阅读说明：本技术 用于减少莱菔硫烷与莱菔素引起的胃肠道反应的油剂 (Oil for reducing gastrointestinal tract reaction caused by sulforaphane and sulforaphane ) 是由 袁其朋 刘朋涛 程立 于 2021-09-08 设计创作，主要内容包括：本发明涉及用于减少莱菔硫烷与莱菔素引起的胃肠道反应的油剂。油剂包含莱菔硫烷与莱菔素作为有效成分,所述莱菔硫烷与莱菔素的重量百分比含量为0.1-50％,制备油剂所使用的辅料植物油为大豆油、玉米油、花生油、芝麻油、棉籽油、亚麻油、蓖麻油、菜籽油、葵花籽油、油茶籽油和橄榄油中的一种或几种混合,将莱菔硫烷与莱菔素与辅料混合后制备成胶囊剂。本发明油剂在减少莱菔硫烷与莱菔素引起的胃肠道反应的表现中显示出非常显著的效果。(The present invention relates to an oil for reducing gastrointestinal reactions caused by sulforaphane and sulforaphane. The oil agent comprises sulforaphane and sulforaphane as effective components, the weight percentage content of the sulforaphane and the sulforaphane is 0.1-50%, the auxiliary material used for preparing the oil agent is one or more of soybean oil, corn oil, peanut oil, sesame oil, cottonseed oil, linseed oil, castor oil, rapeseed oil, sunflower seed oil, camellia seed oil and olive oil, and the sulforaphane, the sulforaphane and the sulforaphane are mixed with the auxiliary material to prepare the capsule. The oil agent of the invention shows very significant effect in reducing gastrointestinal tract reaction caused by sulforaphane and sulforaphane.)

1. An oil for reducing gastrointestinal reactions caused by sulforaphane and sulforaphene, which is characterized in that sulforaphane or/and sulforaphene are/is an effective component of the oil, the weight percentage content of the sulforaphane and the sulforaphene is 0.1-50%, and the oil at least comprises vegetable oil.

2. The oil of claim 1, wherein the sulforaphane and the sulforaphane are natural product extracts, biosynthetic products or chemical synthetic products.

3. An oil as claimed in claim 2, wherein the extract is obtained from a plant selected from brussels sprouts, cabbage, cauliflower, bok choy, kale, collard, broccoli sprouts, cabbage, kohlrabi, mustard, turnip, radish, arugula, and watercress.

4. The oil agent according to claim 1, wherein the added vegetable oil is one or more of soybean oil, corn oil, peanut oil, sesame oil, cottonseed oil, linseed oil, castor oil, rapeseed oil, sunflower seed oil, camellia seed oil and olive oil.

5. The oil agent according to claim 1, wherein the oil agent is a capsule, and is a hard capsule or a soft capsule.

6. The oil agent according to claim 5, wherein the capsule is a sustained-release capsule or a controlled-release capsule loaded with a sustained-release material, or a normal capsule not loaded with a sustained-release material.

7. The oil of claim 5, wherein the capsule is administered orally.

8. The oil of claim 1, further comprising one or more of a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, and a preservative.

9. An oil formulation according to claim 1 for use in reducing gastrointestinal reactions caused by sulforaphane and sulforaphane.

Technical Field

The invention relates to a preparation method of an oil agent for reducing gastrointestinal tract reaction caused by sulforaphane and sulforaphane, which comprises sulforaphane and sulforaphane as effective components, vegetable oil as a main auxiliary material and a capsule as a dosage form.

Background

Cancer is a serious threat to human life and health due to its high mortality rate. An epidemiology of mediterranean areas indicates that some residents who consume cruciferous vegetables more frequently are at a lower risk of developing cancer, indicating the presence of one or more components in cruciferous plants that inhibit tumor cell growth. Further studies confirmed that the active ingredient is an isothiocyanate compound. Among them, Sulforaphane (SFA), which is an isothiocyanate compound isolated from broccoli, is the most studied compound. There have been dozens of clinical trials with sulforaphane worldwide, however, severe gastrointestinal reactions have not resulted in the marketing of any sulforaphane drug. The sulforaphane and the sulforaphane belong to isothiocyanate compounds, the anti-cancer activity of the sulforaphane and the sulforaphane is close to that of the isothiocyanate compounds, and the serious gastrointestinal reaction caused by the sulforaphane is similar to that of the sulforaphane.

Disclosure of Invention

From the background, the sulforaphane has good druggability, but the serious gastrointestinal reaction prevents patients from taking sulforaphane with larger dose, so that the dosage of sulforaphane in multiple second-phase clinics can not reach effective dose on the premise of not reaching toxic dose, therefore, the gastrointestinal reaction is reduced, and the administration dose of patients is increased, so that the effect can be further improved. In the early test, the similar situation is shown by the sulforaphene, and some patients stop taking the medicine in advance due to serious gastrointestinal reaction, and finally, a better clinical result cannot be obtained.

The inventor tries various ways to solve the gastrointestinal tract reaction caused by sulforaphane and sulforaphene, and finds that the gastrointestinal tract reaction caused by sulforaphane and sulforaphene is greatly reduced by slow release and the like as long as the sulforaphane and the sulforaphene are not absorbed in the stomach, so that the sulforaphane and the sulforaphene are finally wrapped by using vegetable oil, and then the oil is prepared into capsules to be absorbed in the small intestine after being disintegrated in the intestinal tract, so that the required concentration is maintained, and the gastrointestinal tract reaction is greatly reduced.

The invention mainly relates to the following aspects:

1. an oil for reducing gastrointestinal reactions caused by sulforaphane and sulforaphene, which is characterized in that sulforaphane or/and sulforaphene are/is an effective component of the oil, the weight percentage content of the sulforaphane and the sulforaphene is 0.1-50%, and the oil at least comprises vegetable oil.

2. The oil solution is characterized in that the sulforaphane and the sulforaphane are natural product extracts, biosynthetic products or chemical synthetic products.

3. The oil is characterized in that the extract is extracted from brussels sprouts, cabbage, cauliflower, Chinese cabbage, kale, broccoli sprouts, cabbage, kohlrabi, mustard, turnip, radish, sesamol or watercress.

4. The oil is characterized in that the added vegetable oil is one or a mixture of more of soybean oil, corn oil, peanut oil, sesame oil, cottonseed oil, linseed oil, castor oil, rapeseed oil, sunflower seed oil, camellia seed oil and olive oil.

5. The oil is characterized in that the oil is a capsule, including a hard capsule and a soft capsule (capsule),

6. the capsule can be a sustained-release capsule, a controlled-release capsule and an enteric-coated capsule which are loaded with sustained-release materials, and can also be a common capsule which is not loaded with sustained-release materials.

7. The capsules are administered orally.

8. The oil agent is characterized by also comprising one or more of a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent and a preservative.

9. The oil is characterized by being used for gastrointestinal reaction caused by sulforaphane and sulforaphane.

The invention relates to a preparation method of an oil agent for reducing gastrointestinal tract reaction caused by sulforaphane and sulforaphane. The composition comprises sulforaphane and sulforaphane as effective components, the auxiliary material used for preparing the oiling agent is vegetable oil, and the sulforaphane, the sulforaphane and the auxiliary material are mixed to prepare the capsule. The composition of the present invention shows a very significant effect in reducing the manifestation of gastrointestinal tract reactions caused by sulforaphane and sulforaphane.

(1) After the test subjects take the sulforaphane and the sulforaphane tablets orally at a dose of 30 mg/person/time, more than half of the patients have abdominal pain and flatulence at different degrees within 10min, a small number of the test subjects have heartburn, the symptoms are gradually relieved after 1 hour of taking the tablets, and the patients basically have no feeling after 2 hours.

(2) After the subject orally takes the sulforaphane and the sulforaphane capsules at a dose of 30 mg/person/time, more than less than one tenth of patients have the feeling of flatulence within 10min, no subject feeds back the feeling of heartburn, and the flatulence disappears within 30 min.

Therefore, the composition has wide applicable population, has effect on most subjects, can obviously improve the administration dosage of the sulforaphane and the sulforaphane, and further improves the activity of the sulforaphane and the sulforaphane.

Drawings

FIG. 1 Electron micrograph of sulforaphene in vegetable oil

FIG. 2 Electron micrograph of sulforaphane in vegetable oil

Detailed Description

The invention relates to a preparation method of an oil agent for reducing gastrointestinal tract reaction caused by sulforaphane and sulforaphane. The composition comprises sulforaphane and sulforaphane as effective components, the auxiliary material used for preparing the oiling agent is vegetable oil, and the sulforaphane, the sulforaphane and the auxiliary material are mixed to prepare the capsule. The composition of the present invention shows a very significant effect in reducing the manifestation of gastrointestinal tract reactions caused by sulforaphane and sulforaphane.

Sulforaphane and sulforaphene according to the present invention may be prepared by any method known in the art, for example, natural product extraction, biosynthesis, chemical synthesis, or the like, as long as the sulforaphane and sulforaphene extracts have the effects of preventing, improving, and treating white hair and alopecia. Sulforaphane and sulforaphene obtained by a natural product extraction method are preferably used in the invention, and the extract can be obtained from brussels sprouts, cabbage, cauliflower, Chinese cabbage, headless cabbage, kale, broccoli sprout, cabbage, broccoli, kohlrabi, mustard, turnip, radish, sesamum indicum, watercress and other plants.

In one embodiment of the present invention, sulforaphane and sulforaphene are prepared by the following steps:

(1) pulverizing or homogenizing radish seeds, radish seed sprouts or broccoli seeds, adding tap water with the volume of 5-20 times that of the radish seeds, deionized water or buffer solution with the pH value of 5.0-8.0, stirring and hydrolyzing at 5-50 ℃ for 10-300 minutes, adding hydrochloric acid to adjust the pH value of the hydrolysate to 1.0-3.0, standing overnight, and filtering under reduced pressure or centrifuging to obtain sulforaphane and sulforaphane hydrolysate.

(2) Extracting sulforaphane and sulforaphene hydrolysate obtained in the step (1) by using an organic solvent, wherein the adding amount of the organic solvent is 0.5-5 times of the volume of the sulforaphane and sulforaphene hydrolysate, extracting for 2-5 times, recovering sulforaphane and sulforaphene in the hydrolysate, collecting an organic solvent extraction layer, distilling under reduced pressure to obtain crude sulforaphane and sulforaphene extracts, and recovering the organic solvent. The organic solvent is an organic solvent generally used in the art, for example, n-hexane, cyclohexane, diethyl ether, n-butanol, chloroform, dichloromethane, ethyl acetate, or the like.

(3) Adding the sulforaphane and sulforaphene crude extract obtained in the step (2) into a molecular distillation device for primary molecular distillation, removing residual organic solvent, water and low-boiling-point impurity components in the sulforaphane and sulforaphene crude extract, and collecting heavy components flowing out of the distillation wall of the primary molecular distillation device to obtain primary molecular distillation heavy components. The conditions of the first-order molecular distillation are as follows: the temperature of the raw material is kept at 30-60 ℃, the vacuum degree is 100-.

(4) And (4) adding the primary molecular distillation heavy component obtained in the step (3) into a molecular distillation device for secondary molecular distillation, removing high-boiling-point impurity components in the primary molecular distillation heavy component, and collecting light components flowing out of a condensation surface of the secondary molecular distillation device to obtain sulforaphane and sulforaphane products. The secondary molecular distillation conditions were: the raw material heat preservation temperature is 30-70 ℃, the vacuum degree is 0.1-10Pa, the distillation temperature is 80-200 ℃, the feeding flow rate is 1-10mL/min, the condensation surface temperature is 0-20 ℃, and the rotating speed of a film scraper is 200 plus 450 rpm.

(5) Adding 200g of sulforaphane and sulforaphane obtained in the step (4) into 9.8kg of vegetable oil such as corn oil to prepare a sulforaphane and sulforaphane oil solution of 2% (mass percentage concentration, the mass percentages of which are not described in the following text). The solution was then stirred for 10min to disperse the solution uniformly, at which point the solution was cloudy. After being placed in a refrigerator at 4 ℃ for 2 hours, the solution is clear and transparent and is light yellow. Storing in a refrigerator at 4 deg.C for use.

The composition of the present invention may be prepared into capsules including hard capsules, soft capsules (gelatin capsules), sustained-release capsules, controlled-release capsules and enteric capsules according to the form of the product, but the present invention is not limited thereto.

The composition of the present invention may be a pharmaceutical, or a daily chemical such as a health product, a food, or a hair care product, and the form of use of the composition of the present invention is not limited thereto as long as the effect of reducing gastrointestinal reactions caused by sulforaphane and sulforaphane can be achieved.

The compositions of the present invention may comprise any pharmaceutically acceptable carrier and/or excipient known in the art, as long as the effect of the oil and capsule on the reduction of the gastrointestinal tract response caused by sulforaphane and sulforaphane is not affected. For example, lactose, glucose, sucrose, sorbitol, mannitol, starch, dextrin, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, super carboxymethyl starch sodium, vegetable oil, animal oil, mineral oil, and the like can be used, but the present invention is not limited thereto.

The composition of the present invention may further comprise other additives such as lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives and the like in addition to the above-mentioned components, as long as the effect of the oil and capsule on the reduction of gastrointestinal tract reactions caused by sulforaphane and sulforaphane is not impaired, and any additives may be added.

The composition of the present invention can achieve the effect of reducing gastrointestinal tract reactions by oral administration, and the administration form of the composition of the present invention is not limited thereto.

The present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

Examples

< preparation of sulforaphane and sulforaphane extracts >

Sulforaphane and a sulforaphene extract were prepared as follows for use in the compositions of the examples described later.

(1) Crushing or homogenizing 100kg of radish seeds, adding 2000L of deionized water with the volume being 20 times that of the radish seeds, stirring and hydrolyzing for 5 hours at room temperature, adding hydrochloric acid to adjust the pH value of the hydrolysate to 2.0, standing overnight, and centrifuging to obtain 2000L of sulforaphane and sulforaphane hydrolysate serving as supernatant; (2) extracting the sulforaphane and sulforaphene hydrolysate obtained in the step (1) by using 6000L of ethyl acetate for 3 times, wherein 2000L of ethyl acetate is used each time, recovering sulforaphane and sulforaphene in the hydrolysate, collecting 6000L of ethyl acetate extraction layers, distilling under reduced pressure at 40 ℃ and the vacuum degree of-0.08 MPa to obtain 200L of sulforaphane and sulforaphene crude extracts, and recovering ethyl acetate at the same time; (3) adding the sulforaphane and the sulforaphene crude extract obtained in the step (2) into a molecular distillation device for primary molecular distillation, removing residual ethyl acetate, water and low-boiling-point impurity components in the sulforaphane and sulforaphene crude extract, and collecting heavy components flowing out of the distillation wall of the primary molecular distillation device to obtain 2000g of primary molecular distillation heavy components; the conditions of the first-order molecular distillation are as follows: the temperature of the raw material is kept at 60 ℃, the vacuum degree is 2000Pa, the distillation temperature is 100 ℃, the feeding flow rate is 2mL/min, the temperature of a condensation surface is 0 ℃, and the rotating speed of a film scraper is 400 rpm; (4) adding the primary molecular distillation heavy component obtained in the step (3) into a molecular distillation device for secondary molecular distillation, removing high-boiling-point impurity components in the primary molecular distillation heavy component, and collecting light components flowing out of a condensation surface of the secondary molecular distillation device to obtain 1000g of sulforaphane and sulforaphane products with mass fraction purity of more than 98%; the secondary molecular distillation conditions were: the temperature of the raw material is kept at 70 ℃, the vacuum degree is 0.1Pa, the distillation temperature is 110 ℃, the feeding flow rate is 1mL/min, the temperature of a condensation surface is 0 ℃, and the rotating speed of a film scraper is 450 rpm.

< preparation of the composition of the present invention containing sulforaphane and sulforaphene as the active ingredients >

The composition of the present invention in the form of granules, tablets and capsules is prepared by mixing sulforaphane and a sulforaphene extract, which are prepared by the above-mentioned methods, as raw materials with other additives.

Example 1Preparation of sulforaphene capsule 1

Adding corn oil 9.8kg into 200g of the sulforaphene obtained in the above steps to prepare a sulforaphene oil solution of 2% (mass percentage concentration, the mass percentage content not described in the following is a mass percentage number). The solution was then stirred for 10min to disperse the solution uniformly, at which point the solution was cloudy. After being placed in a refrigerator at 4 ℃ for 2 hours, the solution is clear and transparent and is light yellow. Storing in a refrigerator at 4 deg.C for use. Mixing glycerol, gelatin and water at a mass ratio of 9:10:1 to prepare capsule coating, and preparing into 500 mg/capsule by a capsule machine.

Example 2Preparation of sulforaphene capsule 2

100g of the sulforaphene extract prepared as above was mixed with 1.9kg of dextrin in 10L of deionized water and dissolved, and spray-dried in the same manner as in example 1 to prepare sulforaphene spray-dried powder having a content of 5%. Then preparing a capsule envelope by using the gelatin and water, and preparing each 500mg of the sulforaphene hard capsule by using a capsule machine.

Example 3Preparation of sulforaphene capsule 3

Adding soybean oil 9.8kg into 200g of the sulforaphane obtained in the above step to prepare a sulforaphane oil solution with the concentration of 2%. The solution was then stirred for 10min to disperse the solution uniformly, at which point the solution was cloudy. After being placed in a refrigerator at 4 ℃ for 2 hours, the solution is clear and transparent and is light yellow. Storing in a refrigerator at 4 deg.C for use. And mixing glycerol, gelatin and water according to the mass ratio of 9:10:1 to prepare a capsule coating, adding 200g of cellulose acetate phthalate as an enteric coating, and preparing the 500mg sulforaphene enteric capsule by a capsule machine.

Example 4Preparation of sulforaphene capsule 4

Adding corn oil 9.6kg into 400g of the sulforaphane obtained in the above steps to prepare a sulforaphane oil solution with the concentration of 4%. The solution was then stirred for 10min to disperse the solution uniformly, at which point the solution was cloudy. After being placed in a refrigerator at 4 ℃ for 2 hours, the solution is clear and transparent and is light yellow. Storing in a refrigerator at 4 deg.C for use. Mixing glycerol, gelatin and water according to the mass ratio of 9:10:1 to prepare a capsule coating, adding 200g of cellulose acetate phthalate as an enteric coating, and preparing the raphanin soft capsule with 500mg per capsule by a capsule machine.

Example 5Preparation of sulforaphene capsule 5

Adding corn oil 9.8kg into 200g of the sulforaphane obtained in the above steps to prepare a sulforaphane oil solution with the concentration of 2%. The solution was then stirred for 10min to disperse the solution uniformly, at which point the solution was cloudy. After being placed in a refrigerator at 4 ℃ for 2 hours, the solution is clear and transparent and is light yellow. Storing in a refrigerator at 4 deg.C for use. Mixing glycerol, gelatin and water at a mass ratio of 9:10:1 to prepare a capsule coating, and preparing the raphanin soft capsule with 250mg per capsule by a capsule machine.

Example 6Preparation of sulforaphane capsule 6

400g of sulforaphane obtained in the above steps is added with 9.6kg of corn oil to prepare 4% sulforaphane oil solution. The solution was then stirred for 10min to disperse the solution uniformly, at which point the solution was cloudy. After being placed in a refrigerator at 4 ℃ for 2 hours, the solution is clear and transparent and is light yellow. Storing in a refrigerator at 4 deg.C for use. Then mixing glycerol, gelatin and water according to the mass ratio of 9:10:1 to prepare a capsule coating, simultaneously adding 100g of polyvinylpyrrolidone as a controlled release coating, and preparing by a capsule machine to obtain the sulforaphane soft capsule of 500mg per capsule.

Example 7Preparation of sulforaphane capsule 7

Adding corn oil 9.8kg into 200g of sulforaphane obtained in the above steps to prepare a sulforaphane oil solution with the concentration of 2%. The solution was then stirred for 10min to disperse the solution uniformly, at which point the solution was cloudy. After being placed in a refrigerator at 4 ℃ for 2 hours, the solution is clear and transparent and is light yellow. Storing in a refrigerator at 4 deg.C for use. Then mixing glycerol, gelatin and water according to the mass ratio of 9:10:1 to prepare a capsule envelope, and preparing the sulforaphane soft capsule with 500mg per capsule by a capsule machine.

Example 8Preparation of sulforaphane capsule 8

100g of the sulforaphane extract prepared as described above was mixed with 1.9kg of dextrin in 10L of deionized water and dissolved, and spray-dried in the same manner as in example 1 to prepare sulforaphane spray-dried powder having a content of 5%. Then preparing a capsule envelope by using the gelatin and water, and preparing the sulforaphane hard capsule with 500mg per capsule by using a capsule machine.