A method of treating diseases caused by a bacterial infection of the colon and method of suppressing bacteria that form colonies in the colon

 

The invention relates to medicine, gastroenterology, and can be used for the treatment of diseases associated with infection of the colon bacterium C. difficile, and the formation of colonies resistant to vancomycin enterococci. Introducing an effective amount of a pharmaceutical composition containing coating which retains its integrity during passage through the gastrointestinal tract and releasing the active ingredient in the colon, while it contains lincocin as an active ingredient, 2 to 20% NaCl and 20 to 180% coverage based on the weight of untreated active component. This invention is intended for the development of tools aimed at treatment of diseases of the colon and to suppress potentially dangerous bacteria that form colonies in the colon, and to develop a delivery means selected lantoine the colon sufficient for effective treatment of the infection. 3 N. and 24 C.p. f-crystals, 8 ill., 11 table.

The technical field,

The invention relates to methods for treating diseases associated with infection of the colon bacterium C. difficile, as well as with Obrosova - antimicrobial substance produced by a microorganism breeding on the food, and is a member of a group of closely structurally substances called antibiotikum (or in this text descriptions - lantoine). Other members of the group include subtilin, epidermin, glidermen and pep 5.

Lowlands is synthesized by the microorganism Lactococcus lactis, subspecies lactis related to serological group N Lancefield (Mattick, A. T. R. and A. Hirsch, 1947, Lancet. 2, 5). Lowlands is a peptide containing 34 amino acid residue and 5 cyclic structures, the United thioester bridging ties, which form lanthionine or betta metallothionin. Thioester bonds are formed by condensation of the sulfhydryl groups of cysteine residues with dihydropyrimidine side chains formed from the remnants of serine or threonine, and are the result of post-translational modifications of the peptide, precursor of nisin.

According to the lowlands acts as a cationic surface-active agent, and its activity can be neutralized anionic surfactants (Ramseier, H. R., 1960, Arch. Environ., 37, 57), and at the molecular level lowlands acts on the cytoplasmic membrane and the plant-bacteria is the result of depolarization of the plasma membrane is dependent on the potential difference), which occurs after injection of the peptide in lipid bilayers, presumably by interaction of neighboring molecules nisin with the formation of a temporary pore or channel. Molecular properties of nisin and the mechanism of its biosynthesis is described in a recent review [G. Jung and H. G. Sahl, 1991, Nisin and novel lantibiotics (Lowlands and new lantibiotic) ESCOM Science Publishers, Leiden].

It is believed that the lowlands are characterized by a narrow spectrum of activity and is mainly active against some gram-positive bacteria, with the exception of actions in a mixture sheetnum agent, when the lowlands shows unexpected activity against gram-negative bacteria and is characterized by increased activity against gram-positive bacteria (U.S. Patent No 5217950 and No 5260271 issued by Blackburn et al.). Lowlands used as an antimicrobial food preservative, approved as a safe product organization JEFCA and a number of other national public authorities to control the use of food additives, including organizations in the USA, the UK and the European Economic Community.

Although preliminary studies on animal models have demonstrated the efficacy of nisin (Mattick, A. T. R. and A. Hirsch, 1947, Lancet. 2:5; Ba the lowlands insufficient for the development of therapeutic drugs with a view to their use in medicine and veterinary.

Clostridium difficile is an anaerobic gram-positive, soobrazuya toxicogenic rod-shaped bacterium, which is sometimes found in considerable quantity in the colon of man. However, due to the resistance of this bacterium to a number of antimicrobials and caused its endemic in hospitals and private hospitals, bacteria may multiply if suppressed the normal bacterial flora of the colon, in most cases after treatment with antimicrobials with a broad spectrum of action. In this case, C. difficile can cause serious illness known as diarrhea and pseudomembranous colitis associated with antibiotic use. The treatment of these disorders involves the use of metronidazole and vancomycin for oral administration. However, at the present time, the use of vancomycin, primarily oral route, was a serious concern, as this antibiotic leads to the selection of a new class vysokorazvynenych intestinal micro-organisms, vancomycin-resistant enterococci (FEV), which can cause serious, untreatable infections in various body parts. Metronidazole is not active against enterococci, and disableai, caused by C. difficile, is extremely high and is approximately 20%; assume that this is due to the formation of spores, which are difficult to eliminate.

The invention

Object of the invention is the development of tools for the treatment of bacteria-caused diseases of the colon and to suppress potentially dangerous bacteria that form colonies in the colon. It is shown that large doses latinincanada of antibiotics (lantoine), such as lowlands, the colon is characterized by unexpectedly high resistance in the colon and absence of toxicity. Consequently, another object of the invention is the development of tools for the delivery of the selected lantoine the colon sufficient for effective treatment of the infection in the colon.

List of drawings and other materials

In Fig.1 shows the sensitivity of the lowland to the enzymes present in the gastrointestinal tract.

In Fig.2 shows the effect of coating thickness of tablets before the beginning of the decomposition tablets in phosphate buffer solution.

In Fig.3 shows the effect of coating thickness of tablets at times to the beginning to complete the decomposition of tablets in phosphate whom and in phosphate buffer solution at pH 6.8.

In Fig.5 shows the dissolution profile of 6 tablets with 40% coating of Eudragit.

In Fig.6 shows the process of tablets with 40% of the thickness of the coating through the gastro-intestinal tract of man in the process of digestion within 7 hours

In Fig.7 shows the process of moving tablet of 120% of the thickness of the coating through the gastro-intestinal tract of man in the process of digestion within 12 hours

In Fig.8 shows the process of tablets with 180% of the thickness of the coating through the gastro-intestinal tract of man in the process of digestion for 16 hours

Information confirming the possibility of carrying out the invention

The subject of the invention is to develop treatments for diseases of the colon, caused by the bacterium C. difficile, and means to suppress bacteria that form colonies in the colon, such as FEV.

In this regard, the authors have shown that the lowlands has high activity against pathogenic strains of various gram-positive bacteria, including FEV (application for issuance of a U.S. patent, registration No 08/667650 included in the text of the description by reference). It is known that the lowlands has activity against putrefactive microorganisms of the genus Clostridium, cause is described by other authors (Kerr et al., 1997, Lancet. 349:1026).

This description shows that the lowlands has a high activity against a large number of clinical isolates of C. difficile, including strains resistant to clindamycin and metronidazole. It is also shown that the lowlands shows low activity in relation to the predominant normal intestinal flora of the human - Bacteroides fragilis. Indeed, there is a significant difference between the concentrations of nisin is active against 50% of the strains of C. difficile, and the range of concentrations effective against 50% of the strains of C. fragilis. This means that in contrast to the recommendations of the Kerr et al., it seems unlikely that effective doses of nisin will have a negative effect on the protective commensal microflora of the intestinal tract. Despite the fact that, as has already been installed, lowlands requires the use of means for potentiating the effects of his activity against most gram-negative bacteria, there are a few exceptions. For example, it is difficult cultured gram-negative bacteria, such as Neisseria gonorrhoeae extremely sensitive to nisin. C. fragilis is difficult cultivated gone anaerobic, whose sensitivity to nisin is so far not known.

So the amounts in the small intestine (see Fig.1), his oral the way for delivery to the local infectious foci in the lower part of the gastrointestinal tract has not previously been discussed. Furthermore, it is not known tolerance of intact lowland when it is delivered into the lower part of the gastrointestinal tract, and it is not known whether lowlands stable enough to wait for the manifestation of its antimicrobial activity in this part of the body.

In the study of subacute intestinal toxicity in animal models, the authors have shown that the lowlands do not intrude on the colon at the second delivery. In addition, it is shown that the intact lowlands cannot be detected in the blood of treated animals, suggesting that in this way the passage of low systemic absorption (and possible systemic toxicity) is unlikely. In addition, in the study of animals, from which part of the colon imposed ligature shown that a significant portion of the valley is preserved in an intact form in situ within a few hours after the introduction of the colon.

Thus, there is a practical need to develop systems for the delivery of nisin or other antimicrobial latiino peptidoglycan way to treat infections of the colon, caused by microorganisms (including, but not limited to C. difficile), sensitive to these peptides, or to suppress sensitive microorganisms, forming colonies in the colon (including, but not limited to, FEV), which represent a potential health hazard to the individual or to other patients. In this regard, another object of the invention is the development of the compositions, which allow us to deliver effective amounts of nisin oral method for the treatment of bacterial infections in the colon.

Pharmaceutical compositions of these peptides include tablets with an appropriate coating or granules, or capsules for oral administration, which allow to preserve the integrity of the dosage form during passage through the stomach and small intestine, and then provide release of the active ingredient in the relevant part of the gastrointestinal tract (from the lower small intestine to the top of the colon). However, it is clear that an effective dosage forms can be used, for example, suppositories and enemas. Specific dosage forms described below, just for p. the properties of nisin in the environment of the colon and the effectiveness of nisin against bacteria of the normal intestinal flora.

Example 1A

The nisin activity against C. difficile

20 Clindamycin-resistant clinical isolates obtained from hospital McGuire Veterans’ Administration Hospital, Richmond, Virginia, research on Brucella agar with sheep blood under anaerobic conditions. Minimum inhibitory concentration (MIC) is defined as the minimum of the investigated concentration that completely inhibits the growth of bacteria observed visually.

As shown in the table.1, all strains were inhibited at a concentration of nisin 0.25 microgram/ml or less.

60 clinical isolates obtained from the University hospital, Florence, Italy, to explore the sensitivity to nisin and to antimicrobial agents, currently used to treat diarrhea and colitis caused by C. difficile, using the above method. As shown in the table.2, the median MIC or MIK50nisin (concentration at which there is a growth inhibition of 50% or more of tested strains) for all of these strains are 0.05 mg/ml, which was significantly lower compared with the amount of vancomycin or metronidazole required for inhibition of the same strains. The MIC90represent concentratee.

The data of this example show that C. difficile is a suitable microorganism target for treatment Nizina or related peptides.

Example 1B

The lack of activity of nisin against Bacteroides fragilis

9 isolates of C. fragilis obtained from the hospital McGuire Veterans’ Administration Hospital, Richmond, Virginia, are examined in a similar way as described above. None of the strains were not inhibited by Nizina even at the highest used concentration of nisin (32 µg/ml). Value MICK nisin against these strains is 64 mcg/ml or more. Similarly, as shown in the table.3, 23 isolates from a University hospital, Florence (Italy) also show relatively low sensitivity to nisin, an average value of MIC is >128 µg/ml.

Example 2

Tolerance to the lowlands in legirovannom the intestines of rabbits

Five rabbits anaesthetize and maintain them in a state of narcolepsy during the whole experiment. Open the abdominal cavity and put the ligature on the bowel, including the ileocecal connection and proximal colostomy. Two rabbits are used as control and three administered 20 mg of untreated depression (i.e., received from the company produces the concealment of corpses after histopathological studies treated intestine show no signs of irritation or toxicity, associated with processing Nizina. The results obtained indicate that the direct introduction of nisin in the colon of rabbits at a dose equal to the dose that can be administered to the person, show no signs of local toxicity, even if the dose is kept in colon artificially for 6 h using overlay ligatures on the intestines.

Example 3

Tolerance to the lowlands at the second delivery in the colon of the dog

Dogs are implanted surgically tube in the proximal region of the colon. After recovery groups of dogs in 6 animals injected with untreated lowlands inside of the intestine through a tube at 0, 50, 125, or 300 mg/kg daily for 28 days, and the dose is divided into two halves for the introduction of approximately 1000and 1600hours.

After autopsy, histopathology and clinical trials show no signs of local irritation or systemic toxicity associated with the treatment Nizina. The results indicate that with the reintroduction of the extremely high doses of nisin in the colon of mammals observed tolerance to the lowlands.

The use of the tests, described above in examples 2 and 3, the animals take blood samples for determination of nisin in the serum.

Rabbits in the model with legirovannym intestine (example 2) blood is taken after 0.5, 2 and 6 h after injection of low. Level lowland define specific enzyme-linked immunosorbent assay (ELISA), detection limit is 1 mg/ml of rabbit serum.

None of the investigated samples have not detected the presence of nisin, which indicates the absence of absorption the valley of the colon in this animal model.

In experiments on dogs (example 3) blood samples taken on the 28th day after 0, 5, 1, 2, 3, 4, 5, 6 and 7 h after the morning injection of low. In this experiment, the serum analyze microbiological method using as the test microorganism Micrococcus luteus, the limit of detection of this method is 0.5 µg/ml of serum of the dog. Of the 18 dogs treated Nizina, 17 withstood the trials and 16 had the correct location of the catheter at autopsy. (The two dogs were observed leakage of material into the abdominal cavity, one had to score in the process and one has stood the test). Serum collected in any period in dogs with government is t about when delivered correctly nisin even in extremely high doses in the colon of mammals is not observed absorption lowland in the systemic circulation and, therefore, it seems unlikely that the lowlands manifests systemic toxicity.

Example 5

Conservation of lowland in the colon of mammals at concentrations sufficient for inhibition of bacterial targets.

In experiments on rabbits as described above in example 2, at necropsy, the contents of the intestinal loops are collected, extracted and analyzed by HPLC. The contents of the bowel control rabbits, raw Nizina use to assess the effectiveness of the extraction procedure. With this objective, these designs add a known quantity of the valley, followed by homogenization and extraction. The most effective method of extraction, which allows you to extract approximately 50% added nisin used for the extraction of the contents of the intestines of rabbits treated with Nizina. From the contents of the intestine treated Nizina rabbits extract up to 24% entered the valley, which is very likely evidence of stability, at least half entered the valley in situ within 6 hours

Concerned with the eating of the colon, approximately 4 l, we can assume that the local concentration of nisin in the colon in a long period of time will achieve higher 40-80 µg/ml (or 40-80 µg/g content of the colon). This value is many times greater than the value of MICK for microorganisms-targets - C. difficile and Enterococcus spp., but equal to or below the limit of sensitivity of the protective gram-positive intestinal flora, such as B. fragilis. The actual dose may be lower or higher than that, of course, will depend on many factors such as the efficiency of opening and dissolving dosage forms in humans, local bioavailability of the active component (the amount of free active component capable of interacting with bacteria compared to the quantity of the component associated with solid material), the severity of the disease, the time of the product in patients with diarrhea and so on, it is also Clear that the lowlands you can enter multiple times (up to 6 times) in any 24-hour period. Accordingly, the range of the intended daily dose is at least about 100 mg and up to a maximum of approximately 6 g, preferably from about 300 mg to about 2 g

As known is about, the obtained in this example, the results indicate that the lowlands or related peptides delivered to the colon in an effective dose can be used to treat bacterial infections caused by susceptible to nisin bacteria, or to suppress potentially dangerous sensitive bacteria that form colonies in the gut.

The examples above indicate that the lowlands and other peptides with similar antimicrobial activity against all expectations will provide the necessary action in the environment of the colon without relapses, without any possible unwanted effects.

Previously developed compositions for delivery of therapeutic amounts of nisin into the colon by oral administration. These compositions are described in examples 6-8. In the experiments presented below, was carried out search for dosage forms, which retain their integrity for at least 4 h at pH of the stomach and for 0.5-3 h at pH 6.8 (pH lower part of the small intestine), and then start to split in the colon or in the nearest to her area.

Preliminary studies were aimed at development of kernel tablets what Ki is a daunting task because of the special physico-chemical properties of the lowland, and in the that a relatively large part of the core tablet is the active drug. Unlike most drugs, including peptides, medical devices, lowlands is amphipatic substance (and hydrophobic). Thus, despite the rather high solubility in water, even at neutral pH, lowlands hardly diffuses from the compressed kernel when immersing the core in a buffer solution. Instead of dissolving, around the tablet forms a layer of gel-like nisin, which limits the access of water into the tablet. In the expanded programme on the development of composition and study of various fillers and disintegrators this unique problem was solved by simply adding in the tablet of the optimal amount of sodium chloride. This additive effectively reduces the gelation and provides a decomposition of the tablets.

The second problem in the development of the composition of the tablets is the strength of the core tablet, because the kernel must withstand the harsh conditions of intense mixing during the formation of successive coatings of tablets using the process in the fluidized bed WusterFluidized. Pills, �82.gif">), are characterized by inadequate for the specified method strength. Deep analysis of the problem leads to the conclusion that due to the nature and physicochemical properties of nisin binding components prevents the captured air, which thus leads to reduced physical strength tablets. This problem is solved by including in the process of manufacturing tablets way roller pressing.

The characteristics of the release (drug) from the music change through the formation of a coating of core tablets using a copolymer of methacrylic acid and methyl methacrylate (EudragitTM). Time before decomposition tablets and time to complete the decomposition of the change in a reproducible way by varying the ratio of the mass of coating and mass of the core tablet.

In examples 6-11 describes the various formulations of the compositions and the results of the study of their suitability for delivery of effective amounts of lantanides according to the present invention in the colon.

Example 6 and

The effect of the cage on the decomposition pill

Prepared core tablets of the following composition.

As disintegrators use Ac-Di-Sol, Explotab and Polyplasdone XL. Times rodeny below.

Tablets containing as disintegrator Ac-Di-Sol, decays faster than tablets containing other investigated disintegrator. Accordingly, the following composition is obtained using Ac-Di-Sol.

Example 6 b

The influence of NaCl on the decomposition of pill

Prepared core tablets of the following composition.

The above results indicate that the presence of sodium chloride in sufficient concentration allows to avoid gelation and to significantly increase the rate of decomposition tablets low at physiological pH values. Studied core tablets containing more than 1% of sodium chloride, break up within 4-6 min, whereas when the concentration of NaCl 1% or less decomposition does not occur even after 1.5 hours in Addition, no significant changes of time decay in the concentration of NaCl to 15.3%. Thus, according to the present invention, it should be expected that the composition containing NaCl in a concentration range of from about 2% to about 20%, suitable for delivery of an effective amount of nisin or other lantation in the colon.

Example 7

Core tablets containing lowlands

NIP (1)

Composition: (relative to the l 5

Sodium chloride 5

Talc 5

Viagrasalemaai components:

Prosolv 90 12,5

Povidone 5

c-Di-Sol 5

Sodium chloride 5

Magnesium stearate 0,5

The weight of the whole tablet =152,5 mg

Properties of tablets:

The crushing strength =2559,45±856,17 kg (5,65±1.8 Kropotov, (kp)) (n=10)

Time decay:

In R. O. water (purified by reverse osmosis)=24,4±2.5 minutes (n=3)

In phosphate buffer solution pH 7.0=33,1±4.5 min (n=3)

NIP (2)

Composition: (percent relative to the weight of the crude lowland)

Vnutrigornye components:

The crude lowlands 100

Prosolv 90 12,5

Ac-Di-Sol 7,5

Sodium chloride 7,5

Talc 2

Viagrasalemaai components:

Prosolv 90 12,5

Povidone 5

Ac-Di-Sol 7,5

Sodium chloride 7,5

Magnesium stearate 0,5

The weight of the whole tablet =162,5 mg

Properties of tablets:

The crushing strength =2518,68±856,17 kg (5,56±1.89 Kropotov, (kp)) (n=10)

Time decay:

In R. O. water =23,9±2,1 min (n=3)

In phosphate buffer solution pH 7.0=29,9±2,7 min (n=3)

It is shown that not only dosage forms have acceptable characteristics by decomposition and the required crushing strength in conditions analogous to the passage of a tablet through the gastrointestinal tract, but found that this juice

1- Ac-Di-Sol = transverse cross-linked sodium carboxymethylcellulose

2- ProSolv = selectiona microcrystalline cellulose

3- Povidone = polyvinylpyrrolidone

Core tablets obtained using the following steps:

1. All components are sieved separately through sieve No. 20 (0.0331’).

2. Weigh the specified amount nutrigenomic components: lowlands, NaCl, Ac-Di-Sol and ProSolv (components No. 1-4). Mix them in a suitable glass vessel.

3. Mix on turbulent the turbula mixer at 50 rpm for 15 minutes

4. Weigh talc (component No. 5) add to the mixed product obtained in stage 3.

5. Mix on turbulent the turbula mixer at 50 rpm for 3 minutes

6. The mixture obtained in stage 5, condense on the roll and tip seal (model TF-mini), pressure rolls =9806,6 kN/m2(100 kg/cm2), the speed of rotation of rolls =6 rpm, speed helical rolling =11 rpm

7. Compacted material obtained in stage 6, sieved on a sieve with a mesh size of 1.0 mm using oscillating granulator (Erweka AR400 Wet-Dry Granulator).

8. Obtained at the stage of 7 pellets compacted into a roll and tip the sealer (model TF-mini), pressure rolls =2941,9 kN/m2(Arial, received at stage 8, sieved on a sieve with a mesh size of 1.0 mm using oscillating granulator.

10. Received at stage 9 pellets compacted into a roll and tip seals, pressure rolls =2941,9 kN/m2(30 kg/cm2), the speed of rotation of rolls =8 rpm auger speed =11 rpm

11. Compacted material obtained in stage 10, sieved on a sieve with a mesh size of 1.0 mm using oscillating granulator.

12. Weigh the specified amount of additional granular portions NaCl, Ac-Di-Sol, Prosolv and Povidone (components No. 6-9). Add to the granules obtained in stage 11.

13. Mix on turbulent the turbula mixer at 50 rpm for 10 minutes

14. Weigh stearate (part No 10). Add to the mixture obtained in stage 13.

15. Mix on turbulent the turbula mixer at 50 rpm for 2 minutes

16. The mixture obtained in stage 15, compacted into a rotary press for tabletting Manesty D3B (pressure seal =679,5 kg (1500 lbs), speed =16 rpm) using a biconcave block size of 7.0 mm

It is shown that obtained by the above method core tablets have the necessary strength and retain integrity during subsequent formation of the cover, as described above stage (A), is prepared as follows.

1. Filter Eudragit L30D-55 through a clean sieve.

2. Weigh the dispersion of Eudragit L30D-55.

3. Weigh the water. In the mixing process to suspension of Eudragit add approximately 2/3 of the water.

4. Weigh triethylcitrate (CHP), in the process of mixing dispersio Eudragit added dropwise CHP. Wash the vessel, which was added TPP, two portions of the remaining amount of water and rinse water is added to the mixture.

5. Stirred for 1 h

6. Weigh the powder, add to the mixture with stirring.

7. Stirred for 1.5 hours

Coating of core tablets formed using a dispersion for

coverage as follows.

1. Core tablets are placed in the apparatus of Wurster fluidized bed.

2. The dispersion for coating placed on the balancer, providing continuous stirring using magnetic stirrer.

3. Coating of tablets form in the following conditions:

Spraying speed:7.0 g/min

The spray pressure: 150 kN/m2(1.5 bar).

Temperature input:50C.

Example 9

The influence of coating thickness on the decomposition of the tablets.

Examine the effect of coating thickness and the Institute of mass of the coating and the mass of the core tablets. The results obtained are shown in Fig.2 and 3, indicate strict proportion to the time before the decomposition and time to complete decomposition of the thickness of the coating of Eudragit L30D. In Fig.4 shows that the lag time between initial contact of the tablet with the buffer and the initial release of nisin depends on the thickness of the coating. Thus, by forming the coating of Eudragit L30D sufficient thickness, it is possible to give the necessary characteristics of prolonged action sufficient to deliver drugs into the colon by oral administration. Moreover, the characteristics of prolonged action can be varied by changing the thickness of the coating.

According to the present invention, it should be expected that the coating thickness in the range from about 20% to about 180% (from 0.15 mm to 1,316 mm measured in the centre) will provide the necessary characteristics of prolonged action songs. According to the best variant of the embodiment of the present invention, the coating thickness is approximately 40% (0,371±0.07 mm, measured in the centre).

Example 10

The release of the drug in initialsize cover 0,371 mm, measured at the center) are obtained using the apparatus for tabletting USP type II in buffer solution pH 6.8 at 37C and under stirring at a speed of 100 rpm Dependence of dissolution of tablets of time is determined first by keeping them in HCl 0.1 N. (environment of the stomach), and then in 50 mm phosphate buffer pH 6.8 (the environment of the colon). The results presented in Fig.5, indicate that it is possible to prepare containing lowlands tablets with reproducible characteristics prolonged action of low (i.e., the delay time of dissolution), necessary for the delivery of nisin into the colon.

Example 11

Illustration of a delivery nisin into the colon of a person using tablets prolonged action

Core tablets containing 100 mg of the crude lowland form when the ratio of the active ingredient and excipients, as described above in example 8, but in addition add the samarium oxide in an amount of 10 mg per tablet. The tablets covered with a layer of Eudragit L30D-55, as indicated in example 8, and form 40% of the coating layer (thickness 0,371 mm measured in the centre). In addition, the form of tablets 120% coating (coating thickness 0,896 mm measured in the centre) and the com part of the non-radioactive samarium (152Sm) turns into a radioactive samarium (153Sm), which allows the observation of the passage of the tablets through the gastro-intestinal tract using scintigraphy [Digenis, G. A. and E. Sandefer Gamma scintigraphy and neutron activation techniques in the in vivo assessment of orally administered dosage forms (Methods gamma-scinti-graphy and neutron activation for monitoring progress introduced oral dosage forms in vivo), Crit.Rev.Ther.Drug Carrier Systems, 7, 309-345 (1991)].

Scintigraphically studies conducted in 12 healthy men. In the first group, six subjects receive one tablet or 40%, 120%, or 180% coating of Eudragit (two subjects for each type of composition). In the second group, four subjects receive one tablet with 40% coverage, and two subjects receive one tablet with 120% coverage. Tablets with 250 ml of ice water. Monitoring is conducted every 30 minutes

In Fig.6, 7 and 8 presents scintigrams of the process of tablets with different composition through the gastrointestinal tract. In Fig.6 shows the path of tablets with 40% coverage in one of the test of Fig.7 - tablet 120% of the floor of Fig.8 tablets with 180% coverage. As can be seen in Fig.6-1 - 6-6, tablet with 40% coverage save the normal colon through 5.5 hours (Fig.6-7 - 6-9). Tablet with 120% of the floor begins to decompose after 12 h, and at this moment she is in the transverse colon (Fig.7-7, 7-8). Tablet with 180% coverage reaches the rectum, while maintaining the integrity (Fig.8-1 to 8-9). The results obtained indicate that the disintegration time of the tablets in vivo and in vitro depends on the thickness of the coating.

The data obtained in the study of 6 subjects who received a pill with 40% coverage, are presented in table.11. Five of the six subjects tablet starts to disintegrate between peripheral ileum and transverse colon rectum, and the progressive splitting of tablets is in the process of passing through the colon.

All six of the subjects that received the composition, the negative effects of tablets is not observed.

The data obtained in this example show that it is possible to form a containing lowlands tablet with the appropriate characteristics prolonged action for local treatment of diseases of the colon of a person that it is possible to provide a breakdown of the contents of the tablets in the colon of a person, and that dose containing 100 mg of the crude lowland, characterized retenu you can use pills, containing from about 50 mg to about 600 mg nisin. You can take several pills (up to 4) for any given course of treatment and apply several courses of treatment (up to 6) in any given 24-hour period of time. The range of daily doses of nisin can be from a minimum of approximately 100 mg to a maximum of approximately 6 g, preferably from about 300 mg to about 2, a Similar dose of the tablets and the daily dose can be applied to other latiina.

Claims

1. A method of treating diseases caused by a bacterial infection of the colon, including the introduction of an effective amount of a pharmaceutical composition containing coating which retains its integrity during passage through the gastrointestinal tract and biswalo the containing lincocin as an active ingredient, 2 - 20% NaCl and 20 - 180% coverage based on the weight of untreated active component.

2. The method according to p. 1, characterized in that as lantoine choose lowlands.

3. The method according to p. 1 or 2, wherein the bacterial infection is C. difficile.

4. The method according to p. 3, wherein the disease is associated with the intake of antibiotic diarrhea or pseudomembranous colitis.

5. The method according to p. 1 or 2, characterized in that lincocin is administered in a daily dose in the range of from at least about 100 mg to a maximum of approximately 6,

6. The method according to p. 5, characterized in that lincocin is administered in a daily dose in the range of from about 300 mg to about 2 g

7. The method according to p. 3, characterized in that lincocin is administered in a daily dose in the range of from at least about 100 mg to a maximum of approximately 6,

8. The method according to p. 4, characterized in that lincocin is administered in a daily dose in the range of from at least about 100 mg to a maximum of approximately 6,

9. The method according to p. 7, characterized in that lincocin is administered in a daily dose in the range of from about 300 mg to about 2 g

10. The method according to p. 8, characterized in that lincocin is administered in a daily dose in the range of from arr is obom.

12. The method according to p. 11, characterized in that lincocin injected in the form of tablets or capsules.

13. The method according to p. 1, characterized in that lincocin administered rectally.

14. The method according to p. 13, characterized in that lincocin injected in the form of a suppository or enema.

15. The method of suppressing bacteria that form colonies in the colon, including the introduction of an effective amount of a pharmaceutical composition containing coating which retains its integrity during passage through the gastrointestinal tract and releasing the active ingredient in the colon, characterized in that the use of a pharmaceutical composition comprising lincocin as an active ingredient, 2 - 20% NaCl and 20 - 180% coverage based on the weight of untreated active component.

16. The method according to p. 15, characterized in that as lantoine choose lowlands.

17. The method according to p. 15 or 16, characterized in that the bacteria are resistant to vancomycin enterococci.

18. The method according to p. 15 or 16, characterized in that lincocin is administered in a daily dose in the range from at least about 100 mg to a maximum of approximately 6,

19. The method according to p. 17, characterized in that lincocin is administered in a daily dose, just a few metres from the clinical topics that lincocin is administered in a daily dose of from about 300 mg to about 2 g

21. The method according to p. 19, characterized in that lincocin is administered in a daily dose of from about 300 mg to about 2 g

22. The method according to p. 15, characterized in that lincocin injected oral way.

23. The method according to p. 22, characterized in that lincocin injected in the form of tablets or capsules.

24. The method according to p. 15, characterized in that lincocin administered rectally.

25. The method according to p. 24, characterized in that lincocin injected in the form of a suppository or enema.

26. Pharmaceutical composition for treating diseases caused by a bacterial infection of the colon that retains its integrity during passage through the gastrointestinal tract and releasing the active ingredient in the colon, characterized in that it contains lincocin as an active ingredient, 2 - 20% NaCl and 20 - 180% coverage based on the weight of untreated active component.

27. Pharmaceutical composition for p. 26, characterized in that as lantoine it contains lowlands.

Priority items:

09.06.1997 - PP.1-14, 16-25, 27;

10.01.2000 - PP.1,15, 26.

 

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FIELD: medicine.

SUBSTANCE: invention proposes agent for suppression of snores noise designated for intramuscular administration. Agent comprises the highly purified clostridium toxin BONT/A or highly purified clostridium toxins BONT/B, BONT/C1, BONT/D, BONT/E, BONT/F and/or BONT/G. Also, agent can be used comprising a fused protein that involves light subunit of clostridium toxins among the group BONT/A, BONT/B, BONT/C1, BONT/D, BONT/E, BONT/F, BONT/G, TeNT, and heavy subunit of another clostridium toxin from the same group, or mixture of fused proteins, or complex comprising clostridium toxin or a fused protein, and one or more therapeutically good tolerable hemagglutinin, and/or one or more pharmaceutically good tolerable nontoxic protein. The proposed therapeutic agent expands assortment of medicinal agent used in the snore therapy. Invention can be used for suppression of snore noise.

EFFECT: enhanced effectiveness of agent.

10 cl, 3 ex

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