In Vitro and In Vivo Behaviors of KinetiSol and Spray-Dried Amorphous Solid Dispersions of a Weakly Basic Drug and Ionic Polymer†.

Oral delivery of poorly water-soluble, weakly basic drugs may be problematic based on the drugs' intrinsic properties. Many drugs in this subset have overcome barriers to delivery following successful formulation as amorphous solid dispersions (ASDs). To process drugs as ASDs, multiple commercially relevant technologies have been developed and become well understood. However, ASD-producing technologies like spray drying and KinetiSol produce ASDs with vastly differing particle characteristics. Ultimately, the objective of this study was to assess whether processing an ASD of identical composition utilizing two different ASD-producing technologies (KinetiSol and spray drying) may impact the oral bioavailability of a weakly basic drug. For this study, we selected a weakly basic drug (Boehringer Ingelheim research compound 639667, BI 667) and processed it with an anionic polymer (hypromellose acetate succinate MMP grade (HPMCAS-MMP)) to evaluate whether the processing technology could modulate drug release in acidic and neutral media. Multiple characterization techniques (specific surface area (SSA), particle size distribution (PSD), scanning electron microscopy (SEM)) were utilized to evaluate the surface characteristics and differences in particles produced by KinetiSol and spray drying. Molecular interactions and drug-polymer miscibility of the processed particles were assessed using Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance, respectively. In vitro nonsink, pH-shift dissolution in biorelevant media and dissolution/permeation studies were conducted to better understand the release of BI 667 based on processing technology and particle size distribution. Finally, an in vivo male Beagle dog study was conducted to assess the impact of processing technology on oral bioavailability. In this study, we demonstrate that particles produced by KinetiSol have enhanced oral bioavailability compared with spray-dried particles when delivering a weakly basic drug processed with an anionic polymer. The findings of this study demonstrate that by utilizing KinetiSol, drug release may be controlled such that supersaturation in acidic media is inhibited and supersaturation of the drug is designed to occur in neutral media, ultimately enhancing oral bioavailability.

Thermally Conductive Excipient Expands KinetiSol® Processing Capabilities.

We report for the first time that incorporation of a thermally conductive excipient (TCE) modifies the thermal conductivity of the ternary drug-polymer-TCE compositions such that high-energy mixing can occur for prolonged periods at a selected steady-state temperature during the KinetiSol process. In this study, candurin, a TCE, is incorporated within a composition that is processed by high-energy mixing from the KinetiSol process to increase the thermal conductivity of the ternary composition. The improved thermal conductivity promotes heat transfer and enables the high-energy mixing applied during the KinetiSol process to be continued for prolonged time intervals at a selected steady-state temperature, instead of undergoing a continued increase in temperature when the TCE is not present in the composition. The addition of candurin does not impact the molecular structure and mixing of the drug and polymer in ASDs from solid-state NMR characterizations. Compositions with candurin achieved a steady-state processing temperature with + 5°C of the target temperature, and these compositions demonstrated the ability to mix for prolonged time periods while maintaining within this steady-state temperature range, thus enabling the formation of an ASD at a temperature that the drug does not chemically degrade. This study demonstrated that inclusion of the TCE modified the composition's thermal conductivity to efficiently dissipate heat to achieve a selected steady-state temperature during the KinetiSol process, thus providing prolonged mixing times at a lower temperature for dissolving the drug into the polymer to achieve an ASD without sacrificing product performance.

Innovations in Thermal Processing: Hot-Melt Extrusion and KinetiSol® Dispersing.

Thermal processing has gained much interest in the pharmaceutical industry, particularly for the enhancement of solubility, bioavailability, and dissolution of active pharmaceutical ingredients (APIs) with poor aqueous solubility. Formulation scientists have developed various techniques which may include physical and chemical modifications to achieve solubility enhancement. One of the most commonly used methods for solubility enhancement is through the use of amorphous solid dispersions (ASDs). Examples of commercialized ASDs include Kaletra®, Kalydeco®, and Onmel®. Various technologies produce ASDs; some of the approaches, such as spray-drying, solvent evaporation, and lyophilization, involve the use of solvents, whereas thermal approaches often do not require solvents. Processes that do not require solvents are usually preferred, as some solvents may induce toxicity due to residual solvents and are often considered to be damaging to the environment. The purpose of this review is to provide an update on recent innovations reported for using hot-melt extrusion and KinetiSol® Dispersing technologies to formulate poorly water-soluble APIs in amorphous solid dispersions. We will address development challenges for poorly water-soluble APIs and how these two processes meet these challenges.

Expanding the Application and Formulation Space of Amorphous Solid Dispersions with KinetiSol®: a Review.

Due to the high number of poorly soluble drugs in the development pipeline, novel processes for delivery of these challenging molecules are increasingly in demand. One such emerging method is KinetiSol, which utilizes high shear to produce amorphous solid dispersions. The process has been shown to be amenable to difficult to process active pharmaceutical ingredients with high melting points, poor organic solubility, or sensitivity to heat degradation. Additionally, the process enables classes of polymers not conventionally processable due to their high molecular weight and/or poor organic solubility. Beyond these advantages, the KinetiSol process shows promise with other applications, such as the production of amorphous mucoadhesive dispersions for delivery of compounds that would also benefit from permeability enhancement.

Improved Vemurafenib Dissolution and Pharmacokinetics as an Amorphous Solid Dispersion Produced by KinetiSol® Processing.

Vemurafenib is a poorly soluble, low permeability drug that has a demonstrated need for a solubility-enhanced formulation. However, conventional approaches for amorphous solid dispersion production are challenging due to the physiochemical properties of the compound. A suitable and novel method for creating an amorphous solid dispersion, known as solvent-controlled coprecipitation, was developed to make a material known as microprecipitated bulk powder (MBP). However, this approach has limitations in its processing and formulation space. In this study, it was hypothesized that vemurafenib can be processed by KinetiSol into the same amorphous formulation as MBP. The KinetiSol process utilizes high shear to rapidly process amorphous solid dispersions containing vemurafenib. Analysis of the material demonstrated that KinetiSol produced amorphous, single-phase material with acceptable chemical purity and stability. Values obtained were congruent to analysis conducted on the comparator material. However, the materials differed in particle morphology as the KinetiSol material was dense, smooth, and uniform while the MBP comparator was porous in structure and exhibited high surface area. The particles produced by KinetiSol had improved in-vitro dissolution and pharmacokinetic performance for vemurafenib compared to MBP due to slower drug nucleation and recrystallization which resulted in superior supersaturation maintenance during drug release. In the in-vivo rat pharmacokinetic study, both amorphous solid dispersions produced by KinetiSol exhibited mean AUC values at least two-fold that of MBP when dosed as a suspension. It was concluded that the KinetiSol process produced superior dosage forms containing vemurafenib with the potential for substantial reduction in patient pill burden.

Generation of a Weakly Acidic Amorphous Solid Dispersion of the Weak Base Ritonavir with Equivalent In Vitro and In Vivo Performance to Norvir Tablet.

Ritonavir is an anti-viral compound that has also been employed extensively as a CYP3A4 and P-glycoprotein (Pgp) inhibitor to boost the pharmacokinetic performance of compounds that undergo first pass metabolism. For use in combination products, there is a desire to minimize the mass contribution of the ritonavir system to reduce patient pill burden in these combination products. In this study, KinetiSol® processing was utilized to produce an amorphous solid dispersion of ritonavir at two times the drug load of the commercially available form of ritonavir, and the composition was subsequently developed into a tablet dosage form. The amorphous intermediate was demonstrated to be amorphous by X-ray powder diffraction and 13C solid-state nuclear magnetic resonance and an intimately mixed single-phase system by modulated differential scanning calorimetry and 1H T1/1H T1ρ solid-state nuclear magnetic resonance relaxation. In vitro transmembrane flux analysis showed similar permeation rates for the KinetiSol-made tablet and the reference tablet dosage form, Norvir®. In vivo pharmacokinetic comparison between the two dosage forms resulted in equivalent exposure with approximately 20% Cmax reduction for the KinetiSol tablet. These performance gains were realized with a concurrent reduction in dosage form mass of 45%.

Development of Itraconazole Tablets Containing Viscous KinetiSol Solid Dispersions: In Vitro and In Vivo Analysis in Dogs.

The formulation factors relevant to developing immediate and controlled release dosage forms containing poorly soluble drugs dispersed in amorphous systems are poorly understood. While the utility of amorphous solid dispersions is becoming apparent in the pharmaceutical marketplace, literature reports tend to concentrate on the development of solid dispersion particulates, which then must be formulated into a tablet. Amorphous solid dispersions of itraconazole in high molecular weight hydroxypropyl methylcellulose were prepared by KinetiSol® Dispersing and tablets were formulated to immediately disintegrate or control the release of itraconazole. Formulated tablets were evaluated by two non-sink dissolution methodologies and the dosage form properties that controlled the gelling tendency of the dispersion carrier, hydroxypropyl methylcellulose, were investigated. Selected formulations were evaluated in an exploratory beagle dog pharmacokinetic study; the results of which indicate potential for a prolonged absorption phase relative to the commercially extruded control.

Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for Poorly Water-Soluble Drug Delivery (Part 2).

The KinetiSol® Dispersing (KSD) technology has enabled the investigation into the use of polyvinyl alcohol (PVAL) as a concentration enhancing polymer for amorphous solid dispersions. Our previous study revealed that the 88% hydrolyzed grade of PVAL was optimal for itraconazole (ITZ) amorphous compositions with regard to solid-state properties, non-sink dissolution performance, and bioavailability enhancement. The current study investigates the influence of molecular weight for the 88% hydrolyzed grades of PVAL on the properties of KSD processed ITZ:PVAL amorphous dispersions. Specifically, molecular weights in the processable range of 4 to 18 mPa · s were evaluated and the 4-88 grade provided the highest AUC dissolution profile. Amorphous dispersions at 10, 20, 30, 40, and 50% ITZ drug loads in PVAL 4-88 were also compared by dissolution performance. Analytical tools of diffusion-ordered spectroscopy and Fourier transform infrared spectroscopy were employed to understand the interaction between drug and polymer. Finally, results from a 30-month stability test of a 30% drug loaded ITZ:PVAL 4-88 composition shows that stable amorphous dispersions can be achieved. Thus, this newly enabled polymer carrier can be considered a viable option for pharmaceutical formulation development for solubility enhancement.

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions.

Thermal processing technologies continue to gain interest in pharmaceutical manufacturing. However, the types and grades of polymers that can be utilized in common thermal processing technologies, such as hot-melt extrusion (HME), are often limited by thermal or rheological factors. The objectives of the present study were to compare and contrast two thermal processing methods, HME and KinetiSol® Dispersing (KSD), and investigate the influence of polymer type, polymer molecular weight, and drug loading on the ability to produce amorphous solid dispersions (ASDs) containing the model compound griseofulvin (GRIS). Dispersions were analyzed by a variety of imaging, solid-state, thermal, and solution-state techniques. Dispersions were prepared by both HME and KSD using polyvinylpyrrolidone (PVP) K17 or hydroxypropyl methylcellulose (HPMC) E5. Dispersions were only prepared by KSD using higher molecular weight grades of HPMC and PVP, as these could not be extruded under the conditions selected. Powder X-ray diffraction (PXRD) analysis showed that dispersions prepared by HME were amorphous at 10% and 20% drug load; however, it showed significant crystallinity at 40% drug load. PXRD analysis of KSD samples showed all formulations and drug loads to be amorphous with the exception of trace crystallinity seen in PVP K17 and PVP K30 samples at 40% drug load. These results were further supported by other analytical techniques. KSD produced amorphous dispersions at higher drug loads than could be prepared by HME, as well as with higher molecular weight polymers that were not processable by HME, due to its higher rate of shear and torque output.

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1).

Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentration-enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole.

Preparation of amorphous solid dispersions by rotary evaporation and KinetiSol Dispersing: approaches to enhance solubility of a poorly water-soluble gum extract.

Acetyl-11-keto-ß-boswellic acid (AKBA), a gum resin extract, possesses poor water-solubility that limits bioavailability and a high melting point making it difficult to successfully process into solid dispersions by fusion methods. The purpose of this study was to investigate solvent and thermal processing techniques for the preparation of amorphous solid dispersions (ASDs) exhibiting enhanced solubility, dissolution rates and bioavailability. Solid dispersions were successfully produced by rotary evaporation (RE) and KinetiSol® Dispersing (KSD). Solid state and chemical characterization revealed that ASD with good potency and purity were produced by both RE and KSD. Results of the RE studies demonstrated that AQOAT®-LF, AQOAT®-MF, Eudragit® L100-55 and Soluplus with the incorporation of dioctyl sulfosuccinate sodium provided substantial solubility enhancement. Non-sink dissolution analysis showed enhanced dissolution properties for KSD-processed solid dispersions in comparison to RE-processed solid dispersions. Variances in release performance were identified when different particle size fractions of KSD samples were analyzed. Selected RE samples varying in particle surface morphologies were placed under storage and exhibited crystalline growth following solid-state stability analysis at 12 months in comparison to stored KSD samples confirming amorphous instability for RE products. In vivo analysis of KSD-processed solid dispersions revealed significantly enhanced AKBA absorption in comparison to the neat, active substance.

Pre-Processing a Polymer Blend into a Polymer Alloy by KinetiSol Enables Increased Ivacaftor Amorphous Solid Dispersion Drug Loading and Dissolution.

This study compares the effects of pre-processing multiple polymers together to form a single-phase polymer alloy prior to amorphous solid dispersion formulation. KinetiSol compounding was used to pre-process a 1:1 (w/w) ratio of hypromellose acetate succinate and povidone to form a single-phase polymer alloy with unique properties. Ivacaftor amorphous solid dispersions comprising either a polymer, an unprocessed polymer blend, or the polymer alloy were processed by KinetiSol and examined for amorphicity, dissolution performance, physical stability, and molecular interactions. A polymer alloy ivacaftor solid dispersion with a drug loading of 50% w/w was feasible versus 40% for the other compositions. Dissolution in fasted simulated intestinal fluid revealed that the 40% ivacaftor polymer alloy solid dispersion reached a concentration of 595 µg/mL after 6 h, 33% greater than the equivalent polymer blend dispersion. Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance revealed changes in the ability of the povidone contained in the polymer alloy to hydrogen bond with the ivacaftor phenolic moiety, explaining the differences in the dissolution performance. This work demonstrates that the creation of polymer alloys from polymer blends is a promising technique that provides the ability to tailor properties of a polymer alloy to maximize the drug loading, dissolution performance, and stability of an ASD.

The effect of drug loading on the properties of abiraterone-hydroxypropyl beta cyclodextrin solid dispersions processed by solvent free KinetiSol® technology.

Abiraterone is a poorly water-soluble drug used in the treatment of prostate cancer. In our previous study, we reported that KinetiSol® processed solid dispersions (KSDs) based on hydroxypropyl ß-cyclodextrin (HPBCD) showed improved dissolution and pharmacokinetics of abiraterone. However, the nature of abiraterone-HPBCD interaction within the KSDs or the effect of drug loading on the physicochemical properties and in vivo performance of HPBCD-based KSDs remain largely unknown. We hypothesize that KinetiSol technology can prepare abiraterone-HPBCD complexes within KSDs and that increasing the drug loading beyond an optimal point reduces the in vitro and in vivo performance of these KSDs. To confirm our hypothesis, we developed KSDs with 10-50% w/w drug loading and analyzed them using X-ray diffractometry and modulated differential scanning calorimetry. We found that KSDs containing 10-30% drug were amorphous. Interestingly, two-dimensional solid-state nuclear magnetic resonance and Raman spectroscopy indicated that the abiraterone-HPBCD complexes were formed. At elevated temperatures, the 10% and 20% drug-loaded KSDs were physically stable, while the 30% drug-loaded KSD showed recrystallization of abiraterone. In vitro dissolution and in vivo pharmacokinetic performances improved as the drug loading decreased; we attribute this to increased noncovalent interactions between abiraterone and HPBCD at lower drug loadings. Overall, the 10% drug loaded KSD showed a dissolution enhancement of 15.7-fold compared to crystalline abiraterone, and bioavailability enhancement of 3.9-fold compared to the commercial abiraterone acetate tablet Zytiga®. This study is first to confirm that KinetiSol, a high-energy, solvent-free technology, is capable of forming abiraterone-HPBCD complexes. Furthermore, in terms of in vitro and in vivo performance, a 10% drug load is optimal.

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity.

We seek to further addresss the questions posed by Moseson et al. regarding whether any residual crystal level, size, or characteristic is acceptable in an amorphous solid dispersion (ASD) such that its stability, enhanced dissolution, and increased bioavailability are not compromised. To address this highly relevant question, we study an interesting heat- and shear-labile drug in development, LY3009120. To study the effects of residual crystallinity and degradation in ASDs, we prepared three compositionally identical formulations (57-1, 59-4, and 59-5) using the KinetiSol process under various processing conditions to obtain samples with various levels of crystallinity (2.3%, 0.9%, and 0.1%, respectively) and degradation products (0.74%, 1.97%, and 3.12%, respectively). Samples with less than 1% crystallinity were placed on stability, and we observed no measurable change in the drug's crystallinity, dissolution profile or purity in the 59-4 and 59-5 formulations over four months of storage under closed conditions at 25 °C and 60% humidity. For formulations 57-1, 59-4, and 59-5, bioavailability studies in rats reveal a 44-fold, 55-fold, and 62-fold increase in mean AUC, respectively, compared to the physical mixture. This suggests that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time.

Production of advanced solid dispersions for enhanced bioavailability of itraconazole using KinetiSol Dispersing.

OBJECTIVES: To investigate the ability of KinetiSol Dispersing to prepare amorphous solid dispersions of itraconazole using concentration-enhancing polymers. METHODS: Concentration-enhancing nature of several cellulosic polymers (HPMC, hypromellose acetate succinate) was studied using a modified in vitro dissolution test. Solid dispersions were prepared by KinetiSol Dispersing and characterized for solid-state properties using X-ray diffraction and differential scanning calorimetry. Potency and release characteristics were also assessed by high-performance liquid chromatography. Oral bioavailability of lead formulations was also assessed in animal models. RESULTS: Screening studies demonstrated superior concentration-enhancing performance from the hypromellose acetate succinate polymer class. Data showed that stabilization was related to molecular weight and the degree of hydrophobic substitution on the polymer such that HF > MF approximately LF, indicating that stabilization was achieved through a combination of steric hindrance and hydrophobic interaction, supplemented by the amphiphilic nature and ionization state of the polymer. Solid dispersions exhibited amorphous solid-state behavior and provided neutral media supersaturation using a surfactant-free pH change method. Rank-order behavior was such that LF > MF > HF. Addition of Carbopol 974P increased acidic media dissolution, while providing a lower magnitude of supersaturation in neutral media because of swelling of the high viscosity gel. In vivo results for both lead compositions displayed erratic absorption was attributed to the variability of gastrointestinal pH in the animals. CONCLUSIONS: These results showed that production of amorphous solid dispersions containing concentration-enhancing polymers through KinetiSol Dispersing can provide improved oral bioavailability; however, additional formulation techniques must be developed to minimize variability associated with natural variations in subject gastrointestinal physiology.

Dissolution enhancement of a drug exhibiting thermal and acidic decomposition characteristics by fusion processing: a comparative study of hot melt extrusion and KinetiSol dispersing.

In this study, hot melt extrusion (HME) and KinetiSol Dispersing (KSD) were utilized to prepare dissolution-enhanced solid dispersions of Roche Research Compound A (ROA), a BCS class II drug. Preformulation characterization studies showed that ROA was chemically unstable at elevated temperatures and acidic pH values. Eudragit L100-55 and AQOAT LF (HPMCAS) were evaluated as carrier polymers. Dispersions were characterized for ROA recovery, crystallinity, homogeneity, and non-sink dissolution. Eudragit L100-55 dispersions prepared by HME required the use of micronized ROA and reduced residence times in order to become substantially amorphous. Compositions containing HPMCAS were also prepared by HME, but an amorphous dispersion could not be obtained. All HME compositions contained ROA-related impurities. KSD was investigated as a method to reduce the decomposition of ROA while rendering compositions amorphous. Substantially amorphous, plasticizer free compositions were processed successfully by KSD with significantly higher ROA recovery values and amorphous character than those achieved by HME. A near-infrared chemical imaging analysis was conducted on the solid dispersions as a measure of homogeneity. A statistical analysis showed similar levels of homogeneity in compositions containing Eudragit L100-55, while differences were observed in those containing HMPCAS. Non-sink dissolution analysis of all compositions showed rapid supersaturation after pH adjustment to approximately two to three times the equilibrium solubility of ROA, which was maintained for at least 24 h. The results of the study demonstrated that KSD is an effective method of forming dissolution-enhanced amorphous solid solutions in cases where HME is not a feasible technique.

Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions.

The treatment of cancer is still a major challenge. But tremendous progress in anticancer drug discovery and development has occurred in the last few decades. However, this progress has resulted in few effective oncology products due to challenges associated with anticancer drug delivery. Oral administration is the most preferred route for anticancer drug delivery, but the majority of anticancer drugs currently in product pipelines and the majority of those that have been commercially approved have inherently poor water solubility, and this cannot be mitigated without compromising their potency and stability. The poor water solubility of anticancer drugs, in conjunction with other factors, leads to suboptimal pharmacokinetic performance. Thus, these drugs have limited efficacy and safety when administered orally. The amorphous solid dispersion (ASD) is a promising formulation technology that primarily enhances the aqueous solubility of poorly water-soluble drugs. In this review, we discuss the challenges associated with the oral administration of anticancer drugs and the use of ASD technology in alleviating these challenges. We emphasize the ability of ASDs to improve not only the pharmacokinetics of poorly water-soluble anticancer drugs, but also their efficacy and safety. The goal of this paper is to rationalize the application of ASD technology in the formulation of anticancer drugs, thereby creating superior oncology products that lead to improved therapeutic outcomes.

Influence of sulfobutyl ether beta-cyclodextrin (Captisol) on the dissolution properties of a poorly soluble drug from extrudates prepared by hot-melt extrusion.

The aim of this study was to investigate the influence of sulfobutyl ether beta-cyclodextrin (SBE(7)-beta-CD; Captisol on the dissolution properties of a poorly water-soluble drug from extrudates prepared by hot-melt extrusion. Ketoprofen was employed as a model drug. Extrudates containing the parent beta-cyclodextrin (beta-CD) were also produced for comparative evaluation to assess the benefits of SBE(7)-beta-CD. Hot-melt extrudates were produced at 100 degrees C, which was close to the melting point of ketoprofen. The physiochemical properties and the in vitro drug release properties of ketoprofen from extrudates were investigated and compared with samples prepared by physical mixing, co-grinding, freeze-drying and heat-treatment. The solubilizing effects and the interactions of ketoprofen with SBE(7)-beta-CD and beta-CD were investigated using phase solubility and NMR studies, respectively. The dissolution rate of ketoprofen from samples prepared by hot-melt extrusion with SBE(7)-beta-CD was significantly faster than both the physical mixture and the hot-melt extrudates prepared with the parent beta-CD. Moisture absorption studies revealed that the hygroscopic nature of SBE(7)-beta-CD led to particle aggregation and a corresponding decrease in drug release rate for all samples. However, the samples prepared by melt extrusion were least affected by exposure to elevated humidity.

High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers.

A nebulized dispersion of amorphous, high surface area, nanostructured aggregates of itraconazole (ITZ):mannitol:lecithin (1:0.5:0.2, w/w) yielded improved bioavailability in mice. The ultra-rapid freezing (URF) technique used to produce the nanoparticles was found to molecularly disperse the ITZ with the excipients as a solid solution. Upon addition to water, ITZ formed a colloidal dispersion suitable for nebulization, which demonstrated optimal aerodynamic properties for deep lung delivery and high lung and systemic levels when dosed to mice. The ITZ nanoparticles produced supersaturation levels 27 times the crystalline solubility upon dissolution in simulated lung fluid. A dissolution/permeation model indicated that the absorption of 3 microm ITZ particles is limited by the dissolution rate (BCS Class II behavior), while absorption is permeation-limited for more rapidly dissolving 230 nm particles. The predicted absorption half-life for 230 nm amorphous ITZ particles was only 15 min, as a result of the small particle size and high supersaturation, in general agreement with the in vivo results. Thus, bioavailability may be enhanced, by decreasing the particle size to accelerate dissolution and increasing permeation with (1) an amorphous morphology to raise the drug solubility, and (2) permeability enhancers.