CN108498455A - A kind of water-soluble medicament nano crystalline substance of oiliness and preparation method thereof - Google Patents
A kind of water-soluble medicament nano crystalline substance of oiliness and preparation method thereof Download PDFInfo
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- CN108498455A CN108498455A CN201810367219.3A CN201810367219A CN108498455A CN 108498455 A CN108498455 A CN 108498455A CN 201810367219 A CN201810367219 A CN 201810367219A CN 108498455 A CN108498455 A CN 108498455A
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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
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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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
- A61K31/351—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 not condensed with another ring
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
Abstract
The present invention provides a kind of water-soluble medicament nano crystalline substances of oiliness, belong to water soluble drug preparing technical field；The water-soluble medicament nano crystalline substance of oiliness includes following components in percentage by weight：The oleaginous base of active medicine 1~50%, stabilizer 0.1~20% and surplus；The active medicine is BCSIII classes drug or BDDCSIII class drugs；The water-soluble medicament nano crystalline substance prepares nanocrystalline acquisition by oleaginous base, stabilizer and active medicine mixing, the permeability of water-soluble medicament nano crystalline substance in vivo is improved, to improve bioavilability.
Description
Technical field
The invention belongs to water soluble drug preparing technical field more particularly to a kind of water-soluble medicament nano crystalline substance of oiliness and its systems
Preparation Method.
Background technology
Oral medication has the advantages that good patient compliance, administration safe ready, be still at present it is clinical recommend most preferably to
Prescription formula.Therefore, the oral administration biaavailability (Foral) of drug is an important category of lead optimization in drug discovery
Property.After oral administration of drugs, the degree and bioavilability of absorption are closely related, and degree of absorption and drug are in gastrointestinal tract pH items
Dissolubility, permeability and enteral metabolic stability are directly related under part.
Drug solubility and infiltrative significance level can also pass through Biopharmaceutics Classification system
(Biopharmaceutics Classification System, BCS) is emerged from.In BCS categorizing systems, BCSIII classes
Drug refers to the drug that dissolubility is good, permeability is low.Wherein, the compound that dissolubility is good, metabolic rate is low can be further according to life
Object pharmacy disposition categorizing system (Biopharmaceutics Drug Disposition Classification System,
BDDCS) it is classified as BDDCSIII.Recent study finds the problem of lipophilic drugs are more easy to that toxicity and drug interaction occurs,
Therefore more and more BDDCSIII class candidate compounds enter the new drug discovery stage.Although this transformation reduces in drug body
Toxicity increases the efficiency to biological target, but the problem of cause oral delivery.Because biomembrane is phospholipid bilayer
Layer structure, the stronger compound enteron aisle membrane permeability of hydrophily usually have some problems, and lower enteron aisle membrane permeability then can
Cause Foral relatively low.But solubility is compared, Intestinal permeability studies the more of complexity, and main cause includes：1. usually measuring
Jejunum effectively permeate (The effective permeation, Peff) all enteron aisles cannot be represented；2. gut metabolism CYP enzymes
Metabolism with flora brings complexity to the infiltration for measuring drug original shape.Therefore molten compared to BCSII class drugs are improved at present
Xie Du improves the research but much less of BCSIII class drug permeabilities.Effective infiltration (The of the drug by enteron aisle is thought in research
Effective permeation, Peff) it is multiple parallel biographies such as Passive diffusion, active transport endocytosis, outer row and cell bypass
The synthesis result of defeated process.Therefore, for the mechanism of intestines infiltration, the scheme for solving BCSIII class drug permeabilities at present is mainly wrapped
It includes：1. permeable membrane sorbefacient (promoting drug cross-cell membrane and cell bypass transhipment) is added；2. improving the fat-soluble of drug (to be made
Prodrug)；3. inhibiting the metabolism of drug intestinal wall and outer row transhipment (enzyme and outer row's transporter inhibitors are added)；4. particle drug delivery system
(liposome, nanoparticle, micro emulsion, from micro emulsion)；5. increasing drug (to float in biologic adhesion preparation, stomach in the residence time of gastrointestinal tract
Floating piece) etc..Although these methods solve the problems, such as some BCSIII class drug Foral, for some high water solubilitys
BDDCSIII drugs, simple one kind using in the above method is extremely difficult to improve permeability, increases the purpose of Foral.
Nano medication is increasingly becoming the hot spot of preparation research and development, wherein nano-carrier preparation, as micella, liposome, nanocapsule,
There are many researchs such as nanoparticle, dendritic copolymer report.These carrier systems can by containing, combination, the modes such as electrostatic attraction
Drug is carried, but these carrier class nanometer formulation majorities have the problem of encapsulation rate is low, unstable, leakage and carrier material toxicity.
Nanocrystalline drug is by drug nanosizing itself, therefore advantage is：1. there is no the restriction of encapsulation rate, contained only in preparation a small amount of
Stabilizer and emulsifier, main ingredient is up to 90% or more, therefore therapeutic dose>The drug of 500mg may be made as nanocrystalline；2. dosage form
Diversification：It is nanocrystalline the dosage forms such as tablet, capsule or injection to be further made by drying；3. nanometer particle size is controllable；4. making
Preparation Method is simple, is easy to convert to clinic：High pressure or media milling process are hardly influenced by drug self property.The U.S. at present
FDA has 8 kinds and goes through to list.But nanocrystalline in currently available technology is to be mainly used for changing using water as decentralized medium
The problem of solubility of kind insoluble drug, there is not document report to solve the infiltrative nanometer crystal technique of water soluble drug.
Invention content
In view of this, the purpose of the present invention is to provide one kind to improve water soluble drug permeability, and then improve it
Water-soluble medicament nano crystalline substance of oiliness of bioavilability and preparation method thereof.
In order to achieve the above-mentioned object of the invention, the present invention provides following technical scheme：A kind of water-soluble medicament nano of oiliness is brilliant, packet
Include following components in percentage by weight：The oleaginous base of active medicine 1~50%, stabilizer 1~10% and surplus；The activity
Drug is BCSIII classes drug or BDDCSIII class drugs；The active medicine exists in the form of nanocrystalline.
Preferably, the oleaginous base is medium chain triglyceride, Unigly GO 102S, capric acid, octanoic acid, oleic acid, linoleic acid
One or more of with vegetablefats oil.
Preferably, the vegetablefats oil includes one or more of cottonseed oil, corn oil, tea oil and castor oil.
Preferably, the stabilizer is Unigly GO 102S, Sefsol 218, tricaprylin, single linoleic acid
Glyceride, fatty acid sorbitan, polysorbate, sorbitan fatty acid ester, polyoxyethylene fatty acid ester/ethers, polyoxy second
Alkene poiyoxypropylene copolymer class, casein, phosphatide, cholesterol, glycerin monostearate, cetanol, stearic acid, oleic acid, oleic acid
One or more of sodium, cholic acid, deoxycholic acid and Deoxycholic scid sodium salt.
Preferably, the average particle size of the water-soluble medicament nano crystalline substance of the oiliness is 100~1000nm.
The present invention provides the preparation methods of the water-soluble medicament nano crystalline substance of the oiliness, include the following steps：
1) stabilizer is uniformly mixed with oleaginous base and obtains oil phase liquid；
2) under 500~1500rpm stirring conditions, by active medicine aqueous solution and the injection oil phase liquid.
3) it is stirred 0.5~12h and obtains the water-soluble medicament nano crystalline substance of oiliness.
Preferably, further include being ultrasonically treated the water-soluble medicament nano crystalline substance of the oiliness after the step 2).
Preferably, the power of the supersound process is 20~300W, and the time of the supersound process is 1~60min.
The present invention provides another preparation methods of the water-soluble medicament nano crystalline substance of the oiliness, include the following steps：
High speed shear after active medicine, stabilizer are mixed with oleaginous base obtains pre-dispersed solution, the high speed shear
Rotating speed be 18000~30000rpm；
The pre-dispersed solution is carried out to high-pressure homogeneous, the water-soluble medicament nano crystalline substance of acquisition oiliness；The high-pressure homogeneous pressure
Power is 200~1200bar.
The present invention provides another preparation methods of the water-soluble medicament nano crystalline substance of the oiliness, include the following steps：
It is described it is high-pressure homogeneous replace with wet-milling, diameter 0.1~0.5mm zirconium oxide beads are added in wet milk and carry out wet-milling, obtain
It is brilliant to obtain the water-soluble medicament nano of oiliness, the grinding rotating speed is 1500rpm~5000rpm.
Beneficial effects of the present invention：The water-soluble medicament nano of oiliness provided by the invention is brilliant, by oleaginous base, stabilizer with
Active medicine mixing prepares nanocrystalline acquisition, and the water-soluble active drug is suspended in the form of nanocrystalline in oleaginous base；
The water-soluble medicament nano crystalline substance administration rear portion drug of oiliness directly can enter blood circulation by intestinal wall cell, a part
Under the action of pipe intestinal digesting liquid and bile, chylomicrons are formed, contribute to the infiltration and absorption of drug, to improve biology
Availability.Rat lymph testing result of the embodiment of the present invention shows not detecting para rice in Peramivir aqueous solution lymph
Wei, and the nanocrystalline lymph accumulation transhipment amount of oiliness Peramivir is 1.0 ± 0.4 μ g, it was demonstrated that drug can pass through lymphatic transport, into
One step increases drug effect.
The water-soluble medicament nano of oiliness provided by the invention is brilliant, since active medicine is suspended in oiliness base in the form of nanocrystalline
In matter, oleaginous base density is small, it is easy to further be concentrated by the modes such as centrifuging, can effectively prepare high concentration, steady
The water-soluble medicament nano of fixed oiliness is brilliant, and water-soluble medicament nano crystalline substance can be prepared into oral solution or be filled in capsule after concentration.
After water-soluble medicament nano crystalline substance administration of the present invention, a part of water-soluble medicament nano crystalline substance can directly pass through intestinal wall
Cell enters blood circulation, and a part of water-soluble medicament nano crystalline substance forms chyle under the action of pipe intestinal digesting liquid and bile
Grain, contributes to drug absorption.Therefore, the bioavilability of water-soluble medicament nano crystalline substance greatly improves.
Part of the embodiment of the present invention is described with Peramivir (BCSIII classes drug) and hydroxyl radical carthamin yellow carthamus A
The oiliness of (BDDCSIII classes drug) is nanocrystalline.The nanocrystalline hour hand shape for grain size average out to 300nm of the Peramivir oiliness
Nanocrystalline, long-term room-temperature, which is placed 1 month, still to be stablized.Internal medicine shows the nanocrystalline biology of Peramivir oiliness for result of study
Availability can be improved to 30% (raw water solution bioavilability is 5%).Lymph intubation experiment shows control group Peramivir water
Solution can't detect in lymph, and Peramivir oiliness is nanocrystalline is absorbed in lymph higher, and Heavy metal is up to 1.02 for 24 hours
±0.4μg.The nanocrystalline hydroxyl radical carthamin yellow carthamus A oiliness is in lump shaped crystalline, and grain size is about 220nm, bioavilability with it is right
10.8 times are improved according to group hydroxyl radical carthamin yellow carthamus A aqueous solution, Cmax improves 18.1 times.
Description of the drawings
Fig. 1 is the nanocrystalline transmission electron microscope picture of Peramivir oiliness；
Fig. 2 is that rat vein gives Peramivir aqueous solution, takes orally to give Peramivir aqueous solution and take orally and give para
The drug-time curve (n=6) of the nanocrystalline 30mg/kg of rice Wei oiliness；
Fig. 3 is to take orally to give lymphatic transport amount curve (n=3) after Peramivir aqueous solution and the nanocrystalline 30mg/kg of oiliness；
Fig. 4 is the drug-time curve for the nanocrystalline 30mg/kg of Peramivir oiliness that Oral Administration in Rats gives not same amount oleaginous base
(n=3)；
Fig. 5 is the nanocrystalline transmission electron microscope picture of hydroxyl radical carthamin yellow carthamus A oiliness；
Fig. 6 is that Oral Administration in Rats gives hydroxyl radical carthamin yellow carthamus A aqueous solution and the nanocrystalline 1mg/ of hydroxyl radical carthamin yellow carthamus A oiliness
The drug-time curve (n=6) of kg.
Specific implementation mode
The present invention provides a kind of water-soluble medicament nano crystalline substances of oiliness, including following components in percentage by weight：Active medicine 1
~50%, the oleaginous base of stabilizer 1~10% and surplus；The active medicine is BCSIII classes drug or BDDCSIII class medicines
Object；The active medicine is suspended in the form of nanocrystalline in oleaginous base.
In the present invention, mass percent of the active medicine in the water-soluble medicament nano crystalline substance of oiliness is 1~50%, preferably
It is 10~45%.The water-soluble active drug is in BCS categorizing systems in the present invention, and dissolubility is good, permeability is low
Drug BCSIII classes drug or the compound BDDCSIII class drugs that dissolubility is good, metabolic rate is low；The activity in the present invention
Though the dissolubility of drug is good, it is using water as decentralized medium that usually this kind of active medicine is nanocrystalline, and permeability is low, biology
Availability is low, such as Peramivir, hydroxyl radical carthamin yellow carthamus A.
In the present invention, mass percentage of the stabilizer in the water-soluble medicament nano crystalline substance of the oiliness be 0.1~
10%, preferably 0.1~8%.The stabilizer uses the drug stabilizing agent of this field routine in the present invention, preferably
It is emulsifier or surfactant.The stabilizer is specifically Unigly GO 102S, propylene glycol Dan Xin in the present invention
Acid esters, Masine 35-1, fatty acid sorbitan, polysorbate, sorbitan fatty acid ester, gathers tricaprylin
Ethylene oxide aliphatic ester/ethers, poloxalkol class, casein, phosphatide, cholesterol, glycerol monostearate
One or more of ester, cetanol, stearic acid, oleic acid, enuatrol, cholic acid, deoxycholic acid and Deoxycholic scid sodium salt.In this hair
In bright, the effect of the stabilizer is suspending, prevents from assembling.The sorbester p17 used in embodiment is stabilizer.
The water-soluble medicament nano crystalline substance of oiliness provided by the invention includes the oleaginous base of surplus, in the present invention, the oiliness
Matrix is the nontoxic oily matter of this field routine, preferably medium chain triglyceride (WL1349), Unigly GO 102S, the last of the ten Heavenly stems
One or more of acid, octanoic acid, oleic acid, linoleic acid and vegetablefats oil.In the present invention, the vegetablefats oil is excellent
Choosing includes one or more of cottonseed oil, corn oil, tea oil and castor oil.In the present invention, active medicine is with nanometer
The form of grain is present in oleaginous base, and the oleaginous base does not influence the absorption of drug as a kind of matrix, but can promote
Medicated Permeation can improve 5~20 times of bioavilability.Simultaneously because active medicine is suspended in oiliness base in the form of nanocrystalline
In matter, oleaginous base density is small, it is easy to it is further concentrated by modes such as centrifugations, supplementary product consumption can be greatly lowered,
Be conducive to the delivering of large dosage of drug.
The present invention provides the preparation methods of the water-soluble medicament nano crystalline substance of the oiliness, include the following steps：1) will stablize
Agent is uniformly mixed with oleaginous base obtains oil phase liquid；2) under 500~1500rpm stirring conditions, by active medicine aqueous solution with
The oil phase liquid is injected, 0.5~12h of mixing is stirred for and obtains the water-soluble medicament nano crystalline substance of oiliness.In the present invention, by stabilizer with
Oleaginous base, which is uniformly mixed, obtains oil phase liquid.It is currently preferred to be mixed the stabilizer with oleaginous base by the way of stirring
It closes uniform.The rotating speed of the stirring is preferably 500~1500rpm, more preferably 1000~1200rpm in the present invention；
The time of the stirring is preferably 1~60min, more preferably 10~50min；The present invention is to the temperature of the stirring without spy
It is different to limit, it is 23~28 DEG C in specific implementation process of the present invention using ordinary room temperature.In the present invention, the stirring
The tool used is the stirring tool of this field routine, preferably magnetic stirring apparatus or mechanical agitator.
The present invention is after obtaining oil phase liquid, under 500~1500rpm stirring conditions, by active medicine aqueous solution and injection
The oil phase liquid.In the present invention, active medicine is preferably dissolved in water by the active medicine aqueous solution in 30~100 DEG C
The saturated solution of middle acquisition；The solution temperature is preferably 37~99 DEG C.The present invention is to the active medicine aqueous dissolution
Temperature afterwards does not limit, without maintaining temperature when dissolving.
The present invention under agitation injects the active medicine aqueous solution after obtaining the active medicine aqueous solution
Oil phase liquid obtains lotion；The rotating speed of the stirring is preferably 800~1300rpm, more preferably 900~1100rpm.
The present invention is preferably ultrasonically treated after obtaining the lotion.The work(of the supersound process in the present invention
Rate is preferably 20~300W, more preferably 50~250W；The time of the supersound process is preferably 1~60min, more preferably
10~50min.
The present invention is stirred again after obtaining the lotion ultrasound, and the time of the stirring is preferably 0.5h~12h, more
Preferably 4~10h.Moisture in present invention active medicine aqueous solution described in whipping process is precipitated with stirring and obtains oil
Property water-soluble medicament nano it is brilliant.
In the present invention, the preparation method of the water-soluble medicament nano crystalline substance of the oiliness can also use second scheme, tool
Body includes the following steps：1A) active medicine, stabilizer are mixed with oleaginous base, the pre-dispersed solution of high speed shear acquisition, it is described
The rate of high speed shear is 18000~30000rpm；The pre-dispersed solution 2A) is subjected to the water-soluble medicine of high-pressure homogeneous acquisition oiliness
Object is nanocrystalline, and the high-pressure homogeneous pressure is 200~1200bar, preferably 500~1200bar.
In the present invention, active medicine, stabilizer are mixed with oleaginous base, high speed shear obtains pre-dispersed solution.
The gross mass of heretofore described oleaginous base and stabilizer and the volume ratio of active medicine aqueous solution are preferably (5~20)：1,
More preferably (10~15):1.The rotating speed of the high speed shear is preferably 18000~30000rpm in the present invention, more preferably
It is 19000~25000rpm；The time of the high speed shear is preferably 1~10min, more preferably 4~8min.In this hair
High speed shear described in bright preferably uses high-speed shearing machine to carry out；The effect of heretofore described high speed shear is by active drug
Object is well-dispersed in acquisition micron-level particle size pre-dispersed liquid in oleaginous base.
The present invention carries out the water-soluble drug of high-pressure homogeneous acquisition oiliness after obtaining pre-dispersed liquid, by the pre-dispersed solution and receives
Meter Jing.It is described in the present invention high-pressure homogeneous preferred using high pressure homogenizer progress；The high-pressure homogeneous program is preferred
For：Successively 200,400,600,800,1000, respectively recycle 2~10 times under the pressure of 1100bar, then with pressure 1200bar
Cycle 2~50 times；Described in the present invention high-pressure homogeneous time and cycle-index are according to high-pressure homogeneous pre-dispersed liquid in the process
Granularity determine, terminate when the average particle size of the pre-dispersed liquid is 100~1000nm.It is heretofore described high-pressure homogeneous
After to obtain the water-soluble medicament nano of oiliness brilliant.
In the present invention, described high-pressure homogeneous also to can be replaced wet-milling.In the present invention, the wet-milling preferably uses wet
Grinding machine carries out, and zirconium oxide bead is filled in the wet milk；The diameter of the zirconium oxide bead is preferably 0.1mm~0.5mm, institute
The volume for stating zirconium oxide bead is preferably 20~100mL.Heretofore described wet-milling is specially optional from 1500~5000rpm
1 to 3 rotating speed grinding, each rotating speed grind 1~3h；In specific implementation process of the present invention, the rotating speed is preferably
3000、4000、5000rpm.It is brilliant that the present invention obtains oiliness water-soluble medicament nano after the wet-milling.
It is preferred further comprising the steps of after the present invention obtains the water-soluble medicament nano crystalline substance of oiliness：Centrifuge the oil
Property it is water-soluble nanocrystalline, after the water-soluble medicament nano crystalline substance of 5~80% oiliness of underlying collection total volume carries out twice ultrasonic suspension
It is prepared into the drug of different dosage forms；Heretofore described dosage form is preferably soft capsule preparation or oral liquid.In this hair
The rotating speed centrifuged described in bright is preferably 500~5000rpm；More preferably 1000~3000rpm, the centrifugation time are excellent
Choosing is 1~60min, more preferably 5~40min.In the present invention preferably from underlying collection total volume after the centrifugation
10~70%, more preferably 20~60%.The twice ultrasonic processing power is preferably 20~300W in the present invention, more
Preferably 50~250W；The time of the twice ultrasonic processing is preferably 1~60min, more preferably 5~40min.
The soft capsule preparation or oral liquid formulations use the preparation method of this field routine in the present invention.
Water-soluble medicament nano crystalline substance of oiliness provided by the invention and preparation method thereof is carried out with reference to embodiment detailed
Illustrate, but they cannot be interpreted as limiting the scope of the present invention.
First, the two kinds of model drugs used in the embodiment of the present invention are carried out as described below：
Two model drug Peramivirs and hydroxyl radical carthamin yellow carthamus A belong to typical BCSIII and BDDCSIII medicines
Object, they have respectively represented two major classes drug：Amphoteric ion type antiviral drugs and Chinese medicine flavonoids drug.Wherein, para rice
Wei is the first-line drug of clinical treatment heavy type influenza virus.But due to Foral limitations, only Peramivir chloride injection
Liquid (Chinese medicines quasi-word H20130029) lists, and greatly limits its clinical application.
And hydroxyl radical carthamin yellow carthamus A is the principal monomer in safflower water soluble ingredient, belongs to chalcone glycosides compound.It
Clinically there is stasis-dispelling and pain-killing, reduce cholesterol, blood pressure lowering and other effects.Recently the study found that hydroxyl radical carthamin yellow carthamus A also has
There are the protection heart, cerebral anoxia, anti-cerebral thrombus and antitumaous effect.But country's hydroxyl radical carthamin yellow carthamus A only has injection (freeze-dried powder at present
Needle), key reason is hydroxyl radical carthamin yellow carthamus A Foral ＜ 1.7%；It furthers investigate its root and essentially consists in extremely strong water
Row's effect outside dissolubility and P-gp, this is also exactly the low common problems of flavonoids Chinese medicine Foral.Therefore, this project selects two major classes
Typical high molten hypotonic drug has stronger representative meaning.
Embodiment 1
It uses Peramivir for research object, its physicochemical property and medicine is conducted in-depth research for feature：1. using
The degree of dissociation and lipophilicity of fask oscillating method and potentiometric determination Peramivir, the results showed that its alkalinity pKa=12.5, it is acid
PKa=4.2.Illustrate that the medicine is typical amphoteric ion (Zwitterions), is ionic state under physiological ph conditions；And pa
Rummy Wei logP=-1.4, lipophilicity is poor, and solubility is high in water；2. the medicine is in Caco-2 Premeabilisation of cells models, apparent infiltration
Coefficient (Papp) average out to 3.29 ± 0.73 × 10-7Cm/s belongs to hypotonicity drug；Outer row leads (Re) average out to 0.23, explanation
There is no the influence of outer row's effect；Two actives of Organic Cation Transporter Gene (OATs) and organic anion transit peptides (OATP1B) turn
Fortune body takes part in the active absorption process of drug；3. after rat oral gavage 30mg/kg, Foral=4.4%.4. mouse tissue is distributed
Researches show that content highest in kidney, and inorganization cumulative appearance；5. after rat intravenous Peramivir amounts of the 72h through homaluria be to
The 81.08% of dose, after people's Single-dose intravenous instillation 300mg, the amount through homaluria is the 82.25% of dosage for 24 hours, is fully said
Bright drug is mainly from homaluria in the form of original shape.Based on the above results, illustrate that the medicine is typical BDDCSIII, Foral is low
Mechanism be：1. being ionic state under the conditions of physiological pH, fat-soluble difference, Passive diffusion is poor；2. process of osmosis has active transporter
Participation, but transit dose very little；3. medicine stability is good, most of quickly to be eliminated through kidney in the form of original shape.
1. the nanocrystalline research of Peramivir oil matrix
The nanocrystalline preparation of 1.1 Peramivir oil matrix
Precision weighs about 24mg Peramivirs, and 0.3mL dissolved in purified water (can suitably heat and increase solubility) is added；Another essence
Magnetic agitation 5min mixings under close weighing WL13493.95g and sorbester p17 (sorbitan fatty acid ester) 50 μ L, 1000rpm,
Obtain oil phase.Under 1500rpm rotating speeds, by pharmaceutical aqueous solution injection oil, to form the breast of W/O under the speed of 15mL/min
Liquid.In 60W ultrasound 10min, magnetic agitation (500rpm) 12h, until nanocrystalline abundant solidification.Obtain 6mg/mL Peramivir oil bases
Matter is nanocrystalline.
The nanocrystalline grain size of 1.2 Peramivir oil matrix
It takes a certain amount of oil matrix nanocrystalline, n-hexane is added and dilutes 5-10 times.Using Darwin's laser particle analyzer
MS2000 measures grain size.The result shows that nanocrystalline average grain diameter is 291.3nm, PDI=0.174.
The nanocrystalline microscopic appearance of 1.3 Peramivir oil matrix
Oil matrix is nanocrystalline to be washed 6 times repeatedly with n-hexane, and n-hexane ultrasound is resuspended, transmission electron microscope observing.The result shows that pa
Rummy Wei is in the oil acicular crystal, and major diameter is about 200nm.The results are shown in Figure 1, and scale is 200nm in Fig. 1.
The nanocrystalline Pharmacokinetics in Rat research of 1.4 Peramivir oil matrix
Male SD rat, 200 ± 20g of weight, respectively vein give Peramivir aqueous solution, oral give Peramivir water
Solution and the oral Drug-time curve given after the nanocrystalline 30mg/kg of Peramivir oiliness in blood plasma are as shown in Figure 2.Pharmacokinetics
Parameter is shown in Table 1.
1 rat vein of table gives Peramivir aqueous solution, takes orally to give Peramivir aqueous solution and take orally and give para rice
The nanocrystalline 30mg/kg of Wei oiliness
By result as it can be seen that Oral Administration in Rats is to aqueous solution and oiliness nano-crystal, there were significant differences by AUC and Cmax, aqueous solution mouth
Foral=4.2 ± 1.4% of clothes administration, and nanocrystalline Foral=27.5 ± 4.5% of oiliness, improve 6.5 times.Meanwhile oiliness
Nanocrystalline to compare aqueous solution, CL and V are significantly reduced.
The nanocrystalline lymphatic transport quantifier elimination of 1.5 Peramivir oil matrix,
Male SD rat, 200 ± 20g of weight apply intestines system lymph intubation.Respectively take orally give Peramivir aqueous solution and
Lymph transhipment amount is shown in Fig. 3 after the nanocrystalline 30mg/kg of oiliness.By experimental result as it can be seen that not having in Peramivir aqueous solution lymph
Detect Peramivir, and the nanocrystalline lymph accumulation transhipment amount of oiliness is 1.0 ± 0.4 μ g.
Influence of the 1.6 oil matrix dosages to Peramivir Foral
Male SD rat, 200 ± 20g of weight take orally give Peramivir aqueous solution and Peramivir oiliness nanometer respectively
Brilliant 30mg/kg.Its medium oil nanocrystalline oil matrix dosage is respectively 1,3,5 and 10mL/kg.After administration when medicine in blood plasma
Curve is as shown in figure 4, the figure among Fig. 4 is the partial enlarged view of master map.
By result as it can be seen that after the Peramivir oiliness of Oral Administration in Rats difference oil base quality is nanocrystalline, respectively Foral
(1mL)=19.6 ± 1.5%, Foral (3mL)=23.1 ± 5.6%, Foral (5mL)=27.5 ± 4.5% and Foral
(10mL)=26.2 ± 1.5%.In addition to 1mL, Foral is not significantly different, and each group Foral compares aobvious with oral solution
It writes and improves between 4.7~6.5 times.
Embodiment 2
The nanocrystalline research of 2 hydroxyl radical carthamin yellow carthamus A oil matrix
The nanocrystalline preparation of 2.1 hydroxyl radical carthamin yellow carthamus A oil matrix
About 10g hydroxyl radical carthamin yellow carthamus As are weighed, soybean oil 90g, WL134910g and sorbester p17 1g, Ultra- is added
TurraxT-25 (high speed dispersor) 24000rpm high speed shears 10min makes drug uniformly be suspended in oil solution.Liquid is fallen
In the grinding chamber (zirconium oxide bead for including 0.3mm) for entering wet milk (Wall treasured nanoscale grinder (DYNO-MILLNPM)), grind
Rotating speed is ground from each 1h of 3000rpm, the nanocrystalline suspension within the scope of 200~300nm of average grain diameter is made.
The nanocrystalline grain size of 2.2 hydroxyl radical carthamin yellow carthamus A oil matrix
It takes a certain amount of oil matrix nanocrystalline, n-hexane is added and dilutes 5-10 times.Using Darwin's laser particle analyzer
MS2000 measures grain size.The result shows that nanocrystalline average grain diameter is 318.5nm, PDI=0.133.
The nanocrystalline microscopic appearance of 2.3 hydroxyl radical carthamin yellow carthamus A oil matrix
Oil matrix is nanocrystalline to be washed 6 times repeatedly with n-hexane, is dried under reduced pressure, is used transmission electron microscope observing.The result shows that hydroxyl is red
Anthoxanthin A nanocrystalline is in lump shaped crystalline, and grain size about 200-300nm is shown in Fig. 5, and scale is 500nm in figure.
The nanocrystalline Pharmacokinetics in Rat research of 2.4 hydroxyl radical carthamin yellow carthamus A oil matrix
Male SD rat, 200 ± 20g of weight take orally give hydroxyl radical carthamin yellow carthamus A aqueous solution and oiliness is nanocrystalline respectively
1mg/kg.Following Fig. 6 of Drug-time curve after administration in blood plasma, pharmacokinetic parameter are shown in Table 2.
2 Oral Administration in Rats of table gives hydroxyl radical carthamin yellow carthamus A aqueous solution and the dominant dynamic ginseng of the nanocrystalline 1mg/kg of oiliness
Number (n=6)
By result as it can be seen that Oral Administration in Rats is to aqueous solution and oiliness nano-crystal, there were significant differences by AUC and Cmax, relatively water-soluble
Liquid, the nanocrystalline Foral of oiliness improve 10.8 times, and Cmax improves 18.1 times.Meanwhile oiliness is nanocrystalline compared to aqueous solution, CL and V are
It significantly reduces.
By above-described embodiment it is found that the water-soluble medicament nano crystalline substance of oiliness provided by the invention by improve drug permeability,
It solves the problems, such as that the bioavilability of two kinds of resistant medicine peramivirs and hydroxyl radical carthamin yellow carthamus A is low, not only promotes two kinds of medicines
Oral administration preparation is researched and developed and the research and development of the oral preparation of the development of clinical application or this two major classes drug provide thinking.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of water-soluble medicament nano of oiliness is brilliant, which is characterized in that including following components in percentage by weight：Active medicine 1~
50%, the oleaginous base of stabilizer 0.1~20% and surplus；The active medicine is BCSIII classes drug or BDDCSIII class medicines
Object；The active medicine exists in the form of nanocrystalline.
2. the water-soluble medicament nano of oiliness according to claim 1 is brilliant, which is characterized in that the oleaginous base is medium chain triglyceride
One or more of three esters, Unigly GO 102S, capric acid, octanoic acid, oleic acid, linoleic acid and vegetablefats oil.
3. the water-soluble medicament nano of oiliness according to claim 2 is brilliant, which is characterized in that the vegetablefats oil includes cotton
One or more of seed oil, corn oil, tea oil and castor oil.
4. the water-soluble medicament nano of oiliness according to claim 1 is brilliant, which is characterized in that the stabilizer is polyglycereol oleic acid
Ester, Sefsol 218, tricaprylin, Masine 35-1, fatty acid sorbitan, polysorbate, Sorbitan
Alcohol fatty acid ester, polyoxyethylene fatty acid ester/ethers, poloxalkol class, casein, phosphatide, cholesterol,
One kind in glycerin monostearate, cetanol, stearic acid, oleic acid, enuatrol, cholic acid, deoxycholic acid and Deoxycholic scid sodium salt
Or it is several.
5. the water-soluble medicament nano of oiliness according to Claims 1 to 4 any one is brilliant, which is characterized in that the oiliness water
The nanocrystalline average particle size of soluble drug is 100~1000nm.
6. the preparation method of the water-soluble medicament nano crystalline substance of oiliness described in Claims 1 to 5 any one, includes the following steps：
1) stabilizer is mixed with oleaginous base, obtains oil phase liquid；
2) under 500~1500rpm stirring conditions, active medicine aqueous solution is injected into the oil phase liquid；
3) it is brilliant to obtain the water-soluble medicament nano of oiliness by 0.5~12h of stirring.
7. preparation method according to claim 6, which is characterized in that further include being ultrasonically treated the oil after the step 2)
Property water-soluble medicament nano it is brilliant.
8. preparation method according to claim 7, which is characterized in that the power of the supersound process is 20~300W, institute
The time for stating supersound process is 1~60min.
9. the preparation method of the water-soluble medicament nano crystalline substance of oiliness described in Claims 1 to 5 any one, includes the following steps：
High speed shear after active medicine, stabilizer are mixed with oleaginous base, obtains pre-dispersed solution, and the high speed shear turns
Speed is 18000~30000rpm；
The pre-dispersed solution is carried out to high-pressure homogeneous, the water-soluble medicament nano crystalline substance of acquisition oiliness, the high-pressure homogeneous pressure is
200~1200bar.
10. the preparation method of the water-soluble medicament nano crystalline substance of oiliness according to claim 9, includes the following steps：
It is described it is high-pressure homogeneous replace with wet-milling, the zirconium oxide bead that 0.1~0.5mm of diameter is added in wet milk carries out wet-milling, obtains
The water-soluble medicament nano of oiliness is brilliant, and the grinding rotating speed of the wet-milling is 1500rpm~5000rpm.
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| CN113081965A (en) * | 2021-04-16 | 2021-07-09 | 烟台大学 | Sensitivity and H based on ROS2S-responsive multifunctional liposome and preparation method and application thereof |
| WO2021258326A1 (en) * | 2020-06-24 | 2021-12-30 | 中国人民解放军军事科学院军事医学研究院 | Application of midazolam nanocrystals in preparing drug for improving blood-brain barrier permeability |
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| WO2021258326A1 (en) * | 2020-06-24 | 2021-12-30 | 中国人民解放军军事科学院军事医学研究院 | Application of midazolam nanocrystals in preparing drug for improving blood-brain barrier permeability |
| CN113081965A (en) * | 2021-04-16 | 2021-07-09 | 烟台大学 | Sensitivity and H based on ROS2S-responsive multifunctional liposome and preparation method and application thereof |
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