ABSTRACT
The modes of drug-particle interactions considerably influence drug delivery by nanoparticulate carrier systems and drug penetration into the skin. The exact mechanism of the drug loading and its release are still ambiguous. Therefore, the loading process, the interaction of the agent and the lipid matrix of solid lipid nanoparticles (SLNs) as well as the uptake of the loaded agent by skin lipids were analysed by electron spin resonance (ESR) and parelectric spectroscopy (PS) using spin probes (TEMPO, TEMPOL, and CAT-1) as model drugs differing in their lipophilicity. The spin probes were closely attached to the particles lipid surface (TEMPO) or located in the layers of the surfactant (CAT-1), respectively. Furthermore, two distinct sub-compartments on the SLN were found. To simulate the processes at the phase boundary SLN dispersion/skin, skin lipid mixtures were prepared and the transfer process of the spin labels was followed by ESR tomography. Transfer rates were related to the lipophilicity of the spin probe, the lipid mixture and the applied pharmaceutical formulation, SLN dispersion and aqueous solution, respectively. In particular, SLN accelerated in particular the distribution of the lipophilic agents.
Subject(s)
Administration, Cutaneous , Drug Carriers/chemical synthesis , Drug Compounding/methods , Drug Delivery Systems/methods , Lipids/chemistry , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Skin Absorption/drug effects , Skin Diseases/metabolism , Drug Carriers/chemistry , Drug Carriers/metabolism , Particle Size , Spin LabelsABSTRACT
For efficient pain reduction in severe skin wounds, topical opioids may be a new option - given that wound healing is not impaired and the vehicle allows for slow opioid release, since long intervals of painful wound dressing changes are intended. We investigated the influence of opioids on the wound healing process via in vitro models, migration assay and scratch test. In fact, morphine, hydromorphone, fentanyl and buprenorphine increased the number of migrated HaCaT cells (spontaneously transformed keratinocytes) twofold. In the scratch test, morphine accelerated the closure of a monolayer wound (scratch). As possible slow release application forms are nanoparticulate systems like solid lipid nanoparticles (SLN) and dendritic core-multishell (CMS) nanotransporters, we evaluated the effect of unloaded nanoparticles on HaCaT cell migration, too. CMS nanotransporters did not inhibit migration, SLN even enhanced it (twofold). Applying morphine plus unloaded nanoparticles reduced morphine effects possibly due to uptake into CMS nanotransporters and adsorption to the surface of SLN. In contrast to SLN, TGF-beta1 was taken up by CMS nanotransporters, too. Both nanoparticles are tolerable by skin and eye as derived from Episkin-SM(TM) skin irritation test and HET-CAM assay. No acute toxic effects were observed either. In conclusion, opioids as well as the investigated nanoparticulate carriers conform the essential conditions for topical pain reduction.
Subject(s)
Analgesics, Opioid/pharmacology , Nanoparticles/administration & dosage , Wound Healing/drug effects , Analgesics, Opioid/chemistry , Animals , Cell Line, Transformed , Cell Movement/drug effects , Cell Movement/physiology , Cells, Cultured , Chickens , Female , Humans , Male , Nanoparticles/chemistry , Skin/drug effects , Skin/pathology , Skin Irritancy Tests/methods , Wound Healing/physiologyABSTRACT
Nanosized particles are of growing interest for topical treatment of skin diseases to increase skin penetration of drugs and to reduce side effects. Effects of the particle structure and size were studied loading nile red to dendritic core-multishell (CMS) nanotransporters (20-30 nm) and solid lipid nanoparticles (SLNs, 150-170 nm). Interaction properties of CMS nanotransporters with the dye molecules--attachment to the carrier surface or incorporation in the carrier matrix--were studied by UV/Vis and parelectric spectroscopy. Pig skin penetration was studied ex vivo using a cream for reference. Interactions of SLN and skin were followed by scanning electron microscopy, internalisation of the particles by viable keratinocytes by laser scanning microscopy. Incorporating nile red into a stable dendritic nanoparticle matrix, dye amounts increased eightfold in the stratum corneum and 13-fold in the epidermis compared to the cream. Despite SLN degradation at the stratum corneum surface, SLN enhanced skin penetration less efficiently (3.8- and 6.3-fold). Viable human keratinocytes showed an internalisation of both nanocarriers. In conclusion, CMS nanotransporters can favour the penetration of a model dye into the skin even more than SLN which may reflect size effects.
Subject(s)
Dendrimers/chemistry , Fluorescent Dyes/chemistry , Nanoparticles , Skin Absorption , Animals , Biological Transport , Chemistry, Pharmaceutical/methods , Fluorescent Dyes/pharmacokinetics , Humans , In Vitro Techniques , Keratinocytes/metabolism , Lipids/chemistry , Microscopy, Confocal , Microscopy, Electron, Scanning , Oxazines/chemistry , Oxazines/pharmacokinetics , Particle Size , Skin/metabolism , SwineABSTRACT
PURPOSE: Topical cyproterone acetate (CPA) treatment of skin diseases should reduce side effects currently excluding the use in males and demanding contraceptive measures in females. To improve skin penetration of the poorly absorbed drug, we intended to identify the active moiety and to load it to particulate carrier systems. MATERIALS AND METHODS: CPA metabolism in human fibroblasts, keratinocytes and a sebocyte cell line as well as androgen receptor affinity of native CPA and the hydrolysis product cyproterone were determined. CPA 0.05% loaded solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), a nanoemulsion and micropheres were characterized for drug-particle interaction and CPA absorption using human skin ex-vivo. RESULTS: Native CPA proved to be the active agent. Application of CPA attached to SLN increased skin penetration at least four-fold over the uptake from cream and nanoemulsion. Incorporation into the lipid matrix of NLC and microspheres resulted in a 2-3-fold increase in CPA absorption. Drug amounts within the dermis were low with all preparations. No difference was seen in the penetration into intact and stripped skin. CONCLUSION: With particulate systems topical CPA treatment may be an additional therapeutic option for acne and other diseases of the pilosebaceous unit.
Subject(s)
Acne Vulgaris/drug therapy , Cyproterone Acetate/pharmacology , Lipids/chemistry , Nanoparticles/chemistry , Skin/drug effects , Administration, Cutaneous , Androgen Antagonists/administration & dosage , Androgen Antagonists/pharmacology , Androgen Antagonists/therapeutic use , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Cyproterone Acetate/administration & dosage , Cyproterone Acetate/chemistry , Drug Compounding/methods , Drug Stability , Drug Storage , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Expression/drug effects , Humans , Imidazoles/administration & dosage , Imidazoles/chemistry , Imidazoles/pharmacology , In Vitro Techniques , Keratinocytes/cytology , Keratinocytes/drug effects , Keratinocytes/metabolism , Microspheres , Nitriles/administration & dosage , Nitriles/chemistry , Nitriles/pharmacology , Particle Size , Receptors, Androgen/genetics , Reverse Transcriptase Polymerase Chain Reaction , Skin/metabolism , Skin/pathology , Temperature , Time FactorsABSTRACT
The microwave absorption at frequencies between 10 MHz and 4 GHz is measured for aqueous brine droplets dispersed in a dielectric medium (epsilon(')=2.0). By varying the size of the droplets, ion type and ion concentration, it is found that the microwave absorption goes through a maximum which depends on the type of ions and their concentration. The absorption process is attributed to the polarization of the microdroplets through surface charges. Means to optimize microwave heating in emulsions is discussed.
