Hydroxy propyl Cyclodextrins: Potential Synergism with Carcinogens

doi:10.1021/js9501324

Journal of Pharmaceutical Sciences

Volume 85, Issue 1, January 1996, Pages 96-100

https://doi.org/10.1021/js9501324 Get rights and content

Abstract

The solubility of the lipophilic carcinogens benzo[a]pyrene and aflatoxin Bi in water increases linearly and substantially with the concentration of hydroxypropyl β-cyclodextrin present. Results of a kinetic study of naphthalene, a model for more potent carcinogens, indicate that the increase in the dissolution rate and in the transport through the aqueous phase into a nonpolar phase is on the same order of magnitude as the increase in solubility. Consequently, hydroxypropyl β-cyclodextrin, when used in pharmaceutical formulations, has the potential to increase the absorption of carcinogens which enter the gastrointestinal tract either as food components or from air pollution through saliva. Only the above mechanism's simple proportionality needs be considered for estimating the increases in carcinogen absorption in the upper gastrointestinal tract and in the colon. In the presence of bile, however, additional factors are involved and the proportionality does not apply. Bile micelles, which themselves are effective solubilizers of lipophilic carcinogens, were disrupted by hydroxypropyl β-cyclodextrin because of the formation of complexes with bile salts. Thus, in the presence of bile, two systems for delivery of carcinogens may coexist: that of cotransport with lipids and that of delivery through solubilization by hydroxypropyl β-cyclodextrin.

References and Notes (17)

M.L. Vazquez et al.
Anal. Chim. Acta
(1992)
S. Janz et al.
Toxicology
(1991)
J.S. Patton et al.
Lipid Res
(1984)
J. Pitha et al.
Pharm. Sci
(1986)
B.N. Ames et al.
Proc. Natl. Acad. Sci. U.S.A
(1990)
C.S. Reddy et al.
N.B. Ellot et al.
Colloid Interface Sci
(1993)

There are more references available in the full text version of this article.

Cited by (13)

Does the Digestibility of Cyclodextrins Influence the In Vivo Absorption of Benzo[a]pyrene in Rats?
2016, Journal of Pharmaceutical Sciences
Citation Excerpt :
The release mechanism of a compound from a cyclodextrin complex upon oral administration has been suggested to be a combination of dilution, which must be assumed to be constant across groups, and competitive displacement by bile salts present within the intestinal tract,20,21 that is, differences in stability constants between cyclodextrins of both compound and bile salts may in theory influence the release and thereby the absorption. To the best of our knowledge, the stability constant between β-cyclodextrin and benzo[a]pyrene has not been determined, but the apparent stability constants measured by phase solubility studies has been reported for 2-HP-β-cyclodextrin to be 5344 M−1 and 25,900 M−1,22,23 the later value measured in the presence of 15 mM sodium taurocholate, that is, with competitive interaction. For γ-cyclodextrin, we have found an apparent stability constant of 37,050 M−1 at 37°C in a phase solubility study (data not shown); the relative affinity of benzo[a]pyrene toward the 2 different classes of cyclodextrins was in the same range.
An important excipient used to overcome poor solubility is cyclodextrin. However, data in the literature suggest that excessive overdosing of cyclodextrins can decrease the absorption of compounds administered with cyclodextrins, due to their lack of release from the complex. γ-Cyclodextrin is digestible in contrast to β-cyclodextrins. This could potentially limit the sensitivity toward overdose, which was evaluated using benzo[a]pyrene in this study, in which rats were administered benzo[a]pyrene and different doses of the 2 cyclodextrins. Both cyclodextrins lowered the area under the curve and therefore the absorption of benzo[a]pyrene by up to a factor of 2 when dosed in high concentrations, thus indicating that overdosing of cyclodextrins may limit the oral absorption of a compound. This limitation may be artificial because the molar ratio of benzo[a]pyrene:cyclodextrin was >1:50,000 at the concentration where a significant decrease in the absorption was observed. No difference was observed between the 2 cyclodextrins, so digestibility seemed less important. More interesting was that the decrease in absorption was relatively small when compared with literature values, suggesting that the effect of overdosing a compound with cyclodextrins was lower than anticipated.
A heuristic model to quantify the impact of excess cyclodextrin on oral drug absorption from aqueous solution
2016, European Journal of Pharmaceutics and Biopharmaceutics
The intestinal drug solubilising capacity $(D_{tot}^{SC})$ of a drug formulated as an aqueous cyclodextrin solution is a recently proposed quantity to predict the cyclodextrin concentration needed to fully solubilise the drug in the intestinal lumen. According to this concept, the cyclodextrin concentration in the drug product must be higher than the amount needed to solubilise the compound, due to the displacement of the drug from the cyclodextrin cavity by bile salts in the intestinal lumen. On the other hand, dosing cyclodextrin at $> D_{tot}^{SC}$ is expected to result in decreased free intestinal drug concentrations and thus potentially a lower fraction absorbed. In this study, data from three previous in vivo studies in rats with fixed concentrations of three compounds (danazol, cinnarizine and benzo[A]pyrene) and various cyclodextrin concentrations $> D_{tot}^{SC}$ were analysed. The model was developed for danazol and applied to the two other compounds. Absorption, as quantified from the area under the plasma concentration–time profile, was predicted by the model to decrease at elevated concentrations of co-administered cyclodextrin in accordance with the in vivo data. In addition, at high cyclodextrin concentrations a delay in T_max and a decrease in C_max were predicted, again in accordance with the experimental observations. These observations were rationalised in terms of the free intestinal drug concentration by a chemical equilibrium model for $D_{tot}^{SC}$ . This model depends on the quantity termed the dimensionless dose concentration, $D_{tot}^{*} = D_{o} / P_{n}$ , given as the fraction of the permeation number (P_n) and dose number (D_o). The model provides the formulation scientist with a critical quality attribute for assessing the implication of having excess cyclodextrin in an oral solution.
Formulations based on alpha cyclodextrin and soybean oil: An approach to modulate the oral release of lipophilic drugs
2012, Journal of Controlled Release
Citation Excerpt :
Lipid digestion products induce secretion of pancreatic and biliary fluids which alter the luminal environment of the small intestine [38]. Bile salts decrease the partition coefficient of drugs in intestinal media [39–41] while pancreatic lipases participate to lipid digestion [42] and contribute to the release of drugs from oil [43]. Thus, the resulting mixed micelles probably increase the amount of IND available for absorption.
The purpose of this work was to investigate the potential of α-cyclodextrin combined to soybean oil-based formulations to modulate the release of a model drug, indomethacin. Dry emulsion, naked and coated beads were prepared from the same initial formulation using the same manufacturing process. Dry emulsion was selected to accelerate drug release while beads coated with α-cyclodextrin were designed to sustain it. Indomethacin-loaded systems were prepared, characterised and evaluated in vitro. Pharmacokinetic studies were performed in fasted and fed rats. The presence of the α-cyclodextrin coat was confirmed by confocal microscopy, and an increase of the mass and diameter of the beads. The layer of α-cyclodextrin improved their resistance in simulated gastro-intestinal fluids. In vitro, the dissolution of indomethacin was slower with coated beads than with emulsion and naked beads. Lipid-based formulations showed an increase of relative bioavailability of IND versus Indocid®. Whatever the formulation, greater and faster release of indomethacin was noticed in sodium taurocholate-rich medium and in fed rats. Compared to naked beads, an increased Cp_max with a shorter T_max was observed with the emulsion while T_max and MRT were increased and Cp_max reduced with the coated beads. Interestingly, formulations based on alpha cyclodextrin and soybean oil can modify the release of a lipophilic drug depending on the system formed.
Co-solubilization of poorly soluble drugs by micellization and complexation
2006, International Journal of Pharmaceutics
The use of combined approach of surfactants and cyclodextrins in solubilization of poorly soluble drugs has been described in literature. In this report, a mathematical model has been developed to provide the quantitative basis for this approach. First, by way of hypothetical examples and simulations, the influence of various interaction parameters on the phase solubility profile is presented. Additionally, the model results are compared with (a) results reported by Yang et al., with NSC-639829, sodium lauryl sulfate (SLS) and sulfobutyl-ether-β-cyclodextrin ((SBE)_7M-β-CD) and (b) solubility of methylprednisolone, a model poorly soluble drug, in the presence of its water-soluble ‘surfactant-like’ prodrug, methylprednisolone 21-hemisuccinate, and (SBE)_7M-β-CD. The model shows good agreement with experimental data. Furthermore, theoretical simulations show that the combined solubility is less than the sum of the individual solubility values in cyclodextrins and surfactants. Based on the hypothetical case and the two examples, the factors affecting the phase solubility profile in mixed solutions of surfactants and cyclodextrins are presented. Finally, the limitations of the model to explain co-solubilization by surfactants and cyclodextrins are discussed.
β-cyclodextrin reduces bioavailability of orally administered [ <sup>3</sup>H]benzo[a]pyrene in the rat
2005, Journal of Pharmaceutical Sciences
Citation Excerpt :
Thus, although cyclodextrins are able to increase solubility of lipophilic compounds like BaP, the rate of release from the complex may be decreased in the in vivo situation. In conclusion, rather than causing enhanced absorption of benzo[a]pyrene as proposed by Horsky and Pitha,9 our results indicate that β‐cyclodextrin may act as a scavenger for such compounds following oral administration, thus reducing the systemic exposure by preventing absorption. This finding emphasizes the need to exercise caution in interpreting in vitrosolubility information data when extrapolating to the in vivosituation.
The excretion and plasma kinetics of total radioactivity were studied following single oral administration of [³H]benzo[a]pyrene after multiple oral administration of β‐cyclodextrin at 0, 5, 50, or 500 mg/kg/day. The AUC and C_max values in male and female rats following administration of [³H]benzo[a]pyrene in combination with 5 to 500 mg/kg β‐cyclodextrin were considerably lower than that in rats administered [³H]benzo[a]pyrene alone. At all dose levels of β‐cyclodextrin, the excretion of total radioactivity was almost entirely via feces, with <2% recovered in urine, demonstrating either that absorption of the orally administered dose was low or that, for any absorbed material, biliary excretion was the main route of excretion. However, following administration of vehicle, up to 5% of the administered radioactivity was recovered in the urine, suggesting that absorption may have been reduced by the presence of β‐cyclodextrin in the intestine. At all dose levels of β‐cyclodextrin, there was minimal retention of radioactivity in the carcase at the end of the collection period. β‐Cyclodextrin did not affect the apparent terminal half‐life of radioactivity. Therefore, the reduced systemic exposure of rats to radioactivity in the presence of β‐cyclodextrin is likely related to a reduced oral bioavailability. © 2004 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:114–119, 2005
Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation
1997, Journal of Pharmaceutical Sciences
The objective of this review is to summarize recent findings on the safety profiles of three natural cyclodextrins (α-, β- and γ-CDs) and several chemically modified CDs. To demonstrate the potential of CDs in pharmaceutical formulations, their stability against non-enzymatic and enzymatic degradations in various body fluids and tissue homogenates and their pharmacokinetics via parenteral, oral, transmucosal, and dermal routes of administration are outlined. Furthermore, the bioadaptabilities of CDs, including in vitro cellular interactions and in vivo safety profiles, via a variety of administration routes are addressed. Finally, the therapeutic potentials of CDs are discussed on the basis of their ability to interact with various endogenous and exogenous lipophiles or, especially for sulfated CDs, their effects on cellular processes mediated by heparin binding growth factors.

View all citing articles on Scopus

: Abstract published in Advance ACS Abstracts, November 1, 1995.

View full text

Hydroxy propyl Cyclodextrins: Potential Synergism with Carcinogens

Abstract

Anal. Chim. Acta

Toxicology

Lipid Res

Pharm. Sci

Proc. Natl. Acad. Sci. U.S.A

Colloid Interface Sci