The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development

Butler, James; Dressman, Jennifer B.

doi:10.1002/jps.22217

Cited by 346 publications

(216 citation statements)

References 96 publications

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“…In terms of in vivo application of nanosuspensions, although oral absorption is considered to be limited by saturation solubility rather than by dissolution rate at high doses, 42) our results revealed that nanosuspensions were effective even at 300 mg/kg for both cilostazol and danazol, in accordance with previous reports that nanosuspensions improved oral absorption in high-dose in vivo studies. [43][44][45][46] The degree of enhancement of AUC 0-24 h by the use of nanosuspensions was higher for cilostazol than for danazol, although the in vitro dissolution rates were increased similarly, and the changes in crystalline properties were not significant for either compound.…”

Section: Discussionsupporting

confidence: 92%

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: Discussionsupporting

confidence: 92%

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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“…This is because in the context of protecting patients, it is more important to ensure changes to products that result in altered in vivo performance are correctly classified rather than the misclassification of those that do not. The limitation of its use as a development tool was highlighted by several authors (Butler et al, 2010;Rinaki et al 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Butler (Butler et al, 2010) presented a Develop-ability Classification System (DCS) linking regions of biopharmaceutical space to formulation strategy. He assessed compounds in regard to their difficulty in formulating to maximum oral absorption.…”

Section: Introductionmentioning

confidence: 99%

Rational formulation strategy from drug discovery profiling to human proof of concept

Ayad

2014

Drug Delivery

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The objective of this paper is to introduce some strategic guidance to a rational formulation strategy of new molecules as oral dosage forms, based on a sound scientific understanding of factors determining the oral bioavailability. The critical implication of permeability and solubility is discussed along with the efficient dose of the drug. The concept of dose-solubility number is introduced as a tool for chemists to assess the develop-ability of different molecules very early during discovery stage. Based on this understanding, a rational formulation strategy for preclinical and early clinical phases is provided. The technical considerations and limitations of different formulation technologies are discussed and illustrated via concrete examples. This approach has the advantage of streamlining the formulation process in order to avoid delaying the development of new drugs due to formulation related issues.

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“…Different decision trees have been published in the literature; some are based on resource considerations (1), whereas others focus more on linking the formulation selection to specific compound properties. In many of these later cases, the Biopharmaceutics Classification System (BCS) (2) or variations of that are used to guide formulation selection (3)(4)(5); however, more complex approaches have also been suggested (6).…”

Section: Introductionmentioning

confidence: 99%

Use of Preclinical Dog Studies and Absorption Modeling to Facilitate Late Stage Formulation Bridging for a BCS II Drug Candidate

Kesisoglou

2013

AAPS PharmSciTech

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Abstract. Formulation changes are common during drug development either due to clinical or manufacturing considerations. These changes especially at later stages of drug development oftentimes raise questions on the potential impact of a new formulation on bioavailability. In this work, the preclinical assessment of formulation bridging risk for a Biopharmaceutics Classification System II development compound is presented. Early clinical studies were conducted using a liquid-filled capsule (LFC). To assess the feasibility of a conventional solid dosage form, an initial analysis was conducted using absorption modeling which indicated conventional formulation of micronized active pharmaceutical ingredient (API) could be a viable option. Subsequently, test formulations were prepared and tested in vivo in dogs. The solid formulations were able to match exposures of the LFC capsule in the dog model; in addition, a sensitivity to API PSD was observed in line with the modeling predictions. When tested in the clinic, the conventional solid formulation resulted in exposures of approximately 25% lower compared to the LFC on an equivalent dose basis; however, bridging with a small dose adjustment would be feasible. The outcome of the clinical study was better predicted by the modeling approach while the dog model appeared to somewhat overestimate absorption. Through the use of preclinical tools and modeling and simulation, a risk assessment around formulation bridging can be conducted and inform formulation decisions or subsequent clinical study designs.

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The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development

Cited by 346 publications

References 96 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

Rational formulation strategy from drug discovery profiling to human proof of concept

Use of Preclinical Dog Studies and Absorption Modeling to Facilitate Late Stage Formulation Bridging for a BCS II Drug Candidate

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