Ïðåäñòàâëåíû îáùèå ïðèíöèïû íàäëåaeàùåãî ïëàíèðîâàíèÿ äîêëèíè÷åñêèõ è êëè-íè÷åñêèõ èññëåäîâàíèé íåôðàêöèîíèðîâàííûõ è íèçêîìîëåêóëÿðíûõ ãåïàðèíîâ ïðè ïîäòâåðaeäåíèè èõ áèîàíàëîãè÷íîñòè. Ïîäòâåðaeäåíèå áèîàíàëîãè÷íîñòè ëåêàðñòâåí-íûõ ïðåïàðàòîâ ãåïàðèíà ÿâëÿåòñÿ îñíîâîé èõ ýôôåêòèâíîñòè è áåçîïàñíîñòè ïðè ïðèìåíåíèè â êà÷åñòâå àíòèêîàãóëÿíòà. Ïðèâåäåíû îñíîâíûå õàðàêòåðèñòèêè êà÷åñò-âà, ýôôåêòèâíîñòè è áåçîïàñíîñòè ïðåïàðàòîâ ãåïàðèíà, à òàêaeå îáúåì äîêëèíè÷åñêèõ è êëèíè÷åñêèõ èññëåäîâàíèé, íåîáõîäèìûõ íà ïðåäðåãèñòðàöèîííîì ýòàïå ðàçðàáîòêè ïðåïàðàòà.Êëþ÷åâûå ñëîâà: íåôðàêöèîíèðîâàííûé ãåïàðèí; íèçêîìîëåêóëÿðíûé ãåïàðèí; àí-òèêîàãóëÿíòíàÿ àêòèâíîñòü; áèîëîãè÷åñêèé ëåêàðñòâåííûé ïðåïàðàò; áèîàíàëîã; áèî-àíàëîãè÷íîñòü; ñîïîñòàâèìîñòü. ÂÂÅÄÅÍÈÅ íàñòîÿùåå âðåìÿ ïðèíÿòî âûäåëÿòü 2 ãðóïïû ãå-ïàðèíîâ -íåôðàêöèîíèðîâàííûå è íèçêîìîëåêóëÿð-íûå.Èñòî÷íèêîì ïîëó÷åíèÿ íåôðàêöèîíèðîâàííîãî ãå-ïàðèíà ñëóaeèò áèîëîãè÷åñêîå ñûðüå, ãëàâíûì îáðà-çîì, ñëèçèñòàÿ îáîëî÷êà êèøå÷íèêà ñâèíåé, ëåãêèå êðóïíîãî ðîãàòîãî ñêîòà. Íèçêîìîëåêóëÿðíûå ãåïàðè-íû ïîëó÷àþò ïðè ïîìîùè ðàçëè÷íûõ ïðîöåññîâ õèìè-÷åñêîé èëè ôåðìåíòàòèâíîé äåïîëèìåðèçàöèè èç íåô-ðàêöèîíèðîâàííîãî ãåïàðèíà [12].Àíòèêîàãóëÿíòíàÿ òåðàïèÿ ãåïàðèíàìè ñòàíäàðòíî ïðèìåíÿåòñÿ äëÿ èíãèáèðîâàíèÿ îáðàçîâàíèÿ è (èëè) àêòèâíîñòè òðîìáèíà â öåëÿõ ïðîôèëàêòèêè òðîìáî-îáðàçîâàíèÿ ó ïàöèåíòîâ ñ ðàçëè÷íûìè çàáîëåâàíèÿ-ìè [10,12]. Íåýôôåêòèâíîñòü ïðîâîäèìîé òåðàïèè ìîaeåò èìåòü òÿaeåëûå ïîñëåäñòâèÿ äëÿ ïàöèåíòà âïëîòü äî ëåòàëüíîãî èñõîäà, ïîýòîìó òàê âàaeíî êîí-òðîëèðîâàòü ïîêàçàòåëè êà÷åñòâà, ýôôåêòèâíîñòè è áåçîïàñíîñòè ïðåïàðàòîâ ãåïàðèíà íà âñåõ ýòàïàõ aeèç-íåííîãî öèêëà ïðåïàðàòà.Ôåäåðàëüíàÿ ñëóaeáà ïî íàäçîðó â ñôåðå çäðàâî-îõðàíåíèÿ (Ðîñçäðàâíàäçîð) èíôîðìèðóåò, ÷òî â ïîñëåäíåå âðåìÿ â àâòîìàòèçèðîâàííóþ èíôîðìàöè-îííóþ ñèñòåìó Ðîñçäðàâíàäçîðà íåîäíîêðàòíî ïîñòó-ïàëè ñèãíàëû î íåýôôåêòèâíîñòè ëåêàðñòâåííûõ ïðå-ïàðàòîâ ãåïàðèíà èëè î âàðèàáåëüíîñòè ôàðìàêîëîãè-÷åñêîãî äåéñòâèÿ ïðè èõ ïðèìåíåíèè [5 -9, 24].Àíàëèç óòâåðaeäåííîé íîðìàòèâíîé äîêóìåíòàöèè íà èíúåêöèîííûå ïðåïàðàòû ãåïàðèíà âûÿâèë áîëü-øóþ âàðèàáåëüíîñòü ïîêàçàòåëåé êà÷åñòâà â óòâåð-aeäåííîé ïðè ðåãèñòðàöèè äîêóìåíòàöèè è îòñóòñòâèå ãàðìîíèçàöèè ñ òðåáîâàíèÿìè ìåaeäóíàðîäíûõ ôàðìà-êîïåé.Íîðìàòèâíûå òðåáîâàíèÿ, ïðåäúÿâëÿåìûå ê îöåíêå êà÷åñòâà, ýôôåêòèâíîñòè è áåçîïàñíîñòè âîñïðîèçâå-äåííûõ õèìè÷åñêèõ ïðåïàðàòîâ, íå ìîãóò áûòü ïðèìå-íåíû ïðè ðàçðàáîòêå íåîðèãèíàëüíûõ áèîëîãè÷åñêèõ ïðåïàðàòîâ.  ñâÿçè ñ ýòèì, ïðîàíàëèçèðîâàâ èññëåäî-âàíèÿ ïî ðàçðàáîòêå íàó÷íûõ ïðèíöèïîâ äëÿ äîêàçà-òåëüñòâà ñõîäñòâà (ïîäîáèÿ) îðèãèíàëüíûõ è íåîðèãè-íàëüíûõ áèîëîãè÷åñêèõ ïðåïàðàòîâ ïî ïîêàçàòåëÿì êà÷åñòâà, ýôôåêòèâíîñòè è áåçîïàñíîñòè, äîêëèíè÷å-ñêèõ è êëèíè÷åñêèõ èññëåäîâàíèé, ïðîâåäåííûå ðåãó-ëÿòîðíûìè îðãàíàìè ðàçâèòûõ ñòðàí [11,12,14,16,17,20,21,23, 25], ìîaeíî ïðåäëîaeèòü êîíêðåòíûå ðå-êîìåíäàöèè ïî ïîäòâåðaeäåíèþ êà÷åñòâà, ýôôåêòèâíî-ñòè è áåçîïàñíîñòè ïðåïàðàòîâ ãåïàðèíà.Áèîëîãè÷åñêàÿ àêòèâíîñòü ãåïàðèíîâ -êëþ÷åâîé ïîêàçàòåëü, îïðåäåëÿþùèé èõ áåçîïàñíîñòü è ýôôåê-òèâíîñòü, â ñâÿçè ñ ýòèì ïðè èõ íîðìèðîâàíèè âàaeíî èñïîëüçîâàòü ñîâðåìåí...

No abstract

In recent years, there has been an increasing interest in the development of combination medicines (fixed drug combinations) containing two or more active ingredients in a single dosage form. Therefore, there is an urgent need to develop an optimal programme of pre-authorisation clinical trials for combination medicines. The aim of the paper was to summarise modern science-based approaches to clinical development of combination medicines and identify possible ways of their practical implementation, taking into account the requirements of the current legislation. The author reviewed scientific publications devoted to creation of fixed drug combinations and analysed the regulatory documents defining regulatory requirements for pre-authorisation clinical studies of medicines in the Eurasian Economic Union, the Russian Federation, and other countries. Based on the results of the analysis the author described the general regulatory requirements for planning clinical studies of combination medicines for the purpose of their subsequent authorisation in the Russian Federation (via the national procedure) and the Eurasian Economic Union (via the centralized procedure). The pre-authorisation clinical development programme should be designed individually for each combination medicine. The selection of an optimal clinical trial strategy will make it possible to obtain sufficient information on the efficacy and safety of a combination medicine for its subsequent authorisation.

A qualitative, or species, study of the microflora of the oral cavity was carried out using the technique of aerobic and anaerobic cultivation in patients with a full adentia of the upper and lower jaw before and after implantation. In patients after dental implantation, a change was observed both in the qualitative composition of the flora (the frequency of isolation of certain species) and the number of microbes secreted, which, in addition, underwent a certain dynamics on the 7th and 14th days of observation. On the 7th and further, on the 14th day of the study, a gradual decrease in the proportion of obligate-anaerobic and, above all, virulent periodontopathogenic species was observed (although their complete disappearance did not occur). In addition, the number of stabilizing microbial species was restored and was approaching normal. As a positive fact, indicating the favorable results of the surgical stage of treatment, it should also be noted that the number of most pathogenic species decreased by the 14th day from the moment of surgery to the minimum values.