CN108210484A - Tamoxifen gel emplastrum and preparation method thereof - Google Patents
Tamoxifen gel emplastrum and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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Abstract
The invention belongs to technical field of medicine, are related to a kind of tamoxifen gel emplastrum and preparation method thereof.The present invention provides a kind of tamoxifen gel emplastrums, and by tamoxifen, solubilizer, crosslinking polymer, crosslinking agent, cross-linking regulator, carbomer, the component of following portions by weight is made:Wherein, the addition of carbomer effectively improves the formation problems of gel plaster stroma;The addition of solubilizer eucalyptus oil and diethylene glycol monoethyl ether is obviously improved solubility of the tamoxifen in gel plaster stroma, solves the problems, such as drug precipitation;Tamoxifen gel emplastrum stable molding, complete appearance prepared by the present invention has Adhesion property good, and percutaneous rate is high, no sensitization and irritation, it is easy to use, not pollution clothes, can take off patch repeatedly, the advantages that low production cost.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of tamoxifen gel emplastrum and preparation method thereof.
Background technology
It is the most common malignant tumour of women prior art discloses breast cancer, there are about 1,300,000 people's quilts in the annual whole world
Breast cancer is diagnosed as, there are about 400,000 people to die of the illness, and its incidence is in ascendant trend year by year.Clinical treatment mammary gland at present
The scheme of cancer includes operative treatment, chemotherapy, radiotherapy, endocrine therapy, molecular targeted therapy, Chinese traditional treatment etc..Studies have shown that
Most of breast cancer cell expresses estrogen receptor, and growth proliferation is in apparent hormonal dependent.In recent years endocrine therapy side
Case is increasingly becoming hot spot, and endocrine therapy is by reducing internal estrogen level or inhibiting the effect of estrogen, reach inhibition
The growth of tumour cell.Know in the industry, tamoxifen is first generation selective estrogen receptor modulators, has estrogen-agonistic
With the double action of antagonism, be in hormone-dependent breast cancer endocrine therapy it is most effective, with a time most permanent line
Endocrine therapeutic agents are mammary gland suitable for the Postmenopausal Breast Cancer women patient of estrogen receptor and the progesterone receptor positive
One of choice drug of the postoperative endocrine auxiliary treatment of cancer.
The administration route of tamoxifen is based on oral at present, and predominantly tablet, granule, capsule, tamoxifen exist
Almost insoluble in water, therefore, clinical practice is shown, it is poor that above-mentioned peroral dosage form is dissolved out there are gastrointestinal tract, leads to bioavilability
It is relatively low, and there are liver first-pass effects, oral blood concentration fluctuation is big, and long-term use, which easily leads to phlebothrombosis and increases, suffers from uterus
The defects of probability of endometrial carcinomas.To reduce the side effect of tamoxifen and increasing clinical efficacy, this field researcher considers will
Administering mode is changed to percutaneous dosing by oral, it is expected that percutaneous preparation can cross effect to avoid issuable liver head is administered orally
Should, it avoids blood concentration fluctuation, reduce drug toxicity and adverse reaction, reduce administration number of times, it is easy to use;Moreover, for
Drug will be made to be directly entered lesions position with the approach of percutaneous permeation, infiltration using percutaneous preparation on mammary gland surrounding skin, continued
It is targetedly administered for a long time, improves the tamoxifen concentration in breast tissue, conducive to breast cancer treatment effect is improved.
Tamoxifen is also known as tamoxifen, molecular weight 371, and fusing point is 96 ~ 98 DEG C, studies have shown that its in water almost
Insoluble, slightly soluble, readily soluble in glacial acetic acid in ethanol, and that reports at present has tamoxifen gelling agent, cream, creme, micro emulsion
A kind of 4-OHT gel preparation is disclosed Deng, CN101065120A, belongs to semisolid preparation;
CN1857242A discloses a kind of externally applied tamoxifen citrate microemulsion preparation, belongs to liquid preparation, also can be made into semisolid
Preparation;CN101711754A further discloses the method that tamoxifen citrate microemulsion is prepared into emplastrum, which adopts
With elevated heating processes, the components such as rosin plasticizer, Medical PSA for being arrived involved in formula are easy to cause skin thorn
Swash property, anaphylaxis.
It there is no the relevant report of tamoxifen gel emplastrum at present.
Present situation based on the prior art, present inventor intend providing a kind of tamoxifen gel emplastrum and its preparation
Method, the present invention can overcome tamoxifen to have the defects of dosage form at present, and the endocrine therapy for breast cancer provides one kind more
Dosage form easily and effectively.
Invention content
The purpose of the present invention is prior art tamoxifen is overcome to have the defects of dosage form, a kind of tamoxifen gel is provided
Emplastrum and preparation method thereof.
Based on gel emplastrum(Former Babu plaster or gel ointment)Mean material medicine and suitable hydrophilic matrix mixing
After be coated on manufactured emplastrum on back lining materials(2015 editions definition of Chinese Pharmacopoeia).
The present invention provides a kind of tamoxifen gel emplastrum, by tamoxifen, solubilizer, crosslinking polymer,
Crosslinking agent, cross-linking regulator, carbomer, the component of following portions by weight are made:The weight percent of wherein described component is:He
Not former times sweet smell 0.1~2, solubilizer 3~13, crosslinking polymer 5~12, crosslinking agent 0. 2~0.4, cross-linking regulator 0. 2~
0.6th, carbomer 0.5~5.Tamoxifen gel emplastrum stable molding, complete appearance prepared by the present invention, it is good with Adhesion property
Good, percutaneous rate is high, no sensitization and irritation, it is easy to use, not pollution clothes, patch can be taken off repeatedly.
In the present invention, the crosslinking polymer of selection is polyacrylic acid part corrective, and hundred are neutralized including Sodium Polyacrylate
Divide the NP-600 for being 70% than i.e. degree of neutralization(Trade name:ViscomateTM), degree of neutralization be 50% NP-700(Trade name:
ViscomateTM), degree of neutralization be 35% NP-800(Trade name:ViscomateTM)One or more of;The reality of the present invention
Apply preferred NP-800 in example;The weight percent of the crosslinking polymer is 5~12%.
In the present invention, the crosslinking agent includes Dihydroxyaluminium Aminoacetate, aluminium hydroxide, aluminium chloride, aluminum sulfate, one kind in alum or several
Kind, preferably Dihydroxyaluminium Aminoacetate;The weight percent of crosslinking agent is 0.2~0.4%.
In the present invention, the cross-linking regulator, be tartaric acid, Chinese holly edge acid, lactic acid, EDTA or one kind in EDTA-2Na or
It is several, wherein, tartaric acid, citric acid, lactic acid etc. provide acid proton environment, crosslinking agent release aluminium ion, aluminium ion and crosslinking
Carboxyl in the type polymer Sodium Polyacrylate structure that i.e. part neutralizes is cross-linked to form the matrix scaffold of gel emplastrum;In the present invention
For the speed of delayed cross-linking, be additionally added in matrix formulations EDTA or EDTA-2Na and above-mentioned carboxyl competitively with chelate aluminum ion
Close, so as to control the viscoelasticity of crosslinked matrix and consistency, it is easy to produce during stirring and coating;The cross-linking regulator
Weight percent is 0.2~0.6%.
In the present invention, carbomer selects model Carbopol®934、Carbopol®934P、Carbopol®940、
Carbopol®941、Carbopol®971P、Carbopol®974P、Carbopol®In 980 one in or it is several, carbomer
Weight percent is 0.5~5%;The carbomer can be effectively improved the molding of gel plaster stroma.
In the present invention, the solubilizer is selected from eucalyptus oil, diethylene glycol monoethyl ether(Trade name can be
TranscutolP)One or both of;The weight percent of solubilizer is 3~13%;The solubilizer can improve tamoxifen
Solubility of the sweet smell in gel plaster stroma solves the problems, such as that drug is precipitated in glue surface.
In the present invention, transdermal enhancer can be also added in the formula of the tamoxifen gel emplastrum, including azone, the third two
One or more of alcohol, oleic acid, laruyl alcohol, isopropyl myristate, menthol, preferably azone;The weight of the transdermal enhancer
It is 0~3% to measure percentage.
In the present invention, filler can be also added in the formula of the tamoxifen gel emplastrum, including kaolin, micro mist silicon
Glue, crosslinked polyvinylpyrrolidone(PVPP), titanium dioxide, silica gel, bentonite, calcium carbonate, zinc oxide, one kind in white bole or
Several, the weight percent of filler is 0~3%;The filler can change the structure of gel plaster stroma and be in honeycomb
Shape is conducive to increase the glue intensity and stripping performance of matrix.
In the present invention, tackifier can be also added in the formula of the tamoxifen gel emplastrum, including carboxymethyl cellulose
Sodium(CMC-Na), methylcellulose, polyvinyl alcohol(PVA), polyvinylpyrrolidone(PVP), gelatin, one kind in Arabic gum
Or several, preferred polyvinyl alcohol, the weight percent of tackifier is 0~3%;The tackifier can inhibit drug crystallization precipitation, increase
Add stickiness, the consistency of gel plaster stroma, improve the adhesive force of skin.
In the present invention, preservative, moisturizer and surfactant can be also added in the tamoxifen gel rubber plaster paste formulation
One or more of;Wherein, preservative is benzoic acid, methyl hydroxybenzoate, ethylparaben, propylben, nipalgin fourth
One or more of ester;Surfactant is polysorbate, one kind in Emulsifier EL-60, OP emulsifiers, paregal O
It is or several;Moisturizer is one or more of propylene glycol, glycerine, 1,3 butanediols, polyethylene glycol.
The tamoxifen gel emplastrum of the present invention uses non-woven fabrics, and for back lining materials, the back lining materials are to gel rubber plaster cream base
Matter plays a supportive role, and flexibility is strong, good-extensibility, can adapt to the body sensitives such as breast position, while its good permeability, energy
It is enough utmostly to reduce irritation of the emplastrum to skin.
Tamoxifen gel emplastrum of the present invention uses the materials such as polyethylene, polypropylene as protective film, and lotion surface is risen
Protective effect is torn off during use.
The present invention provides the preparation method of tamoxifen gel emplastrum, including step:
(1)The additives of solubilizer, transdermal enhancer and other appropriate types are uniformly mixed, add tamoxifen dissolving system
Winner's drug solns or suspension;
(2)By main ingredient solution or suspension, filler, crosslinking agent, cross-linking type auxiliary material, other appropriate types additives add in it is sweet
In oil, stir evenly up to A phases;
(3)The additives of tackifier, carbomer, cross-linking regulator and appropriate type are dissolved in purified water, mixed solution is made
As B phases;
(4)B is added in A phases, quick stirring to appropriate viscosity, coating cuts, packs to get tamoxifen gel rubber plaster
Cream.
Gel emplastrum prepared by the present invention, stable molding, complete appearance are good with Adhesion property, no sensitization and thorn
Swash property, directly stick and without smearing repeatedly, it is easy to use, not pollution clothes, the advantages that patch can be taken off repeatedly, trouble can be significantly improved
The compliance of person's medication;The gel emplastrum water content is high, drugloading rate is big, is particular enable to the solubilizer of carrying high-content and transdermal rush
Into agent, so as to increase the solubility of main ingredient and the effective skin permeation of drug is promoted to go directly the lesions position of breast, hence it is evident that reduce medicine
Concentration and its fluctuation degree of the object in blood circulation reduce phlebothrombosis caused by even avoiding oral tamoxifen and are susceptible to suffer from son
The side effects such as endometrial carcinoma.In addition, the gel emplastrum also there is production process not use organic solvent, explosion precaution largely, no
With high temperature, it is free from environmental pollution, of low cost the advantages that.
Specific embodiments of the present invention are further described in detail below, but the guarantor of the present invention should not be limited with this
Protect range.It is all to be all belonged to the scope of the present invention based on the technology that present disclosure is realized.Obviously, according to the present invention
Hold, according to the ordinary technical knowledge and customary means of this field, under the premise of the basic fundamental thought for not departing from the present invention, go back
The modification, replacement and change of other diversified forms can be made.
Specific embodiment
Solubility test of 1 tamoxifen of embodiment in different medium
Excessive tamoxifen is separately added into 10 kinds of media as shown in Table 1, simultaneously ultrasound 30min is stirred, in isothermal vibration
It is vibrated in device for 24 hours, 1ml supernatants is taken to be placed in test tube, in 10000r/min high speed centrifugations 10min, accurate Aspirate supernatant is used
HPLC measure is carried out after flowing phase dilution suitable multiple;Solubility of the tamoxifen in each medium is as shown in table 1, wherein, he
Not former times sweet smell solubility highest in ethyl alcohol, n-methyl-2-pyrrolidone, secondly eucalyptus oil, propylene glycol, diethylene glycol mono-ethyl
Ether.
Solubility of 1 tamoxifen of table in different medium
Medium | Solubility (μ g/g) |
Water | 0.32±0.25 |
Ethyl alcohol | 37.94±1.88 |
PEG400 | 16.67±0.81 |
Oleic acid | 13.93±0.59 |
Azone | 17.07±0.57 |
Propylene glycol | 19.37±0.85 |
Glycerine | 6.18±0.21 |
Eucalyptus oil | 20.35±0.33 |
Diethylene glycol monoethyl ether | 17.90±1.09 |
N-methyl-2-pyrrolidone | 28.00±0.86 |
2 solubilizer of embodiment is to tamoxifen in water-glycerol(Ratio 50/50)The influence experiment of middle solubility
In the different solubilizer of 28 parts of glycerine, 28 parts of water and 15 parts(As shown in table 2)In the mixed solution of composition, it is separately added into excess
Tamoxifen, stir and ultrasound 30min, be placed in isothermal vibration device and vibrate for 24 hours, take in 1ml supernatants to test tube, in
10000r/min high speed centrifugations 10min, accurate Aspirate supernatant with HPLC measure is carried out after flowing phase dilution suitable multiple, are tied
Fruit shows(As shown in table 2), in water-glycerol(50/50)Mixed system in using diethylene glycol monoethyl ether as solubilizer
Effect it is best.
The different solubilizer of table 2 are to tamoxifen in water-glycerine(Ratio 50/50)The influence of middle solubility
3 comparative experiments of embodiment
3 embodiment 1 of table and comparative example 1-4 prescriptions
Prescription | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Embodiment 1 |
Water | 30.00 | 32.12 | 30.16 | 26.04 | 26.04 |
Tartaric acid | 0.15 | 0.13 | 0.13 | 0.14 | 0.14 |
Tamoxifen | 0.50 | 0.51 | 0.08 | 0.10 | 0.10 |
Glycerine | 15.70 | 12.86 | 12.74 | 13.02 | 13.02 |
Dihydroxyaluminium Aminoacetate | 0.15 | 0.13 | 0.13 | 0.14 | 0.14 |
NP-800 | 3.50 | 3.22 | 3.19 | 3.62 | 3.62 |
Carbomer | 1.03 | 1.02 | 1.16 | 1.16 | |
Eucalyptus oil | 1.53 | 1.73 | 1.73 | ||
Diethylene glycol monoethyl ether | 2.89 | ||||
N-methyl-2-pyrrolidone | 2.89 | ||||
Azone | 0.51 | 0.58 | 0.58 | ||
Tween | 0.51 | 0.58 | 0.58 | ||
Altogether | 50.00 | 50.00 | 50.00 | 50.00 | 50.00 |
Carbomer/TAM | 2 | 12 | 12 | 12 |
Comparative example 1-4 and the gel emplastrum of embodiment 1, observation emplastrum molding situation and drug analysis are prepared according to above-mentioned preparation method
Artificial situation, the results are shown in Table 4;Wherein,
Gel emplastrum prepared by comparative example 1 can not be molded, and in semi-solid gel shape, and visible high amount of drug is precipitated;
Carbomer is added in 2 prescription of comparative example, it is seen that gel plaster stroma cross moulding has certain skin adhesive force, meat
Eye observation is visible to have high amount of drug to be precipitated in emplastrum glue surface;
Comparative example 3 adds in solubilizer eucalyptus oil, gel plaster stroma cross moulding on the basis of comparative example 2, but has a small amount of drug
It is precipitated;
Comparative example 4 adds in n-methyl-2-pyrrolidone, gel plaster stroma cross moulding on the basis of comparative example 3, but still has few
Drug is measured to be precipitated;
As a result it shows.Embodiment 1 adds in diethylene glycol monoethyl ether on the basis of comparative example 3, gel plaster stroma cross moulding,
Glue surface is completely uniform, finds no drug precipitation.
4 embodiment 1 of table is molded with comparative example 1-4 prescriptions and solubilising is evaluated
Prescription | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Embodiment 1 |
Whether it is molded | × | √ | √ | √ | √ |
High amount of drug is precipitated | √ | √ | |||
A small amount of drug is precipitated | √ | √ | |||
No drug is precipitated | √ |
4 comparative experiments of embodiment
5 example 2-6 prescriptions of table
Prescription | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
Water | 26.85 | 26.85 | 23.43 | 24.75 | 24.24 |
Tartaric acid | 0.12 | 0.12 | 0.29 | 0.13 | 0.11 |
Tamoxifen | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 |
Glycerine | 11.74 | 11.74 | 12.3 | 12.58 | 11.28 |
Dihydroxyaluminium Aminoacetate | 0.12 | 0.12 | 0.18 | 0.13 | 0.11 |
NP-800 | 2.93 | 2.93 | 5.36 | 3.14 | |
NP-700 | 2.68 | ||||
Carbomer | 0.94 | 0.94 | 0.34 | 1.01 | 2.8 |
Eucalyptus oil | 1.41 | 1.41 | 1.35 | 1.51 | 1.45 |
Diethylene glycol monoethyl ether | 2.35 | 2.35 | 4.02 | 2.58 | 3.86 |
Azone | 0.94 | 1.01 | 0.65 | ||
Oleic acid | 0.94 | ||||
Tween | 0.47 | 0.47 | 0.51 | 0.50 | 0.52 |
PVA | 0.98 | 0.98 | 1.07 | 1.07 | |
CMC-Na | 1.07 | ||||
PVPP | 1.07 | 1.07 | 1.51 | 1.07 | |
Superfine silica gel powder | 1.07 | ||||
EDTA | 0.08 | ||||
Altogether | 50.00 | 50.00 | 50 | 50.00 | 50 |
Carbomer/TAM | 12 | 12 | 12 | 12 | 35 |
Preparating example 2
It weighs diethylene glycol monoethyl ether, eucalyptus oil, Tween 80 and azone to be uniformly mixed, adds in the tamoxifen of recipe quantity, stir
Simultaneously ultrasound 30min is mixed, tamoxifen suspension is made, it is spare;Tamoxifen suspension, Dihydroxyaluminium Aminoacetate, PVPP are added in glycerine,
Viscomate NP-800 are added after stirring evenly, are stirred evenly to get A phases, separately take tartaric acid, PVA, carbomer adds in distilled water
Middle dissolving stirs 12h, as B phases, B is added in A phases, and quick stirring is to appropriate viscosity, with coating machine with 1.5mm
The specification of thickness is coated, and is cut, and with packaging of aluminium foil bag, obtains tamoxifen gel emplastrum;
Example 3 prepares same example 2, wherein mainly changing transdermal enhancer azone into oleic acid;
Example 4 prepares same example 2, wherein mainly changing filler PVPP into superfine silica gel powders;
Example 5 prepares same example 2, wherein mainly changing tackifier PVA into CMC-Na;
Example 6 prepares same example 2, wherein NP800 mainly is changed into NP700, and adjust dosage.
The experiment of evaluation property:
Test example Ligustrazine hydrochlorides are tested
Ligustrazine hydrochloride experiment is carried out using improved Franz diffusing cells method, transdermal effective diffusion area is 3.14 cm2, reception tank
Volume is about 8 ml, and in vitro pig ear skin is fixed between supply pool and acceptance pool, the stratum corneum side of skin upward, reception tank
In fill 50% ethyl alcohol physiological saline, and ensure that in vitro pig ear skin contacts abundant bubble-free with acceptable solution.By embodiment 2,3,4,
7 tamoxifen gel rubber plaster patch spread on stratum corneum side, open magnetic stirring apparatus(200 r·min-1)And constant temperature(37±0.5)°C
Water-bath recycles, and starts timing, 0.6 ml of acceptable solution is taken, and supplement connecing for the temperature such as 0.6 ml immediately respectively at 6,12,24,48 h
By liquid, for the acceptable solution of taking-up after 0.45 μm of filtering with microporous membrane, HPLC measures tamoxifen concentration, and unit of account area tires out
Product infiltration capacity Qn(µg/cm2), the accumulation infiltration capacity for recording 48h is Q48(μg · cm-2);To accumulate infiltration capacity(Qn)To the time
(t)Linear regression analysis is done, obtains equation of linear regression, the slope of equation is percutaneous rate J [ μ g/(cm2H) ].Increase
Ooze multiple(ER)The ratio between the percutaneous rate of example 4 of percutaneous rate with being free of transdermal enhancer for each transdermal enhancer test group;
The concentration of tamoxifen in penetrating fluid, chromatographic condition are detected using HPLC methods:PLATISILTMODS chromatographic columns(150×
4.6 mm, 5 μm);Mobile phase is methanol:Triethylamine 1%(Glacial acetic acid tune pH to 8.5)It is 89:11(V/V);Volume flow is 1.0
mL /min;238 nm of Detection wavelength;25 DEG C of column temperature;10 μ l of sample size, using quantified by external standard method, with peak area to tamoxifen
Standard solution mass concentration does linear regression, obtains regression equation and is:The A-0.0048 (r=0.9998) of C=0.053, tamoxifen
It is good with peak area linear relationship in the range of 0.081~2.42 μ gml-1.The method rate of recovery and precision meet the requirements;
Transdermal parameter is as shown in table 6, the results show that compared with example 4 is not added with accelerating agent, it is saturating added with the example 2,3,7 of accelerating agent
It crosses rate and is significantly better than example 4;It is compared with example 3 of the oleic acid as accelerating agent, the percutaneous rate of the embodiment 2,7 containing azone is more
It is excellent;
Influence of 6 transdermal enhancer of table to tamoxifen gel emplastrum percutaneous rate
Test example tamoxifen gel emplastrum initial adhesion force is tested
According to《Chinese Pharmacopoeia》(Version in 2015)Four general rules 0952 stick the first method of amylograph(The measure of initial adhesion force).It is just glutinous
Power is measured using spin slope stop method, takes each 3 of example 1-6 samples, removes protective layer, is placed in the inclination that inclination angle is 15 °
Plate center, cream face upward, and the mylar covering of inclined-plane top 10cm and lower part 15cm 0.025mm thickness, centre reserves 5cm cream
Face.The steel ball of different-diameter is taken, is freely rolled down from beveled top end, the ball number of maximum steel ball that can be clung according to glue surface evaluates it
The size of original viscosity, the results are shown in Table 7, and display embodiment initial adhesion force is functional, as a result shows example 1 because not adding tackifier
And filler, the steel ball number that can be sticked are relatively small;Example 2-6 shows that with good initial bonding strength wherein gel emplastrum adds
The initial bonding strength for having PVA is slightly good compared with CMC-Na;
The steel ball number sticked in the experiment of 7 example 1-6 gel emplastrums initial adhesion force of table
Sample | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 |
1 | 18 | 29 | 25 | 30 | 26 | 27 |
2 | 18 | 27 | 26 | 29 | 26 | 25 |
3 | 19 | 28 | 26 | 28 | 25 | 27 |
Test example tamoxifen gel emplastrum adhesion is tested
According to《Chinese Pharmacopoeia》(Version in 2015)Four general rules 0952 stick the 4th method of amylograph(The measure of adhesion).It sticks together
Power is carried out using BLD-200N testing machines, takes example 1-6 gel emplastrums(70cm×50cm)3, stickiness faces upward, and is placed in loading
In module, graduation mark is directed at, the lid lining on both sides is torn to the stickiness face for a little, pushing down both sides exposing respectively with press strip respectively, it is small
The heart is served as a contrast except uncapping, is placed on clamp bottom board naturally between two parties, test sample is made entirely to be fitted on bottom plate, pressing plate level is pressed
Under, bottom plate and pressing plate are fixed with both sides bolt, the test sample stickiness face on rectangular strip is made uniformly to tighten, is put on instrument, it is fixed
Pressure roller is set afterwards moves ahead speed as 600mmmin-1, astern speed 21mmmin-1It is measured, adhesion measurement result
As shown in table 8, meet the standard that gel emplastrum adhesion as defined in version Chinese Pharmacopoeia in 2015 should be 1000~2000mN, it is real
Example 1 is not plus tackifier and filler, adhesion are relatively relatively low;Example 2-6 shows good adhesion, wherein gel emplastrum
It is more preferable compared with CMC-Na added with the adhesion of PVA.
The adhesion of gel emplastrum prepared by 8 each embodiment of table
Sample | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 |
Adhesion(mN) | 1106±61 | 1543±65 | 1586±30 | 1606±65 | 1356±32 | 1610±26 |
Test example tamoxifen gel emplastrum skin irritation test
Experiment is taken to use rabbit 6, for 24 hours rabbit backbone diamond wool is cut net before experiment and carries out depilation processing with depilatory cream, is taken off
The cm of hair range left and right each 3 cm × 3, and check that animal should be divided into two groups, i.e. intact skin group without impaired by skin after depilation
With damaged skin group, wherein damaged skin group is scratched hair removal section skin with No. 16 syringe needles of disinfection before administration, is divided into well word
Shape cut, depth are subject to oozing of blood, and left and right sides skin injury degree is consistent;
Using androgynous left and right sides self-contrast method, the left side hair removal section of two groups of rabbit gives example 2 gel emplastrum, right side depilation
Qu Jun gives bare substrate gel emplastrum, and first ointment is covered with two layers of gauze, then fixed with medical adhesive tape, every after the completion of patch medicine
Animal sub-cage rearing after administration for 24 hours, removes gauze and ointment, and administration area is scrubbed with warm water, respectively at 1h, for 24 hours, 48h and
Observe medicine-feeding part whether there is erythema or oedema phenomenon after 72h, as shown in table 9, the results show that intact skin group, damaged skin group
Rabbit give gel emplastrum after, being showed no hair removal section skin has erythema or oedema phenomenon, loses hair or feathers to same rabbit left and right sides
Area's skin is compared, no abnormality seen, shows tamoxifen gel emplastrum to no skin irritation;
9 rabbit skin irritation test of table
Group | 1h | 24h | 48h | 72h |
Intact skin group | Erythema or oedema are not found | Erythema or oedema are not found | Erythema or oedema are not found | Erythema or oedema are not found |
Damaged skin group | Erythema or oedema are not found | Erythema or oedema are not found | Erythema or oedema are not found | Erythema or oedema are not found |
Test example tamoxifen gel emplastrum skin allergy test
According to State Food and Drug Administration《Chemical induced irritation, anaphylaxis and hemolytic investigative technique guideline》
It carries out,
Experiment is taken to use cavy 30, half male and half female, backbone diamond wool in back is cut net and carried out at depilation with depilatory cream for 24 hours before experiment
Reason, depilation area are respectively 3 × 3cm per side2, it is randomly divided into 3 groups, every group 10, half male and half female;
Cavy medicine-feeding skin region is subjected to warm water wiping, skin is added medicine on the left of 3 groups of animals, respectively 2 tamoxifen gel of example
Emplastrum 3cm2, bare substrate gel emplastrum 3cm2, 1%2,4- dinitro-chloro-benzene 0.2ml, covered after administration with two layers gauze, then
It is fixed with medical adhesive tape, after continuing for 24 hours, removes gauze and ointment, and scrubbed with warm water, the 7th and 14 day, in kind
It is repeated once, observation cavy hair removal section skin whether there is erythema and oedema situation;
Excitation contact:14 days after last sensitization contact, hair removal section gives each group and corresponds to drug on the right side of cavy, after administration
It is covered with two layers of gauze, then is fixed with medical adhesive tape, after continuing 6h, remove gauze and ointment, and scrubbed with warm water, at once
Observe cavy hair removal section skin allergy situation, and in for 24 hours, 48h and 72h observe cavy hair removal section skin allergy situation again, count
Calculate sensitization rate and reaction average value:
Sensitization rate=occur erythema or the total number of animals of edema animal number ÷)× 100%, sensitization rate statistical result is as shown in table 11, causes
Quick response intensity judgment criteria is as shown in table 10;
Reaction average value=(Erythema forms total score+oedema and forms total score)÷ adds up to number of animals
Wherein, skin allergy score value evaluation criteria is:The slightly score value of erythema, moderate erythema, severe erythema and edematous erythema
It is followed successively by 1 point, 2 points, 3 points, 4 points;Mild edema, intermediate edema and the score value of severe edema are followed successively by 1 point, 2 points, 3 points;
Cavy allergic conditions analysis of statistical results is shown:The cavy of bare substrate gel emplastrum group, tamoxifen gel emplastrum group
Hair removal section skin does not occur erythema or oedema within each observation period, shows tamoxifen gel emplastrum to skin without allergy
Property.
10 sensitivity response strength judgment standard of table
Sensitization rate(%) | Response intensity |
0~10 | Weak sensitization |
20~30 | Slight sensitization |
40~60 | Moderate sensitization |
70~80 | Height sensitization |
90~100 | Extreme sensitization |
11 cavy allergic conditions statistical form of table
Index | Drug | At once | 24h | 48h | 72h |
React average value | Blank gel emplastrum | 0 | 0 | 0 | 0 |
2 gel emplastrum of embodiment | 0 | 0 | 0 | 0 | |
2,4- dinitro-chloro-benzenes | 3.1 | 2.3 | 1.8 | 0.5 | |
Sensitization rate (%) | Blank gel emplastrum | 0 | 0 | 0 | 0 |
2 gel emplastrum of embodiment | 0 | 0 | 0 | 0 | |
2,4- dinitro-chloro-benzenes | 100 | 100 | 100 | 50 |
Claims (8)
1. tamoxifen gel emplastrum, which is characterized in that be made of the component of following weight percentage:Tamoxifen, solubilizer,
Crosslinking polymer, crosslinking agent, cross-linking regulator, carbomer,
Tamoxifen 0.1~2
Crosslinking polymer 5~12
Crosslinking agent 0. 2~0.4
Cross-linking regulator 0. 2~0.6
Solubilizer 3~13
Carbomer 0.5~5
It prepares as follows:
(1)The additives of solubilizer, transdermal enhancer and other appropriate types are uniformly mixed, add tamoxifen dissolving system
Winner's drug solns or suspension;
(2)By main ingredient solution or suspension, filler, crosslinking agent, cross-linking type auxiliary material, other appropriate types additives add in it is sweet
In oil, A phases are stirred evenly to obtain;
(3)The additives of tackifier, carbomer, cross-linking regulator and appropriate type are dissolved in purified water, mixed solution is made
As B phases;
(4)B is added in A phases, quick stirring to appropriate viscosity, coating cuts, packs to get tamoxifen gel rubber plaster
Cream.
2. tamoxifen gel emplastrum as described in claim 1, which is characterized in that the crosslinking polymer is polypropylene
Acid moieties corrective, selected from Sodium Polyacrylate percent neutralization, that is, degree of neutralization be 70% NP-600, degree of neutralization be 50% NP-
700th, degree of neutralization is one or more of 35% NP-800.
3. tamoxifen gel emplastrum according to claim 1, which is characterized in that the crosslinking agent be selected from Dihydroxyaluminium Aminoacetate,
One or more of aluminium hydroxide, aluminium chloride, aluminum sulfate, alum;
The cross-linking regulator is selected from one or more of tartaric acid, Chinese holly edge acid, lactic acid, EDTA or EDTA-2Na.
4. tamoxifen gel emplastrum according to claim 1, which is characterized in that the solubilizer is eucalyptus oil, diethyl
One or both of glycol list ethylether.
5. tamoxifen gel emplastrum according to claim 1, which is characterized in that the component also contains transdermal promotion
Agent, the transdermal enhancer are selected from one or more of azone, propylene glycol, oleic acid, isopropyl myristate, menthol;Thoroughly
The weight percent of skin accelerating agent is 0~3%.
6. tamoxifen gel emplastrum according to claim 1, which is characterized in that the component also contains filler, institute
It states filler and is selected from kaolin, superfine silica gel powder, crosslinked polyvinylpyrrolidone, titanium dioxide, silica gel, bentonite, calcium carbonate, oxidation
One or more of zinc, white bole;The weight percent of filler is 0~3%.
7. tamoxifen gel emplastrum according to claim 1, which is characterized in that the component also contains tackifier, institute
Tackifier are stated in sodium carboxymethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, Arabic gum
One or more;The weight percent of tackifier is 0~3%.
8. tamoxifen gel emplastrum according to claim 1, which is characterized in that the component is also containing preservative, guarantor
Humectant and surfactant;Wherein, preservative is selected from benzoic acid, methyl hydroxybenzoate, ethylparaben, propylben, Ni Bo
One or more of golden butyl ester;Surfactant is in polysorbate, Emulsifier EL-60, OP emulsifiers, paregal O
One or more;Moisturizer is selected from one or more of propylene glycol, glycerine, 1,3 butylene glycol, polyethylene glycol.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111166930A (en) * | 2019-11-19 | 2020-05-19 | 北京理工大学 | Sodium alginate hydrogel medical dressing and preparation method thereof |
CN114732843A (en) * | 2022-03-10 | 2022-07-12 | 上海市浦东新区中医医院 | Traditional Chinese medicine gel patch for treating DPN (dipeptidyl peptidase-IV) through medicine penetration and preparation method and application thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1539410A (en) * | 2003-04-25 | 2004-10-27 | 怡 张 | Externally applied combined remedy for treating breast disease and preparation method |
CN1857242A (en) * | 2006-03-16 | 2006-11-08 | 张怡 | Externally applied tamoxifen citrate microemulsion preparation and its preparing process |
CN101065120A (en) * | 2004-10-14 | 2007-10-31 | 法国法杏大药厂 | 4-hydroxy tamoxifen gel formulations |
CN101711754A (en) * | 2009-11-06 | 2010-05-26 | 河南省生物工程技术研究中心 | Tamoxifen citrate emplastrum and preparation method thereof |
CN106074453A (en) * | 2016-06-14 | 2016-11-09 | 浙江中医药大学 | Lappaconitine Gel plaster and preparation method thereof |
-
2016
- 2016-12-11 CN CN201611134835.1A patent/CN108210484B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1539410A (en) * | 2003-04-25 | 2004-10-27 | 怡 张 | Externally applied combined remedy for treating breast disease and preparation method |
CN101065120A (en) * | 2004-10-14 | 2007-10-31 | 法国法杏大药厂 | 4-hydroxy tamoxifen gel formulations |
CN1857242A (en) * | 2006-03-16 | 2006-11-08 | 张怡 | Externally applied tamoxifen citrate microemulsion preparation and its preparing process |
CN101711754A (en) * | 2009-11-06 | 2010-05-26 | 河南省生物工程技术研究中心 | Tamoxifen citrate emplastrum and preparation method thereof |
CN106074453A (en) * | 2016-06-14 | 2016-11-09 | 浙江中医药大学 | Lappaconitine Gel plaster and preparation method thereof |
Non-Patent Citations (3)
Title |
---|
KAPSE ET AL: "Self nanoprecipitating preconcentrate of tamoxifen citrate for enhanced bioavailability", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
SHEN GAO ET AL: "In vitro percutaneous absorption enhancement of a lipophilic drug tamoxifen by terpenes", 《JOURNAL OF CONTROLLED RELEASE》 * |
孟胜男,等: "《药剂学》", 31 January 2016 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111166930A (en) * | 2019-11-19 | 2020-05-19 | 北京理工大学 | Sodium alginate hydrogel medical dressing and preparation method thereof |
CN114732843A (en) * | 2022-03-10 | 2022-07-12 | 上海市浦东新区中医医院 | Traditional Chinese medicine gel patch for treating DPN (dipeptidyl peptidase-IV) through medicine penetration and preparation method and application thereof |
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