Tetrahydromethylpyrimidine carboxylic acid composition, pharmaceutical preparation for nasal cavity and preparation method of pharmaceutical preparation

Abstract

The invention belongs to the field of medicine and cosmetics, and particularly relates to a tetrahydromethylpyrimidine carboxylic acid composition, a nasal medicine preparation and a preparation method of the nasal medicine preparation, the composition comprises tetrahydromethylpyrimidine carboxylic acid and 2-amino-2 '-fluoro-2'-deoxyadenosine, and the nasal medicine preparation comprises the tetrahydromethylpyrimidine carboxylic acid composition and a buffer solution, the mass concentration of the 2-amino-2 '-fluoro-2'-deoxyadenosine is 1.6-2.2%, and the preparation method comprises the following steps: firstly preparing a tetrahydromethylpyrimidine carboxylic acid solution, then preparing a 2-amino-2 '-fluoro-2'-deoxyadenosine solution, heating, then mixing with the tetrahydromethylpyrimidine carboxylic acid solution, and heating and cooling to room temperature. The traditional Chinese medicine preparation is comfortable to use, mild and non-irritating, can prevent impurities from entering the body, also has the effects of inhibiting bacteria, resisting inflammation and repairing damaged nasal mucosa, and particularly, the medicine preparation stays in the nasal cavity for a long time, so that the medicine can fully play a role.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine and cosmetics, and particularly relates to a tetrahydro-methyl pyrimidine carboxylic acid composition and a nasal drug preparation and a preparation method thereof. BACKGROUND

[0002] The nose is the most important olfactory organ of the human body, which perceives the outside world and is more susceptible to the invasion of harmful substances or allergens, thereby causing nasal congestion and swelling, allergic rhinitis, chronic rhinitis, sinusitis and other respiratory diseases. Due to the decline in air quality caused by air pollution, more and more people are allergic to the nose due to pollen, indoor and outdoor dust, bacteria, animal fur, etc. In addition, due to the dryness of winter in the north, the existence of fog or haze, the air is dry or the air quality is poor, the secretion of nasal mucus (nasal mucosa secretes nasal mucus) is affected to a certain extent, especially for special groups such as the elderly and people with less nasal mucus secretion, when the air quality is poor, the secretion of nasal mucus is even less, making the nasal cavity dry, leading to the entry of some bacteria and microorganisms, causing respiratory diseases. In severe cases of dryness, small wounds and bleeding may occur, further exacerbating the occurrence of respiratory diseases such as rhinitis.

[0003] Common preparations for treating nasal congestion and rhinitis mainly include oral (such as tablets) and nasal administration (such as nasal drops and nasal spray). Compared with oral preparations that need to be absorbed by the gastrointestinal mucosa and then circulated to the nose by blood, there are rich capillaries and lymphatic networks under the nasal mucosal cells, which are conducive to the direct absorption of nasal mucosa after nasal administration, with fast onset and high compliance. In addition, the low enzyme environment of the nasal cavity is also conducive to the extension of the efficacy of some drugs that are easily degraded by enzymes or have a first-pass effect. For drugs that may cause systemic side effects (such as hormone drugs), the action site of nasal administration is more local and clear, greatly reducing the side effects on other systems and organs of the body.

[0004] Seawater or saline nasal spray is a more popular method at present. Seawater or saline can clean the nasal cavity, remove allergens, bacteria and inflammatory secretions in the nasal cavity, improve the environment in the nasal cavity, reduce the swelling of the nasal mucosa and alleviate inflammatory symptoms. However, it is not gentle enough when it acts on the nasal cavity, and the human body feels strong discomfort during use. The nasal spray is used for nasal cleaning, and its moisturizing effect is limited, it cannot play the role of nasal mucosal mucus, and it lacks bacteriostatic and anti-inflammatory effects, and more importantly, the action time is short. After the evaporation of water, the nasal cavity will feel even drier, making the nasal cavity even more uncomfortable.

[0005] Tetrahydromethylpyrimidine carboxylic acid as a compatible solute of microbial osmotic pressure regulation has the effect of stabilizing microbial cell membrane, enzymes and nucleic acids, so that it can survive in extreme environments of high salt, high temperature and high ultraviolet radiation. And through research, it is found that ectoine is a cell all-protective agent and an excellent anti-pressure protective molecule, and is a multifunctional active ingredient with moisturizing, anti-inflammatory and repairing effects, and is safe and non-toxic. The main components of the product used abroad for treating rhinitis and nasal congestion include ectoine, sea salt and water, but due to the fluidity of the product and the swing of nasal mucosa cilia at a certain frequency, the residence time of the nasal administration preparation in the nasal cavity is relatively short, so that the drug cannot fully play a role, which brings great difficulty to the absorption of the nasal administration preparation. SUMMARY

[0006] In view of the above problems existing in the prior art, the purpose of the present application is to provide a tetrahydromethylpyrimidine carboxylic acid composition and a nasal drug preparation and a preparation method thereof, which can provide a moist environment for the nasal cavity, is comfortable and mild to use, can block impurities, has the effects of inhibiting bacteria, anti-inflammatory and repairing damaged nasal mucosa, and especially has a long residence time in the nasal cavity, so that the drug can fully play a role.

[0007] The technical scheme provided by the present application is as follows: A tetrahydromethylpyrimidine carboxylic acid composition, which comprises tetrahydromethylpyrimidine carboxylic acid and 2-amino-2'-fluoro-2'-deoxyadenosine.

[0008] Preferably, the mass ratio of tetrahydromethylpyrimidine carboxylic acid and 2-amino-2'-fluoro-2'-deoxyadenosine is 1-30:16-22.

[0009] Preferably, the composition further comprises sodium hyaluronate.

[0010] Further preferably, the sodium hyaluronate is acetylated sodium hyaluronate, the mass ratio of the acetylated sodium hyaluronate to tetrahydromethylpyrimidine carboxylic acid is 0.5-10:1-30, the acetyl substitution degree of the acetylated sodium hyaluronate is 2.7-3.2, and the average molecular weight is 5KDa-5000 KDa.

[0011] A nasal drug preparation, comprising the above-mentioned tetrahydromethylpyrimidine carboxylic acid composition and a buffer solution, wherein the mass concentration of 2-amino-2'-fluoro-2'-deoxyadenosine is 1.6-2.2%, and the mass concentration of tetrahydromethylpyrimidine carboxylic acid is 0.1-3%.

[0012] Preferably, the buffer solution is a PBS buffer solution, the pH is 7.3-7.8, and the mass of sodium hyaluronate is 0.05-0.5%.

[0013] Preferably, the pharmaceutical preparation is a spray or a balm, wherein the balm is a preparation that can be applied in a coating form; when the pharmaceutical preparation is a spray, the mass concentration of sodium hyaluronate is 0.05-0.15%; when the pharmaceutical preparation is a balm, the mass of sodium hyaluronate is 0.05-0.5%.

[0014] Further preferably, when the pharmaceutical preparation is a spray, the mass concentration of sodium hyaluronate is 0.08-0.1%.

[0015] Preferably, the pharmaceutical preparation contains one or more than two of the following: a medical acceptable preservative, a flavoring agent, a solubilizer.

[0016] Further preferably, the preservative is one or more than one of the following: phenoxyethanol, ethylhexylglycerin, methylparaben, ethylparaben, propylparaben, sorbic acid and salts, benzoic acid and salts, etc.; the flavoring agent is one or more than two of the following: peppermint essential oil, lemon essential oil, tea tree essential oil, rosemary essential oil, etc.; the solubilizer is one or more than two of the following: polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene lauryl ether, polyoxyethylene stearate, polyoxyethylene polypropylene oxide ether, polyoxyethylene polypropylene acetyl ether, polyoxyethylene alkyl phenyl ether, butanol polyether-26, polyethylene glycol hydrogenated castor oil, etc.

[0017] A method for preparing a nasal pharmaceutical preparation, comprising the following steps: (1) first mix tetrahydro methyl pyrimidine carboxylic acid with a buffer solution to obtain solution 1; (2) then mix 2-amino-2'-fluoro-2'-deoxyadenosine with a buffer solution and heat to obtain solution 2; (3) then mix solution 1 and solution 2, heat and cool to room temperature.

[0018] Preferably, in steps (2) and (3), the heating temperature is 80-100℃.

[0019] Preferably, when the composition contains sodium hyaluronate, the method for preparing a nasal pharmaceutical preparation comprises the following steps: (1) first mix tetrahydro methyl pyrimidine carboxylic acid with a buffer solution to obtain solution 1, and mix sodium hyaluronate with a buffer solution to obtain solution 3; (2) then mix 2-amino-2'-fluoro-2'-deoxyadenosine with a buffer solution and heat to obtain solution 2; (3) then mix solution 1, solution 2 and solution 3, heat and cool to room temperature.

[0020] The tetrahydromethylpyrimidine carboxylic acid composition, the nasal drug preparation or the pharmaceutical preparation prepared by the preparation method are used for preparing an external preparation for treating respiratory diseases, and the composition and the nasal drug preparation have good curative effects on nasal dryness, congestion, swelling, allergic rhinitis, chronic rhinitis, sinusitis and other respiratory diseases.

[0021] 2-amino-2'-fluoro-2'-deoxyadenosine (2-FA) can be self-assembled in a phosphate buffer solution to prepare a supramolecular hydrogel, which has moisturizing, anti-inflammatory capacity, bacteriostatic activity, certain dilution shear capacity, good biocompatibility, no toxicity to the human body, and can be degraded. The gel has both injectable properties and can be made into a spray form. At present, 2-FA hydrogel is often used in oral surgery, such as tooth extraction surgery, but there is no literature or other prior art that uses 2-FA hydrogel in the field of nasal cavity and respiratory tract. The inventors creatively use 2-FA hydrogel in the field of nasal preparations, which perfectly plays its moisturizing, anti-inflammatory and bacteriostatic properties. The combination of tetrahydromethylpyrimidine carboxylic acid and 2-FA hydrogel effectively improves the retention time of the drug; the effective cooperation of 2-FA hydrogel with tetrahydromethylpyrimidine carboxylic acid and sodium hyaluronate effectively increases the adhesion of 2-FA hydrogel to the nasal mucosa, which is more conducive to increasing the retention time of the drug and more effectively providing a moist environment for the nasal cavity.

[0022] Tetrahydromethylpyrimidine carboxylic acid, also known as 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carboxylic acid, is a penetration protective agent that has a good protective effect on cells and biological macromolecules (biological membranes, proteins, enzymes and nucleic acids) under the stimulation of adverse environments such as high temperature, high salt, freezing, drying and radiation; it can protect cells from radiation or osmotic pressure, has the effects of moisturizing, anti-inflammatory, soothing and calming; its cyclic structure makes it have strong electronegativity, which can enhance the association ability with water molecules, make water molecules arrange directionally around it, change the spatial arrangement of water molecules, and has long-acting moisturizing effect. Tetrahydromethylpyrimidine carboxylic acid combines with the water molecules around it to produce so-called "Ectoin water-electricity complex", and then these complexes surround cells, enzymes, proteins and other biological molecules to form a protective, nourishing and stable hydration shell around them.

[0023] In the present application, 2-FA hydrogel is used as the matrix, so that tetrahydro methyl pyrimidine carboxylic acid can be retained for a long time, better play the drug efficacy, and 2-FA hydrogel has the ability of moisturizing, anti-inflammatory, antibacterial activity, more conducive to cooperate with tetrahydro methyl pyrimidine carboxylic acid, treatment or relieve nasal problems; the introduction of sodium hyaluronate, sodium hyaluronate as a biological adhesive material, is conducive to increasing the adhesion properties of 2-FA hydrogel, and acetylated sodium hyaluronate is obtained by acetylation of sodium hyaluronate, which increases lipophilicity on the basis of hydrophilicity, enhances the affinity and adsorption of HA to the skin, increases the hydration capacity, effectively guarantees the stability of 2-FA hydrogel in the nasal cavity; tetrahydro methyl pyrimidine carboxylic acid and sodium hyaluronate have synergistic effect, which can effectively increase the viscosity and adhesion; and tetrahydro methyl pyrimidine carboxylic acid-sodium hyaluronate combination can significantly improve the morphology of damaged skin tissue, repair damaged cells, and help to quickly repair damaged nasal mucosa. The present application effectively combines tetrahydro methyl pyrimidine carboxylic acid and sodium hyaluronate with 2-FA hydrogel, so that the hydrogel is better fixed on the nasal cavity, effectively avoids the problems of short retention time caused by the flow characteristics of the preparation itself and the beating of nasal mucociliary, effectively solves the problems of nasal cavity such as dryness, hyperemia, swelling, rhinitis and other nasal cavity problems, improves the retention time, and improves the curative effect of the drug.

[0024] The present application provides a tetrahydro methyl pyrimidine carboxylic acid composition and a nasal drug preparation and a preparation method thereof. The gel prepared by using the composition can effectively block impurities in the air, avoid causing nasal allergy, protect the respiratory system, etc.; the preparation is friendly to human health, has no sensitization reaction, is mild and comfortable without irritation, and has good biocompatibility and degradability; the gel has reversibility, i.e. it can change from a gel state to a liquid state and then to a gel state again. The preparation has sprayability and smearability, especially sprayability, so that the preparation is easy to use. The gel can form a gel layer on the inner surface of the nasal cavity, which has the functions of moisturizing, bacteriostasis, anti-inflammatory and allergen rejection, and is helpful to repair damaged cells and quickly repair damaged nasal mucosa. The gel can significantly improve the retention time in the nasal cavity, improve the effect of the drug, improve the curative effect, provide a moist environment, and effectively solve the problems of nasal cavity such as dryness, hyperemia, swelling, rhinitis and other nasal cavity problems. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 SEM image of the gel prepared in Example 1; Figure 2 Inverted image of the gel prepared in Examples 1-5, Comparative Examples 1-2 and Comparative Examples 4-5; Figure 3 Inverted image of the product prepared in Comparative Example 3. DETAILED DESCRIPTION

[0026] It should be noted that the following detailed description is exemplary in nature and is intended to provide further description of the application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0027] The present application provides a tetrahydro methy pyrimidine carboxylic acid composition, which comprises tetrahydro methy pyrimidine carboxylic acid and 2-amino-2'-fluoro-2'-deoxyadenosine, and the mass ratio of tetrahydro methy pyrimidine carboxylic acid to 2-amino-2'-fluoro-2'-deoxyadenosine is 1-30:16-22, and the specific mass ratio can be selected as follows: 1:16, 1:20, 1:22, 3:16, 1:7, 3:22, 11:16, 11:18, 1:2, 1:1|, 23:16, 23:19, 23:22, 30:19, 10:7, 15:11, 5:16, 13:11, etc.

[0028] In order to better improve the residence time, the composition further comprises sodium hyaluronate, and the mass ratio of acetylated sodium hyaluronate to tetrahydro methy pyrimidine carboxylic acid is 0.5-15:1-30, and the specific mass ratio can be selected as follows: 0.5:3, 0.5:7, 0.5:9, 0.5:11, 0.5:13, 0.1:3, 0.5:17, 0.5:19, 0.5:21, 3:1, 3:8, 1:2, 1:5, 1:7, 3:26, 1:10, 7:1, 7:10, 7:24, 7:30, 5:3, 10:17, 10:25, 1:3, 5:22, 1:22, 1:20, 10:11; the acetyl substitution degree of acetylated sodium hyaluronate is 2.7-3.2, and the average molecular weight is 5KDa-5000 KDa, and the specific acetyl substitution degree can be selected as 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, and the average molecular weight can be selected as 10 KDa, 100 KDa, 1000 KDa, 3000 KDa, 5000 KDa, etc.

[0029] A nasal drug preparation comprises a tetrahydro methy pyrimidine carboxylic acid composition and a phosphate buffer solution, and the mass percentage of 2-amino-2'-fluoro-2'-deoxyadenosine in the drug preparation is 1.6-2.2%, and the specific mass concentration can be selected as 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, etc., and the mass concentration of tetrahydro methy pyrimidine carboxylic acid is 0.1-3%, and the specific mass concentration can be selected as 0.1%, 0.2%, 0.5%, 1%, 1.5%, 2%, 2.6%, 3%, etc.

[0030] The buffer solution is a PBS buffer solution, the pH is 7.3-7.8, and the specific pH can be selected as 7.3, 7.4, 7.5, 7.6, 7.7, 7.8; the mass concentration of sodium hyaluronate is 0.05-0.5%.

[0031] The nasal drug preparation of the application can be a spray or a smear, and when it is a spray, the sprayability of the solution is combined with the gel, the convenient spray administration is realized, the retention of the preparation in the nasal cavity is increased, the retention time of the drug in the nasal cavity is increased, and the drug can better play the efficacy. When the drug preparation is a spray, the mass concentration of sodium hyaluronate is 0.05-0.15%, and the specific value can be selected as 0.05%, 0.08%, 0.1%, 0.15% and the like; when the drug preparation is a smear, the mass of sodium hyaluronate is 0.05-0.5%, and the specific value can be selected as 0.05%, 0.08%, 0.1%, 0.15%, 0.2%, 0.5% and the like.

[0032] Further preferably, when the drug preparation is a spray, the mass concentration of sodium hyaluronate is 0.08-0.1%.

[0033] The drug preparation of the application contains one or more than two of the medically acceptable preservatives, flavorings and solubilizers; the preservatives are one or more of phenoxyethanol, ethylhexylglycerin, methylparaben, ethylparaben, propylparaben, sorbic acid and salts, benzoic acid and salts and the like; the flavorings are one or more than two of peppermint essential oil, lemon essential oil, tea tree essential oil, rosemary essential oil and the like; the solubilizers are one or more than two of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene lauryl alcohol ether, polyoxyethylene stearate, polyoxyethylene polypropylene oxide ether, polyoxyethylene polypropylene acetyl ether, polyoxyethylene alkyl phenyl ether, butanol polyether-26, polyethylene glycol hydrogenated castor oil and the like.

[0034] A preparation method of a nasal drug preparation, comprising the following steps: (1) first mix tetrahydro methyl pyrimidine carboxylic acid with a buffer solution to obtain solution 1; (2) then mix 2-amino-2'-fluoro-2'-deoxyadenosine with a buffer solution, heat to obtain solution 2; (3) then mix solution 1 and solution 2, heat and cool to room temperature.

[0035] In steps (2) and (3), the heating temperature is 80-100℃, and the specific heating temperature can be selected as 80℃, 85℃, 90℃, 95℃, 100℃ and the like.

[0036] When the nasal drug preparation contains sodium hyaluronate, the preparation method of the nasal drug preparation comprises the following steps: (1) First, mix tetrahydro methyl pyrimidine carboxylic acid with buffer solution to obtain solution 1, mix sodium hyaluronate with buffer solution to obtain solution 3; (2) Then mix 2-amino-2'-fluoro-2'-deoxyadenosine with buffer solution, heat to obtain solution 2; (3) Then mix solution 1, solution 2 and solution 3, heat and cool to room temperature.

[0037] The above-mentioned tetrahydro methyl pyrimidine carboxylic acid composition or the above-mentioned nasal drug preparation or the drug preparation prepared by the above-mentioned preparation method is used for preparing an external preparation for treating respiratory diseases, and the composition and the nasal drug preparation have good curative effect in the field of nasal dryness, congestion, swelling, allergic rhinitis, chronic rhinitis, sinusitis and other respiratory diseases.

[0038] The specific embodiments are shown in the following.

[0039] The acetyl substitution degree of the acetylated sodium hyaluronate in the following is 2.7, and the average molecular weight is 1000 KDa. Example 1

[0040] A nasal drug preparation, the formula is as follows in terms of mass percentage: 3% tetrahydro methyl pyrimidine carboxylic acid, 2.2% 2-FA, PBS buffer solution (pH=7.4) the rest; The preparation method is as follows: (1) First, mix tetrahydro methyl pyrimidine carboxylic acid with PBS buffer solution (half of the total), and mix to obtain solution 1; (2) Mix 2-amino-2'-fluoro-2'-deoxyadenosine (2-FA) with PBS buffer solution (half of the total), heat to 80℃, and prepare solution 2; (3) Mix solution 1 and solution 2, heat to 80℃, and cool to room temperature to obtain a gel.

[0041] As shown in Figure 1 , the product prepared in Example 1 has a multi-level pore structure of hydrogel, and no obvious pore collapse phenomenon occurs, showing a three-dimensional porous network structure. Example 2

[0042] A nasal drug preparation, the formula is as follows in terms of mass percentage: 0.5% tetrahydro methyl pyrimidine carboxylic acid, 1.6% 2-FA, PBS buffer solution (pH=7.4) the rest; The preparation method is as follows: (1) First, mix tetrahydro methyl pyrimidine carboxylic acid with PBS buffer solution (half of the total), and mix to obtain solution 1; (2) 2-amino-2'-fluoro-2'-deoxyadenosine was mixed with half of the PBS buffer solution, and heated to 90°C to prepare solution 2; (3) Solution 1 and solution 2 were mixed and heated to 90°C and then cooled to room temperature. Example 3

[0043] A nasal drug preparation, the formula is as follows in terms of mass percentage: 2.6% tetrahydro methy pyrimidine carboxylic acid, 2.2% 2-FA, 0.08% acetylated hyaluronic acid sodium, and the balance of PBS buffer solution (pH = 7.4); The preparation method is as follows: (1) Tetrahydro methy pyrimidine carboxylic acid was first mixed with two fourths of the PBS buffer solution to obtain solution 1, and acetylated hyaluronic acid sodium was mixed with one fourth of the PBS buffer solution to obtain solution 3; (2) 2-amino-2'-fluoro-2'-deoxyadenosine was mixed with half of the PBS buffer solution, and heated to 80°C to prepare solution 2; (3) Solution 1 and solution 2 were mixed and heated to 80°C and then cooled to room temperature. Example 4

[0044] The difference from Example 3 is that the formula is: 2% tetrahydro methy pyrimidine carboxylic acid, 2% 2-FA, 0.1% acetylated hyaluronic acid sodium, and the balance of PBS buffer solution (pH = 7.4), and the others are the same as Example 3. Example 5

[0045] The difference from Example 3 is that the formula is: 0.1% tetrahydro methy pyrimidine carboxylic acid, 2.2% 2-FA, 0.15% acetylated hyaluronic acid sodium, and the balance of PBS buffer solution (pH = 7.4), and the others are the same as Example 3. Example 6

[0046] The difference from Example 3 is that the formula is: 2.6% tetrahydro methy pyrimidine carboxylic acid, 2.2% 2-FA, 0.2% acetylated hyaluronic acid sodium, and the balance of PBS buffer solution (pH = 7.4), and the others are the same as Example 3. Example 7

[0047] The difference from Example 3 is that the formula is: 2.6% tetrahydro methy pyrimidine carboxylic acid, 2.2% 2-FA, 0% acetylated hyaluronic acid sodium, and the balance of PBS buffer solution (pH = 7.4), and the others are the same as Example 3.

[0048] Comparative Example 1 The formulation differs from that of Example 1 as follows: 0% tetrahydromethylpyrimidine carboxylic acid, 2.2% 2-FA, and the balance being PBS buffer solution (pH=7.4). All other aspects are the same as in Example 1.

[0049] Comparative Example 2 The formulation differs from that of Example 1 as follows: 3% tetrahydromethylpyrimidine carboxylic acid, 3% 2-FA, and the balance being PBS buffer solution (pH=7.4). All other aspects are the same as in Example 1.

[0050] Comparative Example 3 The formulation differs from that of Example 3 as follows: 2.6% tetrahydromethylpyrimidine carboxylic acid, 0% 2-FA, 0.08% acetylated sodium hyaluronate, PBS buffer solution (pH=7.4) balance, and all other components are the same as in Example 3.

[0051] Comparative Example 4 The formulation differs from that of Example 3 as follows: 4% tetrahydromethylpyrimidine carboxylic acid, 2.2% 2-FA, 0.08% acetylated sodium hyaluronate, with the balance being PBS buffer solution (pH=7.4). All other components are the same as in Example 3.

[0052] Comparative Example 5 The formulation differs from that of Example 3 as follows: 0% tetrahydromethylpyrimidine carboxylic acid, 2.2% 2-FA, 0.08% acetylated sodium hyaluronate, with the balance being PBS buffer solution (pH=7.4), and all other components are the same as in Example 3.

[0053] Test case Inverted test measurement The products prepared in Examples 1-6, Comparative Examples 1-2, and Comparative Examples 4-5 were subjected to an external force (shear force) to transfer the samples into vials. The vials were then inverted. The experimental results are as follows: Figures 2-3 As shown. (Through) Figure 2 This demonstrates that the products of Examples 1-6, Comparative Examples 1-2, and Comparative Examples 4-5 did not fall off after being inverted, indicating that the products formed a stable gel structure. In contrast, the product of Comparative Example 3 fell off immediately after being inverted. Figure 3 As shown, the product in Comparative Example 3 did not form a gel structure.

[0054] Spray test determination Transfer the sample to a spray bottle, apply pressure, observe whether the sample can be sprayed out, and record the morphology of the sprayed sample. The results are shown in Table 1 below.

[0055] Table 1 shows the spray pattern of the samples. Sample Whether or not the spray can be sprayed out Whether or not the spray can form a gel Example 1 Yes Yes Example 2 Yes Yes Example 3 Yes Yes Example 4 Yes Yes Example 5 Yes Yes Example 6 No / Example 7 Yes Yes Comparative Example 1 Yes Yes Comparative Example 2 No / Comparative Example 3 Yes No Comparative Example 4 No / Comparative Example 5 Yes Yes From the results of the above spray test, it can be found that the samples of Examples 1-5, Example 7, Comparative Example 1, Comparative Example 3 and Comparative Example 5 can be sprayed out, and the samples of Examples 1-5, Example 7, Comparative Example 1, Comparative Example 5 form gels after being sprayed out, effectively proving the sprayability of the prepared gels of the present application. Example 6 increases the content of sodium hyaluronate relative to Example 3, and Example 6 cannot be sprayed out, and the content of sodium hyaluronate can affect the sprayability of the product of the present application, and when the content of sodium hyaluronate is too high, the product of the present application can be a balm, which is applied in the nasal cavity. Comparative Example 2 increases the content of 2-FA relative to Example 1, and the sample of Comparative Example 2 cannot be sprayed out, effectively proving that the content of 2-FA is too high, which affects the sprayability of the product; Comparative Example 3 does not add 2-FA relative to Example 3, and although it can be sprayed out, the sample cannot form a gel after being sprayed out, effectively proving that the content of 2-FA is too low, which cannot cause the liquid-gel transition; Comparative Example 4 increases the content of tetrahydro methyl pyrimidine carboxylic acid relative to Example 3, and Comparative Example 4 cannot be sprayed out, because the addition amount of tetrahydro methyl pyrimidine carboxylic acid can affect the viscosity of the system, and when the content is too high, the product cannot be sprayed out. In the system of the present application, only by controlling the specific ratio of tetrahydro methyl pyrimidine carboxylic acid, 2-FA and sodium hyaluronate, can the pharmaceutical preparation of the present application have sprayability, realize the gel-liquid-gel transition of the product, and at the same time ensure the adhesion of the pharmaceutical preparation.

[0056] In vitro adhesion force determination The mucin sheet peeling strength method was used, about 20 ml of the sample was measured into a beaker, the mucin sheet was adhered to the lower end of the texture analyzer probe P / 0.5 with double-sided tape, and before testing, the mucin sheet was soaked in a 5% mucin solution (freshly prepared) for 30 s, then the probe was connected to the texture analyzer, and the test was started. The probe moved downward at a speed of 0.5 mm / s, after contacting the gel and reaching the trigger force value (2 g), it continued to move downward at a speed of 0.5 mm / s, and stopped moving downward when the stress reached 4 g, and remained stationary for 180 s after contacting the gel. The probe moved upward at a speed of 0.5 mm / s to 5 mm and stopped. The stress-time curve was recorded, and the maximum stress value was the maximum force required for peeling, which was used as an index of adhesion force. The test results are shown in Table 2.

[0057] Table 2 Maximum peeling force of different samples Sample Example 3 Example 7 Comparative Example 1 Comparative Example 5 Maximum peeling force (g) 7.871 2.791 2.026 5.114 From the data in Table 1 above, it can be clearly seen that the maximum peeling force of the product of Example 3 is significantly higher than that of Example 7, Comparative Example 1 and Comparative Example 5. Example 3 only added sodium hyaluronate relative to Example 7, and the maximum peeling force was significantly increased, Example 7 added tetrahydro methyl pyrimidine carboxylic acid relative to Comparative Example 1, and the maximum peeling force changed slightly, but the change was very small; Comparative Example 5 added sodium hyaluronate relative to Comparative Example 1, and the maximum peeling force was greatly improved, but the improvement was smaller than that of Example 3. This is because tetrahydro methyl pyrimidine carboxylic acid can improve the adhesion of the hydrogel, but the improvement is small, the addition of hyaluronic acid can increase the adhesion of the hydrogel, but it is significantly less than the addition of tetrahydro methyl pyrimidine carboxylic acid and sodium hyaluronate at the same time, and the adhesion is further improved. The degree of adhesion is greater, which further effectively proves that tetrahydro methyl pyrimidine carboxylic acid and sodium hyaluronate have a significant synergistic effect, which can significantly improve the adhesion of the hydrogel. In order to ensure the adhesion and the sprayability of the product, it is necessary to strictly control the ratio of 2-FA, tetrahydro methyl pyrimidine carboxylic acid and sodium hyaluronate. The product prepared by the present application has high adhesion and can be sprayed, which can better stay in the nasal cavity and improve the stability.

[0058] Ciliary toxicity test The ciliary movement time was taken as an index, and the ciliary toxicity of the gel preparation prepared in Example 3 was investigated by in vitro frog palate test for 30 min and 4 h after administration. Physiological saline was used as a control group, and 10 parallel tests were set in each group. The results are shown in Table 3.

[0059] Table 3 Ciliary movement time of in vitro frog palate Sample Example 3 (30 min) Example 3 (4 h) Physiological saline Ciliary sustained movement time (min) mean ± SD 781.5±15.3 742.6±8.8 785.4±10.4 The above results show that the ciliary movement of the gel prepared by the present application is not significantly different from that of the physiological saline group after 30 min of administration, and the ciliary movement is slightly lower than that of the physiological saline group after 4 h of administration, but the continuous movement time is still more than 10 hours. According to the nasal retention test, the gel prepared by the present application is generally administered for 4 hours, and basically all can be completely removed from the nasal cavity.

[0060] Nasal retention test Examples 3 and Comparative Example 3 were tested, and the rats were sprayed with a single nostril, then the nasal cavity was washed with 4℃ physiological saline after a certain time, and the retention amount of the drug in the nasal cavity was measured. Each group was set with 5 parallel tests, the retention amount of the drug in the nasal cavity was measured, and the average value was taken, and the results are shown in Table 4.

[0061] Table 4 Retention amount of sample in nasal cavity at different times Time (min) Example 3 retention amount (%) Comparative Example 3 retention amount (%) 0 100 100 5 87.3 44.6 15 78.1 31.1 30 66.8 20.9 60 33.5 11.7 120 22.7 8.5 240 12.2 / 480 5.8 / As shown in Table 4, the retention amount of Example 3 is obviously higher than that of Comparative Example 3. Because of the synergistic effect of the rapid gel-forming property of 2-FA and the adhesion of sodium hyaluronate after the product of the present application is administered by spraying, the product is stably adhered to the nasal mucosa, and the retention amount is as high as 12.2% at 240 min, effectively proving that the product of the present application has a longer retention time in the nasal cavity than Comparative Example 3, while the tetrahydro-methylic pyrimidine carboxylic acid and sodium hyaluronate in Comparative Example 3 have a certain adhesion, but are easily removed from the nasal cavity due to their own fluidity and the action of cilia swinging. The present application increases the retention time of the drug in the nasal cavity, providing a favorable guarantee for the drug to fully exert its effect.

[0062] Sensory test 1. Patient information: 80 patients with nasal dryness, itching, nasal congestion, sneezing The 80 patients were randomly divided into 4 groups (Group 1, Group 2, Group 3, Group 4) at a male to female ratio of 1:1, with an age range of 26-55 years old and no other diseases, and each group had 20 people at a male to female ratio of 1:1.

[0063] 2. Test method: Group 1 used the product of Example 3, Group 2 used the product of Example 7, Group 3 used the product of Comparative Example 3, and Group 4 used other nasal gel sprays, which were sprayed once a day in the morning, afternoon and evening, with two sprays in each nostril. After 30 days of use, the scores were evaluated according to the following evaluation rules, and the specific evaluation indicators are shown in Table 5.

[0064] Preparation method of other nasal gel sprays: 2.6% tetrahydro-methylic pyrimidine carboxylic acid and 0.05% acetylated sodium hyaluronate were weighed and added to a PBS buffer solution while stirring. 0.5% poloxamer 188 and 14% poloxamer 407 were weighed and added to the above cooled solution while stirring. After thorough stirring, the solution was stored at 4°C until a clear and bubble-free solution was formed.

[0065] 3. Evaluation rules Item Dryness Itching Stuffy nose Sneezing None at all 0 0 0 0 Some improvement, but not obvious 1 1 1 1 Some improvement, more obvious 2 2 2 2 Some improvement, very obvious 3 3 3 3 Table 5 Sensory test score results (the data in the table are average values) Item Dryness Itching Stuffy nose Sneezing Example 3 2.9 2.8 2.5 2.6 Example 7 2.4 2.1 2.1 2.3 Comparative Example 3 1.5 1.3 1.6 1.8 Other nasal gel sprays 2.3 2.2 2 2.1 From the data of Table 5, it can be seen that Example 3, Example 7 and other nasal gel sprays are obviously better than Comparative Example 3 in treating symptoms such as nasal dryness, itching, nasal congestion, sneezing, etc. Among them, Example 7 does not add hyaluronic acid relative to Example 3, and its effect is slightly lower than that of Example 3, but Example 7 adds 2-FA relative to Comparative Example 3, and its effect has made a very great progress relative to Example 3; other nasal gel sprays change the gel matrix relative to Example 3, and their effects are obviously lower than that of Example 3, effectively showing that different gel matrices, combined with tetrahydro methyl pyrimidine carboxylic acid, produce different effects, effectively showing that the use of 2-FA in combination with tetrahydro methyl pyrimidine carboxylic acid and sodium hyaluronate produces superior effects in treating nasal problems, with significant progress.

[0066] The present application provides a tetrahydro methyl pyrimidine carboxylic acid composition and a nasal drug preparation and a preparation method thereof. The gel prepared by using the composition can effectively block impurities in the air, avoid causing nasal allergy, protect the respiratory system, etc. The preparation is friendly to human health, has no sensitization reaction, is mild, comfortable and non-irritating, and has good biocompatibility and degradability. The gel has reversibility, i.e. it can change from a gel state to a liquid state and then to a gel state again. The preparation has sprayability, smearability, especially sprayability, making it easy to use. The gel can form a gel layer on the inner surface of the nasal cavity, which has moisturizing, antibacterial, anti-inflammatory and allergen-repelling properties, helps to repair damaged cells and quickly repair damaged nasal mucosa. The gel can significantly improve the retention time in the nasal cavity, improve the effect of the drug, improve the curative effect, provide a moist environment, and effectively solve the problems of nasal dryness, congestion, swelling, rhinitis and other nasal problems.

[0067] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Those skilled in the art can make various modifications and changes to the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A tetrahydromethylpyrimidine carboxylic acid composition, characterized in that, The composition comprises tetrahydromethylpyrimidine carboxylic acid and 2-amino-2'-fluoro-2'-deoxyadenosine.

2. The tetrahydromethylpyrimidine carboxylic acid composition according to claim 1, characterized in that, The mass ratio of the tetrahydromethylpyrimidine carboxylic acid and 2-amino-2'-fluoro-2'-deoxyadenosine is 1-30:16-22.

3. The tetrahydromethylpyrimidine carboxylic acid composition according to claim 1, characterized in that, The composition also includes sodium hyaluronate.

4. The tetrahydromethylpyrimidine carboxylic acid composition according to claim 3, characterized in that, The sodium hyaluronate is acetylated sodium hyaluronate, and the mass ratio of acetylated sodium hyaluronate to tetrahydromethylpyrimidine carboxylic acid is 0.5-10:1-30.

5. A nasal pharmaceutical preparation, characterized in that, The composition comprises the tetrahydromethylpyrimidine carboxylic acid composition according to any one of claims 1-4, and a buffer solution; the mass concentration of 2-amino-2'-fluoro-2'-deoxyadenosine is 1.6-2.2%, and the mass concentration of tetrahydromethylpyrimidine carboxylic acid is 0.1-3%.

6. A nasal pharmaceutical preparation according to claim 5, characterized in that, The buffer solution is a PBS buffer solution with a pH of 7.3-7.8; the mass concentration of sodium hyaluronate is 0.05-0.5%.

7. A nasal pharmaceutical preparation according to claim 5, characterized in that, The pharmaceutical preparation is a spray or a topical application; when the pharmaceutical preparation is a spray, the mass concentration of sodium hyaluronate is 0.05-0.15%; when the pharmaceutical preparation is a topical application, the mass concentration of sodium hyaluronate is 0.05-0.5%.

8. A method for preparing a nasal pharmaceutical preparation according to any one of claims 5-7, characterized in that, Includes the following steps: (1) First, mix tetrahydromethylpyrimidine carboxylic acid with the buffer solution to obtain solution 1; (2) Mix 2-amino-2'-fluoro-2'-deoxyadenosine with the buffer solution, heat, and prepare solution 2; (3) Then mix solution 1 and solution 2, heat and cool to room temperature.

9. The method for preparing a nasal pharmaceutical preparation according to claim 8, characterized in that, In steps (2) and (3), heat to 80-100℃.

10. The method for preparing a nasal pharmaceutical preparation according to claim 8, characterized in that, When the pharmaceutical preparation contains sodium hyaluronate, the preparation method includes the following steps: (1) First, mix tetrahydromethylpyrimidine carboxylic acid with a buffer solution to obtain solution 1. Then, mix sodium hyaluronate with a buffer solution to obtain solution 3. (2) Mix 2-amino-2'-fluoro-2'-deoxyadenosine with the buffer solution, heat, and prepare solution 2; (3) Then mix solutions 1, 2 and 3 and heat and cool to room temperature.

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