The relationship between the physical properties of various kinds of lactose on the market and characteristics of their tablets was investigated. For powdered and granular lactoses, the crystallinity, specific surface area, mean particle diameter and water content were determined. The hardness and thickness of tablets prepared with the powdered and granular lactoses were evaluated. For the powdered lactoses, the crystallinity and water content were nearly equal among manufacturers. For the granular lactoses, the crystallinity, specific surface area and water content varied among manufacturers. When the granular lactoses of lower crystallinity than the powdered lactoses were stored at high relative humidity, the crystallinity and water content increased due to crystallization to α-monohydrate. The tablet hardness prepared with the powdered lactoses increased with the increase in specific surface area. In the case of granular lactoses, the tablet hardness decreased linearly with the increase in the crystallinity of the lactose.

Ointments which can be adhered on the oral mucosa were prepared by dispersing various water-soluble polymers in oleaginous bases, and the adhesive characteristics, drug release profiles and liquid-bleeding restriction of the ointments were evaluated in search of an optimal formulation. Among the water-soluble polymers investigated, gelatin showed the largest initial adhesive strength, followed by carboxymethylcellulose sodium (CMC-Na) and pullulan. Among the bases, plastibase was found to be an optimal base with adhesiveness. A preparation in which a mixture of gelatin: CMC-Na: pullulan (1:1:1) was dispersed in plastibase at a concentration of 30% or higher, showed the largest initial adhesion strength among the polymer-containing preparations. However, in terms of bleeding restriction and adhesiveness to the oral mucosa, the optimal polymer content in the base was estimated to be 30%. The preparation also showed a satisfactory drug release profile and durable adhesion characteristics. It is suggested that CMC-Na takes part in the initial adhesion strength of the preparation, while gelatin and pullulan take part in the durability of adhesion. The usefulness of the preparation was also supported by the good durability of adhesion in healthy volunteers.

Various types of scored tablets have been designed recently to adjust doses to match the conditions of individual patients. However, many types of scored tablets are not well designed for dividing. Therefore, it is difficult to divide these tablets evenly, and fairly large weight variation occurs following the division. We analyzed various types of scored tablets by the ANOVA method. As a result, it is believed that factors which affect the divisibility are the hardness of tablet, the depth of score, the angle of score and the thickness of the tablet at the scored location. Based on these analyses, tablets with newly designed score shapes were manufactured. We found that tablets having a score three times wider and two times deeper than conventionally scored tablets, and also having small R shapes at each edge of the score are divided easily by hand into two equal halves with a small weight variation. These tablets are resistant to stress during various processes such as inspection, packaging and transportation. The tablets mentioned above were manufactured using a popular rotary-type tableting machine, and no problems attributed to tablet shape were observed during production.

The accuracy with which the M estimation (ME), a robust analysis, can estimate pharmacokinetic parameters was investigated and compared with that of the nonlinear leastsquared method (NLS). A one-compartment open model in which first-order absorption, with k_a=2.0 (h^-1) or 0.3 (h^-1), k_e=0.15 (h^-1) and V_d=0.2 (ι/kg), was assumed. Data obtained at various sampling times (t) were used; 6-16 points were yielded in a geometric ratio within 24 h. Group A (normal distribution errors added to each data point) and Group B (ten times the normal distribution error added to one point selected randomly and errors added to other points were the same as for Group A data points) data points were generated. The data points in each of these groups were generated from 1,500 data sets generated using Monte Carlo simulation. These data were analyzed by NLS and ME using the adapted Biweight method. Using an absorption rate constant of 2.0 (h^-1), the k_e and V_d estimated using Group A-ME data points were consistent with those estimated using Group A-NLS data points. For Group B-ME data points, k_e and V_d estimated using 7 or more data points and k_a estimated using 10 or more data points were the same as those estimated using Group A-NLS data points. For Group B-NLS data points, V_d and k_a estimated using 14 or more data points were consistent with those estimated using the data points in Group A-NLS, but the k_e estimated, even when a large number of data points was used, was different from that estimated using the data points in Group A-NLS. Using an absorption rate constant of 0.3 (h^-1), the estimatability of k_a using the data points in Group B-ME was improved compared to using the absorption rate constant of 2.0 (h^-1). The application of ME to data collected under nonideal conditions giving rise to non-normal distribution errors was shown to be useful in the estimation of pharmacokinetic parameters.

Oral mucosal bioadhesive films of diltiazem were prepared from the mixture of the drugs chitosan and sodium alginate using glycerol as the plasticizer. In vitro adhesion properties of the films were observed to be comparable to commercial formulation. In vitro release of diltiazem from the bioadhesive films was rapid, with almost 100% release within 2-3 h. When the films were administered to a sublingual site on rabbits, diltiazem from the films was rapidly absorbed from the oral mucosa into systemic blood. The bioavailability of diltiazem was ca. 60% from films with a 1:3 chitosan: alginate weight ratio when administered sublingually to rabbits as compared to ca. 30% by oral administration. The data suggest that films prepared from chitosan and sodium alginate are potential candidates for intraoral drug delivery.

Chitin (CHN) and three kinds of chitosan with deacetylation degrees of 50, 67 and 96%, named CHA 50, CHA 67 and CHA 96, respectively, were used for the preparation of films of CHN, chitosan and chitin-chitosan mixtures. Namely, the CHN or chitin-chitosan mixtures (1:1, w/w) were each dissolved in a trichloroacetic acid-1,2-dichloroethane (7:13, w/w) mixture, and chitosan was dissolved in an aqueous acetic acid solution. After the dopes obtained were cast, films were formed by precipitation. The films of CHA 50 and CHA 67 absorbed water very well, but the other films showed only moderate water absorption. The films, except CHA 50, showed fair film strength against tension under wet conditions. The films, a commercial non-woven cloth known as Beschitin^®-W and gauze alone (control) were applied to dermal burn wounds on rats. The exudate accumulated in the treatment with the CHN film. The films of CHA 50 and CHA 67 disintegrated at 5-7 days after application. The reduction in wound surface area was investigated by determining the ratio of the treated areas to their initial sizes. The films of CHN and each chitosan did not reduce the wound surface area significantly as compared to the control. Beschitin^®-W was not effective in the latter stage. The films of CHA 96 and each chitin-chitosan mixture stuck to the wound surface well, absorbed the exudate well and eliminated the pus. The chitin-chitosan mixture films reduced the wound surface area most extensively.

Capric acid (C10) enclosed in a suppository improved the rectal absorption of phenol red (PR) and cefoxitin sodium (CFX-Na) in a concentration-dependent manner. The optimal C10 concentration was 13%. The best suppository base was a mixture of polyethylene glycol (PEG) 1500 and 4000, in which the composition ratio was 1:3. C10 in the suppository reduced the electric resistance (Rm) of the rectal membrane significantly, indicating enlargement of the paracellular pathway. The concentration of C10 inducing the maximal reduction of Rm was more than 13%, corresponding with that in vivo absorption enhancement. PEG itself tended to reduce Rm, but the effect was very small in comparison with the C10 effect, indicating that the membrane damage by PEG was considered insignificant. One factor affecting the concentration-dependent effects of C10 was the release of C10 from the suppository.

In order to heal deep wounds, a new patch preparation was developed and evaluated. A hydrophilic gel was prepared from an aqueous solution of tamarind gum (Glyloid^®) and sugar. The gel was used as a patch base. A patch preparation was prepared by the addition of silver sulfadiazine (SSD) to the base. A grade III deep wound model was inflicted on rats by excision of the skin and subsequently freezing the excised part with a mixture of dry ice and acetone. The effects of treatment of the wound model were investigated using gauze only as the control, commercially available cream containing SSD (Geben^® cream), the patch base and the patch preparation. The therapeutic effect was evaluated based on the reduction of the wound surface area, the elimination of exudate and exuberant granulation. As a whole, the order of therapeutic effect was evaluated to be patch preparation > patch base ≒ commercial cream > control. The patch preparation produced a more significant effect, especially in the early stage of treatment, than the control and commercial cream. The patch preparation is believed to exhibit a superior therapeutic effect for all of the above therapeutic indices; that is, the reduction of wound surface area, the elimination of exudate and exuberant granulation.