CN102462656A - Macrolide immunosuppressant drug loaded nanomicelle and preparation method thereof - Google Patents
Macrolide immunosuppressant drug loaded nanomicelle and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a macrolide immunosuppressant drug loaded nanomicelle. The drug loaded system adopts a suitable pharmaceutical surfactant molecule and other pharmaceutical excipients which cooperate with drugs according to a certain ratio so as to prepare stable nano-size drug loaded micelle which can disperse uniformly in water. The drug loaded micelle system has characteristics of good water-solubility, small particle size and uniform distribution. Furthermore, the drug loaded micelle has fairly good freeze-drying stability. A freeze-dried powder can redissolve to form a pharmaceutical aqueous solution with an approximate particle size compared with that before freeze drying. The nanomicelle drug loaded system provided by the invention provides a simple and effective solution to the problems of poor water-solubility and complex preparation of the macrolide medicines.
Description
Technical field
The present invention relates to drug preparation technique, particularly water solublity carrier micelle of macrolide immunosuppressants medicine and preparation method thereof.
Background technology
The macrolide immunosuppressants medicine is one type of important organ transplantation clinical application.This type medicine is the metabolite of microorganism, adopts biofermentation to make usually.This type drug main will comprise sirolimus (Sirolimus); Claim rapamycin (Rapamycin), tacrolimus (Tacrolimus again; FK506), everolimus (Everolimus), for sirolimus (Temsirolimus not; CCI-779), ascosin (Ascomycin, FK520) and pimecrolimus (Pimecrolimus) (molecular structure is as follows).Everolimus and be the derivant that sirolimus obtains through chemical modification wherein for sirolimus not.And tacrolimus is enjoyed identical circulus jointly with ascosin, and pimecrolimus is the derivant that ascosin obtains through chemical modification.
The sirolimus everolimus replaces not sirolimus
Tacrolimus ascosin pimecrolimus
This type Macrocyclic lactone compounds generally is insoluble or slightly soluble in water because their characteristics of molecular structure all have low-down water solublity usually.For example, the dissolubility of tacrolimus in water is about 12 μ g/mL.So low water solublity has brought very big difficulty for the medicine preparation.Tacrolimus
injection; The dehydrated alcohol that needs 200mg/mL hydrogenation polyoxyethylene castor oil and 80% just can be processed the self emulsifying intravenous injection of 5mg/mL as solubilizing agent.The ratio of surfactant and medicine was up to 40: 1.The use of a large amount of polyoxyethylene castor oils is easy to bring other side reaction to the patient.The formulation problems that extremely low water solublity brings, and the low bioavailability that causes have brought a lot of restrictions for the preparation and the clinical practice of this medicine series, have had a strong impact on the performance of its drug effect.
In order to solve the water solublity problem of this type medicine, to improve its bioavailability, give full play to the curative effect of such medicine, people have adopted a lot of diverse ways, and drug molecule and preparation process are improved.Comprise mainly that wherein medicine is carried out corresponding PEG to be modified to form water-soluble prodrug (like CN102394867A; And US7605257,6432973 and 6331547); And adopt corresponding nanotechnology; Medicine is ground the particle (CN101175481A) of processing nano-scale, increase the dispersibility of medicine in water etc.Adopt PEG medicine to be modified chemical reaction and the separation and purification process that needs more complicated.Although the nanofabrication technique of Elan (CN101175481A) has obtained successful application on the preparation of rapamycin, its course of processing is complicated, and the control ratio of drug particles size and distribution of sizes is difficulty.Therefore, need to seek more simple and effective method and prepare good water solubility, the macrolide immunosuppressants pharmaceutical preparation that bioavailability is high.
Summary of the invention
The purpose of this invention is to provide a kind of stable water solublity macrolide immunosuppressant carrier micelle and preparation method thereof.Through the intensive research of inventor; Discovery one or more surfactant adjuvant molecules through selecting for use the available structure of pharmaceutical formulations to be fit to; And other corresponding medicinal adjuvant molecules cooperate with corresponding macrolide drug molecule by a certain percentage, can be processed into stable water-soluble nano carrier micelle.
Particularly, the present invention relates to following content:
A kind of water solublity macrolide immunosuppressant carrier micelle, it contains: the macrolide immunosuppressant medicine of (1) treatment effective dose; (2) constitute the surfactant pharmaceutic adjuvant molecule of forming by Polyethylene Glycol hydrophilic portion and hydrophobic portion of carrier micelle with medicine.
The ratio of surfactant adjuvant molecule and macrolide immunosuppressant medicine is 1: 1 to 400: 1, preferred 1: 1 to 40: 1, and more preferably 2: 1 to 20: 1.
Said in the present invention macrolide immunosuppressants medicine includes but not limited to sirolimus (Sirolimus); Claim rapamycin (Rapamycin), everolimus (Everolimus) again, replace not sirolimus (Temsirolimus; CCI-779), tacrolimus (Tacrolimus; FK506), pimecrolimus (Pimecrolimus) and ascosin (Ascomycin, FK520) derivant of macrolide such as grade.Its treatment effective dose is 1 μ g/ml-100mg/ml, preferred 0.1-50mg/ml, more preferably 0.25-25mg/ml.
Surfactant molecule generally is made up of hydrophilic and hydrophobic two parts.The amphiphilic surfactant molecule that the present invention selects for use can be two blocks or the molecule of many blocks.Its hydrophilic segment generally by but be not limited to hydrophilic polymers such as Polyethylene Glycol, methyl Polyethylene Glycol and form, preferred Polyethylene Glycol.Polyethylene Glycol has good water-solubility, nontoxic or low toxicity, and also its distinctive non-immunogenic has lowered the identification and the removing of reticuloendothelial system and macrophage.Thereby increase the life period of medicinal composition in blood circulation, the blood drug level of remaining valid reduces the medication number of times, improves therapeutic effect.
The molecular weight ranges of the hydrophilic portion Polyethylene Glycol of the surfactant molecule of selecting for use among the present invention is 100-20000, because of the difference of its hydrophobic portion has bigger difference.For by the hydrophobic segmental surfactant molecule of micromolecule; The molecular weight of its corresponding Polyethylene Glycol is also smaller; Like Polyethylene Glycol phospholipid, the Polyethylene Glycol vitamin E of deriving of deriving, and Polyethylene Glycol is derived the molecular weight ranges of Polyethylene Glycol wherein such as fatty acid at 100-5000.And for be made up of hydrophobic segmental amphiphile, amphiphilic molecule high molecular polymer, the molecular weight of the Polyethylene Glycol of corresponding hydrophilic portion is also than higher.The molecular weight ratio that the present invention generally selects hydrophilic portion and hydrophobic portion for use was greater than 1: 1 block polymer.
The hydrophobic segmental molecule that constitutes surfactant can be divided into two big types, and one type is long-chain high molecular hydrophobic polymer, and another kind of is the hydrophobic micromolecule of lipid of short chain, like phospholipid, fatty acid, cholesterol, and hydrophobic vitamin etc.
Long-chain high score subclass hydrophobic polymer comprises polyester such as polylactide (PLLA), gathers Acetic acid, hydroxy-, bimol. cyclic ester (PGA), polycaprolactone (PCL), polylactic acid (PLA), poly (lactic acid-glycolic acid) ester (PLGA); And polyoxypropylene (PPO) etc.; The molecular weight ranges of these polyester is 100-20000; Be preferably 500-10000, more preferably 1000-5000.Wherein polylactic acid and poly (lactic acid-glycolic acid) ester etc. all have been proved to be extraordinary biocompatibility and safety.What the polymer that polyoxypropylene and Polyethylene Glycol form comprised the BASF exploitation is hydrophobic segmental poloxamer (Ploxamer) series with polyoxypropylene; Like poloxamer 124,188,237,388 and 407; Also be widely used in the middle of the different preparations; Especially poloxamer 188, have good water solublity, often are used as solubilizing agent and use.
Adopt among the present invention to constitute hydrophobic segmental surfactant molecule by fatty acid be polyethyleneglycol-12-hydroxy stearin (Solutol HS-15).HS-15 is the surfactant amphiphile, amphiphilic molecule that derivative of fatty acid 12-hydroxy stearic acid ester and Polyethylene Glycol constitute.HS-15 is as a kind of water miscible non-ionic surface active agent, and its solubilising power is very strong, and HS-15 compares with polyoxyethylene castor oil and has low anaphylaxis characteristics.
It is polyethyleneglycol modified vitamin e succinate that the vitamin E that the present invention selects for use constitutes hydrophobic segmental surfactant molecule; Be vitamin E polyethylene glycol 1000 succinates (D-alpha-tocopheryl polyethyleneglycol 1000 succinate, TPGS).TPGS is a kind of good polymer amphiphile, amphiphilic molecule; Existing application widely in the different drug preparation; Except increasing the stability of drug, also have the water solublity and the bioavailability that can increase medicine, reduce the irritating effect of medicine to skin and tissue.
The surfactant amphiphile, amphiphilic molecule that the present invention adopted also can be polyethyleneglycol modified phospholipid.Phospholipid is to constitute biomembranous important composition composition, therefore, has fabulous biocompatibility.The used Polyethylene Glycol phospholipid of deriving among the present invention is to use Polyethylene Glycol phospholipid to be carried out chemical modification obtains.Usually Polyethylene Glycol is through covalently bound polar head part at phospholipid.Its phospholipid moiety can be but be not limited to phosphoglyceride.The construction features of phosphoglyceride is to have the hydrophilic head of substituted radical (containing ammonia alkali or the alcohols) formation that is linked to each other by phosphoric acid and the hydrophobic tail that is made up of fatty acid chain, and its hydrophilic polar head comprises PHOSPHATIDYL ETHANOLAMINE, phosphatidylcholine, phosphatidylinositols, Phosphatidylserine or diphosphatidylglycerol.The deutero-phospholipid of Polyethylene Glycol has successful application on liposome and other pharmaceutical dosage forms.
In the water solublity macrolide immunosuppressant carrier micelle of the present invention, the ratio of surfactant adjuvant and medicine (w/w) scope is 1: 1 to 400: 1, preferred 1: 1 to 40: 1, and more preferably 2: 1 to 20: 1.An important deficiency of common medicine carrying system of polymer micelle is exactly lower to many medicine medicine carrying efficient.Need a large amount of surfactant molecules to cooperate and to form metastable medicine-carried system with medicine.Yet introduce surfactant molecule in large quantities and can produce many toxic and side effects.Surfactant of selecting for use in the present invention and drug molecule have good coupling, and the carrier micelle of formation has higher medicine carrying efficient, under than the situation of low surfactant and drug ratios, can form stable carrier micelle.Thereby significantly reduced the use of surfactant molecule in preparation.Simultaneously, the carrier micelle of preparation has very high entrapment efficiency (＞98%, envelop rate=(dosage-residual undissolved dose)/dosage * 100%) in the present invention.
The carrier micelle system of preparation medicine carrying efficient height and good stability needs the molecular structure of medicine and surfactant that good coupling is arranged.Micellar kernel is the binding site of dewatering medicament; The interaction of surfactant hydrophobic portion and medicine directly affects (Yamamoto et al such as micellar stability, drug loading and drug release characteristics; What are determining factors for stable drug incorporation intopolymeric micelle carriers? Consideration on physical and chemical characters ofthe micelle inner core; Journal of Controlled Release 2007; 123,11-18.).The present invention finds that the carrier micelle that molecule and the surfactant molecule of macrolide immunosuppressants structure form shows higher medicine carrying efficient, has simultaneously that particle size is little, the particle homogeneous, and good advantages such as lyophilizing stability.Shown in Figure 1 is the particle diameter and the particle size distribution of a typical carrier micelle among the present invention of measuring of Ma Erwen nano particle size appearance (Nano-S).Can see among the figure that intensity and particle volume diameter have showed good concordance, show that distribution of particles has fabulous homogeneity in this solution system.Shown in Figure 2 for the typical carrier micelle among the present invention before lyophilizing with lyophilizing after the particle diameter and the particle size distribution of redissolving.Can know that particle diameter and the particle size distribution seen before and after the lyophilizing do not have significant change.
We infer that this maybe be relevant with the unique molecular structure of such macrolide immunosuppressants.This type drug molecule all has a similar hydrophobic ring structure; This structure might form unique host-guest chemistry self assembly with the hydrophobic portion of surfactant molecule and interact; That is to say that the hydrophobic molecule ring of macrolide might provide the space of a suitable stable existence for the hydrophobic fragment of surfactant.Two kinds of molecules might fit together through the hydrophobic weak interaction that waits, and form metastable supermolecule composite construction, thereby increase the whole stability of carrier micelle.
The prominent phenomenon of releasing of medicine appears in carrier micelle that surfactant and drug molecule constitute sometimes, causes the pharmacokinetic parameter of medicine-carried system and actual needs not to be inconsistent.The present invention is employed in the available lipid micromolecule of the intrafascicular introducing preparation of polymer latex, comes the rate of release of regulating medicine.Lipid micromolecule described here comprises phospholipid, fatty acid, cholesterol and fatsoluble vitamin etc.
As required, can carry out subsequent treatment such as lyophilizing.The framework material that is used for lyophilized formulations includes but not limited to mannitol, glucose, sucrose, vitamin C, glucosan and water-soluble cellulose etc.
Adopt thin film aquation legal system to be equipped with the carrier micelle of this type of macrolide medicine among the present invention.Bibliographical information to the multiple method for preparing of different surface active agents amphiphile, amphiphilic molecule and medicine formation carrier micelle.The thin film aquation method that the present invention adopts is the characteristics to macrolide medicine and selected surfactant molecule, and the list of references reported method is improved and formed.Method of the present invention comprises medicine and surfactant adjuvant; And the pharmaceutic adjuvant that drug release is regulated in optional being used for is dissolved in common organic solvent; Remove organic solvent then to form thin film, add sterilized water then and carry out aquation, until forming settled solution.
In development process of the present invention, we find that the macrolide carrier micelle needs long hydration process in the preparation process, just can reach a stable status (in the particle size determination of particle, being stable simple spike).So in the present invention, in the preparation process of carrier micelle, the micellar solution that obtains through aquation need be placed on 4 ℃ and spend the night, so that it forms more stable carrier micelle, does subsequent treatment such as lyophilizing again.This phenomenon also with we before the conforming to of surface analysis, such Macrocyclolactone lactone kind medicine molecule probably when forming carrier micelle and the hydrophobic part of surfactant molecule have one be similar to the mutual identification of host-guest chemistry assembling process.The identification assembling process of this Subjective and Objective needs the long time just can reach stable state sometimes.For example people such as Guo a kind of liposome supramolecular system of utilizing host-guest chemistry in water, to set up needs just can reach in about 300 minutes equilibrium state (Guo et al; Surface Modification of Polymeric Vesicles via Host-Guest Inclusion Complexation; Langmuir 2008; 24,10583-10586.).
Particularly, macrolide carrier micelle of the present invention is through following method preparation.With medicine and the deutero-surfactant molecule of Polyethylene Glycol, and other corresponding pharmaceutic adjuvant molecules are dissolved in the common organic solvent, at room temperature remove organic solvent, form thin film, at room temperature add sterilized water then, shake ultrasonic aquation, and 4 ℃ are spent the night.At last, add other necessary pharmaceutic adjuvants.Filtration sterilization, packing.The carrier micelle of the present invention's preparation can be stored with the form of solution form or lyophilized powder as required.
The invention has the advantages that construction features, invented a kind of simple and effective method and prepared water-soluble nano drug-carrying micelle according to this type Macrocyclolactone lactone kind medicine.It is little that this carrier micelle system has size, the characteristics of particle size distribution homogeneous.In addition, the nano drug-carrying micelle that obtains among the present invention has extraordinary lyophilizing stability.The solution that forms after lyophilized powder redissolves does not have significant difference before the granular size of particle and the lyophilizing.
Description of drawings
Shown in Figure 1 is the particle diameter and the particle size distribution of a typical carrier micelle among the present invention of measuring of Ma Erwen nano particle size appearance (Nano-S).
Shown in Figure 2ly before lyophilizing, redissolve the afterwards particle diameter and the particle size distribution of (b) after (a) and the lyophilizing for the typical carrier micelle among the present invention.
The specific embodiment
Be embodiments of the invention below, but following embodiment does not limit the scope of the invention.
Take by weighing the 10mg tacrolimus; Be dissolved in the 1ml dehydrated alcohol; Other takes by weighing the 80mg cetomacrogol 1000 vitamin E (TPGS) of deriving and is dissolved in the 1ml dehydrated alcohol; Above-mentioned solution is mixed the conical flask that places 50ml, volatilize solvent, make medicine and polymer form the thin film of homogeneous on the conical flask surface at room temperature.Add sterilized water 10ml, mix aquation, the thin film on the ultrasonic extremely bottle of the jolting wall all dissolving becomes clear solutions, and 4 ℃ of placements are spent the night.Use the Malvern particle size analyzer, measuring particle diameter is the simple spike less than 100nm.Add an amount of freeze drying bone frame materials such as mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting lyophilized powder and adding water and redissolve, solution becomes the solution of clear, compares no significant change before measuring particle diameter and lyophilizing.
Embodiment 2
Take by weighing the 10mg tacrolimus; Be dissolved in the 1ml dehydrated alcohol; Other takes by weighing 100mg polyethyleneglycol-12-hydroxy stearin (Solutol HS 15) and is dissolved in the 1ml dehydrated alcohol; Above-mentioned solution is mixed the conical flask that places 50ml, volatilize solvent, make medicine and polymer form the thin film of homogeneous on the conical flask surface at room temperature.Add sterilized water 10ml, mix aquation, the thin film on the ultrasonic extremely bottle of the jolting wall all dissolving becomes clear solutions, and 4 ℃ of placements are spent the night.Use the Malvern particle size analyzer, measuring particle diameter is the simple spike less than 100nm.Add an amount of freeze drying bone frame materials such as mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting dry powder and adding water and redissolve, solution becomes the solution of clear, compares no significant change before measuring particle diameter and lyophilizing.
Embodiment 3
Take by weighing the 20mg tacrolimus; Be dissolved in the 2ml dehydrated alcohol; Take by weighing in addition derive distearyl phosphatidyl choline (PEG-DSPE) and 50mg TPGS of 100mg Macrogol 2000 respectively and be dissolved in the 2ml dehydrated alcohol; Above-mentioned solution is mixed the conical flask that places 50ml, volatilize solvent, make medicine and polymer form the thin film of homogeneous on the conical flask surface at room temperature.Add sterilized water 20ml, mix aquation, the thin film on the ultrasonic extremely bottle of the jolting wall all dissolving becomes clear solutions, and 4 ℃ of placements are spent the night.Measure particle diameter less than 100 nanometers, add an amount of freeze drying bone frame materials such as mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting lyophilized powder and adding water and redissolve, solution becomes the solution of clear, compares no significant change before measuring particle diameter and lyophilizing.
Embodiment 4
Take by weighing the 10mg tacrolimus; Be dissolved in the 1ml dehydrated alcohol, take by weighing 100mg HS-15 in addition respectively and be dissolved in the 1ml chloroform, above-mentioned solution is mixed the conical flask that places 50ml with 10mg phospholipid; Volatilize solvent at room temperature, make medicine and polymer form the thin film of homogeneous on the conical flask surface.Add sterilized water 10ml, mix aquation, the thin film on the ultrasonic extremely bottle of the jolting wall all dissolving becomes clear solutions, and 4 ℃ of placements are spent the night.Measure particle diameter less than 100 nanometers, add freeze drying bone frame materials such as proper vitamin C, mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting lyophilized powder and adding water and redissolve, solution becomes the solution of clear, compares no significant change before measuring particle diameter and lyophilizing.
Take by weighing the 10mg tacrolimus; Be dissolved in the 1ml dehydrated alcohol, take by weighing 80mg polylactic acid poly ethylene glycol (PLA-PEG) and be dissolved in the 1ml dehydrated alcohol, above-mentioned solution is mixed the conical flask that places 50ml; Volatilize solvent at room temperature, make medicine and polymer form the thin film of homogeneous on the conical flask surface.Add sterilized water 10ml, mix aquation, the thin film on jolting to the bottle wall all dissolving becomes clear solutions, and simply ultrasonic, 4 ℃ of placements are spent the night.Measure particle diameter less than 100 nanometers, add an amount of freeze drying bone frame materials such as mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting lyophilized powder and adding water and redissolve, solution becomes the solution of clear, does not relatively have significant difference before measuring particle diameter and lyophilizing.
Embodiment 6
Take by weighing the 10mg sirolimus, be dissolved in the 1ml dehydrated alcohol, other takes by weighing 70mg TPGS and is dissolved in the 1ml dehydrated alcohol, and above-mentioned solution is mixed the conical flask that places 50ml, volatilizes solvent at room temperature, makes medicine and polymer form the thin film of homogeneous on the conical flask surface.Add sterilized water 10ml, mix aquation, the thin film on jolting to the bottle wall all dissolving becomes clear solutions, and simply ultrasonic, 4 ℃ of placements are spent the night.Measure particle diameter less than 100 nanometers, add an amount of freeze drying bone frame materials such as mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting lyophilized powder and adding water and redissolve, solution becomes the solution of clear, does not relatively have significant difference before measuring particle diameter and lyophilizing.
Embodiment 7
Take by weighing the 10mg sirolimus; Be dissolved in the 1ml dehydrated alcohol, other takes by weighing 100mg HS15 respectively and 10mg oleic acid is dissolved in the 1ml dehydrated alcohol, above-mentioned solution is mixed the conical flask that places 50ml; Volatilize solvent at room temperature, make medicine and polymer form the thin film of homogeneous on the conical flask surface.Add sterilized water 10ml, mix aquation, the thin film on jolting to the bottle wall all dissolving becomes clear solutions, and simply ultrasonic, 4 ℃ of placements are spent the night.Measure particle diameter less than 100 nanometers, add an amount of freeze drying bone frame materials such as mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting lyophilized powder and adding water and redissolve, solution becomes the solution of clear, does not relatively have significant difference before measuring particle diameter and lyophilizing.
Embodiment 8
Take by weighing the 10mg everolimus; Be dissolved in the 1ml dehydrated alcohol, other takes by weighing 40mg PEG-DSPE respectively and 40mg TPGS is dissolved in the 1ml dehydrated alcohol, above-mentioned solution is mixed the conical flask that places 50ml; Volatilize solvent at room temperature, make medicine and polymer form the thin film of homogeneous on the conical flask surface.Add sterilized water 10ml, mix aquation, the thin film on jolting to the bottle wall all dissolving becomes clear solutions, and simply ultrasonic, 4 ℃ of placements are spent the night.Measure particle diameter less than 100 nanometers, add an amount of freeze drying bone frame materials such as mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting lyophilized powder and adding water and redissolve, solution becomes the solution of clear, does not relatively have significant difference before measuring particle diameter and lyophilizing.
Embodiment 9
Take by weighing the 10mg everolimus; Be dissolved in the 1ml dehydrated alcohol, other takes by weighing 100mg HS15 respectively and 10mg phospholipid is dissolved in the 1ml dehydrated alcohol, above-mentioned solution is mixed the conical flask that places 50ml; Volatilize solvent at room temperature, make medicine and polymer form the thin film of homogeneous on the conical flask surface.Add sterilized water 10ml, mix aquation, the thin film on jolting to the bottle wall all dissolving becomes clear solutions, and simply ultrasonic, 4 ℃ of placements are spent the night.Measure particle diameter less than 100 nanometers, add an amount of freeze drying bone frame materials such as mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting lyophilized powder and adding water and redissolve, solution becomes the solution of clear, does not relatively have significant difference before measuring particle diameter and lyophilizing.
Take by weighing 10mg and replace not sirolimus; Be dissolved in the 1ml dehydrated alcohol, other takes by weighing 100mg HS15 and is dissolved in the 1ml dehydrated alcohol, above-mentioned solution is mixed the conical flask that places 50ml; Volatilize solvent at room temperature, make medicine and polymer form the thin film of homogeneous on the conical flask surface.Add sterilized water 10ml, mix aquation, the thin film on jolting to the bottle wall all dissolving becomes clear solutions, and simply ultrasonic, 4 ℃ of placements are spent the night.Measure particle diameter less than 100 nanometers, add an amount of freeze drying bone frame materials such as mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting lyophilized powder and adding water and redissolve, solution becomes the solution of clear, does not relatively have significant difference before measuring particle diameter and lyophilizing.
Embodiment 11
Take by weighing the 10mg pimecrolimus; Be dissolved in the 1ml dehydrated alcohol; Other takes by weighing 60mg PLA-PEG respectively and 40mg PEG-DSPE is dissolved in the 1ml dehydrated alcohol; Above-mentioned solution is mixed the conical flask that places 50ml, volatilize solvent, make medicine and polymer form the thin film of homogeneous on the conical flask surface at room temperature.Add sterilized water 10ml, mix aquation, the thin film on jolting to the bottle wall all dissolving becomes clear solutions, and simply ultrasonic, 4 ℃ of placements are spent the night.Measure particle diameter less than 100 nanometers, add an amount of freeze drying bone frame materials such as mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting lyophilized powder and adding water and redissolve, solution becomes the solution of clear, does not relatively have significant difference before measuring particle diameter and lyophilizing.
Embodiment 12
Take by weighing 10mg and replace not sirolimus; Be dissolved in the 1ml dehydrated alcohol, take by weighing 100mgTPGS respectively in addition and be dissolved in the 1ml dehydrated alcohol, above-mentioned solution is mixed the conical flask that places 50ml; Volatilize solvent at room temperature, make medicine and polymer form the thin film of homogeneous on the conical flask surface.Add sterilized water 10ml, mix aquation, the thin film on jolting to the bottle wall all dissolving becomes clear solutions, and simply ultrasonic, 4 ℃ of placements are spent the night.Measure particle diameter less than 100 nanometers, add an amount of freeze drying bone frame materials such as mannitol, with 0.2 μ m membrane filtration degerming, lyophilizing.
After getting lyophilized powder and adding water and redissolve, solution becomes the solution of clear, does not relatively have significant difference before measuring particle diameter and lyophilizing.
Claims (22)
1. water solublity macrolide immunosuppressant carrier micelle, it contains: the macrolide immunosuppressant medicine of (1) treatment effective dose; (2) constitute the surfactant pharmaceutic adjuvant molecule of forming by Polyethylene Glycol hydrophilic portion and hydrophobic portion of carrier micelle with medicine.
2. the described water solublity macrolide immunosuppressant of claim 1 carrier micelle, wherein said macrolide immunosuppressant medicine be sirolimus, everolimus, for a kind of or wherein two or more mixture in not sirolimus, tacrolimus, ascosin and the pimecrolimus.
3. the described water solublity macrolide immunosuppressant of claim 1 carrier micelle, wherein said treatment effective dose is 1 μ g/ml-100mg/ml, preferred 0.1-50mg/ml, more preferably 0.25-25mg/ml.
4. two blocks that the described water solublity macrolide immunosuppressant of claim 1 carrier micelle, wherein said surfactant adjuvant molecule are made up of hydrophilic portion and hydrophobic portion or the amphiphile, amphiphilic molecule of many blocks.
5. the described water solublity macrolide immunosuppressant of claim 1 carrier micelle, wherein said hydrophilic portion is that molecular weight ranges is the Polyethylene Glycol fragment of 100-20000.
6. the described water solublity macrolide immunosuppressant of claim 1 carrier micelle, wherein said hydrophobic portion are made up of long-chain high molecular hydrophobic polymer or are made up of the lipid hydrophobic molecule of short chain.
7. the described water solublity macrolide immunosuppressant of claim 6 carrier micelle, wherein said lipid hydrophobic molecule is phospholipid, hydrophobic vitamin or fatty acid.
8. the described water solublity macrolide immunosuppressant of claim 7 carrier micelle; Wherein said phospholipid is phosphoglyceride, and the hydrophilic polar head of said phosphoglyceride is PHOSPHATIDYL ETHANOLAMINE, phosphatidylcholine, phosphatidylinositols, Phosphatidylserine or diphosphatidylglycerol.
9. the described water solublity macrolide immunosuppressant of claim 7 carrier micelle; Wherein said fatty acid is ten dihydroxystearic acids, and the surfactant molecule of described fatty acid and Polyethylene Glycol formation is polyethyleneglycol-12-hydroxy stearin (Solutol HS-15).
10. the described water solublity macrolide immunosuppressant of claim 7 carrier micelle; Wherein said hydrophobic vitamin is the VE succinic acid derivant; And the surfactant molecule that hydrophobic vitamin and Polyethylene Glycol constitute be vitamin E polyethylene glycol 1000 succinates (D-alpha-tocopheryl polyethyleneglycol 1000 succinate, TPGS).
11. the described water solublity macrolide immunosuppressant of claim 6 carrier micelle, wherein said long-chain high molecular polymer is polyester or polyoxypropylene, and the molecular weight ratio of hydrophilic portion and hydrophobic portion was greater than 1: 1.
12. the described water solublity macrolide immunosuppressant of claim 11 carrier micelle; Wherein said polyester comprises polylactide, gathers Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone, polylactic acid and poly (lactic acid-glycolic acid) ester; And the molecular weight ranges of described polyester is 100-20000; Be preferably 500-10000, more preferably 1000-5000.
13. the described water solublity macrolide immunosuppressant of claim 11 carrier micelle, the polymer that wherein said polyoxypropylene and Polyethylene Glycol form comprises poloxamer 124,188,237,388 and 407, wherein preferred poloxamer 188.
14. the described water solublity macrolide immunosuppressant of claim 1 carrier micelle, ratio (w/w) scope of wherein said surfactant adjuvant and medicine is 1: 1 to 400: 1, preferred 1: 1 to 40: 1, and more preferably 2: 1 to 20: 1.
15. the described water solublity macrolide immunosuppressant of claim 1 carrier micelle, wherein said surfactant adjuvant is made up of more than one surfactant.
16. the described water solublity macrolide immunosuppressant of claim 1 carrier micelle, wherein said micelle also contains other following auxiliary material: (1) is used to regulate the pharmaceutic adjuvant of drug release; (2) be used for the framework material of lyophilized formulations.
17. the described water solublity macrolide immunosuppressant of claim 16 carrier micelle, the wherein said pharmaceutic adjuvant that is used to regulate drug release comprises phospholipid, fatty acid, cholesterol and fatsoluble vitamin.
18. the described water solublity macrolide immunosuppressant of claim 16 carrier micelle, the wherein said framework material that is used for lyophilized formulations comprises mannitol, glucose, sucrose, vitamin C, glucosan and water-soluble cellulose.
19. the described water solublity macrolide immunosuppressant of claim 1 carrier micelle, the size＜1000nm of wherein said nano-micelle, preferred＜200nm, more preferably＜100nm.
20. the described water solublity macrolide immunosuppressant of claim 1 carrier micelle is aqueous solution or lyophilized powder form.
21. prepare the method for any one described water solublity macrolide immunosuppressant carrier micelle in the aforesaid right requirement; Said method comprises medicine and surfactant adjuvant; And the pharmaceutic adjuvant that drug release is regulated in optional being used for is dissolved in common organic solvent; Remove organic solvent then to form thin film, add sterilized water then and carry out aquation, until forming settled solution.
22. method according to claim 21, it also comprises the framework material that is used for lyophilized formulations that adding is optional, filtration sterilization, lyophilizing.
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