CN103319413A - Polaprezinc compound - Google Patents
Polaprezinc compound Download PDFInfo
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- CN103319413A CN103319413A CN2013102274016A CN201310227401A CN103319413A CN 103319413 A CN103319413 A CN 103319413A CN 2013102274016 A CN2013102274016 A CN 2013102274016A CN 201310227401 A CN201310227401 A CN 201310227401A CN 103319413 A CN103319413 A CN 103319413A
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- zinc
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- carnosine
- polaprezinc
- histidine
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Abstract
The invention provides a polaprezinc compound. Polaprezinc compound is an L-carnosine complex of zinc, and the chemical name is poly 2-(S)-[mu-[N <alpha> (3-aminoproionyl)-L-histidine (2-)-N<1>,N<2>,O:N <tau>]-zinc). L-carnosine is a dipeptide that consists of beta-phenylalanine and L-histidine, and is an anti-oxidant that can promote wound healing. The polaprezinc compound of the present invention can be rapidly absorbed in vivo and eliminated after single or multi-time drug-feeding; multi-time drug-feeding has no accumulation phenomenon. Within test dosage, the subject can bear better and no light or severe adverse events happen during the whole test process, which means the drug is safe and has good human body tolerance. The improvement rate of chief complaint ulcer is 94.44%.
Description
Technical field
The invention belongs to the pharmaceutical technology field, relate to particularly a kind of zinc L-carnosine compound.
Background technology
Peptide ulceration is 4.57% at China's sickness rate, and mainly take person between twenty and fifty as main, serious threat China labor force population affects China's Economic development.
Peptide ulceration mainly because of smoking, drink, nervous, medicine irritation (such as NAIDS) causes, its pathogenesis focuses on unbalance between the two of invasion and attack factor and defending factors at present, and the difference of individual neuroendocrine response and hereditary predisposition.Antiulcer drug mainly is divided into anti-invasion factor medicine and promotes the defense factor medicine; the anti-invasion factor comprises antacid, presses down sour medicine such as m receptor blocking agent, G receptor antagonist, histamine H2-receptor blocking agent and Proton pump inhibitor and antipepsin medicine, promotes defense factor class cartridge bag to draw together and promotes mucus generation medicine, mucosa protective agent and improve mucous membrane blood circulation medicine.
Zinc L-carnosine is the N-BETA-Alanyl-L-histidine complex compound of zinc, its chemistry poly-2-(S) by name-[μ-[N
α(3-aminopropan acyl group)-L-Histidine (2-)-N
1, N
2, O:N
τ]-zinc].The dipeptides that N-BETA-Alanyl-L-histidine is comprised of β-Phenylalanine and L-group ammonia, it is a kind of antioxidant.Zinc can promote wound healing.Zinc L-carnosine is that it is that first is used for clinical zinc compound by the latest generation medicament for anti-gastric ulcer of Japanese Hamari new drug Industrial Co., Ltd exploitation, and this medicine went on the market in Japan with trade(brand)name Promac in 1994, and formulation is granule.
Experiment shows; zinc L-carnosine has anti-oxidant and membrane stabilizing action; thereby keep the stomach mucous membrane homeostasis; reach the effect of cytoprotective, it also can promote wound healing simultaneously, strengthens the defense factor effect; reach the effect that prevents and treats peptide ulceration; zinc L-carnosine has the effect of obvious inhibition ulcer to peptide ulceration models such as water logging, acetic acid, AAPH gastric mucosa injurys, simultaneously it also to have the mucous membrane tack strong, improve the effect of gastric mucosal defense effect.
Summary of the invention
The object of the present invention is to provide a kind of zinc L-carnosine compound, its structure is poly-2-(S)-[μ-[N
α(3-aminopropan acyl group)-L-Histidine (2-)-N
1, N
2, O:N
τ]-zinc].
Above-mentioned zinc L-carnosine compound, its X-ray powder diffraction collection of illustrative plates are that approximately there is characteristic peak at 8.8 ± 0.2,17.5 ± 0.2 and 19.0 ± 0.2 places at 2 θ.
Above-mentioned zinc L-carnosine compound, its X-ray powder diffraction collection of illustrative plates are that approximately there is characteristic peak at 13.1 ± 0.2,15.6 ± 0.2 and 21.1 ± 0.2 places at 2 θ.
Above-mentioned zinc L-carnosine compound has similar collection of illustrative plates with accompanying drawing 1.
Above-mentioned zinc L-carnosine compound has similar collection of illustrative plates with accompanying drawing 2.
Another object of the present invention is to provide a kind of pharmaceutical composition, it comprises above-claimed cpd and the pharmaceutically acceptable auxiliary material of effective dose.
Description of drawings
Fig. 1 is the x-ray diffractogram of powder of the compound of the embodiment of the invention 1.
Fig. 2 is the differential thermal analysis collection of illustrative plates of the compound of the embodiment of the invention 1.
Embodiment
In order to understand better the present invention, the below will be described in detail and illustrate the present invention and advantage thereof by embodiments of the invention and experimental data, but these embodiment are not limited to the present invention.
Embodiment 1
Phthalyl-N-BETA-Alanyl-L-histidine, add excessive hydrazine hydrate and Glacial acetic acid, get the N-BETA-Alanyl-L-histidine highly finished product with washing with alcohol after the hydrazinolysis reaction, then add sodium hydrate methanol solution, the zinc acetate dihydrate of 2 times of mol ratios fully stirs, and separates out precipitation 20-25% washing with alcohol 3 times, get zinc L-carnosine finished products compound, total recovery 67.89%.Powder x-ray diffraction: use the Cu-K radiation, the X-ray powder diffraction collection of illustrative plates of this compound is seen accompanying drawing 1.Differential scanning calorimetric analysis: the differential thermal analysis collection of illustrative plates of this compound is seen accompanying drawing 2.
1, prescription
2, preparation technology
1) processing of supplementary material
Take by weighing the supplementary material of recipe quantity, zinc L-carnosine was pulverized 200 mesh sieves, N.F,USP MANNITOL, Steviosin and 30 POVIDONE K 30 BP/USP
30Cross 80 mesh sieves after pulverizing, for subsequent use;
2) premix
N.F,USP MANNITOL is disperseed with 40 mesh sieves, get Steviosin and part N.F,USP MANNITOL and carry out equivalent and progressively increase and mix 4 times, cross 80 mesh sieves, get mixture 1.; With 30 POVIDONE K 30 BP/USP
30Add mixture 1., mix, get mixture 2.; With mixture 2., zinc L-carnosine and residue N.F,USP MANNITOL drops in the Mixers with Multi-direction Movement premix approximately 20 minutes;
3) granulation, drying
The pre-mixed drug powder of step 2 is added in the efficient wet nodulizer, slowly add 50% ethanolic soln, make softwood; Use Pendulargranulator, the softwood that makes is granulated with 24 mesh sieves; The wet granular that makes is added in the Hotaircirculatingoven, be dried to moisture≤1.0% in 55～65 ℃;
4) screening, whole grain
Dried particle is sieved with 16 orders and 80 mesh sieves respectively, collect the particle that 16 mesh sieves are following and 80 mesh sieves are above; Particle more than 16 orders with the whole grain of 18 mesh sieves, is collected the particle that 16 mesh sieves are following and 80 mesh sieves are above;
5) total mixed, packing
The zinc L-carnosine midbody particle that step 4 is made drops in the Mixers with Multi-direction Movement, always mixed approximately 10 minutes; After the assay was approved packing, and get final product.
1, prescription
2, preparation technology
1) processing of supplementary material
Take by weighing the supplementary material of recipe quantity, zinc L-carnosine was pulverized 200 mesh sieves, N.F,USP MANNITOL, Steviosin and 30 POVIDONE K 30 BP/USP
30Cross 80 mesh sieves after pulverizing, for subsequent use;
2) premix
N.F,USP MANNITOL is disperseed with 40 mesh sieves, get Steviosin and part N.F,USP MANNITOL and carry out equivalent and progressively increase and mix 4 times, cross 80 mesh sieves, get mixture 1.; With 30 POVIDONE K 30 BP/USP
30Add mixture 1., mix, get mixture 2.; With mixture 2., zinc L-carnosine and residue N.F,USP MANNITOL drops in the Mixers with Multi-direction Movement premix approximately 20 minutes;
3) granulation, drying
The pre-mixed drug powder of step 2 is added in the efficient wet nodulizer, slowly add 50% ethanolic soln, make softwood; Use Pendulargranulator, the softwood that makes is granulated with 24 mesh sieves; The wet granular that makes is added in the Hotaircirculatingoven, be dried to moisture≤1.0% in 55～65 ℃;
4) screening, whole grain
Dried particle is sieved with 16 orders and 80 mesh sieves respectively, collect the particle that 16 mesh sieves are following and 80 mesh sieves are above; Particle more than 16 orders with the whole grain of 18 mesh sieves, is collected the particle that 16 mesh sieves are following and 80 mesh sieves are above;
5) total mixed, packing
The zinc L-carnosine midbody particle that step 4 is made drops in the Mixers with Multi-direction Movement, always mixed approximately 10 minutes; After the assay was approved packing, and get final product.
The clinical trial of test example-zinc L-carnosine granule of the present invention
For studying the dynamic change characteristic of absorption, distribution and the elimination (metabolism and drainage) of zinc L-carnosine granule of the present invention (embodiment 2) in healthy human body, we have carried out the pharmacokinetic of multiple dosing to it.Multiple dosing: the experimenter is morning and take the 75mg medicine with 250ml warm water just before going to bed, gives continuously approximately 13 times.Sample number is 36 examples, and the men and women half and half.Behind zinc L-carnosine particle (embodiment 2) single and the multiple dosing, absorb in vivo rapidly, eliminate very fast; Multiple dosing is without accumulating phenomenon.Under the test dose, the experimenter all can better tolerate, and slight adverse events does not occur whole process of the test, does not also have serious adverse events to occur, and safety of medicine is described, the human tolerance is good.Main suit's ulcer improvement rate 94.44%.
Claims (6)
1. a zinc L-carnosine compound is characterized in that its structure is poly-2-(S)-[μ-[N
α(3-aminopropan acyl group)-L-Histidine (2-)-N
1, N
2, O:N
τ]-zinc].
2. zinc L-carnosine compound according to claim 1 is characterized in that its X-ray powder diffraction is that approximately there is characteristic peak at 8.8 ± 0.2,17.5 ± 0.2 and 19.0 ± 0.2 places at 2 θ.
3. zinc L-carnosine compound according to claim 2 is characterized in that its X-ray powder diffraction is that approximately there is characteristic peak at 13.1 ± 0.2,15.6 ± 0.2 and 21.1 ± 0.2 places at 2 θ.
4. zinc L-carnosine compound according to claim 3 is characterized in that having and accompanying drawing 1 similar collection of illustrative plates.
5. each described zinc L-carnosine compound is characterized in that having and accompanying drawing 2 similar collection of illustrative plates according to claim 1-4.
6. pharmaceutical composition is characterized in that comprising each described compound of claim 1-5 and the pharmaceutically acceptable auxiliary material of effective dose.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310227401.6A CN103319413B (en) | 2013-06-08 | 2013-06-08 | Polaprezinc compound |
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|---|---|---|---|
| CN201310227401.6A CN103319413B (en) | 2013-06-08 | 2013-06-08 | Polaprezinc compound |
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|---|---|
| CN103319413A true CN103319413A (en) | 2013-09-25 |
| CN103319413B CN103319413B (en) | 2015-02-04 |
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|---|---|---|---|
| CN201310227401.6A Active CN103319413B (en) | 2013-06-08 | 2013-06-08 | Polaprezinc compound |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105899520A (en) * | 2014-02-10 | 2016-08-24 | 株式会社德山 | Production method for purified material containing crystalline L-carnosine zinc complex |
| CN106913859A (en) * | 2015-12-25 | 2017-07-04 | 中美华世通生物医药科技（武汉）有限公司 | Pharmaceutical composition and preparation method |
| WO2019049824A1 (en) * | 2017-09-05 | 2019-03-14 | 株式会社トクヤマ | Protected l-carnosine derivative, l-carnosine, and method for producing crystalline l-carnosine zinc complex |
| KR20190031660A (en) * | 2017-09-18 | 2019-03-27 | 하나제약 주식회사 | Wet granulation tablets with improved stability and method for preparing the same |
| CN110314149A (en) * | 2016-10-17 | 2019-10-11 | 吉林省博大伟业制药有限公司 | A kind of Polaprezinc piece and its preparation process |
| CN111196837A (en) * | 2018-11-20 | 2020-05-26 | 皕达生物科技(上海)有限公司 | Preparation method of polaprezinc and polaprezinc preparation |
| CN113769059A (en) * | 2021-09-10 | 2021-12-10 | 北京鑫开元医药科技有限公司 | Popregnen zinc granules and preparation method thereof |
Citations (4)
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| US5238931A (en) * | 1990-07-06 | 1993-08-24 | Zeria Pharmaceutical Co., Ltd. | Inflammatory bowel disease preventive and curative agent containing zinc l-carnosine salt as active ingredient |
| CN1857715A (en) * | 2006-03-23 | 2006-11-08 | 恩泰柯数码科技（北京）有限公司 | Cirrhosis treating medicine |
| JP2011001324A (en) * | 2009-06-22 | 2011-01-06 | Sawai Pharmaceutical Co Ltd | Polaprezinc-containing orally disintegrating tablet |
| CN103120646A (en) * | 2011-11-21 | 2013-05-29 | 四川海思科制药有限公司 | Polaprezinc granules and preparation method thereof |
-
2013
- 2013-06-08 CN CN201310227401.6A patent/CN103319413B/en active Active
Patent Citations (4)
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| US5238931A (en) * | 1990-07-06 | 1993-08-24 | Zeria Pharmaceutical Co., Ltd. | Inflammatory bowel disease preventive and curative agent containing zinc l-carnosine salt as active ingredient |
| CN1857715A (en) * | 2006-03-23 | 2006-11-08 | 恩泰柯数码科技（北京）有限公司 | Cirrhosis treating medicine |
| JP2011001324A (en) * | 2009-06-22 | 2011-01-06 | Sawai Pharmaceutical Co Ltd | Polaprezinc-containing orally disintegrating tablet |
| CN103120646A (en) * | 2011-11-21 | 2013-05-29 | 四川海思科制药有限公司 | Polaprezinc granules and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| TOSHIKAZU YOSHIKAWA 等: "The antioxidant properties of a novel zinc-carnosine chelate compound, N-(3-aminopropionyi)-t.-histidinato zinc", 《BIOCHIMICA ET BIOPHYSICA ACTA(BBA)-GENERAL SUBJIECTS》 * |
| 张清彦: "聚普瑞锌的合成", 《化学工程与装备》 * |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105899520A (en) * | 2014-02-10 | 2016-08-24 | 株式会社德山 | Production method for purified material containing crystalline L-carnosine zinc complex |
| KR20160119058A (en) * | 2014-02-10 | 2016-10-12 | 가부시끼가이샤 도꾸야마 | Production method for purified material containing crystalline l-carnosine zinc complex |
| JPWO2015119235A1 (en) * | 2014-02-10 | 2017-03-30 | 株式会社トクヤマ | Process for producing purified product containing crystalline L-carnosine zinc complex |
| KR102286357B1 (en) * | 2014-02-10 | 2021-08-05 | 가부시끼가이샤 도꾸야마 | Production method for purified material containing crystalline l-carnosine zinc complex |
| CN106913859A (en) * | 2015-12-25 | 2017-07-04 | 中美华世通生物医药科技（武汉）有限公司 | Pharmaceutical composition and preparation method |
| CN110314149B (en) * | 2016-10-17 | 2021-04-02 | 吉林省博大伟业制药有限公司 | Poly-pregnen-zinc tablet and preparation process thereof |
| CN110314149A (en) * | 2016-10-17 | 2019-10-11 | 吉林省博大伟业制药有限公司 | A kind of Polaprezinc piece and its preparation process |
| WO2019049824A1 (en) * | 2017-09-05 | 2019-03-14 | 株式会社トクヤマ | Protected l-carnosine derivative, l-carnosine, and method for producing crystalline l-carnosine zinc complex |
| KR102015516B1 (en) * | 2017-09-18 | 2019-08-28 | 하나제약 주식회사 | Wet granulation tablets with improved stability and method for preparing the same |
| KR20190031660A (en) * | 2017-09-18 | 2019-03-27 | 하나제약 주식회사 | Wet granulation tablets with improved stability and method for preparing the same |
| CN111196837A (en) * | 2018-11-20 | 2020-05-26 | 皕达生物科技(上海)有限公司 | Preparation method of polaprezinc and polaprezinc preparation |
| CN111196837B (en) * | 2018-11-20 | 2023-07-28 | 皕达生物科技(上海)有限公司 | Preparation method of polyprenone and polyprenone preparation |
| CN113769059A (en) * | 2021-09-10 | 2021-12-10 | 北京鑫开元医药科技有限公司 | Popregnen zinc granules and preparation method thereof |
| CN113769059B (en) * | 2021-09-10 | 2024-02-13 | 北京鑫开元医药科技有限公司 | Poly (zinc prasugrel) granule and preparation method thereof |
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|---|---|
| CN103319413B (en) | 2015-02-04 |
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Address after: The 856000 Tibet autonomous region in southern area of Zedang town Xiang Qu Road No. 8 Patentee after: Haisike Pharmaceutical Group Limited by Share Ltd Address before: The 856000 Tibet autonomous region in southern area of Zedang town Xiang Qu Road No. 8 Patentee before: Tibet Haisco Pharmaceutical Group Co., Ltd. |