UA59394C2 - Process of preparing stable fixed dose composition of anti-infective agent with microorganisms as active ingredients - Google Patents

Abstract

Microorganisms are useful in management of diseases including diarrhea and gastrointestinal diseases like pseudomembranous colitis, megacolon etc. They are also useful in prevention of gastrointestinal disturbances and diseases caused by anti-infective agents like imperilling, amoxycillin, cloxacillin, clauvanic acid, cefuroxime, axetel, cephalixin, erythromycin etc. For prevention microorganisms are to be taken along with anti-infective agents. When microorganisms are combined with anti-infective agents for ease of administration and improving compliance and therapeutic effect, the combination is not found to be stable at room temperature as microorganisms are sensitive to anti-infective agents and are destroyed by effect of anti-infective agent in composition. The present invention relates to the process of preparing a stable fixed dose composition of anti-infective agent with microorganism as active ingredient. The process includes preparation of various dosage forms for oral route like capsule, tablet and liquid formulation. The process comprises of providing an appropriate barrier by way of selected coating procedure to one of the active ingredients in such a way that microorganisms are not affected by anti-infective agents. This results in a stable composition. By using an appropriate coating technique composition is made to remain stable over a period of 3-36 months at ambient/room temperature. The ratio of microorganism to anti-infective agents in a composition can be 1:2 to 1:25 by weight. The ratio of 1:5 by weight is found to be optimal for the purpose. The amount of coating is dependent on the type of coating technique, dosage form i.e. capsule, tablet or liquid and desired shelf life. The microorganisms of the composition were found to be active after variable time period. They also provided therapeutic effect and eliminated gastrointestinal disturbances associated with anti-infective agents when evaluated in humans.

Description

Description of the invention

This invention relates to a stable, fixed-dose oral pharmaceutical composition containing 2 at least one antibacterial agent as the first active ingredient | at least one microorganism susceptible to said antibacterial agent as a second active ingredient, as well as methods of its production. Microorganisms in this pharmaceutical composition, when used as a medicinal product, are intended to prevent harmful effects such as diarrhea/which are caused by antibacterial agents.

This invention provides for the production of a medicinal product in which antibacterial agents and susceptible 70 viable microorganisms are combined in such a way that the microorganisms, with their susceptibility to the antibacterial agent, remain viable during the shelf life of this medicinal product and/or until they are used. Susceptible microorganisms are usually combined with antibacterial agents to prevent or minimize harmful effects of antibacterial agents such as diarrhea, diphtheria colitis, megacolon, etc. 12 Microorganisms are classified as pathogenic and common. Pathogenic microorganisms are responsible for various infectious diseases and are not normally present in this organ of the human body. They are also known as agents of infection. Common microorganisms are usually present in various organs of the human body and perform useful functions. They supply the human body with vitamins C, B-12, thiamin, riboflavin, etc.

ISavigoipieviipa igasiv sparieg 65 ip Teh VookK oi Meadisa! Rpuzioiodu ey. Agyeg S Siyop 85 dopp E. Nai, Rybiivpege

Rgivt Vookv (Rmi) TSY. 9 September 1996). They, through various mechanisms, suppress the growth of pathogenic microorganisms (Pe RNagtasoiodisaI Vaziz oi Tpegareshisv ip Soodtap 5 SiShgpap, Sparieg 44, apiitisgobia! adepiv, rr.1042). Antibacterial agents are used to treat/prevent infectious diseases.

They kill microorganisms in different ways. However, they are not always specific for pathogenic microorganisms and kill also ordinary microorganisms (Pe РНаптасоиодиса! Vaziz ой ТНегарециисв ip s boodtap 8 Оіјап, Sparieg 44, apiitisgoria! adepiv, rr.1042). The death or decrease in the number of ordinary Ge) microorganisms leads to a violation of the function performed by these organisms, as a result of which various consequences of this violation are observed | ye RIagtasoiodisaI Vaziv oi Tpegaretsshiisv ip boodtap «

Siytap, SPparieg 44, apiiitisgoriai adepiv, year 1042; Veyaiasiat (Pegaru apa ipieviipa! Poga, dotsgpa! oi

Spetoiipeg. 1995 Mau, 7 vyrri I: 25-31). These effects are known as adverse or side effects of anti-infective therapy. Diarrhea with or without superinfection is one such effect seen with anti-infective Ge'! therapy (Sigtepi Meadis! Oiadpoviv 85: Tgeaitepi, Zbii eayyop, SPparieig 14, apiibioiis azzosiaige(i soiiiv, rr. 580; A.R. VaiYi, SPparieg 7, Tohisviu ip apirioiis apa spetoipegaru, zemepii eaiyop, eai Egapsiv 0" She

Segaga; Oiagoea satsvzei ru apibiois (pegaru, Keu-Rgai. 1996, ap. 15: 46 (2): 171-6І. Diarrhea Ge») is observed as a side reaction to many antibiotics. But it is most often observed with broad-spectrum antibiotics. Cases of diarrhea also depend on the level of absorption from the gastrointestinal tract. They are less often observed when complete absorption is achieved, compared to those cases when complete absorption is not achieved. They also depend on the amount of medicine taken. Antibiotics that cause diarrhea include clindamycin, ampicillin, amoxicillin, cephalosporins (eg, cefuroxime, cefixime, cephalexin ceftriaxone), amoxicillin and clovenic acid, ampicillin z 50 solbcutam, fluoroquinolone, and other combinations of broad-spectrum antibiotics, such as amoxicillin z s cloxacillin |Sygttepi Meadaisa! Oiadpoviv 8: Tgeaitepi, Zbii eayyop, SPparieeg 14, apiirioiis avzzosiaiei soiiiv,

From" year 586; Veiaiasiat (pegaru apa ipieviipa! yoga, doigpai! oi Spetoiieg. 1995 Mau, 7 virri I: 25-31; Oiatoea satsvei ru apiibioiis ipegaru, Keu-Rgai. 1996, add. 15: 46 (2): 171-6; Apiirioiis avzzosiaiei a|iatnoea ip

EATS oi oh ragwop! Orzegmayope, RoI-Tud-iek, 1995 Ber, 50 (36): 45-95 Apiiriokis-ipdisei -soiiiv,

Zetip-Rediai-Zygdu. 1995 Mom, 4 (4): 215-207 Siovigidisht aiyisiye asdtzizyop gaibe apa yv ogoYiee ip i-y pazosoptia! aiatnpoyeea ag a ipimegeyu Pozriai! ip Tygkeu, Eig-)-Eridetioi. 1996 Atsd, 12 (4|: 391-4; Kivk (se) Tasioge azvosiaiei myp o Siovigidiit aisCe diatnoea ip Pozriiailei adyy raiepi a saze-sopigo! zitsdu-zisgaMayee ipdeviop iv poi a opedayme tgizK Tasiog, ipesiSopigoI-Nozr-Eridetioi, 1996 Arg, 17 (4): o 232-5; Siipis sotragizop oi seishgohite ahey apa atohusiShip /siamtsshapage ip (She igeaytepi oi raiepiv mzhmyy (Te) 20 zesopdagu rasiegia! iptesiope oi asshe Bgopspyiv, Siipisai Teg. 1995 Ber-Osi,) 17 (5) 8861-74;

T» readiaiis rayepiv om/yy o ascie oiyiv tedia m/yy epiyiviop, Siiiipisai Teg. 1995 Zer-Osi, 17 (5): 838-51;

Apiirioiis-azvzosiaiei rzepdotetrgapocie soiYiiv: heigozresiime vitsyu oi 48 sovez aiadpozei Bu soIopozsoru,

Tpegarie, 1996, uap-Rer: 51 (1): 81-65 Rhemepiop oi bBeiia-Iasiat-azzosiaieuy aiatpoea bu vzasspagotusev 22 rotsagaii sotraged m/ypy riasero, At. .). (Szavigoepiegoi. 1995 Mag 90 (3): 439-485; Rgorpuihiz addaiipvi

GF) atrisiIyyp-azzosiaie (and aiagttroea m/ypy and Iasiorasi With rgeragayop, At. U), Novzr. RpPagtp. 1979 tsip: 36: 754-757). Diarrhea may be mild and recurrent as a result of temporary dysfunction of the normal colonic flora or due to exposure to antibacterial agents | Oiaggoga satsvzei ru apiibiois (pegaru/ Keu-Rgai. 1996, add. 15: 46 (2): 171-6) or re-infection with pathogenic organisms of the siovigidisht ayisie type, which accompanies the change of 60 normal flora under the influence of antibacterial agents (Apiirioiis azzosiagei aiatpoea ip IdnE oi reggopai! orzegmayop5, Ro!I--ud-iek, 1995 Ber, 50 (36): 45-95 A. R. VaiY 7 apiibioisv ip siipisaY rgasiise, Zspmi2g-Mei-UUospepesig. 1996 Mag 30: 126 (13): 528-34| In this case, it is necessary to stop antibacterial therapy | Sigtepi Medica! Oiadpovziv 8 Tgeaitepi, Zbiy eayop,

Sparieg 14, apiirioiys avzzosiayei soiiiv, year 586; Apirioiis azvosiaiei diatpoea ip dp oi regzopai orzegmayop5, Ro!I--ud-iek, 1995 Ber, 50 (36): 45-95 A. R, VaiYi, Sparieg 7, Tohisyu ip apiiriobiys apa spetoipegaru, zemepii eyiyop, ey, Egapsiv O'Segaga| and the use of other treatment. Other treatments that may be used include using a different type of antibacterial agent, such as metronidazole, vancomycin | Sigtepi Meadis! Oiadpoviz and Tgeaitepi, Zbii eaiiop, SNarieg 14, apiirioiys azvosiayei soiiiv, year 586; Apirioiys-azvzosiaFey rzepdotetrgapoye soiyiv: geiigozresiime vistsau oi 48 savzez adiadpozei Bu soIopozsoru, TPegarye, 1996, dap-Ber: 51 (1): 81-65 Apirioiyis-ipdysey soiyiv,

Zetip-Readiai-Zygu. 1995 Mom, 4 (43: 215-20), teicoplanin and/or the use of such microorganisms as 7/0 Lactic acid bacteria, bifidobacteria, saccharomycetes, zygeriosossiv (Ppeptorpyy5, epiegosossiz Tasesisht 5E 68, | Savzei SO and others. (Vioiegaretsiis adepivz . -azzosiaiedy aiagppoea ru sasspagotusevz brochiagaii sotragedy m/y riasero, At. .. Savigoepiego)y. 1995 Mag 90 (3): 439-481. Good results can be given 7/5 bobtaining their use with complete bowel washing |MUpoie-rome! igidabop az ap adiipsi yu She iigeaitepi oi spgote, geiarvzipud Siovigiditst aisCe soiiiv. 9-Siip-Savigoepiegoii 1996 Arg; 22 (3): 186-9)

Used microorganisms (|Siovigidiit aitisne asativyiop ogaye apa 5 tgoie ip povosotia| a|iatnoea ai a tspimegeyu "pozrigaI ip TigKeu, Eig-9U-Eridegpioi. 1996 A!tsa, 12 (4): 391-4i4 destroy or help in the destruction of pathogenic microorganisms by various mechanisms that include production of hydrogen peroxide or inhibition or binding of pathogenic microorganisms to intestinal cells Antibacterial agents that cause diarrhea / prolong treatment times increase the cost of therapy due to increased number of drugs used, days of hospitalization and consultations, sometimes they cause life-threatening conditions, for example, diphtheria colitis. diadpozei ru soiopozsoru, GPpegarye, 1990, dap-Ger: 51 (1): 81-6; Bide ePesiv apa sopzedcepsev oi itedtsepitsu ivey apiirioiisv ip siipisa! rg asiise, Zspmi2g-Mei-MUospepesit. 1996 Mag 30: 126 (13): 528-34), and) toxic megacolon.

The above-mentioned microorganisms can be used to treat diarrhea when it occurs. They can also be used to prevent diarrhea |Vioipegareciis adepis. A pedieyesiei toaaiiyu tog Te igeaitepi «g zo apa rgemepip oyi zeiesivy ipiezipa! apa madipa! iptesiop5, ZAMA 1996 Mag 20: 275 (11): 870-6;. Rhemepiop oi Beia-Iasiat-azzosiaiei aiiagtroea ru sasspagotusevz Broshiagai sotragei m/y riasero, At. 4). Savigoepiegoi. Me 1995 Mag: 90 (3); 0439-48; Rgorpuyakhiv adaipvi atrisiiyip-azzosiaiei diapgptroea m/p o a Iasiurasiii5 (su rgeragayop, At. U. Novzr. RIapt. 1979 Oip: 36: 754-757) Preparations on sale contain only lactic acid bacteria (Iasiyoga, I asiorasii, I asiosar, I asiomia, Zrogias) or in combination with streptococci me) (Iasiiisup) or saccharomycetes (Iamiez). To prevent diarrhea, microorganisms are prescribed together with antibacterial agents. This requires taking at least two different drugs, that is, an antibacterial agent and microorganisms. This negatively affects the patient's adherence to the regimen and treatment regimen.

Attempts were made to introduce microorganisms and antibacterial agents into one medicine. Some of them are for sale. A commonly used microorganism is lactic acid bacteria. Antibacterial agents used in the medicinal product include ampicillin (for example, Alcilin plus, manufactured by Airipe), amoxicillin (for example, Alox plus from Airipe), ampicillin and cloxacillin (for example, Amplus from Dazoprai, Elclox plus from EiYideg , Penmix plus from UOee RIagta, Pin plus from Zuvioris, Poxin plus from AIripe), and? amoxicillin and cloxacillin (for example, Bicidal plus from Kee Rpagt, Diclox from Stoyog Rpagt, Twinclox plus from AiYiripe). They are all a simple mixture of antibacterial agents and susceptible microorganisms.

However, analysis of medicinal products/ those on sale and those prepared by us revealed that the microorganisms introduced into such a medicinal product do not retain their viability and do not perform any useful function/ for which they were intended . Neither microorganisms nor the results of their vital activity can be detected already 7 days after placing lactic acid bacteria together with various 2) antibiotics such as ampicillin, amoxicillin, amoxicillin and cloxacillin, etc., or in a drug that is available for sale. Although 60 million spores are introduced into the composition, none of them can grow or show viability on an agar plate with glucose yeast extract. They cannot also produce lactic acid, which was established by consuming MAON.

The pharmaceutical composition disclosed in the application is closest to the claimed invention

PCT/O594/13882 dated December 2, 1994. (UMO publication 95/15157 A1 dated 06/08/1995). This pharmaceutical composition contains both an antibacterial agent and live bacteria, which, despite the presence of an antibacterial agent, retain their viability during long-term storage of the composition.

F) The technology of protection of bacterial culture, in accordance with the application PCT/0594/13882, is based on their microencapsulation, which is carried out according to the following scheme: preparing a suspension of bacteria in a suitable solution, adding an enveloping agent to it, pushing the solution through needle nozzles, drying the microdroplets , formed by streams of nitrogen and air, collection of the resulting particles in an aqueous solution, where they gelatinize, washing, instant freezing and lyophilization. After that, the obtained microspheres containing bacteria are used to prepare a vaginal pessary in the form of a suppository, foam, ointment, etc., which excludes the possibility of its use for oral administration.

Thus, the composition according to the application PCT/I594/13882 is a collection of microspheres that include bacteria suspended in a viscous filler containing other active ingredients of the composition. It is clear that such a composition causes a very slow release of bacteria from microcapsules, which gradually dissolve under the influence of intravaginal moisture, which reaches the capsules only after they are completely freed from the surrounding filler.

The basis of this invention is the task of introducing susceptible microorganisms into a pharmaceutical composition containing antibacterial agents and preserving their viability during the shelf life of the composition or before its use by creating a barrier that separates the mass containing microorganisms from the mass containing antibacterial agent, but does not isolate bacteria in microvolumes.

The advantage of such a composition is obvious, because it ensures a much faster and complete release of microorganisms from the composition when it is orally introduced into the human body. 70 Another object of the present invention is to minimize the side effects of antibacterial agents arising from the death/alteration of normal flora by introducing viable organisms together with the antibacterial agent(s).

Another task of the present invention is to strengthen the treatment regimen by reducing/eliminating side effects caused by antibacterial agents. another task of the present invention is to improve the treatment scheme due to the introduction of two drugs in one pharmaceutical composition.

Another task of the present invention is the delivery of microorganisms to the right place.

This description describes and explains in detail the nature of the present invention and how it should be embodied.

Antibacterial agents and microorganisms are identified. The method of application is explained exactly, the dosage form is described.

A susceptible microorganism is introduced into the medicinal product in such a way that the microorganisms remain viable during the shelf life of the medicinal product, regardless of the fact that they are in contact with the antibacterial agent. To protect susceptible organisms from the effects of an antibacterial agent, a protective barrier is created around the microorganisms or the antibacterial agent, so that the antibacterial agent cannot affect the microorganisms. The result is viable microorganisms in the presence of an antibacterial agent. Microorganisms remain viable as long as the mentioned barrier exists. and)

This is similar to applying paint or film to an object to prevent corrosion by isolating it from its surroundings.

The protective barrier is chosen depending on the scheme of introduction and the dosage form of the pharmaceutical composition "g" (antibacterial means and microorganisms).

The pharmaceutical composition produced in this way is tested for stability and effectiveness. Me

The pharmaceutical composition produced in this way is tested under different test conditions of temperature "(9) and humidity (45"C, 37"C at 8095 humidity and at ambient temperature) during time intervals reaching 12 months. me)

Samples of the medicinal product were taken for study at an interval of 3 weeks. The samples were analyzed for the presence of microorganisms using qualitative and quantitative microbiological methods. It was found that the obtained values are comparable to the number of microorganisms introduced into the medicinal product.

Samples of the medicinal product were also analyzed for the presence of antibacterial agent by quantitative evaluation. The values obtained for the antibacterial agent were found to be comparable to those when 70 was introduced into the drug. в с Thus, during the analysis of the medicinal product at different time intervals after exposure in different conditions of the surrounding environment, the presence of microorganisms and an antibacterial agent in the same one was established;" quantity

It was established that the medicinal products created in this way have an increased therapeutic effect, which consists

In reducing/eliminating antibiotic-induced diarrhea. c Usually, ampicillin causes maximum diarrhea among penicillins. Of all known cases, 2,090 are associated with ampicillin. None of the 40 patients, when they were administered ampicillin and lactic acid bacteria in a pharmaceutical composition manufactured according to this invention, did not develop diarrhea and all of them were able to undergo a full 2) course of antibiotic treatment. The absence of diarrhea indicates the effectiveness of the new pharmaceutical composition, 5p, which is produced according to the present invention. The following are examples of medicinal products containing various antibacterial agents and microorganisms susceptible to them. However, this does not mean limiting the scope of the present invention to these examples.

Example | 25 OMg Example II BOOmg 5B Ampicillin bomln Ampicillin bomln

Lactic acid bacteria Lactic acid bacteria (F) Example 25O0OMg Example IM BOOmg co Amoxicillin bomln Amoxicillin bomln

Lactic acid bacteria Lactic acid bacteria in Example U 25OMg Example MI BOOmg

Cloxacillin bOmln Cloxacillin bOmln

Lactic acid bacteria Lactic acid bacteria

Example of MIA 25OMg Example of MIA 125Bmg

Ampicillin 250mg Ampicillin 125Bmg 65 Cloxacillin bOmln Cloxacillin ZOmln

Lactic acid bacteria Lactic acid bacteria

Example IX 25 OMg Example X 125 Bmg

Amoxicillin 250mg Amoxicillin 125Bmg

Cloxacillin bOmln Cloxacillin ZOmln

Lactic acid bacteria Lactic acid bacteria

Example of XI 10b0Omg Example of XII 25OMg

Ampicillin BOOmg Ampicillin 250mg

Sultamycin bomln Probenicid bomln

Lactic acid bacteria Lactic acid bacteria

Example of HYII 25 OMg Example of CHEM BOOmg

Amoxicillin 125Bmg Amoxicillin BOOmg

Clavulanic acid bomln Probenicide bomln

Lactic acid bacteria Lactic acid bacteria

Example of ХУ 25 ОМг Example of ХМИ 25 ОМг

Amoxicillin mg Amoxicillin 150 mg

Bromhexine bOmln Carbocysteine bOmln

Lactic acid bacteria Lactic acid bacteria

Example of CHMI BOOmg Example of CHMI BOOmg

Amoxicillin mg Amoxicillin 150 mg

Bromhexine bomln Carbocisteine bomln

Lactic acid bacteria Lactic acid bacteria

Example XX 25 OMg Example XX BOOmg

Cephalexin bomln Cephalexin bomln

Lactic acid bacteria Lactic acid bacteria p

Example XXI 2BOMg Example XXII 2BOMg o

Cephalexin AmMg Cephalexin 250 mg

Bromhexine bomln Probenicide bomln

Lactic acid bacteria Lactic acid bacteria

Example XXIII BOOmg Example XXIM 125Bmg c

Cephalexin BOOmg Cefuroximaksetil bOmln (e)

Probenicide bOomln Lactic acid bacteria

Lactic acid bacteria o

Example XXU 25 OMg Example XXMI BOOmg (is)

Cefuroximaksetil boOmln Cefuroximaksetil bomln

Lactic acid bacteria Lactic acid bacteria o

Example of ХХМИЯ 200mg Example of ХХМИЯ! AbOmg

Cefixime bomln Cefixime bomln

Lactic acid bacteria Lactic acid bacteria « 70 In the above examples, antibacterial agents can be used for any non-therapeutic purposes, despite the fact that they cause significant harmful effects in therapeutic doses, which can be prevented with the use of microorganisms.

Microorganisms can be any of those that prevent or minimize the harmful effects of antibacterial agents that are administered at the same time. In the above examples, to prevent diarrhea, with 75 diphtheria colitis, instead of lactic acid bacteria, bifidobacteria, zasspogtusev zigeriosossis (Ppeptorpyshv, epiegosossis, etc.) can be used in suitable doses. (Se) Next are examples of creating a barrier for microorganisms for various dosage forms.However, this does not mean limiting the scope of the present invention to these examples.

Mn Example (Se) 50 Capsules:

T» i) Microorganisms can be mixed into a total mass and made in the form of a tablet. The tablet is covered with a barrier film. Microorganisms protected by a film are introduced into the capsule independently.

The antibacterial agent is placed in a capsule containing microorganisms protected by a barrier film. This can also be done in the reverse order. 59 her) Microorganisms can be granulated. Granules containing microorganisms are covered with a barrier

GF) film. The granules, which are covered with a barrier film, are mixed with an antibacterial agent before filling the capsules.

Example II

Tablets: 60 tablets) Tablets:

Microorganisms are covered and pressed into a tablet layer. The other layer(s) of the tablet contains an antibacterial agent. i) Tablets containing mixtures:

Granules of microorganisms are covered with a barrier film, mixed with granulated material of antibacterial agents and pressed into a tablet.

i) Coated tablets:

Antibacterial agents are prepared in the form of pressed tablets, they are provided with a coating. At the coating stage, microorganisms are introduced into the coating. The coating should protect microorganisms from antibacterial agents. On the contrary, you can introduce an antibacterial agent into the coating. them) They make a tablet with a cavity containing an antibacterial agent. The cavity of the tablet is filled with microorganisms. At the final stage, the tablet obtained in this way can be covered with a shell.

Coating/barrier protection is not as necessary compared to the capsule form provided that moisture is controlled and physical separation is maintained within the tablet. The manufactured tablet can be a 7/0 dispersible or a regular tablet.

Example PI Liquid medicinal products: i) Microorganisms are covered with a barrier film mixed with other ingredients (dry form) of the medicinal product, including an antibacterial agent. Before use, the product is converted into a liquid form by adding an adequate amount of liquid. her) Microorganisms are covered with a barrier film and suspended in a liquid containing antibacterial agents, or vice versa. The barrier film is stable in the liquid drug, but dissolves in the body due to changes in the surrounding environment, for example, pH,

C. The following are examples of coating agents that can be used in the manufacture of a stable, fixed-dose pharmaceutical composition containing an antibacterial agent(s) and microorganisms.

However, this does not mean limiting the scope of the present invention to these examples.

Chemical name Trademark 1. Cellulose acetophthalate Adchpagegis

SAR

2. Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, Enpagadiya E 100 (o) lat, methyl methacrylate) 1:2:1 Enagadiya E 12.5 3. Poly(ethyl acrylate, methyl methacrylate) 2:1 Enshagadiya ME 300 (Ranish Etsagadiya 300) "I 4. Poly(methacrylic acid, methyl methacrylate) 1:1 Endgaoy I 125 P

Enagadiya I. 12.5 b» 5. Poly(methacrylic acid, ethyl acrylate) 1:1 Enagadiya G 30 0-55 so

Enagadia G 100-55 6 Poly(methacrylic acid, methyl methacrylate) 1:2 Enagadia 5 100 o

Enpagadiya from 12.5 IS

Ashgadiya 5 125 P 7. Poly(ethyl acrylate, methyl methacrylate, Enpagaodii KI. 100 trimethylammonium methyl methacrylate chloride) 1:2:0.2 Eshpagaodii KI RO "

Eshpdgadoi KI. 300

Emagadiy VI. 12.5 - p 8. Poly(ethyl acrylate, methyl methacrylate, Enpagadiya Kz 100 p trimethylammonium methyl methacrylate chloride) /1:2:0.1 Enpagadiya K5 RO , Eshagadiya EE ZO Yu

Enpagadiya KZ 12.5 9. Castor oil hydrogenated Savigozhakh about Savigozhakh MR 70

Te) Savigo M' AH MR 80

Oraizhakh and Zyty!voi (Se) 20 10. Cetyl alcohol Sgodasaoi С7О

11. Diethyl phthalate Kodapyekh SE

Raiaipoi A 25 12. Ethylcellulose Adpasoai!

HF) Etosei d) Zygeivase 13. Hydroxypropyldelulose Kinse!

Meshose! 60th

Miz5o NRS 14. Hydroxypropylmethylcellulose phthalate - 15. Zein

The following are examples of methods of manufacturing a pharmaceutical composition that is stable in fixed doses. However, this is not intended to limit the scope of the present invention to these examples.

Example I - Two-layer tablet

A layered tablet of stable composition in fixed doses is made using components, the active ingredients of which are an antibacterial agent (agents) and microorganisms. Other components are physiologically acceptable fillers. One of the active ingredients is coated in a coating tank using a process known to those skilled in the art. In the manufacture of tablets, fillers with one of the active ingredients (granules) are also used for lubrication, as required in connection with the purpose. Granules of individual active ingredients are first prepared in a manner known to those skilled in the art. The individual portions of the granules are then compressed on a duplicative rotary tablet press equipped with a stacker at a temperature below 25" and a relative humidity of no more than 5095 by methods known to those skilled in the art, and the tablets are transported to a film coating tank by film coating, known to a person skilled in the art.j) Relative ratio of antibacterial agents and fillers for the production of coating suspension and coating antibacterial agents before granulation: и и

Ingredients Parts by weight

Antibacterial agent 77, BA

Ztil cellulose 2.109

TAZ isopropyl alcohol

Dichloromethane 12.3495 units) The relative ratio of antibacterial agents and fillers for the production of granules:

Ingredients Parts by weight

Antibacterial agent 640895 s 29 Microcrystalline cellulose 264595 Ge)

Starch 9.005

Varnish Sunset Yellow 0.459

Purified water 0.025 " iii) The relative ratio of fillers added to granules containing antibacterial agents, as a lubricant:

Ingredients Parts by weight b

Sodium chloride 31.9195

Roiuriaedope XI. 148996 it)

Microcrystalline cellulose 21.2895

Sodium saccharin 10.64965

Corrigent orange 10.6495 "

Magnesium stearate 5.329 s 40 Talc purified 5.329 With "» them) The relative ratio of microorganisms and fillers for the preparation of granules: и

Ingredients Parts by weight

Microorganisms 18.18965 1 Starch 18.1895 o Microcrystalline cellulose 56.6790

Magnesium stearate 0.9195 and 95) Rouriazdope XI. 3.0396 о 50 Sodium chloride 3.0396 chz» The composition in the form of a layered tablet with a fixed dose, which is made using the described method, contains antibacterial agents as active ingredients | viable microorganisms in appropriate therapeutic concentrations. The composition exhibits pharmacological effects that are complementary to the effects produced (according to the prior art) by each individual ingredient, and is stable for at least 3 to 36 months at room temperature. o Example II - Capsules (name) Capsules with a composition in the form of a stable fixed dose are made using components, the active components of which are antibacterial agents and microorganisms. Other components are physiologically acceptable fillers. First, granules of one of the active components (for example, microorganisms) are prepared in a way known to specialists in this field. The granules obtained in this way are pressed into a tablet using a machine for pressing tablets, which has a stacking device, at a temperature below 257C and a relative humidity of not more than 5095 in a way that is known to specialists in this field. The tablets are transported to a coating tank to be coated in a manner known to those skilled in the art. 65 The second active ingredient is mixed with excipients and filled into gelatin capsules in a manner known to those skilled in the art. Before sealing the capsule, the coated tablet containing the active ingredients is introduced into the capsule by methods known to those skilled in the art. i) Relative ratio of antibacterial agent and fillers for filling the capsule:

Ingredients Parts by weight

Antibacterial agent 91.9495

Gelatinized starch 6.2495

Magnesium stearate 1445

Sodium lauryl sulfate 0.3895 min: p. and PI and her) The relative ratio of microorganisms and fillers for the preparation of granules:

Ingredients Parts by weight

Microorganisms 42.8695

Microcrystalline cellulose 53.9390 12 Magnesium stearate 1.0795

Colloidal silicon dioxide 0.719

Sgovv sapteiose zodiyt 14395 iii) The relative ratio of fillers for the preparation of a coating suspension for coating a tablet containing microorganisms, which is to be placed in a capsule:

Ingredients Parts by weight

Cellulose hydroxypropyl methyl phthalate 43790

Titanium dioxide 0.965 s

Talc refined 01995 Ge)

Polyethylene glycol 09995

Isopropyl alcohol 34.9590

Dichloromethane 58.5495 "

The composition in the form of a capsule with a fixed dose, which is made using the described method, contains as active ingredients antibacterial agents and viable microorganisms in their respective therapeutic concentrations. The composition exhibits pharmacological effects that are complementary to the effects produced (according to the prior art) by each individual ingredient, and is stable for at least 3 to 36 months at room temperature.

C5 Example of FDI - Liquid suspension (iv)

A liquid tablet of the composition in the form of a stable fixed dose is made with the use of components, the active components of which are antibacterial agents and microorganisms. One of the active ingredients is granulated after it is suspended in the coating suspension to obtain granules of 100 µm or less in size, in a manner known to those skilled in the art. The granules obtained in this way are suspended in a liquid medium in a manner known to specialists in this field. The second active ingredient is suspended in a manner known to those skilled in the art so that the final concentration of microorganisms is 2095 antibacterial agent(s). The relative ratio of antibacterial agent to excipients for coated granules is:

Ingredients Parts by weight (9) Antibacterial agent 56.82 so Cellulose acetate phthalate 221390

Isopropyl alcohol 6.829 (95) Dichloromethane 13.6395 o 50 | what Y

The composition in the form of a liquid suspension with a fixed dose, which is made using the described

ChT" of the method, contains as active ingredients antibacterial agents and viable microorganisms in their respective therapeutic concentrations. The composition exhibits pharmacological effects that are complementary to the effects produced (according to the prior art) by each individual ingredient, and is stable for at least 3 to 36 months at room temperature.

Example IM - Composition in the form of a dry powder for the production of a liquid composition upon dilution i) Dry powder of the composition in the form of a stable fixed dose for obtaining a liquid medicinal product by dilution before use is prepared with the use of components that are active ingredients and acceptable fillers. 60 One of the active ingredients is granulated after its suspension in the coating suspension in a manner known to those skilled in the art. The granules thus prepared are dried and mixed with the dry powder containing the second active ingredient, by methods known to those skilled in the art, such that the microorganisms constitute 2095 of the antibacterial agent(s) by weight.

The relative ratio of antibacterial agents and fillers for the preparation of coated 65 granules:

Ingredients Parts by weight

Antibacterial agent (agents) BO

Cellulose hydroxypropylmethyl 4590

K-15M (10,000 rounds)

Water is purified B

The composition in the form of a dry powder with a fixed dose, which is made using the described method, contains as active ingredients antibacterial agents and viable microorganisms in their respective /o therapeutic concentrations. The composition exhibits pharmacological effects that are complementary to those produced (according to the prior art) by each individual ingredient, and is stable for at least 3 to 36 months at room temperature.

The aforementioned composition, when diluted with a liquid before use, remains stable at room temperature for 3-7 days.

Examples of therapeutic doses of various antibacterial agents and microorganisms follow. However, this is not intended to limit the scope of the present invention to these examples.

A. Antibacterial agents:

Antibacterial agents can be penicillins, for example, ampicillin, amoxicillin, cloxacillin, cephalosporins, for example, cephalexinodl, cefadroxil, cefuroximaxetil, cefixime, a beta-lactamase inhibitor of the clavulanic acid type - a macrolide of the erythromycin type, both in the form of a single ingredient and in the form of their combination. i) Solid dosage forms in the form of capsules or tablets contain antibacterial agents equivalent to 125, 250 or 50 mg of the active component, i) Liquid dosage forms usually contain antibacterial agents equivalent to 125 mg of the active component in ML.

B. Microorganisms that can be used for therapeutic purposes, and doses: o 1. Hasiorasiiv Asiorpiiv 10-400 ml 2. I asiorasipiv Zrogevz 30o-vokh1059 « zo 3. I asiorasiiv 5 Iasiiv 10-BOOmln 4. Zperogiosossiv Teptorpiiiv 1Omln (o) 5 zHeriosossiz Iasiiv 1Omln so 6. Zassgogpusev segemihea 1Omln 7. I asiorasiii SO 101Ood, F

IC c)

Claims (1)

The formula of the invention « 20 1. Stable in fixed doses oral pharmaceutical composition, which contains at least one antibacterial agent as the first active ingredient and at least one microorganism susceptible to said antibacterial agent as the second active ingredient, which is characterized by the fact that at least one :c" of said first and second active ingredients has a coating that creates a protective barrier that protects a susceptible microorganism from the effects of an antibacterial agent to maintain said susceptible microorganism in a viable state for at least three months, wherein said antibacterial agent is selected from ampicillin , amoxicillin, cloxacillin from penicillins, clavulanic acid, sultamycin from beta-lactamase inhibitors, cefuroxime axetil, cefadroxil, cephalexin from cephalosporins, (Ce) erythromycin from macrolides, ciprofloxacin, from 8-aminoquinolines, and the mentioned microorganism is selected from these asio rasiiyy5 zrogev, Y asiorasiiyy5 Iasiiv, Zigeriosossiv Ipegorpiisv, 50 Zigeriosossis Iasiiv, Zzassgotusez sehemizea, I asiobasiiiii o and/or their combination. (Ce) 2. Pharmaceutical composition according to claim 1, which is characterized by the fact that it additionally contains physiologically acceptable natural fillers. C. A pharmaceutical composition according to any one of claims 1-2, characterized in that the weight ratio of the antibacterial agent to microorganisms lies in the range from 2:11 to 25:1. 4. The pharmaceutical composition according to item C, which is characterized by the fact that the weight ratio of the antibacterial agent to microorganisms is approximately 5:1. GF) 5. Pharmaceutical composition according to any one of claims 1-4, which differs in that one of the active ingredients is in a compressed coated tablet, and this tablet is in a capsule that contains another active ingredient. in 6. Pharmaceutical composition according to any one of claims 1-4, which is characterized by the fact that it has the form of a layered tablet, where in one layer of said tablet there is said antibacterial agent with one or more physiologically acceptable carriers in the form of granules and in the second layer there is microorganism with one or more physiologically acceptable carriers in the form of granules, in which at least one type of granules is coated. 7. Pharmaceutical composition according to claim 6, characterized in that said layer containing an antibacterial agent contains about 64.08 wt.9o of antibacterial agent, about 26.45 wt.9o of microcrystalline b5 cellulose, about 9.0 wt.9o of starch, about 0.45 wt.9o of Sunset Yellow color varnish and about 0.02 wt.o of purified water, and that the granules containing the antibacterial agent are coated. 8. Pharmaceutical composition according to item b or claim 7, which is characterized by the fact that the mentioned layer containing microorganisms contains approximately 18.18 wt.9o of microorganisms, approximately 18.18 wt.bo of starch, approximately 56.67 wt. microcrystalline cellulose, approximately 0.91 wt.9o of magnesium stearate, approximately 3.03 wt.9o of polyplasdon Hi! and 3.03 wt.bo of sodium chloride, and that the granules containing the antibacterial agent are coated. 9. Pharmaceutical composition according to any one of claims 1-4, which is characterized by having the form of a tablet containing 42.86 wt.9o of microorganisms, 53.93 wt.9o of microcrystalline cellulose, approximately 1.07 wt.bo of stearate 76 magnesium, approximately 0.71 wt.9o colloidal silicon dioxide, approximately 1.43 wt.9o sgoz5 sagteiPove zodiSht. 10. Pharmaceutical composition according to any one of claims 1-4, which is characterized in that it is in the form of a capsule containing 91.94 wt.95 of an antibacterial agent, approximately 6.24 wt.9Uo of pregelatinized starch, approximately 1.44 wt. .9o of magnesium stearate and approximately 0.38 wt.9o of sodium lauryl sulfate. 11. The method of manufacturing a pharmaceutical composition according to any one of claims 6-7, in which, on the one hand, the mentioned antibacterial agent is mixed with a physiologically acceptable filler with the formation of granules, and in which, on the other hand, the microorganism is mixed with a physiologically acceptable filler with the formation of granules, which differs in that at least one type of granules is coated with a shell and then the mixture is pressed into a layered tablet using a duplicate rotary press, strictly observing the conditions that the ambient temperature is lower than 257 and the relative humidity is no more than 50,905. 12. The method of manufacturing a pharmaceutical composition according to claim 11, which is characterized by the fact that the antibacterial agent is coated using a coating suspension containing approximately 77.54 wt.Uo of the antibacterial agent, approximately 2.7 wt. of ethyl cellulose, which is dissolved in approximately 7.42 wt. .9o of isopropyl alcohol and approximately 12.35 wt.9o of dichloromethane. 13. The method of manufacturing a pharmaceutical composition according to any of claims 1-5, which is characterized by the fact that one of the active ingredients is pressed into a tablet and coated, and said coated tablet is placed in a capsule containing another active ingredient. 14. The method of manufacturing the pharmaceutical composition according to claim 13, which is characterized in that the tablet is coated using a coating suspension containing approximately 4.31 wt. 90 hydroxypropyl methylcellulose phthalate, approximately 0.96 wt. 90 titanium dioxide, approximately 0.19 wt. 9 grams of purified talc, approximately 0.91 grams of polyethylene glycol, approximately 4.95 grams of isopropyl alcohol and approximately 58.54 grams of dichloromethane. 15. The method of manufacturing a pharmaceutical composition according to any of claims 1-4, which is characterized by the fact that one of the active ingredients is covered and suspended in a solution containing another active ingredient. with 16. The method according to claim 15, which is characterized by the fact that the antibacterial agent is coated using a coating suspension containing 56.82 wt.9o of the antibacterial agent, approximately 22.73 wt.Uo of Me Zb Cellulose acetate phthalate, approximately 6.82 wt.9o of isopropyl alcohol and approximately 13.63 wt.9o of dichloromethane by weight. yu 17. The method according to claim 15, which is characterized by the fact that the antibacterial agent is coated using a coating suspension containing approximately 50 wt.9o of the antibacterial agent, approximately 45 wt.9o of hydroxypropylmethylcellulose K-15 M (100,000 srz), approximately 5 wt.9o of purified water "Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated circuit boards", 2003, M 9, 15.09.2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. ;" 1 se) (95) o 50 s» F) ime) 60 b5