CN1215838C - Diclofenac sodium pastes and preparation thereof - Google Patents
Diclofenac sodium pastes and preparation thereof Download PDFInfo
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- CN1215838C CN1215838C CN 03129503 CN03129503A CN1215838C CN 1215838 C CN1215838 C CN 1215838C CN 03129503 CN03129503 CN 03129503 CN 03129503 A CN03129503 A CN 03129503A CN 1215838 C CN1215838 C CN 1215838C
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- diclofenac sodium
- sensitive adhesive
- patch
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Abstract
The present invention relates to diclofenac sodium paste and a preparation method thereof, which relate to the technical field of medicine. The paste of the present invention comprises a back lining layer, a medicine storage house and a protective film, wherein the medicine storage house is composed of diclofenac sodium, contact adhesive and penetration enhancer. The contact adhesive is selected from acrylic ester and polyisobutylene, and adhesion performance can be improved by adding a plasticizing agent; the penetration enhancer is selected from organic solvents of alcohol, etc., organic acid of oleic acid, etc., surface active agents of azone, sodium dodecyl sulfate, etc., cutin humectant and softening agents of urea, etc. and terpene of menthol, etc. The present invention has the advantages of good skin penetration effect, firm pasting and no stimulation or sensitization to skin.
Description
Technical field:
The present invention relates to medical technical field, is a kind of diclofenac sodium patch and preparation method thereof.
Background technology:
Diclofenac sodium is the non-steroidal anti-inflammatory analgesics of adjacent amido benzoic acids, its mechanism of action is similar to aspirin, the alternative effect of cutting off prostaglandin cyclooxygenase in the arachidonic acid metabolic series, synthesizing of blocking-up PGE2 (PGF2), and then performance antiinflammatory, detumescence and analgesic, analgesic activity.Its antiinflammatory, refrigeration function are stronger 2～2.5 times than indomethacin, and be stronger 26～50 times than aspirin.Clinical treatment rheumatoid arthritis, osteoarthritis, the ankylosing spondylitis of being mainly used in; Various soft tissues swell and ache, and comprise lumbago and backache, scapulohumeral periarthritis, synovitis, tendon and tenosynovitis, cervical spondylosis; Soft tissue injury, comprise contusion, beat pounce on wound, sprain, lacerated wound, strain; The heating that lupus erythematosus, toothache, dysmenorrhea and cancer, postoperative pain and a variety of causes are caused also has excellent curative.
The existing at home external preparation of diclofenac sodium has gel, ointment, patch etc., with preparation capable of permeating skin such as gel, ointment relatively, it is few that patch has an administration number of times, dosage is advantage accurately.But reported diclofenac sodium patch (diclofenac sodium skin-penetrating delayed plaster, open day on February 25th, 1998, publication number 1174031A,) not enough through its viscous force on probation, peel strength experimental result, engaging force are 80g, well below China's medical rubber cream national standard and Ministry of Public Health standard.Thereby sticking not closely at positions such as joints, activity promptly is moved, is out of shape a little.Therefore, be necessary to seek a kind of viscosity suitable, with skin adhesive firmly, to the non-irritating diclofenac sodium external use plaster of skin.
Summary of the invention;
The invention provides a kind of easy to use, the transdermal performance is good, with skin adhesive firmly and appropriateness, to the non-irritating diclofenac sodium patch of skin.
Diclofenac sodium patch of the present invention comprises backing layer, drug-reservoir and protecting film, and drug-reservoir is made up of diclofenac sodium, pressure sensitive adhesive, penetration enhancer and plasticizer, and their proportioning is as follows: (%w/w)
Diclofenac sodium 1-10
Pressure sensitive adhesive 40-95
Penetration enhancer 1-40
Plasticizer dosage is not less than 10%, is 10～50% of pressure sensitive adhesive consumption
Their composition is respectively:
1. pressure sensitive adhesive can be pressure-sensitive acrylate and polyisobutylene class pressure sensitive adhesive, wherein:
(1) pressure-sensitive acrylate contains the alkyl acrylate of 4-14 carbon atom or alkylmethacrylate and the copolymerization of acrylic or methacrylic acid monomers by one or more alkyl and gets, add plasticizer in the pressure sensitive adhesive and improve adhesion property, plasticizer is selected from: 1. polyhydroxylated polymer, as Polyethylene Glycol; 2. the fatty acid ester that contains 6-20 carbon atom, for example succinate, sebacate; 3. fatty acid is as citric acid, succinic acid etc.Plasticizer dosage is the 10-50% of pressure sensitive adhesive consumption.Can select 1-2 kind plasticizer simultaneously for use.
(2) polyisobutylene class pressure sensitive adhesive is mixed by a kind of low-molecular-weight polyisobutylene and a kind of high molecular weight polyisobutylene, high-molecular weight polyisobutylene mean molecule quantity is 450,000～2,100,000, the low-molecular-weight polyisobutylene mean molecule quantity is 1000～450,000, and the ratio of two kinds of polyisobutylene is 5-95: 95-5%.Low-molecular-weight polyisobutylene is main flexibility and the toughness that plays viscosifying action and improve adhesive layer in pressure sensitive adhesive, improves the wettability to base material; High-molecular weight polyisobutylene mainly increases the peel strength and the cohesive strength of pressure sensitive adhesive.
2. penetration enhancer: be selected from (1) organic solvent class: as ethanol, propylene glycol, fatty acid ester, dimethyl sulfoxide ex hoc genus anne thing; (2) organic acid, aliphatic alcohol: as oleic acid, linoleic acid, lauryl alcohol; (3) azone and homologue thereof; (4) surfactant: be selected from cationic, anionic and nonionic, as sodium lauryl sulphate, Tween 80; (5) cutin is preserved moisture and softening agent: as carbamide, salicylic acid and pyrrolidinone compounds; (6) terpenes: as menthol, Camphora, limonene and eucalyptole.Can select 1-3 kind wherein simultaneously for use.
Diclofenac sodium patch of the present invention comprises the following steps: in front listed composition and ratio preparation
1. prepare pressure sensitive adhesive matrix (seeing embodiment for details)
2. prepare diclofenac sodium patch (seeing embodiment for details)
Diclofenac sodium is added above-mentioned substrate, stir and make dissolving fully; Add penetration enhancer again, make mix homogeneously, be applied to backing behind the ultrasonic removal bubble, 60 ℃ of dry solvents of removing are covered with protecting film.By required size cutting, pack.Usually area is 10-100cm
2
Above-mentioned back lining materials is optional from polyethylene, aluminium foil, polypropylene and polyester etc.The protecting film material is selected from polyethylene, polypropylene etc.
The transdermal of diclofenac sodium patch of the present invention and skin irritation test:
1. transdermal test in vitro experiment (method sees the percutaneous dosing novel form for details. the Lu Bin chief editor. and novel pharmaceutical formulation and new technique. Beijing: the People's Health Publisher, 1998:375)
Adopt improvement Franz diffusion cell, mouse skin is fixed on the diffusion cell, corium is towards receiving chamber, and stratum corneum side is to supply chamber.Patch sticks on stratum corneum side, adds an amount of PH 7.4 phosphate buffers (PBS liquid) in the receiving chamber.32 ℃ of water bath with thermostatic control circulations and 300 rev/mins of magnetic agitation, sampling in 2,4,8,12,24 hours, each 1ml, and additional immediately equal-volume PBS solution, high performance liquid chromatography (HPLC) working sample concentration the results are shown in Table 1, and wherein Q is a unit are accumulation transit dose.
Table 1 diclofenac sodium patch transdermal test in vitro experimental result
| The transdermal time (hour) Q (μ g/cm 2) | 2 20.30 | 4 42.81 | 8 73.55 | 12 135.08 | 24 239.85 |
By table 1 as seen, diclofenac sodium patch percutaneous rate of the present invention is 10.07 μ g/cm
2H, it is 23.97% that accumulation in 24 hours sees through percentage rate, shows that diclofenac sodium patch transdermal of the present invention is functional.
Clingtest (method sees Zheng Jun democracy for details to be compiled. the percutaneous dosing novel form. Beijing: People's Health Publisher, 1997)
The corrosion resistant plate surface is cleaned with organic solvent, and drying is cleaned.The protecting film of diclofenac sodium patch is torn off, be affixed on the corrosion resistant plate, on patch, press one to come and go with 300mm/ minute speed then with pressure roller.Place after 20 minutes, do 180 ℃ turning back, simultaneously adhesion section is uncovered 25mm, be connected on the chest expander, leave behind continuously with 300 ± 20mm/ minute speed at an end of patch.Every the 20mm reading once, read altogether 4 times when leaving behind.Test three different patches, ask for the meansigma methods of 12 measured values, the average pulling force of measurement result is 150g, illustrates that the viscosity of diclofenac sodium patch of the present invention is better, meets the provisions of the relevant regulations issued by the State.
3. skin irritation test [method sees new drug (Western medicine) preclinical study guideline compilation (pharmacy pharmacology's toxicology), bureau of drug administration of the People's Republic of China (PRC), 1993:57,198-208 for details]
3.1 skin hypersensitivity experiment
Laboratory animal: 40 of Cavia porcelluss, male and female half and half, body weight 300 ± 50g is available from laboratory animal institute of The 2nd Army Medical College.
With the depilatory depilation, lost hair or feathers and distinguish the about 3 * 3cm of area in the guinea pig back left side
2, be divided into three groups at random, first group of positive matched group, 14 of animals are given positive sensitizer 0.1%2,4-dinitro-chloro-benzene, (reagent one factory in Shanghai produces, with the preparation of 75% ethanol); Second group for being tried the thing group, and 13 of animals are given the diclofenac sodium patch; The 3rd group of negative matched group, 13 of animals are given the blank patch of negative control thing (except that not containing the diclofenac sodium, all the other compositions are all identical with diclofenac sodium patch of the present invention, down together).After the administration first time the 7th and the 14th day, in kind repeat administration once, each medication depilation in preceding 24 hours.
In last give tried thing sensitization after 14 days (before 24 hours at the depilation of guinea pig back right side, the about 3 * 3cm of area
2), in kind be administered once respectively again in depilation district, Cavia porcellus right side (positive controls give 1% 2, the 4-dinitro-chloro-benzene), remove patch after 6 hours, at once, observed the skin allergy situation in 24,48 and 72 hours.The result shows that positive sensitizer sensitization rate is 100%, and extremely strong sensitization is arranged, and diclofenac sodium patch and negative control thing sensitization rate are 0, all do not have sensitization, illustrates that the diclofenac sodium patch is used for skin outward and does not have sensitization.
3.2 skin irritation test
Animal: 8 of adult healthy rabbit, male and female half and half, body weight 2.5-3.0kg is available from the The 2nd Army Medical College Experimental Animal Center.
Spinal column both sides, the experimental rabbit back rabbit hair is cut, and area is about 10% (about 150cm of body surface area
2), two districts about branch, the about 50cm in every district
2(5cm * 10cm), adjacent two offsets are from about 3cm.The medication after 24 hours of losing hair or feathers sticks diclofenac sodium patch and the blank patch of tester respectively in medication district and check plot, removes patch in 24 hours, observes agents area and has or not situations such as erythema and edema.Continue administration, stick diclofenac sodium patch and above-mentioned blank patch respectively in medication district and check plot, one week of successive administration, 1,24,48 and 72 hour observation agents area behind the removal patch, find that only the show speckle is omited in the medication district of 1 rabbit, and erythema disappears after 24 hours, and the result shows that the diclofenac sodium patch is to the skin nonirritant.
Above-mentioned result of the test shows that diclofenac sodium patch sticking effect of the present invention is good, the non-stimulated and anaphylaxis to skin, and transdermal test in vitro is respond well.
The specific embodiment:
Now in conjunction with the embodiments, diclofenac sodium patch of the present invention and preparation method thereof is described in detail.
Embodiment 1: preparation diclofenac sodium patch, diclofenac sodium content 1mg/cm
2Prescription and proportioning:
Diclofenac sodium 5.0g
Methacrylic acid and methylmethacrylate copolymer 20.0g
Triethyl citrate 6.0g
Citric acid 0.4g
Azone 3.0g
Isopropyl alcohol 6.0g
Ethanol 59.6g
Preparation method:
1.. preparation pressure sensitive adhesive matrix
By said ratio, methacrylic acid and methylmethacrylate copolymer are dissolved in the mixed solvent that isopropyl alcohol and ethanol are formed; Under agitation, slowly add triethyl citrate and citric acid, be stirred into pressure sensitive adhesive matrix.
2. prepare the diclofenac sodium patch
In above-mentioned pressure sensitive adhesive matrix, add diclofenac sodium, stir and make dissolving fully.Add azone again, stir evenly.Ultrasonic removal bubble is coated aluminium foil, and 60 ℃ of dryings 20 minutes cover polyethylene film, cut into 50cm
2/ open, pack.This diclofenac sodium patch engaging force is 120g.
Embodiment 2: preparation diclofenac sodium patch, diclofenac sodium content 1.2mg/cm
2Prescription and proportioning:
Diclofenac sodium 5.0g
Methacrylic acid and methylmethacrylate copolymer 36.0g
Dibutyl sebacate 18.0g
Succinic acid 0.4g
Azone 3.0g
Isopropyl alcohol 2.0g
Ethanol 16g
Acetone 20g
Preparation method:
1. the substrate for preparing pressure sensitive adhesive and plasticizer
By said ratio, methacrylic acid and methylmethacrylate copolymer are dissolved in the mixed solvent that isopropyl alcohol, ethanol and acetone are formed; Under agitation, slowly add dibutyl sebacate and succinic acid, be stirred into pressure sensitive adhesive matrix.
2. prepare the diclofenac sodium patch
With embodiment 1.This diclofenac sodium patch engaging force is 150g.
Embodiment 3: preparation diclofenac sodium patch, diclofenac sodium content 1mg/cm
2Prescription and proportioning:
Diclofenac sodium 5.0g
Polyisobutylene MML-100 3.6g
Polyisobutylene LM-MS 4.4g
Liquid Paraffin 8.0g
Heptane 76g
Azone 3.0g
Preparation method:
1. preparation pressure sensitive adhesive matrix
Polyisobutylene MML-100 and polyisobutylene LM-MS are dissolved in heptane, become pressure sensitive adhesive matrix.
2. prepare the diclofenac sodium patch
Diclofenac sodium is crossed 200 mesh sieves, grinds well with liquid Paraffin, adds in the above-mentioned pressure sensitive adhesive matrix, stirs.Add azone, stir evenly.Ultrasonic removal bubble is coated aluminium foil, and 60 ℃ of dryings 60 minutes are covered with polyethylene film, cut into 50cm
2/ open, pack.This diclofenac sodium patch engaging force is 130g.
Embodiment 4: preparation diclofenac sodium patch, diclofenac sodium content 1mg/cm
2Prescription and proportioning:
Diclofenac sodium 6.0g
Methacrylic acid and methylmethacrylate copolymer 24.0g
Dibutyl sebacate 18.0g
Succinic acid 0.4g
Camphora 3.0g
Isopropyl alcohol 2.0g
Ethanol 16g
Acetone 31g
Preparation method:
1. preparation pressure sensitive adhesive matrix
With embodiment 2.
2. prepare the diclofenac sodium patch
In above-mentioned pressure sensitive adhesive matrix, add diclofenac sodium, stir and make dissolving fully.Camphorate again, stir evenly.Ultrasonic removal bubble is coated aluminium foil, and 60 ℃ of dryings 20 minutes are covered with polyethylene film, cut into 50cm
2/ open, pack.This diclofenac sodium patch engaging force is 160g.
Embodiment 5: preparation diclofenac sodium patch, diclofenac sodium content 1.5mg/cm
2Prescription and proportioning:
Diclofenac sodium 8.0g
Polyisobutylene MML-100 2.4g
Polyisobutylene LM-MS 5.6g
Liquid Paraffin 8.0g
Heptane 73g
Azone 3.0g
Preparation method is with embodiment 3.
This diclofenac sodium patch engaging force is 120g.
Claims (1)
1. a diclofenac sodium patch comprises backing layer, drug-reservoir and protecting film, it is characterized in that drug-reservoir is made of proportioning following (%w/w) diclofenac sodium, pressure sensitive adhesive, penetration enhancer and plasticizer:
Diclofenac sodium 1-10
Pressure sensitive adhesive 40-95
Penetration enhancer 1-40
Plasticizer dosage is not less than 10%, is 10～50% of pressure sensitive adhesive consumption
Said pressure sensitive adhesive is a pressure-sensitive acrylate, pressure-sensitive acrylate is by the alkyl acrylate of one or more 4-14 of containing carbon atom or alkylmethacrylate and the copolymerization of acrylic or methacrylic acid monomers and get, add plasticizer in the pressure sensitive adhesive and improve adhesion property, plasticizer is selected from succinate, citrate, citric acid, succinic acid, can select 1-2 kind plasticizer simultaneously for use.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03129503 CN1215838C (en) | 2003-06-25 | 2003-06-25 | Diclofenac sodium pastes and preparation thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03129503 CN1215838C (en) | 2003-06-25 | 2003-06-25 | Diclofenac sodium pastes and preparation thereof |
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| CN1489996A CN1489996A (en) | 2004-04-21 |
| CN1215838C true CN1215838C (en) | 2005-08-24 |
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Families Citing this family (13)
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| CN1895242B (en) * | 2006-04-13 | 2011-08-31 | 沈阳药科大学 | Diclofenac salt pleximetric paste and its production |
| CN101157612B (en) * | 2007-11-13 | 2013-05-29 | 沈阳药科大学 | Organic acid menthol derivative and transdermal drug delivery preparation having the same |
| FR2937250B1 (en) * | 2008-10-21 | 2013-05-10 | Fabre Pierre Dermo Cosmetique | UREA-BASED FILMOGENOUS SOLUTION FOR THE TREATMENT OF NAIL PSORASIS |
| TWI482645B (en) | 2010-01-07 | 2015-05-01 | Teikoku Seiyaku Kk | External oily plaster containing diclofenac hydroxyethylpyrrolidine |
| HUE037454T2 (en) | 2012-06-20 | 2018-08-28 | Hisamitsu Pharmaceutical Co | Skin patch |
| CN104547472A (en) * | 2014-12-10 | 2015-04-29 | 深圳先进技术研究院 | Pharmaceutical composition for treating rheumatoid arthritis, preparation method and patch thereof |
| CN105250243A (en) * | 2015-11-06 | 2016-01-20 | 中国药科大学 | Long-acting viscose dispersing type transdermal patch and preparing process thereof |
| CN105326818B (en) * | 2015-11-27 | 2018-05-25 | 四川理工学院 | A kind of diclofenac patch |
| CN105708823A (en) * | 2016-04-08 | 2016-06-29 | 中国药科大学 | Long-acting diclofenac transdermal patch and preparation technology thereof |
| CN107669661B (en) * | 2016-12-12 | 2020-05-26 | 山东朱氏药业集团有限公司 | Diclofenac sodium transdermal patch |
| IT202000011686A1 (en) * | 2020-05-20 | 2021-11-20 | Fidia Farm Spa | SLOW RELEASE MEDICATED PATCH |
| CN111821285A (en) * | 2020-06-17 | 2020-10-27 | 南京海纳医药科技股份有限公司 | Transdermal patch containing diclofenac epolamine and preparation method thereof |
| US11872320B2 (en) | 2021-02-25 | 2024-01-16 | Hisamitsu Pharmaceutical Co., Inc. | Method for treating osteoarthritis |
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