CN102772417A - Period effect percutaneous patch of self viscosity elastic body substrate containing testosterone and preparation method thereof - Google Patents
Period effect percutaneous patch of self viscosity elastic body substrate containing testosterone and preparation method thereof Download PDFInfo
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- CN102772417A CN102772417A CN2012102583782A CN201210258378A CN102772417A CN 102772417 A CN102772417 A CN 102772417A CN 2012102583782 A CN2012102583782 A CN 2012102583782A CN 201210258378 A CN201210258378 A CN 201210258378A CN 102772417 A CN102772417 A CN 102772417A
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Abstract
The invention discloses a period effect percutaneous patch of a self viscosity elastic body substrate covering and bearing testosterone and a preparation method thereof. The period effect percutaneous patch comprises a support layer, a medicine taking self viscosity elastic body substrate layer and a separation layer. The support layer is covered on one side of the medicine taking self viscosity elastic body substrate layer, and the separation layer is covered on the other side of the medicine taking self viscosity elastic body substrate layer. The period effect percutaneous patch adopts the lipotropy elastic body substrate with the low melting point to contain the testosterone, and a stable and effective testosterone blood concentration is maintained in 7 days. The patch is excellent in medicine skin penetrating performance, good in adhering performance, high in medicine loading rate, good in air permeability and free of residue when being stripped from the skin. A preparation process of the period effect percutaneous patch of the testosterone uses no machine solvent and is environment-friendly, coating is carried out in a melting state, and the preparation process has the advantages of being high in coating speed, high in production efficiency and low in cost.
Description
Technical field
The present invention relates to a kind of bag carries testosterone and imitates percutaneous patch and method for preparing from week of stickiness elastomeric matrices.
Background technology
Testosterone belongs to androgen, is mainly used in the very few and complication such as the male hypogonadism that causes and the manlike obstacle of secondary sex characteristics of treatment androgen secretion.Because the existence of liver first-pass effect, testosterone is oral invalid, and bioavailability is extremely low; Though drug administration by injection has been avoided first pass effect, can cause that the peak valley effect appears in testosterone concentration in the body.
Therefore, seek a kind of preparation that is suitable for testosterone, be people the problem very be concerned about.
Testosterone (testosterone) transdermal patch (trade name:
) listing of drugs approved by FDA Waston drugmaker exploitation;
is the reservoir devices transdermal patch; Compare matrix type patch (Drug-in-adhesive; DIA) have the slow characteristics of drug absorption; The problem that has intravenous extravasation; Contain ethanol in the bank solution, agents area is produced strong impulse property.
Therefore, the transdermal administration of attempting being used for testosterone with the matrix type patch is in the hope of solving the problem of above-mentioned existence.The medicine-releasing performance of acrylate pressure sensitive adhesive is limited, must just can reach the ideal concentration of drug release through the content that increases principal agent.And the increase of drug content tends to cause other problems, separates out crystallization like medicine between the storage life, and drug loading causes the crude drug waste greatly, and cost increases, and patch uses problems such as back drug residue.
The transdermal testosterone drug-supplying system product that has gone on the market at present mainly contains testosterone patch, testosterone gel and testosterone spray, is 1 administration on the one, patient's medication inconvenience, poor compliance.
Summary of the invention
The purpose of this invention is to provide a kind of bag and carry testosterone and imitate percutaneous patch and method for making, to overcome the defective that prior art exists from week of stickiness elastomeric matrices.
Another object of the present invention provides a kind of bag and carries testosterone from the stickiness elastomeric matrices.
Bag of the present invention carries testosterone from the stickiness elastomeric matrices
Described medicine carrying is made up of following components in weight percentage from stickiness elastomeric matrices layer:
Has lipotropy elastomeric matrices 90～99% from stickiness matter
Preferably, described medicine carrying is made up of following components in weight percentage from stickiness elastomeric matrices layer:
Has lipotropy elastomeric matrices 94～98% from stickiness matter
The said lipotropy elastomeric matrices that has from stickiness matter, form by the component of following parts by weight:
Preferably, the said lipotropy elastomeric matrices that has from stickiness matter, form by the component of following parts by weight:
The described fusing point that has from the lipotropy elastomeric matrices of stickiness matter is 60 ℃～100 ℃, and room temperature is solid down, and high temperature is liquid down;
Said thermoplastic elastomer (TPE) is selected from one or more in the thermoplastic elastomer (TPE)s such as styrene-isoprene-phenylethene (SIS) triblock copolymer, s-B-S (SBS) triblock copolymer, hydroxylation styrene-ethylene/butylene-styrene (SEBS) triblock copolymer, hydroxylation styrene-ethylene/propylene-styrene (SEPS) triblock copolymer;
Styrene-isoprene-phenylethene (SIS) triblock copolymer modulus is low; Have good cohesiveness and stick performance; Flexibility is good, and melting viscosity is little, is prone to coating; Have the good compatibility with other components such as tackifiers, so optimization styrene-isoprene-styrene (SIS) triblock copolymer;
Tackifier is to influence the substrate key component of viscous force and pressure-sensitive just, and the adhesion to skin is provided, the melting viscosity of reduction pressure sensitive adhesive and be beneficial to coating.Can increase the cohesive strength of substrate with the polyglass tackifier that the compatibility is good mutually; Can significantly reduce the elastic modelling quantity and the cohesive strength of substrate with the isoprene rubber tackifier that the compatibility is good mutually; Reduce the softening point of substrate, give just viscous force, pressure-sensitive and peel strength;
Said tackifier is selected from one or more in terpene resin, phenolic resins, indene resin, C5 hydrogenated petroleum resin, C9 hydrogenated petroleum resin, Petropols, abietic resin or the Foral resin etc.Compare abietic resin, it is low that the Foral resin has an acid number, the advantage that skin irritation is little; Petropols have advantages such as acid number is low, of light color, adhesion is good, softening point is low, antioxidant effect is good; Good with the compatibility of thermoplastic elastomer (TPE); When being provided, reduces adhesive force the softening point of pressure sensitive adhesive; Therefore, preferred Foral resin and Petropols are united use as tackifier, and preferred weight ratio is: Foral portions of resin Petropols=1:1～1:3;
80～160 parts of the consumptions of tackifier, preferred 120～140 parts, if consumption is very few, the substrate stickiness is not enough, and the transdermal patch of preparation can not stick with skin during medication; If consumption is too much, the substrate stickiness is strong excessively, causes pain during from skin peeling, produces zest;
Be the liquid of low-viscosity during plasticizer room temperature, can reduce the cohesive strength of thermoplastic elastomer (TPE), improve the flexibility and the original viscosity of substrate, increase the adaptability with skin, reduce the melting viscosity of substrate and be beneficial to coating.Available main plasticizer comprises liquid paraffin, silicone oil, naphthenic oil, mineral oil, Oleum Ricini, olive oil, vaseline, squalane, Squalene, polybutene or polyisobutylene etc.Liquid paraffin and polybutene are with low cost, and be little to skin irritation, so preferred liquid paraffin and polybutene unite use as main plasticizer, and preferred weight ratio is: liquid paraffin: polybutene=1:0.5～1:1.The consumption of main plasticizer is 40～100 parts, and preferred 60～100 parts, if the consumption of main plasticizer is very few, patch is to the bad adaptability of skin, easily from skin peeling; If the consumption of main plasticizer is too much, the cohesiveness of hypothallus significantly descends, and is prone to when patch is peeled off form residue at skin.
Co-plasticizer has the effect that promotes that drug transdermal absorbs when improving the substrate cohesiveness.Available co-plasticizer comprises fatty acid ester (isopropyl myristate; The adipic acid diisopropyl ester; Ethyl sebacate etc.; The lauryl alcohol lactate; Triacetyl glycerine; Ethyl oleate etc.); Phthalate (dibutyl phthalate; Diethyl phthalate etc.); Polyhydric alcohol (Polyethylene Glycol; Propylene glycol; Glycerol; Menthol etc.); Organic acid (oleic acid; Palmic acid; Stearic acid; Salicylic acid; Sad; Capric acid; Lauric acid etc.); Phospholipid (lecithin; Fabaceous lecithin; Phosphatidyl glycerol; PHOSPHATIDYL ETHANOLAMINE etc.); N-methyl pyrrole irons alkane ketone; Azone etc.Isopropyl myristate and Polyethylene Glycol are little to the destruction of substrate; But the transdermal amount of significantly increasing medicament; Cutaneous safety is good; Therefore preferred isopropyl myristate and Polyethylene Glycol are united use as extender plasticizer, and preferred weight ratio is: isopropyl myristate: Polyethylene Glycol=1: 0.5～1:1; The consumption of co-plasticizer is 20～50 parts, preferred 30～40 parts, if the extender plasticizer consumption is very few, can not fully guarantee medicine transit dose for a long time, and blood drug level does not reach treatment concentration; If the co-plasticizer consumption is too much, the increase of skin permeability reaches extreme value, and skin irritation is increased, and destroys the cohesive strength of hypothallus, causes easily when peeling off that skin is residual.
Primary plasticizer and extender plasticizer should have certain ratio, are advisable with 2:1～3:1, and the consumption of further preferred main plasticizer is 60～100 parts, and the consumption of extender plasticizer is 30～40 parts;
Excipient can improve the dissolubility of substrate Chinese medicine; Medicine is steady statue and homodisperse, avoids the formation of drug crystallization, guarantees the skin permeability of medicine; Soft and the high resilience that forms from stickiness lipotropy substrate; Regulate the adhesion and the stability of substrate, made patch compliance is good, a little less than the skin irritation.Available excipient comprises polyvinylpyrrolidone, cellulose derivative (methylcellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose etc.), poloxamer, polyvinyl alcohol, vinylacetate, acrylic acid-2-ethyl caproite, methyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate etc.; Preferably polyethylene ketopyrrolidine and acrylic acid-2-ethyl caproite are united use as excipient, and preferred weight ratio is: polyvinylpyrrolidone: acrylic acid-2-ethyl caproite=1: 1～1:2; Consumption is 10～40 parts, preferred 10～20 parts.
Filler is mainly common inorganic salt and metallic oxide, can improve substrate performance, increases cohesive strength, improves the thermostability of substrate, reduces the substrate cost.The granularity of filler should be as far as possible little, guarantees in substrate, to be uniformly dispersed, and chemical inertness, other components with substrate do not react.Available filler comprises calcium carbonate, magnesium carbonate, silicate, Pulvis Talci, aluminium hydroxide, zinc oxide, titanium oxide, calcium sulfate, Barium Sulfate etc.Zinc oxide particles is little, has slight antiseptic property, can in tackifier in some acidic components, therefore preferred zinc oxide, 10～40 parts of consumptions, preferred 10～20 parts.
Antioxidant can avoid the unsaturated molecule segment in the centre of thermoplastic elastomer (TPE) in the preparation process owing to be heated or oxidation that high-speed stirred takes place with aging.Available antioxidant comprises dibenzylatiooluene (BHT) and esters derivative, tocopherol and esters derivative thereof, ascorbic acid and esters derivative thereof, butylated hydroxyarisol, propyl gallate, 2-mercaptobenzimidazole etc.Preferred dibenzylatiooluene, 2～10 parts of consumptions, preferred 2～5 parts.
The described method for preparing that has from the lipotropy substrate of stickiness matter comprises the steps:
(1) thermoplastic elastomer (TPE), antioxidant, primary plasticizer and extender plasticizer are heated to 160 ℃～180 ℃ under nitrogen protection, are in molten condition until each component;
(2) with thermoregulation to 100 ℃～120 ℃; Add tackifier, excipient and filler; Continue to be heated to each component under the nitrogen protection and stir, cool off, promptly get the lipotropy substrate that has of clear, colorless from stickiness matter; This substrate has lower softening point and coating temperature, sticks functional;
Provided by the invention have in the lipotropy substrate method for preparing of stickiness matter, with an organic solvent do not avoid producing environmental pollution, has the characteristics of energy-conserving and environment-protective.In the preparation process, through secluding air and high-speed stirred, reduce substrate and prepare the heated time in the process, avoid taking place aging and oxidation.
Described bag carries testosterone imitates the percutaneous patch from the week of stickiness elastomeric matrices, comprises that shelf layer, medicine carrying are from stickiness elastomeric matrices layer and release layer;
Said shelf layer covers the side of said medicine carrying from stickiness elastomeric matrices layer, and said release layer covers the opposite side of said medicine carrying from stickiness elastomeric matrices layer;
Said shelf layer is used for covering and supports medicine carrying from stickiness elastomeric matrices layer, preferably good, the impervious material of pliability.The elasticity of shelf layer and draftability guarantee adaptability and the docile property of patch to skin, greatly the Transdermal absorption of the assurance medicine of degree.Optional shelf layer material comprises micro-porous permeable based polyurethane thin film or silicone film, its pore size 20～50 μ m, and porosity is 20%～50%, thickness is 30～50 μ m.The ideal thickness of shelf layer is 10～100 μ m, if thickness is excessive, the elasticity of shelf layer reduces with draftability, makes can not fit the fully variation of skin of patch, and drug transdermal absorbs decline; The present invention simultaneously requires to keep 7 days effect, so the permeability of shelf layer is extremely important, and needing to select air penetrability is 50g/cm
2/ hr～200g/cm
2Polyurethane film that the transparent performance of/hr is good or silicone film material, and assistant micropore design on the material, its pore size 20～50 μ m, porosity is 20%～50%, more can guarantee to stick for a long time the eupnea and the comfort level of skin.
Said release layer is the polyethylene film of fluorination treatment, and thickness is 60～80 μ m.The release layer material is release protecting film, is used for covering and the protection hypothallus, faces with before removing.
Bag of the present invention carries the method for preparing of imitating transdermal composition week of testosterone, comprises the steps:
The lipotropy elastomeric matrices that (1) will have from stickiness matter is heated to fusion (70 ℃～90 ℃) under nitrogen protection, add testosterone, and mix homogeneously is processed the substrate of pastille;
(2) while hot the substrate of pastille is coated shelf layer, the cooling back covers upward release layer, and is die-cut by required area size, obtains bag and carries testosterone from the week of stickiness elastomeric matrices effect percutaneous patch.
Thickness to hypothallus among the present invention does not have strict special restriction.But if coating thickness is thin excessively, adhesion descends, and can not keep the stable release of medicine; If coating thickness is blocked up, the medicine of hypothallus can not thoroughly discharge, and cost increases, and is prone to come off during with contact friction such as medicated clothing.Therefore, preferred coating thickness 20～100 μ m.
What contain testosterone among the present invention imitates transdermal composition week when using, and can it be attached on patient's the intact skin, and dosage is week 1 time, and each 1 pastes, and area is with 30～60cm
2For suitable;
Because testosterone is fat-soluble strong chemical compound, molecular weight is less, and therefore, the present invention is prepared into Percutaneously administrable prepn with it, makes medicine see through skin and slowly discharges into blood and play whole body administration effect, and it is stable to keep blood drug level, and safety is good.
This patch can use the stable release that prolongs the principal agent testosterone in 7 days continuously, has the stability of long term storage, good cutaneous safety and the suitable performance of sticking.
The present invention adopts the novel low melting point that has to hold a year testosterone from the lipotropy substrate of stickiness matter, in 7 days, keeps one and stablizes and effective testosterone blood drug level.Patch drug transdermal performance of the present invention is excellent, stick functional, drug loading is high, good permeability, skin irritation are little, extended storage stability is good, from the skin peeling noresidue, patient's medication is convenient, flexible, compliance is good.Do not use the machine solvent in the preparation process of the weekly-acting percutaneous patch of testosterone among the present invention, environmental friendliness is coated with under molten condition, has the advantages that coating speed is fast, production efficiency is high, with low cost.
Description of drawings
Fig. 1 is the structural representation that contains the weekly-acting percutaneous transdermal composition of testosterone.
Fig. 2 is imitated the release in vitro curve chart of transdermal composition for the week of containing testosterone among the embodiment 3～6.
Fig. 3 is for imitating the transdermal test in vitro accumulation transit dose curve chart of transdermal composition the week of containing testosterone among the embodiment 3～6.
The specific embodiment
Referring to Fig. 1, the week of containing testosterone of the present invention is imitated transdermal composition, comprises shelf layer 1, medicine carrying controlled release matrix layer 2 and release layer 3; Said shelf layer 1 covers a side of said medicine carrying controlled release matrix layer 2, and said release layer 3 covers the opposite side of said medicine carrying controlled release matrix layer 2.
Below in conjunction with specific embodiment, further set forth the present invention.
These embodiment only be used to the present invention is described and be not used in the restriction scope of the present invention.Term " part " is represented " weight portion " in an embodiment, only if definition is arranged in addition.
Have preparation from the lipotropy elastomeric matrices of stickiness matter:
Get 100g styrene-isoprene-phenylethene triblock copolymer (SIS), hydrogenated petroleum resin 140g, naphthenic oil 80g; Isopropyl myristate 10g, Polyethylene Glycol 5g, N-Methyl pyrrolidone 15g; Polyvinylpyrrolidone 10g, zinc oxide 10g, dibenzylatiooluene 2g.SIS, naphthenic oil, isopropyl myristate, Polyethylene Glycol, N-Methyl pyrrolidone and dibenzylatiooluene are heated to 160 ℃ under nitrogen protection; Adjust the temperature to 100 ℃～120 ℃ after each component melts; Add hydrogenated petroleum resin, polyvinylpyrrolidone and zinc oxide; Continue heated and stirred 20min to the colloid that forms transparent and homogeneous, pour out while hot, cooling promptly gets.
Through measuring, the fusing point that has from the lipotropy elastomeric matrices of stickiness matter that makes is 87 ℃.
Have preparation from the lipotropy elastomeric matrices of stickiness matter:
Get styrene-isoprene-phenylethene triblock copolymer (SIS) 100g, hydrogenated petroleum resin and each 60g of Foral resin, each 50g of liquid paraffin and polybutene; Diethyl phthalate 20g; Polyethylene Glycol 10g, lauryl alcohol lactate 10g, acrylic acid-2-ethyl caproite 20g; Zinc oxide 10g, dibenzylatiooluene 5g.SIS, liquid paraffin, polybutene, diethyl phthalate, Polyethylene Glycol, lauryl alcohol lactate and dibenzylatiooluene are heated to 180 ℃ under nitrogen protection; Adjust the temperature to 100 ℃～120 ℃ after each component melts; Add hydrogenated petroleum resin, Foral resin, acrylic acid-2-ethyl caproite and zinc oxide; Continue heated and stirred 20min to the colloid that forms transparent and homogeneous, pour out while hot, cooling promptly gets.
Through measuring, the fusing point that has from the lipotropy elastomeric matrices of stickiness matter that makes is 72 ℃.
The week that contains testosterone is imitated the preparation of transdermal composition:
[prescription] (in 1000)
Get styrene-isoprene-phenylethene triblock copolymer (SIS) 100g, hydrogenated petroleum resin 80g, Foral resin 40g; Liquid paraffin 60g, naphthenic oil 40g, isopropyl myristate 10g; Polyethylene Glycol 10g, N-Methyl pyrrolidone 10g, methyl methacrylate 10g; Polyvinylpyrrolidone 5g, zinc oxide 5g, dibenzylatiooluene 2g.
SIS, liquid paraffin, naphthenic oil, isopropyl myristate, Polyethylene Glycol, N-Methyl pyrrolidone and dibenzylatiooluene are heated to 160 ℃～180 ℃ under nitrogen protection; Adjust the temperature to 100 ℃～120 ℃ after each component melts; Add hydrogenated petroleum resin, Foral resin, polyvinylpyrrolidone, methyl methacrylate and zinc oxide, continue to be heated to each component under the nitrogen protection and stir; With thermoregulation to 70 ℃～90 ℃, add testosterone 22g, continue to be heated to each component mix homogeneously under the nitrogen protection; The substrate of pastille is coated on the shelf layer while hot, and the cooling back covers goes up release layer, die-cut by required area size, processes the weekly-acting percutaneous patch that contains testosterone.
Embodiment 4
The week that contains testosterone is imitated the preparation of transdermal composition:
[prescription] (in 1000)
Get styrene-isoprene-phenylethene triblock copolymer (SIS) 100g, hydrogenated petroleum resin 90g, Foral resin 30g; Naphthenic oil 60g, liquid paraffin 20g, polybutene 20g; Azone 10g, Polyethylene Glycol 10g, N-Methyl pyrrolidone 10g; Acrylic acid-2-ethyl caproite 10g, zinc oxide 10g, dibenzylatiooluene 5g.SIS, naphthenic oil, liquid paraffin, polybutene, azone, Polyethylene Glycol, N-Methyl pyrrolidone and dibenzylatiooluene are heated to 160 ℃～180 ℃ under nitrogen protection; Adjust the temperature to 100 ℃～120 ℃ after each component melts; Add hydrogenated petroleum resin, Foral resin, acrylic acid-2-ethyl caproite and zinc oxide, continue to be heated to each component under the nitrogen protection and stir; With thermoregulation to 70 ℃～90 ℃, add testosterone 7.5g, continue to be heated to each component mix homogeneously under the nitrogen protection; The substrate of pastille is coated on the shelf layer while hot, and the cooling back covers goes up release layer, die-cut by required area size, processes the weekly-acting percutaneous patch that contains testosterone.
The week that contains testosterone is imitated the preparation of transdermal composition:
[prescription] (in 1000)
Get styrene-isoprene-phenylethene triblock copolymer (SIS) 100g, hydrogenated petroleum resin 120g, liquid paraffin 100g, azone 20g, N-Methyl pyrrolidone 10g, polyvinylpyrrolidone 15g, zinc oxide 10g, dibenzylatiooluene 2g.SIS, liquid paraffin, azone N-Methyl pyrrolidone and dibenzylatiooluene are heated to 160 ℃～180 ℃ under nitrogen protection; Adjust the temperature to 100 ℃～120 ℃ after each component melts; Add hydrogenated petroleum resin, polyvinylpyrrolidone and zinc oxide, continue to be heated to each component under the nitrogen protection and stir; With thermoregulation to 70 ℃～90 ℃, add testosterone 18g, continue to be heated to each component mix homogeneously under the nitrogen protection; The substrate of pastille is coated on the shelf layer while hot, and the cooling back covers goes up release layer, die-cut by required area size, processes the weekly-acting percutaneous patch that contains testosterone.
Embodiment 6
The week that contains testosterone is imitated the preparation of transdermal composition:
[prescription] (in 1000)
Get styrene-isoprene-phenylethene triblock copolymer (SIS) 100g, Foral resin 140g, naphthenic oil 100g; Lauryl alcohol lactate 20g, Polyethylene Glycol 10g, polyvinylpyrrolidone 10g; Acrylic acid-2-ethyl caproite 10g, zinc oxide 10g, dibenzylatiooluene 5g.SIS, naphthenic oil, lauryl alcohol lactate and dibenzylatiooluene are heated to 160 ℃～180 ℃ under nitrogen protection; Adjust the temperature to 100 ℃～120 ℃ after each component melts; Add Foral resin, polyvinylpyrrolidone, acrylic acid-2-ethyl caproite and zinc oxide, continue to be heated to each component under the nitrogen protection and stir; With thermoregulation to 70 ℃～90 ℃, add testosterone 15g, continue to be heated to each component mix homogeneously under the nitrogen protection; The substrate of pastille is coated on the shelf layer while hot, and the cooling back covers goes up release layer, die-cut by required area size, processes the weekly-acting percutaneous patch that contains testosterone.
Embodiment 7
The mensuration of sticking performance
1. the first mensuration of viscous force
Use tensile testing machine to measure the first viscous force of patch.The test sample patch is cut out to throwing off release layer after 4cm * 4cm size, sticked in the clean bread board, push down sample 10s with 200g counterweight and dynamometer probe, dynamometer moves down the pulling force of moment record sample to popping one's head in.METHOD FOR CONTINUOUS DETERMINATION 6 times is averaged.The result sees table 1.
2. hold the mensuration of viscous force
Patch is sticked in the bread board of vertical placement, measure with holding the viscous force analyzer.The test sample patch is cut out to throwing off release layer after 5cm * 4cm size; Be parallel to the vertical of plate; Paste at clean rustless steel bread board that is close to and rustless steel load plate middle part; With pressure roller on patch with the speed of (300 ± 10) mm/min back and forth roll extrusion once guarantee that the gluing place does not have bubble and exists.Room temperature is placed behind the 20min its vertical fixing on test stand, along the counterweight of the length direction suspension certain mass of patch, the time that the record patch comes off.METHOD FOR CONTINUOUS DETERMINATION 6 times is averaged.The result sees table 1.
3. the mensuration of peel strength
Adopt 180 ° of disbonded tests to measure the peel strength of patch.The test sample patch is cut out to throwing off release layer after 10cm * 2cm size; Be affixed on the clean corrosion resistant plate; The end is with the adhesive layer and clean mylar gluing of patch; With pressure roller on patch with the speed of (300 ± 10) mm/min back and forth roll extrusion once guarantee that the gluing place does not have bubble and exists.Room temperature is placed 20～40min, and thin film is held on the electronic stripping tester with corrosion resistant plate is upper and lower respectively, and mm/min peels off continuously with (300 ± 10), writes down the peel strength of patch.METHOD FOR CONTINUOUS DETERMINATION 6 times is averaged.The result sees table 1.
Embodiment 8
The mensuration of moisture-vapor transmission
The moisture-vapor transmission of transdermal patch is an important indicator of investigating its comfort level, and moisture-vapor transmission is high more, and breathability is good more, is difficult for causing the stimulation anaphylaxis of skin, and skin is not prone to hydrops or whiting.Adopt the loss of weight method to measure the moisture-vapor transmission of patch.Getting nonhygroscopic floor space is circular test board and the patch to be measured of A, puts into (32 ± 2) ℃, and the bottom covers in the thermostatic drier of anhydrous calcium chloride, takes out behind the balance 6h.The KNO of adding about 2/3rds in test board
3Saturated solution, relative humidity (90 ± 5) % throws off the release layer of test sample patch, contains glue and faces down and cover on the test board, and the test sample patch is also suitably cut out to edge in the sealing back, the precision (W that weighs
1).Test board is put into exsiccator, take out behind the 24h and put to room temperature, (W weighs
2).Calculate moisture-vapor transmission by following formula.METHOD FOR CONTINUOUS DETERMINATION 6 times is averaged.The result sees table 1.
Water vapour permeability=(W1-W2)/A
Table 1 has from the lipotropy substrate adhesion ability of stickiness matter and the result of the test of moisture-vapor transmission
Embodiment 9
The mensuration of patch release in vitro degree
Investigate the release of medicine with transdermal diffusion test appearance.The patch for preparing is thrown off release layer, and shelf layer up, drug faces down and be fixed on the reception tank of Franz diffusion cell, covers first pond and clamp with iron clamp.Accept to add in the pond release medium 60% alcoholic solution of ultrasonic degas.Diffusion area is 3.14cm
2, accepting volume is 7ml, and mixing speed is 250r/min, and the temperature of acceptable solution is controlled at (32 ± 0.5) ℃.Take out release medium 5ml (replenishing the fresh release medium of equality of temperature equivalent simultaneously) respectively at 1,2,4,6,8,10,12,14,24,48,72,96,120,144 and 168h after the experiment beginning, direct injected is measured.Test parallel 3 times for every group.Unit of account area drug accumulation burst size and drug accumulation release rate Q% (being drug per unit area cumulative release amount and the ratio of unit are patch Chinese medicine content).Drug accumulation release rate Q% sees table 2 as a result, and the drug release curve is seen Fig. 2 (a) and (b).
The transdermal test in vitro test
1. the processing of isolated skin
Nude mice is put to death back bark fetching skin, carefully removes subcutaneous fat, cleans up with normal saline, is tiled on the aluminium-foil paper, and-30 ℃ of refrigerator preservation 24h are subsequent use.Face with preceding bark fetching skin and place 20min in room temperature, clean with normal saline, non-woven fabrics blots the water of skin keratin aspect, is cut to suitable big or small skin.
2. transdermal test
Adopt the vertical type diffusion cell to carry out the transdermal test in vitro test.Keratodermatitis upwards is fixed on the reception tank of the Franz diffusion cell that magnetic agitation son is housed, and is affixed on the skin surface after the patch for preparing is thrown off release layer, gets rid of the bubble between patch and skin, covers first pond and clamps with iron clamp.That accepts to add in the pond preheating and ultrasonic degas accepts medium 40%PEG200 solution.The diffusion area of diffusion cell is 3.14cm
2, accepting volume is 7ml, magnetic agitation speed is 250rmin
-1, the temperature of acceptable solution is controlled at (32 scholar 0.5) ℃.Take out the fresh medium of accepting that the 0.5ml acceptable solution also replenishes equal-volume, equitemperature respectively at 1,2,4,6,8,10,12,14 and 24h after the experiment beginning.The acceptable solution that takes out is in 12000rmin
-1Get behind the centrifugal 5min behind the supernatant with its concentration of high-performance liquid chromatogram determination.Chromatographic condition is following: chromatographic column is Shim-packVP-ODS C
18Post (4.6mm * 250mm, 5 μ m); Mobile phase is methanol-water (66:34); Flow velocity: 1.0mlmin
-1Detect wavelength: 241nm; Column temperature: 40 ℃; Sampling volume: 20 μ l, external standard method is quantitative.Test parallel five times, average for every group.According to formula unit of account area accumulation transit dose Q
nThe result sees table 2, and accumulation transdermal test in vitro curve is seen Fig. 3.
The result of weekly-acting percutaneous patch release in vitro of table 2 testosterone and transdermal test in vitro test
Embodiment 11
Stability test
1. test method: after the weekly-acting percutaneous patch of testosterone among the embodiment 3～6 at room temperature stored 3 months, whether the visual observations outward appearance had crystallization to separate out.
2. the patch of result of the test: embodiment 3～6 is through observing, and no crystallization forms, and explains that this patch has good stability.
The skin irritation test
1. test method: get 6 of 2.8～3.0kg healthy rabbits, be equally divided into intact skin group and damaged skin group, 24h loses hair or feathers back part of animal before administration.To receive reagent thing (patch of embodiment 3～6,10cm respectively
2) and control drug (patch of embodiment 1～2,10cm
2) each 5 be affixed on back part of animal respectively tried medicament region and control drug district (50cm2), apply ointment or plaster continuous 7 days every day 1 time.24h removes residue with warm water and normal saline after the last administration; Observe to remove receiving the erythema of reagent thing 1,24,48 and 72h application site and the recovery situation and the time of edema situation and above-mentioned variation, every animal test results is carried out IR scoring and stimulus intensity evaluation.
2. the patch of result of the test: embodiment 1～6 is accomplished skin group and the administration of damaged skin group and is not all seen IR through rabbit skin irritant test.
Embodiment 13
Skin anaphylactic test
1. test method: get 30 of 250g～300g healthy guinea pig, be equally divided into three groups, 10 every group, male and female half and half.24h takes off the about 4 * 4cm of the every side of QUMAO scope with guinea pig back left side (sensitization) or right side (exciting) hair before the administration.The 1st group of subsides receive reagent thing (patch of embodiment 3～6,10cm
2), the 2nd group is pasted control drug (patch of embodiment 1～2,10cm
2), the 3rd group of every side pasted positive sensitizer, and 2,1% alcoholic solution 0.2ml of 4-dinitrochlorobenzene.
Sensitization: get and receive reagent thing (patch of embodiment 3～6,10cm
2) be affixed on depilation district, animal left side skin, fix with rubber plaster, remove behind the lasting 6h and receive the reagent thing.The 7th day and the 14th day in kind respectively repeats once.Negative control group and positive control group of methods are all with being tried drug group.
Excite: after last sensitization 14 days, it was outer to receive the reagent thing to be affixed on depilation district, animal right side, fixes with rubber plaster, continued to remove behind the 6h to receive the reagent thing, observe at once, then in 24,48,72h observes the skin allergy situation once more.Negative control group and positive control group of methods are all with being tried drug group.
Every animal test results is carried out anaphylaxis scoring and irritated intensity evaluation.
2. the patch of result of the test: embodiment 1～6 was not met quick reaction through the guinea pig skin hypersensitive test.
Claims (10)
1. a medicine carrying is characterized in that from the stickiness elastomeric matrices, is made up of following components in weight percentage:
Testosterone 1～10%
Has lipotropy elastomeric matrices 90～99% from stickiness matter.
2. medicine carrying according to claim 1 is characterized in that from the stickiness elastomeric matrices, is made up of following components in weight percentage:
Testosterone 2～6%
Has lipotropy elastomeric matrices 94～98% from stickiness matter.
3. medicine carrying according to claim 1 and 2 is characterized in that from the stickiness elastomeric matrices the said lipotropy elastomeric matrices that has from stickiness matter is made up of the component of following parts by weight:
4. medicine carrying according to claim 3 is characterized in that from the stickiness elastomeric matrices the said lipotropy elastomeric matrices that has from stickiness matter is made up of the component of following parts by weight:
5. medicine carrying according to claim 3 is characterized in that from the stickiness elastomeric matrices, and the described fusing point that has from the lipotropy elastomeric matrices of stickiness matter is 60 ℃～100 ℃, and room temperature is solid down, and high temperature is liquid down.
6. medicine carrying according to claim 3 is from the stickiness elastomeric matrices; It is characterized in that said thermoplastic elastomer (TPE) is selected from one or more in styrene-isoprene-phenylethene (SIS) triblock copolymer, s-B-S (SBS) triblock copolymer, hydroxylation styrene-ethylene/butylene-styrene (SEBS) triblock copolymer, hydroxylation styrene-ethylene/propylene-styrene (SEPS) triblock copolymer;
Said tackifier is selected from one or more in terpene resin, phenolic resins, indene resin, C5 hydrogenated petroleum resin, C9 hydrogenated petroleum resin, Petropols, abietic resin or the Foral resin;
Said primary plasticizer is selected from liquid paraffin, silicone oil, naphthenic oil, mineral oil, Oleum Ricini, olive oil, vaseline, squalane, Squalene, polybutene or polyisobutylene;
Said co-plasticizer is selected from isopropyl myristate, adipic acid diisopropyl ester, ethyl sebacate etc., lauryl alcohol lactate, triacetyl glycerine, ethyl oleate, dibutyl phthalate, diethyl phthalate, Polyethylene Glycol, propylene glycol, glycerol, menthol, oleic acid is arranged, Palmic acid, stearic acid, salicylic acid, sad, capric acid, lauric acid, lecithin, fabaceous lecithin, phosphatidyl glycerol, PHOSPHATIDYL ETHANOLAMINE, N-methyl pyrrole iron alkane ketone or azone;
Said excipient is selected from polyvinylpyrrolidone, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, poloxamer, polyvinyl alcohol, vinylacetate, acrylic acid-2-ethyl caproite, methyl methacrylate, butyl methacrylate or dimethylaminoethyl methacrylate.
7. medicine carrying according to claim 6 is characterized in that from the stickiness elastomeric matrices said tackifier is Foral resin and Petropols, and weight ratio is: Foral portions of resin Petropols=1:1～1:3;
Said primary plasticizer is liquid paraffin and polybutene, and weight ratio is: liquid paraffin: polybutene=1:0.5～1:1;
Said co-plasticizer is isopropyl myristate and Polyethylene Glycol, and weight ratio is: isopropyl myristate: Polyethylene Glycol=1: 0.5～1:1;
Excipient is polyvinylpyrrolidone and acrylic acid-2-ethyl caproite, and weight ratio is: polyvinylpyrrolidone: acrylic acid-2-ethyl caproite=1: 1～1:2.
8. medicine carrying according to claim 7 is characterized in that from the stickiness elastomeric matrices mass ratio of primary plasticizer and co-plasticizer is 2:1～3:1.
9. a bag carries testosterone from the week of stickiness elastomeric matrices effect percutaneous patch, it is characterized in that, comprises that shelf layer, medicine carrying are from stickiness elastomeric matrices layer and release layer;
Said shelf layer covers the side of said medicine carrying from stickiness elastomeric matrices layer, and said release layer covers the opposite side of said medicine carrying from stickiness elastomeric matrices layer;
Said medicine carrying is that each described medicine carrying of claim 1～8 is from the stickiness elastomeric matrices from the material of stickiness elastomeric matrices layer.
10. the described bag of preparation claim 9 carries testosterone from the method for imitating the percutaneous patch week of stickiness elastomeric matrices, it is characterized in that, comprises the steps:
The lipotropy elastomeric matrices that (1) will have from stickiness matter is heated to fusion under nitrogen protection, add testosterone, mixes, and processes the substrate of pastille;
(2) while hot the substrate of pastille is coated shelf layer, the cooling back covers upward release layer, and is die-cut by required area size, obtains bag and carries testosterone from the week of stickiness elastomeric matrices effect percutaneous patch.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201210258378.2A CN102772417B (en) | 2012-07-24 | 2012-07-24 | Period effect percutaneous patch of self viscosity elastic body substrate containing testosterone and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210258378.2A CN102772417B (en) | 2012-07-24 | 2012-07-24 | Period effect percutaneous patch of self viscosity elastic body substrate containing testosterone and preparation method thereof |
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| CN102772417A true CN102772417A (en) | 2012-11-14 |
| CN102772417B CN102772417B (en) | 2014-01-29 |
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| CN201210258378.2A Active CN102772417B (en) | 2012-07-24 | 2012-07-24 | Period effect percutaneous patch of self viscosity elastic body substrate containing testosterone and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103961805A (en) * | 2014-04-04 | 2014-08-06 | 李宏博 | Tissue equivalent filler for cancer radiotherapy |
| CN107754009A (en) * | 2016-08-18 | 2018-03-06 | 浙江海创医疗器械有限公司 | The preparation method and application method of a kind of low high viscosity water colloid of anaphylaxis |
| CN110693935A (en) * | 2019-10-30 | 2020-01-17 | 黑龙江中医药大学 | Garcinia entrapped transdermal patch containing compound obtained by fermenting traditional Chinese medicine starch and fatty oleic acid and self-adhesive matrix and preparation method thereof |
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| CN1131907A (en) * | 1993-08-03 | 1996-09-25 | 瑟拉技术有限公司 | Skin patches and methods for providing testosterone |
| US6010715A (en) * | 1992-04-01 | 2000-01-04 | Bertek, Inc. | Transdermal patch incorporating a polymer film incorporated with an active agent |
| CN1409628A (en) * | 1999-12-15 | 2003-04-09 | 久光制药株式会社 | Adhesive preparations |
| CN101966339A (en) * | 2009-12-22 | 2011-02-09 | 侯玉庆 | Thermoplastic elastomer styrene-isoprene-styrene (SIS) framework material extruded and coated by extruder |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6010715A (en) * | 1992-04-01 | 2000-01-04 | Bertek, Inc. | Transdermal patch incorporating a polymer film incorporated with an active agent |
| CN1131907A (en) * | 1993-08-03 | 1996-09-25 | 瑟拉技术有限公司 | Skin patches and methods for providing testosterone |
| CN1409628A (en) * | 1999-12-15 | 2003-04-09 | 久光制药株式会社 | Adhesive preparations |
| CN101966339A (en) * | 2009-12-22 | 2011-02-09 | 侯玉庆 | Thermoplastic elastomer styrene-isoprene-styrene (SIS) framework material extruded and coated by extruder |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103961805A (en) * | 2014-04-04 | 2014-08-06 | 李宏博 | Tissue equivalent filler for cancer radiotherapy |
| CN103961805B (en) * | 2014-04-04 | 2017-06-20 | 李宏博 | Tissue equivalent filler for cancer radiotherapy |
| CN107754009A (en) * | 2016-08-18 | 2018-03-06 | 浙江海创医疗器械有限公司 | The preparation method and application method of a kind of low high viscosity water colloid of anaphylaxis |
| CN110693935A (en) * | 2019-10-30 | 2020-01-17 | 黑龙江中医药大学 | Garcinia entrapped transdermal patch containing compound obtained by fermenting traditional Chinese medicine starch and fatty oleic acid and self-adhesive matrix and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102772417B (en) | 2014-01-29 |
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Address after: 201203 Shanghai City Harley Road, Zhangjiang High Tech Park of Pudong New Area No. 1111 Patentee after: Shanghai Modern National Pharmaceutical Engineering Research Center Co., Ltd. Patentee after: CHINA?RESOURCES?ZIZHU?PHARMACEUTICAL?CO., LTD. Address before: 201203 Shanghai City Harley Road, Zhangjiang High Tech Park of Pudong New Area No. 1111 Patentee before: Shanghai Modern National Pharmaceutical Engineering Research Center Co., Ltd. Patentee before: Zizhu Pharmaceutical Co., Ltd., Beijing |