CN1193761C - Controllable release system of glucocorticoid and its preparation and use - Google Patents
Controllable release system of glucocorticoid and its preparation and use Download PDFInfo
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- CN1193761C CN1193761C CNB031269885A CN03126988A CN1193761C CN 1193761 C CN1193761 C CN 1193761C CN B031269885 A CNB031269885 A CN B031269885A CN 03126988 A CN03126988 A CN 03126988A CN 1193761 C CN1193761 C CN 1193761C
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Abstract
The present invention discloses a controllable release system of glucocorticoid, a preparation method thereof and an application thereof. The controllable release system of the present invention is a microcapsule of glucocorticoid, which is prepared by using a natural biodegradable polymer material as a substrate material of glucocorticoid medicine and adopting a microencapsulation technology combining supersonic wave emulsifying and mechanical stirring to pack the medicine in a microsphere made of the substrate material. The microcapsule is further made into the powder, a capsule, a paste, a tablet, an injection or a pill of glucocorticoid medicine. The controllable release system can effectively control the release velocity and the stability of glucocorticoid medicine, maintains desired blood concentration, greatly reduces the frequencies of medicine taking or medicine injection, and the side effect of the medicine, can be more effective and convenient than before when clinically used and is suitable for patients who need glucocorticoid taking or injection for a long term to be treated.
Description
Technical field
The invention belongs to drug world, more particularly relate to controllable release system of a kind of glucocorticoid and preparation method thereof.
Background technology
Glucocorticoid is the excretory steroid hormone of a class adrenal cortex, has pharmacological actions such as stronger antiinflammatory, antiallergic, immunosuppressant and mithridatism.Be widely used in treatment of arthritis, ophthalmic inflammation clinically, autoimmune diseases such as the anti-rejection of corneal transplantation postoperative, rheumatoid arthritis, systemic lupus erythematosus (sle), vasculitis etc.
General pharmaceutical carrier is adopted in traditional pharmaceutical preparation, take medicine or inject after incipient stage, blood drug level can slowly increase the absorption of medicine with body, may surpass the poisoning limting concentration when the highest; Along with the release of medicament Chinese medicine, release amount of medicine reduces gradually then, and blood drug level descends gradually, drops to and just loses therapeutical effect under the minimal effective concentration.In order to keep blood drug level necessary in the body, can only adopt altofrequency ground timing for several times on the one to take medicine or inject.
Present existing dosage form mainly is intravenous fluid and oral medicine pill.Intravenous injection glucocorticoid and oral this hormone pill have a lot of defectives.The first, side effect is serious.The second, use inconvenience, need often injection or oral drugs, bring great inconvenience for patient's life, influence patient's quality of life, especially for a kind of especially mental burden of long-term pill taker.The 3rd, be difficult to realize topical, cause other non-infection site also to bear the side effect that medicine brings simultaneously.
In addition, in order to guarantee near the local inflammation tissue enough medicine effective concentrations are arranged, just must inject or oral heavy dose of glucocorticoid, and need a plurality of courses of treatment, this parahormone medicine of life-time service.And heavy dose and long-term prescription can bring serious adverse.Mainly containing hypophysis---the physiological of hypothalamic pituitary adrenal axis suppresses, weight increase, anxious state of mind, myasthenia of limbs, blurred vision, alopecia or hair growth are too fast, and child or adolescent growth are slow, osteoporosis etc.Therefore, even doctor's careful consideration when giving patient's medication, the careful use all is difficult to accurately control to dosage, thereby the risk of using hormone therapy is increased.Thereby patient and doctor press for the glucocorticoid medicine dosage form of science.
Summary of the invention
The object of the present invention is to provide the intelligent controllable release system that discharges, reduces side effect, safe in utilization, convenient, effective glucocorticoid of a kind of medicine;
Another object of the present invention is to provide the preparation method of above-mentioned controllable release system.
The present invention is directed to the clinical handling characteristics of glucocorticoid, itself and appropriate carriers host material are combined into compound system, be designed to the controllable release system of glucocorticoid, medicine can be discharged from host material with constant relatively speed, and speed that discharges and medicine carrying intensity and effectively can artificially control release time.
That the present invention utilizes is biodegradable, the natural biodegradable polymer of safety non-toxic is as the host material of glucocorticoid medicine, the microencapsulation technology that adopts ultrasonic emulsification and mechanical agitation to combine, pharmaceutical pack is ensconced in the microsphere of host material composition, make microcapsule, its maximum drug loading can reach 25mg/g.The degradation characteristic of the bond strength by host material and medicine, the diffusion of medicine itself and host material is controlled the release characteristic of medicine, make medicine keep steady release, and guarantee the active drug concentration that treatment is required, and effectively release time can be above 10 days.
The biodegradable polymer of indication of the present invention can be collagen, chitin, chitosan, alginate or gelatin; Glucocorticoid comprises cortisone, hydrocortisone, prednisone (prednisone), meticortelone (andrographolide), betamethasone and ground thiophene rice pine (dexamethasone) etc.
The controllable release system of glucocorticoid of the present invention prepares as follows:
(1) the collagen solution B with glucocorticoid A and concentration 0.1-1% is mixed in proportion, the mass percent that makes glucocorticoid A and collagen is 10: 1-1: 3, stirring adding down and the isopyknic mass percent concentration of collagen solution is the chitosan solution C of 1-3%, makes the gel D in conjunction with glucocorticoid;
(2) (commodity are called SPAN 20 to add glyceryl monostearate (abbreviation monoglyceride) and sorbitan monolaurate in the saxol, or class of department 20), wherein the volume of paraffin oil be gel D described in (1) 3-4 doubly, monoglyceride is 1-3 with the mass ratio of class of department 20: 1, both mix, and are dissolved in the paraffin oil under the heating condition, and concentration is 1-3%, as water-in-oil emulsifier, get solution E;
(3) agitating solution E slowly adds gel D, continues to stir 15-30 minute, and ultrasonic Treatment obtains emulsion F;
(4) add oil-in-water emulsifiers in the 5-10% aqueous gelatin solution, make the concentration of emulsifying agent reach 3-5%, dispersing and dissolving is solution G;
(5) slowly add emulsion F in the solution G of high-speed stirred, the volume ratio that makes G and F is 3-4: 1, continue to stir 15-30 minute, and ultrasonic Treatment obtains emulsion H;
(6) in emulsion H, add 5-10 doubly to the cross-linking agent I of the contained collagen quality of solution B, after cross-linking reaction 15-45 minute, in emulsification system, add excessive hydrogen peroxide under stirring, continued stirring reaction 5-10 minute, obtain system J;
(7) with the centrifugal breakdown of emulsion of system J, the collecting precipitation thing, behind the organic solvent washing, the reuse distilled water cleans repeatedly, and the gleanings that obtains is the W/O/W type microcapsule that contains glucocorticoid.
The used cross-linking agent of the preparation method of the controllable release system of above-mentioned glucocorticoid can be formaldehyde or glutaraldehyde; Used emulsifying agent can be monoglyceride, sorbitan monolaurate (SPAN 20) or soil temperature series Water-In-Oil, oil-water emulsifiers; Used organic solvent is ethanol or isopropyl alcohol.
To get final product long preservation after the microcapsule drying, drying mode comprises vacuum and heating drying, vacuum lyophilization and spray drying, after during use microcapsule being disperseed with sterilized water dilution, just can make injection and be used for injection for curing; Also further processing and preparing becomes powder, capsule, unguentum, tablet or the pill of glucocorticoid medicine.
Controllable release system of the present invention adopts the biodegradable natural polymer biomedical material of safety non-toxic, use the microencapsulation technology and be prepared into the microcapsule that comprises glucocorticoid medicine, by the diffusion of medicine and the slow degraded of capsule wall material, impel medicine to realize the sustained release of the long period of uniform rate.This system can be processed into various pharmaceutical dosage forms, as cream, subsides, oral tablet and injection, can effectively control the rate of release of glucocorticoid medicine and discharge stability, keeps required blood drug level.Guaranteeing under the therapeutic effect prerequisite, significantly reducing and take medicine or the frequency and the drug side effect of injectable drug that clinical use more effectively and convenient is fit to some needs and takes or inject the patient that glucocorticoid treats for a long time and use.
The specific embodiment
Example 1:
(1) takes by weighing 150mg hydrocortisone powder, mixed 3 minutes, add 1% the chitosan solution of 5ml again, continue to mix with 1% collagen solution of 5ml.Take by weighing 0.64g monoglyceride and 0.36g sorbitan monolaurate (SPAN20) in addition, heating for dissolving is in the 40ml paraffin oil.Subsequently, the ultrasound wave that applies 150W power under the high-speed stirred of 5000rpm is again assisted emulsifying, slowly adds the mixed liquor of hydrocortisone, collagen and chitosan simultaneously, and emulsifying 30 minutes obtains emulsion A.
(2) take by weighing the 12g gelatin, heating for dissolving adds 3g soil temperature 80 simultaneously in the 120ml distilled water, fully dissolving.The ultrasound wave that applies 150W power under the high-speed stirred of 5000rpm is again assisted emulsifying, slowly adds the emulsion A in (1) simultaneously, and emulsifying 30 minutes forms new emulsification system B.
(3) measure the 400ml paraffin oil, add 6.4g monoglyceride and 3.6gSPAN20 respectively, heating for dissolving, high-speed stirred, mixing speed are 5000rpm, slowly add the emulsion of preparation just now again, stir after 15 minutes, the glutaraldehyde solution 5ml of adding 25%, cross-linking reaction adds 30% hydrogen peroxide 2ml after 15 minutes again.Continue to stir stopped reaction after 15 minutes.
Centrifugal 15 minutes breakdowns of emulsion of speed of above-mentioned product 4000rpm with preparation.Collecting precipitation.Centrifugalize again after precipitate usefulness 300ml isopropyl alcohol cleans, the distilled water wash of continuation usefulness equal volume 2 times.Be spray dried to white flavescent powder then, be drug microcapsule.
Embodiment 2
Get that dried drug microcapsule is scattered in the distilled water among a little embodiment 1, microscopically detects its particle shape, is subglobular.Particle Size Analyzer the analysis showed that its particle diameter at the 5-50 mu m range, is mainly 10-20 μ m particle diameter.Scanning electron microscope analysis shows that the microcapsule granule surface is more smooth, but more fold is arranged.
Take by weighing three parts of 0.5g drug microcapsules respectively, add three kinds of different pH value (6.0,7.2 that 50ml prepares in advance, 8.0) PBS buffer solution, 37 ℃ of waters bath with thermostatic control vibration is respectively at 0.5h, 1h, 2h, 3h, 7h, 12h, 24h, 48h, 72h, 120h, the 168h sampling, liquid-phase chromatographic analysis drug release situation.
The result shows, prepared glucocorticoid microcapsule, and maximum drug loading can reach 25mg/g, and the release amount of medicine of 168h (promptly 7 days) is about 70%, and " violent release " phenomenon do not occur.Its drug release curve is steady.
Claims (3)
1, a kind of preparation method of controllable release system of glucocorticoid is characterized in that comprising the steps:
(1) the collagen solution B with glucocorticoid A and concentration 0.1-1% is mixed in proportion, the mass percent that makes glucocorticoid A and collagen is 10: 1-1: 3, stirring adding down and the isopyknic mass percent concentration of collagen solution is the chitosan solution C of 1-3%, makes the gel D in conjunction with glucocorticoid;
(2) in saxol, add glyceryl monostearate and sorbitan monolaurate, wherein the volume of paraffin oil be gel D described in (1) 3-4 doubly, the mass ratio of monoglyceride and sorbitan monolaurate is 1-3: 1, both mix, be dissolved in the paraffin oil under the heating condition, concentration is 1-3%, as water-in-oil emulsifier, gets solution E;
(3) agitating solution E slowly adds gel D, continues to stir 15-30 minute, and ultrasonic Treatment obtains emulsion F;
(4) add oil-in-water emulsifiers in the 5-10% aqueous gelatin solution, make the concentration of emulsifying agent reach 3-5%, dispersing and dissolving is solution G;
(5) add emulsion F in the solution G of high-speed stirred, the volume ratio that makes G and F is 3-4: 1, continue to stir 15-30 minute, and ultrasonic Treatment obtains emulsion H;
(6) in emulsion H, add the doubly cross-linking agent I of the contained collagen quality of solution B in (1) of 5-10, after cross-linking reaction 15-45 minute, in emulsification system, add excessive hydrogen peroxide under stirring, continued stirring reaction 5-10 minute, obtain system J;
(7) with the centrifugal breakdown of emulsion of system J, the collecting precipitation thing, behind the organic solvent washing, the reuse distilled water cleans repeatedly, must contain the W/O/W type microcapsule of glucocorticoid;
Wherein used cross-linking agent is formaldehyde or glutaraldehyde, and used emulsifying agent is monoglyceride, sorbitan monolaurate or soil temperature.
2, the preparation method of the controllable release system of glucocorticoid according to claim 1 is characterized in that described organic solvent is ethanol or isopropyl alcohol.
3, the controllable release system of the glucocorticoid of the described method preparation of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031269885A CN1193761C (en) | 2003-06-25 | 2003-06-25 | Controllable release system of glucocorticoid and its preparation and use |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB031269885A CN1193761C (en) | 2003-06-25 | 2003-06-25 | Controllable release system of glucocorticoid and its preparation and use |
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| CN1470240A CN1470240A (en) | 2004-01-28 |
| CN1193761C true CN1193761C (en) | 2005-03-23 |
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| CNB031269885A Expired - Fee Related CN1193761C (en) | 2003-06-25 | 2003-06-25 | Controllable release system of glucocorticoid and its preparation and use |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101007169B (en) * | 2006-01-23 | 2011-05-25 | 珠海市嘉族生物科技有限公司 | A microcapsule of egg yolk immunoglobulin, preparing process and use thereof |
| CN105878210A (en) * | 2016-05-10 | 2016-08-24 | 北京化工大学常州先进材料研究院 | Method for preparing prednisolone enteric drug particles |
| CN107115324A (en) * | 2017-05-08 | 2017-09-01 | 四川双金多肽生物技术有限责任公司 | One kind promotees to secrete sweetfish squama albumen gonad axis controlled release hormone agent and preparation method thereof |
| CN111051534A (en) * | 2017-08-30 | 2020-04-21 | 百时美施贵宝公司 | Method for monitoring pharmacodynamic response mediated by glucocorticoid administration in vivo |
| CN112972753A (en) * | 2019-12-02 | 2021-06-18 | 太阳雨林（厦门）生物医药有限公司 | Sustained-release embolism microsphere for treating bronchiectasis hemoptysis caused by chronic inflammation |
| CN115350327B (en) * | 2022-07-15 | 2023-05-23 | 华南理工大学 | Cornea repair material with anti-inflammatory effect and preparation method thereof |
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