Long-chain hydrocarbon nasal spray emulsion as well as preparation method and application thereof

Abstract

The invention particularly relates to a long-chain hydrocarbon nasal spray emulsion as well as a preparation method and application thereof. The nasal spray emulsion comprises the following raw materials in percentage by weight: 0.5-30% of long-chain hydrocarbon; 5%-80% of an oil phase; 1%-30% of an emulsifier; 0.5%-20% of a co-emulsifier; 0.001% to 5% of an aromatic agent; 0.001% to 5% of an antioxidant; and the balance of deionized water. The nasal cavity allergen (air particle) blocking agent prepared by the invention is sprayed in a nasal cavity to form a layer of nano film on the surface of nasal mucosa, so that the air particles can be effectively blocked, the concentration of sensitization sources is reduced, and the nasal cavity allergen (air particle) blocking agent is used for preventing and treating allergic rhinitis and asthma caused by particles such as pollen, dust, animal hair and the like and other allergens; the nasal cavity can also be daily cleaned, disinfected and nursed. The nasal spray emulsion not only has no irritation to mucous membranes and skin, has good stability, is not easy to deteriorate, but also is convenient to use, simple and feasible in preparation process and easy to industrialize.

Description

Technical Field

[0001] The present invention belongs to the technical field of Class II medical devices, and particularly relates to a long-chain hydrocarbon nasal spray emulsion, a preparation method thereof, and an application thereof. Background Art

[0002] Petroleum jelly, white soft paraffin, etc. are mainly chemically inert hydrocarbons, which are not hydrophilic and not absorbable. When applied to the skin and mucous membranes, they can form a film on the surface, making it difficult for moisture to evaporate and disperse, and can keep the skin in a moist state, blocking bacteria in the air from contacting the skin and mucous membranes, thereby reducing the adverse stimulation from the outside to the skin and mucous membranes. Petroleum jelly has the characteristics of safety and mildness, and its chemical properties are very stable, not easily spoiled or deteriorated. Most of the existing methods of using petroleum jelly are mainly by smearing, which is inconvenient to use, and long-term use will also cause problems such as bacterial growth. The dosage of petroleum jelly during the smearing process is not easy to control. In the case of excessive dosage, it will also cause inflammation of the skin and mucous membranes.

[0003] A nasal spray is an aerosol specifically for nasal use. Its packaging is equipped with a valve. When in use, the valve is squeezed, and the drug is sprayed onto the nasal mucosa in a mist form, which is a local administration form with good safety. Compared with smearing, the long-chain hydrocarbon nasal spray emulsion has the characteristics of more convenient administration, hygiene, easy to carry, and small dosage.

[0004] An emulsion refers to a non-uniformly dispersed liquid preparation formed by mixing two immiscible liquid phases, in which one liquid phase is dispersed in the other liquid phase in the form of liquid droplets. According to the size of the emulsion droplets, emulsions can be divided into ordinary emulsions, submicron emulsions, and nanoemulsions. A nanoemulsion is a colloidal dispersion system formed by oil, water, an emulsifier, and a co-emulsifier, in which emulsion droplets with a particle size of less than 1000 nm are dispersed in another liquid, and it belongs to a kinetically stable system. Compared with traditional emulsions, nanoemulsions have smaller particle sizes. Through Brownian motion, they can overcome the gravitational force, and are not prone to precipitation during storage. At the same time, they also prevent the generation of flocculent substances, keeping the system homogeneous. Nanoemulsions are generally divided into three types: oil-in-water nanoemulsions, water-in-oil nanoemulsions, and bicontinuous nanoemulsions. Which specific type is formed is determined by the structural properties and ratios of the components in the formulation. No matter which type, the interfacial tension between the phases of the nanoemulsion is relatively low.

[0005] Homogenization technology is already a very important refining and dispersing technology. The smaller the drug particles are, the more conducive it is to improving the dissolution rate of the drug and also beneficial to enhancing the dispersibility of the drug in the dispersion medium. The main forces of the homogenizer are shear force and pressure. Homogenization technology is mainly divided into: high-pressure homogenization technology, which applies high pressure to liquid materials through a pressure device for extrusion, extension, impact, and fragmentation processes, and is suitable for flexible and semi-flexible granular materials; shear homogenization technology, which relies on the high shear force generated by the relative high-speed movement between the stator and rotor to shear and mix the materials, and at the same time disperse and homogenize the material particles; microfluidic homogenization technology, which forms a high-speed jet of liquid materials under high pressure, collides at high speed with another jet in the opposite direction, and makes the materials ultra-finely refined. The microfluidic homogenizer is mainly composed of a dispersion unit and a pressurization mechanism. Under the action of the pressurization mechanism, using the high pressure generated by a hydraulic pump, the fluid passes through a valve core with a pore diameter of about a hundred microns, generating a fluid with several times the speed of sound, and quickly passes through the narrow gap of the dispersion unit for intense high-speed impact. During the impact process, most of the energy of the fluid is instantaneously converted, the pressure inside the fluid drops rapidly to form a supersonic fluid, and the particles inside the fluid collide, cavitate, and form turbulence, making the components of the fluid exist in a completely homogeneous state. The homogenized product has the advantages of no precipitation and high stability. Summary of the Invention

[0006] The object of the present invention is to provide a long-chain hydrocarbon nasal spray emulsion, which is sprayed into the nasal cavity to form a lipid-soluble nano-protective film in the nasal vestibule, has strong adhesion to the nasal cavity without being absorbed, and reduces the inhalation of other allergens such as pollen, dust, and animal hair in the air through adsorption. At the same time, petrolatum also has a certain moisturizing effect and can be used for the prevention and adjuvant treatment of nasal dryness, nasal itching, allergic rhinitis, and asthma.

[0007] The technical solution adopted by the present invention is as follows:

[0008] A long-chain hydrocarbon nasal spray emulsion, the raw materials of which include, by weight percentage: long-chain hydrocarbon: 0.5% - 30%; oil phase: 5% - 80%; emulsifier: 1% - 30%; co-emulsifier: 0.5% - 20%; fragrance: 0.001% - 5%; antioxidant: 0.001% - 5%; deionized water: the balance.

[0009] Preferably, the raw materials of the long-chain hydrocarbon nasal spray emulsion include, by weight percentage: white petrolatum 2% - 15%, oil phase 10% - 40%, emulsifier 3% - 15%, co-emulsifier 1% - 8%, fragrance 0.005% - 0.05%, antioxidant 0.005% - 0.2%

[0010] The above-mentioned long-chain hydrocarbon nasal spray emulsion, wherein the long-chain hydrocarbon is one or more mixtures of white petrolatum, yellow petrolatum, and white soft paraffin.

[0011] Preferably, the long-chain hydrocarbon is white petrolatum.

[0012] The above-mentioned long-chain hydrocarbon nasal spray emulsion, wherein the oil phase is one or more mixtures of soybean oil, peanut oil, sweet almond oil, olive oil, castor oil, sunflower seed oil, coconut oil, camellia oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sesame oil, and isopropyl myristate.

[0013] Preferably, the oil phase is one or more mixtures of olive oil, sunflower seed oil, corn oil, and sesame oil.

[0014] The above-mentioned long-chain hydrocarbon nasal spray emulsion, wherein the emulsifier is one or more mixtures of gum arabic, tragacanth, soybean phospholipid, egg yolk phospholipid, polyoxyethylene hydrogenated castor oil, Tween-80, poloxamer 188, Span-80, sodium oleate, isostearic acid, and polyoxyethylene castor oil.

[0015] Preferably, the emulsifier is one or more mixtures of egg yolk phospholipid, poloxamer 188, sodium oleate, and Tween 80.

[0016] The above-mentioned long-chain hydrocarbon nasal spray emulsion, wherein the co-emulsifier is one or more mixtures of absolute ethanol, 1,2-propanediol, glycerol, isopropyl alcohol, n-butanol, and polyethylene glycol.

[0017] Preferably, the co-emulsifier is glycerol.

[0018] The above-mentioned long-chain hydrocarbon nasal spray emulsion, wherein the flavoring agent is one or more mixtures of peppermint oil, lemon oil, and cinnamon water.

[0019] Preferably, the flavoring agent is peppermint oil.

[0020] The above-mentioned long-chain hydrocarbon nasal spray emulsion, wherein the antioxidant is one or more mixtures of EDTA-2Na, vitamin E, sodium metabisulfite, and citric acid.

[0021] Preferably, the antioxidant is vitamin E.

[0022] The preparation method of the long-chain hydrocarbon nasal spray emulsion according to any one of the above, comprising the following steps:

[0023] 1) Mix the oil phase and the long-chain hydrocarbon according to the formula amount, heat and stir, and mix evenly to obtain the oil phase liquid A;

[0024] 2) Dissolve the emulsifier and co-emulsifier in part of deionized water according to the formula amount, and stir evenly to obtain the aqueous phase liquid B;

[0025] 3) Combine the oil phase liquid A and the aqueous phase liquid B, then add the flavoring agent and antioxidant, heat and stir evenly, add the remaining deionized water, and shear with a high-speed dispersion homogenizer at a high speed to obtain the primary emulsion;

[0026] 4) Transfer the primary emulsion obtained in step 3) to a microfluidic homogenizer or a high-pressure homogenizer, and homogenize repeatedly until the particle size is less than 1000 nm.

[0027] Further, in the above preparation method, in step 1), the temperature is raised to 30°C - 100°C during the heating and stirring process.

[0028] Further, in the above preparation method, in step 3), shear with a high-speed dispersion homogenizer once or more than once, the speed is 12 kr / min, and the time is 10 - 15 min.

[0029] Further, in the above preparation method, in step 4), the pressure of the microfluidic homogenizer or the high-pressure homogenizer is 3000 - 30000 psi, and homogenize twice or more than twice.

[0030] Use of the long-chain hydrocarbon nasal spray emulsion according to any one of the above in the preparation of a drug for treating allergic rhinitis, allergic asthma, nasal dryness and nasal itching.

[0031] The beneficial effects of the present invention are:

[0032] 1. The long-chain hydrocarbon nasal spray emulsion of the present invention is a combination composed of long-chain hydrocarbons such as petrolatum and white soft paraffin and excipients. This combination is a nasal allergen (air particles) barrier. When sprayed into the nasal cavity, it forms a nanoemulsion film on the surface of the nasal mucosa for preventing and treating allergic rhinitis and asthma caused by allergens.

[0033] 2. Through the homogenization of the microfluidic homogenizer, the present invention can reduce the particle size and improve the stability.

[0034] 3. The long-chain hydrocarbon nasal spray emulsion of the present invention is convenient to use and does not affect the user's work, study, social activities, etc.

[0035] 4. The long-chain hydrocarbon nasal spray emulsion of the present invention has no irritation to the skin, can be used by both adults and children, and has a simple preparation process and can be mass-produced. Specific Embodiments

[0036] Example 1

[0037] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formulation:

[0038]

[0039] (2) The preparation method is as follows:

[0040] 1) Mix white petrolatum and soybean oil according to the formulation amount, heat and stir at 80 °C until the petrolatum dissolves, and mix thoroughly to obtain the oil-phase liquid A;

[0041] 2) Dissolve poloxamer 188, soybean phospholipid, sodium oleate, glycerol, and Tween 80 in a part of deionized water according to the formulation amount, and stir evenly to obtain the water-phase liquid B;

[0042] 3) Combine the oil-phase liquid A and the water-phase liquid B, add vitamin E, heat and stir evenly at 80 °C, then add the remaining deionized water in equal amounts in sequence, and shear three times with a high-speed dispersion homogenizer at 12 kr / min for 15 min to prepare the primary emulsion;

[0043] 4) Transfer the primary emulsion obtained in step 3) to a microfluidic homogenizer, homogenize six times at 15000 psi, with a particle size below 1000 nm, to obtain a uniform mixed solution, sterilize, and package to obtain the long-chain hydrocarbon nasal spray emulsion.

[0044] Example 2

[0045] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formulation:

[0046]

[0047]

[0048] (2) Preparation method: The same as Example 1.

[0049] Example 3

[0050] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formulation:

[0051]

[0052] (2) Preparation method: The same as Example 1.

[0053] Example 4

[0054] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formulation:

[0055]

[0056] (2) Preparation method: The same as Example 1.

[0057] Example 5

[0058] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formula:

[0059]

[0060] (2) Preparation method: the same as Example 1.

[0061] Example 6

[0062] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formula:

[0063]

[0064] (2) Preparation method: the same as Example 1.

[0065] Example 7

[0066] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formula:

[0067]

[0068]

[0069] (2) The preparation method is as follows:

[0070] 1) Mix white petrolatum and isopropyl myristate according to the formula amount, heat and stir at 80 °C until the petrolatum dissolves, and mix evenly to obtain the oil-phase liquid A;

[0071] 2) Dissolve poloxamer 188, egg yolk phospholipid, sodium oleate, glycerol, and Tween 80 in part of deionized water according to the formula amount, and stir evenly to obtain the water-phase liquid B;

[0072] 3) Combine the oil-phase liquid A and the water-phase liquid B, then add vitamin E and peppermint oil, heat and stir evenly at 80 °C, and then add the remaining deionized water in equal amounts in turn. Use a high-speed dispersion homogenizer to perform high-speed shearing three times, and perform high-speed shearing at 12 kr / min for 15 min to obtain the primary emulsion;

[0073] 4) Transfer the primary emulsion obtained in step 3) to a microfluidic homogenizer, homogenize six times at 15000 psi, and the particle size is below 1000 nm to obtain a uniform mixed solution, sterilize, and package to obtain the long-chain hydrocarbon nasal spray emulsion.

[0074] Example 8

[0075] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formula:

[0076]

[0077]

[0078] (2) Preparation method: the same as that of Example 7.

[0079] Example 9

[0080] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formula:

[0081]

[0082] (2) Preparation method: the same as that of Example 7.

[0083] Example 10

[0084] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formula:

[0085]

[0086] (2) Preparation method: the same as that of Example 7.

[0087] Example 11

[0088] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formula:

[0089]

[0090] (2) Preparation method: the same as that of Example 7.

[0091] Example 12

[0092] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formula:

[0093]

[0094] (2) Preparation method: the same as that of Example 7.

[0095] Example 13

[0096] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formula:

[0097]

[0098] (2) Preparation method: the same as that of Example 7.

[0099] Example 14

[0100] (1) A long-chain hydrocarbon nasal spray emulsion, with the following formula:

[0101]

[0102] (2) Preparation method: the same as that in Example 7.

[0103] Stability test of Example 15

[0104] Take the long-chain hydrocarbon nasal spray emulsions of Examples 1-14 respectively to conduct light stability test, different temperature stability test, high-speed centrifugation stability test, and long-term stability test to confirm whether there are unstable phenomena such as layering and crystal precipitation.

[0105] (1) Light stability test

[0106] Seal the long-chain hydrocarbon nasal spray emulsions prepared in Examples 1-14 in transparent glass containers and place them under normal light conditions for 10 days. Sampling and observation are carried out on the 1st day, 5th day, and 10th day respectively. The results of the light stability test are shown in Table 1:

[0107] Table 1 Results of light stability test

[0108]

[0109] (2) Different temperature stability test

[0110] Divide the long-chain hydrocarbon nasal spray emulsions prepared in Examples 1-14 into three portions each, seal them in colorless and transparent glass containers, and place them in environments of 4°C, room temperature, and 50°C for 10 days. Sampling and observation are carried out every 5 days. The results of the temperature stability test are shown in Table 2:

[0111] Table 2 Results of different temperature stability test

[0112]

[0113] (3) High-speed centrifugation stability test

[0114] Centrifuge the long-chain hydrocarbon nasal spray emulsions prepared in Examples 1-14 at a speed of 5000 r / min for 15 min, and observe the samples after centrifugation. The results of the high-speed centrifugation stability test are shown in Table 3:

[0115] Table 3 Results of high-speed centrifugation stability test

[0116]

[0117] (4) Long-term stability test

[0118] Seal the long-chain hydrocarbon nasal spray emulsions prepared in Examples 1-14 in colorless and transparent glass containers, and place them under the conditions of 25°C and relative humidity of 75% for 6 months. Sampling and observation are carried out in January, February, March, and June respectively. The results of the long-term stability test are shown in Table 4:

[0119] Table 4 Results of long-term stability test

[0120]

[0121] Example 16 Skin irritation test

[0122] Take 12 healthy mice and use the self-contrast method on the left and right sides of the same body. Apply physiological saline and long-chain hydrocarbon nasal spray emulsion (preferably Formula Examples 11 and 12) to the depilated areas on the left and right sides of each mouse as the control group and the test group, respectively. Depilate the areas on both sides of the spinal column on the back of the mice 24 hours before the test. Take 1 mL of physiological saline and long-chain hydrocarbon nasal spray emulsion and apply them to the back of the mice, and apply continuously for 14 days. On the 14th day, conduct macroscopic observation 1 h, 3 h, 6 h, and 12 h after the application is completed, and record whether there are erythema, edema, etc. at the drug application site in the test group. The results of the skin irritation test are shown in Table 5.

[0123] Table 5 Results of skin irritation test

[0124]

[0125] Note: Non-irritating (−), Mildly irritating (+), Moderately irritating (++), Severely irritating (+++).

Claims

1. A long-chain hydrocarbon nasal spray emulsion, characterized in that, Its raw materials by weight percentage include: long-chain hydrocarbons: 0.5%-30%; oil phase: 5%-80%; emulsifier: 1%-30%; co-emulsifier: 0.5%-20%; fragrance: 0.001%-5%; antioxidant: 0.001%-5%; deionized water: the balance.

2. The long-chain hydrocarbon nasal spray emulsion according to claim 1, characterized in that, The long-chain hydrocarbons are one or more mixtures of white petrolatum, yellow petrolatum, and white soft wax.

3. The long-chain hydrocarbon nasal spray emulsion according to claim 1, characterized in that, The oil phase is one or more mixtures of soybean oil, peanut oil, sweet almond oil, olive oil, castor oil, sunflower seed oil, coconut oil, camellia oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sesame oil, and isopropyl myristate.

4. The long-chain hydrocarbon nasal spray emulsion according to claim 1, wherein The emulsifier is one or more mixtures of gum arabic, tragacanth gum, soybean phospholipid, egg yolk phospholipid, polyoxyethylene hydrogenated castor oil ether, Tween-80, poloxamer 188, Span-80, sodium oleate, isostearic acid, and polyoxyethylene castor oil.

5. The long-chain hydrocarbon nasal spray emulsion according to claim 1, characterized in that, The co-emulsifier is one or more mixtures of absolute ethanol, 1,2-propanediol, glycerol, isopropanol, n-butanol, and polyethylene glycol.

6. The long-chain hydrocarbon nasal spray emulsion according to claim 1, characterized in that, The fragrance is one or more mixtures of peppermint oil, lemon oil, and cinnamon water.

7. The long-chain hydrocarbon nasal spray emulsion according to claim 1, wherein The antioxidant is one or more mixtures of EDTA-2Na, vitamin E, sodium metabisulfite, and citric acid.

8. The preparation method of the long-chain hydrocarbon nasal spray emulsion according to any one of claims 1-7, characterized in that, It includes the following steps: 1) Mix the oil phase and long-chain hydrocarbons according to the formula amount, heat and stir to fully mix evenly to obtain oil-phase liquid A; 2) Dissolve the emulsifier and co-emulsifier in part of the deionized water according to the formula amount, and stir evenly to obtain water-phase liquid B; 3) Combine oil-phase liquid A and water-phase liquid B, then add the fragrance and antioxidant, heat and stir evenly, add the remaining deionized water, and use a high-speed dispersion homogenizer to perform high-speed shearing to obtain the primary emulsion; 4) Transfer the primary emulsion obtained in step 3) to a microfluidic homogenizer or a high-pressure homogenizer, and homogenize repeatedly until the particle size is less than 1000 nm.

9. The preparation method according to claim 8, wherein, In step 1), the temperature is raised to 30°C-100°C during the heating and stirring process; in step 3), shear with a high-speed dispersion homogenizer once or more, the speed is 12 kr / min, and the time is 10-15 min; in step 4), the pressure of the microfluidic homogenizer or the high-pressure homogenizer is 3000-30000 psi, and homogenize twice or more.

10. Use of the long-chain hydrocarbon nasal spray emulsion according to any one of claims 1-7 in the preparation of a drug for treating allergic rhinitis, allergic asthma, and nasal dryness and itching.

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