JP2002516616A - Process for the preparation of a stable fixed dose pharmaceutical composition comprising one or more anti-infective drugs and microorganisms as active ingredients - Google Patents

Abstract

  (57) [Summary] Microorganisms are useful for treating gastrointestinal disorders such as pseudomembranous colitis, macrocolon and diseases including diarrhea. They are also useful for preventing gastrointestinal diseases and diseases caused by anti-infectives such as ampicillin, amoxicillin, cloxacillin, clavulanic acid, cefuroxime axetil, cephalexin, erythromycin. Microorganisms must be taken with anti-infective drugs to prevent it. When microorganisms are mixed with anti-infectives to make them easier to administer or to increase compliance and therapeutic efficacy, the microorganisms are susceptible to the anti-infective and are destroyed by the action of the anti-infective in the composition. For this reason, the mixture has been found to be unstable at room temperature. The present invention relates to a method for producing a stable fixed dosage composition comprising an anti-infective agent together with a microorganism as an active ingredient. The method relates to the preparation of various dosage forms for the oral route, such as capsules, tablets and liquid preparations. The method involves providing a suitable barrier to one of the active ingredients with a coating method selected such that the microorganism is not affected by the anti-infective agent. This gives a stable composition. By using a suitable coating method, the composition can remain stable at ambient / room temperature for 3 to 36 months. The ratio of microorganism to anti-infective agent in the composition can be from 1: 2 to 1:25 on a weight basis. A ratio of 1: 5 on a weight basis has been found to be optimal for the purposes of the present invention. The amount of coating depends on the type of coating, the dosage form, ie, capsules, tablets or liquids, and the desired expiration date. The microorganism of the composition was found to be active after a variable period of time. When evaluated in humans, these compositions also provided a therapeutic effect and alleviated anti-infective drug-related gastrointestinal disorders.

Description

DETAILED DESCRIPTION OF THE INVENTION         Contains one or more anti-infectives and microorganisms as active ingredients                   Method for producing stable fixed dose pharmaceutical composition   The present invention relates to active (surviving) organisms (viable oganisms) susceptible to anti-infective drugs. Both relate to a process for the preparation of a formulation containing the anti-infective agent (s). Weakness The product is used to prevent side effects such as diarrhea caused by anti-infectives.   The present invention is sensitive to anti-infectious agents so that microorganisms can Or susceptibility to anti-infectives in such a way that they remain active until they are used The present invention relates to a method for producing a preparation which is mixed with an active microorganism. Diarrhea, pseudomembranous colitis, giant tuberculosis Susceptible drugs are usually used to prevent or minimize the side effects of anti- Mix with anti-infective drug.   Organisms are divided into pathogens and commonsals. Pathogens are various infections It is the cause of the disease and is not normally present in the body. These are also known as infectious agents . Common monkeys, on the other hand, usually reside in various parts of the body and function effectively . These provide the body with vitamin K, B-12, thiamine, riboflavin, etc. (1) . They inhibit pathogen growth by a number of mechanisms (2). Anti-infectious disease Drugs are used to treat / prevent infections. These are produced by various methods. Kill things. However, they are not always specific for pathogens and Monsars may also be killed (2). Destroy or reduce the number of common monkeys The common monkey loses its function if it is lost, but its various effects have been confirmed (2,5 ). These effects are known as adverse or side effects of anti-infective therapy. Diarrhea associated with co-infection or non-diarrhea associated with This is one of the effects (3,4,6). Diarrhea is an adverse effect on many antibiotics Is recognized. However, these are the most commonly found broad-spectrum antibiotics. You. The incidence of diarrhea also depends on the level of absorption from the gastrointestinal tract. Incompletely absorbed field It does not occur as often, even if it is completely absorbed, as compared to a combination. They are It also depends on the amount of drug used. Clindama is an antibiotic that causes diarrhea Isin, ampicillin, amoxicillin, cephalosporins [eg, Cefuroxime axetil, cefixime, Falexin ceftriaxone], amoxicillin + Clavulanic acid, ampicillin + salbcutam, fluoroquinolones And other combinations of broad-spectrum antibiotics, such as amoxicillin + cloxacillin (3,5,6,7,8,9,10,11,12,13,16,18). Normal bacterial flora due to anti-infective drugs By a pathogen such as Clostridium difficile after replacement of (flora) Diarrhea for transient dysfunction of the colonic normal flora due to superinfection or antiinfectives Is benign and may be derivative (7,4,19,20). In such a case, Discontinuation of infectious disease treatment (3,7,4) and use of other treatments is required. Other available Treatment includes metronidazole, vancomycin (3,13,8), Various types of anti-infectives and / or lactic acid, such as teicoplanin Bacillus, biofidobacterium, Saccharomyces-Bourra Jiri (saccharomyies boulardili), Streptococcus thermophilus, en Enterococcus-facecium SF68, L Casei GG, etc. (14, 15, 16). These can be combined with whole bowel perfusion Good results have been obtained (17). The organism used is to inhibit the attachment of pathogens to enterocytes Or eradicate pathogens by various mechanisms, including the production of hydrogen peroxide , Easy to annihilate. Diarrhea induced by anti-infective drugs prolongs treatment and The number of drugs to be increased (2) increases the cost of treatment, the length of hospital stay and the number of consultation days (3). These include life-threatening situations such as pseudomembranous colitis (4,13,20) and toxic megacolon. May cause.   The organism can be used to treat diarrhea when it occurs. these Can also be used to prevent diarrhea (14,16,18). As commercially available drugs, Lactobacillus [Lactiflora, Lactobacil, Lactocap, Lactovit, Sporlac] alone, Or combined with Streptococcus (Lacticyn) or Saccharomyces (Laviest) Some examples are: In order to prevent diarrhea, the organism must be give. This requires the use of at least two drugs: anti-infectives and organisms. I have to. However, this leaves the patient out of compliance.   Attempts have been made to combine organisms and anti-infectives into one formulation. Some of these are It is commercially available. Lactobacillus is a commonly used organism. Used in formulation Anti-infectives used include ampicillin (for example, Akillin plus made by Alpine), Moxicillin (eg, Alox plus from Alpine), Ampicillin + Cloxacillin (eg For example, Jagsonpal Amplus, Elder Elcloxplus, Dee Pharma Penmixplus, Syst opic Pen plus, Alpine Poxin plus), amoxicillin + cloxacillin (eg For example, Kee Pharma's Bicidal plus, Croford Pharma's Diclox, Alpine's Twinclox  plus). These are all simple mixtures of anti-infectives and susceptible organisms It is. However, when analyzing the commercial products as well as those produced by the applicant, Organisms in the formulation do not remain active and are effective for the intended purpose It did not work. Ampicillin, amoxicillin, ammo Lactobacillus is marketed along with various antibiotics such as xixillin + cloxacillin As soon as 7 days after incorporation in the drug, no organism or its activity can be detected Was. As much as 60 million spores were added to the formulation, but on a glucose yeast extract agar plate However, none of them could grow and their survival could not be confirmed. Due to NaOH consumption When evaluated, no lactic acid was produced.   An object of the present invention is to mix a susceptible organism with a pharmaceutical composition containing an anti- Leaving them viable until the shelf life or use You.   Another object of the present invention is to combine the active organism with the anti-infective agent (s). Side effects of anti-infectives caused by disruption / replacement of normal flora by providing Is to be minimized.   Another object of the present invention is to provide a pharmaceutical composition that is effective after prolonged storage. is there.   Another object of the present invention is to provide a drug by alleviating / sedating the side effects of anti-infective drugs. To increase compliance.   Another object of the present invention is to provide two drugs in one pharmaceutical composition. To increase compliance.   Another object of the present invention is to provide an organism at a desired site.   In the following specification, the essence and method of the present invention to be carried out are specifically described. Place and confirm.   Anti-infective drugs and organisms must be identified. These administration routes and dosage forms To determine.   Keep the organism active for the life of the product despite contact with anti-infectives. Susceptible organisms are incorporated into the formulation, as may be kept. Feeling from the action of anti-infective drugs To protect the recipient organism, ensure that anti-infectives cannot affect the organism, Creates protective barriers around anti-infectives. This allows the organism to live in the presence of anti-infectives Is active. The creature remains active as long as the barrier remains. Is this an environment Similar to applying paint or film over a substance to isolate it from corrosion and prevent corrosion.   The protective barrier depends on the route and form of administration of the pharmaceutical composition (anti-infective drug + organism). select.   The pharmaceutical composition thus produced is evaluated for stability and efficacy.   The pharmaceutical composition thus produced is subjected to temperature and humidity (45 ° C., 80% relative humidity (7 ° C. and ambient temperature) for a period of up to 12 months.   Formulation samples were removed for testing at three week intervals. Quantitative and qualitative microbiological methods The samples were analyzed for the presence of organisms by the method. These values are incorporated into the formulation Was found to be equivalent to biomass.   Formulation samples were also analyzed for the presence of anti-infective drugs by quantitative assessment. Antipathy The value of the stain form was found to be equivalent to the anti-infective drug incorporated into the formulation.   Based on the findings obtained at various time periods, even after exposure of the formulation to various environments The organism and the anti-infective drug were found to be present in the same amounts as before.   Formulations made in this way alleviate / sedate diarrhea induced by antibiotics It has been found to have excellent therapeutic efficacy in doing so.   In general, ampicillin causes the strongest diarrhea among penicillins. Reported The incidence is as high as 20% for ampicillin. As described in this application for 40 patients If ampicillin + lactobacillus is mixed into the pharmaceutical composition prepared in Also have no diarrhea and all patients can complete the entire course of antibiotic treatment. Was. The fact that diarrhea did not occur means that the novel pharmaceutical composition produced according to the present invention It suggests the effect of the thing. 1. The following are examples of formulations containing various anti-infectives and susceptible organisms. But, The scope of the present invention is not limited by these examples. Example I Example II Ampicillin 250mgm Ampicillin 500mgm Lactobacillus 60 million Lactobacillus 60 million Example III Example IV Amoxicillin 250mgm Amoxicillin 500mgm Lactobacillus 60 million Lactobacillus 60 million Example V Example VI Cloxacillin 250mgm Cloxacillin 500mgm Lactobacillus 60 million Lactobacillus 60 million Example VII Example VIII Ampicillin 250mgm Ampicillin 125mgm Cloxacillin 250mgm Cloxacillin 125mgm Lactobacillus 60 million Lactobacillus 30 million Example IX Example X Amoxicillin 250mgm Amoxicillin 125mgm Cloxacillin 250mgm Cloxacillin 125mgm Lactobacillus 60 million Lactobacillus 30 million Example XI Example XII Ampicillin 1000mgm Ampicillin 250mgm Sultamicin 500mgm Probenecid 250mgm Lactobacillus 60 million Lactobacillus 60 million Example XIII Example XIV Amoxicillin 250mgm Amoxicillin 500mgm Clavulanic acid 125mgm Probenecid 500mgm Lactobacillus 60 million Lactobacillus 60 million Example XV Example XVI Amoxicillin 250mgm Amoxicillin 250mgm Bromhexine 8mgm Carbocysteine 150mgm Lactobacillus 60 million Lactobacillus 60 million Example XVII Example XVIII Amoxicillin 500mgm Amoxicillin 500mgm Bromohexine 8mgm Carbocysteine 150mgm Lactobacillus 60 million Lactobacillus 60 million Example XIX Example XX Cephalexin 250mgm Cephalexin 500mgm Lactobacillus 60 million Lactobacillus 60 million Example XXI Example XXII Cephalexin 250mgm Cephalexin 250mgm Bromohexine 4mgm Probenecid 250mgm Lactobacillus 60 million Lactobacillus 60 million Example XXIII Example XXIV Cephalexin 500mgm Cefuroxime Axetil 125mgm Probenecid 500 mgm Lactobacillus 60 million Lactobacillus 60 million Example XXV Example XXVI Cefuroxime Axetil 250mgm Cefuroxime Axetil 500mgm Lactobacillus 60 million Lactobacillus 60 million Example XXVII Example XXVIII Cefixime 200mgm Cefixime 400mgm Lactobacillus 60 million Lactobacillus 60 million   In the above example, therapeutic doses cause severe side effects, but Anti-infective drugs that can prevent side effects by using Can be used. Organisms can prevent adverse reactions of anti-infective drugs taken at the same time. Or any that minimizes. How to prevent diarrhea and pseudomembranous colitis A suitable dosage of biofidobacteria instead of Lactobacillus in the above example. Um (biofidobacterium), Saccharomyces streptococcus thermophilus, It may be Enterococcus. 2. The following examples provide barriers to organisms for various dosage forms. However However, the scope of the present invention is not limited by these examples. Example I capsule: i) The organism was massed and compounded into tablets. Tablets coated with barrier film . The organisms protected by the film were encapsulated one by one. Protected by barrier film The anti-infective drug was placed in a capsule containing the protected organism. The reverse is also possible. Wear. ii) The organism can be granulated. Coating granular material containing living organisms with a barrier film I did it. The granules coated with the barrier film are mixed with an anti- This was filled into capsules. Example II tablet: i) Layered tablets:   The organism was coated and compressed into tablet layers. Tablet other (single or multiple) The (type) layer contains the anti-infective agent. ii) Tablets containing the mixture:   Biological granules are coated with a barrier film and mixed with anti-infective granulation material. And compressed into tablets. iii) coated tablets:   The anti-infective drug is incorporated into the compressed tablet. These are coated. Cotin During the aging step, organisms are introduced into the coating. Is the coating an anti-infective? Must be able to protect living things. The reverse, that is, anti-infective drugs Can be incorporated into the coating. iv) Produce perforated tablets containing anti-infectives. The hole in the tablet is filled with the organism. The tablets thus obtained may be coated for finishing.   As long as water content is controlled and physical sequestration is maintained in the same tablet, Bug / barrier protection is not as required as in the capsule form. Combined tablets are disintegrating tablets It may be an agent or a simple tablet. Example III Liquid formulation: i) Protect organisms with a barrier film mixed with other ingredients (dry form) containing the anti-infective drug Workout. Rebuild product before use by adding the right amount of liquid I do. ii) The organism is coated with a barrier film and suspended in a liquid containing an anti-infective drug. You. The reverse may be the case. Barrier film is stable in liquid formulations, but not In the body, for example, due to a change in pH. 3. The following are stable solids containing anti-infective drug (s) and microorganisms. It is an example of a coating agent that can be used in producing a fixed dose pharmaceutical composition. And However, the scope of the present invention is not limited by these examples.           Chemical name Product name 1.Cellulose acetate phthalate Aquateric                                                        CAP                                                        Cellacefate 2.Poly (butyl methacrylate, (2-dimethylaminoethyl) Eudragit E 100 Methacrylate, methyl methacrylate) 1: 2: 1 Eudragit E 12.5 3.Poly (ethyl acrylate, methyl methacrylate) 2: 1 Eudragit NE 30D                                                   (Formerly Eudragit 30D) 4.Poly (methacrylic acid, methyl methacrylate) 1: 1 Eudragit L 100                                                        Eudragit L 12.5                                                        Eudragit L 12.5P 5.Poly (methacrylic acid, ethyl acrylate) 1: 1 Eudragit L30 D-55                                                        Eudragit L100-55 6.Poly (methacrylic acid, methyl methacrylate) 1: 2 Eudragit S 100                                                        Eudragit S 12.5                                                        Eudragit S 12.5 P 7.Poly (ethyl acrylate, methyl methacrylate, Eudragit RL 100   Trimethylammonioethyl methacrylate chloride) Eudragit RL PO   1: 2: 0.2 Eudragit RL 30 D                                                        Eudragit RL 12.5 8.Poly (ethyl acrylate, methyl methacrylate, Eudragit RS 100   Trimethylammonioethyl methacrylate chloride) Eudragit RS PO   1: 2: 0.1 Eudragit RS 30 D                                                        Eudragit RS 12.5 9. Hydrogenated castor oil Castrowax                                                        Castrowax MP 70                                                        Castrowax MP 80                                                        Opalwax                                                        Simulsol 10.Cetyl alcohol Crodacol C70                                                        Crodacol C90                                                        Crodacol C95 11.Diethyl phthalate Kodaflex DEP                                                        Palatinol A 12.Ethyl cellulose Aquacoat                                                        Ethocel                                                        Surelease 13.Hydroxypropyl cellulose Klucel                                                        Methocel                                                        Nisso HPC 14.Hydroxypropyl methylcellulose phthalate- 15.Zein- 4. The following is an example of a method for producing a stable pharmaceutical composition at a fixed dose. But Therefore, the scope of the present invention is not limited by the following examples. Example I-bilayer tablet   The following ingredients whose active ingredients are an anti-infective drug (s) and a microorganism: Was used to produce stable fixed dose mixed layer tablets. The remaining components are physiologically It was an acceptable excipient. Coating by coating method known to those skilled in the art One of the active ingredients was coated in a pan. Produces lubricating tablets necessary for the purpose When doing so, an excipient was also used along with one of the active ingredients (granules). First individual activity Component granules were prepared by methods known to those skilled in the art. Then, a person known to those skilled in the art Double row with laminating equipment at a temperature of less than 25 ° C and a relative humidity of 50% or less by the method The individual set of granules is compressed on a tally tablet press and the film co- Tablets into coating pans for film coating using a coating process Transferred. i) for preparing coated anti-infective drugs and coating suspensions before granulation Relative ratio of anti-infective drug to excipient: Ingredients by weight Anti-infective drug 77.54% Ethyl cellulose 2.70% Isopropyl alcohol 7.42% Dichloromethane 12.34% ii) Relative ratio of anti-infective drug and excipient to produce granules: Ingredients by weight Anti-infective 64.08% Microcrystalline cellulose 26.45% Starch 9.00% Color sunset yellow lake 0.45% Purified water 0.02% iii) Relative ratio of excipients to be added as lubricant to granules containing anti-infectives: Ingredients by weight Sodium chloride 31.91% Polyplasdone XL 14.89% Microcrystalline cellulose 21.28% Saccharin sodium 10.64% Flavor orange 10.64% Magnesium stearate 5.32% Refined talc 5.32% iv) Relative proportions of microorganisms and excipients for producing the granules: Ingredients by weight Microorganisms 18.18% Starch 18.18% Microcrystalline cellulose 56.67% Magnesium stearate 0.91% Polyplasdone XL 3.03% Sodium chloride 3.03%   A fixed dosage layered tablet composition produced by using the above method is provided by Individual therapeutic concentrations of the active ingredient anti-infective agent and active organism were included. This group The product provides a pharmacological effect that is complementary to that obtained by the individual components (conventional method). And was stable at room temperature for a period of at least 3 to 36 months. Example II-Capsule   A stable fixative using the following ingredients whose active ingredients are anti-infectives and microorganisms: Dose mixed capsules were produced. The remaining components are physiologically acceptable excipients. Was. First, one granular form of the active ingredient (e.g., a microorganism) by methods known to those skilled in the art. Was manufactured. The granules thus formed are subjected to 25 ° C by a method known to those skilled in the art. Compression into tablets with a tablet press with a laminator at a temperature of less than 50% and a relative humidity of not more than 50% Shrank. To coat using coating methods known to those skilled in the art, The tablets were transferred to a printing pan.   The remaining active ingredient is mixed with the excipients and the gelatin capsule is prepared by methods known to those skilled in the art. And filled it. Before sealing the capsule, coated tablets containing the active ingredient Was encapsulated by methods known to those skilled in the art. i) Relative ratio of anti-infective drug and excipient to fill capsule: Ingredients by weight Anti-infectives 91.94% Pre-gelatinized starch 6.24% Magnesium stearate 1.44% Sodium lauryl sulfate 0.38% ii) Relative proportions of microorganisms and excipients for producing granules: Ingredients by weight Microorganisms 42.86% Microcrystalline cellulose 53.93% Magnesium stearate 1.07% Colloidal silicon dioxide 0.71% Croscarmellose sodium (Cross carmellose sodium) 1.43% iii) A coating for coating tablets containing microorganisms to be retained in the capsule. Relative proportions of excipients for producing a printing suspension: Ingredients by weight Hydroxypropylmethyl Cellulose phthalate 4.37% Titanium dioxide 0.96% Refined talc 0.19% Polyethylene glycol 0.99% 34.95% isopropyl alcohol Dichloromethane 58.54%   Fixed dose capsule compositions prepared using the above method may provide individual therapeutic concentrations. Of the above active ingredients, anti-infectives and active organisms. This composition (conventionally Provide pharmacological effects complementary to the effects obtained by the individual components (of Stable for at least 3 to 36 months. Example III-Liquid suspension   The following ingredients whose active ingredients are an anti-infective drug (s) and a microorganism: Used to produce stable fixed dose mixed liquid tablets. By methods known to those skilled in the art. One of the active ingredients is coated to provide granules of After suspending in a suspending suspension, it was granulated. The granules thus produced are It was suspended in a liquid formulation by methods known to those skilled in the art. The final concentration of the microorganism Or 20% of the anti-infective drug (s) using methods known to those of skill in the art. Other active ingredients were introduced into the suspension. Relative proportions of anti-infective drugs and excipients for producing coated granules: Ingredients by weight Anti-infective drug 56.82% Cellulose acetate phthalate 22.73% Isopropyl alcohol 6.82% Dichloromethane 13.63%   Fixed dose liquid suspension compositions prepared using the above methods may be used for individual therapeutic concentrations. Of the active ingredient, anti-infective agent and active organism. This composition is Provide pharmacological effects complementary to those obtained by the individual components For a period of at least 3 to 36 months. Example IV-Dry Powder Composition for Producing a Reconstituted Liquid Composition   Liquid formulation prior to use using the following ingredients, where the active ingredient is an acceptable excipient: A stable fixed dose of mixed dry powder for reconstituting was prepared.   One of the active ingredients is suspended in the coating suspension by methods known to those skilled in the art. After granulation. The granules thus produced are dried and the microorganisms are Or two or more) by means of methods known to those skilled in the art. It was mixed with a dry powder containing the other active ingredients.   The relative proportions of anti-infectives and excipients to produce coated granules are as follows: It was as follows. Ingredients by weight 50% of anti-infective drug (s) Hydroxypropyl methylcellulose 45% K-15M (1,00,000cps) Purified water 5%   Fixed dose dry powder compositions prepared using the above method may have individual therapeutic concentrations. Of the above active ingredients, anti-infectives and active organisms. This composition (conventionally Provide a pharmacological effect complementary to that obtained by the individual components (of the The temperature was stable for a period of at least 3 to 36 months.   Upon reconstitution by addition prior to use, the composition is allowed to stand at ambient room temperature for 3-7 days. It remained stable. 5. The following are examples of various anti-infective and microbial therapeutic dosages. But However, the scope of the present invention is not limited by the following examples. A. Antiinfectives   Anti-infectives include penicillins as a single component or a combination thereof, such as , Ampicillin, amoxicillin, cloxacillin, cephalosporins, eg For example, cephalexin, cefadroxil, cefuroxime axetil, Beta-lactamase inhibitors like shim, clavulanic acid, erythromycin Macrolide. i.Solid medicinal forms such as capsules or tablets may contain up to 125, 250 or 500 mgm of active ingredient. New anti-infective drugs. ii. Liquid dosage forms usually contained an anti-infective drug equivalent to 125 mgm of active ingredient in 5 ml . B. Microorganisms and dosages that can be used for therapeutic purposes were as follows.   1. Lactobacillus asiophilus 10 to 100 × 10⁶   2. Lactobacillus spores 30 to 60 × 10⁶   3. Lactobacillus lactis (Lactobacillus) 10 to 500 × 10⁶   4.Streptococcus thermophilus 10 million   5. Streptococcus lactis (Streptococcus lactis) 10 million   6. Saccharomyces cerevisiae 10 million   7.Lactobacillus GG 10^Tenunit

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), AP (GH, GM , KE, LS, MW, SD, SZ, UG, ZW), EA ( AM, AZ, BY, KG, KZ, MD, RU, TJ, T M), AU, BG, BR, CA, CH, CN, CU, C Z, EE, GE, GH, ID, JP, KE, LT, LV , MD, MW, RO, SD, TT, UA, US, UZ, VN (71) Applicant Bangsar Yatish Kumar             India 380 008, Ahmedabad, Manina             Galle, Near Parimaru Hospital, Bee             / 5 Kinjar Apartment (71) Applicant Kamal Bacresh Mafatral             India 380 006, Ahmedabad, Ellis             Bridge, Gurbay Tecla, Basundha             La Colonie, “Asha Adha” 201 (72) Inventor Modi Rajib Indrabadan             India 380 007, Ahmedabad, Parde             I, New Sharda Mandy Row             Do, Sanjib Baug Society, 13,             "Kakaba" (72) Inventor Bangsar Yatish Kumar             India 380 008, Ahmedabad, Manina             Galle, Near Parimaru Hospital, Bee             / 5 Kinjar Apartment (72) Inventor Kamal Bacresh Mafatral             India 380 006, Ahmedabad, Ellis             Bridge, Gurbay Tecla, Basundha             La Colonie, “Asha Adha” 201

Claims (1)

[Claims]   1. In one composition such as capsules / tablets / liquid drugs manufactured according to conventional methods When taken together as in the present invention, they produce a series of actions that are complementary to each other, An activity with a distinct set of properties that results in a composition that is stable over the course of the month Stable composed of anti-infective drug (s) and microorganisms as ingredients A method of providing a fixed dosage oral pharmaceutical composition.   2. Stable for at least 36 months at ambient temperature, provided by each active ingredient Solid / liquid oral, such as capsule / tablet / liquid drug, with complementary action Mix with a physiologically acceptable excipient selected in the nature and amount to provide a dosage composition. From a mixture of i) a therapeutic concentration of an anti-infective agent and ii) a therapeutic concentration of a microorganism. The method of claim 1 for providing a stable pharmaceutical composition consisting essentially of:   3. The anti-infectives are different groups of anti-infectives, such as ampicillin from penicillin. Phosphorus, amoxicillin, cloxacillin, clavulanic acid, beta-lactamase inhibitor Sultamicin derived from harmful agents, cefuroxime axeti derived from cephalosporins , Cephadroxil, cephalexin, erythromycin derived from macrolides And ciprofloxacin derived from 8-aminoquinolines Or a combination thereof, wherein the organism is Lactobacillus acidophilus, Lactobacillus Shirasu spore, Lactobacillus lactis (Lactobacillus), Streptococcus thermo Fils, Streptococcus lactis, Saccharomyces cerevisiae A stable physician selected from Jie, Lactobacillus GG and / or a combination thereof. The method according to claims 1 and 2 for producing a pharmaceutical composition.   4. Anti-infective drug to organism ratio in the range of 2: 1 to 25: 1, preferably in the range of 5: 1 4. The method according to claims 1 to 3 for providing a stable pharmaceutical composition.   5. The method comprises combining the anti-infective agent and the organism separately with a physiologically acceptable excipient. Mixing to provide a granule at least one of which is coated; Subsequent dubbing under harsh environmental conditions at a temperature of less than 25 ° C and a relative humidity of 50% or less 5. Compression into layered tablets using a rotary compressor. The described method.   6. One of the active ingredients, containing about 77.54% of the coated anti- Ethyl cell dissolved in propyl alcohol about 7.42% and dichloromethane about 12.34% Coating by suspension coating in suspension containing about 2.7% loin The method of claim 1, wherein:   7. Approximately 64.08% of anti-infective agent, microcrystalline cellulose about 26. 45%, Starch about 9.0%, Color Sunset Yellow Lake about 0.45%, Purified water about 0 A mixture mixed with physiologically acceptable excipients by using a .02% mixture A method of producing a coated anti-infective drug granule according to claim 6, wherein the granulate 6. Compression into a layered tablet together with microbial granules. the method of.   8. Approximately 18.18% microbes, 18.18% starch, microcrystals based on mixture weight Cellulose about 56.67%, magnesium stearate about 91%, polyplasdone XL about 3 Physiologically tolerable by using a mixture of .03% and 3.03% sodium chloride Producing a granulate of the organism mixed with a possible salt, followed by the granulation of the anti-infective agent. 6. The method of claim 1, comprising compressing the coated granules into a layered tablet. The described method.   9. One of the active ingredients is compressed into tablets and coated, said coating The method according to claims 1 to 4, wherein the tablet is placed in a capsule containing another active ingredient.   10. About 42.86% of micro-organisms, about 53.93 microcrystalline cellulose based on the weight of the mixture %, Magnesium stearate about 1.07%, colloidal silicon dioxide about 10.71%, Physiologically permitted by using a mixture of about 1.43% scarmellose sodium And producing a tablet microorganism mixed with an acceptable excipient. 9. The method according to 9.   11. Hydroxypropyl methylcellulose phthalate based on suspension weight About 4.31%, about 0.96% titanium dioxide, about 0.19% purified talc, polyethylene glycol About 0.91% coal, about 4.95% isopropyl alcohol, about 58.54% dichloromethane Of the tablets by using a coating suspension containing 10. The method of claims 1-4 and 9 comprising:   12. Approximately 91.94% of anti-infective drug based on weight of mixture, pregelatinized Approximately 6.24% of tarch, approximately 1.44% of magnesium stearate, sodium lauryl sulfate Mixed with physiologically acceptable excipients by using about 0.38% mixture 2. The method of claim 1 comprising providing an anti-infective drug and then filling it into a capsule. 10. The method according to 4 and 9.   13. Coating one of the active ingredients and suspending it in a solution containing another active ingredient The method according to claim 1, wherein   14． About 22.73% by weight of cellulose acetate phthalate, about 6 of isopropyl alcohol Use a coating suspension containing .82% by weight, about 13.63% by weight dichloromethane About 56.82% by weight of the anti-infective agent The anti-infective agent by suspending the anti-infective agent in a liquid. 14. The method according to claims 1 to 4 and 13, comprising the step of:   15. Hydroxypropyl methylcellulose K-15 based on the weight of the mixture Use a coated suspension containing about 45% M (1,00,000 cps) and about 5% purified water. With about 50% of the anti-infective drug was coated by coating with anti-infective 15. The method of claims 1-4 and 14 comprising providing a drug.   16. Liquid formulations with short expiration dates must be prepared in dry form, The dry form contains the two active ingredients and is stable at ambient temperature for 3-7 days upon reconstitution. 5. The method of claim 1, wherein one of the coatings is retained to form a suspension. The described method.   17. Claim 1 and the active ingredients according to Examples 1 to 5 of the Supplementary Complete Specification. Stable fixed-dose physician containing the anti-infective drug (s) and the microorganism A method for producing a drug composition.