CN110302141A - Diclofenac sodium injection situ-gel and preparation method thereof - Google Patents
Diclofenac sodium injection situ-gel and preparation method thereof Download PDFInfo
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- CN110302141A CN110302141A CN201910622377.3A CN201910622377A CN110302141A CN 110302141 A CN110302141 A CN 110302141A CN 201910622377 A CN201910622377 A CN 201910622377A CN 110302141 A CN110302141 A CN 110302141A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention discloses diclofenac sodium injection situ-gels, are made of following supplementary material by mass fraction: C14H10Cl2NNaO2, poloxamer, preservative, complexing agent and water for injection.The invention also discloses the preparation methods of diclofenac sodium injection situ-gel.Diclofenac sodium injection with situ-gel safely, effectively, it is quality controllable, have Thermo-sensitive, be liquid condition at room temperature, gel-type semi-solid medicament reservoir formed after intramuscular injection under body temperature, to have the function that sustained release.For this product compared with conventional Diclofenac Sodium Injection, blood concentration is steady, and efficiency time is long, and administration number of times is reduced, and administration is more convenient, and Animal adaptability is strong.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, it is related to a kind of diclofenac sodium injection situ-gel and preparation method thereof.
Background technique
C14H10Cl2NNaO2 was potent non-steroidal anti-inflammatory drugs, external to be developed first by vapour Ba-Jia Ji company, and in 1974
Listing, it is domestic to be synthesized in 1985, it is clinically used for anti-inflammatory, antipyretic, analgesia and antirheumatic etc., anti-inflammatory, refrigeration function are compared with anti-inflammatory
It is bitterly 2.0 ~ 2.5 times strong, it is 26 ~ 50 times strong compared with aspirin.C14H10Cl2NNaO2 tolerance is good, and dosage is small, and individual difference is small, gastrointestinal tract
Side reaction is also lighter than most of non-mushroom anti-inflammatory agents, using extensive.
Currently, the C14H10Cl2NNaO2 preparation variety of national Bureau of Drugs Supervision's approval has 30, it is respectively: C14H10Cl2NNaO2 enteric
Piece, Diclofenac Sodium Injection, Diclofenac sodium gutta, C14H10Cl2NNaO2, diclofenac sodium gel, diclofenac sodium suppository,
Diclofenac sodium extended action tablet, diclofenac sodium extended release capsule, injection C14H10Cl2NNaO2 lidocaine, C14H10Cl2NNaO2 benefit card
Because injection, aerosol diclofenac sodium on animals, C14H10Cl2NNaO2 piece, spray containing diclofenac sodium, C14H10Cl2NNaO2 liniment, double chlorine are fragrant
The double chlorine of acid sodium-salt lidocaine hydrochloride injection, diclofenac sodium extended action tablet (I), diclofenac sodium extended release capsule (I), injection are fragrant
Acid sodium-salt lidocaine hydrochloride, C14H10Cl2NNaO2 emulsifiable paste, diclofenac sodium dual-release put capsulae enterosolubilis, diclofenac sodium, double chlorine
Fragrant acid sodium bolt (II), diclofenac sodium extended action tablet (IV), diclofenac sodium extended action tablet (V), diclofenac sodium extended release capsule
(III), C14H10Cl2NNaO2 enteric-soluble controlled-release capsule, C14H10Cl2NNaO2 capsulae enterosolubilis, C14H10Cl2NNaO2 patch, compound diclofenac natrium note
Penetrate liquid, gentamicin Diclofenac sodium gutta.
The Diclofenac Sodium Injection that the country has been approved by, people's medication specification are 2 ml:50 mg；Veterinary medicine specification is (1)
5ml:0.25g (2) 100ml:5g.
The Diclofenac Sodium Injection specification that foreign countries have been approved by, (1) 2 ml:75 mg, (2) 3ml:75mg.
In field of pharmaceutical preparations and scope of medication, the report of diclofenac sodium injection situ-gel is had not seen.Double chlorine
Fragrant acid sodium injection situ-gel, can overcome the disadvantages that the deficiency of solution-type Diclofenac Sodium Injection, have a temperature sensitivity, under room temperature
For liquid, after being injected in vivo, gel is formed in body temperature, unique solution-gel phase transformation makes it in the agents area residence time
Extend, C14H10Cl2NNaO2 is gradually discharged from gel, and achievees the purpose that delay release.
C14H10Cl2NNaO2 has a variety of long-acting sustained-release dosage forms such as spansule, sustained release tablets in people's medicine application field.In veterinary drug
Application field, only Diclofenac Sodium Injection dosage form.In veterinary clinic in use, a course for the treatment of generally requires to repeat to infuse for several times
Administration is penetrated, animal compliance is poor, and multiple injection administration is time-consuming and laborious and be easy to cause Animal stress.It prepared by C14H10Cl2NNaO2
At injection situ-gel, single administration can maintain longer effective blood drug concentration, and keep concentration continual and steady, to reduce
Administration number of times uses manpower and material resources sparingly, and reduces Animal stress, improves culture efficiency.
Summary of the invention
For these defects in the prior art, it is an object of that present invention to provide a kind of diclofenac sodium injections to be coagulated in situ
Glue belongs to temperature sensitive hydrogel, temperature sensitive, and room temperature is liquid condition, after intramuscular injection under body temperature, can become half by liquid
Solid gel shape, C14H10Cl2NNaO2 are gradually discharged from gel, to have the function that sustained release.
Another object of the present invention is to provide the preparation method of above-mentioned diclofenac sodium injection temperature-sensitive situ-gel.
To achieve the above object, technical scheme is as follows.
According to an aspect of the present invention, the present invention provides a kind of diclofenac sodium injection situ-gel, the originals
Position gel includes C14H10Cl2NNaO2 and poloxamer.
According to some embodiments of the present invention, the poloxamer includes the first poloxamer and the second poloxamer.
According to some embodiments of the present invention, first poloxamer is poloxamer188.
According to some embodiments of the present invention, second poloxamer is PLURONICS F87.
According to some embodiments of the present invention, the ratio of first poloxamer and the second poloxamer be 2:1~
15:1。
According to some embodiments of the present invention, the situ-gel also includes preservative.
According to some embodiments of the present invention, the preservative is one in benzyl alcohol, anesin and benzyl carbinol
Kind is a variety of.
According to some embodiments of the present invention, the situ-gel also includes complexing agent.
According to some embodiments of the present invention, the complexing agent is in EDTA-2Na, sodium citrate and sodium gluconate
It is one or more.
According to some embodiments of the present invention, the situ-gel also includes water for injection.
According to some embodiments of the present invention, the constituent of the situ-gel and its w/v (unit: g/
Ml, the same below) are as follows:
C14H10Cl2NNaO2 2%~10%
Poloxamer188 15%~20%
PLURONICS F87 1%~10%
Preservative 0.01%~0.09%
Complexing agent 0.01%~0.03%
Water for injection 59.07%~81.98%
According to some embodiments of the present invention, the constituent of the situ-gel and its bulking value ratio are as follows: 2~10g
C14H10Cl2NNaO2,15~20g poloxamer188,1~10g PLURONICS F87,0.01~0.09g preservative, 0.01~0.03g
Complexing agent, water for injection add to 100ml.
According to the preferred embodiment of the present invention, the constituent of the diclofenac sodium injection situ-gel and its again
Measure volume ratio are as follows: 5~6g C14H10Cl2NNaO2,17~18g poloxamer188,3~7g PLURONICS F87,0.05~0.07g
Benzyl alcohol, 0.02~0.03gEDTA-2Na, water for injection add to 100ml.
Further preferred embodiment according to the present invention, the constituent of the diclofenac sodium injection situ-gel
And its bulking value ratio are as follows: 5g C14H10Cl2NNaO2,18g poloxamer188,4g PLURONICS F87,0.05g benzyl alcohol,
0.03gEDTA-2Na, water for injection add to 100ml.
According to an aspect of the present invention, the present invention provides a kind of preparation sides of diclofenac sodium injection situ-gel
Method is, which comprises dissolves and to form solution the first poloxamer and the second poloxamer；Dissolve C14H10Cl2NNaO2；?
The preservative and complexing agent of dissolution are added in Diclofenac sodium solution；Diclofenac sodium solution is added to Poloxamer solution
In, and filter and obtain diclofenac sodium injection situ-gel.
According to some embodiments of the present invention, first poloxamer is poloxamer188.
According to some embodiments of the present invention, second poloxamer is PLURONICS F87.
According to some embodiments of the present invention, described dissolve the first poloxamer and the second poloxamer is that low temperature is molten
Solution.
According to some embodiments of the present invention, the low temperature is 1-5 DEG C.
According to some embodiments of the present invention, the filtering is miillpore filter filtration.
According to some embodiments of the present invention, the miillpore filter filtration is 0.22 μm.
According to some embodiments of the present invention, poloxamer188 and PLURONICS F87 are filled in certain proportion and is penetrated
It is soaked with water, and keeps dissolution in low temperature, until forming sticky, transparent Poloxamer solution；C14H10Cl2NNaO2 is injected
It is dissolved, is stirred evenly with water, the preservative and enveloping agent solution dissolved in advance with a small amount of water for injection is added, stirs evenly, adds
It into Poloxamer solution, stirs evenly, water for injection to full dose, 0.22 μm of miillpore filter filtration obtains C14H10Cl2NNaO2 note
It penetrates and uses situ-gel.According to some embodiments of the present invention, the stirring uses machine mixer, revolving speed 100-400r/
Min is stirred 3-10 minutes.According to some embodiments of the present invention, preservative and complexing are dissolved together with a small amount of water for injection
Agent solution.According to some embodiments of the present invention, preservative and enveloping agent solution are dissolved respectively with a small amount of water for injection, then mix
It closes.
The phase transition temperature of diclofenac sodium injection situ-gel of the present invention is between 35 DEG C~38 DEG C.
Contain preservative in diclofenac sodium injection situ-gel of the present invention, analgesia when playing anti-corrosion and drug administration by injection
Effect.According to some embodiments of the present invention, the preservative is one of benzyl alcohol, anesin and benzyl carbinol
Or it is a variety of.
In diclofenac sodium injection situ-gel of the present invention, also contain complexing agent, the complexing agent plays complexing preparation
Middle metal ion, stabilization formulations guarantee the effect of the quality of the pharmaceutical preparations.According to some embodiments of the present invention, the complexing agent is
One of EDTA-2Na, sodium citrate and sodium gluconate are a variety of.
The method for preparing acid and neutral drug situ-gel using poloxamer is only reported in the prior art, still
The method that the situ-gel of alkaline drug is prepared using poloxamer is not reported.C14H10Cl2NNaO2 of the present invention at alkalinity,
PH value is about 8.0-9.0, such as 8.0-8.5 or 8.5-9.0.Because the invention is to report to prepare alkali using poloxamer for the first time
The situ-gel of property drug.
It is an advantage of the current invention that being prepared for being prepared into injection with the C14H10Cl2NNaO2 for being suitable for phase transition temperature solidifying in situ
Glue is at room temperature liquid condition, convenient for the production operations such as filtering, filling, is also convenient for drug administration by injection operation, injects to animal muscle
Afterwards, gel is formed in injection site.Compared with animal Diclofenac Sodium Injection, diclofenac sodium injection situ-gel,
Single administration can maintain longer effective blood drug concentration, and keep concentration continual and steady, to reduce administration number of times, save manpower
Material resources, convenient drug administration reduce Animal stress, and animal biddability is good, improve culture efficiency.
Detailed description of the invention
Definition
Term used herein " C14H10Cl2NNaO2 " is Non-steroidanalgetic drug, and C14H10Cl2NNaO2, which mainly passes through, inhibits forefront
Parathyrine is synthesized and is worked.
The trade name of term used herein " poloxamer " is Pluronic (Pluronic).The poloxamer is high
Molecule nonionic surfactant.
Term used herein " situ-gel " is referred to and phase transition occurs in agents area immediately after being administered with solution state
, the semisolid preparation of the non-chemical crosslinking of formation.
In the present invention, it is the characteristic of gel that certain density poloxamer188 solution, which has temperature increase transitions, utilizes this
One property can prepare injection situ-gel.
In the present invention, the function of PLURONICS F87 is that cooperation poloxamer188 uses, for adjusting the phase of situ-gel
Temperature.
Term used herein " phase transition temperature " refers to temperature when phase transformation occurs for C14H10Cl2NNaO2.For certainly when low temperature
By the liquid flowed, temperature raising just becomes gel state to a certain extent.
Term used herein " thermal reversibility " refers to that diclofenac sodium gel of the invention is thermal reversion, i.e. phase transition temperature
The following are liquid, are warming up to phase transition temperature or more, become gel state, then cool to phase transition temperature or less and become liquid again.
Diclofenac sodium injection situ-gel
According to an aspect of the present invention, the present invention provides a kind of diclofenac sodium injection situ-gel, the original position is solidifying
Glue includes C14H10Cl2NNaO2 and poloxamer.
According to some embodiments of the present invention, the poloxamer includes the first poloxamer and the second poloxamer.
According to some embodiments of the present invention, first poloxamer is poloxamer188.Certain embodiment party according to the present invention
Formula, second poloxamer is PLURONICS F87.
According to some embodiments of the present invention, the ratio of first poloxamer and the second poloxamer be 2:1~
15:1, such as 2:1~10:1,2:1~5:1,5:1~15:1,5:1~10:1 or 10:1~15:1.It is according to the present invention certain
The ratio of embodiment, first poloxamer and the second poloxamer is 2:1,3:1,4:1,5:1,6:1,7:1,8:1,9:
1,10:1,11:1,12:1,13:1,14:1 or 15:1.
According to some embodiments of the present invention, the situ-gel also includes preservative.Certain realities according to the present invention
Mode is applied, the preservative is one of benzyl alcohol, anesin and benzyl carbinol or a variety of.Certain realities according to the present invention
Mode is applied, the preservative is benzyl alcohol.According to some embodiments of the present invention, the preservative is anesin.Root
According to certain embodiments of the invention, the preservative is benzyl carbinol.According to some embodiments of the present invention, the preservative
It is benzyl alcohol and anesin.According to some embodiments of the present invention, the preservative is benzyl alcohol and benzyl carbinol.According to
Certain embodiments of the invention, the preservative are anesin and benzyl carbinol.According to some embodiments of the present invention,
The preservative is benzyl alcohol, anesin and benzyl carbinol.
According to some embodiments of the present invention, the situ-gel also includes complexing agent.
According to some embodiments of the present invention, the complexing agent is in EDTA-2Na, sodium citrate and sodium gluconate
It is one or more.According to some embodiments of the present invention, the complexing agent is EDTA-2Na.Certain realities according to the present invention
Mode is applied, the complexing agent is sodium citrate.According to some embodiments of the present invention, the complexing agent is sodium gluconate.
According to some embodiments of the present invention, the situ-gel also includes water for injection.
According to some embodiments of the present invention, the C14H10Cl2NNaO2 that the situ-gel includes is 2%~10%, such as 2%
~8%, 2%~6%, 2%~4%, 4%~10%, 4%~8%, 4%~6%, 6%~10%, 6%~8% or 8%~10%.It is according to the present invention
Certain embodiments, the C14H10Cl2NNaO2 that the situ-gel includes are 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.
According to some embodiments of the present invention, the poloxamer188 that the situ-gel includes is 15%~20%, such as
15%~18%, 15%~16%, 16%~20%, 16%~18% or 18%~20%.According to some embodiments of the present invention, the original
The poloxamer188 that position gel includes is 15%, 16%, 17%, 18%, 19% or 20%.
According to some embodiments of the present invention, the PLURONICS F87 that the situ-gel includes is 1%~10%, such as
1%~8%, 1%~6%, 1%~4%, 1%~2%, 2%~10%, 2%~8%, 2%~6%, 2%~4%, 4%~10%, 4%~8%, 4%~
6%, 6%~10%, 6%~8% or 8%~10%.According to some embodiments of the present invention, the pool Lip river that the situ-gel includes is husky
Nurse 188 is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.
According to some embodiments of the present invention, the preservative that the situ-gel includes is 0.01%~0.09%, such as
0.01%~0.06%, 0.01%~0.03%, 0.03%~0.09% or 0.06%~0.09%.Certain embodiment party according to the present invention
Formula, the preservative that the situ-gel includes are 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%
Or 0.09%.
According to some embodiments of the present invention, the complexing agent that the situ-gel includes is 0.01%~0.03%, such as
0.01%~0.02% or 0.02%~0.03%.According to some embodiments of the present invention, the complexing agent that the situ-gel includes
It is 0.01%, 0.015%, 0.02%, 0.025% or 0.03%.
According to some embodiments of the present invention, the water for injection that the situ-gel includes is 59.07%~81.98%,
Such as 59.07%~80%, 59.07%~75%, 59.07%~70%, 59.07%~65%, 65%~81.98%, 65%~80%, 65%
~75%, 65%~70%, 70%~81.98%, 70%~80%, 70%~75%, 75%~81.98%, 75%~80% or 80%~
81.98%.According to some embodiments of the present invention, the water for injection that the situ-gel includes be 59.07%, 60%, 61%,
62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、
81% or 81.98%.
According to some embodiments of the present invention, the constituent of the situ-gel and its w/v (unit: g/
Ml, the same below) are as follows:
C14H10Cl2NNaO2 2%~10%
Poloxamer188 15%~20%
PLURONICS F87 1%~10%
Preservative 0.01%~0.09%
Complexing agent 0.01%~0.03%
Water for injection 59.07%~81.98%
According to some embodiments of the present invention, the constituent of the situ-gel and its bulking value ratio are as follows: 2~10g
C14H10Cl2NNaO2,15~20g poloxamer188,1~10g PLURONICS F87,0.01~0.09g preservative, 0.01~0.03g
Complexing agent, water for injection add to 100ml.
According to the preferred embodiment of the present invention, the constituent of the diclofenac sodium injection situ-gel and its again
Measure volume ratio are as follows: 5~6g C14H10Cl2NNaO2,17~18g poloxamer188,3~7g PLURONICS F87,0.05~0.07g
Benzyl alcohol, 0.02~0.03gEDTA-2Na, water for injection add to 100ml.
Further preferred embodiment according to the present invention, the constituent of the diclofenac sodium injection situ-gel
And its bulking value ratio are as follows: 5g C14H10Cl2NNaO2,18g poloxamer188,4g PLURONICS F87,0.05g benzyl alcohol,
0.03gEDTA-2Na, water for injection add to 100ml.
The preparation method of diclofenac sodium injection situ-gel
According to an aspect of the present invention, the present invention provides a kind of preparation methods of diclofenac sodium injection situ-gel
For, which comprises (1) the first poloxamer and the second poloxamer are dissolved and to form solution；(2) Diclofenac is dissolved
Sodium；(3) preservative of dissolution and complexing agent are added in Diclofenac sodium solution；(4) Diclofenac sodium solution is added to pool
In Luo Shamu solution, and filters and obtain diclofenac sodium injection situ-gel.
Those skilled in the art should know can be double to prepare with the sequence of step in preparation method described in appropriate adjustment
The fragrant sour sodium injection situ-gel of chlorine.
According to some embodiments of the present invention, the preparation method includes: (1) dissolution C14H10Cl2NNaO2；(2) dissolution
Preservative and complexing agent be added Diclofenac sodium solution in；(3) the first poloxamer and the second poloxamer are dissolved and is formed
Solution；(4) Diclofenac sodium solution is added in Poloxamer solution, and filters and obtains diclofenac sodium injection original position
Gel.
According to some embodiments of the present invention, the preparation method includes: (1) by the first poloxamer and the second pool Lip river
Husky nurse dissolves to form solution；(2) preservative and complexing agent dissolved；(3) C14H10Cl2NNaO2 is dissolved；(4) preservative and complexing
Agent is added in Diclofenac sodium solution；(5) Diclofenac sodium solution is added in Poloxamer solution, and it is double to filter acquisition
The fragrant sour sodium injection situ-gel of chlorine.
According to some embodiments of the present invention, the preparation method includes: the preservative and complexing agent of (1) dissolution；(2)
Dissolve C14H10Cl2NNaO2；(3) preservative and complexing agent are added in Diclofenac sodium solution；(4) by the first poloxamer and
Two poloxamers dissolve to form solution；(5) Diclofenac sodium solution is added in Poloxamer solution, and it is double to filter acquisition
The fragrant sour sodium injection situ-gel of chlorine.
According to some embodiments of the present invention, first poloxamer is poloxamer188.It is according to the present invention certain
A little embodiments, second poloxamer is PLURONICS F87.
According to some embodiments of the present invention, described dissolve the first poloxamer and the second poloxamer is that low temperature is molten
Solution.According to some embodiments of the present invention, the low temperature is 1-5 DEG C, such as 1-3 DEG C or 2-5 DEG C.It is according to the present invention certain
Embodiment, the low temperature are 1 DEG C, 2 DEG C, 3 DEG C, 4 DEG C or 5 DEG C.
According to some embodiments of the present invention, the filtering is miillpore filter filtration.Certain implementations according to the present invention
Mode, the miillpore filter filtration is 0.22 μm.It will be understood by a person skilled in the art that also can be used in the prior art other
It is suitble to the method for non-sterile solution for injection filtering.
According to some embodiments of the present invention, the preparation method include by poloxamer188 and PLURONICS F87 with
Certain proportion charging is penetrated to be soaked with water, and keeps dissolution in low temperature, until forming sticky, transparent Poloxamer solution；It will
C14H10Cl2NNaO2 is dissolved with water for injection, is stirred evenly, and the preservative and complexing agent dissolved in advance with a small amount of water for injection is added
Solution stirs evenly, and is added in Poloxamer solution, stirs evenly, water for injection to full dose, 0.22 μm of miillpore filter filtration,
Obtain diclofenac sodium injection situ-gel.
According to some embodiments of the present invention, the stirring uses machine mixer, revolving speed 100-400r/min, stirring
3-10 minutes.According to some embodiments of the present invention, the stirring uses machine mixer.Certain implementations according to the present invention
Mode, revolving speed 100-400r/min such as 100-300r/min, 100-200r/min of the stirring, 200-400r/min,
200-300r/min or 300-400r/min.According to some embodiments of the present invention, the stirring is 3-10 minutes, such as 3-
8 minutes, 3-5 minutes, 5-10 minutes, 5-8 minutes or 8-10 minutes.
According to some embodiments of the present invention, preservative and enveloping agent solution are dissolved together with a small amount of water for injection.Root
According to certain embodiments of the invention, preservative and enveloping agent solution are dissolved respectively with a small amount of water for injection, is remixed.
According to some embodiments of the present invention, the preparation method includes: by poloxamer188 and PLURONICS F87
Solution is formed with water for injection dissolution in low temperature；C14H10Cl2NNaO2 is dissolved with water for injection；The benzyl alcohol and EDTA-2Na of dissolution
It is added in Diclofenac sodium solution；Diclofenac sodium solution is added in Poloxamer solution, water for injection to full dose, 0.22
μm filtering with microporous membrane obtains diclofenac sodium injection situ-gel.
The phase transition temperature of diclofenac sodium injection situ-gel of the present invention is between 35 DEG C~38 DEG C, such as 35~37
DEG C or 36~38 DEG C.According to some embodiments of the present invention, the phase alternating temperature of diclofenac sodium injection situ-gel of the present invention
Degree is 35 DEG C, 36 DEG C, 37 DEG C or 38 DEG C.
Contain preservative in diclofenac sodium injection situ-gel of the present invention, analgesia when playing anti-corrosion and drug administration by injection
Effect.According to some embodiments of the present invention, the preservative is one of benzyl alcohol, anesin and benzyl carbinol
Or it is a variety of.According to some embodiments of the present invention, the preservative is benzyl alcohol.According to some embodiments of the present invention,
The preservative is anesin.According to some embodiments of the present invention, the preservative is benzyl carbinol.According to the present invention
Certain embodiments, the preservative is benzyl alcohol and anesin.According to some embodiments of the present invention, described anti-
Rotten agent is benzyl alcohol and benzyl carbinol.According to some embodiments of the present invention, the preservative is anesin and benzyl carbinol.
According to some embodiments of the present invention, the preservative is benzyl alcohol, anesin and benzyl carbinol.
In diclofenac sodium injection situ-gel of the present invention, also contain complexing agent, the complexing agent plays complexing preparation
Middle metal ion, stabilization formulations guarantee the effect of the quality of the pharmaceutical preparations.According to some embodiments of the present invention, the complexing agent is
One of EDTA-2Na, sodium citrate and sodium gluconate are a variety of.According to some embodiments of the present invention, the complexing
Agent is EDTA-2Na.According to some embodiments of the present invention, the complexing agent is sodium citrate.Certain realities according to the present invention
Mode is applied, the complexing agent is sodium gluconate.
Detailed description of the invention
Attached drawing 1 is medicine after Diclofenac Sodium Injection is administered with 3 diclofenac sodium injection of embodiment with in-situ gel injection
Object-time graph (Drug-time curve) figure.
Specific embodiment
The present invention is further illustrated combined with specific embodiments below, but the embodiment does not form any restrictions to the present invention.
Those skilled in the art are readily apparent that according to the content of this disclosure, can be according to actual needs to each implementation
Example carries out appropriate adjustment and reconfigures, without departing from spirit and scope.
Embodiment 1:2% diclofenac sodium injection situ-gel
The present embodiment prepares 2% diclofenac sodium injection situ-gel.In the present embodiment, first poloxamer is pool Lip river
Husky nurse 407, second poloxamer is PLURONICS F87.In the present embodiment, the preservative is benzyl alcohol.The present embodiment
In, the complexing agent can be EDTA-2Na.
Prescription
C14H10Cl2NNaO2 20g
Poloxamer188 200g
PLURONICS F87 100g
Benzyl alcohol 1g
EDTA-2Na 1g
Water for injection is to 1L
Preparation method: adding water for injection to soak the poloxamer188 of recipe quantity and PLURONICS F87, and keeps 4 DEG C of low temperature molten
Solution, until forming sticky, transparent Poloxamer solution.Recipe quantity C14H10Cl2NNaO2, benzyl alcohol and EDTA-2Na are infused
It penetrates and is dissolved with water, stir evenly (200r/min is stirred 5 minutes), be then added in Poloxamer solution, stir evenly (200r/
Min is stirred 5 minutes), it is solidifying in situ to obtain diclofenac sodium injection for water for injection to full dose, 0.22 μm of miillpore filter filtration
Glue.
Phase transition temperature measurement: the diclofenac sodium injection refrigerated under the conditions of taking 4 DEG C situ-gel 5ml, as in test tube,
And it is inserted into the thermometer for being used for thermometric.Test tube is placed in water-bath, water-bath liquid level need to be higher by tube contents liquid level, slow heating
Heating, heating rate is maintained at increases 1 DEG C per minute.After water temperature reaches 30 DEG C, test tube is taken out into 90 degree of inclination per minute, is seen
When examining tube contents and not flowing, temperature, as phase transition temperature are recorded.Each prescription sample is measured 3 times by this method, is as a result taken
Average value.
Gel time measurement: 25 DEG C of placement 1h of situ-gel solution are placed in the test tube for being pre-heated to 40 DEG C and keep the temperature, note
Record transformation time.
Thermal reversibility measurement, is heated to specific temperature (30,40,50,60,70 DEG C) for gel, then slowly cools to room
Temperature can be regarded as primary heating circulation, examine until gel no longer has Thermo-sensitive or ingredient changes, if being repeated 10 times still
With Thermo-sensitive, it is denoted as cycle-index > 10.
Viscosimetric analysis: using the viscosity of 25 DEG C of NDJ-1 type rotary viscosity design determining situ-gel under room temperature.
PH value measurement: with the pH value of 25 DEG C of situ-gel of acidometer measurement under room temperature.
The external Evaluation results for the situ-gel that embodiment 1 obtains are shown in Table 1.
Embodiment 2:3% diclofenac sodium injection situ-gel
The present embodiment prepares 3% diclofenac sodium injection situ-gel.In the present embodiment, first poloxamer is pool Lip river
Husky nurse 407, second poloxamer is PLURONICS F87.In the present embodiment, the preservative is benzyl alcohol.The present embodiment
In, the complexing agent is EDTA-2Na.
Prescription
C14H10Cl2NNaO2 30g
Poloxamer188 190g
PLURONICS F87 90g
Benzyl alcohol 3g
EDTA-2Na 1g
Water for injection is to 1L
Preparation and detection method are the same as embodiment 1.
The external Evaluation results for the situ-gel that embodiment 2 obtains are shown in Table 1.
Embodiment 3:5% diclofenac sodium injection situ-gel
The present embodiment prepares 5% diclofenac sodium injection situ-gel.In the present embodiment, first poloxamer is pool Lip river
Husky nurse 407, second poloxamer is PLURONICS F87.In the present embodiment, the preservative is benzyl alcohol.The present embodiment
In, the complexing agent is EDTA-2Na.
Prescription
C14H10Cl2NNaO2 50g
Poloxamer188 180g
PLURONICS F87 80g
Benzyl alcohol 5g
EDTA-2Na 3g
Water for injection is to 1L
Preparation and detection method are the same as embodiment 1.
The external Evaluation results for the situ-gel that embodiment 3 obtains are shown in Table 1.
Embodiment 4:7% diclofenac sodium injection situ-gel
The present embodiment prepares 7% diclofenac sodium injection situ-gel.In the present embodiment, first poloxamer is pool Lip river
Husky nurse 407, second poloxamer is PLURONICS F87.In the present embodiment, the preservative is benzyl alcohol.The present embodiment
In, the complexing agent is EDTA-2Na.
Prescription
C14H10Cl2NNaO2 70g
Poloxamer188 170g
PLURONICS F87 70g
Benzyl alcohol 6g
EDTA-2Na 3g
Water for injection is to 1L
Preparation and detection method are the same as embodiment 1.
The external Evaluation results for the situ-gel that embodiment 4 obtains are shown in Table 1.
Embodiment 5:9% diclofenac sodium injection situ-gel
The present embodiment prepares 9% diclofenac sodium injection situ-gel.In the present embodiment, first poloxamer is pool Lip river
Husky nurse 407, second poloxamer is PLURONICS F87.In the present embodiment, the preservative is benzyl alcohol.The present embodiment
In, the complexing agent is EDTA-2Na.
Prescription
C14H10Cl2NNaO2 90g
Poloxamer188 160g
PLURONICS F87 50g
Benzyl alcohol 7g
EDTA-2Na 2g
Water for injection is to 1L
Preparation and detection method are the same as embodiment 1.
The external Evaluation results for the situ-gel that embodiment 5 obtains are shown in Table 1.
Embodiment 6:10% diclofenac sodium injection situ-gel
The present embodiment prepares 10% diclofenac sodium injection situ-gel.In the present embodiment, first poloxamer is pool Lip river
Husky nurse 407, second poloxamer is PLURONICS F87.In the present embodiment, the preservative is benzyl alcohol.The present embodiment
In, the complexing agent is EDTA-2Na.
Prescription
C14H10Cl2NNaO2 100g
Poloxamer188 150g
PLURONICS F87 30g
Benzyl alcohol 9g
EDTA-2Na 2g
Water for injection is to 1L
Preparation and detection method are the same as embodiment 1.
The external Evaluation results for the situ-gel that embodiment 6 obtains are shown in Table 1.
1 diclofenac sodium injection of table is with the external performance evaluation of situ-gel (following s is the second)
| Phase transition temperature DEG C | Gel time s | Thermal reversibility | Viscosity (mpas) | pH | |
| Embodiment 1 | 37.4 | 24 | > 10 | 66 | 8.1 |
| Embodiment 2 | 36.6 | 23 | > 10 | 46 | 8.5 |
| Embodiment 3 | 36.0 | 21 | > 10 | 69 | 8.6 |
| Embodiment 4 | 35.4 | 18 | > 10 | 77 | 8.3 |
| Embodiment 5 | 35.1 | 19 | > 10 | 38 | 8.1 |
| Embodiment 6 | 35.0 | 20 | > 10 | 53 | 8.0 |
Table 1 the result shows that: diclofenac sodium injection obtained by above embodiments is with situ-gel phase transition temperature close to target animals pig
Body temperature, gel time is short, and thermal reversibility is good, repeatedly heating cooling nor affects on drug use, viscosity be suitable for, pH is also being designed
In range, various aspects index is able to satisfy clinical use demand.
Experimental example one:
This experimental example is coagulated for diclofenac sodium injection described in more commercially available 5% Diclofenac Sodium Injection and embodiment 3 in situ
Drug-time graph of the glue for animal administration compares.Currently, commercially available Diclofenac Sodium Injection specification for animals is 5%, implement
Diclofenac sodium content is also 5% in example 3, therefore chooses the identical embodiment 3 of specification in this experimental example and be compared.
Diclofenac sodium injection is given pig with situ-gel in this experimental example.It should be appreciated by those skilled in the art that
Diclofenac sodium injection can be given other livestocks with situ-gel.
Sample: diclofenac sodium injection situ-gel described in embodiment 3, commercially available common 5% diclofenac sodium injection for animals
Liquid (production of Shandong Jian Mu Bioceuticals Inc., lot number 170630).
Method: 10 healthy York boars, 2-3 monthly age, weight 18.5-28.0kg.All pigs grow on farm, feeding
The basic food of corn soybean.All pigs receive basic physical examination, weighing before being administered.Test is divided into 2 groups, every group of 5 pigs,
Commercially available common 5% Diclofenac Sodium Injection for animals of first group of injection, second group of diclofenac sodium injection for embodiment 3 are former
Position gel, two groups are pressed single dose C14H10Cl2NNaO2 2.5mg/kg musculi colli drug administration by injection.Subcutaneous veins of abdomen is taken a blood sample about
5ml, blood sampling time point are 0,0.5,1,1.5,2,3,4,6,9,12,24,36,48h.1000r/min is centrifuged after blood sample condensation
20min separates serum, is stored in -18 DEG C.All blood serum samples are detected using UV/HPLC, obtain blood plasma under each time point
Drug concentration draws Drug-time curve.
Drug-time curve is as shown in Fig. 1.
As can be seen from the figure for Diclofenac Sodium Injection, diclofenac sodium injection situ-gel, tool
There is long-acting slow-release effect, administration number of times can be reduced, reduces Animal stress.
Claims (10)
1. a kind of diclofenac sodium injection situ-gel, the situ-gel includes C14H10Cl2NNaO2 and poloxamer, preferably
The poloxamer includes the first poloxamer and the second poloxamer.
2. situ-gel according to claim 1, wherein first poloxamer is poloxamer188, described second
Poloxamer is PLURONICS F87, and the ratio of preferably described first poloxamer and the second poloxamer is 2:1~15:1.
3. situ-gel according to claim 1, wherein the situ-gel also includes preservative, the preferably described anti-corrosion
Agent is one of benzyl alcohol, anesin and benzyl carbinol or a variety of.
4. situ-gel according to claim 1, wherein the situ-gel also includes complexing agent, the preferably described complexing
Agent is one of EDTA-2Na, sodium citrate and sodium gluconate or a variety of.
5. situ-gel described in any one of -4 according to claim 1, wherein the constituent of the situ-gel and its again
Amount volume ratio (unit: g/ml, the same below) are as follows:
C14H10Cl2NNaO2 2%~10%
Poloxamer188 15%~20%
PLURONICS F87 1%~10%
Preservative 0.01%~0.09%
Complexing agent 0.01%~0.03%
Water for injection 59.07%~81.98%.
6. situ-gel according to claim 5, wherein the constituent and its bulking value ratio of the situ-gel
Are as follows: 2~10g C14H10Cl2NNaO2,15~20g poloxamer188,1~10g PLURONICS F87,0.01~0.09g preservative,
0.01~0.03g complexing agent, water for injection add to 100ml.
7. situ-gel according to claim 6, wherein the constituent and its bulking value ratio of the situ-gel
Are as follows: 5g C14H10Cl2NNaO2,18g poloxamer188,4g PLURONICS F87,0.05g benzyl alcohol, 0.03gEDTA-2Na, injection
Water adds to 100ml.
8. the preparation method of diclofenac sodium injection situ-gel described in a kind of any one of claim 1-7, the method
It include: that the first poloxamer and the second poloxamer are dissolved and to form solution；Dissolve C14H10Cl2NNaO2；The preservative of dissolution and
Complexing agent is added in Diclofenac sodium solution；Diclofenac sodium solution is added in Poloxamer solution, and filters acquisition
Diclofenac sodium injection situ-gel.
9. preparation method according to claim 8, wherein described to be by the first poloxamer and the dissolution of the second poloxamer
Dissolution in low temperature, the preferably described low temperature is 1-5 DEG C.
10. preparation method according to claim 8, wherein the described method includes: by poloxamer188 and poloxamer
188 form solution with water for injection dissolution in low temperature；C14H10Cl2NNaO2 is dissolved with water for injection；The benzyl alcohol and EDTA- of dissolution
2Na is added in Diclofenac sodium solution；Diclofenac sodium solution is added in Poloxamer solution, water for injection to full dose,
0.22 μm of filtering with microporous membrane obtains diclofenac sodium injection situ-gel.
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