Development of Co-processed Plasticized Cellulose Acetate for Sustained Release Matrix Tablets

Cellulose Acetate (CA) is a polymer extensively used in pharmaceutical applications. Because of the hydrophobic nature and good film properties of CA, it is a good polymer candidate for sustained release matrix tablets. Sustained release matrix tablets of cellulose acetate can be prepared by direct compression or wet granulation methods. However, previous studies showed that a large amount of CA was required to achieve the desired sustained release profile for a sparingly soluble drug and it was difficult to formulate a highly water soluble drug by using CA as the retarding agent. Some studies concluded that CA is very sensitive to the solubility of the drug and it is not suitable for retarding the release for highly water soluble drugs. There are two aims in our study. One is to modify the physical characteristic of the CA by using a co-processing technique and increase the capacity of cellulose acetate to control the drug release rate. The other is to modulate the drug release rate from the hydrophobic sustained release tablets and apply these formulation strategies to reduce the burst release and enhance the final release. Three different process methods including heat treatment, wet granulation and spray drying were used to prepare the co-processed excipients with CA, plasticizer and inert excipient. The physical, flow and compaction properties of the co-processed excipients were evaluated. All the co-processed excipients prepared in this study all showed good flow characteristic. The spray dried process produced high porous particles with large surface area. These particles required the least energy for plastic deformation during compression and formed the tablets with highest mechanical strength. The wet granulated excipients showed moderate plastic deformation capacity and resulting tablets with acceptable tensile strength. The heat treated excipients required more energy to deform under compression pressure than the other two methods and the resulting tablets have poor mechanical properties. For all preparation methods, addition of 10% plasticizer increases the plasticity of the final excipient and decreases the tablet tensile strength. The tablets containing hydrophilic plasticizer showed better tensile strength than the hydrophobic plasticizer. The tensile strength of the tablets increased at low plasticizer concentration and the reverse effect was observed on higher plasticizer concentration. Both wet granulated and spray dried excipients showed desired flowability and acceptable compactability which makes them good excipient candidates for direct compression formulation. The sustained release characteristic of the co-processed excipients were evaluated by a freely water soluble drug propranolol hydrochloride. The spray dried co-processed excipients demonstrated slower drug release profile than the excipients prepared by the other two processing methods. The surface morphology and initial water penetration study found the spray dried co-processed excipient can form a continuous film like structure on the tablet surface which can effectively prevent water penetration and drug diffusion. The drug release rate from the matrix tablets containing the novel spray dried excipients can be decreased by increasing the hydrophobicity of the plasticizer and plasticizer concentration. The drug release rate from the matrix was affected by the compression force but not the pH of the dissolution medium. Based on porosity results and drug release mechanism study, addition of plasticizer to the co-processed excipients showed a decrease in the drug release rate due to three reasons: a) decrease in the porosity of the tablet; b) decrease in the effective diffusion coefficient; c) assist in maintaining tablet structure during dissolution. Three different types of pore formers were tried to modulate drug release characteristics from the plastic inert matrix. With the help of pore formers lactose and Starch1500®, both observed improved final release as well as increased burst release. When a small amount of hydrophilic polymer pore former was incorporated into the formulation, it showed a limited burst release initially and complete release at final stage. The optical microscopy results revealed the initial gel formation on the tablet surface with development of a swollen porous structure in the matrix network during dissolution. The drug release rate from this swellable porous matrix system is independent with the type and the particle size of hydrophilic polymer and the pH of dissolution medium. The drug release rate increased when the hydrophilic polymer concentration was less than 5%. Further increase of the hydrophilic polymer concentration to 10% did not further increase the drug release rate. The low viscosity grade hydrophilic polymer resulted in rapid burst release and incomplete final release, while middle to high viscosity grades of hydrophilic polymer avoided these problems. The drug release is controlled by both drug diffusion and polymer relaxation. The Fickian diffusion is the dominant release mechanism at the initial stage and the polymer relaxation becomes dominant thereafter. The spray dried co-processed excipient and the swollen porous matrix system were used to develop the sustained release matrix formulation for three different drugs with different solubility. The optimized formulations for these three drugs either meet the USP specifications or have similar dissolution profile to the commercial product. For a freely water soluble drug propranolol hydrochloride, a roller compaction method was applied to reduce the initial burst release. The tablets prepared by the roller compacted granules showed suppressed burst release and complete final release. For the sparingly water soluble drug theophylline, incorporating 10% hydrophilic polymer can successfully reduce the burst release as well as improve the final release. Two successful sustained release formulations of the poorly water soluble drug glipizide were obtained by using the plasticized co-processed excipient. Both of them have similar dissolution profile as the commercial product Gluctrol XL®. But the formulation prepared with lactose as pore former showed a large variation in dissolution profile while another formulation prepared with both lactose and hydrophilic polymer as pore formers exhibited less variation in dissolution profile and a higher f2 value. In conclusion, the spray dried co-processed plasticized cellulose acetate developed in this study exhibits good physical and mechanical properties. It can be used alone or combined with hydrophilic polymers to control the release rate of the drugs with different solubility

MPC-based interval number optimization for electric water heater scheduling in uncertain environments

In this paper, interval number optimization and model predictive control are proposed to handle the uncertain-but-bounded parameters in electric water heater load scheduling. First of all, interval numbers are used to describe uncertain parameters including hot water demand, ambient temperature, and real-time price of electricity. Moreover, the traditional thermal dynamic model of electric water heater is transformed into an interval number model, based on which, the day-ahead load scheduling problem with uncertain parameters is formulated, and solved by interval number optimization. Different tolerance degrees for constraint violation and temperature preferences are also discussed for giving consumers more choices. Furthermore, the model predictive control which incorporates both forecasts and newly updated information is utilized to make and execute electric water heater load schedules on a rolling basis throughout the day. Simulation results demonstrate that interval number optimization either in day-ahead optimization or model predictive control format is robust to the uncertain hot water demand, ambient temperature, and real-time price of electricity, enabling customers to flexibly adjust electric water heater control strategy

Interval number optimization for household load scheduling with uncertainty

An interval number optimization method is proposed in this paper to tackle the household load scheduling problem with uncertain hot water demand and ambient temperature. The household loads considered include residential thermostatically controlled loads such as electric water heater and air conditioner, and interruptible loads such as clothes washer and pool pump. The uncertain-but-bounded parameters are modelled as interval numbers, based on which the uncertain load scheduling problem is formulated and transformed. A binary particle swarm optimization combined with integer linear programming is introduced to solve the transformed problem. Two schemes, named cost scheme and trade-off scheme, are contrastively discussed to study the economic impacts of different tolerance degrees for constraint violation. Simulation results demonstrate that the proposed method is flexible to different consumer demands and robust to the uncertainties

A Robust Optimization Strategy for Domestic Electric Water Heater Load Scheduling under Uncertainties

In this paper, a robust optimization strategy is developed to handle the uncertainties for domestic electric water heater load scheduling. At first, the uncertain parameters, including hot water demand and ambient temperature, are described as the intervals, and are further divided into different robust levels in order to control the degree of the conservatism. Based on this, traditional load scheduling problem is rebuilt by bringing the intervals and robust levels into the constraints, and are thus transformed into the equivalent deterministic optimization problem, which can be solved by existing tools. Simulation results demonstrate that the schedules obtained under different robust levels are of complete robustness. Furthermore, in order to offer users the most optimal robust level, the trade-off between the electricity bill and conservatism degree are also discussed

<i>HDAC1</i>-Mediated lncRNA Stimulatory Factor of Follicular Development to Inhibit the Apoptosis of Granulosa Cells and Regulate Sexual Maturity through miR-202-3p-<i>COX1</i> Axis

Abnormal sexual maturity exhibits significant detrimental effects on adult health outcomes, and previous studies have indicated that targeting histone acetylation might serve as a potential therapeutic approach to regulate sexual maturity. However, the mechanisms that account for it remain to be further elucidated. Using the mouse model, we showed that Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, downregulated the protein level of Hdac1 in ovaries to promote the apoptosis of granulosa cells (GCs), and thus arrested follicular development and delayed sexual maturity. Using porcine GCs as a cell model, a novel sexual maturity-associated lncRNA, which was named as the stimulatory factor of follicular development (SFFD), transcribed from mitochondrion and mediated by HDAC1, was identified using RNA sequencing. Mechanistically, HDAC1 knockdown significantly reduced the H3K27ac level at the −953/−661 region of SFFD to epigenetically inhibit its transcription. SFFD knockdown released miR-202-3p to reduce the expression of cyclooxygenase 1 (COX1), an essential rate-limited enzyme involved in prostaglandin synthesis. This reduction inhibited the proliferation and secretion of 17β-estradiol (E2) while promoting the apoptosis of GCs. Consequently, follicular development was arrested and sexual maturity was delayed. Taken together, HDAC1 knockdown-mediated SFFD downregulation promoted the apoptosis of GCs through the miR-202-3p-COX1 axis and lead to delayed sexual maturity. Our findings reveal a novel regulatory network modulated by HDAC1, and HDAC1-mediated SFFD may be a promising new therapeutic target to treat delayed sexual maturity

A survey of the status and challenges of green building development in various countries

Since the energy crisis in the 1960s, crucial research and activities were spurred to improve energy efficiency and decrease environmental pollution. To deal with the various problems the construction industry are facing, the concept of green buildings (GBs) has been gradually shaped and put forward all over the world, and green building rating systems (GBRSs) have been developed. The concept of GBs covers a wide range of elements, and its definition is constantly updated as the construction industry develops. This paper compares the development of backgrounds and statuses of green building development in various countries. It also presents an overview of the green building development situation within these countries, summarizing two influences for GB development: one external and the other internal. External factors include GB development policy support, economic benefits, and certification schemes. Internal factors are the development and application of GB technology, the level of building management, and how users interact with the GB technology. Currently, 49 worldwide green building standards and application have been sorted out, including 18 standard expert appraisal systems. Moreover, it discusses the research results and lessons learned from green building projects in different countries and summarizes their achievements and challenges. To correctly understand and use green building technology, it is essential to improve the policy and incentive system, improve the professional quality and technical ability of employees and accredited consultants, constantly develop and update the evaluation system, strengthen technological innovation, and integrate design and management. This paper aims to draw a clear roadmap for national standard development, policy formulation, and construction design companies, provide solutions to remove the obstacles, and suggest research direction for future studies

CC4821 serogroup W meningococcal disease in China

Neisseria meningitidis is a major public health concern worldwide, including China. A few cases of serogroup W meningococcal disease have been reported in southeast China in recent years. Thus far, invasive disease due to W isolates has involved sequence type 11. We report two cases of N. meningitidis infection caused by CC4821 serogroup W strains

Duchenne muscular dystrophy treatment with lentiviral vector containing mini‐dystrophin gene in vivo

Abstract Duchenne muscular dystrophy (DMD) is an incurable X‐linked recessive genetic disease caused by mutations in the dystrophin gene. Many researchers aim to restore truncated dystrophin via viral vectors. However, the low packaging capacity and immunogenicity of vectors have hampered their clinical application. Herein, we constructed four lentiviral vectors with truncated and sequence‐optimized dystrophin genes driven by muscle‐specific promoters. The four lentiviral vectors stably expressed mini‐dystrophin in C2C12 muscle cells in vitro. To estimate the treatment effect in vivo, we transferred the lentiviral vectors into neonatal C57BL/10ScSn‐Dmdmdx mice through local injection. The levels of modified dystrophin expression increased, and their distribution was also restored in treated mice. At the same time, they exhibited the restoration of pull force and a decrease in the number of mononuclear cells. The remissions lasted 3–6 months in vivo. Moreover, no integration sites of vectors were distributed into the oncogenes. In summary, this study preliminarily demonstrated the feasibility and safety of lentiviral vectors with mini‐dystrophin for DMD gene therapy and provided a new strategy to restore truncated dystrophin