WO2012003804A1

WO2012003804A1 - Pharmaceutical composition of silybin and preparation method thereof

Info

Publication number: WO2012003804A1
Application number: PCT/CN2011/076988
Authority: WO
Inventors: 陈建明; 陈明; 朱永宏; 张兰兰; 马晓慧; 赵颖
Original assignee: 天津天士力制药股份有限公司
Priority date: 2010-07-09
Filing date: 2011-07-08
Publication date: 2012-01-12
Also published as: CN102958510B; CN102958510A; CN102309441B; CN102309441A

Abstract

A pharmaceutical composition of silybin and a preparation method thereof. The pharmaceutical composition comprises a silybin infusion solution and a liquid infusion solvent; both are respectively held in a container and packaged together. The silybin infusion solution comprises an active ingredient, a phospholipid, and infusion solvent A. The liquid infusion solvent comprises a bile salt and infusion solvent B.

Description

Silibinin drug combination package and preparation method thereof

Technical field

The invention relates to the technical field of medicine, and relates to a medicine combination package and a preparation method thereof, in particular to a silybin medicine combination package and a preparation method.

Background technique

Silibinin, drug alias: silymarin, Yiganling, Silybin, Silymarin, LEGALON. Silybin is an active ingredient extracted from the seeds of the genus Silybum mananum (L) Gaertn. It is a polyhydroxyphenylchromanone, which has another isomer, called Isosillbmm (Isosillbmm, Isosilybm). Pharmacological studies have found that silybin has a significant protective effect on the liver, which is reflected in the elimination of reactive oxygen species in the body, against lipid peroxidation, inhibition of nitric oxide (NO) production, inhibition of 5-lipoxygenase activity, and resistance. Glutathione (GsH) emptying, and protection of liver cell membrane, promotion of hepatocyte repair, regeneration, immune regulation, anti-fibrosis and other pharmacological effects, in addition to carbon tetrachloride, muscarinic and other liver toxic substances Types of liver damage have obvious protective effects. Therefore, silybin has become one of the widely used hepatoprotective drugs for various liver diseases such as chronic liver disease, toxic hepatitis, cirrhosis, fatty liver, alcoholic liver damage, and other poisoning metabolic liver damage. Treatment.

Various silybin preparations used in early clinical practice are mostly oral preparations, but because they are almost insoluble in water and oil, the bioavailability is low and the absorption is unstable, which greatly reduces the clinical efficacy. In order to improve the curative effect, the oral preparations of silibinin and the phospholipid complex were successively marketed, and although the curative effect was improved, the bioavailability was not significantly improved.

In order to significantly improve the bioavailability of silibinin in vivo, it can be prepared into an injection preparation for use. Since it is directly administered intravenously, the bioavailability can reach 100%, and the effect of silybin on protecting the liver is remarkably improved. For patients, it can shorten the treatment time and save the cost of treatment. At present, many studies on silymarin injection have been prepared as meglumine salts, and then lyophilized powders are prepared by dissolving with alkaline water for injection (pH > 9.0) or aqueous meglumine solution before use. Dosing. Due to the following two shortcomings, its clinical use is limited. First, the alkaline pH of the aqueous meglumine salt solution is too large, pH>9.0, and the normal pH of human blood is 7.35-7.45, which will bring many adverse reactions to the patients, and the silibinin is alkaline. The solution is extremely unstable, and the content will decrease during preparation and clinical use, which will affect the therapeutic effect. Secondly, the complicated preparation process has caused many difficulties for large-scale production. The preparation of silybin-glucosamine salt The residual organic solvent and the loss of the drug, the preparation process of the meglumine salt lyophilized powder is long and complicated, and the preparation cost of the injection is obviously increased.

In view of the above-mentioned deficiencies, the present invention provides a stable and effective silybin injection and a preparation process thereof.

Summary of the invention

The object of the present invention is to solve the shortcomings of the existing silybin preparation, and to provide a silybin pharmaceutical combination package with good stability, small toxic and side effects and remarkable curative effect.

The package of the silybin pharmaceutical composition of the present invention is packaged by a combination of a silybin injection solution and an injection solvent, and the two medicaments are separately loaded in a container and packaged together. It should be specially pointed out that the combination package described here does not care what kind of material is packaged, as long as the material is suitable for packaging as a medicine; it does not care whether the package is like How to package the pharmaceutical composition in any manner, as long as the package is suitable for respectively sealing the silybin injection solution and the injection solvent solution respectively. The two agents described herein are separately loaded in the container, meaning that the two solutions are each closed and do not communicate, and not necessarily the two containers must be spatially isolated from each other. For example, the two containers may be directly related to each other. Connected together, or there may be a pipeline in the middle, which are respectively closed before use, and the pipeline between the two can be opened during use to make the two communicate. In other words, the present specification is only a part of the scope of the present invention, and it is intended that the present invention is not limited to the scope of the present invention.

Wherein, the silybin injection solution of the present invention comprises the following components:

Component content (g / ml)

Active pharmaceutical ingredient 0.01-10.0%,

Phospholipid 0.1-30.0%,

Injection solvent A

among them

The pharmaceutically active ingredient is selected from the group consisting of: silybin or silybin phospholipid complex;

The phospholipid is selected from the group consisting of: soybean lecithin, egg yolk lecithin, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine, preferably soy lecithin and / or egg yolk lecithin;

The solvent A for injection is selected from one or more of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, glycerin, propylene glycol and absolute ethanol, preferably propylene glycol, One or more of water ethanol and polyethylene glycol 400.

Preferably, the silybin injection solution of the present invention consists of the following components:

Component content (g / ml)

Pharmaceutical active ingredient 0.1-5.0%;

Phospholipids 2.0-25%;

Solvent for injection A balance.

More preferably, the silybin injection solution of the present invention consists of the following components:

Component content (g / ml)

Silibinin 0.3%

Soy lecithin 10%

Propylene glycol balance.

Wherein, the injection vehicle of the present invention consists of the following components:

Component content (g / ml)

Bile salt 0.1-20.0%,

Solvent B for injection.

among them,

The bile salt is selected from the group consisting of sodium cholate, sodium deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium hyodeoxycholate, sodium taurocholate and dehydrocholic acid. One or more of sodium, preferably: sodium cholate and/or sodium deoxycholate; The solvent B for injection is selected from the group consisting of: propylene glycol and/or water for injection, preferably water for injection.

Preferably, the injectable vehicle of the present invention consists of the following ingredients:

Component content (g / ml)

Bile salt 5.0-15.0%;

Solvent B for injection.

More preferably, the injectable vehicle of the present invention consists of the following ingredients:

Component content (g / ml)

Sodium deoxycholate 10%;

Solvent B for injection.

In the silybin pharmaceutical combination package of the present invention, the volume ratio of the silybin injection solution to the injection vehicle is 1:99 to 99:1, preferably 1:9 to 9:1.

The formulation of other most preferred silybin pharmaceutical combination packages of the present invention is described in the Examples.

When the silybin pharmaceutical combination package of the present invention is used in clinical use, the two can be mixed and diluted with a diluent to be intravenously administered, and the diluent can be any clinically usable diluent, including but not limited to Glucose injection, physiological saline injection or the like is preferably a glucose injection. The amount of diluent used can be readily determined by the clinician based on the prior art and the basic knowledge at his disposal.

The silybin pharmaceutical combination package of the present invention may further comprise a diluent, and the diluent may be any clinically useful diluent, including but not limited to glucose injection, physiological saline injection, etc., preferably glucose injection.

In the silybin pharmaceutical combination package of the present invention, the volume ratio of the silybin injection solution, the injection vehicle to the diluent is 1-99: 1-99: 1-99, preferably 1-9: 1-9: 1~9.

Another object of the present invention is to provide a method for preparing a silybin pharmaceutical combination package according to the present invention.

The preparation method of the silybin pharmaceutical combination package of the present invention comprises: separately preparing a silybin injection solution and an injection solvent, and packaging them together.

Wherein, the silybin pharmaceutical combination package according to the present invention, when the medicinal active ingredient in the silybin injection solution is silybin, the preparation of the silybin injection solution comprises the following steps:

(1) dissolving the pharmaceutically active ingredient and the phospholipid in an appropriate amount of the solvent A for injection according to the above ratio;

(2) Adding a needle to the above solution to adsorb impurities with activated carbon, filtering, and separating and sterilizing the filtrate.

Specifically, the preparation of the silybin injection solution comprises the following steps:

(1) adding the active ingredient of the drug, phospholipid to an appropriate amount of the solvent A for injection, stirring or shearing at 25-80 Torr, and then diluting to the full amount with the solvent for injection;

(2) Add 0.02% -3.5% (g / ml) of the solution to the above solution and add it to the activated carbon for 30-70 minutes, then filter for 20-70 minutes, then filter and sterilize the filtrate.

In the silybin pharmaceutical combination package of the present invention, if the active ingredient of the silybin injection solution is a silybin phospholipid complex, the silybin phospholipid complex can be purchased from the market, or Prepared according to methods of the prior art, or According to the following formula, it is made by the following methods:

Formula of silybin phospholipid complex: silybin: phospholipid = 1: 0.5-1: 10, the ratio is mass ratio;

Wherein the phospholipid in the silybin phospholipid complex is selected from the group consisting of soy lecithin, egg yolk lecithin, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine One or more, preferably soy lecithin and/or egg yolk lecithin.

The preparation method of the silybin phospholipid complex may specifically be: adding silybin and phospholipid to 5-50 times the amount of absolute ethanol, dissolving in a 40Ό-55 Ό water bath, and then removing the ethanol by rotary evaporation, the obtained powder is A phospholipid complex for silybin.

In the silybin pharmaceutical combination package of the present invention, the preparation of the injection vehicle comprises the following steps: (1) dissolving the bile salt with the solvent B for injection according to the above ratio;

Specifically, the preparation of the injection vehicle includes the following steps:

(1) The bile salt is added to an appropriate amount of the injection solvent B according to the ratio, stirred or sheared and dissolved at 25-80 Torr, and then made up to the full amount with the solvent B for injection;

(2) Add 0.02% -3.5% (g / ml) of the solution in the above solution to the activated carbon, and sorb for 30-70 minutes at 30-75 Torr, then filter, and dispense and sterilize the filtrate.

Wherein, the sterilization of the injection solution and the solvent preparation process of the present invention is carried out by using high-temperature steam, circulating steam or a microporous membrane, preferably by high-temperature steam, wherein the high-temperature sterilization temperature is 100-121 Ό , time 8-45 minutes; filter devices used include, but are not limited to, microporous membranes, sand filter rods, funnels or capsule filters.

The most preferred method for preparing silymarin injection according to the present invention is described in the examples.

Compared with the conventional oral preparation, the silybin pharmaceutical combination package of the invention significantly improves the bioavailability and greatly improves the liver protection effect; compared with the existing silybin injection freeze-dried powder preparation, the present The invention of the silybin pharmaceutical combination package has higher safety and stability and prolongs the shelf life of the product. In addition, the preparation method of the pharmaceutical combination package of the invention is simple, the raw material price is low, and the production cost of the pharmaceutical combination package of the invention is also significantly reduced.

detailed description

The invention is further illustrated by the following specific examples, which are not to be construed as limiting.

Embodiment 1. The silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 0.5 g of silibinin, add 15 g of soy lecithin to an appropriate amount of propylene glycol, cut at 50 Ό (100 rpm) until the drug and phospholipid are completely dissolved, then make up to 150 ml with propylene glycol, add activated carbon with needle 2.5 g to the above solution, adsorbed in 40 30 for 30 minutes, filtered with a microporous membrane, placed in a glass bottle at 1.5 ml / aliquot, routinely filled with nitrogen, sealed, sterilized with a high temperature steam sterilizer 121 15 15 Minutes, that is, the silybin injection solution.

2. Preparation of injection vehicle

Weigh 35 grams of sodium deoxycholate to the appropriate amount of water for injection, stir at 25 使 to dissolve, then dilute to 350 ml with water for injection, add 3.5 g of activated carbon to the above solution, and adsorb for 30 minutes at 35 Torr. , filtered with a microporous membrane, press 3.5 ml / aliquot is placed in a glass bottle, routinely nitrogen-filled, sealed, and sterilized in a high-temperature steam sterilizer for 121 minutes for 15 minutes to obtain a solvent.

In clinical use, a silybin injection solution is uniformly mixed with an injection vehicle, and then diluted in 5% glucose or 10% glucose injection.

Example 2: Silibinin injection of the present invention

1. Preparation of silybin injection solution

Weigh 1 gram of silybin, 20 grams of soy lecithin and add to the appropriate amount of propylene glycol, cut at 50 ° C (8000 rpm) until the drug and phospholipids are completely dissolved, then make up to 150 ml with propylene glycol, add needle 6 g of activated carbon was added to the above solution, adsorbed at 60 ° C for 20 minutes, filtered through a microporous membrane, placed in a glass bottle at 1.5 ml / branch, routinely filled with nitrogen, sealed, and sterilized with a high temperature steam 115 Ό After sterilizing for 18 minutes, the silybin injection solution was obtained.

2. Preparation of injection vehicle

Weigh 17.5 grams of sodium deoxycholate to a suitable amount of water for injection, stir to dissolve at 25 Torr, then dilute to 350 ml with water for injection, add 1.75 g of activated carbon to the above solution, and adsorb for 25 minutes at 45 Torr. It was filtered through a microporous membrane, placed in a glass bottle at 3.5 ml/branch, routinely filled with nitrogen, sealed, and sterilized by a high-temperature steam sterilization pot for 18 minutes for 18 minutes to obtain an injection medium.

Example 3, the silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 1.5 grams of silibinin, 35 grams of egg yolk lecithin and add to the right amount of propylene glycol, cut at 50 Ό

(1000OOrpm) until the drug and phospholipids are completely dissolved, then make up to 300 ml with propylene glycol, add 10.5 g of activated carbon to the above solution, adsorb in 53 30 for 30 minutes, filter with a capsule filter, press 3 ml / support It is divided into glass bottles, routinely filled with nitrogen, sealed, and sterilized by high-temperature steam sterilization pot for 115 minutes for 30 minutes to obtain silybin injection solution.

2. Preparation of injection vehicle

Weigh 15 g of sodium deoxycholate to the appropriate amount of water for injection, stir at 35 使 to dissolve, then dilute to 200 ml with water for injection, add 1.1 g of activated carbon to the above solution, and adsorb for 35 minutes at 55 Torr. Filtered with a capsule filter, placed in a glass bottle at 2 ml / aliquot, routinely nitrogen-filled, sealed, and sterilized in a high-temperature steam sterilizer for 115 minutes for 30 minutes to obtain a solvent.

Example 4, the silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 1.67 g of silibinin, 10 g of soy lecithin and 13 g of egg yolk lecithin and add to the appropriate amount of propylene glycol, and cut at 70 ° C (100 rpm) until the drug and phospholipid are completely dissolved, then dilute to the propylene glycol to 200 ml, activated carbon with needle 4.7 g to the above solution, adsorbed at 30 ° C for 70 minutes, filtered with a sand filter rod, placed in a glass bottle at 2 ml / aliquot, routinely nitrogen-filled, sealed, and sterilized with 100 Torr steam for 35 minutes, ie You can get the silybin injection solution.

2. Preparation of injection vehicle

Weigh 18 g of sodium deoxycholate to an appropriate amount of propylene glycol, stir it at 40 Torr to dissolve it, then dilute to 300 ml with propylene glycol, add 1.5 g of activated carbon to the above solution, and adsorb at 70 Torr for 70 minutes. The filter rod was filtered, placed in a glass bottle at 3 ml/branch, routinely filled with nitrogen, sealed, and sterilized with 100 Torr of steam for 35 minutes to obtain an injection medium.

Example 5, the silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 0.3 g of silibinin, add 6 g of soy lecithin to an appropriate amount of absolute ethanol, cut at 50 Ό (100 rpm) until the drug and phospholipid are completely dissolved, then dilute to 300 ml with absolute ethanol. 5 kg of activated carbon was added to the above solution, adsorbed in 60 Torr for 30 minutes, filtered through a microporous membrane, placed in a glass bottle at 3 ml/branch, routinely filled with nitrogen, sealed, and sterilized with a high temperature steam 121 After sterilizing for 12 minutes, the silybin injection solution was obtained.

2. Preparation of injection vehicle

Weigh 10 g of sodium cholate to an appropriate amount of water for injection, stir at 50 使 to dissolve it, then dilute to 200 ml with water for injection, add 0.4 g of activated carbon to the above solution, and adsorb at 60 30 for 30 minutes. The microporous membrane was filtered, placed in a glass bottle at 2 ml/branch, routinely filled with nitrogen, sealed, and sterilized in a high-temperature steam sterilization pot for 12 minutes for 12 minutes to obtain an injection medium.

In clinical use, mix a silybin injection solution with an injection vehicle and dilute it to 5% glucose or

Instillation in 10% glucose injection.

Example 6. Silibinin injection of the present invention

1. Preparation of silybin injection solution

Weigh 1.67 g of silibinin, 0.75 g of distearoylphosphatidylcholine and add to 40 ml of propylene glycol, and cut at 100 Torr (100 rpm) until the drug and phospholipid are completely dissolved, then make up to 50 with absolute ethanol. ML, add 0.1 g of activated carbon to the above solution, adsorb in 45 Ό for 25 minutes, filter with a capsule filter, and place it in a glass bottle at 0.5 ml/min., routinely fill with nitrogen, seal, and extinguish with high temperature steam. The fungus pot 118 is sterilized for 20 minutes, and the silybin injection solution is obtained.

2. Preparation of injection vehicle

Weigh 36 g of sodium cholate to an appropriate amount of water for injection, stir to dissolve at 50 Torr, then dilute to 450 ml with water for injection, add 0.9 g of activated carbon to the above solution, and adsorb at 45 30 for 30 minutes. It was filtered with a capsule filter, placed in a glass bottle at 4.5 ml/min, routinely filled with nitrogen, sealed, and sterilized by a high-temperature steam sterilization pot for 118 minutes for 20 minutes to obtain an injection medium.

In clinical use, a silybin injection solution is uniformly mixed with an injection vehicle, and then diluted in 5% glucose or 10% glucose injection. Example 7, the silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 45 g of silybin, 82.5 g of soy lecithin and 52.5 g of dipalmitoylphosphatidylcholine into 150 ml of propylene glycol, and cut at 70 Torr (100 rpm) until the drug and phospholipid are completely dissolved, and then polymerized. Ethylene glycol 400 to a volume of 450 ml, add 0.09 g of activated carbon to the above solution, adsorb in 60 20 for 20 minutes, filter with a microporous membrane, and place it in a glass bottle at 4.5 ml/min. , Sealed, sterilized with 100 Ό steam for 35 minutes, that is, Silibinin injection solution.

2. Preparation of injection vehicle

Weigh 5 grams of sodium glycocholate and 5 grams of sodium dehydrocholate to a suitable amount of water for injection, stir at 65 使 to dissolve, then dilute to 50 ml with water for injection, add 0.025 g of activated carbon to the above In the solution, it was adsorbed for 30 minutes at 35 Torr, filtered through a microporous membrane, placed in a glass bottle at 0.5 ml/branch, routinely filled with nitrogen, sealed, and sterilized by circulating steam for 100 minutes for 100 minutes to obtain an injection medium.

Example 8. Silibinin injection of the present invention

1. Preparation of silybin injection solution

Weigh 0.8 g of silibinin, 20.7 g of soy lecithin and add to the appropriate amount of propylene glycol, cut at 65 Ό (100 rpm) until the drug and phospholipid are completely dissolved, then make up to 200 ml with propylene glycol, add activated carbon with needle 6.7 g to the above solution, adsorbed in 60 30 for 30 minutes, filtered with a microporous membrane, placed in a glass bottle at 2 ml / aliquot, routinely filled with nitrogen, sealed, sterilized with a high temperature steam sterilizer 121 10 10 Minutes, that is, the silybin injection solution. 2. Preparation of injection vehicle Weigh 30 grams of sodium deoxycholate to a suitable amount of water for injection, stir at 35 使 to dissolve, then dilute to 300 ml with water for injection, add 10.5 g of activated carbon to the above solution. After adsorption for 30 minutes at 35 Torr, it was filtered through a microporous membrane, and placed in a glass bottle at 3 ml/branch. It was routinely nitrogen-filled, sealed, and sterilized by a high-temperature steam sterilization pot for 10 minutes to obtain an injection medium.

Instillation in 10% glucose injection.

Example 9. Silibinin injection of the present invention

1. Preparation of silybin injection solution

Weigh 0.03 g of silybin, 0.6 g of dimyristoylphosphatidylcholine and 0.4 g of soy lecithin into 200 ml of propylene glycol, and cut at 45 Ό (100 rpm) until the drug and phospholipid are completely dissolved, and then The glycerin is adjusted to 300 ml, 0.5 g of activated carbon is added to the above solution, and adsorbed in 40 Torr for 30 minutes, filtered through a microporous membrane, and placed in a glass bottle at a concentration of 3 ml/branch, conventionally filled with nitrogen, sealed, The silibinin injection solution was obtained by sterilizing with a high-temperature steam sterilization pot 121 for 15 minutes.

2. Preparation of injection vehicle

Weigh 0.1 g of sodium glycodeoxycholate and 0.1 g of sodium dehydrocholate to the appropriate amount of water for injection, stir at 25 使 to dissolve Solution, then make up to 200 ml with water for injection, add 1 gram of activated carbon to the above solution, adsorb at 35 30 for 30 minutes, filter with a microporous membrane, and place in a glass bottle at 2 ml / aliquot. Nitrogen, seal, and sterilize in a high-temperature steam sterilization pot at 121 °C for 15 minutes to obtain a solvent.

Example 10, the silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 0.85 g of silibinin, add 40 g of soy lecithin to an appropriate amount of propylene glycol, cut at 80 Ό (100 rpm) until the drug and phospholipid are completely dissolved, then make up to 150 ml with propylene glycol, add activated carbon with needle 5.7 g to the above solution, adsorbed in 75 Ό for 30 minutes, filtered through a funnel to remove activated carbon, and sterilized by 0.22 μηηι microfiltration membrane, and placed in a glass bottle at 1.5 ml/branch, conventional nitrogen filling. , Sealing, that is, the Silibinin injection solution.

2. Preparation of injection vehicle

Weigh 70 g of sodium deoxycholate to a suitable amount of water for injection, stir at 80 Torr to dissolve it, then make up to 350 ml with water for injection, add 10.5 g of activated carbon to the above solution, and adsorb for 30 minutes at 75 Torr. The activated carbon was filtered through a funnel, filtered and sterilized by a 0.22 μηη microporous membrane filter, and placed in a glass bottle at 3.5 ml/branch. The nitrogen was routinely filled and sealed to obtain an injection medium.

Example 11, the silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 7.5 g of silibinin, 27.5 g of soy lecithin and 5 g of egg yolk lecithin into an appropriate amount of propylene glycol, cut at 50 Torr (100 rpm) until the drug and phospholipid are completely dissolved, then make up to 150 ml with propylene glycol. Add 4 grams of activated carbon to the above solution, adsorb in 40 30 for 30 minutes, filter with microporous membrane, and place it in a glass bottle at 1.5 ml/min., routinely fill with nitrogen, seal, and sterilize with high temperature steam. After sterilizing for 118 minutes, the silybin injection solution was obtained.

2. Preparation of injection vehicle

Weigh 43.8 g of sodium deoxycholate and 8.7 g of sodium cholate to the appropriate amount of water for injection, stir to dissolve at 25 Torr, then dilute to 350 ml with water for injection, and add 2.3 g of activated carbon to the above solution. After adsorption for 30 minutes at 35 Torr, it was filtered through a microporous membrane, and placed in a glass bottle at 3.5 ml/branch. It was routinely nitrogen-filled, sealed, and sterilized by a high-temperature steam sterilization pot for 118 minutes for 15 minutes to obtain an injection medium.

Instillation in 10% glucose injection.

Example 12, the silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 0.73 g of silibinin, 5 g of egg yolk lecithin and add to 70 ml of propylene glycol, and cut at 50 Ό (1000OOrpm) until the drug and phospholipids are completely dissolved, then make up to 150 ml with absolute ethanol, add 3.5 g of activated carbon to the above solution, adsorb in 40 Ό for 30 minutes, filter with microporous membrane, press 1.5 ml / The branch is placed in a glass bottle, routinely filled with nitrogen, sealed, and sterilized with 100 Torr of steam for 45 minutes to obtain a silybin injection solution.

2. Preparation of injection vehicle

Weigh 17.5 grams of sodium taurocholate and 7 grams of sodium ursodeoxycholate to a suitable amount of water for injection, stir to dissolve at 25 ,, then dilute to 350 ml with water for injection, add 10.5 g of activated carbon to the above In the solution, it was adsorbed for 30 minutes at 35 Torr, filtered through a microporous membrane, and placed in a glass bottle at 3.5 ml/branch. It was routinely nitrogen-filled, sealed, and sterilized by circulating steam at 100 Torr for 45 minutes to obtain an injection medium.

Example 13, the silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 3.51 g of silibinin, add 10 g of soy lecithin to 100 ml of propylene glycol, cut at 65 Ό (100 rpm) until the drug and phospholipids are completely dissolved, then dilute to 200 ml with polyethylene glycol 200. Add 3.3 g of activated carbon to the above solution, adsorb in 40 30 for 30 minutes, filter with a capsule filter, place in a glass bottle at 2 ml/branch, routinely fill with nitrogen, seal, and sterilize the pot with high temperature steam. C sterilization for 15 minutes, that is, the silybin injection solution.

2. Preparation of injection vehicle

Weigh 40.5 grams of sodium ursodeoxycholate to a suitable amount of water for injection, stir at 45 使 to dissolve it, then dilute to 300 ml with water for injection, add 6 g of activated carbon to the above solution, and adsorb at 35 Ό. After 30 minutes, it was filtered through a microporous membrane, and placed in a glass bottle at 3 ml/branch. It was routinely nitrogen-filled, sealed, and sterilized by a high-temperature steam sterilization pot for 15 minutes for 15 minutes to obtain an injection medium.

Example 14, the silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 2.1 g of silybin, 17 g of soy lecithin and 27 g of dipalmitoylphosphatidylcholine into 140 ml of propylene glycol, and cut at 40 ° C (l OOOOrpm) until the drug and phospholipid are completely dissolved, then Make up to 400 ml with polyethylene glycol 600, add 10 g of activated carbon to the above solution, adsorb in 40 Ό for 30 minutes, filter with a capsule filter, and place it in a glass bottle at 4 ml/min. Conventional nitrogen filling, sealing, sterilization with a high-temperature steam sterilization pot 118 15 for 15 minutes, that is, the silybin injection solution.

2. Preparation of injection vehicle

Weigh 9 g of sodium taurocholate to a suitable amount of water for injection, stir at 55 使 to dissolve it, then dilute to 100 ml with water for injection, add 1.5 g of activated carbon to the above solution, and adsorb for 30 minutes at 35 Torr. Filtered with a bag filter, placed in a glass bottle at 1 ml / aliquot, routinely nitrogen-filled, sealed, and sterilized in a high-temperature steam sterilizer for 118 minutes for 15 minutes to obtain a solvent. In clinical use, a silybin injection solution is uniformly mixed with an injection vehicle, and then diluted in 5% glucose or 10% glucose injection.

Embodiment 15. The silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 1 gram of silybin, 14 grams of soy lecithin and add to the appropriate amount of propylene glycol, cut at 60 ° C (8000 rpm) until the drug and phospholipids are completely dissolved, then make up to 150 ml with propylene glycol, add needle Activated 4.5 g of activated carbon into the above solution, adsorbed in 40 Ό for 30 minutes, filtered through a microporous membrane, placed in a glass bottle at 1.5 ml/branch, routinely filled with nitrogen, sealed, and sterilized with a high-temperature steam sterilizer 121 In 15 minutes, you can get the silybin injection solution.

2. Preparation of injection vehicle

Weigh 42 grams of sodium hyodeoxycholate to a suitable amount of water for injection, stir at 35 使 to dissolve it, then dilute to 350 ml with water for injection, add 2.6 g of activated carbon to the above solution, and adsorb at 35 Ό. After 30 minutes, it was filtered through a microporous membrane, and placed in a glass bottle at 2 ml/branch. It was routinely nitrogen-filled, sealed, and sterilized by a high-temperature steam sterilization pot for 15 minutes for 15 minutes to obtain an injection medium.

Embodiment 16. The silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 1.2 g of silibinin, 12 g of dimyristoyl phosphatidylcholine and 16 g of lecithin and add to 190 ml of absolute ethanol, and cut at 100 ° C (100 rpm) until the drug and phospholipid are completely dissolved. Then, make up to 300 ml with propylene glycol, add 10 g of activated carbon to the above solution, add adsorption in 40 Torr for 30 minutes, filter with a microporous membrane, and place it in a glass bottle at 3 ml/min. The seal was sterilized by circulating steam at 100 Torr for 35 minutes to obtain a silybin injection solution.

2. Preparation of injection vehicle

Weigh 9 grams of sodium ursodeoxycholate and 10 grams of sodium glycodeoxycholate to a suitable amount of water for injection, stir at 45 使 to dissolve, then dilute to 200 ml with water for injection, add 2.1 g of activated carbon with needle Into the above solution, adsorbed at 35 30 for 30 minutes, filtered through a microporous membrane, packed in a glass bottle at 2 ml/branch, routinely filled with nitrogen, sealed, and sterilized by circulating steam for 100 minutes for 35 minutes. .

Example 17, the silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 0.45 g of silybin, add 45 g of soy lecithin to an appropriate amount of propylene glycol, cut at 80 Ό (100 rpm) until the drug and phospholipid are completely dissolved, then make up to 150 ml with propylene glycol, add activated carbon with needle 0.03 g to the above solution, adsorbed in 75 Ό for 30 minutes, filtered through a funnel to remove activated carbon, and sterilized by 0.22 μηηι microfiltration membrane, and placed in a glass bottle at 1.5 ml/min. , Sealing, that is, the Silibinin injection solution. 2. Preparation of injection vehicle

Weigh 2.6 g of sodium cholate to 170 ml of propylene glycol, stir to dissolve at 25 Torr, then make up to 350 ml with water for injection, add 1.75 g of activated carbon to the above solution, and adsorb for 30 minutes at 35 Torr. The activated carbon was filtered through a funnel, filtered and sterilized by a 0.22 μηη microporous membrane filter, and placed in a glass bottle at 3.5 ml/branch. The nitrogen was routinely filled and sealed to obtain an injection medium.

Example 18, the silybin injection of the present invention

1. Preparation of silybin phospholipid complex

4 g of silybin and 4.8 g of soybean lecithin were added to 168 ml of absolute ethanol, dissolved in a 40 Torr water bath, and then evaporated to remove ethanol, and the obtained powder was a phospholipid complex of silibinin.

2. Preparation of silybin injection solution

Weigh 1.87 g of silybin phospholipid complex, add 22.7 g of soy lecithin to an appropriate amount of propylene glycol, cut at 50 Torr (100 rpm) until the drug and phospholipid are completely dissolved, then make up to 200 ml with propylene glycol, add needle 3.3 g of activated carbon was added to the above solution, adsorbed in 50 Torr for 30 minutes, filtered through a microporous membrane, placed in a glass bottle at 0.5 ml/min, routinely filled with nitrogen, sealed, and annihilated with a high temperature steam sterilizer 115. After 20 minutes of bacteria, the solution of silybin injection solution was obtained.

3. Preparation of injection vehicle

Weigh 36 grams of sodium ursodeoxycholate and 15 grams of sodium taurocholate to 100 milliliters of propylene glycol, stir to dissolve at 25 Torr, then dilute to 300 ml with water for injection, add 9 grams of activated carbon to the above In the solution, adsorb at 35 Ό for 30 minutes, filter with a microporous membrane, and place it in a glass bottle at 4.5 ml/min., routinely nitrogen-fill, seal, and sterilize in a high-temperature steam sterilization pot for 15 minutes. Inject the vehicle.

Example 19, the silybin injection of the present invention

1. Preparation of silybin phospholipid complex

3 g of silybin and 3.8 g of soybean lecithin were added to 100 ml of absolute ethanol, dissolved in a 40 Torr water bath, and then evaporated to remove ethanol, and the obtained powder was a phospholipid complex of silybin.

2. Preparation of silybin injection solution

Weigh 2 g of silybin phospholipid complex, 30 g of soy lecithin and 20 g of egg yolk lecithin into 100 ml of propylene glycol, cut at 55 ° C (8000 rpm) until the drug and phospholipid are completely dissolved, and then use poly Glycol 300 to a volume of 300 ml, add 5 grams of activated carbon to the above solution, adsorb in 40 30 for 30 minutes, filter with a microporous membrane, and install in a glass bottle at 4.5 ml / branch, conventional nitrogen filling , Sealing, sterilizing with high temperature steam sterilization pot 115 25 for 25 minutes, that is, the silybin injection solution.

3. Preparation of injection vehicle Weigh 12 grams of sodium cholate and 10 grams of sodium dehydrocholate to a suitable amount of water for injection, stir to dissolve at 25 ° C, then dilute to 200 ml with water for injection, add 3 g of activated carbon to the above solution Adsorbed at 35 30 for 30 minutes, filtered through a microporous membrane, placed in a glass bottle at 0.5 ml/min, routinely filled with nitrogen, sealed, and sterilized in a high-temperature steam sterilizer for 115 minutes for 25 minutes. .

Instillation in 10% glucose injection.

Example 20, the silybin injection of the present invention

1. Preparation of silybin phospholipid complex

2 g of silybin, 15 g of soybean lecithin and 5 g of egg yolk lecithin were added to 255 ml of absolute ethanol, dissolved in a 40 Torr water bath, and then ethanol was removed by rotary evaporation, and the obtained powder was a phospholipid complex of silibinin.

2. Preparation of silybin injection solution

Weigh 5 g of silybin phospholipid complex, add 42 g of soy lecithin to 100 ml of propylene glycol, cut at 70 °C (SOOOrpm) until the drug and phospholipid are completely dissolved, then dilute to 150 ml with glycerol, add needle 2 g of activated carbon was added to the above solution, adsorbed in 50 Torr for 30 minutes, filtered through a microporous membrane, placed in a glass bottle at 1.5 ml/branch, routinely filled with nitrogen, sealed, and sterilized with a high temperature steam 118 Ό Sterilize for 20 minutes to obtain the silybin injection solution.

3. Preparation of injection vehicle

Weigh 43.7 g of sodium deoxycholate to 150 ml of propylene glycol, stir to dissolve at 45 Torr, then make up to 350 ml with water for injection, add 12.25 g of activated carbon to the above solution, and adsorb for 30 minutes at 35 Torr. It was filtered through a microporous membrane, placed in a glass bottle at 3.5 ml/branch, routinely filled with nitrogen, sealed, and sterilized by a high-temperature steam sterilization pot for 118 minutes for 20 minutes to obtain an injection medium.

Example 21, the silybin injection of the present invention

1. Preparation of silybin phospholipid complex

1.5 g of silybin and 1.5 g of egg yolk lecithin were added to 100 ml of absolute ethanol, dissolved in a 40 Torr water bath, and then evaporated to remove ethanol, and the obtained powder was a phospholipid complex of silibinin.

2. Preparation of silybin injection solution

Weigh 1.8 g of silybin phospholipid complex, 24 g of soy lecithin and 5 g of distearoylphosphatidylcholine into 100 ml of propylene glycol, and cut at 55 Ό (8000 rpm) until the drug and phospholipid are completely dissolved. Then, make up to 300 ml with polyethylene glycol 300, add 4.5 g of activated carbon to the above solution, adsorb in 40 Ό for 30 minutes, filter with a microporous membrane, and place in a glass bottle at 3 ml/min. , routine nitrogen filling, sealing, sterilized with high temperature steam sterilization pot 115 25 for 25 minutes, that is, the silybin injection solution.

3. Preparation of injection vehicle

Weigh 12 grams of sodium cholate and 9 grams of sodium chenodeoxycholate to a suitable amount of water for injection, stir at 25 使 to dissolve, then Make up to 200 ml with water for injection, add 2.9 g of activated carbon to the above solution, add for 30 minutes at 35 Torr, filter with a microporous membrane, and place in a glass bottle at 2 ml/min. Sealed and sterilized in a high-temperature steam sterilizer for 115 minutes for 25 minutes.

Example 22, the silybin injection of the present invention

1. Preparation of silybin injection solution

Weigh 2.67 g of the commercially available silybin phospholipid complex, 26.7 g of soy lecithin and 8 g of distearoylphosphatidylcholine into 200 ml of propylene glycol, and cut (8000 rpm) to the drug at 55 °C. Completely dissolve with phospholipid, then dilute to 400 ml with polyethylene glycol 300, add 4.67 g of activated carbon to the above solution, adsorb for 30 minutes at 40 ° C, filter with microporous membrane, press 4 ml / support Dispense in a glass bottle, routinely nitrogen, seal, sterilize in a high-temperature steam sterilizer for 115 minutes, then get the silybin injection solution.

2. Preparation of injection vehicle

Weigh 10 g of sodium ursodeoxycholate to an appropriate amount of water for injection, stir to dissolve at 25 Torr, then dilute to 100 ml with water for injection, add 1.3 g of activated carbon to the above solution, and adsorb at 35 Ό. After 30 minutes, it was filtered through a microporous membrane, and placed in a glass bottle at a concentration of 1 ml/branch. It was routinely nitrogen-filled, sealed, and sterilized by a high-temperature steam sterilization pot for 15 minutes for 25 minutes to obtain an injection medium.

Drug stability test

This test compares the stability of the formulation of the present invention with a conventional formulation in a glucose solution.

Test sample: The sample of the invention is taken as the sample in the first embodiment; the common sample is the meglumine salt of the silybin, which is prepared according to the literature in the brackets (the quality standard and safety evaluation of the silybin powder, Harbin University of Commerce) Journal, 2007, Vol. 23, No. 1, pp. 15-18. The glucose solution is a 5 % glucose injection.

Chromatographic conditions: Liquid phase conditions: Agilent 1100 LC, Agilent G1314A VWD detector, Agilent

G1311A quaternary pump, Agilent G1314A VWD detector, Agilent LC 1100 chromatography data station, analytical column for Diamonsil C 18 analytical column (5μ, 4.6mmx250mm), methanol-2% glacial acetic acid (55:45) for mobile phase, flow rate 1.0 ml/mm, detection wavelength 288 nm, injection volume 20 μl, external standard method to quantify peak area.

Test method: The sample in Example 1 and the common sample were diluted in 5% glucose injection at 80 μ _§ / ml, and the content of Oh was 100%, and the samples were injected at 0h, 2h, 4h, 6h, and the content was compared.

The test results are shown in Table 1. Table 1 Comparison of the stability of the sample of Example 1 with ordinary samples

Meglumine salt Example 1 sample

Oh 100 % 100 %

2h 90.1 % 100.6 %

4h 82.2 % 101.2 %

6h 75.1 % 99.9 %

The above test proves that the preparation of the present invention is more stable in the glucose injection than the meglumine salt of silybin, and has a more research and development prospect.

It was confirmed by experiments that the other contents of the silybin injection described in the present invention were able to achieve the effects described in the test examples. The specific experimental results are shown in Table 2.

Table 2 Comparison of the stability of samples of Examples 3, 7, 11, 18 and 19 with ordinary samples

Glucosamine salt Example 3 Example 7 Example 11 Example 18 Example 19

Oh 100% 100% 100% 100% 100% 100%

2h 90.1% 100.4% 100.7% 100.2% 100.4% 100.6%

4h 82.2% 101.0% 101.2% 101.5% 101.3% 101.3%

6h 75.1% 99.8% 99.8% 99.9% 99.7% 99.9% efficacy test

【Experimental Materials】

1. Animals: SPF male SD rats, animal certificate number: SCXK (Beijing) 2007-0001.

2. Drugs: The formulations of the invention were sampled in Examples 1, 3 and 7; the common sample was the meglumine salt of silibinin; Yi Shanfu, purchased from Sanofi Aventis.

3. Experimental equipment: Automatic biochemical analyzer.

【experimental method】

1. Grouping and administration

SPF male Sprague-Dawley rats weighing 180-220 g were randomly divided into 7 groups: normal group, model group, test drug group (including the preparation group of the present invention; common sample group; Yishanfu injection group), each group 5 only. The drug is administered by tail vein injection. The dosage of the administration and the preparation method of the drug solution are shown in Table 3.

Table 3 Preparation and dosage of drug solution

Group The preparation group of the invention Ordinary sample group Yishan compound group Commonly used dosage 5ml/kg 5ml/kg 5ml/kg

0.8mg/ml 0.8mg/ml

Drug preparation concentration 12mg/ml

(in the case of a scorpionfish) The drug was prepared according to the above concentrations, and the model group was given an equal amount of 5% glucose injection, the form of prophylactic administration, once a day, and the administration cycle time was 5 days.

2. Model preparation

On the 4th day after the administration, the rats were fasted for 24 hours, and the injection and the model group were subcutaneously injected with 25% CC14 peanut oil solution at 0.5 ml/100 g immediately after the last administration on the fifth day. After 18 hours of modeling, blood was taken from the eye for about 1 ml, centrifuged at 3500 r/min for 10 min, and serum -20 Ό was frozen.

3. Test indicators

Determination of ALT and AST in serum by automatic biochemical analyzer

[Experimental results]

The protective effect of drugs on CC14-induced acute liver injury in rats was significantly higher than that in the normal group. The serum levels of ALT and AST in the model group were significantly higher than those in the normal group (P<0.01). Compared with the model group, the preparation group, the common sample and the Yishanfu group of the invention all significantly reduced the serum ALT and AST contents in the acute liver injury rats, and the difference was significant.

Table 4 Protective effects of drugs on acute liver injury induced by CC1 ₄ (± s )

Compared with the model group: <0.05, "P<0.01.

【Experimental results】

This experiment was administered in a preventive manner for 5 days. The results showed that compared with the model group, the preparation group, the common sample and the Yishanfu group of the invention all significantly reduced the serum ALT and AST contents in the acute liver injury rats, and the difference was significant. The results of preliminary experiments showed that the preparation group of the present invention had a better effect on protecting acute liver injury caused by CC14.

Claims

Claim

A silybin pharmaceutical combination package, characterized in that the combination package comprises a silybin injection solution and an injection vehicle, and the silybin injection solution and the injection solvent are respectively loaded in the respective In the container, the package is packaged together,

Wherein, the silybin injection solution is composed of the following weight/volume percentage components:

Active pharmaceutical ingredient 0.01-10.0%,

Phosphorus month 0.1-30.0%,

Injectable solvent A balance;

Wherein the pharmaceutically active ingredient is selected from the group consisting of: silybin or silybin phospholipid complex;

The phospholipid is selected from the group consisting of: soybean lecithin, egg yolk lecithin, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and dimyristoylphosphatidylcholine;

The solvent A for injection is selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, glycerin, propylene glycol and absolute ethanol;

Wherein the injection vehicle consists of the following weight/volume percentage components:

Bile salt 0.1-20.0%,

Solvent for injection B balance;

Wherein, the bile salt is selected from the group consisting of: sodium cholate, sodium deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium hyodeoxycholate, sodium taurocholate and One or more of sodium hydroxycholate;

The solvent B for injection is selected from the group consisting of: propylene glycol and/or water for injection.

2. The pharmaceutical combination package according to claim 1, wherein the silybin injection solution is composed of the following weight/volume percentage components:

Pharmaceutical active ingredient 0.1-5.0%;

Phospholipids 2.0-25%;

Solvent for injection.

3. The pharmaceutical combination package according to claim 2, wherein the silybin injection solution is composed of the following weight/volume percentage components:

Silibinin 0.3%;

Soy lecithin 10%;

Propylene glycol balance.

4. A pharmaceutical combination package according to any one of claims 1 to 3, wherein the injection vehicle consists of the following weight/volume percentage components:

Bile salt 5.0-15.0%;

The remaining amount of solvent for injection.

The pharmaceutical combination package according to claim 4, wherein the injection vehicle is composed of the following weight/volume percentage components:

Sodium deoxycholate 10%;

Solvent for injection.

The pharmaceutical combination package according to any one of claims 1 to 3, wherein the pharmaceutical combination package further comprises a diluent.

7. The pharmaceutical combination package according to claim 6, wherein the diluent is a glucose injection.

The method for preparing a pharmaceutical combination package according to any one of claims 1 to 7, wherein the method comprises separately preparing a silybin injection solution and an injection vehicle, and packaging them together; wherein, when the silybin When the pharmaceutically active ingredient in the injection solution is silibinin, the preparation of the silibinin injection solution comprises the following steps:

(1) Add silybin and phospholipid to an appropriate amount of injectable solvent A according to the ratio, stir or shear to dissolve at 25-80 Torr, and then make up to the full amount with solvent A for injection;

(2) Adding activated carbon to the needle in the above solution at 0.02% -3.5% of the solution amount, adding the amount by weight and volume, adsorbing at 30-75 Torr for 20-70 minutes, then filtering, and separating the filtrate, Sterilize.

The method for preparing a pharmaceutical combination package according to any one of claims 1 to 7, wherein the method comprises separately preparing a silybin injection solution and an injection vehicle, which are packaged together; wherein the injection medium is The preparation method includes the following steps:

The method for preparing a pharmaceutical combination package according to any one of claims 1 to 7, wherein the method comprises separately preparing a silybin injection solution and an injection vehicle, and packaging them together; wherein, when the silybin When the pharmaceutically active ingredient in the injection solution is a silibinin phospholipid complex, the silybin phospholipid complex is prepared according to the following formula:

Formula of silybin phospholipid complex: silybin: phospholipid = 1 : 0.5-1 : 10, the ratio is mass ratio; wherein the phospholipid is selected from the group consisting of: soybean lecithin, egg yolk lecithin, distearyl One or more of acylphosphatidylcholine, dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine;

The silybin phospholipid complex is prepared by adding silybin and phospholipid to 5-50 times the amount of absolute ethanol, dissolving in a 40Ό-55 Ό water bath, and then removing the ethanol by rotary evaporation to obtain the powder. It is the phospholipid complex of silybin.