CN101961319B - Silybin meglumine enteric agent with high bioavailability and preparation method thereof - Google Patents

Abstract

The invention relates to the field of medical agent, in particular to a silybin meglumine enteric agent with high bioavailability and a preparation method thereof. The preparation method is characterized by comprising the following steps of: preparing the silybin meglumine into solid dispersoid; adding the medical auxiliary materials to prepare to be the grain, the tablet or the pellet; and packing the grain, the tablet or the pellet into an enteric coat. With the unique shape, the silybin meglumine can not be released in the stomach but can be fast dissolved and absorbed in the intestinal canal; and by being prepared to be the solid dispersoid, the silybin meglumine increases the solubility in the water. Therefore, the invention increases the absorbed dose of the silybin meglumine, has higher bioavailability compared with the common tablet or capsule, is good for curing the hepatopathy, and is simple in preparation technology.

Description

Silybin meglumine enteric coated preparation of a kind of high bioavailability and preparation method thereof

Technical field

The present invention relates to field of pharmaceutical preparations, be specifically related to silybin meglumine enteric coated preparation of a kind of high bioavailability and preparation method thereof.

Background technology

Silibinin (silybin or silibinin) is a kind of flavone compound that extraction separation obtains from feverfew Herba Silybi mariani (Silybum marianum Gaertn) fruit; The good curing hyperlipidemia is arranged; Eliminate free radical; Anti-liver lipid peroxidation effect is that medicine is repaired in the hepatic injury of determined curative effect.But because its poor solubility in water, fat-soluble also very poor, oral administration biaavailability is very low.In order to improve the water solublity of silibinin, existing people is combined into silybin meglumine with silibinin and meglumine (1-methylamino-1-deoxidation sorbitol).

Silybin meglumine, English name: Silybin Meglumine, chemical name is: 2-[2,3-dihydro-2-(4-hydroxy 3-methoxybenzene base)-3-(hydroxymethyl)-1; 4-benzo dioxin-6-yl]-2,3-dihydro-3; 5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone, these article are yellow amorphous powder; Odorless almost, the mildly bitter flavor band is puckery, have draw moist.In water, dissolve, dissolve slightly soluble in acetone, soluble,very slightly in chloroform at methanol or ethanol part omitted.The molecular formula of these article is C ₃₂H ₃₉O ₁₅N, molecular weight are 677.66.

When discovering 37 ℃, the saturation solubility of silibinin in water is 32.46 μ g/ml, and the saturation solubility of silybin meglumine in water is 4.56mg/ml.

Clinical practice at present silybin meglumine tablets agent and capsule arranged; In order to improve its bioavailability; Present existing patent is following: silybin meglumine dispersible tablet of treatment hepatitis and preparation method thereof (CN 100348199C); Silybin meglumine oral cavity disintegration tablet and preparation technology thereof (CN 1254240C), the prescription of silibinin-n-methylglucamine drop pills and preparation technology thereof (CN1875962A).Though these silybin meglumine dispersible tablets, oral cavity disintegration tablet and drop pill have improved the oral administration biaavailability of silibinin to a certain extent, its raising is limited.

Summary of the invention

The invention discloses a kind of silybin meglumine preparation of high bioavailability, the invention discloses a kind of silybin meglumine enteric coated preparation, because its dosage form is relatively unique; Institute but can dissolve rapidly, absorb at intestinal so that silybin meglumine does not discharge under one's belt, in addition; Through silybin meglumine is processed solid dispersion; Increased the dissolubility of silybin meglumine in water, thereby increased the absorbtivity of silybin meglumine, this product is higher than conventional tablet or capsular bioavailability; Help the treatment of hepatopathy, and preparation technology is simple.

In order further to improve the bioavailability of silybin meglumine, through more various route of administration, the bioavailability of finding to pass through silybin meglumine behind the duodenal administration is apparently higher than other oral routes.

We compare for respectively rat oral gavage administration and the AUC after the direct administration of duodenum by the dosage of 9.1mg/kg (in silibinin) in the research.The blood medicine through the time concentration curve result see Fig. 1, data obtain AUC through 3P97 software The Fitting Calculation, find AUC _{Duodenal administration}/ AUC _{Gastric infusion}=2.38.Can find out from the data of AUC ratio, silybin meglumine is processed the bioavailability that enteric coated preparation can obviously improve silybin meglumine.

After having confirmed that silybin meglumine is processed enteric coated preparation, we add pharmaceutic adjuvant by conventional method design with silybin meglumine and are prepared into behind granule, tablet or the micropill enteric coated again.In preparation during micropill, we have at first attempted preparing silybin meglumine and containing pill core through extruding round as a ball method, wrap one deck enteric coating film then on this basis again.The result finds, because silybin meglumine has the character of Chinese medical concrete, water or a certain proportion of alcoholic solution are done binding agent and be difficult to prepare the qualified pill core that contains, and have abandoned this kind technology at last.Secondly, we attempt adopting celphere medicine-feeding legal system to be equipped with the silybin meglumine enteric coated micropill.Though the result finds silybin meglumine and compares with silibinin, has improved its water solublity, for ball core medicine-feeding method, dissolubility is still not enough, has only 4.56mg/ml.If directly go preparation to contain pill core with such dissolubility, must cause production efficiency low excessively, the production time of a collection of preparation is long.We have attempted also that in addition silybin meglumine is made into suspension and have directly added medicine to, but the crude drug particle diameter is blocked nozzle than Da Yi.

We consider to adopt the method that increases medicine dissolubility in water based on above research, for its preparation that contains pill core lays the foundation.We adopt silybin meglumine are processed refabrication micropill behind the solid dispersion, and the result has overcome the various shortcoming in the above-mentioned preparation process.

Silybin meglumine and solid dispersion thereof the dissolubility in 37 ℃ of water is seen table 1.The result can find out that the saturation solubility of prepared silybin meglumine solid dispersion in water reaches as high as 500mg/ml, compares with the saturation solubility of silybin meglumine in water and has improved nearly 100 times.

Table 1 silybin meglumine and solid dispersion thereof the dissolubility in 37 ℃ of water

Dissolubility (mg/ml)	Water
		Silybin meglumine	4.56
The silybin meglumine solid dispersion	500

We give the rat oral gavage administration by the dosage of 9.1mg/kg (in silibinin) respectively with silybin meglumine and silybin meglumine solid dispersion in the research; The blood medicine through the time concentration curve result see Fig. 2, data obtain AUC through 3P97 software The Fitting Calculation.Find AUC _{The silybin meglumine solid dispersion}/ AUC _{Silybin meglumine}=1.28.Can find out from the data of AUC ratio, silybin meglumine is processed the bioavailability that the solid dispersion physical ability obviously improves silybin meglumine.

Formed the application's technical scheme based on above-mentioned invention.

Silybin meglumine oral formulations of the present invention is that silybin meglumine is prepared into solid dispersion earlier, adds pharmaceutic adjuvant again and processes granule, tablet or micropill, promptly gets granule, tablet or micropill are enteric coated.

It is routine techniques that silybin meglumine is prepared into solid dispersion, is about to silybin meglumine and makes with solid dispersion carrier commonly used.Can be methods such as solvent method, fusion method or polishing.

The solid dispersion carrier is preferably from Macrogol 4000, polyethylene glycol 6000,30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30,30 POVIDONE K 30 BP/USP 90, poloxamer 188, microcrystalline Cellulose, polyoxyethylene, carbopol, mannitol, sorbitol, xylitol, sucrose, chitosan, galactose, polyacrylic resin base polymer, cellulose acetate-phthalate, phthalic acid hypromellose, carboxylic first and second celluloses one or more.

The solid dispersion carrier more preferably is selected from: Macrogol 4000, polyethylene glycol 6000,30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30, one or more in the 30 POVIDONE K 30 BP/USP 90.

The weight ratio of silybin meglumine and solid dispersion carrier is preferred: 1: 0.1～1: 1.

After accomplishing the preparation of solid dispersion, add pharmaceutic adjuvant and be prepared into granule, micropill or tablet, enteric coated again getting final product.Described pharmaceutic adjuvant is selected from disintegrating agent and binding agent.Also can add diluent, lubricant etc.

Described disintegrating agent is selected from: one or more in low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, the carboxymethyl starch sodium.

Described binding agent is selected from: ethanol/water mixed solution, water, 30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30, one or more in 30 POVIDONE K 30 BP/USP 90, the hydroxypropyl emthylcellulose.

The weight ratio of solid dispersion and pharmaceutic adjuvant is preferred: 1: 2～1: 6.

Enteric-coating material preferred acrylic resins of the present invention.

Enteric-coating material increases weight preferred 5～25%.

The present invention has not only overcome all difficulty of silybin meglumine in preparation; And bioavailability is high; The enteric coated preparation of silybin meglumine solid dispersion and silybin meglumine ordinary preparation compare, and its bioavailability is 4.27 times of ordinary preparation.See Fig. 3.

Description of drawings

Fig. 1 be administration of silybin meglumine rat oral gavage and duodenal administration blood concentration through the time curve

Fig. 2 be silybin meglumine and the administration of silybin meglumine solid dispersion rat oral gavage blood concentration through the time curve

Blood concentration when Fig. 3 is the beasle dog oral administration of silybin meglumine solid dispersion enteric coated capsule of the present invention and commercially available silybin meglumine ordinary tablet through the time curve (n=3)

The specific embodiment

Embodiment 1

Micropill:

Consumption

Silybin meglumine 50mg

30 POVIDONE K 30 BP/USP 30 (PVP K30) 50mg

Sucrose 180mg

Microcrystalline Cellulose 20mg

Suitable (acrylic resin L30D-55) 60mg of refined gram

All on sale on the above-mentioned raw materials market, be prone to purchase.

Above weight is every weight that capsule is contained.

Its preparation method is: feed intake by 1000 capsular amounts.Step 1 places eggplant-shape bottle with silybin meglumine, adds dehydrated alcohol and in 60 ℃ medicine is dissolved fully; After adding 30 POVIDONE K 30 BP/USP 30 dissolvings then eggplant-shape bottle is placed 60 ℃ of evacuation, remove dehydrated alcohol, crushing screening is dissolved in the distilled water; The dissolving back is as the pastille solution for standby; The mixed accessories that other takes by weighing sucrose, microcrystalline Cellulose places fluid bed, will contain drug solns then and be sprayed onto on the mixed accessories, obtains containing pill core; Step 2 takes by weighing refined gram and should (acrylic resin) be made into certain solid content with deionized water, stirs, and as enteric coating liquid, then coating solution is sprayed onto in the step 1 on the gained micropill, promptly gets.

Embodiment 2

Micropill

Consumption

Silybin meglumine 50mg

Macrogol 4000 (PEG4000) 10mg

Starch 200mg

Hydroxypropyl emthylcellulose 10mg

You Teqi (acrylic resin L100-55) 40mg

All on sale on the above-mentioned raw materials market, be prone to purchase.

Above weight is the contained weight of each dosage.

Its preparation method is: feed intake by 1000 capsular amounts.Step 1 is placed on silybin meglumine and Macrogol 4000 mixing in the beaker, and 60 ℃ make the complete fusion of this mixture; Then the fused mass cryogenic quenching is solidified, crushing screening is dissolved in the distilled water that contains hydroxypropyl emthylcellulose E3; The dissolving back is as the pastille solution for standby; Other takes by weighing a certain amount of blank starch ball core and places fluid bed, will contain drug solns then and be sprayed onto on the celphere, obtains containing pill core; Step 2 takes by weighing You Teqi (acrylic resin L30D-55) and is diluted to certain solid content with deionized water, stirs, and as enteric coating liquid, then coating solution is sprayed onto in the step 1 on the gained micropill, promptly gets.

Embodiment 3

Tablet

Consumption

Silybin meglumine 50mg

30 POVIDONE K 30 BP/USP 90 (PVP K90) 15mg

Microcrystalline Cellulose 100mg

Carboxymethyl starch sodium 5mg

Pulvis Talci 3mg

You Teqi (acrylic resin L30D-55) 20mg

Above weight is every contained weight.

Its preparation method is: the amount by 1000 feeds intake.Step 1 is placed on silybin meglumine and 30 POVIDONE K 30 BP/USP 90 (PVP K90) mixing in the ball mill, and speed is 500 rev/mins; Time is 60 minutes, takes out then and pulverizes 80 mesh sieves, with remaining microcrystalline cellulose excipients; Carboxymethyl starch sodium; The Pulvis Talci mixing through tabletting behind the dry granulation, gets the pastille label; Step 2 takes by weighing You Teqi (acrylic resin L30D-55) and is diluted to certain solid content with deionized water, stirs, and as enteric coating liquid, then coating solution is sprayed onto in the step 1 on the gained label, promptly gets.

Embodiment 4

Capsule

Consumption

Silybin meglumine 50mg

30 POVIDONE K 30 BP/USP 90 (PVP K90) 5mg

Microcrystalline Cellulose 50mg

Pulvis Talci 3mg

You Teqi (acrylic resin L30D-55) 30mg

Above weight is every weight that capsule is contained.

Its preparation method is: feed intake by 1000 capsular amounts.Step 1 is placed on silybin meglumine and 30 POVIDONE K 30 BP/USP 90 (PVPK90) mixing in the ball mill, and speed is 600 rev/mins; Time is 30 minutes, takes out then and pulverizes 80 mesh sieves, with remaining microcrystalline cellulose excipients; Pulvis Talci mixing, directly fill hard capsule; Step 2 takes by weighing You Teqi (acrylic resin L30D-55) and is diluted to certain solid content with deionized water, stirs, and as enteric coating liquid, then coating solution is sprayed onto in the step 1 on the gained hard capsule, promptly gets.

Embodiment 5

Capsule

Consumption

Silybin meglumine 50mg

30 POVIDONE K 30 BP/USP 90 (PVP K90) 10mg

Microcrystalline Cellulose 50mg

Pulvis Talci 3mg

You Teqi (acrylic resin L30D-55) 50mg

Above weight is every weight that capsule is contained.

Its preparation method is: feed intake by 1000 capsular amounts.Step 1 is placed on silybin meglumine and 30 POVIDONE K 30 BP/USP 90 (PVPK90) mixing in the ball mill, and speed is 600 rev/mins; Time is 90 minutes, takes out then and pulverizes 80 mesh sieves, with remaining microcrystalline cellulose excipients; The Pulvis Talci mixing is done adhesive system granule with 60% ethanol, 60 ℃ of oven dry; Step 2 takes by weighing You Teqi (acrylic resin L30D-55) and is diluted to certain solid content with deionized water, stirs, and as enteric coating liquid, then coating solution is sprayed onto in the step 1 on the gained granule, and last directly fill hard capsule promptly gets.

Claims (5)

1. silybin meglumine oral formulations; It is characterized in that: silybin meglumine is prepared into solid dispersion earlier; Add pharmaceutic adjuvant again and process granule, tablet or micropill; Promptly get granule, tablet or micropill are enteric coated, wherein the weight ratio of silybin meglumine and solid dispersion carrier is: 1: 0.1～1: 1; The solid dispersion carrier is selected from one or more in Macrogol 4000, polyethylene glycol 6000,30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30, the 30 POVIDONE K 30 BP/USP 90.

2. the silybin meglumine oral formulations of claim 1, wherein pharmaceutic adjuvant is disintegrating agent and binding agent.

3. the silybin meglumine oral formulations of claim 1, wherein the weight ratio of solid dispersion and pharmaceutic adjuvant is: 1: 2～1: 6.

4. the silybin meglumine oral formulations of claim 1, wherein enteric-coating material is an acrylic resin.

5. the silybin meglumine oral formulations of claim 1, wherein the enteric-coating material weightening finish 5～25%.

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