CN113855632A - Benzcycloquine bromide nasal spray and preparation method thereof - Google Patents

Benzcycloquine bromide nasal spray and preparation method thereof Download PDF

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CN113855632A
CN113855632A CN202010608961.6A CN202010608961A CN113855632A CN 113855632 A CN113855632 A CN 113855632A CN 202010608961 A CN202010608961 A CN 202010608961A CN 113855632 A CN113855632 A CN 113855632A
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spray
benzcycloquine
nasal spray
bromide
obstructive pulmonary
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马建洋
王宇杰
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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    • 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
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • 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

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Abstract

The invention belongs to the technical field of pharmacy, and particularly relates to a benzenoquine bromide nasal spray and a preparation method thereof; the invention mainly comprises the main components of the drug, namely the bencycloquine ammonium bromide, a cosolvent, a surfactant, and pharmaceutically acceptable excipients such as a buffering agent, an osmotic pressure regulator and the like. The active ingredients in the preparation can be rapidly absorbed through nasal mucosa to rapidly take effect, has the advantages of high bioavailability, good compliance, and convenient carrying and use, and can be used for treating rhinitis and chronic obstructive pulmonary disease (chronic obstructive pulmonary disease).

Description

Benzcycloquine bromide nasal spray and preparation method thereof
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a benzcycloquine bromide nasal spray and a preparation method thereof.
Background
Rhinitis is a very popular disease, and 4 million people suffer from allergic rhinitis every year in the United states, and is the sixth epidemic disease in the United states. For example, in China, 75% of people suffer from cold more than once every year, the early stage of the cold is mainly acute rhinitis symptom or rhinorrhea and the like, and domestic rhinitis patients and rhinitis patients caused by the cold are 10 hundred million people per year. According to the recent research, the symptoms of early rhinorrhea and the like of the cold are blocked, the pain of a patient is effectively relieved, virus backflow and reproduction can be prevented, and the cold period is effectively shortened.
Chronic obstructive pulmonary disease (chronic obstructive pulmonary disease) is the most common respiratory disease, with increasing incidence and prevalence. At least one hundred million people worldwide suffer from asthma, with COPD constituting the fourth leading cause of death. At present, the number of chronic obstructive pulmonary disease patients in China reaches more than four hundred thousand, and the growth speed is very fast in the next decade. Compared with heart diseases, tumors and the like, the 'popularity' of the slow-obstructive pulmonary disease is not high, but the slow-obstructive pulmonary disease has great fatal harm to human health. The world health organization estimates that by 2020, chronic obstructive pulmonary disease will rise from the fourth leading cause of death in the world to the third position.
For rhinitis, especially nasal hypersecretion (runny nose) and chronic obstructive pulmonary disease, many active ingredients have been used in the treatment, but the results are not satisfactory. For example with the vasoconstrictors aminoethanol or imidazolines, but have to face strong dry mouth and rebound phenomena. In addition, disodium glycinate (DSCG) or steroidal cortisones such as beclomethasone dipropionate are also used but they only alleviate the symptoms of persistent allergic rhinitis-hay fever. Moreover, the long-term use of these preparations has to be faced with specific toxic side effects such as mycosis, loss of bone mineral, increase of blood sugar level and atrophy of mucous membrane. Treatment of various types of nasal hypersecretions and chronic obstructive pulmonary disease can be achieved by topical administration of derivatives of the quaternary ammonium tropane class, which have an atropine-like (vagally-induced Gnti-drug) action (topical application to the mucosa). Nasal sprays and aerosols of, for example, ipratropium are currently the first choice for the treatment of various types of nasal hypersecretion and chronic obstructive pulmonary disease, but the compounds have short half-lives (only 1.6 h) and poor selectivity for the M receptor.
The benzcycloquine bromide is an M choline receptor blocker, is obtained by modification on the basis of the existing non-atropic anticholinergic compound, mainly acts on M1 and M3 subtype receptors, has weak effect on M2 receptors, has few adverse reactions and strong anticholinergic effect, and has the chemical name: 3- { 2-cyclopentyl-2-phenyl) ethoxy } -1-methyl-bromo-1-azabicyclo [2,2,2] octane. The benzcycloquine ammonium bromide is a quaternary ammonium salt, and researches prove that the benzcycloquine ammonium bromide is difficult to enter a circulatory system through a mucous membrane and cannot enter a center, so that after local application, the benzcycloquine ammonium bromide has no central effect, does not influence the clearing function of cilia and can be used for treating chronic obstructive pulmonary disease; and the absorption rate of the bencycloquine ammonium bromide from the mucous membrane part is very low, so that the bencycloquine ammonium bromide has long local retention time and can generate longer functions of bronchiectasis and glandular secretion inhibition. Meanwhile, the half-life period of the drug action is longer, more than several hours, the administration times are greatly reduced compared with the similar drug of the isopropyl atropine, the drug is very stable, the drug can be easily prepared into aqueous solution and small molecular alcohol solution, and the drug can be easily prepared into nasal spray for treating rhinitis and two-phase solution type aerosol for treating chronic obstructive pulmonary disease.
Disclosure of Invention
The invention aims to provide a bencycloquine bromide nasal spray and a preparation method thereof, which are used for treating rhinitis and chronic obstructive pulmonary disease and have the advantages of high bioavailability, good compliance, convenient carrying and use and the like.
The aerosol is a preparation which releases the contents in the form of mist or the like by means of pressure of a hand pump. The invention provides a spray which is convenient to use, easy to absorb, quick in drug effect, good in compliance and capable of reducing side effects.
The invention provides a benzenoquine bromide nasal spray and a preparation method thereof, wherein the spray is composed of a main drug, a cosolvent, a surfactant and pharmaceutically acceptable excipients selected from a buffering agent, an osmotic pressure regulator, a pH regulator and the like.
The main medicine of the benzcycloquine bromide nasal spray is benzcycloquine bromide.
The content of the main medicine in the benzenoquine bromide nasal spray is 1.00-5.00 percent of the total mass percent
The cosolvent used in the phenylcycloquine bromide nasal spray is mainly one or more of polyethylene glycol and absolute ethyl alcohol.
The surfactant used in the phencyclicaquine bromide nasal spray is one or more of sorbitol, oleic acid and phospholipids, such as soybean phospholipid and lecithin.
The buffering agent used in the benzenoquine bromide nasal spray is one or more of phosphate, citrate, acetate and carbonate.
The invention relates to a bencycloquinate bromide nasal spray, wherein the osmotic pressure regulator is one or more of sodium chloride, glucose, mannitol, sorbitol and lactose.
The invention relates to a benzenoquine bromide nasal spray, which is a solution type spray
The preparation process of the benzcycloquine bromide nasal spray comprises the steps of dissolving main medicine components benzcycloquine bromide, cosolvent and/or surfactant at room temperature, adding buffering agent and osmotic pressure regulator for dissolution, filtering by using a microporous filter membrane, and filling into a specific spray device under the condition of avoiding bacteria.
Detailed Description
Unless otherwise specified, the reagents used in the following examples are all common commercial reagents, and the methods used are all conventional in the art.
Example 1: preparation of benzcycloquine bromide nasal spray
Prescription: 100 pieces
Figure DEST_PATH_IMAGE001
The preparation process comprises the following steps: adding a proper amount of benzcycloquine ammonium bromide, polyethylene glycol and sorbitol into a proper amount of container, adding a proper amount of purified water, stirring at room temperature to dissolve the benzcycloquine ammonium bromide, weighing a formula amount of sodium chloride after the benzcycloquine ammonium bromide, the polyethylene glycol and the sorbitol are completely dissolved, adding a proper amount of purified water into the solution, adding a proper amount of disodium hydrogen phosphate and sodium dihydrogen phosphate at the same time, adjusting the pH value of the solution to 4.0-6.5, filtering by using a 0.22 mu m microporous filter membrane to obtain a benzcycloquine ammonium bromide solution, and filling into a specific spraying device under the condition of avoiding bacteria.
Example 2: preparation of benzcycloquine bromide nasal spray
Prescription: 100 pieces
Figure 46881DEST_PATH_IMAGE002
The preparation process comprises the following steps: adding a proper amount of benzcycloquine ammonium bromide, absolute ethyl alcohol and sorbitol into a proper amount of container, adding a proper amount of purified water, stirring at room temperature to dissolve the benzcycloquine ammonium bromide, weighing sodium chloride according to the formula amount after the benzcycloquine ammonium bromide, absolute ethyl alcohol and sorbitol are completely dissolved, adding purified water to 1000mL, simultaneously adding a proper amount of disodium hydrogen phosphate and sodium dihydrogen phosphate, adjusting the pH of the solution to 4.0-6.5, filtering by using a 0.22 mu m microporous filter membrane to obtain a benzcycloquine ammonium bromide solution, and putting the benzcycloquine ammonium bromide solution into a specific spraying device under the condition of avoiding bacteria.
Example 3: preparation of benzcycloquine bromide nasal spray
Prescription: 100 pieces
Figure DEST_PATH_IMAGE003
The preparation process comprises the following steps: adding a proper amount of benzcycloquine ammonium bromide, absolute ethyl alcohol and sorbitol into a proper amount of container, adding a proper amount of purified water, stirring at room temperature to dissolve the benzcycloquine ammonium bromide, weighing sodium chloride according to the formula amount after the benzcycloquine ammonium bromide, absolute ethyl alcohol and sorbitol are completely dissolved, adding purified water to 1000mL, simultaneously adding a proper amount of disodium hydrogen phosphate and sodium dihydrogen phosphate, adjusting the pH of the solution to 4.0-6.5, filtering by using a 0.22 mu m microporous filter membrane to obtain a benzcycloquine ammonium bromide solution, and putting the benzcycloquine ammonium bromide solution into a specific spraying device under the condition of avoiding bacteria.
Comparative example 1
100 prescriptions
Figure 828761DEST_PATH_IMAGE004
The preparation process comprises the following steps: adding a proper amount of benzcycloquine ammonium bromide, polyethylene glycol and sorbitol into a proper amount of container, adding a proper amount of purified water, stirring at room temperature to dissolve the benzcycloquine ammonium bromide, adding the purified water to 1000mL after the materials are completely dissolved, simultaneously adding a proper amount of disodium hydrogen phosphate and sodium dihydrogen phosphate, adjusting the pH of the solution to 4.0-6.5, filtering by using a 0.22-micron microporous filter membrane to obtain a benzcycloquine ammonium bromide solution, and filling into a specific spraying device under the condition of avoiding bacteria.
Comparative example 2
Commercially available cycloquina bromide nasal spray (trade name Billiptin, silver valley pharmaceutical Co., Ltd.)
Table 1: stability test of phenylcycloquine bromide nasal spray
Figure DEST_PATH_IMAGE005
TABLE 2 stability test of the benzcycloquine bromide nasal spray and the change of appearance
Figure DEST_PATH_IMAGE007
Test results and conclusions:
(1) as can be seen from Table 1, the results of the substances of the benzcycloquine bromide nasal spray prepared in examples 1-3 are better than those of comparative example 1 when compared with comparative example 1 in examples 1-3, and the stability test results of the sprays prepared by the invention are similar to those of the sprays sold on the market when compared with comparative example 2, which shows that the sprays prepared by the invention have better stability.
As can be seen from table 2, the appearance of the spray sample prepared in comparative example 1 appeared floccules in the sample under the conditions of three months acceleration and three months long, and the appearance of the sample was not changed and the stability was better in the stability test conditions of the benzcycloquine bromide nasal spray prepared in examples 1-3 and the benzcycloquine bromide nasal spray commercially available in comparative example 2.

Claims (10)

1. The nasal spray is characterized by comprising a main drug, a cosolvent, a surfactant and pharmaceutically acceptable excipients selected from a buffering agent, an osmotic pressure regulator, a pH regulator and the like.
2. The bencycloquinazine nasal spray of claim 1, wherein the principal drug is bencycloquinazine.
3. The composition as claimed in claim 2, wherein the content of the main ingredient is 1.00-5.00% by mass.
4. The spray according to claim 1, wherein the cosolvent is mainly one or more of polyethylene glycol and absolute ethyl alcohol.
5. The spray according to claim 1, wherein the surfactant is one or more of sorbitol, oleic acid, and phospholipids such as soybean phospholipid and lecithin.
6. The spray according to claim 1, wherein the buffer is one or more of phosphate, citrate, acetate and carbonate.
7. The spray according to claim 1, wherein the osmotic pressure regulator is one or more of sodium chloride, glucose, mannitol, sorbitol and lactose.
8. The spray according to claim 1, which is a solution type spray.
9. The preparation process of the phenylcycloquine ammonium bromide nasal spray comprises the steps of dissolving main drug components of phenylcycloquine ammonium bromide, cosolvent and/or surfactant at room temperature, adding a buffering agent and an osmotic pressure regulator for dissolution, filtering by a microporous filter membrane, and loading into a specific spraying device under the condition of avoiding bacteria.
10. The spray according to claim 1, which is useful for the treatment of rhinitis and chronic obstructive pulmonary disease (chronic obstructive pulmonary disease).
CN202010608961.6A 2020-06-30 2020-06-30 Benzcycloquine bromide nasal spray and preparation method thereof Pending CN113855632A (en)

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Publications (1)

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Application publication date: 20211231