CN100515389C - Medicinal emulsion adapted for difficultly soluble medicine and method for preparing the same - Google Patents
Medicinal emulsion adapted for difficultly soluble medicine and method for preparing the same Download PDFInfo
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- CN100515389C CN100515389C CNB2004100528165A CN200410052816A CN100515389C CN 100515389 C CN100515389 C CN 100515389C CN B2004100528165 A CNB2004100528165 A CN B2004100528165A CN 200410052816 A CN200410052816 A CN 200410052816A CN 100515389 C CN100515389 C CN 100515389C
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Abstract
The invention discloses an oil-in-water medicinal emulsion suitable for water-indissoluble medicaments which comprises, (1) 0.5-50 weight parts of active medicament, which contains water-indissoluble substance with a dissolvability of 0.001-10000mg/l of water at 25 deg. C, (2) 5-300 weight parts of emulsifying agent, (3) 0.5-200 weight parts of fatty oil, (4) 500-1500 weight parts of water. The disclosed medicinal emulsion has little side effect, and is especially suitable for extracts of traditional Chinese medicines.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to a kind of Emulsion, its preparation method and using method that is applicable to the poorly water soluble drugs composition.
Background technology
Parenteral canal drug administration, particularly intravenously administrable are that medicine enters one of intravital important channel.The parenteral canal drug administration of shipwreck soluble drug (comprising fat-soluble biomacromolecule) is one of challenging problem of being faced of medicament scholar always.Its direct injection such as poorly water soluble drugs such as paclitaxel, ciclosporin, cortisone, griseoflavin, ibuprofen, stable, interleukin-2, etoposide have very big side effect, may cause haemolysis, phlebitis, high sensitization, organ failure and even death.Make Emulsion and can eliminate or alleviate these side effect, and can obviously increase the dissolubility of poorly water soluble drugs and fat-soluble medicine, improve its bioavailability, strengthen the stability of labile drug, and might control the release of medicine.
Tradition Emulsion particle size range is at 0.25-25 μ m, is divided into two kinds of oil-in-water type and water-in-oil types from structure.In recent years, submicron emulsion and microemulsion are as a kind of application of pharmaceutical carrier, and especially poorly water soluble drugs is at the parenteral canal drug administration, and particularly the application of intravenously administrable aspect more and more causes people's attention.Submicronized emulsion is between traditional Emulsion and microemulsion, and its particle size range is between 100nm-300nm, and the same with traditional Emulsion is the thermodynamic instability system, but compares with traditional Emulsion, and particle diameter is more even, and system is more stable, and the dispersion of medicine is higher.The microemulsion structure found by Englishize scholar Sculman and partner thereof in nineteen forty-three, and proposed in 1974 by Attwood the earliest as a kind of drug-supplying system.Microemulsion is made up of water, oil phase, surfactant as a kind of special Emulsion, can be divided into O/W type, w/o type and co-continuous mutually on the structure.But microemulsion and traditional Emulsion have a great difference.Microemulsion is a thermodynamic stable system, and spontaneous formation, and evenly generally between 10-100nm, traditional Emulsion then is thermodynamic unstable system to particle diameter, and particle diameter is inhomogeneous and greater than 100nm.
After China entered the nineties, Emulsion was as a kind of application of pharmaceutical carrier, and especially lipophilic, poorly water soluble drugs are at the parenteral canal drug administration, and particularly the application of intravenously administrable aspect has had very big progress.
Chinese medicine with thousands of years long histories is the culture rarity of motherland.The curative effect of Chinese medicine is clear and definite, the drug effect gentleness, and toxic and side effects is little.But because the many active component in the Chinese medicine are the slightly water-soluble material, traditional oral, outer application mode administration is difficult to improve its bioavailability, has caused the Chinese medicine dose big, takes effect and waits shortcoming slowly.Hindered further developing of Chinese medicine.The scope of application of Chinese medicine has been expanded in the appearance of Chinese medicine greatly.
The important function of Chinese medicine performance in clinical anxious critical illness treatment provides new means for the Chinese traditional treatment emergency case, has played important function for improving the whole medical level of the traditional Chinese medical science.Chinese medicine both inherited the advantage that the Chinese medicine curative effect is comprehensive, toxic and side effects is low, possessed again the Western medicine effect rapidly, the advantage of determined curative effect; Simultaneously, overcome also that some effective ingredient is difficult to absorbed problem with other mode administrations in the Chinese medicine, its advantage is conspicuous.
Look back the development course of China's Chinese medicine injection, begin the history in existing more than 60 year so far from the earliest injection of Radix Bupleuri.After the foundation, Chinese medicine has entered a new developing period, and no matter the development and production of Chinese medicine injection are still all obtaining significant progress in amount aspect the matter.It is more than 20 kind of representative with the YINHUANG ZHUSHEYE that the sixties have developed." go all out with Chinese herbal medicine motion " of the seventies makes Chinese medicine enter developing period rapidly, interrelated data report sum reaches kind more than 700～1400, but because the big and most product technology of blindness not too reaches a standard, side effect is big, gradually be out in the cold after the Culture Revolution, stayed not so good impression for doctor, patient, seldom last now.Recent two decades comes, and vast Chinese medicine scientific worker uses modern science and technology under Chinese medical theory instructs, develop a collection of Chinese medicine injection.Especially after " Chinese medicine investigative technique guideline " put into effect, Chinese medicine went through again to produce successively.
Up to the present, " Chinese pharmacopoeia is recorded 2 of Chinese medicine kinds to version in 2000, and " national drug standards catalogue " (Gansu Province Drug Testing Institute, 2002) are recorded 122, and present like this have the Chinese medicine of production authentication code above 120.
In general, all contain water miscible in the Chinese medicine in the active component and active component slightly water-soluble.And mostly China's Chinese medicine injection is with water to be the solution of solvent, and small part is an injectable powder.For fat-soluble, slightly water-soluble active component wherein, traditional Chinese medicine is generally by adding cosolvent (as tween etc.) or increasing its dissolubility by effective ingredient is carried out chemical modification.When adding cosolvent (as tween), have a large amount of cosolvents and inject in the body, human body is had certain toxic and side effects.The chemical modification meeting changes the physicochemical property of effective ingredient, reduces its stability and curative effect.In addition, side effect such as injection site pain, phlebitis, haemolysis often appear in the Chinese medicine injection.If make Emulsion particularly microemulsion and submicron emulsion then can improve and eliminate these side effect, and improve the dissolubility of slightly water-soluble composition in the Chinese medicine, strengthen the stability of labile element.
97118433.9) and patent application " a kind of preparation technology and prescription that contains Semen Coicis oil and Oleum Fructus Bruceae composite Nano Emulsion " (application number: 03111312.5) disclose a kind of injection emulsion formulations and preparation method that contains Semen Coicis oil and Oleum Fructus Bruceae complex, fabaceous lecithin, glycerol, water for injection respectively, and the latter also can add poloxamer in Emulsion and sorbitol is made microemulsion formulation patent " a kind of antineoplastic Chinese medicine Emulsion and the preparation method " (patent No.:.
Patent application " Rhizoma Curcumae Longae Extracts Injection and Preparation Method and Use " (application number: 02117217.X), patent application " Curcuma wenyujin extract Injection And Preparation Method And Use " (application number: 02117218.8), 02117219.6) and patent application " sesquiterpene injection and its production and use " (application number: 02117086.X) disclose Rhizoma Curcumae Longae extract respectively patent application " Elemene Injection and Preparation Method and Use " (application number:, common turmeric extract, the new injection type of elemene and sesquiterpene compounds comprises Emulsion, microemulsion.Emulsion, microemulsion by active component, surfactant, come from vegeto-animal oils and fats and water for injection is formed.
Patent " anticancer lichee lectone medicine and preparation method thereof the " (patent No.: 01107594.1) disclose the method for preparing emulsion of forming by anticancer lichee lectone medicine, soybean oil, lecithin and water for injection.
Patent application " nut oil that from the plant kernel, extracts, its extracting method, pharmaceutical composition and application " (application number: 02108864.0) disclose the preparation of the Emulsion of forming by the nut oil that from Semen Ziziphi Spinosae, Pericarpium Zanthoxyli, Semen Juglandis, extracts, phospholipid, Semen sojae atricolor (or egg yolk) lecithin, glycerol.
Chinese patent application " a kind of " Maolansu " fat emulsion as antineoplastic medicine and preparation method " (application number: 03117069.2) disclose a kind of lipomul that contains hair orchid element, soybean oil, soybean phospholipid, glycerol and water for injection and preparation method thereof.
Patent application " Herba Solidaginis injection fat milk and preparation method " (application number: 02136369.2) disclose the injection fat milk of forming by active component, Oleum Glycines, injection phospholipid and water for injection that contains a kind of Hemerocallis citrina Baroni effective site.
Patent application " grease-contained bifendate composition of liquid medicine " (application number: 03146030.5), a kind of grease-contained bifendate composition of liquid medicine is disclosed, can be made into Emulsion, oil preparation, wherein Emulsion is made up of bifendate, oils and fats, emulsifying agent, has improved lipotropy, slightly water-soluble bifendate bioavailability in vivo greatly.
Patent application " a kind of cancer therapy drug novel formulation-yew alcohol micro-emulsion " (application number: 02153674.0) disclose a kind of microemulsion formulation that contains paclitaxel, Polyethylene Glycol-DSPE, egg yolk lecithin phatidylcholine.
Patent application " preparation that contains pharmaceutical grade protein or antigenic lipotropy microgranule and comprise this microgranule " (patent No.: 00800043.3) disclose a kind of emulsion methods that contains protein or peptide medicament or antigen active composition.
Make a general survey of the existing intravenous injection emulsion of China, of less types, or be only applicable to single active component (as bifendate and paclitaxel), or mostly be folk prescription Chinese medicine and active component or be oil: as Semen Coicis oil and the Oleum Fructus Bruceae in patent 97118433.9 and the patent 03111312.5; Patent 02117217.X, 02117218.8,02117219.6 and 02117086.X in sesquiterpene volatile oil; Nut oil in the patent 02108864.0; Herba Solidaginis oil in the patent 02136369.2; Or ester: as the annonaceous acetogenins in the patent 01107594.1; Or be only soluble in the liposoluble substance of organic solvent: as the hair orchid element in the patent 03117069.2.And for herbal mixture, because its active component is very complicated, so its Emulsion kind is few.In addition, the existing Emulsion particle diameter of great majority is bigger, and the uniformity is also relatively poor, so side effect is big and curative effect still is difficult to satisfactory.
As previously mentioned, the many active component in the Chinese medicine are lipophilic slightly water-soluble material, and therefore, this area presses for exploitation and is applicable to slightly solubility active component medicinal Emulsion (especially herbal mixture extract), that side effect is little.
Summary of the invention
The purpose of this invention is to provide a kind of shipwreck soluble drug medicinal Emulsion (especially Chinese medicine extract), that side effect is little and preparation method thereof that is applicable to.
In a first aspect of the present invention, provide a kind of oil-in-water type medicinal Emulsion, this Emulsion contains following composition:
(a) active medicine of 0.5-50 weight portion, described active medicine contains the material of slightly water-soluble, and described slightly water-soluble material is the 0.001-10000mg/ premium on currency at 25 ℃ dissolubility;
(b) emulsifying agent of 5-300 weight portion, described emulsifying agent is selected from down group:
(b1) be selected from down the chemical compound of organizing: VE succinic acid macrogol ester, Polyethylene Glycol, polyethylene glycol monolaurate, polyoxyethylene poly-oxygen propylene aether block polymer poloxamer, glyceryl monooleate, acetoglyceride;
(b2) phospholipid;
(b3) at least two kinds of mixture that emulsifying agent constitutes by (b1) and (b2);
(c) oils and fats of 0.5-200 weight portion, described oils and fats is selected from down group:
(c1) C
1-C
7Short chain oils and fats (as an acetin, glyceryl triacetate);
(c2) C
8-C
10Medium chain length fatty acid triglyceride (as Oleum Cocois);
(c3) C
11-C
20Long-chain fat acid glyceride (as soybean oil, olive oil, safflower oil, Semen Maydis oil, fish oil);
(c4) from the oils and fats of (a) active medicine;
(c5) alpha-tocopherol, alpha-tocopherol acetate;
(c6) at least two kinds of mixture that oils and fats constitutes by above-mentioned (c1), (c2), (c3), (c4) and (c5);
(d) water of 500-1500 weight portion;
And the mean diameter of breast grain is between 10～1000nm in the Emulsion.
In another preference, described active medicine is selected from down group:
(i) chemical compound of single slightly water-soluble is selected from: paclitaxel, ciclosporin, cortisone, griseoflavin, ibuprofen, stable, interleukin-2 or etoposide;
(ii) contain water miscible chemical compound or/and the Chinese medicine extract of the chemical compound of slightly water-soluble is selected from: MAILUONING extract, Radix Salviae Miltiorrhizae extract, compound Salviae Miltiorrhizae extract, living arteries and veins extract, Rhizoma Zingiberis Recens extract, Radix Bupleuri extract, Herba Houttuyniae extract, Chimonanthus Nitens extract or the clean extract of refreshment.
In another preference, described emulsifying agent is VE succinic acid macrogol ester, PEG400, polyethylene glycol monolaurate, Pluronic F-127, glyceryl monooleate, lecithin or its combination.
In another preference, described active medicine is a Chinese medicine extract, as MAILUONING extract.
In another preference, described emulsifying agent is VE succinic acid macrogol ester, lecithin or its combination.
In another preference, described oils and fats is C
8-C
10Medium chain length fatty acid triglyceride (as Oleum Cocois).
In another preference, this Emulsion also contains the additive of organizing under being selected from of 1-200 weight portion: isoosmotic adjusting agent, pH regulator agent, cosolvent.
In another preference, described isoosmotic adjusting agent is selected from down group: glycerol, propylene glycol, glucose, maltose, maltodextrin or its combination;
Described pH regulator agent is selected from down group: sodium hydroxide, potassium hydroxide, hydrochloric acid, glycine, lysine;
Described cosolvent is that alpha-tocopherol is or/and the alpha-tocopherol acetate.
In another preference, wherein the quantity of active medicine is the 2.5-25 weight portion; The quantity of emulsifying agent is the 30-130 weight portion; Greasy quantity is the 10-100 weight portion.
In another preference, the mean diameter of oil phase is between 10～350nm in the Emulsion.
In another preference, described Emulsion is injection.
In a second aspect of the present invention, a kind of the present invention of preparation is provided the preparation method of above-mentioned medicinal Emulsion, comprise step:
I) under nitrogen protection, the emulsifying agent of 5-300 weight portion is heated to 40-80 ℃, described emulsifying agent is selected from down group:
(b1) be selected from down the chemical compound of organizing: VE succinic acid macrogol ester, Polyethylene Glycol, polyethylene glycol monolaurate, polyoxyethylene poly-oxygen propylene aether block polymer poloxamer, glyceryl monooleate, acetoglyceride;
(b2) phospholipid;
(b3) at least two kinds of mixture that emulsifying agent constitutes by (b1) and (b2);
The oils and fats that ii) adds the 0.5-200 weight portion, mixing is heated to 40-80 ℃, and wherein said described oils and fats is selected from down group:
(c1) C
1-C
7Short chain oils and fats (as an acetin, glyceryl triacetate);
(c2) C
8-C
10Medium chain length fatty acid triglyceride (as Oleum Cocois);
(c3) C
11-C
20Long-chain fat acid glyceride (as soybean oil, olive oil, safflower oil, Semen Maydis oil, fish oil);
(c4) from the oils and fats of poorly water soluble drugs;
(c5) alpha-tocopherol, alpha-tocopherol acetate;
(C5) at least two kinds of mixture that oils and fats constitutes by above-mentioned (c1), (c2), (c3), (c4) and (c5);
The poorly water soluble drugs that iii) adds the 0.5-50 weight portion, mixing;
Iv) add emulsifying agent, stirring promptly gets oil phase, wherein step I) and iv) in the emulsifying agent total amount that adds be the 5-300 weight portion;
V) under inert gas atmosphere and shear agitation, the temperature that oil phase is slowly added to the 500-1500 weight portion is in 40-80 ℃ the water, colostrum;
Vi) colostrum is carried out homogenize, obtain Emulsion.
In another preference, in described method, the heating-up temperature scope in step (i) is 50-55 ℃, and (temperature range of water for injection is 60-70 ℃ v) in step.
In another preference, in described method, (ii) also can add the isotonic agent of 10-100 weight portion and/or the cosolvent of 10-100 weight portion simultaneously in step;
In another preference, in described method, step (v) and (vi), also comprise step: with the pH regulator agent regulate pH to pH value be 4-10;
In another preference, in described method, (the homogenize condition vi) is as follows: use two steps high pressure homogenize machine, first step homogenize pressure 480kg/cm in step
2-680kg/cm
2, the second step homogenize pressure 80kg/cm
2-140kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly.Perhaps, directly under agitation slowly add isotonic agent (on demand), placed ultrasound bath 30 ± 20 minutes, obtain homogeneous, transparent Emulsion to first Ruzhong;
In another preference, in described method, comprise that also step (vii): gained Emulsion is filtered and sterilizes, obtain aseptic medicinal Emulsion.
Description of drawings
Fig. 1 has shown the particle diameter difference situation of oil phase in Emulsion example of the present invention.Abscissa is a particle diameter, and unit is (nm), and vertical coordinate is a percent by volume.
Fig. 2 has shown the particle diameter difference situation of oil phase in another Emulsion example of the present invention.Abscissa is a particle diameter, and unit is (nm), and vertical coordinate is a percent by volume.
The specific embodiment
The inventor is through extensive and deep research, find that this area cosolvents such as tween commonly used have stronger haemolysis side effect, therefore through a large amount of experiments, by to emulsifying agent, greasy choose reasonable, prepared the Emulsion that is applicable to poorly water soluble drugs, and in emulsion formulations, significantly reduce the consumption of tween, even do not use tween.Medicinal Emulsion of the present invention is the medicinal Emulsion of even, the stable oil-in-water type of a kind of particle size distribution, and the quality that is fit to Chinese medicine improves and the dosage form improvement, increases the dissolubility and the stability of slightly water-soluble active component in the Chinese medicine.Also can be used as the drug administration by injection system of poorly water soluble drugs.
The present invention is applicable to the Emulsion of shipwreck soluble drug, and its composition mainly comprises: (a) slightly water-soluble active medicine; (b) emulsifying agent; (c) oils and fats; (d) water.
The slightly water-soluble active medicine:
Being used for the material that active medicine of the present invention contains slightly water-soluble, perhaps itself is the material of slightly water-soluble.Described slightly water-soluble material is the 0.001-10000mg/ premium on currency at 25 ℃ dissolubility, is the 0.01-1000mg/ premium on currency at 25 ℃ dissolubility preferably, more preferably is the 0.01-500mg/ premium on currency, is the 0.01-200mg/ premium on currency at 25 ℃ dissolubility best.
Active medicine of the present invention can be single slightly water-soluble chemical compound, as paclitaxel, ciclosporin, cortisone, griseoflavin, ibuprofen, stable, interleukin-2 or etoposide etc.; It also can be the multi-component mixture that contains water soluble compound or do not contain water soluble compound, Chinese medicine extract particularly is as MAILUONING extract, Radix Salviae Miltiorrhizae extract, compound Salviae Miltiorrhizae extract, give birth to arteries and veins extract, Rhizoma Zingiberis Recens extract, Radix Bupleuri extract, the clean extract of refreshment, Herba Houttuyniae extract, Chimonanthus Nitens extract etc.
The consumption of active medicine is the 0.5-50 weight portion, more preferably is the 2.5-25 weight portion.In final Emulsion, the concentration of active medicine is 0.5mg/ml-50mg/ml normally, wherein preferable range 2.5mg/ml-25mg/ml.
Emulsifying agent
Play emulsification in the present invention.Emulsifying agent has the hydrophilic and oleophilic group simultaneously, can be enclosed in around dispersive oil phase, to prevent the assembly again of oil phase.Emulsifying agent can be: one or more
1. the chemical compound that obtains in the mode of isozygotying into is as VE succinic acid macrogol ester, Polyethylene Glycol, polyethylene glycol monolaurate, polyoxyethylene poly-oxygen propylene aether block polymer poloxamer, glyceryl monooleate, acetoglyceride etc.;
2. phospholipid comprises stemming from the phospholipid that egg yolk, Semen sojae atricolor, cattle, pig etc. are organized, as lecithin, soybean phospholipid etc.; Also comprise the phospholipid that obtains in the mode of isozygotying into, as phospholipid.
Wherein, preferably VE succinic acid macrogol ester, PEG400, polyethylene glycol monolaurate, Pluronic F-127 (a kind of commercial poloxamer product), lecithin, glyceryl monooleate.Wherein most preferred emulsifying agent is that the VE succinic acid macrogol ester is or/and lecithin.
The consumption of emulsifying agent is generally the 5-300 weight portion, more preferably is the 30-130 weight portion.In final Emulsion, the concentration of emulsifying agent is 5mg/ml-300mg/ml normally, wherein preferable range 30mg/ml-130mg/ml.
Oils and fats
The oils and fats that is used for medical Emulsion of the present invention is not particularly limited, and can be medical Emulsion field oils and fats commonly used.Representational example comprises (but being not limited to): short chain (C
1-C
7) oils and fats, as an acetin, glyceryl triacetate; Or/and medium chain (C
8-C
10) fatty glyceride, as Oleum Cocois; Or/and long-chain fat acid glyceride such as soybean oil, olive oil, safflower oil, Semen Maydis oil, fish oil; Alpha-tocopherol is or/and the alpha-tocopherol acetate; Or its combination.Wherein, medium chain (C preferably
8-C
10) fatty glyceride.
If, contain oil compounds in the active medicine, or itself be exactly oil compounds, then other greasy consumption can reduce, and does not even use.Therefore, lubricant component also can comprise the oils and fats that derives from active medicine in the present invention.
Greasy consumption is generally the 0.5-200 weight portion, preferably is the 1-150 weight portion, more preferably is the 10-100 weight portion.In final Emulsion, greasy concentration is 0.5mg/ml-200mg/ml normally, and wherein preferable range is 10mg/ml-100mg/ml.
Water
Water is solvent of the present invention, forms successive water in Emulsion.Can be used for water of the present invention and be not particularly limited, can be pure water, sterilized water or distilled water, also can be normal saline.
Optional additive
Emulsion prescription of the present invention can also add this area various additives commonly used, as isoosmotic adjusting agent, pH regulator agent, cosolvent, antioxidant, antiseptic, flavouring agent etc.
PH regulator agent: regulate the pH value of product, so that the pH value of product is close with the pH value of human body fluid as far as possible.Can be alkali such as sodium hydroxide, potassium hydroxide; Also can be acid such as hydrochloric acid, glycine, lysine.
Isoosmotic adjusting agent: regulate the osmotic pressure of product, so that the osmotic pressure of product equates with the osmotic pressure of blood of human body.Can be glycerol, propylene glycol, glucose, maltose, maltodextrin etc.Wherein, preferably glycerol, maltose.
Cosolvent: though cosolvent is not particularly limited, particularly preferred cosolvent is that alpha-tocopherol is or/and the alpha-tocopherol acetate among the present invention.In addition, in Emulsion of the present invention without tween as cosolvent.
Preparation method
Another aspect of the present invention provides the preparation method (two-step method) of this Emulsion:
The first step: preparation colostrum
Under nitrogen protection; an amount of emulsifying agent is heated to 40-80 ℃ of (preferred 50-55 ℃) fusing; add oils and fats (also adding optional isotonic agent or/and cosolvent simultaneously or successively) mixing on demand; be heated to 40-80 ℃ (preferred 50-55 ℃); stir and add an amount of poorly water soluble drugs down; can add an amount of emulsifying agent on demand behind the mixing, stirring promptly gets oil phase.Add an amount of 40-80 ℃ of (preferred 60-70 ℃) fresh water for injection in another container, nitrogen filled protection under shearing blender high-speed stirred, slowly adds water with oil phase with wire, continues fully to stir, and gets colostrum.
As required, available optional an amount of pH regulator agent is regulated the Emulsion pH value to needed pH value scope, and as pH4-10, preferably 5-9 more preferably is 6-8.
Second step: preparation Emulsion
Preparation Emulsion can prepare with conventional method.The condition of preferred preparation Emulsion is as follows:
(a) use two steps high pressure homogenize machine, first step homogenize pressure 480kg/cm
2-680kg/cm
2, the second step homogenize pressure 80kg/cm
2-140kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly.
Perhaps:
(b) directly under agitation slowly add isotonic agent (on demand), place ultrasound bath about 30 ± 20 minutes, obtain homogeneous, transparent Emulsion to first Ruzhong.
Gained Emulsion just can obtain the Emulsion finished product through steps such as filtration, fill, sterilizations.
Dosage form and administering mode
Emulsion of the present invention can be with conventional method preparation cost field commonly used various emulsion dosage forms, especially injection, and this is because the present invention is applicable to that the mean diameter of breast grain in the medicinal Emulsion of poorly water soluble drugs is usually between 10～350nm.
Medicinal Emulsion of the present invention should be with the mode administration of parenteral road, as administering modes such as vein, subcutaneous, intramuscular injection.
Beneficial effect compared with prior art:
1. the present invention is that the medicine (comprising herbal mixture extract and pure compound such as paclitaxel) that contains the slightly water-soluble chemical compound provides a kind of novel drug administration carrier.
2. the present invention is not only applicable to the slightly water-soluble chemical compound of one pack system, and is applicable to multi-component mixture (wherein can water-soluble component be arranged or/and the slightly water-soluble component), is specially adapted to list, herbal mixture extract.
3. the invention provides stable, the uniform Emulsion of particle diameter, its osmotic pressure is similar to blood, and is non-stimulated to wall of vein, can import through PeV.
4. to be wrapped in the oil phase owing to drug main among the present invention, not influence the pH or the osmotic pressure of water, so little to tissue injury.
5. will be wrapped in the oil phase owing to drug main among the present invention, medicine does not contact closely with plasma protein, thereby the decline of the protein binding rate of medicine, and reduced by the influence of internal milieu, and stability increases.
6. the present invention does not use tween, monohydric alcohol or other that adjuvant of clinical side effects is arranged, and has increased clinical application safety.
7. product of the present invention can not use phospholipid according to practical situation, has avoided the haemolysis because of using phospholipid to cause.
8. product of the present invention is rapid-action, good effect, dosage can lower.
9. the resulting product of the present invention is more stable than Chinese medicine aqueous solution injection quality.
10. product of the present invention is compared with aqueous solution injection, and the Emulsion microsphere can make active component be easier to enter cell membrane, is easier to penetrate blood brain barrier.
Can be used for industrialized medicinal Emulsion technology of preparing 11. the invention provides.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
The preparation of embodiment 1 MAILUONING prescription medicinal substances extract
Get Radix Ophiopogonis Flos Lonicerae 500 grams, HERBA DENDROBII 500 grams, Zhejiang Radix Scrophulariae 500 grams and Radix Achyranthis Bidentatae 500 grams, be positioned over after fully mixing by the process of Chinese invention patent 92107848.X and decoct with water secondary, filtered while hot in the reactor.Merge the secondary supernatant, put R501B star sea rotary evaporator (Wuxi City star sea king's biochemical equipment company limited), be evaporated to semi-solid in 70～80 ℃.Add the ethanol precipitating, standing over night, tipping takes out ethanol, still uses R501B star sea rotary evaporator in 45～55 ℃ of decompression recycling ethanols.Surplus alcohol flooding to the greatest extent after, with ethyl acetate extraction 7～10 times, combining extraction liquid, water-bath is reclaimed and is also eliminated ethyl acetate, medicinal substances extract.
The preparation of embodiment 2 Emulsions 1
Under nitrogen protection, 5 gram VE succinic acid macrogol esters are heated to 50-55 ℃ of fusing; add 5 gram Miglyol 812N (available from German Sasol company) and 2.5 and restrain the glycerol mixings; be heated to 50-55 ℃; stir and add the MAILUONING extract that 1 gram embodiment, 1 extraction obtains down; add 0.6 gram injection lecithin behind the mixing again, stir and promptly got oil phase in 2 minutes.Add about 100ml60-70 ℃ fresh water for injection in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18 UltraTberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get brown emulsion.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this colostrum is 1.84 μ m.
Regulate the pH to 8.8-9.2 of colostrum with proper amount of sodium hydroxide.
(Germany), the first step is regulated homogenize pressure to 600kg/cm for APV-1000, APV Homegeniser Group to use two steps high pressure homogenize machine
2, second step re-adjustment homogenize pressure is to 100kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 265nm.
The preparation of embodiment 3 Emulsions 2
Under nitrogen protection, 3 gram VE succinic acid macrogol esters are heated to 50-60 ℃ of fusing and 1 gram Miglyol 812N (available from German Sasol company) and 2.5 and restrain the glycerol mixings; be heated to 50-60 ℃; stir the 1 gram embodiment 1 of adding down and extract the MAILUONING extract that obtains, stir and promptly got oil phase in 2 minutes.Add about 100ml60-70 ℃ fresh water for injection in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18 Ultra Tberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get brown emulsion.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this colostrum is 0.67 μ m.
Regulate the pH to 8.8-9.2 of colostrum with proper amount of sodium hydroxide.
(Germany), the first step is regulated homogenize pressure to 600kg/cm for APV-1000, APV Homegeniser Group to use two steps high pressure homogenize machine
2, second step re-adjustment homogenize pressure is to 100kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 245nm.
The preparation of embodiment 4 Emulsions 3
Under nitrogen protection, 5 gram VE succinic acid macrogol esters are heated to 50-60 ℃ of fusing; restrain the glycerol mixings with 3 gram alpha-tocopherols, 5 gram Miglyol 812N (available from German Sasol company) and 2.5; be heated to 50-60 ℃; stir and add the MAILUONING extract that 1 gram embodiment, 1 extraction obtains down; add 1.2 gram injection lecithin behind the mixing again, stir and promptly got oil phase in 2 minutes.Add about 100ml60-70 ℃ fresh water for injection in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18Ultra Tberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get brown emulsion.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this colostrum is 0.3 μ m.
Regulate the pH to 8.8-9.2 of colostrum with proper amount of sodium hydroxide.
(Germany), the first step is regulated homogenize pressure to 600kg/cm for ApV-1000, APV Homegeniser Group to use two steps high pressure homogenize machine
2, second step re-adjustment homogenize pressure is to 100kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 226nm.
Gained Emulsion filters through filter and pour in the transfusion bag (bottle) of sterilization sealing under nitrogen protection.
Product after the fill places in the rotating type sterilization still, and moist heat sterilization cools off fast with water when sterilization finishes, and obtains product.
The preparation of embodiment 5 Emulsions 4
Under nitrogen protection, 3 gram VE succinic acid macrogol esters are heated to 50-60 ℃ of fusing; restrain the glycerol mixings with 5 gram Miglyol 810N (available from German Sasol company) and 2.5; be heated to 50-60 ℃; stir and add the MAILUONING extract that 1 gram embodiment, 1 extraction obtains down; add 0.6 gram injection lecithin behind the mixing again, stir and promptly got oil phase in 2 minutes.Add 100ml60-70 ℃ of fresh water for injection in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18 Ultra Tberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get brown emulsion.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this colostrum is 0.3 μ m.
Regulate the pH to 8.8-9.2 of colostrum with proper amount of sodium hydroxide.
(Germany), the first step is regulated homogenize pressure to 600kg/cm for APV-1000, APV Homegeniser Group to use two steps high pressure homogenize machine
2, second step re-adjustment homogenize pressure is to 100kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 231nm.
Gained Emulsion filters through filter and pour in the transfusion bag (bottle) of sterilization sealing under nitrogen protection.
Product after the fill places in the rotating type sterilization still, and moist heat sterilization cools off fast with water when sterilization finishes, and obtains product.
The preparation of embodiment 6 Emulsions 5
Under nitrogen protection, 5 gram VE succinic acid macrogol esters are heated to 50-60 ℃ of fusing; restrain the glycerol mixings with 5 gram alpha-tocopherols, 5 gram Miglyol 810N (available from German Sasol company) and 2.5; be heated to 50-60 ℃; stir and add the MAILUONING extract that 1 gram embodiment, 1 extraction obtains down; add 1.2 gram injection lecithin behind the mixing again, stir and promptly got oil phase in 2 minutes.Add about 100ml60-70 ℃ fresh water for injection in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18Ultra Tberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get brown emulsion.
Regulate the pH to 8.8-9.2 of colostrum with proper amount of sodium hydroxide.
(Germany), the first step is regulated homogenize pressure to 600kg/cm for APV-1000, APV Homegeniser Group to use two steps high pressure homogenize machine
2, second step re-adjustment homogenize pressure is to 140kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 293nm.
Gained Emulsion filters through filter and pour in the transfusion bag (bottle) of sterilization sealing under nitrogen protection.
Product after the fill places in the rotating type sterilization still, and moist heat sterilization cools off fast with water when sterilization finishes, and obtains product.
The preparation of embodiment 7 Emulsions 6
Under nitrogen protection, 5 gram VE succinic acid macrogol esters are heated to 50-60 ℃ of fusing; with 3 gram alpha-tocopherols, 7 gram PEG400s and 1 gram Pluronic F-127 (available from German BASF AG) mixing; be heated to 50-60 ℃; stir the 1 gram embodiment 1 of adding down and extract the MAILUONING extract that obtains, stir and promptly got oil phase in 2 minutes.Add about 100ml60-70 ℃ fresh water for injection in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18 Ultra Tberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get brown emulsion.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this colostrum is 2.57 μ m.
Regulate the pH to 8.8-9.2 of colostrum with proper amount of sodium hydroxide.
(Germany), the first step is regulated homogenize pressure to 620kg/cm for APV-1000, APV Homegeniser Group to use two steps high pressure homogenize machine
2, second step re-adjustment homogenize pressure 140kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 296nm.
Gained Emulsion filters through filter and pour in the transfusion bag (bottle) of sterilization sealing under nitrogen protection.
The preparation of embodiment 8 Emulsions 7
Under nitrogen protection, 5 gram VE succinic acid macrogol esters are heated to 50-60 ℃ of fusing; with 1 gram alpha-tocopherol and 5 gram glyceryl monooleate mixings; be heated to 50-60 ℃, stir the 1 gram embodiment 1 of adding down and extract the MAILUONING extract that obtains, stir and promptly got oil phase in 2 minutes.In another container, add about 100ml60-70 ℃ fresh water for injection; adding 5 gram glucoses makes molten entirely; nitrogen filled protection; at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18 Ultra Tberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get brown emulsion.
Regulate the pH to 8.8-9.2 of colostrum with proper amount of sodium hydroxide.
(Germany), the first step is regulated homogenize pressure to 540kg/cm for APV-1000, APV Homegeniser Group to use two steps high pressure homogenize machine
2, second step re-adjustment homogenize pressure is to 80kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 240nm.
Gained Emulsion filters through filter and pour in the transfusion bag (bottle) of sterilization sealing under nitrogen protection.
The preparation of embodiment 9 Emulsions 8
Under nitrogen protection, 5 gram VE succinic acid macrogol esters are heated to 50-60 ℃ of fusing; with 1 gram alpha-tocopherol and 5 gram polyethylene glycol monolaurate mixings; add 1 gram embodiment 1 under the heated and stirred and extract the MAILUONING extract that obtains, stir and promptly got oil phase in 2 minutes.In another container, add about 100ml60-70 ℃ fresh water for injection; adding 5 gram glucoses makes molten entirely; nitrogen filled protection; at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18 Ultra Tberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get brown emulsion.
(Germany), the first step is regulated homogenize pressure to 480kg/cm for APV-1000, APV Homegeniser Group to use two steps high pressure homogenize machine
2, second step re-adjustment homogenize pressure is to 100kg/cm
2,, obtain even Emulsion with colostrum homogenize repeatedly.
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 323nm.
Gained Emulsion filters through filter and pour in the infusion bottle of sterilization sealing under nitrogen protection.
The preparation of embodiment 10 Emulsions 9
Under nitrogen protection, 5 gram VE succinic acid macrogol esters are heated to 50-60 ℃ of fusing; with 3 gram Miglyol 812N (available from German Sasol company) mixing; be heated to 50-60 ℃ of fusing; stir and add the MAILUONING extract that 1 gram embodiment, 1 extraction obtains down; add 0.6 gram lecithin behind the mixing again, stir and promptly got oil phase in 2 minutes.Add about 100ml60-70 ℃ fresh water for injection in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18 Ultra Tberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get brown emulsion.
Stir down and restrain glycine and 10 gram maltose, placed ultrasound bath ultrasonic 30 minutes, obtain homogeneous, transparency emulsion to the slow adding 6 of above-mentioned emulsion.
(UK) recording this microemulsion mean diameter is 27.86nm for Mastersizer S, Malvern Instruments Ltd. to use light scattering particle size determination instrument.
The preparation of embodiment 11 Emulsions 10
Under nitrogen protection, 5 gram VE succinic acid macrogol esters are heated to 50-60 ℃ of fusing; restrain the glycerol mixings with 3 gram Miglyol 812N (available from German Sasol company) and 2.5; be heated to 50-60 ℃ of fusing; stir and add the MAILUONING extract that 1 gram embodiment, 1 extraction obtains down; add 0.6 gram lecithin behind the mixing again, stir and promptly got oil phase in 2 minutes.Add about 100ml60-70 ℃ fresh water for injection in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18 Ultra Tberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get brown emulsion.
Place ultrasound bath ultrasonic 30 minutes, and obtained homogeneous, transparent light brown emulsion.
The result:
(Malvern UK) measures particle diameter for Mastersizer S, Malvern Instruments Ltd., and measurement result shows that mean diameter is 27.34nm as shown in Figure 1 with light scattering particle size determination instrument.
Stability:
Placed 10 days for 60 ℃, color and luster is deepened slightly.Mean diameter is 27.49nm.
The preparation of embodiment 12 Emulsions 11
Under nitrogen protection, 3.0 gram VE succinic acid macrogol esters are heated to 50-60 ℃ of fusing; restrain the glycerol mixings with 1.0 gram alpha-tocopherols, 3.0 gram Miglyol 812N (available from German Sasol company) and 2.5; be heated to 50-60 ℃ of fusing; stir and add the MAILUONING extract that 1.0 gram embodiment, 1 extraction obtains down; add 0.6 gram lecithin behind the mixing again, stir and promptly got oil phase in 2 minutes.Add the about 100ml60-70 ℃ of fresh water for injection that gets in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18 Ultra Tberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get brown emulsion.
Place ultrasound bath ultrasonic 30 minutes, and obtained homogeneous, transparent dark-grey emulsion.
The result:
(Malvern UK) measures particle diameter for Mastersizer S, Malvern Instruments Ltd., and measurement result shows that mean diameter is 66.02nm as shown in Figure 2 with light scattering particle size determination instrument.
Stability:
Placed 10 days for 60 ℃, color and luster is constant.Mean diameter is 62.07nm.
The preparation of embodiment 13 Emulsions 12
Get acetoglyceride 5 grams and be dissolved in 10ml water for injection, add 2.5 gram glycerol, 1.2 gram lecithin, the back that stirs adds MAILUONING extract 1 gram, stirs 5 minutes, treats to add soybean oil 10 grams behind the homodisperse, stirs, and promptly gets oil phase.
Add about 90ml fresh water for injection in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes IKA T18 Ultra Tberrax) under, oil phase is slowly added water with wire; continue to stir 10 minutes, get milky homogeneous emulsion.
(Germany), the first step is regulated homogenize pressure to 620kg/cm for APV-1000, APV Homegeniser Group to use two step high pressure homogenization machines
2, second step re-adjustment homogenize pressure 140kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly.
(UK) recording this microemulsion mean diameter is 270nm for Mastersizer S, Malvern Instruments Ltd. to use light scattering particle size determination instrument.
Embodiment 14 rabbit ear blood vessel perfusion experiments
The preparation of contrast MAILUONING ZHUSHEYE: get embodiment 1 and extract the MAILUONING extract (being equivalent to 500 gram crude drugs) that obtains and add the 200ml water recently distilled, heated and stirred, cooling is filtered.Add the 4ml tween 80, stir, regulate pH value to 8.8-9.2, add water recently distilled and obtain contrasting MAILUONING ZHUSHEYE to 500ml with 20%NaOH solution.
Test method: get healthy rabbits (New Zealand white rabbit), intravenous injection chlorpromazine (15mg/kg) anesthesia, it is fixing to lie on one's side, and gets vascular forceps and clamps rabbit ear root blocking blood flow.Splash into happy formula liquid by the positive middle part of rabbit ear tremulous pulse, cut the outer rim vein, wash down vessel inner blood.Give happy formula liquid.The effusive happy formula number of drops of record per minute 5 minutes.Give test specimen more respectively, the record per minute flows out and dripped several 15 minutes, observes medication front and back per minute and on average flows out the variation of dripping number.Every rabbit ear is made single test, 50 centimetres of liquid levels, and test temperature is a room temperature.
The result:
Get the Emulsion 9 (MAILUONING microemulsion) that embodiment 10 makes, Emulsion 5 (MAILUONING submicron emulsion), the contrast MAILUONING ZHUSHEYE that embodiment 6 makes respectively, be diluted to 25% solution, make rabbit ear blood vessel perfusion experiment in accordance with the law with happy formula liquid.The results are shown in Table one.
The rabbit ear blood vessel perfusion experiment result of table one MAILUONING microemulsion, submicron emulsion and contrast injection
| The medicine name | Average per minute drips number before the administration | Average per minute drips number after the administration | After dripping several administrations, average per minute increases % |
| The contrast injection | 35.4 | 39.2 | 10.7％ |
| Submicron emulsion (embodiment 6) | 51.0 | 59.3 | 16.3％ |
| Microemulsion (embodiment 10) | 23.2 | 27.5 | 18.5％ |
Discuss:
The result shows that Emulsion of the present invention can more effectively make insoluble drug be dissolved in the oil-in-water emulsion, thereby brings into play drug effect better.Compare with the contrast MAILUONING ZHUSHEYE, the medicinal Emulsion of the present invention is because insoluble drug (MAILUONING extract) meltage is big, therefore drug effect is more obvious, thereby the rabbit ear blood vessel of augmentation test rabbit more effectively, wherein average per minute flows out to drip to compare from 10.7% before number and the administration and is increased to 16.3% after the embodiment 6 prepared submicronized emulsion administrations, relatively amplification reaches 52%, and the made microemulsion of embodiment 10 more is increased to 18.5% from 10.7%, and amplification reaches 72% relatively.
The preparation of embodiment 15 Emulsions 13
Under nitrogen protection; restrain paclitaxel with 20 milliliters of anhydrous alcohol solutions with 0.3; add 3.0 gram VE succinic acid macrogol esters, 1.0 gram alpha-tocopherols, 3.0 gram Miglyol 810N (available from German Sasol company), 0.6 gram lecithin and 2.5 gram glycerol in solution, gained solution is put Rotary Evaporators in 40 ℃ of decompression recycling ethanols.Add about 100ml fresh water for injection in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes, IKA T18 Ultra Tberrax) under, the oil phase of removing behind the ethanol is slowly added water with wire; continue to stir 10 minutes, get homogeneous off-white color colostrum.
(Germany), the first step is regulated homogenize pressure to 680kg/cm for APV-1000, APV Homegeniser Group to use two steps high pressure homogenize machine
2, second step re-adjustment homogenize pressure is to 140kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly.
(UK) recording this microemulsion mean diameter is 330nm for Mastersizer S, Malvern Instruments Ltd. to use light scattering particle size determination instrument.
The preparation of embodiment 16 Emulsions 14
Under nitrogen protection; restrain paclitaxel with 30 milliliters of anhydrous alcohol solutions with 0.75; add 7.5 gram VE succinic acid macrogol esters, 4.5 gram Miglyol 812N (available from German Sasol company), 1.8 gram lecithin and 3.75 gram glycerol in solution, gained solution is put Rotary Evaporators in 40 ℃ of decompression recycling ethanols.Add about 150ml fresh water for injection in another container, nitrogen filled protection is at shearing blender high-speed stirred (per minute 22; 000 changes, IKA T18 Ultra Tberrax) under, the oil phase of removing behind the ethanol is slowly added water with wire; continue to stir 10 minutes, get milky emulsion.
Use little fluidization instrument (M-110E, Microfluidics, Newton, MA 02464, USA) under the 1700Bar operating pressure by little fluidizator mixing chamber, handle through little fluidization of 40-50 stroke, the Emulsion particle diameter is reduced gradually.
(UK) recording this microemulsion mean diameter is 220nm for Mastersizer S, Malvern Instruments Ltd. to use light scattering particle size determination instrument.
Gained Emulsion room temperature is placed and was still stablized in 30 days.
The preparation of embodiment 17-24 Emulsion 15-22
Prepare Emulsion 15,16,17,18,19,20,21,22 according to embodiment 10 identical methods, difference only is to replace 1 gram MAILUONING extract respectively with 1 gram Radix Salviae Miltiorrhizae extract, compound Salviae Miltiorrhizae extract, living arteries and veins extract, Rhizoma Zingiberis Recens extract, Radix Bupleuri extract, Herba Houttuyniae extract, Chimonanthus Nitens extract or the clean extract of refreshment.
Measure particle diameter with same procedure, the measurement result mean diameter is between the 20-60nm.After 10 days, the amplitude of variation of mean diameter is less than 10% through 60 ℃ of placements.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (11)
1. medicinal Emulsion of oil-in-water type is characterized in that this Emulsion contains following composition:
(a) active medicine of 2.5-25mg/ml, described active medicine contains the material of slightly water-soluble, and described slightly water-soluble material is the 0.001-10000mg/ premium on currency at 25 ℃ dissolubility;
(b) emulsifying agent of 5-300 weight portion, described emulsifying agent is selected from down group:
(b1) be selected from down the chemical compound of organizing: VE succinic acid macrogol ester, Polyethylene Glycol, polyethylene glycol monolaurate, polyoxyethylene poly-oxygen propylene aether block polymer poloxamer, glyceryl monooleate, acetoglyceride;
(b3) by at least two kinds of mixture that emulsifying agent constitutes in (b1) and the phospholipid;
(c) oils and fats of 0.5-200 weight portion, described oils and fats is selected from down group:
(c2) C
8-C
10Medium chain length fatty acid triglyceride;
(c3) C
11-C
20The long-chain fat acid glyceride;
(c5) alpha-tocopherol, alpha-tocopherol acetate;
(c6) at least two kinds of mixture that oils and fats constitutes by above-mentioned (c2), (c3) and (c5);
(d) water of 500-1500 weight portion;
And the mean diameter of breast grain is between 10～1000nm in the Emulsion.
2. Emulsion as claimed in claim 1 is characterized in that, described active medicine is selected from down group:
(i) chemical compound of single slightly water-soluble is selected from: paclitaxel, ciclosporin, cortisone, griseoflavin, ibuprofen, stable, interleukin-2 or etoposide;
(ii) contain the chemical compound of slightly water-soluble or contain slightly water-soluble and the Chinese medicine extract of water soluble compound, be selected from: MAILUONING extract, Radix Salviae Miltiorrhizae extract, compound Salviae Miltiorrhizae extract, living arteries and veins extract, Rhizoma Zingiberis Recens extract, Radix Bupleuri extract, Herba Houttuyniae extract, Chimonanthus Nitens extract or the clean extract of refreshment.
3. Emulsion as claimed in claim 1, it is characterized in that described emulsifying agent is the combination of VE succinic acid macrogol ester, PEG400, polyethylene glycol monolaurate, Pluronic F-127, glyceryl monooleate, aforesaid compound or the combination of aforementioned at least a chemical compound and lecithin.
4. Emulsion as claimed in claim 1 is characterized in that, also has following feature:
(a) described active medicine is a Chinese medicine extract;
(b) described emulsifying agent is the combination of VE succinic acid macrogol ester or itself and lecithin;
Or
(c) described oils and fats is C
8-C
10Medium chain length fatty acid triglyceride.
5. Emulsion as claimed in claim 1 is characterized in that, this Emulsion also contains the additive of organizing under being selected from of 1-200 weight portion: isoosmotic adjusting agent, pH regulator agent, cosolvent.
6. Emulsion as claimed in claim 5 is characterized in that, described isoosmotic adjusting agent is selected from down group: glycerol, propylene glycol, glucose, maltose, maltodextrin or its combination;
Described pH regulator agent is selected from down group: sodium hydroxide, potassium hydroxide, hydrochloric acid, glycine, lysine.
7. Emulsion as claimed in claim 1 is characterized in that, wherein the quantity of active medicine is the 2.5-25 weight portion; The quantity of emulsifying agent is the 30-130 weight portion; Greasy quantity is the 10-100 weight portion.
8. Emulsion as claimed in claim 1 is characterized in that the mean diameter of oil phase is between 10～350nm in the Emulsion.
9. Emulsion as claimed in claim 5 is characterized in that, described Emulsion comprises alpha-tocopherol or/and the alpha-tocopherol acetate.
10. a preparation method for preparing the described medicinal Emulsion of claim 1 is characterized in that, comprises step:
I) under nitrogen protection, the emulsifying agent of 5-300 weight portion is heated to 40-80 ℃, described emulsifying agent is selected from down group:
(b1) be selected from down the chemical compound of organizing: VE succinic acid macrogol ester, Polyethylene Glycol, polyethylene glycol monolaurate, polyoxyethylene poly-oxygen propylene aether block polymer poloxamer, glyceryl monooleate, acetoglyceride;
(b2) phospholipid;
(b3) at least two kinds of mixture that emulsifying agent constitutes by (b1) and (b2);
The oils and fats that ii) adds the 0.5-200 weight portion, mixing is heated to 40-80 ℃, and wherein said oils and fats is selected from down group:
(c2) C
8-C
10Medium chain length fatty acid triglyceride;
(c3) C
11-C
20The long-chain fat acid glyceride;
(c5) alpha-tocopherol is or/and the alpha-tocopherol acetate;
(c6) at least two kinds of mixture that oils and fats constitutes by above-mentioned (c2), (c3) and (c5);
The poorly water soluble drugs that iii) adds the 0.5-50 weight portion, mixing;
Iv) add emulsifying agent, stirring promptly gets oil phase, and wherein said emulsifying agent is selected from (b1)-(b3), step I) and iv) in the emulsifying agent total amount that adds be the 5-300 weight portion;
V) under inert gas atmosphere and shear agitation, the temperature that oil phase is slowly added to the 500-1500 weight portion is in 40-80 ℃ the water, colostrum;
Vi) colostrum is carried out homogenize, obtains described medicinal Emulsion,
Wherein, contain the emulsifying agent of 5-300 weight portion in the described medicinal Emulsion, described emulsifying agent is selected from down group:
(b1) be selected from down the chemical compound of organizing: VE succinic acid macrogol ester, Polyethylene Glycol, polyethylene glycol monolaurate, polyoxyethylene poly-oxygen propylene aether block polymer poloxamer, glyceryl monooleate, acetoglyceride;
(b3) by at least two kinds of mixture that emulsifying agent constitutes in (b1) and the phospholipid.
11. preparation method as claimed in claim 10 is characterized in that, this method also has following feature:
(a) the heating-up temperature scope in step (i) is 50-55 ℃, and (temperature range of water for injection is 60-70 ℃ v) in step;
(b) at the (ii) also optional isotonic agent of 10-100 weight portion and/or the cosolvent of 10-100 weight portion of adding simultaneously of step;
(c) step (v) and (vi), also comprise step: with the pH regulator agent regulate pH to pH value be 4-10;
(d) (the homogenize condition vi) is as follows: use two steps high pressure homogenize machine, first step homogenize pressure 480kg/cm in step
2-680kg/cm
2, the second step homogenize pressure 80kg/cm
2-140kg/cm
2,, obtain uniform Emulsion with colostrum homogenize repeatedly; Perhaps, directly under agitation slowly add isotonic agent, placed ultrasound bath 30 ± 20 minutes, obtain homogeneous, transparent Emulsion to first Ruzhong; Or
(e) comprise that also step (vii): gained Emulsion is filtered and sterilizes, obtain aseptic medicinal Emulsion.
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| CNB2004100528165A CN100515389C (en) | 2004-07-14 | 2004-07-14 | Medicinal emulsion adapted for difficultly soluble medicine and method for preparing the same |
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| CN101074229B (en) | 2007-06-08 | 2010-09-01 | 无锡杰西医药科技有限公司 | 7-azaindirubin and 7-azaisoindigo derivative production and pharmaceutical use |
| CN101091890A (en) * | 2007-07-26 | 2007-12-26 | 沈阳药科大学 | Composite type emulsifier, and emulsion prepared by using the emulsifier, and preparation method |
| CN101524329B (en) * | 2007-09-20 | 2014-09-03 | 中国医学科学院药物研究所 | Bicyclo-ethanol submicron emulsion and preparation method thereof |
| CN102008436B (en) * | 2010-11-18 | 2012-07-18 | 中国药科大学 | Nocathiacin antibiotic medicament composition containing emulsifying agent |
| CN104027307A (en) * | 2014-07-02 | 2014-09-10 | 蚌埠医学院 | Medicine composition and preparing method thereof |
| CN107126415A (en) * | 2017-05-12 | 2017-09-05 | 苏州富士莱医药股份有限公司 | Injection drug-loaded emulsion and preparation method thereof |
| CN107088185B (en) * | 2017-06-09 | 2020-07-17 | 甘肃新天马制药股份有限公司 | Ozonized oil bicontinuous phase emulsion and preparation method and application thereof |
| CN110237034A (en) * | 2019-06-17 | 2019-09-17 | 宁波海奇合昇环能科技有限公司 | A kind of preparation method of the transparent aqueous dispersions of fat-soluble nutrients medicine |
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