Toxicological Studies of Hydroxypropylmethylcellulose Acetate Succinate : Acute Toxicity in Rats and Rabbits, and Subchronic and Chronic Toxicities in Rats

Hoshi, Noboru; Yano, Hiroko; Hirashima, Kaoru; Kitagawa, Haruo; Fukuda, Yoshihiro

doi:10.2131/jts.10.supplementii_147

Cited by 11 publications

(5 citation statements)

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“…Previous studies also show that they are extensively used in the drug delivery field without toxic effects after acute and chronic administrations. 8 , 13 , 23 , 24 …”

Section: Introductionmentioning

confidence: 99%

“…Previous studies also show that they are extensively used in the drug delivery field without toxic effects after acute and chronic administrations. 8,13,23,24 Pursuing these promising results, in the present work the developed system was orally delivered to T2DM rat model, induced by the combination of streptozotocin (STZ) and nicotinamide drugs. Blood glucose, plasmatic insulin levels, and insulin pancreatic content were quantified over time during this study.…”

Section: Introductionmentioning

confidence: 99%

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In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

et al. 2016

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“…Previous studies also show that they are extensively used in the drug delivery field without toxic effects after acute and chronic administrations. 8 , 13 , 23 , 24 …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

et al. 2016

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“…Additionally, Hoshi et al ( 1985a ) previously evaluated the toxicological effects of HPMC-AS on organ function and the material was found generally without effect although the studies did not include an Irwin, cardiovascular, or GI transit assessment in rats. And, while a separate study from the same authors indicate that behavior was not affected in rats after administration at 2.5 g/kg, it is unclear what behavioral endpoints were measured in the study beyond mortality (Hoshi et al, 1985b ) and thus comparison to results of the present study is not possible.…”

Section: Resultsmentioning

confidence: 57%

Physical Properties and Effect in a Battery of Safety Pharmacology Models for Three Structurally Distinct Enteric Polymers Employed as Spray-Dried Dispersion Carriers

et al. 2016

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Establishing a wide therapeutic index (TI) for pre-clinical safety is important during lead optimization (LO) in research, prior to clinical development, although is often limited by a molecules physiochemical characteristics. Recent advances in the application of the innovative vibrating mesh spray-drying technology to prepare amorphous solid dispersions may offer an opportunity to achieve high plasma concentrations of poorly soluble NCEs to enable testing and establishment of a wide TI in safety pharmacology studies. While some of the amorphous solid dispersion carriers are generally recognized as safe for clinical use, whether they are sufficiently benign to enable in vivo pharmacology studies has not been sufficiently demonstrated. Thus, the physical properties, and effect in a battery of in vivo safety pharmacology models, were assessed in three classes of polymers employed as spray-dried dispersion carriers. The polymers (HPMC-AS, Eudragit, PVAP) displayed low affinity with acetone/methanol, suitable for solvent-based spray drying. The water sorption of the polymers was moderate, and the degree of hysteresis of HPMC-AS was smaller than Eudragit and PVAP indicating the intermolecular interaction of water-cellulose molecules is weaker than water-acrylate or water-polyvinyl molecules. The polymer particles were well-suspended without aggregation with a mean particle size less than 3 μm in an aqueous vehicle. When tested in conscious Wistar Han rats in safety pharmacology models (n = 6–8/dose/polymer) investigating effects on CNS, gastrointestinal, and cardiovascular function, no liabilities were identified at any dose tested (30–300 mg/kg PO, suspension). In brief, the polymers had no effect in a modified Irwin test that included observational and evoked endpoints related to stereotypies, excitation, sedation, pain/anesthesia, autonomic balance, reflexes, and others. No effect of the polymers on gastric emptying or intestinal transit was observed when measured using a barium sulfate tracer material. Finally, in telemetry-instrumented rats the polymers had no effect on acute or 24-h mean blood pressure and heart rate values at doses up to 300 mg/kg. Thus, the properties of the three enteric polymers are appropriate as spray-dried dispersion carriers and were benign in a battery of safety pharmacology studies, demonstrating their applicability to enable in vivo safety pharmacology profiling of poorly soluble molecules during LO.

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“…33,43 HPMC-AS has been used as a pharmaceutical excipient and has a median lethal dose (LD 50 ) higher than 2.5 g kg -1 , which is much higher than the amounts used in our particle formulation. 44 Moreover, the organic solvent used to dissolve the polymer, ethyl acetate (EA), is considered a rather non-toxic organic solvent, 45 and it is believed that no residues of the solvent would be present in the final formulation. In fact, due to its high solubility in water, EA presented a fast 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 diffusion rate to this solvent which allowed the fast solidification of the particles in the collecting solution, after their formation in the microfluidics device.…”

Section: Resultsmentioning

confidence: 99%

“…HPMC-AS has been used as a pharmaceutical excipient and has a median lethal dose (LD 50 ) higher than 2.5 g kg –1 , which is much higher than the amounts used in our particle formulation . Moreover, the organic solvent used to dissolve the polymer, ethyl acetate (EA), is considered a rather nontoxic organic solvent, and it is believed that no residues of the solvent would be present in the final formulation.…”

Section: Resultsmentioning

confidence: 99%

Microfluidic Assembly of a Multifunctional Tailorable Composite System Designed for Site Specific Combined Oral Delivery of Peptide Drugs

et al. 2015

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Multifunctional tailorable composite systems, specifically designed for oral dual-delivery of a peptide (glucagon-like peptide-1) and an enzymatic inhibitor (dipeptidyl peptidase 4 (DPP4)), were assembled through the microfluidics technique. Both drugs were coloaded into these systems for a synergistic therapeutic effect. The systems were composed of chitosan and cell-penetrating peptide modified poly(lactide-co-glycolide) and porous silicon nanoparticles as nanomatrices, further encapsulated in an enteric hydroxypropylmethylcellulose acetylsuccinate polymer. The developed multifunctional systems were pH-sensitive, inherited by the enteric polymer, enabling the release of the nanoparticles only in the simulated intestinal conditions. Moreover, the encapsulation into this polymer prevented the degradation of the nanoparticles' modifications. These nanoparticles showed strong and higher interactions with the intestinal cells in comparison with the nonmodified ones. The presence of DPP4 inhibitor enhanced the peptide permeability across intestinal cell monolayers. Overall, this is a promising platform for simultaneously delivering two drugs from a single formulation. Through this approach peptides are expected to increase their bioavailability and efficiency in vivo both by their specific release at the intestinal level and also by the reduced enzymatic activity. The use of this platform, specifically in combination of the two antidiabetic drugs, has clinical potential for the therapy of type 2 diabetes mellitus.

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Toxicological Studies of Hydroxypropylmethylcellulose Acetate Succinate : Acute Toxicity in Rats and Rabbits, and Subchronic and Chronic Toxicities in Rats

Cited by 11 publications

References 0 publications

In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

Physical Properties and Effect in a Battery of Safety Pharmacology Models for Three Structurally Distinct Enteric Polymers Employed as Spray-Dried Dispersion Carriers

Microfluidic Assembly of a Multifunctional Tailorable Composite System Designed for Site Specific Combined Oral Delivery of Peptide Drugs

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