The purpose of this study is to determine whether incretin-based drugs (used to treat type 2 diabetes) taken either alone or in combination with other anti-diabetic drugs are associated with an increased risk of acute pancreatitis (AP) compared to other combinations of oral hypoglycemic agents (OHA).
The investigators will carry out separate population based cohort studies using administrative health databases in six jurisdictions in Canada, the US, and the UK. Cohorts will be defined by the initiation of a new anti-diabetic drug when incretin-based drugs entered the market, with follow-up until hospitalization for AP. The results from the separate sites will be combined to provide an overall assessment of the risk of AP in users of incretin-based drugs and by class of incretin-based drugs.

开始日期2014-03-01

申办/合作机构

Canadian Institutes of Health Research

NCT03662334 / Completed临床4期

A Phase 4, Double Blind, Single Center, Randomized, Cross-Over Study of Continuous Subcutaneous Insulin Infusion (CSII) Pump Functionality in Subjects With Type 1 Diabetes Comparing Pretreatment vs. No Pretreatment With Recombinant Human Hyaluronidase (rHuPH20)

The goal of this study is to determine if Hylenex recombinant leads to changes in the insulin time-action profiles and glucose responses when preadministered in the setting of continuous subcutaneous insulin infusion (CSII) compared to CSII without Hylenex recombinant (sham injection).

开始日期2013-10-03

申办/合作机构

Halozyme Therapeutics, Inc.

NCT01055808 / CompletedN/A

A Prospective, Non-safety Observational Study in Japanese Type 2 Diabetes Patients(INSIGHTS)

This study is designed to address the gap in the literature related to changing treatment regimen or formulation between different types of insulin, and how this change impacts quality of life, adherence, individual patient treatment satisfaction and glycemic control.

开始日期2010-01-01

申办/合作机构

Eli Lilly & Co.

100 项与 Insulins(Halozyme) 相关的临床结果

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100 项与 Insulins(Halozyme) 相关的转化医学

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100 项与 Insulins(Halozyme) 相关的专利（医药）

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982

项与 Insulins(Halozyme) 相关的文献（医药）

2024-03-01·International journal of clinical pharmacology and therapeutics

Hoarding of insulin and oral antidiabetics in the first phase of the COVID-19 pandemic: Regulatory actions taken to avoid shortage

Article

作者: Zethelius, Björn ; Kälkner, Karl-Mikael ; Ljung, Rickard ; Sundström, Anders ; Nordback, Kenneth

OBJECTIVE:

To report on hoarding of prescribed medicines, with focus on insulins, in the early phase of the COVID-19 pandemic and on regulatory actions taken to avoid shortage.

MATERIALS AND METHODS:

The National Prescribed Drug Register which utilizes the Anatomic Therapeutic Chemical (ATC) Classification System and covers the total Swedish population was used. We calculated the number of packages of insulins (ATC code A10A), oral anti-diabetics (A10B), and all medicines across all ATC codes combined (A-S) dispensed per week in 2019 and 2020. Correspondingly, the number of packages of glucose test strips dispensed was calculated using the data source Concise held by the Swedish eHealth Agency.

RESULTS:

Prompt increases in numbers of dispensed packages were observed in March, peaking at week 11/2020. The absolute numbers of packages dispensed in week 11/2019 and week 11/2020 were: insulin, 49,694 and 95,767, an increase by +92.7%; oral antidiabetics, 55,478 and 82,684, +47.1%; glucose test strips, 18,119 and 23,476, +29:6%; and all medicines across all ATC codes combined, 1,988,456 and 2,659,421, +33.7%. Voluntary restriction of dispensing and a rapid change to applicable regulation were implemented within 2 weeks. A steep decline occurred, which became more pronounced after temporary regulation came in force from April 1, then leveling out during the following months.

CONCLUSION:

A signal of insulin hoarding was detected early in the COVID-19 pandemic. A temporary regulation, reducing dispensing to a maximum supply of 3 months was rapidly implemented. A shortage of vitally important prescribed medicines was avoided.

2024-03-01·Current protein & peptide science

Diabetic Wound: Pathophysiology, Complications and Treatment Strategies

Article

作者: Singh, Rahul Pratap ; Jhawat, Vikas ; Chauhan, Sunita ; Gulia, Monika

Abstract::

Diabetic wound healing is expected to affect 25% of all diabetics, resulting in less severe external factors, economic costs, and less trauma. Topical formulations have been continually improved to achieve a range of amazing properties and have had a significant impact on the management of diabetic wounds. Topical insulin has become one of the most attractive and convenient wound healing techniques due to its excellent biocompatibility, water retention, and therapeutic properties. Multiple versatile topical insulins have been identified and have shown promise over the past few years as they greatly facilitate the management of diabetic wounds as we understand their etiology. The physiological wound healing process repairs damaged tissue and restores skin integrity. For about a century, insulin, a powerful healing agent, and it has been utilized in several clinical and experimental researches research studies to accelerate the healing of various injuries.

2024-02-01·Journal of peptide science : an official publication of the European Peptide Society

Semisynthesis of A6–A11 lactam insulin

Article

作者: Hagemeyer, Christoph E ; Gubbins, Ben ; Karas, John A ; Jap, Edwina ; Xu, Rong

Insulin replacement therapy is essential for the management of diabetes. However, despite the relative success of this therapeutic strategy, there is still a need to improve glycaemic control and the overall quality of life of patients. This need has driven research into orally available, glucose‐responsive and rapid‐acting insulins. A key consideration during analogue development is formulation stability, which can be improved via the replacement of insulin's A6–A11 disulfide bond with stable mimetics. Unfortunately, analogues such as these require extensive chemical synthesis to incorporate the nonnative cross‐links, which is not a scalable synthetic approach. To address this issue, we demonstrate proof of principle for the semisynthesis of insulin analogues bearing nonnative A6–A11 cystine isosteres. The key feature of our synthetic strategy involves the use of several biosynthetically derived peptide precursors which can be produced at scale cost‐effectively and a small, chemically synthesised A6–A11 macrocyclic lactam fragment. Although the assembled A6–A11 lactam insulin possesses poor biological activity in vitro, our synthetic strategy can be applied to other disulfide mimetics that have been shown to improve thermal stability without significantly affecting activity and structure. Moreover, we envisage that this new semisynthetic approach will underpin a new generation of hyperstable proteomimetics.

项与 Insulins(Halozyme) 相关的新闻（医药）

2024-05-16

·PRNewswire

With Once-a-Week Dosing, Insulin Efsitora Alfa Delivers A1C Reduction and Safety Profile Consistent with Daily Insulin

Efsitora met the primary endpoint in both QWINT-2 and QWINT-4 with once-a-week dosing regimen for people living with type 2 diabetes Efsitora was equally safe and effective among adults naïve to insulin therapy currently using and not using GLP-1 receptor agonists INDIANAPOLIS, May 16, 2024 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced positive topline results from the QWINT-2 and QWINT-4 phase 3 clinical trials evaluating once-weekly insulin efsitora alfa (efsitora) in adults with type 2 diabetes using insulin for the first time (insulin naïve) and those who require multiple daily insulin injections. In the treat-to-target clinical trials, efsitora showed non-inferior A1C reduction compared to the most commonly used daily basal insulins globally. "The results of QWINT-2 and QWINT-4 are a significant milestone for the diabetes community and demonstrate that efsitora as a weekly insulin provides blood sugar control equivalent to daily basal insulins," said Jeff Emmick, MD, Ph.D., senior vice president, product development, Lilly. "With efsitora, we have an opportunity to provide an innovative once-weekly solution that safely achieves and maintains A1C control, reduces treatment burden of traditional daily injections and potentially improves adherence for people with diabetes." QWINT-2 evaluated the efficacy and safety of once-weekly efsitora compared to once-daily insulin degludec for 52 weeks. The trial randomized insulin-naïve adults with type 2 diabetes to receive efsitora once weekly or insulin degludec once daily and was also designed to assess efficacy in patients using and not using GLP-1 receptor agonists. The trial met its primary endpoint of non-inferior A1C reduction with efsitora compared to insulin degludec at week 52. For the efficacy estimand1,2, efsitora reduced A1C by 1.34% compared to 1.26% for insulin degludec resulting in an A1C of 6.87% and 6.95% respectively3. In a key secondary endpoint, efsitora was non-inferior to insulin degludec in A1C change among participants using and not using GLP-1 receptor agonists. Further, participants taking efsitora spent 45 minutes more time in range4 and 37 minutes more in tight range5 without additional time in hypoglycemia (blood glucose <54 mg/dL) in comparison to insulin degludec. QWINT-4 evaluated the efficacy and safety of efsitora compared to insulin glargine for 26 weeks in adults with type 2 diabetes who have previously been treated with basal insulin and at least two injections per day of mealtime insulin. The trial randomized participants to receive efsitora once weekly or insulin glargine once daily, both of which were administered with insulin lispro. The trial met its primary endpoint of non-inferior A1C reduction with efsitora compared to insulin glargine at week 26. For the efficacy estimand, both efsitora and insulin glargine reduced A1C by 1.07% resulting in an A1C of 7.12% and 7.11%, respectively6,7. In both QWINT-2 and QWINT-4, efsitora was safe and well-tolerated with estimated combined rates of severe or clinically significant (blood glucose <54 mg/dL) hypoglycemic events per patient-year of exposure of 0.58 with efsitora vs. 0.45 with insulin degludec (QWINT-2) and 6.6 with efsitora vs. 5.9 with insulin glargine (QWINT-4). Detailed results from QWINT-2 will be presented at the European Association for the Study of Diabetes (EASD) Annual Meeting 2024. Topline readouts from QWINT-1, QWINT-3 and QWINT-5 are anticipated later this year. About the QWINT clinical trial program The QWINT phase 3 global clinical development program for insulin efsitora alfa (efsitora) in diabetes began in 2022 and has enrolled more than 4,000 people living with type 1 or type 2 diabetes across five global registration studies. QWINT-2 (NCT05362058) was a parallel-design, open-label, treat-to-target, randomized controlled clinical trial comparing the efficacy and safety of efsitora as a once-weekly basal insulin to insulin degludec for 52 weeks in insulin-naïve adults with type 2 diabetes. The trial randomized 928 participants across the U.S., Brazil, Canada, China, Czechia (Czech Republic), Germany, Greece, Japan, Korea, Mexico and Puerto Rico to receive efsitora once weekly or insulin degludec once daily administered subcutaneously. The primary objective of the trial was to demonstrate non-inferiority in reducing A1C at week 52 with efsitora compared to insulin degludec. The trial was also designed to assess efficacy and safety for patients using and not using GLP-1 receptor agonists. QWINT-4 (NCT05462756) was a parallel-design, open-label, treat-to-target, randomized controlled clinical trial comparing the efficacy and safety of efsitora as a weekly basal insulin to insulin glargine for 26 weeks in adults with type 2 diabetes who have previously been treated with basal insulin and at least two injections per day of mealtime insulin. The trial randomized 730 participants across the U.S., Argentina, Germany, India, Italy, Mexico, Puerto Rico and Spain to receive efsitora once weekly or insulin glargine once daily, both of which were administered subcutaneously along with insulin lispro. The primary objective of the trial was to demonstrate non-inferiority in reducing A1C at week 26 with efsitora compared to insulin glargine. About insulin efsitora alfa Insulin efsitora alfa (efsitora) is a once-weekly basal insulin, a fusion protein that combines a novel single-chain variant of insulin with a human IgG2 Fc domain. It is specifically designed for once-weekly subcutaneous administration, and with its low peak-to-trough ratio, it has the potential to provide more stable glucose levels (less glucose variability) throughout the week. Efsitora is in phase 3 development for adults with type 1 and 2 diabetes. About Lilly Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 51 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram and LinkedIn. P-LLY Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about insulin efsitora alfa as a potential treatment for people with type 2 diabetes and the timeline for future readouts, presentations, and other milestones relating to insulin efsitora alfa and its clinical trials, and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study results to date, that insulin efsitora alfa will prove to be a safe and effective treatment for type 2 diabetes, that insulin efsitora alfa will receive regulatory approval, or that Lilly will execute its strategy as expected. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. 1 The efficacy estimand represents the treatment effect had all participants adhered to the study drug without initiating rescue therapy for persistent severe hyperglycemia. 2 95% CI for treatment difference (-0.22% to 0.061%). 3 From a baseline A1C of 8.21% for efsitora and 8.23% for insulin degludec. 4 Blood glucose 70-180 mg/dL. 5 Blood glucose 70-140 mg/dL. 6 From a baseline A1C of 8.18% for efsitora and insulin glargine. 7 95% CI for treatment difference (-0.13% to 0.14%). SOURCE Eli Lilly and Company

临床结果临床3期

2024-05-16

·BioPharmaDive

Lilly’s once-weekly insulin matches daily shots in late-stage tests

A once-weekly form of insulin being developed by Eli Lilly proved just as effective at controlling blood sugar in adults with diabetes as commonly used daily injections, according to results from two clinical trials that were released by the drugmaker Thursday.Lilly is betting that its experimental drug, dubbed insulin efsitora alfa, could provide a longer-lasting and more convenient option than daily treatment for managing diabetes.“With efsitora, we have an opportunity to provide an innovative once-weekly solution that safely achieves and maintains A1C control, reduces treatment burden of traditional daily injections and potentially improves adherence for people with diabetes, said Jeff Emmick, a senior vice president of product development for Lilly, in a statement on the trial results.Along with rival Novo Nordisk, Lilly is one of the dominant makers of diabetes medicines, selling a range of products that includes several insulins. Recently, more attention has been paid to the companies so-called GLP-1 drugs, which help treat diabetes by boosting the bodys secretion of insulin but have also proved powerfully effective at reducing weight.While those drugs have become overnight blockbusters, inflating Lillys and Novos market value by hundreds of billions of dollars, both companies are still investing in developing new insulin products. Efsitora is Lillys answer to Novos insulin icodec, which is also administered as a once-weekly injection and was recently recommended for approval in Europe. Food and Drug Administration advisers are meeting next week to discuss Novos application for approval in the U.S.Lilly is running five Phase 3 trials of efsitora, two of which read out results Thursday. The first, dubbed QWINT-2, tested efsitora versus once-daily insulin degludec for one year among insulin-naive adults with Type 2 diabetes. At week 52, efsitora treatment had reduced A1C levels a measure of blood sugar by 1.34%, versus 1.26% for insulin degludec. In both groups, A1C levels were below the 7% level that is commonly the goal of treatment.Efsitora was similarly “non-inferior“ to insulin degludec regardless of whether study participants were taking a GLP-1 agonist, Lilly said.The second, QWINT-4, studied efsitora in a sicker group of diabetes who had previously been treated with basal insulin and at least two injections per day of mealtime insulin. After 26 weeks, both efsitoraand the daily comparator, insulin glargine,reduced A1C levels by 1.07%.Lilly described efsitora as safe and well-tolerated in both studies, but didnt break out specific side effects in Thursdays press release excepting severe or clinically significant hypoglycemic events. In QWINT-2, investigators reported 0.58 hypoglycemic events per patient-year of exposure among those given efsitora, compared to 0.45 among those on insulin degludec. The respective rates were 6.6 and 5.9 for efsitora and insulin glargine in QWINT-4.Lilly expects results from studies QWINT-1, QWINT-3 and QWINT-5 later this year. Full data from QWINT-2 and QWINT-4 will be presented at the annual meeting of the European Association for the Study of Diabetes, the company said.Both Lilly and Novo, as well as one-time rival Sanofi, have been in the spotlight for their pricing of currently marketed insulin products. Last year, in response to sustained political pressure, all three lowered the list prices of their on-market insulins. The move coincided with recent changes in law that eliminated a cap on rebates paid into Medicaid, as well as placed a $35 monthly cap on out-of-pocket costs for insulin in Medicare.The companies had been paying substantial rebates to insurers for their insulin products, meaning that net prices of the drugs were substantially lower than their list price. '

临床3期临床结果

2024-05-15

·BioSpace

As Sales of Weight Loss Drugs Skyrocket, the Insulin Market Falters

Pictured: Collage of a man injecting insulin, money, syringes, and injector pens/Taylor Tieden for BioSpace When the Inflation Reduction Act rolled out in January 2023, a key tenet of the legislation was the associated Affordable Insulin Now Act, which caps the price of insulin products at $35 per month for Medicare Part D enrollees. Two months later, Novo Nordisk announced that in response, the firm was going to chop the cost of various insulin products by up to 75%. By November, however, Novo changed its tune: Instead of lowering insulin product Levemir by 65%, the firm announced that it was discontinuing the medication instead. Both FlexPens and vials will be completely off the market by the close of 2024. “[Novo] can’t make a product they’re losing money on, which may be the case with some insulins, and at some point they need to be smart with capital,” BMO Capital Markets analyst Evan Seigerman told BioSpace. Meanwhile, Q1 sales across the Novo portfolio increased 24% year-over-year with quarterly revenue of $9.37 billion due to the sky-high sales of GLP-1 drugs Ozempic and Wegovy, approved for type 2 diabetes and weight loss, respectively. In a similar move, weight-loss competitor Eli Lilly also slashed the cost of insulin drug Humalog by 70% to cost patients approximately $25 per vial. Then in March, the company reported that it was facing Humalog manufacturing constraints and warned that it may be temporarily out of stock of the drug by early April, though so far no shortages have been reported. Also like Novo, Lilly reported strong sales of its GLP-1 weight-loss drug, Zepbound, which was approved last November. In Q1 2024, Zepbound’s first full quarter on the U.S. market, sales of $517.4 million beat analysts’ expectations of $373 million. While below Wegovy’s $1.34 billion in Q1 sales, new Zepbound prescriptions now outpace Wegovy scripts. Lilly also saw continued strong sales of Mounjaro, its GLP-1 for type 2 diabetes. With such strong sales of GLP-1 drugs, questions arise about how crackdowns on insulin pricing will influence pipeline strategies and if pharma firms have a social responsibility to produce insulin, even at a loss. Moreover, if GLP-1s prevent obesity and diabetes on a mass scale, will insulin stay in such high demand? Does Levemir’s Withdrawal From Market Really Matter? Novo decided to discontinue Levemir in the U.S. “due to a combination of factors,” according to comments emailed to BioSpace, “most notably global manufacturing constraints, significant insurance formulary losses impacting patient access effective in January 2024 . . . as well the availability of alternative options in the U.S. market.” Manny Jurado, principal at the life sciences consulting Dedham Group who works with both biopharma and digital health clients in the GLP-1 and insulin space, added that the complexity of the American healthcare system also played a role. “In the U.S., we definitely live in a higher complexity healthcare ecosystem driven by factors like private insurance and . . . vertically integrated organizations like Cigna-ESI [and] Aetna-CVS, which pretty much touch every aspect of healthcare at this point,” Jurado told BioSpace. Considerations like differing state and federal regulations, as well as socioeconomic diversity of patients, makes it challenging for any pharma company to successfully launch their product to the American masses, Jurado said. As for insulin as a product, he said that there are other long-lasting insulins on the market, such as Tresiba, Lantus and Toujeo, among others, so patients are not being left without any insulin at all. However, with pricing caps, the availability of those existing insulins may also change in the future. “I believe manufacturers will continue to re-evaluate their strategic approaches to insulin as supply continues to be an issue,” Jurado said. How Are the GLP-1 and Insulin Markets Connected? Jurado said that few drugs have ever gripped the American public like GLP-1 weight-loss drugs. With all of that media noise and accompanying sales, critics of discontinuing Levemir have questioned whether sales of Novo’s Wegovy and Ozempic could have helped subsidize its production. Seigerman said that when it comes to the strength of GLP-1 sales, there is more that meets the eye. “Yes, on a per-product basis, Wegovy, Ozempic, Mounjaro, and others are profitable,” he said. “[But] you have to remember to get to where these products are now, billions upon billions of dollars were invested. It takes time to recoup; it’s not just the cost of goods.” For now, Seigerman sees the question of GLP-1 success as a completely separate equation from insulin pricing and supply. “Insulin is unique,” he told said. “These products cost money to make, and [Medicare paying] $35 a month is never going to be able to recoup the cost [of production].” If Levemir were reimbursed at a more appropriate rate for the investment, Seigerman argued, the drug may not have been discontinued. Seigerman added that the price caps also discourage drugmakers from developing insulin biosimilars. He noted that there are no biosimilars for Levemir—and that, he said, is the real problem in discontinuing the drug. “There should be biosimilars for these [insulins], and that begs the question of why there’s not.” Future Entanglement of GLP-1s and Insulin Sales Seigerman predicted that the rise of GLP-1s in popularity may impact the rates of diabetes and thus the need for insulin products because there is a “big overlap” between the obese population and diabetes patients. However, he said that it’s too early to tell how these markets will influence each other, and it may take a decade-plus for any such interplay to come to fruition. Jurado acknowledged the common links between obesity, diabetes and cardiovascular indications, along with other chronic conditions that GLP-1s address, but emphasized that it’s not enough to trigger a massive phase-out of insulin. “There will always be a strong need for insulin,” he said. Jurado said that drug manufacturers have social responsibility to people with diabetes—and that most recognize this. “I think these insulin manufacturers acknowledge that these drugs are truly life-time chronic [ones] and are finding ways to continue to support these patients and keep up with supply, despite these manufacturing challenges,” he said. As for the withdrawal of Levemir, Seigerman is of the firm belief that Novo was justified in its decision and not at fault for the lack of a biosimilar. “In the world of pharma, if you have products losing money with no strategic benefit, you have to look at your portfolio and say, is this how we want to use our limited resources? You have to make capital allocation decisions in R&D, manufacturing, and getting the appropriate products to the right patient every time.” Karen Fischer is a freelance science writer based in New Mexico. Reach her at kfischerwrites.com.

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适应症	最高研发状态	国家/地区	公司	日期
2型糖尿病	临床2期	美国	Halozyme Therapeutics, Inc.	2015-08-07
1型糖尿病	临床2期	美国	Halozyme Therapeutics, Inc.	2009-05-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ADA2020	N/A	2型糖尿病	25	Inhaled insulin plus basal insulin	膚簾齋網鬱構製壓壓製(觸糧淵夢選衊衊夢鬱窪) = 觸襯鹹蓋獵繭醖製遞蓋鬱餘醖廠齋積積衊壓獵 (鑰鹽夢糧淵鹽衊鑰鹹醖 )	-	2020-06-01
Pubmed \| J Investig Med	临床3期	2型糖尿病	-	Basal insulin peglispro (BIL)	選網憲蓋鑰繭餘窪鹹顧(築築繭觸窪鹹製淵積鹽) = 積艱獵壓壓鑰襯積鹹簾齋艱廠襯繭餘鑰製艱糧 (構蓋遞製窪簾襯鬱齋獵 )	-	2018-03-01
Pubmed \| J Investig Med	临床3期	2型糖尿病	-	Insulin glargine	選網憲蓋鑰繭餘窪鹹顧(築築繭觸窪鹹製淵積鹽) = 範願衊範製壓襯窪鬱憲齋艱廠襯繭餘鑰製艱糧 (構蓋遞製窪簾襯鬱齋獵 )	-	2018-03-01
NCT00916357 (Pubmed \| Diabetes Technol Ther)	临床2期	2型糖尿病	21	Insulin Lispro with Hyaluronidase	願壓齋鏇襯願簾齋願憲(憲鏇簾鑰廠憲膚鹹壓鹽) = 觸鏇膚築糧廠艱遞夢衊網繭餘遞淵鬱構築齋製 (範鬱窪壓願襯製衊簾願 ) 更多	积极	2012-03-01