UA135665U - PHARMACEUTICAL COMPOSITION FOR TREATMENT OF PROKTOLOGICAL DISEASES - Google Patents

Abstract

The pharmaceutical composition contains a combination of methyluracil, diltiazem and lidocaine in free form or in the form of their pharmaceutically acceptable salts. The composition also comprises a pharmaceutically acceptable anhydrous hydrophilic emulsion base comprising propylene glycol, at least one pharmaceutically acceptable polymer selected from the class of poloxamers, at least one pharmaceutically acceptable emulsifier and at least one pharmaceutically acceptable lipophilic excipient.

Description

The utility model belongs to the field of medicine and the chemical-pharmaceutical industry, namely to rectal preparations of local action in the form of an ointment containing a stimulator of reparative processes, a local anesthetic and a calcium channel blocker, for use in the treatment of proctological diseases.

The problem of treatment of inflammatory diseases in proctology is one of the urgent problems of medicine (Fedorov V.D., Dultsev Yu.V. Proctology. - M.: Medicine, 1984. - 384 p.).

One of the most common and difficult to treat human proctological diseases is anal fissure (Kryilov N.N. Chronic anal fissure // Vestnyk hirurgicheskois gastroznterologii. - 2008. - Mo 1, - p. 5-11.) per 1000 adults, an anal fissure occurs at 20-30 (Vorobyev, G.M. Fundamentals of coloproctology / G.M. Vorobyev. - M. 00O "Medical Information Agency", 2006. - 432 p.). In the structure of diseases of the large intestine, this pathology ranks third after colitis and hemorrhoids in terms of the number of applications; patients with anal fissures are 11-13 95 (Vorobyev, G.M. Scope of treatment and diagnostic measures for non-neoplastic diseases of the distal part of the rectum and anococcal region: methodical material! / G.I. Vorobyev, V.G. Zaitsev. M. , 2000.- 122 p.). An anal fissure is characterized by three main signs: it is accompanied by sharp pain, weak bleeding in the anus, and increased tone (spasm) of the anal sphincter, which prevents the healing of the fissure, causing tissue ischemia. One symptom provokes the growth of another according to the principle of a closed circle: the pain increases during defecation and provokes a spasm of the muscles of the anus, which, in turn, increases the pain and prevents the healing of the crack. Treatment of anal fissures should be aimed primarily at relieving pain and spasm of the sphincter, and then at normalizing bowel movements and healing the fissure itself up to epithelization. Success with conservative therapy can be achieved in approximately 70-95 patients. The difficulties of conservative therapy lead to the fact that, over time, an acute anal fissure turns into a chronic anal fissure, which is accompanied by the growth of scar tissue and the formation of a fibrous anal polyp (Fedorov V.D., Dultsev Yu.V., Proctology. - M.: Medicine, 1984. - 384 pp. Krylov N.N.

Chronic anal fissure // Herald of surgical gastroenterology. - 2008. - Mo 1. - b. 5-11; Vorobyev H.M. Fundamentals of coloproctology / H.M. Vorobyov - M. OO "Medytsynskoe

From the Information Agency", 2006. - 432 p. Vorobyev G.M. Volume of treatment and diagnostic measures for non-neoplastic diseases of the distal part of the rectum and anococcal region: methodical material / G.I. Vorobyev, V.G. Zaitsev. M., 2000. - 122 Sat.).

An anal fissure can be combined with hemorrhoids, which greatly complicates the treatment of the latter and should be taken into account during conservative therapy. When anal fissure and hemorrhoids are combined, complaints of prolapsed hemorrhoidal nodes and profuse rectal bleeding are added (Fedorov

V.D. Dultsev Yu.V. Proctology. - M.: Medicine, 1984. - 384 p.; Vorobyev G.I. The basis! coloproctologists / G.I. Vorobyov - M.: "Medical Information Agency", 2006. - 432 p. Vorobyev H.M. The volume of medical and diagnostic measures for non-neoplastic diseases of the distal part of the rectum and the anococcyge region: methodical material / G.I. Vorobyev, V.G. Zaitsev. M., 2000. - 122 p.). The prevalence of hemorrhoids is very high.

So, according to the literature, 10 million people suffer from hemorrhoids in the USA, which is 4.4 95 of the population. There are 37 cases of hemorrhoidectomy per 100,000 people per year. Thousands of patients after hemorrhoidectomy suffer from postoperative pain, which is the main reason for the extension of their stay in the hospital ("Torisa! aikialet oipitepi ip rovi-

PpetogPpoiidesyutu raip heiyei: A teia-apaiuvov oi hapdotigei sopigoPey imia!ye /U.-). Nyapd ei ai. /Aviap mahttai oi Zygdegu. - 2017. - R. 1-7, pr u/akh.doi.ogd/10.1016/..a5i5yg.2017.06.002). According to other authors, 77,905 patients suffer from postoperative pain after hemorrhoidectomy, 80,95 of whom rate the intensity of pain as moderate to severe. Pain is one of the main reasons for refusing treatment. The main cause of complications and prolonged healing of postoperative wounds after hemorrhoidectomy is the internal spasm of the anal canal (Koagidtse?-

Mopa Sh., OsNnagap-Negpapde7 M.E., Tozsapo-Sagirau 9. Torisa! aiaet og raip ayeg siozeyd

Ppetotpoidesiotu //Nemivia de SavigopiegoYodia de Mechiso. - 2016. -81 (2). - R. 74-79.).

In case of anal fissures, together with surgical treatment, conservative therapy is used, for which drugs containing stimulators of reparative processes, in particular methyluracil, and local anesthetics, for example, lidocaine hydrochloride, are used locally (Compendium 2016 - drug preparation! /Edited by V.N. Kovalenko - K.: MORION, 2016. - 2416 p.). It is known that calcium channel blockers and nitric oxide donors are able to relieve spasm of the anal sphincter. This contributes to pain relief and healing of postoperative wounds and anal fissures, which allows you to avoid surgical intervention m5. pygodiisegip. Evishaio sotragaiiimo /U.9U. Ryspe, M.9U. Sagsia-Sogei, RG Minaira, I. AII-

Maptotsa, 9U.M. Coid //Sigidia Ezraioia (Epodii5y Eaiiop). - 2010. - M. 87, Ivtze 4. - R. 224-230.).

The sublingual use of nifedipine for these purposes has been described, which reduced the activity of the internal anal sphincter both in the control group and in patients with high anal pressure, which allows the use of nifedipine to relieve symptoms in patients with hemorrhoids or anal fissure (EPesi oi pitediripe op hesioapa! toiyu /Spguzo5 E., Hupo5 E., T2omahav o., 7ogaz O.9., Tviaoiv5i5 U., Mazziiakov 5.9. /Oiv Soiop Vesisht. - 1996. - Ger; 39(2). - R. 212-216.) .

The use of diltiazem, as well as its combinations with bethanechol - a medicinal substance of cholinergic action (a selective stimulator of Me-choline receptors) that stimulates bowel movements (Sagareyi B.A.,

Cutt M.A., RpiyShir5 V.K. Toris! Diyalet apa Beiyapesnoi! desgease apai 5rpipsieg rgezzige apa

No! mom! ієззыгев м/йпоці зіде еПесів /Оі5 Soiop Vesisht. - 2000. - Axles; 43(10). - R. 1359-1362).

Both drugs - diltiazem and bethanechol - when used locally reduce the pressure of the anal sphincter, and when they are used, the same effect is achieved as when using nitrates.

Diltiazem is (25,35)-5-(2-(dimethylamino)ethyl|-2-(4-methoxyphenyl)-4-oxo-2,3,4,5- tetrahydro-1,5-benzothiazepine-Z- yl acetate (Eiygoreap Ripaptasoroea. 97 va. EOM. Bigazroishgo:

Soipsii oi Epgore; 2016. 4016).

Diltiazem is effective in treating anal fissures both orally and topically. However, when applied locally, it acts more effectively, reaching the level of activity established with the local application of nitrates, but with significantly fewer manifestations of side effects (A hapdotigea igia| oi ogai! m5. orisai dikia7et og spgopis apai tizzitez /)opaz M., Meai K .VA., Abegsgotrbie ..R., Zspoiieia 9.N. /Oiv Soiop Vesisht. - 2001. - Acd; 44(8). - R. 1074-1078). It is recognized that the local application of diltiazem leads to a significant reduction of pain sensations after hemorrhoidectomy with minimal side effects (Torisa! diyalet oipitepi ip rozi-petopPoidesyutu raip geiiyei A teia-apaiuvov oi hapdotigei sopigoPei iiaie | /M.-3U. Nyapu oei a). /Aviap o docspai! Oi BZygdegu. -2017. -R. 1-7, see //akh.aoi.ogd/10.1016/).а5|5, г.2017.06.002.). Local use of diltiazem preparations (2 95)

Zo is effective in the treatment of chronic anal fissures that cannot be treated with glyceryl trinitrate. Diltiazem is well tolerated. Side effects are rare ("10 95) and appear in the form of itching at the site of application (Dopaz M., Zreake MU., Zspoieieia 9.N. Sikaet peai5 diusegui

Tipigage-gevziviapi spgopis apai yiizzygev: a rgozresiime vischau /Oiv Soiop Vesisht. - 2002. - Atsa; 45(8). - R. 1091-1095.). Local use of diltiazem in chronic anal fissure is an effective method of its conservative treatment and leads to improvement in the quality of life of patients (Omtsaiyu oi Iie ip raiepiv m/yip sNgopis apai gizvyge apeg Yurisa! 'eaiiytepi mn aiyalet /T5ypoda A.,

Kazpimadiga U., Nigoze K., Zavzaki T., Kapo M. /LMopa u. (zavigoipievi. Zygu. - 2012. - Mom. 27; 4(11). -

R. 251-255.).

It has been established that the local application of nitrates, diltiazem or their combinations is effective in the treatment of anal fissures, but studies have not revealed reliable advantages in the effectiveness of the treatment of any of these substances, which is a prerequisite for the wider use of diltiazem due to the absence of side effects inherent to nitrates (Sotragisopoi Iorisai ivozogbride topopiyhage, horisa! diyaget, apa INeig sotbipaiiop ip ipe eaitepi oi spgopis apai iiv5!yge / N. Vshi5, M. Magoi, A. Tab5, A. SozKip // Aviap ChdChoshta! oi Zygdegu. - 2013. -36. - P. 165-169, see //ah.aoi.ogd/10.1016/..а5)5yg.2013.01.010.).

Examples of some drugs containing diltiazem can be given. For example, the well-known local 2 95th gel, which per 100 ml contains 2 g of diltiazem, 10 ml of propylene glycol, 2 g of hydroxyethyl cellulose, canned water up to 100 ml (pyru/mlmly.did-edi/dositepiv/rpattasu/aroshiv/ribiisaiopv/ris /04/aaget. raiyu The shelf life of the drug is 30 days.

Diltiazem Hydrochloride Cream 2 95 is also known

Apopeaf (see /Llymliu.doKiegopiipe.sot/riiv/ep/rayepi iptogtaiyop Ivayei-4382-apopea!-yK. rai- 1510756510.raiu) produced by Te Mogiy Umevi I opdop Nozria!5; one tube (30 g) should be used within three weeks, the course of treatment - no more than eight weeks.

A well-known extemporaneous drug produced by Scu 5 api 5Yi Tpotab, which is 2 95th cream of diltiazem hydrochloride (mmm.diuzapazpotav.py5.ik/gezoigsev/raiepi-iptotptaiop/rpagtasu/ayaget-puagospiogide-2-steat.rai). In addition to diltiazem hydrochloride, the drug contains cetostearyl alcohol, macrogol 20 cetostearyl ether, white soft paraffin, liquid paraffin, phenoxyethanol (antimicrobial preservative) and purified water. The shelf life of the drug after opening the package is 4 weeks, subject to storage at a temperature of 2-8 76. The course of treatment of anal fissure with the drug is from 6 to 8 weeks.

Potential side effects of both creams include a mild headache (less than 1 in 10 people) that is relieved by paracetamol, mild dizziness that goes away quickly when lying down or sitting, and itching at the application site or rectal bleeding.

A well-known combined rectal ointment on a hydrophobic basis produced by UuUeddejos

Rpaptase, which contains diltiazem hydrochloride 2 Cho and lidocaine C to (mly meidejoodih.sot/rgipu/dinaget-iIidosaipe-apaI-oipitepi.piti).

These and other diltiazem preparations have drawbacks. They are not registered in the prescribed manner (they do not have a trade license), they are manufactured as extemporaneous medicines with a limited shelf life.

The main reason for the lack of ready-made medicines with diltiazem for rectal use is the decomposition of diltiazem during storage, that is, with the lack of stability that a ready-made medicine should have. Quality studies of extemporaneous preparations for local use containing 295 diltiazem were conducted. Although 2 95 cream is prescribed according to the prescription, in pharmacies in 50 95 cases they prepare an ointment in which diltizem is in a suspended state. The quantitative content of diltiazem in such drugs was overestimated in 14,95 cases, and underestimated in more than 3,595 cases. These drugs also do not meet the requirements of the US Pharmacopoeia for the uniformity of the distribution of diltiazem (in 40 95 cases when packaged in cans and in 30 956 cases when packaged in tubes), which negatively affects the effectiveness of patient treatment (Ochaiyu oi sotroipaea Iorisai! 2 do diaget puagospiogide Toptiiaiopv og apai! iizvyge /M. zpap, I. Zapaieg, M. Vai, S. Zpagta, I. Vadnamap /L/Mopa uotstai! oi Savzigoepiyeegoiodu. - 2013. -

Zerietreg 14; 19(34). - R. 5465-5650.).

It has been established that the local application of calcium channel blockers is more effective than therapy with oral drugs, and is also not accompanied by frequent manifestations of side effects, but the route of administration does not affect the frequency of recurrence of proctological diseases, which requires the use of these substances in combinations with other medicinal substances (Ohai meg5iv5

Ioris! saisiit spappei! BiosKeti5 Tog spgopis apai iiz5zyge-a zubzietaiis hemiezh apa teia-apaiuvov oi hapdotiei sopigoiIes igia!z /"Zanpebraiu 5.M., Antea K., Segpemesitsie V., Idbaii A., Uuaivn 5.V., douse

M.V. /Lpiegpaiopai mahtpai oi Zygdegu. - 2017. - M. 44, Aydyvi. - R. 87-93.).

From the state of the art, the patent EP 0969813 B1 "Local pharmaceutical composition including a cholinergic agent or a calcium channel blocker" (Torisa! rpagtaseciisai! sotrozyop soptrgizipd a spoiipegdis adepi og a saisisht spappei BiosKeg: Eig. Rai. Mo ER 0 969 813

VI. Rir. Oage 29.09.2004. VyPape 2004/40. 13), which describes a composition for topical use in and around the anal canal for the treatment or prevention of benign anal disorders associated with high anal pressure or spasm of the anal sphincter, which contains from 295 to 5595 diltiazem or a pharmaceutically acceptable salt thereof and from 0.05 95 to 1 95 bethanechol or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier base. The composition may contain a steroid in a concentration of 0.1 90 to 5 95, in particular hydrocortisone, and may be in the form of a gel, ointment or cream. The composition may also contain a nitric oxide donor, in particular trinitroglycerin or a pharmaceutically acceptable salt thereof, isoprenaline, histamine, prostaglandin /-E2, adenosine triphosphate, nicotine, bradykinin, caerulein, glucagon or phentolamine.

The VI compositions described in patent EP 0969813 have significant drawbacks. Their carrier bases contain significant amounts of water in which diltiazem is hydrolyzed. As a result, the use of diltiazem in such compositions as a calcium channel blocker does not allow them to be manufactured as finished medicinal products, but only as extemporaneous medicinal products with a limited shelf life, as well as a low level of standardization and quality assurance compared to finished medicinal products.

Diltiazem is combined with bethanechol - a prokinetic that stimulates bowel movements (Sagareyi E.A., Katt M.A., RaiYire V.K. Toris! Oi5 Soop Nesisht. - 2000. - Osi; 43(10). - R. 1359-1362.; Torisa! diya7et apa reiNnapestoi desteazeye apai 5rpipsieg rgez5y!ige miiipoci 5ide ePesiv / Sagareii E.A., Katt M.A., Emape V.K., RiyShirv A.K. //shi. - 1999. - Mom.; 45(5). - R. 719-722.

Bethanechol is characterized by numerous side effects: diarrhea and involuntary defecation, headache, bradycardia, orthostatic hypotension, cardiac arrest, reflex tachycardia, loss of consciousness, belching and vomiting, bladder spasm, abdominal pain (colic), difficulty breathing associated with bronchospasm, because of increased secretion of hydrochloric acid, etc., in connection with which the use of bethanechol is severely limited and becomes pathogenetically inappropriate (pYr/Lumly.davigozsap.gpy/paparook/144/3609;

Sagareii E.A., Cutt M.A., Ryirz V.K. Toris! diaget apa reiypapesnoi! desgeyease apai 5rpipsieg rgezzige apa peai apa! їїїїге5 м/йпоці вед емпесів /Оів Соіоп Вешіст. - 2000. - Axles; 43(10). - R. 1359-1362.; Toris! Diya7et apa reiNnapestoi desteazeye apai 5rpipsieg rgez5y!ige miiipotsi 5ide ePesiv /Sagareii E.A., Katt M.A., Emap5 V.K., Rnyire A.K. //yshi. - 1999. - Mom.; 45(5). - R. 719-722.;

Starostyn B.D. Gastroesophageal reflux disease // Rus. honey. journal - 1997. - Vol. 5, Mo. 23. A combination with trinitroglycerin, which has the usual side effects for nitrates, is also provided (Compendium 2016 - medicinal drug! /Edited by V.N. Kovalenko. - K.:

MORION, 2016. - 2416 p.; And dove ijipaiipud 5ishau m/yyp 0.1 95, 0.2 95, apa 0.4 95 diusegu! igipigate oipitepi ip rayepibv m/yyp spgopis apai iizvigev /Zspoieieia U.N., Vosk 9U.0., Mapa V., Visnieg N.).,

Ashapaviadiv 5., Rgbiv5 M., Negoia A. /(sci. - 2003. - Geb.; 52(2). - R. 264-269.).

The compositions contain from 2595 to 5095 dimethylsulfoxide (DMSO), which is a powerful penetration enhancer, in connection with which drugs intended for local action can have a systemic effect, not a local one. In addition, high concentrations of DMSO can have a local irritating effect on the skin and mucous membrane of the rectum (Naparook oi

Rpaptaseshiisa! Eksiriepiz /Ed. Bu Vomzhe V.S., ZpezKeu R. u., bookK MU.., Bepiop M.B. 7" wai.

Hopdop: Rpaptaseshiyisa! Rgez5, 2012. 1064). In addition, a long course of treatment for 8 weeks should be noted.

Patent KO 2 592 366 C2 "Pharmacological composition for the treatment of proctological diseases (variants)" is also known from the state of the art, which describes a pharmacological composition for the treatment of proctological diseases containing 3.3-7.5 wt. 9o methyluracil, 0.13-0.3 Fo wt. about nifedipine, 0.13-0.3 wt. isosorbide dinitrate, 1.3-3.0 wt.9o lidocaine and a pharmacologically acceptable carrier (residue). The specified pharmacological composition was chosen as the closest analogue, as it contains a combination of the stimulator of reparative processes methyluracil, two medicinal substances nifedipine and isosorbide dinitrate, which reduce the spasm of the anal sphincter, and the local anesthetic lidocaine, which are in a pharmacologically acceptable base. It is also stated that it is theoretically possible to use any calcium channel blocker, including diltiazem, instead of nifedipine.

However, the composition described in patent-analog KI 2 592 366 C2 has significant drawbacks.

First, the given examples of compositions indicate that diltiazem in such gels will inevitably hydrolyze with the formation of impurity E (see monograph 04/2013:1004 "ritsa7et

Nuagospiogide" of the European Pharmacopoeia - Epigoreap Rpagtasorovia. 9" ey. computer 5 and three times:

Soipsii oi Eigore; 2016. 4016). As a result, the use of diltiazem in such compositions as a calcium channel blocker does not allow them to be manufactured as finished medicinal products, but only as extemporaneous medicinal products with a limited shelf life, as well as a low level of standardization and quality assurance compared to finished medicinal products.

Secondly, the composition contains isosorbide dinitrate, which is characterized by undesirable side effects common to nitrates: headache, dizziness, nausea, hyperemia of the skin, drowsiness, orthostatic hypotension, reflex tachycardia, as well as, less often, bradycardia, collapse, increased angina pectoris (Compendium 2016 - medicinal drug! / Edited by V.N.

Kovalenko. - K.: MORION, 2016. -2416 p.). In 20-25% of patients who used rectally 0.4 UO ointment with glyceryl trinitrate, a temporary but severe headache occurred (A dose

Tipaipu vishau my 0.1 95, 0.2 Us, apa 0.4 95 diusegu! Mipigage oipitepi ip rayepiv m/yy spgopis apai tivzyge5 /Zspoieye a O.N., Vosk 9.0., Magia V., Kispieg N.)., AIpapaviadiv 5., RgbiI5 M., Negoia A. //tsi. - 2003. - Heb.; 52(2). - R. 264-269). Nifedipine is also characterized by such side effects as headache, which occurs in 30 95 patients, drowsiness, dizziness, tachycardia, nausea, swelling of the lower extremities, hyperemia of the skin of the face and upper body in 60 95 patients, and others (Compendium 2016 - drug preparation / Under the editorship of V. N. Kovalenko. - K.: MORION, 2016. - 2416 p.; ., SoMat R., So(Gat V., Raniemapi R. /Lhap. Ved. Stezsepi. Mea.

U. - 2014. - Ats9u; 16(8): e13592.; Toris! piyediripe m/yy Idosaipe oipitepi m5. asiime sopigo! ог игеаитепи ой spgopis apaі ііз5іге: гезіійів5 оі а rgoz5resiime, gtapdotiged, doibie-Biіpa vzitsau / Reitoyi R.,

Vome A., Apigoroii S., Moiipo 0., Apigoroii M., Vaigapo A., Oye 5iepo S., Anepa R. //Oiv. Soyop.

It's funny. - 2002. - Mom; 45(11). - R. 1468-1475.). Probably, as a result of the mentioned side effects, the optimal content of nifedipine and isosorbide dinitrate in the composition turned out to be low - at the level of 0.2 wt. 95 for each substance. Unlike nitrates, diltiazem is well-tolerated

Iosai de Ia yesiziga apa! sgopisa sop diyalet m5. Piigodiisegip Evicaiio sotragaiimo /).U. Ryspe, M...

Sagsia-Sogei, R.H. MiMPaiBra, I. AI-Maptotsa, UM. Coid / Sigidia Ezraioia (Epodiihp Ediiop). - 2010. - M. bo 87, Ivvtse 4. - R. 224-230. A hapdotieay pai! oh wow! m5. Yurisa! aiia?et og sNgopis apai ii55!ygev

/Chopaz M., Meai K.A., Abegsgotrbie U.R., Zspoietva U.N. /Oi5 Soiop Nesiit. - 2001. - Atso; 44(8). - R. 1074-1078.; Hey! megviv horisa! saIsiit spappei! riosKeg5 og spgopis apai iyizzige-a zuzietaiyys hemiem/ apa teia-apaiuvov oi gtapdotigeid sopigoiIvy Ia! /"ZaperaiPu 5.M., ANtea K., Segpemesitsie V., Idbai

A., Mayivp 5.V., douse M.V. /Lpietaiiiiopa! good luck to Zigdegu. - 2017. - M. 44, Atsdivy. - R. 87-93.;

Sotragizop oi orzeguayopai apa sopigoi! Iey siipisa! ойай5 ой аиялет ip ойе igeaitepi ой spgopis apai tizzyge /Meani V., Rgakazi A., Oradnuau 5., Hez5 0., Madam T.0O., Katap I. /Lpaiap. U. Zygu. - 2011. -

Oes.; 73(6). - R. 427-431.; Damzhaid M., Mazooi 7., Zaiit M. Torisa! aiiiaget Nuagospiogde apa diusegu! ipygaye ip ye geaitepi oi spgopis apai yiizvyge //). SoiI. Rnuzisiape Z!ig9. Cancer. - 2009. - Axis.; 19(10). - R. 614-617.; Zapeii V., Maitoodie! M., Mazotsydroshig N. Sotragizop oi Yurisa! aiusegui yiipykate mn aiyiaget oipitepi og igeaitepi oi spgopis apai yiiz5yge. And hapdotigea siipisa! they are! / App.

May Spig - 2009. - bBer-Osi.; 80(5). - R. 379-383.; 5imeptap V., VepaisK R.), Mazmagu N.U. And hapdotigei, rgozresiime, doshibie-Briipa, riasero-sopigoPey Shia! Oi She epPesi oi a saiisiit spappei! riosKeg oipitepi op raip apyeg petoppoidesiotu //Oiv. Soyop. It's funny. - 2005. - Axis.; 48(10). - R. 1913-1916.), and only in isolated cases during treatment with soft drugs with diltiazem were observed the side effects described for it (Compendium 2016 - medicinal preparations / Lod edited by V.N. Kovalenko. - K: MORION, 2016. - 2416 p.), which allows the use of 2 95 diltiazem in these means.

Thirdly, due to the low concentrations of nifedipine and isosorbide dinitrate, the recovery times were long enough; when used 2-3 times a day, 61-68 9% of patients recovered only within 21-28 days (3-4 weeks), and 32-39 95 - within 29-45 days. Also, according to the literature (Kpaieaitag V., Maptotsai M.U., Mobazpegi M. A Yuoshbie-Viipa Napadotigeai Ta!

Sotragipa ie ENesiiimepev5 apa Zaieiiu oi Mitediripe apa Izozotbide Oipiigaye ip Sngopis Apai Rizvite //Maiauz. U. Med. 5 - 2015. - ber; 22(5). - P. 42-49.), nifedipine is more effective for the treatment of chronic anal fissure than isosorbide dinitrate, so the feasibility of their joint use in one drug raises doubts.

Thus, a useful model is aimed at solving the problem of creating a new pharmaceutical composition, which contains a combination of a stimulator of reparative processes, a local anesthetic and a calcium channel blocker, while exerting an influence in many directions on the pathological process in the treatment of anal fissure and hemorrhoids, is

It is pharmacologically acceptable for rectal use, contributes to the detection of a more effective therapeutic effect, shortens the duration of treatment, and also maintains physical and chemical stability for at least two years.

The task is solved by creating a new pharmaceutical composition containing a combination of methyluracil, diltiazem and lidocaine in free form or in the form of their pharmaceutically acceptable salts, as well as a pharmaceutically acceptable anhydrous hydrophilic emulsion base that contains propylene glycol, at least one pharmaceutically acceptable polymer selected from the class of poloxamers , at least one pharmaceutically acceptable emulsifier and at least one pharmaceutically acceptable lipophilic excipient.

In a preferred embodiment, diltiazem in the composition is in the form of diltiazem hydrochloride and/or lidocaine in the composition is in the form of lidocaine hydrochloride.

In a preferred embodiment, the poloxamer is poloxamer 338.

According to a useful embodiment, the emulsifier is selected from the group consisting of hydrophilic emulsifiers, lipophilic emulsifiers, or combinations thereof. Preference is given to combinations of a hydrophilic emulsifier and a lipophilic emulsifier, where the hydrophilic emulsifier is a macrogol 20 cetostearyl ether and the lipophilic emulsifier is a cetostearyl alcohol.

According to a useful embodiment, the lipophilic filler is selected from the group consisting of petroleum jelly, petroleum jelly, and combinations thereof.

In the preferred embodiment, the composition has the following quantitative composition, wt. 9 o'clock:

methyluracil 4.0-7.5 diltiazem hydrochloride 1.5-3.0 lidocaine hydrochloride 2.5-4.0 propylene glycol 37.0-44.5 poloxamer 338 3.0-7.0 macrogol 20 cetostearyl ether 3.0 -5.0 cetostearyl alcohol 3.0-5.0 white petroleum jelly 12.0-14.6 petroleum jelly 20.0-23.4.

Within this ratio, the exact quantitative composition of the composition can be selected from the group consisting of the following:

Composition 1 wt. 9o methyluracil 4.0 diltiazem hydrochloride 1.5 lidocaine hydrochloride 2.5 propylene glycol 37 poloxamer 338 7.0 macrogol 20 cetostearyl ether 5.0 cetostearyl alcohol 5.0 white petroleum jelly 14.6 petroleum jelly 23.4.

Composition 2 wt. 9o methyluracil 5.0 diltiazem hydrochloride 2.0 lidocaine hydrochloride 3.0 propylene glycol 42.0 poloxamer 338 5.0 macrogol 20 cetostearyl - 4.0 ether cetostearyl alcohol 4.0 white petroleum jelly 135.3 petroleum jelly 21.7.

Composition With mass. 9o methyluracil 7.5 diltiazem hydrochloride 3.0 lidocaine hydrochloride 4.0 propylene glycol 44.5 poloxamer 338 3.0 macrogol 20 cetostearyl 30 ether and cetostearyl alcohol 3.0 white petroleum jelly 12.0 petroleum jelly 20.0.

In the above compositions, the components perform the following functional purpose: - methyluracil - a medicinal substance that stimulates reparative processes; - diltiazem hydrochloride - a medicinal substance, a blocker of calcium channels, which relieves spasm of the anal sphincter; - lidocaine hydrochloride - a medicinal substance that has a local anesthetic effect, and also stabilizes diltiazem hydrochloride; - propylene glycol - an auxiliary substance, which is a dispersion medium of the composition, a solvent for diltiazem hydrochloride and lidocaine hydrochloride, a suspension medium for methyluracil, as well as an antimicrobial preservative (Effectiveness of the antimicrobial preservative action of some hydrophilic non-aqueous solvents in aqueous solutions and gels / E.P. Bezuglaya, E. N. Melnikova, E.G. Zhemerova, A.N. Lyapunov, I.A.

Zinchenko. Pharmacist. 2016. Mo. 1. P. 51-59.); - poloxamer 338 - an auxiliary substance that ensures the composition's creamy consistency, its wetting of the skin and mucous membranes, as well as its bioadhesion; - a mixture of white vaseline and vaseline oil - the dispersed phase of the composition, a lipophilic filler that reduces the rate and extent of water absorption; - a mixture of macrogol 20 cetostearyl ether and cetostearyl alcohol - a complex emulsifier necessary to stabilize the emulsion, give it a creamy consistency, as well as reduce the rate and degree of water absorption.

The claimed composition can be a soft dosage form selected from the group consisting of ointment, cream, gel, liniment, paste. In the preferred embodiment, the composition is a rectal ointment.

The claimed composition is intended for the treatment of a proctological disease selected from the group consisting of acute anal fissure, chronic anal fissure, anal trauma, hemorrhoids, and combinations thereof. In a preferred embodiment, the composition is intended for the treatment of acute or chronic anal fissure.

The technical result of the declared useful model consists in ensuring the effective therapeutic effect of the composition at the same time as reducing the duration of treatment compared to analogues, the absence of side effects characteristic of aqueous hydrophilic bases, nitrates and bethanechol, as well as extending the shelf life of the composition due to the preservation of its physical and chemical stability, which enables industrial production of the composition as a finished medicinal product.

A brief description of the figures.

In fig. 1 presents the chromatograms of tested samples of diltiazem hydrochloride solutions stored at a temperature of 25 "C for 2 months, obtained under the conditions of determining concomitant impurities of diltiazem, where 1 is a sample of Mo 1 solution; 2 is a sample of Mo 4 solution; C is a sample of Mo 5 solution; 4 - solvent (methanol).

Note. The peak with EC-4.9 min corresponds to impurity E, the peak with EC-9.5 min corresponds to diltiazem, the peak with KiE-2.2 min corresponds to lidocaine (on the chromatogram Mo 3). Sample solutions are described in Table. 1.

Zo In fig. 2 presents the diagrams of the kinetics of mass change (Dt) of chambers with 3 g samples Mo 1, Mo 2, Mo Z and

Mo 4 (see Table 3) in experiments was obtained by the method of dialysis through a semipermeable membrane.

In fig. The rheograms of the ointment (composition 2) at temperatures from 25 °C to 55 °C are presented.

In fig. Figure 4 shows the dependence of the structural viscosity of the ointment (formulation 2) on the temperature at shear rate gradients of 28.1 s, 41.64 s, and 82.27 s.

In fig. 5 presents the comparative dynamics of hyperemia (in points) during the treatment of acute anal fissure in rats (Notes: 7" - statistically significant values in relation to the KP group; 7" - statistically significant values in relation to the leader group (Mo 5 - DALZMF5).).

In fig. 6 presents the comparative dynamics of swelling (in points) during the treatment of acute anal fissure in rats (Notes: 7" - statistically significant values in relation to the KP group; "" - statistically significant values in relation to the leader group (Mo 5 - DALZMF5).).

In fig. 7 presents the comparative dynamics of healing (in points) during the treatment of acute anal fissure in rats (Notes: 7" - statistically significant values in relation to the KP group; 7" - statistically significant values in relation to the leader group (Mo 5 - DALZMF5).).

In fig. 8 presents the integral efficiency indicator (in points) of test samples on the model of acute anal fissure in rats (Notes: 7 - statistically significant values in relation to the KP group; 7" - statistically significant values in relation to the leader group (Mo 5 - DOLZM5).).

Examples

Example 1

Study of the stability of diltiazem hydrochloride in solutions with different composition of solvents

In the monograph 04/2013:1004 "Biyalet Nuagospiogide" of the European Pharmacopoeia it is indicated that diltiazem hydrochloride is easily soluble in water, in methanol and in methylene chloride, sparingly soluble in anhydrous ethanol (Engoreap Rpaptasoroea. 97 ey. EOM. Bigazroigd: Soshpsi! oi Eigore; 2016. 4016).

Methods for quantitative determination of diltiazem hydrochloride, decomposition products of diltiazem hydrochloride, including impurity E, lidocaine hydrochloride, and methyluracil were previously developed, and validation of these methods was carried out in accordance with the requirements of general article 5.3.M.2 "Validation of analytical methods and tests" of the State Pharmacopoeia of Ukraine ( State Pharmacopoeia of Ukraine: in 3rd volume / State enterprise "Ukrainian Scientific Pharmacopoeia Center for the Quality of Medicines". 2nd ed. Kharkiv: State Enterprise bo "Ukrainian Scientific Pharmacopoeia Center for the Quality of Medicines", 2015. Vol. 1. 1128 p) .

In Table 1 shows the composition of prepared solutions of diltiazem hydrochloride. To make MoMo solutions, 1-3 substances were dissolved in water with stirring for 3-5 minutes at room temperature. For the production of MoMo 4-6 solutions, the substances were dissolved in a suitable hydrophilic non-aqueous solvent with stirring for 5-10 minutes at a temperature of 55-65 "С, after which they were cooled to room temperature. The solutions were placed in a thermal cabinet at temperatures (15:21) "С and (25:51) "C and analyzed for the content of decomposition products of diltiazem hydrochloride after 1 day and 1 month by the method of liquid chromatography (Epgoreap Rpaptasorovia. 9 ey. EOM. 5igazroshigd: Soshpsii oi Eigore; 2016. 4016; State

Pharmacopoeia of Ukraine: in Volume 3 / "State Enterprise "Ukrainian Scientific Pharmacopoeia Center for the Quality of Medicinal Products". 2nd edition Kharkiv: State Enterprise "Ukrainian Scientific Pharmacopoeia Center for the Quality of Medicines", 2015. Vol. 1. 1128 p.). The results of the analyzes are presented in Table. 1, and representative chromatograms are in fig. 1.

Table 1

Compositions of solutions of diltiazem hydrochloride

Me1 | Me2 | mez | Me4 | Me5 | mob substance)"

Nokia LIN PEN ESL ES does not contain any substances

Propylene glycol ss 1 - | - 150 | 980950 -

Water purified in 19801 9501900| - | - | - (Polyethylene glycol 400d -:/ ss 1 - | - 1-1 7-17 - 1980

Table 2

The results of the study of the stability of diltiazem hydrochloride in solutions

Impurity E-0.18 95

Impurity E-0.12 95 NID 1-0.05 95 HB HB

NID" 3-0.33 Fo NID 2-0.06 95

NID 3-0.93 95

Note: "NID - unidentified impurity. HB - not determined.

As can be seen from the data in Table. 2, in water (sample Mo 1) after 1 day of storage at a temperature of 15 "С, 0.18 95 impurity R is formed. As the storage temperature increases to 25" and the storage time, the amount of impurity E increases; so, after 1 month at a temperature of 25 "С, 0.96 95 of impurity E was formed. The presence of water in the solutions causes hydrolysis of diltiazem hydrochloride from the very beginning with the formation of significant amounts of impurity PE.

Polyethylene glycol 400 (sample Mo b) is also not suitable for dissolving diltiazem hydrochloride, because at a temperature of 25 "С. in addition to 0.18 95 of impurity E, three unidentified impurities with a total amount of 1.04 95 are formed in 1 day.

The smallest amount of impurities was found in solutions of diltiazem hydrochloride in propylene glycol (Mo 4-5). At the same time, in the presence of lidocaine hydrochloride, the amount of impurity E was the lowest; after storing sample Mo 5 at a temperature of 25 "C for 1 month, it was only 0.07 95, i.e. 13.7 times less than the content of impurity E in an aqueous solution of diltiazem hydrochloride (sample Mo 1).

Example 2

Study of the kinetics of water absorption by diltiazem hydrochloride preparations based on propylene glycol

According to the results of studies described in Example 1, diltiazem hydrochloride should be introduced into an anhydrous hydrophilic base, the dispersion medium of which is propylene glycol. But the latter is an osmotically active hydrophilic solvent, which in its native form strongly absorbs water and can dehydrate tissues, exerting a local irritant effect on them (Theory and practice of local treatment of purulent wounds / Bezuglaya E.P. et al.; edited by B.M. Datsenko, Kyiv:

Health, 1995. 384 p.). Therefore, research was conducted to reduce the osmotic activity of hydrophilic anhydrous bases containing propylene glycol.

For this, samples of solutions and ointments on hydrophilic anhydrous bases were prepared, in which diltiazem hydrochloride and lidocaine hydrochloride were dissolved in propylene glycol. The compositions of the samples are presented in Table. 3; ointment samples additionally contained 5 96 methyluracil in the form of a suspension.

Table C

Compositions of solution samples and ointments for studying the kinetics of water absorption

Sample Mo 1 | Sample Mo 2 | Sample Mo Z | Sample Mo 4

Methyluracil.і////////77777777111111111Ї1111-1111150.. | 50 | 50

Poloxhammer338. -/-://7s/ | -111 111200 1150 | 50 (Macrogol 20 cetostearyl ether | - | - | 40 | 40 / (Cetostearyl alcohol HER -1 1111-1140 | 40

White petroleum jelly////////777771111111Ї1111 11111111 11133 (Vaselnovemasloy YЇ -1Ї1117 AG

The kinetics of water absorption by the samples was determined in experiments by the method of dialysis through a cellophane membrane (GOST 7730-89) at a temperature of (25:50.1) "С (Methodological recommendations for experimental (preclinical) study of medicinal preparations for the local treatment of purulent wounds / Datsenko B .M., Kalynychenko N.F., Lepakhin V.K. and others - M., 1989. - 45 p.).The initial mass of the sample in the dialyzer chamber was 3.0 g, and the area of the membrane was 12.56 cm: (1-2.0 cm). The chamber with the sample was weighed at certain time intervals and the mass of absorbed water was calculated from the change in the mass of the contents of the chamber. The results of the study are presented in

Table 4 and fig. 2.

Table 4

Change in the mass (A t) of chambers with 3 g samples of Mo 1, Mo 2, Mo C and Mo 4 in experiments using the method of dialysis through a semipermeable membrane

The greater the mass of absorbed water in the first hours of the experiment, the stronger will be the dehydrating effect of the agent on the mucous membrane of the rectum and the more likely the occurrence of local irritation and diarrhea (Stolper Y.M. Development and standardization of vaginal

From suppositories with antimicrobial action: dissertation. ... candidate pharmacy Science: 15.00.03 / State Enterprise "DNSLZ". Kharkiv, 2008. 150 p.).

As can be seen from fig. 2 and Tab. 4, sample Mo 1, which is a solution of active substances in propylene glycol, during the first 2-3 hours absorbs approximately 170-190 wt. 95 water. It can be predicted that such a solution will have a local irritant effect on the rectal mucosa and cause diarrhea. After 24 hours the mass of the contents of the chamber decreases slightly, which is due to the reverse process - the partial diffusion of propylene glycol into the chamber with water (Stolper Yu.M. Development and standardization of vaginal suppositories with antimicrobial action: diss. ... candidate of pharmaceutical sciences: 15.00.03 /DP "DNSLZ ". Kharkiv, 2008. 150 p.).

When 20 wt.9o5 of poloxamer 338, which gives the sample an ointment-like consistency, was added to the composition of the Mo 2 sample, in the first hours of the experiment, the mass of absorbed water decreased slightly compared to the Mo 1 sample, but the time of osmotic action increased significantly - from 5 h. to 22-24 hours, and the mass of absorbed water increased to 321 95, i.e. 1.9 times. Such a composition can also potentially have a local irritant effect on the rectal mucosa and cause diarrhea.

The kinetics of water absorption changed significantly after the MoC in the sample was reduced to 5 wt. 95 concentration of poloxamer 338 and emulsifier of type 1 (macrogol 20 cetostearyl ether) and emulsifier of type 2 (cetostearyl alcohol) were introduced into the composition. The mass of absorbed water during the first 2-3 hours of the experiment decreased to 39-50 Fo, and within 24 hours. the Mo Z sample absorbed only 123 wt. 95 water.

Replacing part of the propylene glycol in the Mo 4 sample with lipophilic fillers (vaseline white and petroleum jelly), which are not osmotically active, further reduced the ability of the sample to absorb water. After 24 hours sample Mo 4 absorbs only 79.0 956 of water, which approximately corresponds to the amount of water absorbed by sample Mo 1 in 0.5 h. Thanks to the optimal selection of auxiliary substances, the rate and degree of water absorption by the Mo 4 sample (anhydrous hydrophilic emulsion-based ointment) turned out to be much lower compared to other samples.

Thus, compared to the Mo 1 sample, during the first 2-3 hours, the Mo 4 sample absorbs 6-7 times less water, while the absorption is prolonged, which practically excludes the occurrence of diarrhea.

The Mo 4 sample at a temperature of 25-30 "C has rheological properties characteristic of soft dosage forms (MLF): plastic type of fluidity (see Fig. 3) and high structural viscosity at different shear rate gradients (see Fig. . 4). As the temperature increases, the rheological parameters of the Mo 4 sample decrease, but it retains an ointment-like consistency up to a temperature of 35 "С. With a further increase in temperature, the fluidity type of the sample is Mo 4

Zo approaches Newtonian, and it acquires a liquid consistency (see Fig. 4).

Example C

Effectiveness of antimicrobial preservative action

In a sample of Mo 4 ointment, the effectiveness of the antimicrobial preservative effect was determined in accordance with the requirements of general article 5.1.3 "Effectiveness of antimicrobial preservatives" of the State Pharmacopoeia

of Ukraine (State Pharmacopoeia of Ukraine: in Z vol. / State enterprise "Ukrainian Scientific Pharmacopoeia Center for the Quality of Medicines". 2nd ed. Kharkiv: State Enterprise "Ukrainian Scientific Pharmacopoeia Center for the Quality of Medicines", 2015. Vol. 1. 1128 p. .).

The results of the research are presented in Table. 5.

Table 5

Effectiveness of antimicrobial preservative effect in a sample of Mo ointment 4 CFU/g

Quantity Quantity

Exposition of tku KUSe 5. ashgey5 |R. aegidiposis)| S. aiIrisapz | A. fit ATSS logarithm | ATOSS logarithm 6538 | ATOS 9027 | IATSS 10231 16404 decrease | reduction of pa 17010718 01e0ne o zvolovova dib | - | - | nv' | nv' | nv' /|050:y10(494)

Note. HB - viable cells of microorganisms were not detected (less than 5 CFU/g for

Z. Ashtetsv, R. Ayegidipoza, S. Airisapz and A. Pideg);

NC - the number of viable cells of microorganisms does not increase;

CFU - colony-forming unit.

As follows from Table. 5, a sample of Mo 4 ointment exceeds the requirements of the DFU for the effectiveness of antimicrobial preservative action in medicinal products for rectal use (State Pharmacopoeia of Ukraine: in Z vol. / State enterprise "Ukrainian Scientific Pharmacopoeia Center for the Quality of Medicines". 2nd ed. Kharkiv: State enterprise "Ukrainian Scientific Pharmacopoeia Center for the Quality of Medicines", 2015. Vol. 1. 1128 p.). Even in the initial culture of viable cells, the bacteria Z. acygei5 and R. aegidipoza, as well as the yeast-like fungus S. aibisap5 were not detected. On the 7th day, the logarithm of the decrease in the number of viable cells of the mold fungus A. podeg was 4.94, and after 14 days, viable cells

A. pods were not detected in sample Mo 4.

Example 4

Production of a pharmaceutical composition as a ready-made medicinal product - ointment

Stage 1. Preparation of a solution of diltiazem and lidocaine

A portion of propylene glycol is loaded into the Mo 1 reactor, heated to a temperature of 55-60 with stirring, after which diltiazem hydrochloride and lidocaine hydrochloride are loaded.

The mixture in reactor Mo 1 is stirred until complete dissolution of diltiazem hydrochloride and lidocaine hydrochloride and a clear solution is obtained.

Stage 2. Production of methyluracil suspension

A portion of propylene glycol and methyl uracil are loaded into the Mo 2 reactor. The mixture in the reactor is stirred using a frame and turbine mixer to obtain a homogeneous suspension of methyluracil.

Stage 3. Production of ointment

White petroleum jelly, petroleum jelly oil, poloxamer 338, cetostearyl alcohol, macrogol 20 cetostearyl ether, and the remainder of propylene glycol are loaded into the MoZ homogenizer reactor. In the MoZ homogenizer reactor, a vacuum with a depth of -0.05 MPa to -0.07 MPa is created and the mixture is heated to a temperature of 65-70"C while stirring with a frame stirrer.

Mixing is carried out until the components are completely melted. Turn off the stirrers and leave the mixture under vacuum without stirring for 15-20 minutes for degassing. Then the mass in

From the reactor-homogenizer, Mo Z is emulsified for 10-15 minutes with stirring by frame and turbine stirrers under a vacuum depth of -0.05 MPa to -0.07 MPa at a temperature of 65-70 "С, after which it is cooled to a temperature of 55-60 " With mixing with a frame stirrer.

A solution of diltiazem hydrochloride and lidocaine hydrochloride is quantitatively transferred to the reactor-homogenizer Mo Z and the mixture is homogenized with the help of frame and turbine stirrers for 15-20 minutes at a temperature of 50-55 "C under a vacuum depth of -0.05 MPa to -0.07 MPa Then the mass in the reactor-homogenizer Mo Z is cooled to a temperature of 35-38 "C while stirring with a frame stirrer under a vacuum depth of -0.05 MPa to -0.07 MPa.

A suspension of methyluracil is quantitatively transferred to the MeZ homogenizer reactor and the mixture is homogenized using a frame and turbine mixer for 15-20 minutes at a temperature of 35-38 "C under a vacuum depth of -0.05 MPa to -0.07 MPa.

The mass in the MeZ homogenizer reactor is cooled to a temperature of about 25 "С under a vacuum with a depth of -0.05 MPa to -0.07 MPa with stirring. From the homogenizer reactor

MoZ samples of ointment are taken and checked for compliance with the requirements of the normative document (ND) for the control of unpackaged products. After receiving the positive results of the analysis, the unpackaged ointment is unloaded from the MoZ homogenizer reactor into intermediate containers for transportation, which are hermetically sealed.

Stage 4. Packing and packaging of the ointment

The unpackaged ointment is transported to the room for packaging, the air temperature in which should be in the range from 18C to 25"C, and unloaded into the hopper of the tube filling machine. The ointment is dosed in 10 g tubes. The filled tubes are folded, while applying the series and date on the tube suitability of the drug. Each tube together with the instructions for medical use is packed in a pack. Packs with tubes are packed in a group package, on which a group label is pasted. Samples of finished products are taken to control all quality indicators provided for by the normative document for quality control of the finished medicinal product.

Example 5

Study of the homogeneity of the distribution of medicinal substances

According to the method described in Example 4, in a homogenizer reactor (Soft drugs: pharmaceutical development and technology transfer / N.A. Lyapunov, E.P. Bezuglaya,

I.A. Zinchenko and others. Pharmaceutical industry. 2014. Mo 5 (46) October. P. 22-28, 31-33.) produced an experimental series of ointment weighing 3 kg, the quantitative composition of which corresponded to Composition 2:

Composition 2 wt. 9o methyluracil 5.0 diltiazem hydrochloride 2.0 lidocaine hydrochloride 3.0 propylene glycol 42.0 poloxamer 338 5.0 macrogol 20 cetostearyl 40 ether and cetostearyl alcohol 4.0 white petroleum jelly 135.3 petroleum jelly 21.7.

9 samples of the manufactured cream were taken from the reactor-homogenizer in a spiral, in which the content of diltiazem hydrochloride, lidocaine hydrochloride and methyluracil was determined. The content of these medicinal substances was standardized as follows: 20.0 mg/g 5 905, 30.0 mg/g zh5 95 and 50 mg/g -5 95, respectively. It was previously shown that the uncertainties of the analytical methods for the quantitative determination of diltiazem hydrochloride, lidocaine hydrochloride, and methyluracil are 0.71 95, 0.68 95, and 0.69 95, respectively, and do not exceed the maximum allowable critical value of the uncertainty of the results of the Dadvtakh-1.6 96 analysis. calculated for tolerances B-5 95 (Ddvtah-o 9020,322:1.6 U).

To assess the homogeneity of the distribution of medicinal substances in the ointment, an approach based on the convergence of the results of their quantitative determination in a series of 9 samples was used. To characterize the convergence, a relative confidence interval was used, which should be smaller than the maximum permissible uncertainty of the analysis results of 1.6 95, which serves as an acceptability criterion (Lyapunov N.A.,

Zinchenko I.A., Bezuglaya EP. Evaluation of the homogeneity of the distribution of medicinal and auxiliary substances in soft medicinal products //Pharmakom. - 2015. - Mo 2. - P. 33-40.). The results of studies of the homogeneity of the distribution of medicinal substances in the ointment are presented in

Table b, 718.

Table 6

Results of quantitative determination of diltiazem hydrochloride in 9 samples taken from different points of the homogenizer reactor

Me | Diltiazem g/x content in the sample, mg/g

GETE word RN NN

A;-y (95 uyu, 9-1)-K505-1.8595-0.3447 Uo- 0.6410 95

Table 7

The results of the quantitative determination of lidocaine hydrochloride in 9 samples taken from different points of the reactor-homogenizer for the determination of the values of 95% of the HeTh dust of 29% 777777111111111111180005.77777111111711111111111111

LETY 22031000 lyu 2

A;-y (95 uyu, 9-1)-K50-1.8595-0.3872 Cho- 0.7200 Fo

Table 8

Results of quantitative determination of methyluracil in 9 samples taken from different points of the reactor-homogenizer

Me | Content of methyluracil in the sample, mg/g | Content of methyluracil (normalized values), b ng: ST: I MON KT te P lower udo Po TET I: shk shi t NYA PO ET Te OO

GB "SKILLS

A;-y (95 uyu, 9-1)-K505-1.8595-0.4048 Uo- 0.7527 90

As it follows from the data of Table. 6, 7 and 8, relative confidence intervals characterizing the convergence of the results of the quantitative determination of diltiazem hydrochloride (4-0.6410 95), lidocaine hydrochloride (D2-0.7200 95) and methyluracil (D2-0.7527 905), approximately 2.5 times, 2.2 times, and 2.1 times, respectively, smaller than the maximum permissible full uncertainty of analysis methods

Dotahe1.6 95 (8-5.0 95). That is, deviations of the quantitative content of each active substance from the average value in each of the 9 samples are within the uncertainty of the method of its quantitative determination and are statistically insignificant. Therefore, the differences in the results of the quantitative determination of the active substances are connected exclusively with the uncertainty of the analysis methods, and the distribution of each of the active substances in the preparation is homogeneous.

Example 6

Study of the stability of the finished medicinal product during storage

Samples of the produced experimental series of ointment weighing 3 kg, the composition of which corresponded to Composition 2, were packaged in tubes of 10 g each and stored at temperatures (15:22) "C and (2552) "b.

The samples were analyzed initially after production and after 3, 6, 9, 12, 18 and 24 months of storage.

Stability testing was carried out in accordance with the recommendations of Nastanov 42-3.3:2004 "Medicinal products. Stability testing" (Guidelines for quality. Medicinal products. Stability testing: Guideline ST-N MOZU 42-3.3:2004 /V. Georgievskii, M. Lyapunov, 0 Bezugla et al.

Kind. officer Kyiv: Ministry of Health of Ukraine, 2004. 68 p. (Legal office "Tsotizhnevyka Apteka")). Ambient humidity in the chambers during sample storage was not controlled, as the samples were hermetically sealed, and aluminum tubes with a membrane and a latex ring do not belong to semipermeable materials. The results of stability studies are presented in Table. 9 and 10.

Table 9

The results of studies of the stability of the ointment during storage at temperature (15:22) "S

Indicator and specification norms Results of analyzes after storage for: и пиУЛеВ 11111112 113 | 4 | 516 7. c

Identification 77711111 11111111 diltiazem g/x (HPLC) lidocaine g/x (HPLC) methyluracil (HPLC) mMBh 11111111

TAMSH103 KUO/g

TUMSx102 KUO/g

Our content: 77711111 diltiazem g/x (HPLC) 2004 2020 2016 2020 |2019 |1996 /|19.89 from 19.0 to 21.0 lidocaine g/x (HPLC) from 28.5 to 31.5 29.18 29.41 29.39 12949 12907 |29.59 d|29.30 methyluracil (HPLC) from 47.5 to 52.5 50.21 50.01 5012 |50.19 149.57 15002 /|49.83

Notes. HPLC - high performance liquid chromatography. MBCH - microbiological purity.

CFU - colony-forming unit. TAMS - aerobic microorganisms. TUMS - yeast and mold fungi. HB - not detected.

Table 10

The results of studies of the stability of the ointment during storage at a temperature of (25:22) "C 11111112 13141 51617. in

Identification: 77711111 mBch 11

Content of P impurities: no more than 1.59510.04 03 10.98 055 1096 |117

Contents: 236.13, 0201 0 1 1 1 1 from 19.0 to 21.0 lidocaine g/x (HPLC) methyluracil (HPLC)

Notes. HPLC - high performance liquid chromatography. MBCH - microbiological purity.

CFU - colony-forming unit. TAMS - aerobic microorganisms. TUMS - yeast and mold fungi. HB - not detected.

During the period during which the stability was studied, there were no significant changes in the preparation that would exceed the limits established in the specification. During long-term tests, the drug met all the specification parameters both at storage temperatures (15:22) "С" and (252) 76.

As can be seen from Table. 9 and 10, according to the indicators "Description", "Identification" (diltiazem hydrochloride, lidocaine hydrochloride, methyluracil), "Microbiological purity" and "Quantitative determination" (diltiazem hydrochloride, lidocaine hydrochloride, methyluracil) at storage temperatures (15:52) " b y (25:52) "Within 24 months, no significant trends to change the quality of the medicinal product were observed.

According to the "Associated impurities" indicator, it can be stated that during long-term tests, the content of impurity E increases. With increasing temperature, this process intensifies. However, after storage at a temperature (15:42) "C, the content of impurity E relative to the content of diltiazem hydrochloride was only 0.55 95, and after storage at a temperature (25:22) "C - 1.41 95, which meets the requirements of the specification.

It should be noted that in the 2 95% aqueous solution of diltiazem hydrochloride after storage for 1 month at a temperature of 25 "С, 0.96 95 of EC impurities were formed, and in the gel containing 2 g of diltiazem hydrochloride, 10 ml of propylene glycol, 2 g of hydroxyethyl cellulose, 0.2 95 of methylparaben and up to 100 ml of water (per//mlum. ad. edi/dositepiv/rpaptasu/aroshiv/rybiisatiopv/ris/04/diiaget.rai) after storage for 3 months at a temperature of 25 "С, 3.94 was formed 95 impurities E.

Thus, the claimed composition ensures the stability of medicinal substances during long-term storage.

Example 5

Study of pharmacological activity on the model of acute complicated anal fissure

For comparative studies of the specific pharmacological action of medicinal products, two preparations known from the state of the art were prepared: a drug analogue of Mo 1 according to the description in pOru/Lymly.dyd.edi/dositepiv/rpaptasu/aroshiv/ribiisaiopv/ris/04/dinaget.rai and the drug -

Zo analogue of Mo 2 according to the description in (patent publication KO 2 592 366), as well as experimental samples of the claimed compositions containing different concentrations of diltiazem hydrochloride, lidocaine hydrochloride and methyluracil, the compositions of which are presented in Table. 11.

Analog drug Mo 1 diltiazem hydrochloride 2.0 g propylene glycol 10.0 ml hydroxyethyl cellulose 20 g

MATANO5OYI 2 25О0ННА ' methylparaben 02g purified water to 100.0 ml

Analog drug Mo 2 methyluracil 5o0g lidocaine hydrochloride 2.00g nifedipine 02g isosorbide dinitrate, diluted, including: isosorbide dinitrate 02g lactose monohydrate OZ g dimethyl sulfoxide 10 (DMSO) and ethanol (96 95) 0.81 g (1, 0 ml) polyethylene glycol 400 Ag propylene glycol 8.49 g carbopol 980 02 g disodium edetate 01 g nipagin (methylparaben) 02 g triethanolamine 1.85 g water purified to 100.0 g (75.65 g)

Table 11

Compositions of experimental samples of ointments for studies of pharmacological activity

The specific effect of samples of known drugs (drug analog Mo 1 and drug analog Mo 2) and claimed compositions (samples drugs Mo 3, Mo 4, Mo 5, Mo 6, Mo 7) on a modified model of acute complicated anal fissure was studied.

Rats under novocaine anesthesia were injected with 0.1 ml of 5 95 formalin solution into the submucosa of the back wall of the anal canal in the region of the transition between the skin and the anoderm. An anal fissure was modeled by dissecting the mucous membrane with a scalpel along the back wall of the anal canal (at b o'clock on the dial), forming a defect measuring 5x2x1 mm.

Treatment was started 24 hours after recreating the anal fissure. Each of the studied test samples of the drugs (see Table 11), the analog drug Mo 1 or Mo 2 was injected into the anal canal using an insulin syringe in the amount of 0.3 ml once a day during the entire experiment (12 days). Evaluation of the therapeutic effect of the studied samples on the model of acute complicated anal fissure was carried out according to the influence on the severity of the course of the pathological process. The assessment of the development of pathology and the effectiveness of treatment was carried out on the basis of a macroscopic examination of the anorectal area of animals according to the following criteria:

- reduction (decrease) of signs of inflammation (hyperemia, edema) from 0 points (absence of pathological manifestation) to 3 points (maximum manifestation of pathology) on the 1st, 6th, 12th day of observation; - speed of crack healing: healing within 8-12 days (1 point), from the 12th to the 16th day (2 points), after the 16th day (Z point).

An integral assessment was carried out, that is, the sum of points calculated for all indicators was determined. A higher integral index (a greater number of points consisting of points for each manifestation of the pathological process) indicates more pronounced signs of pathology and less effectiveness of the drug's therapeutic effect. The lower the integral index, the fewer the manifestations of the pathology and the higher the effectiveness of the treatment.

The experiment was carried out on 48 white non-linear female rats, weighing 200-240 g, which were divided into 8 experimental groups of 6 animals in each: 1 group - animals were treated with a drug analogue of Me 1 (conditional designation D2); Group 2 - animals were treated with a drug analogue of Mo 2 (conditional designation НО,2ИДО,2Л2М5);

Group C - animals were treated with a sample of the drug Mo Z (ДО,5ЛИ1М'1,5); Group 4 - animals were treated with a sample of the drug Me 4 (DTIL2M2.5); Group 5 - animals were treated with a sample of the drug Mo 5 (D2LZM5); Group 6 - animals were treated with a sample of the drug Mo 6 (DZLAM?7.5); Group 7 - animals were treated with a sample of the preparation Mo 7 (DAL5OM10); Group 8 - animals were not treated (control pathology group - KP).

The results of the research are shown in Table. 12, as well as in fig. 5-8.

Table 12

Results of pharmacological studies of the influence of analogue drugs and samples of the declared drugs on the course of acute complicated anal fissure in rats

Swelling, points Integral

Mo indicator immediately Group of animals 1 day b 12 days |1 day | 6 days | 12 days effective d day d d d d d ness, sum in points 1 | to 30 183 10 | 30 2) (0-2) 2.0 and ov) (353)| (153) (052)7 | (353) | yuyu hook |) yuyu 3.0 2.67 2.00 3.0 2.67 217 2.00 17.50

MO2IDOYALYAM" 153) | (ohzuh |(oh2u (33) |Fya3) |c) (153) (Boom 17.17 3.0 2.50 1.67 3.0 2.87 2.33 2.00 1 dooliMt" (323) | (353) (23) 23) (science (353) (eye SYU au | PU 3.0 1.00 0.00 3.0 1.00 0.00 1.00 9.00 delZM" (3-3) (0-0) (323) dolyamtye 1.83 0.83 3.0 1.67 0.83 3.0 What 1.83 13.00 delMto (323) | (1e3uy | (052u7 | (353) 79 Donu chin (vn13) in

Control 3.0 2.83 2.50 3.0 2.83 2.67 2.83 19.67 pathology (CP) (353) | (2-3) (223 (353) | (2-3) | (2-3) (223) (17-21)

Notes: " - values statistically significant in relation to the KP group; "x - values statistically significant in relation to the leader group (Mo 5).

The obtained data indicate that on the 1st day after simulation of anal fissure (AT), animals of all experimental groups showed the most pronounced signs of pathology (hyperemia and swelling of the mucous membrane of the rectum, bleeding was observed in some animals). On the 6th day, the signs of the pathological process in the animals of the control pathology group practically did not change, only in isolated cases a decrease in hyperemia and edema was observed. On the 12th day, none of the animals in the control pathology group showed any signs of spontaneous healing of BP, although the expressiveness of the pathological signs was less.

In groups of animals that received treatment, a decrease in acute manifestations of the inflammatory-destructive process, namely hyperemia and edema, gradual tissue recovery and healing of cracks was observed. On the 6th day, the test samples Mo 2, Mo 5, Mo 6, Mo 7 showed the greatest effectiveness.

On the 12th day of the experiment, test samples Mo 5 and Mo 6 retained the leading positions in terms of indicators of reduction of signs of inflammation and speed of anal fissure healing (Table 12, Figs. 5-8).

Among the studied samples of medicinal products, according to the integral indicator of effectiveness, sample Mo 5 (anhydrous hydrophilic ointment containing a combination of 2 95 diltiazem, C 95 lidocaine hydrochloride and 5 95 methyluracil) was the best, as well as sample Mo 6 (anhydrous hydrophilic ointment , containing a combination of C 95 diltiazem, 4 95 lidocaine and 7.596 methyluracil). Presumably, these samples had the optimal composition of medicinal substances and the optimal composition of the base. According to all indicators characterizing the effectiveness of the treatment of acute complicated anal fissure in rats on the 6th and 12th days, the test samples Mo 5 and Mo 6 were superior to the sample Mo 1 (an analog drug in the form of a gel containing 2 95 diltiazem) and sample Mo 2 (an analog preparation in the form of a gel containing 5,956 methyluracil, 2,95 lidocaine, 0.2,95 nifedipine, and 0.2,95 isosorbide dinitrate (Table 12, Fig. 5-8). That is, the use of 2 .0-3.0 95 diltiazem in combination with 3.0-4.095 lidocaine hydrochloride and 5.0-7.5 95 methyluracil on an anhydrous hydrophilic emulsion base containing propylene glycol as a dispersion medium led to the potentiation of specific wound-healing and anti-inflammatory effects on model of acute complicated anal fissure in rats. On the 12th day, according to the integral indicator of effectiveness, the test sample Me 5 was significantly superior to the analogue preparation Mo 1 by 51.9 95, and the analogue preparation Mo 2 - by 94.4 95. Test- the Mo 6 sample was superior to the anal og Mo 1 at 28.1 95, and the analogue drug Mo 2 - at

Co., Ltd.) 64.0 oo.

Thus, preclinical studies have confirmed that the claimed pharmaceutical composition has specific pharmacological activity on the model of acute complicated anal fissure.

Example 6

Study of the action of the composition in patients with acute anal fissure

Since all components of the declared composition meet the requirements of the corresponding monographs

of the European Pharmacopoeia (Eigoreap Rpagtasorovia. 9" va. EOM. 5igazroigo: Soshpsii oi Eigore; 2016. 4016), the ointment of Composition 2 was manufactured in the conditions of a pharmacy in the amount of 100 tubes and under the supervision of a doctor was used for the treatment of acute anal fissure in 50 After applying the ointment 2-3 times a day, swelling, pain, bloody discharge and spasm of the sphincter were eliminated.

The spasm of the sphincter began to weaken already on the 2nd day of using the ointment, and on the 5th day it was practically absent. Pain syndrome was absent in most patients on the 5th day of treatment. Healing of cracks occurred after 7 days of treatment in 60 95 patients and after 10 days of treatment in 100 95 patients. Side effects from the use of the ointment were not observed.

Thus, the claimed composition makes it possible to reduce the duration of treatment compared to similar drugs by at least 3-4 times.

All of the above indicates the creation of a new pharmaceutical composition, which contains a combination of a stimulator of reparative processes, a local anesthetic and a calcium channel blocker, while it has an impact in many directions on the pathological process in the treatment of anal fissures and hemorrhoids, is pharmacologically acceptable for rectal application, helps to identify effective therapeutic effect and shorter treatment times compared to similar drugs, and also maintains physical and chemical stability for at least two years. This makes it possible to enter the specified composition into industrial production as a ready-made medicine that can be used for the effective treatment of anal fissures, hemorrhoids, and post-hemorrhoidectomy conditions without pronounced side effects and in a shorter time frame.

All prior art documents specified in the application materials are incorporated in their entirety by reference.

Claims (5)

USEFUL MODEL FORMULA 1. A pharmaceutical composition containing a combination of methyluracil, diltiazem and lidocaine in free form or in the form of their pharmaceutically acceptable salts, as well as a pharmaceutically acceptable anhydrous hydrophilic emulsion base that contains propylene glycol, at least one pharmaceutically acceptable polymer selected from the class of poloxamers, at least one a pharmaceutically acceptable emulsifier and at least one pharmaceutically acceptable lipophilic excipient. 2. The composition according to claim 1, which differs in that diltiazem in the composition is in the form of diltiazem hydrochloride. 3. The composition according to claim 1 or claim 2, which differs in that the lidocaine in the composition is in the form of lidocaine hydrochloride. 4. The composition according to any one of claims 1-3, which differs in that the poloxamer is poloxamer 338. 5. The composition according to any one of claims 1-4, characterized in that the emulsifier is selected from the group consisting of hydrophilic emulsifiers, lipophilic emulsifiers or combinations thereof. 6. The composition according to claim 5, which is characterized by the fact that it contains a combination of a hydrophilic emulsifier and a lipophilic emulsifier. 7. The composition according to claim 5 or claim 6, which differs in that the hydrophilic emulsifier is a macrogol 20 cetostearyl ether. 8. The composition according to any of claims 5-7, which is characterized in that the lipophilic emulsifier is cetostearyl alcohol. 9. The composition according to any one of claims 1-8, characterized in that the lipophilic filler is selected from the group consisting of petroleum jelly, petroleum jelly, and combinations thereof. 10. The composition according to any of claims 1-9, which differs in that it has the following quantitative composition, by weight: methyluracil 4.0-7.5 diltiazem hydrochloride 1.5-3.0 lidocaine hydrochloride 2.5- 4.0 propylene glycol 37.0-44.5 poloxamer 338 3.0-7.0 macrogol 20 cetostearyl ether 3.0-5.0 cetostearyl alcohol 3.0-5.0 petroleum jelly white 12.0-14.6 petroleum jelly oil 20.0-23.4. 11. The composition according to claim 10, which differs in that the quantitative composition of the composition is selected from the group consisting of the following: Composition 1 wt. 905 methyluracil 4.0 diltiazem hydrochloride 1.5 lidocaine hydrochloride 2.5 propylene glycol 37 poloxamer 338 7.0 macrogol 20 cetostearyl ether 5.0 cetostearyl alcohol 5.0 white petroleum jelly 14.6 petroleum jelly 23.4; Composition 2 wt. 9o methyluracil 5.0 diltiazem hydrochloride 2.0 lidocaine hydrochloride 3.0 propylene glycol 42.0 poloxamer 338 5.0 macrogol 20 cetostearyl ether 4.0 cetostearyl alcohol 4.0 white petroleum jelly 135.3 petroleum jelly 21.7; Composition With mass. 905 methyluracil 7.5 diltiazem hydrochloride 3.0 lidocaine hydrochloride 4.0 propylene glycol 44.5 poloxamer 338 3.0 macrogol 20 cetostearyl ether 3.0 cetostearyl alcohol 3.0 white petroleum jelly 12.0 petroleum jelly 20.0. 12. The composition according to any one of claims 1-11, which is characterized by the fact that it is a soft dosage form selected from the group consisting of ointment, cream, gel, liniment, paste. 13. The composition according to claim 12, which differs in that it is a rectal ointment. 14. The composition according to any one of claims 1-13, which is characterized in that it is intended for the treatment of a proctological disease selected from the group consisting of acute anal fissure, chronic anal fissure, injuries of the anal opening, hemorrhoids, and combinations thereof. 15. The composition according to claim 14, which is characterized by the fact that the proctological disease is an acute or chronic anal fissure. Mekv! ; and 1 she shi I E | and ! 9 Still | still be M and 25 5 7.5 100 min FIG. and 3500 2 Drettttttttta ha ZO KU zh 23500. in 2 y "chi ne I that 000 CLASS ni VYSH" - --- izoo I Z E I fennnnnnia that 000 s 4 I send write that Olya runes vo id zo 30 30 58 ve and me Time, hours FIG. Z0o; 25 axis Pa y- t Shear stress 2Bo za- a-ny -kh- t Shear stress 200 -Щ zvos ve -ykh- t Shear stress - and its basis 1 ; y t one -e- t Shear stress gi IZ pa NY avas dzh kt sych y y vta a Mo t Y r k-t Shear stress sht, b xx ra r y niy shy y yy sr VI zh rn -ot- t The shear stress in the root veins in the kine НЩ ши х- « Nanoh , sov V V sy -eyah Shear stress 0 Bo 100 isch-. 1/s 200 Shear speed 0077777 FIG, 3 with vv s in Vavyk SHE LE I WHO 5 2 s EE Shy t i shwash shchi: shh, 7 th : shk -i and another shk 7 She ss y V. French duntnntnnntnanntnennat nannya V EK In KV roenyasnnnea pni i5 KI KA 4 Zh 5 5 Temperature, FIG. 4 -E s t ssh 0 What . 7 o ob s with. c 5 IMZ M ZHR226 w w w D :55. 1. 1 s 3 KI UK I VC ВХ ВН у о Y ВУХ В В КК НВ M В ян. wa nn - what. oh shit sh. m p would a o i s. Notes: In - statistically significant values of the KI group; ЖЖ Statistically significant values of shodo of the leader group (Me 5 -- DYLAMUKH FIG. shishshshshshchi o zd i V. she Zh i 7 I | and her: | p Z V por BOKAH shcha PISKY V Kak 5 VV V: I still OV VN oo VV VOO V o VV that RYN B B er schi. M. I. c Mew. and about г. b another 0 GE o o. Kv y o 5 and t. s t 5 0 too, OrIYOIIIIIII S tr TV: V V s: V V VK Z M VV U 1 5. B VV S KS PE S ko i i i-a i- 12-a Notes : There are statistically significant shodo values of the KI group; eat values of statistically significant shodo of the leader group (M 5 - FATE M 5, FIG. b schi o Z no gido glamo z claim 111 vdolamya an UN vyt NN VV EKEEKKEEKKEEKKEEKNEEKNNK i-ya Eh I y ia as OO schi -O- p. op rdalaMm75 ko is s o ! about BE and I and in LALOMtO What Ia Notes: 7 - statistically significant value of shodo group KTYI; ЖЖ - value of statistically significant shodo group-liler (Ме 5 - ДИЛЯМУ). FIG. 7