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1.
Purpose
The purpose of this study was to determine if non-specific COX inhibition could extend pore lifetime in hairless guinea pigs following microneedle treatment.Methods
Hairless guinea pigs were treated with microneedle arrays ± daily application of Solaraze® gel (3% diclofenac sodium (non-specific COX inhibitor) and 2.5% hyaluronic acid); transepidermal water loss was utilized to evaluate pore lifetime. To examine the permeation of naltrexone, additional guinea pigs were treated with microneedles ± daily Solaraze® gel followed by application of a 16% transdermal naltrexone patch; pharmacokinetic analysis of plasma naltrexone levels was performed. Histological analysis was employed to visualize morphological changes following microneedle and Solaraze® treatment.Results
Animals treated with microneedles + Solaraze® displayed extended pore lifetime (determined by transepidermal water loss measurements) for up to 7 days. Enhanced naltrexone permeation was also observed for an extended amount of time in animals treated with microneedles + Solaraze®. No morphological changes resulting from microneedle treatment or COX inhibition were noted.Conclusions
Non-specific COX inhibition is an effective means of extending pore lifetime following microneedle treatment in hairless guinea pigs. This may have clinical implications for extending transdermal patch wear time and therefore increasing patient compliance with therapy. 相似文献2.
Jaspreet Singh Kochhar Parthiban Anbalagan Sandeep Balu Shelar Jun Kai Neo Ciprian Iliescu Lifeng Kang 《Pharmaceutical research》2014,31(7):1724-1734
Purpose
To fabricate microneedle arrays directly off a photomask using a simple photolithographical approach and evaluate their potential for delivering collagen.Methods
A simple photolithographical approach was developed by using photomask consisting of embedded micro-lenses that govern microneedle geometry in a mould free process. Microneedle length was controlled by use of simple glass scaffolds as well as addition of backing layer. The fabricated arrays were tested for their mechanical properties by using a force gauge as well as insertion into human skin with trypan blue staining. Microneedle arrays were then evaluated for the delivery of fluorescent collagen, which was evaluated using a confocal laser scanning microscope.Results
Microneedles with sharp tips ranging between 41.5?±?8.4 μm and 71.6?±?13.7 μm as well as of two different lengths of 1336?±?193 μm and 957?±?171 μm were fabricated by using the photomasks. The microneedles were robust and resisted fracture forces up to 25 N. They were also shown to penetrate cadaver human skin samples with ease; especially microneedle arrays with shorter length of 957 μm penetrated up to 72% of needles. The needles were shown to enhance permeation of collagen through cadaver rat skin, as compared to passive diffusion of collagen.Conclusions
A simple and mould free approach of fabricating polymeric microneedle array is proposed. The fabricated microneedle arrays enhance collagen permeation through skin. 相似文献3.
Koen van der Maaden Sebastiaan J. Trietsch Heleen Kraan Eleni Maria Varypataki Stefan Romeijn Raphäel Zwier Heiko J. van der Linden Gideon Kersten Thomas Hankemeier Wim Jiskoot Joke Bouwstra 《Pharmaceutical research》2014,31(7):1846-1854
Purpose
The aim of the study was to develop a cheap and fast method to produce hollow microneedles and an applicator for injecting vaccines into the skin at a pre-defined depth and test the applicability of the system for dermal polio vaccination.Methods
Hollow microneedles were produced by hydrofluoric acid etching of fused silica capillaries. An electromagnetic applicator was developed to control the insertion speed (1–3 m/s), depth (0–1,000 μm), and angle (10°–90°). Hollow microneedles with an inner diameter of 20 μm were evaluated in ex vivo human skin and subsequently used to immunize rats with inactivated poliovirus vaccine (IPV) by an intradermal microinjection of 9 μL at a depth of 300 μm and an insertion speed of 1 m/s. Rat sera were tested for IPV-specific IgG and virus-neutralizing antibodies.Results
Microneedles produced from fused silica capillaries were successfully inserted into the skin to a chosen depth, without clogging or breakage of the needles. Intradermal microinjection of IPV induced immune responses comparable to those elicited by conventional intramuscular immunization.Conclusions
We successfully developed a hollow microneedle technology for dermal vaccination that enables fundamental research on factors, such as insertion depth and volume, and insertion angle, on the immune response. 相似文献4.
Ryan F. Donnelly Kurtis Moffatt Ahlam Zaid Alkilani Eva M. Vicente-Pérez Johanne Barry Maelíosa T. C. McCrudden A. David Woolfson 《Pharmaceutical research》2014,31(8):1989-1999
Purpose
To investigate, for the first time, the influence of pharmacist intervention and the use of a patient information leaflet on self-application of hydrogel-forming microneedle arrays by human volunteers without the aid of an applicator device.Methods
A patient information leaflet was drafted and pharmacist counselling strategy devised. Twenty human volunteers applied 11?×?11 arrays of 400 μm hydrogel-forming microneedle arrays to their own skin following the instructions provided. Skin barrier function disruption was assessed using transepidermal water loss measurements and optical coherence tomography and results compared to those obtained when more experienced researchers applied the microneedles to the volunteers or themselves.Results
Volunteer self-application of the 400 μm microneedle design resulted in an approximately 30% increase in skin transepidermal water loss, which was not significantly different from that seen with self-application by the more experienced researchers or application to the volunteers. Use of optical coherence tomography showed that self-application of microneedles of the same density (400 μm, 600 μm and 900 μm) led to percentage penetration depths of approximately 75%, 70% and 60%, respectively, though the diameter of the micropores created remained quite constant at approximately 200 μm. Transepidermal water loss progressively increased with increasing height of the applied microneedles and this data, like that for penetration depth, was consistent, regardless of applicant.Conclusion
We have shown that hydrogel-forming microneedle arrays can be successfully and reproducibly applied by human volunteers given appropriate instruction. If these outcomes were able to be extrapolated to the general patient population, then use of bespoke MN applicator devices may not be necessary, thus possibly enhancing patient compliance. 相似文献5.
Naresh Modepalli Seongbong Jo Michael A. Repka S. Narasimha Murthy 《Pharmaceutical research》2013,30(3):889-898
Purpose
Iontophoretic mediated transdermal delivery of ferric pyrophosphate (FPP) in combination with microneedle pretreatment was investigated as a potential treatment for iron deficiency anemia (IDA).Methods
In vitro transdermal delivery studies were performed using hairless rat skin and pharmacodynamic studies were performed in hairless anemic rat model. The hematological and biochemical parameters like hemoglobin, hematocrit and % serum transferrin were monitored in rats at healthy, anemic condition and post treatment. Micropores created by the microneedles were visualized in histological skin sections after staining with hemotoxylin and eosin. The recovery of micropores was investigated in vivo by measuring Transepidermal water loss (TEWL) at different time points.Results
The passive, microneedle and iontophoresis mediated delivery did not lead to significant improvement in hematological and biochemical parameters in anemic rats, when used individually. When iontophoresis (0.15 mA/cm2 for 4 hours) was combined with microneedle pretreatment (for 2 min), therapeutically adequate amount of FPP was delivered and there was significant recovery of rats from IDA.Conclusions
Microneedle and iontophoresis mediated delivery of iron via transdermal route could be developed as a potential treatment for IDA. The transdermal controlled delivery of iron could become a potential, safe and effective alternative to parenteral iron therapy. 相似文献6.
Nicole K. Brogden Stan L. Banks Leslie J. Crofford Audra L. Stinchcomb 《Pharmaceutical research》2013,30(8):1947-1955
Purpose
Microneedles applied to the skin create micropores, allowing transdermal drug delivery of skin-impermeable compounds. The first human study with this technique demonstrated delivery of naltrexone (an opioid antagonist) for two to three days. Rapid micropore closure, however, blunts the delivery window. Application of diclofenac (an anti-inflammatory) allows seven days of naltrexone delivery in animals. The purpose of the current work was to demonstrate delivery of naltrexone for seven days following one microneedle treatment in humans.Methods
Human subjects were treated with microneedles, diclofenac (or placebo), and naltrexone. Impedance measurements were used as a surrogate marker to measure micropore formation, and plasma naltrexone concentrations were measured for seven days post-microneedle application.Results
Impedance dropped significantly from baseline to post-microneedle treatment, confirming micropore formation. Naltrexone was detected for seven days in Group 1 (diclofenac + naltrexone, n?=?6), vs. 72 h in Group 2 (placebo + naltrexone, n?=?2). At study completion, a significant difference in impedance was observed between intact and microneedle-treated skin in Group 1 (confirming the presence of micropores).Conclusion
This is the first study demonstrating week-long drug delivery after one microneedle application, which would increase patient compliance and allow delivery of therapies for chronic diseases. 相似文献7.
Guangsheng Du Laura Woythe Koen van der Maaden Mara Leone Stefan Romeijn Alexander Kros Gideon Kersten Wim Jiskoot Joke A. Bouwstra 《Pharmaceutical research》2018,35(10):189
Purpose
To examine the immunogenicity of diphtheria toxoid (DT) loaded mesoporous silica nanoparticles (MSNs) after coated and hollow microneedle-mediated intradermal immunization in mice.Methods
DT was loaded into MSNs and the nanoparticle surface was coated with a lipid bilayer (LB-MSN-DT). To prepare coated microneedles, alternating layers of negatively charged LB-MSN-DT and positively charged N-trimethyl chitosan (TMC) were coated onto pH-sensitive microneedle arrays via a layer-by-layer approach. Microneedle arrays coated with 5 or 3 layers of LB-MSN-DT were used to immunize mice and the elicited antibody responses were compared with those induced by hollow microneedle-injected liquid formulation of LB-MSN-DT. Liquid DT formulation with and without TMC (DT/TMC) injected by a hollow microneedle were used as controls.Results
LB-MSN-DT had an average size of about 670 nm and a zeta potential of ?35 mV. The encapsulation efficiency of DT in the nanoparticles was 77%. The amount of nano-encapsulated DT coated onto the microneedle array increased linearly with increasing number of the coating layers. Nano-encapsulated DT induced stronger immune responses than DT solution when delivered intradermally via hollow microneedles, but not when delivered via coated microneedles.Conclusion
Both the nano-encapsulation of DT and the type of microneedles affect the immunogenicity of the antigen.8.
Chenchen Guo Rajeshree H. Khengar Mingjing Sun Zheng Wang Aiping Fan Yanjun Zhao 《Pharmaceutical research》2014,31(11):3051-3059
Purpose
The acne skin is characteristic of a relatively lower pH microenvironment compared to the healthy skin. The aim of this work was to utilize such pH discrepancy as a site-specific trigger for on-demand topical adapalene delivery.Methods
The anti-acne agent, adapalene, was encapsulated in acid-responsive polymer (Eudragit® EPO) nanocarriers via nanoprecipitation. The nanocarriers were characterized in terms of particle size, surface morphology, drug-carrier interaction, drug release and permeation.Results
Adapalene experienced a rapid release at pH 4.0 in contrast to that at pH 5.0 and 6.0. The permeation study using silicone membrane revealed a significant higher drug flux from the nanocarrier (6.5?±?0.6 μg.cm?2.h?1) in comparison to that (3.9?±?0.4 μg.cm?2.h?1) in the control vehicle (Transcutol®). The in vitro pig skin tape stripping study showed that at 24 h post dose-application the nanocarrier delivered the same amount of drug to the stratum corneum as the positive control vehicle did.Conclusions
The acid-responsive nanocarriers hold promise for efficient adapalene delivery and thus improved acne therapy. FigurepH liable nanocarriers enhance the adapalene delivery to acne skin. 相似文献
9.
Purpose
Bleomycin-coated microneedles were devised for delivery of bleomycin into the sub-epidermal skin layer for the treatment of warts in order to provide patient convenience and reduce patient pain and fear.Method
Poly-lactic-acid (L-PLA) microneedles were fabricated by a molding process and then the tips were partially coated using a dip-coating method based on a microstructure well. The mechanical strength of the pre-coated polymer microneedles was observed by inserting them in porcine foot and back skin. The holes were stained with trypan blue and the mechanical failure of the microneedles was investigated using a scanning electron microscope (SEM). The initial distribution of a model drug using microneedles was compared with distribution by intralesional injection. The amount of drug leaked below the skin using microneedles was measured and compared with that leaked by intralesional injection. The pharmacokinetic properties of bleomycin-coated microneedles were studied. The bleomycin remaining on the coated microneedles after the in vivo pharmacokinetic study was measured.Results
Bleomycin was successfully coated on the tips of L-PLA microneedles. More than 80% of the bleomycin dissolved into the skin in vitro within 15 min. L-PLA microneedles possessed sufficient mechanical strength to penetrate skin with a thick stratum corneum. Compared to intralesional injection, tip-coated microneedles were more effective in distributing a drug into the sub-epidermal skin layer. A pharmacokinetic study of bleomycin-coated microneedles showed 50 min of Tmax.Conclusions
Bleomycin-coated microneedles appeared to be a convenient and painless alternative to conventional intralesional injection of bleomycin. The microneedles delivered bleomycin into the targeted dermal layer regardless of body site. Bleomycin-coated microneedles therefore provide a suitable method for the treatment of warts.10.
Priyanka Ghosh DoMin Lee Kyung Bo Kim Audra L. Stinchcomb 《Pharmaceutical research》2014,31(1):148-159
Purpose
The purpose of this work was to optimize the structure of codrugs for extended delivery across microneedle treated skin. Naltrexone, the model compound was linked with diclofenac, a nonspecific cyclooxygenase inhibitor to enhance the pore lifetime following microneedle treatment and develop a 7 day transdermal system for naltrexone.Methods
Four different codrugs of naltrexone and diclofenac were compared in terms of stability and solubility. Transdermal flux, permeability and skin concentration of both parent drugs and codrugs were quantified to form a structure permeability relationship.Results
The results indicated that all codrugs bioconverted in the skin. The degree of conversion was dependent on the structure, phenol linked codrugs were less stable compared to the secondary alcohol linked structures. The flux of naltrexone across microneedle treated skin and the skin concentration of diclofenac were higher for the phenol linked codrugs. The polyethylene glycol link enhanced solubility of the codrugs, which translated into flux enhancement.Conclusion
The current studies indicated that formulation stability of codrugs and the flux of naltrexone can be enhanced via structure design optimization. The polyethylene glycol linked naltrexone diclofenac codrug is better suited for a 7 day drug delivery system both in terms of stability and drug delivery. 相似文献11.
Purpose
This study investigated in vitro transdermal delivery of methotrexate through dermatomed porcine ear and cadaver human skin treated with poly (D,L-lactide-co-glycolide) acid microneedles or fractional ablative laser.Methods
PLGA microneedles were fabricated and characterized using scanning electron microscopy and mechanical assessment techniques. The integrity of treated skin was evaluated by rheometer, transepidermal water loss, and skin electrical resistance measurements. Successful skin microporation was demonstrated by dye binding, histology, pore uniformity, confocal laser microscopy, and DermaScan studies. In vitro permeation experiment was performed on Franz diffusion cells to determine drug delivery into and across the skin.Results
Both physical treatments resulted in a considerable decrease in skin resistance and an increase in transepidermal water loss value. The laser-created microchannels were significantly larger than those formed by microneedles (p?<?0.05). An effective force of 41.04?±?18.33 N was required to achieve 100% penetration efficiency of the microneedles. For both porcine ear and human skin, laser ablation provided a significantly higher methotrexate permeability into the receptor chamber and skin layers compared to microneedle poration and untreated skin (p?<?0.05).Conclusions
Both fractional ablative laser and polymeric microneedles markedly enhanced in vitro transdermal delivery of methotrexate into and across skin.Graphical Abstract ?
12.
Himanshu Kathuria Hairui Li Jing Pan Seng Han Lim Jaspreet Singh Kochhar Chunyong Wu Lifeng Kang 《Pharmaceutical research》2016,33(11):2653-2667
Purpose
Current topical treatments using lidocaine (LD) for analgesia have limited applications due to their delayed analgesic actions, resulted from slow drug permeation through skin. The aim of this study is to fabricate a large size microneedle (MN) array patch containing LD, with fast onset of action, for the treatment of acute and chronic pain.Methods
The MN patch was developed through photolithography and tested for its mechanical characteristics. In vitro and in vivo skin permeation, plasma pharmacokinetics, histology and skin irritation testing have also been performed for the MN patches.Results
The MN have a mechanical strength of 10–30 N and more than 90% of the microneedles on the patch penetrated skin. It was shown that LD permeated through skin within 5 min of patch application. Subsequently, the in vivo skin permeation study using a porcine model showed that LD administrated by the MN patch was able to achieve the therapeutic level locally within 10 min and sustained for 8 h. It shows most of the drug diffuses perpendicularly against skin, with little lateral diffusion. After skin permeation LD remains within skin and unquantifiable amount of LD was found in the plasma of the pigs. Minor skin irritations were observed after 6 h of microneedle contact. However, the skin irritations resolved within 1 day following the removal of MN patch.Conclusion
The large size MN patches showed fast onset and sustained delivery of LD through skin, potentially useful to increase the application scope of topical LD for pain management.13.
Purpose
To evaluate the feasibility of coating formulated recombinant human erythropoietin alfa (EPO) on a titanium microneedle transdermal delivery system, ZP-EPO, and assess preclinical patch delivery performance.Methods
Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. EPO liquid formulation was coated onto titanium microneedles by dip-coating and drying. Stability of coated EPO was assessed by SEC-HPLC, CZE and potency assay. Preclinical in vivo delivery and pharmacokinetic studies were conducted in rats with EPO-coated microneedle patches and compared to subcutaneous EPO injection.Results
Studies demonstrated successful EPO formulation development and coating on microneedle arrays. ZP-EPO patch was stable at 25°C for at least 3?months with no significant change in % aggregates, isoforms, or potency. Preclinical studies in rats showed the ZP-EPO microneedle patches, coated with 750?IU to 22,000?IU, delivered with high efficiency (75?C90%) with a linear dose response. PK profile was similar to subcutaneous injection of commercial EPO.Conclusions
Results suggest transdermal microneedle patch delivery of EPO is feasible and may offer an efficient, dose-adjustable, patient-friendly alternative to current intravenous or subcutaneous routes of administration. 相似文献14.
Yunzhe Ma Wenqian Tao Shelly J. Krebs William F. Sutton Nancy L. Haigwood Harvinder S. Gill 《Pharmaceutical research》2014,31(9):2393-2403
Purpose
The objective of this study is to evaluate the feasibility of using coated microneedles to deliver vaccines into the oral cavity to induce systemic and mucosal immune responses.Method
Microneedles were coated with sulforhodamine, ovalbumin and two HIV antigens. Coated microneedles were inserted into the inner lower lip and dorsal surface of the tongue of rabbits. Histology was used to confirm microneedle insertion, and systemic and mucosal immune responses were characterized by measuring antigen-specific immunoglobulin G (IgG) in serum and immunoglobulin A (IgA) in saliva, respectively.Results
Histological evaluation of tissues shows that coated microneedles can penetrate the lip and tongue to deliver coatings. Using ovalbumin as a model antigen it was found that the lip and the tongue are equally immunogenic sites for vaccination. Importantly, both sites also induced a significant (p?0.05) secretory IgA in saliva compared to pre-immune saliva. Microneedle-based oral cavity vaccination was also compared to the intramuscular route using two HIV antigens, a virus-like particle and a DNA vaccine. Microneedle-based delivery to the oral cavity and the intramuscular route exhibited similar (p?>?0.05) yet significant (p?0.05) levels of antigen-specific IgG in serum. However, only the microneedle-based oral cavity vaccination group stimulated a significantly higher (p?0.05) antigen-specific IgA response in saliva, but not intramuscular injection.Conclusion
In conclusion, this study provides a novel method using microneedles to induce systemic IgG and secretory IgA in saliva, and could offer a versatile technique for oral mucosal vaccination. Figure? 相似文献
15.
Zhuangzhi Zhu Huafei Luo Wangding Lu Hansen Luan Yubo Wu Jing Luo Youjie Wang Jiaxin Pi Chee Yen Lim Hao Wang 《Pharmaceutical research》2014,31(12):3348-3360
Purpose
To assess the feasibility of transdermal delivery of exenatide (EXT) using low-molecular-weight sodium hyaluronate (HA) dissolving microneedles (MNs) patches for type 2 diabetes mellitus therapy.Methods
Micromold casting method was used to fabricate EXT-loaded dissolving MNs. The characteristics of prepared MNs including mechanical strength, in vitro/in vivo insertion capacity, dissolution profile and storage stability were then investigated. Finally, the in vivo pharmacokinetics and hypoglycemic effects were compared with traditional subcutaneous (SC) injection.Results
EXT-loaded dissolving MNs made of HA possessed sufficient mechanical strength and the strength could be weakened as the water content increases. The EXT preserved its pharmacological activity during fabrication and one-month storage. With the aid of spring-operated applicator, dissolving MNs could be readily penetrated into the skin in vitro/in vivo, and then rapidly dissolved to release encapsulated drug within 2 min. Additionally, transepidermal water loss (TEWL) determinations showed that skin’s barrier properties disrupted by MNs recovered within 10–12 h. Transdermal pharmacokinetics and antidiabetic effects studies demonstrated that fabricated EXT MNs induced comparable efficacy to SC injection.Conclusions
Our rapidly dissolving MNs patch appears to an excellent, painless alternative to conventional SC injection of EXT, and this minimally invasive device might also be suitable for other biotherapeutics. 相似文献16.
Jing Tu Guangsheng Du M. Reza Nejadnik Juha Mönkäre Koen van der Maaden Paul H. H. Bomans Nico A. J. M. Sommerdijk Bram Slütter Wim Jiskoot Joke A. Bouwstra Alexander Kros 《Pharmaceutical research》2017,34(8):1693-1706
Purpose
To develop a new intradermal antigen delivery system by coating microneedle arrays with lipid bilayer-coated, antigen-loaded mesoporous silica nanoparticles (LB-MSN-OVA).Methods
Synthesis of MSNs with 10-nm pores was performed and the nanoparticles were loaded with the model antigen ovalbumin (OVA), and coated with a lipid bilayer (LB-MSN-OVA). The uptake of LB-MSN-OVA by bone marrow-derived dendritic cells (BDMCs) was studied by flow cytometry. The designed LB-MSN-OVA were coated onto pH-sensitive pyridine-modified microneedle arrays and the delivery of LB-MSN-OVA into ex vivo human skin was studied.Results
The synthesized MSNs demonstrated efficient loading of OVA with a maximum loading capacity of about 34% and the lipid bilayer enhanced the colloidal stability of the MSNs. Uptake of OVA loaded in LB-MSN-OVA by BMDCs was higher than that of free OVA, suggesting effective targeting of LB-MSN-OVA to antigen-presenting cells. Microneedles were readily coated with LB-MSN-OVA at pH 5.8, yielding 1.5 μg of encapsulated OVA per microneedle array. Finally, as a result of the pyridine modification, LB-MSN-OVA were effectively released from the microneedles upon piercing the skin.Conclusion
Microneedle arrays coated with LB-MSN-OVA were successfully developed and shown to be suitable for intradermal delivery of the encapsulated protein antigen.17.
Purpose
Lidocaine hydrochloride (LidH) was formulated in sodium carboxymethyl cellulose/ gelatine (NaCMC/GEL) hydrogel and a ‘poke and patch’ microneedle delivery method was used to enhance permeation flux of LidH.Methods
The microparticles were formed by electrostatic interactions between NaCMC and GEL macromolecules within a water/oil emulsion in paraffin oil and the covalent crosslinking was by glutaraldehyde. The GEL to NaCMC mass ratio was varied between 1.6 and 2.7. The LidH encapsulation yield was 1.2 to 7% w/w. LidH NaCMC/GEL was assessed for encapsulation efficiency, zeta potential, mean particle size and morphology. Subsequent in vitro skin permeation studies were performed via passive diffusion and microneedle assisted permeation of LidH NaCMC/GEL to determine the maximum permeation rate through full thickness skin.Results
LidH 2.4% w/w NaCMC/GEL 1:1.6 and 1:2.3 respectively, possessed optimum zeta potential. LidH 2.4% w/w NaCMC/GEL 1:2.3 and 1:2.7 demonstrate higher pseudoplastic behaviour. Encapsulation efficiency (14.9–17.2%) was similar for LidH 2.4% w/w NaCMC/GEL 1:1.6–1:2.3. Microneedle assisted permeation flux was optimum for LidH 2.4% w/w NaCMC/GEL 1:2.3 at 6.1 μg/ml/h.Conclusion
LidH 2.4% w/w LidH NaCMC/GEL 1:2.3 crossed the minimum therapeutic drug threshold with microneedle skin permeation in less than 70 min. 相似文献18.
Purpose
To apply a combinatorial chemistry approach toward the design of polymeric vectors, and to evaluate their effectiveness as siRNA delivery systems in vitro.Methods
Poly(acrylic acid) (pAA) was synthesized via RAFT polymerization with well-controlled molecular weights (M n: 3 kDa, 5 kDa, 10 kDa and 21 kDa). A polymer library was generated from the pAA precursors by conjugating two distinct moieties, agmatine (Agm) and D-(+)-galactosamine (Gal), at various ratios. Biophysical and cellular characterization was evaluated in vitro for these polymeric vectors using MDA-MB-231-luc+ cells.Results
A critical balance between Agm/Gal content and polymer molecular weight must be attained to achieve favorable transfection efficacies. From the library of 22 polymers, only a few had knockdown efficiencies commensurate with effective siRNA delivery, particularly those with polymer precursor M n of 5 kDa and 10 kDa. Highest protein knockdown of 84% was achieved by a polymer conjugate with a 5 kDa pAA backbone with a side chain composition of 55% Agm and 17% Gal.Conclusions
Effective delivery of siRNA was found to be highly dependent on the molecular structure of the polymeric vector. The combinatorial approach employed provided the tools to identify optimal structural properties leading to efficient siRNA delivery for this class of vector. 相似文献19.
Purpose
Oral bioavailability of low molecular weight heparin (LMWH) can be achieved by several advanced drug delivery approaches. Here, a new preparation method for coacervates (CAs) using non-toxic polyethylene glycol derivates was developed.Methods
LMWH were coacervated with polyaminomethacrylates (Eudragit® RL or RS) using polyethylene glycol (PEG) derivatives as non-toxic solvents. CAs were analyzed for their physicochemical properties and pharmacokinetic parameters were determined for different formulations in rabbits.Results
CAs from both polymer types using various PEGs were of irregular shape and had particle sizes of around 40 μm, encapsulation efficiencies of >90%, and complete LMWH in vitro release was obtained within 2 h. In vivo, oral Absorption at doses of 300 IU/kg was rather low (F?<?2.5%) while dose increase resulted in a maximum at 600 IU/kg (FRL: 6.0?±?1.2%; FRS: 5.8?±?2.5%) and 1,200 IU/kg did not result in higher bioavailability (FRL: 4.6?±?0.4%; FRS: 4.1?±?0.8%). CAs were applicable to various LMWH types where the oral availability decreased in the order fondaparinux>enoxaparin>nadroparin>certoparin depending mainly on the molecular weight.Conclusions
CAs prepared by an organic solvent-free method allowed the oral delivery of LMWHs. The therapeutic efficiency and the simple and solvent-free manufacturing process underlines the high potential of this new preparation method. 相似文献20.
Irene Parisini Sean J. Cheng Digby D. Symons Darragh Murnane 《Pharmaceutical research》2014,31(5):1133-1145