CN108236604A - Eliquis flexible lipidosome - Google Patents
Eliquis flexible lipidosome Download PDFInfo
- Publication number
- CN108236604A CN108236604A CN201810131355.2A CN201810131355A CN108236604A CN 108236604 A CN108236604 A CN 108236604A CN 201810131355 A CN201810131355 A CN 201810131355A CN 108236604 A CN108236604 A CN 108236604A
- Authority
- CN
- China
- Prior art keywords
- eliquis
- flexible lipidosome
- surfactant
- liposome
- phosphatide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
-
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
- A61K9/127—Liposomes
Abstract
The present invention provides a kind of Eliquis flexible lipidosome, Eliquis is a kind of oral selective Xa factor inhibitor, causes bioavilability poor because its hypotonicity is low.Eliquis flexible lipidosome preparation of the present invention is that one kind contains surfactant Eliquis liposome, it can improve Eliquis solubility and permeability, enhance the oral absorption of Eliquis, have broad application prospects, film dispersion method preparation, convenience simple for process can be used.
Description
Technical field
The invention belongs to art of pharmacy, and in particular to a kind of novel Eliquis preparation -- Eliquis flexibility lipid
Body.And verify that it can increase the infiltration transhipment of Eliquis lipid film using parallel artificial membrane permeability experiment.
Background technology
Eliquis is the known compound having following structure：
The chemical name of Eliquis is 4,5,6,7- tetrahydrochysene -1- (4- methoxyphenyls) -7- oxos -6- [4- (2- oxygen
Generation -1- piperidyls) phenyl] -1H- pyrazolos [3,4-c] pyridine-3-carboxamide.Belong to oral Selective activation Xa factor to inhibit
Agent is Global 3G oral anticoagulation.It is developed jointly and developed by Pfizer and Bristol-Myers Squibb Co., passed through within 2012
U.S. Food and Drug Administration (FDA) approval listing is sent out for reducing the palsy of non-valvular atrial fibrillation patient and systemic embolism
Raw risk；The import drug permit that state food and drug administration issues is obtained within 2013, for hip joint
Or knee joint is selected a time the adult patients of displacement technique, prevention venous thromboembolic event (VTE).Eliquis is to be white to faint yellow
Crystalline powder, solubility is 0.04mg/mL in aqueous medium (pH1.2-pH6.8), and Eliquis is non-ionic compound,
Water-soluble is not influenced by pH.The soluble,very slightly in acetonitrile, methanol is dissolved in chloroform.And Eliquis stability is good, it is wet without drawing
Property.Eliquis absolute bioavailability is about 50%, is BCSIII class drugs.Its hypotonicity cause its bioavailability compared with
It is low.
Liposome is the vesicle formed by phospholipid bilayer film, is widely used in controlled release, pharmaceutical carrier, medicine target
To enhancing drug solubility and increase Oral drug absorption.It is improved on the basis of liposome prescription, adds in surface-active
Agent forms a kind of self aggregation vesicle with high deformation, also referred to as flexible lipidosome.I.e. in the original ingredient of liposome not
Add or add cholesterol less, while add film softening agent, mainly surfactant such as sodium taurocholate, deoxysodium cholate, tween
Deng, make liposome lipid membrane have height deformability, be conducive to increase drug oral absorption.
Eliquis is encapsulated in flexible lipidosome by the present invention for the first time, by increasing the solubility of drug, promotes drug
Transmembrane transport reaches improvement Oral drug absorption, improves the effect of bioavilability.
Invention content
The purpose of the present invention is intended to provide a kind of novel Eliquis preparation -- Eliquis flexible lipidosome, increase Ah
The permeability of piperazine sand class, so as to improve the oral absorption of Eliquis and bioavilability.
Based on above-mentioned purpose, this invention takes following technical solutions：Eliquis liposome, mainly by following weight parts
Substance is made：1 part of the Eliquis, phosphatidase 1~100 part, 0~50 part of cholesterol, 0.1~50 part of surfactant.
The phosphatide is selected from egg yolk lecithin, soybean lecithin, hydrogenated soya phosphatide, hydrolecithin, cephalin, heart phosphorus
Fat, phosphatidylinositols, phosphatidylserine, phosphatidyl glycerol, phosphatidic acid, phosphatidyl-ethanolamine, Dilauroyl Phosphatidylcholine,
Two nutmeg phosphatidyl cholines, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, dipalmitophosphatidic acid, two
Palmityl phosphatidyl-ethanolamine, distearoylphosphatidylglycerol, Distearoyl Phosphatidylcholine, Dioleoyl Phosphatidylcholine and two
Oleoylphosphatidyl ethanol amine.
The surfactant be selected from dexycholate, cholate, deoxycholic acid, taurocholate, cholic acid, Tween 80,
Poloxamer and sapn.
The Eliquis liposome is prepared using film dispersion method：By Eliquis, phosphatide, cholesterol and
Fat-soluble surface agent is dissolved in organic solvent, at 20~70 DEG C decompression fling to organic solvent, form film, then add in dissolved with
It is hydrated, then carries out ultrasound or high-pressure homogeneous handles up to Eliquis liposome in the aqueous media of water soluble surfactant active
Liquid preparation.The aqueous media is that pure water, physiological saline, Osmitrol, glucose solution or pH are 4~8
Phosphate buffer, Chinese holly edge phthalate buffer, acetate buffer or Tris-HCl buffer solutions, organic solvent be selected from ethyl alcohol,
Methanol, acetic acid, acetone, ethyl acetate, chloroform and dichloromethane.
In conclusion Eliquis is prepared into Eliquis flexible lipidosome by the present invention for the first time, make as oral preparation
With it can improve the transmembrane transport of Eliquis, be conducive to increase the oral absorption of Eliquis.
Specific embodiment
Eliquis liposome is prepared using film dispersion method in the present invention, and the tool of the present invention is illustrated by example below
Body embodiment, but protection scope of the present invention, it is not limited to this.
The Eliquis liposome of 1 tween 80 of embodiment
The preparation method of Eliquis liposome that the embodiment provides is：Phosphatidase 1 00mg, cholesterol 12.5mg, Ah piperazine
Husky class 5mg, is dissolved in 15mL chloroforms in round-bottomed flask；Rotary evaporation is depressurized in 37 DEG C of waters bath with thermostatic control and flings to organic solvent,
One layer of lipid membrane is formed on bottle inner wall；It is hand with bead to add in PBS (pH 7.4) 20mL containing 32mg Tween 80s, makes eggplant
After lipid membrane on shape bottle completely falls off, 37 DEG C of magnetic agitation 30min；Probe Ultrasonic Searching 3min (intensity 50%；Ultrasonic 2s
Stop 1s).
After testing, the average grain diameter of liposome is 116nm in the liquid preparation, which is 86%, encapsulating
Yield is 82%
Eliquis liposome of the embodiment 2 containing natrii tauroglycocholas
The preparation method of Eliquis liposome that the embodiment provides is：Phosphatidase 1 00mg, natrii tauroglycocholas 12.5mg, Ah
Piperazine sand class 5mg is placed in round-bottomed flask, adds in 15ml chloroform-methanols (2：1) double solvents, water bath sonicator make it fully dissolve；
Rotary evaporation is depressurized in 37 DEG C of waters bath with thermostatic control and flings to organic solvent, one layer of lipid membrane is formed on bottle inner wall；Add in 20mL phosphorus
Phthalate buffer (pH7.4) is hand with bead, after the lipid membrane on eggplant-shape bottle is made to completely fall off, 37 DEG C of magnetic agitations
30min；Probe Ultrasonic Searching 3min (intensity 50%；Ultrasonic 2s stops 1s).
After testing, the average grain diameter of liposome is 102nm in the liquid preparation, which is 86%, encapsulating
Yield is 79%.
3 common Eliquis liposome of embodiment
The preparation method of Eliquis liposome that the embodiment provides is：Phosphatidase 1 00mg, cholesterol 12.5mg, Ah piperazine
Husky class 5mg, is dissolved in 15mL chloroforms in round-bottomed flask；Rotary evaporation is depressurized in 37 DEG C of DEG C of waters bath with thermostatic control and flings to organic solvent,
One layer of lipid membrane is formed on bottle inner wall；It is hand with bead to add in 20mL phosphate buffers (pH7.4), makes on eggplant-shape bottle
Lipid membrane completely fall off after, 37 DEG C of magnetic agitation 30min；Probe Ultrasonic Searching 3min (intensity 50%；Ultrasonic 2s stops 1s).
After testing, the average grain diameter of liposome is 127nm in the liquid preparation, which is 86.33%, packet
It is 80.33% to seal yield
The parallel artificial membrane permeability experiments of embodiment 4-
The Eliquis liposome of Eliquis/PBS suspensions and embodiment 1-3 is taken, utilizes parallel artificial membrane (lipid
Film) the effective infiltration coefficient (Pe) of permeability experiment measure, it the results are shown in Table 1.
Table 1：Embodiment 1-3 artificial membrane permeability experiment results parallel with Eliquis/PBS suspensions
As shown in table 1, Eliquis lipid physical efficiency is effectively increased the passive transference of Eliquis, improves the infiltration of drug
Property, more than conventional liposome, this is conducive to improve Eliquis Eliquis flexible lipidosome raising drug permeability effect
Oral absorption improves drug oral bioavilability.
Claims (5)
1. Eliquis flexible lipidosome, it is characterised in that (1) it can significantly improve the lipid membrane permeability of Eliquis, favorably
In improving drug oral bioavilability, contain surfactant in (2) liposome, mainly by the substance system of following weight parts
Into：1 part of Eliquis, phosphatidase 1~100 part, 0~50 part of cholesterol, 0.1~50 part of surfactant.
2. Eliquis flexible lipidosome as described in claim 1, it is characterised in that the phosphatide is selected from egg yolk lecithin, big
Beans lecithin, hydrogenated soya phosphatide, hydrolecithin, cephalin, cuorin, phosphatidylinositols, phosphatidylserine, phosphatidyl
Glycerine, phosphatidic acid, phosphatidyl-ethanolamine, Dilauroyl Phosphatidylcholine, two nutmeg phosphatidyl cholines, two palmityl phosphatide
Phatidylcholine, dipalmitoylphosphatidylglycerol, dipalmitophosphatidic acid, dipalmitoylphosphatidylethanolamine, distearoylphosphatidyl
Glycerine, Distearoyl Phosphatidylcholine, Dioleoyl Phosphatidylcholine and dioleoylphosphatidylethanolamine.
3. Eliquis flexible lipidosome as described in claim 1, it is characterised in that the surfactant is selected from deoxidation courage
Hydrochlorate, cholate, deoxycholic acid, taurocholate, cholic acid, Tween 80, poloxamer and sapn.
4. Eliquis flexible lipidosome as described in claim 1, preparation method is film dispersion method, concrete operations be by
Eliquis, phosphatide, cholesterol and surfactant are dissolved in organic solvent, at 20~70 DEG C decompression fling to it is organic molten
Agent forms film, and the aqueous media then added in dissolved with water soluble surfactant active is hydrated, and then carries out ultrasound or high pressure
Homogenization is selected from pure water, physiological saline, Osmitrol, glucose up to Eliquis liposome, the aqueous media
Phosphate buffer, Chinese holly edge phthalate buffer, acetate buffer or the Tris-HCl bufferings that aqueous solution either pH is 4~8
Liquid, organic solvent are selected from ethyl alcohol, methanol, acetic acid, acetone, ethyl acetate, chloroform and dichloromethane.
5. Eliquis flexible lipidosome as described in claim 1, suitable for oral medication.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810131355.2A CN108236604A (en) | 2018-02-07 | 2018-02-07 | Eliquis flexible lipidosome |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810131355.2A CN108236604A (en) | 2018-02-07 | 2018-02-07 | Eliquis flexible lipidosome |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108236604A true CN108236604A (en) | 2018-07-03 |
Family
ID=62699722
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810131355.2A Pending CN108236604A (en) | 2018-02-07 | 2018-02-07 | Eliquis flexible lipidosome |
Country Status (1)
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| CN (1) | CN108236604A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109846826A (en) * | 2019-01-25 | 2019-06-07 | 湖南华腾制药有限公司 | Abiraterone acetate flexible lipidosome and preparation method thereof |
| CN112656703A (en) * | 2020-12-28 | 2021-04-16 | 华南理工大学 | Polypeptide flexible liposome and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102802608A (en) * | 2009-06-16 | 2012-11-28 | 美国辉瑞有限公司 | Dosage forms of apixaban |
| US20130045245A1 (en) * | 2010-02-25 | 2013-02-21 | Pfizer, Inc. | Apixaban formulations |
| CN104000783A (en) * | 2014-05-14 | 2014-08-27 | 河南牧翔动物药业有限公司 | Cefquinome liposome |
-
2018
- 2018-02-07 CN CN201810131355.2A patent/CN108236604A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102802608A (en) * | 2009-06-16 | 2012-11-28 | 美国辉瑞有限公司 | Dosage forms of apixaban |
| US20130045245A1 (en) * | 2010-02-25 | 2013-02-21 | Pfizer, Inc. | Apixaban formulations |
| CN104000783A (en) * | 2014-05-14 | 2014-08-27 | 河南牧翔动物药业有限公司 | Cefquinome liposome |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109846826A (en) * | 2019-01-25 | 2019-06-07 | 湖南华腾制药有限公司 | Abiraterone acetate flexible lipidosome and preparation method thereof |
| CN112656703A (en) * | 2020-12-28 | 2021-04-16 | 华南理工大学 | Polypeptide flexible liposome and preparation method and application thereof |
| CN112656703B (en) * | 2020-12-28 | 2023-05-05 | 华南理工大学 | Polypeptide flexible liposome and preparation method and application thereof |
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Application publication date: 20180703 |
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