CN107007839A - A kind of isocorydine inclusion compound and preparation method thereof - Google Patents
A kind of isocorydine inclusion compound and preparation method thereof Download PDFInfo
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- CN107007839A CN107007839A CN201610058893.4A CN201610058893A CN107007839A CN 107007839 A CN107007839 A CN 107007839A CN 201610058893 A CN201610058893 A CN 201610058893A CN 107007839 A CN107007839 A CN 107007839A
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- cyclodextrin
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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Abstract
The present invention relates to a kind of isocorydine inclusion compound and preparation method thereof, isocorydine cyclodextrin or cyclodextrin derivant clathrate, its preparation method, the pharmaceutical composition containing isocorydine cyclodextrin or cyclodextrin derivant clathrate and the purposes in medicine is prepared are referred in particular to, belongs to field of pharmaceutical preparations.A kind of isocorydine inclusion compound, is made up of isocorydine, cyclodextrin or cyclodextrine derivatives, and the molecule mol ratio of isocorydine and cyclodextrin or cyclodextrine derivatives is 1: 11: 50.The advantage of the invention is that：The inclusion compound of the present invention improves the solubility of isocorydine, with good water solubility, Ocular irritation is small the features such as, solve problem present in prior art, it is adaptable to the liquid preparations such as eye drops are made.
Description
Technical field
The present invention relates to a kind of isocorydine inclusion compound and preparation method thereof, isocorydine cyclodextrin or ring paste are referred in particular to
Smart derivative clathrate, its preparation method, the pharmaceutical composition containing isocorydine cyclodextrin or cyclodextrin derivant clathrate
And the purposes in medicine is prepared, belong to field of pharmaceutical preparations.
Background technology
Isocorydine, alias：Isocorydine, English name：Isocorydine, molecular formula：C20H23O4N, molecular weight：
340.36.For white needles or column crystallization；Odorless, taste is extremely bitter.It is almost insoluble in water, it is readily soluble in ethanol.Its structural formula
It is as follows：
Isocorydine is the alkaloid extracted in the dry root of Bai nationality traditional herbal medicines radix dactylicapni, belongs to iloquinoline derivative biological
Alkali, is a kind of non-specific smooth muscles spasmolytic, with obvious spasmolysis.Suitable for adolescent myopia, pseudo-myopia and
Continuously closely using the kopiopia caused by eyesight.Had well for the near-sighted happy eyedrops of main component by isocorydine
Curative effect.But because isocorydine is insoluble in water, need that eye drops is made using hydrochloride in preparation process, because it is hydrochloric it is different can profit
Fixed (valid density 5mg/ml) eye drops pH value is in 4.4-5.6, and Clinical practice process can cause Ocular irritation, therefore limit it
Using.
The content of the invention
The main technical problem to be solved in the present invention is to provide a kind of good water solubility, the isocorydine small to Ocular irritation
Inclusion compound and its preparation.
The invention solves the problems that another technical problem be to provide the preparation side of above-mentioned isocorydine inclusion compound and its preparation
Method.
To achieve the above object, the present invention uses following technical scheme：
A kind of isocorydine inclusion compound, is made up of isocorydine and cyclodextrin or cyclodextrine derivatives；Isocorydine and ring
The molecule mol ratio of dextrin or cyclodextrine derivatives is 1: 1-1: 50.
The cyclodextrin or cyclodextrine derivatives are selected from alpha-cyclodextrin, beta-schardinger dextrin, gamma-cyclodextrin, ethoxy-β-ring paste
Essence, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-beta-schardinger dextrin, methyl-B-cyclodextrin, glucose-cyclodextrin, maltose-ring paste
One or more in essence, maltotriose-cyclodextrin, carboxymethyl-cyclodextrin or sulfoalkyl-cyclodextrin.
The molecule mol ratio of the isocorydine and cyclodextrin or cyclodextrine derivatives is 1: 1-1: 10；The cyclodextrin or
Cyclodextrine derivatives are gamma-cyclodextrin or hydroxypropyl-β-cyclodextrin.Gamma-cyclodextrin, hydroxypropyl-β-cyclodextrin are widely used
With the conglomerate such as food, medicine, cosmetics, manufacturing enterprise is more, and stable preparation process, yield is big, is easier to obtain.
The present invention isocorydine is included by cyclodextrin or cyclodextrine derivatives, make isocorydine molecule embedding in
In the tubular structure of cyclodextrin or cyclodextrine derivatives molecule, the inclusion as isocorydine cyclodextrin or cyclodextrine derivatives
Thing, so as to improve the solubility of isocorydine.Isocorydine is directly prepared into cyclodextrin embedding thing, it is to avoid in the prior art
Cause low ph value eye drops to the irritating of eye using isocorydine hydrochloride to increase the solubility of isocorydine
Situation.
The first preparation method of the isocorydine inclusion compound is as follows：
(1) cyclodextrin or cyclodextrine derivatives are added in solvent 1, it is the molten of 1-90% that mass percent concentration, which is made,
Liquid 1；
(2) solution 2 is made in isocorydine addition solvent 2, solution 2 is added in solution 1, stirring, grinding or ultrasound are mixed
Close, obtain isocorydine cyclodextrin or cyclodextrin derivant clathrate solution or suspension；
(3) after the solution or suspension obtained step (2) suitably concentration, dry and remove solvent, produce isocorydine ring
Dextrin or cyclodextrin derivant clathrate.
The mass percent concentration of solution 1 is 30-90% in the step (1)；
Appropriate concentration refers to the matter for being concentrated into isocorydine cyclodextrin or cyclodextrin derivant clathrate in the step (3)
Amount percent concentration is 10-50%；The drying is freeze-drying, is spray-dried or is concentrated under reduced pressure.
Second of preparation method of the isocorydine inclusion compound is as follows：
(1) cyclodextrin or cyclodextrine derivatives are placed in colloid mill or mortar, add appropriate appropriate vehicle 1 and stir,
Become pastel；
(2) solution 2 is made in isocorydine addition solvent 2, solution 2 is added in the pastel that step (1) is obtained, ground
1-5 hours, obtain homogeneous viscous pastes；
(3) it is concentrated under reduced pressure or is freeze-dried, produces the isocorydine cyclodextrin or cyclodextrin derivant clathrate of solid.
In above two preparation method, the solvent 1 is selected from water, ethanol, methanol, propyl alcohol, isopropanol, ethylene glycol, the third three
Mixture more than one or both of alcohol, acetone, preferably water.
The one kind or two of the solvent 2 in water, ethanol, methanol, propyl alcohol, isopropanol, ethylene glycol, glycerine, acetone
The mixture of the above is planted, preferred volume percent concentration is 10-90% ethanol solution.
Present invention also offers a kind of composition containing isocorydine, the isocorydine cyclodextrin prepared by the above method
Or acceptable carrier composition in cyclodextrin derivant clathrate and pharmaceutics.
The composition containing isocorydine, formulation includes but is not limited to the formulations such as eye drops.When formulation is eye drops,
Can be directly prepared from by isocorydine cyclodextrin or cyclodextrin derivant clathrate solution or suspension, or by it is different can profit
Determine cyclodextrin or cyclodextrin derivant clathrate solid solubilizer is prepared from.
In the composition containing isocorydine, single dose specification is 0.1-1000mg containing isocorydine, preferably single dose
Gauge lattice are 1-10mg containing isocorydine.
A kind of isocorydine eye drops, active component is isocorydine hydroxypropyl-beta-cyclodextrin inclusion, and concentration is 5-
100mg/ml, the pH of eye drops is 5.5-8.5；Sodium chloride isosmoticity conditioning agent and hydrochloric acid, hydroxide can be contained in eye drops
The pH value regulators such as sodium.Wherein the molecule mol ratio of isocorydine and hydroxypropyl-beta-cyclodextrin inclusion is 1: 1-1: 10
Inclusion compound obtained by the present invention is identified with the following method：
(1) nuclear magnetic resonance method
To isocorydine, gamma-cyclodextrin, hydroxypropyl-β-cyclodextrin, isocorydine/gamma-cyclodextrin inclusion compound, it is different can profit
Fixed/hydroxypropyl-beta-cyclodextrin inclusion determines above-mentioned substance using the NMRs of Bruker Avance DRX 5001H
NMR.In isocorydine, isocorydine gamma-cyclodextrin inclusion compound and isocorydine/hydroxypropyl-beta-cyclodextrin inclusion1H
In NMR figures (Fig. 1), it is clear that the Partial Feature peak (appearing near δ 6.5-7.0ppm) for seeing isocorydine, this is special
Levy easily to separate with cyclodextrin proton peak area (near δ 0.5-6.0ppm).Gamma-cyclodextrin is included with isocorydine
Afterwards, its H-3 chemical shift of proton value changes about 0.03ppm, H-5 protons have changed 0.02ppm.And it is same, hydroxy propyl-Beta-
After cyclodextrin and isocorydine inclusion, its H-3 chemical shift of proton value changes about 0.02ppm, H-5 protons change
0.01ppm.Individual in the stereochemical structure of cyclodextrin, itself H-3 and H-5 proton is respectively positioned on the cavity inside of cyclodextrin, wherein H-3
In the big opening end of cyclodextrin, H-5 is located at the osculum end of cyclodextrin, according to the situation of change of H-3 and H-5 chemical shift of proton values,
It should enter cyclodextrin cavity from the big opening end of cyclodextrin to be inferred to isocorydine.
(2) differentia scanning calorimetry (DSC)
To isocorydine, gamma-cyclodextrin, hydroxypropyl-β-cyclodextrin, isocorydine/gamma-cyclodextrin inclusion compound, it is different can profit
Fixed/hydroxypropyl-beta-cyclodextrin inclusion carries out calorimetric analysis using the resistance to thermal analyzer STA449F3 that speeds of Germany to above-mentioned substance.
Experiment condition：Flow velocity：100mL/min；Gas：Nitrogen；Temperature elevating range：25~450 DEG C；Heating rate：10℃/
min.Gamma-cyclodextrin and hydroxypropyl-β-cyclodextrin are between 50-100, with a wider endothermic peak, inflection temperature of absorbing heat
Respectively：78.3 DEG C, produced by 75.6 DEG C of this peaks are due to the moisture that cyclodextrin is sloughed in cavity.From isocorydine
It is low at 216.8 DEG C of arrival peaks as can be seen that it has an endothermic peak, and rapid decrease at 187 DEG C in DSC curve, it is its fusing
Endothermic peak.After isocorydine forms inclusion compound with gamma-cyclodextrin and hydroxypropyl-β-cyclodextrin respectively, its DSC curve such as Fig. 2,
The endothermic peak flex point that water removing is produced in gamma-cyclodextrin cyclodextrin cavity is changed into 99.8 DEG C, hydroxypropyl-β-cyclodextrin from 78.3 DEG C
The endothermic peak flex point that water removing is produced in cavity is changed into 77 DEG C from 75.6 DEG C, and the endothermic peak of isocorydine disappears.Illustrate system
Into isocorydine gamma-cyclodextrin solid clathrates, isocorydine hydroxypropyl-β-cyclodextrin solid clathrates.
(3) X-ray powder diffraction methods
To isocorydine, gamma-cyclodextrin, hydroxypropyl-β-cyclodextrin, isocorydine/gamma-cyclodextrin inclusion compound, it is different can profit
Fixed/hydroxypropyl-beta-cyclodextrin inclusion using PHI 5000VersaProbe II (Cu-K α ()) diffractometer pair
Above-mentioned substance carries out XRD determining.
Experiment condition：Sweep speed：5°/min；Scanning range：2-70 ° of θ=5 °；Voltage：40kV.Isocorydine has allusion quotation
The crystal formation peak of type, gamma-cyclodextrin has a small amount of atypia crystal formation peak, and both are crystalline structure, and hydroxypropyl-β-cyclodextrin is nothing
Stereotyped structure.After isocorydine is included, inclusion compound show for amorphous structure.Isocorydine gamma-cyclodextrin is consolidated
The peak shape of the similar gamma-cyclodextrin of body inclusion compound, but isocorydine and gamma-cyclodextrin crystal formation peak are had no, it is already belonging to amorphous structure；
Isocorydine hydroxypropyl-β-cyclodextrin solid clathrates have similar HP- β-CD peak shape, while also there is not isocorydine
Crystal formation peak.Confirm to form inclusion compound, and inclusion compound between isocorydine and gamma-cyclodextrin and hydroxypropyl-β-cyclodextrin
For undefined structure.
Beneficial effects of the present invention are：The present invention isocorydine cyclodextrin or cyclodextrin derivant clathrate, make it is different can
This fixed active component of profit directly applies to liquid dosage form in the form of inclusion compound.Cyclodextrin or cyclodextrine derivatives are a kind of poison
Property less water-soluble pharmaceutic adjuvant, with its prepare isocorydine cyclodextrin or cyclodextrin derivant clathrate be suitable for being made
Plurality of liquid preparation.The isocorydine cyclodextrin or cyclodextrin derivant clathrate of the present invention, it is special the characteristics of with good water solubility
Shi Yongyu not the liquid preparation such as eye drops.Solve isocorydine water solubility low, it is to avoid liquid is made using its hydrochloride and makes
The problem of producing Ocular irritation into pH value is too low, can be directly used for the formulation of liquid dosage form, especially eye drops.
The present invention will be further described with reference to the accompanying drawings and detailed description, not limitation of the present invention.It is all
The equivalent substitution of any this area carried out according to presently disclosed techniques content, belongs to the scope of the present invention.
Brief description of the drawings
Fig. 1 is that isocorydine/γ-CD, isocorydine/HP- beta-CD inclusions and isocorydine, γ-CD, HP- β-CD exist
1H NMR spectras in 25 DEG C of D20 and CDC13
Fig. 2 be isocorydine, gamma-cyclodextrin, isocorydine/gamma-cyclodextrin inclusion compound, hydroxy propyl-Beta cyclodextrin, it is different can
The dsc analysis figure of sharp fixed/hydroxypropyl-beta-cyclodextrin inclusion
Fig. 3 be isocorydine, gamma-cyclodextrin, isocorydine/gamma-cyclodextrin inclusion compound, hydroxy propyl-Beta cyclodextrin, it is different can
Profit determines/hydroxypropyl-beta-cyclodextrin inclusion XRD
Embodiment
Embodiment 1 prepares isocorydine hydroxypropyl-beta-cyclodextrin inclusion solution
First, prescription (isocorydine: hydroxypropyl-β-cyclodextrin mol ratio 1: 1)
Isocorydine 45mg
Hydroxypropyl-β-cyclodextrin 180mg
2nd, preparation method
(1) hydroxypropyl-β-cyclodextrin 180mg is weighed, adds in 50ml distilled water, is stirred to dissolve；
(2) isocorydine 45mg is weighed, plus that dissolving is made is different for 20% ethanol solution 50ml for concentration of volume percent
It sharp can determine solution, the solution is added dropwise as in above-mentioned hydroxypropyl-β-cyclodextrin solution, mixed liquor is stirred at normal temperatures with stirring means
Mix 2 hours, obtain isocorydine hydroxypropyl-β-cyclodextrin solution；
(3) vacuum rotary steam removes ethanol, plus distilled water 50ml filterings, and removing does not include medicine, produces isocorydine hydroxypropyl
Group-beta-cyclodextrin inclusion complex in solution.
Embodiment 2 prepares solid isocorydine hydroxypropyl-beta-cyclodextrin inclusion
First, prescription (isocorydine: hydroxypropyl-β-cyclodextrin mol ratio 1: 1)
Isocorydine 45mg
Hydroxypropyl-β-cyclodextrin 180mg
2nd, preparation method
Step (1), (2), (3) be the same as Example 1.
Isocorydine hydroxypropyl-beta-cyclodextrin inclusion solution is dried under reduced pressure again, solid isocorydine hydroxyl is produced
Propyl-beta-cyclodextrin inclusion compound.
Embodiment 3 prepares solid isocorydine hydroxypropyl-beta-cyclodextrin inclusion
First, prescription (isocorydine: hydroxypropyl-β-cyclodextrin mol ratio 1: 1)
Isocorydine 45mg
Hydroxypropyl-β-cyclodextrin 180mg
2nd, preparation method
(1) hydroxypropyl-β-cyclodextrin 180mg is weighed, is put into mortar, 2ml distilled water is added, grinding makes into pasty state.
(2) isocorydine 45mg is taken, add 15m concentration of volume percent makes dissolving for 20% ethanol solution, and this is molten
Liquid is added in the hydroxypropyl-β-cyclodextrin solution that step (1) is obtained, and mixed liquor is ground 2 hours, homogeneous pastel is obtained；
(3) be concentrated under reduced pressure drying, produces solid isocorydine hydroxypropyl-beta-cyclodextrin inclusion.
Embodiment 4 prepares isocorydine/gamma-cyclodextrin inclusion complex in solution
First, prescription (isocorydine: gamma-cyclodextrin mol ratio 1: 1)
Isocorydine 45mg
Gamma-cyclodextrin 170mg
2nd, preparation method
(1) gamma-cyclodextrin 170mg is weighed, adds in 50ml distilled water, is stirred to dissolve；
(2) isocorydine 45mg, plus concentration of volume percent are weighed isocorydine solution are made for 20% ethanol solution,
The solution is added dropwise as in above-mentioned gamma-cyclodextrin solution, mixed liquor is stirred 2 hours at normal temperatures with agitating mode, obtain it is different can
Profit determines gamma-cyclodextrin solution；
(3) vacuum rotary steam removes ethanol, plus distilled water 50ml filterings, and removing does not include medicine, produces isocorydine γ-ring
Dextrin solution.
Embodiment 5 prepares solid isocorydine/gamma-cyclodextrin inclusion compound
First, prescription (isocorydine: gamma-cyclodextrin mol ratio 1: 1)
Isocorydine 45mg
Gamma-cyclodextrin 170mg
2nd, preparation method
(1) gamma-cyclodextrin 170mg is weighed, is put into colloid mill, 2ml distilled water is added, grinding makes into pasty state.
(2) isocorydine 45mg is taken, add 15ml concentration of volume percent makes dissolving for 20% ethanol solution, and this is molten
Liquid is added in the gamma-cyclodextrin solution that step (1) is obtained, and mixed liquor is ground 1 hour, homogeneous pastel is obtained；
(3) filter, freeze-drying produces solid isocorydine gamma-cyclodextrin inclusion compound.
Embodiment 6 prepares the eye drops of isocorydine hydroxypropyl-beta-cyclodextrin inclusion
First, prescription (isocorydine: hydroxypropyl-β-cyclodextrin mol ratio 1∶1)
2nd, preparation method
(1) hydroxypropyl-β-cyclodextrin 180mg is weighed, adds in 50ml distilled water, is stirred to dissolve；
(2) isocorydine 45mg is weighed, plus that dissolving is made is different for 20% ethanol solution 50ml for concentration of volume percent
It sharp can determine solution, the solution is added dropwise as in above-mentioned hydroxypropyl-β-cyclodextrin solution, mixed liquor is stirred at normal temperatures with stirring means
Mix 2 hours, obtain isocorydine hydroxypropyl-β-cyclodextrin solution；
(3) vacuum rotary steam removes ethanol, plus distilled water 50ml filterings, and removing does not include medicine, produces isocorydine hydroxypropyl
Group-beta-cyclodextrin inclusion complex in solution；
(4) benzalkonium bromide 0.1g is weighed, adds in above-mentioned inclusion complex in solution, is stirred to dissolve, adding distilled water makes into
100ml, stirs, aseptic subpackaged through 0.22 μm of membrane filtration, produces eye drops.
After measured, the eye drops concentration is 4.5mg/ml, and pH value is 6.45.
Embodiment 7 prepares the eye drops of isocorydine/gamma-cyclodextrin inclusion compound
First, prescription (isocorydine: gamma-cyclodextrin mol ratio 1: 1)
2nd, preparation method
(1) gamma-cyclodextrin 170mg is weighed, is put into colloid mill, 3ml distilled water is added, grinding makes into pasty state.
(2) isocorydine 45mg is taken, add 20ml concentration of volume percent makes dissolving for 20% ethanol solution, and this is molten
Liquid is added in the gamma-cyclodextrin solution that step (1) is obtained, and mixed liquor is ground 1 hour, homogeneous pastel is obtained；
(3) it is freeze-dried, produces solid isocorydine gamma-cyclodextrin inclusion compound.
(4) the isocorydine gamma-cyclodextrin inclusion compound that benzalkonium bromide 0.1g and step (3) are obtained is weighed, appropriate steam is added
Distilled water, is stirred to dissolve, and adding distilled water makes into 100ml, stirs, aseptic subpackaged through 0.22 μm of membrane filtration, produces drop
Ocular fluid.
After measured, the eye drops concentration is 4.5mg/ml, and pH value is 6.75.
Embodiment 8 prepares the eye drops of isocorydine hydroxypropyl-beta-cyclodextrin inclusion
First, prescription (isocorydine: hydroxypropyl-β-cyclodextrin mol ratio 1: 1)
2nd, preparation method
(1) hydroxypropyl-β-cyclodextrin 180mg is weighed, adds in 50ml distilled water, is stirred to dissolve；
(2) isocorydine 45mg is weighed, plus that dissolving is made is different for 20% ethanol solution 50ml for concentration of volume percent
It sharp can determine solution, the solution is added dropwise as in above-mentioned hydroxypropyl-β-cyclodextrin solution, mixed liquor is stirred at normal temperatures with stirring means
Mix 2 hours, obtain isocorydine hydroxypropyl-β-cyclodextrin solution；
(3) vacuum rotary steam removes ethanol, plus distilled water 50ml filterings, and removing does not include medicine, produces isocorydine hydroxypropyl
Group-beta-cyclodextrin inclusion complex in solution；
(4) isocorydine hydroxypropyl-beta-cyclodextrin inclusion solution is dried under reduced pressure again, produces solid isocorydine
Hydroxypropyl-beta-cyclodextrin inclusion；
(5) benzalkonium bromide 0.1g, and the solid isocorydine hydroxypropyl-beta-cyclodextrin inclusion that step (4) is obtained are weighed,
Appropriate distilled water is added, is stirred to dissolve, adding distilled water makes into 100ml, stirs, sterile through 0.22 μm of membrane filtration
Packing, produces eye drops.
After measured, the eye drops concentration is 4.5mg/ml, and pH value is 6.4.
Embodiment 9 prepares solid isocorydine/gamma-cyclodextrin inclusion compound
First, prescription (isocorydine: gamma-cyclodextrin mol ratio 1: 2)
Isocorydine 45mg
Gamma-cyclodextrin 340mg
2nd, preparation method
Step (1), (2), (3) be the same as Example 4.
Isocorydine gamma-cyclodextrin inclusion complex in solution is dried under reduced pressure again, solid isocorydine gamma-cyclodextrin is produced
Inclusion compound.
Embodiment 10 prepares solid isocorydine/gamma-cyclodextrin inclusion compound
First, prescription (isocorydine: gamma-cyclodextrin mol ratio 1: 3)
Isocorydine 45mg
Gamma-cyclodextrin 510mg
2nd, preparation method
Step (1), (2), (3) be the same as Example 5.
Embodiment 11 prepares solid isocorydine/hydroxypropyl-beta-cyclodextrin inclusion
First, prescription (isocorydine: hydroxypropyl-β-cyclodextrin mol ratio 1: 5)
Isocorydine 45mg
Hydroxypropyl-β-cyclodextrin 900mg
2nd, preparation method
Step (1), (2), (3) be the same as Example 1.
Isocorydine hydroxypropyl-beta-cyclodextrin inclusion solution is dried under reduced pressure again, solid isocorydine hydroxyl is produced
Propyl-beta-cyclodextrin inclusion compound.
Embodiment 12 prepares solid isocorydine/hydroxypropyl-beta-cyclodextrin inclusion
First, prescription (isocorydine: hydroxypropyl-β-cyclodextrin mol ratio 1: 6)
Isocorydine 45mg
Hydroxypropyl-β-cyclodextrin 1080mg
2nd, preparation method
(1) hydroxypropyl-β-cyclodextrin 1080mg is weighed, is put into mortar, 5ml distilled water is added, grinding makes into pasty state.
(2) isocorydine 45mg is taken, add 15m concentration of volume percent makes dissolving for 20% ethanol solution, and this is molten
Liquid is added in the hydroxypropyl-β-cyclodextrin solution that step (1) is obtained, and mixed liquor is ground 2 hours, homogeneous pastel is obtained；
(3) be concentrated under reduced pressure drying, produces solid isocorydine hydroxypropyl-beta-cyclodextrin inclusion.
Embodiment 13 prepares solid isocorydine/hydroxypropyl-beta-cyclodextrin inclusion
First, prescription (isocorydine: hydroxypropyl-β-cyclodextrin mol ratio 1: 10)
Isocorydine 45mg
Hydroxypropyl-β-cyclodextrin 1800mg
2nd, preparation method
(1) hydroxypropyl-β-cyclodextrin 1200mg is weighed, is put into mortar, 10ml distilled water is added, grinding makes into pasty state.
(2) isocorydine 45mg is taken, add 15m concentration of volume percent makes dissolving for 20% ethanol solution, and this is molten
Liquid is added in the hydroxypropyl-β-cyclodextrin solution that step (1) is obtained, and mixed liquor is ground 2 hours, homogeneous pastel is obtained；
(3) be concentrated under reduced pressure drying, produces solid isocorydine hydroxypropyl-beta-cyclodextrin inclusion.
Test example 1：Preparation in vitro solubility test is tested
Weighing different amounts of isocorydine and isocorydine cyclodextrin inclusion compound respectively, (embodiment 2 and embodiment 5 are prepared into
To), it is added to by several times in 5mL solvent, often adds once every strength shaking in 5 minutes 30 seconds, observe the dissolving in 30 minutes
During situation, such as invisible particles of solute, that is, be considered as and be completely dissolved, stand, Aspirate supernatant, dilution, using UV methods determine it is different can
Profit determines content, is meltage at a certain temperature.Measurement result is shown in Table 1.
Table 1：Cyclodextrin inclusion compound water-soluble experimental result
Test example 2：Animal eye irritant experiment
Test method：Using consubstantiality own control, adult healthy white rabbit 4, body weight 2.3kg, before medication are taken at random
First observe and record cornea, iris and conjunctiva situation, existing lesion or inflammation person, reject without.Then by embodiment 6, implementation
The isocorydine eyedrops 0.1mL instillation rabbit conjunctiva of left eye of example 7 and embodiment 8 is intracapsular, and opposite side physiological saline is as right
According to making eyes passively close after isocorydine eyedrops 8-10 seconds, 3 times a day, successive administration 7 days is observed after first administration
6th, 24,48, continue to observe 7 days to 7 days, after drug withdrawal within 72 hours, the local reaction situation of eye is diagonal by the standards of grading of table 3.12
Film, iris and conjunctiva are scored respectively, calculate mean scores, and be compared with the eye that compares of same animal.Observe emphatically
The situation of change of cornea and iris, and record the time that stimulate the reaction disappears and recovered.
The standards of grading table of table 2
Table 3：Ocular irritation evaluation criterion
The Ocular irritation result of the test of table 4
Claims (10)
1. a kind of isocorydine inclusion compound, it is characterised in that：It is made up of isocorydine and cyclodextrin or cyclodextrine derivatives；It is different can
Profit is determined and the molecule mol ratio of cyclodextrin or cyclodextrine derivatives is 1: 1-1: 50.
2. a kind of isocorydine inclusion compound according to claim 1, it is characterised in that：The cyclodextrin or cyclodextrin derive
Thing be selected from alpha-cyclodextrin, beta-schardinger dextrin, gamma-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-
Cyclodextrin, methyl-B-cyclodextrin, glucose-cyclodextrin, maltose-cyclodextrin, maltotriose-cyclodextrin, carboxymethyl-ring paste
One or more in essence or sulfoalkyl-cyclodextrin.
3. a kind of isocorydine inclusion compound according to claim 1, it is characterised in that：The isocorydine and cyclodextrin or
The molecule mol ratio of cyclodextrine derivatives is 1: 1-1: 10；The cyclodextrin or cyclodextrine derivatives are gamma-cyclodextrin or hydroxypropyl
Group-beta-cyclodextrin.
4. a kind of preparation method of isocorydine inclusion compound any one of claims 1 to 3, it is characterised in that be with
Lower either method：
Method one：
(1) cyclodextrin or cyclodextrine derivatives are added in solvent 1, the solution 1 that mass percent concentration is 1-90% is made；
(2) solution 2 is made in isocorydine addition solvent 2, solution 2 is added in solution 1, stirring, grinding or ultrasonic mixing are obtained
To isocorydine cyclodextrin or cyclodextrin derivant clathrate solution or suspension；
(3) after the solution or suspension obtained step (2) suitably concentration, dry and remove solvent, produce isocorydine cyclodextrin
Or cyclodextrin derivant clathrate；
Or method two：
(1) cyclodextrin or cyclodextrine derivatives are placed in colloid mill or mortar, add appropriate appropriate vehicle 1 and stir, make it
As pastel；
(2) solution 2 is made in isocorydine addition solvent 2, solution 2 is added in the pastel that step (1) is obtained, 1-5 is ground
Hour, obtain homogeneous viscous pastes；
(3) it is concentrated under reduced pressure or is freeze-dried, produces the isocorydine cyclodextrin or cyclodextrin derivant clathrate of solid.
5. a kind of preparation method of isocorydine inclusion compound according to claim 4, it is characterised in that：Methods described one
The mass percent concentration of solution 1 is 30-90% in step (1)；Appropriate concentration refers to be concentrated into isocorydine ring in step (3)
The mass percent concentration of dextrin or cyclodextrin derivant clathrate is 10-50%, and the drying is freeze-drying, spray drying
Or be concentrated under reduced pressure.
6. a kind of preparation method of isocorydine inclusion compound according to claim 4 or 5, it is characterised in that：The solvent 1
Mixture more than one or both of water, ethanol, methanol, propyl alcohol, isopropanol, ethylene glycol, glycerine, acetone；
The solvent 2 be selected from one or both of water, ethanol, methanol, propyl alcohol, isopropanol, ethylene glycol, glycerine, acetone with
On mixture.
7. a kind of preparation method of isocorydine inclusion compound according to claim 6, it is characterised in that：The solvent 1 is
Water, the solvent 2 is the ethanol solution that concentration of volume percent is 10-90%.
8. a kind of composition containing isocorydine, it is characterised in that：Can as different any one of claims 1 to 3
Profit determines cyclodextrin or cyclodextrin derivant clathrate and pharmaceutically acceptable carrier composition.
9. a kind of composition containing isocorydine according to claim 8, it is characterised in that：The composition is eye drip
Liquid, single dose specification is 0.1-1000mg containing isocorydine, and preferably single dose specification is 1-10mg containing isocorydine.
10. a kind of isocorydine eye drops, it is characterised in that：Active component is isocorydine hydroxypropyl-beta-cyclodextrin inclusion,
Concentration is 5-100mg/ml, and pH value is 5.5-8.5；Sodium chloride isosmoticity conditioning agent and hydrochloric acid, hydrogen-oxygen can be contained in eye drops
Change the pH value regulators such as sodium；Wherein the molecule mol ratio of isocorydine and hydroxypropyl-beta-cyclodextrin inclusion is 1: 1-1: 10.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110420336A (en) * | 2019-08-13 | 2019-11-08 | 郑州大学 | A kind of linarin inclusion compound and its preparation method and application |
| CN110755376A (en) * | 2019-12-05 | 2020-02-07 | 河南省人民医院 | Vorinostat water-soluble eye drops and preparation method thereof |
| CN111330019A (en) * | 2018-12-18 | 2020-06-26 | 中国人民解放军第二军医大学 | Flumazenil clathrate compound and preparation method and application thereof |
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|---|---|---|---|---|
| CN1739508A (en) * | 2005-09-01 | 2006-03-01 | 郭曙平 | Prepn process of isocollidine for eye |
| CN101579403A (en) * | 2008-05-14 | 2009-11-18 | 北京和润创新医药科技发展有限公司 | Ready-to-use Dactylicapnos scandens ophthalmic gel |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1739508A (en) * | 2005-09-01 | 2006-03-01 | 郭曙平 | Prepn process of isocollidine for eye |
| CN101579403A (en) * | 2008-05-14 | 2009-11-18 | 北京和润创新医药科技发展有限公司 | Ready-to-use Dactylicapnos scandens ophthalmic gel |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111330019A (en) * | 2018-12-18 | 2020-06-26 | 中国人民解放军第二军医大学 | Flumazenil clathrate compound and preparation method and application thereof |
| CN111330019B (en) * | 2018-12-18 | 2022-03-15 | 中国人民解放军第二军医大学 | Flumazenil clathrate compound and preparation method and application thereof |
| CN110420336A (en) * | 2019-08-13 | 2019-11-08 | 郑州大学 | A kind of linarin inclusion compound and its preparation method and application |
| CN110755376A (en) * | 2019-12-05 | 2020-02-07 | 河南省人民医院 | Vorinostat water-soluble eye drops and preparation method thereof |
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Application publication date: 20170804 |