CN1364459A - Method for preparing slow-releasing and controlled releasing functional microcapsule - Google Patents
Method for preparing slow-releasing and controlled releasing functional microcapsule Download PDFInfo
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- CN1364459A CN1364459A CN 01119935 CN01119935A CN1364459A CN 1364459 A CN1364459 A CN 1364459A CN 01119935 CN01119935 CN 01119935 CN 01119935 A CN01119935 A CN 01119935A CN 1364459 A CN1364459 A CN 1364459A
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Abstract
The present invention relates to slow-releasing and controlled releasing functional microcapsule and provides the preparation process of the slow-releasing and controlled releasing function microcapsule as a new carrier of medicine. The present invention provides a new kind of medicine applying way.
Description
The invention belongs to microcapsule carrier technology of preparing and pharmaceutical dosage form technical field.
The present invention relates to the preparation method of a kind of slow release, controlled release and functional microcapsule.Further, the present invention is by providing the preparation method of a kind of slow release, controlled release and functional microcapsule, thereby for drug utilization provides a kind of novel carriers, so that medicine has slow release, controlled release and targeting sexual function.This application that can be medicine provides a kind of new approach.
Liposome is a vesicle of being made up of lipid bilayer.The inside and outside both sides of duplicature are hydrophilic area, and the centre is a hydrophobic region, and this film has good permeability.Liposome can suspend at aqueous phase, but coated water-soluble and fat-soluble medicine.The feature of wrapping kmedicine by liposome is non-selectivity (specificity), can be extremely wide by the medicine scope of its parcel, for example, comprise range protein, nucleic acid, saccharide and salt etc.
For drug research and exploitation, find that a kind of new drug can not be considered as work and finish.How can make medicine effectively enter the function of human body with practical realization medicine, be an importance of medicament research and development.This is the problem that route of administration is paid close attention to.Have only whole solutions of new drug research and route of administration, be only whole work of drug research and development.The problem that route of administration is paid close attention to has: the approach that medicine enters human body how, what the obstacle that may run into is and how controls etc.This directly relate to medication be quick-acting or long-acting, be local release or aspects such as treatment and dosage comprehensively.And be related to an application that importance is exactly a pharmaceutical carrier of route of administration.Therefore, development just seems very urgent and important applicable to the package carrier of various medicines.
Phosphatide complexes involved in the present invention is that liposome is the parcel carrier that is suitable for oral various medicines.It is characterized in that, the first, nontoxic to body; The second, can require the effect that reaches slow release, controlled release even reach targeting according to the difference treatment of different pharmaceutical.
The principle and the process of wrapping kmedicine by liposome are: prepare liposome with phospholipids compounds, and in liquid phase, sneak into a certain amount of medicine to be wrapped, in case when phosphatide cpd was converted into the liposome with morphological characteristic by the molecule of no form feature, also to be advanced liposome with fat vacuole by bag be in the microcapsule to dissolved drug in liquid phase.This principle be current various slow-releasing capsule preparation foundation (referring to Gregoriadis, G, Immunlogy Today, 1990,11:89-97).
When the preparation liposome, can be attached to relevant target antibody the cyst wall surface of liposome, thereby make liposome can have certain tropism, Here it is targeting liposome (referring to Hashimoto, Y., CancerResearch, 1983,43:5328-5334).The targeting liposome is a kind of functional liposome, and its trend specificity is determined by the specificity of binding antibody fully.For example, if antibody is the antibody of anti-certain tumor cell, just has the characteristic of this kind of trend tumor cell so by the prepared functional liposome of this antibody.Wherein, this kind tumor cell is a target cell, and corresponding liposome is a target liposomes.
For antibody is connected with liposome, need mediation to solve the water solublity of antibody molecule and the water-insoluble problem of phospholipid molecule.For ease of the combination of two class materials, must or claim " bridging mode " by " connecing the arm mode ", promptly the hydrophobic side of the water-wet side of antibody molecule and phospholipid molecule is tied by a kind of medium, this kind medium is " arm " or " bridge ".
Usually, the microcapsule carrier diameter of preparation generally between 5-2000 μ m, is called micron order microcapsule or microcapsule (referring to Deasy Patrick, Microencapsulation and Related, Drug Process, 1984).Along with the development of microcapsule technology, the microcapsule diameter of preparation can reach between the 1-1000nm less than 1 μ m.This particle diameter is called as Nano capsule or nano-microcapsule at the microcapsule of nanometer range.
The notion of Nano capsule is at first to be put forward by Narty etc. late 1970s.They discover that Nano capsule has unique character and they can be applied in a lot of fields.For example, they find that the medicament nano capsule has good targeting and slow releasing function.Since the eighties in 20th century, the Nano capsule technology begins to be applied to the world of medicine (referring to Max Donbrow, Microcapsules and Nanoparticles inMedicines and Pharmacy, CRC Press, 1992).Now, the Nano capsule The Application of Technology expands fields such as spice, pesticide, fire retardant, oil product and food seasoning rapidly to, has become a noticeable new and high technology.
When drug particle exists with the form of Nano capsule, it is expelled to the obstruction that can not cause blood capillary in the vein, even because the thinnest blood capillary diameter also has 4 μ m thick in the human body, Nano capsule be easy to by.When being used for intramuscular injection,, the stimulation of injection site is also significantly reduced because drug particles is little.The medicament nano capsule can be made the Injectable sustained release medicine.When being expelled to the human body specific part, can make medicine concentrate on this position performance drug effect, and the advantage that the protection drug effect is arranged, reduce drug release concentration, be easy to control.People discover, the carcinogenesis of some material not only is decided by the character of this material itself, and the particle size with in these materials enter human body or animal body the time is relevant.Usually the more little then carcinogenesis of particle is also more little, therefore uses the medicament nano capsule that medicine is reduced the adverse side effect of human body.
People adopt the phospholipid molecule to prepare the axunge plasmid vector usually.Such liposome has only the medicine that wherein is wrapped effect to be arranged to human body, therefore can be called as " single function carrier ".In such carrier, phospholipid molecule is to the not special effect of human body.
The preparation method that the purpose of this invention is to provide a kind of slow release, controlled release and functional microcapsule.Further, by screening the multiple medicine that can be used for preparing the liposome microcapsule carrier, be used for preparing difunctional or multi-functional microcapsule carrier, and wrap up compatibility with it or relevant medicine with this, to strengthen the effect of compatibility of drugs, reach and reduce the medication number of times, alleviate the patient suffering, strengthen the multiple effect of pharmic function.Simultaneously, by using above-mentioned microcapsule carrier so that medicine has slow release, controlled release and targeting sexual function.This application that can be medicine provides a kind of novel form and new way.
This prepares microcapsule as raw material with fat-soluble medicine in the present invention, and with serve as to wrap up carrier to wrap up another kind of medicine.Therefore can be known as a kind of " bifunctional vector ".
Relating to the technology for preparing microcapsule carrier has multiplely, comprises inverted evaporation method, dialysis, supercritical ultrasonics technology and shaking table method etc.Difunctional or the multi-functional microcapsule carrier that the present invention adopts the preparation of shaking table method the present invention relates to.
According to a preferred embodiment of the invention, can be used for preparing the liposoluble substance or the fat-soluble medicine of microcapsule carrier, comprise glyceride type, retinoic acid, rifampicin, vitamin A, vitamin E, sterols (as cholesterol), terpenoid and flavonoid etc.
Can be in extensive range by the medicine of above-mentioned difunctional or multi-functional microcapsule carrier parcel, for example, comprise fat-soluble medicine, water soluble drug, water solublity and fat-soluble blended medicine, extracts of Chinese herbal medicine and multiple nutrients liquid etc.With regard to the molecular weight size, the molecular weight ranges of the material that can be wrapped is 0.4 KD-＞150 KD, comprises from the small organic molecule to the larger molecular organics for example nucleic acid and proteinic all medicines substantially.
According to a preferred embodiment of the invention, by using by technology provided by the present invention, the medicine that can pack comprises: Chinese herbal medicine (comprising fat-soluble and water miscible effective ingredient), Tibetan medicine (comprising fat-soluble and water miscible effective ingredient), through medicine, genomic medicine, protein or the peptide medicament etc. of biochemistry extraction or chemosynthesis.
For example, except can wrapping up medicine in general sense, above-mentioned difunctional or multi-functional microcapsule carrier also can be used as the carrier of immunization therapy, gene therapy and gene transfection.Can enter microcapsule carrier to antibody, gene or the medicine parcel that hope is used for immunization therapy, gene therapy or gene transfection, enter by microcapsule carrier by suitable approach then and wish to obtain medical treatment or the tissue of transfection, just can carry out immunization therapy, gene therapy or gene transfection.For example, according to a preferred embodiment of the invention, use water solublity marked by fluorescein isothiocyanate antibody, and it is entered microcapsule carrier as the medicine parcel that is wrapped, use fluorescence microscope then, just can be at BG
12Excite under the optical filter of sheet and 475nm, see that the yellow-green fluorescence corpusculum enters into above-mentioned microcapsule carrier.
As mentioned above, technology provided by the present invention can be used for the change of pharmaceutical dosage form.According to a preferred embodiment of the invention, technology of the present invention can be converted into peroral dosage form to the insulin of treatment diabetes by the entry needle dosage form, also can prepare the peroral dosage form of hirudin and metallothionein, or the remodeling preparation of preparation vitamin A, vitamin E etc.
The medicine that is wrapped can directly pass through stomach, is positioned intestinal and discharges and absorb.Simultaneously,, therefore can bring great convenience, receive effect preferably for Comprehensive Treatment because the medicine by microcapsule carrier preparation or preparation is the compatibility of two kinds even multiple medicine.
For bifunctional vector involved in the present invention or multifunctional carrier, no matter be slow release and control-release function from medicine, still from the targeted therapy function of medicine, all be present oral drug preparation technology can't be obtained.
According to a preferred embodiment of the invention, can make slow release, controlled release capsule to the rifampicin that the all-trans-retinoic acid used of treatment cancer, treatment pulmonary tuberculosis are used, and the parcel other drug that can use with their compatibilities therein, with comprehensive therapeutic effect of effective these medicines of raising.And, by retinoic acid, rifampicin etc. is made bifunctional vector with their compatibe drug, can suppress their issuable drug resistance, thereby play therapeutical effect preferably.
According to a preferred embodiment of the present invention, can and can make bifunctional vector or multifunctional carrier the treatment insulin used of diabetes with the medicine of its compatibility, effectively transform with existing dosage form insulin, when strengthening its curative effect, make it to become oral drugs, do not accommodate psychological pressure on the body that diabetics may cause because of frequent injection repeatedly thereby significantly reduce.
According to a preferred embodiment of the present invention, when being the feedstock production microcapsule carrier, can obtain nano level functional microcapsule carrier by the reinforcement of shaking speed and the control of solution concentration with above-mentioned cited liposoluble substance.
Perhaps, also can make the powder pin to above-mentioned difunctional or multifunctional carrier.As the dry powder existence form of microcapsule, with the liquid phase ratio, the powder needle set has stable performance, conveniently preserves, is beneficial to advantages such as transportation and prolongation drug effect.For example, according to a preferred embodiment of the present invention, microcapsule formulation involved in the present invention is at room temperature stable, can preserve more than 3 months.
Therefore, the application of microcapsule carrier involved in the present invention can be brought into play its specificity curative effect to medicine, be kept its long-lasting and magnetic target therapy to bring wide application prospect.
Below narrate embodiments of the invention.The preparation method of the microcapsule carrier that the present invention relates to and the technology of packaging medicine will obtain describing in detail in an embodiment of the present invention.It should be noted that the description of the embodiment of the invention only has illustration for the present invention and effect without limits.
Embodiment 1, be encapsulated with the preparation of the soybean phospholipid microcapsule carrier of phosphate medicinal liquid:
The soybean phospholipid 1-2 milliliter that commerce can be got joins in the exsiccant round-bottomed flask, takes out organic solvent by water pump; Add 1-2 milliliter phosphate medicinal liquid, and in bottle, charged into pure nitrogen gas about 20 minutes; Then, on 40 ℃ of constant temperature shaking tables, with the speed continuous oscillation of 120rpm about 40-50 hour.Promptly finish the preparation of the soybean phospholipid microcapsule carrier of sealing the phosphate medicinal liquid.
The preparation of embodiment 2, rifampicin list function microcapsule powder:
Rifampicin is dissolved in the dehydrated alcohol equal solvent, drains, make powder, be single function microcapsule powder through rotary evaporation.
The preparation of embodiment 3, the difunctional microcapsule of retinoic acid:
Retinoic acid is dissolved in the dehydrated alcohol equal solvent, drains, make powder, be retinoic acid list function microcapsule powder through rotary evaporation; This microcapsule powder is added suitable quantity of water dissolubility medicinal liquid carry out hydration, on the shaking table that is interrupted 200-＞200rpm, carry out the hydration pack envelope, be difunctional microcapsule microcapsule water preparation.Then, drain, make powder, be the difunctional microcapsule powder of retinoic acid through rotary evaporation.
The preparation of embodiment 4, alcohol soluble protein, monoglyceride and the multi-functional microcapsule of cholesterol:
Alcohol soluble protein, monoglyceride and cholesterol are pressed alcohol soluble protein: monoglyceride: cholesterol=1-0.01: 0.1-1: the mixed of 0.01-0.1, the method according to embodiment 1,2,3 prepares multi-functional microcapsule then.
Embodiment 5, the difunctional microcapsule carrier of retinoic acid are to the parcel of water solublity Chinese herbal medicine:
Retinoic acid is dissolved in the dehydrated alcohol equal solvent, drains, make powder, be retinoic acid list function microcapsule powder through rotary evaporation; This microcapsule powder is added suitable quantity of water dissolubility herbal liquid medicine carry out hydration, on the shaking table that is interrupted 200-＞200rpm, carry out the hydration pack envelope, be the difunctional microcapsule microcapsule water preparation of parcel Chinese herbal medicine; Then, drain, make powder, be the difunctional microcapsule powder of retinoic acid of parcel Chinese herbal medicine through rotary evaporation.
Embodiment 6, the difunctional microcapsule carrier of monoglyceride are to the parcel of insulin and the change of insulin dosage form:
Monoglyceride is dissolved in the dehydrated alcohol equal solvent, drains, make powder, be monoglyceride list function microcapsule powder through rotary evaporation; The insulin medicinal liquid that can get this microcapsule powder adding suitable quantity of water dissolubility commerce carries out hydration, carries out the hydration pack envelope on the shaking table that is interrupted 200-＞200rpm, is the difunctional microcapsule water preparation of parcel insulin; Then, drain, make powder, be the difunctional microcapsule powder of monoglyceride of parcel insulin through rotary evaporation.With this, the insulin of injection-type just can be modified as the insulin of oral type.And the insulin of this oral type does not discharge under one's belt, and it directly is released in intestinal and is absorbed.
The parcel of embodiment 7, microcapsule carrier antagonist:
With water solublity marked by fluorescein isothiocyanate antibody, it is entered in the monoglyceride list function microcapsule carrier of the foregoing description 6 as enveloped parcel, become the functional microcapsule carrier of parcel antibody.Use fluorescence microscope, can be at BG
12Excite under the optical filter of sheet and 475nm, see that the yellow-green fluorescence corpusculum enters into the above-mentioned functions microcapsule carrier.
The preparation of the functional nano microcapsule carrier of embodiment 8, monoglyceride:
When the above-mentioned monoglyceride microcapsule carrier of preparation, the rotating speed that can be by increasing shaking table and the solution concentration of control monoglyceride obtain the functional nano microcapsule carrier of monoglyceride.The microcapsule carrier of gained respectively with amino black and dimethyl diaminophenazine chloride dyeing, is coated with microscope slide then, adds coverslip, (Olympus) microscopically is observed in the Olympus.The result sees Figure of description 1 and accompanying drawing 2 respectively.The result shows that the diameter of the monoglyceride microcapsule carrier that obtains is the nanoscale microcapsule carrier less than 500 nanometers.
The stability experiment of embodiment 9, functional microcapsule carrier:
The functional microcapsule carrier that the present invention relates to is placed at room temperature, through 3 months time.After testing, the activity of above-mentioned microcapsule carrier remains unchanged.The functional microcapsule carrier that the present invention relates to as can be known at room temperature can be stablized preservation and reach more than 3 months.
The Figure of description explanation:
Fig. 1: through the painted monoglyceride functional nano of amino black microcapsule carrier (amplification is 6750).
Fig. 2: through the painted monoglyceride functional nano of dimethyl diaminophenazine chloride microcapsule carrier (amplification is 6750).
Claims (10)
1. the preparation method of a functional microcapsule is characterized in that this preparation method comprises following step:
(1) raw material that is used for making microcapsule is dissolved in organic solvent;
(2) prepare the functional microcapsule carrier by literature method;
(3) with above-mentioned functional microcapsule carrier packaging medicine.
2. the process of claim 1 wherein that said functional microcapsule is single function, difunctional or multi-functional microcapsule carrier;
3. the process of claim 1 wherein that said functional microcapsule is the nano-microcapsule carrier;
4. the process of claim 1 wherein that the raw material of said manufacturing microcapsule is a liposoluble substance;
5. the process of claim 1 wherein that the raw material of said manufacturing microcapsule is glyceride type, retinoic acid, rifampicin, vitamin A, vitamin E, sterols, terpenoid and Flavonoid substances;
6. the process of claim 1 wherein that said medicine is Chinese herbal medicine, Tibetan medicine, the medicine through the biochemistry extraction, medicine, genomic medicine, protein or the peptide medicament through chemosynthesis;
7. a method that changes pharmaceutical dosage form is characterized in that the functional microcapsule of this method application rights requirement 1 is done carrier, and can realize the conversion of pharmaceutical dosage form between injectable powder type and injection type;
8. the method for claim 7, wherein said medicine are Chinese herbal medicine, Tibetan medicine, biochemical medicine, chemical synthetic drug, genomic medicine, protein or the peptide medicament of extracting;
9. the dosage form of a medicine is characterized in that the functional microcapsule of said preparation form application rights requirement 1 is done carrier, and has the function of slow release, controlled release and magnetic target therapy;
10. the dosage form of claim 9, wherein said medicine are Chinese herbal medicine, Tibetan medicine, biochemical medicine, chemical synthetic drug, genomic medicine, protein or the peptide medicament of extracting.
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| CN 01119935 CN1364459A (en) | 2001-07-02 | 2001-07-02 | Method for preparing slow-releasing and controlled releasing functional microcapsule |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100462070C (en) * | 2003-06-30 | 2009-02-18 | 于美丽 | Retinoic acid release control nanomicrosphere and its preparation method |
| CN101822320A (en) * | 2010-05-22 | 2010-09-08 | 鼎正动物药业（天津）有限公司 | Vitamin water aqua and preparation method thereof |
-
2001
- 2001-07-02 CN CN 01119935 patent/CN1364459A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100462070C (en) * | 2003-06-30 | 2009-02-18 | 于美丽 | Retinoic acid release control nanomicrosphere and its preparation method |
| CN101822320A (en) * | 2010-05-22 | 2010-09-08 | 鼎正动物药业（天津）有限公司 | Vitamin water aqua and preparation method thereof |
| CN101822320B (en) * | 2010-05-22 | 2013-07-03 | 鼎正动物药业（天津）有限公司 | Vitamin water aqua and preparation method thereof |
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