CN107050023A - A kind of preparation of Berberine hydrochloride and the formulation method for covering adverse drug taste - Google Patents
A kind of preparation of Berberine hydrochloride and the formulation method for covering adverse drug taste Download PDFInfo
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- CN107050023A CN107050023A CN201710025998.4A CN201710025998A CN107050023A CN 107050023 A CN107050023 A CN 107050023A CN 201710025998 A CN201710025998 A CN 201710025998A CN 107050023 A CN107050023 A CN 107050023A
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- berberine hydrochloride
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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Abstract
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of preparation of Berberine hydrochloride and the formulation method for covering adverse drug taste.The preparation of the Berberine hydrochloride, by weight, including following components：Berberine hydrochloride 2 3%, Compritol 888 ATO 8 15%, DEXTROSE ANHYDROUS 35 70%, anhydrous citric acid 20 35%, neotame 0.01 2%, Sucralose 0.1 5%, Steviosin 1 30%, essence 0.5 2%；The summation of whole weight percentages of components is 100%；Wherein, Berberine hydrochloride passes through melt process with Compritol 888 ATO.The preparation effectively masks the characteristic of Berberine hydrochloride extremely hardship, can be used as a variety of formulations such as granule, dry suspensoid agent, dispersible tablet, pill, improves the compliance of patient's medication, is particularly suitable for children.The preparation method being related to is simple, can be applied in the preparation process of multi-medicament.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to the preparation and covering adverse drug taste of a kind of Berberine hydrochloride
Formulation method.
Background technology
Berberine hydrochloride (Berberine Hydrochloride), also known as berberine, chemical name：5,6- dihydros -9,10-
Dimethoxy benzo [g]-l, 3- benzodioxolane [5,6-a] quinolizine hydrochloride dihydrate, with following structural formula：
Jamaicin is a kind of morphinane alkaloid, can from ether in many plants for being present in the section 10 of Berberidaceae etc. 4 category
Separate out yellow needle-like crystals；Odorless, taste is extremely bitter；145 DEG C of fusing point；Water is dissolved in, benzene, ether and chloroform is insoluble in.
Up to the present, treatment children enteric infection diarrhoea can only still select cephalosporins, aminoglycoside, big ring
The electuary of lactone antibiotic, but antibiotic is easily caused suprainfection, and the drawbacks of being particularly its drug resistance is endangered very children
Greatly, it is badly in need of the antibacterials of energy substitute antibiotics.The optimal selection of this medicine is exactly berberine (Berberine hydrochloride).
Berberine is as the medical traditional antibacterial of motherland, anti-inflammatory medicine, and existing more than 3,000 years applicating history, curative effect is true
Cut, it is safe and reliable, have no drug resistance, Small side effects approve receiving by numerous medical personals and patient.But the existing coptis in market
Plain preparation is not suitable for children taking, in terms of the result of investigation, is primarily present problems with：
1) formulation is not suitable with：Though berberine curative effect is good, taste is extremely bitter, thus the formulation sold both at home and abroad for many years only has
Capsule and sugar coated tablet, both formulations are unfavorable for children and swallowed, and easy jam throat causes children to suffocate.Then, to
Often tablet is smashed to pieces or takes capsule apart during children taking and is taken, but is due to that berberine taste is extremely bitter, it is difficult to allow children to receive,
Cause its compliance poor.
2) specification is not suitable with：When the specification of the existing berberine tablet in market is generally 100mg, all ages and classes and body weight children taking
Only broken on existing dosage point, it is impossible to accurately hold, thus directly affect curative effect.
It can be seen that, the characteristics of berberine has market in urgent need as the medicine for the treatment of children's enteric infection, but must be to the coptis
Mouthfeel, specification of element etc. carry out the exploitation of adaptability.
Chinese patent literature CN105030689A discloses a kind of masked berberine hydrochloride micro pill, and it is micro- by Berberine hydrochloride
Ball is coated to be made, and wherein coating material includes：Filmogen, plasticizer, caking inhibiter, in order to cover bitter taste, micropill
Particle diameter needs to reach 100-600 microns, although thus having reached the effect of taste masking, the micropill still suffers from sand when swallowing
Gravel sense, compliance in children or bad.
Further, since Berberine hydrochloride is very bitter, although the use energy that the product having passes through a large amount of filmogens, plasticizer etc.
Enough reach certain taste masking effect, but be due to unit dose limitation and it is daily repeatedly take, be easily caused filmogen,
The intake of plasticizer etc. exceedes the limitation that medicine auxiliary material is permitted.For example, Chinese patent literature CN1582926A discloses a kind of salt
Sour jamaicin micro-capsule, it contains 14~77wt% Berberine hydrochloride, 23~86wt% acrylic resin IV or acrylic acid
Resin E100, because the consumption of acrylic resin has strict limitation in children, the application of the micro-capsule is also restrained.
Therefore, the present invention explores the preparation process and preparation compositions that other cover adverse drug taste.
The content of the invention
The present invention provides a kind of preparation of Berberine hydrochloride, by weight, and said preparation includes following components：
The summation of whole weight percentages of components is 100%；
Wherein, Berberine hydrochloride and Compritol 888 ATO are sweet with behenic acid by Berberine hydrochloride powder by melt process
Grease is wrapped up.
The preparation technique effectively reduces the characteristic of Berberine hydrochloride extremely hardship, and anhydrous citric acid, knob are reused in addition
The compositions such as sweet tea, Sucralose, Steviosin, essence (orange taste) further cover bitter taste, so that the purpose of complete taste masking is reached,
It can be used as a variety of formulations such as granule, dry suspensoid agent, dispersible tablet, pill, especially as granule, dry suspensoid agent
Applied to the compliance in children, improving patient's medication.
The present invention also provides a kind of formulation method for covering adverse drug taste, including step：By bulk drug and behenic acid
Glyceride is mixed, and wraps up bulk drug powder with Compritol 888 ATO through melting, then after cooling down, crushing, it is medicinal with other
Packed after auxiliary material mixing after packaging or granulation.This method is simple to operate, can be applied in the preparation process of multi-medicament.
Brief description of the drawings
Fig. 1 is the electron micrograph of Berberine hydrochloride bulk drug.
Fig. 2 is Berberine hydrochloride bulk drug by the electron micrograph after the melt and dissolved parcel of Compritol 888 ATO.
Embodiment
In the present invention, unless otherwise instructed, all numbers are parts by weight, and all percentages are weight percentage.Such as
Without special instruction, using conventional preparation equipment and method.Using commercially available pharmaceutic adjuvant, auxiliary material model used, rank,
Supplier and service limits information refer to Chinese Pharmacopoeia (2015 editions) and auxiliary material database is often used at drug approval center.
The preparation of Berberine hydrochloride of the present invention, by weight, including following components：
The summation of whole weight percentages of components is 100%；
Wherein, Berberine hydrochloride and Compritol 888 ATO are sweet with behenic acid by Berberine hydrochloride powder by melt process
Grease is wrapped up.
In addition to above-mentioned listed component, according to prepared formulation, other necessary excipient and additives, example can be also added
As solvent, colouring agent, disintegrant, filler, stabilizer, glidant, flavouring, preservative, suspending agent, aromatic, pH value are adjusted
Save agent, release retarding agent/accelerator etc..Certainly, above-mentioned preparation also can only comprising listed component, and especially as granule,
During dry suspensoid agent.
The principle of the melting is：By Compritol 888 ATO (fusing point：65-77 DEG C) and bulk drug Berberine hydrochloride (fusing point：
145 DEG C) after mixing, higher than Compritol 888 ATO fusing point and less than heating at a temperature of Berberine hydrochloride fusing point, after heating, mountain
Yu acid glycerides melt and bulk drug is non-fusible, and after room temperature cooling, it is sweet that Berberine hydrochloride bulk drug surface covers one layer of behenic acid
Grease, so as to reach reduction or even cover the purpose of Berberine hydrochloride bitter taste.Fig. 1 and Fig. 2 show Berberine hydrochloride behenyl
Electron micrograph before and after the melt and dissolved parcel of acid glyceride, it was found from figure, Berberine hydrochloride bulk drug is by Compritol 888 ATO
Wrap up, volume increases at least about more than 1.5 times, and maintains the original crystal formation of bulk drug.In the present invention, it is not necessary to mountain
Yu acid glycerides and bulk drug mutually molten i.e. achievable taste masking.The problem of technology solves high-melting-point taste masking, while also not
The crystal formation of feed change medicine, it is consistent with the crystal formation of existing commercially available prod, it is ensured that Drug safety and validity.
In addition, in the present invention, while entering one using compositions such as anhydrous citric acid, neotame, essence (preferably orange taste)
Step covers bitter taste, so as to reach the purpose for covering Berberine hydrochloride bitter taste comprehensively.
On the other hand, it is in the present invention, behenic acid is sweet to ensure the dissolution release of medicine while taste is improved
Grease and the crushing material of Berberine hydrochloride melting cross 100 mesh sieves, can be further ensured that the release of medicine.
The melting can be realized by heating, and be melted for example, being realized by the material after drying box/baking oven Hybrid Heating
Parcel.It is preferred to use the melting that mixed material is heated in drying box/baking oven, it is advantageous that：On the one hand, heat
Temperature-controllable it is strong, it is possible to achieve parcel evenly, high income；On the other hand, it is to avoid such as fluid bed melting mixing
The problems such as the not easy to clean of middle appearance, cross pollution.In preferred embodiments, only to Berberine hydrochloride and behenyl acid glycerol
The mixed material of ester implements melt process.
In a specific embodiment, the preparation of the preparation includes mixing Berberine hydrochloride with Compritol 888 ATO
Close, wrap up Berberine hydrochloride powder with Compritol 888 ATO through melting, then after cooling down, crushing, with other pharmaceutic adjuvants
Mixing carries out wet granulation.
In a specific embodiment, the melting is molten with up to Berberine hydrochloride in Compritol 888 ATO fusing point
Carried out within the scope of the following temperature of point.The fusing point of general Compritol 888 ATO is 65-77 DEG C, and the fusing point of Berberine hydrochloride is
145 DEG C, the temperature of preferred molten is 78-125 DEG C, more preferably 80 DEG C.The thickness that the time of melting tiles according to material is determined, is got over
The thick melting time is longer, can be taken off when observation material becomes viscous.
The material of melting is packed after being mixed after cooling and crushing with other pharmaceutic adjuvants, or passes through conventional system
Agent method, such as wet granulation, are further prepared as required formulation.
In a preferred embodiment, also sieved, wrapped after then being mixed again with other pharmaceutic adjuvants after crushing
Packed after dress or granulation.30-120 mesh sieves are for example crossed, 100 mesh sieves are preferably crossed.Particle after the sieving of use is smaller, is more beneficial to
Dissolution.
In a specific embodiment, the formulation of the preparation can be granule, dry suspensoid agent, dispersible tablet, pill
Deng preferably granule and dry suspensoid agent.
In a specific embodiment, the step of preparing dry suspensoid agent includes：Berberine hydrochloride and behenyl acid glycerol
Ester mixing → melting, crushing, sieving → addition anhydrous citric acid, anhydrous glucose sugar, neotame and essence (orange taste), total mixed → bag
Dress.
In a specific embodiment, the preparation of the Berberine hydrochloride is by weight, composed of the following components：
The summation of whole weight percentages of components is 100%；
Wherein, Berberine hydrochloride passes through melt process with Compritol 888 ATO.
The formulation of the preparation of said components composition is preferably granule or dry suspensoid agent.
In a more particular embodiment, the preparation of the Berberine hydrochloride is by weight, composed of the following components：
Wherein, Berberine hydrochloride passes through melt process with Compritol 888 ATO.
In a specific embodiment, the specification of the preparation is 25mg, 50mg, 100mg, preferably 25mg.
The formulation method for the covering adverse drug taste that the present invention is provided, including step：By bulk drug and behenyl acid glycerol
Ester is mixed, and wraps up bulk drug powder with Compritol 888 ATO through melting, then after cooling down, crushing, with other pharmaceutic adjuvants
Packed after packing or pelletize after mixing.
In a specific embodiment, it is described melting be Compritol 888 ATO fusing point with up to bulk drug fusing point with
Under temperature within the scope of carry out.
In a specific embodiment, the bulk drug is selected from following one or more：Berberine hydrochloride, hydrochloric acid
Bromhexine, ambroxol hydrochloride, pseudoephedrine hydrochloride, chlorphenamine maleate, salbutamol sulfate, paracetamol, Archie
Mycin, Loratadine, Omeprazole, cefadroxil, tebipenem ordinary man's ester etc..
By taking the preparation of the Berberine hydrochloride of preparation as an example, after the taste masking technology and prescription of the present invention, the hardship of berberine
Taste becomes fruity, changes children to taking the repellency of berberine, enhances compliance.Meanwhile, granule can be directly molten
Yu Shui, is easy to less than 3 years old children taking, and children that again can be larger to the age and old man and the crowd of dysphagia take.And
And because specification can be minimum dose 25mg, split flexibly, it is easy to the children of different age group to select to take.
The present invention is expanded on further by the following examples.
1. main raw material(s)
Bulk drug (API)：Berberine hydrochloride, Northeast Pharmaceutical Factory production.
Compritol 888 ATO, the good Master's production of France.
Other auxiliary materials are commercially available conventional pharmaceutical adjuvants.
2. key instrument equipment
Table 1
| Preparation process | Equipment |
| Sieving | Required purpose screen cloth |
| Mixing | Laboratory room small-sized mixer |
| Melting | The permanent electric drying oven with forced convection (DHG-9055A) in Shanghai one |
| Crush | The small pulverizer in laboratory |
| It is total mixed | Same and KCSH-5 is started in Beijing |
3. appraisal procedure
Bitter taste is tested：Specification is brewed in 10ml warm water for 25mg preparation, by 5 sense of taste, normal people carries out bitter taste
Evaluate.The benchmark judged by taste of pure water.People more than half show that same conclusion thinks to evaluate effective, otherwise change other 5
People evaluates again.
Dissolution rate test：Tested with reference to the leaching of Chinese Pharmacopoeia (2015 editions), i.e., dissolution medium is to contain 1% dodecane
Base sodium sulphate is (referred to as：SLS) 1000ml pH6.8 phosphate buffer, basket method, rotating speed 100rpm, 37 DEG C, sampling time point
For 5min, 10min, 15min, 20min, 30min, 45min, 60min, 90min and 120min.Dissolution limit reaches for 45min
More than 65%.
4. embodiment
The lot number of two laboratory scales is done using the difference batch production of same prescription, batch is respectively 50g and 1000g.
Lot number is respectively LNQS038-129 (1) and LNQS038-138, and prescription is shown in Table 2.
Table 2：LNQS038-129 (1) and LNQS038-138 prescription
Production technology：API is with after Compritol 888 ATO melting, pulverizing and sieving, then being mixed with other auxiliary materials, packed.Should
In technique, except puddle, other techniques are carried out according to routine operation.The operation of melting is：First by Berberine hydrochloride and behenyl
Acid glyceride is mixed, and is melted at high temperature, then is cooled down, and is pulverized and sieved.The specific technological process of production and parameter are shown in Table 3.
Table 3：The technological process of production and parameter
After manufacture, taste masking effect and the dissolution of the dry suspensoid agent of LNQS038-138 batches of sample test Berberine hydrochlorides are taken
Degree etc., as a result sees in table 4 and table 5.
Table 4：Taste masking, moisture, sedimentation volume ratio test result
| Lot number | LNQS038-138 |
| Taste | It is not bitter |
| Moisture %* | 0.73 |
| Sedimentation volume ratio * | 1.0 |
* tested with reference to the method for Chinese Pharmacopoeia (2015 editions).
Table 5：Dissolution rate test result
In process control parameter, melting influence taste masking effect and dissolution rate, moisture influence the stability of product, sedimentation
Volume ratio reflects suspension effect.From table 4 and table 5, the dry suspensoid agent taste of obtained Berberine hydrochloride is not bitter, and stability has guarantor
Card, and with good suspension effect and dissolution rate.
5. comparative example
Comparative example 1
Using embodiment lot number LNQS038-138 identical prescriptions, and it is dry according to the preparation of embodiment identical production technology
Supensoid agent, but omit the melting step in production technology.Taste masking effect test is carried out to the dry suspensoid agent of preparation, is as a result taste
It is bitter.
Comparative example 2
Using embodiment lot number LNQS038-138 identical prescriptions, and it is dry according to the preparation of embodiment identical production technology
Supensoid agent, difference is in melting step, in addition to Berberine hydrochloride and Compritol 888 ATO is added, is additionally added DEXTROSE ANHYDROUS
Together carry out melt process.Taste masking effect test is carried out to the dry suspensoid agent of preparation, is as a result bitter.
Comparative example 3
According to the production technology of embodiment, dry suspensoid agent is prepared using the prescription of table 6, wherein Compritol 888 ATO is replaced
For glycerin monostearate.Taste masking effect test is carried out to the dry suspensoid agent of preparation.
Table 6：Prescription LNQS038-57-4
As a result show, Compritol 888 ATO is replaced with as glycerin monostearate can not play prescription of the present invention
Taste masking effect.
Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted.Art technology
Personnel in the case where not departing from the objective and scope of technical solution of the present invention, to technical scheme carry out modification or
Person's equivalent substitution, all should cover among scope of the presently claimed invention.
Claims (10)
1. a kind of preparation of Berberine hydrochloride, it is characterised in that by weight, including following components：
The summation of whole weight percentages of components is 100%；
Wherein, Berberine hydrochloride and Compritol 888 ATO are by melt process, by Berberine hydrochloride powder Compritol 888 ATO
Wrap up.
2. the preparation of Berberine hydrochloride according to claim 1, it is characterised in that the preparation of the preparation includes：By salt
Sour jamaicin is mixed with Compritol 888 ATO, wraps up Berberine hydrochloride powder with Compritol 888 ATO through melting, then cold
But packed after packing or pelletize after, crushing, after being mixed with other pharmaceutic adjuvants.
3. the preparation of Berberine hydrochloride according to claim 2, it is characterised in that the temperature of the melting is 78-125
DEG C, preferably 80 DEG C.
4. the preparation of Berberine hydrochloride according to claim 2, it is characterised in that also sieved after crushing, Ran Houzai
Pelletized with other pharmaceutic adjuvant mixing.
5. the preparation of Berberine hydrochloride according to claim 1, it is characterised in that the formulation of the preparation be granule,
Dry suspensoid agent, dispersible tablet or pill, preferably granule or dry suspensoid agent.
6. the preparation of the Berberine hydrochloride according to claim any one of 1-5, it is characterised in that by weight, by following
Component is constituted：
The summation of whole weight percentages of components is 100%.
7. the preparation of the Berberine hydrochloride according to claim any one of 1-5, it is characterised in that the specification of the preparation is
25mg、50mg、100mg。
8. a kind of formulation method for covering adverse drug taste, it is characterised in that including step：By bulk drug and behenyl acid glycerol
Ester is mixed, and wraps up bulk drug powder with Compritol 888 ATO through melting, then after cooling down, crushing, with other pharmaceutic adjuvants
Packed after packing or pelletize after mixing.
9. method according to claim 8, it is characterised in that the melting is with up to former in Compritol 888 ATO fusing point
Expect to carry out within the scope of the temperature below medicine fusing point.
10. method according to claim 8 or claim 9, it is characterised in that the bulk drug is selected from following one or more：
It is Berberine hydrochloride, bromhexine hydrochloride, ambroxol hydrochloride, pseudoephedrine hydrochloride, chlorphenamine maleate, salbutamol sulfate, right
Paracetamol, azithromycin, Loratadine, Omeprazole, cefadroxil and tebipenem ordinary man's ester.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710025998.4A CN107050023A (en) | 2017-01-13 | 2017-01-13 | A kind of preparation of Berberine hydrochloride and the formulation method for covering adverse drug taste |
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| CN201710025998.4A CN107050023A (en) | 2017-01-13 | 2017-01-13 | A kind of preparation of Berberine hydrochloride and the formulation method for covering adverse drug taste |
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ID=59599288
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107875184A (en) * | 2017-11-17 | 2018-04-06 | 成都乾坤动物药业股份有限公司 | A kind of Radix Berberidis extract and preparation method thereof |
| CN112972398A (en) * | 2021-02-25 | 2021-06-18 | 江苏睿实生物科技有限公司 | Berberine hydrochloride granules and preparation method thereof |
| WO2022113139A1 (en) * | 2020-11-24 | 2022-06-02 | Specchiasol S.R.L. | Formulation for oral administration of active compounds with low bioavailability and corresponding production method |
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| CN1812793A (en) * | 2003-06-27 | 2006-08-02 | 大塚制药株式会社 | Sustained drug-relase particles and process for producing the same |
| CN1853629A (en) * | 2005-04-26 | 2006-11-01 | 北京济通天宇科技有限公司 | Berberine dripping balls and preparation thereof |
| CN103610680A (en) * | 2013-11-07 | 2014-03-05 | 深圳致君制药有限公司 | Cefuroxime axetil composition and preparation method thereof |
| CN103656649A (en) * | 2013-12-12 | 2014-03-26 | 吉林修正药业新药开发有限公司 | Famotidine inclusion compound and preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1812793A (en) * | 2003-06-27 | 2006-08-02 | 大塚制药株式会社 | Sustained drug-relase particles and process for producing the same |
| CN1853629A (en) * | 2005-04-26 | 2006-11-01 | 北京济通天宇科技有限公司 | Berberine dripping balls and preparation thereof |
| CN103610680A (en) * | 2013-11-07 | 2014-03-05 | 深圳致君制药有限公司 | Cefuroxime axetil composition and preparation method thereof |
| CN103656649A (en) * | 2013-12-12 | 2014-03-26 | 吉林修正药业新药开发有限公司 | Famotidine inclusion compound and preparation method |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107875184A (en) * | 2017-11-17 | 2018-04-06 | 成都乾坤动物药业股份有限公司 | A kind of Radix Berberidis extract and preparation method thereof |
| WO2022113139A1 (en) * | 2020-11-24 | 2022-06-02 | Specchiasol S.R.L. | Formulation for oral administration of active compounds with low bioavailability and corresponding production method |
| CN112972398A (en) * | 2021-02-25 | 2021-06-18 | 江苏睿实生物科技有限公司 | Berberine hydrochloride granules and preparation method thereof |
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