CN1509717A - Skin penetrating paste containing ligustrazine free alkali and its preparation - Google Patents
Skin penetrating paste containing ligustrazine free alkali and its preparation Download PDFInfo
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- CN1509717A CN1509717A CNA2003101167649A CN200310116764A CN1509717A CN 1509717 A CN1509717 A CN 1509717A CN A2003101167649 A CNA2003101167649 A CN A2003101167649A CN 200310116764 A CN200310116764 A CN 200310116764A CN 1509717 A CN1509717 A CN 1509717A
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Abstract
A percutaneous picking of liquestrazine free alkali for preventing thrombocyte coagulation, expanding arteriole and improving microcirculation is composed of storage layer, adhesive layer, release controlling film, substrate and protecting layer. Its advantages are stable concentration of medicine in blood, sure curative effect and low by-effect.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of transdermal patch that contains the ligustrazine free alkali and preparation method thereof.
Background technology
Ligustrazine (Tetramethylpyrazine is called for short TMP) is the alkaloid monomer of early seventies extraction separation from umbrella shape GAOMU platymiscium Rhizoma Chuanxiong rhizome.Ligustrazine has blood vessel dilating, increase coronary blood flow, cerebral blood flow and improvement circulation, increase myocardial contraction, control ischemia, anoxia and pours into the pharmacological actions such as cell injury that cause again.Still can pass through blood brain barrier in addition, anticoagulant and reduction biologically active pdgf.Clinical research shows that ligustrazine can obviously improve the content of ischemic cerebrovascular patient's superoxide dismutase, strengthens the removing to reactive oxygen free radical; Can suppress cerebral cortex, strengthen the function of respiratory center and vasomotor center.Be mainly used in acute stage, convalescent period and sequela thereof and the coronary heart disease of treatment ischemic cerebrovascular, angina pectoris etc.
The present common formulations of ligustrazine is ligustrazine phosphate tablet and injection and ligustrazine hydrochloride injection.Disposition all carries out with the form of free alkali TMP after ligustrazine phosphate tablet and the injection medication, and absorption and elimination are all rapid, and biological half-life only is 2.89 ± 0.56 hours.Tablet need be taken medicine three times every day, and can produce stomach discomfort, xerostomia, side effect such as drowsiness; But ligustrazine hydrochloride intramuscular injection or intravenous drip, intramuscular injection is too strong because of acidity, the big and administration in a large number of zest, quiet of clinical many employings, every day 3-4hr, continuous drip 10-15 days is a course of treatment, needs the treatment of a plurality of courses of treatment sometimes.Above-mentioned route of administration or medication give the patient and medical personnel make troubles and misery, therefore is necessary to develop the novel form of ligustrazine to improve the compliance of patient.
Preparation capable of permeating skin can produce the constant blood drug level of similar intravenous drip sample, and does not have the liver first-pass effect that oral administration produces, and can obtain persistent optimum curative effect and side effect can be reduced to minimum, also is a kind of painless undamaged administering mode to the patient simultaneously.Physicochemical properties such as the molecular weight that ligustrazine itself had little (136), fusing point low (80 ℃-82 ℃), easily distillation, profit partition coefficient are moderate also satisfy the requirement of exploitation transdermal drug delivery system to the medicine physical and chemical parameter.
Summary of the invention
The purpose of this invention is to provide a kind of safe, effective, ligustrazine novel form that side effect is little-contain the transdermal patch of ligustrazine free alkali, it has anti-platelet aggregation, expansion small artery, effects such as microcirculation improvement.
Ligustrazine transdermal patch provided by the invention comprises the five-layer structure that bin-storing layer, adhesive layer, release-controlled film, backing layer and protective layer are formed.Wherein bin-storing layer comprises following component and weight percent content.
Ligustrazine free alkali 5-60%
High polymer adjuvant 0.5-15%
Nertralizer 0.2-30%
Ethanol 2-35%
Transdermal enhancer 1-40%
Water surplus %
The gel storage storehouse that the bin-storing layer that reaches of the present invention is made up of ligustrazine free alkali, high polymer adjuvant, nertralizer, ethanol, transdermal enhancer and water.
The ligustrazine free alkali can be the ligustrazine monomer in the bin-storing layer, also can be that the phosphate or the hydrochlorate of ligustrazine becomes the form with the ligustrazine free alkali to exist through pH regulator.
Bin-storing layer be by the prepared gel of medicinal high polymer adjuvant as carrier, described high polymer adjuvant comprises carbomer, hydroxyethyl-cellulose etc.Formed gel can be kept the thermodynamic activity of ligustrazine free alkali maximum and help ligustrazine through skin.
Adding the transdermal enhancer purpose in the bin-storing layer is to increase medicine to see through skin, and the penetration enhancer of employing is menthol, sweetgum oil, Oleum Eucalypti or Azone etc.
Adding nertralizer in the bin-storing layer can be triethanolamine or sodium hydroxide, purpose be in and carbomer, pH6.5-7.5 makes the formation gel, next is to make ligustrazine phosphate or ligustrazine hydrochloride be transformed into easy transdermal free alkali type, and this situation is good to use sodium hydroxide.
Adding ethanol in the bin-storing layer is the dissolubility that increases ligustrazine, improves the activity of ligustrazine in the storage storehouse and is beneficial to see through skin, and ethanol itself also has collaborative short saturating effect.
The function of each layer of ligustrazine transdermal patch of the present invention is:
By backing layer load bin-storing layer; Bin-storing layer is laid on the backing layer and as the carrier of active medicine and above-mentioned each component; Release-controlled film covers on the bin-storing layer and can wrap up bin-storing layer with backing layer temperature-sensitive involution, starts to control the effect of pharmacy thing rate of release; Adhesive layer is to make transdermal patch adhere to skin surface on the release-controlled film by covering of making of silicone pressure-sensitive adhesive; Protective layer is the polyester film that handle through fluorine carbon on the surface, covers to play antiseized effect on the adhesive layer and prevent the mistake of bin-storing layer component ease.
The release-controlled film of being addressed adopts ethylene-vinyl acetate copolymer film (EVA film), and vinyl acetate content is 19-28% in the EVA film.
The adhesive layer of being addressed prepares with silicone pressure-sensitive adhesive.
The backing layer of being addressed is the composite membrane of polyester-aluminium foil-three layers of formation of EVA film, and wherein EVA film tool thermal sensitivity can be store the storehouse with release-controlled film hot sealing parcel; Aluminium foil is good to the barrier property of moisture, light, gas etc., can prevent to store distillation and the ethanol and the transdermal enhancer volatilization of ligustrazine in the storehouse; Polyester material can be moistureproof, gas-tight, and be easy to painted.
The protective layer of being addressed is to cover the polyester film that handle through fluorine carbon on the surface on the adhesive layer, plays antiseized and protects the patch effect, and its surface free energy is lower than the surface free energy of silicone pressure-sensitive adhesive.
Ligustrazine transdermal patch of the present invention can discharge medicine sustainedly and stably in official hour, blood drug level is steady, fundamentally eliminates the defective of ligustrazine injection, tablet existence.And very easy to use, tear protective layer off, patch is affixed on the skin of health appointed part, when medication finished, the patch of tearing got final product.In the medication process, when needing to stop administration, the patch of can tearing has immediately been guaranteed the safety of using temporarily.
The present invention obviously is better than existing other dosage forms of ligustrazine, has that curative effect is clear and definite, a steady quality, safety is good, easy to use, side effect is little characteristics.
The present invention calculates by pharmacokinetics and test determines that the release area is 10cm
2～20cm
2, percutaneous rate is 200 μ g/h.cm
2～800 μ g/h.cm
2, lasting drug release time is 1 day.
The present invention confirms through pharmacokinetics and pharmacodynamics test: the ligustrazine transdermal patch can be kept 24 hours blood drug level in the rabbit body steady, have and slow down ischemia and irritate effect again brain injury, the thrombosis that tissue injury causes be can significantly suppress, thereby the prevention and the treatment of thromboembolism helped;
The present invention confirms through skin allergy, acute toxicity and irritation test: the ligustrazine transdermal patch is extremely light to the stimulation of skin, does not cause allergic reaction non-toxic reaction substantially.
Description of drawings
Fig. 1 is for containing ligustrazine free alkali ground ligustrazine transdermal patch structural representation.
Wherein: the 1-backing layer; The 2-bin-storing layer; The 3-release-controlled film; The 4-adhesive layer; The 5-protective layer.
Fig. 2 is ligustrazine transdermal patch cumulative release figure.
Fig. 3 attaches the average blood drug level-time plot of ligustrazine transdermal patch and oral ligustrazine phosphate ordinary tablet for new zealand rabbit.
Fig. 4 is the inside and outside correlation curve of ligustrazine transdermal patch.
Following test will more help the researcher in this field to understand content of the present invention, but not limit this in any form
The content of invention.
Prescription research:
One, the foundation of design and screening prescription
According to ligustrazine effectively treat blood concentration and quiet pharmacokinetic parameters thereof calculate the patch of keeping effective blood concentration the percutaneous rate that should reach, this percutaneous rate is the important evidence of patch prescription and craft screening.
Effective treatment blood concentration of ligustrazine has not yet to see report, and the present invention is according to the pharmacokinetic parameters of oral, quiet of relevant ligustrazine, intramuscular injection and calculate the steady state characteristic blood concentration of ligustrazine in conjunction with clinical dosage regimen commonly used.Result of calculation is: the quiet minimum blood concentration of stable state with intramuscular injection approaches zero, illustrates that both do not have cumulative action by multiple dose administration.The minimum blood concentration of the stable state of oral 50-100mg ligustrazine phosphate is 0.068-0.137 μ g/ml; The average steady state blood concentration of intramuscular injection 100mg ligustrazine phosphate is 0.1286 μ g/ml; The stable state blood concentration of quiet 40mg ligustrazine hydrochloride is 0.2127 μ g/ml.Therefore the interior ligustrazine optimum blood medicine concentration of body is 0.2127 μ g/ml after the designed patch administration, reaches 0.068 μ g/ml at least.
According to the target blood concentration of aforementioned calculation, with the parameter of quiet of ligustrazine hydrochloride be elimination rate constant (k) and apparent volume of distribution (V) calculate certain area patch the percutaneous rate that should reach.Table 1 is the estimation of ligustrazine patch percutaneous rate.
Table 1.
| ??????????C(μg/ml) | ????0.068 | ????0.137 | ????0.2127 | |
| Quiet parameter | ??K(l/h) | ??????????????????0.4594 | ||
| ??V(l) | ??????????????????66.6 | |||
| Patch medicine-feeding rate (mg/h) | ????2.096 | ????4.192 | ????6.508 | |
| ? *S＝100cm 2 | Percutaneous rate (μ g/cm 2.h) | ????20.95 | ????41.92 | ????65.08 |
| ??S＝50cm 2 | ????41.91 | ????83.83 | ????130.16 | |
| ??S＝25cm 2 | ????83.83 | ????167.66 | ????260.31 | |
| ??S＝20cm 2 | ????104.78 | ????209.58 | ????325.39 | |
| ??S＝10cm 2 | ????209.57 | ????419.15 | ????650.78 | |
*: the area of design ligustrazine patch
Table 1 shows, if control patch administration area is 10 or 20cm
2, then the percutaneous rate of patch should reach 104.79 μ g/cm at least
2.h, preferably can reach 325.39 μ g/cm
2.h level (medicine enters intravital speed when promptly being equivalent to quiet administration).Early-stage Study shows that the ligustrazine saturated aqueous solution only is 20.08 ± 1.83 μ g/cm through the percutaneous rate of application on human skin
2.h, for this reason, the present invention is necessary to use transdermal enhancer so that the patch percutaneous rate reaches above-mentioned requirements.
Two, about the selection of patch type
Ligustrazine easily distils, and preparation matrix type patch easily causes ligustrazine to be separated out in the crystallization of pressure sensitive adhesive face, destroys viscosity; Dosage ligustrazine and volatile transdermal enhancer such as Oleum Eucalypti, menthol etc. big, easily distillation can be carried in the storage storehouse that seals in the film controlling type patch, so adopt the film controlling type patch.
Three, the external diffusion test of ligustrazine patch
1. the preparation of isolated skin
Get SD rat (body weight about 200 gram), male and female all can, etherization is till death.Be close to Rhizoma Imperatae with the elbow eye scissors and wipe out clip skin behind the hair of back, reject subcutaneous tissue and fat.With the aluminium foil parcel, place-40 ℃ of cryogenic refrigerators to preserve, the time is no more than three months.Take out during experiment, after room temperature is thawed naturally, use; Get frozen application on human skin, separate and remove subcutaneous tissue and fat, store method is the same.
2. external diffusion experiment method
Adopt K-C vertical proliferation pond, built-in star stirrer forms Concentraton gradient, 37 ℃ of temperature controls to prevent skin surface.To place with the skin that patch closely pastes on the diffusion cell, fixing.Accept the distilled water of packing in the pond, take a sample fluid infusion immediately respectively at setting-up time point from reception tank.Sample is used HPLC external standard method concentration C after diluting
N surveys, get C by the drug level of formula correction reception tank
The n school=C
N surveys* extension rate+2/15 ∑ C
N surveys* extension rate; Calculate the accumulation transdermal dose of ligustrazine: accumulation transdermal dose Q (μ g/cm
2)=C
The n school* accept cell body to amass/the transdermal area
Spread first law according to Fick, after diffusion reaches stable state, with ligustrazine percutaneous accumulation infiltration capacity Q (μ g/cm
2) to time t mapping or make linear regression, the collinear slope of gained is percutaneous rate J (μ g/cm
2.h).
Four, the influence of more different transdermal enhancers:
Compared different transdermal enhancer (Oleum Eucalypti, Azone and menthol) to the influence of ligustrazine transdermal patch through rat back skin, the result shows short saturating ability Oleum Eucalypti〉Azone〉menthol, table 2 is the influences to the ligustrazine transdermal of different transdermal enhancers.
Table 2
| Time (hr) | Accumulation transdermal amount (ug/cm 2) | |||
| Do not add promoter | Menthol | ??Azone | Oleum Eucalypti | |
| ????1 | ????16.56 | ??60.62 | ??82.97 | ??122.60 |
| ????3 | ????252.89 | ??328.01 | ??441.44 | ??617.60 |
| ????5 | ????504.85 | ??475.01 | ??1012.91 | ??1402.05 |
| ????7 | ????714.86 | ??977.59 | ??1550.53 | ??2409.26 |
| ????9 | ????1017.22 | ??1477.37 | ??2253.86 | ??3449.25 |
| ????11 | ????1235.56 | ??1863.66 | ??2932.82 | ??4139.45 |
| ????24 | ????2820.26 | ??5241.02 | ??7252.85 | ??9604.65 |
Five, the ligustrazine transdermal patch is through rat back skin and application on human skin transmission rates
The ligustrazine transdermal patch is carried out the external diffusion test of rat back whole bark and frozen application on human skin, and table 3 is ligustrazine patch percutaneous rate result (μ g/cm
2.h).
Table 3.
| Skin | Percutaneous rate (μ g/cm 2.h) | ||||||
| ????1 | ????2 | ????3 | ????4 | ????5 | On average | ????SD | |
| Rat back | ??632.10 | ??601.55 | ??627.19 | ??531.71 | ??581.59 | ??594.83 | ??40.75 |
| Application on human skin | ??414.94 | ??416.61 | ??386.50 | ??337.11 | ??388.79 | ??37.12 | |
The ligustrazine transdermal patch is 1.5 times of people's skin of chest through the percutaneous rate of rat back skin.
The patch of being developed is 388.79 μ g/cm through the percutaneous rate of application on human skin
2.h, according to table 1 estimation, ligustrazine patch a drug area of the present invention is decided to be 10-20cm
2
Ligustrazine patch drug release determination
Operate according to 2000 editions appendix XD of Chinese Pharmacopoeia drug release determination method three therapeutic methods of traditional Chinese medicine.With 900ml water is solvent, and bath temperature is 32 ± 0.5 ℃, in the designed time, take a sample, and in time in container, replenish equality of temperature, with the distilled water of volume.Sample is through suitably measuring after the dilution.Other joins ligustrazine reference substance aqueous solution.Using the determined by ultraviolet spectrophotometry trap, calculating every burst size at the different time ligustrazine.Ligustrazine patch release profiles is seen Fig. 2.Discharge and with cumulative release percentage rate (%) the corresponding time is carried out linear regression, show that the 0-16hr release rule is a zero level speed, the 24hr release reaches more than 80%.
The pharmacokinetics test of ligustrazine patch
1. dosage regimen
6 of healthy male new zealand rabbits, 2.5 ± 0.3 kilograms of body weight, 24h before test, back unhairing.After the same day was got blank blood in test, 2 of patches are sticked in rabbit back unhairing zone.After the medication from ear edge vein exploitating blood.Institute's blood sampling is with the centrifugal 10min of 3000rpm, get serum in-18 ℃ of refrigerator and cooled freeze preserve to be measured.
6 of healthy new zealand rabbits, 3.0 ± 0.3 kilograms of body weight, fasting is 24 hours before the test.After the same day was got blank blood in test, 3 of oral ligustrazine phosphate ordinary tablets (50mg/ sheet), the 2ml that takes a blood sample after the administration, centrifuging and taking serum, freezing preservation is to be measured.2. result of the test: 6 rabbits stick the average blood drug level-time plot that records behind preparation capable of permeating skin and 6 the oral ligustrazine phosphate ordinary tablets of rabbit and see Fig. 3.The original blood drug level data of every rabbit are tried to achieve area A UC under the plasma concentration curve by trapezoidal method; Peak time (T
Max) and reach peak concentration (C
Max) use fitting of parabola.Table 4 is the kinetic parameters (n=6) behind the rabbit single dose administration.
Table 4
T
max(h)??????C
max(μg/ml)???????AUC
0-24???????MRT(h)
Ligustrazine
3.375±1.510?????1.242±0.242????15.934±0.833??24.525±8.443
Transdermal patch
Ligustrazine phosphate
0.96±0.20???????2.21±1.07??????3.59±1.05?????3.65±1.01
Ordinary tablet
The blood concentration measurement result shows that the onset of ligustrazine transdermal patch is rapid in the rabbit body, does not have obvious time lag, T
MaxBe 3.375h, C
MaxBe 1.242 μ g/ml, and can in 24 hours, keep than stable blood concentration (MRT=24.525h).Compare with conventional quick releasing formulation, avoided the big ups and downs of blood drug level, reached the re-set target of design.Still can detect drug level at 28 hours after removing patch in 24 hours, it is certain residual to illustrate that ligustrazine has in skin.But the obvious decline of its blood concentration also can illustrate, blood concentration is that the medicine that discharges in by patch is kept stably in 0-24 hour.
The inside and outside dependency of ligustrazine transdermal patch
According to blood drug level in the rabbit body, with PA in the body of Loo-Riegelman formula calculating different time, the release percentage rate external with the identical time carries out the inside and outside correlation research.Return absorbing % (X) in the body with release in vitro % (Y): Y=1.3281X-0.03611, r=0.9896, correlation coefficient have the height statistical significance.Show ligustrazine transdermal patch inside and outside utmost point significant correlation.
The pharmacodynamics test of ligustrazine transdermal patch
1, the influence of ligustrazine transdermal patch rat four cerebral arterieies blocking-up electroencephalogram
Rat four cerebral arterieies blocking-up is multiple irritate after, the ligustrazine transdermal patch can make the right side EEG power spectrum significantly increase, dosage greatly then action intensity reaches the effect length of holding time by force, and the effect of high frequency waves is better than effect to low frequency wave.To the left side EEG power spectrum, the ligustrazine transdermal patch also has remarkable effect.Dosage is big, and then onset time slightly early holds time and omits length, but electroencephalogram power spectral intensity difference with insignificance between each dosage.Showing that the ligustrazine transdermal patch has slows down ischemia and irritates effect to brain injury again.
2, the ligustrazine transdermal patch is to the effect of electricity irritation rat carotid artery thrombosis
Rat breast waist pastes the ligustrazine transdermal patch, the artery occlusion time significant prolongation that the electricity irritation common carotid artery is caused, and its action intensity is relevant with the contact skin area with patch.The result shows that the ligustrazine transdermal patch can significantly suppress the thrombosis that tissue injury causes, thereby helps the prevention and the treatment of cerebral embolism.
The toxicological study of ligustrazine transdermal patch
1, the skin acute toxicity test of ligustrazine transdermal patch
Cavia porcellus breast waist pastes the ligustrazine transdermal patch and removes after 24 hours and observed 7 days continuously, the result remove medicine pasted in first day medicine place skin have slightly rubescent outside, no any other unusual performance.Skin is slight rubescently may store that to contain small amount of ethanol in the storehouse relevant with transdermal patch.Result of the test show the institute under the dosage, ligustrazine transdermal patch non-toxic reaction.
2, the skin anaphylactic test of ligustrazine transdermal patch
Utilize Cavia porcellus breast waist to paste the ligustrazine transdermal patch, cause test hypersensitive and show the ligustrazine transdermal patch in sensitization and excitation process, all do not have any edema reaction.Only there is 1 animal slight erythema to occur.Its reaction meansigma methods and sensitization rate are all extremely low.Show that the ligustrazine transdermal patch does not cause allergic reaction substantially, belong to weak sensitization class.
3, the skin irritation of ligustrazine transdermal patch test
Cavia porcellus breast waist pasted the ligustrazine transdermal patch 24 hours, caused that the erythema degree of skin generation is lighter, substantially in inadequate visible range.Its stimulus intensity is only a little more than nonirritant, and disappearance in 24 hours.Show that the ligustrazine transdermal patch is extremely light to the stimulation of skin, and can in one day, disappear automatically.
The specific embodiment:
Be that the basis describes the present invention in detail below with embodiments of the invention, but the present invention is not limited thereto.
Embodiment 1:
Storage storehouse prescription (1000 paste):
Ligustrazine phosphate 300g
Hydroxyethyl-cellulose 50g
Sodium hydroxide is an amount of
Ethanol 25ml
Oleum Eucalypti 30ml
Water adds to 1000g
Preparation technology:
Hydroxyethyl-cellulose is added to mixing in the water, place and make abundant swelling, add the ligustrazine phosphate of recipe quantity then, regulate pH7, form gel with 15%NaOH solution.To under agitation slowly join in the above-mentioned gel behind ethanol and the Oleum Eucalypti mixing, continue to be stirred to evenly, promptly finish the preparation in gel storage storehouse.Silicone pressure-sensitive adhesive evenly is coated with exhibition on the EVA film, oven dry, the cooling back covers the polyester protective layer of handling through fluorine carbon.Gel is store the storehouse quantitatively annotate to the EVA release-controlled film, cover backing layer, hot sealing, the die-cut ligustrazine transdermal patch that promptly gets.
Embodiment 2:
Storage storehouse prescription (1000 paste):
Ligustrazine 80g
Carbomer 20g
Triethanolamine is an amount of
Ethanol 100ml
Sweetgum oil 50ml
Water adds to 1000g
Preparation technology:
Carbomer is added to mixing in half the water of recipe quantity, place and make abundant swelling, add the ligustrazine of recipe quantity then, be adjusted to pH7, make the formation gel with triethanolamine.With under agitation slowly joining in the above-mentioned gel behind ethanol and the sweetgum oil mixing, continue to be stirred to evenly, promptly finish the preparation in gel storage storehouse.Silicone pressure-sensitive adhesive evenly is coated with exhibition on the EVA film, oven dry, the cooling back covers the polyester protective layer of handling through fluorine carbon.Gel is store the storehouse quantitatively annotate to the EVA release-controlled film, cover backing layer, hot sealing, the die-cut ligustrazine transdermal patch that promptly gets.
Embodiment 3:
Storage storehouse prescription (1000 paste)
Ligustrazine 200g
Carbomer 20g
Triethanolamine is an amount of
Ethanol 20ml
Menthol 10g
Water adds to 1000g
Preparation technology:
Carbomer is added to mixing in half the water of recipe quantity, place and make abundant swelling, add the ligustrazine of recipe quantity then, be adjusted to pH7, make the formation gel with triethanolamine.With under agitation slowly joining in the above-mentioned gel behind the dissolve with ethanol menthol, continue to be stirred to evenly, promptly finish the preparation in gel storage storehouse.Silicone pressure-sensitive adhesive evenly is coated with exhibition on the EVA film, oven dry, the cooling back covers the polyester protective layer of handling through fluorine carbon.Gel is store the storehouse quantitatively annotate to the EVA release-controlled film, cover backing layer, hot sealing, the die-cut ligustrazine transdermal patch that promptly gets.
Claims (11)
- One kind contain the ligustrazine free alkali transdermal patch, form by backing layer, bin-storing layer, release-controlled film, adhesive layer and protective layer, it is characterized in that wherein bin-storing layer comprises following component and weight percent content,Ligustrazine free alkali 5-60%High polymer adjuvant 0.5-15%Nertralizer 0.2-30%Ethanol 2-35%Transdermal enhancer 1-40%Water surplus %
- 2, according to claim 1 contain the ligustrazine free alkali transdermal patch, it is characterized in that the ligustrazine free alkali in the described storage storehouse is the ligustrazine monomer, or ligustrazine phosphate or ligustrazine hydrochloride are regulated by nertralizer the form with the ligustrazine free alkali are existed.
- 3, the transdermal patch that contains the ligustrazine free alkali according to claim 1 is characterized in that described high polymer adjuvant is carbomer or hydroxyethyl-cellulose.
- 4, the transdermal patch that contains the ligustrazine free alkali according to claim 1 is characterized in that described nertralizer adopts sodium hydroxide or triethanolamine.
- 5, the transdermal patch that contains the ligustrazine free alkali according to claim 1 is characterized in that described transdermal enhancer adopts menthol or sweetgum oil or Oleum Eucalypti.
- 6, the transdermal patch that contains the ligustrazine free alkali according to claim 1 is characterized in that described release-controlled film is the ethylene-vinyl acetate copolymer film.
- 7, the transdermal patch that contains the ligustrazine free alkali according to claim 1 is characterized in that described release-controlled film material ethylene-vinyl acetate copolymer film, and wherein vinyl acetate content is 19-28%.
- 8, the transdermal patch that contains the ligustrazine free alkali according to claim 1 is characterized in that described adhesive layer is a silicone pressure-sensitive adhesive.
- 9, the transdermal patch that contains the ligustrazine free alkali according to claim 1 is characterized in that described backing layer is the composite membrane that polyester-aluminium foil-EVA film is formed.
- 10, the transdermal patch that contains the ligustrazine free alkali according to claim 1 is characterized in that the polyester film that described protective layer is handled through fluorine carbon for the surface.
- 11, claim 1-10 each contain the preparation method of the transdermal patch of ligustrazine free alkali, it is characterized in that may further comprise the steps:(1) bin-storing layer preparation: high polymer adjuvant is added in the entry, placement makes abundant swelling, the ligustrazine or ligustrazine phosphate or the ligustrazine hydrochloride that add recipe quantity, with nertralizer transfer to pH7-8 make form gel after, to under agitation be added in the above-mentioned gel behind ethanol and the transdermal enhancer mixing, be stirred to evenly;(2) adhesive layer preparation: silicone pressure-sensitive adhesive is coated with exhibition on release-controlled film, oven dry, the cooling back covers the polyester protective layer of handling through surperficial fluorine carbon on pressure sensitive adhesive;(3) patch preparation: gel is store the storehouse quantitatively annotate to release-controlled film, cover backing layer, hot sealing, the die-cut ligustrazine transdermal patch that promptly gets.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2003101167649A CN1509717A (en) | 2002-12-24 | 2003-11-21 | Skin penetrating paste containing ligustrazine free alkali and its preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN02157693.9 | 2002-12-24 | ||
| CN 02157693 CN1432363A (en) | 2002-12-24 | 2002-12-24 | Transdermal Ligustrazine plaster and its prepn |
| CNA2003101167649A CN1509717A (en) | 2002-12-24 | 2003-11-21 | Skin penetrating paste containing ligustrazine free alkali and its preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1509717A true CN1509717A (en) | 2004-07-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2003101167649A Pending CN1509717A (en) | 2002-12-24 | 2003-11-21 | Skin penetrating paste containing ligustrazine free alkali and its preparation |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3520783A1 (en) * | 2018-01-30 | 2019-08-07 | Nitto Denko Corporation | Transdermal absorption preparation |
-
2003
- 2003-11-21 CN CNA2003101167649A patent/CN1509717A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3520783A1 (en) * | 2018-01-30 | 2019-08-07 | Nitto Denko Corporation | Transdermal absorption preparation |
| US11253484B2 (en) | 2018-01-30 | 2022-02-22 | Nitto Denko Corporation | Transdermal absorption preparation |
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