CN103566055A - Callicarpa nudiflora pellet capsule as well as preparation method thereof - Google Patents
Callicarpa nudiflora pellet capsule as well as preparation method thereof Download PDFInfo
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- CN103566055A CN103566055A CN201310441590.7A CN201310441590A CN103566055A CN 103566055 A CN103566055 A CN 103566055A CN 201310441590 A CN201310441590 A CN 201310441590A CN 103566055 A CN103566055 A CN 103566055A
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Abstract
The invention relates to a callicarpa nudiflora pellet (capsule) as well as a preparation method thereof. The pellet provided by the invention comprises the following components in parts by weight: 30-90 parts of a callicarpa nudiflora extract, 10-75 parts of a diluent, 0.5-10 parts of a disintegrating agent and an optimal binder. The invention further relates to a coating pellet comprising the pellet as well as the preparation method of the pellet. The pellet provided by the invention can be used for preparing a controlled release capsule or an enteric pellet capsule preparation by combining a controlled release or enteric pellet technology. The pellet preparation provided by the invention is reasonable in type and dosage in proportion of the selected main medicines and auxiliary materials, has good yield and has the advantages of stability and safety, high dissolving out rate, high bioavailability, small side effect, and/or convenience in delivery and the like.
Description
Technical field
The invention belongs to field of medicaments, relate to micropill (capsule) of a kind of Callicarpa nudiflora extract and preparation method thereof, be particularly related to and can be used for treating the inflammation that antibacterial infection causes, acute infectious hepatitis, micropill (capsule) that the Callicarpa nudiflora plant extract of respiratory tract and digestive tract hemorrhage is made and preparation method thereof.
Background technology
Callicarpa nudiflora (callicarpanudifloraHook.exArn) is Verenaceae (Verbenaceae) Callicarpa plant, and main product, in China Hainan, is a kind of Hainan authentic medicinal herbs, and also there is distribution in China Guangdong, Guangxi.Mainly be distributed in India, Vietnam and Malaysia abroad.Its root, leaf can be used as medicine, and have antibacterial anti hemorrhagic, eliminating inflammation and expelling toxin, and dissipating blood stasis for subsidence of swelling, the effects such as wind-expelling and dispelling dampness, cure mainly the diseases such as suppurative inflammation, acute infectious hepatitis, respiratory tract and digestive tract hemorrhage, wound hemorrhage, and burn and traumatic hemorrhage etc. are controlled in external.
Prior art all reports that Callicarpa nudiflora extract has corresponding biologic activity, as antibacterial anti hemorrhagic, and eliminating inflammation and expelling toxin, dissipating blood stasis for subsidence of swelling, wind-expelling and dispelling dampness etc. Callicarpa nudiflora bitter in the mouth is cool in nature, and the puckery of holding concurrently is nontoxic.Can clearing away heat and cooling blood, again can astringing to arrest bleeding.The conventional Chinese herbal medicine handbook > > in < < Hainan Island carries this product " dissipating blood stasis for subsidence of swelling, hemostasis.Control epistaxis, hemoptysis, hemoptysis, gastric hemorrhage, treating swelling and pain by traumatic injury, traumatic hemorrhage." < < Fujian traditional herbal medicine > > also calls can " stasis of blood of living, hemostasis, antiinflammatory, resolving depression ", and single is applied to that the intestines and stomach is hemorrhage, the treatment of spitting of blood and epistaxis.This product enters liver, lung, stomach warp, therefore especially allly go out blood disorder through pathogenic heat due to stop up containing to above-mentioned, as spat blood, spit blood, having blood in stool, curative effect is distinguished, and Chang Danyong gets effect.Modern study also shows: Callicarpa nudiflora can reduce vascular permeability, shortens bleeding time and the clotting time of laboratory animal, excited smooth muscle, and pressor effect, thus there is anastalsis; Also have viral hepatitis in addition, still have function for protecting liver and reducing enzyme activity.At present, Callicarpa nudiflora is used for clinical with the dosage form of conventional tablet, capsule, granule, mixture and soft capsule.For example Chinese patent 200910006088.7 discloses and a kind ofly by improving Callicarpa nudiflora extraction process, has prepared its corresponding spray, tablet, capsule, oral liquid or granule, but the disclosed extracting method of this patent need to be used column chromatography (punching adsorbent resin) to carry out purification and separation, not only improved production cost, and caused the loss of Callicarpa nudiflora effective ingredient, reduced drug effect, and prepared ordinary preparation do not have enough stability yet, cannot meet the needs of suitability for industrialized production.And for example Chinese patent 200410088712.x discloses a kind of Callicarpa nudiflora capsule preparations, said preparation adds starch by Callicarpa nudiflora extract and magnesium stearate prepares in granulating and granule is incapsulated, the stability of this conventional capsule is not high, and quality is uncontrollable, be also difficult to meet the requirement of suitability for industrialized production.For another example, Chinese patent 200510020760.x discloses a kind of dispersible tablet of naked flower beautyberry leaf, and this dispersible tablet is prepared from adjuvant by Callicarpa nudiflora extract, dispersible tablet.
Yet the stability of above-mentioned general formulation itself is not high, the bitter taste of Callicarpa nudiflora medical material in addition, can not meet the patient's of the especially old children of clinical different patient and dysphagia the demand of different indications at present.Micropill refers to that diameter is less than the spherical preparation of 2.5mm.Micropill can be evenly distributed in gastrointestinal tract after taking, and medicine is increased at gastrointestinal tract surface distributed area, thereby can improve bioavailability or reduce too high the caused GI irritation of medicine local concentration; At gastrointestinal, absorb and be subject to the impact of gastric emptying less, uniform absorption, bioavailability among individuals difference is little; Good fluidity, is convenient to packing, divided dose.Make rate of release, position and the time of slow release, controlled release or the controlled pharmacy of enteric coated micropill to reach different therapeutic purposes.
About Callicarpa nudiflora, at present not yet there is the report of micropill dosage form and be applied to clinical, because micropill dosage form has, improve bioavailability or too high the caused GI irritation of minimizing medicine local concentration, make the independent body advantages such as rate of release of delaying controlled release or the controlled pharmacy of enteric coated micropill, therefore finding a kind of formula that is suitable for Callicarpa nudiflora plant extract micropill is valuable to those skilled in the art.
Summary of the invention
The object of the present invention is to provide a kind of inflammation that antibacterial infection causes that can be used for treating, acute infectious hepatitis, the preparation method of the Callicarpa nudiflora plant extract micropill of respiratory tract and digestive tract hemorrhage, the capsule of being prepared by this micropill and described micropill and capsule, wherein micropill can be made coating, to overcome the pained suitable problem of taking of Callicarpa nudiflora conventional formulation taste in taking process.In addition, micropill provided by the invention has stability and safety is good, side effect is little, dissolution rate is high, bioavailability is high, taking dose is little and/or the feature of taking convenience.
Summary of the invention
First aspect present invention provides a kind of micropill of Callicarpa nudiflora extract, and this micropill comprises: Callicarpa nudiflora extract 30-90 weight portion, diluent 10-75 weight portion, disintegrating agent 0.5-10 weight portion and optional binding agent.Or, first aspect present invention provides a kind of micropill of Callicarpa nudiflora extract, this micropill comprises: Callicarpa nudiflora extract 30-90 % by weight, diluent 10-75 % by weight, disintegrating agent 0.5-10 % by weight and optional binding agent, and the weight sum of each component is 100 % by weight.
Second aspect present invention provides a kind of coated micropill, and it comprises that micropill and painting described in first aspect present invention any one steep the clothing material in this micropill surface.
Third aspect present invention provides the method for preparing micropill described in first aspect present invention any one.
Detailed Description Of The Invention
First aspect present invention provides a kind of micropill of Callicarpa nudiflora extract, and this micropill comprises: Callicarpa nudiflora extract 30-90 weight portion, diluent 10-75 weight portion, disintegrating agent 0.5-10 weight portion and optional binding agent.Or, first aspect present invention provides a kind of micropill of Callicarpa nudiflora extract, this micropill comprises: Callicarpa nudiflora extract 30-90 % by weight, diluent 10-75 % by weight, disintegrating agent 0.5-10 % by weight and optional binding agent, and the weight sum of each component is 100 % by weight.
In an embodiment of micropill described in first aspect present invention, described Callicarpa nudiflora extract is Callicarpa nudiflora plant extract.In one embodiment, described Callicarpa nudiflora plant extract obtains by the following method: get Callicarpa nudiflora, remove impurity, smash to pieces, with the water heating extraction of 10-15 times of weight 2 times, heat 1 hour at every turn; Merge extractive liquid,, filters, and is concentrated into the extractum of relative density 1.14～1.25 (60 ℃ of heat are surveyed), is spray dried to dried cream powder and obtains Callicarpa nudiflora plant extract.In one embodiment, described Callicarpa nudiflora plant extract obtains by the following method: get Callicarpa nudiflora, remove impurity, smash to pieces, with the water heating extraction of 8 times of weight 2 times, heat 1.5 hours at every turn; Merge extractive liquid,, filters, and is concentrated into the extractum of relative density 1.14～1.25 (60 ℃ of heat are surveyed), is spray dried to dried cream powder and get final product.
In an embodiment of micropill described in first aspect present invention, described diluent is selected from microcrystalline Cellulose, starch, dextrin, lactose and combination thereof.
In an embodiment of micropill described in first aspect present invention, described disintegrating agent is selected from polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose and combination thereof.
In an embodiment of micropill described in first aspect present invention, described diluent is selected from microcrystalline Cellulose, starch, dextrin, lactose and combination thereof, and described disintegrating agent is selected from polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose and combination thereof.The present invention finds, the combination by above-mentioned diluent and disintegrating agent is highly profitable for overcoming micropill yield being lower in coating process.
In an embodiment of micropill described in first aspect present invention, described micropill comprises: Callicarpa nudiflora extract 30-75 weight portion, diluent 25-60 weight portion, disintegrating agent 1-6 weight portion and optional binding agent.In one embodiment, described micropill comprises: Callicarpa nudiflora extract 30-75 % by weight, diluent 25-60 % by weight, disintegrating agent 1-6 % by weight and optional binding agent, and the weight sum of each component is 100 % by weight.
In an embodiment of micropill described in first aspect present invention, described micropill comprises: Callicarpa nudiflora extract 35-65 weight portion, diluent 30-60 weight portion, disintegrating agent 1-6 weight portion and optional binding agent.In one embodiment, described micropill comprises: Callicarpa nudiflora extract 35-65 % by weight, diluent 30-60 % by weight, disintegrating agent 1-6 % by weight and optional binding agent, and the weight sum of each component is 100 % by weight.
In an embodiment of micropill described in first aspect present invention, described micropill comprises: Callicarpa nudiflora extract 40-60 weight portion, diluent 35-60 weight portion, disintegrating agent 2-4 weight portion and optional binding agent.In one embodiment, described micropill comprises: Callicarpa nudiflora extract 40-60 % by weight, diluent 35-60 % by weight, disintegrating agent 2-4 % by weight and optional binding agent, and the weight sum of each component is 100 % by weight.
In an embodiment of micropill described in first aspect present invention, described micropill comprises: the binding agent of 0-10 weight portion, and preferred adhesive is 0-5 weight portion, and preferred adhesive is 0-2.5 weight portion, and preferred adhesive is 0.5-2.5 weight portion.In one embodiment, described micropill comprises: the binding agent of 0-10 % by weight, and preferred adhesive is 0-5 % by weight, and preferred adhesive is 0-2.5 % by weight, and preferred adhesive is 0.5-2.5 % by weight.In one embodiment, described binding agent is selected from polyvidone, methylcellulose, ethyl cellulose, carboxymethyl cellulose, starch slurry, hypromellose, gelatin, Polyethylene Glycol, sodium alginate, water, ethanol and combination thereof.In one embodiment, described binding agent is selected from polyvidone, ethyl cellulose, starch slurry, hypromellose, water and combination thereof.In one embodiment, the consumption of described binding agent adds in right amount according to soft material operation processed.
In an embodiment of micropill described in first aspect present invention, described diluent is that microcrystalline Cellulose and described disintegrating agent are polyvinylpolypyrrolidone.
In an embodiment of micropill described in first aspect present invention, described diluent is that combination and the described disintegrating agent of starch and lactose is carboxymethyl starch sodium.
In an embodiment of micropill described in first aspect present invention, described diluent is that combination and the described disintegrating agent of microcrystalline Cellulose and dextrin is cross-linking sodium carboxymethyl cellulose.
In an embodiment of micropill described in first aspect present invention, described diluent is that combination and the described disintegrating agent of microcrystalline Cellulose and dextrin is polyvinylpolypyrrolidone.
In an embodiment of micropill described in first aspect present invention, described diluent is that combination and the described disintegrating agent of starch, lactose and dextrin is low-substituted hydroxypropyl cellulose.
In an embodiment of micropill described in first aspect present invention, described micropill comprises formula and optional suitable amount of adhesive described in embodiment 1-5 substantially.
Second aspect present invention provides a kind of coated micropill, and it comprises that micropill and painting described in first aspect present invention any one steep the clothing material in this micropill surface.
In an embodiment of coated micropill described in second aspect present invention, wherein said clothing material is extended release coatings, controlled release clothing material or enteric coating material.In one embodiment, wherein said clothing material is enteric coating material.Those skilled in the art are according to the composition of extended release coatings, controlled release clothing material or enteric coating material described in existing Knowledge and be applied to the consumption of micropill of the present invention.
In an embodiment of coated micropill described in second aspect present invention, wherein said clothing material is extended release coatings or controlled release clothing material.In one embodiment, wherein said extended release coatings or controlled release clothing material comprise polymeric material, porogen and antiplastering aid.In one embodiment, wherein said polymeric material is one or more in ethyl cellulose, acrylic resin, cellulose acetate.In one embodiment, wherein said porogen is one or more in hydroxypropyl methylcellulose, Polyethylene Glycol, polyvidone, sucrose, tween, span, xanthan gum.In one embodiment, wherein said antiplastering aid is one or more in Pulvis Talci, magnesium stearate, micropowder silica gel.
In an embodiment of coated micropill described in second aspect present invention, wherein said clothing material is enteric coating material.In one embodiment, wherein said enteric coating material comprises polymeric material.In one embodiment, wherein said polymeric material is one or more in methacrylic acid copolymer, acrylic resin, hydroxypropyl cellulose phthalate ester, CAP, polyvinyl alcohol phthalate ester.
Third aspect present invention provides the method for preparing micropill described in first aspect present invention any one, and it comprises the following steps:
1) get Callicarpa nudiflora extract, add described diluent and disintegrating agent, mix, pulverize;
2) add the binding agent by water and/or ethanol preparation, or directly add the solution of a certain amount of water, ethanol or both different proportions as wetting agent, to material soft material processed;
3) adopt method of extruding and kneading to pellets or centrifugal fluidized granulation legal system for micropill, dry.
In the method for third aspect present invention, described Callicarpa nudiflora extract, diluent, disintegrating agent, binding agent are like described in first aspect present invention.
Described in first aspect present invention, each embodiment of micropill can be carried out combination in any with one or more other embodiments, as long as this combination there will not be contradiction.Certainly, when combining each other, necessary words can be done suitably to modify to individual features.Each embodiment for other side of the present invention can also be carried out combination in any similarly.
Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
In the present invention, while mentioning " weight portion ", it both can refer to the umber of weight, can also refer to percetage by weight, preferably referred to the umber of weight.If be somebody's turn to do the implication that " weight portion " refers to percetage by weight, in this micropill, all the summation of components is 100%.In addition, for given recipe ratio, when each composition represents with the umber of weight, the total amount of each component can be 100 weight portions, can be also 100 weight portions.For example, while mentioning " micropill comprises: Callicarpa nudiflora extract 30-75 weight portion, diluent 25-60 weight portion, disintegrating agent 1-6 weight portion " herein, this micropill can comprise that the ratio of each component is 30 grams of Callicarpa nudiflora extracts, 60 grams of diluent, 1 gram of disintegrating agent; Or this micropill can comprise that the ratio of each component is 75 grams of Callicarpa nudiflora extracts, 60 grams of diluent, 6 grams of disintegrating agents; Or this micropill can comprise that the ratio of each component is approximately 45 grams of Callicarpa nudiflora extracts, approximately 55 grams of diluent, approximately 5 grams of disintegrating agents, each component amounts to 100 grams, and not containing binding agent (take water as wetting agent).
In the present invention, during term " % by weight ", refer to percent by weight.
In one embodiment, micropill of the present invention is comprised of 30%-90% and adjuvant 10%-70%, and wherein adjuvant is diluent, disintegrating agent, binding agent, wherein diluent 10%-60%, disintegrating agent 0.5%-10%, binding agent 0-10%.
In one embodiment, preparation method of the present invention is as follows: the Callicarpa nudiflora 10kg that gets remove impurity and smash to pieces with the water heating extraction of 8-15 times of weight 2 times, heats 1-1.5 hour at every turn; Merge extractive liquid,, filters, and is concentrated into the extractum of relative density 1.14～1.25 (60 ℃ of heat are surveyed), is spray dried to dried cream powder and get final product.
In one embodiment, of the present invention can be quality controllable extractum, one or both mixture in spray-dired powder.
In one embodiment, the diluent described in micropill of the present invention is for using one or more in microcrystalline Cellulose, starch, dextrin, lactose; Disintegrating agent is one or more in polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose.Binding agent is one or more in polyvidone, methylcellulose, ethyl cellulose, carboxymethyl cellulose, starch slurry, hypromellose, gelatin, Polyethylene Glycol and sodium alginate.
In one embodiment, micropill of the present invention can be according to technique scheme, with the preparation method of prior art pellet preparations, is prepared, and also can be prepared by the following method:
(1) get, add adjuvant diluent and disintegrating agent, mix, pulverize;
(2) add the solution of the water, dehydrated alcohol or both different proportions that contain binding agent as binding agent; Or directly add the solution of a certain amount of water, dehydrated alcohol or both different proportions as wetting agent;
(3) adopt method of extruding and kneading to pellets or centrifugal fluidized granulation legal system for micropill.
Micropill of the present invention can be prepared into slow release, controlled release or enteric coated pellets formulation.Be prepared into slow release, controlled release micro pill, wherein polymeric material is one or more in ethyl cellulose, acrylic resin, cellulose acetate; Porogen is one or more in hydroxypropyl methylcellulose, Polyethylene Glycol, polyvidone, sucrose, tween, span, xanthan gum; Antiplastering aid is one or more in Pulvis Talci, magnesium stearate, micropowder silica gel.Be prepared into enteric coated micropill, the polymeric material of enteric coating is wherein one or more in methacrylic acid copolymer, acrylic resin, hydroxypropyl cellulose phthalate ester, CAP, polyvinyl alcohol phthalate ester.Be prepared into pellet capsule, or slow release, controlled release, enteric coated micropill, its preparation method comprises a pot rolling coating method, fluidized bed coating, compression coating, hot melt coating method.
The present invention's discovery, micropill of the present invention has the high finished product rate of making us unexpected.
According to the present invention, the micropill obtaining has following features:
1) micropill volume is little, is evenly distributed in gastrointestinal tract, and medicine is increased at gastrointestinal tract surface distributed area, is subject to the impact of gastric emptying less, and uniform absorption can improve bioavailability and reduce GI irritation;
2) improve the stability of medicine, make material avoid the impact of external environment;
3) storage time of odor barrier, prolongation volatile material;
4) good fluidity, difficult broken, easily fills while making capsule;
5) child and the gerontal patient of being convenient to dysphagia take;
6) make slow release, controlled release or enteric coated micropill, effectively control speed, position and the time of release, extend effective blood drug level, minimizing medication number of times and accumulated dose;
7) preparation method is that to the various extraction times in preparation process, baking temperature, supplementary product kind and addition, through test of many times, research is optimized on the basis of conventional microsphere and its preparation, there is reasonable mixture ratio, technique is simple, be easy to control the feature of constant product quality.
The specific embodiment
Below by specific embodiment/experimental example, further illustrate the present invention, still, should be understood to, these embodiment and experimental example are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention used, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and operational approach are well known in the art.
Preparation example: preparation
Preparation example 1: get 100kg Callicarpa nudiflora medical material, add water 1500kg, soak 2 hours, heated and boiled 1 hour, pour out decocting liquid, in medicinal residues, again add water 1500kg, heated and boiled 90 minutes, merges decocting liquid twice, filter, concentrating filtrate to relative density is 1.14～1.25 (60 ℃ of heat are surveyed), and lyophilization, obtains Callicarpa nudiflora extract
Preparation example 2: the Callicarpa nudiflora 100kg that gets remove impurity and smash to pieces, add water 1000kg heating extraction 2 times at every turn, heat 1 hour at every turn; Merge extractive liquid,, filters, and is concentrated into the extractum of relative density 1.14～1.25 (60 ℃ of heat are surveyed), is spray dried to dried cream powder and get final product.
Preparation example 3: the Callicarpa nudiflora 100kg that gets remove impurity and smash to pieces, add water 800kg heating extraction 2 times at every turn, heat 1.5 hours at every turn; Merge extractive liquid,, filters, and is concentrated into the extractum of relative density 1.14～1.25 (60 ℃ of heat are surveyed), is spray dried to dried cream powder and get final product.
Below used in test, as do not indicated in addition, refer to the present invention above-mentioned preparation example gained.
The preparation of embodiment 1, micropill
Prescription proportioning:
| Component | Consumption (g) | Weight ratio (%) |
| ? | 200 | 40 |
| Microcrystalline Cellulose | 277.5 | 55.5 |
| Polyvinylpolypyrrolidone | 20 | 4 |
| Micropowder silica gel | 2.5 | 0.5 |
| Gross weight | 500 | ? |
Be prepared by the following method:
1) by prescription proportioning, get, add the adjuvants such as microcrystalline Cellulose, polyvinylpolypyrrolidone, pulverize, mix;
2) add polyvidone aqueous solution as binding agent;
3) adopt method of extruding and kneading to pellets to prepare micropill.The material mixing is extruded bar under the extruded velocity of 10-40r/min, controls the addition of binding agent well to control the length of the bar extruded well; Move into rolling circle equipment, first with cutting off extrudate under 40-70Hz rotating speed, then under 30-50Hz speed conditions round as a ball 10-20 minute, make micropill.Move into drying room and be dried, drying condition is 30 ± 2 ℃, 8 hours drying times, dry rear packing.
The preparation of embodiment 2, micropill
Prescription proportioning:
| Component | Consumption (g) | Weight ratio (%) |
| ? | 200 | 40 |
| Starch | 200 | 40 |
| Lactose | 80 | 16 |
| Carboxymethyl starch sodium | 20 | 4 |
| Gross weight | 500 | ? |
Be prepared by the following method:
1) by prescription proportioning, get, add the adjuvants such as starch, lactose, carboxymethyl starch sodium, pulverize, mix;
2) add the alcoholic solution of ethyl cellulose as binding agent;
3) adopt method of extruding and kneading to pellets to prepare micropill.The material mixing is extruded bar under the extruded velocity of 10-40r/min, controls the addition of binding agent well to control the length of the bar extruded well; Move into rolling circle equipment, first with cutting off extrudate under 40-70Hz rotating speed, then under 30-50Hz speed conditions round as a ball 10-20 minute, make micropill.Move into drying room and be dried, drying condition is 30 ± 2 ℃, 12 hours drying times, dry rear packing.
The preparation of embodiment 3, micropill
Prescription proportioning:
| Component | Consumption (g) | Weight ratio (%) |
| ? | 300 | 60 |
| Microcrystalline Cellulose | 165 | 33 |
| Dextrin | 20 | 4 |
| Cross-linking sodium carboxymethyl cellulose | 15 | 3 |
| Gross weight | 500 | ? |
Be prepared by the following method:
1) by prescription proportioning, get, add the adjuvants such as microcrystalline Cellulose, dextrin, cross-linking sodium carboxymethyl cellulose, pulverize, mix;
2) add the aqueous solution of hypromellose as binding agent;
3) adopt method of extruding and kneading to pellets to prepare micropill.The material mixing is extruded bar under the extruded velocity of 10-40r/min, controls the addition of binding agent well to control the length of the bar extruded well; Move into rolling circle equipment, first with cutting off extrudate under 40-70Hz rotating speed, then under 30-50Hz speed conditions round as a ball 10-20 minute, make micropill.Move into drying room and be dried, drying condition is 30 ± 2 ℃, 12 hours drying times, dry rear packing.
The preparation of embodiment 4, micropill
Prescription proportioning:
| Component | Consumption (g) | Weight ratio (%) |
| ? | 250 | 50 |
| Microcrystalline Cellulose | 150 | 30 |
| Dextrin | 80 | 16 |
| Polyvinylpolypyrrolidone | 20 | 4 |
| Gross weight | 500 | ? |
Be prepared by the following method:
1) by prescription proportioning, get, add the adjuvants such as microcrystalline Cellulose, dextrin, polyvinylpolypyrrolidone, pulverize, mix;
2) add the aqueous solution of starch slurry as binding agent;
3) adopt centrifugal fluidized granulation legal system for micropill.
The preparation of embodiment 5, micropill
Prescription proportioning:
| Component | Consumption (g) | Weight ratio (%) |
| ? | 200 | 40 |
| Starch | 150 | 30 |
| Dextrin | 70 | 14 |
| Lactose | 70 | 14 |
| Low-substituted hydroxypropyl cellulose | 10 | 2 |
| Gross weight | 500 | ? |
Be prepared by the following method:
1) by prescription proportioning, get, add the adjuvants such as starch, dextrin, lactose, low-substituted hydroxypropyl cellulose, pulverize, mix;
2) add water as wetting agent;
3) adopt method of extruding and kneading to pellets to prepare micropill.The material mixing is extruded bar under the extruded velocity of 10-40r/min, the addition of binding agent controlling well to control the length of the bar extruded well: moves into rolling circle equipment, first with cutting off extrudate under 40-70Hz rotating speed, round as a ball 10-20 minute under 30-50Hz speed conditions, makes micropill again.Move into drying room and be dried, drying condition is 30 ± 2 ℃, 12 hours drying times, dry rear packing.
Screening: micropill prepared by above embodiment 1-5 sieves, and chooses the piller of diameter 0.8-2.5mm, carries out the following examples 6,7.
The coating of embodiment 6, micropill
Micropill prepared by embodiment 1-5 carries out coating, by using different coating materials, makes micropill become the preparations such as slow release, controlled release or enteric, controls rate of release, position and the time of medicine to reach different therapeutic purposes.
Enteric-coating material proportioning:
| Component | Title | Consumption (g) | Weight ratio (%) |
| Polymer | Methacrylic acid copolymer | 200 | 10 |
| Plasticizer | Triethyl citrate | 20 | 1 |
| Lubricant | Pulvis Talci | 40 | 2 |
| Substrate | Water | 1740 | 87 |
Pulvis Talci, triethyl citrate are added to pure water homogenate, mixture after homogenate is added in methacrylic acid copolymer aqueous dispersion, add a small amount of methyl-silicone oil to make defoamer, during use, slowly stir.
Process conditions: 55 ℃ of gas flow temperatures, 32 ℃ of micropill temperature, atomizing pressure 0.25-0.30MPa, spouting velocity 150mL/min.
The selection of coating weightening finish: according to 2010 editions appendix XC dissolution method first methods of Chinese Pharmacopoeia, hydrochloric acid solution (9 → 1000) 900mL of take is dissolution medium I, rotating speed 50r/min, after 1h, take out and turn basket, then take pH6.8 phosphate buffer 900mL as dissolution medium II, after 2h, sample 20mL, filter, dilution, measures, and calculates the weightening finish that dissolution is selected coating.
When experimental result draws micropill enteric coating weightening finish 25%-40%, its dissolution meets the requirements.
In the present embodiment, coating weightening finish is controlled at 35%.
Coated micropill prepared by the present embodiment packing of can directly bottling, is convenient to select suitable medication dose according to the state of an illness and the crowd of taking medicine., also the coated micropill of preparing in the present embodiment will be able to be entered in hard capsule to every capsules weight 350mg meanwhile.
The coating of embodiment 7, micropill
Micropill prepared by above embodiment carries out coating, by using different coating materials, makes micropill become the capsule preparations such as slow release, controlled release or enteric, controls rate of release, position and the time of medicine to reach different therapeutic purposes.
Sustained-release micro-pill capsules coating material proportioning:
| Component | Consumption (g) | Weight ratio (%) |
| Acrylic resin II | 300 | 25 |
| Hydroxypropyl emthylcellulose | 20 | 2 |
| Titanium dioxide | 50 | 5 |
| Zein | 75 | 7.5 |
| Polyethylene glycol 6000 | 30 | 3 |
| Polyvinyl alcohol | 10 | 1 |
| Glycerol | 15 | 1.5 |
| Water | 500 | 55 |
Process conditions: spouting velocity: 15-60r/min, engine speed: 80-150r/min, for powder speed: 15-50r/min.
The selection of coating weightening finish: according to 2010 editions appendix XC dissolution method first methods of Chinese Pharmacopoeia, hydrochloric acid solution (9 → 1000) 900mL of take is dissolution medium I, rotating speed 50r/min, after 1h, take out and turn basket, then take pH6.8 phosphate buffer 900mL as dissolution medium II, after 2h, sample 20mL, filter, dilution, measures, and calculates the weightening finish that dissolution is selected coating.
When experimental result draws slow-release micro-pill coating weightening finish 27%-41%, its dissolution meets the requirements.
In the present embodiment, coating weightening finish is controlled at 32%.
Coating loss rate is investigated:
In above embodiment 6,7, gained micropill is sieved, remove the piller that diameter is less than 0.5mm (this part think may be in coating process powder micropill broken and form), remainder is thought qualified coated pill.With following formula, calculate coating loss rate (%):
By the method for embodiment 6, carry out the investigation of coating loss rate respectively, the results are shown in Table 1.By the method for embodiment 7, carry out the investigation of coating loss rate respectively, the results are shown in Table 2.From the result of table 1 and 2, micropill of the present invention has acceptable coating loss rate.
Table 1, the result of carrying out the investigation of coating loss rate by the method for embodiment 6
| Element ball sample | Coating loss rate (%) |
| Embodiment 1 | 16.3 |
| Embodiment 2 | 15.5 |
| Embodiment 3 | 13.1 |
| Embodiment 4 | 17.9 |
| Embodiment 5 | 14.5 |
Table 2, the result of carrying out the investigation of coating loss rate by the method for embodiment 7
| Element ball sample | Coating loss rate (%) |
| Embodiment 1 | 13.6 |
| Embodiment 2 | 14.9 |
| Embodiment 3 | 17.1 |
| Embodiment 4 | 15.3 |
| Embodiment 5 | 16.4 |
Dissolution rate is investigated:
The enteric coated-pellet preparation that micropill prepared by embodiment of the present invention 1-5 is prepared according to embodiment 6 methods is in the aqueous hydrochloric acid solution of pH-value about 1～3, and the dissolution rate of the medicine in pastille core core after 2 hours be not higher than approximately 10%; In the phosphate buffered solution of pH-value about 5～8, at least sustainable stripping of medicine in pastille core core approximately 5 hours.
Dissolution test:
Utilize aids drug to implement medicine dissolving out experimental in the dissolution test method of human gastrointestinal tract stripping situation, by the dosage form of embodiment 1 to embodiment 5, the 0.1N aqueous hydrochloric acid solution that is first placed in simulated gastric fluid pH1.2 pH-value stops after sampling in 2 hours, add again 0.2M tertiary sodium phosphate saline solution to make the phosphate buffered solution that forms pH6.8 pH-value with simulated intestinal fluid, dissolution test water bath temperature control is at 37 ± 0.5 ℃, capsule formulation is loaded in the dissolution test device of basket (Basket), coated micropill adopts the dissolution test device of oar (Paddle), all the rotating speed with 100rpm carries out dissolution test.Below the data of time and dissolution rate are listed in table 3, this table has shown the dissolution rate result of the enteric long-acting pellet preparations that the micropill of embodiment 1-5 is prepared according to embodiment 6 methods.
Table 3:
Bioavailability is investigated:
The dissolution rate of Callicarpa nudiflora micropill of the present invention is high, rapid-action, and bioavailability is high.
The effective ingredient index of Callicarpa nudiflora pellet capsule is luteolin.Every capsules is no less than 10mg containing total flavones in luteolin.Guaranteeing that experimenter takes crude drug amount identical in the situation that, tests as follows according to national drug bioavailability guideline.
Test example: by the embodiment of the present invention 1,3 and 5 preparation micropills according to the method for embodiment 6, be prepared into enteric coated-pellet and incapsulate in prepare capsule preparations.
Comparative example 1: the Callicarpa nudiflora capsule of preparing according to the method for Chinese patent 2009100060887 embodiment 5.
Comparative example 2: according to the Callicarpa nudiflora capsule of Chinese patent 200410088712.X embodiment 4 preparations.
Experimental technique: by normal adults 30 people (male 12 people of the heavy be no more than ± 1.5kg of error of identical sex subject, women 8 people) by sex, be divided at random five groups of A, B, C, D, E, every group of personnel take respectively the capsule of 3 embodiment of the present invention, 1,3,5 preparations and the capsule of comparative example 1,2, and after taking medicine, 0,0.5,1.0,1.5,2.0,3.0,5.0,12 hour extracting vein blood blood sample 5ml detects luteolin blood drug level.
Luteolin high performance liquid chromatogram detects:
Chromatographic condition: chromatographic column: Dikma Diamonsil C18 (diamond) (250 * 4.6mm, 5mm), mobile phase: methanol-0.1% phosphoric acid (percent by volume of methanol and phosphoric acid is 62:38), flow velocity 1mL/min; Detect wavelength 348nm, column temperature: room temperature.Number of theoretical plate is not less than 3000 by luteolin note.Sample size 50 μ l.
Blood sample is processed: extracting vein blood 5ml, and separation of serum, quantitatively precision is got 0.1ml, puts into 1.5ml plastic centrifuge tube, adds 0.1ml10% trichloroacetic acid solution, fully mixes, and places 40 minutes, centrifugal with the rotating speed of 10000r/min, gets supernatant direct injected.
Standard curve: get the methanol solution that blank serum adds luteolin, be made into respectively the standard serum sample of 0,0.01,0.02,0.05,0.1,0.2,0.5,1.0,2.0,5.0 μ g/ml etc., measure after processing.With peak height, concentration is made to linear regression, obtain regression curve.C=-0.110+0.0334H (r=0.9995), H: peak height, the mm of unit, C: content, the μ g/ml of unit.This detection method detects and is limited to 0.01 μ g/ml.
Blood drug level according to after average, calculates pharmacokinetic parameter, the results are shown in following table 4:
There is above-mentioned experimental result known, Callicarpa nudiflora pellet preparations of the present invention is not almost allowed at gastric juice (acid solution), and dissolution rate is high and fast in intestinal juice, and can maintain long release, bioavailability is high, and low cost of manufacture, very suitability for industrialized is produced, and can meet the clinical instructions for use of Callicarpa nudiflora.
In addition, it is high that Callicarpa nudiflora preparation of the present invention also has stability, feature safely and effectively, and 40 ℃ of high temperature, lower 6 months of relative humidity 75% ± 5% condition, carries out accelerated test investigation, and outward appearance has no significant change, and dissolution and content all remain on more than 90%.
Claims (11)
1. the micropill of a Callicarpa nudiflora extract, this micropill is prepared from by the component of following weight proportion: Callicarpa nudiflora extract 40-60 weight portion, diluent 35-60 weight portion, disintegrating agent 2-4 weight portion and the micropowder silica gel of 0-1 weight portion, wherein said diluent is selected from microcrystalline Cellulose, starch, dextrin, lactose or wherein any two kinds and above combination, and described disintegrating agent is selected from polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose or wherein any two kinds and above combination.
2. according to the micropill of claim 1, wherein said diluent is that microcrystalline Cellulose and described disintegrating agent are polyvinylpolypyrrolidone.
3. according to the micropill of claim 1, wherein said diluent is that combination and the described disintegrating agent of starch and lactose is carboxymethyl starch sodium.
4. according to the micropill of claim 1, wherein said diluent is that combination and the described disintegrating agent of microcrystalline Cellulose and dextrin is cross-linking sodium carboxymethyl cellulose.
5. according to the micropill of claim 1, wherein said diluent is that combination and the described disintegrating agent of microcrystalline Cellulose and dextrin is polyvinylpolypyrrolidone.
6. according to the micropill of claim 1, wherein said diluent is that combination and the described disintegrating agent of starch, lactose and dextrin is low-substituted hydroxypropyl cellulose.
7. the micropill of claim 1 to 6 any one, wherein said Callicarpa nudiflora extract is Callicarpa nudiflora plant extract.
8. according to the micropill of claim 7, wherein said Callicarpa nudiflora plant extract obtains by the following method: get Callicarpa nudiflora, remove impurity, smash to pieces, with the water heating extraction of 8-15 times of weight 2 times, heat 1-1.5 hour: merge extractive liquid,, filters at every turn, the extractum that is concentrated into relative density 1.14～1.25 (60 ℃ of heat are surveyed), is spray dried to dried cream powder and obtains Callicarpa nudiflora plant extract.
9. a coated micropill, it comprises described in claim 1 to 8 any one that micropill and painting steep the clothing material in this micropill surface.
10. a Callicarpa nudiflora pellet capsule, this capsule comprises the Callicarpa nudiflora micropill described in any one in claim 1 to 9.
The method of the described micropill of 11. preparation claim 1 to 8 any one, it comprises the following steps:
1) get Callicarpa nudiflora extract, add described diluent and disintegrating agent, mix, pulverize;
2) add the binding agent by water and/or ethanol preparation, or directly add the solution of a certain amount of water, ethanol or both different proportions as wetting agent, to material soft material processed;
3) adopt method of extruding and kneading to pellets or centrifugal fluidized granulation legal system for micropill, dry.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105853599A (en) * | 2015-01-19 | 2016-08-17 | 温州医科大学附属第二医院 | Pulsatile release preparation containing Callicarpa nudiflora |
| CN114848728A (en) * | 2022-03-31 | 2022-08-05 | 广东梅州职业技术学院 | Skeleton type beautyberry slow-release granule and preparation method and application thereof |
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| CN1709430A (en) * | 2005-07-01 | 2005-12-21 | 怀化正好制药有限公司 | Medicinal bock greenbrier rhizome micro pill and its preparing method |
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| CN102048909A (en) * | 2009-10-28 | 2011-05-11 | 江西省药物研究所 | Callicarpa nudiflora effective part with hemostatic effect and pharmaceutical preparation thereof |
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| CN1709430A (en) * | 2005-07-01 | 2005-12-21 | 怀化正好制药有限公司 | Medicinal bock greenbrier rhizome micro pill and its preparing method |
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| CN102048909A (en) * | 2009-10-28 | 2011-05-11 | 江西省药物研究所 | Callicarpa nudiflora effective part with hemostatic effect and pharmaceutical preparation thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105853599A (en) * | 2015-01-19 | 2016-08-17 | 温州医科大学附属第二医院 | Pulsatile release preparation containing Callicarpa nudiflora |
| CN114848728A (en) * | 2022-03-31 | 2022-08-05 | 广东梅州职业技术学院 | Skeleton type beautyberry slow-release granule and preparation method and application thereof |
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