CN101152182A - Drug administration preparations of ligustrazine for nasal mucosa and method for preparing the same - Google Patents
Drug administration preparations of ligustrazine for nasal mucosa and method for preparing the same Download PDFInfo
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- CN101152182A CN101152182A CNA2007101575044A CN200710157504A CN101152182A CN 101152182 A CN101152182 A CN 101152182A CN A2007101575044 A CNA2007101575044 A CN A2007101575044A CN 200710157504 A CN200710157504 A CN 200710157504A CN 101152182 A CN101152182 A CN 101152182A
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Abstract
The invention belongs to medical technical field and discloses nasal mucosa medication agent of tetramethylpyrazine and the preparation method. The agent contains tetramethylpyrazine, pharmaceutical excipient and absorption enhancer. The weight percentage is 1:0.1 to 100:0.1 to 10. The tetramethylpyrazine includes tetramethylpyrazine prepared in various methods and salts of tetramethylpyrazine. Formula dosage of tetramethylpyrazine is put into absorption enhancer and additional pharmaceutical solutions of suitable concentration prepared in advance to produce nasal mucosa medication agent, such as nasal drops, spray, aerosol, microsphere agent, liposomes, etc. Via the special physiological structure of nasal cavity, the agent medicates via nasal mucosa and allows tetramethylpyrazine bypasses the blood-brain barrier to enhance the distribution of medicine in brain tissue. The drug can be used to treat migraine, cerebral ischemia, cerebral embolism and emergencies such as angina pectoris, coronary heart disease, myocardial infarction, etc, and the drug has the advantages of complete and rapid absorption, high treating effects, high stability, and few side effects.
Description
Technical field
The present invention relates to medical technical field, relate to nasal mucosa medicine administration preparation of ligustrazine and preparation method thereof, this nasal mucosa preparation can be used for treating migraine, also can be used for the treatment of emergency cases such as cerebral ischemia, cerebral embolism, angina pectoris, coronary heart disease, impatient infraction, have good absorbing, absorb rapid, curative effect is high, good stability, the little advantage of side effect.
Background technology
Suffer from patient's large contingent of central nervous system (central nervous sysem.CNS) disease, comprise migraine headache, the cerebral tumor, central nervous system infection etc.But because the existence of natural physiologic barrier one blood brain barrier (blood-brain barrier.BBB) of cerebral tissue, make that strong medicine can't lose curative effect by blood brain barrier more than 95%.Have a contradictory phenomena in present neural study of pharmacy: the strength more than 99% of global medicine for central nervous system development is used to seek new medicine, has only the strength of less than 1% to be used to study drug delivery system.Therefore, how to open up new drug delivery system and new route of administration, thereby break through blood brain barrier, the research that the medicine directional profile is unified the brain targeting preparation in central nervous system is the break-through point of research.Because there is unique natural link in nasal mucosa with brain on anatomical physiology, therefore in the more than ten years recently, become the focus of research field for this reason.Drug molecule can be by the olfactory region mucosa along surrounding the nervi olfactory bundle conjunctive tissue on every side or aixs cylinder arrival cerebrospinal fluid (the cerebral spinal fluid of nervi olfactory unit behind the nasal-cavity administration, CSF) or brain, thereby can walk around BBB and enter CNS, the performance therapeutical effect.Make medicine pass through the nasal-cavity administration targeting, not only absorb rapidly, avoid liver first-pass effect, improve bioavailability of medicament, reduce toxic and side effects, and can significantly improve the distribution of medicine in cerebral tissue, improve the therapeutic efficiency of medicine in the central nervous system.
Migrainous treatment is a good illustration of being benefited from the nasal cavity medicine-releasing system.Migrainous treatment is approximately 1,700,000,000 pounds (being roughly equal to 26.8 hundred million dollars) in global market value.The whole world has 37% patient not accept the treatment of prescription drugs according to estimates, because traditional prescription drugs causes 40% patient the internal organs side effect to occur.The nasal-cavity administration product sumatriptan that the plain prestige Kanggong department of Ge Lan is developed occupies 55% share on migrainous treatment market, its sumatriptan nasal cavity preparation is got permission in European Union in December, 1996, and in April, 1997 is the trade name listing with Imitrex in the U.S..
The alkaloid monomer of ligustrazine system extraction separation from Umbelliferae Rhizoma Ligustici platymiscium Rhizoma Chuanxiong foundation, main pharmacological is expansion blood vessel, microcirculation improvement and anti-platelet aggregation etc., clinical practice is extensive, be used for the treatment of migraine, central nervous system disease such as cerebral ischemia, cerebral embolism, it also has important effect in emergency cases such as treatment angina pectoris, coronary heart disease, myocardial infarction.But the ligustrazine oral administration biaavailability is very low, influences the performance of its curative effect.It is early on the books, rapid-action in the traditional Chinese medical science by nasal-cavity administration treatment migraine to use Rhizoma Chuanxiong, determined curative effect.Therefore, the nasal cavity administrated preparation of research ligustrazine is used for the treatment of migraine, cerebral ischemia, cerebral embolism not only can increase the distribution of medicine at cerebral tissue, improve therapeutic efficiency, and can avoid the liver first-pass effect, utilize nasal mucosa medicine administration rapid-action, emergency cases such as the characteristics treatment angina pectoris of no first-pass effect, coronary heart disease, myocardial infarction, the drug-supplying system that has independent intellectual property right for development China is significant.
Summary of the invention
The objective of the invention is to make ligustrazine to bring into play clinical efficacy by nasal mucosa medicine administration, a kind of nasal mucosa medicine administration preparation of ligustrazine is provided, they have fast, good absorbing, bioavailability height, the little characteristics of side effect of absorbing.Preparation method is provided simultaneously.
The present invention selects nasal mucosa as route of administration, mainly be because there is unique natural link in nasal mucosa with brain on anatomical physiology, can make medicine avoid the blood brain barrier targeting in the central nervous system, significantly improve the distribution of medicine in cerebral tissue and the therapeutic efficiency of medicine by nasal-cavity administration.Nasal mucosa is very thin, blood flow is abundant, drug absorption is rapid, and can absorb directly into blood and avoid gastrointestinal tract and liver first-pass effect, increase the absorbtivity that ligustrazine sees through nasal mucosa by adding different types of absorption enhancer safely and effectively, provide the convenience of clinical application by making different dosage forms.Thereby the raising bioavailability of medicament can be used for treating migraine, cerebral ischemia, cerebral infarction, is specially adapted to the treatment of emergency cases such as angina pectoris, coronary heart disease, myocardial infarction.
The present invention selects polyethylene glycols, propandiols etc. to increase the dissolubility of ligustrazine under physiological condition as cosolvent; Select the nicotinoyl Ammonia to increase the dissolubility of ligustrazine under physiological condition as cosolvent; Utilize the clathration of cyclodextrin to increase the dissolubility of ligustrazine under physiological condition; Select Tweens, Borneolum Syntheticum class to increase the abundance of ligustrazine at cerebral tissue; Select different types of absorption enhancers such as cyclodextrin and derivant, chitosan and derivatives class thereof and tween, Borneolum Syntheticum to enter systemic blood circulation amount by Nasal Mucosa Absorption to increase ligustrazine; Select two or more absorption enhancer to share to promote ligustrazine to see through the absorption of nasal mucosa.The nasal mucosa medicine administration preparation of ligustrazine is made up of ligustrazine, pharmaceutic adjuvant and absorption enhancer, and its weight percentage composition is: 1: 0.1-100: 0.1-10.Described ligustrazine comprises by the ligustrazine of prepared in various methods and its esters.
Described pharmaceutic adjuvant comprises cosolvent, cosolvent, solubilizing agent, antioxidant, antibacterial, and cosolvent, cosolvent, the consumption of solubilizing agent are between 1-40%, and the consumption of antibacterial is between 0.01-2%.
Cosolvent is polyethylene glycols, propylene glycol, glycerol, ethanol; Cosolvent is cyclodextrin, nicotinamide and other small-molecule substances; Solubilizing agent is the Tweens surfactant.
Described nasal mucosa medicine administration preparation comprises nasal drop, spray, powder spray, aerosol, microball preparation, nano-complex, liposome.
Described " absorption enhancer " comprises cyclodextrin and derivatives class thereof, Borneolum Syntheticum class, polyethylene glycols, Tweens, chitosan class, also can two or more the mixing of absorption enhancer use.
Described cyclodextrin and derivatives class thereof comprise beta-schardinger dextrin-, HP-beta cyclodextrin, dimethyl beta cyclodextrin and other cyclodextrin derivative.
It is characterized in that: the chitosan class of indication comprises chitosan and other chitosan derivatives of the chitosan of different molecular weight, different deacetylations, the trimethyl chitosan of different molecular weight, the chitosan of different sulfydryl substitution values, different Polyethylene Glycol substitution values.
The preparation method of ligustrazine nasal mucosa medicine administration preparation is as follows among the present invention: the ligustrazine of recipe quantity is joined under stirring condition in the in advance dissolved solution that contains suitable concentration absorption enhancer and other additives, make the solution nasal drop.Concentration is close with nasal drop commonly used.Also can be with filled with solution spray delivery in specific container, or pour into a certain amount of propellant with the aerosol form administration by pressing.Can also make the microball preparation and the Liposomal formulation of ligustrazine as required, with solution or spraying, aerosol form nasal mucosa medicine administration.
The ligustrazine nasal mucosa microball preparation of indication can be a chitosan microball among the present invention, also can be derivant microsphere, spherex, gelatine microsphere of chitosan etc.
The ligustrazine nasal mucosa microball preparation of indication can adopt spray drying method for preparation among the present invention, also can adopt the solvent evaporation method preparation.
The oral absorption that the invention solves ligustrazine is bad, and gastrointestinal tract and liver first-pass effect are big, and the problem that cerebral tissue Chinese medicine concentration is low utilizes unique physiological structure of nasal mucosa that medicine is brought into cerebral tissue and avoided blood brain barrier; Utilize the nasal mucosa blood capillary abundant, the characteristics that mucosa is thin make drug absorption rapid, and are rapid-action.The nasal mucosa medicine administration preparation of ligustrazine of the present invention can be made various dosage forms as required, with solution or aerosol or the administration of powder mode, can further improve curative effect, increases the convenience of medication, has reduced side effects of pharmaceutical drugs.
The specific embodiment
Embodiment 1: the preparation of ligustrazine collunarium solution: take by weighing chitosan and make 1% solution, the nicotiamide of adding 7% is as cosolvent.Take by weighing the ligustrazine of recipe quantity, join under stirring condition in above-mentioned chitosan/nicotiamide mixed solution, make the solution that contains ligustrazine 20mg/ml, add the antiseptic benzalkonium bromide, stir, the regulator solution pH value is 6.0, filter, and sterilization, packing, promptly.
Embodiment 2: the preparation of ligustrazine collunarium solution: take by weighing the HP-beta cyclodextrin and make 30% solution, the ligustrazine that takes by weighing recipe quantity joins under stirring condition in the above-mentioned HP-beta cyclodextrin solution, make the solution that contains ligustrazine 20mg/ml, add the antiseptic benzalkonium bromide, stir, the regulator solution pH value is 6.0, filter, sterilization, packing, promptly.
Embodiment 3: the preparation of ligustrazine collunarium solution: take by weighing the HP-beta cyclodextrin and make 30% solution, add the stirring of 1% chitosan and make dissolving.Take by weighing the ligustrazine of recipe quantity, join under stirring condition in above-mentioned chitosan/HP-beta cyclodextrin mixed solution, make the solution that contains ligustrazine 20mg/ml, add the antiseptic benzalkonium bromide, stir, the regulator solution pH value is 6.0, filter, and sterilization, packing, promptly.
Embodiment 4: the preparation of ligustrazine collunarium solution: take by weighing the HP-beta cyclodextrin and make 30% solution, add 1% chitosan, 1% tween, stir and make dissolving.Take by weighing the ligustrazine of recipe quantity, under stirring condition, join in above-mentioned chitosan/HP-beta cyclodextrin/tween mixed solution, make the solution that contains ligustrazine 20mg/ml, add the antiseptic benzalkonium bromide, stir, the regulator solution pH value is 6.0, filters, sterilization, packing, promptly.
Embodiment 5: the preparation of ligustrazine collunarium solution: take by weighing Borneolum Syntheticum and make 1% alcoholic solution in right amount, the nicotiamide of adding 7% is as cosolvent.Take by weighing the ligustrazine of recipe quantity, join under stirring condition in above-mentioned Borneolum Syntheticum/nicotiamide mixed solution, make the solution that contains ligustrazine 20mg/ml, add the antiseptic benzalkonium bromide, stir, the regulator solution pH value is 6.0, filter, and sterilization, packing, promptly.
Embodiment 6: the preparation of ligustrazine collunarium solution: take by weighing Borneolum Syntheticum and make 1% alcoholic solution in right amount, take by weighing the HP-beta cyclodextrin and make 30% solution in right amount.Take by weighing the ligustrazine of recipe quantity, join under stirring condition in above-mentioned Borneolum Syntheticum/HP-beta cyclodextrin mixed solution, make the solution that contains ligustrazine 20mg/ml, add the antiseptic benzalkonium bromide, stir, the regulator solution pH value is 6.0, filter, and sterilization, packing, promptly.
Embodiment 7: the preparation of ligustrazine collunarium solution: take by weighing Borneolum Syntheticum and make 1% alcoholic solution in right amount, take by weighing chitosan and make 1% solution, the nicotiamide of adding 7% is as cosolvent.Take by weighing the ligustrazine of recipe quantity, join under stirring condition in above-mentioned Borneolum Syntheticum/chitosan/nicotiamide mixed solution, make the solution that contains ligustrazine 20mg/ml, add the antiseptic benzalkonium bromide, stir, the regulator solution pH value is 6.0, filter, and sterilization, packing, promptly.
Embodiment 8: the preparation of ligustrazine collunarium solution: take by weighing the HP-beta cyclodextrin and make 30% solution in right amount, add 1% Tween 80.Take by weighing the ligustrazine of recipe quantity, join in the above-mentioned solution under stirring condition, make the solution that contains ligustrazine 20mg/ml, add the antiseptic benzalkonium bromide, stir, the regulator solution pH value is 6.0, filter, and sterilization, packing, promptly.
Embodiment 9: the preparation of ligustrazine collunarium solution: take by weighing the HP-beta cyclodextrin and make 30% solution in right amount, add 1% Tween 80 and 1% Borneolum Syntheticum.Take by weighing the ligustrazine of recipe quantity, join in the above-mentioned mixed solution under stirring condition, make the solution that contains ligustrazine 20mg/ml, add the antiseptic benzalkonium bromide, stir, the regulator solution pH value is 6.0, filter, and sterilization, packing, promptly.
Embodiment 10: the preparation of ligustrazine nasal spray: the ligustrazine collunarium solution branch of above-mentioned preparation is installed in the aerosol apparatus of suitable specification, promptly.
Embodiment 11: the preparation of ligustrazine nose aerosol: the ligustrazine collunarium solution branch of above-mentioned preparation is installed in the aerosol container of suitable specification, and plunging pours into propellant, promptly.
Embodiment 12: the ligustrazine nose is with the preparation of microsphere powder spray agent: the chitosan that takes by weighing recipe quantity is made 2% solution, add 1% tween, the ligustrazine that takes by weighing recipe quantity adds in the chitosan solution (ligustrazine 30mg/ml), adopt the chitosan microball of spray drying method for preparation ligustrazine, the particle diameter of control microsphere is between 30-60um, divide in the automiser spray that installs to suitable specification, promptly.
Above ligustrazine nasal mucosa drug-delivery preparation through the administration of rat nasal mucosa, is got rat and is dorsal position, the administration of bilateral nostril, medicine sees through bronchia mucosal and absorbs rapidly, and rapid-action, medicine blood drug level in 3-5 minute reaches the peak.
Claims (9)
1. the nasal mucosa medicine administration preparation of ligustrazine, it is characterized in that: be made up of ligustrazine, pharmaceutic adjuvant and absorption enhancer, its weight percentage composition is: 1: 0.1-100: 0.1-10.
2. the nasal mucosa medicine administration preparation of ligustrazine according to claim 1, it is characterized in that: described ligustrazine comprises by the ligustrazine of prepared in various methods and its esters.
3. the nasal mucosa medicine administration preparation of ligustrazine according to claim 1, it is characterized in that: described pharmaceutic adjuvant comprises cosolvent, cosolvent, solubilizing agent, antioxidant, antibacterial, cosolvent, cosolvent, the consumption of solubilizing agent is between 1-40%, and the consumption of antibacterial is between 0.01-2%.
4. the nasal mucosa medicine administration preparation of ligustrazine according to claim 3, it is characterized in that: cosolvent is polyethylene glycols, propylene glycol, glycerol, ethanol; Cosolvent is cyclodextrin, nicotinamide and other small-molecule substances; Solubilizing agent is the Tweens surfactant.
5. the nasal mucosa medicine administration preparation of ligustrazine according to claim 1, it is characterized in that: described nasal mucosa medicine administration preparation comprises nasal drop, spray, powder spray, aerosol, microball preparation, nano-complex, liposome.
6. the nasal mucosa medicine administration preparation of ligustrazine according to claim 1, it is characterized in that: described " absorption enhancer " comprises cyclodextrin and derivatives class thereof, Borneolum Syntheticum class, polyethylene glycols, Tweens, chitosan class, also can two or more the mixing of absorption enhancer use.
7. the nasal mucosa medicine administration preparation of ligustrazine according to claim 6, it is characterized in that: described cyclodextrin and derivatives class thereof comprise beta-schardinger dextrin-, HP-beta cyclodextrin, dimethyl beta 3 cyclodextrin and other cyclodextrin derivative.
8. the nasal mucosa medicine administration preparation of ligustrazine according to claim 6, it is characterized in that: the chitosan class of indication comprises chitosan and other chitosan derivatives of the chitosan of different molecular weight, different deacetylations, the trimethyl chitosan of different molecular weight, the chitosan of different sulfydryl substitution values, different Polyethylene Glycol substitution values.
9. the preparation method of the nasal mucosa medicine administration preparation of a ligustrazine as claimed in claim 1, it is characterized in that: the ligustrazine of recipe quantity is joined under stirring condition in the in advance dissolved solution that contains absorption enhancer and other additives, make the nasal mucosa medicine administration preparation.
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| CNA2007101575044A CN101152182A (en) | 2007-10-17 | 2007-10-17 | Drug administration preparations of ligustrazine for nasal mucosa and method for preparing the same |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756954A (en) * | 2010-01-05 | 2010-06-30 | 沈阳药科大学 | Schneiderian membrane medication preparation of isosorbide dinitrate and preparation method thereof |
| CN104323996A (en) * | 2010-07-29 | 2015-02-04 | 湖南康都制药有限公司 | Ligustrazine phosphate lipidosome combined drug, and large-scale production process and application thereof |
| CN104888270A (en) * | 2015-04-13 | 2015-09-09 | 王继宏 | Application of absorbable membrane in sheath tendon |
| CN105147721A (en) * | 2015-08-28 | 2015-12-16 | 施康培医疗科技（武汉）有限公司 | Antibacterial cleaning agent and application method thereof |
| CN105232598A (en) * | 2015-11-04 | 2016-01-13 | 天津市中宝制药有限公司 | Chinese herbal compound quick-acting nasal cavity clip film for relieving heart attack and preparation method thereof |
| CN109528788A (en) * | 2018-12-11 | 2019-03-29 | 广州中医药大学第附属医院 | A kind of load cnidium oil nano-carrier and preparation method thereof of percutaneous dosing treatment ischemic angiocardiopathy and cerebrovascular disease |
| WO2019161761A1 (en) * | 2018-02-23 | 2019-08-29 | 中国中医科学院中药研究所 | A pharmaceutical composition for treating malaria |
| US11667612B2 (en) * | 2017-10-25 | 2023-06-06 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Compositions and methods for delivering pharmaceutical agents |
-
2007
- 2007-10-17 CN CNA2007101575044A patent/CN101152182A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756954A (en) * | 2010-01-05 | 2010-06-30 | 沈阳药科大学 | Schneiderian membrane medication preparation of isosorbide dinitrate and preparation method thereof |
| CN101756954B (en) * | 2010-01-05 | 2013-07-31 | 沈阳药科大学 | Schneiderian membrane medication preparation of isosorbide dinitrate and preparation method thereof |
| CN104323996A (en) * | 2010-07-29 | 2015-02-04 | 湖南康都制药有限公司 | Ligustrazine phosphate lipidosome combined drug, and large-scale production process and application thereof |
| CN104888270A (en) * | 2015-04-13 | 2015-09-09 | 王继宏 | Application of absorbable membrane in sheath tendon |
| CN105147721A (en) * | 2015-08-28 | 2015-12-16 | 施康培医疗科技（武汉）有限公司 | Antibacterial cleaning agent and application method thereof |
| CN105232598A (en) * | 2015-11-04 | 2016-01-13 | 天津市中宝制药有限公司 | Chinese herbal compound quick-acting nasal cavity clip film for relieving heart attack and preparation method thereof |
| US11667612B2 (en) * | 2017-10-25 | 2023-06-06 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Compositions and methods for delivering pharmaceutical agents |
| WO2019161761A1 (en) * | 2018-02-23 | 2019-08-29 | 中国中医科学院中药研究所 | A pharmaceutical composition for treating malaria |
| CN109528788A (en) * | 2018-12-11 | 2019-03-29 | 广州中医药大学第附属医院 | A kind of load cnidium oil nano-carrier and preparation method thereof of percutaneous dosing treatment ischemic angiocardiopathy and cerebrovascular disease |
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