CN110041326A - Berberine hydrochloride and fumaric acid eutectic object and preparation method and its composition and purposes - Google Patents
Berberine hydrochloride and fumaric acid eutectic object and preparation method and its composition and purposes Download PDFInfo
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- CN110041326A CN110041326A CN201810033337.0A CN201810033337A CN110041326A CN 110041326 A CN110041326 A CN 110041326A CN 201810033337 A CN201810033337 A CN 201810033337A CN 110041326 A CN110041326 A CN 110041326A
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- fumaric acid
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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Abstract
The invention discloses Berberine hydrochloride and fumaric acid eutectic object and preparation methods and its composition and purposes.Specifically, the invention discloses one kind using Berberine hydrochloride as active pharmaceutical ingredient, fumaric acid is the new Berberine hydrochloride and fumaric acid eutectic object of eutectic presoma；The preparation method of Berberine hydrochloride and fumaric acid eutectic object；Berberine hydrochloride is preparing the application in prevention and cure of cardiovascular disease, antiviral, anticancer, reducing blood lipid, hypoglycemic, anti-inflammatory, antibacterial and anti-infectives as active pharmaceutical ingredient with fumaric acid eutectic object.
Description
Technical field
The invention discloses Berberine hydrochloride and fumaric acid eutectic object and preparation methods and its composition and purposes.Tool
For body, the invention discloses the eutectic objects that a kind of Berberine hydrochloride and fumaric acid are formed；Berberine hydrochloride and anti-butylene
The preparation method of diacid eutectic object；Berberine hydrochloride prevents and treats the heart in preparation as active pharmaceutical ingredient with fumaric acid eutectic object
Application in vascular diseases, antiviral, anticancer, reducing blood lipid, hypoglycemic, anti-inflammatory, antibacterial and anti-infectives.
Background technique
Pharmaceutical co-crystals refer to that active drug molecule and eutectic ligand with certain proportion, are interacted by non-covalent intermolecular
The crystal that power is formed.On the one hand drug can improve its physicochemical property and improve clinical treatment effect by forming eutectic, another
Aspect eutectic can enrich its crystal form.For chemical bionics drug, original can be broken by the research of eutectic object and ground
The patent protection of medicine enterprise improves the novelty and the market competitiveness of drug.
The present invention is using Berberine hydrochloride as active material, and its chemical name is 5,6- dihydro -9,10- dimethoxy benzos
[g] -1,3- benzodioxolane [5,6-a] quinolizine hydrochloride, molecular formula C20H17NO4HCl, structural formula is as shown in a.Invention
The middle eutectic ligand (cocrystal former) used is fumaric acid, molecular formula C4H4O4, structural formula is as shown in b.
a b
Berberine hydrochloride (Berberine hydrochloride) is quinoline alkaloid hydrochloride, often with solid pharmaceutical preparation shape
Formula (predominantly tablet) is applied to clinic.It is yellow powder that physicochemical property, which records Berberine hydrochloride, in water slightly soluble.It is reported
The crystal form of Berberine hydrochloride shares 6[1-4].The still not no report about Berberine hydrochloride eutectic at present.
Summary of the invention
One of the object of the invention: a kind of Berberine hydrochloride and fumaric acid eutectic object existence and characterization side are provided
Formula.
The two of the object of the invention: the preparation method of Berberine hydrochloride and fumaric acid eutectic object is provided.
The three of the object of the invention: it provides containing Berberine hydrochloride with fumaric acid eutectic object sterling or containing any non-
The hybrid solid substance and its pharmaceutical composition of zero ratio Berberine hydrochloride and fumaric acid eutectic object.
The four of the object of the invention: offer uses Berberine hydrochloride and fumaric acid eutectic object as active pharmaceutical ingredient
Pharmaceutical composition, the daily dosage of Berberine hydrochloride is within the scope of 5~3000mg.The pharmaceutical composition includes piece
Agent, capsule, pill, injection preparation, sustained release or controlled release preparation drug.
The five of the object of the invention: it is to provide Berberine hydrochloride and fumaric acid eutectic substance, compared with Berberine hydrochloride
With more excellent stability, dissolubility.
The six of the object of the invention: Berberine hydrochloride and fumaric acid eutectic object are prevented and treated as effective ingredient in preparation
Application in cardiovascular disease, antiviral, anticancer, reducing blood lipid, hypoglycemic, anti-inflammatory, antibacterial and anti-infectives.
In order to solve the above technical problems, the present invention adopts the following technical scheme:
1. Berberine hydrochloride and fumaric acid eutectic sample morphology feature:
1.1 Berberine hydrochlorides of the present invention and fumaric acid eutectic object, are Berberine hydrochloride and fumaric acid
Eutectic object is formed with the molar ratio of 2:1.
1.2 Berberine hydrochlorides of the present invention and fumaric acid eutectic, when using single-crystal X-ray diffraction analysis,
Anorthic system symmetry, space group P-1 are shown as, cell parameter value is α
=72.26 °, β=85.40 °, γ=88.99 °, unit cell volumeMolecular formula is (C20H18NO4Cl)2·C4H4O4。
Fig. 1 provides Berberine hydrochloride and fumaric acid eutectic three-dimensional structure diagram, and Fig. 2 provides Berberine hydrochloride and fumaric acid eutectic
Structure cell accumulation graph.
1.3 Berberine hydrochlorides of the present invention and fumaric acid eutectic object, are adopted when using powder x-ray diffraction analysis
Use CuKαWhen radiation experiments condition, diffraction maximum position: 2-Theta value (°) or d valueDiffraction maximum relative intensity: peak value
(Height%) or peak area value (Area%) has following feature (table 1, Fig. 3)；Berberine hydrochloride and fumaric object
The x-ray diffractogram of powder spectrum and data of reason mixture are shown in Table 2, Fig. 4.Berberine hydrochloride and fumaric acid eutectic object and hydrochloric acid
The x-ray diffractogram of powder of jamaicin and fumaric physical mixture is composed in diffraction maximum quantity, diffraction maximum position, diffraction
There is notable difference in peak intensity, diffraction maximum topological graph etc., show Berberine hydrochloride and fumaric acid eutectic object with
Berberine hydrochloride and fumaric physical mixture are neither identical nor equivalent.
The powder x-ray diffraction peak value of 1 Berberine hydrochloride of table and fumaric acid eutectic object
The powder x-ray diffraction peak value of 2 Berberine hydrochloride of table and fumaric acid physical mixed
1.4 Berberine hydrochlorides of the present invention and fumaric acid eutectic object are totally reflected fourier infrared using decaying
When spectroscopic methodology is analyzed, 3102,2998,2951,2906,2849,2747,2564,2473,2426,1696,1637,
1620、1602、1568、1506、1480、1458、1423、1393、1368、1352、1332、1306、1277、1236、1215、
1196、1144、1103、1057、1040、1007、994、974、957、940、916、889、872、856、835、779、769、
754、737、713、664cm-1Place is ± 2cm there are infrared spectroscopy characteristic peak, the tolerance of middle infrared spectrum characteristic peak-1
(Fig. 5).
1.5 Berberine hydrochlorides of the present invention and fumaric acid eutectic object, are analyzed using differential canning calorimetry
When, it shows as when heating rate is 10 DEG C per minute, there are 1 endothermic peaks (Fig. 6) at 238 DEG C ± 3 DEG C in DSC map.
The DSC of Berberine hydrochloride, fumaric acid and Berberine hydrochloride and fumaric acid eutectic object comparison map is shown in Fig. 7.Hydrochloric acid is small
Bark of a cork tree alkali and fumaric acid eutectic object and Berberine hydrochloride and fumaric DSC map are in suction/exothermic peak quantity, position etc.
There is notable difference in aspect, show that Berberine hydrochloride and fumaric acid form new substance.
2. the preparation method characteristic of Berberine hydrochloride and fumaric acid eutectic object and hybrid solid substance:
The preparation method of 2.1 Berberine hydrochlorides of the present invention and fumaric acid eutectic object, according to Berberine hydrochloride
It feeds intake with fumaric acid by the molar ratio of 2:1, hydrochloric acid barberry is prepared using the mechanochemistry method of control pressure and temperature
Alkali and fumaric acid eutectic object.The preferred liquid feeding ball-milling method of the mechanochemistry method, the wherein ratio of grinding media to material of liquid feeding ball-milling method
For 1:1~10:1, preferably 6:1~10:1；Rotational speed of ball-mill 20r/min~400r/min；The solvent type of liquid feeding is organic molten
Any one or more in agent combines manufactured mixed solvent through different ratio；The organic solvent be selected from methanol, ethyl alcohol,
Normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, amylalcohol, isoamyl alcohol, n-hexyl alcohol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxy
Six rings, tetrahydrofuran, n-hexane, hexamethylene；Liquid volume added is 0.01~100ml；Milling time is 0.1~10 hour.
The preparation method of 2.2 Berberine hydrochlorides of the present invention and fumaric acid eutectic object, by Berberine hydrochloride with
Example 2:1 feeds intake and is put into clean container fumaric acid in molar ratio, organic solvent is added, suspension is made, be stirred at room temperature 0.1
~4 days, suspension obtained is spontaneously dried by solvent evaporation drying, filtering or filtering vacuum is dry obtained Berberine hydrochloride
With fumaric acid eutectic object.The organic solvent preferably be selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol,
Amylalcohol, isoamyl alcohol, n-hexyl alcohol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, hexamethylene
In any one or more through different ratio combine made of mixed solvent；Keep Berberine hydrochloride and the total matter of fumaric acid
Amount is within the scope of 1mg/ml~500mg/ml with organic solvent solid-to-liquid ratio.
The hybrid solid substance of 2.3 Berberine hydrochlorides and fumaric acid eutectic object of the invention, is by above method system
The standby Berberine hydrochloride and fumaric acid eutectic object ingredient obtained, with other chemical substances according to any non-zero proportions and routine
Method mixed.
3. pharmaceutical preparations composition, dosage feature and system containing Berberine hydrochloride Yu fumaric acid eutectic composition
Medicinal way:
3.1 pharmaceutical compositions of the present invention containing Berberine hydrochloride and fumaric acid eutectic object and pharmaceutically may be used
The carrier of receiving.
3.2 pharmaceutical compositions of the present invention, the hybrid solid containing Berberine hydrochloride Yu fumaric acid eutectic object
Substance and pharmaceutically acceptable carrier.
3.3 pharmaceutical compositions of the present invention, the daily dosage of Berberine hydrochloride is within the scope of 5~3000mg.
3.4 pharmaceutical compositions of the present invention, the pharmaceutical composition are various tablets, capsule, pill, injection
Preparation, sustained release preparation or controlled release preparation.
3.5 the present invention relates to Berberine hydrochlorides and fumaric acid eutectic, Berberine hydrochloride and fumaric acid eutectic object
Hybrid solid substance or pharmaceutical composition prepare prevention and cure of cardiovascular disease, antiviral, anticancer, reducing blood lipid, it is hypoglycemic, anti-inflammatory,
Application in antibacterial and anti-infectives.
The present invention relates to using Berberine hydrochloride of the present invention and fumaric acid eutectic object as the pharmaceutical composition of active ingredient
Object.The pharmaceutical composition can be prepared according to method well known in the art.It can be by by Berberine hydrochloride of the present invention and anti-butylene two
Sour eutectic composition is made in conjunction with one or more pharmaceutically acceptable solids or liquid excipient and/or adjuvant suitable for people
Or any dosage form that animal uses.Berberine hydrochloride of the present invention and content of the fumaric acid eutectic object in its pharmaceutical composition
In 10%~90% weight range.
Berberine hydrochloride of the present invention can be administered in a unit with fumaric acid eutectic object, and administration route can be intestines
Road or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin
Skin, vagina, rectum etc..
Form of administration of the invention is preferably solid dosage forms.Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets,
Lozenge, dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), particle
Agent, powder, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc..
Berberine hydrochloride of the present invention and fumaric acid eutectic object can be made ordinary preparation, may be made as sustained release preparation,
Controlled release preparation, targeting preparation and various particulate delivery systems.
In order to which Berberine hydrochloride of the present invention and fumaric acid eutectic object at tablet, can be widely used known in this field
Various excipient, including diluent, binder, wetting agent, disintegrating agent, lubricant, glidant.Diluent can be starch,
Dextrin, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate
Deng；Wetting agent can be water, ethyl alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution,
Microcrystalline cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl
Cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；It is fine that disintegrating agent can be dried starch, crystallite
Tie up element, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, carbon
Sour hydrogen sodium and citric acid, polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be
Talcum powder, silica, stearate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double
Synusia and multilayer tablet.
In order to which capsule is made in administration unit, effective component Berberine hydrochloride of the present invention can be total to fumaric acid
Brilliant object is mixed with diluent, glidant, and mixture is placed directly in hard capsule or soft capsule.It can also be by the effective component present invention
First particle or pellet is made with diluent, binder, disintegrating agent in Berberine hydrochloride and fumaric acid eutectic object, then is placed in ebonite
In capsule or soft capsule.It is used to prepare various diluents, the bonding of Berberine hydrochloride of the present invention and fumaric acid eutectic object tablet
Agent, wetting agent, disintegrating agent, glidant kind can also be used for preparing the glue of Berberine hydrochloride of the present invention Yu fumaric acid eutectic object
Wafer.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation
Agent.
To reach medication purpose, enhance therapeutic effect, drug of the invention can be administered with any well known medication.
The dosage of Berberine hydrochloride of the present invention and fumaric acid eutectic medicine composition according to being prevented or
The individual instances of the property and severity of disease, patient or animal are treated, administration route and dosage form etc. can have on a large scale
Variation.Above-mentioned dosage with a dosage unit or can be divided into several dosage unit administrations, this depend on the clinical experience of doctor with
It and include the dosage regimen for using other treatment means.
Berberine hydrochloride of the present invention can individually be taken with fumaric acid eutectic object or composition, or with other treatment drug
Or symptomatic drugs merge use.It is cooperateed with when Berberine hydrochloride of the present invention exists with fumaric acid eutectic object with other therapeutic agents
When effect, its dosage should be adjusted according to the actual situation.
4. advantageous effects of the invention: the safety of Berberine hydrochloride and fumaric acid eutectic object, stability and
Dissolubility advantageous characteristic.
4.1 Berberine hydrochlorides and fumaric acid eutectic object of the invention are free of any recrystallisation solvent, used eutectic
Presoma is safe to the human body, has good safety patent medicine advantage.
4.2 Berberine hydrochlorides and fumaric acid eutectic object of the invention are under the conditions of high temperature, high humidity, illumination, pressure 8T
It is stable, crystal phenomenon does not occur, there is stability patent medicine advantage.
4.3 Berberine hydrochlorides and fumaric acid eutectic object of the invention are shown excellent in common 4 kinds of solvent systems
In the dissolution sexual clorminance of Berberine hydrochloride.
Detailed description of the invention
The three-dimensional structure diagram of Fig. 1 Berberine hydrochloride and fumaric acid eutectic
The structure cell accumulation graph of Fig. 2 Berberine hydrochloride and fumaric acid eutectic
The experimental powder X ray diffracting spectrum of Fig. 3 Berberine hydrochloride and fumaric acid eutectic object
The x-ray diffractogram of powder of Fig. 4 Berberine hydrochloride and fumaric physical mixture is composed
The infrared absorpting light spectra of Fig. 5 Berberine hydrochloride and fumaric acid eutectic object
The Differential Scanning Calorimetry of Fig. 6 Berberine hydrochloride and fumaric acid eutectic object
The Differential Scanning Calorimetry of Fig. 7 Berberine hydrochloride and fumaric acid eutectic object and raw material
Fig. 8 Berberine hydrochloride and fumaric acid eutectic object influence factor experimental patterns (a: Berberine hydrochloride influence because
Sketch map spectrum；B: Berberine hydrochloride and fumaric acid eutectic influence factor map)
Fig. 9 Berberine hydrochloride and dissolution linearity curve of the fumaric acid eutectic object in 4 kinds of solvent systems
Specific embodiment
More preferably to illustrate technical solution of the present invention, spy provides following embodiment, but the present invention is not limited to this.
Embodiment 1
The preparation method 1 of Berberine hydrochloride and fumaric acid eutectic object:
According to shown in following table, taking Berberine hydrochloride and fumaric acid to be in right amount that 2:1 is put into mortar according to molar ratio, add
Enter appropriate organic solvent, underhand polish appropriate time.Powder x-ray diffraction analysis, diffracting spectrum and Fig. 3 mono- are carried out to it
It causes, shows that gained sample is Berberine hydrochloride and fumaric acid eutectic object.
The preparation method 2 of Berberine hydrochloride and fumaric acid eutectic object:
According to shown in following table, taking Berberine hydrochloride and fumaric acid to be in right amount that 2:1 is put into ball grinder according to molar ratio,
Appropriate organic solvent is added, selects appropriate ratio of grinding media to material, sets appropriate revolving speed, grinds appropriate time.X-ray powder is carried out to it to spread out
Analysis is penetrated, diffracting spectrum is consistent with Fig. 3, shows that gained sample is Berberine hydrochloride and fumaric acid eutectic object.
The preparation method 3 of Berberine hydrochloride and fumaric acid eutectic object:
According to shown in following table, taking Berberine hydrochloride and fumaric acid to be in right amount that 2:1 is put into clean container according to molar ratio
It is interior, appropriate organic solvent is added, in stirring appropriate time under room temperature, by resulting suspension solvent evaporation drying, filtering
It spontaneously dries or filtering vacuum is dry.Powder x-ray diffraction analysis is carried out to it, diffracting spectrum is consistent with Fig. 3, shows gained
Sample is Berberine hydrochloride and fumaric acid eutectic object.
Embodiment 2
The stability features of Berberine hydrochloride and fumaric acid eutectic object:
Hot test: Berberine hydrochloride and Berberine hydrochloride and fumaric acid eutectic object sample are set into opening clean surface
It in ware, places 10 days at a temperature of 60 DEG C, and was sampled in the 0th day, the 5th day and the 10th day.By sample obtained by above-mentioned sample point into
Row powder x-ray diffraction analysis, the results showed that Berberine hydrochloride and Berberine hydrochloride and fumaric acid eutectic object are in high temperature shadow
It rings and stablizes under factorial experiments.
High humidity test: Berberine hydrochloride and Berberine hydrochloride and fumaric acid eutectic object sample are set into opening clean surface
It in ware, places 10 days under the conditions of 25 DEG C in relative humidity 90% ± 5%, and was sampled in the 0th day, the 5th day and the 10th day.It will be upper
It states sample obtained by sample point and carries out powder x-ray diffraction analysis, the results showed that Berberine hydrochloride is unstable under conditions of high humidity, and
Berberine hydrochloride and fumaric acid eutectic object are stable with this condition.
Exposure experiments to light: Berberine hydrochloride and Berberine hydrochloride and fumaric acid eutectic object sample are set into opening clean surface
In ware, it is placed on the lighting box equipped with fluorescent lamp, is placed 10 days in the condition that illumination is 4500lx ± 500lx, and in the 0th day, the 5th
It was sampled with the 10th day.Sample obtained by above-mentioned sample point is subjected to powder x-ray diffraction analysis, the results showed that Berberine hydrochloride and
Berberine hydrochloride and fumaric acid eutectic object are stablized under illumination effect factorial experiments.
Pressure testing: weighing Berberine hydrochloride and Berberine hydrochloride and each 100mg of fumaric acid eutectic object sample respectively,
It is sampled through pressure 2T, 4T and 8T condition lower sheeting.Grinding, is sieved with 100 mesh sieve, is measured using powder x-ray diffraction, as a result
Show that Berberine hydrochloride and Berberine hydrochloride and fumaric acid eutectic object are stablized under pressure testing.
Embodiment 3
The dissolubility of Berberine hydrochloride and fumaric acid eutectic and Berberine hydrochloride bulk pharmaceutical chemicals in 4 kinds of solvent systems is special
Sign: the selection of vehicle system: the 1. vehicle system with reference to used by dissolution method in pharmacopeia annex；2. with reference in organism
The digestive juice pH value of Different Organs；4 vehicle systems: the 0.1N hydrochloric acid that pH value is 1.0 are provided with according to above 2 reference frames
Solution；The acetate buffer that pH value is 4.5；The phosphate buffer that pH value is 6.8；Aqueous solution.Referring to " normal oral solid
Preparation Dissolution Rate Testing technological guidance principle " it measures, solubility curve compares using model dependent/non-dependent similar factors (f2) method,
Compare the phase of Berberine hydrochloride with its fumaric acid eutectic sample solubility curve in 4 kinds of vehicle systems by the calculating of f2 value
Like property, when f2 value is higher than 50, then it is assumed that two curves are similar, when f2 value thinks that the two has differences lower than 50.Experiment is with salt
Sour jamaicin sample is as reference, computation model dependent/non-dependent similar factors f2 value.Dissolve percentage composition efficient liquid phase
Method measures the content of Berberine hydrochloride at the wavelength of 345nm, calculates it with external standard method and dissolves percentage composition.It is cross with the time
Coordinate, dissolution percentage composition are that ordinate draws solubility curve respectively.Data are as shown in the table:
3 Berberine hydrochloride of table and fumaric acid eutectic object (YSXBJ-FDXES) and Berberine hydrochloride (YSXBJ)
Solubility curve data in 4 kinds of solvents
The Berberine hydrochloride of this patent and fumaric acid eutectic object are in water, hydrochloric acid, acetic acid it can be seen from experimental data
Solubility behavior is superior to Berberine hydrochloride in salt and phosphate system, is embodied in Berberine hydrochloride and fumaric acid eutectic
Object has faster rate of dissolution, is easy and fast to absorption and reaches effective blood drug concentration, realizes the disease treatment effect of drug；Salt
The dissolution linearity curve of sour jamaicin and fumaric acid eutectic object has stable release platform, it is ensured that in treatment of diseases
It is middle to keep stable blood concentration.
Embodiment 4
The preparation method 1 (tablet) of combined pharmaceutical formulation:
A kind of preparation method of composition of medicine tablet, it is characterized in that using Berberine hydrochloride and fumaric acid eutectic object,
Use several excipient as the adjunct ingredient for preparing composition of medicine tablet, proportion is made every and exists containing eutectic according to a certain percentage
The tablet samples of 5~500mg, table 4 provide tablet formulation ratio:
The preparation formula of 4 Berberine hydrochloride of table and fumaric acid eutectic composition of medicine tablet
It is using the method that Berberine hydrochloride is prepared into tablet formulation as bulk pharmaceutical chemicals with fumaric acid eutectic object: will be several
Excipient is uniformly mixed with bulk pharmaceutical chemicals, direct tablet compressing；Or auxiliary material mixing dry granulation again with bulk pharmaceutical chemicals tabletting after mixing, i.e.,
?.
The preparation method 2 (tablet) of combined pharmaceutical formulation:
A kind of preparation method of composition of medicine tablet, it is characterized in that using Berberine hydrochloride and fumaric acid eutectic, making
Use several excipient as the adjunct ingredient for preparing composition of medicine tablet, proportion is made every containing eutectic 5 according to a certain percentage
The tablet samples of~500mg, table 5 provide tablet formulation ratio:
The preparation formula of 5 Berberine hydrochloride of table and fumaric acid eutectic composition of medicine tablet
It is using the method that Berberine hydrochloride is prepared into tablet formulation as bulk pharmaceutical chemicals with fumaric acid eutectic object: will be several
Excipient is uniformly mixed with bulk pharmaceutical chemicals, and 1% sodium cellulose glycolate solution of addition is appropriate, and soft material, sieving granulation is made, and wet grain dries
Dry, whole grain of being sieved, is added magnesium stearate and talcum powder is uniformly mixed, tabletting to get.
The preparation method 3 (capsule) of combined pharmaceutical formulation:
A kind of preparation method of composition of medicine capsule, it is characterized in that being made using Berberine hydrochloride and fumaric acid eutectic object
For bulk pharmaceutical chemicals, use several excipient as the adjunct ingredient for preparing composition of medicine capsule, proportion is made every according to a certain percentage
For piece content of dispersion in the capsule sample of 5~500mg, table 6 provides capsule formula ratio:
The bulk pharmaceutical chemicals and accessory formula of 6 Berberine hydrochloride of table and fumaric acid eutectic object composition of medicine capsule preparations
It is using the method that Berberine hydrochloride is prepared into capsule as bulk pharmaceutical chemicals with fumaric acid eutectic: by several excipient
It is uniformly mixed with bulk pharmaceutical chemicals, 1% sodium cellulose glycolate solution of addition is appropriate, and wet grain drying sieving whole grain is made, is added stearic
Sour magnesium is uniformly mixed, and insertion capsule is made；Or granulation step is not used, and directly by Berberine hydrochloride and fumaric acid raw material
Medicine is uniformly mixed with several excipients, after sieving, is directly loadable into capsule and is made.
Embodiment 5
The dosage 1 (tablet) of Berberine hydrochloride and fumaric acid eutectic object composition of medicine:
The pharmaceutical composition for using Berberine hydrochloride and fumaric acid eutectic object to manufacture as active pharmaceutical ingredient,
It is characterized in that Berberine hydrochloride and active constituent of the fumaric acid eutectic object as drug, being administered daily dosage is 900mg, can
It is prepared into 3 times a day/3 tablets once 100mg conventional tablet respectively, or 3 times a day/1 tablet once 300mg tablet class.
The dosage 2 (capsule) of Berberine hydrochloride and fumaric acid eutectic object composition of medicine:
The pharmaceutical composition for using Berberine hydrochloride and fumaric acid eutectic object to manufacture as active pharmaceutical ingredient,
It is characterized in that using Berberine hydrochloride and fumaric acid eutectic object as the active constituent of drug, it is administered daily dosage are as follows:
1200mg can be prepared into 3 times a day/100mg capsule 4 tablets each time respectively, or 2 times a day/150mg capsule 4 tablets each time.
Need the problem of illustrating: Berberine hydrochloride of the present invention is having with fumaric acid eutectic medicine composition
There are many factors influences on the dosage of effect ingredient, such as: the difference of patient age, body surface area, administration route are given
Medicine number, therapeutic purposes are different and cause the difference of each dosage；Sample room is existing absorb it is different with blood concentration etc.,
It is 0.1-50mg/ that the present invention, which is also resulted in, in each Suitable dosage ranges using Berberine hydrochloride and fumaric acid eutectic composition
Kg weight, preferably 5-30mg/kg weight.It is small different hydrochloric acid should to be formulated according to actual treatment different situations demand when use
Bark of a cork tree alkali and fumaric acid eutectic object effective component accumulated dose scheme, and the completion of multiple or single administration mode can be divided into.
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1240.
[2] Lv Yang, Du Guanhua, Zhou Haohui, Shi Lili, Yang Shiying Berberine hydrochloride crystalline substance D type substance and preparation method and its
Pharmaceutical composition and purposes publication number: 103421002A.
[3] Du Guanhua, Lv Yang, Zhou Haohui, Zhang Hengai, Zhang Li Berberine hydrochloride crystalline substance E type substance and preparation method and its medicine
Compositions and purposes publication number: 103421001A.
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Pharmaceutical composition and purposes disclose (bulletin) number 103421000A.
Claims (15)
1. a kind of Berberine hydrochloride and fumaric acid eutectic object, which is characterized in that Berberine hydrochloride and fumaric acid are with 2:1
Molar ratio formed eutectic object.
2. Berberine hydrochloride according to claim 1 and fumaric acid eutectic object, when using single-crystal X-ray diffraction analysis,
Anorthic system symmetry, space group P-1 are shown as, cell parameter value is α
=72.26 °, β=85.40 °, γ=88.99 °, unit cell volumeMolecular formula is (C20H18NO4Cl)2·C4H4O4。
3. Berberine hydrochloride according to claim 1 and fumaric acid eutectic object, which is characterized in that when using powder X-ray
X ray diffraction analysis x uses CuKαWhen radiation experiments condition, diffraction maximum position: 2-Theta value (°) or d valueDiffraction maximum is opposite
Intensity: peak value (Height%) or peak area value (Area%) have the feature that
4. Berberine hydrochloride according to claim 1 and fumaric acid eutectic object, which is characterized in that be all-trans using decaying
When penetrating Fourier transform infrared spectrometry and being analyzed, 3102,2998,2951,2906,2849,2747,2564,2473,2426,
1696、1637、1620、1602、1568、1506、1480、1458、1423、1393、1368、1352、1332、1306、1277、
1236、1215、1196、1144、1103、1057、1040、1007、994、974、957、940、916、889、872、856、835、
779、769、754、737、713、664cm-1There are infrared spectroscopy characteristic peak, the tolerances of middle infrared spectrum characteristic peak at place
For ± 2cm-1。
5. Berberine hydrochloride according to claim 1 and fumaric acid eutectic object, which is characterized in that use differential scanning
When Calorimetric Techniques are analyzed, show as when heating rate is 10 DEG C per minute, there are 1 at 238 DEG C ± 3 DEG C in DSC map
Endothermic peak.
6. the preparation method of Berberine hydrochloride of any of claims 1-5 and fumaric acid eutectic object, feature
It is, feeds intake according to Berberine hydrochloride and fumaric acid by the molar ratio of 2:1, using the mechanization of control pressure and temperature
Method prepares Berberine hydrochloride and fumaric acid eutectic object.
7. preparation method according to claim 6, which is characterized in that the mechanochemistry method is selected from liquid feeding ball milling
Method, wherein the ratio of grinding media to material of liquid feeding ball-milling method is 1:1~10:1, preferably 6:1~10:1；Rotational speed of ball-mill 20r/min~400r/
min；The organic solvent type of liquid feeding is any one or more through mixed solvent made of different ratio combination；Described is organic
Solvent be selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, amylalcohol, isoamyl alcohol, n-hexyl alcohol, ethylene glycol, acetonitrile,
Acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, hexamethylene；Liquid volume added is 0.01~100ml；Milling time is
0.1~10 hour.
8. the preparation method of Berberine hydrochloride of any of claims 1-5 and fumaric acid eutectic object, feature
It is, by Berberine hydrochloride and fumaric acid, example 2:1 feeds intake and is put into clean container in molar ratio, and organic solvent is added and is made
Suspension is stirred at room temperature 0.1~4 day, and suspension obtained passes through solvent evaporation drying, filtering natural drying or filtering vacuum
It is dry to obtain Berberine hydrochloride and fumaric acid eutectic object.
9. Berberine hydrochloride according to claim 8 and fumaric acid eutectic object preparation method, which is characterized in that described
Organic solvent be selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, amylalcohol, isoamyl alcohol, n-hexyl alcohol, second two
Alcohol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, any one or more in hexamethylene are through difference
Proportion combines manufactured mixed solvent；It keeps Berberine hydrochloride and fumaric acid gross mass and organic solvent solid-to-liquid ratio is 1mg/
Within the scope of ml~500mg/ml.
10. the hybrid solid substance of a kind of Berberine hydrochloride and fumaric acid eutectic object, which is characterized in that contain claim
The amount of the described in any item Berberine hydrochlorides of 1-5 and fumaric acid eutectic object is 1-99.9%, preferably 10-99.9%, then
Preferably 50-99.9%, most preferably 85-99.9%.
11. a kind of pharmaceutical composition, which is characterized in that the hydrochloric acid barberry of any one of claim 1-5 containing effective dose
Alkali and fumaric acid eutectic object and pharmaceutically acceptable carrier.
12. a kind of pharmaceutical composition, which is characterized in that the Berberine hydrochloride described in any one of claim 10 containing effective dose and anti-
Butene dioic acid eutectic object hybrid solid substance and pharmaceutically acceptable carrier.
13. any one of 1 or 12 pharmaceutical composition according to claim 1, which is characterized in that Berberine hydrochloride uses medicament daily
Amount is within the scope of 5~3000mg.
14. any one of 1 or 12 pharmaceutical composition according to claim 1, which is characterized in that the dosage form of described pharmaceutical composition is
Tablet, capsule, pill, injection preparation, sustained release preparation or controlled release preparation.
15. described in Berberine hydrochloride of any of claims 1-5 and fumaric acid eutectic object or claim 10
Berberine hydrochloride and fumaric acid eutectic object hybrid solid substance or the described in any item medicine groups of claim 11 or 12
Object is closed in preparing prevention and cure of cardiovascular disease, antiviral, anticancer, reducing blood lipid, hypoglycemic, anti-inflammatory, antibacterial and anti-infectives
Using.
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| CN112521385A (en) * | 2020-12-02 | 2021-03-19 | 上海工程技术大学 | Berberine hydrochloride eutectic crystal and preparation method thereof |
| CN112624918A (en) * | 2020-12-18 | 2021-04-09 | 深圳市萱嘉生物科技有限公司 | Eutectic of azelaic acid and organic base as well as preparation method and application thereof |
| CN113956250A (en) * | 2021-10-21 | 2022-01-21 | 上海工程技术大学 | Berberine hydrochloride pharmaceutical co-crystal and preparation method and application thereof |
| CN113999225A (en) * | 2021-11-29 | 2022-02-01 | 东南大学成贤学院 | Vinpocetine eutectic compound and preparation method thereof |
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| CN113999225A (en) * | 2021-11-29 | 2022-02-01 | 东南大学成贤学院 | Vinpocetine eutectic compound and preparation method thereof |
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