Nagai Tsuneji

Powder dosage form of insulin for nasal administration

Abstract The present study was an attempt to develop a powder dosage form of insulin for nasal mucosal administration, and to investigate the effect of various excipients on the bioauail-ability of insulin in powder form in comparison with liquid dosage forms. The absorption of insulin in dogs in powder form was better than that in liquid form. The preparations were administered to the nasal cavity of beagle dogs, and the changes in plasma glucose level and in plasma immunoreactive insulin were determined. An effect of solution pH on the absorption of insulin in the powder form was not clear in this study. Different types of enhancement and time curves for absorption were observed with several excipients such as lactose, crystalline cellulose (MCC), hydroxypropyl cetlulose-H (HPQ and neutralized Carbopol 934 (CP-Na), which were added to freeze-dried insulin powder. The absorption of insulin from nasal mucosa was fastest in the preparation with MCC, and was sustained in the preparation with CP-Na. In addition, it was found that a high enhancement of absorption was brought about by the new powder dosage form when that consisted of insulin and Carbopol 934 (CP) freeze-dried together. This final powder dosage form successfully produced hypoglycemia of one-third the extent of that reached by intravenous injection, assuming that the same dose of insulin was administered.

Influence of molecular weight and charge on nasal absorption of dextran and DEAE-dextran in rabbits

Abstract Two dextran derivatives, fluorescein isothiocyanate-dextran (DT) and fluorescein isothiocyanate diethylaminoethyldextran (DE), were administered intranasally to study how the molecular weight and charge influence permeation through nasal mucosa in rabbits. These compounds were used as macromolecular models of water-soluble drugs. The concentration in plasma was determined using a high-performance liquid Chromatograph equipped with a fluorescence spectrometer by means of a fluorescein isothiocyanate-dextran derivative conjugate. The concentration of DT in plasma decreased as the molecular weight of DT increased. The administration of DE (molecular weight less than 10,000) resulted in a significant increase of the concentration of DE in plasma, compared with DT. The concentration of DE in plasma increased conversely to the molecular weight of DE.

Surface potential of liposomes with entrapped insulin

Abstract From microelectrophoretic measurements on multilamellar liposomes as a function of lipid composition and pH of the medium, the pH dependence of the ζ-potential was found to be the same for liposomes in both the absence and presence of insulin. For liposomes without insulin, it is concluded that dicetyl phosphate (DCP) is incorporated at the external surface of bilayers consisting of phosphatidylcholine and cholesterol. Furthermore, the apparent pKa for the -PO4H group of DCP in liposomes was 4.5. On the other hand, insulin entrapped in liposomes did not affect the ζ-potential of liposomes. The amount of entrapped insulin solution was the same as that of entrapped calcein solution, the latter being known to be distributed in the internal aqueous compartment of liposomes. By means of incubating the mixed solution of empty liposomes and insulin, the equilibrium constant for adsorption (k) and the amount of insulin adsorbed to liposomes at saturation (X∞) could be determined from Langmuir plots. The present data suggest that the polar regions of the insulin molecule do not occur at the liposomal surface. This may be the result of the interaction between insulin and liposomes being hydrophobic in nature.

Combined effect of d-limonene and temperature on the skin permeation of ketoprofen

Abstract The effect of temperature on the enhancement action of d -limonene on percutaneous absorption of ketoprofen (KPF) was investigated in rats in vivo and in vitro. The apparent penetration rate ( R p ) of KPF absorbed from alcoholic hydrogels in rats was estimated based on a pharmacokinetic model, which was derived on the assumption of a constant penetration rate through the skin. The R p value increased sigmoidally with increase in the temperature applied, i.e., the R p value was almost constant at the lower temperatures, however, it increased abruptly at the critical temperature ( T c ) of applied heat. The T c value was significantly lowered by increasing the content of d -limonene in the hydrogel. The steady-state permeability coefficients ( P ) of KPF through the skin was determined by employing two-chamber diffusion cells in which the excised rat abdominal skin was mounted. The combined effect of d -limonene and temperature on the P value was also clarified. The Arrhenius plots of P values showed a linear relationship when the skin was pretreated with 30% ethanol without d -limonene. The activation energy of permeation of KPF through the skin was estimated to be 6.49 kJ/mol. When the skin was pretreated with 1.5% d -limonene in 30% ethanol, the Arrhenius plots of P exhibited a convex curvature. Morphological changes of the skin surface were also observed microscopically. The application of heat, along with the synergistic effect of d -limonene, may effectively change the dense barrier structure of the stratum corneum.

Influence of novel percutaneous absorption enhancers, cyclohexanone and piperidone derivatives, on histopathology of rat skin

Abstract The influences of 2- n -octylcyclohexanone, 2- tert -butylcyclohexanone, 1- n -dodecylpiperidone, 1- n -cetylpiperidone and Azone ® on the histopathology of rat skins which were treated with gel ointments containing 1–10% of these enhancers were investigated in order to gain insight into the skin damage caused by the enhancer and its irritation activity. All of the enhancers at each concentration caused epidermal liquefaction and collagen fiber swelling to some extent. The skin damage by the enhancer increased with increasing concentration of enhancer. At 3% concentration of these enhancers, certain recoverabilities of damaged skin were observed within 5 days after removing the test ointments. At low concentration (1%), recoverabilities were significantly observed, especially in the cases of 1- n -dodecylpiperidone and Azone®. No direct correlation was found between the permeation enhancement and the skin irritation of the enhancer.

Effect of bile salts on the nasal mucosa: Membrane potential measurement

Abstract The membrane potential of rabbit nasal mucosa was measured in vitro to investigate the electrical properties of the tissue. The influence of bile salts, that are enhancers for nasal absorption of peptide drugs, on the nasal mucosa was also studied from the viewpoint of membrane potential. The nasal mucosa membrane was negatively charged. The membrane charge density (θ∗) was − 3.4 mmol 1 in KCl solution and − 3.5 mol 1 in NaCl solution. These membrane potentials of the nasal membrane for isotonic solution were not changed by pretreatment with 1% ( w v ) bile salts (sodium glycocholate and dehydrocholate). The membrane potential of nasal mucosa for NaCl and KCl deviated from the simple Donnan equilibrium theorem in the region of low bulk concentration, whereas the membrane potential of the cellulose membrane obeyed the theorem over all the bulk solution concentrations. This difference may be a result of the variation in the amount o ions adsorbed on the nasal mucosa membrane.

A new biodegradable implant consisting of waxy-type poly(ε-caprolactone-co-δ-valerolactone) and estramustine

Abstract Biodegradable waxy-type copolyesters were prepared by direct copolycondensation of e-caprolactone (CL) and δ-valerolactone (VL) in the absence of catalysts, to apply as implantable matrices for drug delivery systems. The copolyesters are much more subject to erosion than their homopolyesters, in which the degradation is further accelerated by the action of lipase-type enzyme. Estramustine was incorporated into a small cylinder of waxy-type poly(CL-co-VL) with 92 mol% CL unit device by the so-called melt-pressing technique. The in vivo capability of this device was evaluated by implanting into the back of male rats. The drug release, although accompanying a burst phenomenon in the initial stage, was kept constant throughout an experimental period of 19 weeks from the 1st to 20th week. In this case, the release pattern was parallel to the degradation pattern, in support of the release being the rate-limiting step in the degradation of the polymer. The results showed about 75% of the initial drug content was still present in the device even after 20 weeks implantation. This finding means that the biodegradable poly(CL-co-VL) wax is very useful as an implantable matrix for a drug delivery system which controls the release over a relatively long period of time.

Evaluation of cyclodextrin polymer as a disintegrating agent

Cyclodextrin polymer was compared to other well known disintegrants concerning the swelling properties /water uptake, moisture uptake, hydration capacity, sedimentation volume in water/. Its high disintegrating effect was proved in directly compressed tablets as well as in tablets made by wet granulation. A remarkable improvement in tablet properties was observed. Not only the disintegration of tablets and the dissolution of the drug was accelerated but also the hardness increased when CDP was used as disintegrant.

The inactivation process of fibroblast interferon-β in the preparation stage and in rabbit nasal absorption of mixed and freeze-dried powder dosage forms

Abstract The present paper is concerned with a new finding with regard to the inactivation and the nasal bioavailability of IFN-β in two different powder dosage forms, i.e. mixed powder (MP) and freeze-dried powder (FP) dosage forms. The two types of preparations which contained bile salts were prepared. The IFN-β titer was determined by bioassay and enzyme immunoassay (EIA). Employing EIA, it was confirmed that the titers of sample MP and sample FP after preparation were different, while their bioavailabilities in the nasal absorption study were not significantly different. In an attempt to clarify the above result, studies of stability and rabbit nasal absorption of IFN-β were performed, additionally investigating the effects of cryoprotectants for sample FP. As a result, in the case of sample MP, rapid inactivation seemed to take place mainly on the nasal mucosal membrane during the absorption stage, while for sample FP it appears mostly during the preparation stage on freeze-drying. Additionally, the pharmacokinetic behavior of IFN-β was found to differ between both samples.