Enabling the Intestinal Absorption of Highly Polar Antiviral Agents: Ion-Pair Facilitated Membrane Permeation of Zanamivir Heptyl Ester and Guanidino Oseltamivir

Miller, Jonathan M.; Dahan, Arik; Gupta, Divender; Varghese, Sheeba; Amidon, Gordon L.

doi:10.1021/mp100050d

Cited by 87 publications

(52 citation statements)

References 36 publications

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“…This counterion, due to its high lipophilicity, relatively strong binding constant, and a history of prior use with drugs such as salmeterol, zanamivir, and oseltamivir makes it an ideal agent to counterbalance the high polarity of several BCS Class III drugs [5,6]. Miller et al utilized HNAP as a counterion to prepare ion-paired complexes of the oral drugs with poor intestinal permeability such as zanamivir heptyl ester (ZHE) and guanidine oseltamivir (GO) [6]. The study results showed a significant (up to 3.7 log units) increase in the lipophilicity of the drugs due to ion-pairing.…”

Section: Ion-pairingmentioning

confidence: 99%

“…Over the years, our laboratories have worked with BCS Class III and similar molecules to address permeability issues; mainly by prodrug and permeation enhancer based approaches. Besides that, researchers have explored several other approaches with an aim to tackle the issue of low drug permeability without compromising critical solubility [3,4,5,6,7]. Among the more commonly studied approaches include prodrugs, permeation enhancers, ion-pairing, and other nanotechnology-based approaches.…”

Section: Introductionmentioning

confidence: 99%

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Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules

Dave

Gupta

et al. 2016

Drug Development and Industrial Pharmacy

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The Biopharmaceutics Classification System (BCS) classifies pharmaceutical compounds based on their aqueous solubility and intestinal permeability. The BCS Class III compounds are hydrophilic molecules (high aqueous solubility) with low permeability across the biological membranes. While these compounds are pharmacologically effective, poor absorption due to low permeability becomes the rate-limiting step in achieving adequate bioavailability. Several approaches have been explored and utilized for improving the permeability profiles of these compounds. The approaches include traditional methods such as prodrugs, permeation enhancers, ion-pairing, etc., as well as relatively modern approaches such as nanoencapsulation and nanosizing. The most recent approaches include a combination/hybridization of one or more traditional approaches to improve drug permeability. While some of these approaches have been extremely successful, i.e. drug products utilizing the approach have progressed through the USFDA approval for marketing; others require further investigation to be applicable. This article discusses the commonly studied approaches for improving the permeability of BCS Class III compounds. AbstractThe Biopharmaceutics Classification System (BCS) classifies pharmaceutical compounds based on their aqueous solubility and intestinal permeability. The BCS Class III compounds are hydrophilic molecules (high aqueous solubility) with low permeability across the biological membranes. While these compounds are pharmacologically effective, poor absorption due to low permeability becomes the rate-limiting step in achieving adequate bioavailability.Several approaches have been explored and utilized for improving the permeability profiles of these compounds. The approaches include traditional methods such as prodrugs, permeation enhancers, ion-pairing, etc., as well as relatively modern approaches such as nanoencapsulation and nanosizing. The most recent approaches include a combination/ hybridization of one or more traditional approaches to improve drug permeability. While some of these approaches have been extremely successful, i.e. drug products utilizing the approach have progressed through the USFDA approval for marketing; others require further investigation to be applicable. This article discusses the commonly studied approaches for improving the permeability of BCS Class III compounds.

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Section: Ion-pairingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules

Dave

Gupta

et al. 2016

Drug Development and Industrial Pharmacy

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“…Experimental octanol-buffer partition coefficients, Log D, for pseudoephedrine and metoprolol at pH 6.5, 7.0, and 7.5 were determined using the traditional shake-flask method (18,19). Briefly, solutions of pseudoephedrine or metoprolol were prepared in octanol-saturated phosphate buffers with pH values of 6.5, 7.0, and 7.5.…”

Section: Determination Of Octanol-buffer Partition Coefficientsmentioning

confidence: 99%

Regional-Dependent Intestinal Permeability and BCS Classification: Elucidation of pH-Related Complexity in Rats Using Pseudoephedrine

Fairstein

Swissa

Dahan

2013

AAPS J

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Abstract. Based on its lower Log P value relative to metoprolol, a marker for the low/high-permeability (P eff ) class boundary, pseudoephedrine was provisionally classified as BCS low-permeability compound. On the other hand, following oral administration, pseudoephedrine fraction dose absorbed (F abs ) and systemic bioavailability approaches 100%. This represents a challenge to the generally recognized P eff -F abs correlation. The purpose of this study was to elucidate the underlying mechanisms behind the confusion in pseudoephedrine's BCS classification. Pseudoephedrine's BCS solubility class was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in vitro and in vivo in rats, considering the complexity of the whole of the small intestine. Pseudoephedrine was found to be unequivocally a high-solubility compound. All of the permeability studies revealed similar phenomenon; at any given intestinal segment/pH, the permeability of metoprolol was higher than that of pseudoephedrine, however, as the intestinal region becomes progressively distal, and the pH gradually increases, pseudoephedrine's permeability rises above that of metoprolol in the former segment. This unique permeability pattern likely explains pseudoephedrine's complete absorption. In conclusion, pseudoephedrine is a BCS Class I compound; no discrepancy between P eff and F abs is involved in its absorption. Rather, it reflects the complexity behind P eff when considering the whole of the intestine. We propose to allow high-permeability classification to drugs with P eff that matches/exceeds the low/high class benchmark anywhere throughout the intestinal tract and not restricted necessarily to the jejunum.

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“…The distinction must be made between using complexation to increase aqueous solubility, which is quite common, and to increase membrane permeability. A recently reported example designed to utilize ion pairing is the enhanced intestinal membrane permeability of two poorly permeable antivirals, zanamivir heptyl ester and guanidino oseltamivir, by inclusion of 1-hydroxy-2-naphthoic acid as a counter-ion (14). Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (also referred to as SNAC) is an absorption enhancer in late-stage clinical trials.…”

Section: Mechanisms Of Absorption Enhancementmentioning

confidence: 99%

Absorption Enhancers: Applications and Advances

Aungst¹

2011

AAPS J

254

119

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Abstract. Absorption enhancers are functional excipients included in formulations to improve the absorption of a pharmacologically active drug. The term absorption enhancer usually refers to an agent whose function is to increase absorption by enhancing membrane permeation, rather than increasing solubility, so such agents are sometimes more specifically termed permeation enhancers. Absorption enhancers have been investigated for at least two decades, particularly in efforts to develop non-injection formulations for peptides, proteins, and other pharmacologically active compounds that have poor membrane permeability. While at least one product utilizing an absorption enhancer for transdermal use has reached the market, quite a few more appear to be at the threshold of becoming products, and these include oral and transmucosal applications. This paper will review some of the most advanced absorption enhancers currently in development and the formulation technologies employed that have led to their success. In addition, a more basic review of the barriers to absorption and the mechanisms by which those barriers can be surmounted is presented. Factors influencing the success of absorption-enhancing formulations are discussed. If ultimately successful, the products now in development should offer noninjection alternatives for several peptide or protein drugs currently only administered by injection. The introduction of new absorption enhancers as accepted pharmaceutical excipients, and the development of formulation technologies that afford the greatest benefit/risk ratio for their use, may create opportunities to apply these enabling technologies more broadly to existing drugs with non-optimal delivery properties.

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Enabling the Intestinal Absorption of Highly Polar Antiviral Agents: Ion-Pair Facilitated Membrane Permeation of Zanamivir Heptyl Ester and Guanidino Oseltamivir

Cited by 87 publications

References 36 publications

Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules

Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules

Regional-Dependent Intestinal Permeability and BCS Classification: Elucidation of pH-Related Complexity in Rats Using Pseudoephedrine

Absorption Enhancers: Applications and Advances

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