CN106806338A - A kind of compound lidocaine emulsifiable paste pharmaceutical composition and preparation method thereof - Google Patents
A kind of compound lidocaine emulsifiable paste pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN106806338A CN106806338A CN201510867656.8A CN201510867656A CN106806338A CN 106806338 A CN106806338 A CN 106806338A CN 201510867656 A CN201510867656 A CN 201510867656A CN 106806338 A CN106806338 A CN 106806338A
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Abstract
The present invention provides a kind of compound lidocaine emulsifiable paste pharmaceutical composition and preparation method thereof.The pharmaceutical composition is as main ingredient raw material, to be prepared from as pharmaceutic adjuvant with Crodaret, Carbomer, NaOH and purified water by the lidocaine of effective dose, prilocaine.Emulsifiable paste lotion of the present invention moistens, smear is good, and impurity content is low, quality is good, small to skin irritation.
Description
Technical field
The present invention relates to a kind of compound lidocaine emulsifiable paste pharmaceutical composition and preparation method thereof, belong to medical science neck
Domain.
Background technology
Local anesthetic refer to can in the range of the restriction of body temporarily, reversibly block nerves fiber impulsion generation and
Conduction, the medicine without making patient's loss of consciousness.
Local anaesthetics presses clinical usage point, there is following a few class usages：It is surface anesthesia, spinal anesthesia, infiltration and block anesthesia, hard
Film is outward and tail bone is anaesthetized etc..General local anaesthetics and adrenaline are used in combination, and can cause vessel retraction, to improve local drug concentration,
Extension and enhancing drug effect, reduce general toxicity.
The local anaesthetics of application is cocaine earliest, is formally applied to clinic within 1884.Cocaine toxicity is larger, there is habituation
Property, and the aqueous solution is unstable.The excellent procaine of local anesthetic action is synthesized within 1904, it is stronger than cocaine local anesthetic action, poison
Property it is low, but penetration power is weak, it is impossible to do surface anesthesia use.Nineteen forty-three Sweden chemistLidocaine is synthesized first
(Lidocaine, 2-Diethylamine-N- (2,6-dimethyl phenyl)-acetamide), its local anesthetic action is than general Shandong
Cacaine is strong 2-9 times, acts on length of holding time, rapid-action.Thereafter a series of phthalein amine local anaesthetics successively synthesize again, such as front three card
Cause, prilocaine, Pyrrocaine, Bupivacaine etc., they at aspects such as local anesthetic action, onset time and stability each not
Together.
Lidocaine also known as lidocaine (Xylocaine), xylocaine (Lignocaine), belong to phthalein amine local anaesthesia
Medicine, is organic weak base, shown in its molecular structural formula such as following formula (I)：
Lidocaine free alkali is white crystalline powder, and 66-70 DEG C of fusing point is soluble in ethanol, chloroform and dichloromethane,
Ether is dissolved in, water is insoluble in, acid, alkali, light and heat are stablized.The amido link contained in the lipophilic moieties of lidocaine is this point
Most weak link, is easily broken because of hydrolysis in son, but stability is still strong compared with ester bond, and has two on two ortho positions of phenyl ring
Individual methyl substituents, increase steric hindrance, and the hydrolysis to amido link serves stabilization.Also exist just because of lidocaine
Hydrolyzed failure rapidly by cholinesterase not as procaine in vivo, just make it have strong drug action, local anesthetic action and hold time
Advantage long.In addition, its hydrophilic parts is tertiary amine, make that the excitant of lidocaine is smaller, local vessel expansion is made when using
With unobvious, local anaesthesia is more suitable for.
Prilocaine (Prilocaine), chemical name is：N- (2- aminomethyl phenyls) -2- propylamine-propionamide, its chemistry knot
Shown in structure formula such as following formula (II)：
Prilocaine free alkali is acicular crystal, and 37-38 DEG C of fusing point, the easy moisture absorption is difficult storage.
Prilocaine is also a kind of local anesthetic, and drug effect fruit is better than procaine, local anesthetic action intensity and speed with
Lidocaine is similar, but action time is longer, and toxicity is smaller, accumulative also smaller because its metabolism is fast.Suitable for epidural anesthesia
Liquor-saturated, conduction anesthesia and infiltration anesthesia etc..
Compound lidocaine emulsifiable paste be by the compound cream preparation of lidocaine, prilocaine, by Astra companies of Sweden in
Last century the eighties take the lead in researching and developing successfully and list (trade name EMLA, En Na), including including China, U.S. etc.
More than ten country's listing.The medicine is difficult to penetrate intact skin mainly for existing arcotic (including injection, latex and solution)
Cuticula and epidermis, into the skin corium felt residing for the nerve endings that disease is felt, the problems such as play analgesic effect, as the
The one active surface anesthetic that can penetrate intact skin.
The formula of EMLA is：Per 1000g emulsifiable pastes containing lidocaine, each 25g of prilocaine, polyoxyethylene sorbitan monoleate 19g, carboxylic gathers
Ethene 10g, NaOH adjust pH value to 9.0, balance of purified water.
CN101209250A provides a kind of compound lidocaine emulsifiable paste, and its auxiliary material includes carbomer 934, Tween-80, also
Azone containing permeation enhancers；Its preparation process includes：Lidocaine prilocaine eutectic is prepared, water-swellable carbomer 934 is purified
And pH to 8-10 is adjusted with sodium hydroxide solution after being stirred into transparent colloid, and add Tween-80 to stir, it is subsequently adding altogether
Fusant and azone, stirring are uniform to emulsifying, and last moisturizing simultaneously stirs uniform to emulsifying.
CN101816642A provide a kind of compound lidocaine emulsifiable paste, its auxiliary material include Crodaret,
Carbomer, preparation process includes：Stirred during Crodaret is added into lidocaine prilocaine eutectic
The oil mixture of Water-In-Oil is made, oil-in-water mixture is then mixed into the soaked Carbomer of purified water, adjust pH
To more than 9, moisturizing is simultaneously stirred into emulsifiable paste.
When formulation and technology research is carried out to above-mentioned existing lidocaine emulsifiable paste, the relevant thing of prilocaine in its sample is found
Matter ortho-aminotoluene content is higher, and up to more than 2%, and commercially available product grace is received and also the impurity is not controlled, and it should on inspection
Relevant content of material is also more than 2%.Ortho-aminotoluene, also known as 2-aminotoluene, easily by the skin of people, respiratory tract and alimentary canal
Invade so as to trigger a series of poisoning symptom of human body in human body, patient the lighter can feel scorching hot face, severe headache, dizziness,
Expiratory dyspnea, is presented cyanosis disease, and severe one may occur in which a series of damages of central nervous system, cardiovascular system and other internal organs
Evil, have developed rapidly after poisoning, it is necessary to actively rescue.Compound lidocaine emulsifiable paste is during Clinical practice particularly long-term use
There is allergic reaction generally relevant with impurity, therefore, how to control the relevant content of material of compound lidocaine emulsifiable paste is this area
Problem demanding prompt solution.
The content of the invention
For drawbacks described above present in compound lidocaine emulsifiable paste prior art and deficiency, the present invention provides a kind of compound
Lidocaine emulsifiable paste pharmaceutical composition and preparation method thereof, its about material ortho-aminotoluene content can as little as about 0.1%, it is maximum not
Know single miscellaneous content 0.02%~0.05%；The emulsifiable paste lotion moistens, smear is good, and impurity content is low, quality is good, to skin irritatin
Property is small.
The present invention is achieved by the following technical solution：
The compound lidocaine emulsifiable paste pharmaceutical composition that the present invention is provided, its every 10 kilograms of emulsifiable paste contains：
Further, the Crodaret is selected from polyoxyl 40 hydrogenated castor oil, the hydrogen of polyoxyethylene 60
Change castor oil, Nikkol HCO80, the Carbomer be selected from CARBOPOL 974P, CARBOPOL 971, carbomer940,
Carbopol, Carbomer981, Carbopol 941, Acritamer 940, carbomer 934, Carbomer PES.
Further, compound lidocaine emulsifiable paste pharmaceutical composition of the present invention, its every 10 kilograms of emulsifiable paste contains：
The present invention also provides the preparation method of the compound lidocaine emulsifiable paste pharmaceutical composition, and it is comprised the following steps：
(1) water is mutually prepared：Carbomer is weighed by recipe quantity, and purifying is measured by 0.5%~2% Carbomer aqueous solution is prepared
Water, Carbomer is slowly added into purified water, and stirring is completely dissolved and water phase is obtained for more than 1 hour；
(2) prepared by oil phase：Lidocaine and prilocaine are measured in main cooker by prescription, mixing are stirred at 40~50 DEG C equal
It is even, be melted to transparency liquid, obtain lidocaine prilocaine eutectic；By recipe quantity Crodaret at 60 DEG C
Added after fusing completely in eutectic, the prepared oil phase that stirs is standby；
(3) 5%~40% sodium hydroxide solution is prepared with purified water by recipe quantity；
(4) emulsify：Measure in the oil phase that surplus purified water adds step (2) preparation, low rate mixing is set and wall stirring is scraped
Be 50 revs/min, after stirring 5 minutes, low rate mixing and to scrape wall mixing speed constant proceeds by emulsification, speed for 2000 turns/
Minute, being emulsified 3 minutes at a high speed every about 1 minute, the cumulative time is not less than 12 minutes；
(5) water obtained in step (1) is added in step (4) emulsion, is stirred 10 minutes, then low rate mixing is set
It is 60 revs/min with wall stirring is scraped, is slowly added into the sodium hydroxide solution of step (3) preparation, continues to stir half an hour, discharging,
Follow-up filling process is carried out, compound lidocaine emulsifiable paste pharmaceutical composition is obtained final product.
Further, the quality of emulsifiable paste intermediate can be controlled in above-mentioned preparation process by monitoring following items：
(1) proterties：White or off-white color emulsifiable paste；
(2) pH value：Take emulsifiable paste directly to determine, pH value should be 8.7~9.7 (two annex VIH of Chinese Pharmacopoeia 2010 edition)；
(3) granularity：Determined according to 2010 editions methods of annex IXE first of Chinese Pharmacopoeia, the emulsion droplet and grain more than 180 μm must not be detected
Son；
(4) dewatering ability：Emulsifiable paste 5g is taken in centrifuge tube, 4000r/min high speed centrifugation 15min there must not be profit point
Layer phenomenon；
(5) mixture homogeneity：Take 10 parts of emulsifiable paste, the theoretical content by external standard method with calculated by peak area relative to labelled amount,
The relative standard deviation of 10 parts of sample sizes cannot be greater than 3.0%.
The invention has the advantages that：
(1) in compound lidocaine emulsifiable paste prior art basis, by improving prescription and preparation method, control relevant
The content of material ortho-aminotoluene, makes its content be reduced to about 0.1% by prior art 2%, substantially increases compound lidocaine
The quality of emulsifiable paste, reduces the generation of side reaction in Clinical practice.
(2) it is also miscellaneous to unknown list to be controlled, its content as little as 0.02%~0.05%, good product quality.
(3) compared with the compound lidocaine emulsifiable paste that CN101816642A is provided, the present invention considerably reduces hydroxide
The usage amount of sodium, reduces basicity in preparation, while also reducing the consumption of Carbomer, reduce production cost.
(4) the emulsifiable paste lotion prepared by moistens, smear is good, medication is convenient, good effect small to skin irritation, and matter
Amount stabilization.
(5) preparation method is simple to operate, and main ingredient is uniformly dispersed in oil-in-water type matrix, and drug quality is good.
Specific embodiment
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.It should be understood by those skilled in the art that the equivalent made to present invention, or be correspondingly improved, still
Belong within protection scope of the present invention.
The preparation of the compound lidocaine emulsifiable paste pharmaceutical composition of embodiment 1
Prescription composition (prepares 10kg emulsifiable pastes)：
Preparation method：
(1) water is mutually prepared：CARBOPOL 974P is weighed by recipe quantity, and is measured by the 1.2% CARBOPOL 974P aqueous solution is prepared
Purified water, CARBOPOL 974P is slowly added into purified water, and stirring is completely dissolved and water phase is obtained for more than 1 hour；
(2) prepared by oil phase：Lidocaine and prilocaine are measured in main cooker by prescription, mixing are stirred at 40~50 DEG C equal
It is even, be melted to transparency liquid, obtain lidocaine prilocaine eutectic；By recipe quantity polyoxyl 40 hydrogenated castor oil 60
DEG C fusing completely after add eutectic in, the prepared oil phase that stirs is standby；
(3) 10% sodium hydroxide solution is prepared with purified water by recipe quantity；
(4) emulsify：Measure in the oil phase that surplus purified water adds step (2) preparation, low rate mixing is set and wall stirring is scraped
Be 50 revs/min, after stirring 5 minutes, low rate mixing and to scrape wall mixing speed constant proceeds by emulsification, speed for 2000 turns/
Minute, being emulsified 3 minutes at a high speed every about 1 minute, the cumulative time is not less than 12 minutes；
(5) water obtained in step (1) is added in step (4) emulsion, is stirred 10 minutes, then low rate mixing is set
It is 60 revs/min with wall stirring is scraped, is slowly added into the sodium hydroxide solution of step (3) preparation, continues to stir half an hour, discharging,
Follow-up filling process is carried out, compound lidocaine emulsifiable paste pharmaceutical composition is obtained final product.
Following items are monitored in preparation process simultaneously to control the quality of emulsifiable paste intermediate：
(1) proterties：White or off-white color emulsifiable paste；
(2) pH value：Take emulsifiable paste directly to determine, pH value should be 8.7~9.7 (two annex VIH of Chinese Pharmacopoeia 2010 edition)；
(3) granularity：Determined according to 2010 editions methods of annex IXE first of Chinese Pharmacopoeia, the emulsion droplet and grain more than 180 μm must not be detected
Son；
(4) dewatering ability：Emulsifiable paste 5g is taken in centrifuge tube, 4000r/min high speed centrifugation 15min there must not be profit point
Layer phenomenon；
(5) mixture homogeneity：Take 10 parts of emulsifiable paste, the theoretical content by external standard method with calculated by peak area relative to labelled amount,
The relative standard deviation of 10 parts of sample sizes cannot be greater than 3.0%.
The preparation of the compound lidocaine emulsifiable paste pharmaceutical composition of embodiment 2
Prescription composition (prepares 45kg emulsifiable pastes)：
Preparation method：
(1) water is mutually prepared：The Acritamer 940 of recipe quantity is slowly added into 18525g purified waters, stirring more than 1 hour it is complete
CL is that water phase is obtained；
(2) prepared by oil phase：Lidocaine and prilocaine are measured in main cooker by prescription, mixing are stirred at 40~50 DEG C equal
It is even, be melted to transparency liquid, obtain lidocaine prilocaine eutectic；By recipe quantity Nikkol HCO80 60
DEG C fusing completely after add eutectic in, the prepared oil phase that stirs is standby；
(3) 10% sodium hydroxide solution is prepared with purified water by recipe quantity；
(4) emulsify：Measure in the oil phase that surplus purified water adds step (2) preparation, low rate mixing is set and wall stirring is scraped
Be 50 revs/min, after stirring 5 minutes, low rate mixing and to scrape wall mixing speed constant proceeds by emulsification, speed for 2000 turns/
Minute, being emulsified 3 minutes at a high speed every about 1 minute, the cumulative time is not less than 12 minutes；
(5) water obtained in step (1) is added in step (4) emulsion, is stirred 10 minutes, then low rate mixing is set
It is 60 revs/min with wall stirring is scraped, is slowly added into the sodium hydroxide solution of step (3) preparation, continues to stir half an hour, discharging,
Follow-up filling process is carried out, compound lidocaine emulsifiable paste pharmaceutical composition is obtained final product.
The preparation of the compound lidocaine emulsifiable paste pharmaceutical composition of embodiment 3
Prescription composition (prepares 10kg emulsifiable pastes)：
Preparation method：
(1) water is mutually prepared：Carbomer 934 is weighed by recipe quantity, and is measured by the 0.5% carbomer 934 aqueous solution of preparation pure
Change water, carbomer 934 is slowly added into purified water, stirring is completely dissolved and water phase is obtained for more than 1 hour；
(2) prepared by oil phase：Lidocaine and prilocaine are measured in main cooker by prescription, mixing are stirred at 40~50 DEG C equal
It is even, be melted to transparency liquid, obtain lidocaine prilocaine eutectic；By recipe quantity Nikkol HCO80 60
DEG C fusing completely after add eutectic in, the prepared oil phase that stirs is standby；
(3) 5% sodium hydroxide solution is prepared with purified water by recipe quantity；
(4) emulsify：Measure in the oil phase that surplus purified water adds step (2) preparation, low rate mixing is set and wall stirring is scraped
Be 50 revs/min, after stirring 5 minutes, low rate mixing and to scrape wall mixing speed constant proceeds by emulsification, speed for 2000 turns/
Minute, being emulsified 3 minutes at a high speed every about 1 minute, the cumulative time is not less than 12 minutes；
(5) water obtained in step (1) is added in step (4) emulsion, is stirred 10 minutes, then set and stir at a slow speed
It is 60 revs/min to mix and stir and scrape wall stirring, is slowly added into the sodium hydroxide solution of step (3) preparation, continues to stir half an hour, is gone out
Material, carries out follow-up filling process, obtains final product compound lidocaine emulsifiable paste pharmaceutical composition.
Following items are monitored in preparation process simultaneously to control the quality of emulsifiable paste intermediate：
(1) proterties：White or off-white color emulsifiable paste；
(2) pH value：Take emulsifiable paste directly to determine, pH value should be 8.7~9.7 (two annex VIH of Chinese Pharmacopoeia 2010 edition)；
(3) granularity：Determined according to 2010 editions methods of annex IXE first of Chinese Pharmacopoeia, the emulsion droplet and grain more than 180 μm must not be detected
Son；
(4) dewatering ability：Emulsifiable paste 5g is taken in centrifuge tube, 4000r/min high speed centrifugation 15min there must not be profit point
Layer phenomenon；
(5) mixture homogeneity：Take 10 parts of emulsifiable paste, the theoretical content by external standard method with calculated by peak area relative to labelled amount,
The relative standard deviation of 10 parts of sample sizes cannot be greater than 3.0%.
The preparation of the compound lidocaine emulsifiable paste pharmaceutical composition of embodiment 4
Prescription composition (prepares 10kg emulsifiable pastes)：
Preparation method：
(1) water is mutually prepared：Carbopol 941 is weighed by recipe quantity, and purifying is measured by the 2% carbomer 934 aqueous solution is prepared
Water, Carbopol 941 is slowly added into purified water, and stirring is completely dissolved and water phase is obtained for more than 1 hour；
(2) prepared by oil phase：Lidocaine and prilocaine are measured in main cooker by prescription, mixing are stirred at 40~50 DEG C equal
It is even, be melted to transparency liquid, obtain lidocaine prilocaine eutectic；By recipe quantity polyoxyl 40 hydrogenated castor oil 60
DEG C fusing completely after add eutectic in, the prepared oil phase that stirs is standby；
(3) 40% sodium hydroxide solution is prepared with purified water by recipe quantity；
(4) emulsify：Measure in the oil phase that surplus purified water adds step (2) preparation, low rate mixing is set and wall stirring is scraped
Be 50 revs/min, after stirring 5 minutes, low rate mixing and to scrape wall mixing speed constant proceeds by emulsification, speed for 2000 turns/
Minute, being emulsified 3 minutes at a high speed every about 1 minute, the cumulative time is not less than 12 minutes；
(5) water obtained in step (1) is added in step (4) emulsion, is stirred 10 minutes, then low rate mixing is set
It is 60 revs/min with wall stirring is scraped, is slowly added into the sodium hydroxide solution of step (3) preparation, continues to stir half an hour, discharging,
Follow-up filling process is carried out, compound lidocaine emulsifiable paste pharmaceutical composition is obtained final product.
Following items are monitored in preparation process simultaneously to control the quality of emulsifiable paste intermediate：
(1) proterties：White or off-white color emulsifiable paste；
(2) pH value：Take emulsifiable paste directly to determine, pH value should be 8.7~9.7 (two annex VIH of Chinese Pharmacopoeia 2010 edition)；
(3) granularity：Determined according to 2010 editions methods of annex IXE first of Chinese Pharmacopoeia, the emulsion droplet and grain more than 180 μm must not be detected
Son；
(4) dewatering ability：Emulsifiable paste 5g is taken in centrifuge tube, 4000r/min high speed centrifugation 15min there must not be profit point
Layer phenomenon；
(5) mixture homogeneity：Take 10 parts of emulsifiable paste, the theoretical content by external standard method with calculated by peak area relative to labelled amount,
The relative standard deviation of 10 parts of sample sizes cannot be greater than 3.0%.
The preparation of the compound lidocaine emulsifiable paste pharmaceutical composition of embodiment 5
Prescription composition (prepares 10kg emulsifiable pastes)：
Preparation method：
(1) water is mutually prepared：Carbomer940 is weighed by recipe quantity, and is measured by the 1.5% carbomer940 aqueous solution is prepared
Purified water, carbomer940 is slowly added into purified water, and stirring is completely dissolved and water phase is obtained for more than 1 hour；
(2) prepared by oil phase：Lidocaine and prilocaine are measured in main cooker by prescription, mixing are stirred at 40~50 DEG C equal
It is even, be melted to transparency liquid, obtain lidocaine prilocaine eutectic；Recipe quantity Cremophor RH60 is existed
Added after 60 DEG C of fusings completely in eutectic, the prepared oil phase that stirs is standby；
(3) 25% sodium hydroxide solution is prepared with purified water by recipe quantity；
(4) emulsify：Measure in the oil phase that surplus purified water adds step (2) preparation, low rate mixing is set and wall stirring is scraped
Be 50 revs/min, after stirring 5 minutes, low rate mixing and to scrape wall mixing speed constant proceeds by emulsification, speed for 2000 turns/
Minute, being emulsified 3 minutes at a high speed every about 1 minute, the cumulative time is not less than 12 minutes；
(5) water obtained in step (1) is added in step (4) emulsion, is stirred 10 minutes, then low rate mixing is set
It is 60 revs/min with wall stirring is scraped, is slowly added into the sodium hydroxide solution of step (3) preparation, continues to stir half an hour, discharging,
Follow-up filling process is carried out, compound lidocaine emulsifiable paste pharmaceutical composition is obtained final product.
Following items are monitored in preparation process simultaneously to control the quality of emulsifiable paste intermediate：
(1) proterties：White or off-white color emulsifiable paste；
(2) pH value：Take emulsifiable paste directly to determine, pH value should be 8.7~9.7 (two annex VIH of Chinese Pharmacopoeia 2010 edition)；
(3) granularity：Determined according to 2010 editions methods of annex IXE first of Chinese Pharmacopoeia, the emulsion droplet and grain more than 180 μm must not be detected
Son；
(4) dewatering ability：Emulsifiable paste 5g is taken in centrifuge tube, 4000r/min high speed centrifugation 15min there must not be profit point
Layer phenomenon；
(5) mixture homogeneity：Take 10 parts of emulsifiable paste, the theoretical content by external standard method with calculated by peak area relative to labelled amount,
The relative standard deviation of 10 parts of sample sizes cannot be greater than 3.0%.
The relevant material of embodiment 6 is investigated
The compound lidocaine emulsifiable paste prepared using the embodiment of the present invention carries out long-term stable experiment investigation.Simulation is commercially available
(25 ± 2 DEG C, relative humidity RH40 is tested bag apparatus long term test condition for ± 5%) lower 18 months.Relevant material testing result point
Not see the table below 1：
The relevant material of table 1 investigates test data sheet
As shown in Table 1, after each embodiment sample is placed 18 months under the conditions of long term test, relevant material ortho-aminotoluene exists
Between 0.10%~0.11%, maximum unknown list is miscellaneous between 0.02%~0.05%, and other known impurity is not detected, this table
Bright compound lidocaine emulsifiable paste impurity content of the present invention is very low, and relevant material ortho-aminotoluene has obtained good control, security
Good, product quality has obtained very big lifting in prior art basis.
The Performance comparision of several emulsifiable pastes of embodiment 7
Compound lidocaine emulsifiable paste is prepared by embodiment in CN101209250A, CN101816642A 1 respectively, with the present invention
Together, four in product appearance shape, phase inversion temperature, pH value, coating homogeneity for the emulsifiable paste and commercially available product EMLA of the preparation of embodiment 1
Whether the aspect comparative results such as layering that are demulsified in placement are as shown in table 2 below：
The Performance comparision of several emulsifiable pastes of table 2
As shown in Table 2, the combination property of compound lidocaine emulsifiable paste prepared by the embodiment of the present invention is optimal.
The allergic reaction experiment of embodiment 8 and skin irritation test
Experiment material：
1. test sample 1：Compound lidocaine emulsifiable paste in the present embodiment 1, lidocaine, prilocaine content are
2.5%, proterties is white emulsifiable paste, acidity-basicity ph 8.9；
2. matrix control group：Excipient without lidocaine, prilocaine, emulsifiable paste is auxiliary in composition only embodiment 1
Material, proterties is white emulsifiable paste；
3. commercially available product control：Commercially available compound lidocaine emulsifiable paste EMLA, lidocaine, prilocaine content are
2.5%, proterties is white emulsifiable paste, acidity-basicity ph 9.7.
Purpose：Whether observation compound lidocaine emulsifiable paste topical cutaneous administration has immunogenicity (anaphylaxis), local thorn
Swash property, the security of compound lidocaine emulsifiable paste is evaluated, for clinical application provides foundation.
Method：
(1) BT experiments：
60 cavys are divided into 5 groups, are respectively 1 group of test sample, matrix control group, commercially available product control group, negative control group
And positive controls, 20 animals of test sample 1 group, every group of 10 animals of remaining 4 control group.At the 1st day, the 7th day, the 14th day
Sensitization is carried out to each group animal, is attacked in the 14th day each group after last sensitization.Observed at once after medicine is removed, then existed
The response situation for visually observing and recording coating part in 24,48 and 72 hours after administration.
(2) repetitively administered skin irritation test：
Intact skin group animal visually observes administration local appearance and has no erythema, oedema etc. after terminating with administration during being administered
Obvious stimulation phenomenon, each group skin irritation reaction grade average is 0.Damaged skin group animal is at the administration initial stage (1~4
My god) visible slight erythema, incrustation phenomenon, no significant difference between each group.Administration mid-term, remaining each group in addition to commercially available product control group
Erythema fades away, and the time of skin healing and degree are basically identical, and skin has no that obvious stimulation is reacted after healing, observation period skin
Skin shows no obvious abnormalities；And the erythema of commercially available product control group disappears then relatively slowly, the skin healing time is also longer.
Conclusion：Under this experimental condition, compound lidocaine emulsifiable paste BT result of the tests of the present invention are feminine gender；Repetitively administered skin
In the property experiment of skin thorn, the normal and damaged skin to Japan large ear rabbit has no obvious irritation, and excitant is weak compared with commercially available product
Some.
Claims (5)
1. a kind of compound lidocaine emulsifiable paste pharmaceutical composition, it is characterised in that every 10 kilograms of emulsifiable pastes contain：
50~1000g of lidocaine,
50~1000g of prilocaine,
10~500g of Crodaret,
10~300g of Carbomer,
15~38g of NaOH,
Purified water adds to 10kg.
2. pharmaceutical composition as claimed in claim 1, it is characterised in that the Crodaret is selected from polyoxy second
The rilanit special of alkene 40, Cremophor RH60, Nikkol HCO80, the Carbomer are selected from Carbomer
974P, CARBOPOL 971, carbomer940, Carbopol, Carbomer981, Carbopol 941, Acritamer 940, carbomer 934,
Carbomer PES.
3. pharmaceutical composition as claimed in claim 2, it is characterised in that every 10 kilograms of emulsifiable pastes contain：
Lidocaine 250g,
Prilocaine 250g,
Polyoxyl 40 hydrogenated castor oil 190g,
CARBOPOL 974P 50g,
NaOH 25g,
Purified water 9235g.
4. a kind of preparation method of compound lidocaine emulsifiable paste pharmaceutical composition as claimed any one in claims 1 to 3, its
It is characterised by, comprises the following steps：
（1）Water is mutually prepared：Carbomer is weighed by recipe quantity, and purified water is measured by 0.5% ~ 2% Carbomer aqueous solution is prepared, by card
Ripple nurse is slowly added into purified water, and stirring is completely dissolved and water phase is obtained for more than 1 hour；
（2）It is prepared by oil phase：Lidocaine and prilocaine are measured in main cooker by prescription, are uniformly mixed at 40 ~ 50 DEG C, melted
Change to transparency liquid, obtain lidocaine prilocaine eutectic；By recipe quantity Crodaret in 60 DEG C of fusings
Added after completely in eutectic, the prepared oil phase that stirs is standby；
（3）By recipe quantity 5% ~ 40% sodium hydroxide solution is prepared with purified water；
（4）Emulsification：Measure surplus purified water and add step（2）In the oil phase of preparation, it is 50 to set low rate mixing and scrape wall stirring
Rev/min, after stirring 5 minutes, low rate mixing and to scrape wall mixing speed constant proceeds by emulsification, and speed is 2000 revs/min
Clock, emulsified 3 minutes at a high speed every about 1 minute, and the cumulative time is not less than 12 minutes；
（5）By step（1）Obtained water is added to step（4）In emulsion, stir 10 minutes, then low rate mixing is set and is scraped
Wall stirring is 60 revs/min, is slowly added into step（3）The sodium hydroxide solution of preparation, continues to stir half an hour, and discharging is carried out
Follow-up filling process, obtains final product compound lidocaine emulsifiable paste pharmaceutical composition.
5. the preparation method of compound lidocaine emulsifiable paste pharmaceutical composition as claimed in claim 4, it is characterised in that prepared
Following items are monitored in journey to control the quality of emulsifiable paste intermediate：
（1）Proterties：White or off-white color emulsifiable paste；
（2）PH value：Take this product directly to determine, pH value should be 8.7~9.7（Two annex VI H of Chinese Pharmacopoeia 2010 edition）；
（3）Granularity：Determined according to 2010 editions methods of annex IXE first of Chinese Pharmacopoeia, the emulsion droplet and particle more than 180 μm must not be detected；
（4）Dewatering ability：This product 5g is taken in centrifuge tube, 4000r/min high speed centrifugation 15min there must not be profit to be layered existing
As；
（5）Mixture homogeneity：Take 10 parts of this product, the theoretical content by external standard method with calculated by peak area relative to labelled amount, 10 parts
The relative standard deviation of sample size cannot be greater than 3.0%.
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| CN106806338B CN106806338B (en) | 2021-05-25 |
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| CN112438963A (en) * | 2020-11-11 | 2021-03-05 | 长沙晶易医药科技有限公司 | External preparation of lidocaine-prilocaine pharmaceutical composition and application thereof |
| CN112704662A (en) * | 2021-02-05 | 2021-04-27 | 华熙生物科技股份有限公司 | Lidocaine cream, preparation method and application thereof |
| CN113398101A (en) * | 2021-07-30 | 2021-09-17 | 温州医科大学附属眼视光医院 | Compound lidocaine gel patch |
| CN114948862A (en) * | 2022-06-09 | 2022-08-30 | 北京中泰邦医药科技有限公司 | Compound tetracaine cream and preparation method thereof |
| CN116098882A (en) * | 2023-04-06 | 2023-05-12 | 山东诚创蓝海医药科技有限公司 | Composition containing lidocaine prilocaine and preparation method thereof |
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