共查询到20条相似文献,搜索用时 31 毫秒
1.
Purpose
To develop a model-based approach for interspecies scaling of the preclinical pharmacokinetics of exenatide and to predict concentration-time profiles in humans.Methods
A target-mediated drug disposition (TMDD) model was simultaneously fit to concentration-time profiles of exenatide over a wide range of intravenous (IV) and subcutaneous (SC) doses obtained from mice, rats, and monkeys. Allometric relationships were incorporated into the model to scale parameters based on species body weight. Human pharmacokinetic profiles following IV and SC administration were simulated using the final model structure and parameter estimates and compared to clinical data.Results
The final model provided a good simultaneous fit to all animal data and reasonable parameter estimates. Exenatide receptor binding affinity and baseline receptor concentrations were species-dependent. Absorption parameters from rat provided the best prediction of exenatide SC absorption in humans, but good predictions could also be obtained using allometric scaling of preclinical absorption parameters.Conclusions
A TMDD model combined with allometric scaling was successfully used to simultaneously describe preclinical data for exenatide from three animal species following both IV and SC administration. The majority of model parameters could be shared among the animal species and further used for projecting exenatide behavior in humans. 相似文献2.
Sandra Reichstetter Gerardo M. Castillo Israel Rubinstein Akiko Nishimoto-Ashfield ManShun Lai Cynthia C. Jones Aryamitra Banjeree Alex Lyubimov Duane C. Bloedow Alexei Bogdanov Jr. Elijah M. Bolotin 《Pharmaceutical research》2013,30(3):670-682
Purpose
To determine and compare pharmacokinetics and toxicity of two nanoformulations of Vasoactive Intestinal Peptide (VIP).Methods
VIP was formulated using a micellar (Sterically Stabilized Micelles, SSM) and a polymer-based (Protected Graft Copolymer, PGC) nanocarrier at various loading percentages. VIP binding to the nanocarriers, pharmacokinetics, blood pressure, blood chemistry, and acute maximum tolerated dose (MTD) of the formulations after injection into BALB/c mice were determined.Results
Both formulations significantly extend in vivo residence time compared to unformulated VIP. Formulation toxicity is dependent on loading percentage, showing major differences between the two carrier types. Both formulations increase in vivo potency of unformulated VIP and show acute MTDs at least 140 times lower than unformulated VIP, but still at least 100 times higher than the anticipated highest human dose, 1–5 μg/kg. These nanocarriers prevented a significant drop in arterial blood pressure compared to unformulated VIP.Conclusions
While both carriers enhance in vivo residence time compared to unformulated VIP and reduce the drop in blood pressure immediately after injection, PGC is the excipient of choice to extend residence time and improve the safety of potent therapeutic peptides such as VIP.Pharmacokinetics of VIP after SC injection of 100 μg/kg in BALB/c mice (n?=?5). (a) Overview of entire 72 h sampling period, (b) the first 6 h shown in detail. VIP quantitation in serum samples was by competitive ELISA. LOD: level of detection. 相似文献
3.
Filipe V Poole R Kutscher M Forier K Braeckmans K Jiskoot W 《Pharmaceutical research》2011,28(5):1112-1120
Purpose
To evaluate the potential of fluorescence single particle tracking (fSPT) for the characterization of submicron protein aggregates in human serum, plasma and formulations containing human serum albumin (HSA).Methods
A monoclonal IgG was covalently labeled with a fluorescent dye and cross-linked with glutaraldehyde. IgG aggregates and fluorescent beads of 0.1 ??m (control) were diluted in buffer, serum and plasma, and their size distributions were analyzed by fSPT and nanoparticle tracking analysis (NTA). In a separate experiment, IgG and HSA, fluorescently labeled with different dyes, were mixed and subjected to heat stress. The stressed sample was analyzed by fSPT using a dual color mode and by NTA.Results
The accuracy and precision of fSPT proved to be comparable to NTA. fSPT was able to successfully measure all the samples in buffer, serum and plasma. The average size of the cross-linked protein aggregates showed a slight increase in biological fluids. Moreover, fSPT analysis showed that a significant proportion of the aggregates formed by subjecting an IgG/HSA mixture to heat stress were composed of both proteins.Conclusion
fSPT is a powerful technique for the characterization of submicron protein aggregates in biological fluids and complex formulations. 相似文献4.
Jianqing Chen Mengmeng Wang Alison Joyce David DeFranco Mania Kavosi Xin Xu Denise M. O’Hara 《Pharmaceutical research》2014,31(10):2810-2821
Purpose
To assess the application of succinimidyl iodobenzoate (SIB) iodination method in labeling biotherapeutics to study their pharmacokinetics (PK) and biodistribution.Method
An IgG molecule (protein-01) and a 40 KDa protein (protein-02) were evaluated. Pharmacokinetics (PK) and biodistribution of the radiolabeled IgG (125I-protein-01) in mice compared parameters from SIB and Iodogen protein iodination labeling methods. In addition, PK of radiolabeled 40 KDa protein (125I-protein-02) using SIB was compared with non-labeled protein-02 analyzed by ligand binding assay (LBA).Results
Up to 72 h following a single IP injection to mice, the percentage of “free-label” determined by the soluble counts after TCA precipitation to total radioactivity in serum samples was 2.8–49.4% vs. <1.0% for 125I-protein-01 iodinated via Iodogen or SIB methods, respectively, suggesting a higher in vivo stability of 125I-protein-01 labeled via the SIB method. The serum exposure of 125I-protein-01 was two-fold higher, and correspondingly, the tissue exposure was also higher (averaging 3.6 fold at 168 h) when using SIB protein labeling method than when using the Iodogen method. In addition, following subcutaneous (SC) administration to mice, the serum exposure of 125I-protein-02 labeled via SIB method was similar to protein-02 measure by LBA.Conclusion
In this study, iodination of proteins using SIB methodology has overcome the dehalogenation problem in vivo which is inherent in Iodogen method, and PK parameters of a protein iodinated via SIB were comparable to the un-labeled protein measured by LBA. The SIB iodination method is an improved labeling approach for biotherapeutics used in studying PK and biodistribution characteristics. 相似文献5.
Nripen Chanda Ravi Shukla Ajit Zambre Swapna Mekapothula Rajesh R. Kulkarni Kavita Katti Kiran Bhattacharyya Genevieve M. Fent Stan W. Casteel Evan J. Boote John A. Viator Anandhi Upendran Raghuraman Kannan Kattesh V. Katti 《Pharmaceutical research》2011,28(2):279-291
Purpose
The purpose of the present study was to explore the utilization of cinnamon-coated gold nanoparticles (Cin-AuNPs) as CT/optical contrast-enhancement agents for detection of cancer cells.Methods
Cin-AuNPs were synthesized by a ??green?? procedure, and the detailed characterization was performed by physico-chemical analysis. Cytotoxicity and cellular uptake studies were carried out in normal human fibroblast and cancerous (PC-3 and MCF-7) cells, respectively. The efficacy of detecting cancerous cells was monitored using a photoacoustic technique. In vivo biodistribution was studied after IV injection of Cin-AuNPs in mice, and also a CT phantom model was generated.Results
Biocompatible Cin-AuNPs were synthesized with high purity. Significant uptake of these gold nanoparticles was observed in PC-3 and MCF-7 cells. Cin-AuNPs internalized in cancerous cells facilitated detectable photoacoustic signals. In vivo biodistribution in normal mice showed steady accumulation of gold nanoparticles in lungs and rapid clearance from blood. Quantitative analysis of CT values in phantom model revealed that the cinnamon-phytochemical-coated AuNPs have reasonable attenuation efficiency.Conclusions
The results indicate that these non-toxic Cin-AuNPs can serve as excellent CT/ photoacoustic contrast-enhancement agents and may provide a novel approach toward tumor detection through nanopharmaceuticals. 相似文献6.
Hyun-Hee Kwak Won-Sik Shim Seongmee Hwang Mi-Kyung Son Yoon-Ji Kim Tae-Hyoung Kim Zee-Hye Yoon Hyun-Jun Youn Ghun-Il Lee Soo-Hyoung Kang Chang-Koo Shim 《Pharmaceutical research》2009,26(11):2504-2512
Purpose
To develop an improved sustained-release (SR) formulation of exenatide (a therapy for patients with type 2 diabetes mellitus) in a biweekly dosage form with therapeutic efficacy comparable to that achieved with twice-daily injections of the drug.Methods
A SR formulation of exenatide, DA-3091, was prepared by single-emulsion solvent evaporation using poly(D,L-lactide-co-glycolide). Plasma exenatide, as well as plasma insulin, non-fasting blood glucose and HbA1c concentrations, and changes in food intake and body weight were evaluated in both Zucker diabetic fatty (ZDF) and ZDF lean control rats.Results
After a single SC administration of DA-3091 (i.e., 2 mg/kg of exenatide), the plasma exenatide concentration increased and remained elevated in both groups. The concentrations of non-fasting blood glucose and HbA1c decreased significantly following a single SC injection of DA-3091 only in ZDF rats, indicating that the effects of exenatide are dependent on blood glucose concentration. On the other hand, both food intake and body weight gain were reduced in ZDF and ZDF lean control rats. A single injection of DA-3091 (i.e., 2 mg/kg of exenatide) lowered non-fasting blood glucose and HbA1c concentrations more effectively than 14 days of twice-daily administration of exenatide (i.e., 1.96 mg/kg of exenatide).Conclusion
DA-3091 has the potential to be used safely and efficaciously in a biweekly dosing regimen. 相似文献7.
Eman Alaaeldin Amr S. Abu Lila Naoto Moriyoshi Hatem A. Sarhan Tatsuhiro Ishida Khaled A. Khaled Hiroshi Kiwada 《Pharmaceutical research》2013,30(9):2344-2354
Purpose
In vivo application of siRNA/PEGylated cationic liposome complex (lipoplex) is impeded by two main obstacles: cytokine responses and anti-PEG IgM responses to PEGylated siRNA-lipoplex. Here, we investigated whether co-administration of oxaliplatin (l-OHP) abrogates the cytokine release and anti-PEG IgM production by PEGylated siRNA-lipoplex.Methods
Free l-OHP was administered either simultaneously or 30 min prior to PEGylated siRNA-lipoplex administration, and cytokine response and anti-PEG IgM production were evaluated. In addition, the effect of the liposomal encapsulation of l-OHP on the immunogenic response of PEGylated siRNA-lipoplex was investigated.Results
Simultaneous co-administration of free l-OHP with PEGylated siRNA-lipoplex caused a significant reduction in anti-PEG IgM production, along with an increase in the cytokine response. Free l-OHP injected prior to the lipoplex injection, however, successfully reduced cytokine release and anti-PEG IgM response. Platination of siRNA by simultaneously administered free l-OHP might facilitate the dissociation of double-stranded siRNA to single-stranded siRNA, resulting in the inducement of a potent immuno-stimulation of siRNA via endosomal toll-like receptors (TLRs). On the other hand, encapsulation of l-OHP into the siRNA-lipoplex resulted in a reduction of both anti-PEG IgM production and cytokine responses.Conclusions
Our results suggest that, besides the expected therapeutic efficacy of co-administration, encapsulation of l-OHP into the PEGylated siRNA-lipoplex has great potential for minimizing the immunostimulation of PEGylated siRNA-lipoplex, resulting in a safe, applicable, and compliant treatment regimen for sequential clinical administration. 相似文献8.
Marieke Veurink Yvonne Westermaier Robert Gurny Leonardo Scapozza 《Pharmaceutical research》2013,30(4):1176-1187
Purpose
To investigate the mechanism behind the aggregation breaking properties of dexamethasone phosphate and related corticosteroids on the IgG1 antibody bevacizumab (Avastin®).Methods
An in silico 3D dimer model is developed to identify the bevacizumab-bevacizumab interface, and different corticosteroids are docked onto the model to distinguish preferred binding sites. In silico predictions are validated by in vitro stability studies, where the antibody is stressed in presence or absence of each corticosteroid and formed aggregates are quantified by asymmetrical flow field-flow fractionation.Results
The dimer model features one close crystal contact area: Lys445 on the Fc region interacts with one Fab arm of the second bevacizumab. Docking reveals an interaction between the phosphate group of dexamethasone phosphate and Lys445, while the rest of the molecule is hindering dimer formation. Predictions are confirmed in vitro, demonstrating that dexamethasone phosphate and betamethasone phosphate partly prevent antibody aggregation, whereas triamcinolone acetonide phosphate does not.Conclusions
Results suggest that bevacizumab monomers follow a specific mechanism to form dimers in which a protein-protein interaction hotspot can be distinguished. The dimer formation can be hindered by corticosteroids in a specific way. This approach allows a simple way to stabilize IgG1 antibodies. 相似文献9.
Purpose
To use noninvasive fluorescence imaging to investigate the influence of molecular weight (MW) of proteins on the rate of loss from a subcutaneous (SC) injection site and subsequent uptake by the draining lymph nodes in mice.Methods
Bevacizumab (149?kDa), bovine serum albumin (BSA, 66?kDa), ovalbumin (44.3?kDa) or VEGF-C156S (23?kDa), labeled with the near infrared dye IRDye 680, were injected SC into the front footpad of SKH-1 mice. Whole body non-invasive fluorescence imaging was performed to quantitate the fluorescence signal at the injection site and in axillary lymph nodes.Results
The half-life values, describing the times for 50% loss of proteins from the injection site, were 6.81?h for bevacizumab, 2.85?h for BSA, 1.57?h for ovalbumin and 0.31?h for VEGF-C156S. The corresponding axillary lymph node exposure, represented as the area of the % dose versus time curve, was 6.27, 5.13, 4.06 and 1.54% dose ? h, respectively.Conclusions
Our results indicate that the rate of loss of proteins from a SC injection site is inversely related to MW of proteins, while lymph node exposure is proportionally related to the MW of proteins in a mouse model. 相似文献10.
Purpose
To investigate in vitro the innate immune response to accelerated stress-induced aggregates of intravenous immunoglobulin (IGIV) using a well-defined human cell-line model, and to correlate the innate response to physical properties of the aggregates.Methods
IGIV aggregates were prepared by applying various accelerated stress methods, and particle size, count and structure were characterized. Immune cell activation as tracked by inflammatory cytokines released in response to aggregates was evaluated in vitro using peripheral blood mononuclear cells (PBMC), primary monocytes and immortalized human monocyte-like cell lines.Results
IGIV aggregates produced by mechanical stress induced higher cytokine release by PBMC and primary monocytes than aggregates formed by other stresses. Results with the monocytic cell line THP-1 paralleled trends in PBMC and primary monocytes. Effects were dose-dependent, enhanced by complement opsonization, and partially inhibited by blocking toll-like receptors (TLR2 and TLR4) and to a lesser extent by blocking Fc gamma receptors (FcγRs).Conclusions
Stress-induced IGIV aggregates stimulate a dose-dependent cytokine response in human monocytes and THP-1 cells, mediated in part by TLRs, FcγRs and complement opsonization. THP-1 cells resemble primary monocytes in many respects with regard to tracking the innate response to IgG aggregates. Accordingly, the measurement of inflammatory cytokines released by THP-1 cells provides a readily accessible assay system to screen for the potential innate immunogenicity of IgG aggregates. The results also highlight the role of aggregate structure in interacting with the different receptors mediating innate immunity.11.
Tuan Hiep Tran Thiruganesh Ramasamy Duy Hieu Truong Beom Soo Shin Han-Gon Choi Chul Soon Yong Jong Oh Kim 《Pharmaceutical research》2014,31(8):1978-1988
Purpose
To investigate whether delivery of a histone deacetylase inhibitor, vorinostat (VOR), by using solid lipid nanoparticles (SLNs) enhanced its bioavailability and effects on multidrug-resistant cancer cells.Methods
VOR-loaded SLNs (VOR-SLNs) were prepared by hot homogenization using an emulsification-sonication technique, and the formulation parameters were optimized. The cytotoxicity of the optimized formulation was evaluated in cancer cell lines (MCF-7, A549, and MDA-MB-231), and pharmacokinetic parameters were examined following oral and intravenous (IV) administration to rats.Results
VOR-SLNs were spherical, with a narrowly distributed average size of ~100 nm, and were physically stable for 3 months. Drug release showed a typical bi-phasic pattern in vitro, and was independent of pH. VOR-SLNs were more cytotoxic than the free drug in both sensitive (MCF-7 and A549) and resistant (MDA-MB-231) cancer cells. Importantly, SLN formulations showed prominent cytotoxicity in MDA-MB-231 cells at low doses, suggesting an ability to effectively counter the P-glycoprotein-related drug efflux pumps. Pharmacokinetic studies clearly demonstrated that VOR-SLNs markedly improved VOR plasma circulation time and decreased its elimination rate constant. The areas under the VOR concentration-time curve produced by oral and IV administration of VOR-SLNs were significantly greater than those produced by free drug administration. These in vivo results clearly highlighted the remarkable potential of SLNs to augment the bioavailability of VOR.Conclusions
VOR-SLNs successfully enhanced the oral bioavailability, circulation half-life, and chemotherapeutic potential of VOR. 相似文献12.
Stefan Dengl Marc Wehmer Friederike Hesse Florian Lipsmeier Oliver Popp Kurt Lang 《Pharmaceutical research》2013,30(5):1380-1399
Purpose
To investigate antibody stability and formation of modified species under upstream processing conditions.Methods
The stability of 11 purified monoclonal human IgG1 and IgG4 antibodies, including an IgG1-based bispecific CrossMab, was compared in downscale mixing stress models. One of these molecules was further evaluated in realistic bioreactor stress models and in cell culture fermentations. Analytical techniques include size exclusion chromatography (SEC), turbidity measurements, cation exchange chromatography (cIEX), dynamic light scattering (DLS) and differential scanning calorimetry (DSC).Results
Sensitivity in downscale stress models varies among antibodies and results in formation of high molecular weight (HMW) aggregates. Stability is increased in cell culture medium and in bioreactors. Media components stabilizing the proteins were identified. Extensive chemical modifications were detected both in stress models as well as during production of antibodies in cell culture fermentations.Conclusions
Protective compounds must be present in chemically defined fermentation media in order to stabilize antibodies against the formation of HMW aggregates. An increase in chemical modifications is detectable in bioreactor stress models and over the course of cell culture fermentations; this increase is dependent on the expression rate, pH, temperature and fermentation time. Consequently, product heterogeneity increases during upstream processing, and this compromises the product quality. 相似文献13.
Purpose
Poor stability and inefficient absorption in the intestinal tract are major barriers confronting oral delivery of siRNA. We aimed to uncover if ternary polymeric nanoparticles (cationic polymer/siRNA/anionic component) can overcome these obstacles through changing the formulation-related parameters.Methods
Ternary polymeric nanoparticles were prepared by ionic gelation of chitosan, N-trimethyl chitosan (TMC), or thiolated trimethyl chitosan (TTMC) with tripolyphosphate (TPP) or hyaluronic acid (HA), and siRNA was simultaneously encapsulated. Structural stabilities and siRNA protection of these nanoparticles were assessed in simulated intestinal milieu. Their transport across ex vivo rat ileum, macrophage uptake, in vitro gene silencing, and in vivo biodistribution after oral administration were investigated.Results
Ternary polymeric nanoparticles formed by TTMC, siRNA, and TPP (TTMC/siRNA/TPP nanoparticles) showed suitable structural stability and siRNA protection in the intestinal tract, good permeability across ex vivo rat ileum, superior cellular uptake and gene silencing efficiency in Raw 264.7 cells, and high systemic biodistribution after oral administration.Conclusions
TTMC/siRNA/TPP nanoparticles demonstrated efficient gene silencing in vitro and systemic biodistribution in vivo, therefore, they were expected to be potential vehicles for oral siRNA delivery. 相似文献14.
Maillet A Congy-Jolivet N Le Guellec S Vecellio L Hamard S Courty Y Courtois A Gauthier F Diot P Thibault G Lemarié E Heuzé-Vourc'h N 《Pharmaceutical research》2008,25(6):1318-1326
Purpose
Despite an increasing interest in the use of inhalation for local delivery of molecules for respiratory diseases and systemic disorders, methods to deliver therapy through airways has received little attention for lung cancer treatment. However, inhalation of anticancer drugs is an attractive alternative route to systemic administration which results in limited concentration of the medication in the lungs, and triggers whole-body toxicity. In this study, we investigated the feasibility of nebulization for therapeutic antibodies, a new class of fully-approved anticancer drugs in oncology medicine.Materials and methods
Cetuximab, a chimeric IgG1 targeting the epidermal growth factor receptor (EGFR), was nebulized using three types of delivery devices: a jet nebulizer PARI LC+®, a mesh nebulizer AeronebPro® and an ultrasonic nebulizer SYST’AM® LS290. Aerosol size distribution was measured using a cascade impactor and aerosol droplets were observed under optical microscopy. The immunological and pharmacological properties of cetuximab were evaluated following nebulization using A431 cells.Results
The aerosol particle clouds generated with the three nebulizers displayed similar aerodynamical characteristics, but the IgG formed aggregates in liquid phase following nebulization with both the jet and ultrasonic devices. Flow cytometry analyses and assays of EGFR-phosphorylation and cell growth inhibitions on A431 demonstrated that both the mesh and the jet nebulizers preserved the binding affinity to EGFR and the inhibitory activities of cetuximab.Conclusions
Altogether, our results indicate that cetuximab resists the physical constraints of nebulization. Thus, airway delivery represents a promising alternative to systemic administration for local delivery of therapeutic antibodies in lung cancer treatment. 相似文献15.
Purpose
To investigate the vaccine effect of a replication-defective recombinant adenovirus 5 (rAd5)-based nanocomplex with chitooligosaccharides (Oligo) and mannosylated polyethyleneimine-triethyleneglycol (mPEI) as adjuvants for human immunodeficiency virus (HIV) infection.Methods
Physical characteristics were determined through detecting the size, zeta potential and morphology of Oligo-mPEI-rAd5 nanocomplex, and in vitro vaccine uptake and transduction efficiency were estimated. Nanocomplexes were then administered intranasally to Balb/c mice to evaluate in vivo rAd5 residence in nasal cavity and HIVgag-specific immune responses using cytotoxic T lymphocyte (CTL), intracellular cytokine staining (ICS) and ELISA assay.Results
The mucoadhesivity of Oligo prolonged nasal residence time, while the dendritic cell (DC) specificity of mPEI improved vaccine uptake. These two adjuvants jointly enhanced transduction efficiency of rAd5. Oligo-mPEI-rAd5 nanocomplex elicited potent HIVgag-specific CTL response and increased IFN-γ positive CD8+T and IL-4 positive CD4+T cells, indicating high cellular immune responses. This vaccine candidate also led to strong humoral immune responses (IgG/IgG1/IgG2a) with balanced Th1/Th2 CD4+T cell activity. Moreover, mice nasally immunized with Oligo-mPEI-rAd5 showed higher levels of SIgA in nasal washes than did mice immunized with rAd5.Conclusions
Intranasal delivery of Oligo-mPEI-rAd5 with a prime-boost regimen is a potential immunization for HIV infection, inducing HIVgag-specific cellular, humoral and mucosal immune responses. 相似文献16.
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17.
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18.
Mary Pat Knadler Tri-Hung Nguyen Kristina Campanale Michael J. De Veer John M. Beals Shun Li Ryan Hansen Angela Siesky M. Dodson Michael Christopher J. H. Porter 《Pharmaceutical research》2016,33(12):2920-2929
Purpose
Determine the pharmacokinetics of insulin peglispro (BIL) in 5/6-nephrectomized rats and study the absorption in lymph duct cannulated (LDC) sheep.Methods
BIL is insulin lispro modified with 20-kDa linear PEG at lysine B28 increasing the hydrodynamic size to 4-fold larger than insulin lispro. Pharmacokinetics of BIL and insulin lispro after IV administration were compared in 5/6-nephrectomized and sham rats. BIL was administered IV or SC into the interdigital space of the hind leg, and peripheral lymph and/or serum samples were collected from both LDC and non-LDC sheep to determine pharmacokinetics and absorption route of BIL.Results
The clearance of BIL was similar in 5/6-nephrectomized and sham rats, while the clearance of insulin lispro was 3.3-fold slower in 5/6-nephrectomized rats than in the sham rats. In non-LDC sheep, the terminal half-life after SC was about twice as long vs IV suggesting flip-flop pharmacokinetics. In LDC sheep, bioavailability decreased to <2%; most of the dose was absorbed via the lymphatic system, with 88%?±?19% of the dose collected in the lymph after SC administration.Conclusion
This work demonstrates that increasing the hydrodynamic size of insulin lispro through PEGylation can impact both absorption and clearance to prolong drug action.19.
《Current medical research and opinion》2013,29(2):279-288
Abstract
Objective:
To compare pharmacokinetics and safety of recombinant human hyaluronidase (rHuPH20)-facilitated subcutaneous (SC) ceftriaxone administration versus SC ceftriaxone preceded by SC saline placebo or intravenous (IV) ceftriaxone administration. 相似文献20.
Leonid Kagan Pavel Gershkovich Kishor M. Wasan Donald E. Mager 《Pharmaceutical research》2014,31(1):35-45