The inclusion complex formation of α-cyclodextrin(α-CD) with various alcohols has been studied by means of titration calorimetry. The titration curve was analyzed successfully by the formation of a 1:1 hostguest complex, and the thermodynamic parameters were determined. The entropies of reaction are estimated from the statistical thermodynamics of molecules. However, the estimated values are found to deviate by an order of magnitude from the experimental ones. To resolve such a discrepancy, α-CD in solution is assumed to include a definite number(n) of water molecules which are replaced by a guest molecule with the progress of reaction. The entropies thus estimated depend extensively on the value of n, and a value of n is determined for each alcohol so that it reproduces just the experimental entropy. The resulting n values are nearly constant for various alcohols studied and are within a reasonable range expected from the data reported in crystal, supporting the model of interpretation.

The pressurized metered dose inhaler (MDI) is a convenient and promising technology for drug delivery to the respiratory tract. For example, steroid MDIs have been applied to the topical therapy instead of oral administration which causes severe systemic side effects such as notable suppression of the hypothalamic-pituitary-adrenal axis, nephrosis, gastric ulcer, moon face and so on. As the topical therapy with MDI improves the therapeutic index by about 10 to 50 times, i.e., increase the local concentration and decrease the systemic content, the patients can reduce the dose or stop oral intake. 1-3)However, these MDIs contain chlorofluorocarbons (CFCs) as a propellant, which are known to contribute to ozone layer depletion.4) Therefore, many aerosol products using non-CFC propellants have been developed. 5) As a propellant for pharmaceutical use, two candidates named hydrofluoroalkanes (HFAs), HFA-134a and HFA-227, are available at this moment.Meanwhile, Stmerin ® D (Astellas Pharma Inc., Tokyo, Japan) was a MDI for the treatment of asthma, which contained isoproterenol sulfate (bronchodilator, b-adrenergic stimulant), atropinemethylbromide (bronchodilator, anticholinergic agent) and dexamethasone (anti-inflammatory drug). This commercial product also contained mixed CFCs (CFC-11/CFC-12/CFC-114) as propellants. So the CFC replacement was carried out due to the environmental problem. Generally the CFC replacement is considered to be very difficult because of the physicochemical differences between CFCs and HFAs.6,7) One of the main reasons is CFC-11, which has been used as a solvent in the aerosol formulations, is able to dissolve many suspending agents or surfactants and is also easily mixed with other CFCs, but the HFAs hardly dissolve such suspending agents. This makes it difficult to disperse the drugs in HFAs.From screening of large amount of suspending agents, we have recently found out that middle chain fatty acid triglyceride (MCT) has potential to suspend the drugs in HFAs. Two preparations with HFA-134a and HFA-227 were prepared.The objective of this study is to evaluate the stability of suspension type aerosol preparations with HFAs as propellants. For such kinds of aerosol preparations, the moisture content in the canister is known to influence the stability of spray performance.8) So the relationship between the moisture content in the canisters and spray performance is also discussed. ExperimentalMaterials Isoproterenol sulfate (Boehringer Ingelheim, Germany) and atropine-methylbromide (Boehringer Ingelheim, Germany) are used after pulverized using the jet mill. Dexamethasone micronised is purchased from Roussel uclaf (Paris, France). These active ingredients are of pharmaceutical grade and used without further purification.HFA-134a (1,1,1,2-tetrafluoroethane, Mistui Dupont Fluoro Chemicals, Japan) and 1,1,2,3,3, Solvey, Germany) are used as a propellant. Middle chain fatty acid triglyceride (MCT, Miglyol 812, Mitsuba, Japan) is used and functions as both a suspending agent and a lubricant for th...

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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. In the binding study, CF-BP bound very rapidly to hydroxyapatite without degradation and carboxyfluorescein was subsequently gradually released by hydrolysis of bound CF-BP. Hydrolysis of CF-BP in buffer solutions followed pseudo-first-order kinetics, and quantitative regeneration of carboxyfluorescein was observed. In addition, regeneration of carboxyfluorescein from CF-BP was accelerated in the presence of fresh rat plasma. These results suggest that CF-BP has the physicochemical properties required for site-specific and controlled delivery of carboxyfluorescein to bones.

Time-Controlled Explosion System (TES) has the time-controlled drug release property with a pre-designed lag time. The drug release from the system is initiated by destruction of the membrane. In this study, metoprolol tartrate was used as a model drug. After five types of TES with different in vitro lag times were orally administrated to dogs, plasma metoprolol concentration was monitored. There existed a good correlation between in vitro and in vivo lag time, while the extent of absorbed metoprolol decreased with prolongation of lag time. Next, the in vivo drug release behavior was directly investigated using five different colored TES with a lag time of two hours. Each TES was consecutively administrated to the fasted dogs at predetermined intervals. The amount of metoprolol released was monitored by recovering the administered TES from the gastrointestinal trace. The in vivo release profile corresponded with the in vitro one. It is demonstrated that TES can release the drug in in vivo conditions similarly to in vitro. Based on these results, the decrease of the absorption is suggested to be caused by increased hepatic first-pass metabolism of the drug due to the retarded release rate with longer lag time.