Assessment of Hydroxypropyl Methylcellulose, Propylene Glycol, Polysorbate 80, and Hydroxypropyl‐β‐Cyclodextrin for use in developmental and reproductive toxicology studies

Enright, Brian; McIntyre, Barry S.; Thackaberry, Evan A.; Treinen, Kimberley A.; Kopytek, Stephan J.

doi:10.1002/bdrb.20273

Cited by 18 publications

(12 citation statements)

References 25 publications

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“…14,15) In general, oral suspensions contain approximately 0.5% (w/v or w/w) of these excipients, and the dosing volumes of the suspensions range from 5 to 10 mL/ kg in toxicology studies. 27,28) Therefore, the following formulation conditions were used in the present study: cellulose polymer derivatives and Tween 80 were used as excipients for the dispersing agents; 0.5% (w/w) quantities of each excipient were used for the dispersing agents; and 100 mg/mL drug concentrations were used in the suspensions with the intention to deliver drug substances up to 1000 mg/kg. HPMC and MC were used as cellulose polymer derivatives, and three grades of HPMCs (3 cP, 50 cP, and 4000 cP) were used to vary the viscosities and molecular weights.…”

Section: Resultsmentioning

confidence: 99%

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and in Vitro/in Vivo Evaluation of Nanosized Poorly Water-Soluble Compounds

Komasaka¹,

Fujimura

Tagawa

et al. 2014

Chem. Pharm. Bull.

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The present study aimed to develop a practical method for preparing nanosuspension formulations of poorly water-soluble compounds for enhancing oral absorption in toxicology studies in the discovery stage. To obtain a suitable nanosuspension formulation for the intended purpose, formulations were optimized with a focus on the following characteristics: i) containing a high drug concentration, ii) consisting of commonly used excipient types in proper quantities for toxicology studies, iii) having long-term stability, and iv) having versatility for use with diverse compounds. Test compounds were milled with various excipients by wet media milling methods using a mixer mill (10 mg/batch) and a rotation/revolution mixer (0.5 g/batch). As a result, 100 mg/mL nanosuspensions of all 11 test compounds could be prepared with an optimized dispersing agent, 0.5% hydroxypropyl methylcellulose (HPMC) (3 cP)-0.5% Tween 80. Notably, it was found that the molecular weight of HPMC influenced not only particle size but also the stability of nanosuspensions and they were stable for 4 weeks at 5°C. The nanosuspensions increased in vitro dissolution rates and provided 3.9 and 3.0 times higher C max and 4.4 and 1.6 times higher area under the concentration-time curve from 0-24 h (AUC 0-24 h ) in rats (oral dose of 300 mg/kg) for cilostazol and danazol, respectively. In conclusion, applying a wet media milling method with the combination of HPMC of a small molecular weight and Tween 80 as a dispersing agent, nanosuspensions can be practically prepared and conveniently utilized for enhancing the oral absorption of poorly water-soluble compounds in toxicology studies in the discovery stage.Key words nanosuspension; toxicology study; wet media milling; mixer mill; rotation revolution mixer; oral absorptionThe proportion of poorly water-soluble compounds among drug candidates in the discovery stage has been increasing for the past decade.1,2) Because of the poor solubility of these compounds, sufficient oral absorption is not observed in animal studies, and the evaluation of pharmacological and toxicological profiles of drug candidates has therefore become more challenging. In particular, this problem frequently occurs in toxicology studies that require high oral absorption and is now a common problem in pharmaceutical companies.3)The application of formulation technologies such as solubilizing excipients, 4) solid dispersions, 5,6) and nanosuspensions 7,8) is an attractive strategy for improving oral absorption of poorly water-soluble compounds. However, the use of solubilizing excipients and solid dispersions for toxicology studies in the discovery stage is practically limited because of toxicities of excipients and amount of drug substances for formulation studies, respectively. On the other hand, nanosuspensions have the potential to solve these problems. Because nanosuspensions can be prepared as highly drug-loaded formulations with small quantities of excipients, adverse effects caused by excipients can be avoided. 9) In addition, n...

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Section: Resultsmentioning

confidence: 99%

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and in Vitro/in Vivo Evaluation of Nanosized Poorly Water-Soluble Compounds

Komasaka¹,

Fujimura

Tagawa

et al. 2014

Chem. Pharm. Bull.

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“…Based on the scores, the low‐ and mid‐dose groups are comparable to the control group, and the high‐dose has ninefold more teratogenic severity than the control. An interesting point to note is the low score for this control group of SD rats (i.e., 5) compared to the above‐mentioned control/vehicle studies (mean score of 11 and 27 in Cappon et al., and Enright et al., , respectively). Again these differences in control group values are likely attributed to different conducting laboratories.…”

Section: Resultsmentioning

confidence: 76%

“…The studies of Cappon et al (2003b) and Enright et al (2010) provide vehicle-treated groups of SD and New Zealand White (NZW) animals for calculation of teratogenic severity scores. The studies with SD rats by these two laboratories produced somewhat different scores (means of groups evaluated: 11 and 27, respectively).…”

Section: Sampling Of Control and Vehicle-treated Groupsmentioning

confidence: 99%

Numeric Estimates of Teratogenic Severity from Embryo–Fetal Developmental Toxicity Studies

Wise¹

2016

Birth Defects Research Pt B

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A developing organism exposed to a toxicant will have a response that ranges from none to severe (i.e., death or malformation). The response at a given dosage may be termed teratogenic (or developmental toxic) severity and is dependent on exposure conditions. Prenatal/embryo-fetal developmental (EFD) toxicity studies in rodents and rabbits are the most consistent and definitive assessments of teratogenic severity, and teratogenesis screening assays are best validated against their results. A formula is presented that estimates teratogenic severity for each group, including control, within an EFD study. The developmental components include embryonic/fetal death, malformations, variations, and mean fetal weight. The contribution of maternal toxicity is included with multiplication factors to adjust for the extent of mortality, maternal body weight change, and other parameters deemed important. The derivation of the formula to calculate teratogenic severity is described. Various EFD data sets from the literature are presented to highlight considerations to the calculation of the various components of the formula. Each score is compared to the concurrent control group to obtain a relative teratogenic severity. The limited studies presented suggest relative scores of two-to

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“…(e): Developmental toxicity parameters: numbers of implantations, pups born alive and dead pups, delivery index, sex ratio, viability index of pups before weaning, pinna unfolding, fur appearance, incisor eruption, eye opening; preputial separation, vaginal opening; reflex ontogeny; pain response, locomotor activity, conditioned avoidance response; necropsy and histopathology of cerebrum, cerebellum, medulla oblongata, pons, spinal cord in the thoracic and lumbar regions, and sciatic nerve; organ weights of brain, liver, spleen, adrenal and kidney. (e): Enright et al (2010) studied polysorbate 80 at a very low dose level of 10 mg/kg bw/day from GD 6 to 17 in rats and from GD 7 to 19 in rabbits and observed no treatment-related developmental effects.…”

Section: Developmental Toxicity Studiesmentioning

confidence: 97%

Scientific Opinion on the re‐evaluation of polyoxyethylene sorbitan monolaurate (E 432), polyoxyethylene sorbitan monooleate (E 433), polyoxyethylene sorbitan monopalmitate (E 434), polyoxyethylene sorbitan monostearate (E 435) and polyoxyethylene sorbitan tristearate (E 436) as food additives

Panel¹

2015

EFS2

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The Panel on Food Additives and Nutrient Sources added to Food (ANS) re-evaluated the safety of polysorbate 20 (E 432), polysorbate 80 (E 433), polysorbate 40 (E 434), polysorbate 60 (E 435) and polysorbate 65 (E 436) as food additives. The Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) derived an Acceptable Daily Intake (ADI) of 25 mg/kg body weight (bw)/day (group ADI for polysorbates 20, 40, 60, 65 and 80) and the Scientific Committee on Food (SCF) derived a group ADI of 10 mg/kg bw/day. Small amounts of polyoxyethylene sorbitans are absorbed. Similar toxicokinetics would be expected for all polysorbates based on their similarities in structure and metabolic fate. The acute toxicity is very low. There is no concern regarding genotoxicity, carcinogenicity or developmental toxicity. From a limited number of studies, there is no indication of reproductive toxicity. The Panel considered the long-term carcinogenicity study in rats with a No Observed Adverse Effect Level (NOAEL) equivalent to 2 500 mg/kg bw/day -consistent with the NOAEL defined in subchronic studies -as the key study and allocated a group ADI of 25 mg/kg bw/day using an uncertainty factor of 100. The estimated exposure of toddlers at the highest level in non-brand loyal scenario remains very close to the ADI (24.5 mg/kg bw/day). The Panel is aware that for three food categories no reported uses have been obtained and that other dietary sources of exposure to polysorbates could not been considered in this opinion and therefore more data (usage and analytical data) are needed to decrease uncertainties in the refined exposure assessment scenario used. 20, 40, 60, 65 and 80 (SCF, 1985). The basis was a No Observed Effect Level (NOEL) equivalent to 1 460 mg/kg bw/day in the diet in the 90-day study in rats with polyoxyethylene sorbitan monostearate (polysorbate 60) (BIBRA, 1981; cited in SCF, 1985). A higher group ADI value of 0-25 mg/kg bw/day was allocated by the Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA, 1974a, b).The Panel was not provided with a newly submitted dossier and based its evaluation on previous evaluations and reviews, additional literature that has become available since then and data available following a public call for data. The Panel noted that not all original studies on which previous evaluations were based were available for re-evaluation by the Panel. Specifications for the polysorbates have been defined in Commission Regulation (EU) No 231/2012 and by JECFA (JECFA, 2006a).The Panel considered the evaluation of polysorbates (E 432-E 436) as a group in one opinion because of their similarities in structure and metabolic fate. These additives are hydrolysed to oxyethylene sorbitans and the relevant fatty acids, the latter being normal constituents of the diet. From the toxicological data as described in this opinion, there is ...

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Assessment of Hydroxypropyl Methylcellulose, Propylene Glycol, Polysorbate 80, and Hydroxypropyl‐β‐Cyclodextrin for use in developmental and reproductive toxicology studies

Abstract: Although HPβCD was not well tolerated in rabbits at doses of 500 and 1,000 mg/kg, PS80 and PG were comparable to MC and should be considered for use in developmental and reproductive toxicology studies.

Cited by 18 publications

References 25 publications

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and <i>in Vitro</i>/<i>in Vivo</i> Evaluation of Nanosized Poorly Water-Soluble Compounds

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and <i>in Vitro</i>/<i>in Vivo</i> Evaluation of Nanosized Poorly Water-Soluble Compounds

Numeric Estimates of Teratogenic Severity from Embryo–Fetal Developmental Toxicity Studies

Scientific Opinion on the re‐evaluation of polyoxyethylene sorbitan monolaurate (E 432), polyoxyethylene sorbitan monooleate (E 433), polyoxyethylene sorbitan monopalmitate (E 434), polyoxyethylene sorbitan monostearate (E 435) and polyoxyethylene sorbitan tristearate (E 436) as food additives

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