CN1762344A - Silybinin lyophilized formulation and its preparation method - Google Patents

Abstract

The invention relates to a silybinin lyophilized formulation and its preparation method, wherein the preparation is prepared from solution containing silybin, glucosamine, alkaline amino acid and pharmaceutically acceptable excipient through freeze-drying. The preparation also comprises one or more selected from pharmaceutically acceptable solvent adjunct, pH regulator, painkiller, anti-oxidant agent, preservative and complexing agent.

Description

Silybinin lyophilized formulation and preparation method thereof

Technical field

The present invention belongs to field of pharmaceutical preparations, specifically, relates to a kind of Silybinin lyophilized formulation and preparation method thereof.

Background technology

Silymarin (Silymarin) is through extracting refining gained bulky powder by feverfew Silybum Herba Silybi mariani [Silybum marianum (L.) Gaertn.] fruit, mildly bitter flavor, have and draw moistly, water insoluble, significant protection is arranged and stablize the liver plasma membrane effect; To carbon tetrachloride, all kinds hepatic injury that hepatotoxic agents such as sulfuration acetamide cause has protection and therapeutical effect in various degree, and the rising of the caused alanine aminotransferase of carbon tetrachloride is had certain interception.Clinically be used for sick treatment such as chronic persistent hepatitis, chronic active hepatitis, first cirrhosis, liver poisoning, for the effect that all has clear improvement of symptom, sign, the liver function of acute and chronic hepatitis.Silymarin is the mixture that contains a plurality of components, and wherein silibinin (silybin) is one of its main component.Silibinin and other effective ingredient are all water insoluble, and oral administration biaavailability is lower, and individual variation is bigger, though existing silybin-N-methylglucamine is soluble in water, still can separate out under one's belt, and influence absorbs and curative effect.Injection administration can address the above problem, but document is not seen the report of this respect as yet, main cause is technical difficulty: as the water-soluble vegetable oil that also is insoluble to of silibinin, being difficult to make with water or oil is the injection of carrier, as make that though alkali metal salt can solve the water solublity problem but pH value of aqueous solution is too high, be difficult on the physiology accept, make the salt or the complex of organic base on the other hand, but its stability is bad, and especially the preparation process complex is degraded easily.

Summary of the invention

In order to overcome the deficiency of prior art, the object of the present invention is to provide a kind of Silybinin lyophilized pharmaceutical preparation, the said preparation stable in properties, be easy to transportation and store, easy to use, solved the preparation process complex difficult problem of degrading easily technically.

Another object of the present invention is to provide a kind of method for preparing above-mentioned Silybinin lyophilized formulation, method is simple for this, helps large-scale production.

The invention provides a kind of Silybinin lyophilized formulation, the solution by containing silibinin and alkaline solubilizing agent and pharmaceutically acceptable excipient makes after lyophilization; The pH value of described solution is 5.5～11, preferred 7～10.

Described pharmaceutically acceptable excipient, be to be generally used for preparing lyophilized formulations, get the filling bracket effect, make exsiccant medicine can keep the material of certain volume, for example material of one or more in mannitol, sorbitol, sodium chloride, glucose, dextran, sucrose, lactose, poloxamer, cysteine or other aminoacid.Preferred mannitol.

Described alkaline solubilizing agent is selected from meglumine, glucosamine, basic amino acid.The preferred arginine of described basic amino acid, lysine, histidine.

The described solution that contains silibinin and alkaline solubilizing agent and pharmaceutically acceptable excipient, can be to be the solution of solvent with water, can be to be the solution of solvent with the organic solvent, also can be to be the solution of solvent with water and organic solvent, described organic solvent can be pharmaceutically acceptable organic solvent.

The described solution that contains silibinin and alkaline solubilizing agent and pharmaceutically acceptable excipient also can contain in pharmaceutically acceptable cosolvent, pH regulator agent, analgesics, antioxidant, antiseptic and the chelating agent one or more.Described pH regulator agent can be at least a pharmaceutically acceptable conventional substances that is used to regulate pH.For example hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, malic acid, succinic acid, tartaric acid, maleic acid, aminoacid, meglumine, sodium hydroxide, sodium carbonate, sodium bicarbonate and the buffer system that contains above-mentioned substance.Described cosolvent is poloxamer, castor oil hydrogenated, surfactant, cyclodextrin, phospholipid.

The present invention further provides a kind of Silybinin lyophilized formulation, by containing silibinin, meglumine and mannitol, pH value is 7～10 aqueous solution, make after lyophilization.

All kinds of adjuvants are conventional amount used in the described lyophilized formulations.

The invention provides a kind of method for preparing Silybinin lyophilized formulation, comprising:

(1) preparation contains silibinin and alkaline solubilizing agent and pharmaceutically acceptable excipient and solvent, and its pH value is 5.5～11 solution;

(2) or earlier make the complex (solid or liquid) that silibinin and alkaline solubilizing agent form, again with pharmaceutically acceptable excipient and solvent, its pH value is 5.5～11 solution;

(3) or the preparation contain silybin meglumine complex and pharmaceutically acceptable excipient and solvent, its pH value is 5.5～11 solution;

(4) remove according to a conventional method impurity, decolour, reduce phlegm and internal heat former;

(5) with (1) or (2) or (3) step gained solution add and put the cillin bottle lyophilization promptly;

(6) or with (1) or (2) or (3) step gained solution tray in lyophilization or spray drying, packing get final product.

Described (1) or (2) or (3) step, can be that described silibinin, alkaline solubilizing agent and described excipient are dissolved in water for injection or other solvent, also can be earlier the reflux dissolving in water or ethanol with silibinin and solubilizing agent, remove with pharmacopedics conventional methods such as drying under reduced pressure then and desolvate, again gained solid and excipient are dissolved in water for injection or other solvent.Can the pH value of gained solution be transferred to 5.5～11 with the pH regulator agent, between preferred 7～10, can also add described cosolvent, and pharmaceutically acceptable other adjuvant, as antioxidant, analgesics, antiseptic and/or network mediating recipe etc.Gained solution can be removed impurity according to a conventional method, removes pyrogen, decolouring, degerming.Described lyophilization step of (5) step can be conventional or known processing step, can carry out lyophilizing according to a conventional method under aseptic condition.After the lyophilization, add the butyl rubber gag, open drying baker, roll the envelope aluminium lid, get product.Also can be with (1) or (2) or (3) step gained solution tray in lyophilization or spray drying, aseptic subpackaged getting final product

Silybinin lyophilized formulation of the present invention dissolves in 5% glucose injection or 0.9% sodium chloride injection or the like and oozes medium before using, and is applied to patient with treatment hepatopathy effective dose.

Silibinin raw material of the present invention, and adjuvant such as described solubilizing agent, excipient all can directly be buied from market.

Silibinin and other effective ingredient are all water insoluble, oral administration biaavailability is lower, individual variation is bigger, though existing silybin-N-methylglucamine is soluble in water, still can separate out under one's belt, influence absorbs, and Silybinin lyophilized formulation can address the above problem, overcome and compared with injection, transfusion, have volume little, carry and advantage such as easy to use, stable in properties, solved the preparation process complex difficult problem of degrading easily simultaneously technically.

The specific embodiment

By the following examples the present invention is further described, but should by any way it be interpreted as limitation of the present invention.Field of pharmaceutical preparations those skilled in the art are conspicuous to be equal to replacement, and corresponding improvement still falls in the protection domain of the present invention.

Embodiment 1

Get silibinin 48.2 grams, meglumine 19.5 grams, heating for dissolving in ethanol, backflow is spent the night, and evaporated under reduced pressure ethanol gets the silybin meglumine solid.

Get silibinin 48.2 grams, glucosamine 17.9 grams, heating for dissolving in ethanol, backflow is spent the night, and evaporated under reduced pressure ethanol gets silibinin glucosamine solid.

Get silibinin 48.2 grams, arginine 17.4 grams, heating for dissolving in ethanol, backflow is spent the night, and evaporated under reduced pressure ethanol gets silibinin arginine solid.

Embodiment 2

Get an amount of embodiment 1 gained silybin meglumine solid and an amount of mannitol, add an amount of water for injection, stirring is dissolved it fully, obtain every milliliter and contain 10 milligrams of silybin meglumines, the solution that mannitol is 30 milligrams, according to the amount adding active carbon of 0.05% (g/ml), 20 ℃ were stirred 30 minutes down, filter, gained filtrate is with 0.22 μ m microporous filter membrane degerming.Solution is sub-packed in the aseptic cillin bottle, press the method lyophilization of embodiment 7 after, sterile sealing, promptly.

Embodiment 3

Get an amount of embodiment 1 gained silibinin glucosamine solid and an amount of mannitol, add an amount of water for injection, stirring is dissolved it fully, obtain every milliliter and contain 15 milligrams of silibinin glucosamine, the solution that mannitol is 35 milligrams, according to the amount adding active carbon of 0.05% (g/ml), 20 ℃ were stirred 30 minutes down, filter, gained filtrate is with 0.22 μ m microporous filter membrane degerming.Solution is sub-packed in the aseptic cillin bottle, press the method lyophilization of embodiment 7 after, sterile sealing, promptly.

Embodiment 4

Get an amount of embodiment 1 gained silibinin arginine solid and an amount of mannitol, add an amount of water for injection, stirring is dissolved it fully, obtain every milliliter and contain 10 milligrams of silibinin arginine, the solution that mannitol is 25 milligrams, according to the amount adding active carbon of 0.05% (g/ml), 20 ℃ were stirred 30 minutes down, filter, gained filtrate is with 0.22 μ m microporous filter membrane degerming.Solution is sub-packed in the aseptic cillin bottle, press the method lyophilization of embodiment 7 after, sterile sealing, promptly.

Embodiment 5

Get an amount of silybin meglumine solid and an amount of mannitol, add an amount of water for injection, stirring is dissolved it fully, with dilute hydrochloric acid pH value is transferred to about 7.5, obtain every milliliter and contain 10 milligrams of silybin meglumines, the solution that mannitol is 30 milligrams, amount according to 0.05% (g/ml) adds active carbon, 20 ℃ were stirred 30 minutes down, filtered, and gained filtrate is with 0.22 μ m microporous filter membrane degerming.Solution is sub-packed in the aseptic cillin bottle, press the method lyophilization of embodiment 7 after, sterile sealing, promptly.

Embodiment 6

Get an amount of silybin meglumine solid and an amount of lactose and an amount of poloxamer, add an amount of water for injection, stirring is dissolved it fully, with dilute hydrochloric acid pH value is transferred to about 7.5, obtains every milliliter and contains 10 milligrams of silybin meglumines, 20 milligrams in mannitol, the solution that poloxamer is 10 milligrams, according to the amount adding active carbon of 0.05% (g/ml), 20 ℃ were stirred 30 minutes down, filter, gained filtrate is with 0.22 μ m microporous filter membrane degerming.Solution is sub-packed in the aseptic cillin bottle, press the method lyophilization of embodiment 7 after, sterile sealing, promptly.

Embodiment 7

Embodiment 2～6 gained solution lyophilizations by the following method:

Pre-freeze: respectively the temperature in the freeze drying box is reduced in advance about-30 ℃, the solution that branch is installed is put into and is carried out pre-freeze on the freeze drying box internal partition.

Sublimation drying: vacuum in the freeze drying box is risen to below the 13.33Pa (0.1mmHg), close freeze dryer.Slowly be heated to about 10 ℃, to supply with ice distillation institute calorific requirement, condenser temperature drops to below-30 ℃, carries out sublimation drying 30 hours.Embodiment 8: the solubility property of the preparation of the present invention that embodiment 2～6 is made is investigated.After adding water for injection, all fine dissolvings of energy, clarity is qualified.

Embodiment 9: stability test

Investigate embodiment 2～6 obtained stability of formulation with damp and hot accelerated test

Preparation of the present invention is placed in the exsiccator that contains saturated sodium-chloride water solution, exsiccator is placed 40 ± 1 ℃, under the condition of relative humidity 75%,, investigate outward appearance, pH value, loss on drying and the content of this product through six months.

Embodiment 10

Embodiment 2～6 gained solution are spray drying by the following method:

Medicinal liquid is sent in the shower nozzle by pipeline, carried out aseptic spray drying: inlet temperature 120-180 ℃, leaving air temp 60-100 ℃, collect sterilized powder, promptly aseptic subpackaged.

The study on the stability result

Project	Preparation	Time
							0	1	2	3	6
		Outward appearance	Embodiment 2	White lyophilizing block	White lyophilizing block	White lyophilizing block						White lyophilizing block	White lyophilizing block
Embodiment 3	White lyophilizing block						White lyophilizing block	White lyophilizing block	White lyophilizing block	White lyophilizing block
			Embodiment 4	White lyophilizing block	White lyophilizing block	White lyophilizing block					White lyophilizing block	White lyophilizing block
Embodiment 5	White lyophilizing block						White lyophilizing block	White lyophilizing block	White lyophilizing block	White lyophilizing block
			Embodiment 6	White lyophilizing block	White lyophilizing block	White lyophilizing block					White lyophilizing block	White lyophilizing block
PH value	Embodiment 2						8.05	8.08	8.00	7.96			7.90
		Embodiment 3	8.26	8.20	8.21	8.12					8.05
	Embodiment 4						8.14	8.10	8.02	8.08		7.88
		Embodiment 5	7.51	7.55	7.38	7.33					7.42
	Embodiment 6						7.47	7.53	7.56	7.41		7.33
		Loss on drying %	Embodiment 2	1.2	1.1	1.6					2.2		2.5
Embodiment 3	1.5						1.9	2.4	2.0	2.8
			Embodiment 4	1.9	2.2	24					2.7	3.3
Embodiment 5	0.9						1.8	1.2	2.2	2.3
			Embodiment 6	1.1	1.6	1.8					1.8	2.2
Content %	Embodiment 2						100.5	100.1	100.9	101.2			100.0
		Embodiment 3	99.2	100.3	99.5	99.0					99.9
	Embodiment 4						102.3	102.6	102.4	101.6		101.8
		Embodiment 5	98.8	99.3	98.6	98.2					98.0
	Embodiment 6						103.5	103.2	102.1	102.6		101.9

Outward appearance, pH value and loss on drying are checked according to a conventional method in the last table, and content is measured with reference to the method among the national drug standards WS-10001-(HD-0925)-2002 of National Drug Administration's promulgation.

The result shows, in the study on the stability six months, this product outward appearance, pH value, loss on drying, content have no significant change, and illustrate that this product is stable.

Claims (10)

1, a kind of Silybinin lyophilized formulation, the complex that is formed by the solution that contains silibinin and alkaline solubilizing agent and pharmaceutically acceptable excipient or silibinin and alkaline solubilizing agent and the solution of pharmaceutically acceptable excipient make after lyophilization; The pH value of described solution is 5.5～11; Its solvent can be the mixture of water or pharmaceutically acceptable organic solvent or water and pharmaceutically acceptable organic solvent.

2, according to the preparation of claim 1, the pH value that it is characterized in that described solution is in 7～10 scopes.

3,, it is characterized in that described alkaline solubilizing agent is selected from meglumine, glucosamine, basic amino acid according to the preparation of claim 1; Or the complex of silibinin and alkaline solubilizing agent formation, as silybin meglumine complex, silibinin glucosamine complex, silibinin basic amino acid complex.

4,, it is characterized in that described basic amino acid is selected from arginine, lysine, histidine according to the preparation of claim 3.

5,, it is characterized in that described pharmaceutically acceptable excipient is selected from one or more the material in mannitol, sorbitol, sodium chloride, glucose, dextran, sucrose, lactose, poloxamer, cysteine or other aminoacid according to the preparation of claim 1.

6,, it is characterized in that described solution also can contain one or more in pharmaceutically acceptable cosolvent, pH regulator agent, analgesics, antioxidant, antiseptic and the chelating agent according to the preparation of claim 1.

7,, it is characterized in that described pH regulator agent is hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, malic acid, succinic acid, tartaric acid, maleic acid, aminoacid, meglumine, sodium hydroxide, sodium carbonate, sodium bicarbonate and the buffer system that contains above-mentioned substance according to the preparation of claim 6.

8, according to the preparation of claim 6, wherein said cosolvent is poloxamer, castor oil hydrogenated, surfactant, cyclodextrin, phospholipid.

9, according to the preparation of claim 1, by main silybin meglumine complex and the mannitol of containing that contain silibinin, meglumine and mannitol or main, pH value is 7～10 aqueous solution, makes after lyophilization.

10, a kind of method for preparing the described lyophilized formulations of claim 1 comprises:

(1) preparation contains silibinin and alkaline solubilizing agent and pharmaceutically acceptable excipient and solvent, and its pH value is 5.5～11 solution;

(2) or earlier make the complex (solid or liquid) that silibinin and alkaline solubilizing agent form, again with pharmaceutically acceptable excipient and solvent, its pH value is 5.5～11 solution;

(3) or the preparation contain silybin meglumine complex and pharmaceutically acceptable excipient and solvent, its pH value is 5.5～11 solution;

(4) remove according to a conventional method impurity, decolour, reduce phlegm and internal heat former;

(5) with (1) or (2) or (3) step gained solution add and put the cillin bottle lyophilization promptly;

(6) or with (1) or (2) or (3) step gained solution tray in lyophilization or spray drying, packing get final product.