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Biomedical subjects

D R Friend

Publications and source records attributed to D R Friend.

31 records · Page 2Linked to original sources
PubMed1991

Cutaneous effects of transdermal levonorgestrel.

The irritation of transdermal devices delivering levonorgestrel and the permeation enhancer ethyl acetate with or without ethanol was evaluated in rabbits. Erythema and oedema were assessed 24, 48 and 72 hr and 7 days after application of the 24-hr delivery system. The devices were found to be mild to moderately irritating, with erythema the primary manifestation. No differences were observed between devices using pure ethyl acetate or ethyl acetate-ethanol (7:3, v/v) as enhancers. Devices using pure ethanol as an enhancer gave levels of irritation similar to those using ethyl acetate-ethanol (7:3) or pure ethyl acetate. Control devices containing only water (no drug) were also found to be mildly irritating to rabbits following a 24-hr exposure period. A histological evaluation of the application sites of two of the formulations confirmed the visual observations of mild subacute irritation. The changes produced by transdermal levonorgestrel were reversible. The problems of skin irritation of transdermal devices is discussed with particular reference to the use of ethyl acetate and ethanol as skin penetration enhancers.

Acetates↗
PubMed1991

Colon-specific delivery of dexamethasone from a glucoside prodrug in the guinea pig.

Dexamethasone-beta-D-glucoside is a potential prodrug for colonic delivery of the antiinflammatory agent, dexamethasone. The ability of this prodrug to deliver dexamethasone selectively to the colon depends not only on its being slowly absorbed from the alimentary canal, but also on its having chemical and enzymatic stability in the stomach and small intestine. Once reaching the large bowel, it should be quantitatively hydrolyzed to release the active agent. The potential of dexamethasone-beta-D-glucoside for colon-specific delivery of dexamethasone is assessed by determining the rates of its hydrolysis down the alimentary canal of the guinea pig, an animal in which an inflammatory bowel disease model has been developed. The hydrolytic activity is examined in tissues and luminal contents of the stomach, proximal and distal segments of the small intestine, cecum, and colon. For the tissues, the greatest hydrolytic activity is in the proximal small intestine, while the stomach, cecum, and colon have only moderate activity. In contrast, the contents of the cecum and colon show greater activity than the contents of the small intestine and stomach. The luminal contents retained beta-glucosidase activity even after repeated centrifugation and resuspension in a buffer. The activity was unaffected by homogenization. These observations suggest that hydrolytic activity is associated with enzymes located on the surface of luminal cells. The movement and hydrolysis of dexamethasone-beta-D-glucoside down the gastrointestinal tract of the guinea pig are also examined. About 20 to 30% of an oral dose appears to reach the cecum. Here the prodrug is rapidly hydrolyzed to the active drug. From intravenous administration of the prodrug and drug, it is apparent that dexamethasone-beta-D-glucoside is poorly absorbed in the gastrointestinal tract (bioavailability, less than 1%). There is a ninefold selective advantage for delivery of dexamethasone in cecal tissues in the guinea pig under the conditions of this experiment. Thus, there is a potential for a decrease in the usual dose and a concomitant reduction in the systemic exposure to dexamethasone. Because humans have much less glucosidase activity in the small intestine, even greater site-selective delivery to the cecum and colon is expected.

Administration, Oral↗
PubMed1991

Relative anti-inflammatory effect of oral dexamethasone-beta-D-glucoside and dexamethasone in experimental inflammatory bowel disease in guinea-pigs.

The relative anti-inflammatory effect of dexamethasone and a prodrug, dexamethasone-beta-D-glucoside, has been assessed in guinea-pigs with experimentally-induced inflammatory bowel disease (IBD). The glucoside prodrug is designed to reach the large intestine following oral administration. The active agent is liberated when the prodrug is hydrolysed by glycosidases of colonic bacteria. Guinea-pigs were administered degraded carrageenan in their drinking water to produce experimental IBD. Starting on day 15, dexamethasone (1.3 mumol kg-1) or dexamethasone-beta-D-glucoside (1.3 or 0.65 mumol kg-1) was administered by gastric intubation once daily for 5 days. Relative to control animals, the drug and prodrug treatments significantly (P less than 0.05) reduced the total number of caecal ulcers. While there was no difference statistically between the drug and prodrug treatments, the data suggest that a lower dose of dexamethasone, administered as its glucoside prodrug, could reduce side-effects without reduced efficacy. These results support the hypothesis that localized delivery of dexamethasone to the large bowel can improve pharmacotherapy of IBD by reducing the side-effects associated with corticosteroids.

Animals↗
PubMed1990

Effect of antibiotic pretreatment on glycoside/glycosidase-based colonic drug delivery.

The effect of antibiotic pretreatment on the intestinal distribution and hydrolysis of the prodrug prednisolone-beta-D-glucoside was studied in rats. A combination of neomycin, lincomycin, and metronidazole was administered twice daily by gastric intubation for three days to young adult male rats. On the fourth day, prednisolone-beta-D-glucoside was administered intragastrically. The distribution of prodrug and drug in the intestinal contents was significantly altered by the antibiotic treatment. In comparison with untreated rats, stomach to cecum transit time appeared to be reduced, and more prodrug was hydrolyzed in the small intestine. In addition, an appreciable amount of the dose was retained longer in the small intestine of treated animals. The total recovery of prodrug and drug was unaltered by the pretreatment. Possible explanations for the observed results are presented.

Animals↗
PubMed1990

In vitro evaluations of transdermal levonorgestrel.

Transdermal delivery systems were prepared and evaluated for their ability to co-deliver the contraceptive agent levonorgestrel and the penetration enhancer ethyl acetate across hairless guinea pig, hairless mouse, and rat skin. The 24 hr devices were prepared with membranes composed of ethylene vinyl acetate [EVAc, 7.5% vinyl acetate (VAc) content] copolymers, and blends of EVAc (7.5% VAc content) and poly(methyl methacrylate) or poly(ethyl methacrylate). The reservoir phase (levonorgestrel-saturated ethyl acetate gelled with 2 wt% hydroxypropyl cellulose) was also evaluated for drug and solvent delivery with each of the rodent skins. Devices were also tested in which levonorgestrel was suspended in the adhesive. The results indicate that all the devices deliver levonorgestrel and the enhancer at about the same rate regardless of the skin type. It appears that the flux of LN follows the flux of EtAc until the devices are nearly depleted of EtAc, when delivery of LN remains relatively high.

Acetates↗
PubMed1990

Transdermal delivery of contraceptives.

Contraceptive agents are administered to the body through a variety of routes. Research has recently been directed at examining the transdermal route for systemic delivery of contraceptive agents, including estrogens and progestins. The transdermal route has several potential advantages over the other routes of administration: (1) improved compliance, (2) once-weekly administration, (3) delivery is easily terminated, and (4) some side effects can be alleviated based on more constant delivery rates. This article reviews the permeability of skin toward contraceptive steroids and how skin permeability is evaluated. The metabolism of contraceptive steroids is also considered. Transdermal delivery systems used to deliver contraceptives are presented, followed by a detailed discussion of several delivery systems for specific contraceptive agents such as levonorgestrel and estradiol. The potential problem of skin irritation is presented as it relates to transdermal contraceptive delivery systems, all of which will be worn chronically.

Administration, Cutaneous↗
PubMed1989

Transdermal delivery of levonorgestrel. IV: Evaluation of membranes.

A series of experiments were performed to evaluate the flux of levonorgestrel (LN), ethyl acetate (EtAc), and ethanol (EtOH) through excised rat skin, through a variety of synthetic membranes and through membranes supported on rat skin. Using a donor phase of EtAc:EtOH (7:3) containing excess solid LN, the flux of LN through rat skin was approximately 1.0 microgramc/cm2.h. The normalized fluxes of LN, EtAc, and EtOH through ethylene vinyl acetate (EVAc) copolymers of varying vinyl acetate (VAc) content (12 to 25%) were 1.3 to 3.1 x 10(-8), 2.6 to 6.8 x 10(-4), and 4.8 to 9.9 x 10(-5) g.cm/cm2.h, respectively. Permeability experiments were also performed with the EVAc membranes supported on rat skin. By selecting the VAc content and thickness of the EVAc membranes, it was possible to control the delivery of enhancer (EtAc:EtOH) through rat skin (membrane-rate control) or to let the skin control the overall delivery of enhancer.

Acetates↗
PubMed1989

Transdermal delivery of levonorgestrel. VII. In vivo studies.

This paper describes the results of transdermal experiments performed in vivo using devices designed for delivery of levonorgestrel. To help evaluate the performance of the transdermal devices on rabbits, a constant infusion experiment was performed using osmotic pumps. Reservoir-type transdermal devices were prepared and tested on rabbits for their ability to deliver 30 to 35 micrograms/d of levonorgestrel. Ethyl acetate and ethanol (0.7:0.3) or neat ethyl acetate were used as permeation enhancers. The results indicated that for rabbits, a rate-limiting membrane was required to control the delivery of enhancer(s) to the skin so that constant plasma levels could be maintained. The devices induced mild erythema and very mild edema over the 24-hour exposure period. The potential use of such a transdermal delivery system in humans is discussed.

Administration, Cutaneous↗
PubMed1989

Transdermal delivery of levonorgestrel. V. Preparation of devices and evaluation in vitro.

Transdermal devices were prepared and evaluated for their ability to codeliver levonorgestrel and the permeation enhancers ethyl acetate and ethanol in vitro. The 24-hr devices were prepared with membranes composed of ethylene vinyl acetate (EVAc) copolymers. The vinyl acetate (VAc) content of the membranes (50 +/- 10 or 100 +/- 10 microns thick) was varied from 12 to 25% to give a range of permeabilities toward the enhancers. The reservoir used was ethyl acetate/ethanol (7:3, v/v; 0.5 ml) containing excess solid levonorgestrel and gelled with 2% hydroxypropyl cellulose. The higher VAc content membranes (18 and 25%) exhibited relatively high release rates of EtAc and EtOH leading to depletion of ethyl acetate and ethanol from the reservoir by the end of 24 hr. As a result, the transdermal flux of levonorgestrel, evaluated using rat skin, reached a maximum at about 8 hr and thereafter diminished to zero by 24 hr. The less permeable membranes (12 and 15% VAc content) led to a more sustained release of enhancers, but due to lower solvent delivery to the skin, levonorgestrel flux was substantially lower. There was a direct relationship between drug delivery through skin and the amount of solvent delivered until release of the enhancers had diminished. The potential use of ethyl acetate in transdermal drug delivery is also discussed.

Acetates↗
PubMed1985

Drug glycosides: potential prodrugs for colon-specific drug delivery.

The influence of prodrug structure on specificity of glycoside/glycosidase based colon-specific drug delivery was studied by preparing nine steroid glycosides, measuring their relative lipophilicities, and hydrolyzing them with bacterial glycosidases from rat intestines. The 21-yl beta-D-glucosides and galactosides of dexamethasone, prednisolone, hydrocortisone, and fludrocortisone and the 21-yl beta-D-cellobioside of prednisolone were prepared by a modified Koenigs-Knorr reaction. The deacetylated glycoside prodrugs, along with the P-nitrophenyl derivatives of beta-D-glucoside, galactoside, and cellobioside, were subjected to hydrolysis by the contents of the rat stomach, proximal small intestine (PSI), distal small intestine (DSI), and cecum. All the prodrugs were hydrolyzed slowly by PSI and stomach contents, more rapidly by contents of the DSI, and most rapidly by cecal contents. This is the basis of the site-specific drug delivery reported earlier (Friend, D. R.; Chang, G. W. J. Med. Chem. 1984, 27, 261). Furthermore, the prodrugs themselves had very different susceptibilities to hydrolysis. Hydrolysis rates catalyzed by DSI contents decreased in the following order: prednisolon-21-yl beta-D-galactoside (10) greater than prednisolon-21-yl beta-D-glucoside (2) greater than prednisolon-21-yl beta-D-cellobioside (13) greater than dexamethason-21-yl beta-D-galactoside (9) greater than dexamethason-21-yl beta-D-glucoside (1). Hydrolysis of cellobioside 13 was only half that of glucoside 2 and one-fourth that of galactoside 10. Hydrolysis of all the prodrugs in cecal contents was rapid, with the exceptions of hydrocortison-21-yl beta-D-glucoside (5) and fludrocortison-21-yl beta-D-glucoside (7), which were hydrolyzed more slowly than the other glucoside prodrugs. Eadie-Hofstee plots for hydrolysis of the glucoside compounds suggested that bacterial beta-D-glucosidase activity in the colon may be more heterogeneous in nature than beta-D-galactosidase activity. Relative lipophilicities of the prodrugs and free steroids were compared by measuring their octanol-buffer partition coefficients (P). The logarithm of the P of cellobioside 13 (-0.56) was considerably lower than that of the other prodrugs, which ranged from 0.11 to 0.84. Log P of the free steroids ranged from 1.54 to 1.73. These relative rates of hydrolysis and relative lipophilicities, along with previously reported animal experiments, enable one to estimate the site specificity of glycoside prodrugs prior to extensive animal studies.

Animals↗
PubMed1984

A colon-specific drug-delivery system based on drug glycosides and the glycosidases of colonic bacteria.

Steroid glycosides and the unique glycosidase activity of the colonic microflora form the basis of a new colon-specific drug-delivery system. Drug glycosides are hydrophilic and, thus, poorly absorbed from the small intestine. Once such a glycoside reaches the colon it can be cleaved by bacterial glycosidases, releasing the free drug to be absorbed by the colonic mucosa. This concept was illustrated with dexamethasone 21-beta-D-glucoside (1) and prednisolone 21-beta-D-glucoside (2), two prodrugs that may be useful in treating inflammatory bowel disease. Hydrolysis of the prodrugs by beta-glucosidase and fecal homogenates in vitro released the free steroids. Glucosides 1 and 2 were administered to rats intragastrically to determine when and where the free steroids were released. Unmodified dexamethasone (3) and prednisolone (4) were also given to rats intragastrically to compare absorption of the glucosides with the free steroids. Both glucosides were found to reach the rat lower intestine in 4-5 h, where they were rapidly hydrolyzed, releasing the free steroids. Delivery of steroid 3 (via glucoside 1) was more specific than that of steroid 4 (via glucoside 2): nearly 60% of an oral dose of glucoside 1 reached the cecum, whereas less than 15% of glucoside 2 reached the cecum. When free steroids 3 and 4 were administered orally, they were almost exclusively absorbed in the small intestine: less than 1% of an oral dose of each reached the cecum.

Administration, Oral↗
PubMedDate not supplied

Polyacrylate resin microcapsules for taste masking of antibiotics.

Various microencapsulated dosage forms were prepared to limit the release of an antibiotic in solution for up to 3 days and in the oral cavity following per oral administration. An experimental antibiotic, clarithromycin (TE-031), was used in these studies. The drug was first encapsulated in gelatin followed in some cases by crosslinking with glutaraldehyde. The gelatin microcapsules were then coated with acrylic resins (Eudragit), whose solubility properties vary according to pH. A non-solvent coacervation technique was used to apply the Eudragit resins. It was found that crosslinking the gelatin retarded release of TE-031 somewhat relative to that from uncrosslinked gelatin microcapsules in a 72h release experiment conducted at room temperature. Coating the gelatin microcapsules with Eudragit resins L100, S100, or E100 slowed the release of TE-031 further still; less TE-031 was released over 72 h from the Eudragit-coated formulations prepared with crosslinked gelatin compared with formulations prepared with uncrosslinked gelatin. The Eudragit E100-coated crosslinked gelatin microcapsule formulation was most effective in preventing release of the TE-031 under simulated conditions of storage in an aqueous solution.

Acrylic Resins↗