Nasal spray preparation containing diketo dioxins and preparation method of nasal spray preparation

Abstract

The invention discloses a nasal spray preparation containing a diketo dioxane compound and a preparation method thereof, and belongs to the technical field of medicines. The technical problem to be solved is to provide the nasal spray preparation containing the diketo dioxins, which is non-irritant and higher in cumulative transmittance. The key point of the technical scheme is as follows: the raw materials comprise an active component, a preservative, glycerol, an isotonic regulator, a humectant and a penetration enhancer, wherein the penetration enhancer is a diketodioxane compound.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a nasal spray formulation containing a diketone dioxin and its preparation method. Background Technology

[0002] For understanding the technical content of this invention: Drug delivery systems have always been an important area of ​​research in pharmaceutical formulation. Traditional methods are affected by the pH environment of the digestive tract and various enzymes, leading to the rapid destruction or inactivation of some bioactive substances, such as calcitonin, insulin, and mucopolysaccharides, in the gastrointestinal tract. Furthermore, due to the inherent physicochemical properties of drugs, some sensitive drugs are prone to degradation, and poorly soluble drugs have low bioavailability. Developing efficient delivery systems can enhance drug efficacy and reduce toxic side effects.

[0003] Against this backdrop, non-invasive drug delivery routes have received widespread attention, with nasal administration being particularly noteworthy due to its unique physiological advantages. The nasal cavity possesses a rich vascular network and a relatively large absorption surface area, enabling rapid drug absorption and onset of action. Simultaneously, nasal administration avoids the first-pass effect in the liver, improving drug bioavailability, and providing an ideal route, especially for the delivery of protein and peptide drugs. However, nasal administration also faces certain challenges. The nasal mucosa, as an important defense barrier of the body, possesses complex physical and chemical barrier functions. For example, the degradation by various enzymes and the epithelial barrier formed by tight junction proteins hinder effective drug penetration.

[0004] Diketopiperazine compounds are a novel type of material that can be used to form drug-loaded microspheres by loading or adsorbing drugs onto their surfaces, thereby improving drug stability and permeability. Drug-loaded microspheres using diketopiperazine compounds as carriers have small diameters, large surface areas, high drug loading capacities, and are easy to manufacture. They are suitable for the preparation of various types of drugs, such as cationic drugs with API molecular weights of 500-140,000 Da, anionic drugs, hydrophilic / lipophilic drugs, peptides, proteins, and small molecule drugs.

[0005] Technosphere® technology, which uses fumarodiketopiperazine (FDKP, CAS: 176738-91-3) as a carrier to prepare microspheres, is a novel drug delivery technology. Mannkind's Afrezza rapid-acting insulin, produced using this technology, was approved by the FDA in 2014 and is currently the only inhaled insulin formulation on the market, fully demonstrating the transmucosal permeation-enhancing function of diketopiperazine compounds as drug carriers.

[0006] FDKP is acidic, and inhalation of Afrezza may cause coughing and other symptoms. When administered nasally, it may irritate sensitive nasal mucosa, causing discomfort to patients. Therefore, designing a series of novel diketopiperazine compounds to overcome the adverse effects of the acidic nature of FDKP is of practical significance for achieving effective drug delivery.

[0007]

[0008] Relevant patent documents retrieved: This document, published in China (CN115991678A) on April 21, 2023, discloses a diketopiperazine compound, its preparation method, and its applications. This invention provides a diketopiperazine compound as shown in the formula, or a pharmaceutically acceptable salt thereof, which can be used as self-assembly loaded drug microspheres to achieve efficient drug delivery.

[0009]

[0010] Relevant non-patent literature retrieved: The journal or book title is *Chinese Health Preservation*, and the article title is "Protective Effect of Ginkgolide Nasal Spray on Cerebral Ischemia-Reperfusion Injury in Rats," Volume 41, Issue 17, Publication Date: September 2023. This article discloses that nasal administration is a convenient method of drug delivery, where active ingredients can be rapidly absorbed through the nasal mucosa, acting locally in the nasal cavity and systemically. Furthermore, it can directly deliver the drug to the brain. Compared to oral or intravenous administration, nasal administration has advantages including non-invasiveness, self-administration, and high bioavailability, making it a hot topic in pharmaceutical research in recent years. Many central nervous system-related diseases have been treated with nasal administration, such as Parkinson's disease, Alzheimer's disease, epilepsy, and addiction.

[0011] The prior art represented by the aforementioned documents has at least the following unresolved technical problems or defects: No publicly available nasal spray formulations using diketol dioxin compounds as raw materials have been found in the prior art. Therefore, developing a nasal spray formulation using a specific diketol dioxin compound as a raw material, and achieving effective drug delivery through the mucosa by employing a novel diketol dioxin compound as a penetration enhancer, is a key research focus for researchers in this field.

[0012] In solving the above problems or overcoming the above defects, the present invention encountered the following difficulties and obstacles: The novel diketogenic dioxin compounds designed in this invention introduce hydroxyl groups into the side chains of diketogenic piperazine compounds and replace the amide bonds in the parent ring with ester bonds, thereby eliminating acid-base linkages and maintaining a neutral molecular structure, effectively reducing irritation to the nasal mucosa. However, long-chain alkyl compounds affect the surface tension of solutions. Their hydrophobic chains can adsorb at the solution interface, reducing intermolecular forces and significantly lowering the surface tension of aqueous solutions. This may lead to the dissolution or rupture of nasal mucosal cells, thus requiring the selection of appropriate isotonic regulators to adjust the osmotic pressure of nasal sprays. The inventors accidentally discovered that adding glycerol to the formulation can effectively regulate the tension of nasal spray solutions. Glycerol can stabilize the osmotic pressure of the solution by forming a hydrogen bond network with the hydroxyl groups in the penetration enhancer molecules. Furthermore, glycerol has low mucosal irritation, good compatibility with long-chain alkyl compounds, and is not prone to inducing phase separation. However, when the proportion of glycerol is too low, it cannot provide sufficient tension regulation; when the proportion is too high, due to its hygroscopic properties, it may conversely draw water from the nasal mucosa, leading to epithelial cell dehydration, ciliary movement disorders, and potentially inducing atrophic rhinitis in the long term. Only when the ratio of glycerin to the penetration enhancer is specific can the nasal spray solution achieve penetration enhancement without causing cell lysis or rupture due to excessively low solution surface tension. Summary of the Invention

[0013] The purpose of this invention is to provide: A nasal spray formulation containing a diketol dioxin compound, its preparation method, and related technologies are disclosed to address technical issues such as providing a non-irritating nasal spray formulation containing a diketol dioxin compound with higher cumulative permeability, or a combination thereof.

[0014] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0015] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0016] The definition of the standard chemical term can be found in the reference "Pharmacopoeia of the People's Republic of China (2020 Edition), China Medical Science and Technology Press: May 2020: 1st Edition."

[0017] Unless otherwise stated, conventional methods within the scope of the art, such as mixing and filtering, shall be used.

[0018] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0019] The term "mixing" as used in this article refers to the process of combining two or more pharmaceutical ingredients (or drugs and excipients) through physical or mechanical means to form a uniformly dispersed formulation. Its core purpose is to ensure the uniformity of the distribution of pharmaceutical ingredients, thereby guaranteeing efficacy, safety, and formulation quality.

[0020] The term "filtration" as used in this article refers to the process of separating solid particles or harmful substances from a fluid through porous media (such as filter paper, filter membrane, sand layer, etc.). Its core principle is to use the difference in particle size to allow liquid (or gas) to pass through the medium while the solid is retained.

[0021] In a first aspect, the present invention provides: a nasal spray formulation containing a diketone dioxin, the raw materials of which include: an active ingredient, a preservative, glycerin, an isotonic modifier, a humectant, and a penetration enhancer, wherein the penetration enhancer is a diketone dioxin.

[0022] This includes technical features such as raw materials, active ingredients, preservatives, isotropic modifiers, humectants, and diketone dioxins.

[0023] Among them, the technically distinctive diketone dioxane compounds are selected from compounds shown in Formula I below:

[0024] Formula I.

[0025] Preferably, the reaction equation for the compound represented by Formula I is as follows:

[0026] Includes the following steps: Step 1: Compounds 11 and 15 undergo a condensation reaction to obtain compound 16; Step 2: Deprotect compound 16 to obtain compound 8.

[0027] The preservative in the technical feature is selected from at least one of the following: methylparaben, ethylparaben, propylparaben, butylparaben, isopropylparaben, isobutylparaben, benzoic acid, sodium benzoate, sorbic acid, and benzalkonium bromide.

[0028] The preferred preservative for the technical features is at least one of methylparaben, isopropylparaben, benzoic acid, sodium benzoate, and benzalkonium bromide.

[0029] The isotropic modifier is selected from at least one of the following: sodium chloride, potassium chloride, potassium dihydrogen phosphate, disodium hydrogen phosphate, sorbitol, and mannitol.

[0030] The preferred isotropic modifier is selected from at least one of sodium chloride, potassium chloride, potassium dihydrogen phosphate, sorbitol, and mannitol.

[0031] The technical feature moisturizer is selected from at least one of the following: propylene glycol, PEG 400, polyvinyl alcohol, carboxyethylene polymer, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl cellulose.

[0032] The preferred moisturizer is selected from at least one of the following: propylene glycol, PEG 400, polyvinyl alcohol, polyvinylpyrrolidone, and sodium carboxymethyl cellulose.

[0033] The preferred active ingredient in the technical feature is an active ingredient acceptable in the field of nasal spray formulations.

[0034] The preferred active ingredients are: cationic drugs, anionic drugs, hydrophilic / lipophilic drugs, peptides, and proteins with an API molecular weight of 500-140000 Da.

[0035] The active ingredient with technical characteristics is further preferably insulin, dulutegravir, semaglutide, sumatriptan succinate, or sildenafil.

[0036] Among them, the technical features are made from raw materials selected from: raw materials also include water.

[0037] The preferred technical feature is that the water is purified water, deionized water, or distilled water.

[0038] The water with the technical characteristic is further preferably purified water.

[0039] The technical features of the raw materials are selected from the following raw materials by mass: 4-85 parts of active ingredient, 0.001-0.025 parts of preservative, 3-33 parts of glycerin, 0.1-65 parts of isotropic modifier, 0.5-28 parts of moisturizer and 5-65 parts of penetration enhancer.

[0040] Any point value or any range of two point values ​​within the above range can achieve the technical effect of this invention. For example: The active ingredient is indicated in parts by weight as 4-85 parts, including but not limited to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, and 43 parts. The quantities are 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, and 85, which will not be listed in detail here.

[0041] The amount of preservative (0.001-0.025 parts) indicates that the mass fraction of the preservative includes, but is not limited to, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.011, 0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, 0.020, 0.021, 0.022, 0.023, 0.024, and 0.025 parts, which will not be listed in detail here.

[0042] The quantity of glycerol is 3-33 parts, which includes, but is not limited to, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, and 33 parts. These will not be listed in detail here.

[0043] Isotonic modifier is indicated in parts from 0.1 to 65 parts. The mass fractions of the isotonic modifier include, but are not limited to, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30 parts. The quantities are 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, and 65, which will not be listed in detail here.

[0044] The quantity of moisturizer from 0.5 to 28 parts indicates that the number of parts by weight of moisturizer includes, but is not limited to, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28 parts, which will not be listed in detail here.

[0045] The indicated amount of penetration enhancer is 5-65 parts. The mass fractions of the penetration enhancer include, but are not limited to, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, and 33 parts. 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, and 65, which will not be listed here.

[0046] The preferred raw materials for the technical features are, by weight, the following: 5-80 parts of active ingredient, 0.002-0.02 parts of preservative, 5-30 parts of glycerin, 0.1-60 parts of isotropic modifier, 0.5-25 parts of humectant, and 5-60 parts of penetration enhancer.

[0047] Any point value or any range of two point values ​​within the above range can achieve the technical effect of the present invention, and will not be elaborated here.

[0048] The mass ratio of glycerol to penetration enhancer is 1-3:1-3.

[0049] Preferably, the mass ratio of glycerol to the penetration enhancer is 1-2:1-2. More preferably, the mass ratio of glycerol to the penetration enhancer is 1.5:1.

[0050] Based on further solutions to the technical problems of the present invention, or simultaneous solutions to multiple technical problems, the preferred solution in the technical solution provided in the first aspect of the present invention includes: First preferred option: The diketodioxane compound is a compound with the structure shown in Formula I below:

[0051] Formula I.

[0052] This technical solution, having already addressed the technical issues of "reducing the irritation of nasal spray formulations and increasing their cumulative permeability," further addresses the technical issues of "further reducing the irritation of nasal spray formulations and further increasing their cumulative permeability."

[0053] The second preferred option: the preservative is selected from at least one of methylparaben, ethylparaben, propylparaben, butylparaben, isopropylparaben, isobutylparaben, benzoic acid, sodium benzoate, sorbic acid, and benzalkonium bromide. This technical solution, having solved the technical problem of "reducing the irritation of nasal spray formulations and increasing their cumulative permeability," further solves the technical problem of "further reducing the irritation of nasal spray formulations and further increasing their cumulative permeability."

[0054] The third preferred option: the preservative is selected from at least one of methylparaben, isopropylparaben, benzoic acid, sodium benzoate, and benzalkonium bromide. This technical solution, having solved the technical problem of "reducing the irritation of the nasal spray preparation and increasing its cumulative permeability," further solves the technical problem of "further reducing the irritation of the nasal spray preparation and further increasing its cumulative permeability."

[0055] The fourth preferred option: the isotropic regulator is selected from at least one of sodium chloride, potassium chloride, potassium dihydrogen phosphate, disodium hydrogen phosphate, sorbitol, and mannitol. This technical solution, having solved the technical problem of "reducing the irritation of the nasal spray formulation and increasing its cumulative permeability," further solves the technical problem of "further reducing the irritation of the nasal spray formulation and further increasing its cumulative permeability."

[0056] The fifth preferred option: the isotropic regulator is selected from at least one of sodium chloride, potassium chloride, potassium dihydrogen phosphate, sorbitol, and mannitol. This technical solution, having solved the technical problem of "reducing the irritation of the nasal spray formulation and increasing its cumulative permeability," further solves the technical problem of "further reducing the irritation of the nasal spray formulation and further increasing its cumulative permeability."

[0057] The sixth preferred option: the moisturizer is selected from at least one of propylene glycol, PEG 400, polyvinyl alcohol, carboxyethylene polymer, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose. This technical solution, having solved the technical problem of "reducing the irritation of nasal spray formulations and improving their cumulative permeability," further solves the technical problem of "further reducing the irritation of nasal spray formulations and further improving their cumulative permeability."

[0058] The seventh preferred option: the moisturizer is selected from at least one of propylene glycol, PEG 400, polyvinyl alcohol, polyvinylpyrrolidone, and sodium carboxymethyl cellulose. This technical solution, having solved the technical problem of "reducing the irritation of nasal spray formulations and increasing their cumulative permeability," further solves the technical problem of "further reducing the irritation of nasal spray formulations and further increasing their cumulative permeability."

[0059] The eighth preferred option: The raw materials also include water. This technical solution, based on solving the technical problem of "reducing the irritation of nasal spray preparations and increasing their cumulative permeability", further solves the technical problem of "further reducing the irritation of nasal spray preparations and further increasing their cumulative permeability".

[0060] The ninth preferred option: the active ingredient is an acceptable active ingredient in the field of nasal spray formulations. This technical solution, based on solving the technical problem of "reducing the irritation of nasal spray formulations and improving their cumulative permeability", further solves the technical problem of "further reducing the irritation of nasal spray formulations and further improving their cumulative permeability".

[0061] The tenth preferred option: The active ingredient is a cationic drug, anionic drug, hydrophilic / lipophilic drug, peptide, or protein with an API molecular weight of 500-140,000 Da. This technical solution, based on solving the technical problem of "reducing the irritation of nasal spray preparations and improving their cumulative permeability", further solves the technical problem of "further reducing the irritation of nasal spray preparations and further improving their cumulative permeability".

[0062] Eleventh preferred option: The active ingredient is selected from insulin, dulutegravir, semaglutide, sumatriptan succinate, or sildenafil. This technical solution, based on solving the technical problem of "reducing the irritation of nasal spray formulations and increasing their cumulative permeability", further solves the technical problem of "further reducing the irritation of nasal spray formulations and further increasing their cumulative permeability".

[0063] The twelfth preferred option, by weight, includes the following raw materials: 4-85 parts active ingredient, 0.001-0.025 parts preservative, 3-33 parts glycerin, 0.1-65 parts isotropic modifier, 0.5-28 parts humectant, and 5-65 parts penetration enhancer. This technical solution, having already addressed the technical problem of "reducing the irritation of nasal spray formulations and increasing their cumulative penetration rate," further addresses the technical problem of "further reducing the irritation of nasal spray formulations and further increasing their cumulative penetration rate."

[0064] The thirteenth preferred option, by weight, includes the following raw materials: 5-80 parts active ingredient, 0.002-0.02 parts preservative, 5-30 parts glycerin, 0.1-60 parts isotropic modifier, 0.5-25 parts humectant, and 5-60 parts penetration enhancer. This technical solution, having already addressed the technical problem of "reducing the irritation of nasal spray formulations and increasing their cumulative penetration rate," further addresses the technical problem of "further reducing the irritation of nasal spray formulations and further increasing their cumulative penetration rate."

[0065] The fourteenth preferred embodiment: the mass ratio of glycerin to the penetration enhancer is 1-3:1-3. This technical solution, based on solving the technical problem of "reducing the irritation of nasal spray formulations and improving their cumulative penetration rate", further solves the technical problem of "further reducing the irritation of nasal spray formulations and further improving their cumulative penetration rate".

[0066] The fifteenth preferred embodiment: the mass ratio of glycerin to the penetration enhancer is 1-2:1-2. This technical solution, based on solving the technical problem of "reducing the irritation of nasal spray formulations and improving their cumulative penetration rate", further solves the technical problem of "further reducing the irritation of nasal spray formulations and further improving their cumulative penetration rate".

[0067] The sixteenth preferred embodiment: the mass ratio of glycerin to the penetration enhancer is 1.5:1. This technical solution, based on solving the technical problem of "reducing the irritation of nasal spray formulations and improving their cumulative penetration rate", further solves the technical problem of "further reducing the irritation of nasal spray formulations and further improving their cumulative penetration rate".

[0068] Secondly, the present invention provides a method for preparing the above-mentioned nasal spray formulation, comprising the following steps: S1: The active ingredient, penetration enhancer and solvent are mixed, and the pH is adjusted to precipitate solids to obtain drug-loaded microsphere solid powder; S2: The drug-loaded microsphere solid powder and the remaining raw materials of the nasal spray formulation are mixed to obtain the nasal spray formulation.

[0069] This includes technical features such as solvents and pH adjustment.

[0070] The technical characteristic solvent is selected from: purified water, ethanol, propylene glycol, glycerol, dimethyl sulfoxide, ethyl acetate, N-methylpyrrolidone, dimethylacetamide, and fatty oils. The reagent used to adjust the pH in this technical feature is an 8-12% aqueous solution of glacial acetic acid (v / v).

[0071] The preferred reagent used for adjusting pH in this technical feature is a 10% aqueous solution of glacial acetic acid (v / v).

[0072] In step S1, the drug-loaded microsphere solid powder needs to pass through a 150-250 mesh sieve, preferably a 200 mesh sieve.

[0073] In step S2, the mixture obtained by mixing needs to be filtered through a 0.4-0.5μm filter element; preferably, it needs to be filtered through a 0.45μm filter element.

[0074] Embodiments 1-5 of this invention at least support the protection scope of claim 1.

[0075] Regarding the claim 1: The technical feature “active ingredient, preservative, isotropic regulator, humectant, and penetration enhancer, wherein the penetration enhancer is a diketol dioxin” is derived from the specific raw materials in the foregoing explanation and / or Examples 1-5, and summarized by the common feature “the raw materials include: active ingredient, preservative, glycerin, isotropic regulator, humectant, and penetration enhancer, wherein the penetration enhancer is a diketol dioxin.” Therefore, those skilled in the art can reasonably infer that the technical feature active ingredient, preservative, isotropic regulator, humectant, and penetration enhancer, wherein the penetration enhancer is a diketol dioxin, its subordinate concepts, substantially equivalent technical means, and technical means that can be replaced by conventional technical means and common knowledge based on the existing level of technology should all fall within the protection scope of claim 1. For example, replacing the active ingredient, preservative, isotropic regulator, humectant, and penetration enhancer, wherein the penetration enhancer is a diketol dioxin, with other technical features unchanged still falls within the protection scope of claim 1 of this invention.

[0076] Embodiments 1-5 of this invention at least support the protection scope of claim 2.

[0077] Regarding claim 2: The technical feature “diketodioxan compound”, as explained above and / or the corresponding technical features in Examples 1-5, refers to compounds with the structure shown in Formula I:

[0078] Formula I.

[0079] The term "diketodioxan compounds" is derived from the common feature "diketodioxan compounds". Therefore, those skilled in the art can reasonably presume that the technical feature "diketodioxan compounds", its subordinate concepts, substantially equivalent technical means, and technical means that can be replaced by conventional technical means and common knowledge based on the existing level of technology should all fall within the protection scope of claim 2.

[0080] Embodiments 1-5 of this invention at least support the protection scope of claims 2-12.

[0081] Regarding claims 2-12: The technical features “preservative, isotropic modifier, humectant, raw materials also include water, and active ingredient” are summarized from the specific raw materials of the corresponding technical features in the foregoing explanation and / or Examples 1-5, and are generalized from the common features “preservative, isotropic modifier, humectant, raw materials also include water, and active ingredient”. Therefore, those skilled in the art can reasonably presume that the technical features “preservative, isotropic modifier, humectant, raw materials also include water, active ingredient”, their subordinate concepts, substantially equivalent technical means, and technical means that can be replaced within the scope of conventional technical means and common knowledge based on the existing level of technology should all fall within the protection scope of claims 2-12. For example, replacing other technical features while keeping them unchanged still falls within the protection scope of claims 2-12 of this invention.

[0082] Embodiments 1-5 of this invention at least support the protection scope of claims 13-14.

[0083] Regarding claims 13-14: The technical feature “amount of raw materials” is derived from the specific raw material amounts explained above and / or the corresponding technical features in Examples 1-5, summarized by the common feature “by mass parts, including the following raw materials: 4-85 parts of active ingredient, 0.001-0.025 parts of preservative, 3-33 parts of glycerin, 0.1-65 parts of isotropic modifier, 0.5-28 parts of humectant, and 5-65 parts of penetration enhancer”. Therefore, those skilled in the art can reasonably presume that the technical features, by weight parts, include the following raw materials: 4-85 parts of active ingredient, 0.001-0.025 parts of preservative, 3-33 parts of glycerin, 0.1-65 parts of isotropic modifier, 0.5-28 parts of humectant, and 5-65 parts of penetration enhancer. Subordinate concepts, substantially equivalent technical means, and technical means that can be replaced within conventional and common knowledge based on the existing level of technology should all fall within the protection scope of claims 13-14. For example, replacing the amount of raw materials with any point value within the above range while keeping other technical features unchanged still falls within the protection scope of claims 13-14 of this invention.

[0084] Embodiments 1-5 of this invention at least support the protection scope of claim 15.

[0085] Regarding claim 15: The technical feature "mass ratio of glycerol to penetration enhancer" is derived from the corresponding technical features 3:1, 1:3, 2:1, 1:2, 3:2, etc. in the foregoing explanation and / or Examples 1-5, summarized by the common feature "1-3:1-3". Therefore, those skilled in the art can reasonably infer that technical feature 1-3:1-3, its subordinate concepts, substantially equivalent technical means, and technical means that can replace 1-3:1-3 based on the existing level of technology and conventional technical means and common knowledge should all fall within the protection scope of claim 15. For example, replacing the mass ratio A of glycerol to penetration enhancer with any point value within this range while keeping other technical features unchanged still falls within the protection scope of claim 15 of this invention.

[0086] Embodiment 5 of this invention at least supports the protection scope of claim 17.

[0087] Regarding claim 17: The technical feature “mass ratio of glycerol to penetration enhancer” is derived from the aforementioned explanation and / or the corresponding technical feature 3:2 in Example 5, which is summarized by the common feature “3:2”. Therefore, those skilled in the art can reasonably presume that technical feature 3:2, its subordinate concepts, substantially equivalent technical means, and technical means that can be replaced by conventional technical means and common knowledge based on the existing level of technology should all fall within the protection scope of claim 17.

[0088] Embodiments 1-5 of this invention at least support the protection scope of claim 18.

[0089] Regarding claim 18: The technical feature "preparation method" is derived from the specific preparation methods of the corresponding technical features explained above and / or in Examples 1-5, summarized by the common feature "preparation method as summarized in claim 18". This invention has at least the following beneficial effects: 1. Compared with the prior art, the present invention has better technical effects in reducing the irritation of nasal spray preparations and improving their cumulative permeability.

[0090] According to experimental tests, the present invention significantly reduces the irritation of nasal spray formulations and significantly increases the cumulative permeability.

[0091] 2. Based on the comparison of Examples 1-5 and Comparative Examples 1-9, the present invention achieves new technical effects by using specific combinations of raw materials and dosages to reduce the irritation of nasal spray formulations and increase their cumulative penetration rate. The combined technical effect is superior to the sum of the effects of each individual technical means. Detailed Implementation

[0092] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0093] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0094] Basic Implementation Example: Preparation of the compound shown in Formula I:

[0095] Includes the following steps: Step 1: Compound 11 (6.0 g, 23.23 mmol), compound 15 (7.90 g, 46.45 mmol), EDCI (7.93 g, 51.10 mmol), and Et3N (10.34 g, 102.2 mmol) were dissolved in 120 mL of anhydrous THF. After reacting overnight at room temperature, the reaction solution was poured into water, and the organic layer was separated. After extraction with aqueous phase EA (60 mL), the organic layers were combined and dried over anhydrous sodium sulfate. After concentration, column chromatography (DCM:MeOH = 10:1~5:1) was performed to obtain 9.8 g of white foamy solid compound 16, with a yield of 75%.

[0096] Step 2: Dissolve compound 16 (6.0 g, 10.66 mmol) in 100 mL of a methanol:water (20:1) mixture. Adjust the pH to 12 with 10% sodium hydroxide aqueous solution. After reacting for 2 h, adjust the pH to 1-2 with 6 N hydrochloric acid. The solid precipitates out, is filtered, washed with water until neutral, and dried to obtain 4.2 g of white solid compound 8. Yield: 82%.

[0097] 1 H NMR (500 MHz, DMSO- d6 , ppm, ppm): 4.90-5.25 (m, 2H), 1.95-2.22 (m,10H), 1.55-1.66 (m, 12H), 0.76-0.92 (m, 4H); MS: 479.23 (M+H).

[0098] Example 1 A nasal spray formulation containing a diketone dioxin compound, with the following raw materials: 5g of insulin Preservative benzoic acid 0.02g 15g of glycerin Other isotropic modifiers: sodium chloride 49.98g 25g of propylene glycol moisturizer 5g of penetration enhancer The preparation method is as follows: Dissolve 5g of insulin in water, then add the drug solution to an ammonia solution containing 5g of a penetration enhancer. Adjust the pH with a 10% glacial acetic acid aqueous solution (v / v) until a solid precipitates. After filtration, washing, drying, pulverizing, and passing through a 200-mesh sieve, obtain drug-loaded microsphere solid powder. Add the drug-loaded microsphere solid powder, 0.02g of benzoic acid, 15g of glycerol, 49.98g of sodium chloride, and 25g of propylene glycol to purified water, stir until completely dissolved, and filter using a 0.45μm filter cartridge to obtain the final product.

[0099] The penetration enhancer is a diketone dioxane compound, and is a compound with the structure shown in Formula I below:

[0100] Formula I.

[0101] Example 2 A nasal spray formulation containing a diketone dioxin compound, with the following raw materials: Durutvir 79.398g Sodium benzoate preservative 0.002g 5g of glycerin Other isotropic modifiers: potassium chloride 0.1g PEG moisturizer 4000.5g 15g of penetration enhancer The preparation method is as follows: 79.398g of dulutegravir was dissolved in water. The drug solution was then added to an ammonia solution containing 15g of a penetration enhancer. The pH was adjusted to precipitate solids using a 10% glacial acetic acid aqueous solution (v / v). The precipitated solids were filtered, washed, dried, pulverized, and passed through a 200-mesh sieve to obtain drug-loaded microsphere solid powder. The drug-loaded microsphere solid powder, along with 0.002g sodium benzoate, 5g glycerol, 0.1g potassium chloride, and 0.5g PEG 400, were added to purified water and stirred until completely dissolved. The solution was then filtered through a 0.45μm filter cartridge to obtain the final product.

[0102] The penetration enhancer is a diketone dioxane compound, and is a compound with the structure shown in Formula I below:

[0103] Formula I.

[0104] Example 3 A nasal spray formulation containing a diketone dioxin compound, with the following raw materials: Sildenafil 40g Preservative methylparaben 0.01g 30g of glycerin Other isotropic regulators: potassium dihydrogen phosphate 2.99g Moisturizer Polyvinyl alcohol 12g 15g of penetration enhancer The preparation method is as follows: 40g of sildenafil is dissolved in water, and then the drug solution is added to an ammonia solution containing 15g of penetration enhancer. The pH is adjusted with 10% glacial acetic acid aqueous solution (v / v) until a solid precipitates. After filtration, washing, drying, pulverizing, and passing through a 200-mesh sieve, drug-loaded microsphere solid powder is obtained. The drug-loaded microsphere solid powder, 0.01g of methylparaben, 30g of glycerol, 2.99g of potassium dihydrogen phosphate, and 12g of polyvinyl alcohol are added to purified water and stirred until completely dissolved. The solution is then filtered through a 0.45μm filter cartridge to obtain the final product.

[0105] The penetration enhancer is a diketone dioxane compound, and is a compound with the structure shown in Formula I below:

[0106] Formula I.

[0107] Example 4 A nasal spray formulation containing a diketone dioxin compound, with the following raw materials: Smegglutide 80g Preservative benzalkonium bromide 0.008g 5g of glycerin Other isotonic regulators: sorbitol 2g Moisturizer polyvinylpyrrolidone 2.992g 10g of penetration enhancer The preparation method is as follows: 80g of smegglutide was dissolved in water, and then the drug solution was added to an ammonia solution containing 10g of a penetration enhancer. The pH was adjusted to precipitate solids with a 10% glacial acetic acid aqueous solution (v / v). After filtration, washing, drying, pulverizing, and passing through a 200-mesh sieve, drug-loaded microsphere solid powder was obtained. The drug-loaded microsphere solid powder, 0.008g of benzalkonium bromide, 5g of glycerol, 2g of sorbitol, and 2.992g of polyvinylpyrrolidone were added to purified water and stirred until completely dissolved. The solution was then filtered through a 0.45μm filter cartridge to obtain the final product.

[0108] The penetration enhancer is a diketone dioxane compound, and is a compound with the structure shown in Formula I below:

[0109] Formula I.

[0110] Example 5 A nasal spray formulation containing a diketone dioxin compound, with the following raw materials: Sumatriptan Succinate 60g Preservative: Isopropylparaben 0.005g 15g of glycerin Other isotonic regulators, mannitol 10g Sodium carboxymethyl cellulose 4.995g (humectant) 10g of penetration enhancer The preparation method is as follows: 60g of sumatriptan succinate was dissolved in water. The drug solution was then added to an ammonia solution containing 10g of a penetration enhancer. The pH was adjusted to precipitate solids using a 10% glacial acetic acid aqueous solution (v / v). The precipitated solids were filtered, washed, dried, pulverized, and passed through a 200-mesh sieve to obtain drug-loaded microsphere solid powder. The drug-loaded microsphere solid powder, along with 0.005g of isopropyl p-hydroxybenzoate, 15g of glycerol, 10g of mannitol, and 4.995g of sodium carboxymethyl cellulose, were added to purified water and stirred until completely dissolved. The solution was then filtered through a 0.45μm filter cartridge to obtain the final product.

[0111] The penetration enhancer is a diketone dioxane compound, and is a compound with the structure shown in Formula I below:

[0112] Formula I.

[0113] Comparative Example 1 A nasal spray formulation containing a diketone dioxin compound is prepared in the same way as in Example 5, except that the mass ratio of glycerol and penetration enhancer is changed to 4:1, while the total weight remains the same, with 20g of glycerol and 5g of penetration enhancer. The rest is the same as in Example 5.

[0114] Comparative Example 2 A nasal spray formulation containing a diketone dioxin compound is prepared in the same way as in Example 5, except that the mass ratio between glycerol and penetration enhancer is changed to 1:4, while the total weight remains the same, with 5g of glycerol and 20g of penetration enhancer. The rest is the same as in Example 5.

[0115] Comparative Example 3 A nasal spray formulation containing a diketone dioxin compound is prepared in the same way as in Example 5, except that glycerin is not used.

[0116] Comparative Example 4 A nasal spray formulation containing a diketone dioxin compound is prepared in the same way as in Example 5, except that glycerol is replaced with sodium chloride, which is an isotonic regulator.

[0117] Comparative Example 5 A nasal spray formulation containing a diketone dioxin compound is prepared in the same way as in Example 5, except that glycerol is replaced with potassium chloride, which is an isotropic regulator.

[0118] Comparative Example 6 A nasal spray formulation containing a diketone dioxin compound is prepared in the same way as in Example 5, except that glycerol is replaced with potassium dihydrogen phosphate, which is an isotonic regulator.

[0119] Comparative Example 7 A nasal spray formulation containing a diketone dioxin compound is prepared in the same way as in Example 5, except that glycerol is replaced with another isotonic regulator, disodium hydrogen phosphate, while the rest is the same as in Example 5.

[0120] Comparative Example 8 A nasal spray formulation containing a diketone dioxin is prepared in the same way as in Example 5, except that the penetration enhancer is replaced with FDKP, otherwise it is the same as in Example 5.

[0121] Comparative Example 9 A nasal spray formulation containing a diketone dioxin compound is prepared in the same way as in Example 5, except that a penetration enhancer is not used.

[0122] Example 1 Nasal sprays prepared in Examples 1-5 and Comparative Examples 1-7 were subjected to nasal mucosal irritation tests.

[0123] Experimental Methods: Seventy-eight healthy adult New Zealand white rabbits (2.5-3.0 kg, half male and half female) were randomly divided into 13 groups according to weight: Examples 1-5, Comparative Examples 1-7, and a negative control group, with six rabbits in each group. The rabbits were administered the corresponding medications, with the negative control group receiving physiological saline. The dosage was 2 sprays per nostril, repeated 10 hours later, for a total of 8 sprays per rabbit per day for 7 consecutive days. Changes in the rabbits' overall condition (respiratory, circulatory, and central nervous system) and local irritation symptoms (such as asthma, cough, vomiting, and suffocation) were observed after administration and before each subsequent administration. Twenty-four hours after the last administration, the rabbits were euthanized, and the nasal mucosa was dissected for visual inspection of the area around the nostrils for secretions or crusting, and the respiratory tract mucosa (nose, throat, trachea, and bronchi) for congestion and swelling. Nasal mucosal irritation response scores and irritation intensity were evaluated according to Tables 1 and 2.

[0124] The test results are shown in Table 3.

[0125] Table 1 Nasal mucosal irritation response score

[0126] Table 2 Evaluation of Nasal Mucosal Irritation Intensity

[0127] Table 3. Results of Nasal Mucosal Irritation Evaluation

[0128] As shown in Table 3, the nasal spray provided by this invention is non-irritating to the nasal mucosa of rabbits. Compared with Examples 1-5, Comparative Examples 1-7 showed increased irritation to the nasal mucosa.

[0129] Example 2 In vitro nasal mucosal permeation tests were conducted on the nasal sprays prepared in Examples 1-5 and Comparative Examples 8-9.

[0130] Experimental method: The Franz diffusion cell method was used, with an effective diffusion area of ​​3.14 cm². 2 The receiving chamber had a volume of 14 mL. An electromagnetic stirrer and 14 mL of physiological saline were added to the receiving chamber, and air bubbles were promptly removed. The porcine nasal mucosa was fixed between the receiving and supply chambers and placed on a thermostatic magnetic stirrer at a water bath temperature of 37℃ and 3000 r / min for equilibration for 20 min. Then, 1 mL of each of the nasal sprays prepared in Examples 1-5 and Comparative Examples 4-5 was added to the nasal mucosa in the supply chamber. Samples of 1 mL were taken at 0, 15, 30, 45, 60, 90, 120, 150, and 180 min, with an equal volume of fresh receiving solution added after each sampling. The obtained samples were filtered through a 0.22 μm filter membrane for analysis, and the cumulative permeability was calculated.

[0131] The test results are shown in Table 4.

[0132] Table 4. Cumulative Transmission Rate of Nasal Mucosa

[0133] Comparative results from Examples 1-5 and Comparative Example 9 show that the novel diketopiperazine compound provided by this invention has a drug penetration-enhancing effect. Comparative results from Examples 1-5 and Comparative Example 8 show that the penetration-enhancing effect of the novel diketopiperazine compound provided by this invention is superior to other diketopiperazine compounds on the market.

[0134] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A nasal spray formulation containing a diketone dioxin, characterized in that, Raw materials include: The active ingredient, preservative, glycerin, isotropic modifier, humectant, and penetration enhancer, wherein the penetration enhancer is a diketone dioxin compound.

2. The nasal spray formulation according to claim 1, characterized in that, The diketodioxane compound is a compound represented by Formula I: Formula I.

3. The nasal spray formulation according to claim 1, characterized in that, The preservative is selected from at least one of methylparaben, ethylparaben, propylparaben, butylparaben, isopropylparaben, isobutylparaben, benzoic acid, sodium benzoate, sorbic acid, and benzalkonium bromide.

4. The nasal spray formulation according to claim 3, characterized in that, The preservative is selected from at least one of methylparaben, isopropylparaben, benzoic acid, sodium benzoate, and benzalkonium bromide.

5. The nasal spray formulation according to claim 1, characterized in that, The isotropic regulator is selected from at least one of sodium chloride, potassium chloride, potassium dihydrogen phosphate, disodium hydrogen phosphate, sorbitol, and mannitol.

6. The nasal spray formulation according to claim 5, characterized in that, The isotropic regulator is selected from at least one of sodium chloride, potassium chloride, potassium dihydrogen phosphate, sorbitol, and mannitol.

7. The nasal spray formulation according to claim 1, characterized in that, The humectant is selected from at least one of propylene glycol, PEG 400, polyvinyl alcohol, carboxyethylene polymer, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl cellulose.

8. The nasal spray formulation according to claim 7, characterized in that, The humectant is selected from at least one of propylene glycol, PEG 400, polyvinyl alcohol, polyvinylpyrrolidone, and sodium carboxymethyl cellulose.

9. The nasal spray formulation according to claim 1, characterized in that, The raw materials also include water.

10. The nasal spray formulation according to claim 1, characterized in that, The active ingredient is an acceptable active ingredient in the field of nasal spray formulations.

11. The nasal spray formulation according to claim 10, characterized in that, The active ingredients are cationic drugs, anionic drugs, hydrophilic / lipophilic drugs, peptides, and proteins with an API molecular weight of 500-140000 Da.

12. The nasal spray formulation according to claim 11, characterized in that, The active ingredient is selected from insulin, dulutegravir, semaglutide, sumatriptan succinate, or sildenafil.

13. The nasal spray formulation according to claim 1, characterized in that, The ingredients, by weight, include the following: 4-85 parts of active ingredient, 0.001-0.025 parts of preservative, 3-33 parts of glycerin, 0.1-65 parts of isotropic modifier, 0.5-28 parts of humectant, and 5-65 parts of penetration enhancer.

14. The nasal spray formulation according to claim 13, characterized in that, Based on parts by weight, it includes the following raw materials: 5-80 parts of active ingredient, 0.002-0.02 parts of preservative, 5-30 parts of glycerin, 0.1-60 parts of isotropic modifier, 0.5-25 parts of humectant, and 5-60 parts of penetration enhancer.

15. The nasal spray formulation according to claim 1, characterized in that, The mass ratio of glycerol to penetration enhancer is 1-3:1-3.

16. The nasal spray formulation according to claim 15, characterized in that, The mass ratio of glycerol to penetration enhancer is 1-2:1-2.

17. The nasal spray formulation according to claim 16, characterized in that, The mass ratio of glycerol to penetration enhancer is 1.5:

1.

18. A method for preparing the nasal spray formulation according to any one of claims 1-17, characterized in that, Includes the following steps: S1: The active ingredient, penetration enhancer and solvent are mixed, and the pH is adjusted to precipitate solids to obtain drug-loaded microsphere solid powder; S2: The drug-loaded microsphere solid powder and the remaining raw materials of the nasal spray formulation are mixed to obtain the nasal spray formulation.

19. The preparation method according to claim 18, characterized in that, In step S1, the reagent used to adjust the pH is an aqueous solution of glacial acetic acid with a volume fraction of 8-12%.

20. The preparation method according to claim 18, characterized in that, In step S1, the drug-loaded microsphere solid powder needs to pass through a 150-250 mesh sieve.

21. The preparation method according to claim 18, characterized in that, In step S2, the mixture obtained by mixing needs to be filtered through a 0.4-0.5μm filter.

Images