CN113197903B - Application of polyprenyl zinc in preparation of medicine for treating castration-resistant prostate cancer - Google Patents
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Abstract
The invention discloses an application of polyprenyl zinc in preparation of a medicine for treating castration-resistant prostate cancer, and belongs to the technical field of biological medicines. The invention firstly provides a new strategy of preparing a medicament for treating CRPC by utilizing Pola and androgen receptor antagonist, and multi-angle and multi-level verification research is carried out. The pharmaceutical composition combining the polyprenyl and the androgen receptor can be used for treating castration-resistant prostate cancer, remarkably improves the castration-resistant prostate cancer inhibition effect of enzalutamide, realizes new application of old medicines, can greatly shorten the time from medicine discovery to clinical transformation, and has important clinical treatment significance.
Description
Technical Field
The invention belongs to the technical field of biological medicines. In particular to application of the polyprenyl zinc in preparing a medicine for treating castration resistant prostate cancer.
Background
Androgen deprivation therapy is the standard treatment for advanced prostate cancer, but patients eventually progress to Castration-resistant prostate cancer (CRPC) after an average of 1-3 years of treatment. So-called CRPC, cui guide 2014: prostate cancer in which disease has progressed following initial sustained Androgen Deprivation Therapy (ADT). The following conditions should be met: (1) serum testosterone was maintained at castrate levels (< 50ng/dL or 1.7 nmol/L); (2) biochemical progress: three consecutive measurements of PSA values rising above 50% of the lowest value and rising with an absolute value > 2ng/ml, one week apart; or the progress of imaging: bone scans presented with two or more new lesions or RECIST was used to assess soft tissue lesion enlargement. It is presently believed that the only symptomatic progression is not sufficient to diagnose CRPC.
At one time, CRPC patients have no effective treatment means but only can receive some palliative treatment, and since docetaxel is proved to prolong the total survival of metastatic castration-resistant prostate cancer (mCRPC) patients in 2004, drugs aiming at mCRPC disease stages such as abiraterone acetate, enzalutamide, cabazitaxel and the like are developed in recent years, so that the treatment status of the patients is changed, but CRPC is difficult to completely reverse finally. Finding an effective combination therapy strategy is therefore another area of research for the treatment of CRPC.
Recently, many researchers have proposed a new tumor cell drug resistance mechanism, namely, a persisting cell (or tumor cell), also called tumor cell plasticity (tumor cell plasticity), minimal residual disease (minimal residual disease), or drug-resistant residues (DTP). The mechanism is characterized in that: under the drug-resistant state, the tumor cells do not depend on the path targeted by the drug any more, but survive through other paths, but the gene of the target point does not have any mutation; drug sensitivity is restored after a period of withdrawal. Three hypotheses are currently proposed to establish this mechanism: firstly, a few drug-tolerant cells (drug-tolerant cells) are pre-stored, and are increased through a Darwinian theory after being treated by drugs; secondly, a small number of cells which are difficult to treat with the drugs are subjected to epigenetic modification by a small number of cancer cells to generate drug-tolerant cells which coexist with residual focuses; and thirdly, dynamically expressing various resistance genes by the tumor cells, and highly expressing the resistance genes during drug treatment, thereby further reconstructing a resistance expression system and generating drug tolerant cells. In recent years, cellular plasticity has emerged as a model for targeted diagnostic escape, a common property of resistance to many cancers. Blocking a new drug resistance pathway and effectively inhibiting the persister cell, such as GPX4 lipid peroxidation pathway, is an effective target point of high expression in a plurality of persister cell states. To date, it is unclear whether CRPC tumors have persister cells and whether new effective targets can be found. Therefore, the research focuses on finding an effective combination drug for treating CRPC from EPI-001 and LNCaP-persiter cell for prostate cancer generated by Enzalutamide.
EPI-001(EPI) is an inhibitor of AR and AR-splice variants (AR-Vs) that is awaiting clinical development, potentially useful for the treatment of CRPC. The target of EPI against CRPC is mainly directed to the N-terminal domain (NTD). Enzalutamide (Enza) is the first approved second generation AR antagonist with 5-8 times higher affinity for AR than traditional antiandrogens. In 2012, the us FDA approved accordingly Enza for CRPC patients. However, whether EPI or Enza, CRPC treatment generally results in resistance in about 18 months. Therefore, other means are urgently needed to overcome drug resistance and delay CRPC.
Polaprezinc (Polaprezinc, Pola) is a chelated form of zinc and levocarnosine. This is a first approved zinc-related drug in japan and has been used clinically for the treatment of gastric ulcers. The results indicate that Pola may be effective in treating pressure ulcers. A 2013 study showed that the combination of Pola may be effective in treating small intestinal mucosal injury caused by chronic aspirin administration.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the drug resistance of the existing drugs, and provide a drug for effectively treating CRPC, namely, the combination of Enza and Pola, so that the curative effect of CRPC is remarkably improved, and an excellent synergistic effect is exerted.
The first purpose of the invention is to provide the application of the polyprenyl zinc in preparing the medicine for treating castration-resistant prostate cancer.
In one embodiment of the invention, the application comprises: the polyprenyl zinc and androgen receptor antagonist are combined to prepare the medicine for treating castration resistant prostate cancer.
A second object of the present invention is to provide a pharmaceutical composition for treating castration-resistant prostate cancer, the composition comprising polyprenyl zinc and an androgen receptor antagonist.
In one embodiment of the present invention, the mass ratio of the androgen receptor antagonist to the polyprenyl zinc is (1-5): 1. wherein the mass ratio of Enza to Pola is preferably 1-2: 1.
In one embodiment of the invention, the androgen receptor antagonist comprises any one or more of: enzalutamide (Enza), EPI-001(EPI), abiraterone, olaparib.
In one embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutical excipient.
In one embodiment of the invention, the pharmaceutical excipients comprise solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, tonicity adjusting agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integration agents, penetration enhancers, pH adjusting agents, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, encapsulation agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, and release retardants.
In one embodiment of the invention, the dosage form of the preparation comprises injection, freeze-dried powder injection for injection, controlled release injection, liposome injection, suspension, implant, suppository, capsule, tablet, pill and oral liquid.
In one embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutical carrier.
In one embodiment of the invention, the drug carrier includes microcapsules, microspheres, nanoparticles, and liposomes.
In one embodiment of the present invention, the present invention has undergone extensive research and research to find a drug for treating CRPC, i.e., a combination of Enza and Pola. Research results show that by establishing an EPI and Enza-resistant LNCaP-drug-resistant-tolerant persister (L-DTP) cell strain for prostate cancer, LNCaP cells generate recoverable drug resistance to EPI and Enza at the moment, the combination of Enza and Pola can obviously inhibit cell growth, the effect of drug combination is verified through CCK8 cell proliferation analysis, and the synergistic effect is determined through a CI value. Meanwhile, a C-MYC over-expression prostate cancer mouse model is constructed, the effect difference of single-use and combined CRPC treatment of Enza and Pola in an animal body is compared, the synergistic effect generated by drug combination greatly improves the inhibition effect of single Enza drugs on CRPC, and the synergistic effect of the Enza drugs and the Pola is verified in vitro and in vivo.
In one embodiment of the invention, the L-DTP recoverable drug-resistant cell strain is established, the CI value is calculated by adopting a CCK8 method and Calcusyn software, and the result shows that the cell strain has a synergistic CRPC (cross-linked immunosorbent assay) resistance effect compared with the case that Enza or Pola is singly given and the in vitro combination of Enza and Pola is adopted. By establishing a C-MYC overexpression prostate cancer mouse model, an Enza and Pola combination group in an animal body is determined under a model that Enza with long-term medicine generates resistance, and the model has more obvious effect of resisting CRPC in the animal body compared with a single medicine group.
The invention has the following beneficial effects:
the invention firstly provides a new strategy for preparing CRPC (chronic obstructive pulmonary disease) treatment medicines by utilizing Pola and based on the combination of Enza and Pola medicines, clarifies the action mechanism of the CRPC treatment medicines, promotes the application of Enza and Pola in the clinical treatment of prostatic cancer and has important significance. The pharmaceutical research requires 8-10 years on average from the compound molecule to the real clinical application, and needs a large amount of manpower and material resources for support, and the time cost and the economic cost are huge. The scheme of the invention can realize the new application of the old medicine and can greatly shorten the time from the discovery of the medicine to the clinical conversion.
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FIG. 1 is an illustration of the recoverable properties of DTP (drug-tolerant persister) after withdrawal; wherein, FIG. 1A is a diagram of DTP and the process of cell recovery after withdrawal of drug; FIG. 1B shows the re-recovery of the sensitivity of DTP-EPI for 3 generations and DTP-Enza for 3 generations.
FIG. 2 is a graph showing the change in the expression level of AR-associated genes in DTP and withdrawal Cell (Recovery Cell) cells; wherein, FIG. 2A shows the change of WB detection protein expression level; FIG. 2B shows the change in the expression level of transcripts detected by q-PCR.
FIG. 3 is a graph of the in vitro potency of EPI, Enza, respectively, in combination with Pola in L-DTP cells; wherein, FIG. 3A is a bar graph of relative survival rate of cells on L-DTP-EPI and L-DTP-Enza cells after combined administration; FIG. 3B is a histogram of CI values on L-DTP-EPI, L-DTP-Enza cells in combination with EPI, Enza, respectively, and Pola, respectively.
FIG. 4 is a graph of the effect of Enza, Pola and combinations on prostate weight change in C-MYC overexpressing prostate cancer in a mouse model of C-MYC after resistance to continuous administration of Enza; wherein, FIG. 4A is a graph of prostate weight change in groups of mice following administration; FIG. 4B is a photograph of prostate gland of mice of each group taken by a camera; FIG. 4C is a graph of the change in body weight of mice in each group with administration.
FIG. 5 is a graph of the effect of combination of Enza, Pola and their combination regimens on C-MYC overexpressing prostate cancer in a mouse model of C-MYC resistant to continuous Enza; wherein, FIG. 5A is the HE staining pattern of prostate tissue sections of each group of mice; FIG. 5B is a PRDX5, AR immunohistochemistry of prostate tissue sections from various groups of mice; and FIG. 5C positive cells quantification histogram.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1EPI, Enza used in the production of DTP by prostate cancer LNCaP cells
The prostate cancer L-DTP cell strains L-DTP-EPI and L-DTP-Enza which are resistant to the EPI and the Enza have recoverable characteristics.
1. The experimental method comprises the following steps:
LNCaP cell 1x106Planting in 10cm cell culture dish, respectively adding EPI and Enza after adherence on the next day, treating for 9 days, and changing fresh culture medium containing medicine every three days; removing the drug after 9 days, replacing fresh culture medium, culturing cells in an incubator normally, transferring on days 6, 12 and 17, and taking cell morphology maps of DTP (day 9), R5 (day 5 of drug removal), R10 and R20 under an inverted microscope. After DTP cells producing DTP and clone, the cells were digested and counted to calculate the percentage of DTP cells in total L-parent cells. Respectively paving L-parent cells and cells of the third generation (R20) after drug withdrawal in a 96-well plate, after overnight adherence, configuring a series of EPI and Enza with high to low concentration, setting a control group to be added into the holes, setting 3 multiple holes for each concentration, incubating for 48h in a cell incubator, adding CCK8, detecting the OD value of the cells with the wavelength of 450nm by using a full-wavelength multifunctional microplate reader after 4h, counting the survival rate and drawing a survival curve.
2. The results are shown in FIG. 1 and Table 1: in FIG. 1, FIG. 1A is a diagram showing the recovery process of DTP and cells after withdrawal of drug; FIG. 1B is a graphical representation of the re-sensitivity of DTP-EPI for 3 rd and DTP-Enza for 3 rd generations.
TABLE 1 cell count following DTP model production by LNCaP cells
| Cell line | DTP(％) | S.D.(N＝3) |
| LNCCaP-1 | 0.82 | 0.08 |
| LNCaP-1cl.A | 0.18 | 0.12 |
| LNCaP-1cl.B | 0.22 | 0.06 |
| LNCaP-1cl.C | 0.54 | 0.03 |
| LNCCaP-a | 0.33 | 0.94 |
| LNCaP-a cl.A | 0.15 | 0.11 |
| LNCaP-a cl.B | 0.24 | 0.21 |
| LNCaP-a cl.C | 0.13 | 0.18 |
The results show that the number of LNCaP-DTP cells generated by EPI and Enza is very small, and the drug-resistant cells generate resistance to EPI and Enza, but the cell morphology and the sensitivity to the drug are recovered after 3 generations of drug withdrawal.
Example 2 characterization of changes in AR-associated Gene expression levels in DTP and withdrawal Cell (Recovery Cell)
The cell morphology of the DTP cells is recovered after 3 generations of drug withdrawal, and the expression quantity of the AR related genes of the cells can also be recovered.
1. The experimental method comprises the following steps:
in LNCaP cells, after overnight adherence, EPI and Enza were added to the cells for 9 days before harvesting, during which time fresh media was changed every 3 days, and the remaining DTP cells were withdrawn and dosed for 20 days before harvesting. Setting LNCaP cells treated with DMSO for 9 days as an NC control group, adding EPI and Enza to treat the cells for 9 days to generate L-DTP-EPI and L-DTP-Enza as a treatment group, setting the cells of the treatment group after drug withdrawal for 20 days as a recovery group, and observing the expression changes of AR-FL and related target proteins, AR-Vs and related target proteins after cell lysis, protein extraction quantification, SDS-PAGE electrophoresis gel, membrane transfer, sealing, primary antibody incubation and secondary antibody incubation and development of the three groups of cells. Meanwhile, the three groups of cells are subjected to q-RTPCR measurement to detect the expression quantity change of AR-FL and related target genes thereof and AR-Vs and related target genes thereof.
2. As shown in FIG. 2, FIG. 2A shows the change in the expression level of WB assay protein in FIG. 2; FIG. 2B shows the change in the expression level of the transcript detected by q-RTPCR.
The results show that the AR and its associated target proteins PSA, TMPRSS 2; AR-Vs and their related target proteins UBE2C, CDC 20; the expression level is reduced in DTP stage to different degrees, and the expression level is recovered after the drug R20 is withdrawn; similarly, AR-Vs and its associated target genes, and growth markers: the expression level of AKT1 and C-MYC is also reduced in the DTP stage, and the expression level of R20 is restored to different degrees.
Example 3EPI, Enza, respectively, were used in combination with Pola drugs.
Further using CCK8, single use and combined use in drug-resistant L-DTP cells respectively show the in vitro anti-tumor effect of Pola drugs in drug-resistant L-DTP (EPI) and L-DTP (Enza) cells.
1. Experimental methods
After adherence of drug-resistant cells L-DTP (including L-DTP (EPI) and L-DTP (Enza)) in 96-well plates, optimal concentrations of Pola drug were found by formulating a series of high to low concentrations of Pola drug, and then using these concentrations to determine the survival rates of the cells in the drug-resistant cells L-DTP (EPI) -Pola), combination [ L-DTP (EPI) -combination (EPI + Pola) ], [ L-DTP (Enza) -combination (Enza + Pola) ], respectively. And finally, calculating a CI value in the L-DTP cell by using Calcusyn software.
2. The results are shown in FIG. 3, FIG. 3A is a bar graph of relative survival rate of drug-combination cells on L-DTP (EPI), L-DTP (Enza) resistant cells; FIG. 3B is a histogram of CI values for EPI, Enza, respectively, in combination with Pola, on L-DTP (EPI), L-DTP (Enz), respectively, drug-resistant cells.
The results show that in the cells which generate drug resistance L-DTP (EPI) after being continuously added with the EPI for 9 days, no obvious inhibition effect is achieved after the EPI is continuously added, and no obvious inhibition rate is achieved after the single addition of the Pola, but the inhibition rate of 55.74 percent can be achieved when the EPI + Pola is combined. Similarly, in the cells which generate drug-resistant L-DTP (Enza) after continuously adding Enza for 9 days, the continuous adding of Enza has no obvious inhibition effect, and Pola is added singly, but the combination (Enza + Pola) can achieve 60.765% inhibition rate. By calculating the CI value, Pola can achieve a high synergistic effect of 0.525 in L-DTP-EPI cells; high synergy of 0.695 can be achieved in L-DTP (Enza) cells.
Example 4 Effect of a combination regimen of Enza and Pola on combination of C-MYC overexpressing prostate cancer in a mouse model of C-MYC after resistance to continuous Enza
The effect of mice relapsed after chemical castration (i.e. sustained use of Enza) by combination of Enza and Pola was further demonstrated in a mouse model of prostate cancer.
1. Experimental methods
Constructing a spontaneous prostate Cancer mouse model of C-MYC (Hi-Myc) overexpression, wherein at 4 months, mice develop mPIN/Cancer transition, the mice are randomly grouped into an NC control group (gastric lavage solvent) and an Enza drug group, the mice are gavaged every three days later, the Enza is 10mg/Kg and are administrated for 30 days, the rear mice are decapitated, prostate Cancer of the mice is photographed and weighed, the disease can be obviously relieved by the Enza, the prostate weight is reduced by half compared with the NC control group, the mice are continuously administrated for 30 days according to the method, the Enza group is found to have relapse, and then the mice are randomly grouped into the following groups (namely the age of the mice is 6 months): NC control group (always intragastric solvent), Enza single drug group, Pola single drug group and Enza and Pola combined drug group, and corresponding administration treatment, wherein the administration is carried out by complete intragastric administration once every three days, the Enza is kept at 10mg/Kg and the Pola is kept at 20mg/Kg every time, and the administration lasts for 30 days. Then, the cervical mice are cut off, and prostate cancer of the mice is taken to be subjected to experiments such as photographing, weighing, immunohistochemistry and the like.
2. The results are shown in FIGS. 4 and 5, in FIG. 4, FIG. 4A is a graph showing the change in prostate weight of each group of mice with administration;
FIG. 4B is a photograph of prostate gland of mice of each group taken by a camera; FIG. 4C is a graph of the change in body weight of mice in each group with administration. In FIG. 5, FIG. 5A is a graph of HE staining of prostate tissue sections of various groups of mice; fig. 5B is an AR, PRDX5 immunohistochemistry and positive cell quantification histogram of each group of mouse prostate tissue sections.
The prostate weight average value of the mice with the continuous Enza for 30 days is 41.2mg, the average value of the NC control group is 85.3mg, the drug administration is continued, the weight average value of the prostate of the mice with the Enza is 78.4mg after 60 days, the average value of the NC control group is 95.6mg, the drug resistance relapse is caused, and the drug combination effect is indicated by the immediate grouping.
The results of the grouping and individual use are shown in table 2:
TABLE 2 Effect of different administrations (30 d) on drug resistance after relapse
| Administration of drugs | Prostate weight mean of mice |
| NC control group | 100.1mg |
| Continuous Enza single medicine group after drug resistance relapse | 83.3mg |
| Pola single drug group after drug resistance relapse | 80.625mg |
| Drug-resistant post-relapse Enza and Pola combination drug group | 53.14mg |
As can be seen from fig. 4 and table 2, the combination of Enza and Pola had a very significant effect compared to both Enza alone and Pola alone, and the prostate weight was reduced to about 53.14mg, while it was seen that Pola alone had almost the same effect as Enza alone, indicating that Pola alone had no significant effect on drug-resistant CRPC.
As can be seen from the tissue slice HE staining results (fig. 5): after the combination is used, the prostate tumor of CRPC has obvious degeneration and fibrosis. From immunohistochemistry, it was shown that the combination of Enza and Pola had a significant decrease in the expression of AR and PRDX5 compared to both Enza alone and Pola alone. The combination effect is proved to be obvious.
The results of the grouping and individual use are shown in Table 3:
TABLE 3 Effect of different administrations (30 d) on drug resistance after relapse
| Administration of drugs | AR expression amount/% | PRDX5 expression amount/%) |
| NC control group | 94 | 61.7 |
| Continuous Enza single medicine group after drug resistance relapse | 71.5 | 93.6 |
| Pola single drug group after drug resistance relapse | 70.4 | 74.2 |
| Drug-resistant post-relapse Enza and Pola combination drug group | 20.5 | 15 |
Claims (10)
1. Use of polyprenyl zinc in the manufacture of a medicament for the treatment of castration resistant prostate cancer.
2. The application according to claim 1, wherein the application comprises: the polyprenyl zinc and androgen receptor antagonist are combined to prepare the medicine for treating castration resistant prostate cancer.
3. A pharmaceutical composition for treating castration-resistant prostate cancer, comprising polyprenyl zinc and an androgen receptor antagonist.
4. The pharmaceutical composition according to claim 3, wherein the mass ratio of the androgen receptor antagonist to the polyprenyl zinc is (1-5): 1.
5. the pharmaceutical composition of claim 3, wherein the androgen receptor antagonist comprises any one or more of: enzalutamide, EPI, abiraterone, olaparib.
6. The pharmaceutical composition of claim 3, further comprising a pharmaceutical excipient.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical excipients comprise solvents, propellants, solubilizers, solubilizing agents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, tonicity adjusting agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integration agents, permeation enhancers, pH adjusting agents, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickening agents, encapsulation agents, humectants, flocculants and deflocculants, filter aids, and release retardants.
8. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition further comprises a pharmaceutical carrier.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical carrier comprises a microcapsule, a microsphere, a nanoparticle, and a liposome.
10. The pharmaceutical composition according to any one of claims 3 to 9, wherein the dosage form of the pharmaceutical composition comprises injection, lyophilized powder for injection, suspension, implant, suppository, capsule, tablet, pill and oral liquid.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110501971.4A CN113197903B (en) | 2021-05-08 | 2021-05-08 | Application of polyprenyl zinc in preparation of medicine for treating castration-resistant prostate cancer |
| JP2023568658A JP2024516326A (en) | 2021-05-08 | 2021-07-26 | Use of polaprezinc in the preparation of a medicament for treating castration-resistant prostate cancer |
| PCT/CN2021/108355 WO2022236963A1 (en) | 2021-05-08 | 2021-07-26 | Use of polaprezinc in preparation of drug for treating castration-resistant prostate cancer |
| US17/829,633 US20220305026A1 (en) | 2021-05-08 | 2022-06-01 | Use of polaprezinc in preparing drug for treating castration-resistant prostate cancer |
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| CN202110501971.4A CN113197903B (en) | 2021-05-08 | 2021-05-08 | Application of polyprenyl zinc in preparation of medicine for treating castration-resistant prostate cancer |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106562976A (en) * | 2016-10-17 | 2017-04-19 | 吉林省博大伟业制药有限公司 | Application of polaprezinc in preparing medicines for treating colon cancer |
| KR20190031660A (en) * | 2017-09-18 | 2019-03-27 | 하나제약 주식회사 | Wet granulation tablets with improved stability and method for preparing the same |
| CN110237228A (en) * | 2019-07-02 | 2019-09-17 | 吉林省博大伟业制药有限公司 | Polaprezinc prevents the postoperative application taken in the drug of ulcer substrate protrusion caused by PPI of scope ESD in preparation |
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| US20090197853A1 (en) * | 2005-11-16 | 2009-08-06 | Pharmacyclics, Inc. | Methods and compositions of treating cancer |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106562976A (en) * | 2016-10-17 | 2017-04-19 | 吉林省博大伟业制药有限公司 | Application of polaprezinc in preparing medicines for treating colon cancer |
| KR20190031660A (en) * | 2017-09-18 | 2019-03-27 | 하나제약 주식회사 | Wet granulation tablets with improved stability and method for preparing the same |
| CN110237228A (en) * | 2019-07-02 | 2019-09-17 | 吉林省博大伟业制药有限公司 | Polaprezinc prevents the postoperative application taken in the drug of ulcer substrate protrusion caused by PPI of scope ESD in preparation |
Non-Patent Citations (2)
| Title |
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| Effectiveness of polaprezinc for low-dose aspirin-induced small-bowel mucosal injuries as evaluated by capsule endoscopy: a pilot randomized controlled study;Ikue Watari 等;《BMC Gastroenterology》;20130704;第1-7页 * |
| 聚普瑞锌在消化系统疾病中的应用进展;刘忆 等;《浙江临床医学》;20151231;第17卷(第11期);第2018-2019页 * |
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| CN113197903A (en) | 2021-08-03 |
| WO2022236963A1 (en) | 2022-11-17 |
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