CN107205982A - A kind of medical composition and its use of chromocor compound - Google Patents
A kind of medical composition and its use of chromocor compound Download PDFInfo
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- CN107205982A CN107205982A CN201680006886.8A CN201680006886A CN107205982A CN 107205982 A CN107205982 A CN 107205982A CN 201680006886 A CN201680006886 A CN 201680006886A CN 107205982 A CN107205982 A CN 107205982A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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Abstract
A kind of pharmaceutical composition fixed containing A Kela, the pharmaceutical composition is self-emulsifying formulation, and self-emulsifying forms O/W type nano-emulsions to said composition in vivo after oral administration, and the particle size range of nano-emulsion is 10 200nm.
Description
The present invention relates to a kind of pharmaceutical composition of chromocor compound, the purposes of the pharmaceutical composition belongs to field of medicaments.
Chromocor compound is that one kind is present in nature, a kind of compound with 2- phenyl chromone structure.Existing research proves that chromocor compound has cardiovascular system activity, antibacterial, antiviral activity and anti-tumor activity.
A Kelading also known as icariine, epimedium aglucone, belong to chromocor compound.A Kelading is the new effective monomer for extracting isolated main active icariin from Herba Epimedii and obtaining through enzymatic conversion, and structure is shown below:
Proposing in the Chinese patent application application No. is 200780039276.9 has the purposes prepared in abnormal cell proliferation, especially cancer drug with the flavone compound that A Kela is set to representative.Application of this flavonoids in preparation selective estrogen receptor modulators is proposed in the Chinese patent application No. is 03129242.9.
However, applicant is when exploitation is set to the flavone compound of representative with A Kela, such compound structure such as formula (I) is shown:
Wherein R is selected from hydrogen, (C1-C4) alkyl, (C1-C4) the alkoxy, (C containing the substitution of one or more halogen atoms1-C4) alkyl, halogen, cyano or the (C replaced containing one or more halogen atoms1-C4) alcoxyl
Base.It is found by the applicant that this kind of compound generally has dissolubility in water poor, the low-down defect of bioavilability is administered orally.This defect constrains making full use of for the above chromocor compound.Therefore, it is necessary to a kind of pharmaceutical compositions for being suitable for the flavone compound as shown in above formula (I), which can be improved the bioavilability of the above drug, and production cost is low, are suitable for industrial production.
Summary of the invention
It is an object of the present invention to provide a kind of chromocor compound pharmaceutical composition, which overcomes that existing chromocor compound pharmaceutical composition bioavilability is low, and high production cost, large-scale production degree is low, the defect of stability difference.
It is a further object of the present invention to provide purposes of the chromocor compound pharmaceutical composition of the present invention in the drug that preparation has related disorders for anti-cell abnormality proliferation.
Another object of the present invention is to provide the drug that a kind of anti-cell abnormality proliferation has related disorders, includes pharmaceutical composition of the invention in the drug.
One aspect of the present invention provides a kind of pharmaceutical composition of chromocor compound, the pharmaceutical composition is self-emulsifying dosage form, self-emulsifying forms O/W type nano-emulsion in vivo after oral administration, the particle size range for forming nano-emulsion in vivo is 10-200nm, and the chromocor compound is the compound for the formula that has following structure:
R is selected from hydrogen, (C1-C4) alkyl, (C1-C4) the alkoxy, (C containing the substitution of one or more halogen atoms1-C4) alkyl, halogen, cyano or the (C replaced containing one or more halogen atoms1-C4) alkoxy.
Preferably, the chromocor compound is the compound for the formula that has following structure:
The R is selected from trifluoromethyl, methyl, ethyl or methoxyl group.
Preferably, the drugloading rate of chromocor compound is 2-30% in described pharmaceutical composition.
Preferably, the pharmaceutical composition includes chromocor compound, oil phase solvent, emulsifier, assistant for emulsifying agent and antioxidant.
Preferably, the mass ratio of the oil phase solvent in described pharmaceutical composition, emulsifier and assistant for emulsifying agent is 1.0:0.7-5.0:1.0-5.0.
Most preferably, the mass ratio of the oil phase solvent in the pharmaceutical composition, emulsifier and assistant for emulsifying agent is 1.0:2.0-3.0:1.5-3.0.
Preferably, the pharmaceutical composition further includes pH adjusting agent.
It is highly preferred that the pH adjusting agent is one or more of citric acid, malic acid and tartaric acid.
Preferably, the emulsifier is the emulsifier of HLB value 12-17.
Most preferably, the emulsifier is the emulsifier of HLB value 14-15.
Preferably, the emulsifier can dissolve the chromocor compound.
Preferably, by quality ratio, the emulsifier is the 20-60% of pharmaceutical composition amount of substance.
Most preferably, by quality ratio, the emulsifier is the 40-45% of pharmaceutical composition amount of substance.
Preferably, the emulsifier is nonionic surfactant.
It is highly preferred that the emulsifier includes selected from one or more of Crodaret, Solutol HS15, hexadecanol and octadecyl alcolol.
Preferably, the oil phase solvent can dissolve the chromocor compound.
Preferably, the oil phase solvent includes selected from one or more of soybean oil, peanut oil, corn oil, castor oil, olive oil, peppermint oil, oleic acid, rapeseed oil, sesame oil, rilanit special, ethyl oleate, olein, glyceryl linoleate, Miglyol 812, isopropyl myristate, isopropyl palmitate, Vitwas E, Sefsol 218, propene carbonate and median chain triglyceride oil.
Preferably, the assistant for emulsifying agent can dissolve the chromocor compound.
Preferably, the assistant for emulsifying agent is alcohols solvent.
Preferably, the assistant for emulsifying agent includes being selected from one or both of isopropanol, ethyl alcohol, polyhydroxy-alcohol.
Preferably, the polyhydroxy-alcohol includes selected from one or more of polyethylene glycol, diethylene glycol monoethyl ether, glycerol and propylene glycol.
The polyethylene glycol includes being selected from polyethylene glycol 200, Liquid Macrogol, polyethylene glycol 400, Macrogol 600, polyethylene glycol 900, cetomacrogol 1000, polyethylene glycol 1500 and polyethylene glycol 2000
One or more.
Another aspect of the present invention additionally provides the purposes of pharmaceutical composition of the invention in the drug that preparation has related disorders for anti-cell abnormality proliferation.
Further aspect of the present invention additionally provides the drug that a kind of anti-cell abnormality proliferation has related disorders, includes pharmaceutical composition of the invention in the drug.
Preferably, the drug is oral preparation or injection.
The oral preparation includes that one of soft capsule, hard capsule, oral solution and suspension are several.
The beneficial effects of the present invention are the present invention overcomes existing chromocor compounds in water with the characteristic that is all difficult to dissolve in oil, and chromocor compound has been made to the mode of self-emulsifying dosage form, has substantially increased the bioavilability of chromocor compound in animal body.This pharmaceutical composition of the invention simultaneously also has the advantages that long shelf-life, all shows good stability in acid, alkalinity, illumination and oxidation experiment.
Fig. 1 shows the pharmaceutical compositions of prescription 1 with 40mg/kg dosage feeding beasle dog, obtained individual and mean blood plasma concentration.
The pharmaceutical composition of Fig. 2 expression prescription 4 is with 40mg/kg dosage feeding beasle dog, obtained individual and mean blood plasma concentration.
Fig. 3 expression 9 A Kelading pharmaceutical composition of prescription is with 40mg/kg dosage feeding beasle dog, obtained individual and mean blood plasma concentration.
Fig. 4 indicates dissolution curve of 3 prescription of embodiment, 1 soft capsule at 40 DEG C, 0 day, 2 weeks and 1 month.
Following embodiment is only used for illustrating the present invention, is not used in the limitation present invention, modification, change, modification for being made in the scope of the present invention etc. are all within the scope of the present invention.
Unless otherwise stated, term " nano-emulsion " herein is also known as " microemulsion ", be the partial size spontaneously formed by water phase, oily phase, surfactant and cosurfactant etc. is nanoscale Thermodynamically stable, isotropism, transparent or translucent homogeneous dispersion system.Common nano-emulsion is divided into three types, it may be assumed that oil-in-water type nano-emulsion, water-in-oil type nanoemulsion and bicontinuous nano-emulsion.
Unless otherwise stated, term herein " self-emulsifying " refer to pharmaceutical composition of the invention by oral administration afterwards meet body fluid can be automatic emulsified.
Unless otherwise stated, term herein " O/W type nano-emulsion " refers to pharmaceutical composition of the invention after oral administration, encounter body fluid can self-emulsifying form O/W type nano-emulsion, while improving bioavilability.
Unless otherwise stated, " drugloading rate " herein, which is calculated by the following formula, obtains: quality/pharmaceutical composition gross mass of the active pharmaceutical ingredient in drugloading rate=pharmaceutical composition.
Unless otherwise stated, " HLB value " herein refers to hydrophilic lipophilic balance, it is used to indicate the difference of emulsifier ability.If HLB is bigger, hydrophilic interaction is bigger, can stabilised oil-in-water emulsified body；Conversely, HLB is smaller, then oleophilic function is bigger, can stablize water-in-oil emulsion system.
Unless otherwise stated, " emulsifier " herein refers to a kind of surfactant.When it is dispersed in dispersate surface, film or electric double layer are formed, dispersed phase can be made with charge, therefore can prevent to condense mutually between dispersed phase droplet, to form stable emulsion.
Unless otherwise stated, " nonionic surfactant " herein does not dissociate when referring to being dissolved in water, lipophilic group in its molecule is roughly the same with the lipophilic group of ionic surfactant, and hydrophilic radical with a certain number of oxygen-containing groups, such as hydroxyl mainly by constituting.
Unless otherwise stated, " median chain triglyceride oil " herein is extracted from coconut oil or from palm oil.They are the mixtures of saturated triglycerides, and important is octanoic acid (C for the acid being connected with glycerol8H16O2) and certain herbaceous plants with big flowers acid (C10H20O2), their content is not less than 95%.
Unless otherwise stated, " polyoxyethylene (40) rilanit special (Cremophor RH40) " herein CAS is 61788-85-0, and place of production BASF AG buys from Wuhan Xin great Di environment-friendly materials Co., Ltd.
Unless otherwise stated, " Vitwas E " herein is produced by BASF AG, is purchased from Guangzhou Fei Rui Chemical Co., Ltd..
Unless otherwise stated, " Solutol HS15 " place of production BASF AG herein buys from Wuhan Xin great Di environment-friendly materials Co., Ltd.
Unless otherwise stated, " median chain triglyceride oil " herein is purchased from Shanghai Ju Hui International Trading Company Ltd, brand Ireland triumphant auspicious (kerry), article number 102148027.
Unless otherwise stated, " single diglyceride " herein is purchased from Alpert (Arbitec) company, CAS 26402-26-6.
Unless otherwise stated, " propene carbonate " herein is purchased from Tai'an Zi Xin Chemical Co., Ltd.,
No. CAS: 108-32-7.
Unless otherwise stated, " diethylene glycol monoethyl ether " herein is purchased from Sinopharm Chemical Reagent Co., Ltd., article number 30059328.
Embodiment 1
The preparation of A Kelading
A Kelading also known as icariine, be extracted from Herba Epimedii it is isolated.
The preparation method of icariine is disclosed in the patent of Publication No. CN 101302548.This method is hydrolyzed using icariin as raw material with beta-glucosidase, and the precipitating acetone solution that hydrolysate is centrifuged, centrifugal filtration obtains supernatant.The supernatant that centrifugation obtains is recrystallized with water again, obtains icariine sterling, icariine sterling is in yellow powder crystal.Icariin in the present invention is purchased from company, Shanxi Jiahe Plant Chemical Co., Ltd., purity 90%.
Embodiment 2
The preparation of formula (I) compound
The preparation route such as scheme 1 of formula (I) compound:
In the method, P is blocking group, and the reaction of the first step is techniques well known, is being applied
It is number to have a detailed description in specification page 12 of 200610165354.7 disclosures, this method is incorporated herein by reference.
Compound vi is can be obtained into the protecting group removing of compound v.According to protecting group difference, the method for removal also corresponding change, referring primarily to " blocking group in organic synthesis ", (Greene T.W etc. is write.John Wiley&Sons, New York, 1991) method therein.Preferably protecting group is benzyl, benzoyl, benzyloxycarbonyl group, TBDMS (t-Butyldimethylsilyl), THP (THP trtrahydropyranyl), methyl, MOM (methoxy), PMB (to methoxy-benzyl) etc..
Compound vi reacts under alkaline condition with isoprenyl bromide, can prepare compound viii.The solvent for being applicable in the reaction includes: methanol, DMF (N, dinethylformamide), THF (tetrahydrofuran), water, toluene, DME (1,2- dimethoxy-ethane) and mixed solvent, such as methanol-water, DMF- water, tetrahydrofuran-water.The solvent used in the reaction is preferably water.Alkali suitable for the reaction includes: such as potassium hydroxide, potassium carbonate, cesium carbonate, sodium methoxide, sodium hydride, potassium tert-butoxide, DBU (1,8- diazabicylo-bicyclic (5,4,0) -7- hendecene), n-BuLi, LDA (lithium diisopropylamine), LHMDS (lithium hexamethyldisilazide) etc., for reaction temperature usually between about 0-100 DEG C, the reaction time is 1-20 hours.
Wherein formula (i) compound phloroglucin is purchased from Yi Nuokai (Acros) company, article number 131040250.
Embodiment 3
Prescription 1
Wherein the structural formula of active constituent is as follows:
The preparation of formula (II) compound
Formula (II) compound is according to 1 preparation route of scheme, and wherein P is methyl, compoundPurchased from Yi Nuokai (Acros) company, article number 125660050；CompoundPurchased from Yi Nuokai (Acros) company, article number 303420010.Formula (II) compound can also be prepared according to method disclosed in WO2013104263 embodiment 1.
1 preparation method of prescription
1. weighing the citric acid of recipe quantity, BHA and BHT in suitable container, ethyl alcohol is then added, dissolves solid all.
2. Cremophor RH40 is heated to 40 DEG C, melting it is that liquid sequentially adds the oleic acid of recipe quantity and the fluid sample of PEG400 then in ethanol solution, and is uniformly dispersed into uniform liquid solution.
3. weighing formula (II) compound of recipe quantity, it is added in above-mentioned solution system under agitation, it makes it completely dissolved, obtain the solution of yellow transparent, it may be necessary to disperse using ultrasound, high speed shear or be heated to the modes such as 40 DEG C to accelerate the dissolution of formula (II) compound.
4. including into soft capsule or being packed into hypromellose (HPMC) hard capsule case and seal above-mentioned solution.
Embodiment 4
Prescription 2
Wherein the molecular structural formula of active constituent is as follows:
The preparation of formula (III) compound
Formula (III) compound is according to 1 preparation route of scheme, and wherein P is methoxy, compoundPurchased from grace wheat (Enamine) company, article number EN300-134167；CompoundPurchased from Yi Nuokai (Acros) company, article number 147980010.
2 preparation method of prescription
The preparation method of the present embodiment and the preparation method of embodiment 3 are close, the difference is that with the oleic acid in Vitwas E alternate embodiment 3 in the present embodiment.
Embodiment 5
Prescription 3
Wherein the structural formula of active constituent is as follows:
The preparation of formula (IV) compound
Formula (IV) compound is according to 1 preparation route of scheme, and wherein P is methoxy, and formula (ii) compound is identical as formula (ii) compound of embodiment 4；CompoundPurchased from Yi Nuokai (Acros) company, article number 305730050.
3 preparation method of prescription
The preparation method of the present embodiment and the preparation method of embodiment 3 are close, unlike in the present embodiment with the oleic acid in Vitwas E alternate embodiment 3, and with polyoxyethylene (40) rilanit special in Solutol HS15 alternate embodiment 3.
Embodiment 6
Prescription 4
Wherein the structural formula of active constituent is as follows:
The preparation of formula (V) compound
Formula (V) compound is according to 1 preparation route of scheme, and wherein P is methoxy, this implementation formula (ii) compound is identical as formula (ii) compound of embodiment 4；CompoundPurchased from Yi Nuokai (Acros) company, article number 153410050.
4 preparation method of prescription
The preparation method of the present embodiment and the preparation method of embodiment 3 are close, the difference is that with the oleic acid in median chain triglyceride oil alternate embodiment 3 in the present embodiment.
Embodiment 7
Prescription 5
Wherein the structural formula of active constituent is as follows:
The preparation of formula (VI) compound
Formula (VI) compound is according to 1 preparation route of scheme, and wherein P is methoxy, and the present embodiment formula (II) compound is identical as formula (II) compound of embodiment 4, compoundPurchased from Acros company, article number 105750010.
Preparation method
The preparation method of the present embodiment and the preparation method of embodiment 3 are close, the difference is that with the oleic acid in single diglyceride alternate embodiment 3 in the present embodiment.
Embodiment 8
Prescription 6
Wherein the structural formula of active constituent is as follows:
The preparation of formula (VII) compound
Formula (VII) compound is according to 1 preparation route of scheme, and wherein P is methoxyl methyl, and the present embodiment formula (ii) compound is identical as embodiment 4 formula (ii) compound, compoundPurchased from Acros company, article number 306350010.
6 preparation method of prescription
The preparation method of the preparation method of the present embodiment and embodiment 3 is close, unlike in the present embodiment with the oleic acid in propene carbonate alternate embodiment 3, and with the polyethylene glycol (PEG400) in diethylene glycol monoethyl ether alternate embodiment 3.
Embodiment 9
Prescription 7
Wherein the structural formula of active constituent is as follows:
The preparation of formula (VIII) compound
Formula (VIII) compound is according to 1 preparation route of scheme, and wherein P is methoxyl methyl, and the present embodiment formula (II) compound is identical as embodiment 4 formula (II) compound, compoundPurchased from Acros company, article number 154550050.
7 preparation method of prescription
The preparation method of the present embodiment and the preparation method of embodiment 3 are close, the difference is that with the polyethylene glycol (PEG400) in diethylene glycol monoethyl ether alternate embodiment 3 in the present embodiment.
Embodiment 10
Prescription 8
Wherein the structural formula of active constituent is as follows:
The preparation of formula (IX) compound
Formula (IX) compound is according to 1 preparation route of scheme, and wherein P is methoxyl methyl, and the present embodiment formula (ii) compound is identical as embodiment 4 formula (ii) compound, compoundPurchased from Acros company, article number 212970050.
8 preparation method of prescription
1. by oleic acid and propylene glycol solution, sequentially add the active constituent of recipe quantity and the fluid sample of polyoxyethylene (40) rilanit special PEG400, it is added in above-mentioned solution system under agitation, it makes it completely dissolved, obtain the solution of yellow transparent, it may be necessary to disperse using ultrasound, high speed shear or be heated to the modes such as 40 DEG C to accelerate the dissolution of formula (IX) compound.And it is uniformly dispersed into uniform liquid solution.
2. including into soft capsule or being packed into hypromellose (HPMC) hard capsule case and seal above-mentioned solution.
Embodiment 11
Prescription 9
Preparation method
1. median chain triglyceride oil is mixed with polyglycol solution, the A Kela for sequentially adding recipe quantity determines and the fluid sample of polyoxyethylene (40) rilanit special PEG400, it is added in above-mentioned solution system under agitation, it makes it completely dissolved, obtain the solution of yellow transparent, it may be necessary to disperse using ultrasound, high speed shear or be heated to the modes such as 40 DEG C to accelerate the fixed dissolution of A Kela.And it is uniformly dispersed into uniform liquid solution.
2. including into soft capsule or being packed into hypromellose (HPMC) hard capsule case and seal above-mentioned solution.
Embodiment 12
Choose healthy beasle dog 2,10.0 ± 1.0kg of weight, male.Test preceding fasting in 16 hours, feed food and water freely administration in 4 hours after administration, 3 capsule of embodiment is administered with the dosage feeding of 40mg/kg, 0.167 after administration, 0.5,1,2,4,6,8,24 hours through forelimb venous blood sampling 1mL, it sets in the plastic tube added with heparin, centrifugation, separated plasma, -20 DEG C of preservations are to be measured.
The elimination half-life period t of drug in blood plasma after 3 capsule of embodiment is administered orally in beasle dog1/2It is 4.8 hours；Peak time TmaxIt is 1.0 hours；Cmax CmaxIt is respectively as follows: 1.5 μ gmL-1；Area AUC0-24 hours under its concentration time curve are 4.6 μ ghmL-1.It is specifically shown in the following table 1, table 2 and attached drawing 1.
Table 1
Table 2
Embodiment 13
Choose healthy beasle dog 2,10.0 ± 1.0kg of weight, male tests preceding fasting in 16 hours, 4 hours feed food and water freelies after administration, the capsule of the dosage feeding administration embodiment 6 of 40mg/kg, 0.167 after administration, 0.5,1,2,4,6,8,24 hours through forelimb venous blood sampling 1mL, set in the plastic tube added with heparin, be centrifuged, separated plasma, -20 DEG C of preservations are to be measured.
The elimination half-life period t of drug in blood plasma after 6 capsule of embodiment is administered orally in beasle dog1/2It is 5.5 hours；Peak time TmaxIt is 0.8 hour；Cmax CmaxIt is respectively as follows: 0.5 μ gmL-1；Area AUC0-24h under its concentration time curve is 2.0 μ ghmL-1.It is specifically shown in the following table 3, table 4 and attached drawing 2.
Table 3
Table 4
Embodiment 14
Choose healthy beasle dog 2,10.0 ± 1.0kg of weight, male.Test preceding fasting in 16 hours, feed food and water freely administration in 4 hours after administration, 11 A Kelading capsule of embodiment is administered with the dosage feeding of 40mg/kg, 0.167 after administration, 0.5,1,2,4,6,8,24 hours through forelimb venous blood sampling 1mL, it sets in the plastic tube added with heparin, centrifugation, separated plasma, -20 DEG C of preservations are to be measured.
The elimination half-life period t of drug in blood plasma after 11 capsule of embodiment is administered orally in beasle dog1/2It is 4.8 hours；Peak time TmaxIt is 1.0 hours；Cmax CmaxIt is respectively as follows: 1.5 μ gmL-1；Area AUC0-24 hours under its concentration time curve are 4.6 μ ghmL-1.It is specifically shown in the following table 5, table 6 and attached drawing 3.
Table 5
Table 6
Embodiment 15
Study on the stability
Select soft capsule prepare from 3 prescription 1 of embodiment to carry out stability study, investigation medicament contg, impurity, dissolution and disintegration time limited variation tendency.Stability setting-out condition is 40 DEG C, and 75% relative humidity, 1 soft capsule of self-emulsifying prescription is packed using single foil sealing, and respectively at 0 day, 2 weeks, 1 month sampling and testing, it is as follows to dissolve out test condition:
Dissolving-out method USP II method (paddle method)
Dissolution medium 0.1N hydrochloric acid
Medium volume 500ml
100 revs/min of revolving speed
37.5 DEG C of temperature
1/glass of proof load
Stability test the results are shown in Table 7.
7 prescription of table, 1 Stability of Soft Capsules test result
The related substance testing result of 8 prescription of table, 1 gelatine capsule stability
9 prescription of table, 1 Stability of Soft Capsules dissolves out test result
It can be seen that 1 soft capsule content of prescription is almost unchanged；Total miscellaneous slightly growth, impurity increases predominantly at relative retention time 0.17 and relative retention time 0.49；40 DEG C, 2 weeks and 40 DEG C, capsule dissolution is compared with 0 day without significant changes within 1 month.
Claims (19)
- A kind of pharmaceutical composition of chromocor compound, the pharmaceutical composition is self-emulsifying dosage form, self-emulsifying forms O/W type nano-emulsion in vivo after oral administration, and the particle size range for forming nano-emulsion in vivo is 10-200nm, and the chromocor compound is the compound for the formula that has following structure:R is selected from hydrogen, (C1-C4) alkyl, (C1-C4) the alkoxy, (C containing the substitution of one or more halogen atoms1-C4) alkyl, halogen, cyano or the (C replaced containing one or more halogen atoms1-C4) alkoxy.
- Pharmaceutical composition according to claim 1, wherein the chromocor compound is the compound for the formula that has following structure:R is selected from trifluoromethyl, methyl, ethyl or methoxyl group.
- Pharmaceutical composition according to claim 1 or 2, which is characterized in that the drugloading rate of chromocor compound is 2-30% in the pharmaceutical composition.
- Pharmaceutical composition according to claim 1 or 2, which is characterized in that the pharmaceutical composition includes chromocor compound, oil phase solvent, emulsifier, assistant for emulsifying agent and antioxidant；Preferably, the mass ratio of oil phase solvent, emulsifier and assistant for emulsifying agent is 1.0:0.7-5.0 in described pharmaceutical composition: 1.0-5.0；Most preferably, the mass ratio of the oil phase solvent in described pharmaceutical composition, emulsifier and assistant for emulsifying agent is 1.0:2.0-3.0:1.5-3.0.
- Pharmaceutical composition according to claim 4, which is characterized in that the pharmaceutical composition further includes pH adjusting agent；Preferably, the pH adjusting agent is one or more of citric acid, malic acid and tartaric acid.
- Pharmaceutical composition according to claim 4, which is characterized in that the emulsifier is the emulsifier of HLB value 12-17；Preferably, the emulsifier is the emulsifier of HLB value 14-15.
- Pharmaceutical composition according to claim 6, which is characterized in that the emulsifier can dissolve the chromocor compound.
- Pharmaceutical composition according to claim 5 or 6, which is characterized in that by quality ratio, the emulsifier is the 20-60% of pharmaceutical composition amount of substance；Preferably, the emulsifier is the 40-45% of pharmaceutical composition amount of substance.
- Pharmaceutical composition according to claim 5 or 6, which is characterized in that the emulsifier is nonionic surfactant.
- Pharmaceutical composition according to claim 5 or 6, which is characterized in that the emulsifier includes selected from one or more of Crodaret, Solutol HS15, hexadecanol and octadecyl alcolol.
- Pharmaceutical composition according to claim 4 or 5, which is characterized in that the oil phase solvent can dissolve the chromocor compound.
- Pharmaceutical composition according to claim 11, it is characterized in that, the oil phase solvent includes selected from one or more of soybean oil, peanut oil, corn oil, castor oil, olive oil, peppermint oil, oleic acid, rapeseed oil, sesame oil, rilanit special, ethyl oleate, olein, glyceryl linoleate, Miglyol 812, isopropyl myristate, isopropyl palmitate, Vitwas E, Sefsol 218, propene carbonate and median chain triglyceride oil.
- Pharmaceutical composition according to claim 4, which is characterized in that the assistant for emulsifying agent can dissolve the chromocor compound.
- Pharmaceutical composition according to claim 13, which is characterized in that the assistant for emulsifying agent is alcohols solvent.
- Pharmaceutical composition according to claim 14, which is characterized in that the assistant for emulsifying agent includes selected from one or both of isopropanol, ethyl alcohol and polyhydroxy-alcohol；Preferably, the polyhydroxy-alcohol includes selected from one or more of polyethylene glycol, diethylene glycol monoethyl ether, glycerol and propylene glycol.
- Pharmaceutical composition according to claim 15, it is characterized in that, the polyethylene glycol includes selected from one or more of polyethylene glycol 200, Liquid Macrogol, polyethylene glycol 400, Macrogol 600, polyethylene glycol 900, cetomacrogol 1000, polyethylene glycol 1500 and polyethylene glycol 2000.
- Purposes of the pharmaceutical composition described in any one of claim 1-16 in the drug that preparation has related disorders for anti-cell abnormality proliferation.
- A kind of anti-cell abnormality proliferation has the drug of related disorders, includes pharmaceutical composition described in any one of claim 1-16 in the drug.
- Drug according to claim 18, it is characterised in that the drug is oral preparation or injection；The oral preparation includes one or more of soft capsule, hard capsule, oral solution and suspension.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510079190 | 2015-02-13 | ||
| CN2015100791905 | 2015-02-13 | ||
| PCT/CN2016/073632 WO2016127925A1 (en) | 2015-02-13 | 2016-02-05 | Drug combination of flavonoid compound and use of same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107205982A true CN107205982A (en) | 2017-09-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201680006886.8A Pending CN107205982A (en) | 2015-02-13 | 2016-02-05 | A kind of medical composition and its use of chromocor compound |
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| Country | Link |
|---|---|
| CN (1) | CN107205982A (en) |
| WO (1) | WO2016127925A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107982249A (en) * | 2016-10-27 | 2018-05-04 | 四川曼赛思医药科技有限公司 | It is a kind of containing icariine and its derivative and the pharmaceutical composition of their salt and solubilizer |
| EP4119139A4 (en) * | 2020-03-10 | 2024-03-20 | Lunan Pharmaceutical Group Corp | Medical use of anyhdroicaritin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101513388A (en) * | 2009-03-27 | 2009-08-26 | 贾晓斌 | Icariin microemulsion and preparation method thereof |
| CN101528038A (en) * | 2006-10-25 | 2009-09-09 | 盛诺基医药科技有限公司 | Compounds and methods for treating estrogen receptor-related diseases |
-
2016
- 2016-02-05 CN CN201680006886.8A patent/CN107205982A/en active Pending
- 2016-02-05 WO PCT/CN2016/073632 patent/WO2016127925A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101528038A (en) * | 2006-10-25 | 2009-09-09 | 盛诺基医药科技有限公司 | Compounds and methods for treating estrogen receptor-related diseases |
| CN101513388A (en) * | 2009-03-27 | 2009-08-26 | 贾晓斌 | Icariin microemulsion and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| WO2016127925A1 (en) | 2016-08-18 |
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