CN118415982B - 2- (4-Methylthiazol-5-yl) ethyl nitrate hydrochloride nasal spray and preparation method thereof - Google Patents
2- (4-Methylthiazol-5-yl) ethyl nitrate hydrochloride nasal spray and preparation method thereof Download PDFInfo
- Publication number
- CN118415982B CN118415982B CN202410449344.4A CN202410449344A CN118415982B CN 118415982 B CN118415982 B CN 118415982B CN 202410449344 A CN202410449344 A CN 202410449344A CN 118415982 B CN118415982 B CN 118415982B
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- CN
- China
- Prior art keywords
- nasal spray
- polyethylene glycol
- sodium
- ethyl nitrate
- methylthiazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 239000007922 nasal spray Substances 0.000 title claims abstract description 45
- 229940097496 nasal spray Drugs 0.000 title claims abstract description 40
- AFJHNVYIRRYUJM-UHFFFAOYSA-N 2-(4-methyl-1,3-thiazol-5-yl)ethyl nitrate;hydrochloride Chemical compound Cl.CC=1N=CSC=1CCO[N+]([O-])=O AFJHNVYIRRYUJM-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 8
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 27
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 27
- 229960003512 nicotinic acid Drugs 0.000 claims abstract description 16
- 235000001968 nicotinic acid Nutrition 0.000 claims abstract description 16
- 239000011664 nicotinic acid Substances 0.000 claims abstract description 16
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims abstract description 16
- 229960001763 zinc sulfate Drugs 0.000 claims abstract description 15
- 229910000368 zinc sulfate Inorganic materials 0.000 claims abstract description 15
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 12
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000003204 osmotic effect Effects 0.000 claims abstract description 11
- 239000008213 purified water Substances 0.000 claims abstract description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 13
- 235000006708 antioxidants Nutrition 0.000 claims description 11
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- 239000003755 preservative agent Substances 0.000 claims description 8
- 230000002335 preservative effect Effects 0.000 claims description 8
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 229940057847 polyethylene glycol 600 Drugs 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 5
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- 235000010241 potassium sorbate Nutrition 0.000 claims description 5
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- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 239000003002 pH adjusting agent Substances 0.000 claims description 4
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 229930003268 Vitamin C Natural products 0.000 claims description 3
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 3
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
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- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- 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 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 235000011008 sodium phosphates Nutrition 0.000 claims description 3
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- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 235000019154 vitamin C Nutrition 0.000 claims description 3
- 239000011718 vitamin C Substances 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- LNGNZSMIUVQZOX-UHFFFAOYSA-L disodium;dioxido(sulfanylidene)-$l^{4}-sulfane Chemical compound [Na+].[Na+].[O-]S([O-])=S LNGNZSMIUVQZOX-UHFFFAOYSA-L 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- 238000010521 absorption reaction Methods 0.000 abstract description 8
- 238000010579 first pass effect Methods 0.000 abstract description 3
- 230000009747 swallowing Effects 0.000 abstract description 3
- 210000003928 nasal cavity Anatomy 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 239000000243 solution Substances 0.000 description 6
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- -1 2- (4-methylthiazole-5-yl) ethyl nitrate hydrochloride Chemical compound 0.000 description 2
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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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
- A61K47/02—Inorganic compounds
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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
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Abstract
本发明公开了一种硝酸2‑(4‑甲基噻唑‑5‑基)乙酯盐酸盐鼻喷剂及其制备方法，所述鼻喷剂各组分重量百分含量如下：硝酸2‑(4‑甲基噻唑‑5‑基)乙酯盐酸盐1％～15％、烟酸不少于0.01％、聚乙二醇不少于1％、硫酸锌0.002％～0.01％、抗氧剂0.005％～0.05％、渗透压调节剂2％～5％、余量为纯化水，pH调节至4.5～6.0。本发明提供了一种稳定的硝酸2‑(4‑甲基噻唑‑5‑基)乙酯盐酸盐鼻喷剂，经鼻腔给药，解决了患者吞咽不便的问题，提高了临床顺应性，起效快，避免口服给药的首关效应。本发明提供的硝酸2‑(4‑甲基噻唑‑5‑基)乙酯盐酸盐鼻喷剂吸收良好，生物利用度高，产品稳定性高。The invention discloses a 2-(4-methylthiazole-5-yl)ethyl nitrate hydrochloride nasal spray and a preparation method thereof, wherein the weight percentage of each component of the nasal spray is as follows: 1% to 15% of 2-(4-methylthiazole-5-yl)ethyl nitrate hydrochloride, not less than 0.01% of nicotinic acid, not less than 1% of polyethylene glycol, 0.002% to 0.01% of zinc sulfate, 0.005% to 0.05% of antioxidant, 2% to 5% of osmotic pressure regulator, and the remainder is purified water, and the pH is adjusted to 4.5 to 6.0. The invention provides a stable 2-(4-methylthiazole-5-yl)ethyl nitrate hydrochloride nasal spray, which is administered through the nasal cavity, solves the problem of inconvenience in swallowing for patients, improves clinical compliance, takes effect quickly, and avoids the first pass effect of oral administration. The 2-(4-methylthiazole-5-yl)ethyl nitrate hydrochloride nasal spray provided by the invention has good absorption, high bioavailability, and high product stability.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride nasal spray and a preparation method thereof.
Background
The 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride is white or white-like crystalline powder, the melting point is 108-110 ℃, the product is very soluble in water, methanol, ethanol, acetone, diethyl ether, ethyl acetate and dichloromethane. The structural formula is as follows:
2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride is useful for preventing and/or treating cardiovascular and cerebrovascular diseases and neurodegenerative diseases by alleviating neurodegeneration, neuroprotection and/or cognitive enhancement in an individual.
Such patients are often elderly and have problems with swallowing inconvenience, with oral administration not being the optimal choice. Administration by injection avoids the inconvenience of swallowing, however administration by injection is often required by a professional caretaker, and in addition, long-term administration may cause damage to the skin, and some patients are fear of "puncturing" and thus are not optimal.
If the 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride is developed into a nasal spray product, the clinical compliance can be greatly improved by nasal administration. In addition, nasal administration can avoid the first pass effect of oral administration, and has the advantages of quick response, high bioavailability and the like.
However, due to the existence of nasal mucosa barrier, the drug often has difficulty in achieving ideal absorption effect, resulting in low bioavailability, and in addition, the drug in solution state has poor stability, which limits the development of the dosage form.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides the 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride nasal spray and the preparation method thereof, which realize that the nasal spray is absorbed by nasal mucosa to enter body fluid circulation, and have the advantages of quick response and suitability for dysphagia patients. The invention surprisingly discovers that the synergistic effect of nicotinic acid and polyethylene glycol can increase the absorption of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride through nasal mucosa, and zinc sulfate can enhance the stability of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride. In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a 2- (4-methylthiazole-5-yl) ethyl nitrate hydrochloride nasal spray, which comprises the following components in percentage by weight:
1% -15% of nitric acid 2- (4-methylthiazol-5-yl) ethyl ester hydrochloride, not less than 0.01% of nicotinic acid, not less than 1% of polyethylene glycol, 0.002% -0.01% of zinc sulfate, 0.005% -0.05% of antioxidant, 2% -5% of osmotic pressure regulator and the balance of purified water, wherein the pH value is regulated to 4.5-6.0.
Polyethylene glycol is a common nasal spray auxiliary material, and is used as an absorption accelerator, and nicotinic acid is also added, so that the bioavailability of the product can be greatly improved under the combined action of the polyethylene glycol and the absorption accelerator.
As a preferable scheme, the weight percentage of the nicotinic acid is 0.01% -0.5%.
As a preferable scheme, the weight percentage of the polyethylene glycol is 1% -10%, and more preferably 3% -6%.
The polyethylene glycol is selected from at least one of polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000 or polyethylene glycol 2000, preferably polyethylene glycol 400 or polyethylene glycol 600.
Preferably, the antioxidant is one or more of sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, thiourea, vitamin C and cysteine.
The pH value is regulated by a pH regulator, wherein the pH regulator is one or more selected from sodium citrate, sodium hydroxide, potassium hydroxide, sodium phosphate, sodium hydrophosphate, sodium carbonate and sodium bicarbonate.
The osmotic pressure regulator is one or more of sodium chloride, glycerol, anhydrous glucose, potassium chloride, sorbitol and mannitol.
The solvent is one or more selected from ethanol and purified water.
The invention relates to a 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride nasal spray, which also comprises a preservative, wherein the preservative is at least one of potassium sorbate, benzalkonium chloride, phenethyl alcohol and benzyl alcohol.
The 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride nasal spray disclosed by the invention can be prepared by adopting the following method, and comprises the following steps of:
1) Adding 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, nicotinic acid, polyethylene glycol, zinc sulfate, an antioxidant, a pH regulator, a preservative and an osmotic pressure regulator into purified water according to the prescription amount, stirring and dissolving to prepare a liquid medicine;
2) And (5) filling the liquid medicine into a nasal spray bottle.
The 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride nasal spray can be used for preventing and/or treating cardiovascular and cerebrovascular diseases and neurodegenerative diseases.
Compared with the prior art, the invention has the beneficial effects that:
The invention provides a stable 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride nasal spray, which is administered through nasal cavity, solves the problem of dysphagia of patients, improves clinical compliance, has quick response and avoids the first pass effect of oral administration;
The formula provided by the invention obviously improves the blood concentration of the medicine through the synergistic effect of the nicotinic acid and the polyethylene glycol, achieves the good absorption effect of the medicine and has high bioavailability, meanwhile, the invention adopts the zinc sulfate which is an unusual ingredient of the nasal spray, realizes the long-term storage stability of the medicine, ensures the reliable quality of the product in the service life, and provides a new thought for the prescription research and development of the nasal spray.
Detailed Description
The technical scheme of the invention is further described in detail below with reference to specific examples and data. It should be understood that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way. The terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art unless otherwise indicated.
In the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
The invention provides a preparation method of a 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride nasal spray, which comprises the following steps:
1) Adding 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, nicotinic acid, polyethylene glycol, zinc sulfate, an antioxidant, a pH regulator, a preservative and an osmotic pressure regulator into purified water according to the prescription amount, stirring and dissolving to prepare the liquid medicine.
2) And (5) filling the liquid medicine into a nasal spray bottle.
As an alternative embodiment, the antioxidant is an antioxidant commonly used in the pharmaceutical field, and one or a combination of several of sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, thiourea, vitamin C, cysteine and the like can be used.
As an alternative embodiment, the pH adjuster is selected from one or a combination of several of sodium citrate, sodium hydroxide, potassium hydroxide, sodium phosphate, sodium hydrogen phosphate, sodium carbonate, and sodium bicarbonate.
As an alternative embodiment, the osmotic pressure regulator is one or a combination of several of sodium chloride, glycerol, anhydrous glucose, potassium chloride, sorbitol, mannitol.
As an alternative embodiment, the solvent is selected from one or a combination of several of ethanol and purified water.
As an alternative embodiment, the preservative is at least one of potassium sorbate, benzalkonium chloride, phenethyl alcohol, and benzyl alcohol.
As an alternative example, the weight percentage of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride as an active ingredient may be 1%, 5%, 10%, 15% and the values therebetween, the weight percentage of niacin may be 0.01%, 0.1%, 0.3%, 0.5% and the values therebetween, the weight percentage of polyethylene glycol may be 1%, 3%, 6%, 10% and the values therebetween, the weight percentage of zinc sulfate may be 0.002%, 0.006%, 0.01% and the values therebetween, the weight percentage of antioxidant may be 0.005%, 0.01%, 0.05% and the values therebetween, and the weight percentage of osmotic pressure regulator may be 2%, 3%, 5% and the values therebetween.
Examples 1 to 5A nasal spray of 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride
The preparation method comprises the following steps:
1. Referring to table 1, 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, nicotinic acid, polyethylene glycol 400, sodium bisulphite, glycerin, potassium sorbate and the like were added to purified water, and dissolved with stirring, and pH was adjusted with sodium hydroxide solution to prepare a medicinal liquid.
2. And (5) filling the liquid medicine into a nasal spray bottle.
Table 1 prescriptions for comparative examples 1-2 and examples 1-5
Rat pharmacokinetic assay:
The main pharmacokinetic parameters of each test animal, namely the peak reaching time, the maximum blood concentration and the AUC 0～t, were measured by selecting 20 rats, each half of the male and female rats, and dividing the rats into 5 groups, wherein each group is 4 rats (the ratio of male to female is 1:1), and the administration of the rats is carried out at a dose of 10mg/kg, and the measurement results are shown in the following table 2.
TABLE 2 results of rat pharmacokinetic experiments
As shown in Table 2, the bioavailability is poor when nicotinic acid and polyethylene glycol are added separately in comparative examples 1 and 2, and the bioavailability is greatly improved when the nicotinic acid and the polyethylene glycol are added simultaneously, and when the mass percentage of the nicotinic acid in the nasal spray is within the range of 0.01% -0.5%, the mass percentage of the polyethylene glycol in the nasal spray is within the range of 1% -10%, the bioavailability of the nasal spray can be greatly improved, thereby playing a good absorption promoting role. And the absorption effect is better along with the increase of the dosage.
Examples 6-8 Effect of different polyethylene glycol types on the bioavailability of nasal sprays according to the invention
Samples were prepared using polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 2000 and subjected to rat pharmacokinetic experiments (administered at about 10 mg/kg) as prescribed in example 3, and the results are shown in Table 3, wherein polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 2000 are example 6, example 7, and example 8, respectively.
TABLE 3 Effect of different polyethylene glycol models on the bioavailability of nasal sprays according to the present invention
As can be seen from Table 3, better bioavailability can be achieved with different types of polyethylene glycol.
Examples 9 to 13 influence of different amounts of Zinc sulphate on the stability of nasal sprays according to the invention
The product is a solution type nasal spray, the stability of the 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride is poor, and the unexpected discovery in the research is that the stability of the product can be improved by adding zinc sulfate into the prescription.
With reference to the recipe of example 3, different amounts of zinc sulfate were designed, see Table 4.
TABLE 4 Effect of different amounts of Zinc sulfate on the stability of nasal sprays according to the present invention
The samples prepared by the prescription are placed in a stability inspection box for acceleration test (the temperature is 40 ℃ plus or minus 2 ℃ and the humidity is 75% plusor minus 5%), and the stability of the products is inspected by detecting key indexes at the time of 0,1 and 3 months respectively. 0. The stability results at 3 months are shown in Table 5.
Table 5 stability investigation results
The results in Table 5 show that the zinc sulfate dosage is in the range of 0.002% -0.01%, and the sample stability is good after accelerating for 3 months.
Comparative examples influence of other commonly used absorption promoters on the bioavailability of nasal sprays according to the present invention
Examples of the absorption enhancer include cyclodextrins (methyl beta cyclodextrin, dimethyl beta cyclodextrin, hydroxypropyl beta cyclodextrin), bile salts (bezoar cholate, hepatocholate), fatty acids and esters thereof (lauric acid, oleic acid), alcohols (lauryl alcohol, propylene glycol), sulfoxides (dimethyl sulfoxide, dimethylformamide), surfactants (polysorbate, sodium dodecyl sulfate), salicylic acids (sodium salicylate), protease inhibitors (azone), and chitosan.
The rat pharmacokinetics test (about 10mg/kg administration) using the commonly used different types of absorption promoters such as hydroxypropyl beta cyclodextrin, bezoar cholate, polysorbate 80, oleic acid, etc., did not achieve the ideal bioavailability effect, the prescription is shown in Table 6, and the bioavailability results are shown in Table 7.
Table 6 contains a comparative example of other commonly used pro-absorbents
The preparation method comprises the following steps:
1. Referring to table 6, 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride, an absorption accelerator, sodium bisulphite, zinc sulfate, glycerin, potassium sorbate and the like were added to purified water, and dissolved by stirring, and pH was adjusted with sodium hydroxide solution to prepare a medicinal solution.
2. And (5) filling the liquid medicine into a nasal spray bottle.
TABLE 7 Effect of different pro-absorbers on bioavailability
It can be seen that, for 2- (4-methylthiazol-5-yl) ethyl nitrate hydrochloride nasal spray, the bioavailability is low when several commonly used absorption promoters are adopted, and the full absorption and utilization of the medicine cannot be ensured.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
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