阅读说明：本技术 一种乙醇类硬化剂及其应用 (Ethanol hardening agent and application thereof ) 是由 李学义 于 2019-04-29 设计创作，主要内容包括：本发明公开了一种乙醇类硬化剂及其应用。该药物组合物含有乙醇、水溶性碘制剂和注射用水；其中,所述乙醇的体积百分数为76-98％；所述水溶性碘制剂与所述组合物的质量体积比为50～300g/L；所述水溶性碘制剂中的碘元素与所述组合物的质量体积比为23～139g/L；注射用水补足余量。本发明的药物组合物在血管内注射时可以自显影,具有较好的栓塞效果和稳定性。(The invention discloses an ethanol hardening agent and application thereof. The pharmaceutical composition comprises ethanol, water-soluble iodine preparation and water for injection; wherein the volume percentage of the ethanol is 76-98%; the mass-volume ratio of the water-soluble iodine preparation to the composition is 50-300 g/L; the mass-volume ratio of iodine element in the water-soluble iodine preparation to the composition is 23-139 g/L; the rest is made up by water for injection. The medicinal composition can be self-developed during intravascular injection, and has good embolization effect and stability.)

1. A pharmaceutical composition comprises ethanol, water-soluble iodine preparation and water for injection; wherein the volume percentage of the ethanol is 76-98%; the mass-volume ratio of the water-soluble iodine preparation to the composition is 50-300 g/L; the mass-volume ratio of iodine element in the water-soluble iodine preparation to the composition is 23-139 g/L; the rest is made up by water for injection.

2. The pharmaceutical composition of claim 1, wherein the volume percent of ethanol is 78-90%;

and/or the mass-volume ratio of the water-soluble iodine preparation to the pharmaceutical composition is 75-260 g/L;

and/or the mass-volume ratio of iodine element in the water-soluble iodine preparation to the composition is 46-121 g/L;

and/or the water-soluble iodine preparation is one or more of iohexol, ioversol and iodixanol.

3. The pharmaceutical composition of claim 2, wherein the volume percent of ethanol is 86-90%;

and/or the mass-volume ratio of the water-soluble iodine preparation to the pharmaceutical composition is 150-260 g/L;

and/or the water-soluble iodine preparation is iohexol.

4. The pharmaceutical composition according to claim 1, wherein each 1000mL of the pharmaceutical composition comprises the following components and contents, and the mass of iodine element in each 1000mL of the pharmaceutical composition is 23-139 g;

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5. The pharmaceutical composition according to claim 4, wherein each 1000mL of the pharmaceutical composition comprises the following components and contents, and the mass of iodine element in each 1000mL of the pharmaceutical composition is 46-119 g;

6. the pharmaceutical composition according to claim 1, wherein each 1000mL of the pharmaceutical composition comprises the following components and contents, wherein the mass of iodine element in each 1000mL of the pharmaceutical composition is 23-139 g;

7. the pharmaceutical composition according to claim 6, wherein each 1000mL of the pharmaceutical composition comprises the following components and contents, wherein the mass of iodine element in each 1000mL of the pharmaceutical composition is 46-71 g;

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8. the pharmaceutical composition according to any one of claims 1 to 7, which consists of the following components in percentage by weight: the ethanol, the water-soluble iodine preparation and water for injection; wherein the volume percentage of the ethanol, the mass-to-volume ratio of the water-soluble iodine preparation to the composition, and the mass-to-volume ratio of elemental iodine in the water-soluble iodine preparation to the composition are as set forth in any one of claims 1 to 7; the water for injection makes up the balance.

9. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 8, comprising the steps of:

Stirring the water-soluble iodine preparation, the ethanol and the water for injection to obtain a transparent clear solution, filling the transparent clear solution into an ampoule bottle, sealing the ampoule bottle, and sterilizing at high temperature.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition is used as an ethanol hardener for preparing a medicament for treating malformed blood vessels.

Technical Field

The invention relates to an ethanol hardener and application thereof.

Background

Vascular malformations, also known as hemangiomas, originate from tumors or malformations of the blood vessels or lymphatic vessels. The pathogenesis of the vascular malformation is not clear, the clinical manifestations are diversified, the vascular malformation can be found in superficial tissues, deep tissues and even internal organs of a human body, the conventional treatment is usually performed by blood supply artery ligation or surgical excision, and the like, but the treatment means has poor prognosis, is easy to relapse and even aggravate, and has large bleeding risk.

With the development of interventional radiology in recent years, sclerosing agents have become the first choice for treating vascular malformations. The hardening agent can effectively treat vascular malformation and varicosity, and the action mechanism of the hardening agent is mainly that vascular endothelial cells are damaged through different ways, so that target blood vessels are hardened to become fiber ropes which are finally absorbed by surrounding tissues, and the aims of improving symptoms, appearance and hemodynamic disorders are fulfilled. The clinically applied hardeners comprise ethanol, polidocanol, lauromacrogol, myristyl sodium sulfate, pingyangmycin and the like, and the hardening effect of the ethanol is obviously better than that of other hardeners.

Ethanol is a very aggressive sclerosing agent, whose dehydration and denudation denatures hemoglobin and destroys vascular endothelial cells, rapidly causing focal tissue necrosis and thrombosis, an erosion mechanism of ethanol for the treatment of vascular malformations. The ethanol has good treatment effect on venous malformation and arteriovenous malformation, and particularly for arteriovenous malformation, the ethanol is the only clinically verified and effective hardening agent.

However, ethanol is also a high risk of use due to its aggressive nature (e.g., inadvertent entry into normal tissues such as nerves, muscles or connective tissue, especially into the supplying blood arteries, can result in irreversible necrosis of normal tissues). Also, it is technically and empirically demanding for clinicians as a sclerosing agent, and currently ethanol sclerosing agents are not approved for the treatment of vascular malformations.

The above risks are mainly due to the fact that ethanol cannot be traced during the vascular injection process. To solve this problem, the literature reports that mixed solution of ethanol and iodized oil can be used to treat vascular malformation, and the mixed solution is injected into blood vessels for tracing.

However, the above method still has the following problems:

a. the use of the ethanol iodized oil mixed solution can dilute the ethanol concentration, reduce the angiosclerosis effect and cause poor treatment effect;

b. The mixed solution needs to be prepared just before use and is unstable, and the mixed solution needs to be repeatedly extruded and uniformly mixed before use, and can be layered after being placed a little;

c. because the iodized oil is not dissolved in the ethanol, after the mixed solution is injected into a blood vessel, the iodized oil can be separated from the ethanol and cannot accurately trace the ethanol;

d. iodized oil is insoluble in water and can disperse into small oil droplets when injected into blood vessels, with the risk of embolism formation.

Therefore, there is a need to develop a safer and more effective hardening agent for ethanol.

Disclosure of Invention

The invention provides an ethanol hardening agent and application thereof, aiming at overcoming the defects that the drug effect of the ethanol hardening agent is not ideal and the ethanol cannot be accurately traced in the prior art. The ethanol hardener can accurately trace ethanol and has a good treatment effect on vascular malformation.

The invention provides a pharmaceutical composition, which contains ethanol, a water-soluble iodine preparation and water for injection; wherein the volume percentage of the ethanol is 76-98%; the mass-volume ratio of the water-soluble iodine preparation to the composition is 50-300 g/L; the mass-volume ratio of iodine element in the water-soluble iodine preparation to the composition is 23-139 g/L; the rest is made up by water for injection.

In the pharmaceutical composition, the ethanol may be conventionally used in the art, such as pharmaceutical injection grade ethanol.

In the pharmaceutical composition, the ethanol may be present in an amount of 78 to 90% (e.g., 80%, e.g., 83%, e.g., 82%), preferably 86 to 90% (e.g., 86%).

In the pharmaceutical composition, the water-soluble iodine preparation refers to organic iodides as conventionally described in the art. The water-soluble iodine preparation can be one or more of iohexol, ioversol and iodixanol, and is preferably iohexol.

In the pharmaceutical composition, the mass-to-volume ratio of the water-soluble iodine preparation to the pharmaceutical composition can be 75-260 g/L (e.g., 100g/L), and preferably 150-260 g/L (e.g., 200 g/L).

In the pharmaceutical composition, the mass-to-volume ratio of the iodine element in the water-soluble iodine preparation to the composition can be 46-121 g/L, such as 49g/L, 69g/L, 71g/L, and 92 g/L.

In the pharmaceutical composition, the water for injection can be water for injection conventionally used in the field, as long as the water for injection meets the regulations of pharmacopoeia and meets the medication standards.

In a preferred embodiment of the invention, each 1000mL of the pharmaceutical composition comprises the following components and contents, and the mass of iodine element in each 1000mL of the pharmaceutical composition is 23-139 g;

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In a preferred embodiment of the invention, each 1000mL of the pharmaceutical composition comprises the following components and contents, and the mass of iodine element in each 1000mL of the pharmaceutical composition is 46-119 g;

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in a preferred embodiment of the invention, each 1000mL of the pharmaceutical composition comprises the following components and contents, wherein the mass of iodine element in each 1000mL of the pharmaceutical composition is 23-139 g;

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in a preferred embodiment of the invention, each 1000mL of the pharmaceutical composition comprises the following components and contents, wherein the mass of iodine element in each 1000mL of the pharmaceutical composition is 46-71 g;

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in a preferred embodiment of the present invention, the pharmaceutical composition comprises the following components in parts by weight: the above ethanol, the above water-soluble iodine preparation and water for injection; wherein the volume percentage of the ethanol is 76-98%; the mass-volume ratio of the water-soluble iodine preparation to the composition is 50-300 g/L; the mass-volume ratio of iodine element in the water-soluble iodine preparation to the composition is 23-139 g/L; the water for injection makes up the balance.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:

Stirring the above water-soluble iodine preparation, ethanol and water for injection to obtain transparent clear solution, packaging in ampoule bottle, sealing, and sterilizing at high temperature.

The method of high-temperature sterilization may be a method conventional in the art. The high-temperature sterilization temperature is preferably 115-121 ℃, for example 121 ℃. The time for high-temperature sterilization is preferably 7-30 min, such as 15 min.

The ampoule bottle can be an ampoule bottle conventional in the field, and is preferably a glass ampoule bottle.

Wherein, the pharmaceutical composition can also be subpackaged in a plurality of ampoule bottles for storage. The volume of the split charging of the pharmaceutical composition is not limited, and preferably 5-15 ml.

The pharmaceutical composition is applied to an ethanol hardener.

The invention also provides an application of the pharmaceutical composition as an ethanol hardener in preparing a medicament for treating malformed blood vessels.

In the invention, the term "room temperature" means 10 to 30 ℃.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

Compared with the prior art, the pharmaceutical composition provided by the invention has the following beneficial effects as an ethanol hardener:

1. The ethanol hardener can be self-developed during intravascular injection, so that irreversible damage caused by mistaken entry of the hardener into normal tissues such as nerves, muscles or connective tissues, particularly blood supply arteries, is avoided;

2. compared with an ethanol iodized oil mixed solution preparation, the ethanol hardening agent is more stable, and the risk of forming thrombus by injecting the iodized oil into blood vessels is avoided;

3. the ethanol hardener has good angiosclerosis effect, and the embolization effect can reach more than 65 percent and can reach 100 percent at most.

Drawings

FIG. 1 is a graph showing the in vitro development effects of the hardeners prepared in examples 1, 5 and 7, comparative example 2 and comparative example 3.

FIG. 2 is a graph showing the effect of the hardeners prepared in examples 1, 5 and 7, comparative example 2 and comparative example 3, which are developed in vitro after being left for 3 minutes.

FIG. 3 is a graph showing the in vivo imaging effect of the sclerosant prepared in example 1 in rats.

FIG. 4 is a graph showing the in vivo imaging effect of the sclerosant prepared in example 5 in rats.

FIG. 5 is a graph showing the in vivo imaging effect of the sclerosant prepared in example 7 in rats.

FIG. 6 is a graph showing the in vivo development effect of the sclerosing agent prepared in comparative example 2 in rats.

FIG. 7 is a graph showing the in vivo development effect of the sclerosing agent prepared in comparative example 3 in rats.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the following examples, iohexol and ioversol were purchased from Teisite pharmaceuticals, Inc., Zhejiang; iodixanol was purchased from hong kong hong zhong pharmacy ltd; ethanol was purchased from Jiuzhan pharmaceutical Co., Ltd, Hunan; water for injection was purchased from Thermofisher corporation; the iodized oil injection is purchased from Nintendo Shanghai pharmaceutical Co., Ltd, the specification is 10ml, the iodized oil injection contains 37% -41% of iodine, the intermediate value is 39% (g/g), and the density is about 1.355 g/ml.