CN1621039A - Targeted preparation via nose to brain of Huperzine and its derivant or its salt - Google Patents
Targeted preparation via nose to brain of Huperzine and its derivant or its salt Download PDFInfo
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- CN1621039A CN1621039A CN 200310108852 CN200310108852A CN1621039A CN 1621039 A CN1621039 A CN 1621039A CN 200310108852 CN200310108852 CN 200310108852 CN 200310108852 A CN200310108852 A CN 200310108852A CN 1621039 A CN1621039 A CN 1621039A
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Abstract
本发明公开了一种石杉碱甲及其衍生物或其盐的经鼻脑靶向制剂。本发明所述制剂能通过鼻腔的嗅觉通道将药物直接输入脑内，可用于预防和治疗老年性痴呆症和中老年记忆障碍或提高青少年记忆和学习能力。本发明所述制剂通过提高药物在脑内的生物利用度，可降低给药量从而减少药物的毒副作用。本发明所述制剂使用方便，能提高病人服药的依从性。The invention discloses a nose-brain targeting preparation of huperzine A and its derivatives or salts thereof. The preparation of the invention can directly inject medicine into the brain through the olfactory channel of the nasal cavity, and can be used for preventing and treating senile dementia and middle-aged and elderly memory impairment or improving the memory and learning ability of teenagers. The preparation of the invention can reduce the dosage of the drug by improving the bioavailability of the drug in the brain, so as to reduce the toxic and side effects of the drug. The preparation of the invention is convenient to use and can improve the compliance of patients taking medicine.
Description
Technical field
The present invention relates to the per nasal brain targeting preparation of huperzine A and derivant thereof or its salt.
Background technology
Huperzine A (Huperzine A), chemistry is by name: (5R, 9R, 11E)-and 5-amino-11-ethylidene-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring cycloocta--2 (1H)-pyridone is to extract the alkaloid that obtains in the phenol part obtain from Chinese herbal medicine Herba Lycopodii serrati [Huperzia serrata (Thunb) Thev], is a kind of efficient, low toxicity and reversible acetylcholinesterase inhibitor (AChEI).Studies show that huperzine A is effective to senile dementia.Research finds that also some derivants of huperzine A have similar curative effect.The present invention relates to following huperzine A and derivant thereof:
X Y Z
I H H NH
2
II H H
III H CH
3 NH
2
IV CH
3 H NH
2
V CH
3 CH
3 NH
2
Wherein, structural formula (I) is huperzine A, finds that through retrieval the preparation of huperzine A has tablet, capsule, preparation capable of permeating skin (comprising percutaneous controlled-release paster), injection and slow release microphere for injection.Because huperzine A is non-brain selectivity acetylcholinesterase inhibitor, no matter existing preparation is oral formulations, injection or preparation capable of permeating skin, and big general toxicity is all arranged.Toxic and side effects mainly shows as: dizzy, feel sick, hyperhidrosis, constipation, xerostomia, cathisophobia, anxiety, vomiting, muscle shake war, changes in heart rate, pupil variation etc.When dosage surpassed effective dose, toxic and side effects increased with dosage.Therefore, press for a kind of novel brain targeting preparation of exploitation, the brain selectivity that is intended to improve acetylcholinesterase inhibitor class medicine huperzine A is a bioavailability in the brain, reduce dosage, reduce the whole body toxic and side effects, and can conveniently use, improve the compliance of patient's medication.
Chinese patent CN 1383824A discloses a kind of huperzine A nasal cavity administrated preparation, it is medicine with the huperzine, adopt the saturating Nasal Mucosa Absorption of penetration enhancer increase medicine such as laurocapram, the stripped permeability test of sheep nasal membrane proves that each administration can have 80～500 microgram huperzines to enter in the body, it still is that preparation capable of permeating skin is the same with oral formulations, injection, per mucous membrane is brought into play curative effect after being absorbed into blood, therefore also has bigger general toxicity.
Summary of the invention
The technical issues that need to address of the present invention are per nasal brain targeting preparations that disclose a kind of huperzine A and derivant or its salt and preparation method thereof, to overcome the above-mentioned defective that prior art exists.
Technical conceive of the present invention is such: as far back as earlier 1900s, researcher is that virus enters a main positions in the brain with regard to the olfactory region of finding nasal cavity, as poliovirus and herpes stomatitis virus.Found afterwards that virus can enter in the brain along nervi olfactory, bred in olfactory bulb.Except virus, researcher finds that also following material also can enter the central nervous system by olfactory region: the potassium ferricyanide, ferric ammonium citrate, albumin, gold colloidal, or the like.Bibliographical information estradiol, dopamine, progesterone, nerve growth factor can directly enter cerebrospinal fluid by nasal-cavity administration.These discoveries make researcher recognize that nasal cavity is a up-and-coming brain target administration approach.
The inventor also studies to brain drug delivery two clean (CN1096514A) per nasal of novel anti trypanocides hydrochloric acid awl.The hydrochloric acid awl is two clean fat-soluble poor, thoroughly blood brain barrier.The inventor has set up the test method of the two clean per nasal of checking hydrochloric acid awl to brain drug delivery by a large amount of literature survey and animal experiments.According to the brain stereotaxic atlas of rat, the intubate position of oriented side ventricles of the brain the best cooperates cisterna puncture to obtain the dynamic changing data of medicine in cerebrospinal fluid with push-pull perfusion.Optimizing prescriptions nasal-cavity administration and quiet notes group are made comparisons with dosage, and the two clean AUC of cerebrospinal fluid hydrochloric acid awl are quiet notes 20.16 times (P＜0.01) behind the optimizing prescriptions rat nasal-cavity administration, the C of cerebrospinal fluid
MaxBeing 211.74ng/ml, is 28.0 times (P＜0.01) of quiet notes.This shows that the hydrochloric acid awl is two clean by behind the nasal-cavity administration, and tangible brain targeting is arranged.This proves further that also nasal cavity has direct conveying medicine to enter the approach of brain.
According to above-mentioned design, it is a kind of as the huperzine A of general formula (1) and the per nasal brain targeting preparation of derivant or its salt thereof that the inventor provides, use with nasal cavity medicines such as nasal drop, nasal spray and insufflations, can be used for prevention and treatment senile dementia and person in middle and old age's dysmnesia or improve teenager memory and learning capacity.This novel formulation can directly be imported medicine in the brain by the olfactory sensation passage of nasal cavity, improves the brain selectivity of acetylcholinesterase inhibitor class medicine, reduces the whole body toxic and side effects.
Wherein, said salt is the chemical compound of structural formula (I), structural formula (II), structural formula (III), structural formula (IV) and structural formula (IV) and the salt of hydrochloric acid, acetic acid, phosphoric acid, sulphuric acid, lactic acid, citric acid or maleic acid be combined into.
The per nasal brain targeting preparation of huperzine A of the present invention and derivant thereof or its salt is a kind of aqueous solution that contains the alcohol cosolvent, and its component and weight percent content comprise:
Huperzine A 0.001～10%
Alcohol cosolvent 1～30%
Water surplus.
Said alcohol cosolvent comprises one or more in ethanol, propylene glycol, glycerol, Polyethylene Glycol or the benzyl alcohol;
The per nasal brain targeting preparation of huperzine A of the present invention and derivant thereof or its salt is a kind of cyclodextrin clathrate, and its component and weight percent content comprise:
Huperzine A 0.001～10%
Cyclodextrin 1～40%
Water surplus.
The ratio of cyclodextrin and medicine is 1: 1～1: 100, mol ratio, and said cyclodextrin comprises alpha-cyclodextrin, a kind of or its mixture in beta-schardinger dextrin-or the gamma-cyclodextrin or derivatives thereof;
The per nasal brain targeting preparation of huperzine A of the present invention and derivant thereof or its salt is a kind of microemulsion, and its component and weight percent content comprise:
Huperzine A 0.001～10%,
Cosurfactant 1～10%,
Surfactant 1～10%,
Oil 1～10%,
Water surplus.
Wherein cosurfactant comprises one or more in ethanol, propylene glycol, glycerol, Polyethylene Glycol or the benzyl alcohol;
Said surfactant comprises one or more of phospholipid, Tweens, Myrij class (Myrjs), brejs (Brijs), polyoxyethylene castor oil condensation substance, polyoxyethylene hydrogenated Oleum Ricini condensation substance or polyethers;
Said oil comprises fatty acid polyethyleneglycol glyceride series (LABRAFIL
), isopropyl myristate, ethyl oleate, glycerol list linoleate (Maisine 35-1), isostearic acid isostearate (Isostearyl isostearate), sad/certain herbaceous plants with big flowers acid glycerol three esters (Captex 355), median chain triglyceride oil Miglyol 812 (capric caprylic triglycerides), ethyl laurate, soybean oil one or more;
The microemulsion particle diameter is between 2～20nm.
The per nasal brain targeting preparation of huperzine A of the present invention and derivant thereof or its salt is a kind of surfactant vesicle solution, and its component and weight percent content comprise:
Huperzine A 0.001～10%
Surfactant 1～10%
Water surplus.
Said surfactant comprises one or more in phospholipid, Tweens (Tweens), Myrij class (Myrjs), brejs (Brijs), polyoxyethylene castor oil condensation substance and polyoxyethylene hydrogenated Oleum Ricini condensation substance (Cremophors) and the polyethers (Pluronics);
The vesicle particle diameter is between 2～10nm.
The per nasal brain targeting preparation of huperzine A of the present invention and derivant thereof or its salt is a kind of nanoparticle, and the molecular weight ranges that comprises the huperzine A of nanoparticle weight 2～50% and nanoparticle weight 50～98% is the biodegradable medicinal high polymer adjuvant between 5000～1000000;
Said medicinal high polymer adjuvant is selected from one or both or the two or more mixing wherein of polylactide-co-glycolide, polylactic acid, polyglycolic acid, poly butyric ester, polylactic acid-polyglycolic acid, polylactic acid-glycollic acid, poly-adjacent ester, polylactone, polyanhydride, poly butyric ester-hydroxyl pentanoate copolymer, polyglycolic acid, polypropylene glucosan, hydroxyacetic acid, polylactic acid-polyglycol, polyglycolic acid-Polyethylene Glycol.The nanoparticle particle diameter is between 20～200nm.
The per nasal brain targeting preparation of huperzine A of the present invention and derivant thereof or its salt can pass through the direct administration of nasal cavity, use with nasal cavity medicines such as nasal drop, nasal spray and insufflations, can be used for prevention and treatment senile dementia and person in middle and old age's dysmnesia or improve teenager memory and learning capacity.This novel formulation can directly be imported medicine in the brain by the olfactory sensation passage of nasal cavity, improves the brain selectivity of acetylcholinesterase inhibitor class medicine, reduces the whole body toxic and side effects.
The specific embodiment
Embodiment 1
Huperzine A 0.1g
Anhydrous alcohol for medical use 20g
Distilled water adds to 100g
Method for making: huperzine A is added medicinal anhydrous alcohol solution, and adding distil water to capacity gets final product.Can directly make nasal cavity medicines such as nasal drop, nasal spray uses.
Embodiment 2
Huperzine A 0.1g
HP-10g
Distilled water adds to 100g
Method for making: after the 10g HP-added the 40g dissolved in distilled water, add huperzine A again, 50 ℃ of heating in water bath stir, medicine is dissolved fully after, adding distil water to capacity gets final product.Can directly make nasal cavity medicines such as nasal drop, nasal spray uses.Or lyophilization, again the sterilized powder that makes being added an amount of 0.9% sodium chloride solution, collunarium or spray nose use behind the suspendible; Or sterilized powder added the carrier of an amount of Grapefruit Essential Oil, as one or more of lactose, mannitol, starch or beta-schardinger dextrin-, fill behind the mixing, suck with powder inhalation device by nose and to use.
Embodiment 3
Huperzine A 0.1g
Polyoxyethylene hydrogenated Oleum Ricini condensation substance (Cremophor RH40) 8.1g
Anhydrous alcohol for medical use 3g
Linoleic acid polyethyleneglycol glyceride 1.25g
Distilled water adds to 100g
Method for making: earlier huperzine A is added medicinal anhydrous alcohol solution, adds polyoxyethylene hydrogenated Oleum Ricini condensation substance (Cremophor RH40) and linoleic acid polyethyleneglycol glyceride again and make dissolving, slowly add distilled water to capacity promptly.The microemulsion particle diameter is between 2～18nm.Can directly make nasal cavity medicines such as nasal drop, nasal spray uses.
Embodiment 4
Huperzine A 0.1g
Polyoxyethylene hydrogenated Oleum Ricini condensation substance (Cremophor RH40) 10g
Distilled water adds to 100g
Method for making: after polyoxyethylene hydrogenated Oleum Ricini condensation substance (Cremophor RH40) added the 40g dissolved in distilled water, add huperzine A again, 50 ℃ of heating in water bath stir, medicine is dissolved fully after, adding distil water to capacity gets final product.The vesicle particle diameter is between 2～10nm.Can directly make nasal cavity medicines such as nasal drop, nasal spray uses.
Embodiment 5
Huperzine A 0.1g
Polylactic acid-polyglycol block copolymer (MW:10 ten thousand) 0.5g
Oxolane 50g
Distilled water 200g
Method for making: principal agent huperzine A and polylactic acid-polyglycol block copolymer are dissolved in the oxolane altogether, above-mentioned organic facies are slowly splashed into 1: 4 volume ratio stir aqueous phase down, dialysis removal oxolane, promptly.Can directly make nasal cavity medicines such as nasal drop, nasal spray uses.Or add 1% HP-and make caffolding agent, lyophilization, the aseptic nanoparticle powder that will make again adds an amount of 0.9% sodium chloride solution, and collunarium or spray nose use behind the suspendible; Or aseptic nanoparticle powder added the carrier of an amount of Grapefruit Essential Oil, as one or more of lactose, mannitol, starch or beta-schardinger dextrin-, fill behind the mixing, suck with powder inhalation device by nose and to use.
The present invention is illustrated by above description and embodiment, more than is described as nonrestrictively, does not limit claim scope of the present invention.
Claims (15)
1. one kind as the huperzine A of general formula (1) and the per nasal brain targeting preparation of derivant or its salt thereof, it is characterized in that, for a kind of olfactory sensation passage by nasal cavity is directly imported medicine in the brain, the brain selectivity that improves acetylcholinesterase inhibitor class medicine is a bioavailability in the brain, reduce dosage, thereby reduce the per nasal brain targeting preparation of whole body toxic and side effects;
X Y Z
I H H NH
2
II H H
III H CH
3 NH
2
IV CH
3 H NH
2
V CH
3 CH
3 NH
2
2. the per nasal brain targeting preparation of huperzine A according to claim 1 and derivant or its salt, it is characterized in that huperzine A and derivant thereof are the chemical compounds of structural formula (I), structural formula (II), structural formula (III), structural formula (IV) or structural formula (IV).
3. the per nasal brain targeting preparation of huperzine A according to claim 1 and derivant or its salt, it is characterized in that huperzine A and derivant thereof or its salt are the chemical compound of structural formula (I), structural formula (II), structural formula (III), structural formula (IV) and structural formula (IV) and the salt of hydrochloric acid, acetic acid, phosphoric acid, sulphuric acid, lactic acid, citric acid or maleic acid be combined into.
4. according to the per nasal brain targeting preparation of the wherein said huperzine A of claim 1 and derivant or its salt, it is characterized in that, is nasal drop, nasal spray or insufflation.
5. according to the per nasal brain targeting preparation of each described huperzine A of claim 1～4 and derivant or its salt, it is characterized in that, is a kind of aqueous solution that contains the alcohol cosolvent, and component and weight percent content comprise:
Huperzine A 0.001～10%
Alcohol cosolvent 1～30%
Water surplus.
6. the per nasal brain targeting preparation of huperzine A according to claim 5 and derivant or its salt is characterized in that the alcohol cosolvent comprises one or more in ethanol, propylene glycol, glycerol, Polyethylene Glycol or the benzyl alcohol.
7. according to the per nasal brain targeting preparation of each described huperzine A of claim 1～4 and derivant or its salt, it is characterized in that, is a kind of cyclodextrin clathrate, and component and weight percent content comprise:
Huperzine A 0.001～10%
Cyclodextrin 1～40%
Water surplus.
8. the per nasal brain targeting preparation of huperzine A according to claim 7 and derivant or its salt, it is characterized in that, the ratio of cyclodextrin and medicine is 1: 1～1: 100, mol ratio, said cyclodextrin comprises alpha-cyclodextrin, a kind of or its mixture in beta-schardinger dextrin-or the gamma-cyclodextrin or derivatives thereof.
9. according to the per nasal brain targeting preparation of each described huperzine A of claim 1～4 and derivant or its salt, it is characterized in that, is a kind of microemulsion, and component and weight percent content comprise:
Huperzine A 0.001～10%,
Cosurfactant 1～10%,
Surfactant 1～10%,
Oil 1～10%,
Water surplus.
10. the per nasal brain targeting preparation of huperzine A according to claim 9 and derivant or its salt is characterized in that cosurfactant comprises one or more in ethanol, propylene glycol, glycerol, Polyethylene Glycol or the benzyl alcohol; Surfactant comprises one or more of phospholipid, Tweens, Myrij class (Myrjs), brejs (Brijs), polyoxyethylene castor oil condensation substance, polyoxyethylene hydrogenated Oleum Ricini condensation substance (Cremophors) or polyethers (Pluronics);
Said oil comprises fatty acid polyethyleneglycol glyceride series (LABRAFIL
), isopropyl myristate, ethyl oleate, glycerol list linoleate (Maisine 35-1), isostearic acid isostearate (Isostearyl isostearate), sad/certain herbaceous plants with big flowers acid glycerol three esters (Captex 355), median chain triglyceride oil Miglyol 812 (capric caprylic triglycerides), ethyl laurate, soybean oil one or more.
11., be a kind of surfactant vesicle solution, it is characterized in that component and weight percent content comprise according to the per nasal brain targeting preparation of each described huperzine A of claim 1～4 and derivant or its salt:
Huperzine A 0.001～10%
Surfactant 1～10%
Water surplus.
12. the per nasal brain targeting preparation of huperzine A according to claim 11 and derivant thereof or its salt, it is characterized in that said surfactant comprises one or more in phospholipid, Tweens (Tweens), Myrij class (Myrjs), brejs (Brijs), polyoxyethylene castor oil condensation substance and polyoxyethylene hydrogenated Oleum Ricini condensation substance (Cremophors) and the polyethers (Pluronics).
13. per nasal brain targeting preparation according to each described huperzine A of claim 1～4 and derivant or its salt, it is characterized in that, be a kind of nanoparticle, the molecular weight ranges that comprises the huperzine A of nanoparticle weight 2～50% and nanoparticle weight 50～98% is the biodegradable medicinal high polymer adjuvant between 5000～1000000.
14. the per nasal brain targeting preparation of huperzine A according to claim 13 and derivant thereof or its salt, it is characterized in that said medicinal high polymer adjuvant is selected from one or both or the two or more mixing in polylactide-co-glycolide, polylactic acid, polyglycolic acid, poly butyric ester, polylactic acid-polyglycolic acid, polylactic acid-glycollic acid, poly-adjacent ester, polylactone, polyanhydride, poly butyric ester-hydroxyl pentanoate copolymer, polyglycolic acid, polypropylene glucosan, hydroxyacetic acid, polylactic acid-polyglycol, the polyglycolic acid-Polyethylene Glycol.
15. the per nasal brain targeting preparation of huperzine A according to claim 13 and derivant thereof or its salt is characterized in that the nanoparticle particle diameter is between 20～200nm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310108852 CN1621039A (en) | 2003-11-25 | 2003-11-25 | Targeted preparation via nose to brain of Huperzine and its derivant or its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310108852 CN1621039A (en) | 2003-11-25 | 2003-11-25 | Targeted preparation via nose to brain of Huperzine and its derivant or its salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1621039A true CN1621039A (en) | 2005-06-01 |
Family
ID=34758751
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200310108852 Pending CN1621039A (en) | 2003-11-25 | 2003-11-25 | Targeted preparation via nose to brain of Huperzine and its derivant or its salt |
Country Status (1)
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| CN (1) | CN1621039A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100528844C (en) * | 2007-04-20 | 2009-08-19 | 中国科学院昆明植物研究所 | Huperzine A derivative, preparation method and application thereof |
| CN101264058B (en) * | 2007-03-13 | 2010-09-01 | 中国科学院上海药物研究所 | Huperzine A and its derivative or salts sustained-release nanometer granule and preparing method thereof |
| WO2012019439A1 (en) * | 2010-08-13 | 2012-02-16 | 中国科学院上海药物研究所 | Huperzine a ophthalmic microemulsion and preparation method thereof |
| WO2015043404A1 (en) * | 2013-09-24 | 2015-04-02 | 万邦德制药集团股份有限公司 | (-)-huperzine-a salt |
| WO2022111742A1 (en) | 2020-11-24 | 2022-06-02 | Centro De Neurociencias De Cuba | Pharmaceutical composition of naphthalene derivatives as multi-target therapeutic agents for the treatment of alzheimer's disease |
-
2003
- 2003-11-25 CN CN 200310108852 patent/CN1621039A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101264058B (en) * | 2007-03-13 | 2010-09-01 | 中国科学院上海药物研究所 | Huperzine A and its derivative or salts sustained-release nanometer granule and preparing method thereof |
| CN100528844C (en) * | 2007-04-20 | 2009-08-19 | 中国科学院昆明植物研究所 | Huperzine A derivative, preparation method and application thereof |
| WO2012019439A1 (en) * | 2010-08-13 | 2012-02-16 | 中国科学院上海药物研究所 | Huperzine a ophthalmic microemulsion and preparation method thereof |
| CN102370617A (en) * | 2010-08-13 | 2012-03-14 | 中国科学院上海药物研究所 | Ophthalmic huperzine A microemulsion and preparation method thereof |
| CN102370617B (en) * | 2010-08-13 | 2013-09-11 | 中国科学院上海药物研究所 | Ophthalmic huperzine A microemulsion and preparation method thereof |
| WO2015043404A1 (en) * | 2013-09-24 | 2015-04-02 | 万邦德制药集团股份有限公司 | (-)-huperzine-a salt |
| WO2022111742A1 (en) | 2020-11-24 | 2022-06-02 | Centro De Neurociencias De Cuba | Pharmaceutical composition of naphthalene derivatives as multi-target therapeutic agents for the treatment of alzheimer's disease |
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