CN102178680B - Long-acting and high-content Huperzine plaster and preparation method thereof - Google Patents

Abstract

The invention relates to a Huperzine paster and a preparation method thereof. The Huperzine paster is a flaky transdermal absorption preparation formed by overlapping an adhesive layer, a medicament substrate and a supporting layer, wherein the medicament layer comprises the Huperzine, pharmaceutically acceptable salt, lecithin and paster conventional auxiliary materials; the weight ratio of the lecithin to the Huperzine is 1:(0.4-2.5); the medicament substrate is coated on the adhesive layer and the coating thickness is 0.35 to 0.6 mm; and the pH value of the paster is between 5.0 and 8.0. The Huperzine paster is administrated through a transdermal penetration route, overcomes the defects of the original Huperzine paster, can be absorbed in a human body quickly, has long-term effectiveness and high content, solves the problem of high medicament residual ratio of the common paster, and is used for treating or preventing nerve system diseases such as Parkinson's disease, senile dementia, depression and the like.

Description

A kind of long-acting high-load huperzine A paster and preparation method thereof

(1) technical field: the present invention relates to a kind of external used medicine paster, be specifically related to a kind of huperzine A paster and preparation method thereof.

(2) background technology: at present, whole world alzheimer disease number of the infected is up to 2,000 ten thousand.In the U.S., surpass 4,000,000 people and suffer from this disease, become the fourth-largest killer who is only second to cardiovascular diseases, cancer and apoplexy.Country's " 95 " brainstorm subject group has been accomplished the large sample Epidemiological study that China carries out dementia first in 2002.Investigation finds that China has 8,811 10,000 65 years old and above old men now, and dull-witted number of patients surpasses 6,000,000.A large amount of senile dementia patients brings white elephant for household, society.

In recent years, medical circle is paid attention to the treatment of alzheimer disease day by day, and Drug therapy has had very great development.Cholinesterase inhibitor is acknowledged as topmost treatment alzheimer disease medicine.Huperzine A belongs to the high selectivity cholinesterase inhibitor, has the advantages that to penetrate blood brain barrier.Research proof, the mechanism of action system of huperzine A is through suppressing acetylcholine esterase active in the brain, improves levels of acetylcholine and plays a role.Its significant advantage is that cerebral cortex relevant with memory and the inhibition acetylcholine esterase effect of Hippocampus obviously are better than other brain district; Persistent period was 6 hours; And can obviously promote the cholinergic transmission at neuromuscular junction place, its action intensity is greater than similar medicine.Huperzine A all has tangible effect to improving person in middle and old age's hypomnesis and patients with Alzheimer disease memory ability and cognitive competence, is the most effectively one of medicine of current treatment degenerative brain disorder.Simultaneously, huperzine A also has better effects to improving adolescence student memory and school grade.

Because alzheimer disease needs long-term prescription; And according to patient's own characteristic; Forget the clothes or the thing that misses even take medicine more through regular meeting, thus the untoward reaction that causes the uncontrollable or long-term drug overdose of the state of an illness to cause, and therefore novel huperzine A paster very is fit to this type patient's medication.

The correlational study of domestic existing huperzine A paster discloses a kind of huperzine A percutaneous absorption patch like Chinese patent CN95111588, and it shows good when the animal Transdermal absorption is tested behind transdermal test in vitro absorption and QUMAO; But can't reach re-set target in the actual human body test, infiltration rate is slower, and is long to peak time; Not high because of drug loading simultaneously; Its drug effect was only kept 3-4 days, showed that to using the back to pass through the detection of sheet paster the remaining rate of medicine is high; Drug waste is bigger, also causes using dosage inaccurate simultaneously.

(3) summary of the invention: task of the present invention is the defective that overcomes existing huperzine A paster; Provide a kind of at human body fast Absorption, long-acting, high-load huperzine A paster and preparation method thereof, this paster has solved the high problem of the remaining rate of medicine of common paster simultaneously.

One of task of the present invention provides a kind of to human body safety, fast Absorption, long-acting, high-load huperzine A paster; Form by adhesion coating, drug matrices and supporting layer; Drug matrices is coated on the adhesion coating; It is characterized in that: medicine layer comprises huperzine A and pharmaceutically acceptable salt, lecithin and conventional adjuvant, and wherein the part by weight of lecithin and huperzine A is 1: 0.4-2.5.

The pH value of paster of the present invention is controlled between the 5.0-8.0.

Preferred dose is that every square centimeter contains huperzine A 0.1-1.0mg in the huperzine A paster of the present invention's preparation.

The present invention also provides a kind of method for preparing of huperzine A paster, comprises the preparation drug matrices, is applied to drug matrices on the adhesion coating, and drying is covered with supporting layer, and step is following:

(1) gets recipe quantity lecithin, huperzine A mix homogeneously;

(2) alcoholic solution of adding an amount of 80% in mixture is regulated pH value to 1.0-3.0 with hydrochloric acid, and vibration is dissolved mixture fully, obtains lysate;

(3) in above-mentioned lysate, add the conventional adjuvant of paster, regulate pH value to 5.0-8.0 with buffer; Wherein buffer is selected from a kind of in the phosphate buffer, Borax-calcium chloride buffer, ammonia-chloride buffer solution of pH value 7.0-8.5;

(4) with the above-mentioned solution that regulates; Be dried to relative density on the following vibration of 85 ℃ conditions limit and be 1.10～1.15 thick liquid, promptly drug matrices is applied to drug matrices on the adhesion coating of paster then; Thickness is between the 0.35-0.6 millimeter; Drying is covered with supporting layer, after shearing, obtains the huperzine A paster.

Huperzine A is a kind of alkaloid, and itself has alkalescence, but because huperzine A dissolubility in water is very little; Need in acid solution, dissolve; And the paster that low pH value is processed not only has stimulation to human body skin, and can cause infiltration rate to slow down, and absorbtivity reduces.

Huperzine A belongs to liposoluble substance, high spot reviews of the present invention liposoluble substance influence that the medicine percutaneous is passed through, screening obtains making huperzine A to produce the lecithin of better transdermal penetration; Optimizing prescriptions, huperzine A is found through human trial with after lecithin fully mixes; Its skin absorbs speed is obviously accelerated, and its metabolism time lengthening in vivo is more suitable for the long-acting treatment in paster simultaneously; Solve the high problem of the remaining rate of medicine of common paster simultaneously, obtained remarkable result.

This paster is used for treatment or prevention nervous system disease, like parkinson disease, senile dementia, depression etc.

(4) description of drawings:

Fig. 1 Fig. 1 is two kinds of different huperzine A paster human bioavailability comparison diagrams in the embodiment of the invention 7, and two kinds of different huperzine A pasters are respectively by the huperzine A paster ofCN95111588 embodiment 1 preparation and the huperzine A paster for preparing through the embodiment of theinvention 1.

(5) specific embodiment: following embodiment is used to further specify and describe the present invention, but and does not mean that the present invention only limits to this.

Embodiment 1: the preparation ofhuperzine A paster 1

Prescription:

Method for preparing comprises the preparation drug matrices, is applied to drug matrices on the adhesion coating, and drying is covered with supporting layer, shears, and obtains the huperzine A paster, and step is following:

I, take by weighing recipe quantity huperzine A and lecithin, mix homogeneously;

II, in mixture, add an amount of 80% alcoholic solution, regulate pH value to the 1.0-3.0 with hydrochloric acid, vibration is dissolved mixture fully;

III, in above-mentioned lysate, add adjuvant: polyacrylate (national of the United States's starch company; The 387-2287 type) 170g; Laurocapram 4g, lauric acid 7g, propylene glycol 17g; And regulate pH value to 5.0-8.0 with the ammonia of pH8.5-chloride buffer solution, also can adopt the buffer of other pH value 7.0-8.5 to regulate pH value;

IV, with the above-mentioned solution that regulates; (85 ℃ of water-baths; Prompt experimental apparatus Manufacturing Co., Ltd in HH-S2 thermostatic type Changzhou) be dried to relative density in while vibrating and be 1.10～1.15 thick liquid, promptly drug matrices is used automatic coating machine (the triumphant company of the Shanghai iron of fine quality then; The TB-04 type) above-mentioned drug matrices is coated on the adhesion coating (siliconised paper), coating thickness is 0.5 millimeter;

V, 60 ℃ of oven dry were covered with supporting layer after 5 minutes, and are promptly transferable, again that paster is die-cut or cut into last thin slice, obtainhuperzine A paster 1, and recording huperzine A content is every square centimeter of 300 μ g.

Embodiment 2: the preparation of huperzine A paster 2

Prescription:

Method for preparing is withembodiment 1, and the coating thickness of huperzine A paster 2 is 0.6 millimeter, and recording huperzine A content in the product is every square centimeter of 900 μ g.

Embodiment 3: the preparation of huperzine A paster 3

Prescription:

Method for preparing is withembodiment 1, and the coating thickness of huperzine A paster 3 is 0.35 millimeter, and recording huperzine A content in the product is every square centimeter of 100 μ g.

Embodiment 4: the preparation of huperzine A paster 4

Prescription:

Method for preparing is withembodiment 1, and the coating thickness of huperzine A paster 4 is 0.45 millimeter, and recording huperzine A content in the product is every square centimeter of 350 μ g.

Embodiment 5: animal pharmacokinetics is measured

I, instrument: Shimadzu LC-10A high performance liquid chromatograph, SPD-10A UV-detector, C-R6A data process machine.Shim-Pack CLC-ODS post (6.0X150mm)

II, method

A, QUMAO: in the domesticated dog back with depilatory (6%Na₂SO₃) take off the skin of two 4X6CM2 sizes, and clean up with clear water;

B, paster: paste the huperzine A paster in domesticated dog depilation place, and behind 120h, take off paster;

C, get blood: after medication, got domesticated dog femoral vein blood in 2,4,6,8,10,24,32,48,56,72,84,96,108,120,132,148,150 hours;

D, detection:, detect huperzine content in the blood with the high performance liquid chromatograph ultraviolet absorption method with the U.S. hot internal standard method of diindyl diindyl.

III, result

Prepare the huperzine A paster byCN95111588 embodiment 1 respectively with the embodiment of theinvention 1, be affixed on domesticated dog QUMAO place, wherein contained huperzine A total content is 4mg in the paster, and the medicine of respectively accomplishing 6 domesticated dogs is for mensuration, average result such as following table:

IV, analysis

With the huperzine A paster contrast of CN95111588 preparation, huperzine A paster peak time on domesticated dog of the present invention's preparation is faster, and the EDD prolongation, and drug release is more mild.

Embodiment 6: the healthy human body tolerance test

A, Test Example number: according to " chemicals CLINICAL PHARMACOKINETIS STUDY ON technological guidance principle " (second original text) of national drug food Surveillance Authority announcement in 2004; The huperzine A paster is taked dosage escalation regimens; Designing maximum dosage is 12mg/ people/day, and the single-dose tolerance test is totally 28 people.

B, medication: external.Be affixed on clean dry, not damaged chest (under the clavicle) skin immediately after removing the protective layer on the paster.

C, untoward reaction are observed: mainly observe uncomfortable main suit, the medication local response is often seen biochemical indicator.

D, result:

According to the standard that work out at Ministry of Public Health adverse drug reaction supervision center, assessment is made in the association that possibly exist between adverse events and the test medication by " certainly, probably, possible, suspicious, impossible " Pyatyi classification method.The huperzine A paster of the embodiment of theinvention 1 preparation; Through 28 experimenters test; In human tolerance test, find to reach the adverse events of above rank (comprise certainly, probably, maybe), explain that huperzine A paster prepared in accordance with the present invention safety is good with these article.

Embodiment 7: the test of healthy human body single pharmacokinetics

Carried out the pharmacokinetics test according to " chemical drugs CLINICAL PHARMACOKINETIS STUDY ON guideline ".

A, administering mode

Huperzine A paster (containing huperzine A 10mg) is affixed on clean dry, not damaged skin of chest (under the clavicle) to the 8th day morning and takes off.

B, sampled point

Adopted experimenter's blood sample in 8,16,24,32,40,48,60,72,84,96,108,120,132,144,156,168,192,216,240 hours before the administration with after the administration.

C, assay method: LC-MS-MS (liquid phase tandem mass spectrum, tinidazole internal standard method)

Reagent:

Huperzine A reference substance: provide by Nat'l Pharmaceutical & Biological Products Control Institute;

Tinidazole reference substance: provide by Nat'l Pharmaceutical & Biological Products Control Institute;

Methanol: chromatographically pure, Merck Company;

Acetonitrile: chromatographically pure, Merck Company;

Formic acid: chromatographically pure, Tedia Company Inc..

Instrument:

Prunus mume (sieb.) sieb.et zucc. Teller-Tuo benefit AE240 electronic balance (Shanghai Mettler-Toledo, Inc.);

API4000LC/MS/MS combined instrument (u.s.a. applied biosystem company), chromatographic work station: Analyst 1.4.2;

Prunus mume (sieb.) sieb.et zucc. Teller-Tuo benefit Delta320A/CPH counts (Shanghai Mettler-Toledo, Inc.);

Biofuge PrimoR high-speed refrigerated centrifuge (German Heraeus company);

Millipore Drict-Q5 ultrapure water machine (French Millipore company).

D, result

With LC-MS-MS (liquid phase tandem mass spectrum, tinidazole internal standard method) assay determination according to the human bioavailability of the human bioavailability of the huperzine A paster ofCN95111588 embodiment 1 preparation and the huperzine A paster through the embodiment of theinvention 1 preparation.The result sees the following form:

Fig. 1 is seen in contrast more intuitively.

Above-mentioned data show; In the human body experimenter, the huperzine A paster that the huperzine A paster drug releasing rate of the present invention's preparation obviously prepares faster than CN95111588, and also peak time is also faster; Drug level with hold time more lasting; Slow release effect is more obvious, in the medication concentration of can both remaining valid in the process in 7 days, is more suitable for long-time application.

Embodiment 8: paster medicine residue detection

Huperzine A paster to after embodiment 6 uses carries out the medicine residue detection; The result is respectively 3.23mg and 3.11mg by the last medicine remnants of huperzine A paster of CN95111588 preparation, and is respectively 1.87mg and 1.45mg by the last medicine remnants of huperzine A paster of the present invention's preparation.Explain that the huperzine A paster through the present invention's preparation sees through human body skin, drug utilization Du Genggao more easily.

Claims (3)

1. huperzine A paster; Form by adhesion coating, drug matrices and supporting layer; Drug matrices is coated on the adhesion coating; It is characterized in that: drug matrices comprises huperzine A and pharmaceutically acceptable salt, lecithin and conventional paster adjuvant, and the part by weight of lecithin and huperzine A is 1: 0.4-2.5; Earlier with huperzine A and lecithin mix homogeneously, its step was following when drug matrices prepared: (1) will write out a prescription lecithin, huperzine A mix homogeneously; (2) alcoholic solution of adding an amount of 80% in mixture is regulated pH value to 1.0-3.0 with hydrochloric acid, and vibration is dissolved mixture fully, obtains lysate; (3) in above-mentioned lysate, add conventional paster adjuvant, regulate pH value to 5.0-8.0 with buffer; (4) with the above-mentioned solution that regulates, be dried to relative density on the following vibration of 85 ℃ conditions limit and be 1.10 ~ 1.15 thick liquid, promptly drug matrices is applied to drug matrices on the adhesion coating of paster, and thickness is the 0.35-0.6 millimeter, is covered with supporting layer.

2. huperzine A paster according to claim 1 is characterized in that every square centimeter contains the 0.1-1mg huperzine A in the said paster.

3. huperzine A paster according to claim 1 is characterized in that described buffer is a kind of in phosphate buffer, Borax-calcium chloride buffer, the ammonia-chloride buffer solution.

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