CN109692153B - Aqueous solution preparation of rupatadine fumarate - Google Patents
Aqueous solution preparation of rupatadine fumarate Download PDFInfo
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- CN109692153B CN109692153B CN201711007053.6A CN201711007053A CN109692153B CN 109692153 B CN109692153 B CN 109692153B CN 201711007053 A CN201711007053 A CN 201711007053A CN 109692153 B CN109692153 B CN 109692153B
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- castor oil
- hydrogenated castor
- formulation
- rupatadine fumarate
- rupatadine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Abstract
The invention provides a stable rupatadine fumarate aqueous solution preparation which does not contain an organic solvent and cyclodextrin. The rupatadine fumarate aqueous solution preparation contains (1) rupatadine fumarate with concentration of 0.5g-1.5g/L (calculated as rupatadine), and (2) polyoxyethylene hydrogenated castor oil with concentration of not less than 3.0 g/L.
Description
Technical Field
The invention relates to an aqueous solution preparation of rupatadine fumarate and application thereof in treating diseases, belonging to the technical field of medicines.
Background
Rupatadine fumarate, chemical name 8-chloro-6, 11-dihydro-11- [1- [ (5-methyl-3-pyridinyl) methyl ] -4-piperidinylidene ] -5H-benzo [5, 6] cyclohepta [1, 2-b ] pyridine fumarate. Rupatadine fumarate is a novel, potent antiallergic agent developed by Uriach pharmaceutical company, Spain, as a selective histamine H1 receptor inverse agonist and a Platelet Activating Factor (PAF) antagonist. In animal experiments, the product shows strong histamine H1 receptor antagonism and PAF receptor blocking effect; has inhibitory effect on mast cell degranulation, neutrophil and eosinophil migration, and cytokine release. The product was first marketed in spain 3/15/2003. Compared with loratadine, cetirizine and the like, the compound has better curative effect and smaller side effect, does not find cardiac toxicity, and can be used as a first-line medicament for treating allergic rhinitis.
The solubility of rupatadine fumarate in different pH media (CN103108635) is as follows:
from the above table, rupatadine fumarate has good solubility under acidic conditions and low solubility under neutral conditions. While rupatadine fumarate in acidic solution forms an adduct of fumaric acid and rupatadine (compound I), as shown in the following formula.
Compound I
Therefore, to prepare a stable rupatadine fumarate solution, the above problems of solubility and stability need to be solved.
Patent CN103108635 discloses a rupatadine fumarate liquid preparation, the pH range of which is 4.0-6.5, and co-solvents of propylene glycol, glycerin, ethanol, polyethylene glycol and the like are added, so that the problems of solubility and stability of main components in rupatadine fumarate oral solution are well solved. However, the preparation has a problem that a relatively large amount of organic solvent is used in the prescription, and patients who use the preparation, including children, are mainly used for treating allergic diseases, and the use of the organic solvent inevitably causes safety concerns.
Patent CN101926762 discloses rupatadine fumarate eye drops, wherein the adopted cosolvent is polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20. In the research process, the inventor finds that when the oral liquid is prepared by using polysorbate 80 as a cosolvent and is placed at the high temperature of 60 ℃ for 10 days, the color of the oral liquid is changed into orange red, and the degradation product I (namely the compound I) and total impurities are known to be remarkably increased, so that the stability of the oral liquid is poor.
Patents CN101669926 and CN101669901 disclose a nasal administration liquid preparation and an eye administration liquid preparation of rupatadine fumarate, respectively, wherein sulfobutyl-beta-cyclodextrin, methyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin are added to increase the solubility of the main drug. The cyclodextrin compound has high price generally, and in addition, the cyclodextrin auxiliary materials are contained for long-term application, so that the cyclodextrin compound is used for treating diseases of children and can also cause damage to teeth of the children.
Therefore, the rupatadine fumarate urgently needs a solution which does not contain an organic solvent, does not contain a cyclodextrin solubilizer, is thermodynamically stable and is suitable for children.
Disclosure of Invention
In order to overcome the defects of the existing rupatadine fumarate preparations, the invention provides a rupatadine fumarate aqueous solution preparation which has good stability and simple preparation process.
The rupatadine fumarate aqueous solution preparation contains
(1) Rupatadine fumarate at a concentration of 0.5g to 1.5g/L (as rupatadine), and
(2) polyoxyethylene hydrogenated castor oil in a concentration of not less than 3.0 g/L.
The liquid preparation does not contain cyclodextrin adjuvant, and is suitable for children or patients with dysphagia.
An aqueous rupatadine fumarate solution preparation, which contains polyoxyethylene hydrogenated castor oil with the concentration of 5-20g/L, more preferably 5-15g/L, and most preferably 10 g/L; the rupatadine fumarate contained in the composition has a concentration of 1 g/L.
The rupatadine fumarate aqueous solution preparation contains polyoxyethylene hydrogenated castor oil such as PEG-20 hydrogenated castor oil, PEG-40 hydrogenated castor oil, and PEG-60 hydrogenated castor oil, preferably PEG-40 hydrogenated castor oil.
The rupatadine fumarate aqueous solution preparation also contains one or more of pH regulator, flavoring agent, antiseptic bacteriostatic agent and coloring agent.
The pH regulator is a substance capable of changing the pH of the solution or stabilizing the pH of the solution at a given pH, and comprises a pharmaceutically applicable alkaline substance or a buffering agent. Wherein the pH adjusting agent may preferably be selected from one or more of disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide, sodium citrate, citric acid/phosphate buffer, acetate buffer.
The rupatadine fumarate aqueous solution preparation has a pH value of 4-7, preferably 4.5-6. The pH of the liquid medicine is adjusted to the required range by adding a proper amount of the pH regulator.
The rupatadine fumarate aqueous solution preparation can be added with a proper amount of flavoring agent for improving taste and patient compliance, wherein the flavoring agent is a pharmaceutically applicable substance for improving or shielding the unpleasant odor and taste of the medicine, and comprises a sweetening agent, an aromatic agent and a mucilage, wherein the sweetening agent is any pharmaceutically applicable natural or artificial substance capable of endowing sweet taste to the aqueous solution or dispersion liquid, and is preferably one or more of sucrose, xylitol, fructose, saccharin sodium, aspartame and stevioside. The flavoring agent is used for improving odor of the preparation, preferably fruit essence such as banana essence, orange essence, lemon essence, peach essence, and grape essence. The amount of flavoring agent is determined by the taste requirement and is within the limits of the FDAIIG or food additive.
The rupatadine fumarate aqueous solution preparation can contain or does not contain antibacterial preservative, the preservative is added into an oral liquid preparation packaged in multiple doses, and the preservative is selected from one or more of nipagin esters, sorbic acid and salts thereof, benzoic acid and salts thereof, and is preferably selected from one or more of nipagin methyl ester, nipagin ethyl ester, nipagin propyl ester and nipagin butyl ester.
The present invention also provides a method for treating allergic diseases, which comprises administering to a subject in need of such treatment an effective amount of the above-described formulation, wherein the disorder is allergic rhinitis, urticaria.
The invention also provides the use of the preparation for the preparation of a medicament for the treatment of allergic diseases, wherein the diseases are selected from allergic rhinitis or urticaria.
Detailed Description
The present invention will be described in detail below by way of examples, but the present invention is not limited to the examples.
Comparative example 1, comparative example 2, example 1:
the compositions of comparative example 1, comparative example 2 and example 1 are shown in the following table.
TABLE 1 compositions of the formulations of comparative example 1, comparative example 2 and example 1
| Examples/comparative examples | Comparative example 1 | Comparative example 2 | Example 1 |
| Rupatadine fumarate (g) | 0.064 | 0.064 | 0.064 |
| Propylene glycol (g) | 10 | / | / |
| Polysorbate 80 | / | 0.1795g | / |
| PEG-40 hydrogenated Castor oil | / | / | 0.1775 |
| Sucrose (g) | 15 | 15 | 15 |
| Nipagin methyl ester (g) | 0.05 | 0.05 | 0.05 |
| Citric acid (g) | 0.2548 | 0.2548 | 0.2548 |
| Disodium hydrogen phosphate (g) | 0.921 | 0.921 | 0.921 |
| 2mol/LNaOH solution (ml) | / | 0.25 | 0.25 |
| Adding purified water to (ml) | 50 | 50 | 50 |
Comparative example 1, comparative example 2 and example 1 preparation process:
weighing the materials according to the above table, adding the other materials except purified water and 2mol/L NaOH solution into 20ml of purified water, stirring, adding purified water to 45ml, stirring for dissolving, adding 2mol/L NaOH solution, stirring uniformly, filtering with 0.45 micrometer and 0.22 micrometer filter membranes, and separating the liquid medicine
Examples 9-15 stability: see table above.
According to the low-temperature examination result, the concentration of the main drug is 0.64-1.92g/L (0.5-1.5 g/L calculated by rupatadine), and the dissolution assisting effect of the polyoxyethylene hydrogenated castor oil is better.
According to the result of high temperature 60 ℃, the liquid medicine contains different buffering agents, the concentration of the main drug is 0.64-1.92g/L, and the stability is good under the condition of pH 4-7.
Claims (12)
1. An aqueous solution preparation of rupatadine fumarate comprises
(1) Rupatadine fumarate at a concentration of 0.5g to 1.5g/L based on rupatadine, and
(2) polyoxyethylene hydrogenated castor oil in a concentration of not less than 3.0 g/L.
2. The formulation of claim 1, wherein the polyoxyethylene hydrogenated castor oil is selected from one or more of PEG-20 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil.
3. The formulation of claim 1, wherein the polyoxyethylene hydrogenated castor oil has a concentration of 5 to 20 g/L.
4. The formulation according to claim 1, which contains rupatadine fumarate at a concentration of 1 g/L.
5. The formulation according to any one of claims 1-4, which contains one or more of a pH adjusting agent, a flavoring agent, a preservative and a coloring agent.
6. The formulation of claim 5, wherein the pH adjusting agent is selected from one or more of disodium phosphate, dipotassium phosphate, sodium hydroxide, sodium citrate, citric acid/phosphate buffer, acetate buffer.
7. The formulation according to any one of claims 1 to 4, having a pH value between 4 and 7.
8. The formulation according to any one of claims 1 to 4, having a pH value between 4.5 and 6.
9. The formulation of claim 5, wherein the flavoring agent is selected from one or more of sucrose, xylitol, fructose, sodium saccharin, aspartame, stevioside, fruit flavors.
10. The formulation of claim 5, wherein the preservative bacteriostatic agent is selected from one or more of methyl paraben, ethyl paraben, propyl paraben and butyl paraben.
11. Use of a formulation according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of allergic disease.
12. The use according to claim 11, wherein the disease is allergic rhinitis or urticaria.
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| CN201711007053.6A CN109692153B (en) | 2017-10-24 | 2017-10-24 | Aqueous solution preparation of rupatadine fumarate |
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| CN109692153B true CN109692153B (en) | 2021-01-22 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109535127B (en) * | 2018-12-05 | 2020-10-16 | 杭州仟源保灵药业有限公司 | Rupatadine fumarate derivative, preparation method, intermediate and application thereof |
| CN110123756A (en) * | 2019-05-14 | 2019-08-16 | 扬子江药业集团江苏紫龙药业有限公司 | A kind of Rupatadine fumarate nasal spray and preparation method thereof |
| CN112315903A (en) * | 2020-11-20 | 2021-02-05 | 北京华氏开元医药科技有限公司 | Rupatadine fumarate oral solution and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6635654B1 (en) * | 2003-01-09 | 2003-10-21 | Allergan, Inc. | Ophthalmic compositions containing loratadine |
| CN101669901A (en) * | 2008-09-11 | 2010-03-17 | 东莞太力生物工程有限公司 | Liquid preparation for dosing eyes and method for making the same |
| CN102670488A (en) * | 2011-12-09 | 2012-09-19 | 东莞达信生物技术有限公司 | Rupatadine syrup composition and preparation method thereof |
| CN103108635A (en) * | 2010-06-30 | 2013-05-15 | J·乌里亚奇·Y股份有限公司 | Liquid formulations of rupatadine fumarate |
| US20160338951A1 (en) * | 2015-05-20 | 2016-11-24 | Gavis Pharmaceuticals | Process of preparing aqueous ophthalmic solution of olopatadine |
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2017
- 2017-10-24 CN CN201711007053.6A patent/CN109692153B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6635654B1 (en) * | 2003-01-09 | 2003-10-21 | Allergan, Inc. | Ophthalmic compositions containing loratadine |
| CN101669901A (en) * | 2008-09-11 | 2010-03-17 | 东莞太力生物工程有限公司 | Liquid preparation for dosing eyes and method for making the same |
| CN103108635A (en) * | 2010-06-30 | 2013-05-15 | J·乌里亚奇·Y股份有限公司 | Liquid formulations of rupatadine fumarate |
| CN102670488A (en) * | 2011-12-09 | 2012-09-19 | 东莞达信生物技术有限公司 | Rupatadine syrup composition and preparation method thereof |
| US20160338951A1 (en) * | 2015-05-20 | 2016-11-24 | Gavis Pharmaceuticals | Process of preparing aqueous ophthalmic solution of olopatadine |
Non-Patent Citations (1)
| Title |
|---|
| 氯雷他定自乳化释药系统的制备和质量评价;李剑惠等;《中南药学》;20080924;第6卷(第4期);第414-416页 * |
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