CN106727288A - Water-soluble progesterone injection composition and preparation method - Google Patents
Water-soluble progesterone injection composition and preparation method Download PDFInfo
- Publication number
- CN106727288A CN106727288A CN201610989780.6A CN201610989780A CN106727288A CN 106727288 A CN106727288 A CN 106727288A CN 201610989780 A CN201610989780 A CN 201610989780A CN 106727288 A CN106727288 A CN 106727288A
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- China
- Prior art keywords
- progesterone
- injection
- water
- preparation
- tromethamine
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Classifications
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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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Abstract
The present invention relates to a kind of progesterone water soluble parenteral solution and preparation method thereof, the progesterone injection contains progesterone, hydroxypropyl beta cyclodextrin, tromethamine and water for injection；The solubilization cooperateed with by hydroxypropyl beta cyclodextrin and tromethamine, significantly reduces the consumption of hydroxypropyl beta cyclodextrin.The safety in utilization of parenteral solution is improve, present invention also offers the preparation method of water-soluble progesterone injection.
Description
Technical field
The invention belongs to field of medicine preparations, it is related to a kind of progesterone injection composition using water as solvent and its system
Preparation Method.
Background technology
Progesterone is the sex hormone drug being clinically commonly used, and with regulation hormonal balance effect, progesterone has
The general action of progestational hormone, is clinically widely used, and is mainly used in menstrual disorder, such as functional uterine bleeding of amenorrhoea, yellow
Body function deficiency, threatened abortion and habitual abortion, the treatment of premenstrual tension syndrome, confrontation is used with the estrogen cycle
Simple effect of the estrogen to inner membrance.
Progesterone is liposoluble substance, water insoluble, outer except being administered orally on the market at present, also mainly have vagina administration with
Two kinds of methods of administration of injection.Progesterone more than 90% in blood plasma is combined with protein, and free only accounts for 3%, and its metabolin is main
Combined with glucuronic acid, from homaluria.Progesterone injection common on the market at present is oil-soluble injection, this kind of injection
Pain reaction is larger when agent is injected, and excitant is big, easy allergy, and easily causes medicine alluvial partial musculature to cause lump pain
Deng to patient, especially long-term use person is inconvenient, is made troubles to Clinical practice.To solve this problem, China is specially
Are used in sharp CN101152186A and progestin drugs are prepared Submicron Emulsion and then progesterone injection is prepared into, the method is certain
The pain and anaphylaxis of the progesterone injection of traditional oil solution are improved in degree, it may have less excitant and long-term
Using tolerance, but water phase, oil phase are also increased in preparation technology and is prepared, heat the processes such as homogeneous, cooling dilution, technique is more
For complicated.Also there is document using HP-β-CD as solubilizer, when consumption reaches certain proportion, corpus luteum can be increased
Solubility of the ketone in water, and then aqueous solution progesterone injection is prepared into, but although HP-β-CD has preferably
Solubilization, but in order to realize its solubilization to progesterone, HP-β-CD is up to 40%, note in prescription
Penetrating liquid safety in utilization can have certain risk.
Cyclodextrin and its derivative with can with medicine formed complex moiety purpose be in order to protect, be sustained or solubilising,
In this case, guest molecule still will finally discharge from cyclodextrin and play a role.There are some researches show causing or accelerate object
Molecule release principal element is change in concentration and competitive substitution, and temperature and pH influences are smaller.Its research and application will
By more and more attention.HP-β-CD is more easy to form compound with progesterone compared with cyclodextrin, because of hydroxypropyl substitution 2,
Increase cyclodextrin cavity length after 3 hydroxyl H atoms, hydroxyl is likely to that new hydrogen bond can be formed with progesterone on hydroxypropyl, increases
Plus complex stabilities.
Present invention mainly solves progesterone indissoluble in water is solved the problems, such as, the use of HP-β-CD is reduced
Amount, mainly employs HP-β-CD and tromethamine as mixed solubilizers, because the collaboration solubilising of tromethamine is made
With, the consumption of HP-β-CD is significantly reduced, the security of preparation is improve, instead of traditional progesterone oil
Property parenteral solution when injecting pain reaction it is strong, progesterone is developed into a kind of water soluble parenteral solution, pain reaction is small during injection, thorn
Swash the small injection of property.
The content of the invention
The present invention relates to a kind of progesterone injection and preparation method thereof.
HP-β-CD（Hydroxypropylcyclodextrin, HPCD）It is that the class of cyclodextrin one is unformed multigroup
Divide chemical derivative, obtained by 2,3 or 6 hydroxyl H atoms of hydroxypropyl substituted cyclodextrin, cyclodextrin and its derivative typically pass through
Progesterone forms compound with cavity Non-covalent binding.Recombination reaction is a dynamic process, and progesterone is constantly multiple with cyclodextrin
Close, while also constantly solution is compound.
Controlling the reaction condition such as temperature, concentration of substrate, acid-base value of reaction makes reaction to being conducive to compound direction to shift, meeting
Obtain more compounds.The more former cyclodextrin of HP-β-CD be more easy to progesterone molecule forming composite, because hydroxypropyl takes
Increase cyclodextrin cavity length after 2,3 hydroxyl H atoms of generation, hydroxyl is likely to that new hydrogen can be formed with guest molecule on hydroxypropyl
Key, increases complex stabilities.
The technical proposal of the invention is realized in this way：
A kind of progesterone injection, contains progesterone, HP-β-CD and tromethamine, water for injection.
The specification of described progesterone injection is 5mg:1ml, 10mg:1ml, 20mg:1ml, 25mg:1ml
Further, the shared weight fraction in injection of described HP-β-CD and progesterone is 1:5-1:15.
The shared ratio in whole solution of tromethamine is 0.1%-2%, and preferred ratio is 0.5-2%, preferred ratio
Example is 0.8-1.5%.
The preparation method of heretofore described water-soluble progesterone injection, comprises the following steps that：
Step a：With liquid：It is HP-β-CD, tromethamine stirring and dissolving, well mixed.
Step b：Medicine dissolves：Progesterone is added, at a certain temperature stirring and dissolving, adjust pH.
Step c:The liquid that will be prepared carries out prefiltration with 0.45 μm of miillpore filter, and filtrate is filtered with 0.22 μm of micropore
Film carries out refined filtration.
Step d：It is filling to melt envelope：By the medicine liquid irrigation after refined filtration loaded in ampoule bottle, melt envelope HP-β-CD
Step e：Using flowing steam sterilization（100 DEG C, 30min）Or pressure sterilizing（121 DEG C, 15min）Condition sterilizes.
Compared with prior art, water-soluble progesterone injection that the present invention is provided and preparation method thereof has following excellent
Point：
The progesterone injection prepared in the present invention is aqueous solution injection, with oil-soluble progesterone injection common on the market
Compare, progesterone aqueous solution injection process is simple is easily cleared out a gathering place, and pain reaction is smaller during injection, and property is also more stable.
In order to increase the dissolution velocity of progesterone in step b, solution temperature can be improved, and temperature is higher, the dissolving of progesterone
Speed is faster, 40-60 DEG C of the temperature of this step in the present invention.
Progesterone can add osmotic pressure regulator and buffer salt, sodium chloride, the sylvite of phosphoric acid, sodium salt etc. as needed.
Regulation process of the process of step b comprising drug solution acid-base value, the pH of drug solution of the present invention is 5.0-8.0.
It is further described following for the features of the present invention, there is provided tests below example and its results contrast, but with
Lower test example is not as limitation of the present invention.
2nd, progesterone injection irritation test in the present invention.
Using stock and muscle of back drug administration by injection method, sample is selected from progesterone injection, commercially available oil solution progesterone and notes
Penetrate liquid, using HP-β-CD as solubilizer water-soluble progesterone injection, specification is 20mg:1ml.Take strong
Health rabbit 12, male and female dual-purpose, body weight 2.5kg ~ 3.0kg is randomly divided into four groups, every group 3.First group to physiological saline,
Two groups of water-soluble progesterone injections to preparation in the present invention, the 3rd group is given commercially available oil solution progesterone injection, the 4th group
To using HP-β-CD as solubilizer aqueous solution progesterone injection.Dosage 1ml/, injection speed 1ml/
Min, once a day, successive administration 5 days observes whether animal has restless reaction after 5 days, observation injection site has unchanged.
The different progesterone injection irritation test result of table 1
Be can be seen that using the Huang prepared as solubilizer using HP-β-CD in the present invention by above experimental result
The excitant of body ketone parenteral solution is significantly less than is injected using HP-β-CD as progesterone prepared by solubilized agent method
Liquid, compared with commercially available oil solution progesterone injection, in the injection present invention during progesterone injection, the restless reaction of animal subject
Conspicuousness reduction, thus when progesterone injection of the present invention is injected, the pain reaction of user will also have and substantially change for deducibility
It is kind.
Specific embodiment
With reference to embodiment, the present invention will be further described, but following examples are not as to limit of the invention
System.
The progesterone injection of embodiment 1（Specification：5mg:1ml）
Prescription：
Progesterone 5g
HP-β-CD 25g
Tromethamine 2g
The g of sodium chloride 0.2
Water for injection adds to 1L
Weigh recipe quantity HP-β-CD, tromethamine, sodium chloride to be added to the water, stirring and dissolving, add recipe quantity medicine
Thing progesterone, sodium chloride, 60 DEG C of stirring and dissolvings adjust pH to 7.5 or so.The liquid that will be prepared is entered with 0.45 μm of miillpore filter
Row prefiltration, refined filtration is carried out by filtrate with 0.22 μm of miillpore filter.By the medicine liquid irrigation after refined filtration loaded in ampoule bottle, melt envelope.Adopt
Use pressure sterilizing（121 DEG C, 15min）, obtain progesterone injection.
The progesterone injection of embodiment 2（Specification：10mg:1ml）
Progesterone 10g
HP-β-CD 120g
Tromethamine 5g
Sodium chloride 0.1g
Water for injection 1L
Weigh recipe quantity HP-β-CD, tromethamine, sodium chloride to be added to the water, stirring and dissolving, add recipe quantity yellow
Body ketone medicine, 50 DEG C of stirring and dissolvings of sodium chloride, adjust pH to 7.0 or so.The liquid that will have been configured is entered with 0.45 μm of miillpore filter
Row prefiltration, refined filtration is carried out by filtrate with 0.22 μm of miillpore filter.By the medicine liquid irrigation after refined filtration loaded in ampoule bottle, melt envelope.Adopt
Use pressure sterilizing（121 DEG C, 15min）Obtain progesterone injection.
The progesterone injection accelerated test of table 2（2,40 ± 2 DEG C of embodiment, 75% ± 5%RH）As a result.
| Appearance character | pH | Content（mg/ml） | Relevant material（%） | |
| 0 | Water white transparency supernatant liquid | 6.3 | 9.90 | 0.86 |
| 1 | Water white transparency supernatant liquid | 6.2 | 9.91 | 0.90 |
| 2 | Water white transparency supernatant liquid | 6.2 | 9.88 | 0.98 |
| 3 | Water white transparency supernatant liquid | 6.1 | 9.90 | 1.04 |
| 6 | Water white transparency supernatant liquid | 6.3 | 9.85 | 1.27 |
The progesterone injected sample of embodiment 2 is carried out into accelerated test, as shown by data：Aqueous solution progesterone injection is adding
40 ± 2 DEG C of speed, 75% ± 5%RH accelerates to set 6 months, there are no significant the change of content, pH indices, and relevant material slightly has increasing
Plus, show：Progesterone injection of the present invention is stable in properties.
The progesterone injection of embodiment 3（Specification：20mg:1ml）
The g of progesterone 20
The g of HP-β-CD 200
The g of tromethamine 4
The g of dibastic sodium phosphate 0.2
Water for injection 1L
Weigh recipe quantity HP-β-CD, tromethamine, sodium chloride to be added to the water, stirring and dissolving, add recipe quantity medicine
Thing progesterone, dibastic sodium phosphate, 50 DEG C of stirring and dissolvings, the liquids that will prepare of the regulation of pH to 6.0 or so are with 0.45 μm of miillpore filter
Prefiltration is carried out, filtrate is carried out into refined filtration with 0.22 μm of miillpore filter.By the medicine liquid irrigation after refined filtration loaded in ampoule bottle, melt envelope.
Using pressure sterilizing（121 DEG C, 15min）Condition sterilizes, and obtains progesterone injection.
The progesterone injection of embodiment 4（Specification：25mg:1ml）
The g of progesterone 25
HP-β-CD 300g
Tromethamine 8g
The g of potassium hydrogen phosphate 0.2
Water for injection adds to 1L
Weigh recipe quantity HP-β-CD, tromethamine, sodium chloride to be added to the water, stirring and dissolving, add recipe quantity yellow
Body ketone, potassium hydrogen phosphate, 40 DEG C of stirring and dissolvings adjust pH to 7.0 or so.The liquid that will be prepared is carried out with 0.45 μm of miillpore filter
Prefiltration, refined filtration is carried out by filtrate with 0.22 μm of miillpore filter.By the medicine liquid irrigation after refined filtration loaded in ampoule bottle, melt envelope.Using
Flowing steam（100 DEG C, 30min）Condition sterilizes, and obtains progesterone injection.
Claims (5)
1. a kind of water-soluble progesterone injection, it is characterised in that parenteral solution use HP-β-CD and tromethamine for
Collaboration solubilizer.
2. progesterone injection as claimed in claim 1, solvent used is water for injection.
3. progesterone injection according to claim 2, it is characterised in that described HP-β-CD and progesterone
Ratio be 1:5-1:15.
4. progesterone injection according to claim 3, it is characterised in that described tromethamine consumption is whole injection
Liquid weight than 0.1-2%.
5. progesterone injection according to claim 4, it is characterised in that described progesterone injection specification is 5mg:
1ml, 10mg:1ml, 20mg:1ml, 25mg:1ml.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610989780.6A CN106727288A (en) | 2016-11-10 | 2016-11-10 | Water-soluble progesterone injection composition and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610989780.6A CN106727288A (en) | 2016-11-10 | 2016-11-10 | Water-soluble progesterone injection composition and preparation method |
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| CN106727288A true CN106727288A (en) | 2017-05-31 |
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| CN201610989780.6A Pending CN106727288A (en) | 2016-11-10 | 2016-11-10 | Water-soluble progesterone injection composition and preparation method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107441039A (en) * | 2017-08-25 | 2017-12-08 | 南京斯泰尔医药科技有限公司 | A kind of progesterone suspension injection and preparation method thereof |
| CN108159058A (en) * | 2018-02-09 | 2018-06-15 | 上海礼璞生物医药科技有限公司 | Purposes of the progesterone in the drug for inhibiting HIF-1 alpha expressions is prepared |
| CN108159057A (en) * | 2018-02-09 | 2018-06-15 | 上海礼璞生物医药科技有限公司 | The purposes of progesterone and its pharmaceutically acceptable derivates in the drug for inhibiting the expression of α smooth muscle actins is prepared |
| CN109381424A (en) * | 2018-11-21 | 2019-02-26 | 南京泽恒医药技术开发有限公司 | Water-soluble injection of stable progesterone and preparation method thereof |
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| WO1997018245A1 (en) * | 1995-11-14 | 1997-05-22 | Farmarc Nederland B.V. | Complex of naproxen and beta-cyclodextrin |
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| US20060058262A1 (en) * | 2004-09-16 | 2006-03-16 | Altergon S.A. | New injectable formulations containing progesterone |
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| WO1997018245A1 (en) * | 1995-11-14 | 1997-05-22 | Farmarc Nederland B.V. | Complex of naproxen and beta-cyclodextrin |
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| US20060058262A1 (en) * | 2004-09-16 | 2006-03-16 | Altergon S.A. | New injectable formulations containing progesterone |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107441039A (en) * | 2017-08-25 | 2017-12-08 | 南京斯泰尔医药科技有限公司 | A kind of progesterone suspension injection and preparation method thereof |
| CN108159058A (en) * | 2018-02-09 | 2018-06-15 | 上海礼璞生物医药科技有限公司 | Purposes of the progesterone in the drug for inhibiting HIF-1 alpha expressions is prepared |
| CN108159057A (en) * | 2018-02-09 | 2018-06-15 | 上海礼璞生物医药科技有限公司 | The purposes of progesterone and its pharmaceutically acceptable derivates in the drug for inhibiting the expression of α smooth muscle actins is prepared |
| CN109381424A (en) * | 2018-11-21 | 2019-02-26 | 南京泽恒医药技术开发有限公司 | Water-soluble injection of stable progesterone and preparation method thereof |
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Application publication date: 20170531 |