Four commercially available colloidal silica were used as coating materials in nine different R values (range of 5 - 100). The obtained results suggested that the higher R value leads to the superior properties of powder mixtures, such as better flowability, as well as compacts with higher tensile strength and lower friability. Moreover, it was observed that the type of coating material impacts the properties of liquisolid systems due to the different arrangement of particles in the liquisolid mixture. To confirm the noted dependency of R value and coating material type, the one- and two-way ANOVA, linear regression and principal component analysis (PCA) techniques were performed. In addition, a comparison of results with the properties of loaded NUS2 itself revealed that LSS with sufficient properties may be prepared even without the coating material.

Oligonucleotide Delivery across the Caco-2 Monolayer: The Design and Evaluation of Self-Emulsifying Drug Delivery Systems (SEDDS).

Oligonucleotides (OND) represent a promising therapeutic approach. However, their instability and low intestinal permeability hamper oral bioavailability. Well-established for oral delivery, self-emulsifying drug delivery systems (SEDDS) can overcome the weakness of other delivery systems such as long-term instability of nanoparticles or complicated formulation processes. Therefore, the present study aims to prepare SEDDS for delivery of a nonspecific fluorescently labeled OND across the intestinal Caco-2 monolayer. The hydrophobic ion pairing of an OND and a cationic lipid served as an effective hydrophobization method using either dimethyldioctadecylammonium bromide (DDAB) or 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). This strategy allowed a successful loading of OND-cationic lipid complexes into both negatively charged and neutral SEDDS. Subjecting both complex-loaded SEDDS to a nuclease, the negatively charged SEDDS protected about 16% of the complexed OND in contrast to 58% protected by its neutral counterpart. Furthermore, both SEDDS containing permeation-enhancing excipients facilitated delivery of OND across the intestinal Caco-2 cell monolayer. The negatively charged SEDDS showed a more stable permeability profile over 120 min, with a permeability of about 2 × 10-7 cm/s, unlike neutral SEDDS, which displayed an increasing permeability reaching up to 7 × 10-7 cm/s. In conclusion, these novel SEDDS-based formulations provide a promising tool for OND protection and delivery across the Caco-2 cell monolayer.

Relevance of the theoretical critical pore radius in mesoporous silica for fast crystallizing drugs.

Formulation of poorly water-soluble drugs with mesoporous silica has become a thriving field of pharmaceutics. The theoretical critical pore diameter has been introduced as a maximum value below which an undesired drug crystallization is suppressed by spatial confinement. Currently, only few values have been reported and study of fast crystallising drugs is missing especially at relevant storage temperatures. This study investigated the critical pore diameter of three model drugs with a poor glass-forming ability (i.e. haloperidol, carbamazepine and benzamide) using different mesoporous carriers (Parteck® SLC 500, Neusilin® US2, Syloid® XDP 3050 and Aeroperl® 300 Pharma) and subsequently monitored physical formulation stability over three months by X-ray powder diffraction. The selected drugs showed clear differences in their estimated critical pore diameters, whereas a temperature dependence was barely relevant for pharmaceutical storage conditions. Superior stability was noted for the formulations containing benzamide in line with its predicted relatively large critical pore diameter of 29.5 nm. Contrarily, impaired physical stability depending on drug loading was observed in the case of haloperidol representing a compound with a rather small critical pore diameter (8.4 nm). These findings confirm the importance of estimating the critical pore diameter, especially for poor glass-forming drugs.

Mechanistic aspects of drug loading in liquisolid systems with hydrophilic lipid-based mixtures.

Despite the increasing interest in pharmaceutical use of mesoporous silica, there is still only limited knowledge on mechanisms of pore loading and subsequent drug desorption and release. Hence the aim of this work was to address the mechanistic aspects of drug loading into the mesoporous silica pores and to minimise the risk of pore clogging. Hydrophilic solvents (polysorbate 20 and polyethylene glycol 200) with high dissolving capacity for the model drug celecoxib were studied for their surface tension as well as dynamic viscosity by considering hydration. As an innovation in liquisolid systems preparation, a rather simple drug loading method on a mesoporous carrier was introduced by using semi-volatile solvent mixtures. Fast liquid loading into the pores was achieved due to the lowered viscosity and surface tension of the whole solvent system. Drug release kinetics suggested that lipid-based formulations belonging to class IV of Lipid Formulation Classification System may exhibit a lower risk of incomplete desorption from a carrier. The utilisation of volatile solvents during preparation had no negative impact on the liquisolid systems' dissolution behaviour. All prepared formulations showed similar significantly faster dissolution profiles compared to the physical mixture. The novel approach has potential to promote liquisolid applications in pharmaceutics.

Evaluation and Comparison of Three Types of Spray Dried Coprocessed Excipient Avicel® for Direct Compression.

As coprocessed excipients (CPE) gain a lot of focus recently, this article compares three commercially available CPE of Avicel brand, namely, CE 15, DG, and HFE 102. Comparison is based on measured physical properties of coprocessed mixtures, respectively, flow properties, pycnometric density, mean particle size, specific surface area, moisture content, hygroscopicity, solubility, pH leaching, electrostatic charge, SEM images, and DSC. Tablets were made employing three pressure sets. Viscoelastic properties and ejection force were assessed during compression, as well as pycnometric density, mass uniformity, height, tensile strength, friability, disintegration, and wetting times. Avicel CE 15 is of mid-range flow properties, contains mid-size and nonspherical particles, and has high hygroscopicity, growing negative charge, best lubricity, lowest tensile strength, and mid-long disintegration times. Avicel DG possesses the worst flow properties, small asymmetrical particles, lowest hygroscopicity, stable charge, intermediate lubricity, and tensile strength and exhibits fast disintegration of tablets. Finally, Avicel HFE 102 has the best flow properties, large symmetrical particles, and middle hygroscopicity and its charge fluctuates throughout blending. It also exhibits inferior lubricity, the highest tensile strength, and slow disintegration of tablets. Generally, it is impossible to select the best CPE, as their different properties fit versatile needs of countless manufacturers and final products.

The influence of stevia on the flow, shear and compression behavior of sorbitol, a pharmaceutical excipient for direct compression.

Good flow and compaction properties are necessary for the manipulation of particulate material in the pharmaceutical industry. The influence of the addition of an alternative sweetener, rebaudioside A, in a concentration 0.2% w/w and 0.5% w/w on the flow, shear and compaction properties of sorbitol for direct compaction, Merisorb® 200, was investigated in this work. Rebaudioside A worsened the flow properties of sorbitol: the Hausner ratio, the compressibility index and the mass flow rate through the aperture of a model hopper. Using a Jenike shear cell revealed a significant increase in cohesion leading to the decrease of the flow function; moreover, the addition of rebaudioside A increased the total energy for compression of tablets and plasticity estimated by the force-displacement method. Finally, the tablets showed a higher tensile strength and needed longer time to disintegrate compared to the tablets made of sorbitol itself. In view of the results for the free-flowable excipient, sorbitol, the effects of stevia even for a 0.2% w/w concentration have to be carefully considered, particularly whenever used in pharmaceutical formulations of poor flow properties.

The effect of superdisintegrants on the properties and dissolution profiles of liquisolid tablets containing rosuvastatin.

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.

Experimental Design for Determination of Effects of Superdisintegrant Combinations on Liquisolid System Properties.

The preparation of liquisolid systems presents a promising and innovative possibility for enhancing dissolution profiles and improving the bioavailability of poorly soluble drugs. This study aims to evaluate the differences in the properties of liquisolid systems containing combinations of 3 commercially used superdisintegrants (sodium starch glycolate, crospovidone, and croscarmellose sodium). Multiple regression models and contour plots were used to study how the amount and the type of superdisintegrant used affected the quality parameters of liquisolid tablets. The results revealed that an increased amount of crospovidone in the mixture improves disintegration and wetting time and enhances drug release from the prepared liquisolid tablets. Moreover, it was observed that a binary blend of crospovidone and sodium starch glycolate improved tablet disintegration. Considering the obtained results, it could be stated that crospovidone showed the best properties to be used as superdisintegrant for the preparation of liquisolid systems containing rosuvastatin.

EVALUATION OF SORPTIVE PROPERTIES OF VARIOUS CARRIERS AND COATING MATERIALS FOR LIQUISOLID SYSTEMS.

The basic principle of liquisolid systems formulation lies in the conversion of the drug in a liquid state into an apparently dry, free-flowing and readily compressible powder by its blending (or spraying) with specific carriers and coating materials. The selection of the most suitable carrier and coating material depends especially on their values of flowable liquid retention potential (Φ), which is defined as the maximum mass of liquid that can be retained per unit mass of powder material, while maintaining an acceptable flowability. The presented work focused on the determination of the maximum amount of propylene glycol (PG), which can be retained by several selected carriers and coating materials while maintaining acceptable flow properties of the liquisolid powder blend. Granulated forms of magnesium aluminometasilicates (Neusilin® US2 and Neusilin® NS2N), dibasic calcium phosphate (Fujicalin®) and microcrystalline cellulose (Avicel® PH 101) were tested due to their frequent use. Powdered forms of magnesium aluminometasilicate (Neusilin® UFL2) and colloidal silica (Aerosil® 200) were used as common coating materials. From the evaluation of liquisolid mixtures with different amounts of liquid, it could be observed that 1 g of Neusilin® US2, Neusilin® UFL2, Neusilin® NS2N, Aerosil® 200, Fujicalin® and Avicel® PH 101 can retain 1.00, 0.97, 0.54, 0.04, 0.25 and 0.12 g of propylene glycol, respectively, while maintaining acceptable flowing properties for further processing.

[Enhancing of drug bioavailability using liquisolid system formulation]. / Zvysování biologické dostupnosti léciv pomocí formulace liquisolid systému.

One of the modern technologies of how to ensure sufficient bioavailability of drugs with limited water solubility is represented by the preparation of liquisolid systems. The functional principle of these formulations is the sorption of a drug in a liquid phase to a porous carrier (aluminometasilicates, microcrystalline cellulose, etc.). After addition of further excipients, in particular a coating material (colloidal silica), a powder is formed with the properties suitable for conversion to conventional solid unit dosage forms for oral administration (tablets, capsules). The drug is subsequently administered to the GIT already in a dissolved state, and moreover, the high surface area of the excipients and their surface hydrophilization by the solvent used, facilitates its contact with and release to the dissolution medium and GI fluids. This technology, due to its ease of preparation, represents an interesting alternative to the currently used methods of bioavailability improvement. The article follows up, by describing the specific aspects influencing the preparation of liquid systems, on the already published papers about the bioavailability of drugs and the possibilities of its technological improvement.Key words: liquisolid systems bioavailability porous carrier coating material preformulation studies.

[Bioavailability and factors influencing its rate]. / Biologická dostupnost léciva a moznosti jejího ovlivnování.

Bioavailability can be defined as the rate and range of active ingredient absorption, when it becomes available in the systemic circulation or at the desired site of drug action, respectively. Drug bioavailability after oral administration is affected by anumber of different factors, including physicochemical properties of the drug, physiological aspects, the type of dosage form, food intake, biorhythms, and intra- and interindividual variability of the human population. This article is the first from the series dealing with the bioavailability and methods leading to its improvement. The aim of the present paper is to provide an overview of aspects influencing the rate of bioavailability after oral administration of the active ingredient. Subsequentarticles will provide detailed descriptions of methods used for dug bioavailability improvement, which are here only summarized.

Modern evaluation of liquisolid systems with varying amounts of liquid phase prepared using two different methods.

Liquisolid systems are an innovative dosage form used for enhancing dissolution rate and improving in vivo bioavailability of poorly soluble drugs. These formulations require specific evaluation methods for their quality assurance (e.g., evaluation of angle of slide, contact angle, or water absorption ratio). The presented study is focused on the preparation, modern in vitro testing, and evaluation of differences of liquisolid systems containing varying amounts of a drug in liquid state (polyethylene glycol 400 solution of rosuvastatin) in relation to an aluminometasilicate carrier (Neusilin US2). Liquisolid powders used for the formulation of final tablets were prepared using two different methods: simple blending and spraying of drug solution onto a carrier in fluid bed equipment. The obtained results imply that the amount of liquid phase in relation to carrier material had an effect on the hardness, friability, and disintegration of tablets, as well as their height. The use of spraying technique enhanced flow properties of the prepared mixtures, increased hardness values, decreased friability, and improved homogeneity of the final dosage form.

Methods used in Pharmaceutical Technology to Increase Bioavailability of Poorly Soluble Drugs after Oral Administration.

Bioavailability increasing of poorly soluble drugs has become one of the main topics of modern pharmaceutical technology. Many methods based on the chemical modification, physical modification or new technological processes have been already used to improve bioavailability. Some of these methods (e.g. micronization, preparation of solid dispersions, formulation of an inclusion complex, etc.) have been for many years successfully used by pharmaceutical companies. On the other hand, methods such as liquisolid system and self-emulsifying drug delivery systems are still in the early stages of their development. It is expected that this novel methods could play a significant role in the preparation of modern dosage forms. The aim of this paper is to provide the summary of methods improving bioavailability of poorly soluble drugs used in the field of pharmaceutical technology.