Aspects of the degradation kinetics of doxorubicin in aqueous solution

Beijnen, Jos H.; Houwen, O.A.G.J. van der; Underberg, W.J.M.

doi:10.1016/0378-5173(86)90170-5

Cited by 128 publications

(78 citation statements)

References 11 publications

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“…Nevertheless, this gain is obtained i) by association of the drug with non-toxic ion, ii) at acidic pH conditions that allows to prevent DOX from degradation, known to be a serious problem at basic pH. 23) In view of this, the DOX-oleate association could have interesting perspectives.…”

Section: Liquid-liquid Extraction Of Dox In Presence Of Oleate Ionsmentioning

confidence: 99%

On the Interaction of Doxorubicin with Oleate Ions: Fluorescence Spectroscopy and Liquid-Liquid Extraction Study

Munnier

Tewes

Cohen-Jonathan

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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Doxorubicin (DOX) is an antineoplastic agent of the anthracycline family used as a first-line treatment in numerous neoplastic diseases, particularly in breast cancer.1) The progression of tumor cell resistance, in particular multidrug resistance (MDR), is one of the main factors which limit its employment.2) MDR is generally associated with a decreased intracellular accumulation of drug related to a membrane glycoprotein, the P-gp that contributes to a rapid expelling of the drug from the cell.3) An interesting way to overcome this active efflux would be to support the drug accumulation into the cell, in particular by increasing its capacity to cross lipidic membranes. One can act upon the membrane fluidity or act upon the hydrophilic/lipophilic properties of the drug.DOX molecule (see structure on Fig. 1) is considered hydrophilic at physiological pH because it presents a positive charge on the sugar moiety. The more lipophilic molecular form of DOX is dominant at moderately alkaline pHs, between 8.2 and 9.5, the pK a values of the amine and the phenol in position 11 respectively.4) The hydrophilicity of DOX is also depending on the drug concentration, since beyond a concentration of 30 mM DOX molecules are prone to form less hydrophilic dimmers (stacking effect) which precipitate in aqueous solution. The increase of the pH, i.e. of the neutral form percentage, is in favor of the stacking phenomenon. 5,6) It has been recently shown that lipophilicity of cationic drugs 7,8) can be increased by association with an anion, namely with a long chain ion of a fatty acid.9,10) Nevertheless, no study is devoted to the molecular interaction between the drug and the ion. On the other hand, combined use of an anticancer drug, paclitaxel, with different fatty acids, has been shown to enhance mortality of cancer cells in vitro.11) It has not yet been established whether this gain in efficacy is dependent on an assembly between the drug and the fatty acid ion.Association DOX-fatty acid could be more lipophilic than DOX alone, and enter more efficiently into the cell. It could also facilitate drug encapsulation into pharmaceutical formulations based on hydrophobic polymers or liposomes. 7,9) Oleic acid is a good candidate for such an association within a feasibility study: it is the simplest of the w-9 fatty acid family (Fig. 1), and possesses a long hydrophobic chain that could contribute to a gain of lipophilicity of the association. Moreover, oleates are non-toxic and the behavior of oleic acid and its ion (oleate, OA Ϫ ) in aqueous solution is rather well studied. [12][13][14][15] Fluorescence spectroscopy has been successfully used to study interactions between DOX and its surrounding, for instance when the drug intercalates DNA 16,17) or penetrates within membrane models or liposomal drug carriers. 18,19) Indeed, the dihydroanthraquinone moiety of DOX is a well known fluorophore excitable with visible light (absorption maxima at 480-500 nm). Fluorescence spectroscopy Increase of lipophilicity of cationic doxorubicin (DO...

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Section: Liquid-liquid Extraction Of Dox In Presence Of Oleate Ionsmentioning

confidence: 99%

On the Interaction of Doxorubicin with Oleate Ions: Fluorescence Spectroscopy and Liquid-Liquid Extraction Study

Munnier

Tewes

Cohen-Jonathan

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Among them the ammonium ion gradient method 10) and pH gradient method 11) are the most effective to achieve a high drug to lipid ratio and their acidic pH in the liposome interior is favorable for the chemical stability of doxorubicin. 12) Higher exterior buffer pH is better from the point of view of encapsulation efficiency, however, the exterior buffer pH should be kept below 7.0 during the manufacturing process because doxorubicin is extremely unstable in alkaline pH.…”

Section: Designing a Formulation To Achieve Optimized Properties As Dmentioning

confidence: 99%

Development of Liposomal Anticancer Drugs

Hyôdô

Yamamoto

Suzuki

et al. 2013

Biological & Pharmaceutical Bulletin

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Liposomes are drug delivery systems that can alter the pharmacokinetic properties of compounds. The adverse effects of anticancer agents are a limiting factor for cancer chemotherapy, therefore, liposomal formulations have the potential to improve the therapeutic efficacy of anticancer agents by enhancing their accumulation in tumors and reducing non-selective distribution to normal tissues, which is known as the enhanced permeability and retention effect. To develop a liposomal anticancer agent as a drug product, its formulation must be designed to ensure its quality until it is administered to patients and to exert maximum potency in clinical use rather than in animal experiments. The chemical stability and physicochemical stability of the ingredients are key factors in the design of liposomal formulations. Drug release rates are critical factors in the therapeutic efficacy of liposomal drug products because the encapsulated drug has no pharmacological activity, and only released drug can exert antitumor/toxic activities. Liposomes should maintain the drug in a stable state in the circulation and then promptly release it after accumulation in the target tissue in order to achieve a sufficient drug concentration. To understand the profile of the formulation and to guarantee the quality of drug product, a reliable analytical method that can determine the released and encapsulated drugs in biological fluids is required. Simple online solid phase extractions of the released and encapsulated drugs using a column-switching HPLC system meet the requirements and this system enables accurate in vitro release testing and in vivo pharmacokinetic evaluation. This review introduces the process of liposomal drug product development from various viewpoints.

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“…Thus, to ensure a high drug loading whilst maintaining doxorubicin's therapeutic properties, the reaction was carried out at a slightly lower pH of 8.5. According to Beijnen et al, who generated a pH-dependent decomposition profile for doxorubicin at 50 °C corrected for buffer and ionic strength influences [27], the decomposition rate of doxorubicin at pH 8.5 is approximately 35% less than at pH 9.0.…”

Section: Triple Functionalisation Of Swcntsmentioning

confidence: 99%