CN1546099A - Preparation of Resina Draconis dispersing tablet - Google Patents

Abstract

The invention relates to a process for preparing traditional Chinese medicinal dragons blood dispersion tablet, which is a tablet comprising dragons blood as the principal reactive ingredient and easy cracking findings. Physical means such as mechanical method or spray drying method are employed to obtain minisized dragons blood, or alcohol dissolving method can be utilized to obtain high molecular compound i.e. polyvinyl pyrrolidon (PVP), a solid dispersion of dragons blood.

Description

A kind of preparation method of Sanguis Draxonis dispersible tablet

Technical field the present invention relates to a kind of preparation method of Chinese medicine Sanguis Draxonis dispersible tablet.

The background technology Sanguis Draxonis also claims Sanguis Draxonis, and as the history in existing more than 1500 year of rare Chinese medicine, it has effects such as promoting blood circulation to remove blood stasis, anti-inflammatory analgetic, astringing to arrest bleeding, promoting tissue regeneration and ulcer healing, blood yiqi, is described as the panacea of invigorating blood circulation in China.As a class medical material, Sanguis Draxonis records in the national standard of National Drug Administration's promulgation in 1999, produces 95% ethanol extraction of resin for Liliaceae dracaena plant Dracaena cochinchinensis.In recent years, along with to the deepening continuously of Sanguis Draxonis pharmacodynamics and clinical application research, Sanguis Draxonis begun to be applied to treat cardiovascular disease, anal and rectal diseases, diabetes, gynaecopathia, digestive system disease, cervical spondylosis and some difficult assorted [Wu Ping, Du Qingyun. the chemical constituent of Sanguis Draxonis is made progress with clinical application research. Strait Pharmaceutical Journal 2000.12 (2): 1)].Yet, because Sanguis Draxonis is a resin, water insoluble, bioavailability is very low in human body, and at present commercially available prod such as powder, capsule, tablet are that the former medicine of Sanguis Draxonis is pulverized, directly be used as medicine into preparation, in treatment, must use heavy dose, therefore, explore the water miscible method of a kind of raising Sanguis Draxonis, can improve bioavailability, improve the Sanguis Draxonis curative effect.

Dispersible tablet is a kind of newtype drug dosage form that improves the insoluble medicine bioavailability that development in recent years is got up, be characterized in forming solid dispersion with the insoluble medicine granular or with polymer substance, with medicine of handling and the adjuvant mix homogeneously that is easy to disintegrate, make tablet then.Said preparation is taken more convenient, can be oral as conventional tablet, also can put into water, and make solid suspension and take.The purpose of this invention is to provide a kind of Sanguis Draxonis dispersible tablet, with the effective utilization that reaches medicine and the raising of curative effect with high bioavailability.

The Sanguis Draxonis dispersible tablet of summary of the invention indication of the present invention is meant that to handle Sanguis Draxonis be main active, is equipped with the adjuvant that is easy to disintegrate again and the tablet of making.

Used processing Sanguis Draxonis is meant granular Sanguis Draxonis or Sanguis Draxonis solid dispersion in the dispersible tablet.Granular is meant utilizes physical method such as Mechanical Method or spray drying method that Sanguis Draxonis is become fine particle.Mechanical Method is as making microgranule with methods such as grinding, pulverizer, comminution by gas stream with Sanguis Draxonis, and the particle size of granular should be less than 200 orders, preferably less than 500 orders.Spray drying method is Sanguis Draxonis to be dissolved in a kind of solvent make solution, adopts the spray drying mode that solvent evaporates is obtained pressed powder then.Make solution in the ethanol as Sanguis Draxonis is dissolved in, adopt spray drying can get granular Sanguis Draxonis granule then.The solvent mode prepares solid dispersion and is meant that Sanguis Draxonis and polymer substance form sol dispersion.The purpose of handling Sanguis Draxonis is to make the interfacial area of Sanguis Draxonis and liquid to increase, to reach the purpose that dissolubility increases.About utilizing solid dispersion technology to increase the method for Sanguis Draxonis dissolubility, Li Zhongkun etc. delivered a kind of Sanguis Draxonis spongy body preparation method [Li Zhongkun etc. the development of Sanguis Draxonis sandwich rubber wafer. Chinese Journal of New Drugs .2001.10 (12): 918]: the 20g gelatin is soaked 4h in 180ml water, in 50 ℃ of water-baths, stir and make it dissolving, make foaming at 38 ℃ with the eggbeater stirring, add 4.4% formaldehyde 17ml in the stirring, when producing a large amount of uniform and smooth foam, add the 20g Sanguis Draxonis, stir,-10 ℃ freezing dry afterwards, gets spongy body, and the main effect of this method is to utilize the gelfoam adhesive attraction, to prolong Sanguis Draxonis action time, improve curative effect.Chinese patent CN1096852C has proposed a kind of preparation of Sanguis Draxonis solid dispersion, is characterized in water-soluble solid dispersion Sanguis Draxonis being dispersed into fine particles by mixed method.This invention proposes two kinds and prepares Sanguis Draxonis dispersion method: wet grinding method and dry grinding method.The dry grinding method be with solid dispersion and Sanguis Draxonis in (16～0.2): 1 ratio, fully grind, sieve promptly.Wet grinding is that solid dispersion is ground well by 0.3～3 times of amount with water earlier, add Sanguis Draxonis solution then, fully grind, make solid dispersion that Sanguis Draxonis is dispersed into superfine microgranule, the dry then dispersion that gets, the drying mode that this method adopts is 40 ℃ of dryings, vacuum lyophilization or vacuum dryings.

The related dispersant of this invention is that α, β, gamma-cyclodextrin, molecular weight are 1000～20000 Polyethylene Glycol, methylcellulose, hydroxypropyl cellulose, cellulose acetate-phthalate, hydroxypropyl methylcellulose phthalate, carboxymethylethylcellulose, microcrystalline Cellulose, poloxamer 188 and Myrij class surfactant.The main feature of this invention is to utilize Sanguis Draxonis insoluble characteristics in water, and the solid dispersion aqueous solution is disperseed Sanguis Draxonis, to form comparatively tiny Sanguis Draxonis granule.The present invention proposes a kind of method that more effectively prepares the Sanguis Draxonis dispersion, this method relates to Sanguis Draxonis and mixes the solid-state colloidal sol of formation with macromolecular compound, particularly, adopt pure solubleness high molecular compound polyvinylpyrrolidone (PVP), mix with Sanguis Draxonis by a certain percentage and be dissolved in ethanol (unless otherwise indicated, indication ethanol is the alcoholic solution of dehydrated alcohol or concentration 〉=85% (v/v) among the present invention) in, form solution, then, ethanol evaporation, drying makes the Sanguis Draxonis dispersion.This dispersion adds adjuvant and makes dispersible tablet through being ground into the granule of film-making granularity that agent requires.The characteristics of this method are to utilize the unbodied ins and outs of PVP [Xi Nianzhu, pharmaceutics, People's Health Publisher (1996), Beijing, 270], in alcoholic solution, fully mix, in solvent evaporation with the Sanguis Draxonis molecule, PVP combines with the Sanguis Draxonis molecule, suppress the gathering of Sanguis Draxonis molecule, thereby do not form big Sanguis Draxonis granule, formed solid is amorphous existence after the solvent evaporation, thereby it is water-soluble to help Sanguis Draxonis, improves the Sanguis Draxonis bioavailability.In order to make PVP and Sanguis Draxonis form amorphous solid in the above described manner, avoid the big particulate formation of Sanguis Draxonis in the solid, PVP and Sanguis Draxonis amount are carried out following experiment, dispersion dissolving situation is meant 1g solid dispersion dissolving situation in 30ml water in the table 1.

Table 1 PVP and Sanguis Draxonis different proportion form dispersion relatively

Test	Sanguis Draxonis (g)	PVP (g)	Volumes of aqueous ethanol (ml)	The alcoholic solution situation	Dispersion dissolving situation
						1	1	0.1	60	Brown-red solution	Shallow salmon liquid has a large amount of larger particles
2	1	0.5	60	Brown-red solution	Shallow salmon liquid has more fine particle
						3	1	1	60	Brown-red solution	The pale red emulsion liquid has tiny red granules.
4	1	2	60	Brown-red solution	Shallow salmon liquid
						5	1	3	60	Brown-red solution	Shallow salmon liquid
6	1	5	60	Brown-red solution	Salmon liquid
						7	1	8	60	Brown-red solution	Salmon liquid
8	1	10	60	Brown-red solution	Salmon liquid

As can be seen from Table 1, as PVP: during Sanguis Draxonis (weight ratio) 〉=2: 1, can form ideal dispersion, consider and dispersion further must be made preparation that the PVP amount should not be too big; And weaken gradually with the effect that this ratio reduces PVP, disperse the effect of Sanguis Draxonis also to weaken, particularly as PVP: Sanguis Draxonis is during less than 0.5: 1, and the dispersion of formation will not reach purpose of the present invention as if not doing further processing.In sum, the present invention determines suitable PVP: Sanguis Draxonis=(0.5～5): 1 is advisable.

The difference of Sanguis Draxonis dispersion of the present invention and other Sanguis Draxonis microparticle dispersions is, utilize the special nature of PVP, PVP is fully combined with Sanguis Draxonis and form amorphous solid, this solid dispersion has the PVP water-wet behavior, so be easy to be scattered in the water, form colloid solution, and other materials such as PEG do not have this characteristic [Xi Nianzhu, pharmaceutics, People's Health Publisher (1996), Beijing, 271].Sanguis Draxonis dispersion good water solubility with this method preparation helps absorbing of organism, has good bioavailability, thereby can give full play to the effect of Sanguis Draxonis, improves curative effect.

Indication dispersible tablet of the present invention is characterized in that to handle Sanguis Draxonis be main active, contains a kind of disintegrating agent at least.It is 50%～90% that the processing Sanguis Draxonis accounts for dispersible tablet anharmonic ratio example; It is 1%～7% that disintegrating agent accounts for dispersible tablet anharmonic ratio example.Common disintegrating agent is guar gum, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, carboxymethyl cellulose sodium, microcrystalline Cellulose, amylum pregelatinisatum etc. or two kinds compositions wherein, in the dispersible tablet preparation process, disintegrating agent can in add, also can add, also can inside and outside all add.As: in add microcrystalline Cellulose, add crospolyvinylpyrrolidone; In add carboxymethyl cellulose sodium, add outer microcrystalline Cellulose etc.It is coarse granule that the disintegrating agent that adds makes disintegration of tablet, in the disintegrating agent that adds make coarse granule disintegrate once more, to reach the high purpose of dispersion efficiency.Two kinds of adjuvant part by weight of disintegrating agent compositions are (1%～99%): (99%～1%).In order to increase powder flowbility in the dispersible tablet preparation process, select for use micropowder silica gel to make fluidizer.Disintegrate and outward appearance in order further to improve the Sanguis Draxonis dispersible tablet add filler in the pelletization, filler is lactose, microcrystalline Cellulose, carboxymethyl cellulose etc.; Binding agent is polyvinylpyrrolidone (PVP) commonly used, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose etc.; Lubricant is a magnesium stearate.The part by weight of above-mentioned adjuvant is a filler 10～30 in the dispersible tablet adjuvant; Binding agent 0.01～0.1; Fluidizer 0.1～1; Lubricant 0.005～0.05.All supplementary materials of preparation dispersible tablet all should be crossed 120 mesh sieves.

The invention will be further described by the following examples for the specific embodiment, but the present invention is not subjected to this limitation (following drying is if nothing specializes, and pressure is normal pressure):

The preparation of embodiment 1 dispersion: under the room temperature, get Sanguis Draxonis 10g, PVP40g mixes, add ethanol 300ml, constantly stirred 40 minutes, can get dark red solution, solution is poured in the evaporating dish, 80 ℃ of heating, and constantly stir, up to becoming thick liquid (relative density is 1.2～1.3), stop to stir, continue heating, till drying, get dark red solid, be the Sanguis Draxonis dispersion.

The preparation of embodiment 2 dispersions: under the room temperature, get 5% Sanguis Draxonis alcoholic solution 100ml and do not stir down, add 15gPVP, 1h is stirred in continuation, gets dark red solution, and 80 ℃ of heating down make solvent evaporates, get the dark red solid thing, are the Sanguis Draxonis dispersion.

Embodiment 3 dispersions preparation: under the room temperature, get Sanguis Draxonis 5g, PVP25g, be dissolved in 30ml respectively, in the 200ml ethanol, get solution separately, Sanguis Draxonis solution is peony, and PVP solution is water white transparency, under constantly stirring, Sanguis Draxonis solution is added in the PVP solution, continue to stir 40 minutes, get dark red solution, solution is carried out spray drying, 80 ℃ of temperature, charging flow velocity 5ml/ minute, hot air flowrate 100L/ minute, collecting powder was the Sanguis Draxonis dispersion.

The preparation of embodiment 4 dispersible tablets: under the room temperature, the comminution by gas stream fine powder of dragons blood 300g that learns from else's experience,, granularity should be less than 500 orders, disintegrating agent carboxymethyl base Starch Sodium 20g, and filler microcrystalline Cellulose 10g, mix homogeneously, stand-by.The 1g polyvinylpyrrolidone is dissolved in 40ml 50% alcoholic solution as binding agent.In stirring, binder solution is added in the solid mixture, granulate with 40 mesh sieves, with wet grain drying 5 hours,, mixes under 70 ℃ with 5g micropowder silica gel, 0.5g magnesium stearate with dried granule 20 order granulate, tabletting must the Sanguis Draxonis dispersible tablet 1000.

Embodiment 5 dispersible tablets preparation: under the room temperature, comminution by gas stream fine powder of dragons blood 100g learns from else's experience, granularity should be less than 500 orders, and the Sanguis Draxonis dispersion 200g of method preparation is ground into 120 order fine powders described in the embodiment 2, disintegrating agent carboxymethyl base Starch Sodium 20g, filler microcrystalline Cellulose 10g, mix homogeneously is dissolved in 40ml 50% alcoholic solution as binding agent with the 1g polyvinylpyrrolidone.In stirring, binder solution is added in the solid mixture, granulate with 40 mesh sieves, with wet grain drying 5 hours,, mixes under 70 ℃ with 5g micropowder silica gel, 0.5g magnesium stearate with dried granule 20 order granulate, tabletting must the Sanguis Draxonis dispersible tablet 1000.

Embodiment 6～10 dispersible tablets preparation: under the room temperature, get the Sanguis Draxonis dispersion 300g of method preparation described in the embodiment 2, be ground into 120 order fine powders, get and mix disintegrating agent (ratio sees Table 2) 20g, filler microcrystalline Cellulose 5g, mixing.Get 3% low-substituted hydroxypropyl cellulose, 50% alcoholic solution 50ml, in stirring, add in the mixture, granulate wet granular, 60 ℃ of following dry 5h must do granule through 20 order granulate, with 5g micropowder silica gel and 0.5g magnesium stearate mix homogeneously, tabletting, get 1000 of Sanguis Draxonis dispersible tablets.Disintegrating agent A is a crospolyvinylpyrrolidone among the embodiment 6～10, and disintegrating agent B is a carboxymethyl starch sodium.

Table 2 embodiment 6～10 mixes the disintegrating agent part by weight

The embodiment numbering	Disintegrating agent A (%)	Disintegrating agent B (%)
			????6	????1	????99
????7	????30	????70
			????8	????50	????50
????9	????70	????30
			????10	????99	????1

Embodiment 11～13 dispersible tablets preparation: under the room temperature, get the Sanguis Draxonis dispersion 300g that executes method preparation described in the example 3, cross 120 mesh sieves.Get disintegrating agent carboxymethyl base Starch Sodium and filler microcrystalline Cellulose consumption by table 3, mixing adds 3% hydroxypropyl cellulose, 40% alcoholic solution 50ml, in the stirring, add in the hybrid solid material, granulate, 60 ℃ of dry 5h must do granule and cross 20 mesh sieve granulate, add 5g micropowder silica gel and 0.5g magnesium stearate, mix, tabletting gets 1000 of Sanguis Draxonis dispersible tablets.

Table 3 embodiment 11～13 disintegrating agent consumptions

The embodiment numbering	Disintegrating agent consumption (g)	Account for the dispersible tablet weight ratio	Filling dose (g)
				????11	????1.70	????0.5％	????35.8
????12	????16.98	????5％	????20.52
				????13	????33.95	????10％	????3.55

Embodiment 14～16 dispersible tablets preparation: at room temperature, get Sanguis Draxonis dispersion 300g by 1 describing method preparation of embodiment, be ground into 120 order fine powders, get disintegrating agent by table 4, embodiment 14, in getting with disintegrating agent low-substituted hydroxypropyl cellulose 20g, filler lactose 15g and Sanguis Draxonis dispersion powder mixing; Embodiment 15, in getting with disintegrating agent microcrystalline Cellulose 20g, with Sanguis Draxonis dispersion powder mixing; Embodiment 16, get filler lactose 10g, carboxymethyl cellulose 10g, with Sanguis Draxonis dispersion powder mixing; Add 3% polyvinylpyrrolidone, 30% alcoholic solution 40ml in above three kinds of solid mixtures, stir, granulate with 50 eye mesh screens, 70 ℃ of dry 4h get dried particles 20 order granulate.Add 5g micropowder silica gel and 0.5g magnesium stearate, mix homogeneously among the embodiment 14 in the dried particles; Add among the embodiment 15 and add disintegrating agent crospolyvinylpyrrolidone 15g, 5g micropowder silica gel and 0.5g magnesium stearate; Adding adds disintegrating agent low-substituted hydroxypropyl cellulose 15g, 5g micropowder silica gel and 0.5g magnesium stearate among the embodiment 16, and mix homogeneously with above-mentioned three kinds of hybrid particles difference tabletting, gets the Sanguis Draxonis dispersible tablet.

Table 4 embodiment 14-16 disintegrating agent addition manner

The embodiment numbering	In add	Add
			????14	Low-substituted hydroxypropyl cellulose 20g	-
????15	Microcrystalline Cellulose 20g	Crospolyvinylpyrrolidone 15g
			????16	-	Low-substituted hydroxypropyl cellulose 15g

Embodiment 17,18 dispersible tablets preparation: under the room temperature, get Sanguis Draxonis dispersion 300g; get each 20g of disintegrating agent low-substituted hydroxypropyl cellulose and microcrystalline Cellulose and crospolyvinylpyrrolidone (weight ratio 2: 3) mixture; disintegrating agent is by weight by the preparation of 3 describing methods of embodiment; in add 2/3rds, outside 1/3rd.Get filler mixing lactose 10g, carboxymethyl cellulose 10g, with Sanguis Draxonis dispersion and 2/3rds disintegrating agent and filler mix homogeneously.Disintegrating agent is a low-substituted hydroxypropyl cellulose among the embodiment 17, disintegrating agent is microcrystalline Cellulose and crospolyvinylpyrrolidone mixture among the embodiment 18, add 3% polyvinylpyrrolidone, 40% alcoholic solution 40ml respectively in two kinds of mixture, stir, 40 orders are granulated, 70 ℃ of dry 4h, 20 order granulate add residue 1/3rd disintegrating agents, 5g micropowder silica gel and 0.5 magnesium stearate in dried granule, tabletting gets the Sanguis Draxonis dispersible tablet respectively.

Claims (9)

1, a kind of Sanguis Draxonis dispersible tablet is characterized in that to handle Sanguis Draxonis be active component, is equipped with to help disintegration of tablet again

Adjuvant and excipient and the tablet made.

2, the processing Sanguis Draxonis described in the claim 1 is meant PVP-Sanguis Draxonis solid dispersion that granular Sanguis Draxonis, macromolecular material polyvinylpyrrolidone (PVP) and Sanguis Draxonis form and in granular Sanguis Draxonis and the PVP-Sanguis Draxonis solid dispersion compositions any.

3, the Sanguis Draxonis of granular described in the claim 2 is meant with mechanical means the Sanguis Draxonis micronize.The Sanguis Draxonis grain graininess of mechanical means granular is less than 200 orders.

4, the preparation of the Sanguis Draxonis of PVP-described in the claim 2 solid dispersion is characterized in that PVP and Sanguis Draxonis forming solution, and fully mixing by being dissolved in the ethanol, volatilization ethanol and the solid dispersion that obtains.

5, PVP described in the claim 4: Sanguis Draxonis (weight ratio)=(0.5～5): 1.

6, the part by weight of Sanguis Draxonis of granular described in the claim 2 and PVP-Sanguis Draxonis solid dispersion compositions is (10%～90%): (90%～10%).

7, to account for dispersible tablet anharmonic ratio example be 50%～90% to the processing Sanguis Draxonis described in the claim 1.

8, the adjuvant that helps disintegration of tablet described in the claim 1 is meant any one or two kinds of compositionss in guar gum, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, carboxymethyl cellulose sodium, sodium alginate, microcrystalline Cellulose, the amylum pregelatinisatum.Disintegrating agent add, add in can adopting or in add and add combination.It is 1%～7% that disintegrating agent accounts for dispersible tablet anharmonic ratio example.Two kinds of adjuvant part by weight of disintegrating agent compositions are (1%～99%): (99%～1%), two kinds of adjuvants can mix, add in the employing, add or in add combination, also can adopt to add in a kind of, another kind of outer add mode prepares dispersible tablet.

9, excipient described in the claim 1 be meant filler (diluent) in the lactose, microcrystalline Cellulose, carboxymethyl cellulose any; Binding agent is any in polyvinylpyrrolidone (PVP), hydroxypropyl cellulose, the low-substituted hydroxypropyl cellulose; Fluidizer is micropowder silica gel, and lubricant is a magnesium stearate.The part by weight that other excipient account for dispersible tablet adjuvant amount is a filler 10～30; Binding agent 0.01～0.1; Fluidizer 0.5～1; Lubricant 0.01～0.05.