CN116850159A - Levalbutamol hydrochloride aerosol inhalation solution composition and preparation method thereof - Google Patents
Levalbutamol hydrochloride aerosol inhalation solution composition and preparation method thereof Download PDFInfo
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- 239000000203 mixture Substances 0.000 title claims abstract description 37
- 239000000443 aerosol Substances 0.000 title claims abstract description 31
- 229940041682 inhalant solution Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims description 19
- OWNWYCOLFIFTLK-YDALLXLXSA-N 4-[(1r)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;hydron;chloride Chemical compound Cl.CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 OWNWYCOLFIFTLK-YDALLXLXSA-N 0.000 claims abstract description 58
- 239000003381 stabilizer Substances 0.000 claims abstract description 47
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229940087642 levalbuterol hydrochloride Drugs 0.000 claims abstract description 30
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 230000003204 osmotic effect Effects 0.000 claims abstract description 22
- OPGYRRGJRBEUFK-UHFFFAOYSA-L disodium;diacetate Chemical compound [Na+].[Na+].CC([O-])=O.CC([O-])=O OPGYRRGJRBEUFK-UHFFFAOYSA-L 0.000 claims abstract description 16
- 229960005219 gentisic acid Drugs 0.000 claims abstract description 16
- 239000001632 sodium acetate Substances 0.000 claims abstract description 16
- 235000017454 sodium diacetate Nutrition 0.000 claims abstract description 16
- 239000000243 solution Substances 0.000 claims description 53
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000008215 water for injection Substances 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- 229940124274 edetate disodium Drugs 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 4
- 239000004973 liquid crystal related substance Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 28
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 14
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 abstract description 6
- 241000289690 Xenarthra Species 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000003860 storage Methods 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000002035 prolonged effect Effects 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 13
- 239000003708 ampul Substances 0.000 description 11
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 7
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical group O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- CXAKAZXGEIIFTO-UHFFFAOYSA-N 5-[2-(tert-butylamino)-1-hydroxyethyl]-3-(hydroxymethyl)benzene-1,2-diol Chemical compound CC(C)(C)NCC(O)C1=CC(O)=C(O)C(CO)=C1 CXAKAZXGEIIFTO-UHFFFAOYSA-N 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 229960002052 salbutamol Drugs 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 239000000924 antiasthmatic agent Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- RNGYKBNYRUYCIV-LBPRGKRZSA-N 5-[(1R)-2-(tert-butylamino)-1-hydroxyethyl]-2-hydroxybenzaldehyde Chemical compound CC(C)(C)NC[C@H](O)C1=CC=C(O)C(C=O)=C1 RNGYKBNYRUYCIV-LBPRGKRZSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
Abstract
The invention provides a levalbuterol hydrochloride aerosol inhalation solution composition and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The composition comprises levosalbutamol hydrochloride, a co-stabilizer, an osmotic pressure regulator, a pH regulator and a solvent, disodium edentate, gentisic acid and sodium diacetate are taken as the co-stabilizer, the stability of the composition is improved and the storage time is prolonged through the action of the co-stabilizer, and the composition simplifies the preparation process under the protection of no nitrogen charging, reduces the requirement on production equipment, and is simple and easy to operate and low in production cost.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a levalbuterol hydrochloride aerosol inhalation solution composition and a preparation method thereof.
Background
Asthma is the most common respiratory disease in the world at present, and has high prevalence. Currently, the medicines for controlling asthma mainly comprise beta 2 receptor agonists, glucocorticoids, systemic hormones and the like, wherein the beta 2 receptor agonists are the most widely clinically applied anti-asthma medicines, and account for about 60% of the market share of the anti-asthma medicines. At present, in the treatment of bronchial asthma at home and abroad, the racemized salbutamol takes a significant role. In vitro studies show that the affinity of albuterol levorotatory with beta receptor is 100 times stronger than that of dextrorotatory, and most of the physiological effects of racemate are provided by levorotatory; in addition, the dextroabutamol can cause adverse reactions such as headache, dizziness, palpitation, tremble fingers and the like. Clinical studies show that compared with the raceme thereof, the levalbuterol hydrochloride has the advantages of high curative effect, slight side effect and good tolerance.
In 3 1999, the U.S. Food and Drug Administration (FDA) approved the replacement of racemic salbutamol with levosalbutamol hydrochloride for use in the treatment of asthma, and therefore the replacement of existing racemic drugs with single optically active forms is a necessary trend for clinical use. According to the United states pharmacopoeia standard, the levalbuterol hydrochloride is atomized and inhaled into the solution, the 5-hydroxy albuterol is less than or equal to 0.10 percent, and the impurity D is less than or equal to 0.08 percent.
The structural formula of the impurity D is as follows:
(R) -5- [2- (tert-butylamino) -1-hydroxyethyl ] -2-hydroxybenzaldehyde
The components of the patent US6451289B are levosalbutamol hydrochloride, sodium chloride and water for injection. The patent discloses a preparation method of a levalbuterol hydrochloride aerosol inhalation solution, wherein nitrogen is needed to replace oxygen from the solution in the preparation process until dissolved oxygen is less than 1ppm, and the headspace of a filled product needs to be protected by nitrogen filling, and then the residual oxygen in a container is ensured to be less than 2% in an aluminum plastic film which is packaged and is impermeable to oxygen. The nitrogen filling of the liquid preparation tank, the nitrogen filling of the headspace of the low-density polyethylene ampoule and the nitrogen filling protection in the aluminum plastic bag have certain difficulty in production, and the damage and the leakage are easy to cause in the transportation process.
A levalbuterol hydrochloride solution preparation for inhalation of Chinese patent CN110898039A and a preparation method thereof comprise the following steps: levalbuterol hydrochloride, and/or hydrates thereof; osmotic pressure regulator; a pH regulator; stabilizer and solvent the levalbuterol hydrochloride solution preparation for inhalation provided by the invention. In this patent, by using sodium bisulphite, sodium sulfite, sodium metabisulfite, sodium thiosulfate or acetylcysteine as a stabilizer, nitrogen protection is not required during encapsulation, but the levalbuterol hydrochloride solution preparation can reach about 0.256% in total after 30 days of storage at 40 ℃, and there is no mention about the inhibition of the increase of impurity D, because the stability of the levalbuterol hydrochloride solution preparation of this patent is still to be improved.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a levalbuterol hydrochloride aerosol inhalation solution composition and a preparation method thereof.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides a levalbuterol hydrochloride aerosol inhalation solution composition, which comprises levalbuterol hydrochloride, a co-stabilizer, an osmotic pressure regulator, a pH regulator and a solvent; wherein, the liquid crystal display device comprises a liquid crystal display device,
the co-stabilizer is edetate disodium, gentisic acid and sodium diacetate.
Further, the levosalbutamol hydrochloride aerosol inhalation solution composition comprises 0.033mg/mL-0.500mg/mL of levosalbutamol hydrochloride, 0.050mg/mL-0.500mg/mL of co-stabilizer and 5.00mg/mL-15.00mg/mL of osmotic pressure regulator, and is adjusted to a pH value of 3.30-4.50 by the pH regulator, and the balance is solvent.
Preferably, the levosalbutamol hydrochloride aerosol inhalation solution composition comprises 0.103mg/mL-0.417mg/mL of levosalbutamol hydrochloride, 0.067mg/mL-0.133mg/mL of co-stabilizer, 8.00mg/mL-10.000mg/mL of osmotic pressure regulator, and is adjusted to a pH value of 3.70-4.30 by a pH regulator, and the balance is solvent.
More preferably, the levosalbutamol hydrochloride aerosol inhalation solution composition comprises 0.360mg/mL levosalbutamol hydrochloride, 0.100mg/mL co-stabilizer, 9.000mg/mL osmotic pressure regulator, and is adjusted to a pH value of 4.11 by a pH regulator, the remainder being solvent.
Preferably, in the co-stabilizer, the weight ratio of edetate disodium, gentisic acid and sodium diacetate is 1:0.5-1.2:0.3-0.7. Further, the weight ratio of edetate disodium to gentisic acid to sodium diacetate is 1:0.7-0.9:0.4-0.6. More preferably, the weight ratio of edetate disodium, gentisic acid and sodium diacetate is 1:0.77:0.44.
Preferably, the osmolality adjusting agent is an inorganic salt; the inorganic salt is at least one of sodium chloride, magnesium chloride or calcium chloride.
Preferably, the pH adjuster is an acid; the acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid or citric acid.
Preferably, the solvent is water for injection.
The single dose of the levalbuterol hydrochloride aerosol inhalation solution composition of the present invention is 3mL.
The invention also provides a preparation method of the levalbuterol hydrochloride aerosol inhalation solution composition, which comprises the following steps:
s1, adding an osmotic pressure regulator and a co-stabilizer into a solvent for dissolution to obtain a solution A;
s2, regulating the pH value of the solution A to a target value by using a pH regulator to obtain a solution B;
s3, adding levosalbutamol hydrochloride into the solution B, and then adding a solvent to fix the volume to obtain a solution C;
s4, filtering the solution C to obtain the product.
Further, in the step S1, the temperature of the solvent is less than or equal to 30 ℃; preferably, the temperature of the solvent is 10-25 ℃.
Further, in the step S2, the target value of the pH is 3.3-4.5; preferably, the target value of the pH is 3.7-4.3.
Further, in the step S4, the filtering refers to filtering by a microporous filter membrane with the pore diameter less than or equal to 3 μm; preferably, the filtration means two times filtration with a microporous filter membrane having a pore size of 0.22 μm.
Compared with the prior art, the invention has the following beneficial effects:
(1) The stability of the levosalbutamol hydrochloride aerosol inhalation solution composition is improved under the action of the co-stabilizer, 5-hydroxy salbutamol and impurity D are not detected after the composition is stored for 6 months at 40 ℃, and the total impurity is less than or equal to 0.08%, so that the stability of the levosalbutamol hydrochloride aerosol inhalation solution composition can be greatly improved, and the storage time is prolonged;
(2) The levalbuterol hydrochloride aerosol inhalation solution composition is sealed under the protection of no nitrogen filling, so that the preparation process is simplified, the requirements on production equipment are reduced, the operation is simple and easy, the production cost is low, and the industrial production is easy.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way. The following is merely exemplary of the scope of the invention as claimed and many variations and modifications of the invention will be apparent to those skilled in the art in light of the disclosure, which are intended to be within the scope of the invention as claimed.
The invention is further illustrated by means of the following specific examples. The various chemical reagents used in the examples of the present invention were obtained by conventional commercial means unless otherwise specified.
Example 1
Levalbutamol hydrochloride aerosol inhalation solution composition
Prescription: 0.033mg/mL of levosalbutamol hydrochloride, 0.050mg/mL of co-stabilizer and 5.00mg/mL of sodium chloride, and the balance of water for injection through hydrochloric acid until the pH value is 3.30.
The co-stabilizer is disodium edentate, gentisic acid and sodium diacetate with the mass ratio of 1:1.2:0.7.
The preparation method comprises the following steps:
s1, adding an osmotic pressure regulator and a co-stabilizer into a solvent with the volume of 50% of the unit dose according to the prescription amount to obtain a solution A; wherein the single dose volume of this example is 3mL; the prescription amount is based on the volume of single dose, and the corresponding addition amount is obtained according to the corresponding concentration of the levalbuterol hydrochloride, the co-stabilizer and the osmotic pressure regulator;
s2, adjusting the pH value of the solution A to 3.30 by using hydrochloric acid to obtain a solution B;
s3, adding levosalbutamol hydrochloride into the solution B according to the prescription amount, and then adding water for injection to the unit dosage volume to obtain a solution C;
s4, filtering the solution C for 2 times by using a filter membrane with the aperture of 0.22 mu m, transferring the solution C into an ampoule, and directly sealing the ampoule under the condition of no nitrogen filling.
Example 2
Levalbutamol hydrochloride aerosol inhalation solution composition
Prescription: 0.500mg/mL of levosalbutamol hydrochloride, 0.500mg/mL of co-stabilizer, 15.00mg/mL of sodium chloride, and the balance of water for injection by sulfuric acid until the pH value is 4.50.
The co-stabilizer is disodium edentate, gentisic acid and sodium diacetate with the mass ratio of 1:0.5:0.3.
The preparation method comprises the following steps:
s1, adding an osmotic pressure regulator and a co-stabilizer into a solvent with the volume of 90% of the unit dose according to the prescription amount to obtain a solution A; wherein the single dose volume of this example is 3mL; the prescription amount is based on the volume of single dose, and the corresponding addition amount is obtained according to the corresponding concentration of the levalbuterol hydrochloride, the co-stabilizer and the osmotic pressure regulator;
s2, regulating the pH value of the solution A to 4.50 by using sulfuric acid to obtain a solution B;
s3, adding levosalbutamol hydrochloride into the solution B according to the prescription amount, and then adding water for injection to the unit dosage volume to obtain a solution C;
s4, filtering the solution C for 2 times by using a filter membrane with the aperture of 0.22 mu m, transferring the solution C into an ampoule, and directly sealing the ampoule under the condition of no nitrogen filling.
Example 3
Levalbutamol hydrochloride aerosol inhalation solution composition
Prescription: 0.103mg/mL of levosalbutamol hydrochloride, 0.067mg/mL of co-stabilizer, 8.000mg/mL of calcium chloride, and the balance of water for injection by phosphoric acid until the pH value is 3.75.
The co-stabilizer is disodium edentate, gentisic acid and sodium diacetate with the mass ratio of 1:0.7:0.4.
The preparation method comprises the following steps:
s1, adding an osmotic pressure regulator and a co-stabilizer into a solvent with the volume of 80% of the unit dose according to the prescription amount to obtain a solution A; wherein the single dose volume of this example is 3mL; the prescription amount is based on the volume of single dose, and the corresponding addition amount is obtained according to the corresponding concentration of the levalbuterol hydrochloride, the co-stabilizer and the osmotic pressure regulator;
s2, regulating the pH value of the solution A to 3.75 by using phosphoric acid to obtain a solution B;
s3, adding levosalbutamol hydrochloride into the solution B according to the prescription amount, and then adding water for injection to the unit dosage volume to obtain a solution C;
s4, filtering the solution C for 2 times by using a filter membrane with the aperture of 0.22 mu m, transferring the solution C into an ampoule, and directly sealing the ampoule under the condition of no nitrogen filling.
Example 4
Levalbutamol hydrochloride aerosol inhalation solution composition
Prescription: 0.500mg/mL of levosalbutamol hydrochloride, 0.500mg/mL of co-stabilizer, 15.00mg/mL of sodium chloride, and the balance of water for injection, wherein the pH value is 4.32 through citric acid.
The co-stabilizer is disodium edentate, gentisic acid and sodium diacetate with the mass ratio of 1:0.9:0.6.
The preparation method comprises the following steps:
s1, adding an osmotic pressure regulator and a co-stabilizer into a solvent with 79% of the unit dosage volume according to the prescription amount to obtain a solution A; wherein the single dose volume of this example is 3mL; the prescription amount is based on the volume of single dose, and the corresponding addition amount is obtained according to the corresponding concentration of the levalbuterol hydrochloride, the co-stabilizer and the osmotic pressure regulator;
s2, adjusting the pH value of the solution A to 4.32 by using citric acid to obtain a solution B;
s3, adding levosalbutamol hydrochloride into the solution B according to the prescription amount, and then adding water for injection to the unit dosage volume to obtain a solution C;
s4, filtering the solution C for 2 times by using a filter membrane with the aperture of 0.22 mu m, transferring the solution C into an ampoule, and directly sealing the ampoule under the condition of no nitrogen filling.
Example 5
Levalbutamol hydrochloride aerosol inhalation solution composition
Prescription: 0.360mg/mL of levosalbutamol hydrochloride, 0.100mg/mL of co-stabilizer, 9.00mg/mL of sodium chloride, and the balance of water for injection through hydrochloric acid until the pH value is 4.11.
The co-stabilizer is disodium edetate, gentisic acid and sodium diacetate with the mass ratio of 1:0.77:0.44.
The preparation method comprises the following steps:
s1, adding an osmotic pressure regulator and a co-stabilizer into a solvent with the volume of 65% of the unit dose according to the prescription amount to obtain a solution A; wherein the single dose volume of this example is 3mL; the prescription amount is based on the volume of single dose, and the corresponding addition amount is obtained according to the corresponding concentration of the levalbuterol hydrochloride, the co-stabilizer and the osmotic pressure regulator;
s2, adjusting the pH value of the solution A to 4.11 by using hydrochloric acid to obtain a solution B;
s3, adding levosalbutamol hydrochloride into the solution B according to the prescription amount, and then adding water for injection to the unit dosage volume to obtain a solution C;
s4, filtering the solution C for 2 times by using a filter membrane with the aperture of 0.22 mu m, transferring the solution C into an ampoule, and directly sealing the ampoule under the condition of no nitrogen filling.
Comparative example 1
The comparative example differs from example 5 in that the weight ratio of edetate disodium, gentisic acid and sodium diacetate is 1:0.4:0.2, the remainder remaining as in example 5.
Comparative example 2
The difference between this comparative example and example 5 is that the weight ratio of edetate disodium, gentisic acid and sodium diacetate in the co-stabilizer is 1:1.5:1, the remainder remaining as in example 5.
Comparative example 3
The difference between this comparative example and example 5 is that disodium edentate is the co-stabilizer, and the remainder remains the same as example 5.
Comparative example 4
The difference between this comparative example and example 5 is that gentisic acid was used as the co-stabilizer, and the remainder was the same as example 5.
Comparative example 5
The difference between this comparative example and example 5 is that sodium diacetate was used as the co-stabilizer, and the remainder was kept the same as example 5.
Comparative example 6
The difference between this comparative example and example 5 is that no co-stabilizer was used, and the nitrogen-filled seal was made in S4 of the production method, and the remainder was kept the same as in example 5.
Experimental example
Stability test and investigation
The purpose of the stability experiments for examples 1-5 and comparative examples 1-6 is to examine the effect of different prescription amounts on the stability of the formulations by comparing the results of the tests of properties, pH, content, related substances, etc., according to the Chinese pharmacopoeia, and the results are shown in tables 1-3 below.
TABLE 1
The results show that: the levalbuterol hydrochloride aerosol inhalation solution compositions of examples 1 to 5 were not detected with 5-hydroxy albuterol and impurity D after storage at 40 ℃ for 6 months, and the total impurity was 0.08% or less, and thus the levalbuterol hydrochloride aerosol inhalation solution composition provided by the invention has excellent stability.
TABLE 2
The results show that: when the concentration and the dosage of the co-stabilizer which is not used in the levalbuterol hydrochloride aerosol inhalation solution are beyond the range of the invention, 5-hydroxy albuterol and impurity D are in a growing trend in the process of accelerating the stability for 0-6 months, and the total impurities are increased.
TABLE 3 Table 3
From the above table, it is clear that the levalbuterol hydrochloride aerosol inhalation solution does not use a stabilizer, or all components are added simultaneously in the preparation process, 5-hydroxy albuterol and impurity D are in a growing trend in the process of accelerating the stability for 0-6 months, and the total impurities are increased.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (10)
1. A levosalbutamol hydrochloride aerosol inhalation solution composition, which is characterized by comprising levosalbutamol hydrochloride, a co-stabilizer, an osmotic pressure regulator, a pH regulator and a solvent; wherein, the liquid crystal display device comprises a liquid crystal display device,
the co-stabilizer is edetate disodium, gentisic acid and sodium diacetate.
2. The composition of claim 1, wherein the composition comprises 0.033mg/mL to 0.500mg/mL of levosalbutamol hydrochloride, 0.050mg/mL to 0.500mg/mL of co-stabilizer and 5.00mg/mL to 15.00mg/mL of osmotic pressure regulator, and the composition is adjusted to a pH of 3.30 to 4.50 by pH regulator, and the remainder is solvent.
3. The composition of claim 2, comprising 0.103mg/mL to 0.417mg/mL of levosalbutamol hydrochloride, 0.067mg/mL to 0.133mg/mL of co-stabilizer and 8.00mg/mL to 10.000mg/mL of osmotic pressure regulator, and adjusted to a pH value of 3.70 to 4.30 by means of pH regulator, the remainder being solvent.
4. The levalbuterol hydrochloride aerosol inhalation solution composition according to claim 1, characterized in that the weight ratio of edetate disodium, gentisic acid and sodium diacetate in the co-stabilizer is 1:0.5-1.2:0.3-0.7.
5. The levalbuterol hydrochloride aerosol inhalation solution composition according to claim 4, wherein the weight ratio of edetate disodium, gentisic acid and sodium diacetate in the co-stabilizer is 1:0.7-0.9:0.4-0.6.
6. The levalbuterol hydrochloride aerosol inhalation solution composition according to any one of claims 1-5, wherein the osmotic pressure regulator is an inorganic salt;
the inorganic salt is at least one of sodium chloride, magnesium chloride or calcium chloride.
7. The levalbuterol hydrochloride aerosol inhalation solution composition according to any one of claims 1-5, wherein the pH adjuster is an acid;
the acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid or citric acid.
8. The levalbuterol hydrochloride aerosol inhalation solution composition according to any one of claims 1-5, wherein the solvent is water for injection.
9. A process for the preparation of an aerosol inhalation solution composition having levosalbutamol hydrochloride as claimed in any one of claims 1 to 8, wherein: comprising the following steps:
s1, adding an osmotic pressure regulator and a co-stabilizer into a solvent for dissolution to obtain a solution A;
s2, regulating the pH value of the solution A to a target value by using a pH regulator to obtain a solution B;
s3, adding levosalbutamol hydrochloride into the solution B, and then adding a solvent to fix the volume to obtain a solution C;
s4, filtering the solution C to obtain the product.
10. The method according to claim 9, wherein in step S1, the temperature of the solvent is equal to or less than 30 ℃.
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