We scaled up a film coating technique with a centrifugal rotary fluidized bed using a highly concentrated coating solution. The efficiency of production was increased by using a larger number of spray guns under the same spray mist conditions. We employed an apparatus with an appropriate ratio of rotating and slit air to identify the motion of granules, and optimized the peripheral speed and controlled the exhaust air rate. We used the same spray gun and spray mist conditions identified as optimal for use on a small scale. This technique was applicable to the production scale, and coated products on scales of 5, 30 and 100 kg were of the same quality. The results obtained with this coating technique at the small scale can translate well to the production scale.
The purpose of this study is to determine a specific enhancer to increase the skin permeation of only lipophilic or hydrophilic drugs. Seven kinds of enhancers were evaluated about the specificity or selectivity of their skin permeation-enhancing effects by an in vitro permeation study using 2-chamber diffusion cells and excised hairless rat skin. Isosorbide dinitrate and antipyrine were used as models for typical lipophilic and hydrophilic drugs. The enhancement factors were calculated by dividing the obtained steady-state flux of the drugs with each enhancer by that without enhancer (control), and the specificity of the enhancers was evaluated using these factors. As a result, the effect of each enhancer was greatly related to the lipophilicity of the drugs. The enhancers were therefore divided by the values of the factors into type 1 enhancers, which specially increased the skin permeation of the lipophilic drug isosorbide dinitrate such as lauric acid and lauryl alcohol; type 2 enhancers, which promoted the permeation of the hydrophilic drug antipyrine such as α-terpineol, l-menthol and N-methyl-2-pyrrolidone; and type 3 enhancers, which enhanced the permeation of both drugs such as isopropyl myristate and Azone®. The difference in the specificity in the enhancing effects might be the result of the skin permeation-enhancing mechanism. The mechanism may be related to structural properties of the enhancers rather than their physicochemical characteristics.
We investigated film formation on granules by a highly concentrated coating solution from both the mechanism of equipment and characteristics of the coating solution. As the result, the highly concentrated coating solution showed the following characteristics: the contact angle was high and the penetration rate was very slow, so it was difficult for the solution to permeate into the granules. We used a centrifugal rotary-type fluidized bed granulator equipped with a side spray nozzle at a low position. Because of the mechanical action for rotating and revolving the granules and the increased pressure and flow rate of air to control the sprayed droplets of coating solution, it was possible to effectively cover the granule surface with the highly concentrated coating solution. Consequently, it was found that the film coating technique using a highly concentrated coating solution depends on the physical and mechanical factors of the centrifugal rotary-type fluidized bed granulator.
PEG-liposomes were prepared from distearoylphosphatidylcholine (DSPC)/cholesterol (1:1, mol/mol) and 6 mol% DSPE-PEG with an average molecular weight of 2,000 and sized to 110-120 nm in mean diameter by extrusion. Encapsulation of doxorubicin (DXR) was done by either the transmembrane pH gradient or ammonium sulfate gradient methods. The trapping efficiency of DXR by either gradient method was over 90%. The stability in vitro of DXR-PEG-liposomes was estimated in serum at 37°C. The release of DXR from PEG-liposomes prepared by the pH gradient method over 24 h was low, at less than 5% of initial content. In contrast, DXR release from that prepared by the ammonium sulfate gradient method was much higher, at 20% of initial content. After i. v. administration to mice, DXR-PEG-liposomes prepared by the pH gradient method remained in the systemic circulation longer. DXR-PEG-liposomes prepared by the pH gradient method should be clinically useful.
The usefulness of penetration enhancers on the in vitro iontophoretic transport of morphine through excised hairless rat skin was investigated using a 2-chamber diffusion cell. An l-menthol (3%), ethanol (20%) and water-mixed system (MEW system) and Azone (3% Azone in 0.1% Tween 20 aqueous solution) were used as enhancers. One cell facing the stratum corneum was filled with water, the MEW system or Azone containing 1% morphine hydrochloride, and the dermis side with saline solution. Platinum wires and a constant direct current of 0.5 mA cm-2 were used as electrodes and the iontophoretic power supply, respectively. Time course of potential difference across the skin at the iontophoresis was followed as well as the morphine permeation. The electrical power required for a fixed amount of morphine delivery was calculated from the obtained potential difference and applied current. No synergetic effect was observed in the constant-current iontophoresis with the enhancers. When the enhancers were used, however, the resistance and potential difference across the skin were dramatically decreased, requiring only one-third the electric power for skin transport of 0.532 μmol cm-2 morphine as compared to that without any enhancer. It is suggested from the results that the simultaneous use of iontophoresis with permeation enhancers has no further penetration-enhancing effect under a constant-current, but an electric power-saving effect to transport a fixed amount of drug.
We previously reported that the targeted therapeutic potency in the pleiotropic in vivo biological activity of a cytokine could be emphasized by optimum bioconjugation, which is achieved by choosing a polymeric modifier according to the properties of a cytokine and the purposes of bioconjugation. In this study, we modified TNF-α with the copolymer of divinyl ether and maleic anhydride (DIVEMA), which has anti-tumor activity and induces interferon, in order to enhance its anti-tumor potency synergistically. Because DIVEMA contains abundant anhydride moieties reactive to amino groups of Lys residues of TNF-α, the crosslinkage between TNF-α moiety via DIVEMA forms, resulting in loss of the specific activity. Therefore, in order to avoid the crosslinkage, 2, 3-dimethylmaleic anhydride (DMMAn), which can pH-dependently bind to amino groups, was applied in the bioconjugation. The DIVEMA-modified-TNF-α (DIVEMA-TNF-α) were separated into two fractions by gel filtration chromatography. By use of DMMAn, the fraction that would not contain crosslinked products retained almost the same specific activity as that of native TNF-α. This fraction (DIVEMA-TNF-α (+) Fr. 2) showed approximately 100 times greater anti-tumor potency than unmodified TNF-α. In addition, at the dose of more than 100 Japan reference units (JRU) of DIVEMA-TNF-α (+) Fr. 2, complete regression was obtained in all mice. On the other hand, toxic side effects such as body weight reduction and sudden death were not observed in any mice treated with DIVEMA-TNF-α (+) Fr. 2. These findings suggest that optimum bioconjugation of TNF-α with DIVEMA could selectively enhance the targeted anti-tumor potency without toxic side effects. DIVEMA-TNF-α (+) Fr. 2 may facilitate potential anti-tumor therapeutic use.
Lollipops of clonidine hydrochloride, an α2-adrenergic agonist, for the preanesthetic medication of pediatric patients were prepared using the drug, sucrose and starch syrup. The lollipops were designed to contain 10 μg/g of clonidine hydrochloride, and made of 2,3 and 5 g formulations. The lollipops were also prepared at different composition ratios of sucrose and starch syrup. Three different commercial products of the starch syrup, with various water contents, were used. The coefficient of variation of clonidine hydrochloride content in the lollipops was 1.2%. Good content uniformity was shown. In the clinical examination, 14 patients, aged 2-7 yr and weighing 10-26.2 kg, each received a lollipop with approximately 2 μg/kg clonidine hydrochloride 90 min before entering the operating room. All patients were willing to accept the lollipop. The quality of separation from parents and a mask acceptance was improved in approximately 50% of the patients.
To improve the oral absorption of water-insoluble Ginkgo biloba extract (GBE), acacia was added to GBE by the spray-drying of a solution containing GBE and acacia. As an indicator of the oral absorptivity of GBE, the concentrations of GBE-derived flavonoid aglycones, such as quercetin, kaempferol and isorhamnetin, in the plasma of rat were determined with time after the administration of GBE (150 mg/kg). Acacia-added GBE showed greater AUC (0-24h), by about 90% (p<0.05), than that with GBE without acacia. In particular, the enhanced absorption of quercetin was observed. Examination of acaciaadded GBE by X-ray diffractometry indicated that GBE and acacia each crystallize basically in lamellar structures though their crystallite sizes are small. The interplanar spacings of GBE and acacia are seriously decreased when they are hydrated. However, even under hydration conditions, the addition of acacia prevents the lamellar structure of GBE from shrinking, which possibly promotes the access of gastrointestinal juice onto the lamella of GBE followed by an increase in the dissolution of GBE in the juice.