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Biomedical subjects

T Loftsson

Publications and source records attributed to T Loftsson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Soft drugs based on hydrocortisone: the inactive metabolite approach and its application to steroidal antiinflammatory agents.

PURPOSE: The soft drug approach was applied to the design of analogs of highly potent synthetic steroids but with a metabolically labile ester group which at the same time served as an activating group. METHODS: Several structural modifications of soft antiinflammatory steroids were synthesized and tested in several assays of biological activity. The hydrolytic stability of the compounds was also determined. RESULTS: One of the compounds synthesized was determined to be a very potent steroid and had a highly significant separation of topical from systemic activity. However, the compound demonstrated greater than expected stability in the hydrolysis studies. CONCLUSIONS: The goal of the soft drug approach has been achieved with the development of a highly potent drug which displays little or no systemic activity as measured in the tests presented here. The anticipated hydrolytic instability of the compounds was not corroborated; however, in view of other results, the interpretation is allowed that the rapid hydrolysis of the unbound fraction of the drug is an important factor in its lack of systemic effects.

Animals↗
PubMed1999

Diacyl glyceryl ester prodrugs for slow release in the skin: synthesis and in vitro degradation and absorption studies for naproxen derivatives.

Diacyl glyceryl ester derivatives of naproxen were synthesized and tested for transdermal and dermal administration. Diacyl derivatives of aliphatic acids of various chain length were compared. The pharmaceutical properties of these compounds, such as lipophilicity, hydrolysis in a buffer solution at various pH values and degradation in human serum and hairless mouse skin homogenate, were investigated. All the diacyl derivatives were relatively stable in a neutral buffer solution, but were rapidly degraded to release naproxen in human serum and hairless mouse skin homogenate. The diacyl compounds could not penetrate hairless mouse skin in vitro. However, significant absorption into the skin could be measured, and this increased with increasing lipophilicity. A more than 100-fold difference in absorption was observed. The prodrugs were slowly hydrolyzed to naproxen inside the skin. The release of naproxen to the receptor compartment of diffusion cells showed that this type of prodrug could be used for controlled drug delivery.

Animals↗
PubMed1998

Co-administration of a water-soluble polymer increases the usefulness of cyclodextrins in solid oral dosage forms.

PURPOSE: The aim of this study was to investigate the effect of cyclodextrins (beta-CD, HP-beta-CD and (SBE)7m-beta-CD), and co-administration of a water-soluble polymer (HPMC) and cyclodextrins, on the oral bioavailability of glibenclamide in dogs. METHODS: Effects of cyclodextrins on the aqueous solubility of glibenclamide, with and without hydroxypropylmethylcellulose (HPMC), were determined by a phase-solubility method. Solid inclusion complexes were prepared by freeze-drying. Glibenclamide was administered orally and intravenously to beagle dogs. RESULTS: Aqueous solubility of glibenclamide increased as a function of cyclodextrin concentration, showing an AL-type diagram for beta-CD and an Ap-type diagrams for both of the beta-CD derivatives studied. HPMC enhanced the solubilising effect of cyclodextrins, but did not affect the type of phase-solubility diagram. Orally administered glibenclamide and its physical mixture with HP-beta-CD showed poor absolute bioavailability, while orally administered glibenclamide/cyclodextrin-complexes significantly enhanced the absolute bioavailability of glibenclamide. Orally administered glibenclamide/beta-CD/HPMC and glibenclamide/(SBE)7m-beta-CD/HPMC complexes showed similar absolute bioavailability compared to formulations not containing HPMC, even though 80% (in the case of (SBE)7m-beta-CD) or 40% (in the case of beta-CD) less cyclodextrin was used. CONCLUSIONS: The oral bioavailability of glibenclamide was significantly increased by cyclodextrin complexation. HPMC increased the solubilising effect of cyclodextrins and, therefore, the amount of cyclodextrin needed in the solid dosage form was significantly reduced by their co-administration. In conclusion, the pharmaceutical usefulness of cyclodextrins in oral administration may be substantially improved by co-administration of a water-soluble polymer.

Administration, Oral↗
PubMed1998

Aqueous hydrocortisone mouthwash solution: clinical evaluation.

Patients often experience difficulties in applying topical steroids in orabase to the oral mucosa, particularly when large areas need to be covered. An aqueous hydrocortisone mouthwash solution has been developed, one that was anticipated to be more acceptable to patients. The solution contains hydrocortisone (0.3% w/v) in a 4.5% (w/v) 2-hydroxypropyl-beta-cyclodextrin solution. Hydroxypropylmethylcellulose (0.5% w/v) was used to increase the viscosity of the solution and to promote the hydrocortisonecyclodextrin complex. One hundred and two patients with aphthous ulceration, lichen planus, and other mucosal conditions used the mouthwash in an open clinical efficacy study. Most patients reported some or considerable improvement following a 2-week course of treatment with the mouthwash: 26 of 33 (78.8%) patients with aphthous ulceration were 'much better', as were 26 of 54 (48.1%) patients with lichen planus and 5 of 16 (31.3%) patients with other mucosal lesions. No serious side effects were reported. Aqueous mouthwash solutions offer a potential vehicle for topical steroid therapy of oral mucosal lesions.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1998

Effect of cod-liver oil extract on the buccal permeation of ergotamine tartrate.

Ergotamine tartrate (ET) is used clinically in the treatment of migraines. However, the bioavailability of ET is rather poor following oral administration. Therefore, we tried to improve ET delivery using buccal administration. The purpose of this study was to investigate the characteristics of the permeation of ET through the hamster cheek pouch in vitro using a two-chamber diffusion cell, and to evaluate the effect of permeation enhancers on the transbuccal delivery of ET. Cod-liver oil extract (CLOE), polyoxyethylene hydrogenated castor oil (HCO 60), sodium glycocholate (GC), and sodium caprate (CA) were selected as premeation enhancers considering their low irritancy of the mucosa. When the enhancers were added to the donor cell at a 5% concentration each, the ET permeation rate markedly increased compared with that in a control not containing enhancer. Among these enhancers, CLOE exhibited the greatest effect. Because CLOE is composed of 16 kinds of fatty acids, the enhancement action of each of the major components was separately determined. As major fatty acids, palmitic acid, oleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) were selected and their enhancing effects were studied. The enhancing effect of each fatty acid was significantly lower than that of CLOE.

Animals↗
PubMed1998

Cyclodextrin solubilization of ETH-615, a zwitterionic drug.

Therapeutic usefulness of many zwitterionic drugs is hampered by their very low aqueous solubility. The purpose of this work was to investigate the effects of cyclodextrins on the solubility of the zwitterionic drug ETH-615, the role that charge might play in the cyclodextrin complexation, and the influence of polymers and ion-pairing agents on the cyclodextrin solubilization. The effects of five different beta-cyclodextrin derivatives were evaluated, i.e., the anionic beta-cyclodextrin sulfobutyl ether sodium salt and carboxymethyl-beta-cyclodextrin sodium salt, the uncharged 2-hydroxypropyl-beta-cyclodextrin and randomly methylated beta-cyclodextrin, and the cationic 2-hydroxy-3-trimethyl-ammoniopropyl-beta-cyclodextrin. The uncharged cyclodextrins had much larger solubilizing effect on ETH-615 than the charged ones. However, due to the highly polar zwitterionic structure of ETH-615 the stability constants of its cyclodextrin complexes were several orders of magnitude smaller than those commonly observed for uncharged lipophilic compounds. Cyclodextrin solubilization of ETH-615 was enhanced by water-soluble polymers and ion-pairing agents.

Choline↗
PubMed1998

Increasing the cyclodextrin complexation of drugs and drug biovailability through addition of water-soluble polymers.

For a variety of reasons, including cost, production capabilities and toxicology, the amounts of cyclodextrin (CD) that can be included in drug formulations is limited and, thus, it is important to develop methods which can be applied to enhance the complexation efficacy. Moreover, bioavailability of drugs in CD containing vehicles can be rather limited resulting in less than optimal drug delivery. Addition of small amounts of a water-soluble polymer to the aqueous complexation media enhances the CD complexation of drugs. Thus, less CD is needed to dissolve a given amount of drug when a polymer is present than when it is not present in the aqueous complexation media. Furthermore, the bioavailability of drugs is enhanced through addition of polymers. In general, the water-soluble polymers improve both pharmaceutical and biological properties of drug-CD complexes. This polymer enhancement of drug complexation and bioavailability is independent of the physiochemical properties of the drug. Thermodynamic studies and other physicochemical observations indicate that the polymers participate directly in the drug-CD complexation.

Animals↗
PubMed1997

Unsaturated glycerol monoethers as novel skin penetration enhancers.

A mixture of glycerol monoethers was extracted from the liver oil of deep sea shark (Centroporus squamosus). It consisted mainly of monoethers of glycerol and linear monounsaturated octadecanol, and glycerol and linear monounsaturated hexadecanol. Only about 11% of the extract consisted of glycerol monoethers derived from linear saturated fatty alcohols. The glycerol monoether extract was somewhat less effective as skin penetration enhancer than oleic acid and other potent fatty acid penetration enhancers, but it was still a very effective enhancer in the hairless mouse skin model used in this study.

Animals↗
PubMed1997

Effect of various marine lipids on transdermal drug delivery--in vitro evaluation.

The effects of several marine lipids on the penetration of hydrocortisone and nitroglycerin through excised hairless mouse skin have been studied. Fatty acid extracts obtained by hydrolysis of Portuguese dog-fish-liver-oil or by hydrolysis of cod-liver-oil were shown to be effective skin penetration enhancers. Phospholipid obtained from squid was also shown to be effective enhancer. However, the enhancing effect of the marine products could generally be associated with their content of free unsaturated fatty acids. The fatty acid extract obtained from cod-liver-oil caused insignificant skin irritation when incorporated into an ointment base and applied to human skin.

Administration, Cutaneous↗
PubMed1996

Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization.

Cyclodextrins are cyclic oligosaccharides which have recently been recognized as useful pharmaceutical excipients. The molecular structure of these glucose derivatives, which approximates a truncated cone or torus, generates a hydrophilic exterior surface and a nonpolar cavity interior. As such, cyclodextrins can interact with appropriately sized molecules to result in the formation of inclusion complexes. These noncovalent complexes offer a variety of physicochemical advantages over the unmanipulated drugs including the possibility for increased water solubility and solution stability. Further, chemical modification to the parent cyclodextrin can result in an increase in the extent of drug complexation and interaction. In this short review, the effects of substitution on various cyclodextrin properties and the forces involved in the drug-cyclodextrin complex formation are discussed. Some general observations are made predicting drug solubilization by cyclodextrins. In addition, methods which are useful in the optimization of complexation efficacy are reviewed. Finally, the stabilizing/destabilizing effects of cyclodextrins on chemically labile drugs are evaluated.

Carbohydrate Sequence↗
PubMed1996

Dexamethasone-cyclodextrin-polymer co-complexes in aqueous eye drops. Aqueous humor pharmacokinetics in humans.

PURPOSE: To test an aqueous eye drop solution containing a high concentration of dexamethasone in a cyclodextrin-based drug delivery system. This system increases both drug solubility in aqueous eye drops and drug permeability into the eye, through drug cyclodextrin-polymer co-complexes. METHODS: 2-hydroxypropyl-beta-cyclodextrin is a water-soluble oligosaccharide that can be used to dissolve lipophilic drugs, such as dexamethasone, in aqueous solutions. Co-complexation with a polymer further increases the solubility and increases drug permeability through biologic membranes. Eye drops containing dexamethasone (0.32% and 0.67%), 2-hydroxypropyl-beta-cyclodextrin, and polymer were given to patients before cataract surgery, and the resultant dexamethasone concentration was measured from aqueous humor samples. RESULTS: The dexamethasone-cyclodextrin drops give a significantly higher concentration of dexamethasone in aqueous humor than dexamethasone alcohol 0.1% (Maxidex). Heating of the dexamethasone-cyclodextrin-polymer co-complexes appears to enhance the permeability of the drug into the eye. CONCLUSIONS: The cyclodextrin-based drug delivery system enhances both the solubility of dexamethasone in aqueous eye drops and the permeability of the drug into the human eye. Dexamethasone concentration levels in the human aqueous humor exceed those reported with currently available steroid eye drops.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1996

Design and in vivo testing of 17 beta-estradiol-HP beta CD sublingual tablets.

17 beta-Estradiol is almost insoluble in water. The effect of various cyclodextrins and two different polymers, polyvinylpyrrolidone (PVP) and carboxymethylcellulose (CMC), on the aqueous solubility of 17 beta-estradiol was investigated. 17 beta-Estradiol was dissolved in aqueous 50% w/v 2-hydroxypropyl-beta- cyclodextrin (HP beta CD) solution containing 0.25% (w/v) CMC and the dry 17 beta-estradiol-HP beta CD complex formed by lyophilisation of the solution. Sublingual tablets from the dry complex were produced by direct compression. The dissolution of 17 beta-estradiol from tablets containing the drug in a lyophilised HP beta CD complex was determined. For reference the dissolution of 17 beta-estradiol was determined from tablets containing physical mixture of 17 beta-estradiol and HP beta CD or tablets containing 17 beta-estradiol without HP beta CD. Sublingual tablets containing 17 beta-estradiol-HP beta CD in the lyophilised complex demonstrated the fastest dissolution profile and those tablets were selected for further studies in humans. Six postmenopausal women received a sublingual tablet containing 17 beta-estradiol-HP beta CD complex equivalent to 100 micrograms 17 beta-estradiol. Blood samples were collected over a 12 h period and the 17 beta-estradiol plasma concentration was determined. 17 beta-Estradiol was rapidly absorbed from the sublingual tablets, resulting in a peak 17 beta-estradiol plasma concentration of 568 +/- 97 pmol/l 15 min after administration of the tablets, followed by a biphasic elimination.

Administration, Sublingual↗
PubMed1995

Preparation, characterization, and anesthetic properties of 2-hydroxypropyl-beta-cyclodextrin complexes of pregnanolone and pregnenolone in rat and mouse.

Prototype formulations of the progesterone derivatives pregnanolone and pregnenolone were prepared by solubilizing the steroids in 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). The aqueous solubility of the steroids was increased as a function of HP beta CD concentration generating linear (AL) or curvilinear (AP) phase-solubility profiles. While the solubility of pregnanolone could not be increased with the addition of water-soluble pharmaceutical polymers, the concentration of pregnenolone in HP beta CD was increased more than 60% by the addition of small amounts (0.10%) of (hydroxypropyl)methylcellulose. Mice studies found that while pregnanolone was highly potent in an HP beta CD vehicle, pregnenolone was devoid of activity. Since pregnenolone and pregnanolone differ marginally in structure and physicochemical profile, the data suggest that these derivatives interact via a specific receptor and not via nonspecific membrane perturbations. Sex differences in the action of the pregnanolone complex was observed in that parenteral (i.v. and i.p.) drug administration was more effective in males than females. These data are in contrast to observations made in the case of alfaxalone, a related steroid anesthetic, in which the sex difference favored female animals. On the other hand, females appeared to be more sensitive to the effects of the pregnanolone complex when administered orally. Finally, parenteral pregnanolone was more toxic to males than females with LD50 (i.v.) values of 355 and 548 micromol/kg, respectively.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1995

Fatty acids from cod-liver oil as skin penetration enhancers.

A fatty acid extract is discharged during the refining of medicinal cod-liver oil. The fatty acid composition of the extract was determined and it was found to contain an vast variety of fatty acids. About 17% of the fatty acids consisted of saturated fatty acids, the rest was unsaturated fatty acids. The extract was an effective transdermal penetration enhancer and this effect was found to be associated with the unsaturated portion of fatty acids.

Administration, Cutaneous↗
PubMed1994

Topically effective ocular hypotensive acetazolamide and ethoxyzolamide formulations in rabbits.

The effect of topically active 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) eye-drop formulations containing solutions of acetazolamide, ethoxyzolamide or timolol on the intra-ocular pressure (IOP) was investigated in normotensive conscious rabbits. Both acetazolamide and ethoxyzolamide were active but their IOP-lowering effect was less than that of timolol. The IOP-lowering effects of acetazolamide and ethoxyzolamide and that of timolol appeared to be to some extent additive. Combination of acetazolamide and timolol or ethoxyzolamide and timolol in one HP-beta-CyD formulation resulted in a significant increase in the duration of activity compared with HP-beta-CyD formulations containing only acetazolamide, ethoxyzolamide or timolol. Also, it was possible to increase the IOP-lowering effect of acetazolamide by formulating the drug as a suspension in an aqueous HP-beta-CyD vehicle.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1994

Pharmacy in Iceland.

OBJECTIVE: To summarize the practice of pharmacy in Iceland. DATA SOURCES: Human resources were the primary sources of data for this publication. Personal observation by Cleary is the basis of this publication. DATA EXTRACTION AND SYNTHESIS: Data on areas related to Icelandic history, practice of pharmacy, Icelandic health system, and the European Economic Community and Education were obtained through interviews. Information is presented to give an appreciation of pharmacy practice in a Nordic country. CONCLUSIONS: Pharmacy education and practice is progressive and flourishing in Iceland's National Health Service. Clinical pharmacy services are in their infancy; however, the potential for growth is immense. The Fulbright experience was educational and beneficial for all parties involved.

Education, Pharmacy↗