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Biomedical subjects

T Loftsson

Publications and source records attributed to T Loftsson.

At least 19 recordsLinked to original sources
PubMed2006

Influence of aqueous diffusion layer on passive drug diffusion from aqueous cyclodextrin solutions through biological membranes.

Most drugs permeate biological membranes via passive diffusion and it is generally assumed that the main barrier is the lipophilic structure of the membrane. However, we have observed that the unstirred water layer adjacent to the membrane surface can in some cases be a barrier just as effective as the lipophilic membrane itself. Hydrophilic cyclodextrins can enhance drug delivery through biological membranes by increasing the availability of dissolved drug molecules immediate to the membrane surface, i.e. by increasing drug delivery through the unstirred water layer. Cyclodextrins and drug/ cyclodextrin complexes are, in most cases, unable to permeate lipophilic membranes. Thus, excess cyclodextrin, more than is needed to solubilize the drug in the aqueous exterior, will hamper drug delivery through biological membranes.

Animals↗
PubMed2004

Preparation of solid drug/cyclodextrin complexes of acidic and basic drugs.

One of the main obstacles in pharmaceutical applications of cyclodextrins is their increase of the formulation bulk. Even at maximum incorporation 500 mg of a solid drug/cyclodextrin complex will only contain between 50 and 125 mg of the drug, assuming a low molecular weight drug (MW 200 to 400 Dalton) and an average molecular weight cyclodextrin (MW about 1500 Dalton). In general, the complexation efficiency is low and consequently the complex powder contains a significant amount of empty cyclodextrin molecules. In the present study the complexation efficiency is increased by ionization of the drug molecule through addition of volatile acid (i.e. acetic acid) or base (i.e. ammonia) to the aqueous complexation media of basic or acidic drugs, respectively. The volatile acid or base was then removed during lyophilization and heating in a vacuum oven resulting in formation of solid cyclodextrin complexes of the unionized drug. Thus, the complexation efficiency was temporary increased by the ionization but then again decreased leading to formation of the thermodynamically unstable solid drug/cyclodextrin complexes. When dissolved the energy of the system was lowered by expelling the drug molecules from the cyclodextrin cavities resulting in formation of supersaturated drug solutions and ultimately precipitation of the drug.

Acetates↗
PubMed2004

Marine lipids as building blocks for soft quaternary ammonium compounds and their antibacterial activity.

Environmental friendly antibacterial agents have to degrade relatively rapid to non-toxic and inactive products after they have had their desired effect. Environmental friendly quaternary ammonium agents were designed according to Bodor's soft drug approach and evaluated in vitro. Structure-activity relationship (SAR) studies showed that the antibacterial activity of a given soft agent will only be acceptable if its chemical stability is adequate to allow the agent to express its activity for sufficient duration of time. However, the studies also showed that increasing the lipophilicity of a chemically labile antibacterial agent could increase its potency. Two of the lipophilic quaternary ammonium antibacterial agents evaluated had minimum inhibitory concentration (MIC) against Staphylococcus aureus as low as 2 microg/ml and estimated degradation half-life less than 4 to 6 days at room temperature. Decreased MIC could only be obtained by increasing the degradation half-life of the agents.

Administration, Cutaneous↗
PubMed2003

Soft antibacterial agents.

Hard drugs have been defined as drugs that are biologically active and non-metabolizable in vivo. Soft drugs are defined as drugs, which are characterized by predictable and controllable in vivo destruction (i.e. metabolism) to form non-toxic products after they have achieved their therapeutic role. Quaternary ammonium compounds, such as benzalkonium chloride, are hard antibacterial agents. Their toxicity limits their usage in humans and animals, and their chemical stability limits their usage for general environmental sanitation. Furthermore, due to their stability they are prone to induce selective antimicrobial pressure and bacterial resistance. Soft analogs of the currently available hard antibacterial agents are less toxic. However, although the soft analogs have been shown to possess antibacterial activity in in vitro studies, it is likely that their in vivo activity will be hampered by their chemical instability.

Anti-Bacterial Agents↗
PubMed2002

The use of chemically modified cyclodextrins in the development of formulations for chemical delivery systems.

Retrometabolic drug design provides a highly useful and directed approach for identifying new drug candidates with improved therapeutic indices based on predictable/controlled metabolism and/or site-targeted delivery. In the process, formulation becomes an important and integral concern especially for brain-targeting chemical delivery systems (CDS) based on the need for appropriate dosage form stability, solubility and dissolution characteristics. Adjuncts that have been useful in this regard are chemically modified, water soluble cyclodextrin derivatives such a 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). These starch-derived excipients can interact with drugs via dynamic complex formation resulting in a number of beneficial pharmaceutical effects including increased apparent water solubility and stability as well as improved aesthetic and excipient compatibility properties. This cyclodextrin is approved in a number of product in the US and world-wide. HP beta CD has contributed to the development and preclinical/clinical testing of a number of CDS including E2 (estradiol)-CDS, AZT (zidovudine)-CDS, DEX (dexamethasone)-CDS and a neuropeptide CDS based on an enkephalin derivative. In these contexts, HP beta CD provided for stable and water-soluble dosage forms intended for parenteral administration.

Cyclodextrins↗
PubMed2001

Cyclodextrins in topical drug formulations: theory and practice.

Cyclodextrins are cyclic oligosaccharides with a hydrophilic outer surface and a somewhat lipophilic central cavity. Cyclodextrins are able to form water-soluble inclusion complexes with many lipophilic water-insoluble drugs. In aqueous solutions drug molecules located in the central cavity are in a dynamic equilibrium with free drug molecules. Furthermore, lipophilic molecules in the aqueous complexation media will compete with each other for a space in the cavity. Due to their size and hydrophilicity only insignificant amounts of cyclodextrins and drug/cyclodextrin complexes are able to penetrate into lipophilic biological barriers, such as intact skin. In general, cyclodextrins enhance topical drug delivery by increasing the drug availability at the barrier surface. At the surface the drug molecules partition from the cyclodextrin cavity into the lipophilic barrier. Thus, drug delivery from aqueous cyclodextrin solutions is both diffusion controlled and membrane controlled. It appears that cyclodextrins can only enhance topical drug delivery in the presence of water.

Administration, Topical↗
PubMed2001

Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray.

The cyclodextrin solubilization of three benzodiazepines, i.e. alprazolam, midazolam and triazolam, was investigated. The cyclodextrin solubilization was enhanced through ring-opening of the benzodiazepine rings and ionization of the ring-open forms. Additional enhancement was obtained through interaction of a water-soluble polymer with the cyclodextrin complexes. The ring-opening was pH-dependent and completely reversible, the ring-open forms dominating at low pH but the ring-closed forms at physiologic pH. The ring-closed forms were rapidly regenerated upon elevation of pH. In freshly collected human serum in vitro at 37 degrees C, the half-life for the first-order rate constant for the ring-closing reaction was estimated to be less than 2 min for both alprazolam and midazolam. Midazolam (17 mg/ml) was solubilized in aqueous pH 4.3 nasal formulation containing 14% (w/v) sulfobutylether beta-cyclodextrin, 0.1% (w/v) hydroxypropyl methylcellulose, preservatives and buffer salts. Six healthy volunteers received 0.06 mg/kg midazolam intranasally and 2 mg intravenously, and blood samples were collected up to 360 min after the administration. Midazolam was absorbed rapidly reaching maximum serum concentrations of 54.3+/-5.0 ng/ml at 15+/-2 min. The elimination half-life of midazolam was 2.2+/-0.3 h and the absolute availability was 73+/-7%. All mean values+/-SEM.

Administration, Intranasal↗
PubMed2001

Intranasal administration of midazolam in a cyclodextrin based formulation: bioavailability and clinical evaluation in humans.

Intranasal administration of midazolam has been of particular interest because of the rapid and reliable onset of action, predictable effects, and avoidance of injections. The available intravenous formulation (Dormicum i.v. solution from Hoffmann-La Roche) is however less than optimal for intranasal administration due to low midazolam concentration and acidity of the formulation (pH 3.0-3.3). In this study midazolam was formulated in aqueous sulfobutylether-beta-cyclodextrin buffer solution. The nasal spray was tested in 12 healthy volunteers and compared to intravenous midazolam in an open crossover trial. Clinical sedation effects, irritation, and serum drug levels were monitored. The absolute bioavailability of midazolam in the nasal formulation was determined to be 64 +/- 19% (mean +/- standard deviation). The peak serum concentration from nasal application, 42 +/- 11 ng ml-1, was reached within 10-15 min following administration and clinical sedative effects were observed within 5 to 10 min and lasted for about 40 min. Intravenous administration gave clinical sedative effects within 3 to 4 min, which lasted for about 35 minutes. Mild to moderate, transient irritation of nasal and pharyngeal mucosa was reported. The nasal formulation approaches the intravenous form in speed of absorption, serum concentration and clinical sedation effect. No serious side effects were observed.

Administration, Intranasal↗
PubMed2000

Dermal delivery of ETH-615, a zwitterionic drug.

ETH-615 is an amphoteric drug that forms a water-insoluble zwitterion at intermediate pH values. Increasing the aqueous solubility of ETH-615 through cyclodextrin complexation did not enhance transdermal delivery of the drug from saturated aqueous solutions. However, increasing the lipophilicity of the drug through masking of the anionic group with a pro-moiety increased the dermal and transdermal delivery of the drug. Furthermore, masking the anionic group enhanced the chemical stability of the drug, resulting in significant improvement of the shelf life of the drug in both aqueous and nonaqueous solutions.

Administration, Cutaneous↗
PubMed2000

Marine lipids for prodrugs, soft compounds and other pharmaceutical applications.

In the present review we discuss different approaches to pharmaceutical applications of marine lipids. Investigation of the use of marine lipids as dermal permeation enhancers, the synthesis of triacylglycerols highly enriched in polyunsaturated fatty acids, dermal pro-drugs derivatives of unsaturated fatty acids and diacyl glyceryl derivatives, and the possible synthesis of soft disinfectants from marine fatty acids.

Fatty Acids, Unsaturated↗
PubMed2000

Methazolamide 1% in cyclodextrin solution lowers IOP in human ocular hypertension.

PURPOSE: To formulate aqueous eye drops containing methazolamide 1% in cyclodextrin solution and to evaluate their effect on intraocular pressure (IOP) in a double-blind randomized trial in humans. Methazolamide, a carbonic anhydrase inhibitor (CAI), has been used in oral doses in the treatment of glaucoma but hitherto has not been successfully formulated in eye drops. In this study the effects of methazolamide are compared with those of dorzolamide (Trusopt). METHODS: Methazolamide 1% was formulated in a 2-hydroxypropyl-beta-cyclodextrin with hydroxypropyl methylcellulose in aqueous solution. Eight persons with ocular hypertension were treated with the methazolamide-cyclodextrin eye drops and eight persons with dorzolamide (Trusopt), both groups at dosages of three times a day for 1 week. IOP was measured before treatment was begun and on days 1, 3, and 8 at 9 AM (peak) and 3 PM (trough). RESULTS: After 1 week of treatment, the peak IOP in the methazolamide group had decreased from 24.4 +/- 2.1 mm Hg (mean +/- SD) to 21.0 +/- 2.0 mm Hg, which is a 14% pressure decrease (P: = 0.006). In the dorzolamide group, the peak IOP decreased from 23.3 +/- 2.1 mm Hg to 17.2 +/- 3.1 mm Hg, which is a 26% pressure decrease (P: < 0.001). On average, the IOP declined 3.4 +/- 1.8 mm Hg after methazolamide administration and 6.1 +/- 3.6 mm Hg after dorzolamide. CONCLUSIONS: Through cyclodextrin complexation, it is possible to produce topically active methazolamide eye drops that lower IOP. This is the first double-blind clinical trial that demonstrates the efficacy of the classic CAIs in eye drop formulation.

Carbonic Anhydrase Inhibitors↗
PubMed2000

Lipophilic metronidazole derivatives and their absorption through hairless mouse skin.

Previously we have shown that the diacyl glyceryl ester of naproxen is absorbed into excised mouse skin and slowly degraded to release naproxen. In the present work we have synthesised some organic acid and fatty acid derivatives of metronidazole, and studied the in-vitro degradation in aqueous buffer solutions and serum as well as their permeation through hairless mouse skin. The derivatives were enzymatically degraded in serum to form metronidazole. Only the acetic acid and butyric acid derivatives were able to permeate hairless mouse skin intact. The fatty acid derivatives released metronidazole within the skin. The metronidazole delivery through the skin was significant when the metronidazole oleate was used. This compound could therefore be considered as a suitable pro drug for dermal applications.

Administration, Topical↗
PubMed1999

Influence of cyclodextrins on the stability of the peptide salmon calcitonin in aqueous solution.

The influence of beta-cyclodextrin (betaCD), and various betaCD derivatives, on both the chemical and the physical stability of the polypeptide hormone salmon calcitonin (sCT) in aqueous solutions was investigated at elevated temperature (55 degrees C). Also, the influence of various betaCD derivatives on the enzymatic degradaton of sCT was evaluated. At pH 6, the effect of CDs on the chemical stability of sCT was negligible at CD concentrations below 5% (w/v). The only exception was the negatively charged carboxymethyl-betaCD (CMbetaCD), which increased sCT stability. The charged CDs, i.e. 2-hydroxytrimethylammonio-propyl-betaCD (TMAbetaCD) and CMbetaCD, promoted degradation in concentrated solutions of sCT at pH 6. 2-Hydroxypropyl-betaCD (HPbetaCD) and randomly methylated betaCD (RMbetaCD) not only inhibited aggregation, they also solubilised dimers formed in the test solutions, thereby increasing the physical stability. All the CDs tested accelerated the alpha-chymotryptic degradation of sCT. Maltosyl-betaCD (G(2)betaCD), HPbetaCD and RMbetaCD showed an inhibition of leucine aminopeptidic and tryptic degradation.

Calcitonin↗
PubMed1999

Cyclodextrins as permeation enhancers: some theoretical evaluations and in vitro testing.

It is well known that cyclodextrins can enhance the permeation of poorly soluble drugs through biological membranes. However, the permeability will decrease if cyclodextrin is added in excess of the concentration needed to solvate the drug. The mechanism of cyclodextrin effect on drug permeability has not been fully explained. The effect of cyclodextrins can not be explained as solely due to increased solubility of the drug in the aqueous donor phase nor can it be explained by assuming that cyclodextrins act as classical permeation enhancers, i.e. by decreasing the barrier function of the lipophilic membrane. In the present work we have modeled the effect of cyclodextrins in terms of mixed barrier consisting of both diffusion and membrane controlled diffusion, where the diffusion of the drug in the aqueous diffusion layer is significantly slower than in the bulk of the donor. This diffusion model is described by simple mathematical equation where the properties of the system are expressed in terms of two constants P(M)/Kd and M1/2. Data for the permeation of hydrocortisone through hairless mouse skin in the presence of various cyclodextrins, and cyclodextrin polymer mixtures, were fitted to obtain values for these two constants. The rise in flux with increased cyclodextrin complex concentration and fall with excess cyclodextrin was accurately predicted. Data for the permeation of drugs through semi-permeable cellophane membrane could also be fitted to the equation. It was concluded that cyclodextrins act as permeation enhancers carrying the drug through the aqueous barrier, from the bulk solution towards the lipophilic surface of biological membranes, where the drug molecules partition from the complex into the lipophilic membrane.

Animals↗
PubMed1999

Effect of cyclodextrins and polymers on triclosan availability and substantivity in toothpastes in vivo.

The aqueous solubility of triclosan is only about 10 microg/mL. This very low solubility can hamper its biological activity in the oral cavity, which could explain the mixed clinical results obtained from triclosan toothpaste trials. Triclosan availability in a silica-based toothpaste was improved through cyclodextrin solubilization. The triclosan in vivo availability was optimized through a series of phase-solubility studies and triclosan release studies. It was found that in toothpastes, natural beta-cyclodextrin (betaCD) was just as good a solubilizer as the more water-soluble betaCD derivatives. Furthermore, the amount of cyclodextrin could be reduced by as much as 60% through the addition of a small amount of carboxymethylcellulose (CMC), without affecting triclosan release from the toothpaste. Optimally, cyclodextrins resulted in an almost 3-fold enhancement of triclosan availability compared to an identical toothpaste containing no cyclodextrin. In vivo studies in humans showed that replacing triclosan with triclosan/betaCD in the toothpaste resulted in only moderate improvement in triclosan substantivity. However, replacing triclosan with triclosan/betaCD/CMC complex resulted in significant improvement in triclosan substantivity. Furthermore, the in vivo studies showed that replacing free triclosan with triclosan/betaCD/CMC complex resulted in an almost 3-fold increase in initial triclosan concentration in saliva after brushing and about 2-fold increase in duration of activity.

Adult↗