Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates

Introduction: Present article reviews solid dispersion (SD) technologies and other patented inventions in the area of pharmaceutical SDs, which provide stable amorphous SDs.

Areas covered: The review briefly compiles different techniques for preparing SDs, their applications, characterization of SDs, types of SDs and also elaborates the carriers used to prepare SDs. The advantages of recently introduced SD technologies such as RightSize^?, closed-cycle spray drying (CSD), Lidose® are summarized. Stability-related issues like phase separation, re-crystallization and methods to curb these problems are also discussed. A patented carrier-screening tool for predicting physical stability of SDs on the basis of drug–carrier interaction is explained. Applications of SD technique in controlled drug delivery systems and cosmetics are explored. Review also summarizes the carriers such as Soluplus®, Neusilin®, Solumer^TM used to prepare stable amorphous SD.

Expert opinion: Binary and ternary SDs are found to be more stable and provide better enhancement of solubility or dissolution of poorly water-soluble drugs. The use of surfactants in the carrier system of SD is a recent trend. Surfactants and polymers provide stability against re-crystallization of SDs, surfactants also improve solubility and dissolution of drug.     

Pharmaceutical cocrystals and poorly soluble drugs

In recent years cocrystal formation has emerged as a viable strategy towards improving the solubility and bioavailability of poorly soluble drugs. In this review the success of numerous pharmaceutical cocrystals for the improvement of the solubility and dissolution rates of poorly soluble drugs is demonstrated using various examples taken from the literature. The role of crystal engineering principles in the selection of appropriate coformers and the nature of the supramolecular synthons present within the crystals are described. Evidence for improved animal pharmacokinetic data is given for several systems. A summary is provided of our current understanding of the relationship between cocrystal structure and solution phase interactions on solubility as well as those factors that influence overall cocrystal thermodynamic stability.     

Melt extrusion with poorly soluble drugs

Melt extrusion (ME) over recent years has found widespread application as a viable drug delivery option in the drug development process. ME applications include taste masking, solid-state stability enhancement, sustained drug release and solubility enhancement. While ME can result in amorphous or crystalline solid dispersions depending upon several factors, solubility enhancement applications are centered around generating amorphous dispersions, primarily because of the free energy benefits they offer. In line with the purview of the current issue, this review assesses the utility of ME as a means of enhancing solubility of poorly soluble drugs/chemicals. The review describes major processing aspects of ME technology, definition and understanding of the amorphous state, manufacturability, analytical characterization and biopharmaceutical performance testing to better understand the strength and weakness of this formulation strategy for poorly soluble drugs. In addition, this paper highlights the potential advantages of employing a fusion of techniques, including pharmaceutical co-crystals and spray drying/solvent evaporation, facilitating the design of formulations of API exhibiting specific physico-chemical characteristics. Finally, the review presents some successful case studies of commercialized ME based products.     

On the mechanism of solubilization of drugs in the presence of poorly soluble additives

A model is proposed which describes the solubilization of a poorly soluble drug in the presence of an insoluble excipient which forms an easily soluble compound with the drug. For sulfathiazole-calcium carbonate system as an example, it is demonstrated using sulfathiazole single crystals and powdered samples that the presence of insoluble additive causes an increase in dissolution rate and solubility of the drug.     

Solubilization of poorly soluble lichen metabolites for biological testing on cell lines

The depside atranorin and depsidone fumarprotocetraric acid, isolated from the lichens Stereocaulon alpinum and Cetraria islandica, respectively, were chosen as prototypes for poorly soluble natural compounds in an effort to facilitate testing in pharmacological models. Solubilizing agents previously identified as being non-toxic towards a malignant leukemic (K-562) cell line and suitable for testing of anti-proliferative activity of the dibenzofuran lichen metabolite (+)-usnic acid were used in solubilization studies of the depside and depsidone. Cyclodextrin derivatives were found to be most suitable for solubilizing the lichen compounds, the greatest rise in solubility being witnessed for fumarprotocetraric acid, increasing almost 300-fold from 0.03 mg/ml in water to 8.98 mg/ml in 10% 2-hydroxypropyl-β-cyclodextrin (HPβCD). Subsequently, the lichen compounds, including (+)-usnic acid, were solubilized in 10% HPβCD and tested for effects on three malignant human cell lines; T-47D (breast), Panc-1 (pancreas) and PC-3 (prostate) in a standard proliferation assay. Atranorin and fumarprotocetraric acid did not exhibit anti-proliferative effects but usnic acid was active against all test cell lines with EC₅₀ values of 4.3–8.2 μg/ml. The non-toxic solubilizing agents used in this study could prove useful for pharmacological testing of other poorly soluble natural products.     

Preparation and characterization of polymeric micelles for solubilization of poorly soluble anticancer drugs.

The objective of this study is to investigate the solubilization of poorly water-soluble anticancer drugs, octaethylporphine (OEP), meso-tetraphenyl porphine (mTPP) and camptothecin (CPT), in Pluronic and polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) polymeric micelles. Three different Pluronic and PEG-DSPE polymers with various chain lengths were chosen and micelle formulations were prepared by using various drug:polymer ratios. Formulations were characterized by critical micellization concentration (CMC) values of copolymers, micelle particle size and distribution, zeta potential, loading efficiency and stability. Polymers formed very stable, low CMC micelles with smaller sizes than 100 nm. It was shown that drug loading efficiency highly depends on the polymer type, drug type and their ratios. The most efficient drug loading was obtained by loading mTPP in PEG2000-DSPE and Pluronic F127 micelles. This result is attributed to phenyl groups in mTPP might lead to attraction between alkyl groups in the polymer and increase drug incorporation. PEG-DSPE formulations had higher zeta potential values indicating that they would be more stable against aggregation than Pluronic micelles. From the drug assay aspect Pluronic micelles remained more stable in 3-month long stability test. These results showed that besides their solubilizing effects, polymeric micelles could be useful as novel drug carriers for hydrophobic drugs.     

Fundamental aspects of solid dispersion technology for poorly soluble drugs

The solid dispersion has become an established solubilization technology for poorly water soluble drugs. Since a solid dispersion is basically a drug–polymer two-component system, the drug–polymer interaction is the determining factor in its design and performance. In this review, we summarize our current understanding of solid dispersions both in the solid state and in dissolution, emphasizing the fundamental aspects of this important technology.KEY WORDS: Solid dispersion, Poorly soluble drug, Phase separation, Drug–polymer interaction     

Intraorally fast-dissolving particles of a poorly soluble drug: Preparation and in vitro characterization

In this study, the dissolution rate of a poorly soluble drug, perphenazine (PPZ) was improved by a solid dispersion technique to permit its usage in intraoral formulations. Dissolution of PPZ (4 mg) in a small liquid volume (3 ml, pH 6.8) within one minute was set as the objective. PVP K30 and PEG 8000 were selected for carriers according to the solubility parameter approach and their 5/1, 1/5 and 1/20 mixtures with PPZ (PPZ/polymer w/w) were prepared by freeze-drying from 0.1 N HCl solutions. The dissolution rate of PPZ was improved with all drug/polymer mixture ratios compared to crystalline or micronized PPZ. A major dissolution rate improvement was seen with 1/5 PPZ/PEG formulation, i.e. PPZ was dissolved completely within one minute. SAXS, DSC and XRPD measurements indicated that solid solutions of amorphous PPZ in amorphous PVP or in partly amorphous PEG were formed. DSC and FTIR studies suggested that PPZ dihydrochloride salt was formed and hydrogen bonding was occurred between PPZ and the polymers. It was concluded that molecular mixing together with salt formation promoted the dissolution of PPZ, especially in the case of the 1/5 PPZ/PEG dispersion, making it a promising candidate for use in intraoral formulations.     

Physicochemical characterization and toxicity evaluation of steroid-based surfactants designed for solubilization of poorly soluble drugs

To overcome poor water-solubility of new drug candidates, four innovative surfactants based on naturally-occuring hydrophilic and hydrophobic moities were designed and synthesized: cholesteryl-glutamic acid, cholesteryl-poly[N-2-hydroxyethyl-l-glutamine] (PHEG), ursodeoxycholanyl-PHEG (UDCA-PHEG) and ursodeoxycholanyl-poly-l-glutamic acid (UDCA-PGA). Their self-assembling capacity was evaluated using pyrene fluorescence measurements which allow to determine their critical aggregation concentration (CAC). Size measurements were carried out using dynamic light scattering (DLS). Surfactant cytotoxicity was investigated on human umbilical vein endothelial cells (HUVEC) by determining tetrazolium salt (MTT) activity and lactate dehydrogenase (LDH) release. In addition, surfactant haemolytic activity was assessed using rat red blood cells (RBCs). Finally, the ability of these surfactants to solubilize a model poorly soluble drug was quantified. Surfactant self-assembly, cytotoxicity and solubilization properties were compared to those obtained with polysorbate 80, a model solubilizer. Except for cholesteryl-glutamic acid, surfactants were water-soluble. UDCA-PGA was not able to self-assemble or to increase significantly drug solubility. Results showed that cholesteryl-PHEG and UDCA-PHEG were self-assembling with low CAC values (17 and 120μg/ml) into nano-structures with mean diameters of 13 and 250nm, respectively. Cholesteryl-PHEG was the most efficient surfactant in increasing drug solubility (2mg/ml) but exhibited a similar or higher toxicity than polysorbate 80. UDCA-PHEG did not present any cytotoxicity but was far less efficient to solubilize the drug (0.2mg/ml). These results evidence interesting properties of cholesteryl-PHEG and UDCA-PHEG as novel solubilizers.     

Nanosuspensions for the formulation of poorly soluble drugs: I. Preparation by a size-reduction technique

A basic problem of poorly soluble drugs is often an insufficient bioavailability. To allow the i.v. injection of these drugs, they were formulated as nanosuspensions by high pressure homogenization. The effect of the production parameters pressure and cycle number on the mean particle size and on the polydispersity of the nanosuspension was investigated with special attention to contamination by microparticles — the limiting factor for i.v. injection. Properties of the nanosuspensions are increased saturation solubility C_s and dissolution rate dc/dt. These phenomena are explained using the Prandtl and the Ostwald–Freundlich equations. These properties promote the dissolution of the nanosuspensions in the blood after i.v. injection. The size distribution obtained and the use of an APV Gaulin homogenizer (FDA approved for parenterals) lead to a pharmaceutical product considered acceptable by the regulatory authorities.     

Development of novel ibuprofen-loaded solid dispersion with improved bioavailability using aqueous solution

To develop a novel ibuprofen-loaded solid dispersion with enhanced bioavailability, various ibuprofen-loaded solid dispersions were prepared with water, HPMC and poloxamer. The effect of HPMC and poloxamer on aqueous solubility of ibuprofen was investigated. The dissolution and bioavailability of solid dispersion in rats were then evaluated compared to ibuprofen powder. When the amount of carrier increased with a decreased in HPMC/poloxamer ratio, the aqueous solubility of ibuprofen was elevated. The solid dispersion composed of ibuprofen/HPMC/poloxamer at the weight ratio of 10:3:2 improved the drug solubility approximately 4 fold. It gave significantly higher initial plasma concentration, AUC and Cmax of drug than did ibuprofen powder in rats. The solid dispersion improved the bioavailability of drug about 4-fold compared to ibuprofen powder. Thus, this ibuprofen-loaded solid dispersion with water, HPMC and poloxamer was a more effective oral dosage form for improving the bioavailability of poor water-soluble ibuprofen.     

The solubilization of the poorly water soluble drug nifedipine by water soluble 4-sulphonic calix[n]arenes.

In this study, the solubilizing effect of 4-sulphonic calix[n]arenes on the poorly water soluble drug nifedipine was investigated. 4-Sulphonic calix[n]arenes are water-soluble phenolic cyclooligomers that form complexes with neutral molecules such as nifedipine. Solubility experiments were performed at 30 degrees C using the Higuchi rotating bottle method. The amount of nifedipine in solution was determined by HPLC. The results showed that the size of the 4-sulphonic calix[n]arenes, the pH of solubility medium, and the concentration of the calix[n]arenes all significantly changed the solubility of nifedipine. 4-Sulphonic calix[8]arene improved the solubility of nifedipine the most, about 3 times the control at 0.008 M and pH 5, followed by 4-sulphonic calix[4]arene, about 1.5 times the control at 0.008 M and pH 5, while in the presence of 4-sulphonic calix[6]arene, the solubility of nifedipine was decreased. The possible mechanisms involving in the complexation between 4-sulphonic calix[4]arenes, 4-sulphonic calix[8]arene and nifedipine may be a combination of hydrogen bonding, hydrophobic bonding, and possibly electron donor-acceptor interactions. However, the degree to which these forces promote the formation of nifedipine:4-sulphonic calix[n]arene complexes with increased solubility was limited by conformational changes in the 4-sulphonic calix[n]arene molecules.     

Improving the dissolution and oral bioavailability of the poorly water‐soluble drug aloe‐emodin by solid dispersion with polyethylene glycol 6000

Solid dispersions (SDs) of aloe‐emodin (AE) and polyethylene glycol 6000 (PEG6000) with different drug loadings were prepared, characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) and evaluated for solubility and in vitro release. The oral bioavailability of AE from SD in rats was compared with the crystalline drug. Plasma concentrations of AE were determined by HPLC. After administration of crystalline AE (35 mg·kg^?1) in rats, the AUC_0‐600 and C_max were 393.6±77.1 mg·min·l^?1 and 1.87±0.30 mg·l^?1, respectively. For the PEG6000 SD of AE, AUC_0‐600 and C_max were boosted to 1310.5±111.9 mg·min·l^?1 and 5.86±0.47 mg·l^?1, respectively. The results indicated that the oral bioavailability of AE was increased significantly. Simultaneously, the T_max value of AE for AE crystalline was decreased from 75.6±17.3 min to 44.8±14.8 min for SD. The earlier T_max for AE from SD indicated the higher extent of absorption for SD due to their improved dissolution rate in rat intestine. This SD approach can therefore be used to enhanced dissolution and bioavailability for poorly water‐soluble drugs. Drug Dev Res, 2009. © 2009 Wiley‐Liss, Inc.     

Release performance of a poorly soluble drug from a novel, Eudragit-based multi-unit erosion matrix

Mechanisms governing the release of drugs from controlled delivery systems are mainly diffusion, osmosis and erosion. For poorly soluble drugs, the existing mechanisms are limited to osmosis and matrix erosion, that are commonly observed in single unit matrix dosage forms. This study reports formulation and dissolution performance of Eudragit L 100 55 and Eudragit S 100 based multi-unit controlled release system of a poorly soluble thiazole based leukotriene D(4) antagonist, that was obtained by an extrusion/spheronization technique. Effect of triethyl citrate, that was incorporated in the matrix, on the dissolution performance of the drug was also evaluated. In vitro matrix erosion and drug release from the pellets were determined by the use of USP Dissolution Apparatus I, pH 6.8 phosphate buffer, gravimetry and UV spectrophotometry, respectively. Results obtained demonstrated that matrix erosion and drug release occurred simultaneously from the pellets. Pellets eroded with a consequent reduction in size without any change in the pellet geometry for over 12 h. Matrix erosion and drug release followed zero order kinetics. Data obtained strongly suggested a polymer controlled, surface erosion mechanism.     

Application of novel chitosan derivatives in dissolution enhancement of a poorly water soluble drug

Solid dispersions of the poorly water soluble drug dexamethasone and newly synthesized chitosan derivatives (chitosan succinate, CS, and chitosan phthalate, CP) were prepared by spray drying. The resulting microspheres were evaluated in terms of their drug loading or encapsulation efficiency as well as drug release profile. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and infrared spectroscopy (IR) were used to evaluate the solid dispersion for possible interactions between drug and polymers. The pure drug was evaluated in the same manner for comparison purposes. High loading levels (>74%) were achieved using CP and CS as polymer matrices. Drug release rate was accelerated significantly upon the formation of the solid dispersions; the drug release rate was increased with increasing percentage of the chitosan derivatives in the microspheres. IR studies showed no chemical interaction while the X-ray studies showed a significant change in the crystallinity of the drug upon formation of solid dispersions.     

增加难溶性药物溶解度方法新进展

如何增加难溶性药物溶解度是药剂学设计的重点。现就近年来微粉化技术、环糊精包含技术、固体分散技术等传统技术和其它一些新方法对增加难溶性药物溶解度的新进展作一综述。     

Effect of 4-sulphonato-calix[n]arenes and cyclodextrins on the solubilization of niclosamide, a poorly water soluble anthelmintic

The present study investigated the effect of water-soluble 4-sulphonato-calix[n]arenes, cyclodextrins, and combinations of these macromolecules on the aqueous solubility of a poorly water-soluble drug, niclosamide. Complexation between the macromolecules and niclosamide was confirmed by thermal analysis and phase solubility studies in a pH 7.0 Mcllvaine buffer kept at 30 degrees C. Results show that the increase in solubility ranked as follows: 4-sulphonato-calix[6]arene + hydroxypropyl-beta-cyclodextrin (HP-beta-CD) > 4-sulphonato-calix[6]arene + beta-cyclodextrin > 4-sulphonato-calix[6]arene + gamma-cyclodextrin = HP-beta-CD > 4-sulphonato-calix[6]arene > 4-sulphonato-calix[8]arene = 4-sulphonato-calix[4]arene > beta-cyclodextrin . Type B phase solubility profiles were observed, indicating a decrease in solubility at concentrations > 0.004 to 0.005 mol/L of the 4-sulphonato-calix[n]arenes or combinations of 4-sulphonato-calix[6]arene and the cyclodextrins. However, below this concentration, the greatest increase in the aqueous solubility niclosamide was observed when 4-sulphonato-calix[6]arene and HP-beta-CD were combined. This increase in solubility was additive.     

Review of solubilization techniques for a poorly water-soluble drug: carbamazepine

Solubility behavior of drugs remains one of the most challenging aspects in formulation development. With the introduction of various solubility improvement techniques it should be possible to overcome solubility-linked issues. Several years of research and various novel techniques for improvement of drug solubility have resulted in only a few marketed products. There are various techniques that were studied in depth to improve carbamazepine (CBZ) solubility. Several in vitro and in vivo studies have shown significant improvement in dissolution and bioavailability of CBZ. This article begins with an overview of the historical background and definitions of the various techniques, including the novel ones. The second part of the article is devoted to the techniques, materials used, procedures, and characterization of various developed formulations. The current review is further extended specifically to drug dissolution in relation to drug crystalline in various solubilization approaches.     

Pseudolarix acid B, a new tubulin-binding agent, inhibits angiogenesis by interacting with a novel binding site on tubulin

Tubulin-binding agents have received considerable interest as potential tumor-selective angiogenesis-targeting drugs. Herein, we report that pseudolarix acid B (PAB), isolated from the traditional Chinese medicinal plant Pseudolarix kaempferi Gordon, is a tubulin-binding agent. We further demonstrate that PAB significantly and dose-dependently inhibits proliferation, migration, and tube formation by human microvessel enthothelial cells. It is noteworthy that PAB eliminated newly formed endothelial tubes and microvessels both in vitro and in vivo. In addition, PAB dramatically arrested the cell cycle at G2/M phase. PAB also induced endothelial cell retraction, intercellular gap formation, and promoted actin stress fiber formation in conjunction with disruption of the tubulin and actin cytoskeletons. All of these effects occurred at noncytotoxic concentrations of PAB. We found that these effects of PAB are attributable to depolymerization of tubulin by direct interaction with a distinct binding site on tubulin compared with those of colchicine and vinblastine. Taken together, these findings show that PAB is a candidate antiangiogenic agent for use in cancer therapy, and they provide proof of principle for targeting this novel binding site on tubulin as a new strategy for treating cancer.