Formulation strategies in immunotherapeutic pharmaceutical products

Development of immunologic-based biopharmaceutical products have strikingly increased in recent years and have made evident contributions to human health.Antibodies are the leading entity in immunotherapy,while chimeric antigen receptor T cells therapies are the advent of a novel strategy in this area.In order to enable antibody candidates or cells available as products,formulation is critical in terms of stabilize molecules or cells to achieve practical shelf life,storage and handling conditions.Here we provide a concise and contemporary review of ongoing formulation strategies and excipients used in approved antibodies and cellular therapeutic products.Excipients are categorized,and their function in formulations are discussed.

Co-integration Analysis of the Relationship between New Product Output and R&D Investment in China’s Pharmaceutical Industry

Objective To study the possible relationship between the output of new products in China’s pharmaceutical industry and the investment in research and development(R&D),and to provide a theoretical basis for the decision-making of relevant enterprises and institutions.Methods The econometric software Stata 14 was used to perform unit root test on the relevant data.Then,a co-integration regression equation was established after stabilization,which was analyzed through co-integration test(E-G two-step method).Results and Conclusion There is a long-term equilibrium and short-term error correction relationship between the output of new products and the investment of R&D funds in China’s pharmaceutical industry.During the lagging periods from 1 to 6,R&D investment is the Granger reason for the output of new products.The investment of R&D funds has a positive effect on the output of new products and the effect is significant.Therefore,more investment should be made in R&D to enhance the output of new products.

A New Model for a New Central Purchasing Unit for Health Products to Support Reaching the Objectives of a Lasting Development and Facing Sanitary Crisis

Medicines are a global, strategic and diplomatic issue [1]. The UN General Secretary’s High Level Task Force [2] on Access to Medicines calls for a new approach to reduce the gap between medical innovations and access to medicines. Inequality in access to quality pharmaceutical products in a framework of global health democracy poses a threat to the ethical and equitable management of the provision of quality health care, particularly during global health crises. In French-speaking Africa, the lack of a unified production of pharmaceutical medicines forces wholesalers （public and private） to import almost all of their medicine demands resulting in a risk of dependence and major pharmaceutical quality defects. These central purchasing units are therefore often faced with the major challenge of guaranteeing the performance of their services and the security of their supplies. In order to achieve component 3 （“Access to Health”） of the SDOs （sustainable development goals）, in particular the access to affordable medicines, it is essential for a country to have a strategy of pharmaceutical independence [3] by anticipating the epidemiological transition and the management of health crises. This strategy of pharmaceutical independence is based in the short and medium term on the strengthening of central purchasing units and the establishment of a public-private partnership between central purchasing units and wholesalers, and in the long term on the establishment of competitive production units that comply with international standards. However, recent health crises have shown the fragility of public central purchasing units and make it difficult to anticipate health crises.

Integrating traditional Chinese (herbal) medicines into risk based regulation-With focus on non-clinical requirements to demonstrate safety

Within the public health sector of Hong Kong(China),there is a consensus around the important role of traditional Chinese medicines.For Hong Kong(China)to play a bridging role to bring Chinese medicines to the global market requires a concerted effort from the government,academic institutes and industries.The release of the final version of the European Medicines Agencies guidance document,which details the acceptance of minimum requirements to nonclinical package in bibliographical applications,grants the opportunity for well-established and traditional herbal medicines to demonstrate an‘acceptable safe’status for registration in the European Union.It is anticipated that this minimum nonclinical package can be applied to demonstrate the safe use of many traditional Chinese medicines regardless of their eligibility to be registered under the simplified procedure within the European Union.This paper conceptualizes an integration of a simplified evaluation route for eligible proprietary Chinese medicines(pCm)with long history of use into the existing drug regulatory framework in Hong Kong(China).Such integration utilizing the minimum nonclinical package,based on bibliographical data or expert report,as proof of evidence to demonstrate safety for pCm with long history of use requires less demand in scientific resources.With Hong Kong(China)conducting‘first hand’review for eligible pCm,it provides an option for overseas and local pharmaceutical companies to register their products in Hong Kong(China)without the need to rely on issuance of Certificate of Pharmaceutical Product from other countries.This could bring eligible pCm with long history of use to reach international risk-based standard and to be marketed globally as‘medicines’to reach their full therapeutic potential.An important process to positioning Hong Kong(China)to compete with other countries in promoting importation and exportation of pCm to better serve the global health.

A review on analytical methods for pharmaceutical and personal care products and their transformation products

Pharmaceutical and personal care products(PPCPs)and corresponding transformation products have caused widespread concern due to their persistent emissions and potential toxicity.They have wide octanol-water partition coefficients(K_(ow))and different ionization constants(pK_(a))resulting in a poor analysis accuracy and efficiency.A suitable analytical method is the first prerequisite for further research on their environmental behavior to prioritize the substances.This study reviewed a full-scale analytical protocol for environmental samples in the recent ten years:from sampling to instrumental methods.Passive sampling techniques were compared and recommended for long-term continuous and scientific observation.A quick and effective sample extraction and clean-up method are highly required.Chromatographic methods coupled to mass spectrometry for determining PPCPs with a wide range of logK_(ow)(-7.53 to 10.80)were summed up.High-resolution mass spectrometry was confirmed to be a promising strategy for screening unknown transformation products,which would provide a nanogram level of detection limits and more accurate mass resolution.Screening strategies and mass change principles were summarized in detail.The recovery rate was important in multiple contaminants analysis identification and factors affecting the recovery rate of PPCPs were also discussed in this review,including sample matrix,target compounds characteristics,extraction method and solid-phase adsorbent.This review provides useful information for the selection of appropriate analytical methods and future development directions.

Facile in situ growth of highly dispersed palladium on phosphotungstic-acid-encapsulated MIL-IOO（Fe） for the degradation of pharmaceuticals and personal care products under visible light

A simple, facile in situ reduction approach is reported for the synthesis of Pd- nanoparticle-decorated phosphotungstic acid （PTA）-MIL-100（Fe） nanocomposites （Pd-H3PW12040-MIL-100（Fe）, denoted Pd-PTA-MIL-100（Fe））. During the in situ synthesis, PTA is encapsulated into the matrix of MIL-100（Fe） and serves as a UV-switchable reducing agent, resulting in highly dispersed Pd NPs. Using the photocatalytic degradation of pharmaceuticals and personal care products as model reactions, the ternary Pd-PTA-MIL-100（Fe） hybrids exhibited enhanced photocatalytic activity compared with their foundation matrices, the binary PTA-MIL-100（Fe） nanocomposite. Based on photoelectrochemical analyses, the improved photocatalytic performance can be attributed to the well-known electronic conductivity of the Pd NPs, the fast electron transport of PTA, the intense visible-light absorption of MIL-100（Fe）, and the matched energy levels of the three components： MIL-100（Fe）, PTA, and Pd NPs. Importantly, almost no Fe and W ions were leached from the samples during the reaction, demonstrating the photostability of the Pd-PTA-MIL-100（Fe） composite. In addition, possible photocatalytic reactions mechanisms have also been investigated.

Pharmaceuticals and personal care products (PPCPs) in the freshwater aquatic environment

Pharmaceuticals and personal care products(PPCPs)are a unique group of emerging environmental contaminants,due to their inherent ability to induce physiological effects in human at low doses.An increasing number of studies has confirmed the presence of various PPCPs in different environmental compartments,which raises concerns about the potential adverse effects to humans and wildlife.Therefore,this article reviews the current state-of-knowledge on PPCPs in the freshwater aquatic environment.The environmental risk posed by these contaminants is evaluated in light of the persistence,bioaccumulation and toxicity criteria.Available literature on the sources,transport and degradation of PPCPs in the aquatic environment are evaluated,followed by a comprehensive review of the reported concentrations of different PPCP groups in the freshwater aquatic environment(water,sediment and biota)of the five continents.Finally,future perspectives for research on PPCPs in the freshwater aquatic environment are discussed in light of the identified research gaps in current knowledge.

Occurrence, sources and fate of pharmaceuticals and personal care products in the groundwater: A review

The presence of pharmaceuticals and personal care products(PPCPs)in the aquatic environment may pose potential threat to the ecosystem and human health,hence PPCPs have aroused much concern over the world.The contamination of PPCPs in the groundwater,the main source of drinking water supply in many countries and regions,has been extensively studied in the last decade.This paper reviews the occurrence of frequently detected PPCPs,including antibiotics,anti-inflammatories,lipid-regulators,carbamazepine,caffeine,and N,N-diethyl-m-toluamide in groundwater,with special concern to the progress made over the past three years.Possible emission sources for PPCPs in groundwater,such as wastewater and contaminated surface water,landfills,septic systems,livestock breeding and sewer leakage,are summarized.Besides,adsorption,migration and degradation,the dominant mechanisms in the subsurface transport and fate of PPCPs,are discussed,and the insights into the future study of PPCPs in the groundwater are provided.

An efficient resin for solid-phase extraction and determination by UPLCMS/MS of 44 pharmaceutical personal care products in environmental waters

In this study,a hydrophilic resin named GCHM was fabricated based on poly(N-vinyl pyrrolidone-codivinylbenzene),characterized,and applied as a solid-phase extraction(SPE)material.Up to 44 pharmaceuticals and personal care products(PPCPs)belonging to 10 classes were recovered in environmental water samples.Different variables affecting extraction,such as adsorbent amount,sample pH,and loading speed,were optimized.Under optimal conditions,the average absolute recovgy of 44 PPCPs was 75.6%using GCHM,indicating a better performance than the commercial Oasis^HLB.SPE with home-made hydrophilic polymeric sorbent followed by ultra-performance liquid chromatography and tandem mass spectrometry was validated,and the method achieved good linearity(r2>0.991,for all analytes).In addition,the method detection limits of target compounds ranged from 0.03 to 0.6 ng/L.The developed method was applied to determine PPCPs in 10 environmental water samples taken from the Yangtze River,Huaihe River,and Taihu Lake,1 groundwater sample from Changzhou in Jiangsu Province,1 wastewater sample from Xiamen and 2 seawater samples from the Jiulong River in Fujian Province,China.In these samples,22 compounds were determined at levels ranging from 0.5 to 1590 ng/L.

Occurrence,seasonal variation and human exposure to pharmaceuticals and personal care products in surface water,groundwater and drinking water in Lagos State,Nigeria

The occurrence of 28 pharmaceuticals and personal care products(PPCPs)was investigated in 17 surface water samples(rivers,canals,and lagoons),12 groundwater samples(wells and boreholes,which can also be consumed for drinking)and 8 drinking water samples(bottles and sachets)during dry and rainy seasons in Lagos state,Nigeria.The most prevalent compound detected in all samples was amoxicillin(an antibiotic)at median concentrations of 1614,238 and 358 ng/L in surface water,ground water and drinking water,respectively.This is of concern due to potential impact on development of antibioticresistant microbial strains.Other frequently-detected compounds include acetaminophen,nicotine,ibuprofen,and codeine with detection frequencies of more than 70%.Investigation of seasonal variability revealed that glyburide,caffeine,naproxen and diclofenac concentrations were significantly(P<0.05)higher during the dry season(winter),while Nicotine and Codeine levels were higher during the rainy season(summer).The factors influencing such seasonal variability include:dilution by extensive rainfall,agricultural activity(for nicotine)and usage patterns of pharmaceuticals among the local community.Measured concentrations in drinking water samples were used to assess inadvertent human exposure to PPCPs in Nigerian adults.Results revealed average daily exposures of 81,14 and 3 ngƩPPCPs/kg BW/day via drinking borehole,sachet water and bottled water,respectively.While there exists no health-based limit value(HBLV)for chronic exposure to mixtures of PPCPs,our results raise concern and warrant further investigation of the potential health implications of such unintended PPCPs exposure.

Occurrence and discharge of pharmaceuticals and personal care products in dewatered sludge from WWTPs in Beijing and Shenzhen

This study mainly focused on the occurrence of pharmaceutical and personal care products(PPCPs)in sewage dewatered sludge and their discharges through sludge disposal from wastewater treatment plants(WWTPs).The data were obtained and calculated from seven PPCPs in dewatered sludge collected from 12WWTPs in two typical cities,Beijing and Shenzhen in China.Four of seven PPCPs,diclofenac acid,carbamazepine,mefenamic acid and N,N-diethyl-m-toluamide were detectable in dewatered sludge from Beijing and Shenzhen with concentration up to 4240,11,060,92 and 219μg/kg respectively.While,the other three compounds,trimethoprim,chloramphenicol and bezafibrate were not detected in collected samples from these two cities.The highest discharge of diclofenac acid and carbamazepine were 1023 g/d and 494 g/d respectively.In addition,the total discharge of these four detected PPCPs from each plant ranged from 5 to 1092 g/d in Beijing and 4e497 g/d in Shenzhen.Thus,PPCP discharge through sludge disposal cannot be neglected,and further research on transfer of PPCPs during sludge disposal onto agriculture land and influence of sludge application is required and essential.

Occurrence of pharmaceutical and personal care products(PPCPs)in wastewater and receiving waters in South Africa using LC-Orbitrap™MS

There is continued interest in the occurrence and monitoring of emerging contaminants(ECs)in wastewater treatment plants(WWTPs)to assess their potential impact when released into the environment.The objective of this study was to determine the occurrence of pharmaceutical and personal care products(PPCPs)in WWTP influents and effluents and receiving river waters in Pretoria,South Africa.Targeted screening and identification of PPCPs in the samples was done using liquid chromatography(LC)coupled with high resolution mass spectrometry(HRMS)Orbitrap™HRMS,after clean-up and preconcentration with Waters Oasis®hydrophilic-lipophilic-balanced(HLB)solid phase extraction(SPE)cartridges.Of the 156 target analytes screened in the study,120 could be satisfactorily determined under the study conditions,with 71 and 73 compounds being detected and quantified in the influent and effluent samples,respectively.Concentrations in the influents ranged from<ILOQ-14.2 mgL^-1and those in the effluent from<ILOQ-2.45 mgL^-1.It was found that 84%of the quantified compounds belonged to various classes of pharmaceuticals.Ibuprofen,caffeine,paracetamol and estradiol were the major individual contaminants in influent samples with average concentrations of 14.2,8.68,4.79 and 1.02 mgL^-1,respectively.In the effluent samples,the highest concentrations were recorded for estradiol(2.45 mgL^-1),ibuprofen(1.03 mgL^-1)and efavirenz(0.58 mgL^-1).The highest mean concentrations(above 0.5 mgL^-1)recorded in the river water samples were for ibuprofen,(4.14 mgL^-1downstream;3.19 mgL^-1upstream),caffeine(2.98 mgL^-1downstream;1.42 mgL^-1upstream),paraxanthine(1.22 mgL^-1downstream;0.798 mgL^-1upstream).Analysis of river water samples also revealed that PPCP contamination in the river system cannot be solely attributed to the WWTP effluents.Twenty-four compounds presented in this study are reported for the first time in South African surface waters.

Discharge inventory of pharmaceuticals and personal care products in Beijing,China

Pharmaceuticals and personal care products(PPCPs)are emerging environmental contaminants,whose potential risk for the ecological environment has caused wide attention in recent years.In China,quite a large amount of PPCPs were annually emitted into the environment.Their existence in different matrix has been reported frequently,including river water,sediment and soil.However,the contribution from different sources was seldom reported and still unclear in China.Wastewater treatment plant(WWTP)was usually considered to be the main source to the urban river,but livestock and aquaculture farms were also reported as significant pollution sources of PPCPs due to poor environmental management in China.This study summarized environmental discharges of different PPCPs from various sources and obtained the discharge data through different environment media in Beijing,the statistical source of PPCPs was analyzed in detail.The sources comprised WWTPs,excess sludge,hospital wastewater,municipal untreated wastewater,aquaculture wastewater and landfill leachate.This article helps understand the general situation and the potential risk of PPCPs in Beijing.

Determination and occurrence of endocrine disrupting compounds, pharmaceuticals and personal care products in fish （Morone saxatilis）

Endocrine disrupting compounds （EDCs）, pharmaceuticals and personal care products （PPCPs） have attracted much attention due to widespread contamination in aquatic environment. In this study, we determined 13 EDCs and PPCPs in fish blood, bile and muscle by using gas chromatography-mass spectrometry （GC-MS）. The limits of quantitation （LOQ） were in the ranges of 0.23-2.54, 0.22-2.36ng·mL^-1, and 0.24-2.57 ng· g^-1 dry weight （dw） for fish blood, bile and muscle, respectively. Recoveries of target compounds spiked into sample matrices and passed through the entire analytical procedure ranged from 65% to 95%, from 60% to 92% and from 62% to 91% for blood, bile and muscle, respectively. The methods were applied to the analysis of fish from a lake in California. Target compounds were relatively low in bile, and only bisphenol A （BPA） and diclofenac were measurable near the LOQ. Seven of 13 compounds were detected in blood, with total concentrations up to 39 ng· g^-1. Only BPA was frequently found in muscle, with mean concentration of 7.26 ng· g^-1 dw. The estimated daily intake of BPA through fish consumption for U.S. resident was significantly lower than the tolerable daily intake recommended by the European Food Safety Authority. This study showed that the exposure to the bisphenol A from fish diet is unlikely to pose a health risk.

Pay special attention to the transformation products of PPCPs in environment

Pharmaceuticals and personal care products(PPCPs)have received increasing attention.However,their transformation products(TPs)and metabolites,sometimes even with environmental concentration and/or toxicity higher than their parent compounds,received attention far from enough.This study gives useful insight on the occurrence,fate and toxicity of PPCP TPs or metabolites in WWTPs,surface water and even drinking water,highlighting the necessity of studying the PPCP TPs formation,occurrence,toxicity and environment risk,and further evaluating the environmental risk caused by PPCPs comprehensively.

Enhanced antibiotic degradation performance of Cd_(0.5)Zn_(0.5)S/Bi_(2)MoO_(6) S-scheme photocatalyst by carbon dot modification

S-scheme heterojunction engineering is an effective strategy to attain distinctive photocatalysts.Herein,a carbon dots modulated S-scheme hetero-structured photocatalyst of Cd_(0.5)Zn_(0.5)S nanoparticles/Bi_(2)MoO_(6) microspheres/carbon dots (CZCBM),aiming to conquer the photo-corrosion and strengthen the photocatalytic property of Cd_(0.5)Zn_(0.5)S,was developed via a facile solvothermal route.Under visible light,the optimal CZCBM-2 affords a 1.8-,1.5-,or 0.6-time reinforcement in the oxytetracycline degradation rate constant compared to Bi_(2)MoO_(6),Cd_(0.5)Zn_(0.5)S or Cd_(0.5)Zn_(0.5)S/Bi_(2)MoO_(6),which is credited to the strengthened visible-light response,increased reactive sites,and efficient dissolution of photo-carriers with optimal redox capacity because of the co-effect of carbon dots and S-scheme heterostructure.Significantly,the photo-corrosion of Cd_(0.5)Zn_(0.5)S is significantly suppressed and CZCBM-2 affords superior stability and reusability during cycling tests.Besides,CZCBM-2 can be well adapted to various environments.The toxicology appraisement unravels the decreased eco-toxicity of most intermediates compared to oxytetracycline.Lastly,an S-scheme charge transfer mechanism with carbon dots as electron reservoir in CZCBM is deduced,which uncloses that •O_(2)− and h+ dominantly account for oxytetracycline eradication and detoxification.This study demonstrates the design of unique carbon dots favored S-scheme heterostructures as an effective “Two Birds with One Stone” strategy to achieve high anti-photo-corrosion performance and reinforced photocatalytic performance of sulfides.

Analysis of Emerging Contaminants in Surface Water,Aquaculture Ponds and Wastewater Treatment Facilities in the Taige Canal Basin

Emerging contaminants(ECs)have aroused great concerns due to their widespread presence as well as their potential health and ecological risks.Currently monitoring data about ECs in Chinese rural areas are still limited.In this study,Taige Canal basin was selected as a typical rural area for a pilot study.The occurrence of ECs,including pharmaceutical and personal care products(PPCPs),pesticides,plasticizers and flame retardants,in surface water and aquaculture ponds,as well as in wastewater treatment facilities,was comprehensively investigated.The effectiveness of rural decentralized wastewater treatment facilities and centralized wastewater treatment plant(WWTP)in removing ECs was also analyzed.Among 126 commonly used pesticides for target analysis,25 compounds were detected in surface water with high frequency of>80%.Besides,55 PPCPs,21 pesticides and 18 other industrial products were identified by non-target analysis using high resolution mass spectrometry(HRMS).Totally 18 compounds were detected in surface water with a frequency of>60%and 6 of them were found in all samples,including irbesartan,valsartan,propazine,buprofezin,bis(2-ethylhexyl)phthalate(DEHP)and tri-(2-chloroisopropyl)phosphate(TCPP),with mean concentrations of 3022,195,125,218,3738 and 545 ng/L,respectively.There are 29 compounds(11 PPCPs,8 pesticides and 10 other industrial products)detected in water samples from the aquaculture ponds,of which 13 compounds were found in all three ponds.The removal efficiencies of ECs in wastewater treatment facilities are generally limited,except valsartan(82%–86%),nobiletin(100%)and diisodecylphthalate(100%)were found to be significantly removed.

Effects of rural domestic sewage reclaimed irrigation and regulation on heavy metals,PPCPs,water and nitrogen utilization,and microbial diversity in paddy field

Rural domestic reclaimed water(RDRW)is rural domestic sewage that being safely treated,the irrigation and reuse of RDRW are an effective way to alleviate the contradiction between supply and demand of water resources in South China.In this study,four kinds of irrigation water sources(primary and secondary treated water R1 and R2,purified water R3 and river water CK)and three kinds of water level regulations(low,medium,and high field water level control of W1,W2 and W3)were set to study the impact of RDRW on soil and crop safety,water and nitrogen utilization and biodiversity for establishing the regulation mechanism of RDRW irrigation with field experiment,and monitoring was carried out in RDRW irrigation demonstration area to assess the effectiveness of RDRW.The results showed that,under RDRW irrigation,the contents of Cd and Pb increased slightly,while the contents of Cr,Cu and Zn decreased in paddy soil.The heavy metals content decreased along the direction of stem,leaf and grain in rice plants,but did not increase significantly in rice grains.With the increase of field water level,pharmaceutical and personal care products(PPCPs)content in 60-80 cm soil layer was accumulated,and the PPCPs content in rice husks was higher than that in grains,but it was at a very low level.Compared to CK,RDRW irrigation can effectively increase rice yield,rainwater use efficiency(RUE)and nitrogen use efficiency(NUE)by 5.4%-7.6%,6.7%-9.4%and 21.7%-24.2%,respectively,and the species diversity,community diversity and richness in rice fields were improved.Additionally,water level regulation of W3 with R2 water resource irrigation was conducive to the exertion of comprehensive benefits.The monitoring of demonstration area showed that the consumption of fresh water was reduced by 530 mm,yield was increased by 9.6%,and the soil and crop were both safety.Short-term irrigation of RDRW did not cause soil and crops pollution,however,it is still necessary to track and monitor the effect of the system on soil,crop,and underground water with long-term reclaimed water irrigation.

DBP formation from degradation of DEET and ibuprofen by UV/chlorine process and subsequent post-chlorination

The formation of disinfection by-products（DBPs） from the degradation of N,N-diethyl-3-methyl benzoyl amide（DEET） and ibuprofen（IBP） by the ultraviolet irradiation（UV）/chlorine process and subsequent post-chlorination was investigated and compared with the UV/H_2O_2 process.The pseudo first-order rate constants of the degradation of DEET and IBP by the UV/chlorine process were 2 and 3.1 times higher than those by the UV/H_2O_2 process, respectively, under the tested conditions. This was due to the significant contributions of both reactive chlorine species U（RCS） and hydroxyl radicals（HO） in the UV/chlorine process. Trichloromethane, 1,1,1-trichloro-2-propanone and dichloroacetic acid were the major known DBPs formed after 90% of both DEET and IBP that were degraded by the UV/chlorine process. Their yields increased by over 50%after subsequent 1-day post-chlorination. The detected DBPs after the degradation of DEET and IBP comprised 13.5% and 19.8% of total organic chlorine（TOCl）, respectively, and the proportions increased to 19.8% and 33.9% after subsequent chlorination, respectively. In comparison to the UV/H_2O_2 process accompanied with post-chlorination, the formation of DBPs and TOCl in the UV/chlorine process together with post-chlorination was 5%–63% higher,Ulikely due to the generation of more DBP precursors from the attack of RCS, in addition to HO.