CN108653290A - Application of the huperzine in preparing the percutaneous drug administration preparation for treating or preventing epileptics - Google Patents
Application of the huperzine in preparing the percutaneous drug administration preparation for treating or preventing epileptics Download PDFInfo
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- CN108653290A CN108653290A CN201810863752.9A CN201810863752A CN108653290A CN 108653290 A CN108653290 A CN 108653290A CN 201810863752 A CN201810863752 A CN 201810863752A CN 108653290 A CN108653290 A CN 108653290A
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- huperzine
- drug administration
- administration preparation
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- epileptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Abstract
The invention discloses a kind of application of huperzine in preparing the percutaneous drug administration preparation for treating or preventing epileptics.With huperzine or its medically acceptable various salt etc. for main component, daily huperzine is entered by design flow through skin internal the percutaneous drug administration preparation.After first administration, in 12 hours, huperzine blood plasma is no more than 0.1 0.3ng/ml, mean blood plasma concentration ranging from 0.3 5.0ng/ml, and at least maintains 3 days.Huperzine shows good anti-epileptic drug effect in the zebra fish epilepsy model that pentylenetetrazole (PTZ) induces.When being prevented for epileptics due to the percutaneous drug administration preparation of the present invention, huperzine blood plasma is steady, controllable, therefore, can effectively avoid because instant blood concentration rise it is too fast, excessively high due to induces the possibility that the patient had an epileptic fit, it is safe to use effective.
Description
Technical field
The present invention relates to huperzine percutaneous drug administration preparation technical fields, and in particular to a kind of huperzine is treated preparing
Or the application in the percutaneous drug administration preparation of prevention epileptics.
Background technology
Epilepsy (epilepsy) is chronic one kind caused by cerebral neuron paradoxical discharge, repeated relapsing, transience brain
Nervous system syndrome caused by dysfunction.
There are about 50,000,000 people to suffer from epilepsy, about kainogenesis 2,000,000 every year, at present in the hair of developing country in the whole world
Sick rate will be far above developed country, and about 70%~90% epileptic does not obtain appropriate treatment.Serious
In chronic active Patients with Epilepsy, the danger annual up to 1% of epilepsy sudden death.It is reported that there are 4000 people's epilepsies in European Union every year
Sudden death.
It is shown according to Chinese cri dernier cri disease data, the epileptic of China about 9,000,000 or so, wherein 500~600
Ten thousand be movable Patients with Epilepsy, while newly increasing epileptic about 400,000 every year, and it is only secondary to have become neurology department in Chinese epilepsy
In the second largest common disease of headache.
Due to the difference at the starting position and transfer mode of paradoxical discharge, the complicated clinical manifestation of epileptic attack is various, can
Show as the dysfunctions such as movement, feeling, autonomic nerve, consciousness and spirit.Cause the cause of disease of epilepsy also varied.
Currently, epileptic passes through regular Antiepileptic Drugs, its breaking-out of about 70% patient is can be controlled
System, but still there is about 30% patient to be unable to control because of drug resistance.The out of contior epileptic of drug is adopted mostly now
Operative treatment is taken, but the patient of operation is suitble to only to account for wherein very little part.Therefore, finding safely effectively antiepileptic is
One of the hot spot of current new drug research both at home and abroad.
Huperzine is Chinese pharmaceutical science man in last century the eighties from medicinal Pteridophytes " feet added to a snake by an ignorant artist grass " Huperzia
The novel chemical substance for having the effect of significantly inhibiting to acetylcholinesterase out is excavated in serrate (Thunb.) Trevis..
Now, huperzine (Huperzine A) has been researched and developed into China for treating old benign memory deficits, improving by intracerebral courage
Alzheimer's disease patient's memory dysfunction caused by alkali energy functional defect, and alleviate the new of the diseases such as myasthenia gravis
Medicine.
Huperzine A have new indication to find again recently other than having the purposes such as the old benign memory deficits for the treatment of：
The scientist of medical college of Emory University of the U.S. has found that Huperzine A have enhancing small in the screening of antiepileptic animal model
Epiletic model induces the effect of epileptic attack resistance.In particular, showing the potentiality for preventing fever seizure, this is
Dravet syndromes (a kind of serious childhood epilepsy) feature (Expert Review of Neurotherapeutics,
2016,16 (6):1-10).
Huperzine A act on machine to the mechanism of epileptics with the inhibition cholinesterase for being originally intended to old benign memory deficits
Reason is different.American scientist is found：Huperzine A act on 4 β 2nAChRs receptors of α 7nAChRs and α, and generating one kind has by force
The anti-inflammatory response of power, and IL-1 β are reduced, TNF-α protein expression and inhibition transcriptional activation NF- κ B signals, therefore, it is provided
Protection to neuronal excitability toxicity and neuronal death, and increase and the relevant gamma amino butyric acid energy of anticonvulsion activity
Neurotransmitter transmission.
Scientist also found that Huperzine A can make the neuron of SCN1A mutation patients inhibit the balance between excitement
Normalization, to prevent the generation of epilepsy.(Frontiers in Pharmacology, 2016,7：357).
Since the Huperzine A mechanism for preventing epileptics treats the Alzheimers of old benign memory deficits with it
Disease is different, therefore its dosage is also different from effective blood drug concentration, and requires very harsh.
Zebra fish is considered as at home and abroad one of the useful model for studying epileptics, its SCN1A and the mankind
SCN1A genetic homologies are up to 85%, and signal transduction pathway is substantially approximate with the mankind.U.S. Scott Baraban teach and
Colleagues have carried out primary screening to the compound in the drug data library of " U.S. Food and Drug Administration " (FDA) approval, send out
Existing compound Clemizole inhibits in the zebra fish that the SCN1A for carrying similar childhood epilepsy " Dravet syndromes " is mutated
Spontaneous spasm behavior and electroencephalogram epileptic attack.Due to the SCN1A of zebra fish and the SCN1A overwhelming majority function of the mankind and spy
Levy identical, therefore, zebra fish has been widely used in the research of antiepileptic new drug.(Nat Commun.2013Sep
3)
We have found in the experiment of zebra fish epilepsy model, and in certain dosage range, Huperzine A can be generated
Very strong antiepileptic efficacy, antiepileptic action higher than clinically common dilantin sodium (see
Embodiment 1).
Since Huperzine A pieces are found in the clinical test for the treatment of children's language retardation, there are a small number of merging insane
The infant of epilepsy is due to inducing epileptic attack the case where stopped treatment.For this purpose, State Food and Drug Administration's approval
Epileptic is classified as taboo (Journal of in Huperzine A tablets (" double benefits are flat " piece) specification book
Pediatric Pharmacy 2002,8 (1)：27).
Inherent cause plays an important role in the morbidity of epilepsy.Encode the SCN1A bases of I type Voltage-gated sodium channels
Because being considered as the main gene of curing the disease of epilepsy.The different types of mutation of SCN1A genes can cause different epilepsy syndromes.
In recent years, we have finally found Huperzine A and induce part by the research of SCN1A Gene Mutated Zebrafishs
The reason of epileptic patient epileptic attack is：Since Huperzine A are too fast, excessively high into internal instant blood concentration rising,
Excessive acetylcholine is caused to break caused by the balance between the neuron inhibition and excitement of SCN1A mutation patients (see implementing
Example 2).
For this purpose, to realize targets of the Huperzine A for epileptics prevention, it is necessary to solve stringent control drug and enter people
The rate of body blood and the key technology of dose, by blood concentration control in a both safe and effective range.The present invention
Percutaneous drug administration preparation can meet this clinical needs.When medication, huperzine blood plasma is steady, controllable, can effectively avoid i.e.
When blood concentration rise possibility that is too fast, excessively high and inducing epilepsy, safely and effectively.
So far there are no is useful for preventing the report of the Huperzine A percutaneous drug administration preparations of epileptics.
Invention content
In view of prevention epilepsy medicament preparation particular/special requirement, the present invention provides a kind of huperzine prepare treatment or
Prevent the application in the percutaneous drug administration preparation of epileptics, when which prevents for epileptics, huperzine blood medicine
Concentration is steady, controllable.
A kind of application of huperzine in preparing the percutaneous drug administration preparation for treating or preventing epileptics, it is described percutaneous to give
Medicine preparation be with huperzine or its medically acceptable various salt, analog, derivative, pro-drug and they
Mixture is the percutaneous drug administration preparation that epileptics is treated or prevented made of main component.There is the huperzine of design flow saturating daily
Skin is crossed to enter in vivo.After its first administration, in 1-2 hours, huperzine blood plasma is no more than 0.1-0.3ng/ml, average blood
Concentration ranging from 0.3-5.0ng/ml, and at least maintain 3 days, it is safe to use effective.Said preparation can accurately control huperzine
Skin permeation makes huperzine blood plasma control the safe range prevented in epileptics, avoids because in instant blood concentration
Possibility that is too fast, excessively high and inducing epilepsy is risen, it is safe to use effective.
Huperzine containing sufficient amount makes to reach internal blood concentration in 0.3-5.0ng/ml ranges through skin, and
At least maintain effective blood drug concentration 3 days；
The percutaneous drug administration preparation, after first administration, in 1-2 hours, huperzine blood plasma is no more than 0.1-
0.3ng/ml。
The percutaneous drug administration preparation, the huperzine mean blood plasma concentration ranging from 0.3-5.0ng/ after first administration
Ml, and at least maintain 3 days.
The percutaneous drug administration preparation, wherein the huperzine can be huperzine and its medically acceptable
Various salt, analog, derivative, pro-drug.
The percutaneous drug administration preparation, wherein the preparation is the preparation that local application generates general action.
The percutaneous drug administration preparation is polymer release-control type percutaneous dosing paster, and the present invention uses ethylene-vinyl acetate
Copolymer (EVA) is used as polymer release-control material.
The percutaneous drug administration preparation, wherein the preparation is adhesive polymer matrix type control release paster, ethylene-
Acetate ethylene copolymer (EVA) is used as polymer release-control material, and polyacrylate is adhesive.
The percutaneous drug administration preparation is made of the raw material of following parts by weight：
Further preferably, the percutaneous drug administration preparation is made of the raw material of following parts by weight：
Most preferably, the percutaneous drug administration preparation is made of the raw material of following parts by weight：
A kind of preparation method of percutaneous drug administration preparation, includes the following steps：
Huperzine is weighed, is dissolved with ethyl alcohol, penetration enhancer is added, is uniformly mixed；It is separately that ethylene-vinyl acetate is total
Polymers and polyacrylate are dissolved with ethyl acetate；The two is uniformly mixed, vacuum outgas, backing is uniformly layered on after cleared bubble
On layer, most of organic solvent is flung at 10 DEG C~40 DEG C, is dried in baking oven, takes out cooling, adherent layer is covered, with segment machine-cut
It cuts to obtain percutaneous dosing paster.
Dry condition is in the baking oven：Dry 1h~3h is placed in 60 DEG C~90 DEG C baking ovens further preferably to set
The dry 2h in 80 DEG C of baking ovens.
Taking-up is cooled to 10 DEG C~40 DEG C.
Ethylene-the acetate ethylene copolymer (Ethylene/vinyl acetate) is controlled release matrix, wherein acetic acid
Ethylene (vinyl acetate) content range is 3.5% -50% (average weight), and optimum content range is 15% -45%,
Further preferably 30% -45%.
Polyacrylate (average molecular weight 17749, solid content 30%) is adhesive.
The penetration enhancer is isopropyl myristate (IPM), dimethyl sulfoxide (DMSO) (DMSO), lauryl alcohol (LA), oil
Sour (OA), Laurocapram (AZ), capric acid (CA) or decyl alcohol (DeA).
The percutaneous drug administration preparation, it is other be with huperzine and its medically acceptable various salt, analog,
The percutaneous drug administration preparation of epileptics is treated or prevented made of derivative, pro-drug and their mixture.It gives for the first time
After medicine, in 1-2 hours, huperzine blood plasma is no more than 0.1-0.3ng/ml, Mean steady state concentration of blood drug ranging from 0.3-
5.0ng/ml, and at least maintain 3 days.
When the percutaneous drug administration preparation of the present invention is prevented for epileptics, huperzine blood plasma is steady, controllable, therefore, energy
Effectively avoid because instant blood concentration rise it is too fast, excessively high due to induces the possibility that the patient had an epileptic fit, it is safe to use effective.
Description of the drawings
Fig. 1 is that Hup A antiepileptic actions evaluate zebra fish movement locus figure in embodiment 1；
Fig. 2 is the quick move distance of zebra fish (mm) figure compared with model control group after Hup A processing in embodiment 1；
Fig. 3 is zebra fish antiepileptic action figure compared with model control group after Hup A processing in embodiment 1；
Fig. 4 is the peak valley curve (n of Hup-A percutaneous drug administration preparations and Hup-A oral tablet multiple dose administrations in embodiment 5
=6), ■ is the peak valley curve of Hup-A percutaneous drug administration preparations (Multiple dose patches), ▲ it is Hup-A oral tablets
The peak valley curve of multiple dose administration (Multipile dose oral tablets).
Specific implementation mode
The present invention is further illustrated in embodiment given below, but the embodiment of the present invention is only used for illustrating this hair
It is bright, rather than limiting the invention, so, any simple modifications of the present invention are belonged under the premise of the method for the present invention
The scope of protection of present invention.
Embodiment 1 (antiepileptic action of Huperzine A)
1 test method：
210 tail after fertilization, 6 days wild type AB system zebra fish are randomly selected in 96 orifice plates, 1 tail zebra is handled per hole
Fish, 12 holes/group.It is water-soluble respectively to give Hup A 6.9,20.8,62.5 and 100 μM of concentration, 300 μM of positive control drug dilantin sodium
Concentration is 200 μ L per pore capacities, while Normal group (the normal zebra fish of fish culture water processing) and model control group is arranged.
After each group handles 1h, in addition to Normal group, the water-soluble pentylenetetrazole of giving of remaining experimental group induces zebra fish to establish epilepsy model,
The motion conditions of zebra fish in pentylenetetrazole 1h are given using movement/behavioural analysis instrument record.The quick fortune of analysis statistics zebra fish
Dynamic (seizure, V>20mm/s) distance (D), with the results of statistical analysis evaluation Hup A of the quick move distance of zebra fish
The antiepileptic action for the epilepsy model zebra fish that (Huperzine A, huperzine) induces pentylenetetrazole, statistical procedures result
It is indicated with mean ± SE.
With variance analysis and Dunnett ' s T- inspection carries out statistical analysis, p<0.05 shows with significant difference.
2 test results
For test result as shown in table 1, Fig. 1, Fig. 2 and Fig. 3, Fig. 1 is that Hup A antiepileptic actions evaluate zebra in embodiment 1
Fish movement trajectory diagram；Fig. 2 is the quick move distance of zebra fish (mm) after Hup A processing in embodiment 1 compared with model control group
Figure,***p<0.001；Fig. 3 is zebra fish antiepileptic action figure compared with model control group after Hup A processing in embodiment 1,***p<
0.001。
The 2.1 quick move distances of model control group zebra fish (1871mm) p compared with Normal group (27mm)<0.001,
Show model foundation success.
2.2 300 μM of the positive control drug dilantin sodium quick move distances of concentration group zebra fish (689mm) and model control group
Compare p<0.001, antiepileptic action 63.2% prompts dilantin sodium to have apparent antiepileptic action.
2.3 20.8 μM of Hup A, 62.5 μM and 100 μM of quick move distances of concentration group zebra fish are respectively 872,133 and
5mm, the p compared with model control group<0.001, antiepileptic action is divided into 53.4%, 92.9% and 99.7%.Prompt Hup A exist
20.8, apparent antiepileptic action is all had under 62.5 and 100 μM of concentration conditions.Refer to table 1, Fig. 1, Fig. 2 and Fig. 3.
Qualitative evaluation is carried out to the anti-epileptic therapeutic effect of compound according to the method in embodiment 1.It is respectively administered in Hup A
Under dosage compared with epilepsy model group, the quick movement locus of zebra fish significantly reduces.Fig. 1 is according to the quick move distance of zebra fish
The column diagram that average value mean ± SE is drawn, as shown in Figure 1, Hup A have insane under 20.8 μM, 62.5 μM and 100 μM concentration
Epilepsy therapeutic effect relatively has significant difference (P with model control group<0.001), therapeutic efficiency is respectively：19.1%,
53.4%, 92.9%, 99.7% (P<0.001).
Table 1.Hup A antiepileptic action evaluation experimental results (mean ± SE, n=10)
Compared with model control group,***p<0.001
3 conclusion (of pressure testing)s
Huperzine A are in 20.8,62.5 and 100 μM of concentration, to zebra fish epileptic attack (quick move distance>
Resistance 20mm/s), dose-effect relationship is clear, prompts, and Huperzine A have apparent antiepileptic action.
Embodiment 2
Researchs of the Huperzine A to SCN1A Gene Mutated Zebrafishs
1 test method：
The Behavioral change of 1.1 electro photoluminescence zebra fish
CN1A Gene Mutated Zebrafishs 60 are randomly divided into 5 groups (n=10).Control group gives the stimulation of 0 electric current puppet, remaining 4
Group gives electric current 25,50,100,1000 μ A respectively, after stimulating 1s, observes the reaction of zebra fish.
Effects of the 1.2 Hup A to zebra fish electric stimulus inducing epilepsy model
150 tail SCN1A Gene Mutated Zebrafishs are randomly selected in 96 orifice plates, 1 tail zebra fish is handled per hole, 12 holes/
Group.It is water-soluble respectively to give μM concentration of Hup A 20.8,62.5,100,130 and 160, it is 200 μ L per pore capacities, while mould is set
Type control group.After zebra fish each group drug-treated 1h, electric current stimulation appropriate is given, after stimulating 1s, by following index observing spot
Horse fish Behavioral change：1. frightened reaction of jerking：Before alter, jump, whipping or rapidly circle round.2. reaction of fainting from fear：Whole body is straight and upright, motionless；After
And turn on one's side, stupor or dead.
1.3 statistical method
For statistical analysis using SPSS19.0 softwares, group difference, P are compared in Chi-square Test<0.05 has significantly for difference
Property meaning.
2 test results
The Behavioral change of 2.1 electro photoluminescence zebra fish
After giving 25,50,100 μ A stimulations 1s of electric current, zebra fish performance：Before alter, jump, whipping or convolution characteristic reaction row
For (frightened reaction of jerking)；After 1000 μ A stimulations of electric current, zebra fish performance：Whole body is straight and upright, motionless；Then it turns on one's side, stupor or dead
It dies (reaction of fainting from fear).
Animal model control group gives 25 μ A electric currents stimulation zebra fish, and 50% zebra fish alters, jumps before occurring, whipping or returns
The frightened reaction of jerking of rotation；50,100 μ A electric currents alter, jump before stimulating zebra fish, 100% zebra fish to occur, whipping or convolution it is frightened jerk it is anti-
It answers；1000 μ A electro photoluminescence zebra fish, it is straight and upright motionless that whole body occurs in zebra fish, and then 4 rollover and dead occur, remaining 6
Restore successively after 2min normal.The result shows that after giving 25 μ A stimulations 1s of electric current, part SCN1A gene mutations can be caused
Zebra fish tic reaction model；After giving electric current 50,100 μ A stimulations 1s, all SCN1A Gene Mutated Zebrafishs can be caused to send out
Raw tic reaction；After giving 1000 μ A stimulations of electric current, SCN1A Gene Mutated Zebrafish convulsions reaction models can be caused.Experiment
The results detailed in Table 2.
2 electric stimulus inducing SCN1A Gene Mutated Zebrafishs Behavioral change (mean ± SE, n=10) of table
Effects of the 2.2 Hup A to zebra fish model
150 tail SCN1A Gene Mutated Zebrafishs are randomly selected in 96 orifice plates, 1 tail zebra fish is handled per hole, 12 holes/
Group.It is water-soluble respectively to give μM concentration of Hup A 20.8,62.5,100,130 and 160, it is 200 μ L per pore capacities, while mould is set
Type control group.After zebra fish each group drug-treated 1h, give electric current 25 μ A stimulations, after stimulating 1s, by following index observing zebra
Fish Behavioral change：1. frightened reaction of jerking：Before alter, jump, whipping or rapidly circle round.2. reaction of fainting from fear：Whole body is straight and upright, motionless；Then
It turns on one's side, stupor or dead.Experimental result refers to table 3.
Effects (mean ± SE, n=10) of the 3 Hup A of table to zebra fish model
3 conclusion (of pressure testing)s
Huperzine A can provide epilepsy in 20.8,62.5 and 100 μM of concentration to SCN1A Gene Mutated Zebrafishs
Breaking-out protection, dose-effect relationship is clear, prompts, and Huperzine A, which have, significantly prevents epilepsy effect.
Huperzine A are in 130 and 160 μM of concentration, the protective effect to SCN1A Gene Mutated Zebrafish epileptic attacks
Switching to induce SCN1A Gene Mutated Zebrafishs generation twitch and reaction of fainting from fear, there is a certain amount to imitate relationship, test result prompts,
Huperzine A can induce epilepsy at high concentrations.Its possible reason is analyzed, since Hup A are the suppressions of invertibity cholinesterase
Preparation may lead to excessive acetyl if Huperzine A are too fast, excessively high into internal instant blood concentration rising
Choline destroys the balance between the neuron inhibition and excitement of SCN1A mutation patients, to induce epilepsy.
Embodiment 3
Huperzine A 20mg are weighed, are placed in beaker, are dissolved with 2.5g ethyl alcohol, addition 0.27g penetration enhancers (see
Table 4), it is uniformly mixed；Separately weigh 3g ethylene-acetate ethylene copolymer (Dupont, 40W, VA content=40%), 1g poly- third
Olefin(e) acid ester (national of the United States's starch chemical company, Duro-Tak 87-4098, average molecular weight 17749, solid content 30%) is used
8.5g ethyl acetate dissolves；The two is uniformly mixed, vacuum outgas, back sheet (Minnesota Mining and Manufacturing Company is uniformly layered on after cleared bubble
Polyester aluminum-plastic composite membrane) on, fling to most of organic solvent at 25 DEG C of room temperature, be placed in re-dry 2h in 80 DEG C of baking ovens, take out
It is cooled to 25 DEG C of room temperature, covers adherent layer, cuts to get adhesive polymer framework controlled release type percutaneous dosing paster.
Drug release rate test method：
It is tested using Valia-Chien two-chamber osmotics pond, is sticked in nude mice skin stratum corneum side and throw off adherent layer
Patch, receiving chamber add 40%PEG400/NS, circulator bath temperature to be 37 DEG C ± 0.5 DEG C, and time sampling, is used at regular intervals
HPLC methods measure the Hup-A concentration in receiving chamber's penetrating fluid.
HPLC analysis methods：Instrument：Shimadzu HPLC-10A, chromatographic column：Shim-Pack CLC-DOS(6.0×150mm).
Detection wavelength 313nm, mobile phase：Methanol：Water (55：45), per 500ml water in be added 40 μ l triethylamines, flow velocity 1ml/min, into
20 μ l of sample amount measure peak area after sample introduction, with quantified by external standard method, calculate the skin permeation amount of Hup-A.
This law range of linearity：0.70-22.3 μ g/ml, related coefficient：0.9999；The rate of recovery：98.0 ± 2.0%, variation lines
Number：2.04%, Hup-A keep stablizing for 96 hours in acceptable solution.
The nude mice skin infiltration rate of different embodiments is provided below, the results are shown in Table 4.
HupA nude mice skin infiltration rates under the conditions of the different penetration enhancers of table 4a
a:IPM (isopropyl myristate)；DMSO (dimethyl sulfoxide (DMSO))；LA (lauryl alcohol)；OA (oleic acid)；AZ (bay nitrogen
Tall and erect ketone)；CA (capric acid)；DeA (decyl alcohol).
Embodiment 4
Provide a kind of ethylene-acetate ethylene copolymer (EVA) framework controlled release type percutaneous drug administration preparation.The release of drug
Speed is by copolymer composition control.By adjusting vinyl acetate (VAc) content in ethylene-acetate ethylene copolymer (EVA),
The percutaneous drug administration preparation of different rates of release can be obtained.
Experimental method is used as penetration enhancer with embodiment 3, also, using IPM (isopropyl myristate), the results are shown in Table
5。
Influence of vinyl acetate (VAc) content to HupA infiltration rates in 5 ethylene of table-acetate ethylene copolymer (EVA)a
aUsing nude mice skin, tested in Valia-Chien two-chamber osmotics pond.
Embodiment 5
Huperzine A 20mg are weighed, are placed in beaker, are dissolved with 2.5g ethyl alcohol, 0.27g penetration enhancer (meat is added
Isopropyl myristate), it is uniformly mixed；It is another weigh 3g ethylene-acetate ethylene copolymer (Dupont, 40W, VA contents=
40%), 1g polyacrylate (national of the United States's starch chemical company, Duro-Tak 87-4098, average molecular weight 17749, admittedly contain
30%) amount uses 8.5g ethyl acetate to dissolve；The two is uniformly mixed, vacuum outgas, it is (beautiful that back sheet is uniformly layered on after cleared bubble
The polyester aluminum-plastic composite membrane of 3M companies of state) on, most of organic solvent is flung at 25 DEG C of room temperature, is placed in re-dry in 80 DEG C of baking ovens
2h, taking-up are cooled to 25 DEG C of room temperature, cover adherent layer, are cut to get percutaneous dosing paster with segment cutter.
The Beagle dog pharmacokinetics of Hup A percutaneous drug administration preparations and oral tablet multiple dose administration compares to be handed over using binary cycle
Fork experiment.
Percutaneous drug administration preparation：In Beagle dogs back depilatory agent (6%Na2SO3 the skin of two pieces of 4 × 6cm sizes) is taken off,
After depilatory agent dries 12hr with clear water edulcoration, each a piece of 10cm of patch at depilation2The patch of (2mg containing Hup-A) size,
Total 20cm2.Administration continues 84 hours every time, is administered 4 times altogether.Blood is taken after being 3 times administered within the 24th hour, 84 hours, the 4th
The the 4th, 6,8,10,24,32,48,56,72,84 hour and the 84th hour the 12nd, 20 hour removed after patch after secondary administration
Take blood.
Oral tablet：Hup-A pieces 10 are administered once for every 24 hours, are administered 5 times altogether.The 3rd after being administered at first 4 times is small
When, take blood within 24 hours, the 5th administration after take blood within the 0.5th, 1,1.5,2,3,4,5,6,8,10,12,24 hour.
The interval time that percutaneous drug administration preparation intersects administration with oral tablet is 1 week.
The dog Beagle multi-dose pharmacokinetics tests of Hup-A percutaneous drug administration preparations and oral tablet show multi-dose
After administration reaches stable state, Tmax significantly extends (P when percutaneous drug administration preparation stable state reaches peak<0.01) it, is surely significantly dropped up to Cmax Cmax
Low (P<0.01).Blood concentration peak valley fluctuation degree (FI%) percutaneous drug administration preparation is 48%, and oral tablet is 160%, is percutaneously given
The blood concentration fluctuation degree of medicine preparation is significantly less than oral tablet (P<0.01).
Realize purposes of the Huperzine A for epileptics prevention, it is necessary to which the control of Huperzine A blood concentrations exists
In one both safe and effective range.The present invention has captured the pass that stringent control drug enters the rate and dose of blood of human body
Key technology can meet clinical treatment needs in use, huperzine blood plasma is steady, controllable, peak valley fluctuation degree is small.The present invention
Percutaneous drug administration preparation compared with existing oral tablet administration, have the advantages that notable.
It must be noted that the above is merely illustrative of the application of principle of the present invention.Those skilled in the art can do
Go out many changes and modification, but all without departing from the principle and range of the present invention.
Claims (9)
1. a kind of application of huperzine in preparing the percutaneous drug administration preparation for treating or preventing epileptics.
2. application according to claim 1, which is characterized in that the percutaneous dosing system of the treatment or prevention epileptics
Agent is adhesive polymer framework controlled release type percutaneous dosing paster.
3. application according to claim 1, which is characterized in that the percutaneous drug administration preparation, by the original of following parts by weight
Material is made：
4. application according to claim 3, which is characterized in that be made of the raw material of following parts by weight：
5. application according to claim 3, which is characterized in that vinyl acetate in the ethylene-acetate ethylene copolymer
Content range is 15~45%.
6. application according to claim 3, which is characterized in that the penetration enhancer is isopropyl myristate, two
Methyl sulfoxide, lauryl alcohol, oleic acid, Laurocapram, capric acid or decyl alcohol.
7. application according to claim 3, which is characterized in that the preparation method of the percutaneous drug administration preparation, including with
Lower step：
Huperzine is weighed, is dissolved with ethyl alcohol, penetration enhancer is added, is uniformly mixed；Separately by ethylene-acetate ethylene copolymer
It is dissolved with ethyl acetate with polyacrylate；The two is uniformly mixed, vacuum outgas, back sheet is uniformly layered on after cleared bubble
On, most of organic solvent is flung at 10 DEG C~40 DEG C, is dried in baking oven, is taken out cooling, covered adherent layer, cut with segment cutter
Obtain percutaneous dosing paster.
8. application according to claim 7, which is characterized in that dry condition is in the baking oven：Be placed in 60 DEG C~
Dry 1h~3h in 90 DEG C of baking ovens.
9. application according to claim 7, which is characterized in that taking-up is cooled to 10 DEG C~40 DEG C.
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| CN201810863752.9A CN108653290B (en) | 2018-08-01 | 2018-08-01 | Application of huperzine A in preparing transdermal drug delivery preparation for treating or preventing epilepsy |
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| CN201810863752.9A CN108653290B (en) | 2018-08-01 | 2018-08-01 | Application of huperzine A in preparing transdermal drug delivery preparation for treating or preventing epilepsy |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1111987A (en) * | 1995-04-10 | 1995-11-22 | 浙江省医学科学院 | Transcutaneous huperzing sticker |
| US6352715B1 (en) * | 1998-02-19 | 2002-03-05 | Sagittarius Life Science Corp | Transdermal rate-controlled delivery of Huperzine A for treatment of alzheimer's disease |
| CN1450882A (en) * | 1999-11-04 | 2003-10-22 | 美国爱科赛尔制药有限公司 | Transdermal administration of huperzine |
| US20060264454A1 (en) * | 2005-05-23 | 2006-11-23 | Schachter Steven C | Use of huperzine for neuropathic pain |
| WO2013166468A1 (en) * | 2012-05-04 | 2013-11-07 | Insero Health Inc. | Compositions and methods for treating neurodegenerative diseases |
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2018
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Patent Citations (5)
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|---|---|---|---|---|
| CN1111987A (en) * | 1995-04-10 | 1995-11-22 | 浙江省医学科学院 | Transcutaneous huperzing sticker |
| US6352715B1 (en) * | 1998-02-19 | 2002-03-05 | Sagittarius Life Science Corp | Transdermal rate-controlled delivery of Huperzine A for treatment of alzheimer's disease |
| CN1450882A (en) * | 1999-11-04 | 2003-10-22 | 美国爱科赛尔制药有限公司 | Transdermal administration of huperzine |
| US20060264454A1 (en) * | 2005-05-23 | 2006-11-23 | Schachter Steven C | Use of huperzine for neuropathic pain |
| WO2013166468A1 (en) * | 2012-05-04 | 2013-11-07 | Insero Health Inc. | Compositions and methods for treating neurodegenerative diseases |
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| U.DAMAR等: "Huperzine A as a neuroprotective and antiepileptic drug: a review of preclincal research", 《EXPERT REVIEW OF NEUROTHERAPEUTICS》 * |
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| CN108653290B (en) | 2021-04-13 |
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