Drug Development and Registration

Introduction. Silymarin is one of the main components used in preparations for hepatotropic therapy. Silymarin is contained in the dry extract of seeds and fruits of milk thistle ( Silybum marianum L. Gaertn.), however it has poor bioavailability due to the crystalline state and low solubility of silymarin flavolignans in water at room temperature, as well as their poor absorption. One of the methods for increasing the bioavailability of medicinal substances consists in their introducing into solid dispersion systems (SDS). The most suitable method for obtaining SDS with extracts is the solvent method, since it does not require the use of a high temperature regime during the obtaining process of SDS. Aim. To develop the technology for solid dispersion system from milk thistle dry extract by solvent method to increase the bioavailability of this phytosubstance. Material and methods. The obtaining of the solid dispersion systems from milk thistle dry extract by solvent method was carried out with polyvinylpyrrolidone (PVP K-29/32), polyvinylpyrrolidone vinyl acetate 6 : 4 (PVPVA 64), hydroxypropylmethylcellulose (HPMC), gelatin and sodium lauryl sulfate (SLS). The quality indicators of the SDS: particle size distribution, bulk density, residual humidity and hygroscopicity were carried out according to the methods of the State Pharmacopoeia of the Russian Federation (GP RF) XV edition. The quantitative determination of biologically active substances (BAS) was carried out in accordance with the GP RF XV ed. by the amount of flavolignans in terms of silybin. Results and discussion. During the development of solid dispersion systems by solvent method, SDS samples from milk thistle dry extract (MTDE) with different polymers were studied. As a result of studying the particle size distribution, several SDS samples were selected. The SDS samples were compared with the MTDE sample. The "Dissolution" test showed that the micronization of MTDE in form of SDS by solvent method, containing polyvinylpyrrolidone vinyl acetate – PVP VA 64 is the best alternative for increasing the silybin releasing-degree from the extract and increasing its bioavailability. According to the content of the sum of flavolignans in terms of silybin, the selected SDS sample meets the requirements of the normative documentation for milk thistle dry extract. In addition, the conditions for the development of SDS do not significantly affect the quantitative content of silybin compared with the content of the control sample of MTDE. The technological characteristics of SDS have been investigated and their qualitative improvement compared to the MTDE sample has been established. The interaction between the polymer carrier and the milk thistle extract was evaluated by the IR-fourier spectroscopy method. Conclusion. The SDS from milk thistle dry extract was developed by solvent method. For the developed SDS, quality indicators such as the content of the sum of flavolignans in terms of silybin, residual humidity, bulk density, particle size distribution and hygroscopicity were determined. The solid dispersion system from milk thistle extract was analyzed by IR-fourier spectroscopy. The physico-chemical compatibility between the milk thistle extract and the polymer-carrier polyvinylpyrrolidone vinyl acetate is shown. The development of the SDS from milk thistle dry extract significantly increased the bioavailability of the phytosubstance by increasing the silybin releasing-degree of the SDS by 3 times compared with the control sample of MTDE.

B. A. Perez

I. E. Kauhova

I. I. Terninko

O. N. Abrosimova

E. V. Vishnyakov

N. S. Pivovarova

Drug development & registration

Development of solid dispersion system from milk thistle dry extract by solvent method

溶剂法制备水飞蓟干提取物固体分散系统的开发

Introduction. «Dissolution test» for drugs is one of the key studies of control and, in many ways, is designed to simulate the bioavailability of the active substance under the conditions of use. However, there are several drugs containing active pharmaceutical substances that are poorly soluble under standard conditions. For this substances action is local, so, they are practically not absorbed in the human body, but showed the necessary therapeutic effect. This work discusses the development of conditions for «Dissolution test» in lipophilic-based suppositories containing natamycin, which is an antifungal agent related to tetraene macrolides, poorly soluble in water and, therefore, in standard buffer solutions intended for this test. Aim. Choose the conditions for conducting «Dissolution test», under which it will be possible to achieve complete release of the active substance from lipophilic-based suppositories on «Pimafucin» and «Primacin». Materials and methods. The objects of the study are lipophilic-based suppositories containing natamycin. The study was carried out using dissolution testers (Rotating Basket and Flow Cell apparatus) and an HPLC system to define the amount of natamycin released. Results and discussion. The research objects were analyzed under «Dissolution test». The work shows the possibility of conducting a test with complete release of the active substance by adding surfactants and an organic solvent, which is acceptable for quality control dissolution medias. Conclusion. Conditions for «Dissolution test» have been developed for suppositories containing natamycin.

A. V. Meleshko

A. M. Volkova

V. S. Tyukova

A. V. Panov

S. A. Kedik

Development of the «Dissolution» test method for vaginal suppositories Pimafucin®

阴道栓剂Pimafucin®的“溶出度”测试方法开发

Introduction. Currently, neurological diseases occupy one of the first places in terms of the DALY (Disability-adjusted life year) index and are the second cause of death in the world. There is a tendency towards rejuvenation and an increase in morbidity. Drug therapy aimed at neuroprotection and improving the restoration of neurological functions according to clinical recommendations includes a succinate-containing drug – Cytoflavin. However, these recommendations are based on a very limited number of studies (4 studies for cytoflavin). Due to the huge amount of work in the field of the use of succinate-containing drugs as neuroprotectors, the lack of quantitative assessment of research results, it seems promising to conduct systematic reviews and meta-analysis in this area. Aim. Evaluation of the efficacy and safety of cytoflavin as a neuroprotector based on a systematic review. Materials and methods. A systematic review of the research results was conducted according to the criteria of PRISMA 2020. The search for publications was carried out using PubMed, Medline databases, as well as Russian scientific electronic libraries eLibrary.Ru and RSCI. Materials were also searched in the systems of the national and international registry of clinical trials. Results and discussion. The review included 18 publications, including a description of the therapy of 10 pathologies of neurological origin. The largest part of the studies was devoted to the treatment of ischemic stroke ( n = 4/18; 22.22 %) and manifestations of cognitive dysfunction ( n = 5/18; 27.78 %). The pool of materials included studies of various designs, but most of them were represented by open comparative randomized/non-randomized studies. An analysis of the sources showed that the positive effect of the use of cytoflavin and the expediency of including its therapy regimen is noted in all publications. However, many studies have low statistical power due to the small sample sizes of patients, their heterogeneity and incompleteness of providing treatment data and the lack of randomization. Conclusion. According to the results of most clinical studies, it has been shown that the use of cytoflavin is safe, and its administration in neurological diseases of various origins is advisable due to a decrease in the frequency of adverse neurological outcomes in patients. For an objective research result, a meta-analytical assessment of the publications included in the review is required.

E. K. Krasova

I. A. Titovich

K. O. Sidorov

S. V. Okovityi

Evaluation of the efficacy and safety of cytoflavin as a neuroprotector based on a systematic review

基于系统评价的细胞黄素作为神经保护剂的疗效和安全性评估

Introduction. The polypill in the form of a hard gelatin capsule containing mini-tablets of the original antihypertensive combination is being developed at the Saint-Petersburg State Chemical and Pharmaceutical University. One of the components of the polypill is Candesartan, which has high antihypertensive activity and organoprotective properties. The active pharmaceutical ingredient (API) of Candesartan Cilexetil is characterized by low solubility in water and gastrointestinal tract media, therefore increasing the solubility of this substance can lead to a significant improving the bioavailability. Aim. Comparative analysis of technological approaches to increasing the bioavailability of the poor soluble API Сandesartan Сilexetil in a mini-tablet dosage form. Materials and methods. API Сandesartan Сilexetil, β-cyclodextrin (β-CD), copolymer of polyvinylpyrrolidone and vinyl acetate and excipients for the production of mini-tablets, such as diluents, binders, disintegrant, dusting components were used. The release profiles of Candesartan Cilexetil from the developed mini-tablets were assessed in comparison with the original drug Atacand®, 8 mg tablets. The complex of candesartan cilexetil with β-CD in a 1 : 1 ratio was prepared by three methods: dry mixing, paste method and lyophilization. A solid dispersion (SD) of candesartan was obtained by hot melt extrusion. The API complexes with β-CD and SD were characterized by FTIR-spectroscopy and differential scanning calorimetry. Tablet mixtures were produced by dry mixing and wet granulation technology. Mini-tablets were obtained on a laboratory automatic single-punch tablet press. Quality control of the mini-tablets was conducted by the methods of State Pharmacopoeia of the Russian Federation XV ed. and United State Pharmacopeia methods. Results and discussion. Comparative analysis of technological approaches to increasing the bioavailability of Candesartan Cilexetil showed, that preparation of a complex including API with β-CD in a 1 : 1 ratio using the paste method with further using of wet granulation technology allowed to obtain mini-tablets with improved release of poor soluble API compared to the original drug. On the contrary, the use of TDS in mini-tablet technology led to a slower release of API compared to the original drug. The developed mini-tablets of Candesartan composition № 7 met pharmacopoeial requirements by all acceptance criteria. Conclusion. The creation of complex of Candesartan Cilexetil with β-CD by the paste method with further using of wet granulation technology is the optimal technological approach to increasing the bioavailability of the poor soluble API Candesartan Cilexetil in mini-tablets.

K. M. Tserkovnaya

E. S. Surbeeva

K. A. Gusev

E. V. Flisyuk

I. A. Narkevich

Technological approaches to improve the bioavailability of the poor soluble substance Candesartan Cilexetil in mini-tablets

提高难溶性物质坎地沙坦酯在迷你片剂中生物利用度的技术方法

Introduction. The symptoms of Parkinson's disease are mainly associated with the formation of intraneuronal protein inclusions with Lewy bodies, and the progressive loss of dopaminergic neurons of the Substantia nigra and their axons. Existing diagnostic criteria for the diagnosis of Parkinson's disease often take into account symptoms occurring in the later stages of the disease. Thus, for a more accurate diagnosis in the early stages, it is necessary to confirm pathologic changes in brain tissue by molecular imaging methods such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). At the same time SPECT is a more accessible method of diagnostics of neurodegenerative diseases in comparison with PET, because of the possibility to obtain medical radionuclides for SPECT imaging using mobile generator systems, in particular 99 Mo/ 99m Tc generator. Among the formulations based on 99m Tc and tropane derivatives proposed for dopamine transporter (DAT) imaging, [ 99m Tc]Tc-TRODAT-1 (technetium-99m-labeled tropantiol) is the most effective. Currently, various compositions of the freeze-dried kits for the synthesis of [ 99m Tc]Tc-TRODAT-1 have been proposed, facilitating the process of its production in situ , which, together with the availability of technetium-99m generator in a healthcare facility, as well as favorable pharmacokinetics, makes [ 99m Tc]Tc-TRODAT-1 a drug of choice for routine use in clinical practice. Text. In this review, various approaches to design and optimize the composition of the freeze-dried kits for the synthesis of [ 99m Tc]Tc-TRODAT-1, including the amount and ratio of active ingredient and excipients, synthesis conditions, in particular the temperature regime, synthesis time and pH of the reaction mixture, have been considered. Conclusion. Development and optimization of the composition of the freeze-dried kits for the synthesis of [ 99m Tc]Tc-TRODAT-1 is an urgent task in the context of improving its use in clinical practice. Based on the published data, clear dependencies can be traced, which may form the basis for further development and optimization of the composition of the freeze-dried kits for [ 99m Tc]Tc-TRODAT-1 synthesis for the diagnosis of Parkinson's disease and other neurodegenerative diseases by SPECT in the Russian Federation.

E. P. Pavlenko

A. O. Malysheva

A. A. Larenkov

Pharmaceutical development and practical approach to synthesis of tropantiol radiopharmaceutical ([99mTc]Tc-TRODAT-1) for diagnostic of neurodegenerative diseases (review)

神经退行性疾病诊断用放射性药物（[99mTc]Tc-TRODAT-1）的药物开发与合成实践方法（综述）

Publication Information	Publisher: Center of Pharmaceutical Analytics，Publishing cycle: ，Journal Type: journal，Open Access Journals: Yes
Basic data	Year of publication: 2019，Proportion of original research papers: 0.00%，Self Citation Rate:N.A.， Gold OA Rate: 0.00%
Average review cycle	网友分享经验：8 Weeks

Drug Development and Registration

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Development of solid dispersion system from milk thistle dry extract by solvent method

Development of the «Dissolution» test method for vaginal suppositories Pimafucin®

Evaluation of the efficacy and safety of cytoflavin as a neuroprotector based on a systematic review

Technological approaches to improve the bioavailability of the poor soluble substance Candesartan Cilexetil in mini-tablets

Pharmaceutical development and practical approach to synthesis of tropantiol radiopharmaceutical ([99mTc]Tc-TRODAT-1) for diagnostic of neurodegenerative diseases (review)

Development of solid dispersion system from milk thistle dry extract by solvent method

Development of the «Dissolution» test method for vaginal suppositories Pimafucin®

Evaluation of the efficacy and safety of cytoflavin as a neuroprotector based on a systematic review

Technological approaches to improve the bioavailability of the poor soluble substance Candesartan Cilexetil in mini-tablets

Pharmaceutical development and practical approach to synthesis of tropantiol radiopharmaceutical ([99mTc]Tc-TRODAT-1) for diagnostic of neurodegenerative diseases (review)

ISSN	2305-2066, 2658-5049
h-index	7