CN102440957B - Terlipressin acetate nasal cavity spray and preparation method thereof - Google Patents
Terlipressin acetate nasal cavity spray and preparation method thereof Download PDFInfo
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- CN102440957B CN102440957B CN2011104276360A CN201110427636A CN102440957B CN 102440957 B CN102440957 B CN 102440957B CN 2011104276360 A CN2011104276360 A CN 2011104276360A CN 201110427636 A CN201110427636 A CN 201110427636A CN 102440957 B CN102440957 B CN 102440957B
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Abstract
The invention relates to a terlipressin acetate nasal cavity spray and a preparation method thereof. The spray is composed by terlipressin acetate, absorption enhancer, osmotic pressure regulator, preservative and PH regulator. The preparation method of the spray mainly comprises raw material preparing, dissolving, bottle washing, filling, packing and the like. The spray has the main functions of contracting smooth muscles of visceral vessels and reducing blood flow volume of the viscera, accordingly, the portal vein blood flow and portal vein pressure are reduced, and meanwhile, the spray can be used for the smooth muscles of the esophagus and the uterus. The spray is convenient to dose, has high bioavailability, and is beneficial to patients to accept.
Description
Technical field:
The present invention relates to formulation art, specifically is a kind of nasal mist of acetic acid terlipressin and preparation method thereof.
Background technology:
Terlipressin is artificial synthetic polypeptide, analog for the lobus posterior hypophyseos secreting hormone, it is a kind of long-acting vasopressin of novel synthetic, it is a kind of prodrug, non-activity own, in vivo through the amino peptidase effect, slough 3 glycyl residues of its N-terminal after, slowly release activated Schweine-Vasopressin.It is to shrink the visceral vessel smooth muscle that terlipressin mainly acts on, and reduces SBF, thereby reduces portal venous flow, reduction portal pressure, also can act on smooth muscle such as esophagus and uterus simultaneously.This medicine at present clinically application forms be mainly injection, injection uses and to need particular environment, generally is confined to hospital, use inconvenience, and patient will bear certain misery and higher financial burden.The nasal mist convenient drug administration that the present invention relates to, particularly along with the raising of nasal spray device investigative technique, nasal mist utilization ratio of drug height, the patient is easier to accept.
Summary of the invention:
The objective of the invention is to prepare a kind of is the nasal mist of active component with the acetic acid terlipressin, has convenient drug administration, is subjected to medicine even, advantages such as bioavailability height.
The present invention has prepared a kind of nasal mist that contains acetic acid terlipressin medicine, and it comprises acetic acid terlipressin, absorption enhancer, osmotic pressure regulator, antiseptic, PH regulator.
The present invention has prepared a kind of nasal mist that contains acetic acid terlipressin medicine, and its absorption enhancer is selected from disodiumedetate, sodium deoxycholate, beta-schardinger dextrin-, hydroxypropyl emthylcellulose, cyclodextrin derivative, azone, chitosan etc.; Its antiseptic is selected from chlorobutanol, benzoic acid, sorbic acid, methyl parahydroxybenzoate, benzalkonium chloride etc.; Its osmotic pressure regulator is selected from sodium chloride, potassium chloride, mannitol, glucose, phosphate, citrate, phosphate etc.; The PH regulator is selected from hydrochloric acid, acetic acid, phosphoric acid, the acid of structure rafter or sodium hydroxide etc.
Through a large amount of optimization experiment, the present invention has found that most preferably prescription is formed.Wherein, the preferred disodiumedetate of its absorption enhancer, the preferred sodium chloride of osmotic pressure regulator, the preferred chlorobutanol of antiseptic, the preferred acetic acid of PH regulator, pH is 5.0-6.5 most preferably.
In addition, the present invention also provides preparation to contain the method for the nasal mist of acetic acid terlipressin medicine.Its technology is as follows:
(1) absorption enhancer, osmotic pressure regulator, antiseptic is soluble in water, fully dissolving;
(2) in the middle aqueous solution that obtains of step (1), add terlipressin or its pharmaceutically acceptable salt, and it is fully dissolved;
(3) in the middle aqueous solution that obtains of step (2), add the pH regulator agent, be adjusted to required pH value;
(4) solution of purified water standardize solution step (3) acquisition, 0.22 μ m filtering with microporous membrane;
(5) fill and adds the bottle cap that has the dosing pump of spraying to sterilized spray bottle after the passed examination; The labeling packing.
The specific embodiment:
In conjunction with the embodiments embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only is used for explanation the present invention, and should not be considered as limiting scope of the present invention.
Embodiment 1:
Embodiment 1 acetic acid terlipressin nasal spray agent prescription is: 1.0mg/ml acetic acid terlipressin, and the 0.1%w/v disodiumedetate, 0.80%w/v sodium chloride, the 0.30%w/v chlorobutanol, it is 5.5 that acetic acid is regulated pH.
Its preparation process is as follows: precision takes by weighing the 100mg disodiumedetate, 800mg sodium chloride, the 300mg chlorobutanol is in the 1000ml beaker, adding purified water fully dissolves, add 1000mg acetic acid terlipressin then, it is fully dissolved, and adding an amount of acetic acid adjusting pH value is 5.5, the purified water standardize solution.0.22 μ m filtering with microporous membrane, fill and adds the bottle cap that has the dosing pump of spraying to sterilized spray bottle after the passed examination; The labeling packing gets acetic acid terlipressin nasal mist.
Made by present embodiment and to contain 1.0mg/ml acetic acid terlipressin nasal mist 10 spray and injection terlipressin 10 pins, by zoopery, its pharmacokinetics and bioavailability are investigated.
With 8 grow up, healthy beasle dog is divided into two groups, 4 every group immediately.Give above-mentioned two groups of beasle dogs respectively with nasal mist and the injection terlipressin of above-mentioned acetic acid terlipressin, measure main pharmacokinetic parameter, comprise medicine removing half-life (t
1/2), clearance rate (CL), apparent volume of distribution (Vd), the result is as shown in table 1 for its meansigma methods:
Table 1 acetic acid terlipressin nasal mist and injection pharmacokinetic parameter
By table 1 as can be seen, acetic acid terlipressin nasal mist and the injection terlipressin of the present invention's preparation compare, and the pharmacokinetics index is more excellent, and it is easy to use, no pain, patient's acceptance level height can substitute this conventional dosage forms of injection terlipressin fully.
Simultaneously, the present invention also adopts in body toad palate modelling, the acetic acid terlipressin nasal mist of present embodiment preparation is investigated the influence of nose fibre swing time, and be matched group with the normal saline, assessed its stimulation to nasal membrane.The result shows that acetic acid terlipressin nasal mist is contrast with the normal saline, and the nasal mucosa fibre swing time is not had influence.
Moreover, the present invention also utilizes rat experiment, acetic acid terlipressin nasal mist nasal mucosa form influence to the present embodiment preparation is investigated, be matched group with the normal saline, the result shows that the acetic acid terlipressin nasal mist of present embodiment preparation is non-stimulated to nasal mucosa morphogenetic stimulus rank.
Embodiment 2:
Embodiment 2 acetic acid terlipressin nasal spray agent prescriptions are: 1.0mg/ml acetic acid terlipressin, and the 0.5%w/v sodium deoxycholate, the 1.0%w/v glucose, the 0.40%w/v chlorobutanol, it is 5.5 that acetic acid is regulated pH, its preparation technology is as follows:
Its preparation process is as follows: precision takes by weighing the 500mg sodium deoxycholate, the 1000mg glucose, the 400mg chlorobutanol is in the 1000ml beaker, adding purified water fully dissolves, add 1000mg acetic acid terlipressin then, it is fully dissolved, and adding an amount of acetic acid adjusting pH value is 5.5, the purified water standardize solution.0.22 μ m filtering with microporous membrane, fill and adds the bottle cap that has the dosing pump of spraying to sterilized spray bottle after the passed examination; The labeling packing gets acetic acid terlipressin nasal mist.
Made by present embodiment and to contain 1.0mg/ml acetic acid terlipressin nasal mist 10 spray and injection terlipressin 10 pins, by zoopery, its pharmacokinetics and bioavailability are investigated.
With 8 grow up, healthy beasle dog is divided into two groups, 4 every group immediately.Give above-mentioned two groups of beasle dogs respectively with nasal mist and the injection terlipressin of above-mentioned acetic acid terlipressin, measure main pharmacokinetic parameter, comprise medicine removing half-life (t
1/2), clearance rate (CL), apparent volume of distribution (Vd), the result is as shown in table 2 for its meansigma methods:
Table 2 acetic acid terlipressin nasal mist and injection pharmacokinetic parameter
By table 2 as can be seen, acetic acid terlipressin nasal mist and the injection terlipressin of the present invention's preparation compare, and the pharmacokinetics index is poor slightly, but it is easy to use, no pain, patient's acceptance level height can substitute this conventional dosage forms of injection terlipressin.
Simultaneously, the present invention also adopts in body toad palate modelling, the acetic acid terlipressin nasal mist of present embodiment preparation is investigated the influence of nose fibre swing time, and be matched group with the normal saline, assessed its stimulation to nasal membrane.The result shows that acetic acid terlipressin nasal mist is contrast with the normal saline, and is slightly influential to the nasal mucosa fibre swing time.
Moreover, the present invention also utilizes rat experiment, acetic acid terlipressin nasal mist nasal mucosa form influence to the present embodiment preparation is investigated, be matched group with the normal saline, the result shows that the acetic acid terlipressin nasal mist of present embodiment preparation is non-stimulated to nasal mucosa morphogenetic stimulus rank.
Embodiment 3:
Embodiment 3 acetic acid terlipressin nasal spray agent prescriptions are: 1.5mg/ml acetic acid terlipressin, 0.5%w/v disodiumedetate, 0.5%w/v chitosan, 1.0%w/v sodium chloride, the 0.30%w/v chlorobutanol, it is 6.5 that acetic acid is regulated pH, its preparation technology is as follows:
Its preparation process is as follows: precision takes by weighing the 500mg disodiumedetate, the 500mg chitosan, 1000mg sodium chloride, the 300mg chlorobutanol is in the 1000ml beaker, add purified water and fully dissolve, add 1500mg acetic acid terlipressin then, it is fully dissolved, adding an amount of acetic acid adjusting pH value is 6.5, the purified water standardize solution.0.22 μ m filtering with microporous membrane, fill and adds the bottle cap that has the dosing pump of spraying to sterilized spray bottle after the passed examination; The labeling packing gets acetic acid terlipressin nasal mist.
Made by present embodiment and to contain 1.5mg/ml acetic acid terlipressin nasal mist 10 spray and injection terlipressin 10 pins, by zoopery, its pharmacokinetics and bioavailability are investigated.
With 8 grow up, healthy beasle dog is divided into two groups, 4 every group immediately.Give above-mentioned two groups of beasle dogs respectively with nasal mist and the injection terlipressin of above-mentioned acetic acid terlipressin, measure main pharmacokinetic parameter, comprise medicine removing half-life (t
1/2), clearance rate (CL), apparent volume of distribution (Vd), the result is as shown in table 3 for its meansigma methods:
Table 3 acetic acid terlipressin nasal mist and injection pharmacokinetic parameter
By table 3 as can be seen, acetic acid terlipressin nasal mist and the injection terlipressin of the present invention's preparation compare, and the pharmacokinetics index is more excellent, and it is easy to use, no pain, patient's acceptance level height can substitute this conventional dosage forms of injection terlipressin fully.
Simultaneously, the present invention also adopts in body toad palate modelling, the acetic acid terlipressin nasal mist of present embodiment preparation is investigated the influence of nose fibre swing time, and be matched group with the normal saline, assessed its stimulation to nasal membrane.The result shows that acetic acid terlipressin nasal mist is contrast with the normal saline, and the nasal mucosa fibre swing time is not had influence.
Moreover, the present invention also utilizes rat experiment, acetic acid terlipressin nasal mist nasal mucosa form influence to the present embodiment preparation is investigated, be matched group with the normal saline, the result shows that the acetic acid terlipressin nasal mist of present embodiment preparation is minimal irritation to nasal mucosa morphogenetic stimulus rank.
Claims (3)
1. acetic acid terlipressin nasal mist is characterized by: contain 1000mg acetic acid terlipressin, and the 100mg disodiumedetate, 800mg sodium chloride, the 300mg chlorobutanol, it is 5.5 that acetic acid is regulated pH; Its preparation technology is as follows: precision takes by weighing the 100mg disodiumedetate, 800mg sodium chloride, the 300mg chlorobutanol is in the 1000ml beaker, adding purified water fully dissolves, add 1000mg acetic acid terlipressin then, it is fully dissolved, and adding an amount of acetic acid adjusting pH value is 5.5, the purified water standardize solution; 0.22 μ m filtering with microporous membrane, fill and adds the bottle cap that has the dosing pump of spraying to sterilized spray bottle after the passed examination; The labeling packing gets acetic acid terlipressin nasal mist.
2. acetic acid terlipressin nasal mist is characterized by: contain 1000mg acetic acid terlipressin, and the 500mg sodium deoxycholate, the 1000mg glucose, the 400mg chlorobutanol, it is 5.5 that acetic acid is regulated pH; Its preparation technology is as follows: precision takes by weighing the 500mg sodium deoxycholate, the 1000mg glucose, the 400mg chlorobutanol is in the 1000ml beaker, adding purified water fully dissolves, add 1000mg acetic acid terlipressin then, it is fully dissolved, and adding an amount of acetic acid adjusting pH value is 5.5, the purified water standardize solution; 0.22 μ m filtering with microporous membrane, fill and adds the bottle cap that has the dosing pump of spraying to sterilized spray bottle after the passed examination; The labeling packing gets acetic acid terlipressin nasal mist.
3. acetic acid terlipressin nasal mist is characterized by: contain 1500mg acetic acid terlipressin, and the 500mg disodiumedetate, the 500mg chitosan, 1000mg sodium chloride, the 300mg chlorobutanol, it is 6.5 that acetic acid is regulated pH; Its preparation technology is as follows: precision takes by weighing the 500mg disodiumedetate, the 500mg chitosan, 1000mg sodium chloride, the 300mg chlorobutanol is in the 1000ml beaker, add purified water and fully dissolve, add 1500mg acetic acid terlipressin then, it is fully dissolved, adding an amount of acetic acid adjusting pH value is 6.5, the purified water standardize solution; 0.22 μ m filtering with microporous membrane, fill and adds the bottle cap that has the dosing pump of spraying to sterilized spray bottle after the passed examination; The labeling packing gets acetic acid terlipressin nasal mist.
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| CN2011104276360A CN102440957B (en) | 2011-12-16 | 2011-12-16 | Terlipressin acetate nasal cavity spray and preparation method thereof |
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| CN2011104276360A CN102440957B (en) | 2011-12-16 | 2011-12-16 | Terlipressin acetate nasal cavity spray and preparation method thereof |
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| CN102440957B true CN102440957B (en) | 2013-09-25 |
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| CN112969449A (en) * | 2018-06-15 | 2021-06-15 | 费灵有限公司 | Terlipressin composition and application thereof |
| US20220080023A1 (en) * | 2018-12-21 | 2022-03-17 | Arecor Limited | Novel composition |
| JP2022533759A (en) * | 2019-05-22 | 2022-07-25 | バイオヴァイ インコーポレイテッド | Formulations of terlipressin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126439A (en) * | 1993-06-29 | 1996-07-10 | 凡林有限公司 | Compositions for nasal administration of desmopressin |
| CN1126440A (en) * | 1993-06-29 | 1996-07-10 | 凡林有限公司 | Stabilized pharmaceutical peptide compositions |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126439A (en) * | 1993-06-29 | 1996-07-10 | 凡林有限公司 | Compositions for nasal administration of desmopressin |
| CN1126440A (en) * | 1993-06-29 | 1996-07-10 | 凡林有限公司 | Stabilized pharmaceutical peptide compositions |
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Address after: 518057 Nanshan District, Guangdong Province, a high tech in the middle of the road No. ten Shenzhen biological incubation base, building 412, room 2, No. Applicant after: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. Address before: 518000, overseas student Pioneer Building, 29 South Ring Road, Nanshan hi tech Zone, Guangdong, Shenzhen 1702 Applicant before: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. |
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Application publication date: 20120509 Assignee: Nanjing Xingyin Pharmaceutical Group Co.,Ltd. Assignor: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. Contract record no.: 2015440020183 Denomination of invention: Terlipressin acetate nasal cavity spray and preparation method thereof Granted publication date: 20130925 License type: Exclusive License Record date: 20150519 |
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Effective date of registration: 20161209 Address after: Zi street Jinhui road Shenzhen 518118 Guangdong province Pingshan pit No. 14 Shenzhen Biomedical Innovation Industrial Park Building No. 7 Patentee after: Shenzhen Jianxiang Biological Pharmaceutical Co Ltd Address before: 518057 Nanshan District, Guangdong Province, a high tech in the middle of the road No. ten Shenzhen biological incubation base, building 412, room 2, No. Patentee before: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. |