CN1127634A - Controlled release hormone microsphere injection and preparing method thereof - Google Patents
Controlled release hormone microsphere injection and preparing method thereof Download PDFInfo
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- CN1127634A CN1127634A CN 95111307 CN95111307A CN1127634A CN 1127634 A CN1127634 A CN 1127634A CN 95111307 CN95111307 CN 95111307 CN 95111307 A CN95111307 A CN 95111307A CN 1127634 A CN1127634 A CN 1127634A
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- microsphere
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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Abstract
The hormone slow-released injection comprises two components of aseptic powder containing polylactic acid, polyhydroxyl acetic acid, polylactic acid-polyethylene glycol, polyhydroxyacetic acid-polyethylene glycol, polylactic acid-polyhydroxyacetic acid, polyamino acid, gelatin and arabic gum, as well as hormone such as estradiol valerate, estriol, testosterone propioate, or thyroid powder, and 0.9% physiological saline containing silica oil and emulsifier. Its sex hormone preparation serves to cure senile diseases caused by low sex hormone level. Its thyroxine preparation is used to cure obesity.
Description
The present invention is a kind of controlled release hormone microsphere injection and preparation method thereof, belongs to biomedical sector.
Increasing sharply of world population causes significant stress not only for resource, environment, economic development, and along with the continuous increase of old people's quantity, one of difficult problem that aging problem is anxious to be solved especially.The exploitation aged's human resources, improve old people's health level and quality of life solve beyond doubt this difficult problem than good method, can make old people's happiness spend old age blessedly like this, can make them again is that society makes certain contribution.
The most outstanding variation is that sex hormone level is low after climacteric and climacteric in the old human body, and therefore causes Senile disease such as climacteric syndrome, osteoporosis.Suitably improve the sex hormone level of old people after climacteric and climacteric, can excite old people's youthful vigor, improve old people's quality of life, solve and postpone the generation of Senile disease, improve old people's health level.And existing gonadal hormone preparation (tablet and injection) all can not long-acting slow-release, thereby does not reach above-mentioned target.The Development of New Generation long-acting sustained-release injection then can reach suitable raising old people hormonal readiness, and can avoid because of long-term a large amount of various side effect of using hormone medicine to cause.
The control-release microspheres such as medicine of macromolecule Biodegradable materials such as polylactic acid (PLA) and Polyethylene Glycol parcel are used existing recent two decades history.Just there is the seventies PLA to contain the contraceptive microsphere of luteinizing hormone-releasing hormone and is the peaceful microsphere of Piao Min of carrier with the Polyethylene Glycol.The medicine of PLA that recent two decades makes and Polyethylene Glycol parcel and other get more and more, as treat the implantation Polyethylene Glycol erythromycin controlled release agent of sand holes, the PLA insulin controlled release agent of China's Taiwan's scholars, the PLA antitumor drug and the GnRF microsphere controlled release agent of treatment tumor.But do not see in the document that having with PLA or PLA-Polyethylene Glycol etc. is estradiol valerate, estriol, the androlin of film material, the research of thyroid powder microsphere controlled release injection.
The purpose of this research is that with polylactic acid, polyglycolic acid, polylactic acid-polyglycol, polyglycolic acid-Polyethylene Glycol, polylactic acid-polyglycolic acid, polyamino acid, gelatin, arabic gum be material, seek suitable process conditions, the preparation estradiol valerate, estriol, androlin, thyroid powder (T
4), sodium triiodothyronine (T
3) wait the sustained-release microspheres injection of hormone.
Technical scheme of the present invention is: controlled release hormone microsphere injection adopts subpackage type, promptly is made up of sterilized powder and aseptic liquor.Controlled release hormone microsphere is a sterile injection powder, and 0.9% normal saline that includes emulsifying agent and silicone oil II is the injection liquor.
The inclusion material of controlled release hormone microsphere injection of the present invention is biodegradable biomedical material: polylactic acid, polyglycolic acid, polylactic acid-polyglycol, polyglycolic acid-Polyethylene Glycol, polylactic acid-polyglycolic acid, polyamino acid, gelatin, arabic gum, its weight average molecular weight range are 3.0 * 10
4～10.0 * 10
4
If exceed this scope, the hormone microsphere of preparation can not be controlled at 30～90 days scopes and discharge medicine, or is difficult to make microsphere to be shaped in the preparation process.
As controlled release hormone microsphere injection of the present invention is estradiol valerate, estriol, androlin, thyroid powder (T by the inclusion hormone
4), sodium triiodothyronine (T
3).The weight ratio of hormone and biomedical material is 1: 5～50.
If exceed this scope, hormone can not be aggregated the thing inclusion by process of the present invention, or can not be controlled at 30～90 days scopes release time by its hormone of the hormone microsphere of inclusion.
Inclusion technology as controlled release hormone microsphere injection of the present invention is a:O/W type (to oil-soluble medicine) and W
1/ O/W
2Type (to water soluble drug); B: on the basis of a, wrap up with Cera Flava in the microsphere outside.
If do not adopt this inclusion technology, can not obtain controlled release hormone microsphere.
Organic facies as controlled release hormone microsphere injection of the present invention is dichloromethane, chloroform, ethyl acetate, dioxane, ether, dichloromethane-vegetable oil, chloroform-acetone; The percetage by weight of polymer inclusion material in organic facies is 5.0～30.0.
Inside and outside water as controlled release hormone microsphere injection of the present invention is PVA, PVP, and the PMANa aqueous solution, its percetage by weight at interior aqueous phase is 1.0～15.0, the aqueous phase percetage by weight is 0.5～10.0 outside.
If exceed this scope, oil phase or outer aqueous phase in then interior water or oil phase can not be dispersed in well can not be controlled at below 10 μ thus obtained microsphere particle diameter.
Emulsifying agent as controlled release hormone microsphere injection of the present invention is oil phase: the HLB value is 4.5～6.0 nonionic emulsifier; Water: the HLB value is 14.0～15.5 nonionic emulsifier, and its percetage by weight in inside and outside water, oil phase is 0.1～12.0.
If exceed this scope, can not get the following microsphere of particle diameter 10 μ, or the too for a short time microspheres with solid powder that can not get of particle diameter.
As the organic facies of controlled release hormone microsphere injection of the present invention and the volume ratio of water, be: 1: 5～100 to the O/W type; To W
1/ O/W
2Type, interior nuclear phase (W
1/ O) being water: organic facies=1: 3.0～10.0, the foreign minister is organic facies (W
1/ O): water (W
2)=1: 5～100.
If exceed this scope, microsphere can not get good dispersion, and particle diameter can not be controlled at below 10 μ, or the microsphere dispersion is very good, and productive rate is obviously descended.
Sterilization method and condition as controlled release hormone microsphere injection of the present invention are: oxirane was sterilized 48 hours down at 30～45 ℃, and residual ethylene oxide content is less than 5ppm.
If residual ethylene oxide content is then harmful to health greater than 5ppm.
Controlled release hormone microsphere sterilized powder of the present invention injects aseptic 0.9% normal saline liquor earlier, and suspendible evenly back injects in the body.Injecting method: intramuscular injection.
The controlled release hormone microsphere injection that adopts preparation method of the present invention to make is a kind of biomedical material preparation that contains hormone.The gonadal hormone preparation is in order to alleviating after climacteric and climacteric because of hormonal readiness reduces the Senile disease that causes in vivo, but also double as diseases associated treatment therewith.The micro-slow release of thyroxine preparation is used for obesity patient's fat-reducing, and double as diseases associated treatment therewith.Because said preparation has the effect of slow release, has not only brought convenience to the patient aspect medication, and also avoided because of long-term a large amount of various side effect of using hormone medicine to cause.
Be embodiments of the invention below.Provide following example explanation the present invention, do not limit its protection domain.
Embodiment 1: the emulsifying agent of 80mg androlin, 400mg polylactic acid, 400mgHLB=4.5 is dissolved in the 8ml dichloromethane, with syringe under high degree of agitation with it to being equipped with in the three-necked bottle of 0.5%PMANa that 40ml includes the 2gHLB=14 emulsifying agent, after fully emulsified 1 hour 40 ℃ of following solvent flashings of normal pressure 3 hours.Reactant is moved to centrifugalize in the beaker, with distilled water wash reactant three times, oven dry back fill in 40 ℃ of vacuum drying ovens, specification is every and contains medicine microsphere 20mg, sterilized 48 hours down at 40 ℃ with oxirane in the leak detection back, guarantee residual ethylene oxide content less than 5ppm, promptly get Injectable sterile hormone microsphere powder.
With the emulsifying agent of 0.1gHLB=14,0.1g2
#Silicone oil joins in the 100ml0.9% normal saline, is every loading amount 1ml fill with specification, and the leak detection back promptly gets the Injectable sterile liquor with 20 pounds of pressure high-temperature sterilizations 40 minutes.
Embodiment 2: 80mg estradiol valerate, 4g polylactic acid-polyglycol, 13mgHLB=6 emulsifying agent are dissolved in the 13ml chloroform, with syringe under high degree of agitation with it to being equipped with in the three-necked bottle of 5%PVA that 450ml includes the 45mgHLB=15.5 emulsifying agent, emulsifying after 1 hour at 0.06MPa pressure and 30 ℃ decompression solvent flashing 4 hours down, reactant is moved in the beaker, centrifugalize, contain in the mellisic diethyl ether solution of 200mg with under agitation it being dropped into 20ml behind the distilled water wash reactant three times, and under agitation rapidly it is transferred to aqueous phase.Treat that ether volatilization finishes and microsphere is put into 35 ℃ of vacuum drying ovens dry, contain the fill of medicine microsphere 50mg specification by every, sterilized 48 hours down at 30 ℃ with oxirane in the leak detection back, keep residual ethylene oxide content less than 5ppm, promptly get and be enclosed with mellisic Injectable sterile controlled release hormone microsphere powder.
Emulsifying agent, 2g2 with 2gHLB=15.5
#Silicone oil joins in the 100ml0.9% normal saline, is the fill of 1ml specification by every loading amount, and the leak detection back promptly gets the Injectable sterile liquor with 20 pounds of pressure high-temperature sterilizations 40 minutes.
Embodiment 3: with 100mg thyroid powder (T
4) be dissolved in the aqueous solution that 10ml contains 1.5gPVP, 100mgHLB=15 emulsifying agent, the dissolving back includes it in ethyl acetate solution of 2gPLA, 5mgHLB=5.5 emulsifying agent under high degree of agitation with syringe to 7ml, fully emulsified back formation W
1/ O type emulsion includes it in 3%PMANa solution of 20mgHLB=15 emulsifying agent under high degree of agitation with syringe to 200ml, emulsifying formed W after 1 hour once more
1/ O/W
2The type emulsion is at 0.04MPa pressure and 35 ℃ decompression solvent flashing 3 hours down.Reactant is moved to centrifugalize in the beaker, with distilled water wash reactant three times, oven dry back fill in 45 ℃ of vacuum drying ovens, specification is every and contains medicine microsphere 40mg, sterilized 48 hours down at 45 ℃ with oxirane in the leak detection back, keep residual ethylene oxide content less than 5ppm, promptly get Injectable sterile hormone microsphere powder.
Emulsifying agent, 0.5g2 with 0.5gHLB=15
#Silicone oil joins in the 100ml0.9% normal saline, is that every loading amount is the 1ml fill by specification, and the leak detection back promptly gets the Injectable sterile liquor with 20 pounds of pressure high-temperature sterilizations 40 minutes.
Claims (12)
1. a controlled release hormone microsphere injection is characterized in that being made up of controlled release hormone microsphere and sterilization liquor.
2. according to the injection of claim 1, it is characterized in that microsphere inclusion material is for mainly containing biomedical materials such as biodegradable polylactic acid, polyglycolic acid, polylactic acid-polyglycol, polyglycolic acid-Polyethylene Glycol, polylactic acid-polyglycolic acid, polyamino acid, gelatin or arabic gum.
3. according to the injection of claim 1, it is characterized in that being comprised estradiol valerate, estriol, androlin, thyroid powder (T by the hormone of inclusion
4) or sodium triiodothyronine (T
3).
4. require 1 injection according to power, the weight that it is characterized in that controlled release hormone microsphere is 5.0～50.0mg, and the release in vitro hormone time is 30～90 days; The sterilization liquor is to contain 0.9% normal saline that percentage by weight is 0.1～5% silicone oil II, 0.1～5% emulsifying agent, and the HLB value of emulsifying agent is 14～15.5.
5. according to claim 1,2,3 or 4 injection, it is characterized in that biodegradable medical material weight average molecular weight range is: 3.0 * 10
4～10.0 * 10
4, the percetage by weight that accounts for microsphere is: 80-98; The percetage by weight that is accounted for microsphere by the inclusion hormone is: 2～20.
6. according to the preparation method of the injection of claim 1, it is characterized in that for the oil-soluble hormone, microsphere inclusion process using oil-in-water type, the volume ratio of organic facies and water is: 1: 5～100.
7. according to the preparation method of the injection of claim 1, it is characterized in that for water-soluble hormones, microsphere inclusion process using forms the kernel of water-in-oil type earlier, and then formation water bag kernel microsphere, the volume ratio of kernel water and organic facies is: 1: 3～10, and the volume ratio of outer field interior nuclear phase and water is: 1: 5～100.
8. according to the method for claim 6 or 7, it is characterized in that microsphere external Cera Flava parcel.
9. according to the method for claim 6 or 7, it is characterized in that the organic facies that adopts in the microsphere inclusion process comprises dichloromethane, chloroform, ethyl acetate, dioxane, ether, dichloromethane-vegetable oil or chloroform-acetone; The emulsifying agent that organic facies adopts is: the nonionic emulsifier of HLB value=4.5～6.0, consumption are 0.1～12% of organic facies; The percetage by weight of biodegradable medical material in organic facies is: 5.0～30.0; The water that adopts comprises polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), sodium polymethacrylate (PMANa) aqueous solution; PVA, PVP, PMANa in the percetage by weight of kernel aqueous phase are: 1.0～15.0, the percetage by weight of aqueous phase is outside: 0.5～10.0, the emulsifying agent of aqueous phase is: the nonionic emulsifier of HLB value=14.0～15.5, consumption are 0.1～12% of water.
10. method according to Claim 8, it is characterized in that dissolving mellisic solvent is chloroform, ether or vegetable oil, the percetage by weight that Cera Flava accounts for solvent is: 0.5～10.0.
11. according to the injection of claim 1, it is characterized in that the aseptic powder of injection hormone microsphere adopts epoxyethane sterilization, conditions for sterilization is: 30～45 ℃, 48 hours; Residual ethylene oxide content is less than 5.0ppm, and injection sterilization liquor conditions for sterilization is: 20 pounds autoclave sterilization 20-40 minute.
12., it is characterized in that microsphere is suspended in the sterilization liquor back and injects in the body injecting method: intramuscular injection according to the application of the injection of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95111307 CN1127634A (en) | 1995-04-06 | 1995-04-06 | Controlled release hormone microsphere injection and preparing method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95111307 CN1127634A (en) | 1995-04-06 | 1995-04-06 | Controlled release hormone microsphere injection and preparing method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1127634A true CN1127634A (en) | 1996-07-31 |
Family
ID=5078609
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95111307 Pending CN1127634A (en) | 1995-04-06 | 1995-04-06 | Controlled release hormone microsphere injection and preparing method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1127634A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023057088A1 (en) | 2021-10-06 | 2023-04-13 | Pharmathen S.A. | Sustained release injectable pharmaceutical formulation of levothyroxine and process for preparation thereof |
| GB2613656A (en) * | 2021-12-13 | 2023-06-14 | Pharmathen Sa | Sustained release injectable pharmaceutical formulation of levothyroxine and process for preparation thereof |
-
1995
- 1995-04-06 CN CN 95111307 patent/CN1127634A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023057088A1 (en) | 2021-10-06 | 2023-04-13 | Pharmathen S.A. | Sustained release injectable pharmaceutical formulation of levothyroxine and process for preparation thereof |
| GB2613656A (en) * | 2021-12-13 | 2023-06-14 | Pharmathen Sa | Sustained release injectable pharmaceutical formulation of levothyroxine and process for preparation thereof |
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