CN101856329B - Rizatriptan benzoate oral spray - Google Patents
Rizatriptan benzoate oral spray Download PDFInfo
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- CN101856329B CN101856329B CN2010101912849A CN201010191284A CN101856329B CN 101856329 B CN101856329 B CN 101856329B CN 2010101912849 A CN2010101912849 A CN 2010101912849A CN 201010191284 A CN201010191284 A CN 201010191284A CN 101856329 B CN101856329 B CN 101856329B
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Abstract
The invention discloses a rizatriptan benzoate oral spray taking water as a solvent and containing the following components by content: 3.6-14.5 g/100 ml of rizatriptan benzoate, 0.1-50 g/100 ml of solubilizers, 0.05-5 g/100 ml of sorbefacients and 0.01-3 g/100 ml of flavoring agents. The rizatriptan benzoate oral spray sprays for drug administration through an oral cavity or a hypoglossis, and then drugs can be absorbed by mucosae of the oral cavity or the hypoglossis so as to avoid liver first-pass effect and food influence and realize fast absorption, quick effect and high bioavailability; in addition, the rizatriptan benzoate oral spray is convenient to use without being taken with water during drug administration and is especially suitable for patients who are not obedient to oral administration and injection drug administration; and besides, the rizatriptan benzoate oral spray is a liquid formulation, has no dust in the production process, and has easy labor protection and lower cost of mass production.
Description
Technical field
The present invention relates to a kind of Lizakuputan benzoate preparation.
Technical background
Lizakuputan benzoate is second filial generation 5-hydroxy tryptamine (5-HT) receptor stimulating agent, is used to treat acute migraine in U.S. listing in 1998, advantage such as have that rapid-action, good effect, dosage are low, applied range, side effect are little.Oral Lizakuputan benzoate 5mg is higher than the general smooth type medicine sumatriptan 100mg of the first generation to migrainous remission rate, and side effect is light than sumatriptan, can be used for having or the acute treatment of absence of aura migraine, and is effective to the recurrent migraine.The outstanding feature of Lizakuputan benzoate is that 5-HT1B and 5-HT1D are had high affinity; And it is lower to other 5-HT1 receptor and 5-HT7 receptor affinity; 5-HT2,5-HT3, epinephrine, DA, histamine, choline or BZ receptor are not had obvious activity, therefore can be used for hyperpietic's migraine treatment.
The bioavailability of Lizakuputan benzoate oral administration is merely 45%, and reaching maximum plasma concentration needs 1～1.5 hour, biological half-life (t approximately
1/2) be about 2-3 hour.Though the bioavailability of food para Toluic Acid rizatriptan does not have tangible influence, make peak time postpone about 1 hour.
At present; The Lizakuputan benzoate preparation of listing has tablet, oral cavity disintegration tablet, freeze-dried instant sheet and capsule etc.; Be oral solid formulation, onset is slower, headache remission rate only 13～28% after oral 30 minutes; Remission rate is 70% after 2 hours, is pressing for of migraineur and alleviate the headache symptom rapidly.Though the dissolution rate of freeze-dried instant sheet is fast, the production cost of freeze-dry process is high.Simultaneously, the first pass effect of Lizakuputan benzoate oral administration is obvious, and bioavailability is lower, needs to adopt preparation technique to improve its bioavailability.
Summary of the invention
The object of the present invention is to provide a kind of Rizatriptan benzoate oral spray and preparation method thereof,, meet clinical needs better to overcome the defective that prior art exists.Rizatriptan benzoate oral spray of the present invention is a solvent with water, contains the component of following content:
Lizakuputan benzoate 3.6-14.5g/100ml
Solubilizing agent 0.1-50g/100ml
Absorption enhancer 0.05-5g/100ml
Correctives 0.01-3g/100ml
Wherein: 100ml refers to, and is that 100ml is a benchmark with the volume of said Rizatriptan benzoate oral spray;
Said solubilizing agent is also referred to as cosolvent, can select in alcohols, organic acid or the surfactant more than one for use;
Said alcohols is selected from more than one in ethanol, propylene glycol, glycerol or the Polyethylene Glycol;
Said organic acid is selected from more than one in acetic acid, citric acid, tartaric acid or the malic acid;
Said surfactant is selected from more than one in tween, poloxamer, Myrij or the sodium laurylsulfate;
The purpose of using solubilizing agent is to improve the dissolubility of Lizakuputan benzoate and/or correctives;
Said absorption enhancer is selected from more than one in water solublity azone, sad capric acid polyethyleneglycol glyceride (labrasol), Capric acid sodium salt, Borneolum Syntheticum, chitosan, carbopol or the hydroxypropyl methyl fiber etc.; Preferred Capric acid sodium salt, sad capric acid polyethyleneglycol glyceride or carbopol; Be used for mainly promoting that Lizakuputan benzoate sees through the absorption of oral mucosa, thereby improve bioavailability;
Said correctives comprises more than one in sweeting agent and the fragrant correctives; Said sweeting agent is selected from more than one in acesulfame potassium, aspartame, neotame, sucralose, sucrose, saccharin sodium, stevioside, aspartame, glycyrrhizin, cyclamate or the xylitol, and said fragrant correctives is selected more than one in Oleum menthae, menthol, Herba Menthae essence or the fruit essence etc. for use;
Further, said Rizatriptan benzoate oral spray also includes antioxidant, and content is 0.02～2g/100ml, and said antioxidant is more than one in vitamin C, sodium sulfite, sodium pyrosulfite or the disodiumedetate (EDTA-2Na);
Further, Rizatriptan benzoate oral spray of the present invention also includes antibacterial, and content is 0～1g/100ml, and said antibacterial is more than one in p-Hydroxybenzoate, sorbic acid or the benzyl alcohol;
Preferably, described Rizatriptan benzoate oral spray, contain the component of following content:
Lizakuputan benzoate 7.3～14.5g/100ml
Absorption enhancer 0.1～2g/100ml
Solubilizing agent 1～40g/100ml
Correctives 0.2～1.5g/100ml
Wherein, more than one in absorption enhancer preferably octanoic acid capric acid polyethyleneglycol glyceride, Capric acid sodium salt or the hydroxypropyl methylcellulose;
In solubilizing agent optimization citric acid, ethanol, propylene glycol or the poloxamer more than one;
In the preferred menthol of correctives, aspartame or the acesulfame potassium more than one.
Preferred, described Rizatriptan benzoate oral spray, contain the component of following content:
Lizakuputan benzoate 7.3g/100ml
Absorption enhancer 0.2～1g/100ml
Solubilizing agent 10～30g/100ml
Correctives 0.2～1g/100ml
Wherein, more than one in absorption enhancer preferably octanoic acid capric acid polyethyleneglycol glyceride or the hydroxypropyl methylcellulose;
Solubilizing agent preferred alcohol and propylene glycol, the part by weight of the two are 0.2: 1～1: 0.2;
In preferred menthol of correctives or the aspartame more than one;
The method for preparing of Rizatriptan benzoate oral spray of the present invention comprises the steps:
Solubilizing agent is soluble in water, add Lizakuputan benzoate and make dissolving, add absorption enhancer, correctives, antioxidant and antibacterial again; Dissolving, standardize solution is to 100ml, and solution is crossed 0.22 μ m microporous filter membrane; Can obtain said Rizatriptan benzoate oral spray; Its fill in the spray bottle that has proportional valve, can be used, and spray volume is 0.1ml at every turn.
Rizatriptan benzoate oral spray of the present invention can be used for having or the acute treatment of absence of aura migraine, hyperpietic's migraine treatment; Can put on the patient who needs treatment through sublingual spraying or mouthspray approach; Dosage is generally 7.3～14.6mg/ time; Specifically can determine by the doctor according to patient's the state of an illness, age etc.
Rizatriptan benzoate oral spray of the present invention, after trans-oral or the sublingual spraying administration, but medicine trans-oral or hypoglossis mucous membrane absorb, avoid the influence of liver first-pass effect and food, thus absorb rapid, rapid-action, bioavailability is high.Simultaneously, spray is easy to use, need not use water delivery service during administration, is particularly suitable for not being obedient to patient oral and injection.In addition, spray is a liquid preparation, and production process does not have dust, is easy to labor protection, and the large-scale production cost is lower.
The specific embodiment
Embodiment 1
Prescription: Lizakuputan benzoate 7.3g
Capric acid sodium salt 0.3g
Aspartame 0.5g
Ethanol 25g
Propylene glycol 10g
Menthol 0.4g
EDTA-2Na 0.05g
Sorbic acid 0.1g
Distilled water adds to 100ml
Method for making: get Lizakuputan benzoate 7.3g, add 25g ethanol, 10g propylene glycol and 50ml distilled water, stir and make dissolving.Add Capric acid sodium salt 0.3g, aspartame 0.5g, EDTA-2Na 0.05g, sorbic acid 0.1g, menthol 0.4g, dissolving back adding distil water is settled to 100ml.Solution is crossed 0.22 μ m microporous filter membrane, and fill is in the spray bottle that has proportional valve.
Embodiment 2
Prescription: Lizakuputan benzoate 3.6g
Water solublity azone 0.8g
Ethanol 10g
Propylene glycol 10g
Hydroxypropyl methylcellulose 0.1g
Neotame 0.3g
Fructus Citri Limoniae essence 0.2g
EDTA-2Na 0.1g
Potassium sorbate 0.15g
Distilled water adds to 100ml
Method for making: the 0.1g hydroxypropyl methylcellulose is dissolved in the 70ml pure water, adds ethanol 10g, propylene glycol 10g, Lizakuputan benzoate 3.6g, stir and make dissolving.Add water solublity azone 0.8g, neotame 0.6g, Fructus Citri Limoniae essence 0.2g, EDTA-2Na0.1g, potassium sorbate 0.15g, after the dissolving, adding distil water is settled to 100ml.Solution is crossed 0.22 μ m microporous filter membrane, and fill is in the spray bottle that has proportional valve.
Embodiment 3
Prescription: Lizakuputan benzoate 14.5g
Citric acid 2g
Propylene glycol 15g
Ethanol 25g
Sad capric acid polyethyleneglycol glyceride 0.5g
Sucralose 0.3g
Menthol 0.4g
EDTA-2Na 0.1g
Methyl hydroxybenzoate 0.15g
Distilled water adds to 100ml
Method for making: citric acid 2g is dissolved in 15g ethanol, 15g propylene glycol and the 50g water, adds Lizakuputan benzoate 14.5g, stirs to make dissolving.Add sucralose 0.3g, methyl hydroxybenzoate 0.15g, EDTA-2Na 0.1g, after the dissolving, add the alcoholic solution 10g of dissolving 0.4g menthol and the sad capric acid polyethyleneglycol glyceride of 0.5g, mixing, adding distil water is settled to 100ml.Solution is crossed 0.22 μ m microporous filter membrane, and fill is in the spray bottle that has proportional valve.
Embodiment 4
Press embodiment 2 preparation Rizatriptan benzoate oral sprays, give the lumbar injection phenobarbital postanesthetic SD rat in 5mg/kg dosage (with Leeza Qu Putan) mouthspray, rat body weight 250 ± 10g, drug main will be sprayed on Sublingual and oral mucosa.Other prepares the normal saline solution of Lizakuputan benzoate, gives SD rat with mouthspray and filling stomach respectively with above-mentioned identical dosage, and as contrast, every group is 6 rats.Get the about 0.5ml of blood respectively at different time after the administration from the eye socket vein,, calculate the peak concentration (C of rizatriptan in the blood plasma with the concentration of rizatriptan in the HPLC method mensuration blood plasma
Max), reach C
MaxRequired time (T
Max), eliminate half-life (t
1/2) and blood drug level-time graph under area (AUC).The result sees table 1.
Table 1 Lizakuputan benzoate spray is through the pharmacokinetic parameters of the administration of rat mouthspray, aqueous solution spraying and gastric infusion
Claims (1)
1. Rizatriptan benzoate oral spray is characterized in that, is made up of following component:
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010101912849A CN101856329B (en) | 2010-06-02 | 2010-06-02 | Rizatriptan benzoate oral spray |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101912849A CN101856329B (en) | 2010-06-02 | 2010-06-02 | Rizatriptan benzoate oral spray |
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| CN101856329A CN101856329A (en) | 2010-10-13 |
| CN101856329B true CN101856329B (en) | 2012-06-06 |
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| CN2010101912849A Active CN101856329B (en) | 2010-06-02 | 2010-06-02 | Rizatriptan benzoate oral spray |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019143925A1 (en) * | 2018-01-22 | 2019-07-25 | Insys Development Company, Inc. | Liquid rizatriptan compositions |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3154338B1 (en) * | 2014-06-10 | 2020-01-29 | Biomatrica, INC. | Stabilization of thrombocytes at ambient temperatures |
| CN109381426A (en) * | 2017-08-11 | 2019-02-26 | 北京人福军威医药技术开发有限公司 | A kind of ibuprofen oral spray and preparation method thereof |
| CN111407726A (en) * | 2020-04-13 | 2020-07-14 | 牡丹江医学院 | Medicinal preparation for treating stomatitis and preparation method thereof |
| CN111840267A (en) * | 2020-08-05 | 2020-10-30 | 牡丹江医学院 | Medicine for treating children's oral mucosa diseases and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1662228A (en) * | 2002-05-23 | 2005-08-31 | Umd公司 | Compositions and method for transmucosal drug delivery and cryoprotection |
| WO2008013929A3 (en) * | 2006-07-28 | 2008-07-31 | Novadel Pharma Inc | Anti-migraine oral spray formulations and methods |
| CN101574330A (en) * | 2009-06-12 | 2009-11-11 | 上海现代药物制剂工程研究中心有限公司 | Rizatriptan benzoate film agent |
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2010
- 2010-06-02 CN CN2010101912849A patent/CN101856329B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1662228A (en) * | 2002-05-23 | 2005-08-31 | Umd公司 | Compositions and method for transmucosal drug delivery and cryoprotection |
| WO2008013929A3 (en) * | 2006-07-28 | 2008-07-31 | Novadel Pharma Inc | Anti-migraine oral spray formulations and methods |
| CN101574330A (en) * | 2009-06-12 | 2009-11-11 | 上海现代药物制剂工程研究中心有限公司 | Rizatriptan benzoate film agent |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019143925A1 (en) * | 2018-01-22 | 2019-07-25 | Insys Development Company, Inc. | Liquid rizatriptan compositions |
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| CN101856329A (en) | 2010-10-13 |
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