Abstract：
:Antibody therapeutics with poor solubility in the subcutaneous matrix may carry unintended risks when administered to patients. The objective of this work was to estimate the risk of antibodies that precipitate in vitro at neutral pH by determining the impact of poor solubility on distribution of the drug from the injection site as well as immunogenicity in vivo. Using fluorescence imaging in a mouse model, we show that one such precipitation-prone antibody is retained at the injection site in the subcutaneous space longer than a control antibody. In addition, we demonstrate that retention at the injection site through aggregation is concentration-dependent and leads to macrophage association and germinal center localization. Although there was delayed disposition of the aggregated antibody to draining lymph nodes, no overall impact on the immune response in lymph nodes, systemic exposure of the antibody, or enhancement of the anti-drug antibody response was evident. Unexpectedly, retention of the precipitated antibody in the subcutaneous space delayed the onset of the immune response and led to an immune suppressive response. Thus, we conclude that precipitation due to poor solubility of high doses of antibody formulations delivered subcutaneously may not be of special concern in terms of exposure or immunogenicity.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Kinderman F,Yerby B,Jawa V,Joubert MK,Joh NH,Malella J,Herskovitz J,Xie J,Ferbas J,McBride HJdoi
10.1016/j.xphs.2019.01.015subject
Has Abstractpub_date
2019-06-01 00:00:00pages
1953-1963issue
6eissn
0022-3549issn
1520-6017pii
S0022-3549(19)30031-0journal_volume
108pub_type
杂志文章abstract：:It is now becoming apparent that a common pathway of protein aggregation involves the unimolecular structural rearrangement from the native state to a slightly expanded aggregation-competent species. It is the goal of this study to understand the aggregation and the effects of buffer on the stability of IFN-tau. In th...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.20471
更新日期：2006-06-01 00:00:00
abstract：:The use of second generation cationic liposomes to deliver cytotoxic drugs to solid tumors is a rational and promising therapeutic approach, given the natural affinity of cationic carrier molecules for the tumor microvasculature. Cationic liposomal therapeutics are effective in the treatment of cancers that are resist...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章,评审
doi：10.1002/jps.21458
更新日期：2009-02-01 00:00:00
abstract：:beta-Cyclodextrin was ethylated at the 2- and 6-hydroxyl positions. Diethyl sulfate was employed as an alkylating reagent. NMR spectra data indicate that heptakis(2,6-di-O-ethyl)-beta-cyclodextrin (DCD) is the principal component of the product obtained. In addition, the FAB mass spectra obtained in nitrobenzyl alcoho...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600840819
更新日期：1995-08-01 00:00:00
abstract：:Spectrophotometric assay for cycloserine based on the interaction of the drug with 9-methoxyacridine as a chromogenic agent is described. The highly colored substituted acridine product was identified as 9-(d-4-imino-3-isoxazolidinone)acridine. Color development was affected by time and temperature of heating and by t...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600770519
更新日期：1988-05-01 00:00:00
abstract：:The relationship between the lone tryptophan residue at position 214 and drug binding sites (Sites I and II) in human serum albumin (HSA) was studied by fluorescence energy transfer. The distance between the lone tryptophan residue and ligands bound to HSA was estimated by Förster's equation, taking into consideration...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600760510
更新日期：1987-05-01 00:00:00
abstract：:Systematic structural modifications were performed on the natural sesquiterpene lactone tenulin to define those groupings essential to, or significant in, its in vivo antitumor activity. Accordingly, the following tenulin analogs were prepared: dihydrotenulin, 2,3-epoxytenulin, isotenulin, dihydroisotenulin, 2,3-epoxy...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600680616
更新日期：1979-06-01 00:00:00
abstract：:In vitro iontophoretic administration of drugs through a microporous polyolefin membrane with hydrophilic urethane polymerfilled pores was done for the ionized drugs dexamethasone sodium phosphate, hydrocortisone sodium phosphate, and prednisolone sodium succinate, and for a nonionizable drug cortisone acetate. Curren...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600780308
更新日期：1989-03-01 00:00:00
abstract：:The purpose of this study was to examine the role of multidrug resistance-associated protein-1 and -2 (Mrp1 and Mrp2) in the efflux transport of organic anions across the blood-cerebrospinal fluid (CSF) barrier. The CSF concentration of estradiol-17beta-glucuronide (E(2)17betaG) and 2,4-dinitrophenyl-S-glutathione (DN...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.10521
更新日期：2004-01-01 00:00:00
abstract：:The effects of aspirin on 14C-pirprofen disposition in the rat were studied. An oral 60-mg/kg dose of aspirin significantly reduced plasma radioactivity during the 1--8-hr interval after an intravenous 5-mg/kg injection of 14C-pirprofen. The aspirin-treated group had only 69% as much area under the radioactivity curve...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600680820
更新日期：1979-08-01 00:00:00
abstract：:Aggregation of therapeutic monoclonal antibodies has a potential risk of immunogenicity, requiring minimization of aggregate formation. We have developed a fitting formula for antibody aggregation at 40°C based on physicochemical parameters, including colloidal and conformational stabilities. An IgG1 monoclonal antibo...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1016/j.xphs.2019.10.038
更新日期：2020-01-01 00:00:00
abstract：:Spray freeze-drying is an evolving technology that combines the benefits of spray-drying and conventional lyophilization techniques to produce drug substance and drug product as free-flowing powders. The high surface-to-volume ratio associated to the submillimeter spray-frozen particles contributes to shorter drying a...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1016/j.xphs.2019.01.011
更新日期：2019-06-01 00:00:00
abstract：:An F(ab')2 fragment of an IgG has been spray-dried on a bench-top machine to examine the presence of insoluble particulates in the redissolved powder product. Preliminary experiments showed that treatment of the F(ab')2 in aqueous solution in a water bath at 65°C for 1 h produced fragmentation and also insoluble parti...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.23891
更新日期：2014-04-01 00:00:00
abstract：:Using quantitative structure-retention relationships (QSRR) methodologies the Kovats gas chromatographic retention indices for both apolar (DB-1) and polar (DB-Wax) columns for 48 compounds from Ylang-Ylang essential oil were empirically predicted from calculated and experimental data on molecular structure. Topologic...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1021/js960196u
更新日期：1997-05-01 00:00:00
abstract：:A sensitive high-performance liquid chromatographic (HPLC) assay for N-acetylcysteine in human plasma and urine has been developed. The method employs a prechromatographic stage to produce the dinitrophenyl derivative of N-acetylcysteine, which is chromatographed on a 5-microns C18 bonded reverse-phase column using an...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600730736
更新日期：1984-07-01 00:00:00
abstract：:The disposition of the beta-blocking drug talinolol is controlled by P-glycoprotein in man. Because talinolol is marketed as a racemate, we reevaluated the serum-concentration time profiles of talinolol of a previously published study with single intravenous (30 mg) and repeated oral talinolol (100 mg for 14 days) bef...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.10054
更新日期：2002-02-01 00:00:00
abstract：:Low-density lipoproteins (LDLs), the physiological vehicles for lipids, are potentially useful drug delivery devices for (hydrophobic) drugs. The physicochemical characteristics of LDL loaded with the adriamycin derivative AD 32 or the N-mustard derivative WB 4291 were compared to that of native and reconstituted LDL ...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600840204
更新日期：1995-02-01 00:00:00
abstract：:Dolasetron mesilate (Anzemet) ((2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-1 H-indole-3-carboxylate monomethane-sulfonate) is a 5-HT3 receptor antagonist, which is in development for the treatment of chemotherapy-induced emesis. The ketone moiety of dolasetron is rapidly reduced...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1021/js960041m
更新日期：1996-07-01 00:00:00
abstract：:The effect of caffeine on the absorption of ergotamine from the rat small intestine was studied. The results of a series of experiments showed that caffeine significantly enhanced absorption of ergotamine from solutions of pH 5.0 when both substances were in solution and when an intact blood supply was either absent (...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600700619
更新日期：1981-06-01 00:00:00
abstract：:Many pathophysiological circumstances vary during 24 h periods. Many physiologic processes undergo biological rhythms, including the sleep-wake rhythm and metabolism. Disruptive effect in the 24 h variations can manifest as the emergence or exacerbation of pathological conditions. So, chronotherapeutics is gaining inc...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章,评审
doi：10.1002/jps.22656
更新日期：2011-09-01 00:00:00
abstract：:Thirty-four vasodilators were screened in several in vitro biochemical assays related to smooth muscle excitation-contraction coupling, binding to beta 1-,beta 2-, and alpha-adrenergic receptors, inhibition of phosphodiesterase activity, and antagonism of calcium accumulation. Isoproterenol and perhexiline only exhibi...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600710123
更新日期：1982-01-01 00:00:00
abstract：:Daunorubicin (DAUN) and doxorubicin (DOX) are used to treat a variety of cancers. The use of DAUN and DOX is hampered by the development of cardiotoxicity. Clinical evidence suggests that patients with leukemia and Down syndrome are at increased risk for anthracycline-related cardiotoxicity. Carbonyl reductases and al...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1016/j.xphs.2016.03.013
更新日期：2016-06-01 00:00:00
abstract：:In this study a 3D printed capsule designed to break from the physiological pressures in the antropyloric region was evaluated for its ability to deliver the synthetic octapeptide octreotide in beagle dogs when co-formulated with the permeation enhancer sodium caprate. The pressure sensitive capsules were compared to ...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1016/j.xphs.2020.10.066
更新日期：2021-01-01 00:00:00
abstract：:Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and solid-state NMR (SSNMR) techniques are used to analyze the structures of two nonsolvated polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid. These polymorphs are enantiotropically-related with a...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.21336
更新日期：2008-11-01 00:00:00
abstract：:We report a semiquantitative method for determining trace amounts (<1%) of thermodynamically stable forms in polymorphic mixtures, focusing on sample preparation effects on solid phase transitions. Tegafur [5-fluoro-1-(oxolan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione] was used as a model material in this study. The...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.23323
更新日期：2012-12-01 00:00:00
abstract：:The purpose of this study was to examine the external predictability of an in vitro-in vivo correlation (IVIVC) for a metoprolol hydrophilic matrix extended-release formulation, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. In addition, this report evaluat...
journal_title：Journal of pharmaceutical sciences
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1002/1520-6017(200010)89:10<1354::aid-jps13>3.0
更新日期：2000-10-01 00:00:00
abstract：:Determining the aggregation propensity of protein-based biotherapeutics is an important step in the drug development process. Typically, a great deal of data collected over a large period of time is needed to estimate the aggregation propensity of biotherapeutics. Thus, candidates cannot be screened early on for aggre...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.22758
更新日期：2012-01-01 00:00:00
abstract：:Single-dose oral administration of a commercial polychlorinated biphenyl product containing 54% chlorine provided data with which to plot the time course of total polychlorinated biphenyl and individual components in the blood of swine and sheep. Pharmacokinetic parameters describing absorption from the gut and elimin...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600640807
更新日期：1975-08-01 00:00:00
abstract：:The ratio between ocular and systemic drug concentrations describes the relative safety of ophthalmic dosage forms of the same drug in terms of its systemic side effects. In this study, we evaluated the effects of epinephrine pretreatment and solution pH on the aqueous humor:plasma and iris-ciliary body:plasma ratios ...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600790808
更新日期：1990-08-01 00:00:00
abstract：:Water evaporation rates were measured from thin samples of a model layered structure of stratum corneum lipids with 32% water. A model with only free fatty acids present gave the lowest evaporation rates, while a model with only oleic acid gave values approximately 50% higher. Using the total lipid spectrum of stratum...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600780808
更新日期：1989-08-01 00:00:00
abstract：:The synthesis, local anesthetic and antiarrhythmic properties, and CNS toxicity of 14 2-(3-alkylaminoalkylamido)-pyrroles are described. Most of the compounds exhibited local anesthetic activity by the guinea pig wheal test, with seven showing comparable or greater activity than lidocaine. Most compounds also exhibite...
journal_title：Journal of pharmaceutical sciences
pub_type： 杂志文章
doi：10.1002/jps.2600700519
更新日期：1981-05-01 00:00:00
