CN1660076A - Sustained release formulation of milk thistle - Google Patents

Abstract

A slowlly-releasing silymarinum is prepared through preparing the dispersed solid silymarinum from PEG, PVP and Puliunike and preparing its inclusion compound by use of beta-CD or HB-beta-CD. Another process is also disclosed.

Description

Sustained release formulation of milk thistle

Technical field: the present invention relates to a sustained-release preparation of milk thistle and a preparation method thereof.

Background technology: Milk thistle is a kind of flavonoid compound extracted and isolated from the fruit of the plant Asteraceae Silybum marianum. Silymarin was discovered by West German pharmacists represented by H. Wagner in the late 1960s, including silybin, silydianin, silychristin and silymarin Alcohol (silybonol), collectively known as silymarin (silymarin). Silybin meglumine is an adduct of silybin and meglumine, which belongs to the water-soluble derivative of silybin.

Chinese patent application 1543943 (Application No. 200310105194.3) discloses "oral silymarin sustained-release preparation and preparation method thereof". The technology is to prepare silymarin into a solid dispersion with PVPK15 as a carrier and then make a sustained-release preparation.

Summary of the invention: The present invention is to develop a slow-release preparation of milk thistle, mainly to solve the problem of slow-release of the insoluble drug silymarin, firstly to improve the solubility of the insoluble drug. For soluble drugs, if common pharmacy methods such as micronization and adding surfactants are used, their solubility cannot be significantly improved, resulting in low bioavailability in vivo. Only some new technologies in pharmacy such as preparation of solid dispersions can be used. , Cyclodextrin inclusion compound, such as preparing silymarin solid dispersion by using PEG, PVP, prosulfuric acid, using β-CD, HP-β-CD to prepare inclusion compound, can significantly improve its solubility, thereby improving its bioavailability or adopt the water-soluble derivatives of silybin, silybin-meglumine salt, silybin-phthalic acid monoester sodium salt, silybin-cyclodextrin, silybin-phosphatidylcholine double salt , and then by adding sustained and controlled release materials such as hydroxypropyl methylcellulose (HPMC), glyceryl behenate (Comprital 888 ATO), ethyl cellulose, acrylic resin, carbopol, stearyl alcohol, stearic acid , sodium carboxymethylcellulose, sodium alginate, etc. to control the release of drugs.

The invention prepares the solid dispersion of silymarin-PEG4000, silymarin-PEG6000, silymarin, PEG6000 and Tween-80 mixed carrier, and its dissolution rate is significantly improved compared with silymarin. The release of the drug is controlled by adding some slow-release materials.

The invention prepares solid dispersions of silymarin-PVP _k15 , silymarin-PVP _k25 , silymarin-PVP _k30 , silymarin-PVP _k60 and silymarin-PVP _k90 , whose dissolution rate is significantly improved compared with silymarin. Among them, the stability of silymarin-PVP _k25 , silymarin-PVP _k30 , silymarin-PVP _k60 and silymarin-PVP _k90 is significantly better than that of silymarin-PVP _k15 . Studies have shown that silymarin-PVP _k15 is more likely to precipitate and crystallize, and the resulting solid dispersion has poor stability. Moreover, silymarin-PVP _k60 and silymarin-PVP _k90 solid dispersions have a certain sustained-release effect, and silymarin-PVP _k60 and silymarin-PVP _k90 solid dispersions can achieve sustained-release effects by adding common fillers such as low-viscosity HPMC. Adding silymarin-PVP _k25 and silymarin-PVP _k30 to high-molecular-weight HPMC or low-molecular-weight HPMC can achieve sustained-release effects, but the ratio is slightly different. The feature of the present invention is that the solid dispersion of silymarin prepared by PVP _k25 , PVP _k30 , PVP _k60 , and PVP _k90 can not only have better stability, but also improve the solubility of the drug. A certain slow-release effect.

The invention prepares the silymarin-HP-β-CD clathrate, the dissolution rate of which is significantly improved compared with silymarin, and the addition of a surfactant increases the dissolution rate together. Then add some matrix materials to control the release of drugs.

The present invention is on the basis of the obtained silymarin solid dispersion and clathrate or adopts silybin-meglumine, adding conventional slow-release materials such as hydroxypropyl methylcellulose, ethyl cellulose, Ulmus Glyceryl Acid, Carbopol, Sodium Alginate, Stearyl Alcohol, Sodium Carboxymethylcellulose, Stearic Acid, Stearyl Alcohol, Carnauba Wax, Glyceryl Monostearate, Beeswax, Polyvinyl Alcohol, Acrylic Resin etc. Commonly used fillers, lubricants, glidants, surfactants, binders, disintegrants, bleaching aids, foaming agents, etc. can be added, such as surfactants Tween, lauryl sulfate Sodium, etc., glidant stearic acid, magnesium stearate, talcum powder, micropowder silica gel, etc., foaming agent carbonate, bicarbonate, carbonate and citric acid, bicarbonate and tartaric acid, etc. It can be compressed into a commonly used matrix tablet, or a double-layer matrix tablet composed of a part of immediate release and a part of sustained release, or bleaching aids such as stearyl alcohol, cetyl alcohol, stearic acid, stearyl alcohol, carnauba wax, Glyceryl monostearate, beeswax, etc., gastric retention tablets made of foaming agent carbonate, bicarbonate, combination of carbonate and citric acid, combination of bicarbonate and tartaric acid, or solid silymarin Dispersion, clathrate, silibinin-meglumine and common excipients are used to make common tablet cores and pellet cores, and coating materials such as ethyl cellulose, acrylic resin, and cellulose acetate are used to achieve Sustained release.

The sustained-release preparation of milk thistle is characterized in that: the preparation contains PEG, PEG-surfactant, PVP as a carrier of silymarin solid dispersion, and contains H-β-CD as a carrier of silymarin clathrate, wherein silymarin The ratio to the carrier is 1:1-15.

The sustained-release preparation of milk thistle is characterized in that: the main ingredient of the preparation is silybin meglumine, a water-soluble derivative of silybin.

The sustained-release preparation of milk thistle is characterized in that it also contains a hydrophilic gel matrix material, a waxy lipid matrix material, an insoluble matrix material or any combination thereof.

The sustained-release preparation of milk thistle is characterized in that the ratio of silymarin or silybin meglumine:hydrophilic gel skeleton material, wax lipid skeleton material, insoluble skeleton material or any combination thereof is 1:0.1～10 .

The slow-release preparation of milk thistle is characterized in that: the addition of hydrophilic gel skeleton material is hydroxypropyl methylcellulose, carbopol, sodium carboxymethylcellulose, sodium alginate or any combination thereof; The skeleton material is stearyl alcohol, glyceryl behenate, stearic acid, stearyl alcohol, carnauba wax, glyceryl monostearate, beeswax or any combination thereof; the insoluble skeleton material is ethyl cellulose, acrylic acid Resin, polyvinyl chloride, polyvinyl alcohol or any combination thereof.

The slow-release preparation of milk thistle is characterized in that: methylcellulose, polyvinylpyrrolidone, lactose, microcrystalline cellulose, starch, powdered sugar, sodium lauryl sulfate, Tween, sodium bicarbonate or wherein any combination.

The slow-release preparation of milk thistle is characterized in that, silymarin or silybin meglumine: hydroxypropyl methylcellulose, ethyl cellulose, glyceryl behenate, carbopol, sodium alginate, ten Octyl alcohol, cetyl alcohol, sodium carboxymethylcellulose, stearic acid, stearyl alcohol, carnauba wax, glyceryl monostearate, beeswax, polyvinyl alcohol, acrylic resin, or any combination thereof in a ratio of 1 : 0.1~10.

The slow-release preparation of milk thistle is characterized in that silymarin, silybin meglumine: hydroxypropyl methylcellulose: carbopol, stearyl alcohol, cetyl alcohol, sodium carboxymethylcellulose, beeweed The ratio of glyceryl ellic acid, stearic acid, glyceryl monostearate, beeswax, polyvinylpyrrolidone, ethyl cellulose, polyvinyl alcohol, acrylic resin, sodium alginate or any combination thereof is 1:0.1～10 : 0.1~10.

The sustained-release preparation of milk thistle is characterized in that the preparation can be oral sustained-release, controlled-release capsules, wherein the filler is a matrix-type pellet, film-controlled release tablet or film-controlled release pellet; the preparation can be oral sustained-release , Controlled-release tablets, wherein these tablets are matrix tablets, double-layer matrix tablets, intragastric retention tablets, membrane-controlled release tablets, and osmotic pump tablets.

The preparation method of the sustained-release preparation of milk thistle is characterized in that, silymarin or silybin meglumine: hydrophilic gel skeleton material, waxy lipid skeleton material, insoluble skeleton material or any combination thereof in the ratio of 1: 0.1～10 After mixing, directly compress tablet, or adopt dry granulation and compression, or adopt wet granulation and compression, or adopt solid dispersion method for granulation and compression, or make pellets, use ethyl cellulose, acrylic resin, Cellulose acetate for coating.

Description of drawings:

Fig. 1 is the dissolution curve of embodiment 1 silymarin tablet

Fig. 2 is the release curve of embodiment 2 silymarin sustained-release tablets

Fig. 3 is the release curve of embodiment 3 silymarin sustained-release tablets

Fig. 4 is the release curve of embodiment 4 silymarin sustained-release tablets

Fig. 5 is the release curve of embodiment 5 silymarin sustained-release tablets

Fig. 6 is the release curve of embodiment 6 silymarin sustained-release tablets

Fig. 7 is the release curve of embodiment 7 silymarin sustained-release tablets

Fig. 8 is the release curve of embodiment 8 silymarin sustained-release tablets

Fig. 9 is the release curve of embodiment 9 silymarin sustained-release tablets

Figure 10 is the release curve of silymarin intragastric floating tablets in Example 10

Figure 11 is the release curve of silymarin sustained-release tablets in Example 11

Figure 12 is the release curve of silymarin sustained-release tablets in Example 12

Figure 13 is the release curve of silymarin intragastric floating tablets in Example 13

Figure 14 is the release curve of silymarin sustained-release tablets in Example 14

Figure 15 is the release curve of silymarin osmotic pump tablet in Example 16

Figure 16 is the release curve of embodiment 18 silybin meglumine sustained-release tablets

Figure 17 is the release curve of embodiment 19 silybin meglumine sustained-release tablets

Figure 18 is the release curve of embodiment 20 silybin meglumine sustained-release tablets

Figure 19 is the release curve of silybin meglumine gastric floating tablet in embodiment 21

Figure 20 is the release curve of silybin meglumine osmotic pump tablet of embodiment 24

Detailed ways:

Comparative Example 1 Preparation of Silymarin Capsules

...

Silymarin 105g

Polyvinylpyrrolidone (K15) 525g

Microcrystalline Cellulose 100g

Preparation Process:

Prepare a solid dispersion of silymarin and polyvinylpyrrolidone (K15) by a solvent method, pulverize through a 100-mesh sieve, add microcrystalline cellulose, mix evenly, and press into tablets. Among them, this example shows that in the process of setting out the stability, it is very easy to precipitate crystals, and the dissolution is slow.

Dissolution Determination:

According to "Chinese Pharmacopoeia" 2000 edition two appendix XD first method adopts the device of dissolution assay (appendix XC first method), get silymarin sustained-release tablet, take distilled water as solvent, rotating speed is 100 revolutions per minute, respectively at 10 , 20, 30 minutes to take 5ml of the solution, and at the same time add the same temperature, the same volume of distilled water, the sample taken was filtered immediately, and the subsequent filtrate was taken for determination. Take an appropriate amount of reference substance, and calculate the dissolution rate by the external standard method.

Example 2 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Silymarin 105g

Polyvinylpyrrolidone (K60) 525g

Ethylcellulose (45cps) 60g

Microcrystalline Cellulose 50g

Preparation Process:

Prepare a solid dispersion of silymarin and polyvinylpyrrolidone (K60) by solvent method, pulverize through a 100-mesh sieve, add ethyl cellulose and microcrystalline cellulose, mix evenly, and press into tablets. Silymarin: ethyl cellulose = 1:0.57, can effectively release.

Determination of release rate of sustained-release tablets:

According to "Chinese Pharmacopoeia" 2000 edition two appendix XD first method adopts the device of dissolution determination method (appendix XC first method), take silymarin slow-release tablet, take distilled water as solvent, rotating speed is 100 revolutions per minute, respectively in 1 , 2, 4, 6, 8, 12 hours to take 5ml of the solution, and at the same time add the same temperature, the same volume of distilled water, the sample taken was filtered immediately, and the subsequent filtrate was taken for determination. Take an appropriate amount of the reference substance, and calculate the release rate by the external standard method.

Example 3 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Silymarin 105g

Polyvinylpyrrolidone (K30) 420g

Ethylcellulose (45cps) 100g

Microcrystalline Cellulose 50g

Preparation Process:

Prepare a solid dispersion of silymarin and polyvinylpyrrolidone (K30) by a solvent method, pulverize through a 100-mesh sieve, add ethyl cellulose and microcrystalline cellulose, mix evenly, and press into tablets. Silymarin: ethyl cellulose = 1:0.95, can effectively release.

Example 4 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Silymarin 105g

Polyvinylpyrrolidone (K30) 525g

Hydroxypropyl Methyl Cellulose (K4M) 100g

Microcrystalline Cellulose 50g

Preparation Process:

Prepare a solid dispersion of silymarin and polyvinylpyrrolidone (K30) by a solvent method, pulverize through a 100-mesh sieve, add hydroxypropyl methylcellulose and microcrystalline cellulose, mix evenly, and press into tablets. Silymarin: hydroxypropyl methylcellulose (K4M) = 1:0.95, can effectively release.

Example 5 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Silymarin 52.5g

Polyvinylpyrrolidone (K90) 262.5g

Hydroxypropyl Methyl Cellulose (15cps) 60g

Microcrystalline Cellulose 50g

Preparation Process:

Prepare a solid dispersion of silymarin and polyvinylpyrrolidone (K90) by a solvent method, pulverize through a 100-mesh sieve, add hydroxypropyl methylcellulose and microcrystalline cellulose, mix evenly, and press into tablets. Silymarin: hydroxypropyl methylcellulose (15cps) = 1: 1.14, can effectively release. It shows that the solid dispersion of silymarin is prepared by PVP _k90 , and the solid dispersion itself has a certain slow-release effect, and the slow-release effect can be achieved by adding low-viscosity HPMC.

Example 6 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Silymarin 105g

Polyvinylpyrrolidone (K30) 525g

Hydroxypropyl Methyl Cellulose (15cps) 150g

Microcrystalline Cellulose 50g

Preparation Process:

Silymarin, polyvinylpyrrolidone (K30) and hydroxypropyl methylcellulose were prepared as solid dispersion by solvent method, crushed through a 100-mesh sieve, added microcrystalline cellulose, mixed evenly, and pressed into tablets. Silymarin: hydroxypropyl methylcellulose (15cps) = 1: 1.43, can effectively release. It shows that the solid dispersion of silymarin is prepared by PVP _k30 , and the slow-release effect can also be achieved by adding low-viscosity HPMC.

Example 7 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Silymarin 52.5g

Polyvinylpyrrolidone (K30) 525g

Glyceryl Behenate 50g

Lactose 50g

Preparation Process:

Prepare a solid dispersion of silymarin and polyvinylpyrrolidone (K30) by a solvent method, pulverize through a 100-mesh sieve, add glyceryl behenate and lactose, mix evenly, and press into tablets. Silymarin: glycerol behenate = 1:0.95, can effectively release.

Example 8 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Silymarin 52.5g

Polyvinylpyrrolidone (K25) 210g

Carbopol (941) 30g

Microcrystalline Cellulose 50g

Sodium Lauryl Sulfate 20g

Preparation Process:

Prepare silymarin and polyvinylpyrrolidone (K25) into a solid dispersion by solvent method, pulverize and pass through a 100-mesh sieve for later use. Take 2/3 of the solid dispersion, add carbopol, microcrystalline cellulose, and sodium lauryl sulfate, mix evenly, and press into tablets. Add the remaining 1/3 of the solid dispersion to compress the tablet. Silymarin: Carbopol = 1:0.57, can effectively release. Due to the slow release rate due to the addition of Carbopol, a compressed double-layer tablet is adopted to satisfy its quick-release and sustained-release effects.

Example 9 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Silymarin 52.5g

Polyvinylpyrrolidone (K30) 210g

Sodium alginate 25g

Microcrystalline Cellulose 50g

Sodium Lauryl Sulfate 20g

Preparation Process:

Prepare silymarin and polyvinylpyrrolidone (K30) into a solid dispersion by solvent method, pulverize and pass through a 100-mesh sieve for later use. Take 2/3 of the solid dispersion, add sodium alginate, microcrystalline cellulose, and sodium lauryl sulfate, mix evenly, and press into tablets. Add the remaining 1/3 of the solid dispersion to compress the tablet. Silymarin: sodium alginate = 1:0.48, which can effectively slow release. Since the release rate is slow by adding sodium alginate, a compressed double-layer tablet is adopted to satisfy its quick-release and sustained-release effects.

Example 10 Preparation of silymarin intragastric floating tablets

Quantity of 1000 pieces

Silymarin 52.5g

Polyvinylpyrrolidone (K60) 420g

Octadecanol 70g

Stearyl alcohol 40g

Microcrystalline Cellulose 50g

Sodium bicarbonate 2g

Sodium Lauryl Sulfate 20g

Preparation Process:

Prepare silymarin and polyvinylpyrrolidone (K60) into solid dispersion by solvent method, crush and pass through a 100-mesh sieve for later use. Add stearyl alcohol, stearyl alcohol, microcrystalline cellulose, sodium bicarbonate, sodium lauryl sulfate, mix well, and press into tablets. Silymarin: octadecyl alcohol: stearyl alcohol = 1: 1.33: 0.76, which can effectively slow release. The tablet floats in the artificial gastric juice for about 5 minutes, and has been floating in the artificial gastric juice. In this embodiment, stearyl alcohol, stearyl alcohol and sodium bicarbonate are added as bleach starting materials, and the purpose of sustained release is achieved by delaying the time for them to enter the small intestine.

Example 11 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Silymarin 52.5g

Macrogol 4000 525g

Ethylcellulose (45cps) 100g

Microcrystalline Cellulose 50g

Preparation Process:

Prepare a solid dispersion by melting silymarin and polyethylene glycol 4000, pulverize through a 100-mesh sieve, add ethyl cellulose and microcrystalline cellulose, mix evenly, and press into tablets. Preparation of polyethylene glycol 4000-silymarin solid dispersion, silymarin: ethyl cellulose = 1: 1.90, can effectively slow release.

Example 12 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Silymarin 105g

Macrogol 6000 525g

Tween-80 20g

Hydroxypropyl Methyl Cellulose 100g

Pregelatinized starch 50g

Preparation Process:

Prepare a solid dispersion by melting silymarin, polyethylene glycol 6000, and Tween-80, crush it through a 100-mesh sieve, add hydroxypropyl methylcellulose and microcrystalline cellulose, mix evenly, and press into tablets. Preparation of polyethylene glycol 6000, Tween-80-silymarin solid dispersion, silymarin: hydroxypropyl methylcellulose = 1:0.95, can effectively slow release.

Example 13 Preparation of silymarin intragastric floating tablets

Quantity of 1000 pieces

Silymarin 105g

Macrogol 6000 525g

Cetyl alcohol 55g

Glyceryl Behenate 80g

Pregelatinized starch 50g

Sodium carbonate 10g

Preparation Process:

Prepare a solid dispersion by melting silymarin, polyethylene glycol 6000, and Tween-80, crush it through a 100-mesh sieve, add glyceryl behenate, cetyl alcohol, pregelatinized starch, and sodium carbonate, mix evenly, and press into tablets. Preparation of polyethylene glycol 6000-silymarin solid dispersion, silymarin: glyceryl behenate: stearyl alcohol = 1: 0.76: 0.52, can effectively slow release. The tablet floats in the artificial gastric juice for about 5 minutes, and has been floating in the artificial gastric juice. In this embodiment, cetyl alcohol, glyceryl behenate and sodium carbonate, a bleaching aid material, are added to achieve the purpose of sustained release by delaying the time for them to enter the small intestine.

Example 14 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Silymarin 52.5g

H-β-CD 525g

Tween-80 20g

Hydroxypropyl Methyl Cellulose 30g

Lactose 80g

Preparation Process:

Prepare a solid dispersion by melting silymarin, polyethylene glycol 6000, and Tween-80, crush it through a 100-mesh sieve, add hydroxypropyl methylcellulose and microcrystalline cellulose, mix evenly, and press into tablets. Preparation of H-β-CD, Tween-80-silymarin inclusion complex, silymarin: hydroxypropyl methylcellulose = 1:0.57, can effectively slow release. The H-β-CD-silymarin inclusion compound itself has a certain slow-release effect.

Example 15 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Chip

Silymarin 52.5g

Polyvinylpyrrolidone (K30) 525g

Microcrystalline Cellulose 50g

Coating material

Ethyl cellulose 100g

Acrylic resin 20g

Polyethylene glycol 5g

Castor Oil 5g

Diethyl phthalate 5g

Proper amount of acetone solution

Preparation Process:

Prepare a solid dispersion of silymarin and polyvinylpyrrolidone (K30) by a solvent method, pulverize through a 100-mesh sieve, add microcrystalline cellulose, mix evenly, and press into tablets. The above-mentioned coating material is used for coating, and the release degree is controlled by increasing the weight. Slow release can be achieved for 4-24 hours by adjusting its weight gain.

The above-mentioned tablets can be compressed into microtablets, coated with sustained-release materials, and then loaded into capsules; they can also be directly compressed and coated to obtain common sustained-release coated tablets.

Example 16 Preparation of Silymarin Osmotic Pump Tablets

Quantity of 1000 pieces

Chip

Silymarin 52.5g

Polyvinylpyrrolidone (K25) 420g

Microcrystalline Cellulose 50g

Coating material

Cellulose acetate 100g

Polyethylene glycol 10g

Proper amount of acetone solution

Preparation Process:

Prepare a solid dispersion of silymarin and polyvinylpyrrolidone (K25) by a solvent method, pulverize through a 100-mesh sieve, add microcrystalline cellulose, mix evenly, and press into tablets. Coat with the above-mentioned coating material, and then make a small hole on the coated tablet. Get osmotic pump tablets.

Example 17 Preparation of silymarin sustained-release tablets

Quantity of 1000 pieces

Chip

Silymarin 52.5g

Macrogol 4000 315g

Microcrystalline Cellulose 50g

Coating material

Acrylic resin No. II 80g

Polyethylene glycol 10g

castor oil 8g

Diethyl phthalate 5g

Proper amount of acetone solution

Preparation Process:

Prepare a solid dispersion of silymarin and polyethylene glycol 4000 by melting method, pulverize through a 100-mesh sieve, add microcrystalline cellulose, mix evenly, and press into tablets. The above-mentioned coating material is used for coating, and the release degree is controlled by increasing the weight. The purpose of sustained release for 4 to 24 hours can be achieved through the difference in tablet weight gain.

The above-mentioned tablets can be compressed into microtablets, coated with sustained-release materials, and then loaded into capsules; they can also be directly compressed and coated to obtain common sustained-release coated tablets.

Example 18 Preparation of Silybin Meglumine Sustained Release Tablets

Quantity of 1000 pieces

Silybin Meglumine 150g

Hydroxypropyl Methyl Cellulose 100g

Microcrystalline Cellulose 50g

Sodium Lauryl Sulfate 20g

Pregelatinized starch 50g

Magnesium stearate 10g

Preparation Process:

Mix micronized silybin meglumine, hydroxypropyl methylcellulose, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, granulate, add magnesium stearate, and mix well , Tablets. Silybin meglumine: hydroxypropyl methylcellulose = 1:0.67, can effectively release.

Example 19 Preparation of Silybin Meglumine Sustained Release Tablets

Quantity of 1000 pieces

Silybin Meglumine 150g

Ethyl cellulose 200g

Lactose 50g

Sodium Lauryl Sulfate 20g

Magnesium stearate 10g

Preparation Process:

Mix micronized silybin meglumine, ethyl cellulose, lactose and sodium lauryl sulfate evenly, granulate, add magnesium stearate, mix evenly, and compress into tablets. Silybin meglumine: ethyl cellulose = 1: 1.33, can effectively release.

Example 20 Preparation of Silybin Meglumine Sustained Release Tablets

Quantity of 1000 pieces

Silybin Meglumine 150g

Glyceryl Behenate 140g

Microcrystalline Cellulose 50g

Tween-80 10g

Preparation Process:

The micronized silybin meglumine, behenic acid glyceride, and Tween-80 were melted to prepare a solid dispersion, crushed through a 100-mesh sieve, added microcrystalline cellulose, mixed evenly, and pressed into tablets. Silybin meglumine: behenic acid glyceride = 1:0.93, can effectively slow release.

Example 21 Preparation of silybin meglumine intragastric floating tablets

Quantity of 1000 pieces

Silybin Meglumine 150g

Hydroxypropyl Methyl Cellulose 100g

Octadecanol 80g

Lactose 50g

Sodium bicarbonate 20g

Sodium Lauryl Sulfate 10g

80% ethanol

Preparation Process:

Mix micronized silybin meglumine, hydroxypropyl methylcellulose, stearyl alcohol, lactose, and sodium bicarbonate evenly, add wetting agent, make soft material, granulate, dry, sieve, and prepare Granules, add sodium lauryl sulfate, mix evenly, and compress into tablets. Silybin meglumine: hydroxypropyl methylcellulose: stearyl alcohol = 1: 0.67: 0.53, which can effectively sustain the release. The tablet floats in the artificial gastric juice for about 5 minutes, and has been floating in the artificial gastric juice. In this embodiment, stearyl alcohol as a bleach starting material and sodium bicarbonate as a bleaching aid material are added to achieve the purpose of sustained release by delaying the time for them to enter the small intestine.

Example 22 Preparation of Silybin Meglumine Sustained Release Tablets

Quantity of 1000 pieces

Chip

Silybin Meglumine 150g

Lactose 50g

Sodium Lauryl Sulfate 20g

Talc powder 10g

5% PVP80% ethanol

Coating material

Ethyl cellulose 80g

Polyethylene glycol 20g

castor oil 10g

Diethyl phthalate 10g

Proper amount of acetone solution

Preparation Process:

Mix micronized silybin meglumine, lactose, and sodium lauryl sulfate evenly, add binder, make soft material, granulate, dry, sieve, granulate, add talcum powder, mix evenly, press piece. The above materials are used for coating, and the release rate is controlled by increasing the weight. A sustained-release effect of 4 to 24 hours can be achieved.

The above-mentioned tablets can be compressed into microtablets, coated with sustained-release materials, and then loaded into capsules; they can also be directly compressed and coated to obtain common sustained-release coated tablets.

Example 23 Preparation of silybin meglumine sustained-release capsules

Quantity of 1000 pieces

Ball core

Silybin Meglumine 150g

Appropriate amount of starch

Dextrin Appropriate amount

80% ethanol

Coating material

Acrylic resin No. II 80g

Polyethylene glycol 20g

castor oil 10g

Diethyl phthalate 10g

Proper amount of acetone solution

Preparation Process:

Mix micronized silybin meglumine, starch and dextrin evenly, use 80% ethanol solution in a coating pan to make pellet cores, coat with the above materials, and control the release degree by increasing the weight. Capsules are then filled. A sustained-release effect of 4 to 24 hours can be achieved.

Example 24 Preparation of Silybin Meglumine Osmotic Pump Tablets

Quantity of 1000 pieces

Chip

Silybin Meglumine 150g

Lactose 50g

Sodium Lauryl Sulfate 20g

Talc powder 10g

5% PVP80% ethanol

Coating material

Cellulose acetate 80g

Polyethylene glycol 20g

Diethyl phthalate 10g

Proper amount of acetone solution

Preparation Process:

Mix micronized silybin meglumine, lactose, and sodium lauryl sulfate evenly, add binder, make soft material, granulate, dry, sieve, granulate, add talcum powder, mix evenly, press piece. Coating is carried out with the above-mentioned coating solution, so that the thickness of the coating film is within a certain range, and holes are punched on the coating film. Osmotic pump tablets were prepared. Sustained release in vivo can be achieved.

Claims (10)

1, the slow releasing preparation of Herba Silybi mariani, it is characterized in that: containing PEG, PEG-surfactant, PVP in the said preparation is the silymarin solid dispersion of carrier, containing H-β-CD is the silymarin clathrate of carrier, and wherein the ratio of silymarin and carrier is 1: 1～15.

2, the slow releasing preparation of Herba Silybi mariani is characterized in that: the principal agent composition of said preparation is the soluble derivative silybin meglumine of silibinin.

3, according to claim 1,2 one of described slow releasing preparation, it is characterized in that also containing hydrophilic gel matrix material, wax lipid framework material, insoluble framework material or wherein combination arbitrarily.

4, slow releasing preparation according to claim 3 is characterized in that silymarin or silybin meglumine: hydrophilic gel matrix material, wax lipid framework material, insoluble framework material or the ratio that wherein makes up arbitrarily are 1: 0.1～10.

5, according to claim 3,4 one of described slow releasing preparation, it is characterized in that: the adding hydrophilic gel matrix material is hydroxypropyl emthylcellulose, Ka Bopu, sodium carboxymethyl cellulose, sodium alginate or wherein combination arbitrarily; Wax lipid framework material is octadecanol, Rikemal B 200, stearic acid, stearyl alcohol, Brazil wax, glyceryl monostearate, Cera Flava or wherein combination arbitrarily; Insoluble framework material is ethyl cellulose, acrylic resin, polrvinyl chloride, polyvinyl alcohol or wherein combination arbitrarily.

6, slow releasing preparation according to claim 3 is characterized in that: can add methylcellulose, polyvinylpyrrolidone, lactose, microcrystalline Cellulose, starch, Icing Sugar, sodium lauryl sulphate, tween, sodium bicarbonate or wherein combination arbitrarily.

7, the slow releasing preparation one of described according to claim 1 to 4, it is characterized in that silymarin or silybin meglumine: hydroxypropyl emthylcellulose, ethyl cellulose, Rikemal B 200, Ka Bopu, sodium alginate, octadecanol, hexadecanol, sodium carboxymethyl cellulose, stearic acid, stearyl alcohol, Brazil wax, glyceryl monostearate, Cera Flava, polyvinyl alcohol, acrylic resin or the ratio that wherein makes up arbitrarily are 1: 0.1～10.

8, the slow releasing preparation one of described according to claim 1 to 5, it is characterized in that silymarin, silybin meglumine: hydroxypropyl emthylcellulose: Ka Bopu, octadecanol, hexadecanol, sodium carboxymethyl cellulose, Rikemal B 200, stearic acid, glyceryl monostearate, Cera Flava, polyvinylpyrrolidone, ethyl cellulose, polyvinyl alcohol, acrylic resin, sodium alginate or the ratio that wherein makes up arbitrarily are 1: 0.1～10: 0.1～10.

9, the slow releasing preparation one of described according to claim 1 to 8 is characterized in that said preparation can be oral sustained release, controlled release capsule, and wherein implant is piller, film controlled release small pieces or the film controlled release piller of matrix type; Said preparation can be oral sustained release, controlled release tablet, and wherein these tablets are matrix tablet, double-deck matrix tablet, Entogastric lingering sheet, film controlled release tablet, osmotic pump tablet.

10, according to the preparation method of one of the described slow releasing preparation of claim 1 to 8, it is characterized in that, with silymarin or silybin meglumine: after hydrophilic gel matrix material, wax lipid framework material, insoluble framework material or wherein make up arbitrarily mixes with 1: 0.1～10, direct compression or employing dry granulation tabletting or employing wet granule compression tablet or employing solid dispersion method pelletizing press sheet, perhaps make micropill, adopt ethyl cellulose, acrylic resin, cellulose acetate to carry out coating.

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