Vol 2, No 2 (2020)

From the editor
From the editor
Perelygin V.V.

This issue of the journal "Formulas of Pharmacy" has been prepared under the conditions of combined remote work of members of the editorial Board and editorial staff.

Pharmacy Formulas. 2020;2(2):1
Pharmaceutical Sciences
Basevich A.V., Kaukhova I.E., Kodash A.A., Bitkina T.A., Smirnova E.M., Stepchenkov V.I.

This article provides an overview on draft GMP EC Annex 1 revision progress and, as a consequence, the GMP PIC/S. The role and position of Russia in the pharmaceutical market, its inclusion in international organizations involved in the regulation of the production and circulation of drugs has been indicated. The interconnection between economic integration processes, changes in international regulatory requirements and national legislation has been demonstrated.

The article shows how changes in the laws governing the pharmaceutical industry entail changes in the organization of manufacturing or in the approach to the manufacturing process at the organizational level and/or lead to material expenses to eliminate incompliance. Keeping track of possible future changes in legislation allows to pre-build a plan for eliminating incompliance. When analyzing the changes in the Draft Appendix 1 regarding the current version of Appendix 1, it has been revealed that the documents have significant differences. To eliminate significant incompliances with a number of paragraphs of the draft Appendix 1, it is necessary to make changes not only in the operating procedures, but also in the planning solutions of production sites.

Based on the results of the work carried out, it has been established that the introduction of the draft Annex 1 GMP PIC/S and its implementation in the GMP EAEU requirements will lead to incompliance at existing pharmaceutical enterprises, the elimination of which requires a lot of organizational work. Significant changes at the existing enterprise are required in accordance with 14 points of the draft. This article presents clauses 5.9, clause 5.21, clause 8.7, clause 8.16, clause 8.29, clause 9.17, clause 9.33 - this is due to that most of these requirements are absent in the current valid requirements of GMP EAEU and Russian GMP rules.

The comparison made is an occasion for pharmaceutical companies to conduct internal audits for compliance with the requirements of the draft GMP PIC/S Annex 1 in order to preventively identify incompliances and develop an action plan to address them.

Pharmacy Formulas. 2020;2(2):8-19
Structural analysis of drugs assortment for etiopathogenetic therapy of children with acute viral infections
Narkevich I.A., Nemyatykh O.D., Timchenko V.N., Siukaeva D.D., Terninko T.M., Alekseeva V.A.

The purpose evaluated the range of drugs for the etiopathogenetic treatment of children with acute viral infections. The methods of content analysis, data aggregation, comparative analysis are used. The research information base was made up of State Register of Medicines and National Registry of Medicines data as of 26 November 2019, as well as instructions for the medical use of drugs. It is shown that in the Russian Federation 201 trade names of drugs (35 INN) and 57 substances are registered. The leading positions in the structure of the supply of drugs and substances are held by russian manufacturers (76,00% and 70,00%, respectively).
At the same time, structuring by dosage forms allows one to isolate tablets and powders (39,00% and 78,00% for finished dosage forms and substances, respectively). Acyclovir prevails in the structure of the range of medicines (25,00% and 19,00% for international non-proprietary and trade names, respectively). The largest share in the structure of the assortment of substances is covered by interferon alfa-2b (17,50%). The results of the analysis demonstrate that for most drugs, the manufacturer carries out all stages of production, including issuing quality control (67,00%). For 2015-2019, the renewal index of the assortment of the study group was 22,38%.

Given the uncontrolled increase in the incidence rate, the presented assortment of antiviral and immunomodulating agents is sufficient to satisfy the needs of Russian pediatrics. One of the promising vectors for the development of the pharmaceutical industry in terms of providing medicines for children with acute viral infections is the development of drugs in the form of children's corrected forms.


Pharmacy Formulas. 2020;2(2):20-28
Experimental study of the liposomal form of fenoterol after improving the method of obtaining it
Ustinova T.M., Vengerovich N., Judin M.A.

The effect of different concentrations of cryoprotector (sucrose) on the efficiency of fenoterol inclusion in the lipid matrix during lyophilization has been studied. It has been shown that the liposomal form with the content of cryoprotector in the internal environment of liposomes – 2.5 % and in the external environment equal to 2 % provides long-term preservation of the drug in the liposome cavity. Under these conditions, it is possible to achieve a monodisperse distribution of particles with an average diameter of 4.28±1.62 μm. The assumed quantitative composition of the cryoprotector ensures the manufacturability of the liposome production process, increases the stability of the lyophilizate structure and prevents the particles from sticking together, ensuring their uniformity.

The profile of two-stage release of fenoterol from the liposomal form has been shown in vitro. The first stage of rapid release was characterized by a transition to free form within 15 minutes to 42 % of the encapsulated fenoterol. At the second stage, the active principle was released more slowly for 480 minutes.

The model of bronchospasm induced by 1% histamine has shown the advantage of the liposomal form of fenoterol in comparison with its free form in the form of an aqueous solution. Intra-tracheal administration of the liposomal form of fenoterol at a dose of 17 ukg/kg provided for 360 minutes the preservation of external respiratory function at the level of initial values, despite histamine inhalation, while the duration of action of fenoterol did not exceed 120 minutes.

Pharmacy Formulas. 2020;2(2):30-37
Determination of the marker compounds for standardization medicinal herbal species «Pectorales tea №1» and «Proctofitol»
Terninko I.I., Vishnyakov E.V., Romanova M.A., Generalova Y.E.

The State Pharmacopoeia of the Russian Federation 14th ed. suggests to standardize herbal teas using the procedures presented in the pharmacopoeia monographs but this approach is not always relevant due to complexity of this dosage form composition.

The purpose of investigation is to estimate quality of herbal teas utilizing monographs recommended by the State Pharmacopoeia of the Russian Federation 14th ed. for the individual components of teas and suggest feasible alternative approaches to standardization of multicomponent herbal drugs.

The objects of investigation – Pectorales species № 1 and Proctofitol®. Detection of substances was carried out using chromatographic (TLC and HPLC) and spectrophotometric methods recommended by the State Pharmacopoeia of the Russian Federation 14th ed. for individual components measured in term of marker biological active substances or substances found in the course of quality analysis.

It has been found out that the content of flavonoids measured in terms of giperosid surpasses over the equivalent figure in terms of luteolin in the extractions from Pectorales species № 1. The content of hydroxycinnamic acids in the same tea measured in terms of rosmarinic acid surpasses over the equivalent figure in terms of chlorogenic acid. Analysis of anthracene derivates in the Proctofitol® has shown that the adsorption maximum of phenolate solution of anthracene derivates (523 nm) coincides with maximum by which was calculated the mass attenuation coefficient of sennoside B (523 nm) (for chrysophanic acid λ = 515 nm) and the maximum of adsorption of extraction from the tea with using alcohol solution of magnesium acetate (515 nm) coincides with maximum by which was calculated the mass attenuation coefficient of glucofrangulin A. Preliminary cleaning Proctofitol® off anthracene derivates allowed to estimate the content of glycyrrhizic acid more completely.

The giperosid was suggested as a marker substance for determination of flavonoids, rosmarinic acid was suggested as a standard for hydroxycinnamic acids in Pectorales species № 1. The sennoside B was suggested as a marker for estimating of content of anthracene derivates in the Proctofitol® and the necessity of cleaning this tea off anthracene derivates when defining glycyrrhizic acid was proven.

Pharmacy Formulas. 2020;2(2):38-47
Biomedical Sciences
Gravicentric approach to Type 2 Diabetes therapy. The success prediction. A proof-of-concept
levit S., Torban N., Boaz M., Weichman M., Azuri J., Manisterski Y., Merzon E., Ryder D., Ginossar G., Gavra T., Levit V., Domuschiev I., Musin I., Ryder C.H.

This study is the proof-of-concept of our "Gravicentric" theory. This concept is based on several fundamental points: obesity as the main foe; rapid reversibility of the disease; as well as a new perspective on the roles different pharmacological classes play in general, and the role of insulin and GLP-1 analogs, in particular. The paper presents and discusses our experience of the implementation of insulin and GLP-1 analogs. The possibility of "insulin weaning"; the therapeutic approach for over-treated patients; and physiological dosing of insulin is also discussed therein.


Primary: To evaluate the long-term efficacy of GLP-1 analogs in insulin-treated Type 2 Diabetes Mellitus (T2DM) patients.

Secondary: To analyze which patient would most likely benefit from this combined treatment.


In 54 T2DM patients with a mean disease duration of 17.5 years and a mean extent of insulin therapy of 4.5 years, additional GLP-1 analogs therapy was prescribed. Mean duration of GLP-1 treatment was 25.8 months (2.15 years).

During the intervention, clinical, biochemical, and anthropometric parameters were analyzed. Compliance, Hypoglycemia and Metabolic Index (MI) assessments were implemented.


Mean Glycated hemoglobin (HbA1C) decreased from 9.28 ± 1.43 to 8.54 ± 1.4% on GLP-1 analogs, p < 0.01. Total Daily dose of Insulin (TDI) showed considerable reduction: 80.6 ± 42.7 U/day before starting GLP-1 vs.41.0 ± 30.7 U/day on GLP-1, p< 0.01. These changes were directly linked to weight loss: BMI has dropped from 35.1 ± 4.8 kg/cm2 before, to 32.8 ± 5.0 kg/cm2 on GLP-1 analogs, with patients losing 6.7 kg on average. Moreover, 13 (24%) participants discontinued at least one kind of insulin, while 7 (13%) stopped taking insulin completely, with simultaneous improvement in diabetes control. No clinically significant hypoglycemia was observed.

Post-hoc, the participants were categorized according to each patient’s ability to reduce TDI by more than 20 U/day, and then split into two groups. Group A – 34 patients (64.2%) who successfully reduced TDI; Group B – 19 patients (35.8%) who failed to do so. The comparison of the two groups showed the following:

  1. Significantly larger – virtually twice as large – baseline TDI in Group A (97.4±40.4 U/day vs. 52.2±31.0 U/day), p< 0.001.
  2. Very effective BMI reduction (ΔBMI 3.3 ± 2.4 kg/cm2 0.9 ± 1.2 kg/cm2, p< 0.001) and much better compliance (1.4 ± 1.1 vs. 2.2 ± 1.0, p< 0.02) in Group A.
  3. A considerable decline of insulin requirements in group A, on GLP-1 therapy (ΔTDI on GLP-1 was -62.4 ± 31.9 U/day) with no TDI reduction in Group “B” (ΔTDI on GLP-1 was +0.03 ± 14.1 U/day, p< 0.001).

Thus, in spite of the fact that on GLP1 therapy HbA1C has declined to the same levels in both groups, patients from group A became much leaner and metabolically healthier.

We suggest overtreatment as the critical factor of obesity in Group A.


Adding GLP-1 analogs to insulin in poorly controlled, insulin-treated T2DM patients resulted in an impressive weight (BMI) reduction with significant improvements in glucose control. This provided for a further decline in insulin resistance and insulin requirements. We suggest that the best candidate for successful GLP-1 analogs therapy is an obese, overtreated and compliant T2DM person. Changes in Metabolic Index (MI) rather than surrogate glycemic parameters (HbA1C) are better predictors of a successful T2DM therapy. Neither the duration of diabetes nor the length of insulin therapy in the past is likely to have a critical role in predicting success. These findings are proof-of-concept of our Gravicentric theory in T2DM.

Pharmacy Formulas. 2020;2(2):48-60
Shamrey V.K., Baurova N.N., Kurasov E.S., Svechnikov D.V., Medvedeva J.I.

The paper considers pictopolygraphic method in the objective diagnosis of affective disorders. 70 patients with symptoms of anxiety and depression were examined. Clinical psychopathologic and pictopolygraphic (by Software and Methodological Support Complex Egoscope) methods were implemented in the research. Pictopolygraphic method allows to carry out psychometric examination automatically using standardized questionnaires and scales while recording a number of physiological parameters: heart rate (HR), photoplethysmogram (PPG), electroencephalogram (EEG), galvanic skin response (GSR) and pictographic data. To assess the patient's subjective perception of the severity of anxiety and depressive disorders, the examinees completed the Hospital Anxiety and Depression Scale (HADS).It has been established that the assessment of the condition of patients with affective disorders based exclusively on clinical and psychopathological method is not sufficiently informative and does not always correspond to the actual severity of existing affective disorders. The use of the pictographic method in the examination of patients with anxiety-depressive disorders of a non-psychotic level can optimize the diagnostic process, improve the accuracy and quality of the diagnostic findings. The basic correlations of physiological pictographic indicators with patient complaints has been determined.  It has been shown that the most informative and sensitive component of the objective assessment of patients with anxiety-depressive disorders is the change of the heart rate.

Pharmacy Formulas. 2020;2(2):62-69
Pathogenetic mechanisms of antinociceptive activity of antidepressants
Scheidegger J.M., Dorovskiкh I.V., Pavlova T.A.

The article attempts to generalize the currently known pathogenetic mechanisms of antinociceptive effects of the most widely used antidepressants and to highlight the currently available data of experimental models of various pain disorders in laboratory animals and the results of clinical studies both in groups of patients with comorbid
pain symptoms and in patients with pain symptoms of various origins without the presence of pronounced affective disorders. The article presents the results of evidence-based studies of the analgesic activity of tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI) and drugs with a special receptor mechanism of action. The involvement of various neurotransmitters: serotonin, dopamine, norepinephrine, melatonin, enkephalin, GABA, glutamate, adenosine, etc. in the implementation of the analgesic effect of antidepressants has been examined. The most common side effects of mentioned antidepressants of frequent cause of patients refusing treatment were highlighted as well. Taking into account the considered features of the treatment of comorbid patients with pain, recommendations on the choice of the drug not only according to the severity of its antidepressant and antinociceptive actions, but also the possible development of undesirable effects of long-term therapy were made. New groups of antidepressants with an alternative mechanism of action deserve special attention.

Pharmacy Formulas. 2020;2(2):70-83
Biological sciences
Chaga and its bioactive complexes: history and perspectives
Zmitrovich I.V., Denisova N.P., Balandaykin M.E., Belova N.V., Bondartseva M.A., Perevedentseva L.G., Perelygin V., Yakovlev G.P.

A review of research field related to well-known Russian medicinal fungal material, Chaga, is caused by the need to summarize information about the effects of its individual compounds on molecular targets of cancer cells. Chaga raw material (sterile bodies of the fungus Inonotus obliquus) is a complex fungus tissue which includes wood degradation products, and products of assimilation wood tissue components by the fungus. Chaga raw material is rich in polyphenols, triterpenoids of fungal and plant origin, and polysaccharides. In the early 1960s, Chaga raw material was included in the USSR State Pharmacopoeia and was recommended for use as a non-specific drug for the treatment of gastritis, stomach ulcers, polyposis, precancerous diseases and some forms of malignant tumors in cases where radiation therapy and surgical intervention are not destinated. However, large pharmacological potential of Chaga at the current moment seems to be still not realized. First of all, the multidirectional effect of various Chaga bioactive complexes on the molecular targets of the cancer cell is obvious: inhibiting cyclin-dependent kinases and proapoptotic (triterpenoids), immuno-mediated cytotoxic and pro-inflammatory (polysaccharides), genoprotective and antiapoptotic (polyphenols). It is obviously that complex action of these substances on cancer tissue has less pronounced effect than the targeted one. Consequently, the clinical trials of purified bioactive complexes of chaga, primarily of proapoptotic (inotodiol, betulinic acid) and anti-inflammatory (3,4-dihydroxybenzalacetone) action, are on the agenda. Based on the data reviewed, it is suggested that careful study of Chaga raw material in the future may lead to elaboration of new and more effective pharmaceuticals

Pharmacy Formulas. 2020;2(2):84-93
Retracrion Notice
Retraction Notice Gabidova A., Galynkin V. A unified and simplified flow diagram of the production of active pharmaceutical ingredients and the finished dosage form // Pharmacy Formulas. - 2019. - Т. 1. - №1. - C. 32-37. doi: 10.17816/phf18552
Gabidova A.E., Galynkin V.

The article «Risk Analysis in the Production of Medicines” publishe in Pharmacy Formulas 1(1) 2019 by A. E. Gabidova and V.A. Galynkin is a duplicate of the article «Unified and simplified technological scheme in the production of the active pharmaceutical substances and finished pharmaceutical products» published in the Bulletin of the Saint Petersburg State Institute of Technology (Technical University). 2016; 36: 93-98. That was the reason for retraction.
Revealed February 20, 2020 by the Editorial Board

Pharmacy Formulas. 2020;2(2):101
Information and Prevention
Electronic workflow for healthcare
Kiryushkin S.

The transition to EDI in healthcare is one of the components of the Information Society Development Strategy in the Russian Federation, which was approved by the president in 2017. This strategy is calculated for 2017-2030

Pharmacy Formulas. 2020;2(2):102-103
Grigory Yakovlevich Kogan: Director of the Leningrad Pharmaceutical Institute in 1938-1941
Narkevich I.A., Stepanov S., Zvyagin Y., Vorobeva S., Perelygin V., Dobrova D.

On the basis of archival and little-known documents, the biography of a specialist in pharmaceutical chemistry in the field of galena drugs technology, was reconstructed in the article. Grigory Yakovlevich Kogan (1889-1956), D.Sc. in Pharmaceutical Sciences, Professo held senior positions in the 1920s and 1930s in the leading pharmaceutical institutions: the Leningrad Military-Medical Preparations Plant, the Leningrad Scientific and Pharmaceutical Society. In 1938-1941 G. Kogan was the Director of the Leningrad Pharmaceutical Institute (now Saint Petersburg State Chemical Pharmaceutical University), after the war, he headed the Department of Technology of Medicinal Forms and Galena Drugs at the Moscow Pharmaceutical Institute (now I. M. Sechenov First Moscow State Medical University). Based on the analysis of his scientific and pedagogical activities, his contribution to the development of national and world pharmacy and training of specialists in the USSR has been revealed.

Pharmacy Formulas. 2020;2(2):104-109
Sergey Kholodkevich: "I quite often came up with original ideas, which then turned out to be in demand»
Zvyagin Y.Y.

«Значительную часть жизни я занимался тем, над чем сначала смеялись. Через некоторое время оказывалось, что этим занимаются или хотят заниматься - многие». Пожалуй, эти слова являются самой точной характеристикой пути в науке этого ученого.

В апреле доктор технических наук, профессор, заведующий лабораторией биоэлектронных методов геоэкологического мониторинга Научно-исследовательского центра экологической безопасности РАН Сергей Викторович Холодкевич отметил свое семидесятилетие. Но, кажется, юбиляр не очень замечает свой возраст. Все так же полон новых идей и планов, все так же стремится оказаться хоть на шаг, но впереди времени.

Pharmacy Formulas. 2020;2(2):110-115

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