CN118806761A - Loratadine oral preparation and preparation method thereof - Google Patents
Loratadine oral preparation and preparation method thereof Download PDFInfo
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- CN118806761A CN118806761A CN202411151146.6A CN202411151146A CN118806761A CN 118806761 A CN118806761 A CN 118806761A CN 202411151146 A CN202411151146 A CN 202411151146A CN 118806761 A CN118806761 A CN 118806761A
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- Prior art keywords
- loratadine
- oral
- methylparaben
- formulation
- tryptophan
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- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229960003088 loratadine Drugs 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 66
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims abstract description 78
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims abstract description 58
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims abstract description 39
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims abstract description 39
- 229960002216 methylparaben Drugs 0.000 claims abstract description 39
- JUXHBGFABDBELU-UHFFFAOYSA-N methyl benzoate;sodium Chemical compound [Na].COC(=O)C1=CC=CC=C1 JUXHBGFABDBELU-UHFFFAOYSA-N 0.000 claims abstract description 38
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000003381 stabilizer Substances 0.000 claims abstract description 22
- 229960004799 tryptophan Drugs 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 19
- 239000000796 flavoring agent Substances 0.000 claims abstract description 11
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 11
- 235000011187 glycerol Nutrition 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 10
- 239000004376 Sucralose Substances 0.000 claims abstract description 8
- 235000019408 sucralose Nutrition 0.000 claims abstract description 8
- 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 abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 37
- 239000000243 solution Substances 0.000 claims description 22
- 238000009472 formulation Methods 0.000 claims description 21
- 239000011259 mixed solution Substances 0.000 claims description 12
- 239000002131 composite material Substances 0.000 claims description 9
- 240000000851 Vaccinium corymbosum Species 0.000 claims description 8
- 235000003095 Vaccinium corymbosum Nutrition 0.000 claims description 8
- 235000017537 Vaccinium myrtillus Nutrition 0.000 claims description 8
- 235000021014 blueberries Nutrition 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 238000004806 packaging method and process Methods 0.000 claims description 6
- 244000241257 Cucumis melo Species 0.000 claims description 3
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 3
- 240000009088 Fragaria x ananassa Species 0.000 claims description 3
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 3
- 244000290333 Vanilla fragrans Species 0.000 claims description 3
- 235000009499 Vanilla fragrans Nutrition 0.000 claims description 3
- 235000012036 Vanilla tahitensis Nutrition 0.000 claims description 3
- 244000144730 Amygdalus persica Species 0.000 claims description 2
- 235000005979 Citrus limon Nutrition 0.000 claims description 2
- 244000131522 Citrus pyriformis Species 0.000 claims description 2
- 235000009847 Cucumis melo var cantalupensis Nutrition 0.000 claims description 2
- 235000006040 Prunus persica var persica Nutrition 0.000 claims description 2
- 235000011034 Rubus glaucus Nutrition 0.000 claims description 2
- 235000009122 Rubus idaeus Nutrition 0.000 claims description 2
- 239000003205 fragrance Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 244000235659 Rubus idaeus Species 0.000 claims 1
- 235000019640 taste Nutrition 0.000 abstract description 8
- 229940100688 oral solution Drugs 0.000 abstract description 5
- 238000002156 mixing Methods 0.000 abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000686 essence Substances 0.000 description 23
- 230000000052 comparative effect Effects 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 239000003814 drug Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000006188 syrup Substances 0.000 description 6
- 235000020357 syrup Nutrition 0.000 description 6
- 235000019658 bitter taste Nutrition 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229940003960 loratadine oral solution Drugs 0.000 description 4
- 239000000463 material Substances 0.000 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 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 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 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 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- NOEGNKMFWQHSLB-UHFFFAOYSA-N 5-hydroxymethylfurfural Chemical compound OCC1=CC=C(C=O)O1 NOEGNKMFWQHSLB-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 240000000560 Citrus x paradisi Species 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 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 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 240000007651 Rubus glaucus Species 0.000 description 1
- 206010052568 Urticaria chronic Diseases 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- RJGBSYZFOCAGQY-UHFFFAOYSA-N hydroxymethylfurfural Natural products COC1=CC=C(C=O)O1 RJGBSYZFOCAGQY-UHFFFAOYSA-N 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to an oral solution containing loratadine, belonging to the field of pharmaceutical preparations. The oral solution contains loratadine, a stabilizer and a flavoring agent, and is prepared by stirring the loratadine and hot glycerin, heating pure water to dissolve sodium methyl benzoate, L-tryptophan and methylparaben, mixing the above solutions, adding sucralose and the flavoring agent, stirring, filtering and split charging. The oral solution prepared by the invention has the characteristics of remarkably improved stability, good taste and high compliance of children, is simple in preparation process, is suitable for industrial production, and has wider market popularization value.
Description
Technical Field
The invention relates to a loratadine oral preparation and a preparation method thereof, belonging to the technical field of pharmaceutical preparations and preparation.
Background
Loratadine (loratadine) is a second generation antihistamine drug, is clinically used for improving or treating allergic symptoms, can be used for treating allergic rhinitis, chronic urticaria, allergic conjunctivitis, allergic asthma and the like, and is a common drug applicable to allergic diseases of children.
Currently, the formulations of loratadine on the market in China comprise tablets, syrups, oral liquids and the like. Because loratadine is almost insoluble in water, the phenomena of poor drug dissolution, slow onset of action and low bioavailability are common in solid pharmaceutical preparations.
In the liquid preparation, syrup and oral liquid are preparations with higher sweetness and higher medication compliance for children because of containing essence, but because of higher sucrose amount, sucrose is inevitably dehydrated at high temperature in the production process to generate 5-hydroxymethylfurfural, in addition, after long-term standing at normal temperature, the preparation has poor stability because of light, heat and other reasons, the loratadine is extremely easy to be converted into 2-hydroxymethylcloratadine and 4-hydroxymethylcloratadine impurities, and the color is changed, sediment is generated, gas or other phenomena are generated, so that related substances exceed standards.
The problems have great influence on the medication safety of children. Therefore, it is of great importance to find a loratadine customization agent which has higher dissolution rate and higher stability and is more suitable for children to take.
CN114788809B provides a light-stable loratadine liquid preparation, the auxiliary materials used are sucralose, glycerin, ethanol, tartaric acid, sorbitol, sodium chloride and hydroxypropyl methylcellulose, and the prepared liquid preparation has the advantages of being capable of being stored and transported in a transparent container without being packaged in a brown container for storage and transportation.
CN114767677B provides a loratadine syrup product, and the used auxiliary materials are benzoic acid, glycerol, propylene glycol, anhydrous citric acid, sucrose and essence, so that the impurity growth speed of the product is obviously lower than that of an original grinding preparation within 1 month (40 ℃ and 75% RH), and the stability is good.
CN104856948B provides a loratadine syrup product, using gamma-cyclodextrin as inclusion agent, using citric acid as PH regulator, using grapefruit essence or orange essence as corrigent, accelerating test at 60 deg.c for 10 days, the product character, PH value and impurity content are in accordance with requirements.
However, in view of the fact that syrups, oral liquids and the like are generally bottled, and the syrups, oral liquids and the like are not used up in time after unsealing and are stored at normal temperature, the improvement of the stability improvement degree, the types and the usage amount of auxiliary materials and the preparation process of the method still need to be further optimized.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a loratadine oral preparation and a preparation method thereof, which are used for overcoming the defects of the prior art, and experiments prove that the loratadine degradation condition is obviously improved, the stability of the medicament can be obviously prolonged, the bioavailability can be improved, the safety of children administration is ensured, and the preparation process is simple and suitable for industrial popularization.
The inventor tries to improve the stability of the product, and occasionally discovers that the environment of the active ingredients can be effectively improved when the adding sequence is regulated, which is beneficial to improving the stability of the medicine, and meanwhile discovers that the sodium methyl benzoate, L-tryptophan and methylparaben can synergistically exert the stabilization effect of the loratadine by regulating the type and the dosage of the stabilizer, so that the loratadine is not easy to decompose when stored under the conventional condition. Based on the above, the inventor verifies the technical effect of the invention through a large number of experiments, and finally provides the loratadine oral solution with satisfactory stability and taste.
The loratadine oral solution disclosed by the invention contains loratadine, a cosolvent, a stabilizer, a flavoring agent and purified water.
Furthermore, the cosolvent in the loratadine oral solution is hot glycerin, the stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the flavoring agent is sucralose.
The loratadine oral solution comprises the following components in percentage by weight:
the stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 0.5 to 1.5:2 to 5.
Preferably, the composition of the oral preparation is:
further, the stabilizer is prepared by mixing sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 1:3.5.
In addition, the oral preparation further comprises a flavoring agent, preferably, the flavoring agent is any one or more of blueberry essence, orange essence or strawberry essence, vanilla essence, cantaloupe essence, lemon essence, juicy peach essence and raspberry essence.
In terms of the weight ratio of the components, loratadine: fragrance = 1:5 to 15 hours.
Specifically, the composition of the oral preparation is as follows:
Further, the stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 1.5:2.
A second object of the present invention is to provide a method for preparing an oral preparation of loratadine, comprising the steps of:
(1) Heating glycerin, adding loratadine, and stirring to prepare a loratadine-glycerin mixed solution;
(2) Heating 1/2 pure water, adding sodium methyl benzoate, L-tryptophan and methylparaben in sequence while the pure water is hot, and stirring uniformly;
(3) Adding the mixed solution obtained in the step (1) into the step (2) while the mixed solution is hot to obtain a loratadine composite solution;
(4) Adding sucralose and a flavoring agent into the loratadine composite solution in the step (3) at normal temperature, adding the rest water, and uniformly stirring;
(5) Filtering the solution obtained in the step (4), and sub-packaging to obtain the loratadine oral preparation.
Preferably, in the preparation method of the oral preparation, the step (1) heats the glycerin to 80-100 ℃.
Preferably, in the preparation method of the oral preparation, in the step (2), water is heated to 60-80 ℃.
Compared with the prior art, the invention has the beneficial effects that:
(1) The oral preparation of the invention can obviously reduce the degradation of the loratadine under the alkali and heat conditions and can obviously improve the stability of the preparation by optimizing the types and weight ratio of auxiliary materials, especially when the sodium methyl benzoate, the L-tryptophan and the methylparaben are mixed to be used as the stabilizer;
(2) The formula and the preparation process of the oral preparation do not need to control the PH of the product within the range of strong acid, have small irritation to intestines and stomach, and are more suitable for children to take by adding specific essence;
(3) The preparation method is simple and easy to operate, has low cost and can be suitable for industrial popularization and application.
Drawings
FIG. 1 is a graph showing the percentage content of 2-hydroxymethylcloratadine for each example group;
FIG. 2 is a graph showing the percentage of 4-hydroxymethyl chloride Lei Tade content in each example group;
FIG. 3 is a graph showing the percentage of total impurities in each example group;
FIG. 4 is a graph of the percent content of loratadine for each example group;
fig. 5 is a taste score chart of oral solutions.
Detailed Description
The invention is further illustrated by the following specific examples, which are not to be construed as limiting the invention in any way, as will be appreciated by those skilled in the art.
Example 1 chlorine oral preparation of ratadine
The composition is as follows:
The stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 1:3.5.
The preparation method comprises the following steps:
(1) Heating glycerin to 80-85 ℃, adding loratadine, and stirring to prepare a loratadine-glycerin mixed solution;
(2) Heating 1/2 pure water to 65-70 ℃, adding sodium methyl benzoate, L-tryptophan and methylparaben respectively in sequence while the pure water is hot, and uniformly stirring;
(3) Adding the mixed solution obtained in the step (1) into the step (2) while the mixed solution is hot to obtain a loratadine composite solution;
(4) Adding sucralose into the loratadine composite solution in the step (3) at normal temperature, adding the rest water, and uniformly stirring;
(5) Filtering the solution obtained in the step (4), and sub-packaging to obtain the loratadine oral preparation.
Example 2 chlorine oral preparation of ratadine
The composition is as follows:
the stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 1:3.5, the aromatic is blueberry essence.
The preparation method comprises the following steps:
(1) Micronizing loratadine to 150nm, sieving, heating glycerin to 80-85 ℃, adding loratadine, and stirring to prepare loratadine-glycerin mixed solution;
(2) Heating 1/2 pure water to 65-70 ℃, adding sodium methyl benzoate, L-tryptophan and methylparaben respectively in sequence while the pure water is hot, and uniformly stirring;
(3) Adding the mixed solution obtained in the step (1) into the step (2) while the mixed solution is hot to obtain a loratadine composite solution;
(4) Adding sucralose and a flavoring agent into the loratadine composite solution in the step (3) at normal temperature, adding the rest water, and uniformly stirring;
(5) Filtering the solution obtained in the step (4), and sub-packaging to obtain the loratadine oral preparation.
Example 3 chlorine oral preparation of ratadine
The composition is as follows:
The stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 0.5:2, the aromatic is orange essence.
The preparation method is the same as in example 2.
EXAMPLE 4 chlorine oral preparation of ratadine
The composition is as follows:
the stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 1.5:2, the aromatic is Hami melon essence.
The preparation method is the same as in example 2.
EXAMPLE 5 chlorine oral preparation of ratadine
The composition is as follows:
The stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 1.5: and 5, the aromatic is strawberry essence.
The preparation method is the same as in example 2.
Example 6 chlorine oral preparation of ratadine
The composition is as follows:
the stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 1.5:2, the aromatic is vanilla essence.
The preparation method is the same as in example 2.
Comparative example 1 oral preparation of loratadine
The composition is as follows:
The stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 1.5:2, the aromatic is blueberry essence.
The preparation method is the same as in example 2.
Comparative example 2 oral preparation of loratadine
The composition is as follows:
The stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 5:10, wherein the aromatic is blueberry essence.
The preparation method is the same as in example 2.
Comparative example 3 oral preparation of loratadine
The composition is as follows:
the stabilizer is sodium methyl benzoate and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: methylparaben=1: 1, wherein the aromatic is blueberry essence.
The preparation method is the same as in example 2.
Comparative example 4 oral preparation of loratadine
The composition is as follows:
The preparation method is the same as in example 2, and the aromatic is blueberry essence.
Comparative example 5 oral preparation of loratadine
The composition is as follows:
The preparation method comprises the following steps:
Mixing glycerol and ethanol, heating to 45deg.C, adding loratadine, stirring, adding purified water heated to 45deg.C and 80% of the formula, mixing, adding sucralose, tartaric acid, sorbitol, sodium chloride and hydroxypropyl methylcellulose, stirring, adding the rest purified water, fixing volume, filtering with 0.22 μm microporous membrane, and packaging.
Comparative example 6 oral preparation of loratadine
The composition is as follows:
The preparation method comprises the following steps:
(1) Adding methylparaben and propylparaben into boiled purified water, stirring for 20 minutes, and cooling to normal temperature;
(2) Adding loratadine, sorbitol, sodium dihydrogen phosphate, disodium hydrogen phosphate, edetate disodium and blueberry essence into the solution in the step (1), stirring until the components are dissolved, adding purified water to fix the volume, and sub-packaging.
Verification embodiment one: stability investigation
(One) Effect of light on stability of oral formulations
The raw material medicines and the stability test guidelines of the preparation are referred to in Chinese pharmacopoeia (2020 edition) 9001, and are examined under the condition of illumination (4500+/-500 lux,25 ℃).
The oral solutions of loratadine prepared in examples 1-4 and comparative examples 1-4 were separately contained in transparent PET bottles, wherein the stability at day 0, day 30 and day 60 after the preparation was measured by HPLC method, respectively.
The test results are shown in the following table:
TABLE 1 clarification and impurity content of solutions of examples
As can be seen from the table, the oral solution of loratadine prepared by each group of the embodiment of the invention has better illumination stability.
(II) Effect of acceleration test on stability of oral formulations
The raw material medicaments and the stability test guidelines of the preparation are referred to in Chinese pharmacopoeia (2020 edition) 9001, and are inspected under the conditions of the temperature of 40+/-2 ℃ and the relative humidity of 75+/-5%.
The oral solutions of loratadine prepared in examples 2,3, 5 and comparative examples 2,3, 5 were taken for testing, and sampling assays were performed at 0, 1, 3, 6, respectively, wherein the sample detection methods such as light tests were performed while recording the 2-hydroxymethylcloratadine and 4-hydroxymethylcloratadine contents, respectively.
The test results are shown in FIGS. 1 to 4. Fig. 1 is a graph showing the content of 2-hydroxymethylcloratadine in each example group, fig. 2 is a graph showing the content of 4-hydroxymethylcloribine Lei Tade in each example group, fig. 3 is a graph showing the total impurity content in each example group, and fig. 4 is a graph showing the content of loratadine in each example group. As can be seen from the figures, the oral solutions of loratadine prepared in the groups 2,3 and 5 have better stability during the test, and are significantly better than those in the group of comparative examples.
Verification embodiment two: taste investigation
Grading is carried out according to the conditions of table 2 after tasting by a test taker, wherein the age of the test taker is selected to be 22-50 years old, and men and women are half-aged. Before taking a test, the person should rinse the mouth first and then taste each solution sequentially, so as to ensure that the test solution is taken for 10 seconds.
The formulations tested were set forth in examples 2-6, and comparative examples 2-6, respectively.
The scoring results were counted using SPSS 22.0.
Table two oral solution taste score reference table
| Level of | Standard of | Scoring of |
| 1 | Poor experience, obvious bitter taste or peculiar smell | 1-2 |
| 2 | The experience is general, the bitter taste or peculiar smell is weak | 3-4 |
| 3 | Has general experience, no bitter taste or weak peculiar smell | 5-6 |
| 4 | Has good experience, and weak bitter taste or peculiar smell | 7-8 |
| 5 | Has good experience and no bitter taste or peculiar smell | 9-10 |
The experimental results are shown in FIG. 5. From the results, the invention has better taste after the aromatic is added, which is obviously better than the comparative example.
The embodiment proves that the loratadine oral preparation prepared by the invention has good stability, is better than the conventional positive preparation sold in the market, has simple preparation process and better taste, is suitable for children to take, and has higher industrial popularization value.
Claims (9)
1. An oral loratadine formulation, characterized in that the oral loratadine formulation comprises the following components:
the stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 0.5 to 1.5:2 to 5.
2. The oral loratadine formulation of claim 1, wherein the composition of the oral formulation is:
The stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 1:3.5.
3. The oral loratadine formulation according to claim 1, further comprising a flavoring agent, preferably, the flavoring agent is one or more of blueberry essence, orange essence or strawberry essence, vanilla essence, cantaloupe essence, lemon essence, juicy peach essence, raspberry essence.
4. An oral loratadine formulation according to claim 3, wherein, in the oral formulation, loratadine is present in a weight ratio: fragrance = 1:5 to 15.
5. The oral loratadine formulation of claim 3, wherein the composition of the oral formulation is:
The stabilizer is sodium methyl benzoate, L-tryptophan and methylparaben, and the weight ratio of the sodium methyl benzoate is as follows: l-tryptophan: methylparaben=1: 1:3.5.
6. The oral loratadine formulation according to claims 1-5, characterized in that the process for the preparation of the oral formulation is:
(1) Heating glycerin, adding loratadine, and stirring to prepare a loratadine-glycerin mixed solution;
(2) Heating pure water, adding sodium methyl benzoate, L-tryptophan and methylparaben while the pure water is hot, and uniformly stirring to obtain a mixed stabilizer solution;
(3) Adding the loratadine-glycerol mixed solution obtained in the step (1) into the mixed stabilizer solution obtained in the step (2) at a controlled speed and slowly while the mixed solution is hot, and uniformly stirring to obtain a loratadine composite solution;
(4) After the temperature of the loratadine composite solution in the step (3) is reduced to normal temperature, adding sucralose and a flavoring agent into the loratadine composite solution in the step (3), and simultaneously adding a proper amount of pure water and uniformly stirring;
(5) Filtering the solution obtained in the step (4), and sub-packaging to obtain the loratadine oral preparation.
7. The oral loratadine formulation according to claim 6, wherein the loratadine is pulverized to 120-180 nm in step (1) in the process for producing the oral formulation.
8. The oral loratadine formulation according to claim 6, wherein the glycerin is heated to 80-100 ℃ in step (1) of the process for producing the oral formulation.
9. The oral loratadine formulation according to claim 6, wherein the water is heated to 60-80 ℃ in step (2) of the process for preparing the oral formulation.
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