CN116392443A - Mometasone furoate nasal spray and preparation method thereof - Google Patents
Mometasone furoate nasal spray and preparation method thereof Download PDFInfo
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- CN116392443A CN116392443A CN202310453661.9A CN202310453661A CN116392443A CN 116392443 A CN116392443 A CN 116392443A CN 202310453661 A CN202310453661 A CN 202310453661A CN 116392443 A CN116392443 A CN 116392443A
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- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 title claims abstract description 39
- 229960002744 mometasone furoate Drugs 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000007922 nasal spray Substances 0.000 title claims abstract description 25
- 229940097496 nasal spray Drugs 0.000 title claims abstract description 24
- 239000000725 suspension Substances 0.000 claims abstract description 78
- 239000003814 drug Substances 0.000 claims abstract description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 74
- 239000008213 purified water Substances 0.000 claims abstract description 66
- 238000010008 shearing Methods 0.000 claims abstract description 53
- 238000002156 mixing Methods 0.000 claims abstract description 46
- 238000009210 therapy by ultrasound Methods 0.000 claims abstract description 44
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000007853 buffer solution Substances 0.000 claims abstract description 42
- 239000000243 solution Substances 0.000 claims abstract description 32
- 238000009924 canning Methods 0.000 claims abstract description 21
- 238000011049 filling Methods 0.000 claims abstract description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 11
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 42
- 238000003756 stirring Methods 0.000 claims description 38
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 31
- 238000001816 cooling Methods 0.000 claims description 30
- 238000010438 heat treatment Methods 0.000 claims description 20
- 239000011259 mixed solution Substances 0.000 claims description 20
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 19
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 19
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 17
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 17
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 16
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 16
- 229920000053 polysorbate 80 Polymers 0.000 claims description 16
- 229940068968 polysorbate 80 Drugs 0.000 claims description 16
- 229960004123 mometasone furoate monohydrate Drugs 0.000 claims description 15
- 235000011187 glycerol Nutrition 0.000 claims description 14
- 239000001509 sodium citrate Substances 0.000 claims description 14
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 238000001132 ultrasonic dispersion Methods 0.000 claims description 12
- 239000002131 composite material Substances 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 238000009835 boiling Methods 0.000 claims description 9
- 238000005520 cutting process Methods 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 229920000136 polysorbate Polymers 0.000 claims description 3
- 229950008882 polysorbate Drugs 0.000 claims description 3
- 238000011010 flushing procedure Methods 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 abstract description 9
- 238000000265 homogenisation Methods 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000005507 spraying Methods 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 230000003993 interaction Effects 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 230000002776 aggregation Effects 0.000 description 8
- 238000004220 aggregation Methods 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 239000003899 bactericide agent Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 3
- 210000002850 nasal mucosa Anatomy 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 206010039085 Rhinitis allergic Diseases 0.000 description 2
- 201000010105 allergic rhinitis Diseases 0.000 description 2
- 239000003093 cationic surfactant Substances 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 239000003595 mist Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
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- 210000004379 membrane Anatomy 0.000 description 1
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- 230000004060 metabolic process Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K9/0012—Galenical forms characterised by the site of application
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- A61P11/02—Nasal agents, e.g. decongestants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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Abstract
The invention belongs to the technical field of medicines, and in particular relates to a mometasone furoate nasal spray and a preparation method thereof. The preparation method of the mometasone furoate nasal spray comprises the steps of purified water treatment, preparation of suspension base solution, preparation of main medicine suspension, preparation of buffer solution, total mixing and shearing and nitrogen filling canning. The invention improves the stability of the mometasone furoate serving as the medicine active ingredient through the interaction of the components, combines variable frequency ultrasonic treatment, repeated shearing and homogenization treatment in the production process, and obtains the mometasone furoate nasal spray with good dispersion performance, high stability and excellent spraying effect.
Description
Technical Field
The invention belongs to the technical field of medicines, and in particular relates to a mometasone furoate nasal spray and a preparation method thereof.
Background
Mometasone furoate (CAS: 83919-23-7, mometasoneFuroate) is a new topical potent glucocorticoid hormone formulation developed and manufactured by the company Pieribaya, U.S., and was first marketed in the United states in 1987.
Mometasone furoate is a topical glucocorticoid which has obvious local antiallergic effect without causing obvious systemic effect, enhances the stability of endothelial cells, smooth muscle cells and lysosome membranes, inhibits the release of medium, promotes the metabolism thereof, inhibits the immune response and reduces the synthesis of antibodies; inhibit capillary exudation, reduce viscous cell, and relieve symptoms rapidly. Allergic rhinitis is not systemic reaction, nasal mucosa is the only effector organ, and pathophysiological processes of attacks are concentrated in the nasal mucosa. The mometasone furoate nasal spray directly acts on nasal mucosa, only plays a part in hormone action, has low bioavailability, can be applied for a long time, does not generate systemic side effect under the treatment dosage, and is one of the effective medicaments for treating allergic rhinitis at present.
The main medicine mometasone furoate in the mometasone furoate nasal spray has very low addition amount, and is particularly important how to fully and uniformly mix the main medicine and improve the medicine stability.
Disclosure of Invention
The invention aims to provide a mometasone furoate nasal spray and a preparation method thereof, wherein the stability of a medicine active ingredient mometasone furoate is improved through the interaction of the components, and meanwhile, variable frequency ultrasonic treatment, repeated shearing and homogenization treatment are combined in the production process to obtain the mometasone furoate nasal spray which has good dispersion performance, high stability and excellent spraying effect.
In order to achieve the above purpose, the present application adopts the following technical scheme:
the invention provides a preparation method of mometasone furoate nasal spray, which comprises the following steps:
s1, purified water treatment: heating and boiling purified water for 20+/-2 min, and cooling to below 40 ℃ for standby;
the purified water is heated and boiled, so that dissolved oxygen in the purified water can be effectively removed, and the water has a bactericidal effect, and is beneficial to the stability of the pharmaceutical preparation.
S2, preparing a suspension base solution: adding purified water accounting for 1% -3% of the total prescription amount and microcrystalline cellulose-sodium carboxymethyl cellulose into a material mixing tank, carrying out ultrasonic mixing uniformly, and then carrying out pre-shearing to obtain suspension base solution;
in the invention, microcrystalline cellulose-sodium carboxymethyl cellulose is used as a suspending agent, and the inventor discovers that after the microcrystalline cellulose-sodium carboxymethyl cellulose is subjected to pre-shearing dispersion in the production process, the product stability is facilitated, and if the microcrystalline cellulose-sodium carboxymethyl cellulose is not pre-dispersed and directly added to be mixed with other components, the solution is easy to generate layering phenomenon in the storage process.
S3, preparing a main medicine suspension: adding purified water accounting for 1% -3% of the total amount of the prescription into a clean container, heating to 70-80 ℃, then adding benzalkonium chloride, ultrasonically dissolving, and cooling to 40-50 ℃; adding polysorbate 80, ultrasonically dissolving, cooling to below 30deg.C, adding mometasone furoate monohydrate, performing frequency conversion ultrasonic dispersion, and homogenizing to obtain main medicine suspension;
when the main medicine suspension is prepared, benzalkonium chloride, polysorbate 80 and mometasone furoate monohydrate are added. Benzalkonium chloride is a cationic surfactant, belongs to a non-oxidizing bactericide, is added with the bactericide to provide a sterile environment at the beginning, avoids the influence of mixed bacteria on the preparation, and effectively improves the stability of the preparation in later storage; polysorbate-80 is an oil/water type emulsifier, and can be used as a wetting agent, so that water can be unfolded or infiltrated into the surface of mometasone furoate by reducing surface tension or interfacial tension, and the main drug mometasone furoate is uniformly dispersed in water and has uniform content.
The main medicine mometasone furoate is very low in addition amount, so that the main medicine is fully and uniformly mixed, when the main medicine is dispersed, variable frequency ultrasonic treatment and homogenization treatment are combined in the process, the mechanical vibration and cavitation of ultrasonic wave can accelerate the vibration and diffusion of molecules, so that the main medicine is uniformly dispersed, the variable frequency ultrasonic treatment can not damage the structure of main medicine components, the homogenization treatment can disperse the mixture into a suspension with a certain granularity, and the dispersion of the mometasone furoate as the main medicine is improved.
S4, preparing a buffer solution: adding purified water accounting for 1% -2% of the total prescription into a clean container, adding citric acid and sodium citrate, stirring and dissolving to obtain a buffer solution;
the pH of the preparation can be stabilized at 4.4-4.8 by adding buffer solution.
S5, total mixing and shearing: sequentially adding glycerol, main drug suspension and buffer solution into the suspension base solution obtained in the step S1 under stirring, respectively flushing a container for containing the main drug suspension and the buffer solution with the rest purified water, combining the washings into a batching tank, performing ultrasonic treatment for 10-15min at the ultrasonic frequency of 35-45KHz, detecting pH, and performing total mixing and shearing to obtain a total mixed solution;
s6, filling nitrogen and canning: and (3) canning the total mixed solution under stirring, vacuumizing, filling nitrogen and capping to obtain the composite material.
In step S2, the ultrasonic frequency of the ultrasonic uniform mixing is 20-30KHz, and the ultrasonic time is 5-10min.
Further, in S2, the pre-cutting is: 6-8 reciprocating cuts were made at a cutting frequency of 90.0 Hz.
In step S3, the ultrasonic frequency of ultrasonic dissolution is 30-40KHz, and the ultrasonic time is 5-10min.
Further, in S3, the variable frequency ultrasonic dispersion is: the low-frequency ultrasonic frequency is 25-35KHz, the high-frequency ultrasonic frequency is 50-60KHz, the low-frequency and high-frequency ultrasonic alternate treatment is carried out, each ultrasonic section is treated for 5-6min, and the total treatment time is 30-40min.
Further, in S3, the homogenizing speed is 4500-5500rpm, and the time is 3-5min.
Further, in S5, the pH is 4.4 to 4.8;
the total mixing shear is as follows: 4-6 reciprocating cuts were made at a cutting frequency of 90 Hz.
Another aspect of the invention is to provide a mometasone furoate nasal spray obtained by the above preparation method.
Further, the pharmaceutical composition is prepared from 0.02-0.08% of mometasone furoate monohydrate, 1-3% of microcrystalline cellulose-sodium carboxymethyl cellulose, 1-4% of glycerin, 0.005-0.03% of polysorbate, 0.1-0.3% of citric acid, 0.1-0.4% of sodium citrate, 0.01-0.03% of benzalkonium chloride and the balance of purified water according to weight percentage.
The microcrystalline cellulose-sodium carboxymethyl cellulose has a unique network structure, can adsorb mometasone furoate, slow down the sedimentation speed of the medicine in an aqueous medium, increase the uniform degree of medicine dispersion and strengthen the stability in the storage process; the glycerol can be used as osmotic pressure regulator to regulate the osmotic pressure of the liquid medicine, and has the effect of promoting the drug stabilization; benzalkonium chloride is a bacteriostatic agent, so that the quality of the medicine is stable; polysorbate 80 is a wetting agent, so that the main drug mometasone furoate is uniformly dispersed in water and the content is uniform; the citric acid and sodium citrate are used as pH regulator to stabilize the pH value of the preparation at 4.4-4.8.
Compared with the prior art, the beneficial effects are that:
1. when the main medicine suspension is prepared, benzalkonium chloride, polysorbate 80 and mometasone furoate monohydrate are added. Benzalkonium chloride is a cationic surfactant, belongs to a non-oxidizing bactericide, is added with the bactericide to provide a sterile environment at the beginning, avoids the influence of mixed bacteria on the preparation, and effectively improves the stability of the preparation in later storage; polysorbate-80 is an oil/water type emulsifier, and can be used as a wetting agent, so that water can be unfolded or infiltrated into the surface of mometasone furoate by reducing surface tension or interfacial tension, and the main drug mometasone furoate is uniformly dispersed in water and has uniform content.
The main medicine mometasone furoate is very low in addition amount, so that the main medicine is fully and uniformly mixed, when the main medicine is dispersed, variable frequency ultrasonic treatment and homogenization treatment are combined in the process, the mechanical vibration and cavitation of ultrasonic wave can accelerate the vibration and diffusion of molecules, so that the main medicine is uniformly dispersed, the variable frequency ultrasonic treatment can not damage the structure of main medicine components, the homogenization treatment can disperse the mixture into a suspension with a certain granularity, and the dispersion of the mometasone furoate as the main medicine is improved.
2. The mometasone furoate nasal spray with good dispersion performance, high stability and excellent spraying effect is obtained by combining variable frequency ultrasonic treatment, repeated shearing and homogenization treatment.
3. The preparation method is simple, short in production period, low in energy consumption and suitable for large-scale production.
Detailed Description
The above-described features of the invention and those specifically described in the following (example embodiments) may be combined with each other to constitute new or preferred embodiments, but the invention is not limited to these embodiments, nor is they limited to them in any way.
The experimental methods in the following examples are conventional methods unless otherwise specified. The preparations according to the examples below are commercially available and are commercially available unless otherwise specified.
The mometasone furoate nasal spray in the following examples is prepared from, by weight, mometasone furoate monohydrate 0.05%, microcrystalline cellulose-sodium carboxymethyl cellulose 2%, glycerin 2.1%, polysorbate 80.01%, citric acid 0.2%, sodium citrate 0.28%, benzalkonium chloride 0.02% and the balance purified water.
The invention is described in further detail below with reference to examples:
example 1: preparation of mometasone furoate nasal spray
S1, purified water treatment: heating and boiling purified water for 20min, and cooling to below 40deg.C for use;
s2, preparing a suspension base solution: adding purified water accounting for 3% of the total prescription and microcrystalline cellulose-sodium carboxymethyl cellulose into a material mixing tank, performing ultrasonic treatment at an ultrasonic frequency of 25KHz for 8min, setting a shearing frequency of 90.0Hz after ultrasonic mixing, and performing 7 times of reciprocating shearing to obtain a suspension base solution;
s3, preparing a main medicine suspension: adding purified water accounting for 2% of the total amount of the prescription into a clean container, heating to 80 ℃, then adding benzalkonium chloride, performing ultrasonic treatment at an ultrasonic frequency of 35KHz for 8min, and cooling to 45 ℃; adding polysorbate 80, performing ultrasonic treatment at ultrasonic frequency of 35KHz for 8min, cooling to below 30deg.C, adding mometasone furoate monohydrate, performing low-frequency and high-frequency ultrasonic alternating treatment according to low-frequency ultrasonic frequency of 25KHz and high-frequency ultrasonic frequency of 50KHz, treating each ultrasonic section for 5min, total treatment time of 30min, performing ultrasonic dispersion, and homogenizing at 5000rpm for 4min to obtain non-aggregation uniform main medicine suspension;
s4, preparing a buffer solution: adding purified water accounting for 2% of the total prescription into a clean container, adding citric acid and sodium citrate, and stirring for dissolution to obtain a buffer solution;
s5, total mixing and shearing: under the stirring state, the stirring rotation speed is 50rpm, glycerin, main medicine suspension and buffer solution are sequentially added into the suspension base solution obtained in the step S1, a container for containing the main medicine suspension and the buffer solution is respectively washed by the residual purified water, the washing liquid is combined into a batching tank, ultrasonic treatment is carried out for 10min at the ultrasonic frequency of 40KHz, the pH value is detected to be 4.5, the shearing frequency is set to be 90Hz, and 5 times of reciprocating total mixing shearing are carried out, so that a total mixed solution is obtained;
s6, filling nitrogen and canning: and (3) canning the total mixed solution under stirring, vacuumizing, filling nitrogen and capping to obtain the composite material.
Example 2: preparation of mometasone furoate nasal spray
S1, purified water treatment: heating purified water to boil for 22min, and cooling to below 40deg.C;
s2, preparing a suspension base solution: adding purified water accounting for 2% of the total prescription and microcrystalline cellulose-sodium carboxymethyl cellulose into a material mixing tank, performing ultrasonic treatment for 6min at an ultrasonic frequency of 30KHz, setting a shearing frequency of 90.0Hz after ultrasonic mixing, and performing 6 times of reciprocating shearing to obtain a suspension base solution;
s3, preparing a main medicine suspension: adding purified water accounting for 3% of the total amount of the prescription into a clean container, heating to 75 ℃, then adding benzalkonium chloride, performing ultrasonic treatment at an ultrasonic frequency of 40KHz for 6min, and cooling to 50 ℃; adding polysorbate 80, performing ultrasonic treatment at ultrasonic frequency of 40KHz for 6min, cooling to below 30deg.C, adding mometasone furoate monohydrate, performing low-frequency and high-frequency ultrasonic alternating treatment according to low-frequency ultrasonic frequency of 30KHz and high-frequency ultrasonic frequency of 55KHz, treating each ultrasonic section for 6min, total treatment time of 36min, performing ultrasonic dispersion, and homogenizing at 4500rpm for 5min to obtain non-aggregation uniform main medicine suspension;
s4, preparing a buffer solution: adding purified water accounting for 2% of the total prescription into a clean container, adding citric acid and sodium citrate, and stirring for dissolution to obtain a buffer solution;
s5, total mixing and shearing: under the stirring state, the stirring rotation speed is 50rpm, glycerin, main medicine suspension and buffer solution are sequentially added into the suspension base solution obtained in the step S1, a container for containing the main medicine suspension and the buffer solution is respectively washed by the residual purified water, the washing liquid is combined into a batching tank, ultrasonic treatment is carried out for 15min at the ultrasonic frequency of 35KHz, the pH value is detected to be 4.7, the shearing frequency is set to be 90Hz, and 4 times of reciprocating total mixing shearing are carried out, so that total mixed solution is obtained;
s6, filling nitrogen and canning: and (3) canning the total mixed solution under stirring, vacuumizing, filling nitrogen and capping to obtain the composite material.
Example 3: preparation of mometasone furoate nasal spray
S1, purified water treatment: heating and boiling purified water for 18min, and cooling to below 40deg.C for use;
s2, preparing a suspension base solution: adding purified water accounting for 2% of the total prescription and microcrystalline cellulose-sodium carboxymethyl cellulose into a material mixing tank, performing ultrasonic treatment for 10min at an ultrasonic frequency of 20KHz, setting a shearing frequency of 90.0Hz after ultrasonic mixing, and performing 8 times of reciprocating shearing to obtain a suspension base solution;
s3, preparing a main medicine suspension: adding purified water accounting for 2% of the total amount of the prescription into a clean container, heating to 70 ℃, then adding benzalkonium chloride, performing ultrasonic treatment at an ultrasonic frequency of 30KHz for 10min, and cooling to 40 ℃; adding polysorbate 80, performing ultrasonic treatment at ultrasonic frequency of 30KHz for 10min, cooling to below 30deg.C, adding mometasone furoate monohydrate, performing low-frequency and high-frequency ultrasonic alternating treatment according to low-frequency ultrasonic frequency of 35KHz and high-frequency ultrasonic frequency of 60KHz, treating each ultrasonic section for 5.5min for 33min, performing ultrasonic dispersion, and homogenizing at 5500rpm for 3min to obtain non-aggregation uniform main medicine suspension;
s4, preparing a buffer solution: adding purified water accounting for 2% of the total prescription into a clean container, adding citric acid and sodium citrate, and stirring for dissolution to obtain a buffer solution;
s5, total mixing and shearing: under the stirring state, the stirring rotation speed is 50rpm, glycerin, main medicine suspension and buffer solution are sequentially added into the suspension base solution obtained in the step S1, a container for containing the main medicine suspension and the buffer solution is respectively washed by the residual purified water, the washing liquid is combined into a batching tank, ultrasonic treatment is carried out for 12min at the ultrasonic frequency of 35KHz, the pH value is detected to be 4.6, the shearing frequency is set to be 90Hz, and 6 times of reciprocating total mixing shearing are carried out, so that a total mixed solution is obtained;
s6, filling nitrogen and canning: and (3) canning the total mixed solution under stirring, vacuumizing, filling nitrogen and capping to obtain the composite material.
Comparative example 1
S1, purified water treatment: heating and boiling purified water for 20min, and cooling to below 40deg.C for use;
s2, preparing a suspension base solution: adding purified water accounting for 3% of the total prescription and microcrystalline cellulose-sodium carboxymethyl cellulose into a material mixing tank, performing ultrasonic treatment at an ultrasonic frequency of 25KHz for 8min, setting a shearing frequency of 90.0Hz after ultrasonic mixing, and performing 7 times of reciprocating shearing to obtain a suspension base solution;
s3, preparing a main medicine suspension: adding purified water accounting for 2% of the total amount of the prescription into a clean container, heating to 80 ℃, then adding polysorbate 80, performing ultrasonic treatment at an ultrasonic frequency of 35KHz for 8min, and cooling to 45 ℃; adding benzalkonium chloride, performing ultrasonic treatment at ultrasonic frequency of 35KHz for 8min, cooling to below 30deg.C, adding mometasone furoate monohydrate, performing low-frequency and high-frequency ultrasonic alternating treatment according to low-frequency ultrasonic frequency of 25KHz and high-frequency ultrasonic frequency of 50KHz, treating each ultrasonic section for 5min, total treatment time of 30min, performing ultrasonic dispersion, and homogenizing at 5000rpm for 4min to obtain non-aggregation uniform main medicine suspension;
s4, preparing a buffer solution: adding purified water accounting for 2% of the total prescription into a clean container, adding citric acid and sodium citrate, and stirring for dissolution to obtain a buffer solution;
s5, total mixing and shearing: under the stirring state, the stirring rotation speed is 50rpm, glycerin, main medicine suspension and buffer solution are sequentially added into the suspension base solution obtained in the step S1, a container for containing the main medicine suspension and the buffer solution is respectively washed by the residual purified water, the washing liquid is combined into a batching tank, ultrasonic treatment is carried out for 10min at the ultrasonic frequency of 40KHz, the pH value is detected to be 4.4, the shearing frequency is set to be 90Hz, and 5 times of reciprocating total mixing shearing are carried out, so that a total mixed solution is obtained;
s6, filling nitrogen and canning: and (3) canning the total mixed solution under stirring, vacuumizing, filling nitrogen and capping to obtain the composite material.
Comparative example 2
S1, purified water treatment: heating and boiling purified water for 20min, and cooling to below 40deg.C for use;
s2, preparing a suspension base solution: adding purified water accounting for 3% of the total prescription and microcrystalline cellulose-sodium carboxymethyl cellulose into a material mixing tank, performing ultrasonic treatment at an ultrasonic frequency of 25KHz for 8min, setting a shearing frequency of 90.0Hz after ultrasonic mixing, and performing 7 times of reciprocating shearing to obtain a suspension base solution;
s3, preparing a main medicine suspension: adding purified water accounting for 2% of the total amount of the prescription into a clean container, heating to 80 ℃, then adding benzalkonium chloride, performing ultrasonic treatment at an ultrasonic frequency of 35KHz for 8min, and cooling to 45 ℃; adding polysorbate 80, performing ultrasonic treatment at ultrasonic frequency of 35KHz for 8min, cooling to below 30deg.C, adding mometasone furoate monohydrate, performing ultrasonic treatment at ultrasonic frequency of 25KHz for 30min, performing ultrasonic dispersion, and homogenizing at 5000rpm for 4min to obtain non-aggregation uniform main drug suspension;
s4, preparing a buffer solution: adding purified water accounting for 2% of the total prescription into a clean container, adding citric acid and sodium citrate, and stirring for dissolution to obtain a buffer solution;
s5, total mixing and shearing: under the stirring state, the stirring rotation speed is 50rpm, glycerin, main medicine suspension and buffer solution are sequentially added into the suspension base solution obtained in the step S1, a container for containing the main medicine suspension and the buffer solution is respectively washed by the residual purified water, the washing liquid is combined into a batching tank, ultrasonic treatment is carried out for 10min at the ultrasonic frequency of 40KHz, the pH value is detected to be 4.6, the shearing frequency is set to be 90Hz, and 5 times of reciprocating total mixing shearing are carried out, so that a total mixed solution is obtained;
s6, filling nitrogen and canning: and (3) canning the total mixed solution under stirring, vacuumizing, filling nitrogen and capping to obtain the composite material.
Comparative example 3
S1, purified water treatment: heating and boiling purified water for 20min, and cooling to below 40deg.C for use;
s2, preparing a suspension base solution: adding purified water accounting for 3% of the total prescription and microcrystalline cellulose-sodium carboxymethyl cellulose into a material mixing tank, performing ultrasonic treatment at an ultrasonic frequency of 25KHz for 8min, setting a shearing frequency of 90.0Hz after ultrasonic mixing, and performing 7 times of reciprocating shearing to obtain a suspension base solution;
s3, preparing a main medicine suspension: adding purified water accounting for 2% of the total amount of the prescription into a clean container, heating to 80 ℃, then adding benzalkonium chloride, performing ultrasonic treatment at an ultrasonic frequency of 35KHz for 8min, and cooling to 45 ℃; adding polysorbate 80, performing ultrasonic treatment at ultrasonic frequency of 35KHz for 8min, cooling to below 30deg.C, adding mometasone furoate monohydrate, performing ultrasonic treatment at ultrasonic frequency of 50KHz for 30min, performing ultrasonic dispersion, and homogenizing at rotation speed of 5000rpm for 4min to obtain non-aggregation uniform main medicine suspension;
s4, preparing a buffer solution: adding purified water accounting for 2% of the total prescription into a clean container, adding citric acid and sodium citrate, and stirring for dissolution to obtain a buffer solution;
s5, total mixing and shearing: under the stirring state, the stirring rotation speed is 50rpm, glycerin, main medicine suspension and buffer solution are sequentially added into the suspension base solution obtained in the step S1, a container for containing the main medicine suspension and the buffer solution is respectively washed by the residual purified water, the washing liquid is combined into a batching tank, ultrasonic treatment is carried out for 10min at the ultrasonic frequency of 40KHz, the pH value is detected to be 4.5, the shearing frequency is set to be 90Hz, and 5 times of reciprocating total mixing shearing are carried out, so that a total mixed solution is obtained;
s6, filling nitrogen and canning: and (3) canning the total mixed solution under stirring, vacuumizing, filling nitrogen and capping to obtain the composite material.
Comparative example 4
S1, purified water treatment: heating and boiling purified water for 20min, and cooling to below 40deg.C for use;
s2, preparing a suspension base solution: adding purified water accounting for 3% of the total prescription and microcrystalline cellulose-sodium carboxymethyl cellulose into a material mixing tank, performing ultrasonic treatment for 8min at an ultrasonic frequency of 25KHz, setting a shearing frequency to 90.0Hz after ultrasonic mixing, and performing 3 times of reciprocating shearing to obtain a suspension base solution;
s3, preparing a main medicine suspension: adding purified water accounting for 2% of the total amount of the prescription into a clean container, heating to 80 ℃, then adding benzalkonium chloride, performing ultrasonic treatment at an ultrasonic frequency of 35KHz for 8min, and cooling to 45 ℃; adding polysorbate 80, performing ultrasonic treatment at ultrasonic frequency of 35KHz for 8min, cooling to below 30deg.C, adding mometasone furoate monohydrate, performing low-frequency and high-frequency ultrasonic alternating treatment according to low-frequency ultrasonic frequency of 25KHz and high-frequency ultrasonic frequency of 50KHz, treating each ultrasonic section for 5min, total treatment time of 30min, performing ultrasonic dispersion, and homogenizing at 5000rpm for 4min to obtain non-aggregation uniform main medicine suspension;
s4, preparing a buffer solution: adding purified water accounting for 2% of the total prescription into a clean container, adding citric acid and sodium citrate, and stirring for dissolution to obtain a buffer solution;
s5, total mixing and shearing: under the stirring state, the stirring rotation speed is 50rpm, glycerin, main medicine suspension and buffer solution are sequentially added into the suspension base solution obtained in the step S1, a container for containing the main medicine suspension and the buffer solution is respectively washed by the residual purified water, the washing liquid is combined into a batching tank, ultrasonic treatment is carried out for 10min at the ultrasonic frequency of 40KHz, the pH value is detected to be 4.5, the shearing frequency is set to be 90Hz, and 3 times of reciprocating total mixing shearing are carried out, so that the total mixed solution is obtained;
s6, filling nitrogen and canning: and (3) canning the total mixed solution under stirring, vacuumizing, filling nitrogen and capping to obtain the composite material.
Comparative example 5
S1, purified water treatment: heating and boiling purified water for 20min, and cooling to below 40deg.C for use;
s2, preparing a suspension base solution: adding purified water accounting for 3% of the total prescription and microcrystalline cellulose-sodium carboxymethyl cellulose into a material mixing tank, performing ultrasonic treatment at an ultrasonic frequency of 25KHz for 8min, setting a shearing frequency to 90.0Hz after ultrasonic mixing, and performing 10 times of reciprocating shearing to obtain a suspension base solution;
s3, preparing a main medicine suspension: adding purified water accounting for 2% of the total amount of the prescription into a clean container, heating to 80 ℃, then adding benzalkonium chloride, performing ultrasonic treatment at an ultrasonic frequency of 35KHz for 8min, and cooling to 45 ℃; adding polysorbate 80, performing ultrasonic treatment at ultrasonic frequency of 35KHz for 8min, cooling to below 30deg.C, adding mometasone furoate monohydrate, performing low-frequency and high-frequency ultrasonic alternating treatment according to low-frequency ultrasonic frequency of 25KHz and high-frequency ultrasonic frequency of 50KHz, treating each ultrasonic section for 5min, total treatment time of 30min, performing ultrasonic dispersion, and homogenizing at 5000rpm for 4min to obtain non-aggregation uniform main medicine suspension;
s4, preparing a buffer solution: adding purified water accounting for 2% of the total prescription into a clean container, adding citric acid and sodium citrate, and stirring for dissolution to obtain a buffer solution;
s5, total mixing and shearing: under the stirring state, the stirring rotation speed is 50rpm, glycerin, main medicine suspension and buffer solution are sequentially added into the suspension base solution obtained in the step S1, a container for containing the main medicine suspension and the buffer solution is respectively washed by the residual purified water, the washing liquid is combined into a batching tank, ultrasonic treatment is carried out for 10 minutes at the ultrasonic frequency of 40KHz, the pH value is detected to be 4.5, the shearing frequency is set to be 90Hz, and 10 times of reciprocating total mixing shearing are carried out, so that a total mixed solution is obtained;
s6, filling nitrogen and canning: and (3) canning the total mixed solution under stirring, vacuumizing, filling nitrogen and capping to obtain the composite material.
Test example 1
The mometasone furoate nasal sprays prepared in examples 1 to 3 and comparative examples 1 to 6 were subjected to an accelerated stability test, test method: the accelerated stability test for 6 months is carried out under the conditions that the temperature is 40+/-2 ℃ and the relative humidity is 75+/-5% by referring to 9001 raw material medicaments and preparation stability test guiding principle in Chinese pharmacopoeia of 2020 edition, and the properties, viscosity, total impurity content, fog drop distribution and microorganism limit indexes are checked on the 0 th day and the 6 th month respectively, and the related inspection project operation method is referred to Chinese pharmacopoeia of 2020 edition, and the result is shown in table 1.
TABLE 1 stability test results
In comparative example 1, after the addition sequence of benzalkonium chloride and polysorbate 80 was exchanged, serious delamination occurred after 6 months of standing, and the microbial index did not meet the regulations.
When the main medicine suspensions in comparative examples 2 and 3 are prepared, the fog drop granularity is not fine and smooth in example 1 after frequency conversion ultrasonic treatment is not adopted, layering and slight layering occur after the suspension is placed for 6 months, and the stability is poor.
When the pre-shearing times and the total mixing shearing times in comparative examples 4 and 5 are 3 times and 10 times respectively, the obtained nasal spray mist drops have the particle sizes which are not up to the requirements, and after the nasal spray mist drops are placed for 6 months, serious layering and slight layering phenomena appear, so that the stability is poor.
In conclusion, the nasal spray medicine granularity and the fog drop granularity obtained by the formula and the preparation method are small, fine and smooth, uniform in dispersion, good in stability, more beneficial to absorption, free from waste and side effects.
Finally, it should be emphasized that the foregoing description is merely illustrative of the preferred embodiments of the invention, and that various changes and modifications can be made by those skilled in the art without departing from the spirit and principles of the invention, and any such modifications, equivalents, improvements, etc. are intended to be included within the scope of the invention.
Claims (9)
1. The preparation method of the mometasone furoate nasal spray is characterized by comprising the following steps of:
s1, purified water treatment: heating and boiling purified water for 20+/-2 min, and cooling to below 40 ℃ for standby;
s2, preparing a suspension base solution: adding purified water accounting for 1% -3% of the total prescription amount and microcrystalline cellulose-sodium carboxymethyl cellulose into a material mixing tank, carrying out ultrasonic mixing uniformly, and then carrying out pre-shearing to obtain suspension base solution;
s3, preparing a main medicine suspension: adding purified water accounting for 1% -3% of the total amount of the prescription into a clean container, heating to 70-80 ℃, then adding benzalkonium chloride, ultrasonically dissolving, and cooling to 40-50 ℃; adding polysorbate 80, ultrasonically dissolving, cooling to below 30deg.C, adding mometasone furoate monohydrate, performing frequency conversion ultrasonic dispersion, and homogenizing to obtain main medicine suspension;
s4, preparing a buffer solution: adding purified water accounting for 1% -2% of the total prescription into a clean container, adding citric acid and sodium citrate, stirring and dissolving to obtain a buffer solution;
s5, total mixing and shearing: sequentially adding glycerol, main drug suspension and buffer solution into the suspension base solution obtained in the step S1 under stirring, respectively flushing a container for containing the main drug suspension and the buffer solution with the rest purified water, combining the washings into a batching tank, performing ultrasonic treatment for 10-15min at the ultrasonic frequency of 35-45KHz, detecting pH, and performing total mixing and shearing to obtain a total mixed solution;
s6, filling nitrogen and canning: and (3) canning the total mixed solution under stirring, vacuumizing, filling nitrogen and capping to obtain the composite material.
2. The method according to claim 1, wherein in S2, the ultrasonic frequency of the ultrasonic mixing is 20-30KHz, and the ultrasonic time is 5-10min.
3. The method according to claim 1, wherein in S2, the pre-cutting is: 6-8 reciprocating cuts were made at a cutting frequency of 90.0 Hz.
4. The method according to claim 1, wherein in S3, the ultrasonic frequency of the ultrasonic dissolution is 30-40KHz and the ultrasonic time is 5-10min.
5. The method according to claim 1, wherein in S3, the variable frequency ultrasonic dispersion is: the low-frequency ultrasonic frequency is 25-35KHz, the high-frequency ultrasonic frequency is 50-60KHz, the low-frequency and high-frequency ultrasonic alternate treatment is carried out, each ultrasonic section is treated for 5-6min, and the total treatment time is 30-40min.
6. The method according to claim 1, wherein in S3, the homogenizing speed is 4500-5500rpm for 3-5min.
7. The method according to claim 1, wherein in S5, the pH is 4.4 to 4.8;
the total mixing shear is as follows: 4-6 reciprocating cuts were made at a cutting frequency of 90 Hz.
8. A mometasone furoate nasal spray obtainable by the process of any one of claims 1 to 7.
9. The mometasone furoate nasal spray of claim 8 wherein the mometasone furoate monohydrate is prepared from, by weight, 0.02% -0.08%, microcrystalline cellulose-sodium carboxymethyl cellulose 1% -3%, glycerin 1% -4%, polysorbate 80.005% -0.03%, citric acid 0.1% -0.3%, sodium citrate 0.1% -0.4%, benzalkonium chloride 0.01% -0.03% and the balance purified water.
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