CN107865870A - Preparation and application as EV71 viruses and the phosphatide complexes of CAV16 viral inhibitors - Google Patents
Preparation and application as EV71 viruses and the phosphatide complexes of CAV16 viral inhibitors Download PDFInfo
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- CN107865870A CN107865870A CN201610856055.1A CN201610856055A CN107865870A CN 107865870 A CN107865870 A CN 107865870A CN 201610856055 A CN201610856055 A CN 201610856055A CN 107865870 A CN107865870 A CN 107865870A
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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Abstract
The invention provides a kind of preparation and application as EV71 viruses and the phosphatide complexes of CAV16 viral inhibitors.A kind of EV71 viruses and the method for CAV16 viral inhibitors TJAB 1099 phosphatide complexes of preparing includes：TJAB 1099 and phosphatide are mixed and added into organic solvent；Return stirring 0.5~3 hour, obtains reaction solution at a temperature of 30~60 DEG C；Reaction solution is evaporated under reduced pressure at a temperature of 30~60 DEG C, removes organic solvent；And dry, obtain the phosphatide complexes of TJAB 1099.The compound that TJAB 1099 is formed with phosphatide can effectively improve the Lipophilicity of medicine, and phosphatide has good biological sympathy.Body absorption ability is improved, and bioavilability improves.
Description
Technical field
The present invention relates to medicinal composition, more particularly, to the phosphatide as EV71 viruses and CAV16 viral inhibitors
The preparation method and application of compound and its oral formulations.
Background technology
People's hand-foot-and-mouth disease (Hand-foot-mouth disease, HFMD) is common acute infectious disease, and is distributed in complete
Ball.Hand-foot-and-mouth disease incubation period is 2-10 days, and average 3-5 days, the course of disease is generally 7-10 days.Occur heating paresthesia, oral cavity during onset
Mucous membrane occurs being dispersed in bleb, and maculopapule, bleb occur in brothers and buttocks, can there is inflammatory blush around bleb, and liquid is less in blister.
And with symptoms such as cough, runny nose, poor appetites.A small number of cases, particularly EV71 infect infant, may occur in which meningitis, encephalitis,
Encephalomyelitis, neural source, property pulmonary edema, dyshaemia etc., the state of an illness is dangerous, lethal can die or leave sequelae.Cause people brothers
The virus of stomatosis is：2,4,5,7,9,10,16 types of Coxsackie virus A group (Coxasckievirus A, CVA) etc.；COxsackie
1,2,3,4,5 types of viral B groups (Coxasckievirus B, CVB) etc.；Enterovirns type 71 (Human Enterovirus
71,EV71)；Echovirus (Echovirus, ECHO) etc..It is wherein relatively conventional with EV71 and CVA16 types.Existing conventional treatment
The antiviral drugs of hand-foot-and-mouth disease has：ACV, GCV, interferon, Ribavirin etc., mostly broad-spectrum antiviral drug
Thing, no specificity.
EV71 viruses and CAV16 viral inhibitors (TJAB-1099) are Tianjin International Joint Academy of Biotechnology ＆ Medicine presidents
Rao Zi and one kind of team's research and development are for hand-foot-mouth disease EV 71 virus and the highly efficient depressor of CAV16 viruses.Pass through EV71 viruses
With the high-resolution three-dimensional structure of CAV16 viruses, it have devised a kind of EV71 virus CAV16 viruses that can suppress and undress the complete of shell process
Noval chemical compound-TJAB-1099, CN104744433A (data of publication of application：On July 1st, 2015).The compound can be effective
Duplication of the EV71 viruses in human body is blocked, so as to specific treatment brothers' mouth as caused by EV71 viruses and CAV16 viruses
Disease.But TJAB-1099 is a kind of compound of water-insoluble, its water solubility limits its oral absorption rate, makes its clinic should
It is greatly limited with formulation development.
The content of the invention
, should the invention provides a kind of as EV71 viruses and the phosphatide complexes oral formulations of CAV16 viral inhibitors
Method have prepare it is easy, absorb the spies such as fast, bioavilability is high, biological sympathy is good and suitable industry's enlarging production requires
Point.The invention provides a kind of phosphatide complexes preparation method and the application in antiviral drugs is prepared.
A kind of EV71 viruses and CAV16 viral inhibitors (TJAB-1099) phosphatide complexes, the phosphatide is natural phospholipid
And synthetic phospholipid.The compound is with mol ratio 1 by the inhibitor and phosphatide：1~20 compound.TJAB-1099 knot
Structure formula is as follows：Wherein, R is hydrogen, C1-C5The various substituents such as alkyl；
EV71 viruses of the present invention and CAV16 viral inhibitors (TJAB-1099) phosphatide complexes are in accordance with the following methods
Prepare：TJAB-1099 and phosphatide are mixed and added into organic solvent according to proportional quantity.With 30~60 degrees Celsius of return stirrings 0.5
~3 hours.By 30~60 degrees Celsius of reduction vaporizations of reaction solution, organic solvent is removed, to drying, TJAB-1099 phosphatide is obtained and answers
Compound.The ingredient proportion of TJAB-1099 and phosphatide is mol ratio 1：1~20.Organic solvent used is dichloromethane, three chloromethanes
Alkane, n-hexane, hexamethylene or its combination.The phosphatide is natural phospholipid or synthetic phospholipid.Natural phospholipid is soybean lecithin, egg
Yellow lecithin or its combination.Synthetic phospholipid is DPPC (DPPC), DPPE (two palmityl phosphatidyl ethanols
Amine), DSPC (DSPC) or its combination.
Present invention also offers a kind of method that TJAB-1099 phosphatide complexes are prepared into oral formulations.It is described oral
Preparation is by TJAB-1099 phosphatide complexes and deionized water or appropriate buffer solution with 1：1~20 ratio aquation.It is prepared into liquid
Preparation.Phosphatide complexes after aquation are added into suitable carrier material, make soft, are pelletized, are dried.It is prepared into various forms of solid
Body preparation.The carrier material includes：Lactose, sucrose, dextrin, mannitol, superfine silica gel powder, microcrystalline cellulose, water soluble starch
Or its any combination.The liquid preparation includes：Supensoid agent, syrup.The solid pharmaceutical preparation includes：Tablet, capsule, particle
Agent, electuary, effervescent, effervescent tablet.
EV71 viruses and CAV16 viral inhibitors TJAB-1099 phosphatide complexes are prepared the invention provides a kind of
Method, including：TJAB-1099 and phosphatide are mixed and added into organic solvent；At a temperature of 30~60 DEG C return stirring 0.5~
3 hours, obtain reaction solution；The reaction solution is evaporated under reduced pressure at a temperature of 30~60 DEG C, removes the organic solvent；And
Dry, obtain TJAB-1099 phosphatide complexes.
In the above-mentioned methods, wherein, the phosphatide is natural phospholipid or synthetic phospholipid.
In the above-mentioned methods, wherein, the natural phospholipid is soybean lecithin, yolk phospholipid or its combination.
In the above-mentioned methods, wherein, the synthetic phospholipid is DPPC, two palmityl phosphatidyl ethanols
Amine, DSPC or its any combination.
In the above-mentioned methods, wherein, the organic solvent is dichloromethane, chloroform, n-hexane, hexamethylene or its group
Close.
In the above-mentioned methods, wherein, in the step of mixing TJAB-1099 with phosphatide, the TJAB-1099 with it is described
The mol ratio of phosphatide is 1：1~20.
Present invention also offers the TJAB-1099 phosphatide complexes prepared according to the above method.
Present invention also offers a kind of medicine for including TJAB-1099 phosphatide complexes, the medicine is oral administration solution system
Agent, wherein, the pharmaceutical solutions that takes is supensoid agent, syrup.
Present invention also offers a kind of medicine for including TJAB-1099 phosphatide complexes, the medicine is oral administration solid system
Agent, the oral solid formulation are tablet, capsule, granule, electuary, effervescent or effervescent tablet.
Beneficial effects of the present invention are embodied in：
Chinese patent CN104744433A (data of publication of application：On July 1st, 2015) EV71 virus and CAV16 HIV suppressions
Agent (TJAB-1099) discloses chemical constitution and preparation method, but the compound is not soluble in water, is insoluble in ethanol and oil.Mouthful
It is not notable without exposed amount, drug effect in body during clothes administration.The compound that TJAB-1099 is formed with phosphatide can effectively improve medicine
Lipophilicity, and phosphatide has good biological sympathy.Body absorption ability is improved, and bioavilability carries
It is high.The method of the present invention has the characteristics that easy, suitable industry's enlarging production requirement.The preparation of the present invention is for children
With the high and biological sympathy of bioavilability it is good the characteristics of.
Brief description of the drawings
The formation that phosphatide complexes are verified by differential scanning calorimetry is shown respectively in Figure 1A to Fig. 1 D, and sweep speed is
10cel/min, range ability are 30-320 DEG C, wherein, Figure 1A is shown to be TJAB-1099；Figure 1B is shown to be egg yolk lecithin；Figure
1C is shown to be TJAB-1099 and egg yolk lecithin physical mixture；Fig. 1 D are TJAB-1099 and egg yolk lecithin compound.
Fig. 2A shows TJAB-1099 and egg yolk lecithin compound 31P NMR spectras；Fig. 2 B show egg yolk lecithin
31P NMR spectras.
Fig. 3 shows that rat intravenous injection and gavage give mean blood plasma concentration-time song of TJAB-1099 phosphatide complexes
Line chart.
Embodiment
The present invention is specifically addressed below in conjunction with specific case study on implementation, but protection scope of the present invention is not limited only to
This.
Embodiment 1：The preparation of EV71 viruses and CAV16 viral inhibitors (TJAB-1099) phosphatide complexes
TJAB-1099 raw material 0.10g, egg yolk lecithin 0.36g are weighed, adds chloroform 5mL, 40 DEG C, reaction 3 is small
When, to clarification.Vacuum rotary steam vapors away chloroform to drying, is dried in vacuo 24 hours, it is close to obtain phosphatide complexes 0.46g.
Package fills, and is preserved in 4 DEG C of refrigerators.
Embodiment 2：The preparation of EV71 viruses and CAV16 viral inhibitors (TJAB-1099) phosphatide complexes
TJAB-1099 raw material 0.10g, egg yolk lecithin 0.36g are weighed, adds dichloromethane 5mL, 40 DEG C, reaction 0.5 is small
When, to clarification.Vacuum rotary steam vapors away dichloromethane to drying, is dried in vacuo 24 hours, it is close to obtain phosphatide complexes 0.46g.
Package fills, and is preserved in 4 DEG C of refrigerators.
Embodiment 3：The preparation of EV71 viruses and CAV16 viral inhibitors (TJAB-1099) phosphatide complexes
TJAB-1099 raw material 0.10g, egg yolk lecithin 0.36g are weighed, hexamethylene 5mL is added, 60 DEG C, reacts 3 hours,
To clarification.Vacuum rotary steam vapors away dichloromethane to drying, is dried in vacuo 24 hours, obtains phosphatide complexes 0.46g. sealed bundles
Dress, preserved in 4 DEG C of refrigerators.The formation of its compound is confirmed through heat analysis and nuclear magnetic resonance, as shown in Figure 1A to Fig. 2 B.
Embodiment 4：The preparation of TJAB-1099 phosphatide complexes solutions.
By the phosphatide complexes 0.46g obtained by embodiment 2, deionized water 10mL is added, carries out film water to completely molten
Solution.Form homogeneous solution.Add sucrose 1g, sodium benzoate 50mg, beta carotene 20mg, flavoring essence 0.1mL, citric acid
20mL, tragacanth 20mg, it is well mixed.
Embodiment 5：The preparation of TJAB-1099 phosphatide complexes instant effervescent particles
By the phosphatide complexes 0.46g obtained by embodiment 3, deionized water 10mL is added, carries out film water to completely molten
Solution.Lactose 2.5g is added to be well mixed.Dry.Citric acid 3.0g, sodium acid carbonate 5.5g are added, adds lactose 4.5g.With
7.5% PVP ethanol solution 4mL (adds strawberry essence 0.1mL) in ethanol solution, be fully ground, and pelletizes.Forced air drying.It is close
Package fills, room temperature preservation.
Embodiment 6：The preparation of TJAB-1099 phosphatide complexes tablets
By the phosphatide complexes 0.46g obtained by embodiment 3, deionized water 10mL is added, carries out film water to completely molten
Solution.Lactose 2.5g is added to be well mixed.Dry.Citric acid 3.0g, sodium acid carbonate 5.5g are added, adds lactose 4.5g.With
10% PVP ethanol solution 4mL (adds strawberry essence 0.1mL) in ethanol solution, be fully ground, and pelletizes.Forced air drying is whole
Grain, adds talcum powder 0.1g, tabletting.Pack, room temperature preservation.
Embodiment 7：The determination experiment of TJAB-1099 phosphatide complexes solution bioavilabilities
By the preparation method of the TJAB-1099 phosphatide complexes solutions described in embodiment 4, obtained 0.5mg/mL phosphorus
Fat complexes solution, tail vein and oral administration are carried out to rat with 1mg/kg and 5mg/kg.Tail vein is administered, orbital vein
Clump blood sampling time point be：0,2min, 5min, 15min, 30min, 45min, 1h, 2h, 4h, 6h, 8h, 10h, 12h after administration,
24h.Gastric infusion, orbital venous plexus blood sampling time point are：0min, 5min, 15min, 30min, 45min, 1h, 2h after administration,
4h, 6h, 8h, 10h, 12h, 24h.50 μ L plasma samples are taken, add 200 μ L internal standard compounds (100ng/mL RMI 9918s, methanol/second
Nitrile (1:1) solution), vortex mixed 30s, centrifugation 10min (10000rpm) takes supernatant 100ul, adds 100ul methanol/waters (1:
1) solution, vortex mix, sample introduction 5ul to water generation company ultrahigh pressure liquid phase mass spectrometry system Waters Quattro
Premier XE/Acquity UPLC (Solvent containing Binary manager, Sample manager, Quattro
Premier XE MS, Masslynx V4.1 chromatographic work stations) carry out quantitative analysis.Oral and intravenously administrable blood concentration-
Time graph, as shown in Figure 3.Absolute bioavailability is 2.37%.
It will be understood by those skilled in the art that above example is only exemplary embodiment, in the spirit without departing substantially from the present invention
In the case of scope, a variety of changes can be carried out, replaces and changes.
Claims (9)
1. a kind of method for preparing EV71 viruses and CAV16 viral inhibitors TJAB-1099 phosphatide complexes, including：
TJAB-1099 and phosphatide are mixed and added into organic solvent；
Return stirring 0.5~3 hour, obtains reaction solution at a temperature of 30~60 DEG C；
The reaction solution is evaporated under reduced pressure at a temperature of 30~60 DEG C, removes the organic solvent；And
Dry, obtain TJAB-1099 phosphatide complexes；
Wherein, the structural formula of the TJAB-1099 is：
R is hydrogen, C1-C5Alkyl.
2. according to the method for claim 1, wherein, the phosphatide is natural phospholipid or synthetic phospholipid.
3. according to the method for claim 2, wherein, the natural phospholipid is soybean lecithin, egg yolk lecithin or its group
Close.
4. according to the method for claim 2, wherein, the synthetic phospholipid is DPPC, two palmityls
Phosphatidyl-ethanolamine, DSPC or its combination.
5. according to the method for claim 1, wherein, the organic solvent is dichloromethane, chloroform, n-hexane, ring
Hexane or its combination.
6. the method according to claim 11, wherein, in the step of mixing TJAB-1099 with phosphatide, the TJAB-
1099 with the mol ratio of the phosphatide be 1：1~20.
7. TJAB-1099 phosphatide complexes prepared by the method according to any one of claim 1-6.
8. a kind of medicine of the TJAB-1099 phosphatide complexes comprising described in claim 7, the medicine is oral administration solution system
Agent, wherein, the oral solution formulation is supensoid agent, syrup.
9. a kind of medicine of the TJAB-1099 phosphatide complexes comprising described in claim 7, the medicine is oral administration solid system
Agent, the oral solid formulation are tablet, capsule, granule, electuary, effervescent or effervescent tablet.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610856055.1A CN107865870A (en) | 2016-09-27 | 2016-09-27 | Preparation and application as EV71 viruses and the phosphatide complexes of CAV16 viral inhibitors |
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| CN201610856055.1A CN107865870A (en) | 2016-09-27 | 2016-09-27 | Preparation and application as EV71 viruses and the phosphatide complexes of CAV16 viral inhibitors |
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| CN201610856055.1A Pending CN107865870A (en) | 2016-09-27 | 2016-09-27 | Preparation and application as EV71 viruses and the phosphatide complexes of CAV16 viral inhibitors |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111249319A (en) * | 2020-01-17 | 2020-06-09 | 天津国际生物医药联合研究院 | Phospholipid complex of Eurycoma longifolia extract and preparation method thereof |
| CN115429812A (en) * | 2022-08-31 | 2022-12-06 | 深圳海王医药科技研究院有限公司 | Molnbupiravir phospholipid complex and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101704838A (en) * | 2009-11-30 | 2010-05-12 | 浙江大学 | Baicalein phospholipid complex and preparation method thereof |
| CN104744433A (en) * | 2013-12-30 | 2015-07-01 | 中国科学院生物物理研究所 | ALD and application thereof as EV71 virus and CAV16 virus inhibitor |
-
2016
- 2016-09-27 CN CN201610856055.1A patent/CN107865870A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101704838A (en) * | 2009-11-30 | 2010-05-12 | 浙江大学 | Baicalein phospholipid complex and preparation method thereof |
| CN104744433A (en) * | 2013-12-30 | 2015-07-01 | 中国科学院生物物理研究所 | ALD and application thereof as EV71 virus and CAV16 virus inhibitor |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111249319A (en) * | 2020-01-17 | 2020-06-09 | 天津国际生物医药联合研究院 | Phospholipid complex of Eurycoma longifolia extract and preparation method thereof |
| CN111249319B (en) * | 2020-01-17 | 2022-04-19 | 天津国际生物医药联合研究院 | Phospholipid complex of Eurycoma longifolia extract and preparation method thereof |
| CN115429812A (en) * | 2022-08-31 | 2022-12-06 | 深圳海王医药科技研究院有限公司 | Molnbupiravir phospholipid complex and preparation method thereof |
| CN115429812B (en) * | 2022-08-31 | 2023-11-17 | 深圳海王医药科技研究院有限公司 | Monnpiravir phospholipid complex and preparation method thereof |
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Application publication date: 20180403 |