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Composition and method for reducing drug levels in tissues when orotate derivative is given

An orotate, level technology, applied in drug combinations, pharmaceutical formulations, anti-tumor drugs, etc., can solve problems such as reducing toxicity and side effects of drugs, and reducing drug levels in non-cancer tissues.

Inactive Publication Date: 2014-12-10
SAVVIPHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, the present invention can be differentiated from the prior art because the prior art does not address the problem of preventing and / or reducing drug levels in non-cancerous tissues through strategies to reduce toxicity and drug side effects

Method used

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  • Composition and method for reducing drug levels in tissues when orotate derivative is given
  • Composition and method for reducing drug levels in tissues when orotate derivative is given
  • Composition and method for reducing drug levels in tissues when orotate derivative is given

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Chemical Synthesis of Doxorubicin Orotate

[0059] figure 2 The synthesis of doxorubicin orotate is illustrated. Orotic acid (1.0 g) was dissolved in 200 mL of water at 65°C. Potassium hydroxide (KOH) (1 equiv) was added to orotic acid, and the mixture was stirred at 85 °C until a clear solution appeared. The solution was cooled and the precipitate was collected by filtration to give a colorless solid (0.95g) which was dried in vacuo for 24 hours. Mass spectroscopy indicated that the structure was potassium orotate.

[0060] Potassium orotate (0.4 g) synthesized in the above step was dissolved in 150 mL of water at 65°C. The solution was degassed under vacuum and protected with argon. Doxorubicin hydrochloride (1.0 g, 1 equiv) was added and the resulting red solution was treated with excess amberlite IR120H resin at the same temperature for 2 hours. After filtration, the solution was frozen with dry ice and lyophilized to obtain 1.35 g of doxorubicin orotate (J...

Embodiment 2

[0062] Response of SC CAKI-1 renal tumors to treatment with doxorubicin hydrochloride and doxorubicin orotate

[0063] The purpose of this experiment was to evaluate the effect of doxorubicin hydrochloride (DOX) and its orotate derivative (DOX orotate) on subcutaneous (SC) in male athymic NCr-nu / nu mice. Antitumor effectiveness of implanted CAKI-1 human kidney tumor xenografts. The hearts of animals treated with equal doses of DOX and DOX orotate were analyzed and the concentration of DOX in the hearts of these animals was determined.

[0064] Pharmaceutical preparation - DOX solution at 0.8 mg / mL (doxorubicin hydrochloride USP28, Yick-Vic Chemical & Pharmaceuticals (HK) Ltd, Kowloon, Hong Kong, lot number M050705), freshly prepared with normal saline on each day of treatment. The 0.8 mg / mL solution was diluted to 0.53 and 0.35 mg / mL with saline.

[0065] DOX orotate (Catalog No. J1220-13-II) was synthesized from USP28, Lot No. M050705, as described in Example 1. DOX orot...

Embodiment 3

[0073] Embodiment 3 Determination of doxorubicin in mouse heart

[0074] Doxorubicin concentrations were determined by HPLC mass / mass spectrometry. Animals receiving an IV DOX dose of 8.0 mg / kg / dose averaged 7,398 ng / g of heart tissue (Group 2) and animals receiving an IV DOX dose of 9.75 mg / kg / dose averaged 5,264 ng / g / g Heart tissue (Group 5). In other words, the level of doxorubicin was reduced by 28% in the heart tissue of DOX orotate-treated animals compared to the heart tissue of DOX-treated animals. Importantly, cardiac tissue samples were obtained one day after the last IV injection, thus illustrating a significant decrease in DOX levels with DOX orotate compared with DOX hydrochloride, even one day after intravenous administration of the two different forms of DOX. Those skilled in the art would expect that the difference in DOX levels in hearts between the two groups would be even greater over the long term. This is because the effectiveness of DOX hydrochloride...

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Abstract

The invention relates to the field of reconstruction of drug chemical structure by preparation of orotate derivatives, and the drug is known to have side effect to cause tissue toxicity. More specifically, the invention relates to anthracycline, doxorubicin and daunorubicin orotate derivatives, and the orotate derivatives which and can reduce drug levels in non cancer tissues. The orotate derivatives are equally effective in inhibiting animal SCCAKI-1 renal tumor, and compared with doxorubicin hydrochloride, doxorubicin reduction in heart tissue shows that toxicity induced by production of anthracycline free radicals is reduced.

Description

field of invention [0001] The present invention relates to orotate derivative drugs, and in particular the conversion of anticancer drugs to orotate derivatives to reduce drug tissue levels in non-cancerous tissues susceptible to drug toxicity. 1. Background of the invention [0002] The present invention relates to the field of remodeling the chemical structure of drugs known to have side effects of causing toxicity in non-cancerous tissues or adverse drug reactions by preparing orotate derivatives. More specifically, the present invention relates to derivatives of anthracyclines, doxorubicin and daunorubicin for use as anticancer drugs. [0003] The antibiotic doxorubicin (DOX) and its derivatives, as well as other cationic anthracyclines, are now of great clinical interest in the treatment of cancer, including leukemia and solid tumors. [0004] Great promise has been focused on the use of liposomes as delivery systems for bioactive drugs. The use of liposomes for antin...

Claims

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Application Information

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IPC IPC(8): A61K31/704A61K31/513A61P35/00A61P35/02A61P35/04
Inventor 拉希达·A·卡马利
Owner SAVVIPHARM INC
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