CN106137947B - Mexiletine hydrochloride emulsifiable paste and preparation method thereof - Google Patents
Mexiletine hydrochloride emulsifiable paste and preparation method thereof Download PDFInfo
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- CN106137947B CN106137947B CN201610586147.2A CN201610586147A CN106137947B CN 106137947 B CN106137947 B CN 106137947B CN 201610586147 A CN201610586147 A CN 201610586147A CN 106137947 B CN106137947 B CN 106137947B
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- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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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
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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Abstract
The present invention relates to a kind of emulsifiable pastes.More specifically, the present invention relates to a kind of mexiletine hydrochloride emulsifiable pastes, component including following mass fraction: mexiletine hydrochloride 10~12%, stearic acid 10.1~12.3%, octadecyl alcolol 10.3~12.5%, liquid paraffin 16.8~18.9%, ethyl hydroxy benzoate 0.08~0.1%, triethanolamine 2.8~4.3%, Laurocapram 1.5~2.0%, 2,6-di-tert-butyl p-cresol 0.08~0.1%, disodium ethylene diamine tetraacetate 0.09~0.14%, glycerol 35~38% and water 7.0~8.8%.Also invent the preparation method for further relating to the mexiletine hydrochloride emulsifiable paste.The present invention provides a kind of side effect is smaller, safety is good, the good mexiletine hydrochloride emulsifiable paste of emulsifying effectiveness, and it is preferable to additionally provide a kind of precision, stability and repeatability, and the preparation method of the mexiletine hydrochloride emulsifiable paste of mexiletine hydrochloride stable content.
Description
Technical field
The present invention relates to a kind of emulsifiable pastes.It is more particularly related to a kind of mexiletine hydrochloride emulsifiable paste and its preparation side
Method.
Background technique
Mexiletine hydrochloride belongs to Ib class antiarrhymic, inhibits cardiac muscle cell Na+Interior stream and promotion K+Outflow effect, shortens
Pu Shi Fibers Action Potential time-histories and effective refractory period delay indoor conduction, improve ventricular fibrillation threshold, for caused by a variety of causes
Ventricular arrhythmia.Mexiletine hydrochloride, which removes, has antiarrhythmic effect, also has the function of local anaesthesia, but be generally mouth
It is used in clothes, is easy to damage the liver of patient in this way, and cause the adverse reaction of gastrointestinal tract.
Summary of the invention
It is an object of the invention to solve at least the above problems, and provide the advantages of at least will be described later.
A further object of the invention provides that a kind of side effect is smaller, and safety is good, the good mexiletine hydrochloride of emulsifying effectiveness
Emulsifiable paste.
It is a still further object of the present invention to provide a kind of precision, stability and repeatability are preferable, and mexiletine hydrochloride
The preparation method of the mexiletine hydrochloride emulsifiable paste of stable content.
In order to realize object of the present invention and further advantage, a kind of mexiletine hydrochloride emulsifiable paste is provided, including following
The component of mass fraction:
Mexiletine hydrochloride 10~12%, stearic acid 10.1~12.3%, octadecyl alcolol 10.3~12.5%, liquid paraffin 16.8
~18.9%, ethyl hydroxy benzoate 0.08~0.1%, triethanolamine 2.8~4.3%, Laurocapram 1.5~2.0%, bis- uncle of 2,6-
Butyl paracresol 0.08~0.1%, disodium ethylene diamine tetraacetate 0.09~0.14%, glycerol 35~38% and water 7.0~
8.8%.
Preferably, in the mexiletine hydrochloride emulsifiable paste, the component including following quality:
Mexiletine hydrochloride 106.17g, stearic acid 106.78g, octadecyl alcolol 106.82g, liquid paraffin 177.91g, oxybenzene second
Ester 0.90g, triethanolamine 37.1g, Laurocapram 18.6g, DBPC 2,6 ditertiary butyl p cresol 0.90g, ethylenediamine tetra-acetic acid two
Sodium 0.97g, glycerol 368.76g and water 75.09g.
The present invention also provides the preparation methods of the mexiletine hydrochloride emulsifiable paste described in one kind, comprising the following steps:
Step 1: according to following mass fraction by glycerol 35~38%, 0.09~0.14% and of disodium ethylene diamine tetraacetate
Ethyl hydroxy benzoate 0.08~0.1% is added in water 7.0~8.8%, is heated to 78~82 DEG C, stirs evenly, spare；
Step 2: according to following mass fraction by stearic acid 10.1~12.3%, octadecyl alcolol 10.3~12.5%, 2,6- bis-
Butylated Hydroxytoluene 0.08~0.1%, Laurocapram 1.5~2.0% and liquid paraffin 16.8~18.9% mix, and are heated to
74~76 DEG C, stops heating, stir evenly；
Step 3: the mixture in step 1 is added in the mixture in step 2, following mass fraction is added
Triethanolamine 2.8~4.3%, stirring, when mixture temperature is cooled to 40 DEG C, be added following mass fraction hydrochloric acid U.S. west
Rule 10~12%, continues to be stirred until homogeneous to get mexiletine hydrochloride emulsifiable paste.
Preferably, in the preparation method of the mexiletine hydrochloride emulsifiable paste, the mixing speed in the step 1 is
2000~2500r/min.
Preferably, in the preparation method of the mexiletine hydrochloride emulsifiable paste, the heating temperature in the step 1 is 80
℃。
Preferably, in the preparation method of the mexiletine hydrochloride emulsifiable paste, the mixing speed in the step 2 is
2600~2800r/min.
Preferably, in the preparation method of the mexiletine hydrochloride emulsifiable paste, the heating temperature in the step 2 is 75
℃。
Preferably, in the preparation method of the mexiletine hydrochloride emulsifiable paste, the mixing speed in the step 3 is
2900~3000r/min.
The present invention is include at least the following beneficial effects: caused by mexiletine hydrochloride emulsifiable paste prepared by the present invention is suitable for injection
Noninvasive skin or soft tissue pain caused by pain and other factors, have the effect of topical pain relief, while avoiding oral
It is damaged caused by the liver of patient and the adverse reaction of caused gastrointestinal tract.And preparation method of the invention is easy to operate,
Precision, stability and repeatability are preferable, are suitable for large-scale industrial production.
Further advantage, target and feature of the invention will be partially reflected by the following instructions, and part will also be by this
The research and practice of invention and be understood by the person skilled in the art.
Detailed description of the invention
Fig. 1 is the high-efficient liquid phase chromatogram of reference substance solution of the invention；
Fig. 2 is the high-efficient liquid phase chromatogram of test solution of the invention；
Fig. 3 is the high-efficient liquid phase chromatogram of negative control solution of the invention.
Specific embodiment
Present invention will be described in further detail below with reference to the accompanying drawings, to enable those skilled in the art referring to specification text
Word can be implemented accordingly.
It should be appreciated that such as " having ", "comprising" and " comprising " term used herein do not allot one or more
The presence or addition of a other elements or combinations thereof.
The present invention provides a kind of mexiletine hydrochloride emulsifiable paste, the component including following mass fraction:
Mexiletine hydrochloride 10~12%, stearic acid 10.1~12.3%, octadecyl alcolol 10.3~12.5%, liquid paraffin 16.8
~18.9%, ethyl hydroxy benzoate 0.08~0.1%, triethanolamine 2.8~4.3%, Laurocapram 1.5~2.0%, bis- uncle of 2,6-
Butyl paracresol 0.08~0.1%, disodium ethylene diamine tetraacetate 0.09~0.14%, glycerol 35~38% and water 7.0~
8.8%.
In the mexiletine hydrochloride emulsifiable paste, the component including following quality:
Mexiletine hydrochloride 106.17g, stearic acid 106.78g, octadecyl alcolol 106.82g, liquid paraffin 177.91g, oxybenzene second
Ester 0.90g, triethanolamine 37.1g, Laurocapram 18.6g, DBPC 2,6 ditertiary butyl p cresol 0.90g, ethylenediamine tetra-acetic acid two
Sodium 0.97g, glycerol 368.76g and water 75.09g.
A kind of preparation method of mexiletine hydrochloride emulsifiable paste, comprising the following steps:
Step 1: according to following mass fraction by glycerol 35~38%, 0.09~0.14% and of disodium ethylene diamine tetraacetate
Ethyl hydroxy benzoate 0.08~0.1% is added in water 7.0~8.8%, is heated to 78~82 DEG C, stirs evenly, spare, this is water phase
Preparation method.
Step 2: according to following mass fraction by stearic acid 10.1~12.3%, octadecyl alcolol 10.3~12.5%, 2,6- bis-
Butylated Hydroxytoluene 0.08~0.1%, Laurocapram 1.5~2.0% and liquid paraffin 16.8~18.9% mix, and are heated to
74~76 DEG C, stop heating, stir evenly, this is the preparation method of oily phase.
Step 3: the mixture in step 1 is added in the mixture in step 2, following mass fraction is added
Triethanolamine 2.8~4.3%, stirring, when mixture temperature is cooled to 40 DEG C, be added following mass fraction hydrochloric acid U.S. west
Rule 10~12%, continue to be stirred until homogeneous to get mexiletine hydrochloride emulsifiable paste.
In the preparation method of the mexiletine hydrochloride emulsifiable paste, the mixing speed in the step 1 is 2000~2500r/
min。
In the preparation method of the mexiletine hydrochloride emulsifiable paste, the heating temperature in the step 1 is 80 DEG C.
In the preparation method of the mexiletine hydrochloride emulsifiable paste, the mixing speed in the step 2 is 2600~2800r/
min。
In the preparation method of the mexiletine hydrochloride emulsifiable paste, the heating temperature in the step 2 is 75 DEG C.
In the preparation method of the mexiletine hydrochloride emulsifiable paste, the mixing speed in the step 3 is 2900~3000r/
min。
The present invention, using the method that oily phase is added in water phase, first has to control in mexiletine hydrochloride emulsifiable paste preparation process
Temperature required by two-phase, has followed by regulated and controled mixing speed, mixing speed start it is unsuitable too fast, with two-phase mixtures amount by
It is cumulative more, it can gradually accelerate mixing speed, too fast to be also easy to produce bubble, excessively slow mixing is uneven, too fast or too slow to will affect cream
Change effect.
1 instrument and reagent
1.1 instrument, 1200 type high performance liquid chromatograph (Agilent company of the U.S.)；AL204 type electronic balance (plum Teller-support
Benefit Instrument Ltd.)；HH-S24S digital display thermostat water bath (Shanghai Jun Zhu instrument manufacturing Co., Ltd)；JJ-1 type reinforcement
Electric blender (medical apparatus and instruments factory of Community of Jin Tan County city).
1.2 reagent mexiletine hydrochloride reference substances (content >=98%, lot number 20151211Solarbio LIFE
SCIENCES)；Stearic acid (lot number 101820150204, Changsha Liuyang biological medicine industry park), octadecyl alcolol (lot number
10520150302, Hu'nan Erkang Pharmaceutical Co., Ltd.), liquid paraffin (lot number 150801, Jilin Jilin Chemical river city grease
Chemical industry Co., Ltd), ethyl hydroxy benzoate (lot number 20150406, Taishan City Xinning pharmaceutical Co. Ltd), triethanolamine (lot number
20150402, Jiangxi Alpha's high-tech pharmaceutcal corporation, Ltd), Laurocapram (asparagus cochinchinensis victory pharmaceutical Co. Ltd, lot number
141001), 2,6-di-tert-butyl p-cresol (lot number 2014081201, Chengdu Ke Long chemical reagent factory), ethylenediamine tetra-acetic acid
Disodium (lot number 20150102, Hu'nan Erkang Pharmaceutical Co., Ltd.), glycerol (control interest gummy shark pharmacy by lot number 141105, traditional Chinese medicines
Co., Ltd), anhydrous sodium acetate (content >=99%, lot number 2015061701, Chengdu Ke Long chemical reagent factory), glacial acetic acid
(lot number 20151108, Taishan City Xinning pharmaceutical Co. Ltd), methanol are chromatographically pure (silent winged scientific and technological (China) limited public affairs of generation that of match
Department), (self-control, lot number: 160301,160302,160303), water is ultrapure water to mexiletine hydrochloride emulsifiable paste, other reagents are point
It analyses pure.
2 results
2.1 chromatographic condition
YMC-Triart C18 chromatographic column (250nm × 4.6mm, 5um)；Column temperature: 30 DEG C；Mobile phase: methanol -0.1mol
L-1Sodium acetate solution (51:49, glacial acetic acid tune pH5.8 ± 0.1)；Flow velocity: 1mlmin-1；Detection wavelength: 262nm；Sample volume
20μl。
The preparation of 2.2 solution
2.2.1 the preparation of reference substance solution
Precision weighs mexiletine hydrochloride reference substance 12.42mg, sets in 25ml measuring bottle, adds mobile phase 0.1molL-1Sodium acetate
Solution is settled to scale, and obtaining concentration is 0.4968mgml-1Reference substance stock solution.
2.2.2 the preparation of test solution
Cream products prepared by the present invention about 2g is taken, it is accurately weighed, add 0.1molL-1Appropriate sodium acetate solution sets 70 DEG C
Make to dissolve in water-bath, let cool to room temperature, is transferred in 100ml measuring bottle, adds 0.1molL-1Sodium acetate solution shakes up to scale,
After ice bath is 2 hours cooling, filtration discards primary filtrate, takes subsequent filtrate as test solution.
Mexiletine hydrochloride is soluble easily in water, using 0.1molL in mobile phase-1Sodium acetate solution, can be with as sample solvent
Reduce solvent peak interference.When preparing test solution, oil is mutually not soluble in water, 0.1molL can be added in test sample-1Sodium acetate is molten
In liquid, heating water bath, water-oil separating, then ice bath is cooling again, filters to get test solution.
2.2.3 the preparation of negative control solution
The blank emulsifiable paste about 2g of scarce mexiletine hydrochloride is taken, it is accurately weighed, feminine gender is made using sample solution preparation method
Contrast solution.
2.3 system suitability
It is accurate respectively to draw reference substance solution, 20 μ of test solution and negative control solution according to 2.1 chromatographic condition
L injects liquid chromatograph, measures to get the result is shown in Figure 1~3, wherein peak 1 is mexiletine hydrochloride peak, negative noiseless, specially
Attribute is good, and number of theoretical plate is calculated by mexiletine hydrochloride peak is not less than 3000.
2.4 linear relationships are investigated
The reference substance solution for taking 2.2.1, adds 0.1molL-1Sodium acetate solution dilute to obtain concentration be respectively 0.4968,
0.3974、0.2981、0.1987、0.0994mg·ml-1Reference substance solution record chromatography by 2.1 chromatographic condition sample introduction
Figure, with reference substance concentration (C) for abscissa, peak area (A) is ordinate, carries out linear regression, obtains regression equation A=1201c+
(3.5247 r=0.9999).The result shows that mexiletine hydrochloride is in 0.0994~0.4968mgml-1 concentration range in good
Linear relationship.
2.5 Precision Experiment
Taking concentration is 0.4968mgml-1Reference substance solution record peak face by chromatographic condition continuous sample introduction 6 times of 2.1
Product, as a result the RSD of peak area is 0.86% (n=6), shows that the precision of the method for the present invention is good.
2.6 stability experiment
Take mexiletine hydrochloride emulsifiable paste about 2g (lot number: it is 160301), accurately weighed, it is molten that test sample is made by the method for 2.2.2
Liquid records peak area, calculating RSD is 1.76% (n=6), shows test liquid 24 respectively at 0,2,4,8, sample introduction measurement for 24 hours
It is basicly stable in hour.
2.7 repeated experiment
Taking 6 parts of same batch test sample respectively, (lot number: 160301), every part of about 2g is accurately weighed, by the method system of 2.2.2
At test solution, sample introduction measurement records peak area, and calculating RSD is 0.84% (n=6), shows that this method repeatability is good.
The experiment of 2.8 rate of recovery
Take 9 parts of (known content 119.5mgg of mexiletine hydrochloride emulsifiable paste-1), every part of about 2g is accurately weighed, by 2.2.2
Method test solution is made, take every part of 0.5ml of the solution, set in 5ml measuring bottle, then accurate mexiletine hydrochloride reference substance is added
Solution (0.4968mgml-1) in right amount, point 3 groups of basic, normal, high concentration is separately added into 0.5ml, 1ml, 2ml, is settled to scale,
Sample introduction measurement, record peak area simultaneously calculate the rate of recovery, as a result the rate of recovery of basic, normal, high three kinds of concentration be respectively 101.76%,
101.23%, 101.62%, RSD=0.38% (n=9), the results are shown in Table 1.
1 rate of recovery experimental result (n=9) of table
The measurement of 2.9 sample sizes
Take mexiletine hydrochloride emulsifiable paste 3 batches prepared by the present invention (lot number: 160301,160302,160303), by 2.2.2's
Test solution is made in method, and sample introduction measurement the results are shown in Table 2.
2 mexiletine hydrochloride emulsifiable paste sample size measurement result (n=9) of table
2.10 pain sensitivity is tested
This experiment randomly chooses 4 subjects, is applied on the inside of right finesse with blank emulsifiable paste, is pricked after 15min with blood taking needle
At wrist, as the negative control of every subject, the mexiletine hydrochloride emulsifiable paste of various concentration is then applied to a subject left side
On the inside of wrist, pricked the hand at wrist after same 15min with blood taking needle, statistics mitigates the effect of pain, the results are shown in Table 3.Wherein, this experiment
The effect of subject for pain's degree is counted using digital staging (NRS), represents different degrees of pain with 0~10,0 is nothing
Bitterly, 10 be severe pain.Subject oneself is allowed to iris out the number that can most represent itself pain degree.Pain degree grade scale
Are as follows: 0 indicates painless；1~3 indicates mild pain；4~6 indicate moderate pain；7~10 indicate severe pain, and the method is in the world
On it is more general, "+" number is corresponding with the number in digital staging.
3 pain sensitivity test result of table
Using blood taking needle to pain sensitivity experiment is carried out on the inside of wrist before and after smearing mexiletine hydrochloride emulsifiable paste, as a result
Show that mexiletine hydrochloride emulsifiable paste has the function of mitigating pain, and its concentration is positively correlated with pain degree is mitigated.
Although the embodiments of the present invention have been disclosed as above, but its is not only in the description and the implementation listed
With it can be fully applied to various fields suitable for the present invention, for those skilled in the art, can be easily
Realize other modification, therefore without departing from the general concept defined in the claims and the equivalent scope, the present invention is simultaneously unlimited
In specific details and legend shown and described herein.
Claims (7)
1. a kind of mexiletine hydrochloride emulsifiable paste, which is characterized in that the component including following mass fraction:
Mexiletine hydrochloride 10~12%, stearic acid 10.1~12.3%, octadecyl alcolol 10.3~12.5%, liquid paraffin 16.8~
18.9%, ethyl hydroxy benzoate 0.08~0.1%, triethanolamine 2.8~4.3%, Laurocapram 1.5~2.0%, the tertiary fourth of 2,6- bis-
Base paracresol 0.08~0.1%, disodium ethylene diamine tetraacetate 0.09~0.14%, glycerol 35~38% and water 7.0~8.8%；
The preparation method of the mexiletine hydrochloride emulsifiable paste, comprising the following steps:
Step 1: being added to the water glycerol, disodium ethylene diamine tetraacetate and ethyl hydroxy benzoate according to the mass fraction, it is heated to
It 78~82 DEG C, stirs evenly, it is spare；
Step 2: according to the mass fraction by stearic acid, octadecyl alcolol, DBPC 2,6 ditertiary butyl p cresol, Laurocapram and
Liquid paraffin mixing, is heated to 74~76 DEG C, stops heating, stirs evenly；
Step 3: the mixture in step 1 is added in the mixture in step 2, the mass fraction is added
Triethanolamine, stirring are added the mexiletine hydrochloride of the mass fraction, continue to stir when mixture temperature is cooled to 40 DEG C
It mixes to uniformly to get mexiletine hydrochloride emulsifiable paste.
2. mexiletine hydrochloride emulsifiable paste as described in claim 1, which is characterized in that the component including following quality:
Mexiletine hydrochloride 106.17g, stearic acid 106.78g, octadecyl alcolol 106.82g, liquid paraffin 177.91g, ethyl hydroxy benzoate
0.90g, triethanolamine 37.1g, Laurocapram 18.6g, DBPC 2,6 ditertiary butyl p cresol 0.90g, disodium ethylene diamine tetraacetate
0.97g, glycerol 368.76g and water 75.09g.
3. mexiletine hydrochloride emulsifiable paste as described in claim 1, which is characterized in that the mixing speed in the step 1 is 2000
~2500r/min.
4. mexiletine hydrochloride emulsifiable paste as claimed in claim 3, which is characterized in that the heating temperature in the step 1 is 80
℃。
5. mexiletine hydrochloride emulsifiable paste as described in claim 1, which is characterized in that the mixing speed in the step 2 is 2600
~2800r/min.
6. mexiletine hydrochloride emulsifiable paste as claimed in claim 5, which is characterized in that the heating temperature in the step 2 is 75
℃。
7. mexiletine hydrochloride emulsifiable paste as described in claim 1, which is characterized in that the mixing speed in the step 3 is 2900
~3000r/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610586147.2A CN106137947B (en) | 2016-07-22 | 2016-07-22 | Mexiletine hydrochloride emulsifiable paste and preparation method thereof |
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Citations (5)
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| CN1385150A (en) * | 2001-05-11 | 2002-12-18 | 张国智 | Anesthetic cream of tracheal catheter surface anesthesia |
| CN101209250A (en) * | 2006-12-27 | 2008-07-02 | 上海复星医药（集团）股份有限公司 | Compound lignocaine emulsifiable paste and preparing technique |
| CN102727422A (en) * | 2011-04-15 | 2012-10-17 | 中国人民解放军济南军区第四零一医院 | Nano-silver emulsifiable paste and its preparation method |
| CN102846661A (en) * | 2012-08-16 | 2013-01-02 | 中国人民解放军济南军区第四〇一医院 | Compound nano-silver emulsifiable paste and preparation method thereof |
| CN104688717A (en) * | 2015-03-18 | 2015-06-10 | 华控创新（北京）药物研究院有限公司 | Drug combination containing lidocaine and prilocainum |
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2016
- 2016-07-22 CN CN201610586147.2A patent/CN106137947B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1385150A (en) * | 2001-05-11 | 2002-12-18 | 张国智 | Anesthetic cream of tracheal catheter surface anesthesia |
| CN101209250A (en) * | 2006-12-27 | 2008-07-02 | 上海复星医药（集团）股份有限公司 | Compound lignocaine emulsifiable paste and preparing technique |
| CN102727422A (en) * | 2011-04-15 | 2012-10-17 | 中国人民解放军济南军区第四零一医院 | Nano-silver emulsifiable paste and its preparation method |
| CN102846661A (en) * | 2012-08-16 | 2013-01-02 | 中国人民解放军济南军区第四〇一医院 | Compound nano-silver emulsifiable paste and preparation method thereof |
| CN104688717A (en) * | 2015-03-18 | 2015-06-10 | 华控创新（北京）药物研究院有限公司 | Drug combination containing lidocaine and prilocainum |
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Effective date of registration: 20190516 Address after: 610083 West War Zone General Hospital, 270 Rongdu Avenue, Jinniu District, Chengdu City, Sichuan Province Patentee after: General Hospital of the Western War Zone of the Chinese People's Liberation Army Address before: 610083 Pharmaceutical Department, Chengdu Military Region General Hospital, 270 Rongdu Avenue, Jinniu District, Chengdu City, Sichuan Province Patentee before: Jin Weihua |