Functionality assessment of systematically developed site-specific intelligent biodegradable long-acting formulation (SIBLAF)

The main objective of this study was the development of pH-independent controlled release valsartan matrix tablet in Quality by design (QbD) framework. The quality target product profile (QTPP), critical quality attributes (CQAs) and critical material attributes (CMAs) were defined by science and risk-based methodologies. Potential risk factors were identified with Fishbone diagram. Following, CMAs were further investigated with a semi-quantitative risk assessment method, which has been revised with mitigated risks after development and optimization studies. According to defined critical material attributes, which one of them was determined to be the dissolution, formulation optimization study was performed by using a statistical design of experiment. Formulation variables have been identified and fixed first with a ‘One factor at a time (OFAT)’ approach. After OFAT studies, a statistical experimental design was conducted with the most critical material attributes. Statistical design space and mathematical prediction equations have been developed for dissolution and hardness, which is important to predict drug dissolution behavior. In conclusion, a pH-independent release has been achieved for weakly acidic drug valsartan with a deeper understanding of drug product quality, with the science and risk-based approaches of QbD tools.

Implementation of quality by design principles in the development of microsponges as drug delivery carriers: Identification and optimization of critical factors using multivariate statistical analyses and design of experiments studies

The purpose of the study was to develop a model to predict the critical quality attribute (CQA) of tablets during continuous and batch manufacturing using only critical material attributes (CMAs). Experiments were performed using ethenzamide as the active pharmaceutical ingredient processed with batch and continuous high-shear granulators. The disintegration time of tablets was defined as the CQA, and the particle-size distribution of granules and tablet hardness were defined as the CMAs. We first investigated the influence of granulation conditions on particle-size distribution during batch and continuous granulation. We then proceeded to construct the CQA estimation model by producing tables using batch and continuous granulation. The results indicated the similarity of the granulation mechanisms, as observed by the bimodality of the distributions and the significant causal factors. Principal component analysis revealed that the CQA was influenced strongly by the particle-size distribution and that the CMA–CQA correlations were similar for both processes. Finally, a model based on partial least-squares regression could be developed that could reasonably estimate the CQA using CMAs without involving any process parameters. This approach of using process-independent CQA prediction could enable flexible switching between batch and continuous manufacturing during a product life cycle, thus offering new possibilities for efficient life cycle management.

Introduction. One of the modern remedies used to treat vaginal infections are suppositories "Depantol", which have an antiseptic, regenerating effect due to the combination of chlorhexidine and dexpanthenol. The initial stage in the life cycle of any medicinal product (MP) is pharmaceutical development, a systematic approach to which implies the principle of Quality-by-Design (QbD), which is based on obtaining reliable scientific data and risk management for quality. With this approach, pharmaceutical development begins with a preliminary determination of significant factors in the creation of a drug.Aim. Aim of study was to design Quality Target Product Profile, Critical Quality Attributes, Critical Material Attributes – the initial data necessary for the development of composition and technology of a generic drug in accordance with the QbD methodology of ICH Guidance Q8 "Pharmaceutical Development".Materials and methods. Objects of study: chlorhexidine bigluconate, dexpanthenol, PEG-400 and PEG-1500, pharmaceutical development documents. Methods of study: content analysis, system analysis; FMECA method (Failure Modes, Effects and Criticality Analysis).Results and discussion. In order to implement the QbD for the production of a drug of good quality, initial data for the development of the composition and technology of two-component suppositories were obtained. Quality Target Product Profile (QTPP) was compiled taking into account the data of the original drug was used as reference. Based on the compiled QTPP, Critical Quality Attributes (CQAs) were identified. The determination of CQAs from QTPP parameters was based on the strength of the potential harm to the product. Due to the fact that we developed a well-known dosage form, quality indicators were chosen that are standard for hydrophilic suppositories. In order to determine the parameters of the drug components that affect the Critical Quality Attributes, for each of the active pharmaceutical ingredients (APIs) suppositories contain, the Critical Material Attributes (CMAs) were determined. For example, for liquid ingredients, according to the specification of the substance manufacturer, these are pH, viscosity, impurities, identification, assay, refraction index. For the initial risk assessment, risk assessment matrices of the influence of the Сritical Material Attributes of the components on the Critical Quality Attributes were compiled. When evaluating the effect of chlorhexidine bigluconate on the critical characteristics of the final product, attention was paid to all parameters from the manufacturer's specification, since any deviations in pH, density, presence of related substances and extraneous impurities, assay and identification of the substance may signal the chemical unsuitability of the component. The weight uniformity of suppositories is affected only by the parameters of the technological process. The influence of CMAs of dexpanthenol on the Critical Quality Attributes of the finished product is generally similar to the influence of the parameters of chlorhexidine bigluconate. The difference in the influence of pH and water content on the microbial limits: unlike chlorhexidine bigluconate, which has antiseptic properties, dexpanthenol is more susceptible to microbial contamination. The effect of base CMAs on identification, content uniformity, and assay is not critical. Whereas the pH, assay and identification of PEG-400 and PEG-1500 have a significant impact on the dissolution profile of the active ingredients from the finished dosage form.Conclusion. The data required for the pharmaceutical development of a generic drug, two-component suppositories, was obtained: Quality Target Product Profile, Critical Quality Attributes, Critical Material Parameters. The impact of the critical characteristics of the raw materials on the critical quality attributes of the developed suppositories was assessed.

Objective To understand the Helicobacter pylori （ Hp） infection eradication rate of standard tri-ple therapy in Guangdong Meizhou and the drug resistance situation for metronidazole ,clarithromycin ,amoxicillin and levofloxacin ,in order to look for the treatment countermeasures in Hp eradication failure .Methods 297 cases of Hp positive patients because of gastrointestinal symptoms to our hospital examined from April 2011 and March 2013,were randomly assigned into three standard triple therapy groups：A （ OCA ） group and B （ OCM ） group and C （ OCL ） group.The Hp eradication rate was analyzed .Patients with primary treatment failure were selected as group D （OBAL）,proceed to （PPl＋B＋A＋L）7 d therapy,the Hp eradication rate was analyzed .230 Hp strains were isola-ted and cultured from 297 cases received the first eradication therapy and 87 cases received again eradication therapy . The minimum inhibitory concentration （MIC） of metronidazole,clarithromycin,amoxicillin and levofloxacin were tested by E-test,in order to determine the resistance of these four antibiotics in clinical isolated Hp strains .Results With intention-to-treat（ITT） analysis,the Hp eradication rates of group A （OCA）,group B（OCM） and group C（OCL） were 72.0%（72/100）,63.0%（63/100） and 72.2%（70/97）,respectively.With per-protocol（PP） analysis,the Hp eradication rates of group A （OCA）,group B（OCM） and group C（OCL） were 72.7%（72/99）,64.3%（63/98）,73.7%（70/95）,respectively.The eradication rate among three standard triple therapy groups had no obvi-ous difference （ITT：P=0.278,PP：P=0.288,P〉0.05）.With ITT analysis,the Hp eradication rate in the quadrup-le therapy group D（OBAL） was 92.0%（80/87）.With per-protocol（PP） analysis,the Hp eradication rate in the quadruple therapy group D（OBAL） was 97.6%（80/82）,which was higher than that of the three standard triple ther-apy groups（ITT：P=0.000,PP：P=0.000）.In 230 clinical isolated Hp strains,the resistant rates of levofloxacin,amoxicillin,clarithromycin and metronidazole were 6.08%（14/230）,6.52%（15/230）,25.65%（59/230）, 70.87%（163/230）,respectively.Of those 37 strains were mixed resistance,the mixed resistant rate was 16.09%（37/230）.The resistant rate of metronidazole was higher than levofloxacin , amoxicillin and clarithromycin （ P =0.000,P〈0.01）,the resistant rate of clarithromycin was higher than levofloxacin and amoxicillin （P=0.000）,no statistically significant difference between amoxicillin and levofloxacin （P=0.848）.Conclusion The Hp resistance is similar to the national average in Guangdong Meizhou ,the eradication rate of standard triple therapy is lower than 80%,contain bismuth agent of quadruple therapy is good rescue therapy . Key words: Helicobacter pylori; Drug sensitive test; Drug resistance,bacterial; Rescue therapy

Obligate anaerobes are closely involved in the pathogenesis of oral and focal infections. The objective of this study was to evaluate the susceptibility profiles of obligate anaerobes of oral origin to telithromycin (TLM), moxifloxacin (MXF), and other antibiotics that are commonly used in dentistry. The study sample comprised 172 obligate anaerobes isolated from the saliva of 43 adult volunteers. The minimum inhibitory concentrations (MICs) were determined by the agar dilution technique in Brucella agar medium supplemented with vitamin K, haemin and 5% (volume/volume) laked sheep blood, and incubated under anaerobic conditions. The Clinical and Laboratory Standards Institute methodology was followed and its criteria were used for the qualitative interpretation of the results. The antibiotics evaluated were: amoxicillin (AMX), amoxicillin-clavulanic acid (AMX-CLA), clindamycin (CM), metronidazole (MTZ), azithromycin (AZM), TLM and MXF. Resistance to AMX (MIC(90) > or = 16 mg/l) was observed in 45.3% of the obligate anaerobes and resistance to CM (MIC(90) > or = 16 mg/l) was found in 18.6%. All the isolates were sensitive to MTZ (MIC(90) = 1 mg/l) and 98.8% were sensitive to AMX-CLA (MIC(90) = 2 mg/l). The MIC(90) values for AZM, TLM and MXF were > or =16, > or =8 and > or =2 mg/l, respectively. Pathogenic, opportunistic and non-pathogenic obligate anaerobes showed high percentages of resistance to AMX and CM, and high MIC values for AZM in the absence of recently administered antibiotics. MXF showed a higher activity than TLM, similar to that detected for AMX-CLA and MTZ. In consequence, MXF could represent a possible alternative antimicrobial against obligate anaerobes of oral origin, particularly in those patients with allergy, intolerance or lack of response to AMX-CLA or MTZ.

BackgroundQuality by design (QbD) is an advanced drug quality control concept that has been gradually implemented in the optimization of manufacturing processes of Chinese medicines. However, the variation of Chinese medicinal material quality has rarely been considered in published works. Because manufacturing processes may lower the variation introduced through different batches of materials, a material quality control strategy should be developed considering the influences of manufacturing processes.MethodsIn this work, the processes of extraction, concentration, water precipitation, and chromatography for notoginseng total saponin (NTS) production were investigated while considering Panax notoginseng quality variation as a sample. Ten process parameters were studied simultaneously using a definitive screening design. After the process critical quality attributes (CQAs) were determined, critical process parameters (CPPs) and critical material attributes (CMAs) were identified simultaneously. Then, models utilizing the CMAs, CPPs, and process CQAs were developed. The design space was then calculated using a Monte Carlo simulation method with an acceptable probability of 0.90. A material quality control strategy considering the influences of manufacturing processes was proposed.ResultsThe ginsenoside Rd purity and total saponin purity in the eluate were identified as process CQAs. The ethanol solution concentration used for extraction, the ethanol solution concentration used for elution, and elution time were identified as CPPs. The extractable dry matter content of Panax notoginseng was one of the CMAs. The extractable contents of notoginsenoside R1, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rd were the other CMAs. The inequalities implemented to discriminate the high quality and low quality of Panax notoginseng were developed according to the NTS standard of the Xuesaitong injection. Low quality Panax notoginseng should not be released for NTS production. High quality Panax notoginseng can be treated with feasible manufacturing processing parameters. Verification experiments were carried out successfully for 2 batches of high quality Panax notoginseng.ConclusionsIn this work, a quality control strategy for herbal materials was developed considering the matching of process characteristics and material quality attributes. This strategy is promising for application to other Chinese medicines.

Objective: The purpose of this research is to find the best way for designing carvedilol pulsatile drug delivery system capsules. Methods: The research paves the way to improve the method of preparing carvedilol pulsatile drug delivery by adjusting critical material attributes (CMA) such as coating polymer concentration, critical process parameters (CPP) such as inlet temperature and atomizing air pressure, and their impact on critical quality attributes (CQA) like particle size (PS in nm), entrapment efficiency in percentage (% EE) and amount of drug delivered in percent (%ADR) at 12 h in the carvedilol pulsatile pellets filled capsules by applying the Box-Behnken design. By varying the polymer concentration and process parameters, nearly 15 formulations were created. Results: Based on the influence of CMA, CPP on CQA, the formulation CP13 was determined to be the most optimized formulation among the 15 formulations. The optimized levels of CMA were found to be-1 level of coating polymer concentration and CPP was found to be-1 level of inlet temperature, 0 level of atomizing air pressure and it optimized CQA like PS was found to be 1017.5±8.4 nm, % EE was found to be 96.8±2.8 %, % ADR at 12 h was found to be 88.4±3.4 %. Carvedilol Pulsatile drug delivery system was designed by using optimized fluidized bed coater in order to decrease the usage of attributes, decrease the productivity cost and enhance the usage of specific attributes at fixed concentration for further manufacturing scale. Conclusion: By the current results it was concluded that the optimized CMA and CPP that shown in the results are the suitable attributes for the best formulation of carvedilol pulsatile drug delivery system capsules.

Amoxicillin-Clavulanic Acid: Additions and Corrections: In reply

This study evaluates the antimicrobial susceptibility and composition of subgingival biofilms in generalized aggressive periodontitis (GAP) patients treated using mechanical/antimicrobial therapies, including chlorhexidine (CHX), amoxicillin (AMX) and metronidazole (MET). GAP patients allocated to the placebo (C, n = 15) or test group (T, n = 16) received full-mouth disinfection with CHX, scaling and root planning, and systemic AMX (500 mg)/MET (250 mg) or placebos. Subgingival plaque samples were obtained at baseline, 3, 6, 9 and 12 months post-therapy from 3–4 periodontal pockets, and the samples were pooled and cultivated under anaerobic conditions. The minimum inhibitory concentrations (MICs) of AMX, MET and CHX were assessed using the microdilution method. Bacterial species present in the cultivated biofilm were identified by checkerboard DNA-DNA hybridization. At baseline, no differences in the MICs between groups were observed for the 3 antimicrobials. In the T group, significant increases in the MICs of CHX (p < 0.05) and AMX (p < 0.01) were detected during the first 3 months; however, the MIC of MET decreased at 12 months (p < 0.05). For several species, the MICs significantly changed over time in both groups, i.e., Streptococci MICs tended to increase, while for several periodontal pathogens, the MICs diminished. A transitory increase in the MIC of the subgingival biofilm to AMX and CHX was observed in GAP patients treated using enhanced mechanical therapy with topical CHX and systemic AMX/MET. Both protocols presented limited effects on the cultivable subgingival microbiota.

Intelligent industry-oriented oro-solid formulation of famotidine: Advanced statistical optimization and Ex-Vivo characterization

Objective: The objective of this study was to develop a polymeric composite of the poorly soluble antidepressant drug felodipine with help of PVP K-30 and PEG 6000, using a Quality by Design (QbD) approach to enhance its solubility and, consequently, its bioavailability. Methods: In this work, the quality target product profile (QTTP) was defined and Critical Quality Attributes (CQAs) were identified. Additionally, risk assessment analyses were carried out using the Ishikawa fishbone diagram to identify the Critical Material Attributes (CMAs) and/or Critical Process Parameters (CPPs) associated with the development of polymeric composite that could influence the Critical Quality Attributes (CQAs) of the drug product. The solubility of felodipine hydrochloride was improved by creating various polymeric composites with various concentrations of Poly Vinyl Pyrrolidone K30 (PVP-K 30) and Poly Ethylene Glycol 600 (PEG 600) by solvent evaporation method as Critical material attribute (CMA) as identified by risk assessment study and the and CQAs viz drug solubility, drug content and drug release. These composites were designed using a 32 Face Central composite Design (FCCD) with a face-centered approach implemented in Design Expert software. Results: After defining QTTP and CQA, risk assessment analysis was successfully used to identify CMA as well as CPPs. A total of thirteen PVP-PEG polymeric composites were developed and evaluated for FTIR spectra, Differential Scanning Colorimetry (DSC), X-Ray diffraction (XRD), and Scanning electron Microscopy (SEM). Data optimization was performed using response surface methodology, including contour and overlay plots. Solubility, drug content, and drug release of the optimized batch were found to be 21.55 mg/ml, 100%, and 78.314%, respectively. Three Validation Check batches (VC1-VC3) were developed and validated. Percent error for solubility ranges between-0.0019 to 0.0061, drug content ranges between 0.0005 to 0.0031 and solubility ranges between 0.0005 to 0.0011 that were very close to the predicted value, hence verifying the optimized data. Thus, by carefully using the QbD technique, the solubility of felodipine was enhanced by the effective development of a PVP-PEG polymeric composite. Conclusion: The QbD approach was to be an effective tool to develop an optimized polymeric composite of PVP 30K and PEG 6000 of felodipine with improved solubility without exhaustive research.

Flutamide which isused to treat prostate cancer and other diseases induces liver damage during and after the therapy. The aim of this study was to develop a flutamide/piperineco-loaded self-emulsifying drug delivery system (FPSEDDS) to inhibit flutamide-induced liver injury by utilizing piperine as a metabolic inhibitor. The development of SEDDS was carried out following a quality by design (QbD) approach. The risk assessment study was performed to identify critical quality attributes (CQAs) and critical material attributes (CMAs)/critical process parameters (CPPs). I-optimal mixture design was executed with three CMAs as the independent variables and CQAs as the dependable variables. The effectiveness of optimized SEDDS to circumvent flutamide-induced hepatotoxicity was assessed in mice. The numerical optimization suggested an optimal formulation with a desirability value of 0.621, using CQAs targets as optimization goals with 95% prediction intervals (α = 0.05). The optimal formulation exhibited the grade A SEDDS characteristics with the guarantee of high payloads in self-formed oily droplets. The design space was also obtained from the same optimization goals. All CQA responses of verification points were found within the 95% prediction intervals of the polynomial models, indicating a good agreement between actual versus predicted responses within the design space. These obtained responses also passed CQAs acceptance criteria. Finally, hematoxylin-eosin staining revealed the minimal flutamide-induced hepatotoxicity from the optimal SEDDS formulation as compared to the control and flutamide/piperine normal suspension. We demonstrate that the piperine containing optimized SEDDS formulation developed by QbD significantly reduces the flutamide-induced liver injury in mice.

Background: It is helpful in clinical practice to predict the effects of eradication therapy on Helicobacter pylori. Aim: To develop a useful predictor of the response to metronidazole (MNZ)-containing second-line regimens by combining minimal inhibitory concentrations (MICs) of both amoxicillin (AMX) and MNZ, and the results of urea breath test (UBT) before the treatment. Methods: We enrolled 107 patients who showed eradication failure following first-line triple therapy with a proton pump inhibitor, AMX and clarithromycin. The eradication resistance index was defined as: [pre-treatment UBT result (‰)] × [AMX MIC (µg/ml)] × [MNZ MIC (µg/ml)]. Second-line eradication therapy with lansoprazole, AMX and MNZ was administered for 1 week. Eradication was confirmed by the UBT. Results: The eradication resistance index in subjects showing eradication failure and those showing successful eradication was 9.72 ± 6.63 and 1.25 ± 2.31, respectively (p < 0.001). When a cutoff value of 3 was used, the eradication resistance index predicted the response to therapy with a specificity of 93.8%, sensitivity of 81.8%, and accuracy of 92.5%. Conclusions: The eradication resistance index is a more useful predictor of response to MNZ-containing regimens for second-line treatment than only pretreatment UBT results or MNZ resistance.

AimTo determine the minimum inhibitory concentrations (MICs) of commonly used antibiotics against Helicobacter Pylori (H. pylori) in South China and compare their resistance rates by using EUCAST breakpoints and other breakpoints.MethodsPatients who had not previously received H. pylori treatment in clinical centers in South China were enrolled in this study from 2017 to 2020. Gastric biopsies were obtained for H. pylori culture. The MICs of amoxicillin (AMX), clarithromycin (CLA), metronidazole (MTZ), levofloxacin (LEV), tetracycline (TET) and furazolidone (FZD) were tested by broth microdilution method and assessed by two different breakpoints. ATCC43504 standard strain served as a control.ResultsA total of 208 H. pylori strains were isolated from patients’ biopsy samples. The MICs of AMX, CLA, MTZ, LEV, TET and FZD for H. pylori were 0.0156-256mg/L (MIC50 0.125mg/L, MIC90 4mg/L), 0.0156- >256 mg/L (MIC50 0.0312mg/L, MIC90 64mg/L), 0.0156- >256mg/L (MIC50 8mg/L, MIC90 256mg/L), 0.0156-256mg/L (MIC50 0.25mg/L, MIC90 16mg/L), 0.0156-256mg/L (MIC50 0.0625mg/L, MIC90 4mg/L), and 0.0156- >256mg/L (MIC50 0.0312mg/L, MIC90 2mg/L), respectively. The MICs of AMX, CLA, MTZ, LEV, TET and FZD for ATCC43504 strain were 0.25mg/L, 0.0625mg/L, 64mg/L, 0.5mg/L, 1mg/L and 0.25mg/L, respectively. The resistance rate of FZD was 11.05%. The overall resistance rates according to EUCAST breakpoints and other breakpoints were 57.21% and 14.90% for AMX (p<0.001), 38.94% and 38.94% for CLA (p = 1), 39.42% and 50.96% for MTZ (p<0.001), 12.98% and 10.58% for TET (p = 0.025), 35.10% and 35.10% for LEV (p = 1), respectively.ConclusionsOur results demonstrate that AMX, FZD, and TET, but not MTZ, CLR or LEV, showed good anti-H. pylori activity in vitro in South China. When different breakpoints were used, similar results were found with CLA, and LEV, but not with AMX, MTZ, or TET.