CN108653290B - Application of huperzine A in preparing transdermal drug delivery preparation for treating or preventing epilepsy - Google Patents
Application of huperzine A in preparing transdermal drug delivery preparation for treating or preventing epilepsy Download PDFInfo
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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 an application of huperzine A in preparing a transdermal drug delivery preparation for treating or preventing epilepsy. The transdermal preparation contains huperzine A or its pharmaceutically acceptable salts as main ingredient, and the huperzine A can penetrate into human body per day according to the designed amount. After the first administration, the huperzine blood concentration is not more than 0.1-0.3ng/ml within 1-2 hours, the average blood concentration is 0.3-5.0ng/ml, and the huperzine blood concentration is maintained for at least 3 days. The huperzine A shows good antiepileptic effect in a zebrafish epilepsy model induced by Pentylenetetrazol (PTZ). When the transdermal drug delivery preparation is used for preventing and treating epilepsy, the huperzine blood concentration is stable and controllable, so that the possibility of inducing the epileptic seizure of a patient due to too fast and too high instant blood concentration can be effectively avoided, and the transdermal drug delivery preparation is safe and effective to use.
Description
Technical Field
The invention relates to the technical field of huperzine A transdermal drug delivery preparations, in particular to application of huperzine A in preparing transdermal drug delivery preparations for treating or preventing epilepsy.
Background
Epilepsy (epilepsy) is a nervous system syndrome caused by chronic, recurrent, transient cerebral dysfunction due to abnormal firing of neurons in the brain.
About 5000 million people worldwide suffer from epilepsy, about 200 million new cases occur each year, the incidence in developing countries is currently much higher than in developed countries, and about 70% -90% of epileptic patients are not treated properly. In severe chronic active epileptic patients, the risk of sudden epileptic death is up to 1% per year. It is reported that 4000 sudden epileptic deaths occur annually in the european union.
According to the latest epidemiological data in China, about 900 million epilepsy patients exist in China, 500-600 million of the epilepsy patients are active epilepsy patients, about 40 million epilepsy patients are newly increased every year, and epilepsy has become the second most common disease of the neurology department, second to headache, in China.
Because of the differences in the initiation site and transmission pattern of abnormal discharges, the clinical manifestations of epileptic seizures are complex and diverse, and can be manifested as dysfunction of movement, sensation, autonomic nerves, consciousness, spirit and the like. The causes of epilepsy are also diverse.
At present, epileptic patients are treated with regular antiepileptic drugs, and seizures can be controlled in about 70% of patients, but are still uncontrollable in about 30% of patients due to drug resistance. The majority of epilepsy patients who cannot be controlled by medicines are treated by surgery, but patients who are suitable for surgery only account for a small part of the patients. Therefore, the search for safe and effective antiepileptic drugs is one of the hotspots of the current new drug research at home and abroad.
Huperzine is a novel chemical substance which is developed by Chinese pharmaceutical scientists in the eighties of the last century from the fern medicinal plant Huperzia serrate (Thunb.) Trevis. Huperzine A has been developed in China as a new drug for treating senile benign memory disorder, improving memory dysfunction of Alzheimer's disease patients caused by cholinergic dysfunction in brain, and relieving myasthenia gravis and other diseases.
Huperzine A has not only the application of treating senile benign dysmnesia, but also new indications: in the screening of an antiepileptic animal model, scientists at medical college of Emmeriy university in the United states find that Huperzine A has the function of enhancing the resistance of a mouse epilepsy model to induce epileptic seizure. In particular, the potential to prevent febrile seizures has been shown, which is characteristic of Dravet syndrome, a severe childhood epilepsy (Expert Review of neuro-surgery, 2016, 16(6): 1-10).
The mechanism of Huperzine A on epilepsy is different from the action mechanism of cholinesterase inhibition originally used for senile benign dysmnesia. Scientists in the united states found: huperzine A acts on receptors for α 7nAChRs and α 4 β 2nAChRs to produce a potent anti-inflammatory response, and reduces IL-1 β, TNF- α protein expression and inhibits the transcriptional activation of NF- κ B signaling, thus providing protection against neuronal excitotoxicity and neuronal death and increasing the neurotransmission of GABAergic events associated with anticonvulsant activity.
Scientists have also found that Huperzine a normalizes the balance between neuronal inhibition and excitation in patients with SCN1A mutation, thereby preventing the occurrence of epilepsy. (Frontiers in Pharmacology,2016, 7: 357).
The mechanism of Huperzine A for preventing and treating epilepsy is different from that of Alzheimer's disease for treating senile benign dysmnesia, so the administration dosage and the effective blood concentration are different, and the requirements are very strict.
The zebrafish is considered as one of useful models for researching epilepsy at home and abroad, the SCN1A of the zebrafish has the homology of up to 85 percent with the human SCN1A gene, and the signal transduction path of the zebrafish is basically similar to that of the human. Professor Scott Baraban, USA, and colleagues, performed a single screening of the compound in the drug library approved by the United states Food and Drug Administration (FDA), and found that Clemizole inhibited spontaneous spasmodic behavior and electroencephalogram seizure in zebrafish carrying the SCN1A mutation resembling the Dravet syndrome in childhood epilepsy. Since the function and characteristics of the SCN1A of the zebra fish are the same as those of the SCN1A of human beings, the zebra fish has been widely applied to the research of new anti-epileptic drugs. (Nat Commun.2013Sep 3)
In the test of zebra fish epilepsy model, Huperzine A is found to produce strong antiepileptic effect in a certain dosage range, and the antiepileptic effect is higher than that of clinically common phenytoin sodium (see
Example 1).
As Huperzine A tablets are found in clinical tests for treating children language hypoevolutism, a few children with epilepsy are in a condition of stopping treatment due to the induction of epileptic seizures. For this reason, the descriptions of Huperzine A tablets (the "Shuangyiping" tablets) approved by the State food and drug administration list epilepsy patients as contraindications (Journal of Pediatric Pharmacy 2002, 8 (1): 27).
Genetic factors play an important role in the pathogenesis of epilepsy. The SCN1A gene encoding a type i voltage-gated sodium channel is considered to be the major therapeutic gene for epilepsy. Different types of mutations in the SCN1A gene can trigger different epileptic syndromes.
In recent years, through the research of zebra fish with SCN1A gene mutation, the reason that Huperzine A induces partial epileptic seizure is finally found out as follows: the immediate blood level of Huperzine A into the body rises too quickly and too high, resulting in excess acetylcholine breaking the balance between neuronal inhibition and excitation in SCN1A mutant patients (see example 2).
Therefore, in order to realize the aim of using Huperzine A for preventing and treating epilepsy, a key technology for strictly controlling the speed and dosage of the medicine entering the blood of a human body must be solved, and the blood concentration is controlled in a safe and effective range. The transdermal formulations of the present invention meet this clinical need. When the medicine is used, the huperzine blood concentration is stable and controllable, the possibility of inducing epilepsy due to the fact that the instant blood concentration rises too fast and too high can be effectively avoided, and the medicine is safe and effective.
To date, no Huperzine A transdermal drug delivery preparation for preventing and treating epilepsy has been reported.
Disclosure of Invention
In view of the special requirements of the pharmaceutical preparation for preventing and treating epilepsy, the invention provides the application of huperzine A in preparing the transdermal drug delivery preparation for treating or preventing epilepsy.
The transdermal preparation is prepared with huperzine A or its pharmaceutically acceptable salt, analog, derivative and precursor medicine and their mixture as main components. The designed amount of huperzine A is introduced into the body through the skin every day. After the first administration, the huperzine blood concentration is not more than 0.1-0.3ng/ml within 1-2 hours, the average blood concentration range is 0.3-5.0ng/ml, and the huperzine blood concentration is maintained for at least 3 days, so the huperzine blood concentration medicament is safe and effective to use. The preparation can accurately control the skin permeation rate of huperzine, control the huperzine blood concentration in the safe range of epilepsy prevention and treatment, avoid the possibility of inducing epilepsy due to the fact that the instant blood concentration rises too fast and too high, and is safe and effective to use.
Contains huperzine A in sufficient amount to reach a blood level of 0.3-5.0ng/ml through the skin and maintain an effective blood level for at least 3 days;
the transdermal drug delivery preparation has the advantages that after the first drug delivery, the blood concentration of huperzine is not more than 0.1-0.3ng/ml within 1-2 hours.
The average blood concentration of the huperzine after the first administration of the transdermal drug delivery preparation is 0.3-5.0ng/ml and is maintained for at least 3 days.
The transdermal preparation, wherein the huperzine A may be huperzine A, and various pharmaceutically acceptable salts, analogues, derivatives and prodrugs thereof.
The transdermal drug delivery preparation, wherein, the preparation is a preparation which is used for local application and generates systemic effect.
The transdermal drug delivery preparation is a polymer controlled release type transdermal drug delivery patch, and the invention adopts ethylene-vinyl acetate copolymer (EVA) as a polymer controlled release material.
The transdermal drug delivery preparation is an adhesive polymer framework type controlled release patch, ethylene-vinyl acetate copolymer (EVA) is used as a polymer controlled release material, and polyacrylate is used as an adhesive.
The transdermal drug delivery preparation is prepared from the following raw materials in parts by weight:
further preferably, the transdermal drug delivery preparation is prepared from the following raw materials in parts by weight:
most preferably, the transdermal drug delivery preparation is prepared from the following raw materials in parts by weight:
a method for preparing a transdermal drug delivery preparation comprises the following steps:
weighing huperzine A, dissolving with ethanol, adding penetration enhancer, and mixing; dissolving ethylene-vinyl acetate copolymer and polyacrylate with ethyl acetate; mixing the two materials, vacuum degassing, removing bubbles, spreading on backing layer, volatilizing most organic solvent at 10-40 deg.C, drying in oven, cooling, covering with anti-sticking layer, and cutting with cutting machine to obtain transdermal patch.
The drying conditions in the oven are as follows: drying in an oven at 60-90 deg.C for 1-3 h, preferably 80 deg.C for 2 h.
Taking out and cooling to 10-40 ℃.
The Ethylene-vinyl acetate copolymer (Ethylene/vinyl acetate) is a controlled release matrix, wherein the content of vinyl acetate is in the range of 3.5% to 50% (by weight average), preferably 15% to 45%, and more preferably 30% to 45%.
Polyacrylate (average molecular weight 17749, solids content 30%) is an adhesive.
The penetration enhancer is isopropyl myristate (IPM), dimethyl sulfoxide (DMSO), dodecanol (LA), Oleic Acid (OA), laurocapram (AZ), Capric Acid (CA) or decanol (DeA).
The transdermal drug delivery preparation, other transdermal drug delivery preparations for treating or preventing epilepsy, which are prepared from huperzine A, various pharmaceutically acceptable salts, analogues, derivatives, prodrugs and mixtures thereof. After the first administration, the huperzine blood concentration is not more than 0.1-0.3ng/ml within 1-2 hours, the average steady state blood concentration range is 0.3-5.0ng/ml, and the huperzine blood concentration is maintained for at least 3 days.
When the transdermal drug delivery preparation is used for preventing and treating epilepsy, the huperzine blood concentration is stable and controllable, so that the possibility of inducing epileptic seizure of a patient due to too fast and too high instant blood concentration can be effectively avoided, and the transdermal drug delivery preparation is safe and effective to use.
Drawings
FIG. 1 is a graph of the locus of movement of zebrafish evaluated for the antiepileptic effect of Hup A in example 1;
FIG. 2 is a graph comparing the fast moving distance (mm) of zebrafish after treatment with Hup A in example 1 with a model control group;
FIG. 3 is a graph comparing the anti-epileptic effects of zebrafish after treatment with Hup A in example 1 with a model control group;
fig. 4 is a plot of peak to valley for Multiple dose administration of the Hup-A transdermal formulation of example 5 with Hup-A oral tablet (n-6), ■ is a plot of peak to valley for the Hup-A transdermal formulation (Multiple dose patches) and a plot of peak to valley for Multiple dose administration of the Hup-A oral tablet (Multiple dose oral tablets).
Detailed Description
The following examples are given to further illustrate the present invention, but the examples are only for illustrating the present invention and not for limiting the present invention, so any simple modification of the present invention in the premise of the method of the present invention falls within the scope of the claimed invention.
Example 1 (antiepileptic action of Huperzine A)
Test method 1:
randomly selecting 210 wild AB line zebra fishes 6 days after fertilization into a 96-well plate, and treating 1 zebra fish per well with 12 wells/group. Hup A was dissolved in water at concentrations of 6.9, 20.8, 62.5 and 100. mu.M, respectively, and a positive control drug, phenytoin sodium, at a concentration of 300. mu.M, was dissolved in water at a volume of 200. mu.L per well, and a normal control group (normal zebrafish treated with water for fish farming) and a model control group were set. After each group is treated for 1h, the rest experimental groups except the normal control group are dissolved in water and give pentylenetetrazol induced zebra fish to establish an epilepsy model, and a movement/behavior analyzer is used for recording the movement condition of the zebra fish within 1h given pentylenetetrazol. Analyzing and counting the distance (D) of the zebra fish moving rapidly (V >20mm/s), and evaluating the anti-epileptic effect of Huperzine A (Huperzine A) on the zebra fish of the pentylenetetrazol-induced epilepsy model according to the statistical analysis result of the zebra fish moving rapidly distance, wherein the statistical processing result is expressed by mean +/-SE.
Statistical analysis using analysis of variance and Dunnett's T-test indicated significant differences with p < 0.05.
2 results of the test
The test results are shown in table 1, fig. 2 and fig. 3, and fig. 1 is a graph of the locus of motion of zebrafish evaluated for the anti-epileptic effect of Hup a in example 1; FIG. 2 is a graph comparing the fast moving distance (mm) of zebrafish after Hup A treatment in example 1 with that of a model control group,***p<0.001; FIG. 3 is a graph comparing the anti-epileptic effect of zebrafish after treatment with Hup A in example 1 with that of a model control group,***p<0.001。
2.1 the model is successfully established by comparing the fast moving distance (1871mm) of the zebra fish in the model control group with the p <0.001 in the normal control group (27 mm).
2.2 the positive contrast drug phenytoin sodium 300 mu M concentration group zebra fish rapid movement distance (689mm) and the model contrast group compare p <0.001, the anti-epileptic action is 63.2%, suggesting that phenytoin sodium has obvious anti-epileptic action.
2.3 Hup A20.8 μ M, 62.5 μ M and 100 μ M concentration groups of zebrafish rapid movement distance 872, 133 and 5mm respectively, compared with the model control group, p is less than 0.001, and antiepileptic effect is 53.4%, 92.9% and 99.7%. Hup A is suggested to have obvious anti-epileptic effect under the concentration conditions of 20.8, 62.5 and 100 mu M. See table 1, fig. 2 and fig. 3 for details.
The antiepileptic therapeutic effect of the compound was qualitatively evaluated in the same manner as in example 1. Compared with an epilepsy model group, the fast movement track of the zebra fish is obviously reduced under the administration doses of the Hup A. FIG. 1 is a bar graph plotted according to mean + -SE of the fast moving distances of zebrafish, and it can be seen from FIG. 1 that Hup A has epilepsy treating effect at 20.8. mu.M, 62.5. mu.M and 100. mu.M, and has statistical difference (P <0.001) compared with the model control group, and the treating efficiency is: 19.1%, 53.4%, 92.9%, 99.7% (P < 0.001).
Table 1. evaluation of anti-epileptic effect of Hup a experimental results (mean ± SE, n ═ 10)
Compared with the model control group,***p<0.001
3 conclusion of the test
Huperzine A has definite dose-effect relationship on the resistance of zebrafish to epileptic seizure (rapid movement distance is more than 20mm/s) at the concentrations of 20.8, 62.5 and 100 mu M, and the Huperzine A is prompted to have obvious anti-epileptic effect.
Example 2
Study of Huperzine A on SCN1A gene mutant zebra fish
Test method 1:
1.1 Electrical stimulation of behavioral changes in Zebra Fish
60 zebra fish strips mutated by the CN1A gene are randomly divided into 5 groups (n is 10). The control group was given a 0 current pseudo-stimulus and the remaining 4 groups were given currents of 25, 50, 100, 1000 μ a, respectively, and after 1s of stimulation, the zebrafish response was observed.
1.2 Effect of Hup A on electric stimulation of Zebra fish to induce epilepsy model
Randomly selecting 150 SCN1A gene mutation zebra fishes in a 96-well plate, and treating 1 zebra fish per well with 12 wells/group. Hup A was dissolved in water at concentrations of 20.8, 62.5, 100, 130 and 160. mu.M, respectively, and the volume per well was 200. mu.L, while model control groups were set. After each group of zebra fish is treated for 1h, appropriate current stimulation is given, and after 1s of stimulation, the behavior change of the zebra fish is observed according to the following indexes: surprise tic response: leap forward, jump, drift, or spin rapidly. ② convulsion reaction: the whole body is straight and immobile; and then turn over, coma or death occurs.
1.3 statistical methods
Statistical analysis is carried out by using SPSS19.0 software, differences among groups are compared by chi-square test, and the difference has significance when P < 0.05.
2 results of the test
2.1 Electrical stimulation of behavioral changes in Zebra Fish
After current 25, 50, 100 μ a stimulation for 1s, zebrafish appeared: forward leap, jump, tail flick, or gyrate characteristic response behavior (convulsive response); after 1000 muA stimulation, zebrafish appeared: the whole body is straight and immobile; and then rollover, coma or death (convulsive response) occurs.
The control group of the animal model is given 25 muA current to stimulate the zebra fish, and 50 percent of the zebra fish have forward fleeing, jumping, tail flicking or convulsive convulsion reaction; 50. stimulating zebra fish by 100 muA current, wherein 100 percent of zebra fish have forward leaping, jumping, tail flicking or convulsive convulsion reaction; the zebra fish electrically stimulated by 1000 muA all appeared straight and immobile, then 4 of the zebra fish appeared on side and died, and the rest 6 of the zebra fish were continuously recovered to be normal after 2 min. The result shows that the zebra fish convulsion reaction model with partial SCN1A gene mutation can be caused after the stimulation for 1s by the current of 25 muA; after the stimulation is carried out for 1s by 50 and 100 mu A of current, all SCN1A gene mutant zebra fishes can be caused to generate twitch reaction; after 1000 muA stimulation is given, a convulsion response model of the SCN1A gene mutant zebra fish can be caused. The results are detailed in table 2.
Table 2 electrical stimulation induced behavioral changes in SCN1A gene mutant zebrafish (mean ± SE, n ═ 10)
2.2 Effect of Hup A on Zebra Fish models
Randomly selecting 150 SCN1A gene mutation zebra fishes in a 96-well plate, and treating 1 zebra fish per well with 12 wells/group. Hup A was dissolved in water at concentrations of 20.8, 62.5, 100, 130 and 160. mu.M, respectively, and the volume per well was 200. mu.L, while model control groups were set. After the zebra fish groups are treated by the medicines for 1h, the zebra fish groups are stimulated by 25 muA of current for 1s, and the behavioral changes of the zebra fish are observed according to the following indexes: surprise tic response: leap forward, jump, drift, or spin rapidly. ② convulsion reaction: the whole body is straight and immobile; and then turn over, coma or death occurs. The results are detailed in table 3.
Table 3 effect of Hup a on zebrafish model (mean ± SE, n ═ 10)
3 conclusion of the test
Huperzine A can provide seizure protection for SCN1A gene mutation zebra fish at the concentration of 20.8, 62.5 and 100 mu M, and the dose-effect relationship is clear, which indicates that Huperzine A has obvious effect of preventing epilepsy.
The Huperzine A has a certain dose-effect relationship when the Huperzine A has the concentration of 130 and 160 mu M, the protection effect on the SCN1A gene mutation zebra fish seizure is converted into the induction of the convulsion and convulsion reaction of the SCN1A gene mutation zebra fish, and the test result indicates that the Huperzine A can induce the seizure when the Huperzine A has the concentration of high concentration. Analyzing the possible reason, since Hup A is a reversible cholinesterase inhibitor, if the immediate blood concentration of Huperzine A entering the body rises too fast and too high, the excess acetylcholine may be caused to destroy the balance between neuronal inhibition and excitation of the SCN1A mutant patient, thereby inducing epilepsy.
Example 3
Weighing Huperzine A20 mg, placing in a beaker, dissolving with 2.5g ethanol, adding 0.27g penetration enhancer (see Table 4), and mixing well; 3g of an ethylene-vinyl acetate copolymer (DuPont, 40W, 40% VA) and 1g of a polyacrylate (Duro-Tak 87-4098, average molecular weight 17749, 30% solids, USA) were separately weighed and dissolved in 8.5g of ethyl acetate; mixing the two materials, vacuum degassing, removing bubbles, spreading on backing layer (polyester aluminum plastic composite film of 3M company in USA), volatilizing most organic solvent at 25 deg.C, drying in 80 deg.C oven for 2hr, cooling to 25 deg.C, covering with anti-sticking layer, and cutting to obtain the final product.
Drug release rate test method:
a Valia-Chien double-chamber permeation cell is adopted for testing, a patch with an anti-adhesion layer removed is pasted on the skin cutin layer of a nude mouse, 40% PEG400/NS is added in a receiving chamber, the temperature of a circulating water bath is 37 +/-0.5 ℃, sampling is carried out according to specified interval time, and the concentration of Hup-A in the permeation liquid of the receiving chamber is measured by an HPLC method.
HPLC analytical method: the instrument comprises the following steps: shimadzu HPLC-10A, column: Shim-Pack CLC-DOS (6.0X 150 mm). Detection wavelength 313nm, mobile phase: methanol: water (55: 45), adding 40 mul triethylamine into every 500ml water, the flow rate is 1ml/min, the sample volume is 20 mul, measuring the peak area after sample injection, and calculating the skin permeation volume of Hup-A by an external standard method.
The linear range of the method is as follows: 0.70-22.3. mu.g/ml, correlation coefficient: 0.9999; and (3) recovery rate: 98.0 ± 2.0%, coefficient of variation: 2.04% and Hup-A remains stable in the receiving solution for 96 hours.
The skin permeation rates for different embodiments of nude mice are provided below, and the results are shown in table 4.
TABLE 4 skin permeation rates of HupA nude mice under different permeation enhancer conditionsa
a IPM (isopropyl myristate); DMSO (dimethyl sulfoxide); LA (dodecanol); OA (oleic acid); AZ (laurocapram); CA (decanoic acid); DeA (decanol).
Example 4
An ethylene-vinyl acetate copolymer (EVA) skeleton controlled release transdermal drug delivery preparation is provided. The release rate of the drug is controlled by the copolymer composition. Transdermal preparations with different release rates can be obtained by adjusting the content of vinyl acetate (VAc) in ethylene-vinyl acetate copolymer (EVA).
The experimental procedure was as in example 3 and IPM (isopropyl myristate) was used as the penetration enhancer, the results of which are shown in Table 5.
TABLE 5 Effect of vinyl acetate (VAc) content in ethylene-vinyl acetate copolymer (EVA) on HupA permeation Ratea
aThe test was performed on the skin of nude mice in a Valia-Chien two-chamber permeation cell.
Example 5
Weighing Huperzine A20 mg, placing in a beaker, dissolving with 2.5g ethanol, adding penetration enhancer (isopropyl myristate) 0.27g, and mixing well; 3g of an ethylene-vinyl acetate copolymer (DuPont, 40W, 40% VA) and 1g of a polyacrylate (Duro-Tak 87-4098, average molecular weight 17749, 30% solids, USA) were separately weighed and dissolved in 8.5g of ethyl acetate; mixing the two materials, vacuum degassing, removing bubbles, spreading on backing layer (polyester aluminum plastic composite film of 3M company, USA), volatilizing most organic solvent at room temperature of 25 deg.C, drying in 80 deg.C oven for 2hr, cooling to room temperature of 25 deg.C, covering with anti-sticking layer, and cutting with cutting machine to obtain transdermal patch.
Comparative Beagle canine pharmacokinetics of Hup A transdermal formulations and oral tablet multiple dose dosing using a two cycle crossover test.
Transdermal preparation: depilatory (6% Na) on the back of Beagle dogs2SO3) removing two pieces of skin with size of 4 × 6cm, cleaning depilatory with water, drying for 12hr, and applying one piece of depilatory onto the depilatory2(containing Hup-A2 mg) area size patch of 20cm in total2. Each administration lasted 84 hours, 4 times in total. Blood was taken at 24 hours and 84 hours after the first 3 doses, at 4, 6, 8, 10, 24, 32, 48, 56, 72, 84 hours after the 4 th dose, and at 12 and 20 hours after the 84 hour patch was removed.
Oral tablet preparation: Hup-A tablets were administered 1 time every 24 hours for a total of 5 times. Blood was taken at 3 hours and 24 hours after the first 4 doses, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after the 5 th dose.
The interval between transdermal preparation and oral tablet is 1 week.
Dog Beagle multi-dose pharmacokinetic testing of Hup-A transdermal formulations and oral tablets showed that after multiple doses reached steady state, Tmax at steady state of transdermal formulations was significantly prolonged (P <0.01) and steady peak concentration Cmax was significantly reduced (P < 0.01). The blood concentration peak-valley fluctuation (FI%) of the transdermal preparation is 48%, while the blood concentration fluctuation of the oral tablet is 160%, and the blood concentration fluctuation of the transdermal preparation is obviously smaller than that of the oral tablet (P < 0.01).
In order to achieve the purpose of Huperzine A for preventing and treating epilepsy, the blood concentration of Huperzine A must be controlled within a safe and effective range. The invention overcomes the key technology of strictly controlling the rate and dosage of the medicament entering the blood of a human body, and when the huperzine composition is used, the huperzine blood concentration is stable and controllable, the peak-valley fluctuation degree is small, and the clinical treatment requirement can be met. Compared with the existing oral tablet administration, the transdermal administration preparation has remarkable advantages.
It must be noted that the above description merely illustrates the application principles of the present invention. Many changes and modifications may be made by one of ordinary skill in the art without departing from the spirit and scope of the invention.
Claims (6)
1. The application of huperzine A in preparing a transdermal drug delivery preparation for treating or preventing epilepsy is characterized in that the transdermal drug delivery preparation is prepared from the following raw materials in parts by weight:
2 parts of huperzine A;
15-50 parts by weight of a penetration enhancer;
100-500 parts by weight of an ethylene-vinyl acetate copolymer;
30-150 parts by weight of polyacrylate;
80-400 parts by weight of ethanol;
600-1000 parts by weight of ethyl acetate;
the penetration enhancer is isopropyl myristate, dimethyl sulfoxide, dodecanol, oleic acid, laurocapram, decanoic acid or decanol;
the content range of vinyl acetate in the ethylene-vinyl acetate copolymer is 15-45%;
after the transdermal drug delivery preparation is administered for the first time, the huperzine blood concentration is 0.1-0.3ng/ml within 1-2 hours, the average blood concentration range is 0.3-5.0ng/ml, and the huperzine blood concentration is maintained for at least 3 days.
2. The use of claim 1, wherein said transdermal formulation for the treatment or prevention of epilepsy is an adhesive polymer matrix controlled release transdermal patch.
3. The application of the composition as claimed in claim 1, which is prepared from the following raw materials in parts by weight:
2 parts of huperzine A;
22-32 parts of a penetration enhancer;
200-400 parts by weight of an ethylene-vinyl acetate copolymer;
40-120 parts of polyacrylate;
150-350 parts by weight of ethanol;
750-950 parts by weight of ethyl acetate.
4. The use of claim 1, wherein said transdermal formulation is prepared by a process comprising the steps of:
weighing huperzine A, dissolving with ethanol, adding penetration enhancer, and mixing; dissolving ethylene-vinyl acetate copolymer and polyacrylate with ethyl acetate; mixing the two materials uniformly, vacuum degassing, removing bubbles, uniformly spreading on a back lining layer, volatilizing most of organic solvent at 10-40 ℃, drying in an oven, taking out, cooling, covering an anti-sticking layer, and cutting with a cutting machine to obtain the transdermal drug delivery patch.
5. The use according to claim 4, wherein the conditions for drying in the oven are: drying the mixture for 1 to 3 hours in an oven at the temperature of between 60 and 90 ℃.
6. The use according to claim 4, wherein the removal is cooled to 10-40 ℃.
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Citations (4)
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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 |
| WO2013166468A1 (en) * | 2012-05-04 | 2013-11-07 | Insero Health Inc. | Compositions and methods for treating neurodegenerative diseases |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3056200B1 (en) * | 2005-05-23 | 2023-09-06 | President and Fellows of Harvard College | Huperzine for use in treating seizure |
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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 |
| WO2013166468A1 (en) * | 2012-05-04 | 2013-11-07 | Insero Health Inc. | Compositions and methods for treating neurodegenerative diseases |
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| Huperzine A as a neuroprotective and antiepileptic drug: a review of preclincal research;U.Damar等;《Expert Review of neurotherapeutics》;20160420;1-10 * |
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