CN116898799B - Desloratadine oral preparation and preparation method thereof - Google Patents
Desloratadine oral preparation and preparation method thereof Download PDFInfo
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- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960001271 desloratadine Drugs 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 69
- 239000011259 mixed solution Substances 0.000 claims abstract description 42
- 238000003756 stirring Methods 0.000 claims abstract description 38
- 239000003814 drug Substances 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 239000002738 chelating agent Substances 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 13
- 239000002562 thickening agent Substances 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 11
- 239000003765 sweetening agent Substances 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 230000008961 swelling Effects 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 24
- 238000009472 formulation Methods 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000000796 flavoring agent Substances 0.000 claims description 10
- 235000013355 food flavoring agent Nutrition 0.000 claims description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- 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 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004376 Sucralose Substances 0.000 claims description 4
- 241000289690 Xenarthra Species 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 239000001509 sodium citrate Substances 0.000 claims description 4
- 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 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 235000010356 sorbitol Nutrition 0.000 claims description 4
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 4
- 235000019408 sucralose Nutrition 0.000 claims description 4
- 101000801619 Homo sapiens Long-chain-fatty-acid-CoA ligase ACSBG1 Proteins 0.000 claims description 3
- 102100033564 Long-chain-fatty-acid-CoA ligase ACSBG1 Human genes 0.000 claims description 3
- 235000010634 bubble gum Nutrition 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical group OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
- 238000005286 illumination Methods 0.000 abstract description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 6
- 229960003943 hypromellose Drugs 0.000 description 5
- 229960004063 propylene glycol Drugs 0.000 description 5
- 235000013772 propylene glycol Nutrition 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000013557 residual solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000008372 bubblegum flavor Substances 0.000 description 2
- XUPYJHCZDLZNFP-UHFFFAOYSA-N butyl butanoate Chemical compound CCCCOC(=O)CCC XUPYJHCZDLZNFP-UHFFFAOYSA-N 0.000 description 2
- 229940113256 desloratadine oral solution Drugs 0.000 description 2
- 229940124274 edetate disodium Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical group C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 206010052568 Urticaria chronic Diseases 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- 229940117955 isoamyl acetate Drugs 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention belongs to the technical field of pharmacy, and particularly discloses a desloratadine oral preparation and a preparation method thereof. The preparation method comprises mixing chelating agent, sweetener and correctant, stirring for dissolving to obtain first mixed solution; adding a thickening agent into the first mixed solution, swelling, cooling, stirring and dissolving to form a second mixed solution; mixing the latent solvent and the pH regulator, adding the second mixed solution, and stirring and dissolving to obtain a third mixed solution; and adding the desloratadine crude drug into the third mixed solution, and stirring and dissolving to obtain the desloratadine oral preparation. The desloratadine oral preparation is stored at high temperature under illumination, the stability is greatly improved, the desloratadine oral preparation can be uniformly mixed for 10 seconds, and the desloratadine oral preparation has good content uniformity.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and in particular relates to a desloratadine oral preparation and a preparation method thereof.
Background
Desloratadine, its chemical name is: 8-chloro-11- (piperidin-4-alkylene) -6, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridine having the structural formula:
Desloratadine is a novel third generation antihistamine, a non-sedating long-acting histamine antagonist for alleviating systemic and local symptoms of chronic urticaria and allergic rhinitis. The medicament taking the desloratadine as the active ingredient has the advantages of quick response, strong efficacy, no cardiotoxicity, less side effects of the medicament, no food contraindication and the like.
However, because desloratadine is hardly soluble in water and is not resistant to high temperature and high humidity, and is sensitive to light irradiation, and is easily oxidized in air to deteriorate, desloratadine is generally prepared into oral preparations, including solutions, capsules, tablets, syrups, dry suspensions and dispersible tablets. For example, chinese patent application CN114588106a discloses a desloratadine oral solution preparation and a preparation production process thereof, wherein the preparation is composed of desloratadine bulk drug and auxiliary materials; the preparation and production steps of the preparation and production of the medicine sequentially dissolve disodium edentate, hypromellose and other auxiliary materials including sorbitol, sucralose, citric acid, sodium citrate and bubble gum essence, and finally dissolve the raw material medicines of propylene glycol and desloratadine together to prepare concentrated preparation liquid. Manufactured by moesadong Co., ltdAs a reference preparation, the preparation produced by the invention has the same administration route, the same treatment period and the same indication, and is safe and reliable. For example, chinese patent application CN112220748a discloses a desloratadine oral liquid preparation and a preparation method thereof, wherein the desloratadine oral liquid preparation is an aqueous solution, and comprises desloratadine active ingredient, stabilizer, pharmaceutically acceptable auxiliary material and solvent water.
However, the uniformity of the content of the desloratadine in the prior art cannot meet the production requirement, and a long stirring time is required to make the content uniform, so that a preparation process capable of making the uniformity of the content of the desloratadine better is currently required.
Disclosure of Invention
As used herein, the singular forms "a," "an," and "the" include the singular and plural referents unless the context clearly dictates otherwise. The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that corresponding range, and the endpoints recited.
Aiming at the problems in the prior art, the invention provides a desloratadine oral preparation and a preparation method thereof, and the desloratadine oral preparation prepared by the preparation method has better stability and content uniformity.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides a preparation method of desloratadine oral preparation, which comprises the following steps:
s1, mixing a chelating agent, a sweetener and a flavoring agent, and stirring for dissolution to obtain a first mixed solution;
s2, adding a thickening agent into the first mixed solution, swelling, cooling, stirring and dissolving to form a second mixed solution;
S3, mixing the latent solvent and the pH regulator, adding the mixture into the second mixed solution, and stirring and dissolving the mixture to obtain a third mixed solution;
S4, adding desloratadine raw material medicines into the third mixed solution, and stirring and dissolving to obtain the desloratadine.
Preferably, the chelating agent of step S1 comprises disodium edentate, the sweetener comprises sorbitol and/or sucralose, and the flavoring agent comprises bubble gum flavor.
Preferably, the thickener of step S2 comprises hypromellose.
Preferably, the latent solvent in step S3 comprises propylene glycol, and the pH adjuster comprises citric acid and/or sodium citrate.
Preferably, the stirring conditions in step S1 are: the temperature is 60-70 ℃, the rotating speed is 50-100r/min, and the time is 2-3 minutes.
Preferably, the swelling time in the step S2 is 5-8 minutes, and the temperature of the cooling is 30-40 ℃.
Preferably, the stirring conditions in step S2 are: the rotating speed is 50-100r/min, and the time is 30-40 minutes.
Preferably, the stirring conditions in step S3 are: the temperature is 30-35 ℃, the rotating speed is 50-100r/min, and the time is 30-40 minutes.
Preferably, the stirring conditions in step S4 are: the temperature is 0-20 ℃, the rotating speed is 50-100r/min, and the time is 1-2 hours.
The invention also provides a desloratadine oral preparation prepared by the preparation method.
Preferably, the desloratadine oral preparation consists of desloratadine bulk drugs and auxiliary materials, wherein the auxiliary materials comprise chelating agents, thickening agents, latent solvents, sweeteners, pH regulators and flavoring agents.
Preferably, the chelating agent comprises disodium edentate, the sweetener comprises sorbitol and/or sucralose, the flavoring agent comprises bubble gum flavor, the thickening agent comprises hypromellose, the latent solvent comprises propylene glycol, and the pH regulator comprises citric acid and/or sodium citrate.
Preferably, the mass ratio of the desloratadine bulk drug to the thickener to the chelating agent is 1:2-6:0.5-1.5.
Compared with the prior art, the invention has the following beneficial effects:
the desloratadine oral preparation prepared by the method is stored at high temperature under illumination, so that the stability is greatly improved, and the stability of the preparation is ensured under the condition that impurities are not abnormally increased; the desloratadine oral preparation prepared by the preparation process provided by the invention can be stirred for 10 seconds to ensure that the desloratadine oral preparation is uniform in content and good in content uniformity.
Detailed Description
The following description of the present invention is provided by way of specific examples to facilitate understanding and grasping of the technical solution of the present invention, but the present invention is not limited thereto, and the described examples are only some, but not all, examples of the present invention.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, shall fall within the scope of the invention. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials, unless otherwise specified, are commercially available.
It should be noted that:
Raw material purchase information in the present invention: desloratadine drug substance (manufacturer: morepen Laboratories ltd. (india), record No. Y20170000139, execution standard is internal control quality standard).
The bubble gum essence mainly comprises propylene glycol, isoamyl acetate, isobutyl acetate and butyl butyrate.
Example 1 preparation method of Desloratadine oral preparation
The preparation method of the desloratadine oral preparation comprises the following steps:
the formulation of desloratadine oral formulation is shown in table 1;
s1, mixing a chelating agent, a sweetener, a flavoring agent and 75% of a solvent, and stirring at 65 ℃ for 2 minutes to dissolve the mixture to obtain a first mixed solution;
S2, adding a thickening agent into the first mixed solution, swelling for 6 minutes, cooling to 35 ℃, stirring for 35 minutes at 100r/min, and dissolving to form a second mixed solution;
S3, mixing the latent solvent and the pH regulator, adding the mixture into the second mixed solution, stirring at 32 ℃ for 35 minutes and dissolving at 100r/min to obtain a third mixed solution;
S4, adding the desloratadine bulk drug and the residual solvent into the third mixed solution, and stirring at 10 ℃ for 1.5 hours at 100r/min to dissolve the desloratadine bulk drug.
Table 1 table of formulations of desloratadine oral formulations in example 1
Example 2 preparation method of Desloratadine oral preparation
The preparation method of the desloratadine oral preparation comprises the following steps:
the formulation of desloratadine oral formulation is shown in table 2;
s1, mixing a chelating agent, a sweetener, a flavoring agent and 75% of a solvent, and stirring at 60 ℃ for 3 minutes at 100r/min to dissolve to obtain a first mixed solution;
S2, adding a thickening agent into the first mixed solution, swelling for 5 minutes, cooling to 30 ℃, stirring for 30 minutes at 100r/min, and dissolving to form a second mixed solution;
S3, mixing the latent solvent and the pH regulator, adding the mixture into the second mixed solution, stirring at 30 ℃ for 30 minutes at 100r/min, and dissolving to obtain a third mixed solution;
S4, adding the desloratadine bulk drug and the residual solvent into the third mixed solution, and stirring at 100r/min for 1.0 hour at the temperature of 0 ℃ to obtain the desloratadine.
Table 2 table of formulations of desloratadine oral formulations in example 2
Example 3 preparation method of Desloratadine oral preparation
The preparation method of the desloratadine oral preparation comprises the following steps:
The formulation of desloratadine oral formulation is shown in table 3;
S1, mixing a chelating agent, a sweetener, a flavoring agent and 75% of a solvent, and stirring at 70 ℃ for 3 minutes at 50r/min to dissolve to obtain a first mixed solution;
s2, adding a thickening agent into the first mixed solution, swelling for 8 minutes, cooling to 40 ℃, stirring for 40 minutes at 50r/min, and dissolving to form a second mixed solution;
S3, mixing the latent solvent and the pH regulator, adding the mixture into the second mixed solution, and stirring for 40 minutes at 35 ℃ for dissolving at 50r/min to obtain a third mixed solution;
s4, adding the desloratadine bulk drug and the residual solvent into the third mixed solution, and stirring for 2.0 hours at 20 ℃ for dissolution at 50r/min to obtain the desloratadine.
Table 3 table of formulations of desloratadine oral formulations in example 3
Comparative example 1 preparation method of desloratadine oral preparation
Compared with example 1, the only difference is that: the amounts of edetate disodium and hypromellose were different, the amount of edetate disodium of comparative example 1 was 2.4 mL/bottle, and the amount of hypromellose was 35.0 mL/bottle. Comparative example 2 preparation method of desloratadine oral preparation
The preparation method of the desloratadine oral preparation comprises the following steps:
the formulation of desloratadine oral formulation is shown in table 1;
S1, mixing a chelating agent with 75% of a solvent, and stirring at 65 ℃ for 2 minutes for dissolution at 100r/min to obtain a first mixed solution;
S2, adding a thickening agent into the first mixed solution, swelling for 6 minutes, cooling to 35 ℃, stirring for 35 minutes at 100r/min, and dissolving to form a second mixed solution;
S3, adding the sweetener, the pH regulator and the flavoring agent into the second mixed solution, stirring at 32 ℃ for 35 minutes and dissolving at 100r/min to obtain a third mixed solution;
S4, adding a latent solvent into the third mixed solution, cooling to 10 ℃, adding the desloratadine raw material medicine and the residual solvent, stirring for 1.5 hours at 100r/min, and dissolving to obtain the desloratadine.
Comparative example 3 preparation method of desloratadine oral preparation
Compared with example 1, the only difference is that: the latent solvent is 1, 2-propanediol.
Effect example
Examination of stability and content uniformity of desloratadine oral solutions of examples 1-3 and comparative examples 1-3, determination of related substances and content was performed by high-phase liquid chromatography (rule 0512 in the fourth edition of the chinese pharmacopoeia 2020), chromatographic conditions: octadecylsilane chemically bonded silica was used as a filler (YMC J' sphere ODS-M80.6 mm. Times.250 mm,4 μm); buffer salt solution (0.865 g of sodium dodecyl sulfate is taken, 1000ml of water is added, 0.5ml of trifluoroacetic acid is added, so that the sodium dodecyl sulfate is dissolved) -acetonitrile (57:43) is taken as a mobile phase; the flow rate is 1.0ml per minute; the detection wavelength is 280nm; the column temperature is 30 ℃; the sample volume was 10. Mu.l.
(1) Stability detection: according to the four guidelines 9001 of the Chinese pharmacopoeia of 2020 edition and the stability test guidelines of the preparation, the desloratadine oral solutions of examples 1-3 and comparative examples 1-3 are subjected to an influence factor test, the samples are placed at a high temperature of 60 ℃ under illumination conditions, and the samples are respectively detected according to stability key investigation projects when the samples are placed for 10 days and 30 days.
TABLE 4 stability test results at 60℃high temperature
TABLE 5 stability test results under illumination
By adopting the prescription process, a sample with stable quality can be prepared. Compared with the comparative example, the properties, pH and related substances of the composition are not obviously changed at high temperature of 60 ℃ under illumination, the stability is better, and the total impurities are not more than 0.1%.
(2) Acceleration test: the desloratadine oral solutions of examples 1-3 and comparative examples 1-3 were placed under accelerated test (temperature 40 ℃ + -2 ℃/humidity 75% + -5%) and sampled and assayed at 6 months.
TABLE 6 accelerated test results
The desloratadine oral preparation prepared by the preparation process has good stability, and the properties, pH and related substances in an acceleration test are not obviously changed, and the total impurities are not more than 0.1 percent.
(3) Content uniformity performance detection
10Ml of desloratadine oral solution preparations of the examples and the comparative examples are respectively taken, and after stirring for 10 seconds, 30 seconds and 60 seconds, upper layer, middle layer and lower layer of the liquid medicine are sampled, so that the uniformity of desloratadine content is studied.
TABLE 7 uniformity results
The desloratadine oral preparation prepared by the preparation method and the formula can be uniformly mixed for about 10 seconds (the content difference of the upper layer, the middle layer and the lower layer is not more than 1 percent), and the content uniformity is good.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (2)
1. A preparation method of desloratadine oral preparation, which is characterized in that: the method comprises the following steps:
s1, mixing a chelating agent, a sweetener and a flavoring agent, and stirring for dissolution to obtain a first mixed solution;
s2, adding a thickening agent into the first mixed solution, swelling, cooling, stirring and dissolving to form a second mixed solution;
S3, mixing the latent solvent and the pH regulator, adding the mixture into the second mixed solution, and stirring and dissolving the mixture to obtain a third mixed solution;
s4, adding desloratadine raw material medicines into the third mixed solution, and stirring and dissolving to obtain the desloratadine;
the chelating agent in the step S1 is disodium edentate, the sweetener is sorbitol and sucralose, and the flavoring agent is bubble gum essence; the thickener in the step S2 is hydroxypropyl methylcellulose; the latent solvent in the step S3 is 1, 3-propylene glycol, and the pH regulator is citric acid and/or sodium citrate;
the stirring conditions in the step S1 are as follows: the temperature is 60-70 ℃, the rotating speed is 50-100r/min, and the time is 2-3 minutes;
The swelling time in the step S2 is 5-8 minutes, and the temperature of the cooling is 30-40 ℃;
the stirring conditions in the step S2 are as follows: the rotating speed is 50-100r/min, and the time is 30-40 minutes; the stirring conditions in the step S3 are as follows: the temperature is 30-35 ℃, the rotating speed is 50-100r/min, and the time is 30-40 minutes;
the stirring conditions in the step S4 are as follows: the temperature is 0-20 ℃, the rotating speed is 50-100r/min, and the time is 1.0-2.0 hours;
The mass ratio of the desloratadine bulk drug to the thickener to the chelating agent is as follows: 1:2-6:0.5-1.5.
2. An oral desloratadine formulation characterized by: is prepared by the preparation method of claim 1.
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