CN110041325A - Berberine hydrochloride and brufen eutectic object and preparation method and its composition and purposes - Google Patents
Berberine hydrochloride and brufen eutectic object and preparation method and its composition and purposes Download PDFInfo
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- CN110041325A CN110041325A CN201810033332.8A CN201810033332A CN110041325A CN 110041325 A CN110041325 A CN 110041325A CN 201810033332 A CN201810033332 A CN 201810033332A CN 110041325 A CN110041325 A CN 110041325A
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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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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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
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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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- C—CHEMISTRY; METALLURGY
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Abstract
The invention discloses Berberine hydrochloride and brufen eutectic object and preparation methods and its composition and purposes.Specifically, the invention discloses one kind using Berberine hydrochloride as active pharmaceutical ingredient, brufen is the new Berberine hydrochloride and brufen eutectic of eutectic presoma；The preparation method of Berberine hydrochloride and brufen eutectic；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 brufen eutectic.
Description
Technical field
The invention discloses Berberine hydrochloride and brufen eutectic object and preparation methods and its composition and purposes.It is specific and
Speech, the invention discloses the eutectic objects that a kind of Berberine hydrochloride and brufen are formed；Berberine hydrochloride and brufen eutectic object
Preparation method；Berberine hydrochloride and brufen eutectic object as active pharmaceutical ingredient prepare prevention and cure of cardiovascular disease, it is antiviral,
Application in 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 brufen, molecular formula C13H18O2, structural formula is as shown in 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 brufen eutectic object existence and characteristic manner are provided.
The two of the object of the invention: the preparation method of Berberine hydrochloride and brufen eutectic object is provided.
The three of the object of the invention: it provides containing Berberine hydrochloride and brufen eutectic object sterling or contains any non-zero ratio
The hybrid solid substance and its pharmaceutical composition of example Berberine hydrochloride and brufen eutectic object.
The four of the object of the invention: offer uses Berberine hydrochloride and drug of the brufen eutectic object as active pharmaceutical ingredient
Composition, the daily dosage of Berberine hydrochloride is within the scope of 5~3000mg.The pharmaceutical composition includes tablet, glue
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 brufen eutectic substance, has compared with Berberine hydrochloride
Preferably dissolution sexual clorminance.
The six of the object of the invention: it is to provide Berberine hydrochloride and brufen eutectic substance in treatment lysis due to altogether
Eutectic substance and improve blood concentration in organism and play the effective therapeutic effect of drug.
The seven of the technical problem to be solved in the present invention: Berberine hydrochloride is being made with brufen eutectic as effective ingredient
Application in standby prevention and cure of 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 brufen eutectic sample morphology feature:
1.1 Berberine hydrochlorides of the present invention and brufen eutectic object, are Berberine hydrochloride and brufen rubbing with 1:1
You form eutectic object by ratio.
1.2 Berberine hydrochlorides of the present invention and brufen eutectic object, are used when using powder x-ray diffraction analysis
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. 1)；The physics of Berberine hydrochloride and brufen is mixed
The x-ray diffractogram of powder spectrum and data for closing object are shown in Table 2, Fig. 2.Berberine hydrochloride and brufen eutectic object and Berberine hydrochloride and
The x-ray diffractogram of powder of the physical mixture of brufen is composed in diffraction maximum quantity, diffraction maximum position, diffraction peak intensity, diffraction
There is notable difference in peak topological graph etc., show Berberine hydrochloride and brufen eutectic object and Berberine hydrochloride and Bu Luo
Fragrant physical mixture is neither identical nor equivalent.
The powder x-ray diffraction peak value of 1 Berberine hydrochloride of table and brufen eutectic
The powder x-ray diffraction peak value of 2 Berberine hydrochloride of table and brufen physical mixed
1.3 Berberine hydrochlorides of the present invention and brufen eutectic are totally reflected Fourier transform infrared spectrometry using decaying
When being analyzed, 3102,3043,3009,2952,2899,2869,2849,2563,1720,1638,1622,1604,
1570、1508、1480、1458、1421、1392、1374、1343、1306、1277、1234、1217、1191、1173、1149、
1111、1060、1043、998、976、958、946、931、915、875、855、836、796、781、752、737、729、705、
661cm-1Place is ± 2cm there are infrared spectroscopy characteristic peak, the tolerance of middle infrared spectrum characteristic peak-1(Fig. 3).
1.4 Berberine hydrochlorides of the present invention and brufen eutectic, when being analyzed using differential canning calorimetry, performance
For when heating rate is 10 DEG C per minute, there are 1 endothermic peaks (Fig. 4) at 200 DEG C ± 3 DEG C in DSC map.Hydrochloric acid barberry
The DSC map of alkali, brufen and eutectic is shown in Fig. 5.Berberine hydrochloride and brufen eutectic object and Berberine hydrochloride and brufen
DSC map suction/exothermic peak quantity, in terms of there is notable difference, show that Berberine hydrochloride is formd with brufen
New substance.
2. the preparation method characteristic of Berberine hydrochloride and brufen eutectic object and hybrid solid substance:
The preparation method of 2.1 Berberine hydrochlorides of the present invention and brufen eutectic object, according to Berberine hydrochloride and cloth
Ibuprofen feeds intake by the molar ratio of 1:1, prepares Berberine hydrochloride and cloth Lip river using the mechanochemistry method of control pressure and temperature
Fragrant eutectic object.The preferred liquid feeding ball-milling method of the mechanochemistry 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 solvent type of liquid feeding is any one in organic solvent
Kind is a variety of through mixed solvent made of different ratio combination；The organic solvent is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropyl
Alcohol, n-butanol, the tert-butyl alcohol, amylalcohol, isoamyl alcohol, n-hexyl alcohol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydro furan
It mutters, 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 brufen eutectic object, by Berberine hydrochloride and cloth Lip river
Fragrant example 1:1 in molar ratio, which feeds intake, to be put into clean container, organic solvent is added, suspension is made, be stirred at room temperature 0.1~4 day, institute
The suspension of acquisition is spontaneously dried by solvent evaporation drying, filtering or filtering vacuum is dry obtains Berberine hydrochloride and brufen
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, any one in hexamethylene
Or it is a variety of through mixed solvent made of different ratio combination；Keep Berberine hydrochloride and brufen gross mass and organic solvent solid-liquid
Than within the scope of 1mg/ml~500mg/ml.
The hybrid solid substance of 2.3 Berberine hydrochlorides and brufen eutectic object of the invention is to obtain above method preparation
Berberine hydrochloride and brufen eutectic object ingredient, with other chemical substances according to any non-zero proportions and conventional method into
Row mixing.
3. pharmaceutical preparations composition, dosage feature and pharmaceutical purpose containing Berberine hydrochloride Yu brufen eutectic composition
On the way:
3.1 pharmaceutical compositions of the present invention contain Berberine hydrochloride and brufen eutectic object and pharmaceutically acceptable
Carrier.
3.2 pharmaceutical compositions of the present invention, the hybrid solid substance containing Berberine hydrochloride Yu brufen eutectic object
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, which is characterized in that the pharmaceutical composition be various tablets, capsule,
Pill, injection preparation, sustained release preparation or controlled release preparation.
3.5 the present invention relates to the mixing of Berberine hydrochloride and brufen eutectic object, Berberine hydrochloride and brufen eutectic object
Solid matter or pharmaceutical composition are preparing prevention and cure of cardiovascular disease, antiviral, anticancer, reducing blood lipid, hypoglycemic, anti-inflammatory, antibacterial
And the application in anti-infectives.
The present invention relates to using Berberine hydrochloride of the present invention and brufen eutectic object as the pharmaceutical composition of active ingredient.It should
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 brufen eutectic composition
In conjunction with one or more pharmaceutically acceptable solids or liquid excipient and/or adjuvant, it is made and is used suitable for human or animal
Any dosage form.Berberine hydrochloride of the present invention and content of the brufen eutectic object in its pharmaceutical composition are in 10%~90% weight
It measures in range.
Berberine hydrochloride of the present invention can be administered in a unit with brufen eutectic object, administration route can for enteron aisle or
Non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, yin
Road, 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 brufen 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 tablet is made in Berberine hydrochloride of the present invention and brufen eutectic object, can be widely used well known in the art
Various excipient, including diluent, binder, wetting agent, disintegrating agent, lubricant, glidant.Diluent can be starch, paste
Essence, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；
Wetting agent can be water, ethyl alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, micro-
Crystalline cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl are fine
Tie up element, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrating agent can be dried starch, microcrystalline cellulose
Element, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, carbonic acid
Hydrogen sodium and citric acid, polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be cunning
Mountain flour, 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.
It, can be by effective component Berberine hydrochloride of the present invention and brufen eutectic object in order to which capsule is made in administration unit
It is mixed with diluent, glidant, mixture is placed directly in hard capsule or soft capsule.It can also be by effective component hydrochloric acid of the present invention
First particle or pellet is made with diluent, binder, disintegrating agent in jamaicin and brufen eutectic object, then is placed in hard capsule or flexible glue
In capsule.It is used to prepare the various diluents of Berberine hydrochloride of the present invention and brufen eutectic object tablet, binder, wetting agent, collapses
Solution agent, glidant kind can also be used for preparing the capsule of Berberine hydrochloride of the present invention Yu brufen eutectic object.
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 brufen eutectic pharmaceutical composition is according to being prevented or be treated disease
The individual instances of the property and severity of disease, patient or animal, administration route and dosage form etc. can have large-scale variation.On
Stating dosage with a dosage unit or can be divided into several dosage unit administrations, this depends on the clinical experience of doctor and includes transporting
With the dosage regimen of other treatment means.
Berberine hydrochloride of the present invention can individually be taken with brufen eutectic object or composition, or with other treatment drug or right
Disease drug, which merges, to be used.When Berberine hydrochloride of the present invention and brufen eutectic object and other therapeutic agents, which exist, to act synergistically,
Its dosage should be adjusted according to the actual situation.
4. advantageous effects of the invention: safety, dissolubility and the biology of Berberine hydrochloride and brufen eutectic object
Activity advantage feature.
4.1 Berberine hydrochlorides and brufen eutectic object of the invention are free of any recrystallisation solvent, have good safety
Patent medicine advantage.
4.2 Berberine hydrochlorides and brufen eutectic object of the invention are shown in water and hydrochloric acid system better than hydrochloric acid barberry
The dissolution sexual clorminance of alkali is especially presented as that rate of dissolution makes marked progress (Fig. 6).
The drug and its pharmaceutical composition that 4.3 Berberine hydrochlorides of the invention and brufen eutectic are developed as active constituent
After by oral administration biological absorption effect, it is characterised in that used containing Berberine hydrochloride as described in claim 1 with
Brufen eutectic substance is as active constituent, by being rapidly reached maximum concentration value in gastrointestinal tract or blood in disease preventing and treating
The advantage function of performance and application (Fig. 7).Berberine hydrochloride and brufen eutectic solid matter of the invention improves drug in life
Blood concentration in object, to play the more efficient therapeutic effect of drug.
Detailed description of the invention
The x-ray diffractogram of powder of Fig. 1 Berberine hydrochloride and brufen eutectic object is composed
The x-ray diffractogram of powder of the physical mixture of Fig. 2 Berberine hydrochloride and brufen is composed
The infrared absorpting light spectra of Fig. 3 Berberine hydrochloride and brufen eutectic object
The Differential Scanning Calorimetry of Fig. 4 Berberine hydrochloride and brufen eutectic object
The Differential Scanning Calorimetry of Fig. 5 Berberine hydrochloride and brufen eutectic object and raw material
The dissolution linearity curve of Fig. 6 Berberine hydrochloride and Berberine hydrochloride and brufen eutectic object
Fig. 7 Berberine hydrochloride and Berberine hydrochloride and brufen eutectic object absorb the Drug-time curve of 0-2h in Oral Administration in Rats
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 brufen eutectic object:
According to shown in following table, taking Berberine hydrochloride and brufen to be in right amount that 1:1 is put into mortar according to molar ratio, it is added suitable
Measure organic solvent, underhand polish appropriate time.Powder x-ray diffraction analysis is carried out to it, diffracting spectrum is consistent with Fig. 1, table
Bright gained sample is Berberine hydrochloride and brufen eutectic object.
The preparation method 2 of Berberine hydrochloride and brufen eutectic object:
According to shown in following table, taking Berberine hydrochloride and brufen to be in right amount that 1:1 is put into ball grinder according to molar ratio, it is added
Appropriate organic solvent selects appropriate ratio of grinding media to material, sets appropriate revolving speed, grinds appropriate time.Powder x-ray diffraction point is carried out to it
Analysis, diffracting spectrum is consistent with Fig. 1, shows that gained sample is Berberine hydrochloride and brufen eutectic object.
The preparation method 3 of Berberine hydrochloride and brufen eutectic object:
According to shown in following table, taking Berberine hydrochloride and brufen to be in right amount that 1:1 is put into clean container according to molar ratio,
Appropriate organic solvent is added, in stirring appropriate time under room temperature, by resulting suspension solvent evaporation drying, filtering nature
Dry or filtering vacuum is dry.Powder x-ray diffraction analysis is carried out to it, diffracting spectrum is consistent with Fig. 1, shows gained sample
For Berberine hydrochloride and brufen eutectic object.
Embodiment 2
The 0.1N hydrochloric acid that Berberine hydrochloride and brufen eutectic object and Berberine hydrochloride bulk pharmaceutical chemicals are 1.0 in pH value is investigated
Dissolubility feature in solution and aqueous solution system.It is surveyed referring to " normal oral solid pharmaceutical preparation Dissolution Rate Testing technological guidance principle "
Fixed, solubility curve compares using model dependent/non-dependent similar factors (f2) method, compares Berberine hydrochloride by the calculating of f2 value
With the similitude of Berberine hydrochloride and brufen eutectic object sample solubility curve in 2 kinds of vehicle systems, when f2 value be higher than 50, then
Think that two curves are similar, when f2 value thinks that the two has differences lower than 50.It tests using Berberine hydrochloride sample as reference,
Computation model dependent/non-dependent similar factors f2 value.It dissolves percentage composition and uses the measurement at the wavelength of 345nm with high-efficient liquid phase technique
The content of Berberine hydrochloride calculates it with external standard method and dissolves percentage composition.Using the time as abscissa, dissolution percentage composition is vertical sits
Mark draws solubility curve (Fig. 6) respectively.Data are as shown in the table:
3 Berberine hydrochloride of table and brufen eutectic object (YSXBJ-BLF) and Berberine hydrochloride (YSXBJ) are in 4 kinds of solvents
Solubility curve data
Berberine hydrochloride and brufen eutectic object by this patent it can be seen from experimental data is molten in water and hydrochloric acid system
Solution behavior is superior to Berberine hydrochloride, and being embodied in Berberine hydrochloride and brufen eutectic object has faster dissolution speed
Rate is easy and fast to absorption and reaches effective blood drug concentration, realizes the disease treatment effect of drug；Berberine hydrochloride and brufen eutectic
The dissolution linearity curve of object has stable release platform, it is ensured that keeps stable blood concentration in the course of disease treatment.
Embodiment 3
Berberine hydrochloride and brufen eutectic object are in rat body absorption feature and blood concentration feature:
6 SD rats are randomly divided into 2 groups, and every group 3,12h is deprived of food but not water before being administered.Rat body weight is weighed, is pressed
100mg·kg-1Berberine hydrochloride dosage calculate, by Berberine hydrochloride and Berberine hydrochloride and brufen eutectic object sample
It is packed into solid form delivery device, is directly placed in medicinal powder in rat stomach by oral cavity.Distinguish 5min, 15min, 30min after administration,
45min, 1h, 1.5h, 2h, 4h, 8h, 12h take blood to set in test tube of hepari pipe in the intraocular corner of the eyes, and 4 DEG C, 4000rpm centrifugation 10min freeze
In to be measured in -40 DEG C of refrigerators.Precision measures 100 μ L of blood plasma, sets in 1.5ml EP pipe, and the work of 10 μ L internal standard carbamazepines is added
Liquid adds 290 μ L acetonitriles (protein precipitant), and 5min fullys shake, and is centrifuged (13400rpm, 10min), takes upper solution
100 μ L are added 100 μ L water and adjust sample solvent ratio in another centrifuge tube.It is vortexed and mixes, take upper solution in internal lining pipe
It is spare.
Testing conditions: Agilent ZORBAX SB-C18 (2.1 × 100mm, 3.5 μm, USA)；Mobile phase is acetonitrile: water
(containing 0.1% formic acid)=30:70 (v:v)；Flow velocity 0.3mL/min；30 DEG C of column temperature；Sample volume: 20 μ L；Runing time: 8min；Matter
Spectrum signal: the source ESI (positive ion detection mode), for the ion m/z=237 (carbamazepine) of quantitative analysis, m/z=336 is (small
Bark of a cork tree alkali), fragmentation voltage is respectively 145V (jamaicin), 130V (carbamazepine), gain coefficient 1.5, and dry gas stream is
11.0L/min, spray chamber's voltage are 35psig, and dryer temperature is 350 DEG C, and capillary voltage is 3000V (just), 3000V
(negative).
Table 4 provides rat oral and takes Berberine hydrochloride (YSXBJ) and Berberine hydrochloride and brufen (YSXBJ-BLF) eutectic
After object sample in blood each time point blood concentration；Table 5 provides rat oral and takes Berberine hydrochloride and Berberine hydrochloride and cloth
The pharmacokinetic parameter of ibuprofen eutectic object sample 0-2h shows that Berberine hydrochloride and brufen eutectic object have infiltration rate
Fastly, blood concentration is high, acts on the dominant feature of prolonged plateau.
Each time point of table 4 blood concentration (n=3,)
After table 5SD Oral Administration in Rats Berberine hydrochloride (YSXBJ) and Berberine hydrochloride and brufen (YSXBJ-BLF) eutectic object
Pharmacokinetic parameter
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 brufen eutectic object, using
Several excipient as the adjunct ingredient for preparing composition of medicine tablet, according to a certain percentage proportion be made every containing eutectic 5~
The tablet samples of 500mg, table 6 provide tablet formulation ratio:
The preparation formula of 6 Berberine hydrochloride of table and brufen eutectic composition of medicine tablet
It is using the method that Berberine hydrochloride is prepared into tablet formulation as bulk pharmaceutical chemicals with brufen eutectic object: by several figurations
Agent is uniformly mixed with bulk pharmaceutical chemicals, direct tablet compressing；Or auxiliary material mixing dry granulation again with bulk pharmaceutical chemicals after mixing tabletting to get.
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 brufen eutectic object, using
Several excipient as the adjunct ingredient for preparing composition of medicine tablet, according to a certain percentage proportion be made every containing eutectic 5~
The tablet samples of 500mg, table 7 provide tablet formulation ratio:
The preparation formula of 7 Berberine hydrochloride of table and brufen eutectic object composition of medicine tablet
It is using the method that Berberine hydrochloride is prepared into tablet formulation as bulk pharmaceutical chemicals with brufen eutectic: by several excipient
It is uniformly mixed with bulk pharmaceutical chemicals, 1% sodium cellulose glycolate solution of addition is appropriate, and soft material, sieving granulation, wet grain drying, mistake is made
Sieve whole grain, magnesium stearate and talcum powder be added and 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 using Berberine hydrochloride and brufen eutectic object as original
Material medicine uses several excipient as the adjunct ingredient for preparing composition of medicine capsule, and proportion is made every and contains according to a certain percentage
For dose in the capsule sample of 5~500mg, table 8 provides capsule formula ratio:
The bulk pharmaceutical chemicals and accessory formula of 8 Berberine hydrochloride of table and brufen eutectic object composition of medicine capsule preparations
Be using the method that Berberine hydrochloride is prepared into capsule as bulk pharmaceutical chemicals with brufen eutectic object: by several excipient with
Bulk pharmaceutical chemicals are uniformly mixed, and 1% sodium cellulose glycolate solution of addition is appropriate, and wet grain drying sieving whole grain is made, stearic acid is added
Magnesium is uniformly mixed, and insertion capsule is made；Or do not use granulation step, and directly by Berberine hydrochloride and brufen bulk pharmaceutical chemicals with it is several
Kind excipients are uniformly mixed, and after sieving, are directly loadable into capsule and are made.
Embodiment 5
The dosage 1 (tablet) of Berberine hydrochloride and brufen eutectic object composition of medicine:
The pharmaceutical composition for using Berberine hydrochloride and brufen eutectic object to manufacture as active pharmaceutical ingredient, it is special
Sign is Berberine hydrochloride and active constituent of the brufen eutectic object as drug, and being administered daily dosage is 900mg, can be prepared respectively
At 3 times a day/3 tablets once 100mg conventional tablet, or 3 times a day/1 tablet once 300mg tablet class.
The dosage 2 (capsule) of Berberine hydrochloride and brufen eutectic object composition of medicine:
The pharmaceutical composition for using Berberine hydrochloride and brufen eutectic object to manufacture as active pharmaceutical ingredient, it is special
Sign is to use Berberine hydrochloride and brufen eutectic object as the active constituent of drug, is administered daily dosage are as follows: 1200mg can divide
It is not prepared into 3 times a day/100mg capsule 4 tablets each time, or 2 times a day/150mg capsule 4 tablets each time.
Need the problem of illustrating: Berberine hydrochloride of the present invention and brufen eutectic medicine composition effectively at
There are many factors influences on the dosage divided, such as: the difference of patient age, body surface area, administration route, administration time
Number, therapeutic purposes are different and cause the difference of each dosage；Sample room is existing to be absorbed different with blood concentration etc., is also made
It in each Suitable dosage ranges using Berberine hydrochloride and brufen eutectic object ingredient is 0.1-50mg/kg body at the present invention
Weight, preferably 5-30mg/kg weight.When use different Berberine hydrochlorides should be formulated according to actual treatment different situations demand
With brufen eutectic object effective component accumulated dose scheme, and can be divided into multiple or single administration mode completion.
Bibliography
[1]BENSON M.KARIUKI.Five Salts of Berberine.Acta Cryst.1995,C51,1234-
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.
[4] Du Guanhua, Lv Yang, Zhou Haohui, Chen Bonian, Yang Shiying Berberine hydrochloride crystalline substance F type substance and preparation method and its
Pharmaceutical composition and purposes disclose (bulletin) number 103421000A.
Claims (14)
1. a kind of Berberine hydrochloride and brufen eutectic object, which is characterized in that Berberine hydrochloride and brufen are with 1:1 molar ratio shape
At eutectic object.
2. Berberine hydrochloride according to claim 1 and brufen eutectic object, which is characterized in that when using X-ray powder
Diffraction analysis uses CuKαWhen radiation experiments condition, diffraction maximum position: 2-Theta value (°) or d valueDiffraction maximum is relatively strong
Degree: peak value (Height%) or peak area value (Area%) have the feature that
3. Berberine hydrochloride according to claim 1 and brufen eutectic object, which is characterized in that use decaying total reflection Fu
When vertical leaf infra-red sepectrometry is analyzed, 3102,3043,3009,2952,2899,2869,2849,2563,1720,1638,
1622、1604、1570、1508、1480、1458、1421、1392、1374、1343、1306、1277、1234、1217、1191、
1173、1149、1111、1060、1043、998、976、958、946、931、915、875、855、836、796、781、752、737、
729、705、661cm-1Place is ± 2cm there are infrared spectroscopy characteristic peak, the tolerance of middle infrared spectrum characteristic peak-1。
4. Berberine hydrochloride according to claim 1 and brufen eutectic object, which is characterized in that use differential scanning calorimetry
When technology is analyzed, show as when heating rate is 10 DEG C per minute, there are 1 heat absorptions at 200 DEG C ± 3 DEG C in DSC map
Peak.
5. the preparation method of Berberine hydrochloride of any of claims 1-4 and brufen eutectic object, which is characterized in that
It feeds intake according to Berberine hydrochloride and brufen by the molar ratio of 1:1, using the mechanochemistry method system of control pressure and temperature
Standby Berberine hydrochloride and brufen eutectic object.
6. preparation method according to claim 5, the preferred liquid feeding ball-milling method of the mechanochemistry method, wherein liquid feeding ball
The ratio of grinding media to material of mill method is 1:1~10:1, preferably 6:1~10:1；Rotational speed of ball-mill 20r/min~400r/min；Liquid feeding it is organic
Solvent type is any one or more through mixed solvent made of different ratio combination；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, acetic acid second
Ester, dioxane, tetrahydrofuran, n-hexane, hexamethylene；Liquid volume added is 0.01~100ml；Milling time is 0.1~10 hour.
7. the preparation method of Berberine hydrochloride of any of claims 1-4 and brufen eutectic object, which is characterized in that
By Berberine hydrochloride and brufen, example 1:1 feeds intake and is put into clean container in molar ratio, organic solvent is added, suspension, room is made
Temperature stirring 0.1~4 day, suspension obtained is spontaneously dried by solvent evaporation drying, filtering or filtering vacuum is dry obtains
Berberine hydrochloride and brufen eutectic object.
8. Berberine hydrochloride according to claim 7 and brufen eutectic object preparation method, the organic solvent are preferred
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, any one or more in hexamethylene are made through different ratio combination
Mixed solvent；It keeps Berberine hydrochloride and brufen gross mass and organic solvent solid-to-liquid ratio is 1mg/ml~500mg/ml range
It is interior.
9. the hybrid solid substance of a kind of Berberine hydrochloride and brufen eutectic object, which is characterized in that appoint containing claim 1-4
The amount of Berberine hydrochloride described in one and brufen eutectic object is 1-99.9%, preferably 10-99.9%, is further preferably 50-
99.9%, most preferably 85-99.9%.
10. a kind of pharmaceutical composition, which is characterized in that the hydrochloric acid barberry of any one of claim 1-4 containing effective dose
Alkali and brufen eutectic object and pharmaceutically acceptable carrier.
11. a kind of pharmaceutical composition, which is characterized in that Berberine hydrochloride and cloth as claimed in claim 9 containing effective dose
Ibuprofen eutectic object hybrid solid substance and pharmaceutically acceptable carrier.
12. any one of 0 or 11 pharmaceutical composition according to claim 1, which is characterized in that Berberine hydrochloride uses medicament daily
Amount is within the scope of 5~3000mg.
13. any one of 0 or 11 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.
14. Berberine hydrochloride of any of claims 1-4 and brufen eutectic object or hydrochloric acid as claimed in claim 9
Jamaicin is being prepared with brufen eutectic object hybrid solid substance or the described in any item pharmaceutical compositions of claim 10 or 11
Application in prevention and cure of cardiovascular disease, antiviral, anticancer, reducing blood lipid, hypoglycemic, anti-inflammatory, antibacterial and anti-infectives.
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