CN115531314A - Low-irritation levocabastine hydrochloride nasal spray and preparation method thereof - Google Patents
Low-irritation levocabastine hydrochloride nasal spray and preparation method thereof Download PDFInfo
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- CN115531314A CN115531314A CN202211245761.4A CN202211245761A CN115531314A CN 115531314 A CN115531314 A CN 115531314A CN 202211245761 A CN202211245761 A CN 202211245761A CN 115531314 A CN115531314 A CN 115531314A
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- levocabastine hydrochloride
- nasal
- poloxamer
- nasal spray
- injection
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- PIZLBWGMERQCOC-UHFFFAOYSA-N dibenzyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OCC1=CC=CC=C1 PIZLBWGMERQCOC-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229960001828 levocabastine hydrochloride Drugs 0.000 title claims abstract description 44
- 239000007922 nasal spray Substances 0.000 title claims abstract description 34
- 229940097496 nasal spray Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
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- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 17
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 9
- 230000001954 sterilising effect Effects 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 9
- 239000007921 spray Substances 0.000 claims description 8
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims description 7
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
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- 210000002850 nasal mucosa Anatomy 0.000 abstract description 12
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 2
- 206010028748 Nasal obstruction Diseases 0.000 description 2
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
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Classifications
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- 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
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Abstract
The invention relates to a low-irritation levocabastine hydrochloride nasal spray and a preparation method thereof. The levocabastine hydrochloride nasal spray disclosed by the invention reduces the damage to nasal mucosa and the stimulation to nasal cilia by optimizing the formula, protects the nasal cavity environment of a patient, has the function of clearing the nasal mucocilia, can be stored for a long time at room temperature without using a preservative. Has remarkable curative effect on allergic rhinitis, nasosinusitis and the like, can effectively improve the symptoms of patients, such as nasal itching and the like, and can greatly relieve the pain of the patients.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a levocabastine hydrochloride nasal spray with low irritation and a preparation method thereof.
Background
Allergic rhinitis, also known as Allergic Rhinitis (AR), is a nasal mucosa non-infectious inflammatory disease which causes inflammatory mediator release and acts on effector organs by immunoglobulin (IgE) as an intermediate medium after specific allergen is contacted with specific individual, and is mainly clinically manifested by nasal itching, sneezing, watery nasal discharge and/or nasal obstruction, and nasal mucosa pallor edema, nasal turbinate hypertrophy and more cool and refreshing secretions in nasal cavity can be seen in physical examination. AR is classified into persistent and indirect types according to onset, and often causes diseases simultaneously or after being induced by diseases such as allergic asthma and allergic conjunctivitis.
Most patients with allergic rhinitis suffer from physical fatigue, mood fluctuation, sleep disorder and the like in the course of disease, and even psychological diseases such as depression. Anxiety, alcoholism and the like have adverse effects on children such as hyperactivity and sleep disorder, seriously affect the daily life and work of people and cause huge social and economic burden. In recent years, the incidence of the disease on the global scale tends to rise, and the disease is a common and difficult disease which seriously troubles patients and has high incidence rate and easy relapse.
At present, levocabastine hydrochloride is one of the most commonly used medicines for treating allergic rhinitis. Levocabastine hydrochloride is an antiallergic drug, and is mainly used for treating allergic diseases, such as allergic rhinitis and allergic conjunctivitis. There are two formulations of levocabastine hydrochloride: one is a nasal spray; the other is eye drops. The nasal spray is mainly used for treating allergic rhinitis, and has good relieving effect on symptoms such as rhinorrhea, sneezing, nasal obstruction, rhinocnesmus and the like caused by the allergic rhinitis.
The eye drops are mainly used for treating allergic conjunctivitis, and also have good relieving effect on symptoms such as eye itching, lacrimation, eye congestion and the like caused by the allergic conjunctivitis. The levocabastine hydrochloride is safe for clinical use, and temporary and local stimulation symptoms can appear in individual patients.
In addition, nasal medicines (especially aqueous preparations) are easily polluted by microorganisms due to repeated contact with the nasal cavity bacteria environment in the administration process and the characteristic of an aqueous medium, so that the nasal spray usually uses a preservative to achieve the effect of preventing the infection and reproduction of the microorganisms and ensure the quality of the medicines. However, the use of preservatives in nasal sprays increases the fluidity and permeability of the film, causing morphological abnormalities in the cells of the nasal mucosa, resulting in cell damage. In addition, the use of preservatives can irritate the nasal mucosa, impairing the ciliary clearance function of the nasal mucosa.
Therefore, how to reduce the irritation of levocabastine hydrochloride nasal spray and ensure the quality of medicines still remains one of the technical problems to be solved urgently by the technical personnel in the field.
Disclosure of Invention
Based on the background technology, the technical problem to be solved by the invention is to provide a low-irritation levocabastine hydrochloride nasal spray and a preparation method thereof. In order to realize the purpose of the invention, the following technical scheme is adopted:
the invention relates to a levocabastine hydrochloride nasal spray which contains levocabastine hydrochloride, sodium hyaluronate, poloxamer, disodium edetate and water for injection.
In a preferred embodiment of the invention, the weight ratio of levocabastine hydrochloride, sodium hyaluronate, poloxamer, disodium edetate and water for injection is 0.5-1, 6-12.
In a preferred embodiment of the invention, the weight ratio of levocabastine hydrochloride, sodium hyaluronate, poloxamer, disodium edetate and water for injection is 0.5.
In a preferred embodiment of the invention, the levocabastine hydrochloride nasal spray further comprises a pH adjuster.
In a preferred embodiment of the invention, the levocabastine hydrochloride nasal spray has a pH of 5.5 to 6.5; preferably 5.8-6.2.
In a preferred embodiment of the present invention, the poloxamer is poloxamer 407, poloxamer 188 or the like; poloxamer 407 is preferred.
In a preferred embodiment of the invention, the levocabastine hydrochloride nasal spray does not contain preservatives and/or antibacterial agents.
In a preferred embodiment of the invention, the levocabastine hydrochloride nasal spray may or may not contain other active ingredients.
The invention also relates to a preparation method of the levocabastine hydrochloride nasal spray, which comprises the following steps:
(1) Dissolving the disodium ethylene diamine tetraacetate according to the prescription amount by using the injection water with the formula amount of 1/4-1/2, stirring and mixing uniformly, and sterilizing through a sterilizing filter with the diameter of 0.22 mu m;
(2) Homogenizing and dispersing the sodium hyaluronate with the prescription amount by using the injection water with the formula amount of 1/4-1/2, and sterilizing;
(3) Homogenizing and mixing the levocabastine hydrochloride, the sterile solution obtained in the step 2) and poloxamer in a mixing container to obtain a levocabastine hydrochloride suspension;
(4) Mixing the levocabastine hydrochloride suspension with the disodium ethylene diamine tetraacetate solution obtained in the step 1), adjusting the pH value, adding sterile water for injection to fix the volume to 100%, and filling the obtained suspension into a nasal spray bottle with an air passage.
In another aspect of the invention, the invention also relates to the application of the levocabastine hydrochloride nasal spray in preparing a medicine for treating and/or preventing allergic rhinitis.
Advantageous effects
The nasal spray preparation prepared by the formula of the invention has the following beneficial effects: the levocabastine hydrochloride nasal spray disclosed by the invention has the advantages that the damage to nasal mucosa and the stimulation to nasal cilia are reduced through the optimization of the formula, the nasal environment of a patient is protected, the nasal cilia removing function of the nasal mucosa is realized, a preservative can not be used, and the levocabastine hydrochloride nasal spray can be stored at room temperature for a long time. Has obvious curative effect on allergic rhinitis, nasosinusitis and the like, can effectively improve the symptoms of patients, such as nasal itching and the like, and can greatly relieve the pain of the patients.
Detailed Description
In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.
Examples 1 to 4 and comparative examples 1 to 2: preparation of levocabastine hydrochloride nasal spray
The levocabastine hydrochloride nasal spray is prepared according to the formula of the table 1 by adopting the following steps
(1) Dissolving the disodium ethylene diamine tetraacetate with the amount of the prescription by using the injection water with the amount of 1/3 of the prescription amount, stirring and mixing uniformly, and sterilizing through a sterilizing filter with the diameter of 0.22 mu m;
(2) Homogenizing and dispersing sodium hyaluronate or sodium carboxymethylcellulose with the amount of the prescription with injection water with the amount of 1/3 of the formula amount, and performing damp-heat sterilization at 121 ℃ for 5min;
(3) Homogenizing and mixing the levocabastine hydrochloride with the sterile solution obtained in the step 2) and poloxamer-407 or tween-80 in a mixing container to obtain levocabastine hydrochloride suspension;
(4) Mixing the levocabastine hydrochloride suspension with the disodium ethylene diamine tetraacetate solution obtained in the step 1), adding sterile citric acid to adjust the mixture to 6.0, adding sterile water for injection to fix the volume to 100%, and filling the obtained suspension into a nasal spray bottle with an air passage.
TABLE 1 preparation of levocabastine hydrochloride nasal spray (mg)
After the sample is prepared, the content of the key technical index main drug is detected, and the detection steps and results are as follows:
5 prepared samples are taken and simultaneously placed in a proper clean container, the container is placed in an environment with the temperature of 40 ℃ and the humidity of 75%, samples are taken at 0 hour, 1 month, 2 months, 3 months and 6 months, the content of the main drug in the samples is detected, and the average value is obtained, and the results are shown in the following table 2.
TABLE 2 detection of the content of the principal drug
The experimental results show that the nasal spray of examples 1-4 of the present invention is more helpful to maintain the stability of the main drug than comparative example 1.
Nasal mucosa irritation test:
70 rabbits, half of which are male and female, each weighing 2.0-3.0kg, were selected and randomly divided into 7 groups, namely, 6 treatment groups (total) of examples 1-4 and comparative examples 1-2 and a normal control group, 10 rabbits in each group were normally bred in cages, and the normal control group was normally bred without administration of drugs.
In the former 6 groups, the spray of examples 1-4 and comparative examples 1-2 were applied, 35 μ g of levocabastine hydrochloride liquid medicine was dripped into each nasal cavity by a dropper, the rabbit was measured by the average body weight of 2.5kg, 24h after the last administration, the animal was sacrificed and the nasal mucosa was taken out, compared with the blank control group, and the secretion, scab, nasal mucosa congestion, edema, erythema and the like around the nostril were observed. The degree of irritation was evaluated according to the following criteria: without irritation, the score is less than 0.5; at mild irritation, the score was less than 3.0; at moderate irritation, the score is less than 6.0; when the intensity is irritant, the score is less than 8.0.
The results of the experiment are shown in table 3 below, in which the total mean score = (erythema score + edema score)/total number of animals tested in the same group
TABLE 3 nasal mucosa irritation test results
| Animals (only) | Erythema score | Edema scores | Mean score | |
| Normal control group | 10 | 0 | 0 | 0 |
| Example 1 | 10 | 0.12±0.05 | 0.16±0.06 | 0.14 |
| Example 2 | 10 | 0.21±0.06 | 0.25±0.08 | 0.23 |
| Example 3 | 10 | 0.25±0.05 | 0.27±0.07 | 0.26 |
| Example 4 | 10 | 0.38±0.04 | 0.38±0.09 | 0.38 |
| Comparative example 1 | 10 | 2.34±0.13 | 2.58±0.23 | 2.46 |
| Comparative example 2 | 10 | 1.82±0.14 | 1.88±0.21 | 1.85 |
The above experimental results show that the formulations of examples 1-4 of the present invention showed no significant erythema and edema, the total average value was less than 0.5, no irritation, and the irritation of the example 1 group was the lowest. The comparative examples 1 and 2 had mild irritation, with the comparative example 1 having slightly more irritation, indicating that the levocabastine hydrochloride nasal spray prepared according to examples 1-4 of the present invention was a low irritation nasal spray.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.
Claims (10)
1. A levocabastine hydrochloride nasal spray comprises levocabastine hydrochloride, sodium hyaluronate, poloxamer, disodium ethylene diamine tetraacetate and water for injection.
2. The spray according to claim 1, wherein the weight ratio of levocabastine hydrochloride, sodium hyaluronate, poloxamer, disodium edetate and water for injection is 0.5-1, 0.2-0.6.
3. The spray according to claim 1, wherein the weight ratio of levocabastine hydrochloride, sodium hyaluronate, poloxamer, disodium edetate and water for injection is 0.5.
4. The spray according to claim 1, further comprising a pH adjusting agent.
5. The spray according to claim 1, wherein the pH value of the levocabastine hydrochloride nasal spray is 5.5-6.5.
6. The spray according to claim 1, wherein the poloxamer is poloxamer 407, poloxamer 188 or the like; poloxamer 407 is preferred.
7. The spray according to claim 1, which is free of preservatives and/or antibacterial agents.
8. The spray according to claim 1, which contains or does not contain other active ingredients.
9. A process for the preparation of a levocabastine hydrochloride nasal spray according to any one of claims 1 to 8, comprising the steps of:
(1) Dissolving the disodium ethylene diamine tetraacetate according to the prescription amount by using the injection water with the formula amount of 1/4-1/2, stirring and mixing uniformly, and sterilizing through a sterilizing filter with the particle size of 0.22 mu m;
(2) Homogenizing and dispersing the sodium hyaluronate with the prescription amount by using the injection water with the formula amount of 1/4-1/2, and sterilizing;
(3) Homogenizing and mixing the levocabastine hydrochloride, the sterile solution obtained in the step 2) and poloxamer in a mixing container to obtain a levocabastine hydrochloride suspension;
(4) Mixing the levocabastine hydrochloride suspension with the disodium ethylene diamine tetraacetate solution obtained in the step 1), adjusting the pH value, adding sterile water for injection to fix the volume to 100%, and filling the obtained suspension into a nasal spray bottle with an air passage.
10. Use of levocabastine hydrochloride nasal spray according to any one of claims 1-8 for the preparation of a medicament for the treatment and/or prevention of allergic rhinitis.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104546716A (en) * | 2014-01-14 | 2015-04-29 | 中国药科大学 | Nasal temperature-sensitive type hydrogel spray |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546716A (en) * | 2014-01-14 | 2015-04-29 | 中国药科大学 | Nasal temperature-sensitive type hydrogel spray |
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| Title |
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| 黄峻，黄祖瑚, 中国医药科技出版社 * |
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