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1.
Acta Biomater ; 113: 210-216, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32623099

ABSTRACT

Surface-eroding polymers are of significant interest for various applications in the field of controlled drug delivery. Poly(ethylene carbonate), as an example, offers little control over the rate of degradation and, thus, drug release, which usually conflicts with the requirements for long-acting medications. Here, we challenged an option to decelerate the degradation of poly(ethylene carbonate) in vitro and in vivo. When polymer films loaded with distinct antioxidants (vitamins) along with the model drugs leuprorelin and risperidone were incubated in superoxide radical solution and phagocyte culture, the mass loss and drug release from the delivery vehicle was a function of the type and dose of the utilized antioxidant. Once the polymer surface was "attacked" by reactive oxygen species, the antioxidants were released on demand quenching the polymer-degrading radicals. Accordingly, specific combinations of polymer and radical scavengers resulted in controlled release medications with an extended "life-time" of one month or longer, which is difficult to achieve for poly(ethylene carbonate) in the absence of antioxidants. A comparable degradation and drug release behavior was observed when antioxidant-loaded poly(ethylene carbonate) films were implanted in rats. Furthermore, linear correlations were obtained between the mass loss of the polymer films and the released fraction of drug (with slopes close to 1), a clear indication for the surface erosion of poly(ethylene carbonate) in vitro and in vivo. Overall, an addition of antioxidants to poly(ethylene carbonate)-based controlled drug delivery vehicles represents a reasonable approach to modify the performance of long-acting medications, especially when a "life time" of weeks to months needs to be achieved. STATEMENT OF SIGNIFICANCE: Surface-eroding poly(ethylene carbonate) (PEC) is of significant interest for long-acting injectable formulations. However, PEC offers only little control over the rate of degradation and, thus, drug release kinetics. We describe an option to decelerate the degradation rate of PEC in vitro and in vivo. When polymer films loaded with distinct antioxidants along with model drugs were incubated in superoxide radical solution, phagocyte culture and implanted in rats, their mass loss and drug release was a function of the type and dose of the utilized antioxidant. Accordingly, specific combinations of polymer and radical scavengers resulted in controlled release medications with an extended "life-time" of one month or longer, which is difficult to achieve for PEC in the absence of antioxidants.


Subject(s)
Antioxidants , Drug Delivery Systems , Animals , Dioxolanes , Drug Liberation , Polymers , Rats
2.
Exp Dermatol ; 28(3): 261-269, 2019 03.
Article in English | MEDLINE | ID: mdl-30650201

ABSTRACT

Rosacea is a prevalent skin condition dependent on the individual genetic profile. The current pharmacological management of this condition is mostly based on small molecule drugs predominately effective in ameliorating the inflammatory condition. Emerging molecular approaches could present an opportunity for managing rosacea conditions at transcriptomic level, and in the future allow personalized approaches. RNA medicines, such as small RNA interference (siRNA), could provide a flexible and applicable tool reaching this aim. However, the topical siRNA delivery by dermatological emulsions, commonly used in the daily management of rosacea, is still largely unexplored. Consequently, RNA interference application to rosacea was defined on molecular bases by genetic expression meta-data analysis. Based on this, a siRNA directed against TLR2 was designed and validated in vitro on murine macrophages and fibroblasts. Next, siRNA was dispersed in the continuous phase of emulsions and was characterized for commonly used dermatologic bases. Finally, the potential delivery performance of the topical emulsions was tested in vivo on healthy Balb/c mice. It was found that the interaction of siRNA with combination of excipients, such as urea and glycerol, is likely to favour the siRNA delivery, inducing genetic silencing of TLR2. These findings provide a foundation for the future development of topical RNA-based dispersions for topical molecular medicines, by emphasizing on the formulation and therapeutic-based opportunities with dermatological treatments.


Subject(s)
Drug Delivery Systems , RNA, Small Interfering/pharmacology , Rosacea/drug therapy , Skin/metabolism , Animals , Computer Simulation , Disease Models, Animal , Emulsions , Excipients/chemistry , Female , Gene Silencing , Glycerol/chemistry , Humans , Mice , Mice, Inbred BALB C , RNA Interference , RNA, Double-Stranded/metabolism , Toll-Like Receptor 2/metabolism , Urea/chemistry
3.
Molecules ; 24(2)2019 Jan 11.
Article in English | MEDLINE | ID: mdl-30642009

ABSTRACT

Many anti-cancer drugs are difficult to formulate into an oral dosage form because they are both poorly water-soluble and show poor permeability, the latter often as a result of being an intestinal efflux pump substrate. To obtain a more water-soluble formulation, one can take advantage of the higher solubility of the amorphous form of a given drug, whereas to increase permeability, one can make use of an efflux pump inhibitor. In this study, a combination of these two strategies was investigated using the co-amorphous approach, forming an amorphous mixture of two anti-cancer drugs, docetaxel (DTX) and bicalutamide (BIC). The efflux substrate, DTX, was combined with the efflux inhibitor, BIC, and prepared as a single phase co-amorphous mixture at a 1:1 molar ratio using vibrational ball milling. The co-amorphous formulation was tested in vitro and in vivo for its dissolution kinetics, supersaturation properties and pharmacokinetics in rats. The co-amorphous formulation showed a faster in vitro dissolution of both drugs compared to the control groups, but only DTX showed supersaturation (1.9 fold) compared to its equilibrium solubility. The findings for the co-amorphous formulation were in agreement with the pharmacokinetics data, showing a quicker onset in plasma concentration as well as a higher bioavailability for both DTX (15-fold) and BIC (3-fold) compared to the crystalline drugs alone. Furthermore, the co-amorphous formulation remained physically stable over 1.5 years at 4 °C under dry conditions.


Subject(s)
Anilides/pharmacology , Docetaxel/chemistry , Docetaxel/pharmacokinetics , Nitriles/pharmacology , Tosyl Compounds/pharmacology , Administration, Oral , Animals , Biological Availability , Docetaxel/administration & dosage , Drug Stability , Drug Synergism , Humans , Rats , Solubility , X-Ray Diffraction
4.
J Control Release ; 268: 40-48, 2017 Dec 28.
Article in English | MEDLINE | ID: mdl-28993169

ABSTRACT

The design and production of an oral dual-compartmental dosage unit (dcDU) was examined in vitro and in vivo with the purpose of physically isolating and modulating the release profile of an anti-tuberculosis drug combination. Rifampicin (RIF) and isoniazid (ISO) are first line combination drugs for treatment of tuberculosis (TB) that negatively interact with each other upon simultaneous release in acidic environment. The dcDUs were designed in silico by computer aided design (CAD) and fabricated in two steps; first three-dimensional (3D) printing of the outer structure, followed by hot-melt extrusion (HME) of the drug-containing filaments. The structure of the fabricated dcDUs was visualized by scanning electron microscopy (SEM). The 3D printed compartmentalized shells were loaded with filaments containing active pharmaceutical ingredient (API) and selectively sealed to modulate drug dissolution. The drug release profile of the dcDUs was characterized by pH-transfer dissolution in vitro and pharmacokinetics studies in rats, and resulted in modified release of the APIs from the dcDUs as compared to the free filaments. Furthermore, the selective physical sealing of the compartments resulted in an effective retardation of the in vitro API release. The findings of this study support the development of controllable-by-design dcDU systems for combination therapies to enable efficient therapeutic translation of oral dosage forms.


Subject(s)
Antitubercular Agents/administration & dosage , Drug Delivery Systems , Isoniazid/administration & dosage , Rifampin/administration & dosage , Administration, Oral , Animals , Antitubercular Agents/blood , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacokinetics , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacokinetics , Dosage Forms , Drug Combinations , Drug Design , Drug Liberation , Isoniazid/blood , Isoniazid/chemistry , Isoniazid/pharmacokinetics , Male , Printing, Three-Dimensional , Rats, Sprague-Dawley , Rifampin/blood , Rifampin/chemistry , Rifampin/pharmacokinetics
5.
Eur J Pharm Biopharm ; 115: 140-148, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28238837

ABSTRACT

Poly(ethylene carbonate) (PEC) is a unique biomaterial showing significant potential for controlled drug delivery applications. The current study investigated the impact of the molecular weight on the biological performance of drug-loaded PEC films. Following the preparation and thorough physicochemical characterization of diverse PEC (molecular weights: 85, 110, 133, 174 and 196kDa), the degradation and drug release behavior of rifampicin- and bovine serum albumin-loaded PEC films was investigated in vitro (in the presence and absence of cholesterol esterase), in cell culture (RAW264.7 macrophages) and in vivo (subcutaneous implantation in rats). All investigated samples degraded by means of surface erosion (mass loss, but constant molecular weight), which was accompanied by a predictable, erosion-controlled drug release pattern. Accordingly, the obtained in vitro degradation half-lives correlated well with the observed in vitro half-times of drug delivery (R2=0.96). Here, the PEC of the highest molecular weight resulted in the fastest degradation/drug release. When incubated with macrophages or implanted in animals, the degradation rate of PEC films superimposed the results of in vitro incubations with cholesterol esterase. Interestingly, SEM analysis indicated a distinct surface erosion process for enzyme-, macrophage- and in vivo-treated polymer films in a molecular weight-dependent manner. Overall, the molecular weight of surface-eroding PEC was identified as an essential parameter to control the spatial and temporal on-demand degradation and drug release from the employed delivery system.


Subject(s)
Drug Liberation/physiology , Polyethylenes/chemistry , Polyethylenes/metabolism , Polymers/chemistry , Rifampin/metabolism , Serum Albumin, Bovine/metabolism , Animals , Cells, Cultured , Delayed-Action Preparations/chemistry , Drug Carriers/chemistry , Drug Carriers/metabolism , Drug Delivery Systems/methods , Half-Life , Macrophages/drug effects , Male , Mice , Molecular Weight , RAW 264.7 Cells , Rats , Rats, Sprague-Dawley , Rifampin/chemistry , Serum Albumin, Bovine/chemistry , Sterol Esterase/metabolism
6.
J Biomed Mater Res A ; 104(10): 2466-75, 2016 10.
Article in English | MEDLINE | ID: mdl-27213764

ABSTRACT

Triggering of the early healing events, including the recruitment of progenitor cells, has been suggested to promote bone regeneration. In implantology, local drug release technologies could provide an attractive approach to promote tissue regeneration. In this study, we targeted the chemotactic SDF-1α/CXCR4 axis that is responsible e.g. for the homing of stem cells to trauma sites. This was achieved by local delivery of plerixafor, an antagonist to CXCR4, and/or SDF-1α, from titanium implants coated with mesoporous titania thin films with a pore size of 7.5 nm. In vitro drug delivery experiments demonstrated that the mesoporous coating provided a high drug loading capacity and controlled release. The subsequent in vivo study in rat tibia showed beneficial effects with respect to bone-implant anchorage and bone-formation along the surface of the implants when plerixafor and SDF-1α were delivered locally. The effect was most prominent by the finding that the combination of the drugs significantly improved the mechanical bone anchorage. These observations suggest that titanium implants with local delivery of drugs for enhanced local recruitment of progenitor cells have the ability to promote osseointegration. This approach may provide a potential strategy for the development of novel implant treatments. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2466-2475, 2016.


Subject(s)
Chemokine CXCL12/administration & dosage , Coated Materials, Biocompatible/chemistry , Delayed-Action Preparations/chemistry , Heterocyclic Compounds/administration & dosage , Receptors, CXCR4/antagonists & inhibitors , Stem Cells/drug effects , Titanium/chemistry , Animals , Benzylamines , Bone Regeneration/drug effects , Cell Movement/drug effects , Chemokine CXCL12/pharmacology , Cyclams , Drug Delivery Systems , Heterocyclic Compounds/pharmacology , Male , Osseointegration/drug effects , Osteogenesis/drug effects , Porosity , Rats, Sprague-Dawley , Stem Cells/cytology
7.
J Mater Sci Mater Med ; 26(1): 5337, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25577217

ABSTRACT

An attractive approach in implant technology is local drug delivery, and design of efficient, safe and reliable treatments. Our hitherto strategy has been to coat Ti implants with a thin mesoporous TiO2 film that in turn is loaded with an osteoporosis drug, such as Alendronate (ALN) that is known to suppress osteoclastic activity. This system has proven highly successful and results in excellent osseointegration. However, more detailed information about drug-release and distribution at the bone/implant interface is needed. In this study, (14)C-ALN loaded titanium implants were placed up to 8 weeks into rat tibia and the spatial-temporal distribution of the drug was evaluated. Autoradiography data demonstrated a sustained release of (14)C-ALN and the released drug remained bound to bone in close vicinity, within 500 micrometers, of the implants. Liquid scintillation counting experiments confirmed that the distal transport of released (14)C-ALN was extremely low. The results are favorable as they show that ALN stays for a long time in the vicinity of the implant and may therefore improve for a long time the mechanical fixation of bone anchored implants. Moreover, these findings suggest due to the low systemic spreading a minimal risk of Alendronate related systemic side effects.


Subject(s)
Alendronate/metabolism , Bone and Bones/metabolism , Dental Implants , Titanium , Animals , In Vitro Techniques , Male , Rats , Rats, Sprague-Dawley
8.
Biomaterials ; 31(18): 4795-801, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20363497

ABSTRACT

Titanium (Ti) is a well known metallic biomaterial extensively used in dental, orthopaedic-, and occasionally also in blood contacting applications. It integrates well to bone and soft tissues, and is shown upon blood plasma contact to activate the intrinsic pathway of coagulation and bind complement factor 3b. The material properties depend largely on those of the nm-thick dense layer of TiO(2) that becomes rapidly formed upon contact with air and water. The spontaneously formed amorphous Ti-oxide has a pzc approximately 5-6 and its water solubility is at the order of 1-2 micromolar. It is often subjected to chemical- and heat treatments in order to increase the anatase- and rutile crystallinity, to modify the surface topography and to decrease the water solubility. In this work, we prepared sol-gel derived titanium and smooth PVD titanium surfaces, and analysed their oxide and protein deposition properties in human blood plasma before and after annealing at 100-500 degrees C or upon UVO-treatment for up to 96 hours. The blood plasma results show that complement deposition vanished irreversibly after heat treatment at 250-300 degrees C for 30 minutes or after UVO exposure for 24 hours or longer. XPS and infrared spectroscopy indicated change of surface water/hydroxyl binding upon the heat- and UVO treatments, and increased Ti oxidation. XRD analysis confirmed an increased crystallinity and both control (untreated) and annealed smooth titanium displayed low XRD-signals indicating some nanocrystallinity, with predominantly anatase phase. The current results show that the behaviour of titanium dioxide in blood contact can be controlled through relatively simple means, such as mild heating and illumination in UV-light, which both likely irreversibly change the stoichiometry and structure of the outmost layers of titanium dioxide and its OH/H(2)O binding characteristics.


Subject(s)
Complement System Proteins/metabolism , Hot Temperature , Ozone , Plasma/metabolism , Titanium/chemistry , Ultraviolet Rays , Adsorption , Biocompatible Materials/chemistry , Blood Proteins/metabolism , Humans , Phase Transition , Protein Binding , Surface Properties , Titanium/metabolism
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