CN102525886B - Diclofenac diethylamine emulgel and preparation method thereof - Google Patents
Diclofenac diethylamine emulgel and preparation method thereof Download PDFInfo
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- CN102525886B CN102525886B CN 201210009904 CN201210009904A CN102525886B CN 102525886 B CN102525886 B CN 102525886B CN 201210009904 CN201210009904 CN 201210009904 CN 201210009904 A CN201210009904 A CN 201210009904A CN 102525886 B CN102525886 B CN 102525886B
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- diclofenac
- propylene glycol
- isopropyl alcohol
- emulgel
- isopropyl myristate
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Abstract
The invention discloses diclofenac diethylamine emulgel. In the emulgel, isopropyl myristate, isopropyl alcohol and propylene glycol are combined as a penetration enhancer; carbomer 980 is used as a water-based gel substrate matrix; liquid paraffin is used as an oil-phase matrix; and polysorbate 80 and glycerol monostearate/distearate are used as emulsifiers. The diclofenac diethylamine emulgel disclosed by the invention is high in in-vitro penetration absorption speed, takes effect quickly, and is favorable for easing the pain of a patient in time; and moreover, the diclofenac diethylamine emulgel has the characteristics of less skin irritation and high stability.
Description
Technical field
The present invention relates to a kind of diclofenac diethylamine emulgel and preparation method thereof.
Background technology
Diclofenac diethylammonium is a kind of non_steroidal anti_inflammatory drug, has antiinflammatory, analgesic activity, topical application, and the penetrable skin of its effective ingredient reaches areas of inflammation, alleviates the Acute and chronic inflammation reaction, makes that inflammatory swelling alleviates, pain relief.Domestic existing diclofenac diethylamine gel agent and emulsion agent listing, but because diclofenac diethylammonium has stronger hydrophilic, and common local administration preparation percutaneous permeability is poor, and drug effect is slow, bioavailability is undesirable.Use emulsifying technology at preparation technique, can increase to a certain extent the fat-soluble of diclofenac diethylammonium, such as the domestic diclofenac diethylamine emulgel that has now gone on the market (commodity are called the diclofenac latex), adopt isopropyl alcohol, propylene glycol, card pool nurse, west tell horse brother, liquid paraffin, aliphatic alcohol sad/the adjuvant preparations such as certain herbaceous plants with big flowers acid esters, aromatic and water, but its transdermal efficient is still undesirable, onset is slower, is difficult to satisfy the requirement of clinical quickly alleviating pain.For this reason, need a kind of diclofenac diethylammonium percutaneous permeability, the product that makes its quick acting and method of increasing of research and development.
Summary of the invention
The object of the present invention is to provide the diclofenac diethylamine emulgel that a kind of percutaneous permeability is good, drug effect is fast.Another object of the present invention is to provide the preparation method of diclofenac diethylamine emulgel.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
A kind of diclofenac diethylamine emulgel is comprised of the composition of following mass percent:
Described Percutaneous absorption enhancer is isopropyl myristate, isopropyl alcohol and propylene glycol, and the mass ratio of described isopropyl myristate, isopropyl alcohol and propylene glycol is followed successively by 0.8-2: 0.8-3: 1.
Preferably, the mass percent of described composition is:
Described aqueous gel substrate is carbomer, poloxamer, water-soluble cellulose polymer or derivant, alginate etc., can be one or more combination wherein.Described oil phase substrate is white vaseline, liquid paraffin, octadecanol etc., can be one or more combination wherein.Described emulsifying agent is tween, single glycerol distearate, polyoxyethylene stearic acid ester etc., can be one or more combination wherein.
Preferably, the mass ratio of described isopropyl myristate, isopropyl alcohol and propylene glycol is followed successively by 1: 1: 1.
The further preferred Carbopol of the present invention is as aqueous gel substrate, and liquid paraffin is as oil phase substrate, and the mixture of polyoxyethylene sorbitan monoleate and single glycerol distearate is as emulsifying agent, and the mass ratio of described polyoxyethylene sorbitan monoleate and single glycerol distearate is 1: 1.
The present invention further provides the preparation method of diclofenac diethylamine emulgel, it is characterized in that may further comprise the steps:
(1) propylene glycol is mixed with water, the rear adding aqueous gel substrate that stirs, being swelling to becomes transparent gel, regulates pH value to 6.5～7.5, stirs, evenly mixed;
(2) diclofenac diethylammonium is added isopropyl alcohol, heating joins in (1) dissolving, solution, is heated to 70～85 ℃ and stirs, insulation;
(3) oil phase substrate, emulsifying agent, isopropyl myristate are heated to 70～85 ℃ together, stir into solution, this solution is under agitation joined in (2), emulsifying, insulation;
(4) continue to be stirred to cooling, fill and get final product.
The emulsion agent that the present invention makes to faint yellow butterfat sample gel, has special fragrance for white.
Emulsion agent diclofenac diethylammonium unit are that the present invention makes accumulation transit dose is: be not less than 8.7 μ g/cm in 0.5 hour
2, be not less than 27.0 μ g/cm in 1 hour
2, be not less than 71.7 μ g/cm in 2 hours
2, be not less than 163.0 μ g/cm in 4 hours
2
The emulsion agent that the present invention makes, its effective ingredient comparatively fast transdermal reach areas of inflammation, alleviate the Acute and chronic inflammation reaction, make that inflammatory swelling alleviates, pain relief.Clinical mild to moderate pain for alleviating muscle, soft tissue and joint.As: the pain that alleviate the spraining of muscle, soft tissue, pull, dampen, strain, lower back damage causes and arthralgia etc.The symptomatic treatment that also can be used for osteoarthritis.
Beneficial effect of the present invention:
(1) Transdermal absorption is effective.The present invention adopts isopropyl myristate, isopropyl alcohol, three kinds of combinations of propylene glycol as Percutaneous absorption enhancer, and in the Transdermal absorption test, diclofenac diethylammonium unit are accumulation transit dose is: 0.5 hour 8.7761 μ g/cm
2, 1 hour 26.9926 μ g/cm
2, 2 hours 71.7096 μ g/cm
2, 4 hours 180.9681 μ g/cm
2, 6 hours 260.9314 μ g/cm
2, 8 hours 365.0795 μ g/cm
2, and commercially available prod diclofenac diethylammonium unit are accumulation transit dose is: 0.5 hour 4.3641 μ g/cm
2, 1 hour 12.3034 μ g/cm
2, 2 hours 30.5054 μ g/cm
2, 4 hours 94.7534 μ g/cm
2, 6 hours 177.4286 μ g/cm
2, 8 hours 279.8678 μ g/cm
2Be 2 times of commercially available prod when 0.5 hour, 1 hour, 2 hours and 4 hours by the visible diclofenac diethylammonium unit are of the present invention accumulation of above data transit dose, show that transdermal effect of the present invention significantly is better than the commercially available prod, onset is faster, more is conducive to the pain of timely reduction of patient.
(2) safety is good.The diclofenac diethylamine emulgel that adopts the preferred aqueous gel substrate of the present invention, oil phase substrate and emulsifying agent to make, the toxicological test result is: the diclofenac diethylammonium latex to rabbit intact skin and damaged skin without the obvious stimulation effect, sensitization rate to guinea pig skin is 0%, without sensitization.Show that the present invention without obvious skin irritation and sensitization, does not have toxic and side effects, the clinical practice safety is good.
(3) good stability.Diclofenac diethylamine emulgel emulsion droplet diameter of the present invention＜20 μ m, centrifugal 30 minutes of 3000rpm is not stratified, breakdown of emulsion not.Stability test shows the emulsion agent stable in properties, diclofenac diethylammonium degraded＜0.5%.
Description of drawings
Fig. 1 is transdermal test accumulative total transit dose contrast test curve chart.
Fig. 2 is transdermal test unit area transit dose contrast test curve chart.
The specific embodiment
Following embodiment is used for further specifying the present invention, but does not limit the scope of the invention.
The test of embodiment 1 isopropyl myristate prescription screening
Select respectively the isopropyl myristate of different amounts to make diclofenac diethylamine emulgel, it is carried out the Transdermal absorption test, measure diclofenac diethylammonium unit are accumulation in 1 hour transit dose, concrete outcome sees Table 1.
Table 1 isopropyl myristate prescription screening result (unit: g/100g)
Result of the test shows: isopropyl myristate has significant Transdermal absorption facilitation to diclofenac diethylammonium, its consumption is when 10-20%, the Transdermal absorption best results, but when the consumption of isopropyl myristate reaches 10% left and right sides, its Transdermal absorption facilitation namely reaches peak value, the continuation increase of its consumption can not bring appreciable impact to the Transdermal absorption of diclofenac diethylammonium, and therefore selecting its optimum amount is 10%.
The test of embodiment 2 isopropyl alcohol prescription screenings
Select respectively the isopropyl alcohol of different amounts to make diclofenac diethylamine emulgel, it is carried out the Transdermal absorption test, measure diclofenac diethylammonium unit are accumulation in 1 hour transit dose, concrete outcome sees Table 2.
Table 2 isopropyl alcohol prescription screening result (unit: g/100g)
Result of the test shows: isopropyl alcohol has significant Transdermal absorption facilitation to diclofenac diethylammonium, its consumption is when 10-20%, the Transdermal absorption best results, but when the consumption of isopropyl alcohol reaches 10% left and right sides, its Transdermal absorption facilitation namely reaches peak value, the increase of its consumption can not increase the Transdermal absorption of diclofenac diethylammonium, and therefore selecting its optimum amount is 10%.
Embodiment 3 emulsifying agents and the test of oil phase prescription screening
Select respectively emulsifying agent and the oil phase of different amounts to make diclofenac diethylamine emulgel, it is carried out outward appearance and microexamination, and centrifugal observation layering situation, concrete outcome sees Table 3.
Table 3 emulsifying agent and oil phase prescription screening result (unit: g/100g)
Result of the test shows: select polyoxyethylene sorbitan monoleate and single glycerol distearate as emulsifying agent, select simultaneously liquid paraffin as oil phase, can obtain the emulsion agent of stable and uniform.When the consumption of polyoxyethylene sorbitan monoleate and single glycerol distearate respectively 0.5% the time, the consumption of oil phase 2% the time, best results.
Embodiment 4-6
A kind of diclofenac diethylamine emulgel, made by the raw material described in the table 4:
Table 4 embodiment 4-6 component table (unit: Kg)
The preparation method step is:
(1) propylene glycol is mixed with water, the rear adding card pool nurse 980 that stirs, being swelling to becomes transparent gel, regulates pH value to 6.5～7.5 with diethylamine, stirs, evenly mixed;
(2) diclofenac diethylammonium is added isopropyl alcohol, heating joins in (1) dissolving, solution, is heated to 70～85 ℃ and stirs, insulation;
(3) liquid paraffin, polyoxyethylene sorbitan monoleate, single glycerol distearate, isopropyl myristate are heated to 70～85 ℃ together, stir into solution, this solution is under agitation joined in (2), emulsifying, insulation;
(4) continue to be stirred to cooling, fill and get final product.
The emulsion agent that embodiment 4-6 is made carries out the Transdermal absorption test, and concrete grammar is as follows:
Test apparatus: TK-12A type percutaneous dispersion test instrument, the triumphant scientific and technological trade Co., Ltd of the Shanghai iron of fine quality.
Contrast medicine: the diclofenac of different batches
Test skin: the skin of abdomen of the male rat that exsomatizes, remove hair and subcutaneous tissue, before use preparation, every skin at random in two, wherein half is used for the self-control sample, and second half skin is used for commercially available diclofenac latex, the error that is produced to eliminate the animal skin difference as far as possible.Every kind of sample parallel testing 6 times.
The test accepting medium: water for injection, the volume of accepting medium are 7ml.
Test temperature: 37 ℃.
Stirrer rotating speed: 300rpm during test.
Sample time (hour): 0.5,1,2,4,6,8.
Sample volume: 7ml, namely every sub-sampling takes the acceptable solution in the diffusion cell, replenishes the acceptable solution of same volume again.Error when the method can be eliminated sampling and fluid infusion.
Assay method: adopt the HPLC method to measure the content of diclofenac diethylammonium in the sample liquid.
Test method: rat skin is fixed between the diffuser casing and receiving chamber of disperser keratodermatitis subtend diffuser casing; The 7ml acceptable solution is injected in receiving chamber, and liquid level just contacts with skin inner layer, discharges bubble, starts agitator, and constant temperature to 37 ℃, then evenly is coated with the 2g latex at epiderm skin, detects respectively at sampling in 0.5,1,2,4,6,8 hour.Calculate drug accumulation transit dose and drug per unit area accumulation transit dose, the result is shown in table 5, accompanying drawing 1,2.
Table 5 transdermal result of the test
The result shows the latex that makes according to the present invention, and the speed of permeation test in vitro obviously is better than the commercially available prod, points out its onset faster, more is conducive to the pain of timely reduction of patient, and clinical have a significant advantage.
The emulsion agent that the present invention is made has carried out toxicological study, and result of study shows that diclofenac diethylammonium without obvious stimulation effect and sensitization, does not have toxic and side effects, clinical practice safety:
(1) skin irritation
Diclofenac diethylamine emulgel and excipient matched group after 7 days, stimulated score value to be 0 minute in 1～72 hour to rabbit intact skin and damaged skin administration continuously; Pathological examination results, diclofenac diethylammonium latex group and excipient matched group rabbit intact skin and damaged skin change similar the histology of drug withdrawal 1 hour and drug withdrawal 72 hours and blank group.The diclofenac diethylammonium latex to rabbit intact skin and damaged skin without the obvious stimulation effect.
(2) skin hypersensitivity
Diclofenac diethylammonium latex group and vehicle group are 0% to the sensitization rate of guinea pig skin, without sensitization.
Emulsion agent to embodiment 4-6 preparation has carried out stability study, and concrete result of the test is as follows:
(1) thermal cycling test
Experimental condition: each organizes sample, places first the fresh-keeping chamber of refrigerator, takes out after two days (48 hours) and places 40 ℃ baking oven, so circulates three times, and after the off-test, sampling is investigated, and result of the test sees Table 6.
The stable thermal cycling test result of table 6
The result shows: each organizes the every investigation index of sample does not have to change substantially, and property of latex is stable.
(2) accelerated test
Each organizes sample, and to place 30 ± 2 ℃, relative humidity be test 6 months under 65 ± 5% conditions, detects respectively at sampling in 1,2,3,6 month, the results are shown in Table 7.
Table 7 Accelerated stability test result
The result shows: accelerated test 6 months, and the character of medicine, content, related substance, acid-base value and microexamination have no significant change, and centrifugal not stratified, limit test of microbe is qualified, packaging material outward appearance no abnormality seen.
Claims (4)
1. diclofenac diethylamine emulgel is characterized in that being comprised of the composition of following mass percent:
Described Percutaneous absorption enhancer is isopropyl myristate, isopropyl alcohol and propylene glycol, and the mass ratio of described isopropyl myristate, isopropyl alcohol and propylene glycol is followed successively by 0.8-2: 0.8-3: 1,
Described aqueous gel substrate is Carbopol, and oil phase substrate is liquid paraffin, and emulsifying agent is polyoxyethylene sorbitan monoleate and single glycerol distearate, and the mass ratio of described polyoxyethylene sorbitan monoleate and single glycerol distearate is 1: 1.
2. diclofenac diethylamine emulgel as claimed in claim 1 is characterized in that the mass percent of described composition is:
3. diclofenac diethylamine emulgel as claimed in claim 1 or 2 is characterized in that the mass ratio of described isopropyl myristate, isopropyl alcohol and propylene glycol is followed successively by 1: 1: 1.
4. the preparation method of a diclofenac diethylamine emulgel is characterized in that may further comprise the steps:
(1) propylene glycol is mixed with water, the rear adding aqueous gel substrate that stirs, being swelling to becomes transparent gel, regulates pH value to 6.5～7.5, stirs, evenly mixed;
(2) diclofenac diethylammonium is added isopropyl alcohol, heating joins in (1) dissolving, solution, is heated to 70～85 ℃ and stirs, insulation;
(3) oil phase substrate, emulsifying agent, isopropyl myristate are heated to 70～85 ℃ together, stir into solution, this solution is under agitation joined in (2), emulsifying, insulation;
(4) continue to be stirred to cooling, fill and get final product,
Wherein, the mass percent of diclofenac diethylammonium is 1-1.2%, and aqueous gel substrate is 0.4-1%, and oil phase substrate is 1-6%, and emulsifying agent is that 0.4-3%, Percutaneous absorption enhancer are 25-50%,
Described Percutaneous absorption enhancer is isopropyl myristate, isopropyl alcohol and propylene glycol, and the mass ratio of described isopropyl myristate, isopropyl alcohol and propylene glycol is followed successively by 0.8-2: 0.8-3: 1,
Described aqueous gel substrate is Carbopol, and oil phase substrate is liquid paraffin, and emulsifying agent is polyoxyethylene sorbitan monoleate and single glycerol distearate, and the mass ratio of described polyoxyethylene sorbitan monoleate and single glycerol distearate is 1: 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| BE1026073B1 (en) * | 2018-03-05 | 2019-10-07 | Purna Pharmaceuticals Nv | Improved method for making a pharmaceutical emulsion |
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| CN105601525A (en) * | 2015-12-18 | 2016-05-25 | 中南大学湘雅医院 | Preparation process of diclofenac diethylamine |
| CN116869976A (en) * | 2023-09-07 | 2023-10-13 | 晶易医药科技(成都)有限公司 | Diclofenac diethylamine gel plaster composition, gel plaster and preparation method thereof |
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| US6235314B1 (en) * | 2000-08-08 | 2001-05-22 | Sarfaraz K. Niazi | Analgesic, anti-inflammatory and skeletal muscle relaxant compositions |
| CN1316967C (en) * | 2004-09-04 | 2007-05-23 | 林冶 | Diclofenac diethylamine gel agent |
| RU2463038C2 (en) * | 2006-10-17 | 2012-10-10 | Нуво Рисерч Инк. | Diclofenac gel |
| EP2055298A1 (en) * | 2007-10-30 | 2009-05-06 | Novartis AG | Topical composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| BE1026073B1 (en) * | 2018-03-05 | 2019-10-07 | Purna Pharmaceuticals Nv | Improved method for making a pharmaceutical emulsion |
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