Drug Extended-Release System Utilizing Micelle Formation of Highly Water-Soluble Drugs and a Counter Polymer.

The objective of this study is to clarify the mechanism of extending release of highly water-soluble drugs via counter polymer (CP) utilization in poly(ethylene oxide) (PEO)/polyethylene glycol (PEG) matrix tablets. Carbomer, poly(acrylic acid), was used as a CP, which has the opposite charges to the drugs. The in vitro release of several highly water-soluble drugs from PEO/PEG tablet with or without CP were tested, the relationship between the sustained release effect by a CP (SRE) and the physicochemical properties of the drugs was investigated. The results demonstrated that the utilization of CP can extend the release of some highly water-soluble drugs by effectively controlling the drug diffusion through matrices. On the other hand, the effectiveness of CP was different depending on the drugs applied. There were not statistical correlations between SRE and physicochemical properties such as solubility, molecular weight, and charge intensity of the drugs, while a micelle forming property of the drugs played an important role in SRE by CP. It was concluded that CP, Carbomer, having negative charges could effectively interact with opposite charges on the surface of stable drug micelles, which could result in a significant decrease in drug diffusion leading to extended drug release. It is considered that the system utilizing CP is a promising approach to achieve extended release of highly water-soluble drugs with a reasonable tablet size, especially in the case of large drug loading.

Drug delivery to the intestinal lymph by oral formulations.

Oral drug delivery systems (DDS) targeting lymphocytes in intestinal lymphatic vessels, ducts, and nodes are useful for treating diverse diseases. The intestinal lymph harbors numerous lymphocyte subsets, and DDS containing lipids such as triglycerides and fatty acids can deliver drugs to the lymph through the chylomicron pathway. DDS are efficient, thus allowing the administration of reduced drug doses, which mitigate systemic adverse effects. Here we review orally administered lipid formulations comprising oil solutions, suspensions, micro/nanoemulsions, self-micro/nano emulsifying DDS, liposomes, micelles, solid lipid nanoparticles, and nanostructured lipid carriers for targeting drugs to the lymph. We first describe the structures of lymphatic vessels and lymph nodes and the oral absorption of lipids and drugs into the intestinal lymph. We next summarize the effects of the properties and amounts of lipids and drugs delivered into the lymph and lymphocytes, as well as their effects on drug delivery ratios of lymph to blood. Finally, we describe lymphatic DDS containing saquinavir, tacrolimus, and methotrexate, and their potency that reduces drug concentrations in blood, which are associated with systemic adverse effects.

Novel Orally Disintegrating Tablets Produced Using a High-Pressure Carbon Dioxides Process.

It is well known that high-pressure carbon dioxide (CO2) lowers the glass transition temperature (Tg) of polymers. We therefore investigated whether Tg depression of high-pressure CO2 results in interparticle bridging of a polymer and the tablet characteristics that makes the manufacture of an orally disintegrating tablet (ODT) possible. Copolyvidone (Kollidon®) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) were examined and found to exhibit a large Tg depression. Placebo ODTs were prepared and hardness, disintegration rate, porosity, and change in thickness and appearance were evaluated before and after the high-pressure CO2 treatment. This enabled the establishment of the optimal conditions for pressure, temperature, and treatment time under pressure. Experimental results showed that it was possible to manufacture ODTs comprising Kollidon® as a water-soluble polymer with CO2 treatment under the suitable conditions such as temperature at 45°C, pressure lower than 8 MPa, and a treatment time shorter than 30 min, which is a new ODT manufacturing process called "Carbon Dioxide Assisted Tablet Formation Scheme" (CATS). In comparison to the conventional processes, which require high temperatures or humidity, CATS is expected to be applicable to drugs that are unstable at high temperature and humidity, and to functional drug particles used for bitter taste masking, sustained release, and other uses.

Formulation design and evaluation of liposomal sepantronium bromide (YM155), a small-molecule survivin suppressant, based on pharmacokinetic modeling and simulation.

PURPOSE: Sepantronium bromide (YM155) is administered by 168-hour continuous infusions in clinical studies due to its time-dependent pharmacological efficacy and rapid elimination from plasma. To enable more convenient administration, i.e., bolus injections with low frequency, we prepared liposomal formulations of YM155 and evaluated their antitumor activities. METHODS: A kinetic simulation model of liposomal YM155 to predict the free drug concentration in both tumor and plasma was developed. A liposomal formulation with the target drug release rate was prepared based on the simulation. Antitumor activities of the formulation were examined in various tumor xenograft mouse models. In addition, antitumor activities of liposomal formulations with different drug release rates were compared in order to confirm the validity of the simulation-based prediction. RESULTS: Liposomal YM155 with the release half-life of 48 h was prepared as a promising formulation. This formulation showed significantly potent antitumor activities in tumor xenograft models by weekly bolus injections. Further studies demonstrated that this release rate was optimal for YM155 in terms of both efficacy and safety. CONCLUSIONS: We successfully developed a liposomal formulation of YM155 that could substitute for long-term continuous infusion of the drug solution in clinical settings by being given as weekly bolus injections.

Influence of binder droplet dimension on granulation rate during fluidized bed granulation.

Here, we statistically identified the critical factor of the granulation rate during the fluidized bed granulation process. Lactose was selected as the excipient and was granulated with several binders, including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. The viscosity, density, and surface tension of the binder solution, contact angle, and the work done during adhesion and cohesion between the binder and lactose, mist diameter, Stokes number, and the dimension of the droplet were considered. The Stokes number was defined as the ratio of the inertial force to the viscous-damping force of a particle. We confirmed that droplet diameter after adhesion had the highest correlation coefficient with the granulation rate constant in our investigated parameters. Partial least squares regression revealed two critical principal components of the granulation rate: one relating to the droplet dimension, which is composed of mist diameter and diameter and thickness of the droplet after adhesion of the binder to the lactose surface; and the other relating to wettability, which involves the work done during adhesion and cohesion, surface tension, and the thickness of the droplet after adhesion of the binder to the lactose surface.

Effect of aminoalkyl methacrylate copolymer E/HCl on in vivo absorption of poorly water-soluble drug.

This study aimed to investigate in vivo absorption of tacrolimus formulated as a solid dispersion using Eudragit E®/HCl (E-SD). E-SD is an aminoalkyl methacrylate copolymer that can be dissolved under neutral pH conditions. E-SD was used alone as a solid dispersion carrier and/or was mixed with tacrolimus primarily dispersed with hydroxypropylmethylcellulose (HPMC). Tacrolimus was formulated with E-SD at several different ratios. Formulations with tacrolimus/E-SD ratio of 1/3 showed higher in vivo absorption, compared to tacrolimus dispersed in the excipients (primarily HPMC) found in commercially available tacrolimus capsules, using a rat in situ closed loop method. Good correlation was observed between in vitro drug solubility and in vivo drug absorption. In vitro solubility tests and rat oral absorption studies of tacrolimus/HPMC solid dispersion formulations were also conducted after mixing the HPMC dispersion with several ratios of E-SD. E-SD/tacrolimus/HPMC formulations yielded high in vitro drug solubility but comparatively low in vivo absorption. Dog oral absorption studies were conducted using capsules containing a formulation of tacrolimus/E-SD at a ratio of 1/5. The E-SD formulation-containing capsule showed higher in vivo drug absorption than tacrolimus dispersed in the standard HPMC capsule. These studies report enhancement of the in vivo absorption of a poorly water-soluble drug following dispersion with E-SD when compared to formulation in HPMC.

Influence of manufacturing factors on physical stability and solubility of solid dispersions containing a low glass transition temperature drug.

In this study, we investigated the effect of manufacturing factors such as particle size, water content and manufacturing method on the physical stability and solubility of solid dispersion formulations of a low-glass-transition-temperature (T(g)) drug. Solid dispersions were prepared from polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) by hot melt extrusion or spray drying. Water content of solid dispersions prepared by hot melt extrusion determined by dynamic moisture sorption measurement was increased drastically with relative humidity below a certain level of particle size. The blends with a lower water content (0.8%) prepared by hot melt extrusion during storage were more stable than those with a higher water content (3.5%) prepared by spray drying, which caused rapid recrystallization. Physical stability in the hot melt blends may be attributed to reduced molecular mobility due to a higher T(g). Dissolution study revealed that solid dispersions prepared by hot melt extrusion with the smallest particle size showed decreased solubility, attributed to reduced wetting properties (surface energy), which is not predictable by the Noyes-Whitney equation. Taken together, these results indicate that the control of particle size concerned in water content or wetting properties is critical to ensuring the physical stability or enhancing solubility of low-T(g) drugs. Further, hot melt extrusion, which can reduce water content, is a suitable manufacturing method for solid dispersions of low-T(g) drugs.

Polymer combination increased both physical stability and oral absorption of solid dispersions containing a low glass transition temperature drug: physicochemical characterization and in vivo study.

The purpose of this study was establishing a solid dispersion formulation containing a low glass transition temperature (T(g)) and poorly water-soluble drug. Drug/polymer blends with differing physicochemical stabilities and oral absorption were prepared from copolyvidone (PVP-VA), polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC) by a hot melt extrusion. HPMC drastically increased the drug oral absorption property, while PVP-VA or PVP stabilized solid dispersions during storage by increasing the T(g) in proportion to polymer concentration. Experimental T(g) values corresponded closely with theoretical T(g) values; indeed, the T(g) values of solid dispersion with HPMC did not increase significantly compared to the T(g) value for the drug alone. A solid dispersion formulation incorporating two different polymers-HPMC and either PVP-VA or PVP-maintained increased T(g), physicochemical stability, solubility, and bioavailability of the solid dispresions owing to each polymer. These findings suggested that both oral absorption and physicochemical stability of low-T(g) drug will be improved using less amount of solid dispersion of combined two polymers than polymer alone.

Evaluation of models for predicting spray mist diameter for scaling-up of the fluidized bed granulation process.

We evaluated models for predicting spray mist diameter suitable for scaling-up the fluidized bed granulation process. By precise selection of experimental conditions, we were able to identify a suitable prediction model that considers changes in binder solution, nozzle dimension, and spray conditions. We used hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), or polyvinylpyrrolidone (PVP) binder solutions, which are commonly employed by the pharmaceutical industry. Nozzle dimension and spray conditions for oral dosing were carefully selected to reflect manufacturing and small (1/10) scale process conditions. We were able to demonstrate that the prediction model proposed by Mulhem optimally estimated spray mist diameter when each coefficient was modified. Moreover, we developed a simple scale-up rule to produce the same spray mist diameter at different process scales. We confirmed that the Rosin-Rammler distribution could be applied to this process, and that its distribution coefficient was 1.43-1.72 regardless of binder solution, spray condition, or nozzle dimension.

Extended release of a large amount of highly water-soluble diltiazem hydrochloride by utilizing counter polymer in polyethylene oxides (PEO)/polyethylene glycol (PEG) matrix tablets.

The purpose of this study was to evaluate the feasibility of using a counter polymer in polyethylene oxide (PEO)/polyethylene glycol (PEG) polymeric matrices for the sustained release of a large amount of highly water-soluble drug. PEO/PEG matrix tablets (CR-A) containing four drugs with different water solubilities were prepared to investigate the effect of drug solubility on the drug-release and diffusion properties of PEO/PEG matrices. Cross-linked carboxyvinyl polymer (CVP)/PEO/PEG matrix tablets (CR-B) containing a water-soluble drug, diltiazem hydrochloride (DTZ), were also prepared, and their in vitro characteristics were compared with those of CR-A. Their in vitro drug release properties were evaluated using a dissolution test, and the polymeric erosion and drug diffusion properties of the matrices were also calculated. Drugs with higher solubility in water were released faster for the CR-A. The drug-release rate also increased with the amount of drug loaded. CR-A containing 50% DTZ (by weight) extended drug release by only 6h. This confirms the difficulty experienced when trying to formulate PEO/PEG matrices for the sustained release of a large amount of highly water-soluble drugs due to large drug diffusion. In an attempt to control this issue, a polymer bearing a charge opposite that of the drug was used to effectively decrease the diffusion of DTZ, resulting in sustained release for 24h or longer. These results suggested that including counter polymer in the PEO/PEG matrix tablet is a useful tool for achieving the sustained release of a large amount of highly water-soluble drug.

Ion-Responsive Drug Delivery Systems.

BACKGROUND: Some kinds of cations and anions are contained in body fluids such as blood, interstitial fluid, gastrointestinal juice, and tears at relatively high concentration. Ionresponsive drug delivery is available to design the unique dosage formulations which provide optimized drug therapy with effective, safe and convenient dosing of drugs. OBJECTIVE: The objective of the present review was to collect, summarize, and categorize recent research findings on ion-responsive drug delivery systems. RESULTS: Ions in body fluid/formulations caused structural changes of polymers/molecules contained in the formulations, allow formulations exhibit functions. The polymers/molecules responding to ions were ion-exchange resins/fibers, anionic or cationic polymers, polymers exhibiting transition at lower critical solution temperature, self-assemble supramolecular systems, peptides, and metalorganic frameworks. The functions of ion-responsive drug delivery systems were categorized to controlled drug release, site-specific drug release, in situ gelation, prolonged retention at the target sites, and enhancement of drug permeation. Administration of the formulations via oral, ophthalmic, transdermal, and nasal routes has showed significant advantages in the recent literatures. CONCLUSION: Many kinds of drug delivery systems responding to ions have been reported recently for several administration routes. Improvement and advancement of these systems can maximize drugs potential and contribute to patients in the world.

Development of extended-release solid dispersion granules of tacrolimus: evaluation of release mechanism and human oral bioavailability.

OBJECTIVES: We aimed to prepare a once-daily modified-release oral formulation of tacrolimus by utilizing an extended-release granules (ERG). METHODS: Extended-release granules were prepared using ethylcellulose (EC), hydroxypropylmethylcellulose (HPMC) and lactose via a solvent evaporation method with ethanol. Physicochemical and biopharmaceutical studies were performed to determine the formulation with optimum release profile of tacrolimus from ERG. KEY FINDINGS: Tacrolimus existed in an amorphous state in ERG. Tacrolimus release from ERG was attenuated by EC and facilitated by lactose, suggesting that drug release kinetics could adequately be regulated by these components. Those release profiles were consistent with Higuchi's equation, suggesting a diffusion-type release mechanism. Smooth surface of ERG changed to the structure with pores after the release test, likely derived from the dissolution of HPMC and lactose. But ERG structure formed by EC was still maintained after the release test, leading to the longer maintenance of diffusion-type release. Two ERG formulations selected by blood concentration simulation successfully provided long-term retention of tacrolimus in blood in a human absorption study. CONCLUSIONS: We successfully developed the formulation exhibiting a significant reduction in Cmax , the longer mean residence time and AUC close to that of an immediate-release tacrolimus formulation, being preferred from the viewpoint of safe and effective immunosuppressant pharmacotherapy.

Effects of absorption promoters on insulin absorption through colon-targeted delivery.

The aim of this study were to investigate the effect of sodium glycocholate (GC-Na) as an absorption promoter and the effects of the co-administration of GC-Na and various absorption promoters on orally administered insulin absorption utilizing a colon-targeted delivery system. The system containing insulin and GC-Na (CDS) was administered to dogs, and plasma glucose and insulin levels were then measured at 24h after administration. For CDS, the C(max) in plasma glucose level was significantly higher than a reference formulation without GC-Na. The pharmacological availability for CDS was not significantly higher than the reference formulation. In contrast, CDS with poly(ethylene oxide) as a gelling agent (CDSP) showed prolonged hypoglycemia effects. The pharmacological availability was 5.5% and significantly different from the reference formulation. The absolute bioavailability for CDS was 0.25%, and for CDSP it was 0.42%. Consequently, the results of this study demonstrated that colon-specific delivery of insulin with GC-Na was more effective in increasing hypoglycemic effects after oral administration, and the combination of GC-Na and poly(ethylene oxide) tended to prolong the colonic absorption of insulin and might be more effective for improvement of orally administered insulin absorption utilizing the colon-targeted delivery system.

Preparation of extended release solid dispersion formulations of tacrolimus using ethylcellulose and hydroxypropylmethylcellulose by solvent evaporation method.

OBJECTIVES: Tacrolimus is a poorly water-soluble compound that is used to prevent allograft rejection. We aimed to prepare an extended release formulation of tacrolimus to achieve both an extended release profile and improved solubility of tacrolimus. METHODS: Extended release granules (ERG) of tacrolimus were prepared with lactose, ethylcellulose (EC) and hydroxypropylmethylcellulose (HPMC) via the solvent evaporation method. KEY FINDINGS: In an in vitro release study, ERG had an extended release profile, and the release rate of tacrolimus was regulated by the quantity of lactose, EC and HPMC in the formulation. HPMC-containing ERG successfully enhanced and maintained supersaturation of tacrolimus even after 24 h in a supersaturated release study. In contrast, the extent of supersaturation rapidly decreased after 4 h and the concentration nearly reached the same level as that of crystalline tacrolimus at 24 h for ERG without HPMC. In vivo absorption characteristics were compared between ERGs and immediate release (IR) formulation of tacrolimus. Successful and sustained absorption of tacrolimus without reducing bioavailability compared with IR formulation was observed for ERG. CONCLUSIONS: These results suggest the feasibility of combining an EC-based formulation with solid dispersion utilizing HPMC for the extended release of oral formulations and sustained absorption of tacrolimus.

Oral sustained-release suspension based on a lauryl sulfate salt/complex.

The objective of this study was to evaluate the feasibility of lauryl sulfate (LS) salt/complex as a novel carrier in oral sustained-release suspensions. Mirabegron, which has a pH-dependent solubility, was selected as the model drug. Sodium lauryl sulfate (SLS) was bound to mirabegron in a stoichiometric manner to form an LS salt/complex. LS salt/complex formulation significantly reduced the solubility of mirabegron and helped mirabegron achieve sustained-release over a wide range of pH conditions. Microparticles containing the LS salt/complex were prepared by spray drying with the aqueous dispersion of ethylcellulose (Aquacoat® ECD). The diameter of the microparticles was less than 200µm, which will help avoid a gritty taste. In vitro results indicated the microparticles had slower dissolution profiles than the LS salt/complex. The dissolution rate could be controlled flexibly by changing the amount of Aquacoat® ECD. The microparticle suspension retained the desired sustained-release property and dissolution profile after being stored for 30days at 40°C. In addition, the suspension displayed sustained-release behavior in dogs without a pronounced Cmax peak, which will help prevent side effects. These results suggest that microparticles containing LS salt/complex may be useful as a novel sustained-release suspension for oral delivery.

Influence of water soluble fillers in hydroxypropylmethylcellulose matrices on in vitro and in vivo drug release.

The purpose of this study was to investigate the effect of fillers in gel-forming matrix on in vivo drug release after oral dosing. A further purpose was to predict the in vivo performance from in vitro dissolution test. Three controlled-release acetaminophen tablets containing hydroxypropylmethylcellulose (HPMC) with or without highly water soluble fillers, lactose or polyethylene glycol 6000 (PEG6000), were prepared. Water penetration into the matrix was enhanced by addition of fillers in the matrices, but the three tablets showed similar in vitro dissolution profiles, indicating that fillers in the HPMC matrices little affected the in vitro drug release. In contrast, the fillers in HPMC matrices did affect the in vivo performance in dogs. The absorption profile of HPMC matrix with PEG6000 was the fastest, followed by that with lactose and without water soluble filler, in that order. As the matrix with PEG6000 had a large amount of water and gelated a large portion of the matrix when in contact with water, the gel layer would be disintegrated by the gastrointestinal motility. It was found that dissolution of gel-forming HPMC matrices under mechanical stress by glass beads well correlated with the in vivo performance of the matrix, with little correlation by the conventional paddle method.

Antitumor efficacy and biodistribution of liposomal sepantronium bromide (YM155), a novel small-molecule survivin suppressant.

Sepantronium bromide (YM155) exhibits time-dependent antitumor activity, although the plasma half-life of YM155 after a bolus intravenous (i.v.) administration is very short. Therefore, greater antitumor efficacy is obtained by continuous infusion than by bolus i.v. administration. In the present study, we attempted to liposomalize YM155 to obtain a longer circulation time than that achieved by bolus i.v. administration and yet retain sufficient antitumor activity. Encapsulation of YM155 in polyethylene glycol-coated liposomes extended the half-life of the drug, and high tumor accumulation of the drug was observed. Bolus i.v. administration of liposomal YM155 by a weekly administration regimen showed antitumor activity comparable to that obtained by the continuous infusion without severe toxicity in a murine xenograft model. Therefore, this liposomal formulation can be a new dosage form of YM155 that achieves sufficient efficacy and safety and is a more convenient administration regimen for users. It should be noted that liposomal YM155 showed unexpectedly high accumulation in the kidneys. This is a specific finding for liposomal YM155, offering important information for the consideration of the potential toxicity of liposomal YM155.

Development of qualitative and quantitative analysis methods in pharmaceutical application with new selective signal excitation methods for 13 C solid-state nuclear magnetic resonance using 1 H T1rho relaxation time.

Most pharmaceutical drug substances and excipients in formulations exist in a crystalline or amorphous form, and an understanding of their state during manufacture and storage is critically important, particularly in formulated products. Carbon 13 solid-state nuclear magnetic resonance (NMR) spectroscopy is useful for studying the chemical and physical state of pharmaceutical solids in a formulated product. We developed two new selective signal excitation methods in (13) C solid-state NMR to extract the spectrum of a target component from such a mixture. These methods were based on equalization of the proton relaxation time in a single domain via rapid intraproton spin diffusion and the difference in proton spin-lattice relaxation time in the rotating frame ((1) H T1rho) of individual components in the mixture. Introduction of simple pulse sequences to one-dimensional experiments reduced data acquisition time and increased flexibility. We then demonstrated these methods in a commercially available drug and in a mixture of two saccharides, in which the (13) C signals of the target components were selectively excited, and showed them to be applicable to the quantitative analysis of individual components in solid mixtures, such as formulated products, polymorphic mixtures, or mixtures of crystalline and amorphous phases.

pH- and ion-sensitive polymers for drug delivery.

INTRODUCTION: Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body. AREAS COVERED: Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(ß-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations. EXPERT OPINION: Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.

Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug-bile interaction.

The aim of this study was to find out polymeric compounds that can inhibit the interaction between YM466, a novel anticoagulant, and bile to improve its oral bioavailability. In vitro ultrafiltration method using extract gall powder was useful to detect the formation of insoluble complex of YM466 with bile and also used to select a polymer that can inhibit the interaction between YM466 and bile. The in vitro studies revealed that aminoalkylmethacrylate (AAM) copolymer E, a polymethacrylate, dose-dependently inhibited the interaction between YM466 and bile and that this polymer could interact with bile salt, but not with YM466, possibly by electrostatic and/or hydrophobic interactions. The coadministration of AAM copolymer E with YM466 to rats dose-dependently increased the plasma concentration of YM466 and it was found that the oral dose of the polymer three times of YM466 (polymer to drug ratio in weight, P-D ratio, 3) significantly increased AUC0-1 h of YM466 to 2.6-fold of that of YM466 alone. Considering the condition of therapeutic use of YM466 and the maximum tolerated dose of the polymer, the formulation of P-D ratio 3 would be clinically practical and promising from the viewpoint of safety.