Kazuo Tomono

Interaction between Cycloamylose and Various Drugs

Cycloamylose (CA), has a cyclic structure like cyclodextrin (CD), but has a very large number of molecules, and its physical properties are still unclear. The CA used in this study was supplied by Ezaki Glico Co., Ltd, and was a mixture (mean molecular weight 7720). Predonisolone, cholesterol, digoxin, digitoxin and nitroglycerin were chosen as guest molecules. We evaluated the interaction between CA and the guest molecules using the solubility method described by Higuchi and Connors. The concentration of each dissolved guest molecule was determined by HPLC. This solubility method was performed at a temperature of 5 °C. The phase solubility diagrams of drugs with CA showed type A or type B profiles. Cholesterol, digoxin, digitoxin and predonisolone formed a complex with CA, but nitroglycerin did not.

Evaluation of a Sulfobutyl Ether β-Cyclodextrin as a Solubilizing/Stabilizing Agent for Several Drugs

To evaluate the potential use of beta-cyclodextrin sulfobutyl ether, 7 sodium salt (SBE7-beta-CD) as a drug solubilizing and stabilizing agent, the solubilizing effects of SBE7-beta-CD on 22 different poorly water-soluble drugs were compared with those of intact beta-CD and heptakis-(2,6-di-O-methyl)-beta-CD (DMCD). SBE7-beta-CD was generally a more effective solubilizer for poorly water-soluble drugs than was intact beta-CD, but SBE7-beta-CD was not as effective as DMCD. The effects of SBE7-beta-CD on the acid hydrolysis rate of prostaglandin I2, the alkaline hydrolysis rate of indomethacin, the dehydration of prostaglandin E1, and the isomerization of prostaglandin A1 were also investigated and compared to those for intact beta-CD, DMCD, and 2,3,6 partially methylated-beta-CD (PMCD). The stabilizing effects of SBE7-beta-CD on chemically unstable drugs were generally higher than those of other CDs.

Interaction of Antimalarial Agent Artemisinin with Cyclodextrins

To obtain an effective solution of the poorly water soluble antimalarial agent artemisinin, the use of several kinds of cyclodextrins (CDs) as solubilizers was examined. The following CDs were used in this study: α-CD, β-CD, γ-CD as parent CDs, 2-hydroxypropyl-β-CD (HP-β-CD), sulfobutyl ether β-CD (SBE7-β-CD), heptakis (2,6-di-O-methyl)-β-CD (DM-β-CD), 2,3,6-partially methylated-β-CD (PM-β-CD) as modified CDs, and glucosyl-β-CD (G1-β-CD), and maltosyl-β-CD (G2-β-CD) as branched CDs. The solubility curves of artemisinin with CDs can all be classified as type AL. The apparent stability constants for artemisinin-parent CD complexes increased in the order of α- < γ- ≤ β-CD. The constants for artemisinin-β-CD derivative (and β-CD) complexes increased in the order of G2-β-CD ≅ G1-β-CD cong; PM-β-CD ≅ β-CD < HP-β-CD < SBE7-β-CD < DM-β-CD. These results suggest that the addition of CDs enables the solubilization of artemisinin.

Homogeneous nanoparticles to enhance the efficiency of a hydrophobic drug, antihyperlipidemic probucol, characterized by solid-state NMR

A low absorption in the gastrointestinal tract of hydrophobic pharmaceutical compounds in use today considerably limits their bioavailability, and therefore they are taken in large doses in order to reach the therapeutic plasma concentration, which inevitably results in undesired side effects. In this study, we demonstrate a new nanoparticle approach to overcome this problem, and our experimental results show that this approach has a high efficiency of drug loading and is easily adaptable to industrial scale. Characterization of nanoparticles containing a cholesterol-lowering hydrophobic drug, probucol, using a variety of biophysical techniques revealed higher homogeneity of these particles compared to those prepared using other approaches. Intermolecular interactions of these nanoparticles are probed at high resolution by magic angle spinning solid-state NMR experiments.

P-glycoprotein mediates brain-to-blood efflux transport of buprenorphine across the blood-brain barrier

The involvement of P-glycoprotein (P-gp) in buprenorphine (BNP) transport at the blood–brain barrier (BBB) in rats was investigated in vivo by means of both the brain uptake index technique and the brain efflux index technique. P-gp inhibitors, such as cyclosporin A, quinidine and verapamil, enhanced the apparent brain uptake of [3H]BNP by 1.5-fold. The increment of the BNP uptake by the brain suggests the involvement of a P-gp efflux mechanism of BNP transport at the BBB. [3H]BNP was eliminated with an apparent elimination half-life of 27.5 min after microinjection into the parietal cortex area 2 regions of the rat brain. The apparent efflux clearance of [3H]BNP across the BBB was 0.154 ml/min/g brain, which was calculated from the elimination rate constant (2.52 × 10− 2 min− 1) and the distribution volume in the brain (6.11 ml/g brain). The efflux transport of [3H]BNP was inhibited by range from 32 to 64% in the presence of P-gp inhibitors. The present results suggest that BNP is transported from the brain across the BBB via a P-gp-mediated efflux transport system, at least in part.

Nanoparticle processing in the solid state dramatically increases the cell membrane permeation of a cholesterol-lowering drug, probucol.

High cholesterol levels (or hypercholesterolemia) are linked with many diseases, particularly with the risk of coronary heart diseases. Probucol is commonly used to reduce cholesterol in blood. While the effectiveness of this drug highly depends on its solubility, unfortunately, it is nearly insoluble (solubility is 5 ng/mL in water). Therefore, it is essential to develop approaches to increase its solubility and bioavailability and to enhance the efficiency of the drug. Here we show that a new method increases the solubility of probucol in water and its ability to permeate cell membranes. This new method of processing the drug in a nanoparticle utilizes the grinding of PBC probucol together with sodium dodecylsulfate and methacrylic copolymer. Solid-state NMR experiments reveal the polymorphic state of probucol and the conversion of this drug from crystalline to the amorphous state, and determine its nearness to the copolymer due to the grinding process that enables the formation of nanoparticles.

Characterization of multicomponent crystal formed between indomethacin and lidocaine

Purpose: Crystalline complex was formed between indomethacin (IDM) and lidocaine (LDC) at molar ratio 2:1 from ethanol solution. The purpose of this study was elucidation of an interactive manner between IDM and LDC in ethanol solution and mechanism of the complex formation through solid state as well as liquid state. Methods: The chemical and physical nature of the complex was clearly elucidated by the alliance of powder X-ray diffractometry, differential scanning calorimetry, and infrared spectroscopy. The complex was also formed via solid-state reaction by cogrinding and heating treatment without any solvent. Results: The complexation process was estimated to be as follows: (i) mixing and contact of two components, (ii) disorder of crystalline LDC by grinding or fusion, and then (iii) crystal growth by heating. In addition, 1H-NMR coupled with microchanneled cell for synthesis monitoring revealed that a primary interactive force between IDM and LDC molecule was coulomb energy.

Novel pharmaceutical cocrystal consisting of paracetamol and trimethylglycine, a new promising cocrystal former

Paracetamol (APAP), a frequently used antipyretic drug, has poor compression moldability. In this study, we identified a novel cocrystal consisting of APAP and trimethylglycine (TMG) that exhibits improved tabletability. TMG was used instead of oxalic acid (OXA), which is a coformer reported previously. The cocrystal (APAP-TMG at a molar ratio of 1:1) was characterized by X-ray analysis, infrared spectroscopy, and thermal analysis. The crystal structure of APAP-TMG revealed that it was a cocrystal, since no proton was transferred between the APAP and TMG molecules. The compression and dissolution properties of APAP-TMG were similar to that of the APAP-OXA cocrystal. In addition, taste sensing measurements suggested that TMG has a sweet and umami taste, indicating that TMG should suppress the bitterness of APAP. From these results, TMG could be a safe and promising cocrystal former that could replace OXA, which can irritate tissues.

Involvement of an Influx Transporter in the Blood-Brain Barrier Transport of Naloxone

Naloxone, a potent and specific opioid antagonist, has been shown in previous studies to have an influx clearance across the rat blood–brain barrier (BBB) two times greater than the efflux clearance. The purpose of the present study was to characterize the influx transport of naloxone across the rat BBB using the brain uptake index (BUI) method. The initial uptake rate of [3H]naloxone exhibited saturability in a concentration‐dependent manner (concentration range 0.5 µM to 15 mM) in the presence of unlabeled naloxone. These results indicate that both passive diffusion and a carrier‐mediated transport mechanism are operating. The in vivo kinetic parameters were estimated as follows: the Michaelis constant, Kt, was 2.99±0.71 mM; the maximum uptake rate, Jmax, was 0.477±0.083 µmol/min/g brain; and the nonsaturable first‐order rate constant, Kd, was 0.160±0.044 ml/min/g brain. The uptake of [3H]naloxone by the rat brain increased as the pH of the injected solution was increased from 5.5 to 8.5 and was strongly inhibited by cationic H1‐antagonists such as pyrilamine and diphenhydramine and cationic drugs such as lidocaine and propranolol. In contrast, the BBB transport of [3H]naloxone was not affected by any typical substrates for organic cation transport systems such as tetraethylammonium, ergothioneine or L‐carnitine or substrates for organic anion transport systems such as p‐aminohippuric acid, benzylpenicillin or pravastatin. The present results suggest that a pH‐dependent and saturable influx transport system that is a selective transporter for cationic H1‐antagonists is involved in the BBB transport of naloxone in the rat. Copyright

Interaction of Cyclomaltononaose (δ-CD) with Several Drugs

The effects of δ-cyclodextrin (δ-CD; cyclomaltononaose) on solubility of 14 drugs that are slightly soluble or insoluble in water were studied and compared with those of conventional cyclodextrins (CDs) such as α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD). In general, δ-CD had a weak complex-forming ability with the drugs examined in comparison with β-CD and γ-CD. However, in the case of digitoxin, δ-CD enhanced solubility of the guest molecules. To determine the mechanism of inclusion complex formation of δ-CD with digitoxin, the interaction of both drugs was investigated by the solubility method and spectroscopic methods such as ultraviolet (UV) and 1H-NMR (nuclear magnetic resonance). The changes in chemical shift (1H) and hypsochromic shift of UV suggested that digitoxin was partially included in the cavity of δ-CD.