CN102210673A - Cyclodextrin inclusion compound containing ligustilide, and preparation method thereof - Google Patents

Abstract

The invention provides a cyclodextrin inclusion compound containing ligustilide, comprising ligustilide and hydroxypropyl-beta-cyclodextrin, wherein the ligustilide is included in the hydroxypropyl-beta-cyclodextrin to form an inclusion compound, the percentages by weight of the ligustilide and the hydroxypropyl-beta-cyclodextrin are 10-20%, and the cyclodextrin inclusion compound further contains povidone K29/32 which accounts for 10-50% of the hydroxypropyl-beta-cyclodextrin by weight. The cyclodextrin inclusion compound containing the ligustilide can be prepared into tablets, capsules, powder or powder injections as medicaments for treating dysmenorrhea.

Description

Comprise cyclodextrin clathrate of ligustilide and preparation method thereof

Technical field

The invention belongs to biomedicine field, be specifically related to cyclodextrin clathrate that comprises ligustilide and preparation method thereof.

Background technology

Ligustilide is the main effective ingredient in China's tradition conventional Chinese medicine Radix Angelicae Sinensis, the Rhizoma Chuanxiong volatile oil, accounts for 35% and 58% of Radix Angelicae Sinensis, Rhizoma Chuanxiong volatile oil respectively, is the important indicator of estimating Chinese crude drug quality such as Radix Angelicae Sinensis, Rhizoma Chuanxiong.Ligustilide has multiple biological activitys such as spasmolytic, relieving cough and asthma, menstruction regulating and pain relieving, but its deep preparation research also almost is blank, main cause is that the ligustilide chemical property is very unstable, and improving constantly along with refining degree, unstability is more outstanding, becomes the bottleneck of the high-quality preparation of restriction.

The content of ligustilide in medical material changes bigger because of the medical material place of production, collecting season, fresh and dried degree difference.The ligustilide chemical property is very active, and along with ligustilide the improving constantly of content in extract, the instability of ligustilide is more outstanding, very easily isomery turns to other cyclobutenyl furan lactone compounds, the multiple complicated product of the long-time slightly also oxidable one-tenth of placement disappears to last, brings very big inconvenience for preservation and preparation.Therefore,, must further investigate, take the stabilisation measure that suits at the stability problem of its existence.

Clathrate is all or part ofly in a kind of space structure of molecule to wrap into another kind of molecule and form, and claims molecular capsule again.Cyclodextrin is because its structure has the particularity of " outer hydrophilic, interior hydrophobic " and nontoxic premium properties, can with multiple object inclusion, adopt the clathrate of proper method preparation that some character of object is improved.

The cyclodextrin molecular structure is formed by connecting by α-1,4 glycosidic bond by 6 above glucoses, is tubbiness.Form the hydrophobicity cavity in the bucket, can absorb the hydrophobic small molecules material or the group of a certain size and shape, form stable non-covalent complex.By six, seven, eight glucose monomers are α-CD by the cyclodextrin that α-1,4 glycosidic bond is formed by connecting, β-CD, γ-CD respectively.β-CD is one of best enclose material of known effect, is most widely used in three types.

(HP-β-CYD) not only chemical compound lot is had good envelope effect improves by the envelope Stability of Substance HP-, and it also has the water solublity height and improves by the rate of release of envelope medicine and bioavailability in vivo.HP-β-CYD hemolytic activity is low on the other hand, and show activity is low, to skin and muscle nonirritant, is a kind of good cosolvent.

Therefore, ligustilide is carried out cyclodextrin inclusion compound, can improve its stability, prolong the resting period.

Summary of the invention

The purpose of this invention is to provide a kind of cyclodextrin clathrate that comprises ligustilide.

The present invention also provides the method for the described clathrate of preparation.

The present invention comprises the cyclodextrin clathrate of ligustilide, ligustilide, HYDROXYPROPYL BETA-CYCLODEXTRIN have been closed, the ligustilide enclose forms clathrate in HYDROXYPROPYL BETA-CYCLODEXTRIN, wherein, the percentage by weight of ligustilide and HYDROXYPROPYL BETA-CYCLODEXTRIN is 10%-20%, and the percentage by weight of preferred ligustilide and HYDROXYPROPYL BETA-CYCLODEXTRIN thing is 12%-15%.

The present invention comprises the cyclodextrin clathrate of ligustilide, further comprise 30 POVIDONE K 30 BP/USP 29/32, the percentage by weight that its consumption accounts for HYDROXYPROPYL BETA-CYCLODEXTRIN is that the percentage by weight that preferred 30 POVIDONE K 30 BP/USP 29/32 consumption of 10%-50% accounts for HYDROXYPROPYL BETA-CYCLODEXTRIN is 25%-30%.

The present invention also comprises the Pharmaceutical composition that comprises described cyclodextrin clathrate, and in described compositions, the percentage by weight that cyclodextrin clathrate accounts for compositions is 1%-10%.

Described Pharmaceutical composition can be tablet, capsule, powder or injection powder injection.

Described tablet, capsule, powder also comprise the excipient that pharmaceutically is suitable for, for example filler, disintegrating agent, wetting agent, binding agent, effervescent, surfactant, lubricant, fluidizer, correctives, the strong excipient of smelling the solid preparation of agent, coloring agent and other kinds.

Filler can be selected from one or more the combination of following material: calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, sucrose, lactose, fructose, xylitol, mannitol, starch and derivant thereof, dextrin, microcrystalline Cellulose.

Disintegrating agent can be selected from one or more the combination of following material: starch, alginic acid, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, low substituted hydroxy-propyl methylcellulose, microcrystalline Cellulose, methylcellulose.

Effervescent can be selected from the combination of citric acid, tartaric acid, boric acid, maleic acid etc. and carbonate, or selects phosphatic combination for use, or selects succinic anhydrides for use, organic acid anhydride classes such as citron anhydride.

Surfactant can be selected from one or more combination of following material: sodium lauryl sulphate, poloxamer, Tweens, bromination hexadecane trimethylamine, sodium laurylsulfate, stearyl alcohol sodium sulfonate, polyoxyethylene high fatty alcohol, sucrose ester, sorbitol fatty ester, soybean phospholipid etc.

Wetting agent can be selected from one or more the combination of following material: distilled water, ethanol, starch slurry, dodecyl sodium sulfate, Tweens surfactant.

Binding agent can be selected from one or more the combination of following material: arabic gum, gelatin, Tragacanth, dextrin, polyvinylpyrrolidone, starch and derivant thereof, sodium alginate, sorbitol, syrup, hydroxypropyl emthylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, ethyl cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, glucose, polymethacrylates.

Lubricant can be selected from one or more the combination of following material: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline Cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, magnesium stearate, stearyl fumarate, Pulvis Talci, zinc stearate, Polyethylene Glycol.

Fluidizer can be selected from one or more the combination of following material: silica sol, Powderd cellulose, magnesium trisilicate, silicon dioxide and Pulvis Talci.

Correctives can be selected from aspartame, stevioside, fructose, glucose, syrup, Mel, xylitol, mannitol, lactose, sorbitol, maltose alcohol, glycyrrhizin, phyllodulcin and various essence, rectify and to smell agent and can select aromatic oil for use, the artificial or synthetic pigment of the optional usefulness of coloring agent.

Understand easily as those skilled in the art institute, for solid orally ingestible, above-mentioned substance enumerate the restriction that does not constitute technical scheme, the used excipient of the solid preparation of other that do not enumerate equally also goes for this programme, thereby is also included within this programme.

The present invention also comprises the Preparation methods of cyclodextrin inclusion complexes that comprises ligustilide, comprises the steps:

(1) preparation HYDROXYPROPYL BETA-CYCLODEXTRIN aqueous solution;

(2) add 30 POVIDONE K 30 BP/USP 29/32, mix homogeneously;

(3) be heated to 30 ℃-50 ℃;

(3) under agitation add ligustilide, the maintenance temperature also stirred 1-6 hour;

(4) lyophilization or rotary evaporation are removed organic solvent.

Promptly get the cyclodextrin clathrate that the present invention comprises ligustilide.

The specific embodiment

The preparation of HYDROXYPROPYL BETA-CYCLODEXTRIN aqueous solution

The 50g HYDROXYPROPYL BETA-CYCLODEXTRIN is dissolved in the 50ml water, stirs, add 30 POVIDONE K 30 BP/USP 29/32, be diluted to 100ml. with water

The preparation of inclusion complex in solution

Under stirring fast, ligustilide 10g is extremely transparent with the HYDROXYPROPYL BETA-CYCLODEXTRIN aqueous solution for preparing, be diluted to 200ml with water.

Freeze-drying prepares clathrate

The above-mentioned inclusion complex in solution for preparing is placed on is suitable for refrigerated and has in the ampoule of stopper, be positioned in the freezer dryer.

Claims (7)

1. the cyclodextrin clathrate that comprises ligustilide, it is characterized in that contain ligustilide, HYDROXYPROPYL BETA-CYCLODEXTRIN, the ligustilide enclose forms clathrate in HYDROXYPROPYL BETA-CYCLODEXTRIN, wherein, the percentage by weight of ligustilide and HYDROXYPROPYL BETA-CYCLODEXTRIN is 10%-20%.

2. the cyclodextrin clathrate that comprises ligustilide as claimed in claim 1 is characterized in that, the percentage by weight of ligustilide and HYDROXYPROPYL BETA-CYCLODEXTRIN thing is 12%-15%.

3. the cyclodextrin clathrate that comprises ligustilide as claimed in claim 1 is characterized in that, further comprises 30 POVIDONE K 30 BP/USP 29/32, and the percentage by weight that its consumption accounts for HYDROXYPROPYL BETA-CYCLODEXTRIN is 10%-50%.

4. the cyclodextrin clathrate that comprises ligustilide as claimed in claim 1 is characterized in that, the percentage by weight that 30 POVIDONE K 30 BP/USP 29/32 consumption accounts for HYDROXYPROPYL BETA-CYCLODEXTRIN is 25%-30%.

5. comprise as the arbitrary described Pharmaceutical composition that comprises the cyclodextrin clathrate of ligustilide of claim 1 to 4, it is characterized in that, in described compositions, the percentage by weight that cyclodextrin clathrate accounts for compositions is 1%-10%.

6. Pharmaceutical composition as claimed in claim 5 is characterized in that, it is tablet, capsule, powder or injection powder injection.

7. as the arbitrary described Preparation methods of cyclodextrin inclusion complexes that comprises ligustilide of claim 1 to 4, comprise the steps:

(1) preparation HYDROXYPROPYL BETA-CYCLODEXTRIN aqueous solution;

(2) add 30 POVIDONE K 30 BP/USP 29/32, mix homogeneously;

(3) be heated to 30 ℃-50 ℃;

(3) under agitation add ligustilide, the maintenance temperature also stirred 1-6 hour;

(4) lyophilization or rotary evaporation are removed organic solvent promptly.