CN110452156A - Donepezil and Irbesartan eutectic object and preparation method and its composition and purposes - Google Patents
Donepezil and Irbesartan eutectic object and preparation method and its composition and purposes Download PDFInfo
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Abstract
The invention discloses donepezils (English name: donepezil) to combine the eutectic substance (such as Formulas I) to be formed and its preparation method and its composition and purposes with non-covalent bond with Irbesartan (English name: irbesartan).Specifically, the invention discloses the eutectic material solid stastus formats that donepezil and Irbesartan are formed；The preparation method for the eutectic state of matter form that donepezil and Irbesartan are formed；The eutectic state of matter form solid matter that donepezil and Irbesartan are formed prepare the various applications for preventing and/or treating in cardiovascular diseases and its neurodegenerative disease such as the Alzheimer diseases such as heart failure, myocardial ischemia, hypertension, vascular lesions, angina pectoris, hyperlipemia, atherosclerosis or diabetic complication and the concurrent disease medicament of above-mentioned a variety of diseases as active pharmaceutical ingredient.
Description
Technical field
The present invention relates to have found donepezil and Irbesartan existing a kind of eutectic solid matter in the solid state
Stastus format；It is related to having invented the preparation method of donepezil Yu Irbesartan eutectic object；It is related to having invented and contains donepezil
With Irbesartan eutectic object or the pharmaceutical composition containing any non-zero proportions donepezil Yu the mixed crystal of Irbesartan eutectic object；This
Invention further relates to donepezil and Irbesartan eutectic object as effective ingredient, is preparing various prevention and treatment heart failure, the heart
The cardiovascular diseases such as myocardial ischemia, hypertension, vascular lesions, angina pectoris, hyperlipemia, atherosclerosis or diabetic nephropathy
And its application in neurodegenerative disease such as Alzheimer disease and the concurrent disease medicament of above-mentioned a variety of diseases.
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 chemicals, original can be broken by the research of eutectic object and grind medicine enterprise
The patent protection of industry improves the novelty and the market competitiveness of drug.
Donepezil belongs to acetylcholinesterase inhibitor, and for structural formula as shown in a, hydrochloride is commonly used on Present clinical
A kind of anti senile dementia drug.Alzheimer disease is that one kind is showed with hypomnesia to be main, with other cognitive functions
The acquired hypophrenia of damage.
Irbesartan belongs to angiotensin II receptor antagonist, is generated by the AT1 receptor to Angiotensin II non-
Emulative inhibition, to realize the contracting blood vessel for mitigating Angiotensin II and promote proliferative effect, structural formula is as shown in b.It is oral
Bioavilability 60%~80%, protein binding rate 90%, TmaxIt is 4~6 hours, t1/2It is 11~15 hours.
Irbesartan is mainly used for the treatment of essential hypertension, compares the excellent of other angiotensin receptor antagonists
Influence when gesture is decompression to heart rate is smaller[1]。
Irbesartan also has important Renoprotective Effect, can slow down the progress of diabetic nephropathy[2].For 2 type glycosurias
Sick nephrotic, if suffering from hypertension simultaneously, Irbesartan can slow down the progress of nephrosis[3].Irbesartan combines amiodarone can be right
Patients with Pacemaker auricular fibrillation has apparent coordinate repression[4]。
Crystal form about donepezil is studied: Yeoojin park[5]Etc. 4 kinds of crystal forms for reporting donepezil, and provide
Its mono-crystalline structures, wherein all crystal forms studied are the crystal form of single compound, with the present invention on material composition composition
There are essential difference, the donepezil bulk pharmaceutical chemicals that this patent uses are crystalline substance I type.
Crystal form and eutectic about Irbesartan, which are studied, to be had been reported that, and in patent CN201310446196.2[6]It discloses
One Irbesartan Repaglinide is total to amorphous article.In Chinese patent CN201510175133.7, Suzhou Netac biotechnology
The Zhang Jian of Co., Ltd[7]Et al. disclose the eutectic compound an of Irbesartan Yu Sha Kubi song
In report disclosed above, another group in related Irbesartan eutectic material composition in addition to Irbesartan
Point, there are structures and qualitative notable difference for the donepezil used with this patent.
Donepezil is current most widely used anti-Alzheimer disease drug, and Irbesartan is current anti-hypertension one
Line medication, it is more with donepezil and other drugs combination and Irbesartan and the open report of other drugs combination, but have no more
The combination of both donepezil and Irbesartan, and there are no the two to form eutectic solids Quality Research report.
In conclusion have no that donepezil and Irbesartan form eutectic or the altogether unformed research report for closing object so far,
Physical form, state of matter, portfolio ratio, preparation method and in terms of, also have no similar or conflict with the present invention
Research contents.
The present invention is by being prepared into the specific eutectic solid coexisted in specific lattice for donepezil and Irbesartan
Substance to form the novel substance for being different from donepezil, Irbesartan and the application of the two simple association, and then finds the present invention
Peculiar advantage of the new eutectic solid matter in above-mentioned cardiovascular and nervous system disorders disease.
Summary of the invention
One of the technical problem to be solved in the present invention: donepezil and Irbesartan eutectic object existence and characterization are provided
Mode.
The second technical problem to be solved by the present invention: the preparation method of donepezil and Irbesartan eutectic object is provided.
The third technical problem to be solved by the present invention: it provides containing donepezil and Irbesartan eutectic object sterling or contains
There is the hybrid solid substance and combinations thereof of any non-zero proportions donepezil Yu Irbesartan eutectic object.
The four of the technical problem to be solved in the present invention: offer uses donepezil and Irbesartan eutectic object living as drug
The pharmaceutical composition of property ingredient, each dosage is within the scope of 5-1000mg.The pharmaceutical composition includes tablet, glue
Capsule, pill, injection preparation, sustained release or controlled release preparation drug.
The five of the technical problem to be solved in the present invention: being to provide donepezil and Irbesartan eutectic substance, and individual
Irbesartan is compared, and dissolution rate and the amount of dissolution all have patent medicine advantage.
The six of the technical problem to be solved in the present invention: it is to provide donepezil and Irbesartan eutectic object, since the two is non-
Covalent effect power in conjunction with and improve drug bioavailability, it is more preferable to play drug therapy effect.
The seven of the technical problem to be solved in the present invention: there is provided donepezils to have with Irbesartan eutectic object as drug
Ingredient is imitated, various preventions and/or treatment heart failure, myocardial ischemia, hypertension, vascular lesions, angina pectoris, high blood are being prepared
The cardiovascular diseases such as rouge disease, atherosclerosis or diabetic nephropathy and its neurodegenerative disease such as Alzheimer disease and
Application in the concurrent disease medicament of above-mentioned a variety of diseases.
In order to solve the above technical problems, the present invention adopts the following technical scheme:
1. donepezil and Irbesartan eutectic object sample morphology feature:
1.1 donepezils of the present invention and Irbesartan eutectic object, are that donepezil and Irbesartan are rubbed with 1:1
You form eutectic object by ratio.
1.2 donepezils and Irbesartan eutectic object of the invention, do not contain recrystallisation solvent or crystalline water content, work as use
Powder x-ray diffraction analysis when CuK α radiation experiments condition, shows as diffraction maximum position: 2-Theta value (°) or d value
Diffraction maximum relative intensity peak value (Height%) or peak area value (Area%) have solid matter when following characteristic peaks
(table 1, Fig. 1).The x-ray diffractogram of powder modal data of the physical mixture of donepezil raw material and Irbesartan raw material see Fig. 2,
Table 2.Donepezil is penetrated with Irbesartan eutectic object and the powder X-ray of donepezil raw material and the physical mixture of Irbesartan raw material
It is obvious poor that ray diffraction diagram spectrum exists in terms of diffraction maximum quantity, diffraction maximum position, diffraction peak intensity, diffraction maximum
It is different, show the physical mixture neither phase of donepezil with Irbesartan eutectic object and donepezil raw material and Irbesartan raw material
With also not equivalent.
The powder x-ray diffraction peak value of 1 donepezil of table and Irbesartan eutectic object
The powder x-ray diffraction peak value of the physical mixture of 2 donepezil raw material of table and Irbesartan raw material
1.3 donepezils of the present invention and Irbesartan eutectic object are totally reflected Fourier infrared spectrum using decaying
When method is analyzed, 3613,3424,3052,2948,2870,2331,1723,1690,1625,1605,1592,1500,
1455、1440、1404、1344、1317、1286、1266、1219、1199、 1157、1124、1111、1072、1038、1011、
949、928、907、835、820、770、753、707cm-1Absorption peak presented by donepezil and Irbesartan eutectic object
Infrared spectroscopy characteristic peak positions.The tolerance of its middle infrared spectrum characteristic peak is ± 2cm-1(Fig. 3).
1.4 donepezils of the present invention and Irbesartan eutectic object, when being analyzed using differential canning calorimetry, table
It is now when heating rate is 10 DEG C per minute, to contain 1 at 152 DEG C ± 3 DEG C in DSC map within the scope of 30~210 DEG C
A endothermic peak (Fig. 4).Donepezil, Irbesartan, eutectic object, physical mixture DSC Comparative map see Fig. 5.Donepezil
With the DSC map of Irbesartan eutectic object and the physical mixture of donepezil, Irbesartan and the two in suction/heat release peak number
There is notable difference in amount, position etc., show that donepezil and Irbesartan form new substance.
2. the preparation method characteristic of donepezil and Irbesartan eutectic object and hybrid solid substance:
The preparation method of 2.1 donepezils of the present invention and Irbesartan eutectic object, according to donepezil and shellfish in distress
The molar ratio of husky smooth 1:1 feeds intake, and prepares donepezil and Irbesartan using the mechanochemistry method of control pressure and temperature
Eutectic object.The mechanochemistry method is hand-ground or ball-milling method, preferred liquid feeding ball-milling method, wherein the ball of liquid feeding ball-milling method
Material is than being 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
Manufactured mixed solvent is combined through different ratio for any one or more；The organic solvent is selected from methanol, ethyl alcohol, positive third
Alcohol, isopropanol, n-butanol, the tert-butyl alcohol, amylalcohol, isoamyl alcohol, n-hexyl alcohol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxy six
Ring, tetrahydrofuran, chloroform, methylene chloride, dichloroethanes, ether, petroleum ether, water；Milling time is 0.1~10 hour.
The preparation method of 2.2 donepezils of the present invention and Irbesartan eutectic object, by donepezil and E Beisha
The smooth 1:1 of example in molar ratio, which feeds intake, to be put into clean container, organic solvent is added, suspension is made, be stirred at room temperature 6 hours~4 days,
Suspension obtained is spontaneously dried by solvent evaporation drying, filtering or filtering vacuum is dry obtains donepezil and E Beisha
Smooth eutectic object.The organic solvent preferably is 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, chloroform, methylene chloride, dichloroethanes, dioxane, tetrahydrofuran,
N-hexane, hexamethylene, in petroleum ether any one or more through different ratio combine made of mixed solvent；Keep it is more how piperazine
It is together within the scope of 1mg/ml~1000mg/ml with Irbesartan gross mass and organic solvent solid-to-liquid ratio.
The hybrid solid substance of 2.3 donepezils and Irbesartan eutectic object of the invention is to obtain above method preparation
Donepezil and Irbesartan eutectic object ingredient, with other chemical substances according to any non-zero proportions and conventional method into
Row mixing.
3. crystal form ingredient, dosage and the pharmaceutical preparations composition feature of donepezil and Irbesartan eutectic:
3.1 pharmaceutical compositions of the present invention contain donepezil and Irbesartan eutectic object and pharmaceutically acceptable
Carrier.
3.2 pharmaceutical compositions of the present invention, the hybrid solid substance containing donepezil Yu Irbesartan eutectic object
And pharmaceutically acceptable carrier.
The daily dosage of 3.3 pharmaceutical compositions of the present invention, donepezil and Irbesartan eutectic object exists
Within the scope of 5mg~1000mg.
3.4 compositions of the present invention, the dosage form of described pharmaceutical composition are various tablets, capsule, pill, injection
Preparation, sustained release preparation or controlled release preparation.
3.5 donepezils of the present invention are mixed with Irbesartan eutectic object, donepezil and Irbesartan eutectic object
It closes solid matter or pharmaceutical composition and is preparing various preventions and/or treatment heart failure, myocardial ischemia, hypertension, vascular
The cardiovascular diseases such as lesion, angina pectoris, hyperlipemia, atherosclerosis or diabetic complication and its neurodegenerative disease
Such as the application in Alzheimer disease and the concurrent disease medicament of above-mentioned a variety of diseases.
3.6 the present invention relates to a kind of pair of Treating CHF controlling based on donepezil and Irbesartan eutectic object
New strategy is treated, it is characterized in that reaching by the comprehensive effect for mitigating cardiac afterload and heart overload being inhibited to operate two aspects
Improve the purpose of cardiac function, the basis realized is that donepezil and Irbesartan eutectic object can play both sides simultaneously
Effect, and the change due to the present invention to absorption and blood concentration, reach optimal therapeutic effect.
The 3.7 treatment new strategies of the present invention to chronic heart failure, it is characterized in that Irbesartan passes through antagonism blood
Angiotensin II (AT) receptor plays expansion blood vessel, reduces blood pressure, mitigates cardiac afterload；Donepezil is by inhibiting acetyl
Cholinesterase improves parasympathetic nerve activity, improve failure heart sympathetic hyperfunction, and parasympathetic functions are low
Imbalance state promotes cardiac function reparation, reaches the inaccessiable therapeutic effect of other measures in treatment heart failure.
The 3.8 treatment new strategies of the present invention to chronic heart failure, it is characterized in that including Irbesartan
Other can reduce the similar drugs of afterload and improve secondary hand over the acetylcholinesterase that is able to suppress including donepezil
The drug for feeling neural activity forms application of the eutectic object in treatment heart failure.
The present invention relates to donepezil of the present invention and Irbesartan eutectic composition, donepezil of the present invention and Irbesartan
Pharmaceutical composition of the eutectic mixing crystal form solid matter as active ingredient.The pharmaceutical composition can be according to side well known in the art
Method preparation.It can be by by donepezil of the present invention and Irbesartan eutectic composition, donepezil of the present invention and Irbesartan eutectic
Crystal form solid matter is mixed in conjunction with one or more pharmaceutically acceptable solids or liquid excipient and/or adjuvant, is made
Any dosage form used suitable for human or animal.Donepezil of the present invention and Irbesartan eutectic composition, donepezil of the present invention and
Content of the Irbesartan eutectic mixing crystal form solid matter in its pharmaceutical composition is usually 0.1-95 weight %.
Donepezil of the present invention and Irbesartan eutectic object, donepezil of the present invention are solid with Irbesartan eutectic mixing crystal form
Body substance can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle or non-bowel, such as mouth
Clothes, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, 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,
Sustained release tablets, controlled release tablet, lozenge, dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule,
Capsulae enterosolubilis), granule, powder, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc..
Donepezil of the present invention and Irbesartan eutectic object, donepezil of the present invention are solid with Irbesartan eutectic mixing crystal form
Body substance 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 donepezil of the present invention is mixed with Irbesartan eutectic object, donepezil of the present invention with Irbesartan eutectic
Tablet is made in crystal form solid matter, and various excipient well known in the art, including diluent, adhesive, profit can be widely used
Humectant, disintegrating agent, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorb
Alcohol, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, ethyl alcohol, isopropanol etc.；It is viscous
Mixture can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, mucialga of arabic gummy, gelatine size, carboxylic first
Base sodium cellulosate, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyethylene pyrrole
Pyrrolidone, polyethylene glycol etc.；Disintegrating agent can be dried starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyethylene
Pyrrolidones, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol rouge
Fat acid esters, 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.
It, can be by effective component donepezil of the present invention and Irbesartan eutectic in order to which capsule is made in administration unit
Object, donepezil of the present invention are mixed with Irbesartan eutectic mixing crystal form solid matter with diluent, glidant, and mixture is straight
It connects and is placed in hard capsule or soft capsule.It can also be by effective component donepezil of the present invention and Irbesartan eutectic composition, the present invention
Particle or pellet first is made with diluent, adhesive, disintegrating agent with Irbesartan eutectic mixing crystal form solid matter in donepezil,
It is placed in hard capsule or soft capsule again.Be used to prepare donepezil of the present invention and Irbesartan eutectic composition, the present invention it is more how piperazine
Together with various diluents, adhesive, wetting agent, disintegrating agent, the glidant of Irbesartan eutectic mixing crystal form solid matter tablet
Kind can also be used for preparing donepezil of the present invention and Irbesartan eutectic object, donepezil of the present invention and Irbesartan eutectic are mixed
The capsule of synthetic type solid matter.
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 or pharmaceutical composition well known can be given with any
The administration of prescription method.
The dosage of donepezil of the present invention and Irbesartan eutectic medicine composition is according to being prevented or be treated
The individual instances of the property and severity of disease, patient or animal, administration route and dosage form etc. can have large-scale variation.
Above-mentioned dosage with a dosage unit or can be divided into several dosage unit administrations, this depend on doctor clinical experience and including
With the dosage regimen of other treatment means.
Donepezil of the present invention can individually be taken with Irbesartan eutectic object or composition, or with other treatment drug or right
Disease drug, which merges, to be used.When donepezil of the present invention and Irbesartan 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 donepezil and Irbesartan eutectic object
Activity advantage feature.
4.1 donepezils and Irbesartan eutectic object of the invention are free of any recrystallisation solvent, have good safety
Patent medicine advantage.
4.2 donepezils and Irbesartan eutectic object of the invention dissolve out system in water and 0.5% lauryl sodium sulfate
In show patent medicine advantage (Fig. 6) better than Irbesartan.
4.3 donepezils of the present invention and Irbesartan eutectic object (referred to as: eutectic), have any different in donepezil,
Irbesartan is used alone and is used in mixed way metabolic characteristic in animal body；With the physical mixed of donepezil and Irbesartan
Object (referred to as: physical mixture) is compared, and under identical dosage, there is higher bioavilability and blood concentration；With mostly how
The neat raw material of piperazine is compared with the physical mixture of Irbesartan raw material, and the pharmacokinetics such as bioavilability improve in animal body,
Can reach higher blood concentration and AUC (Fig. 7, Fig. 8) in vivo, be more advantageous to cardiovascular and neurodegenerative disease treatment and
Prevention；Compared with donepezil and Irbesartan monomeric compound, animal body intracellular metabolite half-life period, the pharmacokinetics such as peak time
Parameter significantly improves, and wherein donepezil half-life period significantly extends, and can more effectively promote parasympathetic nerve excitability, and improvement declines
Exhaust cardiac sympathetic nerve hyperfunction, the low imbalance state of parasympathetic functions；Irbesartan half-life period significantly extends, can
Renin-Angiotensin System excitability in more effective control volume mitigates cardiovascular system pressure, painstaking effort in advantageous protective
Guard system tissue and organ are conducive to cardiovascular and neurodegenerative disease treatment and prevention.
Detailed description of the invention
The x-ray diffractogram of powder of Fig. 1 donepezil and Irbesartan eutectic object is composed
The x-ray diffractogram of powder of the physical mixture of Fig. 2 donepezil and Irbesartan is composed
The infrared absorpting light spectra of Fig. 3 donepezil and Irbesartan eutectic object
The Differential Scanning Calorimetry of Fig. 4 donepezil and Irbesartan eutectic object
Fig. 5 donepezil and the differential of Irbesartan eutectic object and donepezil, Irbesartan, the two physical mixture are swept
Retouch calorimetric comparison map
The dissolution curve of Fig. 6 donepezil and Irbesartan eutectic object and Irbesartan
Fig. 7 donepezil and Irbesartan eutectic object and physical mixture are in the intracorporal blood concentration-time curve of rat
Fig. 8 donepezil and Irbesartan eutectic object and the physical mixture area under the drug-time curve in rat body
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
Donepezil and Irbesartan eutectic object preparation method 1:
According to shown in following table, taking donepezil and Irbesartan to be in right amount that 1:1 is put into mortar according to molar ratio, it is added suitable
Measure solvent, underhand polish appropriate time.Powder x-ray diffraction analysis is carried out to it, diffracting spectrum is consistent with Fig. 1, shows institute
Obtaining sample is donepezil and Irbesartan eutectic object.
Donepezil and Irbesartan eutectic object preparation method 2:
According to shown in following table, taking donepezil and Irbesartan 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 donepezil and Irbesartan eutectic object.
Donepezil and Irbesartan eutectic object preparation method 3:
According to shown in following table, taking donepezil and Irbesartan 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 donepezil and Irbesartan eutectic object.
Embodiment 2
The In Vitro Dissolution release characteristic of donepezil and Irbesartan eutectic object
It is water-soluble in aqueous solution and 0.5%SDS with Irbesartan bulk pharmaceutical chemicals with Irbesartan eutectic object donepezil has been investigated
Dissolubility feature in 2 systems of liquid.It is measured referring to " normal oral solid pharmaceutical preparation Dissolution Rate Testing technological guidance principle ", dissolution
Curve compares using model dependent/non-dependent similar factors (f2) method, by the calculating of f2 value compare raw material and physical mixture and
The similitude of donepezil and Irbesartan eutectic object sample solubility curve in 2 kinds of vehicle systems, when f2 value be higher than 50, then recognize
It is similar for two curves, when f2 value thinks that the two has differences lower than 50.Experiment is calculated using Irbesartan sample as reference
Model dependent/non-dependent similar factors f2 value.Percentage composition is dissolved using high-efficient liquid phase technique is used, its is calculated with external standard method and dissolves percentage
Content.Using the time as abscissa, dissolution percentage composition is that ordinate draws solubility curve (Fig. 6) respectively.Data are shown in Table 3,4.
Testing conditions: detection system: Aligent 1200, chromatographic column: Agilent Eclipse XDB-C18 (4.6 ×
250mm,5μm)；Mobile phase: -0.1% phosphoric acid water of acetonitrile (40:60, v/v)；Flow velocity: 1mLmin-1；Column temperature: 25 DEG C；Detect wave
It is long: Irbesartan: 220nm；Sample volume: 10 μ l.
The dissolution curve data (dissolution medium: water) of 3 donepezil of table and Irbesartan eutectic object Irbesartan
Dissolution curve data (the dissolution medium: 0.5% dodecyl sulphate of 4 donepezil of table and Irbesartan eutectic object
Sodium)
Dissolution is the results showed that donepezil is shown in above two digestion series with Irbesartan eutectic object
Faster dissolution rate also has bigger the amount of dissolution compared with Irbesartan bulk pharmaceutical chemicals in water, has apparent dissolubility patent medicine
Advantage.
3 donepezil of embodiment and Irbesartan eutectic object are in rat body absorption feature and blood concentration feature:
The animal body intracellular metabolite feature of donepezil and Irbesartan eutectic object according to the present invention, including following mistake
Journey:
By 9 SD rats, it is randomly divided into 3 groups, every group 3.12h is deprived of food but not water before being administered.Rat body weight is weighed, is pressed
The Irbesartan dosage of 100mgkg-1 calculates, by the physical mixture and Irbesartan of donepezil and Irbesartan
Raw material, donepezil and Irbesartan eutectic object sample are packed into solid form delivery device, and medicinal powder is directly placed in rat by oral cavity
In stomach.Respectively after administration 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours,
6 hours, 9 hours, 12 hours and 24 hours eyes are bared veniplex blood sampling and are set in test tube of hepari pipe, and 4 DEG C, 4000rpm centrifugation 10min freeze
It is stored in be measured in -40 DEG C of refrigerators.Precision measures 100 μ L of rat plasma, adds 100 μ L of inner mark solution, ethyl acetate 1.2mL, vibrates
It is sufficiently mixed sample within 5 minutes, 12800rpm is centrifuged 10 minutes, supernatant is taken, with N2Air-blowing is dry, adds 100 μ L ethyl acetate multiple
Molten sample takes 90 μ L of supernatant, sample detection after centrifugation.
Chromatographic condition: using -0.1% phosphate aqueous solution of acetonitrile as mobile phase, gradient elution, elution requirement such as following table institute
Show:
Different samples are shown in Table 5 in the intracorporal donepezil pharmacokinetic data of rat, Valsartan pharmacokinetics
Parameter is shown in Table 6, and as shown in Figure 7, area under the drug-time curve (AUC) Comparative map is shown in Fig. 8 institute to blood concentration-time curve
Show.Donepezil is improved in rat vivo biodistribution availability compared with physical mixture with Irbesartan eutectic object.With reach peak
Time is long, and blood concentration is high, acts on the dominant feature of prolonged plateau.
5 donepezil pharmacokinetic parameter table of table
6 Irbesartan pharmacokinetic parameter table of table
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 donepezil and Irbesartan eutectic object sterling,
Or the mixed crystal solid matter for containing brilliant II type of arbitrary proportion as composition of medicine bulk pharmaceutical chemicals, use several excipient as preparing
The adjunct ingredient of composition of medicine tablet, every content of dispersion is made in the tablet samples of 5~500mg, table in proportion according to a certain percentage
7 provide tablet formulation ratio:
The preparation formula of 7 donepezil of table and Irbesartan eutectic object composition of medicine tablet
It is using the method that donepezil is prepared into tablet formulation as bulk pharmaceutical chemicals with Irbesartan 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 donepezil and Irbesartan 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 8 provide tablet formulation ratio:
The preparation formula of 8 donepezil of table and Irbesartan eutectic object composition of medicine tablet
It is using the method that donepezil is prepared into tablet formulation as bulk pharmaceutical chemicals with Irbesartan 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 pure using donepezil and Irbesartan eutectic object substance
Product or the mixed crystal solid matter for containing brilliant II type of arbitrary proportion as composition of medicine bulk pharmaceutical chemicals, use several excipient as
The adjunct ingredient of composition of medicine capsule is prepared, every content of dispersion is made in the capsule-like of 10~500mg in proportion according to a certain percentage
Product, table 9 provide capsule formula ratio:
The bulk pharmaceutical chemicals and accessory formula of 9 donepezil of table and Irbesartan eutectic object composition of medicine capsule preparations
By mixed crystal bulk pharmaceutical chemicals system of the donepezil with Irbesartan eutectic object substance sterling or containing brilliant II type of arbitrary proportion
It is standby to be at the method for tablet formulation: several excipient being uniformly mixed with bulk pharmaceutical chemicals, it is suitable that 1% sodium cellulose glycolate solution is added
Amount is made wet grain drying sieving whole grain, magnesium stearate is added and is uniformly mixed, insertion capsule is made；Or granulation step is not used, and
Directly donepezil is uniformly mixed with Irbesartan eutectic object raw material of substance medicine with several excipients, after sieving, directly
Capsule is packed into be made.
Embodiment 5
The dosage 1 (tablet) of donepezil and Irbesartan eutectic object composition of medicine:
The pharmaceutical composition for using donepezil and Irbesartan eutectic object sample to manufacture as active pharmaceutical ingredient,
It is characterized in that using donepezil and Irbesartan eutectic object as the active constituent of 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 donepezil and Irbesartan eutectic object composition of medicine:
The pharmaceutical composition for using donepezil and Irbesartan eutectic object sample to manufacture as active pharmaceutical ingredient,
It is characterized in that using donepezil and Irbesartan eutectic object as the active constituent of drug, being administered daily dosage is 1200mg,
It can be prepared into 3 times a day/100mg capsule 4 tablets each time respectively, or 2 times a day/300mg capsule 2 tablets each time.
Need the problem of illustrating: donepezil of the present invention and Irbesartan 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；Between crystal form samples it is existing absorb it is different with blood concentration etc.,
It is 0.1-10mg/kg that the present invention, which is also resulted in, in each Suitable dosage ranges using donepezil and Irbesartan eutectic object ingredient
Weight, preferably 0.2-5mg/kg weight.Should be formulated according to actual treatment different situations demand when use it is different it is more how piperazine
Together with Irbesartan eutectic object substance effective component accumulated dose scheme, and can be divided into multiple or single administration mode completion.
Bibliography
[1] Chen Xinqian, Jin Youyu, Tang Guang edit the 16th edition People's Health Publisher .2007:402. of new pharmacology
[2]Tapan Behl,Anita Kotwani,Potential of angiotensin II receptor
blockers in the treatment of diabetic retinopathy,Life Sciences,2017,176:1-9,
[3] Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E,
Atkins RC, Rohde R, Raz I；Collaborative Study Group.Renoprotective effect of
the angiotensin-receptor antagonist irbesartan in patients with nephropathy
Due to type 2diabetes.N Engl J Med.2001,345 (12): 851-60.
[4] Fang Yu, Yan Ji amiodarone and Irbesartan are combined to the treatment after sick sinus syndrome cardiac pacing
Imitate Chinese Clinical Health Care .2008,11 (1): 25-26.
[5]Park Y,Lee J,Sun H L,et al.Crystal Structures of Tetramorphic
Forms of Donepezil and Energy/Temperature Phase Diagram via Direct Heat
Capacity Measurements[J]. Crystal Growth&Design,2013,13(12):5450-5458.
[6] Chinese patent CN201310446196.2
[7] Chinese patent CN201510175133.7.
Claims (18)
1. a kind of donepezil and Irbesartan eutectic object, which is characterized in that donepezil and Irbesartan are with 1:1 molar ratio shape
At eutectic object.
2. donepezil according to claim 1 and Irbesartan eutectic object, which is characterized in that without containing recrystallisation solvent or
Crystalline water content, when using CuK α radiation experiments condition using powder x-ray diffraction analysis, diffraction maximum position 2-Theta value
(°) or d valueDiffraction maximum relative intensity peak value Height% or peak area value Area% have following indicate:
3. donepezil according to claim 1 and Irbesartan eutectic object, which is characterized in that use decaying total reflection Fu
When vertical leaf infra-red sepectrometry is analyzed, 3613,3424,3052,2948,2870,2331,1723,1690,1625,1605,
1592、1500、1455、1440、1404、1344、1317、1286、1266、1219、1199、1157、1124、1111、1072、
1038、1011、949、928、907、835、820、770、753、707cm-1There are infrared spectroscopy characteristic peak, middle infrared spectrums at place
The tolerance of characteristic peak is ± 2cm-1。
4. donepezil according to claim 1 and Irbesartan eutectic object, which is characterized in that use differential scanning calorimetry
It when technology is analyzed, shows as within the scope of 30~210 DEG C, when heating rate is 10 DEG C per minute, at 152 DEG C in DSC map
There are 1 endothermic peaks at ± 3 DEG C.
5. the preparation method of donepezil of any of claims 1-4 and Irbesartan eutectic object, which is characterized in that
It feeds intake according to donepezil and Irbesartan by the molar ratio of 1:1, using the mechanochemistry method system of control pressure and temperature
Standby donepezil and Irbesartan eutectic object.
6. preparation method according to claim 5, the mechanochemistry method is hand-ground or ball-milling method.
7. preparation method according to claim 5, the mechanochemistry method is selected from liquid feeding ball-milling 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, chloroform, methylene chloride, dichloroethanes, ether, petroleum ether, water；Milling time is 0.1~10
Hour.
8. the preparation method of donepezil of any of claims 1-4 and Irbesartan eutectic object, which is characterized in that
By donepezil and Irbesartan, example 1:1 feeds intake and is put into clean container in molar ratio, organic solvent is added, suspension is made, stir
It mixes 6 hours~4 days, suspension obtained is spontaneously dried by solvent evaporation drying, filtering or the dry acquisition of filtering vacuum is more
Donepezil and Irbesartan eutectic object.
9. donepezil according to claim 8 and Irbesartan eutectic object preparation method, the organic solvent are 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, second
It is acetoacetic ester, chloroform, methylene chloride, dichloroethanes, dioxane, tetrahydrofuran, n-hexane, hexamethylene, any in petroleum ether
It is one or more to combine manufactured mixed solvent through different ratio；Keep donepezil and Irbesartan gross mass and organic solvent
Solid-to-liquid ratio is within the scope of 1mg/ml~1000mg/ml.
10. the hybrid solid substance of a kind of donepezil and Irbesartan eutectic object, which is characterized in that contain claim 1-4
The amount of described in any item donepezils and Irbesartan eutectic object is 1-99.9%, preferably 10-99.9%, further preferably for
50-99.9%, most preferably 85-99.9%.
11. a kind of pharmaceutical composition, which is characterized in that the salt of any one of claim 1-4 containing effective dose mostly how piperazine
Together with Irbesartan eutectic object and pharmaceutically acceptable carrier.
12. a kind of pharmaceutical composition, which is characterized in that the donepezil as claimed in claim 9 containing effective dose and shellfish in distress
Husky smooth 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 donepezil and Irbesartan eutectic
The daily dosage of the adult of object is within the scope of 5~1000mg.
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. donepezil of any of claims 1-4 and Irbesartan eutectic object or described in any one of claim 10 more
Donepezil is being made with Irbesartan eutectic object hybrid solid substance or the described in any item pharmaceutical compositions of claim 11 or 12
Application in the standby drug for preventing or treating cardiovascular disease or neurodegenerative disease or above-mentioned a variety of disease complications.
16. application according to claim 15, which is characterized in that the cardiovascular disease include heart failure, myocardial ischemia,
Hypertension, vascular lesions, angina pectoris, hyperlipemia, atherosclerosis or diabetic complication；The nervus retrogression
Disease includes Alzheimer disease.
17. application according to claim 16, which is characterized in that prevention or treatment heart failure disease be by and meanwhile mitigate the heart
Dirty afterload and inhibition heart overload operate two aspects and play a role.
18. application according to claim 17, which is characterized in that the mitigation cardiac afterload is to pass through antagonizing angiotensin
II (AT) receptor plays expansion blood vessel, reduces blood pressure and realize；Inhibiting heart overload operating is by inhibiting acetylcholine ester
Enzyme improves parasympathetic nerve activity, improves the low unbalance shape of failure heart sympathetic hyperfunction, parasympathetic functions
State promotes cardiac function reparation and realizes.
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|---|---|---|---|---|
| CN103497179A (en) * | 2013-09-26 | 2014-01-08 | 郑州大学 | Pyrimidine derivatives with benzimidazole structural units as well as preparation method and application thereof |
| CN106146471A (en) * | 2015-04-15 | 2016-11-23 | 苏州朗科生物技术有限公司 | A kind of Irbesartan compound of double action |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497179A (en) * | 2013-09-26 | 2014-01-08 | 郑州大学 | Pyrimidine derivatives with benzimidazole structural units as well as preparation method and application thereof |
| CN106146471A (en) * | 2015-04-15 | 2016-11-23 | 苏州朗科生物技术有限公司 | A kind of Irbesartan compound of double action |
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| YEOJIN PARK，等: "Crystal Structures of Tetramorphic Forms of Donepezil and Energy/ Temperature Phase Diagram via Direct Heat Capacity Measurements", 《CRYSTAL GROWTH & DESIGN》 * |
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