Uracil dermatological formulations

A uracil preparation technology, applied in the field of uracil skin drug preparations, can solve the problem of reducing curative effect

Pending Publication Date: 2022-04-29
纳诺麦缇科斯有限责任公司(经营别称为PHD生物科学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Typically, capecitabine dosing schedule changes are implemented after the onset of grade 2 HFS, with evidence that prolonged treatment interruptions or dose reductions reduce efficacy in its approved indications

Method used

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  • Uracil dermatological formulations
  • Uracil dermatological formulations
  • Uracil dermatological formulations

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0090] Example 1 Preparation

[0091] Prepare the four cream preparations described in Table 1 below

[0092]

[0093] Each preparation described in Table 1 above was prepared by the following procedure:

[0094] Phase A is prepared by mixing the components of phase A in an auxiliary container of appropriate size. Mix ingredients until uracil is completely dissolved. The mixture was heated slightly below 50 ° C to accelerate dissolution. The phase a auxiliary container now contains the completed phase a. In another auxiliary container of appropriate size (phase B auxiliary container), phase B is prepared by mixing the components of phase B and heating to 50-60 ℃. Mix these ingredients until most of the p-hydroxybenzoate is dissolved. Transfer phase a to phase B auxiliary container. The alkalinity of phase a contributes to the dissolution of p-hydroxybenzoate. Phase A and phase B are mixed until all components are dissolved while the temperature is maintained at 50-60 ℃. The pha...

example 2

[0096] Example 2 preliminary clinical study of uracil preparation

[0097] In order to evaluate the efficacy of topical administration of uracil, composition No. 2 in Table 1 above conducted a randomized, double-blind, placebo-controlled phase 1-2 clinical study in 18 patients with metastatic breast cancer undergoing capecitabine treatment. Nine patients were randomly assigned to placebo (PTO, composition 1 in Table 1). In each of the twice daily capecitabine treatments, the patient was instructed to completely rub the preparation (composition 2 (uracil) or composition 1 (placebo)) into the palms of both hands and soles of both feet twice a day. Capecitabine was administered at an approved dose of 1250mg / m on days 1-14 of each 21 day cycle 2 Oral administration twice a day. Treatment lasts up to 6 cycles unless tumor progression, unacceptable toxicity, or withdrawal of consent are recorded.

[0098] Adverse events (AES), including hand foot syndrome (HFS), were evaluated on days ...

example 3

[0106] Example 3 protective effect of uracil on 5-FU in cultured human keratinocytes

[0107] Under standard culture conditions, in the presence of 10 μ M 5-FU、10 μ M 5-FU+100 μ M uracil or 10 μ M5-FU+300 μ In the case of M uracil, primary human epidermal keratinocytes (hpek cells) were cultured for 120 hours, and the cell viability was measured after 120 hours of culture. With the increase of uracil concentration, an increase in relative cell viability was observed, such as Figure 4 As shown in.

[0108] Example 4 uracil topical cream preparation and manufacturing information

[0109]Although the optimized composition in table 1o is not completely effective, it is found that the composition in table 1o is not completely effective. Therefore, several additional preparations were prepared. The preparation optimization work focuses on the development of a preparation that exhibits (1) enhanced penetration of uracil into the skin and minimal penetration into the systemic circulatio...

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Abstract

The present invention provides a topical pharmaceutical formulation comprising uracil and a penetration enhancer and a method of administering the same. Also provided is a method of treating or preventing a skin disease associated with the administration of 5-fluorouracil or a precursor or prodrug thereof, such as capecitabine. The penetration enhancer is selected from the group consisting of dimethyl isosorbide, isopropyl myristate, isopropyl palmitate, octyldodecanol, oleic acid, oleyl alcohol, polyoxyglyceride, pyrrolidone, thymol, trioctyl extract, triolein, myristic acid, medium chain triglyceride, linoleic acid, lauric acid, sugar furfuryl alcohol, glyceryl monooleate, ethyl oleate and dimethyl sulfoxide; and dibutyl sebacate and mixtures thereof.

Description

Background technology [0001] Capecitabine, originally named Roche, is a prodrug of 5-fluorouracil (5-FU), a widely used oral chemotherapy drug. Capecitabine is suitable for metastatic breast cancer (MBC), auxiliary colon cancer and metastatic colorectal cancer in the United States, Canada and the world. In addition, it is often used in addition to indications to treat cancer patients such as gastric cancer and esophageal cancer. [0002] Capecitabine is absorbed unchanged from the gastrointestinal tract and metabolized into 5-FU through three enzymatic steps. Thymidine phosphorylase (TP) has a high concentration in some tumors. It can selectively catalyze the third metabolic step of 5-FU activation and make it a metabolite with anticancer activity by interfering with RNA synthesis and inhibiting thymidylate synthase. [0003] The main toxicity associated with capecitabine is hand foot syndrome (HFS), also known as palmar toe sensory loss erythema syndrome, which occurs in 60-70% o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/513C07D239/54A61K9/06
CPCA61K31/513C07D239/54A61K9/0014A61K9/107A61K47/22A61K31/7068A61K2300/00A61P17/00A61K47/02A61K47/10A61K47/12A61K47/14A61K47/18A61K47/26A61K47/34
Inventor S·艾萨克曼A·B·马翁
Owner 纳诺麦缇科斯有限责任公司(经营别称为PHD生物科学
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