Yuji Tokunaga

Bone-specific delivery and sustained release of diclofenac, a non-steroidal anti-inflammatory drug, via bisphosphonic prodrug based on the Osteotropic Drug Delivery System (ODDS).

We have newly synthesized osteotropic diclofenac with bisphosphonic moiety (DIC-BP) based on the concept of Osteotropic Drug Delivery System (ODDS) and investigated its potency of site-specific and controlled delivery of diclofenac to the bone in rats. After intravenous injection into rats, DIC-BP was predominantly distributed in the skeleton. DIC-BP once incorporated in the bone was gradually eliminated (t(1/2)=9.7 days), releasing diclofenac into the bone compartment. As a result, the bone concentration of regenerated diclofenac was apparently constant over 28 days. Furthermore, we evaluated the anti-inflammatory effects of DIC-BP compared with diclofenac (sodium salt) in adjuvant-induced arthritic rats. The mean effective doses (ED(50)) were 0.55 mg/kg and 1.3 mg/kg for daily oral administration of diclofenac and weekly intravenous injection of DIC-BP, respectively. Considering the frequency of medication of 17 times for diclofenac and 4 times for DIC-BP in the experimental period, ED(50) was corrected to 9.4 and 5.2 mg/kg (per experimental period) for diclofenac and DIC-BP, respectively. Moreover, DIC-BP exhibited no side effects of gastrointestinal damage, typical of non-steroidal anti-inflammatory drugs. Thus, ODDS of diclofenac shows promise as an approach for highly potent and non-toxic therapy of diclofenac, with less frequent medication.

Preparation of olefins and acetylenes via reductive elimination with SmI2-HMPA

Abstract Reaction of β-hydroxy or acetoxy sulfones with Sml2 in the presence of HMPA caused effectively reductive elimination to provide olefins. Treatment of enol phosphates, readily synthesized from β-hydroxy sulfones via keto sulfones, under the same conditions efficiently produced mono- and disubstituted acetylenes.

Relationship between physicochemical and osteotropic properties of bisphosphonic derivatives: rational design for osteotropic drug delivery system (ODDS).

AbstractPurpose. The objective of this investigation is to develop a rational design of Osteotropic Drug Delivery System (ODDS), which we have proposed as a novel method for drug delivery to the skeleton via bisphosphonic prodrug, based on the relationship between physicochemical and pharmacokinetic properties of bisphosphonates. Methods. The theoretical octanol/water partition coefficients (clog P) of 13 bisphosphonates were calculated by computer software, CLOGP ver. 3.05 (Daylight C.I.S., Inc. Irvine, CA) and related to pharmacokinetic or osteotropic parameters after intravenous injection into rats. On the other hand, to optimize ODDS of diclofenac (DIC–BP), the effects of doses or infusion rates on the in vivo disposition were investigated in relation to solubility product value (Ksp) of DIC–BP–calcium complex. Results. Clog P had good correlations with total plasma clearance, apparent distribution volume and the fraction dose delivered to the whole skeleton after bolus injection into rats (r = −0.868 ∼ −0.914). The targetability of bisphosphonates to the skeleton was linearly decreased with an increase in clog P value and the more hydrophilic bisphosphonates were suitable for ODDS in bolus administration. On the other hand, DIC–BP, a relatively lipophilic bisphosphonate, was effectively and selectively delivered to the skeleton only when administered as a slow infusion to keep plasma concentration lower than that calculated from Ksp value where DIC–BP could precipitate with calcium in the plasma circulation. Conclusions. Our results suggest the possibility of a rational design of ODDS via bisphosphonic prodrugs, after consideration of compound lipophilicity and precipitability of bisphosphonate–calcium complex.

Osteotropic Drug Delivery System (ODDS) Based on Bisphosphonic Prodrug. I: Synthesis and in Vivo Characterization of Osteotropic Carboxyfluorescein

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug was designed as a novel method for site-specific and controlled delivery of drugs to the bone. Due to the chemical adsorption of bisphosphonic promoiety to the mineral component, hydroxyapatite, a bisphosphonic prodrug is predominantly taken up into the bone. To verify the concept, bisphosphonic promoiety was chemically introduced into 6-carboxyfluorescein (CF) as a model compound and the disposition after intravenous injection was studied in rats. The bisphosphonic prodrug of CF, disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP) was highly taken up to the skeleton (62.1% of dose) and the remainder was excreted into the urine (35.9% of dose). Subsequently, regeneration of CF by hydrolysis of CF-BP in the bone was observed. The microscopic observation showed that CF-BP was buried into the bone with a calcification of the bone. According to the remodeling of the bone, bisphosphonic prodrug buried was supposed to be released in the vicinity of the osteoclast or resorption surface of the bone. Thus, it is suggested that ODDS has a potential to achieve osteoclast-specific or resorption surface-specific targeting of the drugs.

Improvement of pulmonary absorption of cyclopeptide FK224 in rats by co-formulating with β-cyclodextrin

FK224 is a cyclopeptide drug with a low aqueous solubility. Following oral administration to rats, poor absorption was observed due to proteolysis in the gastrointestinal tract. The objective of this study was to investigate the effect of the pulmonary route on the systemic absorption of FK224 in comparison with other administration routes, and to determine the bioavailability (BA) of FK224 following pulmonary administration in rats using various dosage forms. From absorption studies on the Polyethylene Glycol 400 solution given by various routes (intranasal, subcutaneous, intratracheal and intravenous as reference), it was shown that pulmonary administration was a potentially attractive route for FK224. In the pulmonary absorption studies, after administration of the aqueous suspension, the BA was reduced to 2.7% compared with 16.8% for the solution. However, beta-cyclodextrin (beta-CyD) was found to be an effective additive as far as improving the solubility of FK224 was concerned. The BA of the aqueous suspension containing beta-CyD was increased to 19.2%. Pressurized metered dose inhalers were prepared by formulating beta-CyD with various molar ratios of 1:0, 1:1 and 1:7 (FK224/beta-CyD), and the resulting BAs were 4.3%, 29.0% and 91.2%, respectively. It was observed that both the C(max) and AUC of FK224 were increased as the amount of beta-CyD increased. The plasma profiles showed sustained absorption. In conclusion, we have seen that the lung is a suitable route for absorption of FK224, and beta-CyD is an extremely effective additive as far as improving the pulmonary absorption of FK224 is concerned. beta-CyD or derivatives with various degrees of aqueous solubility are potential drug carriers for controlling pulmonary absorption.

In vivo performance of time-controlled explosion system (TES) in GI physiology regulated dogs

Abstract In vivo oral absorption study of time-controlled explosion system (TES), using gastrointestinal (GI) physiology regulated dogs, was carried out to predict the feasibility in humans. TES is characterized by rapid drug release with a pre-programmed lag time, which can provide a programmed release system synchronized with circadian rhythm (e.g. asthma attack in the morning), a colon targeting system and a sustained release system with different lag times. In this study, TES containing diclofenac sodium with different lag times of 3 and 6 h (TES-3h and TES-6h) were prepared. TES-3h exhibited good performance in all six GI physiology regulated dogs without remarkable reduction of AUC. In the case of TES-6h, drug absorption was observed ∼6 h after administration in four of six dogs, but plasma level was low. Further, the location of the dosage forms after oral administration was estimated from the gastric emptying time (GET) and the small intestinal transit time (SITT) using a double marker method. As a result, in vivo performance of TES correlated with the intestinal location. It was concluded that TES-3h would perform well in humans and that the environmental water content in the GI tract affected the in vivo dissolution profile of TES when the drug release was initiated after entering the colon.

Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. III: pharmacokinetics and targeting characteristics of osteotropic carboxyfluorescein

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. The pharmacokinetics and the targeting efficiency of a bisphosphonic prodrug of carboxyfluorescein (CF), disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP), was investigated in rats. After intravenous injection, CF-BP was rapidly taken up into the skeleton, and subsequently cleared from the bone by hydrolysis of its ester linkage at a half-life of 3.2 days. On the other hand, the bone concentration of regenerated CF gradually increased to reach the maximum at 14 days and slowly decreased up to 56 days. Kinetical analysis revealed that bone tissue acts as a reservoir of regenerated CF to supply the parent compound into the systemic circulation. In contrast with CF-BP, CF injected intravenously showed rapid clearance from the plasma and extremely low bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for CF in the bone and plasma after injection of CF-BP and CF, were 1551 and 6689, respectively. These results suggest that ODDS has a potential to improve not only apparent potency but also therapeutic index of the drugs which exhibit their pharmacological effects in the bone.

Physicochemical Characterization of Bisphosphonic Carboxyfluorescein for Osteotropic Drug Delivery

Disodium (fluorescein‐6−carbonyloxy)acetoaminomethylene bisphosphonate (CF‐BP), a prodrug of 6−carboxy‐fluorescein, is efficiently absorbed by the skeleton where it hydrolyses to carboxyfluorescein. An osteotropic drug‐delivery system based on this bisphosphonic prodrug has been developed as a novel method for site‐specific and controlled delivery of drugs to the bone. In this study the physicochemical properties of the prodrug have been characterized by investigating the affinity of CF‐BP for hydroxyapatite and the hydrolysis of the compound to carboxyfluorescein.

1,3-DIPOLAR CYCLOADDITION OF 1-CARBOXYNITRONE : DIFFERENT STEREOSELECTIVITY CAUSED BY SALT EFFECT

Abstract Treatments of 1-carboxynitrone 1 with monosabstituted olefins 2 caused a 1,3-dipolar cycloadditions to give cis-isoxazolidines 3 with high stereoselection. On the other hand, reactions of 1 with olefins in the presence of triethylamine afforded trans-isomers 4 predominantly.

A simple total synthesis of (±)-spirojatamol and (±)-erythrodiene via intramolecular 1,3-dipolar cycloaddition

An efficient synthesis of spirobicyclic sesquiterpenes, (±)-spirojatamol 1 and (±)-erythrodiene 2, using an intramolecular 1,3-dipolar cycloaddition as the pivotal step is described.