富马酸泰诺福韦酯与工业设计
戴强UOP先进甲醇制烯烃技术助力烯烃行业发展Reduced
19
煤到聚合物– 操作成本
煤通过MTO制取聚合物 : 富有竞争力的操作成本和富有吸引力的投资回报率
20
MTO 总结
• 乙烯和丙烯需求保持强劲增长。
• MTO技术提供了一条从煤或天然气为原料甲醇制乙烯、丙烯的新路径。
– 富有竞争力的先进的工艺技术
– 轻烯烃产品收率高(> 89%) ；生产每吨轻烯烃仅消耗2.6吨甲醇
– 现金成本= $523/MT 聚合物
– 净成本= $1000/MT 聚合物投资回收期短, 内部投资回报收益高, 高净现值
– 投资回报年限 = 2.6 年 – 投资回报率 = 20.0% – 净现值 (20 年) = $34 亿
Advanced MTO enables excellent Coal to Polymers economics
– 低催化剂磨损，每处理一吨甲醇进料催化剂损耗仅为0.17公斤
– 高压力设计，投资低
– 宽泛的丙乙比(1.25 到1.8)
– 单系列装置轻烯烃产能可达180万吨/年
– 副产品C4烯烃可以生产后续的B1-B2和丁二烯
• 2013 首次在南京惠生清洁能源公司, 到2106年底有3套装置投入运行
• 与全球煤和天然气的利用息息相关
收率提升受益于OCP 集成设计
100 90 80
Other high value products Ethylene Propylene
70
60
50
40
30
20
10
0 Naphtha
MTP
MTO
Advanced MTO
12
2.6 甲醇消耗每吨生产轻烃
100
90
80
15 Design for Quality
using a process called tailor welding -- manufacturers now laser weld two sheet metal blanks of different thickness and then stamp the blank.
9
Tailor-Welded Blank Example
5
B. Design Reviews
n
Nearly all companies today have formal design review processes (periodic reviews of product & process designs). These reviews involve multiple disciplines (cross-functional) n design engineers, process engineers, manufacturing, marketing n goals: product~process integration and product~customer integration While most companies use cross-functional design reviews, authority levels may vary by degree of functional integration (next slide).
15 design for quality designquality productstqm pathammett designingquality ntoproducts "design designcost lever product (design) engineering 10:1* process engineering 4:1* factory conditions 1:1* effectiveforce quality costs (non-world class) cost worldclass manufacturers design costsassociated poorquality influencedmore product/process design than factory operations. design quality productstqm pathammett measuringdesign quality whichfunctional requirements design(fitness use,feature- based quality). designpermits rational manufacturing (design specificationrequirements achievable(realistic tolerances). designlasts reasonablelife (low failure rate) lowmaintenance costs (reliability). sometechniques used designquality ntoproducts robustdesign designreview teams/ concurrent engineering assembly(dfma) nspection(install poke-yoke devices) qualityfunction deployment (qfd) failuremode effectsanalysis (fmea) al echniques pr ovi de st ruct ure designi ng qual product designquality productstqm pathammett robustdesign
富马酸泰诺福韦酯片说明书(英文)
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use VIREAD safely and effectively. See full prescribing informationfor VIREAD.VIREAD® (tenofovir disoproxil fumarate) tabletsInitial U.S. Approval: 2001WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OFHEPATITISSee full prescribing information for complete boxed warning. • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use ofnucleoside analogs, including VIREAD. (5.1)• Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic functionshould be monitored closely in these patients. Ifappropriate, resumption of anti-hepatitis B therapy may bewarranted. (5.2)---------------------------RECENT MAJOR CHANGES--------------------------- Indications and Usage (1.2) 10/2010 Dosage and Administration (2.1, 2.2, 2.3) 10/2010 Warnings and PrecautionsNew Onset or Worsening Renal Impairment (5.3) 10/2009Decreases in Bone Mineral Density (5.6) 03/2010----------------------------INDICATIONS AND USAGE--------------------------- VIREAD is a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor.VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. (1)VIREAD is indicated for the treatment of chronic hepatitis B in adults. (1)---------------------------DOSAGE AND ADMINISTRATION-------------------- • Recommended dose for the treatment of HIV-1 or chronic hepatitis B in adults: 300 mg once daily taken orally withoutregard to food. (2.1)• Recommended dose for the treatment of HIV-1 in pediatric patients (≥12 years of age and ≥35 kg): 300 mg once daily taken orally without regard to food. (2.2)• Dose recommended in renal impairment in adults:Creatinine clearance 30-49 mL/min: 300 mg every 48 hours.(2.3)Creatinine clearance 10-29 mL/min: 300 mg every 72 to 96 hours.(2.3)Hemodialysis: 300 mg every 7 days or after approximately 12hours of dialysis. (2.3)-----------------------DOSAGE FORMS AND STRENGTHS-------------------- Tablets: 300 mg. (3)--------------------------------CONTRAINDICATIONS------------------------------ None. (4)--------------------------WARNINGS AND PRECAUTIONS--------------------- • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with VIREAD. Monitor CrCl and serum phosphorus in patients at risk. Avoid administeringVIREAD with concurrent or recent use of nephrotoxic drugs. (5.3) • Coadministration with Other Products: Do not use with other tenofovir-containing products (e.g., ATRIPLA and TRUVADA). Do not administer in combination with HEPSERA. (5.4) • HIV testing: HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. VIREAD should only be used as part of an appropriate antiretroviralcombination regimen in HIV-infected patients with or without HBV coinfection. (5.5)• Decreases in bone mineral density (BMD): Observed in HIV-infected patients. Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.6)• Redistribution/accumulation of body fat: Observed in HIV-infected patients receiving antiretroviral combination therapy. (5.7)• Immune reconstitution syndrome: Observed in HIV-infected patients. May necessitate further evaluation and treatment. (5.8)• Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and considertreatment modification. (5.9)-----------------------------ADVERSE REACTIONS--------------------------------In HIV-infected subjects: Most common adverse reactions (incidence ≥10%, Grades 2 - 4) are rash, diarrhea, headache, pain, depression, asthenia, and nausea. (6)In HBV-infected subjects with compensated liver disease: most common adverse reaction (all grades) was nausea (9%). (6)In HBV-infected subjects with decompensated liver disease: most common adverse reactions (incidence ≥10%, all grades) were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia. (6)To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or /medwatch------------------------------DRUG INTERACTIONS--------------------------------• Didanosine:Coadministration increases didanosineconcentrations. Use with caution and monitor for evidence ofdidanosine toxicity (e.g., pancreatitis, neuropathy). Considerdose reductions or discontinuations of didanosine if warranted.(7.1)• Atazanavir:Coadministration decreases atazanavirconcentrations and increases tenofovir concentrations. Useatazanavir with VIREAD only with additional ritonavir; monitor for evidence of tenofovir toxicity. (7.2)• Lopinavir/ritonavir:Coadministration increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.3)----------------------------USE IN SPECIFIC POPULATIONS-------------------• Pregnancy: There is a registry available. Enroll patients by calling 1-800-258-4263.• Nursing mothers: Women infected with HIV should be instructed not to breast feed. (8.3)• Safety and efficacy not established in patients less than 12 years of age. (8.4)See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved Patient LabelingRevised: October 2010 FULL PRESCRIBING INFORMATION: CONTENTS*WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS1 INDICATIONS AND USAGE1.1 HIV-1 Infection1.2 Chronic Hepatitis B2 DOSAGE AND ADMINISTRATION2.1 Recommended Dose in Adults2.2 Recommended Dose in Pediatric Patients (≥12 Years ofAge and ≥35 kg)2.3 Dose Adjustment for Renal Impairment in Adults3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis5.2 Exacerbation of Hepatitis after Discontinuation ofTreatment5.3 New Onset or Worsening Renal Impairment5.4 Coadministration with Other Products5.5 Patients Coinfected with HIV-1 and HBV5.6 Decreases in Bone Mineral Density5.7 Fat Redistribution5.8 Immune Reconstitution Syndrome5.9 Early Virologic Failure6 ADVERSE REACTIONS6.1 Adverse Reactions from Clinical Trials Experience6.2 Postmarketing Experience7 DRUG INTERACTIONS7.1 Didanosine7.2 Atazanavir7.3 Lopinavir/Ritonavir7.4 Drugs Affecting Renal Function8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Patients with Impaired Renal Function10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.3 Pharmacokinetics12.4 Microbiology13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES14.1 Clinical Efficacy in Patients with HIV-1 Infection14.2 Clinical Efficacy in Patients with Chronic Hepatitis B16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION AND FDAAPPROVED PATIENT LABELING* Sections or subsections omitted from the full prescribing information are not listedFULL PRESCRIBING INFORMATIONWARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITHSTEATOSIS and POST TREATMENT EXACERBATION OF HEPATITISLactic acidosis and severe hepatomegaly with steatosis, including fatalcases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals [See Warnings and Precautions (5.1)].Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical andlaboratory follow-up for at least several months in patients who discontinueanti-hepatitis B therapy, including VIREAD. If appropriate, resumption ofanti-hepatitis B therapy may be warranted [See Warnings and Precautions(5.2)].1 INDICATIONS AND USAGEInfection1.1 HIV-1VIREAD® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.The following points should be considered when initiating therapy with VIREAD for the treatment of HIV-1 infection:• VIREAD should not be used in combination with TRUVADA® or ATRIPLA® [See Warnings and Precautions (5.4)].1.2 Chronic Hepatitis BVIREAD is indicated for the treatment of chronic hepatitis B in adults.The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection:• This indication is based primarily on data from treatment of subjects who were nucleoside-treatment-naïve and a smaller number of subjects who had previously received lamivudine or adefovir dipivoxil. Subjects were adults with HBeAgpositive and HBeAg-negative chronic hepatitis B with compensated liver disease [See Clinical Studies (14.2)].• VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease. [See Adverse Reactions (6.1), Clinical Studies(14.2)]• The numbers of subjects in clinical trials who had lamivudine- or adefovirassociated substitutions at baseline were too small to reach conclusions ofefficacy [See Microbiology (12.4), Clinical Studies (14.2)].2 DOSAGE AND ADMINISTRATION2.1 Recommended Dose in AdultsFor the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.2.2 Recommended Dose in Pediatric Patients (≥12 Years of Age and ≥35 kg) For the treatment of HIV-1 in pediatric patients 12 years of age and older with body weight ≥35 kg (≥77 lb): The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.2.3 Dose Adjustment for Renal Impairment in AdultsSignificantly increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment [See Clinical Pharmacology (12.3)]. Therefore, the dosing interval of VIREAD should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients [See Warnings and Precautions (5.3)].No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment [See Warnings and Precautions (5.3)].Table 1 Dosage Adjustment for Patients with Altered Creatinine ClearanceCreatinine Clearance(mL/min)aHemodialysis Patients≥50 30–49 10–29Recommended 300 mg Dosing Interval Every 24hoursEvery 48hoursEvery 72 to96 hoursEvery 7 days or after a total ofapproximately 12 hours ofdialysis ba. Calculated using ideal (lean) body weight.b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration.VIREAD should be administered following completion of dialysis.The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients.No data are available to make dose recommendations in pediatric patients 12 years of age and older with renal impairment.3 DOSAGE FORMS AND STRENGTHSVIREAD is available as tablets. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil. The tablets are almond-shaped, light blue, film-coated, and debossed with “GILEAD” and “4331” on one side and with “300” on the other side.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Lactic Acidosis/Severe Hepatomegaly with SteatosisLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).5.2 Exacerbation of Hepatitis after Discontinuation of Treatment Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.5.3 New Onset or Worsening Renal ImpairmentTenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD [See Adverse Reactions (6.2)].It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA®.Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 mL/min [See Dosage and Administration (2.3)]. No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity.VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent.5.4 Coadministration with Other ProductsVIREAD should not be used in combination with the fixed-dose combination products TRUVADA or ATRIPLA since tenofovir disoproxil fumarate is a component of these products.VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil) [See Drug Interactions (7.4)].Coinfected with HIV-1 and HBV5.5 PatientsDue to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen.HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD.5.6 Decreases in Bone Mineral DensityAssessment of bone mineral density (BMD) should be considered for adults and pediatric patients 12 years of age and older who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.In HIV-1 infected adult subjects treated with VIREAD in Study 903 through 144 weeks, decreases from baseline in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the VIREAD group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through Week 144. Twenty-eightpercent of VIREAD-treated subjects vs. 21% of the stavudine-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the VIREAD group and 6 subjects in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) in the VIREAD group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the VIREAD group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range.In a clinical study of HIV-1 infected pediatric subjects 12 years of age and older (Study 321), bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in this age group. In this study, the mean rate of bone gain was less in the VIREAD-treated group compared to the placebo group. Six VIREAD treated subjects and one placebo treated subject had significant (>4%) lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated pediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults.The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2)].The bone effects of VIREAD have not been studied in patients with chronic HBV infection.Redistribution5.7 FatIn HIV-infected patients redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.8 Immune Reconstitution SyndromeImmune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.5.9 Early Virologic FailureClinical studies in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.6 ADVERSEREACTIONSThe following adverse reactions are discussed in other sections of the labeling:• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning, Warnings and Precautions (5.1)].• Severe Acute Exacerbation of Hepatitis [See Boxed Warning, Warnings and Precautions (5.2)].• New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)]. • Decreases in Bone Mineral Density [See Warnings and Precautions (5.6)].• Immune Reconstitution Syndrome [See Warnings and Precautions (5.8)].6.1 Adverse Reactions from Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Clinical Trials in Adult Patients with HIV-1 InfectionMore than 12,000 subjects have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access studies. A total of 1,544 subjects have received VIREAD 300 mg once daily in clinical trials; over 11,000 subjects have received VIREAD in expanded access studies.The most common adverse reactions (incidence ≥10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.Treatment-Naïve PatientsStudy 903 - Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve subjects received VIREAD (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness.Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 2.Table 2Selected Treatment-Emergent Adverse Reactions a (Grades 2–4) Reported in≥5% in Any Treatment Group in Study 903 (0–144 Weeks)VIREAD + 3TC + EFVd4T + 3TC + EFV N=299 N=301 Body as a WholeHeadache Pain Fever Abdominal pain Back painAsthenia 14%13% 8% 7% 9% 6% 17% 12% 7% 12% 8% 7% Digestive SystemDiarrhea Nausea Dyspepsia Vomiting 11% 8% 4% 5% 13% 9% 5% 9% Metabolic Disorders Lipodystrophy b1% 8%Musculoskeletal Arthralgia Myalgia 5% 3% 7% 5% Nervous SystemDepression InsomniaDizziness Peripheral neuropathy cAnxiety 11%5% 3% 1% 6% 10% 8% 6% 5%6% Respiratory Pneumonia 5% 5% Skin and Appendages Rash event d18% 12%a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationshipto study drug.b. Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.c. Peripheral neuropathy includes peripheral neuritis and neuropathy.d. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.Laboratory Abnormalities: With the exception of fasting cholesterol and fastingtriglyceride elevations that were more common in the stavudine group (40% and 9%)compared with VIREAD (19% and 1%) respectively, laboratory abnormalities observedin this study occurred with similar frequency in the VIREAD and stavudine treatmentarms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 3.Table 3 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-TreatedSubjects in Study 903 (0–144 Weeks)VIREAD + 3TC + EFV d4T + 3TC + EFVN=299 N=301Any ≥ Grade 3 Laboratory Abnormality 36% 42%Fasting Cholesterol (>240 mg/dL) 19% 40%Creatine Kinase (M: >990 U/L; F: >845 U/L) 12% 12%Serum Amylase (>175 U/L) 9% 8%AST (M: >180 U/L; F: >170 U/L) 5% 7%ALT (M: >215 U/L; F: >170 U/L) 4% 5%Hematuria (>100 RBC/HPF) 7% 7%Neutrophils (<750/mm3) 3%1% Fasting Triglycerides (>750 mg/dL) 1% 9%Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviralnaïve subjects received either VIREAD + EMTRIVA® administered in combination withefavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz(N=254). Adverse reactions observed in this study were generally consistent with thoseseen in previous studies in treatment-experienced or treatment-naïve subjects(Table 4).Table 4Selected Treatment-Emergent Adverse Reactions a (Grades 2–4) Reported in≥5% in Any Treatment Group in Study 934 (0–144 Weeks) VIREAD b + FTC + EFV AZT/3TC + EFVN=257 N=254 Gastrointestinal Disorder Diarrhea Nausea Vomiting9% 9% 2% 5% 7% 5% General Disorders and Administration Site Condition Fatigue9% 8% Infections and Infestations SinusitisUpper respiratory tract infectionsNasopharyngitis 8% 8%5% 4% 5%3% Nervous System Disorders Headache Dizziness 6% 8% 5% 7%Psychiatric Disorders Depression Insomnia9% 5% 7% 7% Skin and Subcutaneous TissueDisorders Rash eventc7%9%a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationshipto study drug.b. From Weeks 96 to 144 of the study, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVAwith efavirenz. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, andrash vesicular. Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 5).Table 5 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in AnyTreatment Group in Study 934 (0–144 Weeks)VIREAD a + FTC + EFV AZT/3TC + EFVN=257 N=254Any ≥ Grade 3 Laboratory Abnormality 30% 26%Fasting Cholesterol (>240 mg/dL) 22% 24%Creatine Kinase (M: >990 U/L; F: >845 U/L) 9% 7%Serum Amylase (>175 U/L) 8% 4%Alkaline Phosphatase (>550 U/L) 1% 0%AST (M: >180 U/L; F: >170 U/L) 3% 3%ALT (M: >215 U/L; F: >170 U/L) 2% 3%Hemoglobin (<8.0 mg/dL) 0% 4%Hyperglycemia (>250 mg/dL) 2% 1%Hematuria (>75 RBC/HPF) 3% 2%Glycosuria (≥3+) <1% 1%Neutrophils (<750/mm3) 3%5% Fasting Triglycerides (>750 mg/dL) 4% 2%a. From Weeks 96 to 144 of the study, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVAwith efavirenz.Treatment-Experienced PatientsTreatment-Emergent Adverse Reactions: The adverse reactions seen in treatmentexperienced subjects were generally consistent with those seen in treatment naïvesubjects including mild to moderate gastrointestinal events, such as nausea, diarrhea,vomiting, and flatulence. Less than 1% of subjects discontinued participation in theclinical studies due to gastrointestinal adverse reactions (Study 907).A summary of moderate to severe, treatment-emergent adverse reactions that occurredduring the first 48 weeks of Study 907 is provided in Table 6.。
泰诺福韦的合成工艺研究
泰诺福韦的合成工艺研究王志刚;聂静;王治国【摘要】泰诺福韦是制备抗病毒药物泰诺福韦酯富马酸盐的关键中间体，以腺嘌呤和（ R）－1，2－亚丙基碳酸酯为原料，经开环缩合、取代和水解3步反应制得泰诺福韦。
反应过程用高效液相色谱仪（ HPLC ）进行监测，探讨了反应的最佳工艺：①开环缩合的最佳反应温度为145℃，最佳反应时间为5．5 h；②以叔丁醇镁为碱，取代反应的最佳反应时间为10 h；③采用廉价的三甲基氯硅烷和溴化钠进行水解，最佳反应时间为24 h。
在最优化的条件下总收率达到49．6％。
%Tenofovir is the key intermediate for the antiviral drug tenofovir disoproxil fumarate .Tenofovir is synthesized by adenine and propyl carbonate through ring -opening condensation , substitution reaction and hydrolysis reaction .The process of reaction is monitored by using High Performance Liquid Chromatography ( HPLC) .The optimal reaction conditions are discussed:①The best synthesis condition of ring -opening condensation is at 145 ℃ for 5.5 h.②The best reaction time of substitution reaction is 10 h with magnesium tert-butoxide as alkali .③The best reaction time of hydrolysis reaction is 24 h using cheap trimethylchlorosi-lane and sodium bromide.The overall yield of 49.6 % is obtained under optimal conditions.【期刊名称】《湖北理工学院学报》【年(卷),期】2015(000)005【总页数】4页(P46-49)【关键词】泰诺福韦;合成;工艺【作者】王志刚;聂静;王治国【作者单位】湖北理工学院化学与化工学院，湖北黄石435003; 湖北理工学院矿区环境污染控制与修复湖北省重点实验室，湖北黄石435003;湖北理工学院化学与化工学院，湖北黄石435003; 湖北理工学院矿区环境污染控制与修复湖北省重点实验室，湖北黄石435003;湖北理工学院化学与化工学院，湖北黄石435003; 湖北理工学院矿区环境污染控制与修复湖北省重点实验室，湖北黄石435003【正文语种】中文【中图分类】O626Key words：tenofovir;synthesis;process泰诺福韦(Tenofovir)，化学名是R-9-(2-磷酸甲氧基丙基)腺嘌呤，CAS号：147127-20-6，是抗病毒药物泰诺福韦酯的关键中间体。
诺氏制药产品DA创意设计提案--songny888资料文档
作品 － 凯洛欣标志设计
7 拥有庞大的管理资料库
产品标志设计方案一
简单的线条勾勒出大脑的形状，同时对中文“凯”字进行变形，让二者有机 的结合在一起。生命如同一棵正茁壮生长的大树，而凯洛欣正是保护、滋养这棵 大树的根系。 本标志构图简洁，融合国际化的设计理念，生命绿与科技蓝更好的昭示出用 科技创造新生的概念。
本画面极具视觉冲击，
张力十足，从而使受众群 体产生强烈的震撼，最终 由此及彼达到对药品药性 的记忆与传播。
创意说明：
腾空而起的新式战斗机代
表了强势及征服，这预示 着凯洛欣一飞冲天的发展 势头，同时飞向不同方向 的三个飞机，有力的阐释 凯洛欣的三重作用功效， 背景中的人物享受的表情 仿佛在幻想，如此强劲的 三重作用机制，真棒.
诺氏制药 产品DA创意设计提案
1 拥有庞大的管理资料库
产品一：凯洛欣产品标志及DA封面创意设计
产品介绍：
诺氏制药集团近年来致力于神经保护剂的开发,如对曲克芦丁脑蛋白水解物注 射液(普洛迪) 和脑苷肌肽注射液(凯洛欣)都进行了一些初步的临床和基础研究。 这些研究遵循了规范的原则并克服了药物单一靶点作用的困惑,初步显示出一 定的疗效。
普洛迪中含有曲克芦丁和脑蛋白水解物，分别作用于神经细胞和血管，体现了双 靶位作用。其中，曲克芦丁能抑制血小板的聚集，有防止血栓形成的作用。同时能对 抗5－羟色胺、缓激肽引起的血管损伤，增加毛细血管抵抗力，降低毛细血管通透性， 可防止血管通透性升高引起的水肿。本品所含的大量活性多肽、多种氨基酸等能透过 血脑屏障，以多种形式作用于中枢神经，调整和改善神经元的代谢，并影响其呼吸链， 具有激活、改善脑内神经递质和酶的活性，保护神经细胞免受各种缺血和神经毒素的 损害。能增加脑组织对葡萄糖的利用，改善脑细胞缺氧状态，对缺氧的脑组织有保护 作用。体现出普洛迪的双重疗效。因此是认知功能障碍及脑卒中恢复期治疗的首选用 药。
年产16000吨L-天门冬氨酸建设项目环境影响报告表
础上编制完成了该项目环境影响报告书。 在报告书编写过程中得到了烟台市环保局、龙口市环保局、相关专家以及建 设单位的大力支持和协助，在此一并表示衷心的感谢。 由于水平所限，书中不足之处难免，敬请专家、领导批评指正。 项目组 2017 年 3 月
年产 16000 吨 L-天门冬氨酸建设项目
总论
第 1 章 总论
1-1
年产 16000 吨 L-天门冬氨酸建设项目
总论
号)； （5） 《国务院关于印发节能减排综合性工作方案的通知》 （国发[2007]15 号） ； （6） 《关于进一步加强危险废物和医疗废物监管工作的意见》 （环发 [2011]19 号） ； （7） 《关于实施〈环境空气质量标准〉 (GB3095-2012) 的通知》 ( 环发 [2012]11 号)； （8） 《环境保护部关于进一步加强环境影响评价管理防范环境风险的通 知》(环发[2012]77 号)； （9） 《关于切实加强风险防范严格环境影响评价管理的通知》 ( 环发 [2012]98 号)； （10） 《危险废物转移联单管理办法》 （国家环境保护总局令 第 5 号） ； （11） 《关于执行大气污染物特别排放限值的公告》 （环境保护部公告 2013 年 第 14 号） ； （12） 《关于印发<建设项目环境影响评价政府信息公开指南>（试行）的 通知》 （环办[2013]103 号） ； （13） 《关于切实加强环境影响评价监督管理工作的通知》(环办[2013]104 号)； （14） 《 关 于 发 布 < 一 般 工 业 固 体 废 物 贮 存 、 处 置 场 污 染 控 制 标 准 > （GB18599- 2001）等 3 项国家污染物控制标准修改单的公告》 （环境保护部公告 2013 年 第 36 号） ； （15） 《关于加强企业环境信用体系建设的指导意见》 （环发[2015]161 号） ； （16） 《关于印发<建设项目环境影响评价信息公开机制方案>的通知 《 （环 发[2015]162 号） ； （17） 《关于发布 < 环境保护部审批环境影响评价文件的建设项目目录 （2015 年本）>的公告》 （环保部公告 2015 年第 17 号） ； （18） 《工业和信息化部关于促进化工园区规范发展的指导意见》 （工信部 原[2015]433 号） ； （19） 《环境保护公众参与办法》 （环境保护部令 2015 年第 35 号） ；
VersaFlow Coriolis 6000选型指南说明书
TABLE V
Hazardous Area Approvals
Hygienic/Sanitary Approvals
None ATEX Ex ia (T1-T6) IEC Ex ia (T1-T6) cFMus Class 1 Div 1 (USA standards) cFMus (Canadian Standards) / Dual seal for liquids’ cFMus (Canadian Standards) / Dual seal for gases’ None NACE according to MRO175 / ISO 15156 and MRO103
SmartLine® VersaFlow Coriolis 6000
CM74 Size 25 Stainless Steel or Hastelloy C
Model Selection Guide
36-CM-16-42
Issue 7
• Broad Range of Operating Temperatures
(Alu or SS mandatory for Cryogenic or High Temperature)
3 point mass flow calibration
5 point mass flow calibration
3 point volume flow calibration
5 point volume flow calibration
TWC 9400 Compact Mount (Not for High Temperature) TWC 9400 Field Mount Other
Requires a separate MSG# to be entered. Either
泰诺福韦中间体PMPA市场调研
泰诺福韦，简称PMPA一、产品信息中文名(R)-9-(2-磷酸甲氧基丙基)-腺嘌呤，泰诺福韦酯中间体PMPA，替诺福韦分子式英文名1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid，TenofovirCAS No. 147127-20-6分子式C9H14N5O4P分子量287.21二、合成方法三、生产厂家厂家设计产能生产状态备注上海迪赛诺化学制药200吨/年泰诺福韦在生产上海迪赛诺同大丰海天医药合作在盐城建设有限公司生产，目前属于上海迪赛诺的控股公司，15年9月更名盐城迪赛诺制药有限公司安徽贝克联合制药有在生产主要出口替诺福韦原料药600吨/年富马酸替诺限公司福韦二吡呋酯中间体荆门市帅邦化学科技有限公司300吨/年在生产16年月出口印度PMPA14.7吨乐平市赛复乐医药化工有限公司100吨/年在生产16年通过贸易公司出口至少PMPA9.8吨，富马酸泰诺福韦酯至少2.275吨埃斯特维华义制药有限公司2012年环评显示90吨/年，实际产能约200吨/年在生产16年出口143.75吨富马酸泰诺福韦酯，属于出口量最大的一家，埃斯特维华义制药有限公司是西班牙ESTEVEQUIMICA公司与杭州华东医药集团子公司（义乌市华义投资有限公司）的第二家合资公司，主要从事非专利化学原料药的研发、生产与销售。
四、国内外下游产品客户1、下游产品及用途1.1泰诺福韦简介泰诺福韦（Tenofovir），化学名R-9-（2-磷酸甲氧基丙基）腺嘌呤（简称PMPA），是抗病毒药物富马酸泰诺福韦酯的关键中间体。
富马酸泰诺福韦酯是一种新型的开环核苷酸类逆转录酶抑制剂，是一种酯类前药，口服吸收后迅速转变成泰诺福韦。
美国FDA在2001年和2008年分别批准其用于艾滋病（HIV）和慢性乙型肝炎（HBV）的治疗。
富马酸泰诺福韦酯，中文名：替诺福韦，通用名称：富马酸替诺福韦二吡呋酯片；商品名称：韦瑞德，英文名称：Tenofovir Disoproxil Fumarate Tablets，替诺福韦是世界卫生组织WHO艾滋病治疗指南推荐的艾滋病抗病毒一线药物。