Eutectic mixture and amorphous solid dispersion: Two different supersaturating drug delivery system strategies to improve griseofulvin release using saccharin.

This study evaluated the ability of different sweeteners to improve dissolution and to form and stabilize supersaturated solutions of griseofulvin (GSF), comparing a eutectic mixture and amorphous formulations. Among the sweeteners tested, only saccharin (SAC) was able to delay drug precipitation in buffer (area under the curve (AUC) increase of 40%) and in fasted state simulated intestinal Fluid (FaSSIF, AUC increase of 20%) compared to pure media. GSF solubility was not affected by the presence of isomalt (ISO), maltitol (MALT) and SAC in buffer pH 6.5 but was reduced in FaSSIF. The quenched cooled amorphous formulation GSF-SAC QC -with the carrier that forms a eutectic mixture with GSF -provided higher drug release in buffer than amorphous formulations with ISO and MALT. In FaSSIF, SAC slightly changed the microenvironment's hydrophobicity (observed in fluorescence studies) and both its amorphous formulation (GSF-SAC QC) and its eutectic mixture (GSF-SAC EM) dissolved at concentrations above drug solubility, achieving supersaturation ratio (SR, Eq. (1)) of 4.14 and 3.15, respectively. The main finding of this study was that for the first time a eutectic mixture acted as a supersaturating drug delivery system, emphasizing the importance of investigating EMs during preformulation studies of fast-crystallizing poorly water-soluble drugs.

Could the small molecules such as amino acids improve aqueous solubility and stabilize amorphous systems containing Griseofulvin?

Griseofulvin (GSF) is an antifungal drug that has low aqueous solubility and low oral bioavailability. Amorphous systems are capable to promote rapid drug dissolution, usually affording concentrations above drug solubility in the gastrointestinal tract (supersaturation) in order to promote better absorption. Thus, the aim of this work was to evaluate the ability of amino acids, as hydrophilic carriers, to improve drug kinetic solubilization and to stabilize GSF supersaturated solutions, as well as to stabilize GSF amorphous systems at solid-state. The effect of 5 amino acids on GSF precipitation behavior was investigated by solvent shift method. Amorphous systems were developed by ball milling (GSF + amino acid 1:1 M ratio) and Quench Cooling (to obtain GSF QC) techniques. The samples were characterized by solid-state techniques, submitted to in vitro kinetic solubility studies and evaluated under stability tests. Aspartic acid, methionine, valine and tryptophan demonstrated similar anti-precipitant abilities in phosphate buffer pH 6.5. However, in FaSSIF biorelevant medium, tryptophan was only one able to slow down the drug precipitation. The characterization of milled samples showed that an amorphous system was obtained just using the combination of the drug with tryptophan (GSF-TRYP BM). At the higher dose tested (0.850 mmol L-1) during in vitro kinetic solubility studies, this amorphous system increased the AUC in FaSSGF (88.6%) and FaSSIF (58.2%) media when compared to GSF QC. Thus, the ability of this amino acid to inhibit GSF precipitation appears to be dependent on its concentration in solution and could be optimized. During the stability study, TRYP inhibited GSF recrystallization in the solid-state for a period of 12 months, whereas GSF QC recrystallized in 1 week.

New supersaturating drug delivery system as strategy to improve apparent solubility of candesartan cilexetil in biorelevant medium.

Candesartan cilexetil (CC) is a poorly soluble antihypertensive drug with in vivo absorption limited by its low aqueous solubility. Aiming to generate CC supersaturation as strategy to improve its absorption and bioavailability, amorphous solid dispersions (ASDs) of CC with hydroxypropylmethylcellulose acetate succinate type M (HPMCAS M) were developed and evaluated by in vitro and in vivo techniques. The ASDs were characterized by several solid-state techniques and evaluated regarding the supersaturation generation and maintenance under non-sink conditions in biorelevant medium. Stability studies at different storage conditions and in vivo pharmacodynamics studies were performed for the best formulation. The ASD developed presented appropriate drug amorphization, confirmed by solid state characterization, and CC apparent solubility increases around 85 times when compared to the pure crystalline drug. Supersaturation was maintained for up to 24 h in biorelevant medium. The in vivo pharmacodynamics studies revealed that ASD of CC with the polymer HPMCAS M presented an onset of action about four times faster when compared to the pure crystalline drug. The CC-HPMCAS ASD were successfully developed and demonstrated good physical stability under different storage conditions as well as promising results that indicated the ASD potential for improvement of CC biopharmaceutical properties.

How tenofovir disoproxil fumarate can impact on solubility and dissolution rate of efavirenz?

Efavirenz (EFZ) and tenofovir disoproxil fumarate (TDF) can be used simultaneously in the treatment of human immunodeficiency virus type1 infection. In this work the impact of TDF, a hydrophilic drug, on the solubility and dissolution rate of EFZ, a poorly water-soluble drug, was evaluated. EFZ/TDF binary mixtures in different molar ratios were prepared. Differential scanning calorimetry (DSC) results indicate the formation of a eutectic mixture, the molar ratio of 65/35 being the eutectic point. It was observed an increase in the EFZ solubility in water and acidic conditions (0.1 N HCl and biorelevant medium), in the presence of TDF. On the other hand, there was a decreasing on EFZ solubility in phosphate buffer pH 6.8, probably influenced by the lower solubility of TDF in this medium. The high solubility of TDF in water and acidic medium may have contributed to improve the solubility of EFZ, as well as the formation of a eutectic mixture, supported by X-ray powder diffraction (XRPD) and Fourier Transform infrared spectroscopy (FTIR) analyses. However, TDF solubility and dissolution rate was not significantly influenced by the presence of EFZ.

The role of sodium alginate on the supersaturation state of the poorly soluble drug chlorthalidone.

Solid dispersions (SDs) of chlorthalidone (CTD) are promising systems to enhance drug dissolution rate, generate and maintain drug supersaturation levels in gastrointestinal fluids. In this work, SDs of CTD were prepared by spray drying using sodium alginate (SA) as carrier. Six formulations were prepared, varying the drug loading and composition, through the combination of SA with surfactants (sodium lauryl sulfate (SLS) or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL)). In all SDs, except when SA was used alone at low drug loading, CTD was in the amorphous form. At sink conditions, all SDs showed a faster dissolution rate than the crystalline drug. At non-sink conditions, the SDs prepared with SA and SLS at low drug loading exhibited the best performance to maintain supersaturating drug levels. All SDs, except those prepared with SA alone or SA-SLS at high drug loading, presented no drug recrystallization after 34 months of storage.

HPMCAS as an effective precipitation inhibitor in amorphous solid dispersions of the poorly soluble drug candesartan cilexetil.

Among the strategies to improve the biopharmaceutic properties of poorly soluble drugs, Supersaturating Drug Delivery Systems like polymer-based amorphous solid dispersions (SD) have been successfully applied. The screening of appropriate polymeric carriers to compose SD is a crucial point on their development. In this study, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS) types L, M and H and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL) were evaluated by in vitro supersaturation studies regarding their anti-precipitant ability on the poorly soluble drug candesartan cilexetil (CC) under two different media, including biorelevant conditions. According to the results, HPMCAS M was considered the best carrier to develop SD containing CC among all the polymers tested, due to its good anti-precipitant performance in both media. In addition, the medium used in the in vitro supersaturation studies played an important role on the results, and its selection should be carefully done.

Investigation of novel supersaturating drug delivery systems of chlorthalidone: The use of polymer-surfactant complex as an effective carrier in solid dispersions.

Supersaturating drug delivery systems (SDDS), as solid dispersions (SDs), stand out among strategies to enhance bioavailability of poorly soluble drugs. After oral administration, their dissolution in gastrointestinal fluids often leads to supersaturation, which drives to a rapid and sustained absorption. Polymers and surfactants play important roles in SDs through inhibiting precipitation caused by transitions from amorphous into crystalline form, in supersaturated solutions, and also through improving SDs physical stability. Novel chlorthalidone SDs, a BCS IV drug, were developed using polymeric and non-polymeric carriers, specially a polymer-surfactant complex. SDs drug releases were evaluated using sink and non-sink conditions in water and biorelevant medium. Their physical stability was also monitored under different storage conditions. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL), sodium lauryl sulfate (SLS) and a combination of both showed promising results in apparent solubility studies, and therefore they were selected to compose the spray dried SDs. Dissolution studies demonstrated the SOL-SLS complex potential for providing chlorthalidone fast release (>80% in 15min), producing and maintaining in vitro supersaturation. This formulation comprising high drug loading (75%) reached a high supersaturation degree under non-sink condition (up to 6-fold the equilibrium solubility) once maintained for 6h in biorelevant medium. In addition, this SD presented better physical stability when compared to the chlorthalidone neat amorphous. The SOL-SLS complex impacts positively on chlorthalidone release and physical stability, highlighting its potential as carrier in SDDS of a poorly soluble drug.

Carnauba wax as a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of highly soluble drugs.

Mini-tablets are a new tendency in solid dosage form design for overcoming therapeutic obstacles such as impaired swallowing and polypharmacy therapy. Among their advantages, these systems offer therapeutic benefits such as dose flexibility and combined drug release patterns. The use of lipids in the formulation has also drawn considerable interest as means to modify the drug release from the dosage form. Therefore, this paper aimed at developing sustained release mini-tablets containing the highly soluble drugs captopril and metformin hydrochloride. Carnauba wax was used as a lipid component in melt granulation, targeting the improvement of the drugs poor flowability and tabletability, as well as to sustain the drug release profiles in association with other excipients. To assist sustaining the drug release, Ethocel™ (EC) and Kollicoat® SR 30D associated with Opadry® II were employed as matrix-forming and reservoir-forming materials, respectively. The neat drugs, granules and the bulk formulations were evaluated for their angle of repose, compressibility index, Hausner ratio and tabletability. Mini-tablets were evaluated for their weight variation, hardness, friability, drug content and in-vitro drug release. The results indicated that melt granulation with carnauba wax improved the flow and the tabletability of the drugs, allowing the preparation of mini-tablets with adequate tensile strength under reduced compaction pressures. All mini-tablet formulations showed acceptable hardness (within the range of 1.16 to 3.93Kp) and friability (<0.1%). The melt-granulated captopril in matrix systems containing 50% EC (45P, 100P or 100FP) and the melt-granulated metformin hydrochloride in reservoir systems coated with Kollicoat® SR 30D and Opadry® II (80:20 with 10% weight gain or 70:30 with 20% weight gain) exhibited release profiles adequate to sustained release formulations, for over 450min. Therefore, carnauba wax proved to be a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of soluble drugs.

Ball-milled solid dispersions of BCS Class IV drugs: Impact on the dissolution rate and intestinal permeability of acyclovir.

Acyclovir, an analog of 2'-deoxyguanosine, is one of the most important drugs in the current approved antiviral treatment. However, it's biopharmaceutical properties, contribute to acyclovir's poor oral bioavailability, which restricts the clinical use of the drug. In this view, the aim of this work was to improve the dissolution rate and intestinal permeability of acyclovir through the development of ball milling solid dispersions with the hydrophilic carriers Pluronic F68®, hydroxypropylmethyl cellulose K100M® and chitosan. Solid dispersions were obtained and completely characterized through different solid state techniques. The solid state data demonstrated a decrease in the crystallinity (amorphous phase and defects) and the presence of hydrogen bonds for SD HPMC and SD CTS. The enhancement of dissolution rates was observed for all SDs developed. In addition, no detrimental effects over the in vitro antiviral activity were detected. The solid dispersions with Pluronic F68® significantly improved the intestinal permeability of acyclovir across Caco-2 cells. In summary, the SDs developed in this study could be considered as potential systems for solid dosage forms containing acyclovir with superior biopharmaceutical properties.