CN1279065A - Medicinal composition for treating dysmnesia and senile dementia - Google Patents
Medicinal composition for treating dysmnesia and senile dementia Download PDFInfo
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- CN1279065A CN1279065A CN 99109457 CN99109457A CN1279065A CN 1279065 A CN1279065 A CN 1279065A CN 99109457 CN99109457 CN 99109457 CN 99109457 A CN99109457 A CN 99109457A CN 1279065 A CN1279065 A CN 1279065A
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- huperzine
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- senile dementia
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Abstract
A medicinal composition for treating dysmnesia and senile dementia by nasal cavity application contains transcutaneous huperzine or its similar, or the pharmaceutically receptable salt of transcutaneous huperzine or its similar and pharmaceutically receptable carrier. Its advantages include convenient application, high biological utilization rate and low by-effect.
Description
The present invention relates to a kind of pharmaceutical composition for the treatment of dysmnesia and senile dementia, especially for pharmaceutical composition that contains huperzine and analog thereof of nasal-cavity administration and preparation method thereof.
Serious day by day along with world's ageing phenomenon, benign memory deficits, and brain device matter dysmnesia and dull-witted, Alzheimer (Alzheimer ' s disease, AD) become senile common disease, more and more seriously endanger the healthy of people, also bring severe social problem.Existing studies show that, primary disease may make the damage of (Ach) nerve conduction because of brain neurotransmitter acetylcholine (Ach) level reduces, and causes the cholinergic system nonfunction, thereby dementia symptom such as dysmnesia occurs.Pass through to suppress the degraded of AchE with reversibility AchE inhibitor, thereby improve the level of Ach in the brain, treat senile dementia clinically and obtained effect preferably Ach.Relevant research report, with physostigmine, tacrine (tacrine), E2020 and huperzine are first-class comparatively detailed, and physostigmine has serious toxicity, and tacrine also has more serious hepatotoxicity, and this is restricted them in the use.And huperzine A has efficient selective to AchE in the brain, and the AchE at other position of health is not had effect; And different with tacrine and E2020, huperzine A can not cause the receptor of side effect in conjunction with the central nervous system, as muscarine M
1Receptor, M
2Receptor, this high selectivity make huperzine A to senile dementia and simple dysmnesia significant curative effect be arranged all, and side effect is seldom, but general spontaneous remission (Acta Pharmacologica Sinica, 12 (3), 250-252,1991).
The pharmacodynamics (Acta Pharmacologica Sinica, 1986,7:110-3) of the huperzine A injection that Wang Yue-e etc. have reported; The Orally administered composition of huperzine A is disclosed among the Chinese patent CN94103416.But because of the medication cycle of treatment dysmnesia and medicine for senile dementia longer, long term injections is brought very big inconvenience to the patient, and permanent oral patient's liver function is had adverse influence.Chinese patent CN95111588 discloses a kind of transcutaneous huperzing sticker, and to improve the comfort level of administration, but known owing to this area, this kind administering mode biology degree is low.So how both to have guaranteed its bioavailability, make things convenient for patient's long term administration again, alleviate its side effect, be a new problem.
Therefore, the purpose of this invention is to provide a kind of huperzine or its analog of containing, or the acceptable salt of medicine that forms of they and acid as active component pharmaceutical composition, said composition is suitable for passing through nasal-cavity administration, can guarantee the bioavailability of huperzine A, easy to use, less to the influence of human nasal ciliary movement.
The present invention also provides the preparation method of above-mentioned composition.
Pharmaceutical composition of the present invention is applicable to the treatment myasthenia gravis, Alzheimer (AD), and senile dementia and benign memory deficits, brain organic dysmnesia etc. also are used to prevent above-mentioned disease.
The huperzine of indication of the present invention and analog thereof have following structural formula (formula one):
R in the formula
1, R
2, R
3Can be respectively H or the low alkyl group that contains 1-7 carbon atoms.
The acceptable salt of pharmacy of the present invention can be the chemical compound and the organic acid of formula one, for example citric acid, oxalic acid, maleic acid, tartaric acid, benzoic acid, acetic acid, propanoic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid etc., it also can be the mineral acid example hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, the salt that nitric acid etc. form.
The chemical compound of preferred formula one is huperzine A or huperzine B.
Pharmaceutical composition of the present invention also contains the medicine acceptable carrier except active component, as: cyclodextrin and/or other saccharide and/or sugar alcohol and/or aromatic and/or be selected from a kind of in starch, polyacrylic acid, carbomer (Carbomer), polyvinyl alcohol, methylcellulose and the derivant thereof.
" cyclodextrin " refers to the cyclic oligosaccharide that is linked by 6～12 glucose molecules, as α-, β-, γ-cyclodextrin and derivant thereof, preferably methylated β-cyclodextrin and derivant thereof.In prescription, cyclodextrin plays stabilizing agent, solubilizing agent, absorption enhancer.Other saccharide refers to disaccharides, and for example lactose, maltose, sucrose also refer to polysaccharide, glucosan for example, and mean molecule quantity is preferably 40,000 to 70,000 between 10,000 to 100,000." sugar alcohol " refers to mannitol and Sorbitol.Aromatic is that the olfactory sensation to the people has good stimulation, has the material of aromatic odor, as Oleum menthae, Mentholum, Borneolum Syntheticum (Borneolum Syntheticum), Camphora, muscone etc.Traditional medicine thinks that they have the effect of " causing resuscitation with aromatic drugs, refreshment do not have through not reaching "; They can promote Transdermal absorption the modern medicine proof.In this pharmaceutical composition, they can play fragrant seasoning, sorbefacient effect, and its consumption is about between 0.001 to 0.5%w/w.Starch refers to degradable starch.Methylcellulose and derivant thereof refer to methylcellulose, hydroxypropyl emthylcellulose etc.Carbomer means acrylic acid-allyl sucrose copolymer, is preferably carbomer 934, and molecular weight is 3 * 10
6About.
Compositions of the present invention can randomly use other this area can the conventional excipient that uses, and antiseptic for example is as benzalkonium chloride, bromo geramine, phenethanol etc.; Buffer agent is a phosphate buffer etc.; Isoosmotic adjusting agent such as sodium chloride etc.; PH regulator and viscosifier, antioxidant, cosolvent, surfactant, adhesive, emulsifying agent etc.Its consumption and addition manner can be implemented by this area routine techniques.
This pharmaceutical composition can be any form of pharmaceutically receptible energy by nasal-cavity administration, as being liquid (as Emulsion, solution, suspension, viscosity liquid), solid (as powder, microsphere), semi-solid (as gel) form.This pharmaceutical composition can be by any device of nasal-cavity administration that is suitable for as utilizing administrations such as dropper, suction pipe, aerosol apparatus or sponge ball.Can also utilize aerosol drug delivery, propellant can be selected for use as closing Chlorofluorocarbons (CFCs) (CFC), hydrofluorocarbon (HFC), carbon dioxide or other suitable gas.
Preparation can provide with single dose or multiple dose form.
Be noted that especially powder formulation demonstrates high bioavailability and advantages of excellent stability, and adding preservative agent not in the powder formulation, antiseptic can produce harm to the nasal cavity ciliary movement.
Preparation of drug combination of the present invention can adopt the pharmaceutical field known method.As the solution of preparation process, water separately, for example distilled water or pure water, or use ethanol preparation, also available water and physiology acceptable other solvents, for example mixed solvent of ethanol, propylene glycol, Polyethylene Glycol such as PEG400 preparation.
The preparation method of powder formulation is, at first preparation contains the solution of active component and excipient, vapors away solvent by lyophilization or other modes such as spray drying then, with this area routine techniques it is crushed to the powder of desired particle size then.At last,, obtain particle diameter, preferably between the granule of 50 to 100 μ m less than 100 μ m with the sieve in suitable aperture.
The pH value of pharmaceutical composition of the present invention should be preferably 5-7 in 4-7 scopes, be most preferably 5.5～6.5.
Pharmaceutical composition of the present invention, liquid, semi-solid form in this way, dosage is the each 0.05ml to 0.15ml in each nostril normally, and preferably each nostril is O.1ml.As be powder type, dosage is usually between 1mg to 15mg, preferably each nostril 5-10mg.Zoopery shows that huperzine A is t behind vein and nasal-cavity administration
1/2α is respectively 6.6min and 7.4min, t
1/2β is respectively 150 ± 53.0 and 180 ± 50.0min, and the bioavailability of nasal cavity applied medicine is about 98.3%.As seen after the administration of huperzine A via intranasal application, it is fast to play a role, and can guarantee its bioavailability.
So pharmaceutical composition advantage of the present invention is: by nasal-cavity administration, can overcome blood brain barrier, make medicine directly be delivered to the brain lesion place.In addition, because the nasal mucosa blood capillary is abundant, drug absorption is rapid, and directly enters the body circulation, no liver first-pass effect, its bioavailability is generally higher, can near or above injection system, thereby dosage is little.
Therefore, nasal administration composition of the present invention has easy to usely, is fit to long term administration, characteristics such as bioavailability height.
Following non-limiting example further specifies the present invention, and the preparation method among the embodiment is a preparation method general in this area.
Embodiment 1 huperzine liquid A prescription huperzine 30mg2,6-dimethyl-β-every 100ml solution of cyclodextrin 2.5g menthol 0.010g benzalkonium chloride 0.010gEDTA-Na 0.010g D-sorbite 2.0g distilled water 100ml contains huperzine 30mg
Embodiment 2 Huperzine B liquid A prescription huperzine 150mg2,6-dimethyl-β-every 100ml solution of cyclodextrin 2.50g menthol 0.010g benzalkonium chloride 0.010gEDTA-Na 0.010g D-sorbite 2.0g distilled water 100ml contains Huperzine B 150mg
Embodiment 3 huperzine gel A prescription huperzine 30mg2,6-dimethyl-β-cyclodextrin 1.50g benzalkonium chloride 0.01gEDTA-every 100ml gel of Na 0.1g D-sorbite 5g hydroxypropyl methylcellulose 1.5g pure water 100ml contains huperzine 30mg
Embodiment 4 huperzine gel B prescription huperzine 30mg β-every 100ml gel of cyclodextrin 1.50g polyvinyl alcohol 4g benzalkonium chloride 0.01g distilled water 100ml contains huperzine 30mg
The every 100ml gel of embodiment 5 Huperzine B gel A prescription Huperzine B 150mg carbomer 934 1.50g triethanolamine 1.0g menthol 0.01g distilled water 100ml contains Huperzine B 150mg
Embodiment 6 powders A prescription huperzine A 30mg2,6 dimethyl-β-every 10g powder of cyclodextrin 4.4g mannitol 5.57g contains huperzine A 0.030g
The every 10g powder of embodiment 7 powder B prescription huperzine A 30mg glucosan (mean molecule quantity 70,000) 9.97g contains huperzine A 30mg
Embodiment 8 powder C prescription huperzine 30mg β-every 10g powder of cyclodextrin 0.5g lactose 9.47g contains huperzine 30mg
The every 10g powder of embodiment 9 powder D prescription huperzine 30mg borneol 0.10g sucrose 9.87g contains huperzine 30mg
Embodiment 10 microballoons prescription huperzine 30mg degradable starch 10.0g adding distil water to the every 10g spherex of 100ml freeze drying contains huperzine 30mg
Claims (8)
1, a kind of pharmaceutical composition that is used for nasal-cavity administration treatment dysmnesia disease and senile dementia, contain huperzine or its analog and/or the acceptable salt of its medicine and the medicine acceptable carrier of following structural:
R in the formula
1, R
2, R
3Can be respectively H or the low alkyl group that contains 1-7 carbon atoms.
2, pharmaceutical composition as claimed in claim 1, described huperzine are huperzine A or huperzine B.
3, pharmaceutical composition as claimed in claim 1, described huperzine are huperzine A.
4, pharmaceutical composition as claimed in claim 1, its preparation are the dry powder nasal spray preparation.
5, pharmaceutical composition as claimed in claim 1, its preparation are the nasal drop body preparation.
6, pharmaceutical composition as claimed in claim 1, described medicine acceptable carrier are cyclodextrin or derivatives thereof and/or other saccharide and/or sugar alcohol and/or aromatic and/or are selected from starch, polyacrylic acid, carbomer, polyvinyl alcohol, methylcellulose or derivatives thereof.
7, preparation of drug combination method as claimed in claim 1 is characterized in that active component is prepared mutually with the medicine acceptable carrier.
8, pharmaceutical composition as claimed in claim 1 is the medicine as nasal-cavity administration treatment dysmnesia disease and senile dementia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99109457 CN1279065A (en) | 1999-07-06 | 1999-07-06 | Medicinal composition for treating dysmnesia and senile dementia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99109457 CN1279065A (en) | 1999-07-06 | 1999-07-06 | Medicinal composition for treating dysmnesia and senile dementia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1279065A true CN1279065A (en) | 2001-01-10 |
Family
ID=5273928
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 99109457 Pending CN1279065A (en) | 1999-07-06 | 1999-07-06 | Medicinal composition for treating dysmnesia and senile dementia |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003004024A1 (en) * | 2001-07-03 | 2003-01-16 | Shandong Luye Pharmaceutical Co., Ltd. | Injectable sustained-release microspheres of huperzine a compounds |
| WO2006056129A1 (en) * | 2004-11-26 | 2006-06-01 | Delong Xie | Compositions of huperzia serrata alkaloids comprising huperzine a and huperzine b and preparation thereof |
| EP1977735A1 (en) | 2003-03-14 | 2008-10-08 | Debio Recherche Pharmaceutique S.A. | Subcutaneous delivery system, process for the preparation of the same and use of the same for the treatment of cholinergic deficient disorders |
| CN101244026B (en) * | 2007-02-14 | 2011-03-16 | 中国科学院上海药物研究所 | Huperzine and its derivant or its salt implantation agent, its preparation method and application |
| CN1961879B (en) * | 2005-11-09 | 2011-11-30 | 上海医药工业研究院 | Pharmaceutical composition for nose administered in-situ gel spray of Huperzine A, preparation process and use thereof |
| CN103386005A (en) * | 2012-05-12 | 2013-11-13 | 石家庄以岭药业股份有限公司 | Application of traditional Chinese medicinal composition in preparation of medicines for treating study and memory disorders |
-
1999
- 1999-07-06 CN CN 99109457 patent/CN1279065A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003004024A1 (en) * | 2001-07-03 | 2003-01-16 | Shandong Luye Pharmaceutical Co., Ltd. | Injectable sustained-release microspheres of huperzine a compounds |
| DE10297018B4 (en) * | 2001-07-03 | 2010-01-28 | Shandong Luye Pharmaceutical Co., Ltd., Yantai City | Depot microspheres for the injection of huperzine A compounds |
| EP1977735A1 (en) | 2003-03-14 | 2008-10-08 | Debio Recherche Pharmaceutique S.A. | Subcutaneous delivery system, process for the preparation of the same and use of the same for the treatment of cholinergic deficient disorders |
| WO2006056129A1 (en) * | 2004-11-26 | 2006-06-01 | Delong Xie | Compositions of huperzia serrata alkaloids comprising huperzine a and huperzine b and preparation thereof |
| US8574633B2 (en) | 2004-11-26 | 2013-11-05 | Delong Xie | Huperzia serrata (Thunb.) Trev. composition comprising compounded Huperzine A and Huperzine B and methods for preparing it |
| CN1961879B (en) * | 2005-11-09 | 2011-11-30 | 上海医药工业研究院 | Pharmaceutical composition for nose administered in-situ gel spray of Huperzine A, preparation process and use thereof |
| CN101244026B (en) * | 2007-02-14 | 2011-03-16 | 中国科学院上海药物研究所 | Huperzine and its derivant or its salt implantation agent, its preparation method and application |
| CN103386005A (en) * | 2012-05-12 | 2013-11-13 | 石家庄以岭药业股份有限公司 | Application of traditional Chinese medicinal composition in preparation of medicines for treating study and memory disorders |
| CN103386005B (en) * | 2012-05-12 | 2017-08-25 | 石家庄以岭药业股份有限公司 | A kind of application of Chinese medicine composition in the medicine for preparing treatment learning memory disorder |
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