Toshiaki Nishihata

Overall mechanism behind matrix sustained release (SR) tablets prepared with hydroxypropyl methylcellulose 2910

Abstract The mechanisms of sustained release (SR) from tablet matrices prepared with hydroxypropyl methylcellulose (HPMC) 2910 polymers were investigated to define the conditions for selection of appropriate polymers for SR formulation development. It is well known that the two important parameters for the release of drug from tablet matrices are the infiltration rate of medium into the matrix, for those drugs with reasonable aqueous solubility, and the erosion rate of the matrix system, for those drugs with poor aqueous solubility. In addition, the amount of drug loaded into the tablet also influences the release rate of the drug. The infiltration rate of medium into the matrix can be controlled by changes in the interspace volume of the matrix by the use of higher levels of materials such as lactose, which quickly rinse out of matrix system. The larger interspace volumes produced by the higher ratio result in more rapid release of the drug. The viscosity of HPMC polymers is related to the molecular weight and has a large influence on the erosion rate of matrix tablet. Use of a low viscous grade HPMC polymer is desirable for drugs that are poorly water soluble since the erosion rate of the tablet matrix is the controlling factor for drug release. The release rate of poorly soluble drug can be controlled by the rate of tablet erosion. The tablet erosion rate can also be adjusted by the choice of HPMC polymer viscosity or by mixing HPMC of different viscosity grades.

Enhancement of rectal absorption of insulin using salicylates in dogs

Sodium salicylate and 5‐methoxysalicylate both increased the rectal absorption of insulin in dogs when co‐administered with insulin in various formulations. Microenema formulations containing 4% gelatin showed the highest insulin biavailability of the formulations studied whereas microenemas (without gelatin) and suppository formulations were not as effective in enhancing the rectal absorption of insulin.

Use of shed snake skin as a model membrane for in vitro percutaneous penetration studies : comparison with human skin

The potential usefulness of shed snake skin as a model membrane for transdermal research was examined. There are similarities between shed snake skin and human stratum corneum in terms of structure, composition, lipid content, water permeability, etc. The permeability of various compounds and the contribution of several functional groups to the permeability were also found to be similar between shed snake skin and human skin. Moreover, the permeability of compounds through shed snake skin was increased by Azone, one of the most extensively studied transdermal penetration enhancers. Considering the similarities between shed snake skin and human skin, ease of storage and handling, and low cost, shed snake skin may offer a good model membrane for transdermal research.

Enhanced Intestinal Absorption of Insulin in Rats in the Presence of Sodium 5-Methoxysalicylate

Sodium 5-methoxysalicylate, previously shown to enhance the rectal absorption of several drugs, facilitates the absorption of insulin from the upper gastrointestinal tract, resulting in significantly elevated insulin levels and lowered glucose concentrations in the plasma of rats. Restricting the movement of insulin and adjuvant down the intestine by either ligation or use of a more viscous vehicle further increased the absorption of insulin.

Application of model-independent and model analysis for the investigation of effect of drug solubility on its release rate from hydroxypropyl methylcellulose sustained release tablets

The effect of drug solubility on the dissolution from the sustained release (SR) matrix tablet prepared with hydroxypropyl methylcellulose (HPMC) 2910 4000 cps was investigated using model-independent moment analysis and Higuchi-type model analysis. In this study, seven model drugs which have various solubilities in the dissolution medium were used for preparation of tablets and dissolution studies were then performed. To determine the mechanisms behind the sustained release, the infiltration rate of the medium into the matrix tablet and the erosion rate of the matrix tablet were also investigated. The model-independent moment parameters i.e. mean dissolution time (MDT), mean medium infiltration time (MIT), mean tablet erosion time (MET), mean swelling time (MSWT) and mean diffusion time (MDFT) as well as Higuchi-type model analysis which, based on release mechanisms, were demonstrated for optimization of HPMC matrix tablets. Both in the model-independent and model analyses, the relationships obtained between drug solubility and release characteristics were similar. Regarding the poorly soluble drug, U-78875, the observed dissolution rate is slower than the erosion rate of the matrix tablet, which indicates that the main rate limiting factor for the dissolution is erosion of the matrix tablet. In the case of drugs whose solubilities are between 0.5 mg/ml and 5 mg/ml (methyl-paraben, ethyl-paraben and propyl-paraben), dissolution rates are observed between the erosion rate of the matrix tablet and the infiltration rate of medium into the matrix tablet, and. the dissolution rate increases with increasing drug solubility. Regarding highly soluble drugs, whose solubilities are more than 5 mg/ml (procaine hydrochloride, acetaminophen, and theophylline), the dissolution rates are not influenced so much by drug solubility but show a similar rate of medium infiltration into matrix. In the latter two cases, the primary rate limiting factor of dissolution is infiltration of medium into the matrix tablet. The reported MDT and MDFT values were within the range 3.16-8.75 h and 1.11-6.70 h, respectively, except for U-78875. Also, MIT, MET and MSWT values as device matrix characteristics were 2.05, 12.05 and 10.00 h, respectively. The model-independent moment parameters, MDT, MIT, MET, MSWT and MDFT are directly comparable to each other. Further, these parameters would be applicable in comparing the device and dissolution characteristics of different types of formulation. These model-independent analytical approaches allow us to optimize the SR matrix formulation at the development stage.

New alkyl N,N-dialkyl-substituted amino acetates as transdermal penetration enhancers.

New alcohol derivatives of N,N-disubstituted amino acids with a low toxicity have been synthesized and evaluated for their transdermal penetration enhancing effects on the transport of indomethacin from petrolatum ointments across shed skin of black rat snake (Elaphe obsoleta). The derivatives show excellent penetration enhancement of indomethacin, as high as 3.8 times that of Azone, with decyl N,N-dimethylamino acetate as the lead compound in the series. The release of indomethacin from an ointment containing 1% indomethacin, 5% dodecyl N,N-dimethylamino acetate, and 94% petrolatum was 3.15 µg/min1/2/cm2. Saturation studies performed by incorporating varying concentrations of indomethacin, from 0.1 to 10%, into the ointments and determination of the fluxes of indomethacin demonstrated that the saturated concentration of indomethacin in petrolatum base was approximately 1%. Penetration fluxes of indomethacin (1%) through snake skin increased linearly as the concentration of dodecyl N,N-dimethylamino acetate increased from 2.5 to 15%. Experiments involving the pretreatment of the snake skins with dodecyl N,N-dimethylamino acetate indicated that pre-treatment of the skin increased the skin permeability significantly. Electron micrograph studies on the snake skin treated with dodecyl N,N-dimethylamino acetate show clearly that the enhancer interacted with both the lipid-rich layer (mesos phase) and the keratin-rich layers (both alpha and beta phases).

A Method to Predict the Percutaneous Permeability of Various Compounds: Shed Snake Skin as a Model Membrane

Penetration of various compounds through shed snake skin was measured in vitro to examine the effect of lipophilicity and molecular size of a compound on permeability through this model membrane. The permeabilities were found to be controlled by the lipophilicity and the molecular size of the permeant. The smaller and the more lipophilic the compound, the greater the permeability. Equations have been developed to predict the permeability from the molecular weight and the distribution coefficient of a compound. Further, the lipophilicity of shed snake skin is similar to that of human skin and the response of shed snake skin to the molecular size of a permeant is more similar to human skin than to hairless mouse skin. Considering the similarities between shed snake skin and human stratum coraeum in terms of structure, composition, and permeability characteristics, the same considerations may apply to permeability through human stratum corneum.

Enhanced bioavailability of insulin after rectal administration with enamine as adjuvant in depancreatized dogs

Rectal absorption of insulin by depancreatized dogs was significantly enhanced by the coadministration of enamine as a suppository adjuvant and if this was followed by a further suppository containing enamine alone, the insulin absorption was even further enhanced. The additional enamine suppository resulted in high serum insulin concentrations for a longer time and effected a significant decrease in serum glucose concentrations. To decrease serum glucose concentrations effectively in depancreatized dogs, serum insulin levels had to remain high for a long period of time, rather than be transient.

Comparison of the effects of sodium salicylate, disodium ethylenediaminetetraacetic acid and polyoxyethylene-23-lauryl ether as adjuvants for the rectal absorption of sodium cefoxitin

Sodium salicylate, disodium ethylenediaminetetraacetic acid (EDTA) and polyoxyethylene−23‐lauryl ether (POE) significantly enhanced the absorption of cefoxitin from the rectum but with the following differences. (1) The effectiveness of salicylate or EDTA was enhanced by sodium chloride, whereas the activity of POE was not. (2) Although the ratios of plasma cefoxitin peak values to cefoxitin dose were constant with POE or EDTA, the peak to dose ratios with salicylate decreased with increasing cefoxitin concentration. (3) Phlorizin and 4, 4′‐diisothiocyanostilbene−2, 2′‐disulfonic acid (DIDS) inhibited the effectiveness of salicylate, but did not influence the adjuvant action of either POE or EDTA. (4) Although treatment with salicylate resulted in slightly less protein release than treatment with NaCl, both POE and EDTA increased the release of protein from the rectal mucosa. It appears that the effects of salicylate occur at the protein fraction of the rectal mucosa through a saturable process whereas the adjuvant action of POE and EDTA appears to involve some irreversible disruption of the membrane.

Effects of sodium salicylate on epithelial cells of the rectal mucosa of the rat: a light and electron microscopic study.

Using a ligation method, rat rectal epithelium was exposed to 2% sodium salicylate, and light and electron microscopic methods were used to assay for: 1) permeability of the epithelium to a marker dye, trypan blue, and 2) damage expressed in terms of disruption of the epithelial surface. Rectal mucosa was exposed to salicylate at pH 4.8, 7.0, and 9.0, and the effects of pretreatment with phlorizin were also studied. Results indicated that 2% sodium salicylate does very little damage to rectal epithelial cells at pH 7.0 while enhancing their permeability to trypan blue, an effect that is reversed upon washing out the sodium salicylate. The major cellular change induced by salicylate was a reduction in the length or distribution of glycocalyx filaments on microvilli of epithelial cells. It was also noted that pretreatment with phlorizin counteracted some of the effects of salicylate treatment.