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.

Supersaturating drug delivery systems containing fixed-dose combination of two antihypertensive drugs: Formulation, in vitro evaluation and molecular metadynamics simulations.

The purpose of this study was to associate the poorly water-soluble antihypertensive drugs candesartan cilexetil (CC) and hydrochlorothiazide (HCTZ) as fixed-dose combination, in the form of ternary Amorphous Solid Dispersions (ASD), using hydroxypropylmethylcellulose acetate succinate (HPMCAS) type M as polymeric carrier. The potential of the system to generate and to maintain supersaturation of both drugs was also evaluated. The ASDs were prepared by ball milling technique and solid-state characterization was performed by differential scanning calorimetry (DSC), Fourier transformed infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). Interaction between drugs and polymer in solid-state was evaluated by molecular metadynamics simulations. In vitro supersaturation profiles were determined in biorelevant medium. Physicochemical stability of ASDs was also evaluated under different storage conditions. Amorphization of both drugs was confirmed by solid-state characterization techniques. Molecular metadynamics simulations indicated that CC has stronger interaction with HMPCAS than HCTZ. In vitro supersaturation studies have shown that ternary ASDs could generate and maintain supersaturation of both drugs in biorelevant medium. The polymer reduced the desupersaturation of both drugs. Ternary ASDs also showed physicochemical stability over a period of 90 days, demonstrating the potential of the polymer in reducing the drugs recrystallization over the time. Ternary ASDs of CC, HCTZ and HPMCAS can be considered a promising system to associate the drugs as fixed-dose combinations. Also, these systems generate and maintain supersaturation of both drugs in biorelevant medium, with great storage stability. HPMCAS M was a good carrier for reducing the desupersaturation of associated HCTZ and CC.

It is Possible to Achieve Tablets With Good Tabletability From Solid Dispersions - The Case of the High Dose Drug Gemfibrozil.

BACKGROUND: Solid Dispersions (SDs) have been extensively used to increase the dissolution of poorly water-soluble drugs. However, there are few studies exploring SDs properties that must be considered during tablet development, like tabletability. Poorly water-soluble drugs with poor compression properties and high therapeutic doses, like gemfibrozil, are an additional challenge in the production of SDs-based tablets. OBJECTIVE: This study evaluates the applicability of SDs to improve both tabletability and dissolution rate of gemfibrozil. A SD-based tablet formulation was also proposed. METHODS: SDs were prepared by ball milling, using hydroxypropyl methylcellulose (HPMC) as a carrier, according to a 23 factorial design. The formulation variables were gemfibrozil:HPMC ratio, milling speed, and milling time. The response in the factorial analysis was the tensile strength of the compacted SDs. Dissolution rate and solid-state characterization of SDs were also performed. RESULTS: SDs showed simultaneous drug dissolution enhancement and improved tabletability when compared to corresponding physical mixtures and gemfibrozil. The main variable influencing drug dissolution and tabletability was the gemfibrozil:HPMC ratio. Tablets containing gemfibrozil- HPMC-SD (1:0.250 w/w) and croscarmellose sodium showed fast and complete drug release, while those containing the same SD and sodium starch glycolate exhibited poor drug release due to their prolonged disintegration time. CONCLUSION: SDs proved to be effective for simultaneously improving tabletability and dissolution profile of gemfibrozil. Tablets containing gemfibrozil-HPMC-SD and croscarmellose sodium as disintegrating agent showed improved drug release and good mechanical strength, demonstrating the potential of HPMC-based SDs to simultaneously overcome the poor dissolution and tabletability properties of this drug.

Eutectic mixtures as an approach to enhance solubility, dissolution rate and oral bioavailability of poorly water-soluble drugs.

Eutectic mixtures have been known for a long time in the pharmaceutical field. However, its potential as a system to improve the solubility and dissolution of poorly water-soluble drugs remains little explored. Studies involving the microstructural characterization and the preparation of solid dosage forms containing eutectic mixtures are also an issue to be developed. Recently, the number of studies involving the preparation of eutectic mixtures to improve the solubility and oral bioavailability of poorly soluble drugs has increased considerably, including drug-carrier and drug-drug mixtures. In this review is discussed the potential of eutectic mixtures as an alternative pharmaceutical solid system to enhance drugs solubility, dissolution rate or oral bioavailability. Different aspects like history, physico-chemical, microstructural properties, preparation methods, mechanisms involved in solubility/dissolution enhancement, techniques for solid state characterization, in vivo studies, advantages, limitations and formulation perspective are also discussed.

Development of curcumin-loaded chitosan/pluronic membranes for wound healing applications.

The emergence of new materials with improved antibacterial, anti-inflammatory and healing properties compared to conventional wound dressings has both social and economic appeal. In this study, novel chitosan-based (CTS) membranes containing curcumin (CUR) incorporated in Pluronic (PLU) copolymers were developed and characterized to obtain suitable properties for applications as a wound healing dressing. The mechanical, thermal, swelling, wettability, release and permeation properties were evaluated by DSC, TGA, water contact angle measurements, FTIR, fluorescence and microscopic techniques. Membranes containing PLU and CUR presented wettability close to the ideal range for interaction with cellular components (contact angle ~40-70°), improved mechanical properties, higher thermal stability, high swelling degree (>800%) and CUR release (~60%) compared to samples without PLU addition. A higher retention of CUR in the epidermis than in the dermis layer was observed, which also was confirmed by confocal microscopy. Furthermore, the CTS-PLU membranes loaded with CUR showed to be active against Staphylococcus aureus and Pseudomonas aeruginosa (MIC = 25 and 100 mg mL-1, respectively), the microbial species most present in chronic wounds. Overall, the CTS-PLU-CUR membranes presented suitable properties to act as a new wound healing dressing formulation and in vivo studies should be performed to confirm these benefits.

Liquisolid Pellets and Liqui-Pellets Are Not Different.

Our research group has pioneered the development of liquisolid pellets as a new drug delivery system targeting at the improvement of the dissolution rates of poorly water-soluble drugs, combining the technological and biopharmaceutical advantages of both multiparticulate and liquisolid systems. Recently, Lam and collaborators claimed the invention of "liqui-pellets" as "the emerging next-generation oral dosage form which stems from liquisolid concept in combination with pelletization technology". However, the concept of liqui-pellet is not novel. As we demonstrate in this commentary, liqui-pellets are the same type of preparation as our previously and extensively reported liquisolid pellets. Liquisolid pellets have been disclosed in a patent application and public peer-reviewed articles covering the concept, preparation and challenges associated with these systems. There are no technical differences that justify excluding our previous reports as the first reports on liquisolid pellets or liqui-pellets. This commentary highlights the similarities between liquisolid pellets and liqui-pellets, focusing on the anteriority of liquisolid pellets as disclosed by our group.

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.

Understanding the interaction between Soluplus® and biorelevant media components.

Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) is a solubilizing copolymer commonly applied as carrier in solid dispersions of poorly soluble drugs. This polymer is used to increase the apparent solubility of drugs with low aqueous solubility and consequently enhance drug absorption by the human gastrointestinal tract. To select the appropriate carrier to compose solid dispersions, in vitro supersaturation studies were applied as a pre-formulation tool, using different dissolution media. During in vitro supersaturation studies performed for the poorly soluble drug candesartan cilexetil, it was found that Soluplus® may interact with components of the biorelevant medium Fasted State Simulated Intestinal Fluid, lowering the drug apparent solubility. Dynamic Light Scattering and Transmission Electron Microscopy analyses were performed, as well as fluorescence measurements, aiming to characterize the interaction behavior and determine the polarity of the microenvironment. It was evidenced that Soluplus® interacted preferentially with lecithin, forming mixed micelles with a more polar microenvironment, which lowered the candesartan cilexetil solubilization capacity and consequently reduced its apparent solubility in the biorelevant medium. These findings are important to emphasize the key role of the media selection for in vitro solubility-supersaturation studies, where media that could mimic the human gastrointestinal environment are recommended.

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.

Liquisolid pellets: A pharmaceutical technology strategy to improve the dissolution rate of ritonavir.

Liquisolid pellets (LPs) prepared by extrusion-spheronization are promising delivery systems to improve the dissolution rate of poorly water-soluble drugs. However, developing LPs for high dose drugs (e.g. antiretroviral ritonavir, RTV) is a major challenge due to technical and quality constraints. In this study, formulations LP1 and LP2 were obtained (RTV 100 mg/unit dose) using microcrystalline cellulose (carrier), Kollidon® CL-SF (coating and disintegrating material) and high load (30%, w/w) of Kolliphor® EL or PEG 400 (non-volatile solvent). LP1 and LP2 had narrow size distribution, good morphological properties, and excellent flowability. The partial conversion of RTV polymorph I to the less soluble form II occurred during the preparation of the liquid medications. LP1 (containing Kolliphor® EL) achieved 82.64 ±â€¯2.17% of drug dissolved in 30 min (Q30min), compared with 53.14 ±â€¯0.6% and 42.42 ±â€¯2.09% for LP2 (containing PEG 400) and Norvir® tablets, respectively. Also, LP1 promoted 1.9-fold/1.7-fold and 8.19-fold/8.29-fold increases in Q30min/DE60min (dissolution efficiency) as compared to neat RTV polymorphs I and II, respectively.

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.

Liquisolid systems: Understanding the impact of drug state (solution or dispersion), nonvolatile solvent and coating material on simvastatin apparent aqueous solubility and flowability.

The drug in a solid dosage form must undergo dissolution before it is available for absorption from the gastrointestinal tract. Liquisolid system (LS) is a technology used for increasing aqueous solubility of the drugs, which has an important role in the dissolution and absorption phenomena. However, many factors can influence the performance and success of LS. Therefore this study aimed to evaluate through a factorial design, the factors such as drug state (solution or dispersion), nonvolatile solvent and coating material that influence the increase simvastatin (BSC II drug) apparent aqueous solubility and LS flow properties. Through numerical optimization the best formulation was selected to develop a liquisolid compact (LC) and it was evaluated by dissolution tests over commercial tablets using two dissolution media. Analyzing the data, the type of nonvolatile solvent and the state of the drug (solution or dispersion) were the factors with the greatest effects on the apparent aqueous solubility response (p < 0.0001 for both). Regarding the responses that evaluated the flow properties, the type of coating material and the type of nonvolatile solvent were the factors that influenced the Carr index (p < 0.0006, p < 0.0023, respectively) and Hausner ratio (p < 0.0006, p < 0.0014, respectively), where formulations containing Kollidon® CL were more efficient than Aerosil® (which is the most commonly used coating material for LS manufacture). These results enabled us to identify which factors were most influential and to move towards the use of new excipients in the case of Kollidon® CL. In addition, allowed a wider evaluation and understanding of LS, which is considered an important technological alternative for the increase of drug solubility.

New Approach for the Application of USP Apparatus 3 in Dissolution Tests: Case Studies of Three Antihypertensive Immediate-Release Tablets.

The USP Apparatus 3 is a compendial dissolution Apparatus that has been mainly used to assess the performance of modified-release drug products. However, this Apparatus can be applied to dissolution testing of immediate-release tablets as well, with several advantages such as lower consumption of dissolution media, reduced setup time in quality control routine, and minimized hydrodynamic issues. In this work, three immediate-release (IR) tablets containing antihypertensive drugs of different Biopharmaceutic Classification System (BCS) classes were evaluated in order to assess the possible interchangeability between the official dissolution method using typical USP Apparatus 1 or 2 and the proposed methods using USP Apparatus 3. Depending on the selection of the appropriate operational conditions, such as dip rate and sieve mesh size, it was observed that USP Apparatus 3 could provide similar dissolution profiles compared to USP Apparatus 1 or 2 to the drug products tested. In addition, USP Apparatus 3 avoided conning issues related to USP Apparatus 2. The successful application of USP Apparatus 3 in dissolution tests for IR drug products depends on the definition of specific test conditions for each product, considering all the equipment variables, as well as drug and formulation characteristics.

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.

Sodium alginate as a potential carrier in solid dispersion formulations to enhance dissolution rate and apparent water solubility of BCS II drugs.

The solid dispersion technique is the most effective method for improving the dissolution rate of poorly water-soluble drugs, however it depends on a suitable carrier selection. The work explored the use of the biopolymer sodium alginate (SA) as a potential carrier in solid dispersions (SD). The data demonstrated that SA was able to improve the biopharmaceutical properties of the BCS II drug telmisartan (TEL) of low solubility even using relative small drug:polymer ratio. A solid state grinding process was used to prepare the solid dispersions (SD) during 45 min. The SD were prepared in different proportions of drug and carrier of 1:1, 1:3, 1:5, 1:7 and 1:9 (mass/mass). DSC, XRPD, FTIR and Raman confirmed the presence of molecular interactions between TEL and the carrier. FTIR supports the presence of hydrogen bonds between TEL and the carrier. SD_1:5, SD_1:7 and SD_1:9 enhanced the dissolution rate of the drug releasing more than 80% of the drug in just 30 min (83%, 84% and 87%). The the t-test results demonstrated equal dissolution efficiency values for SD_1:7 and Micardis(®), however the similarity (f2) and difference (f1) fit factors showed that the SD and Micardis(®) are statistically different. The physical stability studies demonstrated that SD using sodium alginate as a carrier remained unchanged during the period of 90 days at room temperature, showing that the sodium alginate acts as a good anti plasticizer agent, preventing the drug recrystallization.

The effect of mechanical grinding on the formation, crystalline changes and dissolution behaviour of the inclusion complex of telmisartan and ß-cyclodextrins.

Telmisartan (TEL) was entrapped into ß-cyclodextrin aiming the improvement of its biopharmaceutical properties of low solubility. A solid state grinding process was used to prepare the molecular inclusion complex (MIC) for up to 30min. The inclusion ratio of drug and ß-cyclodextrin was established as 1:2 and 1:3 (mol/mol) by phase solubility study and Job Plot. DSC, XRPD and FTIR confirmed the molecular interactions between TEL and ß-cyclodextrin. Computer molecular modeling supports the presence of hydrogen bonds between guest and host and demonstrated the most probable complexes configuration. MIC_1:2_30 and MIC_1:3_30 enhanced the dissolution rate of the drug achieving a delivery rate comparable with the reference medicine available in the market (81% and 87% in 5min, for MIC_1:3_30 and Micardis(®), respectively). These formulations showed rapid and effective antihypertensive effect against angiotensin II in rats up to 180min, with statistically significant results against placebo and control in the first 30min after administration.

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.