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Lipophilic Drugs (lipophilic + drug)
Selected AbstractsEffect of lipid bilayer alteration on transdermal delivery of a high-molecular-weight and lipophilic drug: Studies with paclitaxelJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2004Ramesh Panchagnula Abstract Skin forms an excellent barrier against drug permeation, due to the rigid lamellar structure of the stratum corneum (SC) lipids. Poor permeability of drugs can be enhanced through alteration in partition and diffusion coefficients, or concentration gradient of drug with an appropriate choice of solvent system, along with penetration enhancers. The aim of the current investigation was to assess applicability of lipid bilayer alteration by fatty acids and terpenes toward the permeation enhancement of a high-molecular-weight, lipophilic drug, paclitaxel (PCL) through rat skin. From among the fatty acids studied using ethanol/isopropyl myristate (1:1) vehicle, no significant enhancement in flux of PCL was observed (p,>,0.05). In the case of cis mono and polyunsaturated fatty acids lag time was found to be similar to control (p,>,0.05). This suggests that the permeation of a high-molecular-weight, lipophilic drug may not be enhanced by the alteration of the lipid bilayer, or the main barrier to permeation could lie in lower hydrophilic layers of skin. A significant increase in lag time was observed with trans unsaturated fatty acids unlike the cis isomers, and this was explained on the basis of conformation and preferential partitioning of fatty acids into skin. From among the terpenes, flux of PCL with cineole was significantly different from other studied terpenes and controls, and after treatment with menthol and menthone permeability was found to be reduced. Menthol and menthone cause loosening of the SC lipid bilayer due to breaking of hydrogen bonding between ceramides, resulting in penetration of water into the lipids of the SC lipid bilayer that leads to creation of new aqueous channels and is responsible for increased hydrophilicity of SC. This increased hydrophilicity of the SC bilayer might have resulted in unfavorable conditions for ethanol/isopropyl myristate (1:1) along with PCL to penetrate into skin, therefore permeability was reduced. The findings of this study suggest that the permeation of a high-molecular-weight and lipophilic drug cannot be enhanced through bilayer alteration by penetration enhancers, and alteration in partitioning of drug into skin could be a feasible mode to enhance the permeation of drug. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2177,2183, 2004 [source] Comparison of the lymphatic transport of a lipophilic drug from vehicles containing ,-tocopherol and/or triglycerides in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2001P. B. Nielsen The applicability of ,-tocopherol as a lymphotropic carrier for a highly lipophilic drug has been evaluated. Transport to the intestinal lymph of the highly lipophilic model drug, Lu28,179, in rats after administration to the stomach in an ,-tocopherol emulsion was compared with lymphatic transport after administration of a sesame oil emulsion and an ,-tocopherol/sesame oil emulsion. Lymphatic transport of the triglycerides and of ,-tocopherol was determined. A conscious rat model was used, and the mesenteric lymph was collected. There was no significant difference between the cumulative masses of triglyceride from the two emulsions containing triglyceride 24 h after administration. Administration of an ,-tocopherol emulsion seemed to induce mobilization of endogenous triglyceride. The lymphatic transport of ,-tocopherol was less than 1 mg 24 h after administration of both emulsions containing ,-tocopherol. The absorption of Lu28,179 from the ,-tocopherol emulsion was very low, with a lymphatic recovery of 0.05%. When administered in an ,-tocopherol/sesame oil emulsion, the recovery of Lu28,179 increased sevenfold to 0.35%. However, after administration of Lu28,179 in a sesame oil emulsion, the lymphatic recovery increased a further 13-fold to 4.5%. In conclusion, the study showed that ,-tocopherol did not promote lymphatic absorption of Lu28,179 and thus was not a good lymphotropic carrier, as compared with sesame oil. ,-Tocopherol in combination with sesame oil was not a good lymphotropic carrier either. The non-absorbed ,-tocopherol fraction in the intestine might be able to prevent the absorption of Lu28,179. [source] Topical treatment with aqueous solutions of rofleponide palmitate and budesonide in a pollen-season model of allergic rhinitisCLINICAL & EXPERIMENTAL ALLERGY, Issue 5 2004C. Ahlström-Emanuelsson Summary Background Rofleponide palmitate is an esterified glucocorticosteroid pro-drug with a promising pre-clinical profile designed to deliver topical airway treatment for allergic rhinitis and asthma in a novel manner. Thus, the rofleponide palmitate pro-drug is designed to provide topical exposure of the mucosa to the inactive lipophilic drug, which would be locally metabolized to the more hydrophilic and readily cleared drug rofleponide. Objective To examine whether rofleponide palmitate affects nasal symptoms and peak inspiratory flow (PIF) in a pollen-season model of allergic rhinitis and to compare any such effects with those of another glucocorticosteroid (i.e., budesonide). Methods During the pollen-free season, 40 patients with strictly seasonal allergic rhinitis received topical nasal spray treatment with an aqueous solution of rofleponide palmitate 400 ,g and an aqueous solution of budesonide 128 ,g once daily for 10 days in a double-blind, placebo-controlled, and crossover study. After 3 days of drug treatment, individualized allergen challenges were given once daily for 7 days while the treatment continued. The washout periods between each of the challenge series were 2 weeks. Nasal symptoms and PIF were recorded in the morning and evening, as well as 10 and 20 min after each allergen challenge. The mean recordings obtained during the last 3 days of the allergen-challenge series, when symptoms were established and when the treatment had lasted for 8,10 days, were used in the analysis. Results Both active treatments reduced nasal symptoms and improved nasal PIF compared with placebo (P<0.01,0.001). There was no overall difference in efficacy between rofleponide palmitate 400 ,g and budesonide 128 ,g. Conclusions Topical treatment with aqueous solutions of rofleponide palmitate attenuates nasal symptoms and improves nasal PIF in allergic rhinitis. The overall efficacy of 400 ,g of rofleponide palmitate is similar to that of 128 ,g of budesonide in the pollen-season model used in this study. [source] Characterization of basic drug,human serum protein interactions by capillary electrophoresisELECTROPHORESIS, Issue 17 2006María A. Martínez-Gómez Abstract Drug,protein interactions are determining factors in the therapeutic, pharmacodynamic and toxicological drug properties. The affinity of drugs towards plasmatic proteins is apparently well established in bibliography. Albumin (HSA) especially binds neutral and negatively charged compounds; ,1 -acid glycoprotein,(AGP) binds many cationic drugs, lipoproteins bind to nonionic and lipophilic drugs and some anionic drugs while globulins interact inappreciably with the majority of drugs. In this paper, the characterization of the interaction between cationic drugs, ,-blockers and phenotiazines towards HSA, AGP, and both HSA + AGP mixtures of proteins under physiological conditions by CE-frontal analysis is presented. Furthermore, the binding of these drugs to all plasmatic proteins is evaluated by using ultrafiltration and CE. The results indicate that the hydrophobic character of compounds seems to be the key factor on the interaction between cationic drugs towards proteins. In fact, hydrophobic basic drugs bind in great extension to HSA, while hydrophilic basic drugs present low interactions with proteins and bind especially to AGP. [source] Degradable, Surfactant-Free, Monodisperse Polymer-Encapsulated Emulsions as Anticancer Drug CarriersADVANCED MATERIALS, Issue 18 2009Sri Sivakumar Anticancer emulsions: Degradable, surfactant- free, micrometer- to sub-micrometer-sized polymer-encapsulated emulsions loaded with lipophilic drugs (doxorubicin and 5-fluorouracil) are prepared. In vitro drug-release studies demonstrate controlled release under redox conditions and incubation with human colorectal cancer cells triggers cell death with greater efficiency (,106 fold) than the free drug. [source] Multinuclear NMR characterisation and dermal delivery of fluorinated drugs in soybean-microemulsion systemsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2009Sonja Hoeller Abstract The present study evaluated the effect of different commercially available soybean lecithins in microemulsion systems in terms of microstructure transformation, physicochemical properties and transport of selected entrapped fluorinated drugs through skin. Physicochemical characterisations by particle size and polydispersity index (PDI) measurements were performed and a direct correlation with NMR self-diffusion coefficients of the individual components was found. An increase of lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE) and lysophosphatidylethanolamine (LPE) in the phospholipid mixtures increased the mean particle sizes and PDI. Bicontinous microemulsion structures were proven by 1H and 31P NMR in the placebo microemulsions. Reasonable permeation of the lipophilic drugs of all microemulsions systems was confirmed in standard diffusion studies using porcine skin. This could be due to the incorporation of the drugs in the surfactant structure of the lecithin based bicontinous micro textures, as proven by 19F NMR self-diffusion studies. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2686,2695, 2009 [source] Solvent-mediated solid phase transformations of carbamazepine: Effects of simulated intestinal fluid and fasted state simulated intestinal fluidJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2009Paula Lehto Abstract Solvent-mediated transformations of carbamazepine (CBZ) anhydrate form III were investigated in Simulated Intestinal Fluid, a simple USP buffer medium, and in FaSSIF, which contains sodium taurocholate (STC) and lecithin, important surfactants that solubilize lipophilic drugs and lipids in the gastrointestinal tract. Raman spectroscopy (in situ) was utilized to reveal the connection between the changes in solid phase composition and dissolution rate while simultaneously detecting the solid state and the dissolved amount of CBZ. Initial dissolution rate was clearly higher in FaSSIF, while the solid phase data revealed that the crystallization of CBZ dihydrate was inhibited in both the dissolution media, albeit by different mechanisms. In SIF this inhibition was related to extensive needle growth, which impeded medium contact with the solid surface by forming a sterical barrier leading to retarded crystallization rates. Morphological changes from the needle-like dihydrate crystals to plate-like counterparts in FaSSIF, combined with the information that the transformation process was leveled off, evidenced strong hydrogen bonding behavior between the CBZ and STC molecules. These results underline the importance of biologically representative dissolution media in linking the in vitro dissolution results of solids that are capable of hydrate formation to their in vivo dissolution behavior. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:985,996, 2009 [source] High-throughput determination of the free fraction of drugs strongly bound to plasma proteinsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2004Joachim Schuhmacher Abstract Quantification of protein binding of new chemical entities is an important early screening step during drug discovery and is of fundamental interest for the estimation of safety margins during drug development. In this publication, we describe the development of a new high-throughput assay for the determination of the free drug fraction in plasma (fu). The new technique is an enhancement of the previously published erythrocytes partition method. It is based on the distribution of drugs between plasma water, plasma proteins, and solid-supported lipid membranes (Transil®). The execution of protein binding studies by partitioning is dramatically simplified by substituting erythrocytes with commercially available Transil® beads, and makes the method particularly suitable for high-throughput studies. Eight Bayer compounds from different compound classes covering a wide range of lipophilicities (log P,=,1.9,5.6) and fu values (0.018,35%) were selected for validation of the assay. The results obtained by the new method and by either the erythrocytes partitioning technique or more conventional methods (ultrafiltration and equilibrium dialysis) are identical, confirming that the new method produces valid results even for drugs that are strongly bound to plasma proteins. Precision and accuracy of the data in the cases of very low and high fu values are comparable, indicating that the method is especially suited for highly lipophilic drugs that tend to adsorb to surfaces compared with other methods, like ultrafiltration or equilibrium dialysis, that may produce biased data. The method is also useful for the determination of binding parameters and the pH dependence of fu. In summary, this assay is well suited for high-throughput determination of protein binding during drug discovery and for extended protein binding studies during drug development. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 816,830, 2004 [source] Using the polymer partitioning method to probe the thermodynamic activity of poorly water-soluble drugs solubilized in model lipid digestion productsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2003Ben J. Boyd Abstract The thermodynamic activity of solubilized drug is an important determinant of the extent of absorption of lipophilic drugs from the gastrointestinal tract. In this study, the polymer partitioning method was evaluated for its use in the determination of the thermodynamic activity of lipophilic drugs when solubilized in colloidal digestion products, using drug in dilute solution as a reference ideal solution. The lipophilic drugs griseofulvin, diazepam, and danazol partitioned into a polymeric receiver phase from non-micellar solution as a function of drug lipophilicity. The concentration of drug that partitioned into the polymer was linearly proportional to the concentration of free drug in solution, and this allowed the measured partition coefficient to be utilized as an indicator of the drug activity coefficient. The addition of a solubilizing species such as bile salt micelles caused a reduction in drug activity of a similar magnitude to that predicted from micelle equilibrium solubility data in the identical micellar solutions. The addition of micelle swelling lipids such as lecithin and fatty acids resulted in further reductions in activity coefficient. The ability to measure drug activity in model digestive systems has potential for application in the rational development of improved lipid-based formulations of poorly water-soluble drugs for oral administration. © 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:1262,1271, 2003 [source] Liposomes in investigative dermatologyPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 5 2001Daniel B. Yarosh Liposomes are microscopic spheres, usually composed of amphiphilic phospholipids. They may be useful without skin penetration if they simply protect or sequester compounds that would otherwise be unstable in the formulation. Liposomes that remain on the skin surface are useful as light-absorbers, agents to deliver color or sunscreens, or as depots for timed-release. Liposomes that penetrate the stratum corneum have the potential to interact with living tissue. Topically applied liposomes can either mix with the stratum corneum lipid matrix or penetrate the stratum corneum by exploiting the lipid-water interface of the intercellular matrix. There are at least four major routes of entry into the skin: pores, hair follicles, columnular spaces and the lipid:water matrix between squames. A major force driving liposome penetration is the water gradient, and flexible liposomes are best able to exploit these delivery opportunities. Some liposomes release their contents extracellularly. Topical application of photosensitizers may be enhanced by encapsulation in liposomes. Higher and longer-lasting drug concentrations may be produced in localized areas of skin, particularly at disease sites where the stratum corneum and the skin barrier function are disrupted. The liposome membrane should be designed to capture lipophilic drugs in the membrane or hydrophilic drugs in the interior. Other types of liposomes can be engineered to be taken up by cells. Once inside cells, the lysosomal sac and clatherin-coated pit are the dead-end destinations for liposomes unless an escape path has been engineered into the liposome. A novel method has been developed to allow delivery into cells of the skin, by escape from the lysosomal sac. These liposomes have been used to topical deliver active DNA repair enzymes from liposomes into epidermal cells and to enhance DNA repair of UV-irradiated skin. From these studies a tremendous amount has been learned about the relationship of DNA damage and skin cancer. Both mutations and immunosuppression appear to be essential to skin cancer and both are induced by DNA damage. DNA damage produces immediate effects by inducing the expression of cytokines, which means that DNA damage can induce signaling in neighboring, undamaged cells. The repair of only a fraction of the DNA damage has a disproportionate effect on the biological responses, clearly demonstrating that not all DNA damage is equivalent. This technology demonstrates that biologically active proteins can be delivered into the cells of skin, and opens up a new field of correcting or enhancing skin cell metabolism to improve human health. [source] | ||||||||||