CN118903478A - 13C urea orally disintegrating tablet, and preparation method and application thereof - Google Patents
13C urea orally disintegrating tablet, and preparation method and application thereof Download PDFInfo
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- CN118903478A CN118903478A CN202410962447.0A CN202410962447A CN118903478A CN 118903478 A CN118903478 A CN 118903478A CN 202410962447 A CN202410962447 A CN 202410962447A CN 118903478 A CN118903478 A CN 118903478A
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- Prior art keywords
- urea
- orally disintegrating
- disintegrating tablet
- preparation
- water
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title claims abstract description 263
- 239000004202 carbamide Substances 0.000 title claims abstract description 135
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 101
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 31
- 239000000463 material Substances 0.000 claims abstract description 30
- 239000002994 raw material Substances 0.000 claims abstract description 18
- 210000000214 mouth Anatomy 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims description 31
- 238000004108 freeze drying Methods 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 20
- 239000000796 flavoring agent Substances 0.000 claims description 20
- 235000013355 food flavoring agent Nutrition 0.000 claims description 19
- 239000003755 preservative agent Substances 0.000 claims description 19
- 230000002335 preservative effect Effects 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- 238000011049 filling Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 159000000000 sodium salts Chemical class 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 10
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 9
- 238000007907 direct compression Methods 0.000 claims description 9
- 239000008101 lactose Substances 0.000 claims description 9
- 229960001375 lactose Drugs 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 8
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 8
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 8
- 238000007789 sealing Methods 0.000 claims description 8
- 108010010803 Gelatin Proteins 0.000 claims description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 6
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- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 206010019375 Helicobacter infections Diseases 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 229960004106 citric acid Drugs 0.000 claims description 5
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- 235000010355 mannitol Nutrition 0.000 claims description 5
- 229960001855 mannitol Drugs 0.000 claims description 5
- 239000001509 sodium citrate Substances 0.000 claims description 5
- 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 5
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- 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 4
- 239000004376 Sucralose Substances 0.000 claims description 4
- 239000000605 aspartame Substances 0.000 claims description 4
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 4
- 235000010357 aspartame Nutrition 0.000 claims description 4
- 229960003438 aspartame Drugs 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 4
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 4
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- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 4
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- 229960003415 propylparaben Drugs 0.000 claims description 4
- 229960001790 sodium citrate Drugs 0.000 claims description 4
- 235000011083 sodium citrates Nutrition 0.000 claims description 4
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- 235000019408 sucralose 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
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 claims description 3
- 108010024636 Glutathione Proteins 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 3
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 claims description 3
- 239000004383 Steviol glycoside Substances 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 claims description 3
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 claims description 3
- 229940088679 drug related substance Drugs 0.000 claims description 3
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 3
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 3
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 3
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 3
- 229960003180 glutathione Drugs 0.000 claims description 3
- 229960002449 glycine Drugs 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- 229960001462 sodium cyclamate Drugs 0.000 claims description 3
- 239000004334 sorbic acid Substances 0.000 claims description 3
- 235000010199 sorbic acid Nutrition 0.000 claims description 3
- 229940075582 sorbic acid Drugs 0.000 claims description 3
- 235000019411 steviol glycoside Nutrition 0.000 claims description 3
- 229930182488 steviol glycoside Natural products 0.000 claims description 3
- 150000008144 steviol glycosides Chemical class 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims 1
- 235000019634 flavors Nutrition 0.000 claims 1
- 239000003826 tablet Substances 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 3
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- 239000000047 product Substances 0.000 description 13
- 239000008213 purified water Substances 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
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- 239000008187 granular material Substances 0.000 description 6
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- 241000590002 Helicobacter pylori Species 0.000 description 5
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- 108010046334 Urease Proteins 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 2
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides 13 C urea orally disintegrating tablets and a preparation method and application thereof, and relates to the technical field of pharmaceutical preparations, the components of the 13 C urea orally disintegrating tablets comprise 13 C urea as a raw material and an auxiliary material excipient, the 13 C urea orally disintegrating tablets are prepared by using 13 C urea as a raw material and the auxiliary material, the 13 C urea orally disintegrating tablets do not need water or only need a small amount of water during taking, chewing is not needed, after the tablets are rapidly disintegrated in oral cavity in saliva, the tablets with gastric efficacy can be taken by swallowing power, and the tablets are convenient to take, quick in effect, high in bioavailability and good in compliance of clinical application.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to 13 C urea orally disintegrating tablets and a preparation method and application thereof.
Background
Helicobacter pylori is a gram-negative bacterium that is predominantly distributed in gastric mucosal tissue. Helicobacter pylori has definite carcinogenesis, and light people after infection can cause chronic superficial gastritis, can progress to chronic atrophic gastritis after long-term infection, can also form gastric ulcer and duodenal ulcer, and the ulcer can be complicated with bleeding or canceration, even part of people directly appear gastric cancer or gastric mucosa lymphoma. The pathogenesis of helicobacter pylori is the result of the combined action of a number of factors, such as the synergistic action of bacterial flagella, adhesins, ureases, proteases, vacuolated toxins, endotoxins, etc. Among them, a large number of highly active ureases decompose urea into ammonia and carbon dioxide. Ammonia neutralizes gastric acid, thereby allowing the bacteria to survive in the highly acidic stomach. The accumulation of urease and ammonia also damages gastric mucus layers and mucosal cells, disrupting the mucus-bicarbonate barrier, causing protons to reflux toward the mucosa, leading to peptic ulcers.
13 The principle of the C urea expiration test is that 13 C marked urea is orally taken to the stomach, decomposed by urease generated by helicobacter pylori to generate ammonia gas and 13 C-carbon dioxide, the collected gas is analyzed on a specific instrument through the expiration test, and whether helicobacter pylori exists or not is determined according to a specific detection value of 13 C-carbon dioxide. 13 The structural formula of the urea C is as follows:
13 C urea exhale test diagnostic kit, the product on the market is generally tablet, granule etc., need dissolve in water before putting to take for the testee when taking, and ordinary tablet and granule dissolving process generally need 3-5 minutes and constantly stir just can dissolve completely, when the testee is more, need take longer and more loaded down with trivial details operation, very inconvenient.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims at providing 13 C urea orally disintegrating tablets. The 13 C urea orally disintegrating tablet comprises the raw material medicine 13 C urea and auxiliary materials excipient, wherein the 13 C urea orally disintegrating tablet is prepared by using the raw material medicine 13 C urea and the auxiliary materials, the 13 C urea orally disintegrating tablet does not need water or only needs a small amount of water when being taken, does not need chewing, can be rapidly disintegrated in the oral cavity when meeting saliva, and can enter the stomach to take effect by swallowing power.
The second purpose of the invention is to provide a preparation method of 13 C urea orally disintegrating tablet, which prepares the bulk drug 13 C urea and a proper amount of other auxiliary materials into orally disintegrating tablet by a freeze drying method or a powder direct compression method, improves the stability of the bulk drug 13 C urea, simplifies the clinical dispensing process and is convenient for clinical administration.
The invention further aims to provide an application of 13 C urea orally disintegrating tablet in preparing a product for diagnosing helicobacter pylori infection.
In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:
In a first aspect, the invention provides 13 C urea orally disintegrating tablets, and the 13 C urea orally disintegrating tablets comprise raw material medicines 13 C urea and auxiliary excipients.
Further, the 13 C urea orally disintegrating tablet unit dose comprises 50-150 mg of raw material medicine 13 C urea and auxiliary excipients.
Further, the weight ratio of 13 C urea to excipient is 1:0.3-1:15;
Preferably, the excipient comprises at least one of povidone K30, polyethylene glycol 4000, polyethylene glycol 6000, citric acid, sodium citrate, mannitol, sorbitol, xylitol, lactose, gelatin, glycine and glutathione.
Further, the 13 C urea orally disintegrating tablet also comprises auxiliary materials of flavoring agents;
Preferably, the weight of the flavoring agent is less than or equal to 1% of the total weight of the 13 C urea orally disintegrating tablet;
Preferably, the flavoring agent comprises at least one of aspartame, sodium cyclamate, sodium saccharin, steviol glycosides and sucralose.
Further, the 13 C urea orally disintegrating tablet also comprises auxiliary materials preservative;
preferably, the weight of the preservative is less than or equal to 1% of the total weight of the 13 C urea orally disintegrating tablet;
Preferably, the preservative comprises at least one of methylparaben and its sodium salt, ethylparaben and its sodium salt, propylparaben and its sodium salt, benzoic acid and its sodium salt, and sorbic acid and its potassium salt.
In a second aspect, the invention provides a preparation method of the 13 C urea orally disintegrating tablet, and the preparation method of the 13 C urea orally disintegrating tablet comprises the following steps:
the raw material drug 13 C urea and auxiliary materials with the formula amount are dissolved in a solvent, and the orally disintegrating tablet is prepared by a freeze drying method or a powder direct compression method.
Further, dissolving the 13 C urea, the excipient, the flavoring agent and the preservative in a solvent according to the formula amount, and preparing into orally disintegrating tablets by a freeze drying method or a powder direct compression method;
Preferably, the solvent comprises water, and the excipient, the flavoring agent and the preservative are all water-soluble;
preferably, the concentration of the mixture of the bulk drug and the auxiliary materials in water is 40-250g/L.
Further, the preparation of the 13 C urea orally disintegrating tablet by adopting a freeze drying method comprises the following steps:
And dissolving 13 C urea serving as a raw material with auxiliary materials in a formula amount in a solvent, and then sequentially filling, freeze-drying and sealing to prepare the 13 C urea orally disintegrating tablet.
In a third aspect, the invention provides an application of 13 C urea orally disintegrating tablet in preparing a product for diagnosing helicobacter pylori infection.
Further, when the 13 C urea orally disintegrating tablet is used, the 13 C urea orally disintegrating tablet is placed in the oral cavity or placed in 1-2ml of water, and can be disintegrated or dissolved.
Compared with the prior art, the invention has at least the following beneficial effects:
The 13 C urea orally disintegrating tablet provided by the invention takes 13 C urea as a raw material drug, an excipient is added, the excipient is taken as a freeze-drying framework material, and is sublimated along with the water in the freeze-drying process to form porous massive solid which is in an amorphous state, so that the dissolubility of the tablet can be improved, and the tablet can be rapidly dissolved in an oral cavity, and the 13 C urea orally disintegrating tablet provided by the invention has the characteristics of rapid disintegration in the oral cavity or rapid disintegration with a small amount of water, is convenient to take, and improves the compliance in clinical use.
According to the preparation method of the 13 C urea orally disintegrating tablet, the freeze-drying method or the powder direct-compression method is adopted to prepare the bulk drug 13 C urea and a proper amount of other auxiliary materials into the tablet which can disintegrate in a small amount of water, so that the stability of the bulk drug 13 C urea is improved, the clinical dispensing process is simplified, and the clinical administration is facilitated.
The 13 C urea orally disintegrating tablet provided by the invention is clinically applied to diagnosis of helicobacter pylori infection, when the 13 C urea orally disintegrating tablet is used, the orally disintegrating tablet is placed in an oral cavity or 1-2 ml of water, can be rapidly disintegrated or dissolved within 30 seconds, and is convenient to take, quick in effect and good in compliance of clinical application.
Detailed Description
Unless defined otherwise herein, scientific and technical terms used in connection with the present application shall have the meanings commonly understood by one of ordinary skill in the art. The meaning and scope of terms should be clear, however, in the event of any potential ambiguity, the definitions provided herein take precedence over any dictionary or extraneous definition. In the present application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "include" and other forms is not limiting.
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. 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, are intended to be within the scope of the invention.
The invention provides a 13 C urea orally disintegrating tablet, and the components of the 13 C urea orally disintegrating tablet comprise crude drug 13 C urea and auxiliary excipients.
In the invention, 13 C urea is used as a bulk drug, an excipient is added, the excipient is used as a freeze-drying framework material, and water sublimates along with the freeze-drying process to form porous block solid which is in an amorphous state, so that the dissolubility of the tablet can be improved, and the 13 C urea orally disintegrating tablet provided by the invention has the characteristics of rapid disintegration in the oral cavity or rapid disintegration with a small amount of water, is convenient to take, and improves the compliance in clinical use.
Further, the 13 C urea orally disintegrating tablet unit dose comprises 50-150 mg of raw material medicine 13 C urea and auxiliary excipients.
Taking a unit dose of 13 C urea orally disintegrating tablet as an example, in each tablet of the orally disintegrating tablet, the content of the raw material medicine 13 C urea is 50-150 mg, for example, 50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、134mg、140mg、145mg、150mg and the like;
the content of 13 C urea in the orally disintegrating tablet is more preferably 75 mg/tablet.
Further, the weight ratio of 13 C urea to the excipient is 1:0.3-1:15, for example, 1:0.3、1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8、1:8.5、1:9、1:9.5、1:10、1:10.5、1:11、1:11.5、1:12、1:12.5、1:13、1:13.5、1:14、1:14.5、1:15, etc.;
Preferably, the excipient comprises at least one of povidone K30, polyethylene glycol 4000, polyethylene glycol 6000, citric acid, sodium citrate, mannitol, sorbitol, xylitol, lactose, gelatin, glycine and glutathione.
In the invention, the excipient is used as a freeze-drying framework material, and sublimates along with the freeze-drying process to form porous massive solid which is in an amorphous state, so that the dissolubility of the tablet can be improved, and the tablet can be rapidly dissolved in the oral cavity. Wherein excipients such as povidone K30, polyethylene glycol 4000, polyethylene glycol 6000, gelatin and the like have certain adhesiveness, and the tablet can maintain certain structural strength only by using a small amount, so that the tablet is not easy to break into powder.
Further, the 13 C urea orally disintegrating tablet also comprises auxiliary materials of flavoring agents;
Preferably, the weight of the flavoring agent is 1% or less of the total weight of the 13 C urea orally disintegrating tablet, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, etc.;
Preferably, the flavoring agent comprises at least one of aspartame, sodium cyclamate, sodium saccharin, steviol glycosides and sucralose.
In the invention, the taste of the orally disintegrating tablet is improved by adding the flavoring agent, and the taste of the orally disintegrating tablet can be improved by only needing a small amount of flavoring agent, so that the adaptability of clinical application is improved, and the dosage of the flavoring agent is not more than 1% of the total weight of the orally disintegrating tablet.
Further, the 13 C urea orally disintegrating tablet also comprises auxiliary materials preservative;
Preferably, the weight of the preservative is 1% or less of the total weight of the 13 C urea orally disintegrating tablet, for example, may be 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, etc.;
Preferably, the preservative comprises at least one of methylparaben and its sodium salt, ethylparaben and its sodium salt, propylparaben and its sodium salt, benzoic acid and its sodium salt, and sorbic acid and its potassium salt.
In the invention, the preservative is mainly added for excipients which are easy to grow by microorganisms, such as saccharides, amino acids and proteins, so that the growth of microorganisms in the excipients can be inhibited, the stability of the product is improved, the quality of the product in the effective period is ensured, and the dosage of the preservative is lower and is not more than 1% of the total weight of the orally disintegrating tablet.
The second aspect of the invention provides a preparation method of the 13 C urea orally disintegrating tablet, and the preparation method of the 13 C urea orally disintegrating tablet comprises the following steps:
the raw material drug 13 C urea and auxiliary materials with the formula amount are dissolved in a solvent, and the orally disintegrating tablet is prepared by a freeze drying method or a powder direct compression method.
In the invention, the drug substance 13 C urea and a proper amount of other auxiliary materials are prepared into a tablet which can be disintegrated in a small amount of water by adopting a freeze drying method or a powder direct compression method, so that the stability of the drug substance 13 C urea is improved, the clinical dispensing process is simplified, and the clinical administration is convenient.
Further, dissolving the 13 C urea, the excipient, the flavoring agent and the preservative in a solvent according to the formula amount, and preparing into orally disintegrating tablets by a freeze drying method or a powder direct compression method;
Preferably, the solvent comprises water, and the excipient, the flavoring agent and the preservative are all water-soluble;
preferably, the concentration of the mixture of the bulk drug and the auxiliary materials in water is 40-250g/L.
In the invention, water is used as a solvent to prepare the freeze-dried intermediate solution, and the concentration of the total solid matters of raw materials and auxiliary materials in the water is 4-25% (w/v).
Further, the preparation of the 13 C urea orally disintegrating tablet by adopting a freeze drying method comprises the following steps:
And dissolving 13 C urea serving as a raw material with auxiliary materials in a formula amount in a solvent, and then sequentially filling, freeze-drying and sealing to prepare the 13 C urea orally disintegrating tablet.
In the invention, the 13 C urea orally disintegrating tablet freeze-drying process comprises the following steps: and (3) dissolving 13 C urea, a water-soluble excipient, a flavoring agent and a preservative in water according to a certain proportion, filling the mixture into an aluminum-plastic bubble cap, freeze-drying, and hot-pressing and sealing the aluminum-plastic bubble cap and an aluminum foil after drying to prepare the orally disintegrating tablet.
The invention provides an application of 13 C urea orally disintegrating tablet in preparing a product for diagnosing helicobacter pylori infection.
Further, when the 13 C urea orally disintegrating tablet is used, the 13 C urea orally disintegrating tablet is placed in the oral cavity or placed in 1-2ml of water, and can be disintegrated or dissolved.
When the 13 C urea orally disintegrating tablet is used, the orally disintegrating tablet is placed in an oral cavity or 1-2 ml of water, can be rapidly disintegrated or dissolved within 30 seconds, and has the advantages of convenient administration, rapid onset of action and better compliance in clinical application.
The invention is further illustrated by the following examples. The materials in the examples were prepared according to the existing methods or were directly commercially available unless otherwise specified.
Example 1
This example provides 13 C urea orally disintegrating tablets, the formulation of which is shown in table 1 below.
TABLE 1
The preparation method of the 13 C urea orally disintegrating tablet comprises the following steps:
(1) Weighing 3000ml of purified water;
(2) Weighing 13 C urea and lactose with the prescribed amount, adding the purified water, stirring and dissolving, and adding the purified water to a volume of 4000ml;
(3) Filling the solution into aluminum-plastic bubble caps, and filling 3ml in each bubble cap;
(4) Transferring to a freeze dryer for freeze drying, wherein the freeze drying parameters are shown in the following table 2;
TABLE 2
(5) And (5) performing hot-pressing sealing on the freeze-dried sample by using aluminum foil to obtain the product.
Example 2
The embodiment provides 13 C urea orally disintegrating tablets, wherein in the formula, the dosage of 13 C urea is 150g, the lactose is 45g, and in the preparation process, raw and auxiliary materials are dissolved, and then purified water is added to fix the volume to 3000ml.
The remainder was identical to example 1.
Example 3
The embodiment provides 13 C urea orally disintegrating tablets, wherein in the formula, the dosage of 13 C urea is 70g, the lactose is 81g, and in the preparation process, raw and auxiliary materials are dissolved, and then purified water is added to fix the volume to 3000ml.
The remainder was identical to example 1.
Example 4
The embodiment provides 13 C urea orally disintegrating tablets, wherein the excipient adopts povidone K30 in the formula.
The remainder was identical to example 3.
Example 5
The embodiment provides 13 C urea orally disintegrating tablets, wherein the excipient adopts 75g lactose and 6g povidone K30.
The remainder was identical to example 3.
Example 6
The embodiment provides 13 C urea orally disintegrating tablet, wherein 0.75g of aspartame serving as a flavoring agent and 74.25g of lactose are added into the formulation.
The remainder was identical to example 5.
Example 7
This example provides a 13 C urea orally disintegrating tablet, the formulation of which is shown in table 3 below, to which is added 0.75g of sodium benzoate as preservative, 73.5g of lactose, the remaining steps being identical to those of example 6.
TABLE 3 Table 3
Example 8
This example provides a 13 C urea orally disintegrating tablet, the formulation of which is shown in table 4 below.
TABLE 4 Table 4
The preparation method of the 13 C urea orally disintegrating tablet comprises the following steps:
(1) 1800ml of purified water is taken and heated to 80 ℃;
(2) Weighing the prescription amount of methylparaben and propylparaben, stirring and dissolving, and cooling to 60 ℃;
(3) Adding gelatin, stirring for dissolving, standing and defoaming;
(4) Adding 13 C urea, sorbitol and sucralose, stirring to dissolve, and adding purified water to a volume of 2500ml;
(5) Filling the solution into aluminum-plastic bubble caps, and filling 2.5ml of each bubble cap;
(6) Transferring to a freeze dryer for freeze drying, wherein the freeze drying parameters are as follows:
TABLE 5
(7) And (5) performing hot-pressing sealing on the freeze-dried sample by using aluminum foil to obtain the product.
Example 9
This example provides 13 C urea orally disintegrating tablets, the formulation of which is shown in table 6 below.
TABLE 6
The preparation method of the 13 C urea orally disintegrating tablet comprises the following steps:
(1) 4000ml of purified water was taken;
(2) Weighing the citric acid and sodium citrate with the prescription amount, and stirring and dissolving;
(3) Adding 13C urea, mannitol and stevioside, stirring to dissolve, and adding purified water to a volume of 5000ml;
(4) Filling the solution into aluminum-plastic bubble caps, and filling 5ml in each bubble cap;
(5) Transferring to a freeze dryer for freeze drying, wherein the freeze drying parameters are as follows:
TABLE 7
(6) And (5) performing hot-pressing sealing on the freeze-dried sample by using aluminum foil to obtain the product.
Comparative example 1
The comparative example is a tablet containing 13 C urea, the formulation of which is shown in table 8 below.
TABLE 8
Tablets containing 13 C urea were prepared as follows:
(1) Pulverizing the raw materials and the auxiliary materials, sieving with an 80-mesh sieve, and weighing for later use;
(2) Mixing 13 C urea and magnesium stearate uniformly;
(3) Tabletting to obtain the final product.
Comparative example 2
The comparative example is a granule containing 13 C urea, the formulation of which is shown in Table 9 below.
TABLE 9
The preparation process of the granules containing 13 C urea comprises the following steps:
(1) Pulverizing the raw materials and the auxiliary materials, sieving with an 80-mesh sieve, and weighing for later use;
(2) Adding 13 C urea, mannitol, citric acid, sodium citrate and stevioside into a wet granulator, uniformly mixing, adding 70% ethanol, and granulating;
(3) Granulating the wet granules by a swing granulator, wherein the mesh number of a screen is 16 meshes;
(4) Vacuum drying the prepared particles in a vacuum drying oven at 60 ℃ for 3 hours;
(5) Finishing the dried granules with 14 meshes, and removing fine powder by a 80-mesh sieve;
(6) Filling into bottle with filling amount of 5 g/bottle, and sealing.
Test example 1
Test sample: the performance of the 13 C urea orally disintegrating tablets prepared in examples 1-14 and the 13 C urea preparation prepared in comparative examples 1-2 were compared, and the specific results are shown in Table 10 below.
Table 10
As can be seen from the data of each example in table 10, in examples 1 to 4, the dissolution time of the product of example 1 was relatively prolonged due to the higher density, and the dissolution time of the product of example 4 was relatively prolonged due to the formation of micelles by dissolution of a large amount of povidone; gelatin in the product of example 8 forms a gel, resulting in a relatively small increase in dissolution time; according to experiments, the products in the examples 7-9 are stronger in stability and more convenient to carry and transport; in clinical use, compared with the comparative example, the 13 C urea orally disintegrating tablet in the embodiment of the invention can be rapidly dissolved by only a small amount of water, and can be dissolved in oral cavity by saliva or only a small amount of water by clinical oral administration, thus being easy to take and having better compliance; the comparative example can be taken after being stirred in more warm water for a plurality of minutes to be dissolved; therefore, the 13 C urea orally disintegrating tablet in the embodiment of the invention is convenient to take, does not need to be dissolved and dispensed in clinical use, reduces the burden of medical staff, has better patient compliance and has obvious advantages.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. The 13 C urea orally disintegrating tablet is characterized in that the components of the 13 C urea orally disintegrating tablet comprise crude drug 13 C urea and auxiliary excipients.
2. The 13 C urea orally disintegrating tablet according to claim 1, wherein the 13 C urea orally disintegrating tablet unit dose comprises 50-150 mg of a drug substance 13 C urea and an auxiliary excipient.
3. The 13 C urea orally disintegrating tablet according to claim 1, wherein the weight ratio of 13 C urea to the excipient is 1:0.3-1:15;
Preferably, the excipient comprises at least one of povidone K30, polyethylene glycol 4000, polyethylene glycol 6000, citric acid, sodium citrate, mannitol, sorbitol, xylitol, lactose, gelatin, glycine and glutathione.
4. The 13 C urea orally disintegrating tablet of claim 1, wherein the components of the 13 C urea orally disintegrating tablet further comprise an auxiliary material flavoring agent;
Preferably, the weight of the flavoring agent is less than or equal to 1% of the total weight of the 13 C urea orally disintegrating tablet;
Preferably, the flavoring agent comprises at least one of aspartame, sodium cyclamate, sodium saccharin, steviol glycosides and sucralose.
5. The 13 C urea orally disintegrating tablet of claim 1, wherein the components of the 13 C urea orally disintegrating tablet further comprise an adjuvant preservative;
preferably, the weight of the preservative is less than or equal to 1% of the total weight of the 13 C urea orally disintegrating tablet;
Preferably, the preservative comprises at least one of methylparaben and its sodium salt, ethylparaben and its sodium salt, propylparaben and its sodium salt, benzoic acid and its sodium salt, and sorbic acid and its potassium salt.
6. A process for the preparation of 13 C urea orally disintegrating tablets according to any one of claims 1 to 5, wherein the process for the preparation of 13 C urea orally disintegrating tablets comprises the steps of:
the raw material drug 13 C urea and auxiliary materials with the formula amount are dissolved in a solvent, and the orally disintegrating tablet is prepared by a freeze drying method or a powder direct compression method.
7. The method of preparing an orally disintegrating tablet of 13 C urea according to claim 6, wherein the orally disintegrating tablet is prepared by dissolving a formulation of 13 C urea, excipients, flavors and preservatives in a solvent, and freeze drying or powder direct compression;
Preferably, the solvent comprises water, and the excipient, the flavoring agent and the preservative are all water-soluble;
preferably, the concentration of the mixture of the bulk drug and the auxiliary materials in water is 40-250g/L.
8. The method of claim 6, wherein the preparation of 13 C urea orally disintegrating tablet by freeze-drying comprises the steps of:
And dissolving 13 C urea serving as a raw material with auxiliary materials in a formula amount in a solvent, and then sequentially filling, freeze-drying and sealing to prepare the 13 C urea orally disintegrating tablet.
9. Use of 13 C urea orally disintegrating tablet according to any one of claims 1 to 5 for the preparation of a product for diagnosing helicobacter pylori infection in the stomach.
10. The use of 13 C urea orally disintegrating tablet according to claim 9, wherein when in use, the 13 C urea orally disintegrating tablet is disintegrated or dissolved by placing the 13 C urea orally disintegrating tablet in the oral cavity or in 1-2ml of water.
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