CN1961874A - Pharmaceutical composition of Silybin and preparation method thereof - Google Patents

Abstract

The invention provides a silibinin-phospholipid complex, which is made into a capsule preparation. The preparation has high dissolution rate, is suitable for oral administration, and is convenient for clinical use; the invention also provides the silibinin-lecithin complex The preparation method of the substance and the capsule preparation thereof has the advantages of simple process and high yield, is suitable for large-scale production, and can meet the requirements of the drug quality management standard (GMP).

Description

Medicinal composition of silybin and preparation method thereof

technical field

The invention relates to the field of drug compound, preparation and preparation method thereof, in particular to silybin drug compound, preparation and preparation method thereof.

technical background

In the late 1960s and 1980s, West German pharmacists represented by H. Wagner extracted and separated the active ingredient from the fruit of Silybum marianum, a plant of the genus Silybum marianum in the family Asteraceae, called silymarin, which is a class of A novel flavonoid compound with a C-9 substituent, that is, flavonoid lignans formed by condensation of dihydroflavonols and phenylpropanoid derivatives. Silybin (Silybin, silibinin) is one of the main components of milk thistle. Pharmacological and toxicological studies have shown that it can protect and stabilize liver cell membranes, promote liver cell recovery, and improve liver function. It has different degrees of protective and therapeutic effects on liver damage caused by various poisons, such as carbon tetrachloride, thioacetamide, muscarine, phalloidin, hyosostigmine, etc. It can be used for acute and chronic hepatitis, early cirrhosis, fatty liver, toxic or drug-induced liver disease.

Since silibinin is insoluble in water and general organic solvents, its oral absorption is poor, and its bioavailability is low, thus affecting its clinical efficacy. In order to improve its bioavailability, domestic and foreign pharmaceutical workers have done a lot of work. Measures to improve the absorption of poorly soluble drugs generally include ultrafine pulverization, salt formation, and addition of co-solvents. In recent years, methods such as making cyclodextrin inclusion complexes, solid dispersions, synthesizing phospholipid complexes, and making different dosage forms have been used. Studies have shown that the dissolution rate and bioavailability have been greatly improved.

From the perspective of solid preparations, phospholipid complex is a relatively special solid dispersion, which has a fixed melting point and is a molecular compound (complex) that is relatively stable in chemical nature and different from drugs and phospholipids. Compounds vary with the type of phospholipids and the ratio of drug phospholipids. One phospholipid molecule can be combined with different numbers of drug molecules. The spectroscopic characteristics of the complex infer that the drug has a strong interaction with the polar group of the phospholipid, which inhibits the free rotation of the single chain in the molecule, while the two long fatty acid chains of the phospholipid do not participate in the complex reaction and can move freely , which wraps the polar part of the phospholipids to form a lipophilic surface, making the complex more lipophilic. It changes the physical and chemical properties of the drug, making the drug more fat-soluble and water-soluble. Promote the combination of drug molecules and cell membranes to promote absorption and improve the bioavailability of drugs.

Xu Jianwen etc. (comparison of the preparation process of silybin-lecithin complex, Chinese Journal of Biochemical Medicine-2002, 5th period, 245-246) disclose a kind of silibinin-lecithin complex and preparation method thereof, the The complex is composed of silibinin and lecithin. The preparation method is as follows: Weigh 43g of silibinin, dissolve it in 1350ml of ethanol to obtain a red clear liquid, add 68g of lecithin, heat and stir until the lecithin is completely dissolved until it becomes clear, About 5-6 minutes, connect the reflux device, react at 55°C for 1 hour, remove the reflux device, evaporate and concentrate while shaking, and immediately pour it into 3150ml of n-hexane when the volume of the liquid evaporates to 270ml, the upper layer of the solution is yellow turbid liquid, and the lower layer is red oily The red oily matter was taken and dried in vacuum to obtain 30 g of red dry matter with a yield of 27%. The method is complex in operation, low in yield, uses a toxic and harmful solvent, has no industrial application value, and does not disclose a method for preparing a preparation suitable for clinical application.

Contents of the invention

Technical problem solved

The invention provides a pharmaceutical composition of silibinin, which is made into a preparation, the preparation has high dissolution rate, is suitable for oral administration, and is convenient for clinical use; the invention also provides the pharmaceutical composition of silybin The compound and the preparation method thereof, the preparation method has the advantages of simple process and high yield, is suitable for large-scale production, and can meet the requirements of the drug quality management standard (GMP).

Technical solutions

A pharmaceutical composition of silybin, comprising silibinin, phospholipids and auxiliary materials, wherein the sum of the weight of silibinin and phospholipids accounts for 10-60% of the total weight of the composition, and silybin and The weight ratio of phospholipids is 1:1-40.

In the medicinal composition of silibinin, the phospholipid in it changes the physical and chemical properties of the drug, increases the fat solubility of the drug, promotes the combination of the drug molecule and the cell membrane to promote absorption, and improves the bioavailability of the drug. The combination of these components and the above-mentioned percentage range of each component are determined through a large number of experiments, the above-mentioned combination and the percentage range make the pharmaceutical composition of silybin of the present invention have good dissolution rate, and its bioavailability is high .

In the above pharmaceutical composition of silibinin, the weight sum of silybin and phospholipid preferably ranges from 30-50% of the total weight of the composition, most preferably 40%. The weight ratio of silibinin to phospholipid is preferably 1:1.5-4, most preferably 7:13.

The phospholipid used in the pharmaceutical composition of silibinin of the present invention can be any kind of phospholipid, such as glycerophospholipid and sphingomyelin, glycerophospholipid such as phosphatidylcholine (also known as lecithin), phosphatidylethanolamine (also known as cephalin), phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, polyene phosphatidylcholine, cardiolipin, etc., phospholipids can be artificially synthesized or natural phospholipids, such as egg yolk phospholipids and soybean phospholipids, etc., preferably phospholipids Acylcholine-based soybean phospholipid or lecithin.

In the pharmaceutical composition of above-mentioned silybin, auxiliary material includes but not limited to filler, glidant and disintegrant, and filler accounts for 10-50% (w/w) of composition, preferably 40% (w/w) /w), the glidant accounts for 10-30% (w/w) of the composition, preferably 15% (w/w), and the disintegrant accounts for 1-30% (w/w) of the composition, preferably 5% (w/w). Fillers include but are not limited to maltose, microcrystalline cellulose, glucose, lactose, sucrose, dextrin, and starch, etc., which can be used alone or in combination, preferably lactose; glidants include but are not limited to micronized silica gel, talc powder, Hydrated sodium silicate, magnesium stearate, etc., can be used alone or in combination, preferably talc; disintegrants include but not limited to microcrystalline cellulose, magnesium stearate, sodium carboxymethyl starch, cross-linked carboxy Sodium methylcellulose and the like can be used alone or in combination, preferably sodium carboxymethyl starch (CMS).

The present invention also provides the above-mentioned pharmaceutical composition preparation of silybin, which can be any pharmaceutically acceptable oral preparation suitable for clinical application, such as capsule or tablet, preferably capsule preparation.

The present invention also provides the preparation method of the above-mentioned pharmaceutical composition containing silybin:

1) Take an appropriate amount of silibinin and phospholipids;

2) adding dehydrated ethanol, whose volume (ml) is 5-15 times of the sum of silibinin and phospholipid mass (g), heating to reflux to clarify the solution;

3) Concentrate under reduced pressure to a thick shape;

4) Add auxiliary materials, carry out one-step granulation drying, sieving and crushing.

Wherein, the volume (ml) of absolute ethanol added in step 2) is preferably 6-8 times the sum of the mass (g) of silibinin and phospholipid, most preferably 6 times.

Wherein, the temperature of step 3) concentrating under reduced pressure is 40-80°C, preferably 50-70°C. At the above temperature, the drying rate of the silibinin-phospholipid liquid copolymer can reach 60kg/hour.

Wherein, the one-step granulation drying in step 4) is spray granulation drying, and the temperature is 50-75°C, preferably 65°C.

Beneficial effect

The invention provides a pharmaceutical composition containing silibinin and a preparation method thereof. The method uses a non-toxic solvent and meets the requirements of medicine; moreover, the yield of silybin is high, up to 98%. Granulation and drying technology, simple process flow, shortened production cycle, can improve production efficiency, and meet GMP requirements; the product has good fluidity, high dissolution rate, an average of 98.5%, and uniform dissolution rate. The problem of large-scale industrial production of the medicinal composition of silybin is solved.

Detailed ways

The following examples further illustrate the present invention, but the present invention is not therefore limited within the scope of specific examples.

The dissolution test method adopts the first method of the dissolution test method of the second appendix XC of the Pharmacopoeia of the People's Republic of China in 2005.

Example 1

Preparation of silybin

Take a certain amount of silibinin seeds, crush them, place them in a Soxhlet extractor and extract them with ethyl acetate for 20 hours, concentrate the extract in a rotary evaporator, recover the solvent, and obtain a brownish yellow extract, wash the surface oil with petroleum ether, and obtain Paste crude silibinin. After degreasing, recrystallization and drying, 350 g of silybin was obtained.

Preparation of silybin medicinal composition

Add 6000ml of absolute ethanol to 350g of silibinin and 650g of soybean lecithin, heat to reflux to clarify the solution, concentrate under reduced pressure at 60°C until thick, add 1000g of lactose, 375g of talc, 125g of sodium carboxymethyl starch (CMS), 65 ℃ Spray granulation, dry, pass through a No. 2 sieve, and pulverize to obtain capsule fillings, which are divided into capsules to obtain a total of 10,000 finished products. A total of 3 batches of products were prepared according to the above method, the capsule filling yields were respectively 97.0%, 97.2% and 97.2%, and the dissolution rates were respectively 97.4%, 97.9% and 98.1%.

Example 2

The preparation of silibinin is the same as embodiment 1

Preparation of silybin medicinal composition

Add 350g of silibinin and 350g of soybean lecithin to 3500ml of absolute ethanol, heat to reflux to clarify the solution, concentrate under reduced pressure at 40°C until thick, add 460g of lactose, 70g of talc, 70g of sodium carboxymethyl starch (CMS), 50 ℃ Spray granulation, dry, pass through a No. 2 sieve, and pulverize to obtain capsule fillings, which are divided into capsules to obtain a total of 10,000 finished products. A total of 3 batches of products were prepared according to the above method, the capsule filling yields were respectively 97.5%, 97.3% and 97.2%, and the dissolution rates were respectively 97.7%, 97.9% and 98.3%.

Example 3

The preparation of silibinin is the same as embodiment 1

Preparation of silybin medicinal composition

Add 86,100ml of absolute ethanol to 350g of silibinin and 14,000g of lecithin, heat to reflux to clarify the solution, concentrate under reduced pressure at 80°C until thick, add 70,000g of lactose, 40,000g of talc, 19,150g of sodium carboxymethyl starch (CMS), 50 ℃ Spray granulation, dry, pass through a No. 2 sieve, and pulverize to obtain capsule fillings, which are divided into capsules to obtain a total of 10,000 finished products. A total of 3 batches of products were prepared according to the above method, the capsule filling yields were respectively 97.5%, 97.4% and 97.1%, and the dissolution rates were respectively 97.8%, 98.0% and 98.5%.

Example 4

The preparation of silibinin is the same as embodiment 1

Preparation of silybin medicinal composition

Add 350g of silibinin and 1400g of lecithin to 20500ml of absolute ethanol, heat to reflux to clarify the solution, concentrate under reduced pressure at 50°C until thick, add 600g of lactose, 300g of talc, 350g of sodium carboxymethyl starch (CMS), 65 ℃ Spray granulation, dry, pass through a No. 2 sieve, and pulverize to obtain capsule fillings, which are divided into capsules to obtain a total of 10,000 finished products. A total of 3 batches of products were prepared according to the above method, the capsule filling yields were respectively 97.5%, 97.3% and 97.2%, and the dissolution rates were respectively 97.8%, 97.9% and 98.3%.

Example 5

The preparation of silibinin is the same as embodiment 1

Preparation of silybin medicinal composition

Add 350g of silibinin and 650g of soybean lecithin to 10500ml of absolute ethanol, heat to reflux to make the solution clear, concentrate under reduced pressure at 60°C until thick, add 1000g of lactose, 375g of talc, 125g of sodium carboxymethyl starch (CMS), 75 ℃ Spray granulation, dry, pass through a No. 2 sieve, and pulverize to obtain capsule fillings, which are divided into capsules to obtain a total of 10,000 finished products. A total of 3 batches of products were prepared according to the above method, the capsule filling yields were respectively 97.4%, 97.5% and 97.2%, and the dissolution rates were respectively 97.9%, 98.2% and 98.3%.

Example 6

The preparation of silibinin is the same as embodiment 1

Preparation of silybin medicinal composition

Add 6000ml of absolute ethanol to 350g of silibinin and 650g of soybean lecithin, heat to reflux to clarify the solution, concentrate under reduced pressure at 60°C until thick, add 1000g of lactose, 375g of talc, 125g of sodium carboxymethyl starch (CMS), 65 ℃ Spray granulation, dry, pass through a No. 2 sieve, and pulverize to obtain capsule fillings, which are divided into capsules to obtain a total of 10,000 finished products. A total of 3 batches of products were prepared according to the above method, the capsule filling yields were respectively 97.5%, 97.5% and 97.0%, and the dissolution rates were respectively 97.5%, 98.0% and 98.1%.

Claims (10)

1. A pharmaceutical composition of silybin, comprising silybin, phospholipid and auxiliary material, wherein the sum of the weight of silybin and phospholipid accounts for 10-60% of the total weight of the composition, and silybin The weight ratio of phospholipid to phospholipid is 1:1-40. 2. The pharmaceutical composition of silibinin according to claim 1, wherein the phospholipid is soybean lecithin or lecithin based on phosphatidylcholine, and the auxiliary material is a filler, a glidant and a disintegrant. 3. The pharmaceutical composition of silibinin as claimed in claim 2, wherein the sum of the weight of silibinin and phospholipids accounts for 30-50% of the total weight of the composition, and the weight of silibinin and phospholipids The ratio is 1:1.5-4. 4. the pharmaceutical composition of silybin described in claim 3, wherein the sum of the weight of silibinin and phospholipid accounts for 40% of composition gross weight, and the ratio of the weight of silybin and phospholipid is 7:13, filler, glidant and disintegrant account for 40%, 15% and 5% of the total weight of the composition respectively. 5. The pharmaceutical composition of silybin as claimed in claim 4, wherein the filler is lactose, the glidant is talc, and the disintegrant is sodium carboxymethyl starch (CMS). 6. A pharmaceutical composition preparation of silybin, which is prepared by packing the pharmaceutical composition of silibinin according to claim 1, 2, 3, 4 or 5 into capsules. 7. The preparation method of the pharmaceutical composition of silibinin according to claim 1, 2, 3 or 4, comprising the following steps: 1) Take an appropriate amount of silibinin and phospholipids; 2) adding dehydrated ethanol, whose volume (ml) is 5-15 times of the sum of silibinin and phospholipid mass (g), heating to reflux to clarify the solution; 3) Concentrate under reduced pressure to a thick shape; 4) Add auxiliary materials, carry out one-step granulation drying, sieving and crushing. 8. The preparation method of the pharmaceutical composition of silibinin according to claim 7, wherein the temperature of the reduced-pressure concentration in step 3) is 40-80°C. 9. The preparation method of the pharmaceutical composition of silybin according to claim 7, wherein the one-step granulation drying in step 4) is spray granulation drying. 10. The preparation method of the pharmaceutical composition of silibinin according to claim 7, wherein the temperature of granulation and drying in step 4) is 50-75°C.