Nasal spray composition and use thereof
By using non-hormonal small molecule compounds as active ingredients in nasal spray compositions, combined with appropriate formulations, the problems of long-term use difficulties and side effects of hormonal nasal sprays are solved, and a more efficient and safe rhinitis treatment effect is achieved. .
Patent Information
- Application Number
- CN202410890254.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2023-07-20
- Filing Date
- 2024-07-03
- Publication Date
- 2025-01-21
AI Technical Summary
Existing hormone nasal sprays are used to treat rhinitis with long-term difficulties in use and major side effects.
A nasal spray composition is provided, comprising a non-hormonal small molecule compound as an active ingredient, combined with a penetration enhancer, a pH adjuster, a solvent, water, and an optional osmotic pressure adjuster, thickening agent or suspending agent and surface active agent.
The nasal spray composition has good physical and chemical stability, significantly improves the effect of treating rhinitis, especially in the treatment of allergic rhinitis, improves medication compliance and quality of life, and improves clinical efficacy and safety. sex.
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Figure CN119326720A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of pharmaceutical compositions, and in particular relates to a nasal spray composition and uses thereof. Background Art
[0002] As a systemic administration route with rapid absorption, high bioavailability, little damage to the body and easy use, nasal administration has attracted more and more attention.
[0003] The human nasal cavity is an effective organ for the absorption of pharmacologically active ingredients. Since the 1980s, with the continuous improvement of scientific and technological levels, the research and development of new preparations that absorb pharmacologically active ingredients through the nasal mucosa to exert local or systemic therapeutic effects, collectively known as nasal drug delivery systems, has progressed rapidly.
[0004] Glucocorticoids are one of the most commonly used drugs for the treatment of allergic diseases. The use of nasal sprays containing hormone drugs has been successfully used for the prevention and treatment of allergic (including seasonal or non-seasonal) rhinitis. For example, there are commonly used budesonide nasal sprays, mometasone furoate nasal sprays, fluticasone propionate nasal sprays, etc. However, the above are all hormone drugs, which are difficult to use for a long time and have significant side effects.
[0005] Aryl Hydrocarbon Receptor (AHR) is a transcriptional regulator that can bind to ligands in cells. Studies have shown that AHR (aryl hydrocarbon receptor) is involved in physiological processes such as cell physiology, host defense, immune cell proliferation and differentiation, and detoxification. AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T cells, and NK cells. Since the ligand binding site of AHR is structurally flexible, many small molecules can serve as ligands, including exogenous ligands such as polycyclic aromatic hydrocarbons, dioxins, and polychlorinated biphenyls; endogenous ligands such as metabolites of tryptophan degradation, ligands from food sources, and products of bacterial and microbial metabolic pathways. The activation of AHR can directly trigger the expression of proteins such as CYP1A1 and CYP1A2, and these enzymes play a vital role in the metabolism of aromatic compounds: they are not only responsible for the metabolism of exogenous toxic substances, but also affect the biological metabolism of a variety of drugs. In addition, recent studies have also found that the AHR signaling pathway is of great significance in maintaining the balance of the immune system and is considered to be a magic all-rounder of immune regulation.
[0006] Therefore, based on the above background, the present disclosure provides a novel nasal spray composition of non-hormonal small molecule compounds to more effectively treat rhinitis. Summary of the invention
[0007] In order to improve the above technical problems, the present disclosure provides a nasal spray composition, wherein the nasal spray composition comprises the following components: an active ingredient, a permeation enhancer, a pH regulator, a solvent, water, and optionally an osmotic pressure regulator, optionally a thickener or a suspending agent, and optionally a surfactant, characterized in that the active ingredient is selected from at least one of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof;
[0008]
[0009] In some embodiments of the present disclosure, the nasal spray composition is a solution-type nasal spray or a suspension-type nasal spray.
[0010] In some embodiments of the present disclosure, the compound represented by formula (I) may be an E-type or Z-type isomer, preferably an E-type isomer represented by the following formula (I-1):
[0011]
[0012] In some embodiments of the present disclosure, the compound represented by formula (I) is benvimod.
[0013] In some embodiments of the present disclosure, the pharmaceutically acceptable salt may be selected from addition salts of the compound represented by formula (I) and a base.
[0014] In some embodiments of the present disclosure, the nasal spray composition contains only the compound represented by formula (I) as the active ingredient, and preferably contains only the E-isomer represented by formula (I-1) (i.e., benvimod) as the active ingredient.
[0015] In some embodiments of the present disclosure, in the nasal spray composition, the weight portion of the active ingredient is 0.1 to 8 parts, such as 0.5 to 5 parts, and exemplified by 0.5 parts, 0.75 parts, 1 parts, 1.5 parts, 2 parts, 3 parts, and 4 parts.
[0016] In some embodiments of the present disclosure, in the nasal spray composition, wherein the nasal spray composition is a suspension nasal spray, the active ingredient is micronized, and preferably, the particle size of the micronized active ingredient is less than 20 μm, preferably less than 10 μm, and more preferably less than 7 μm.
[0017] In some embodiments of the present disclosure, in the nasal spray composition, wherein the nasal spray composition is a suspension nasal spray, the active ingredient is crushed by a crushing device so that its particle size is less than 20 μm, preferably less than 10 μm, and more preferably less than 7 μm, which is conducive to uniform mixing of the active ingredient in the suspension liquid.
[0018] In some embodiments of the present disclosure, in the nasal spray composition, the nasal spray composition is a solution-type nasal spray, and the solution-type nasal spray is an aerosol-type nasal spray or a spray-type nasal spray.
[0019] In some embodiments of the present disclosure, the nasal spray composition further comprises an antioxidant; and / or
[0020] Chelating agents; and / or
[0021] Antibacterial agents;
[0022] Preferably, the antioxidant is selected from one or more of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid or its salts, sodium thiosulfate and dl-α-tocopherol;
[0023] Preferably, the chelating agent is a metal ion chelating agent, and the metal ion chelating agent is selected from one or more of ethylenediaminetetraacetic acid, gluconic acid, nitrilotriacetic acid, tartaric acid, citric acid and salts thereof;
[0024] Preferably, the antibacterial agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, polyquaternium salt, disodium edetate, calcium sodium edetate, benzethonium chloride, sorbic acid, benzyl alcohol, phenethyl alcohol, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, phenethyl alcohol, benzyl alcohol, potassium sorbate, methylparaben, ethylparaben and propylparaben.
[0025] In some embodiments of the present disclosure, in the nasal spray composition, the penetration enhancer is selected from one or more of ethanol, propylene glycol, diethylene glycol monoethyl ether, sorbitol, glycerol, menthol, castor oil and cottonseed oil; and / or
[0026] The pH regulator is selected from one or more of phosphoric acid and its salts, boric acid and its salts, citric acid and its salts, acetic acid and its salts, tartaric acid and its salts, sulfuric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tromethamine and chlorobutanol; and / or
[0027] The solvent is selected from one or more of ethanol, propylene glycol, diethylene glycol monoethyl ether, sorbitol, glycerol, polyethylene glycol 400, castor oil and cottonseed oil.
[0028] In some embodiments of the present disclosure, in the nasal spray composition, the osmotic pressure regulator is selected from one or more of sodium chloride, anhydrous glucose, glycerol, propylene glycol, potassium chloride, sorbitol, mannitol and glucose monohydrate; and / or
[0029] The thickener or suspending agent is selected from one or more of microcrystalline cellulose-sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, povidone K90, povidone K30, sodium hyaluronate, hydroxyethyl cellulose, polyvinyl alcohol, carboxyvinyl polymer, dextran, polyvinyl pyrrolidone, carbomer and polyvinyl alcohol; and / or
[0030] The surfactant is selected from one or more of sodium dodecyl sulfate (SDS), dodecyl-beta-D-maltoside, sorbitan monolaurate (Span 20), polyoxyethylene castor oil 60, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol stearate, polyethylene glycol, lecithin, sucrose ester, polyoxyethylene alkyl ether, polyoxystearate, polyoxyethylene-polyoxypropylene glycol, tyloxapol, polysorbate 80 and polysorbate 20.
[0031] In some embodiments of the present disclosure, in the nasal spray composition, the weight portion of the penetration enhancer is 0.1 to 72 parts, such as 0.1 to 50 parts, and exemplified by 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, and 40 parts.
[0032] In some embodiments of the present disclosure, in the nasal spray composition, the weight proportion of the solvent is 5 to 99 parts, for example 10 to 60 parts, exemplified by 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, and 60 parts.
[0033] In some embodiments of the present disclosure, in the nasal spray composition, the weight portion of the osmotic pressure regulator is 1 to 10 parts, such as 2 to 8 parts, exemplified by 2 parts, 3 parts, 5 parts, 7 parts, and 8 parts.
[0034] In some embodiments of the present disclosure, in the nasal spray composition, the weight portion of the thickener or suspending agent is 0.01 to 2 parts, such as 0.02 to 1.5 parts, exemplified by 0.02 parts, 0.05 parts, 0.5 parts, and 1.5 parts.
[0035] In some embodiments of the present disclosure, in the nasal spray composition, the weight portion of the surfactant is 0.01 to 10 parts, such as 0.5 to 8 parts, and exemplified by 0.5 parts, 1 parts, 3 parts, 5 parts, and 8 parts.
[0036] In some embodiments of the present disclosure, in the nasal spray composition, the weight portion of the antioxidant is 0.01 to 1 part, such as 0.05 to 0.5 part, and exemplified by 0.05 part, 0.1 part, 0.2 part, 0.3 part, and 0.5 part.
[0037] In some embodiments of the present disclosure, in the nasal spray composition, the weight portion of the chelating agent is 0.01 to 1 part, such as 0.05 to 0.5 part, exemplified by 0.05 part, 0.1 part, 0.2 part, 0.3 part, and 0.5 part.
[0038] In some embodiments of the present disclosure, in the nasal spray composition, the weight portion of the antibacterial agent is 0.01 to 1 part, such as 0.05 to 0.5 part, and exemplified by 0.05 part, 0.1 part, 0.2 part, 0.3 part, and 0.5 part.
[0039] In some embodiments of the present disclosure, in the nasal spray composition, the solvent is selected from water, preferably purified water.
[0040] In some embodiments of the present disclosure, in the nasal spray composition, the pH of the composition is 4 to 7, preferably 4 to 6, for example 4.5, 5, 5.1, 5.2, 5.5.
[0041] In some embodiments of the present disclosure, the above-mentioned penetration enhancer also serves as a solvent for the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof, an antioxidant and / or an antibacterial agent.
[0042] In some embodiments of the present disclosure, the nasal spray composition includes the following components in parts by weight: 0.1 to 8 parts of active ingredient, 10 to 60 parts of permeation enhancer, 1 to 10 parts of osmotic pressure regulator, 0.01 to 1 part of chelating agent, 0.01 to 0.2 parts of antioxidant, 0.01 to 0.3 parts of antibacterial agent, 20 to 60 parts of solvent and an appropriate amount of pH regulator;
[0043] The active ingredient is a compound represented by formula (I), preferably the E-type isomer represented by the above formula (I-1) as the active ingredient;
[0044] Preferably, the pH of the nasal spray composition is 4-7.
[0045] According to an embodiment of the present disclosure, the nasal spray composition includes the following components in parts by weight: 0.1 to 8 parts of active ingredient, 10 to 60 parts of permeation enhancer, 1 to 10 parts of osmotic pressure regulator, 0.01 to 1 part of chelating agent, 0.01 to 1 part of thickening agent or suspending agent, 0.01 to 0.2 parts of antioxidant, 0.01 to 0.3 parts of preservative, 20 to 60 parts of solvent and pH adjuster;
[0046] The active ingredient is a compound represented by formula (I), preferably the E-type isomer represented by the above formula (I-1) as the active ingredient;
[0047] Preferably, the pH of the nasal spray composition is 4-6.
[0048] According to an embodiment of the present disclosure, the nasal spray composition may further include a second active ingredient.
[0049] The present disclosure also provides a method for preparing the above nasal spray composition, comprising mixing the components.
[0050] Preferably, the preparation method comprises the following steps:
[0051] (1) stirring at least one solvent evenly, then adding the active ingredient, the penetration enhancer and the osmotic pressure regulator, and stirring to dissolve the active ingredient to form a solution containing the active ingredient;
[0052] Alternatively, the active ingredient, antioxidant, antibacterial agent, solvent, osmotic pressure regulator, and permeation enhancer are mixed to form a solution containing the active ingredient;
[0053] (2) mixing an optional thickener or suspending agent with the solution formed in step (1) to form a mixed solution;
[0054] (3) adding the mixed solution of step (2) to the solution formed in step (1), mixing evenly, and then adding a pH adjuster to adjust the pH of the system, preferably to 4 to 7;
[0055] (5) adding a solvent to make up the weight to obtain the nasal spray composition.
[0056] In some embodiments of the present disclosure, in the nasal spray composition, the mass percentage of the active ingredient (i.e., the compound represented by formula (I) and at least one of its pharmaceutically acceptable salts) is 0.1-8%, for example, 0.5-5%, exemplified by 0.5%, 0.75%, 1%, 1.5%, 2%, 3%, and 4%.
[0057] The present disclosure provides a pharmaceutical preparation, comprising the above-mentioned nasal spray composition.
[0058] According to an embodiment of the present disclosure, the nasal spray composition or the pharmaceutical preparation is used in the preparation of a medicament for treating and / or preventing rhinitis, preferably in the preparation of a medicament for treating and / or preventing allergic rhinitis.
[0059] According to an embodiment of the present disclosure, the pharmaceutical preparation comprises a container for containing the nasal spray composition. Preferably, the container is a light-proof, airtight container.
[0060] In one embodiment, the pharmaceutical preparation further comprises a spray device for spraying the nasal spray composition in the form of a spray on the affected area.
[0061] In one embodiment, the pharmaceutical formulation further comprises a propellant.
[0062] In one embodiment, the nasal spray composition or the pharmaceutical preparation is administered topically, or is further combined with an oral administration preparation or other topical administration preparations.
[0063] The present disclosure also provides a method for treating and / or preventing rhinitis, comprising administering an effective amount or a therapeutically effective amount of the nasal spray composition or the pharmaceutical preparation to a patient; the rhinitis is preferably allergic rhinitis.
[0064] Definitions and explanations of terms
[0065] Unless otherwise specified, the definitions of terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of the description of this application.
[0066] The term "effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present disclosure sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and the disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by a person of ordinary skill in the art. The specific dosage will vary depending on the specific compound selected, the dosage regimen relied upon, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system carried.
[0067] The term "optional" or "optional" means that the event or environment described later may but does not necessarily occur, and includes both the occurrence and non-occurrence of the event or environment. For example, "optionally containing an antioxidant" includes both the occurrence and non-occurrence of the antioxidant.
[0068] The term "patient" refers to a patient who needs to prevent or treat a disease associated with anaerobic bacteria, wherein the patient is a mammal, for example selected from rodents, cattle, pigs, dogs, cats and primates, in particular humans.
[0069] The term "plurality" means two or more than two.
[0070] Beneficial Effects
[0071] The present disclosure provides a nasal spray composition with good physical and chemical stability. The active ingredient of the composition is a non-hormonal small molecule compound, which is a novel AhR compound. The composition is used to treat rhinitis, preferably allergic rhinitis, and has a good therapeutic effect, significantly improves the patient's medication compliance and quality of life, and improves clinical efficacy and safety. DETAILED DESCRIPTION
[0072] The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.
[0073] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
[0074] Embodiment 1-11
[0075] The following Examples 1-11 were prepared according to the preparation method described in the specification, and the specific prescriptions are shown in Table 1 and Table 2:
[0076] Table 1
[0077]
[0078]
[0079] Table 2
[0080]
[0081] Example 12 Transdermal Test
[0082] The purpose of this experiment is to conduct an in vitro skin permeation test on the sample of Example 7 to evaluate the intradermal retention.
[0083] Experimental steps: Pig skin (thickness 0.8-1.0 mm) was mounted on a LOGAN System 918 vertical diffusion cell, exposing 1.77 cm 2 surface area. The diffusion cell was connected to a multichannel pump at a speed of 600 rpm, and the receiving fluid was normal saline (0.9% sodium chloride solution). Each cell was placed in a heating manifold to balance the temperature to ensure that the skin surface temperature was 32°C (at least 30 minutes before administration). The sample load was 0.3g. The receiving fluid was collected at 4, 8, 12, 16, and 24 hours to measure the active ingredients that penetrated through the skin. At the end of the 24-hour sampling, the skin was wiped with a cotton swab to remove any residual test sample that was considered not to penetrate the skin. The skin layer was cut into pieces and methanol was added for ultrasonic extraction of the drug. The recovered drug concentration was used to calculate the amount of retention in the skin.
[0084] Results: The retention amount of the active ingredient of the sample of Example 7 in the skin was measured to be 36.54 μg / g.
[0085] Example 13 Clinical efficacy test
[0086] The sample of Example 7 was selected for administration.
[0087] 1. Dosage: Nasal spray, once in the morning and evening, two sprays in each nostril each time, for two weeks;
[0088] 2. Dosing population: 30 adult patients with allergic rhinitis were selected as volunteers, whose main allergic symptoms were: itchy eyes, sneezing, nasal congestion, runny nose, itchy nose, etc.
[0089] 3. Result collection: Fill out the questionnaire based on the improvement of each symptom, and then count the questionnaire results.
[0090] 4. Results and statistics
[0091] Each patient was given a score based on the improvement of rhinitis, and the overall improvement was obtained. 20% of patients were basically or completely improved, 60% of patients were greatly improved, 15% of patients were improved, and only 5% of patients reported no improvement, and no patient reported allergic symptoms.
[0092] The above describes the implementation methods of the present disclosure. However, the present disclosure is not limited to the above implementation methods. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present disclosure shall be included in the protection scope of the present disclosure.
Claims
1. A nasal spray composition, wherein the nasal spray composition comprises the following components: an active ingredient, a penetration enhancer, a pH adjuster, a solvent, water, and optionally an osmotic pressure regulator, optionally a thickener or a suspending agent, and optionally a surfactant, characterized in that: The active ingredient is selected from at least one of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof; 2. The nasal spray composition according to claim 1, wherein the nasal spray composition is a solution-type nasal spray or a suspension-type nasal spray.
3. The nasal spray composition according to claim 1 or 2, wherein The compound represented by the formula (I) is an E-type or Z-type isomer, preferably an E-type isomer represented by the following formula (I-1): Preferably, in the nasal spray composition, the active ingredient is present in an amount of 0.1 to 8 parts by weight.
4. The nasal spray composition according to any one of claims 1 to 3, wherein the nasal spray composition is a suspension nasal spray, and the active ingredient is micronized, preferably, the particle size of the micronized active ingredient is less than 20 μm.
5. The nasal spray composition according to any one of claims 1 to 3, wherein the nasal spray composition is a solution-type nasal spray, and the solution-type nasal spray is an aerosol-type nasal spray or a spray-type nasal spray.
6. The nasal spray composition according to any one of claims 1 to 5, wherein the nasal spray composition further comprises an antioxidant; and / or Chelating agents; and / or Antibacterial agents; Preferably, the antioxidant is selected from one or more of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid or its salts, sodium thiosulfate and dl-α-tocopherol; Preferably, the chelating agent is a metal ion chelating agent, and the metal ion chelating agent is selected from one or more of ethylenediaminetetraacetic acid, gluconic acid, nitrilotriacetic acid, tartaric acid, citric acid and salts thereof; Preferably, the antibacterial agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, polyquaternium salt, disodium edetate, calcium sodium edetate, benzethonium chloride, sorbic acid, benzyl alcohol, phenethyl alcohol, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, phenethyl alcohol, benzyl alcohol, potassium sorbate, methylparaben, ethylparaben and propylparaben.
7. The nasal spray composition according to any one of claims 1 to 6, wherein the penetration enhancer is selected from one or more of ethanol, propylene glycol, diethylene glycol monoethyl ether, sorbitol, glycerol, menthol, castor oil and cottonseed oil; and / or The pH regulator is selected from one or more of phosphoric acid and its salts, boric acid and its salts, citric acid and its salts, acetic acid and its salts, tartaric acid and its salts, sulfuric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tromethamine and chlorobutanol; and / or The solvent is selected from one or more of ethanol, propylene glycol, diethylene glycol monoethyl ether, sorbitol, glycerol, polyethylene glycol 400, castor oil and cottonseed oil.
8. The nasal spray composition according to any one of claims 1 to 7, wherein the osmotic pressure regulator is selected from one or more of sodium chloride, anhydrous glucose, glycerol, propylene glycol, potassium chloride, sorbitol, mannitol and glucose monohydrate; and / or The thickener or suspending agent is selected from one or more of microcrystalline cellulose-sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, povidone K90, povidone K30, sodium hyaluronate, hydroxyethyl cellulose, polyvinyl alcohol, carboxyvinyl polymer, dextran, polyvinyl pyrrolidone, carbomer and polyvinyl alcohol; and / or The surfactant is selected from one or more of sodium dodecyl sulfate (SDS), dodecyl-beta-D-maltoside, sorbitan monolaurate (Span 20), polyoxyethylene castor oil 60, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol stearate, polyethylene glycol, lecithin, sucrose ester, polyoxyethylene alkyl ether, polyoxystearate, polyoxyethylene-polyoxypropylene glycol, tyloxapol, polysorbate 80 and polysorbate 20.
9. The nasal spray composition according to any one of claims 1 to 8, wherein The pH of the nasal spray composition is 4-7.
10. Use of the nasal spray composition according to any one of claims 1 to 9 in the preparation of a medicament for treating and / or preventing rhinitis, preferably in the preparation of a medicament for treating and / or preventing allergic rhinitis.