Abstract:
A stable fixed dose oral pharmaceutical formulation is provided. The formulation contains at least one anti-infective agent and at least one susceptible microorganism as active ingredients. At least one of the active ingredients is coated to provide a protective barrier around the active ingredient, the active ingredients being contained in a single pharmaceutical formulation. The formulation may be a tablet, a capsule, or a powder which may be made into a stable liquid. The protective barrier protectis the susceptible micro-organism from the effect of the anti-infective agent to maintain the susceptible micro-organism in a viable form for a period of at least three months. The anti-infective agent can be an antibiotic such as an amoxycillin and the microorganism can be  Lactobacillus acidophilus.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
         [0001]    This is a division of copending application Ser. No. 09/045,890 filed Mar. 23, 1998. Priority of Indian application 174/BOM/97 filed Mar. 27,1997 is claimed under 35 U.S.C. § 119.  
         STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT  
         [0002]    Not Applicable.  
         BACKGROUND OF THE INVENTION  
         [0003]    The present invention relates to a process of manufacturing a formulation containing anti-infective agent(s) with viable organisms, which are susceptible to anti-infective agents. Microorganisms are used to prevent adverse effects like diarrhea caused by anti-infective agents.  
           [0004]    The present invention is directed to a formulation wherein anti-infective agents and susceptible viable organisms are combined in such a way that microorganisms, though susceptible to anti-infective agent, remain viable for the shelf life of a formulation and/or until they are consumed. Susceptible organisms are usually combined with anti-infective agents to prevent or minimize adverse effects of anti-infective agents like diarrhea, pseudomembranous colitis, mega colon, etc.  
           [0005]    Organisms are classified as pathogens and commensals. Pathogens are responsible for various infectious diseases and are not normally present in that part of the body. They are also known as infectious agents. Commensals are normally present in various parts of body and perform useful functions. They provide vitamin K. B-12, Thiamine. Riboflavin etc. to the body. They inhibit the growth of pathogens by a variety of mechanisms. 2  Anti-infective agents are used to treat or prevent infectious diseases. They kill organisms by various ways. However they are not always specific for pathogens and also kill commensals. 2  Destruction or reduction in the number of commensals results in loss of function of commensals and various effects of these are seen. 2.5  These effects are known as adverse effects or side effects of anti-infective therapy. Diarrhea with or without super-infection is one of such effects seen with anti-infective therapy. 3 4 6 Diarrhea is seen as an adverse reaction to many antibiotics, but it is most commonly seen with broad-spectrum antibiotics. The incidence of diarrhea also depends on the level of absorption from the G. I. tract. It is less frequent with those getting completely absorbed compared to incompletely absorbed. It also depends on the amount of drug used. The antibiotics causing diarrhea include clindamycin. ampicillin, amoxycillin, cephalosporins (e.g. cefuroxime axetil, cefixime, cepahlexin ceftriaxone), amoxycillin+clauvanic acid, ampicillin+salbcutam, fluoroquinolens and other combinations of broad spectrum antibiotics, e.g. amoxycillin+cloxacillin.  3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16, 18  Diarrhea can be benign and secondary to transient dysfunction of normal colonic flora due to anti-infective agents 6  or super-infection by pathogens like clostridium difficile following alteration of normal flora by anti-ineffective agents. 7, 4,19, 20  Management in such an event requires cessation of anti-infective therapy 3, 7, 4  and use of other therapies. Other therapies which can be used include different kinds of anti-infective agents e.g. metronidazole, vancomycin, 3, 13, 8  teicoplanin and/or use of organisms like lactobacilli, biofidobacterium, saccharomyies boulardili, streptococcus thermophilus, enterococcus facecium SF 68, L Casei GG etc. 14, 15, 16  These can be combined with whole bowel irrigation with good results. 17  The organisms used 9  eradicate or help in eradicating pathogens by a variety of mechanisms, which include production of hydrogen peroxide or inhibition or adherence of pathogens to intestinal cells. Anti-infective agents-induced diarrhea prolongs treatment and increases the cost of therapy by increased number of  1 drugs to be used,  2 days of hospitalization and consultations. Sometimes it creates a life threatening situation, e.g. pseudemembranous colitis,  4,13,20  toxic megacolon. The organisms named above can be used to treat diarrhea when it occurs. They can also be used to prevent diarrhea. 14, 16, 18  Commercially available preparations include lactobacillus alone (Lactiflora, Lactobacil. Lactocap, Lactovit, Sporlac) or in combination with streptococcus (Lacticyn) or Sacchromyces (Laviest). To prevent diarrhea, organisms are given along with the anti-infective agents. This requires consumption of a minimum of two different drugs, i.e. an anti-infective agent and an organism. This decreases compliance of a patient.  
           [0006]    Attempts have been made to put organisms and anti-infective agents into one formulation. Some of these are commercially available. Lactobacillus is a commonly used organism. Anti-infective agents used in the formulation include ampicillin, (e.g. Alcillin plus from Alpine), amoxicycillin (e.g. Alox plus from Alpine), ampicillin+cloxacillin (e.g. Amplus from Jagsonpal, Elclox plus from Elder, Penmix plus from Dee Pharma, Pen plus from Systopic, Poxin Plus from Alpine), amoxicycillin+cloxacillin (e.g. Bicidal plus from Kee Pharma, Diclox from Croford Pharma, Twinclox plus from Alpine). They all are a simple admixture of anti-infective agents and susceptible organisms. However, analysis of commercially available admixtures, as well as those prepared by us revealed that organisms incorporated into the formulation does not remain viable and did not perform any useful function for which they were to be used. Neither organisms nor their activity could be detected as early as seven days after putting lactobacilli with various antibiotics like ampicillin, amoxycillin, amoxycillin+cloxacillin etc. or in a commercially available preparation. Though 60 million spores are put into formulation, none of them could be grown or demonstrated viable on glucose yeast extract agar plate. It also failed to produce lactic acid as evaluated by consumption of NaOH.  
         REFERENCES  
         [0007]    1. Gastrointestinal tracts chapter 65 in Text Book of Medical Physiology ed. Arther C. Guyton &amp; John E. Hall, Publishers Prism Books (Pvt.) Ltd., 9th edition 1996  
           [0008]    2. pp. 1042 anti-microbial agents, chapter 44 in the Pharmacological Basis of Therapeutics in Goodman &amp; Gillman  
           [0009]    3. PP-586 antibiotic associated colitis, Chapter 14 in Current Medical Diagnosis &amp; Treatment 36th edition.  
           [0010]    4. A. P. Ball, Chapter 7, Toxicity in antibiotic and chemotherapy seventh edition. edit. Francis O&#39;Gerard  
           [0011]    5. Betalactam therapy and intestinal flora, Journal of Chemother. 1995 May; 7 suppl 1: 25-31  
           [0012]    6. Diarrhea caused by antibiotic therapy. Rev-Prat. 1996 January 15; 46 (2): 171-6  
           [0013]    7. Antibiotic associated diarrhea in light of personal observations. Pol-Tyg-Lek. 1995 September; 50 (36): 45-9  
           [0014]    8. Antibiotic-induced colitis. Semin-Pediatr-Surg. 1995 November; (4 (4): 215-20  
           [0015]    9. Clostridium difficile acquisition rate and its role in nosocomial diarrhea at a University Hospital in Turkey. Eur-J-Epidemiol. 1996 August; 12 (4): 391-4  
           [0016]    10. Risk factors associated with Clostridium difficile diarrhea in hospitalized adult patients: a case-control study—sucralfate ingestion is not a negative risk factor. Infect-Control-Hosp-Epidemiol. 1996 April; 17 (4): 232-5  
           [0017]    11. Clinical comparison of cefuroxime axetil and amoxycillin/clavulanate in the treatment of patients with secondary bacterial infections of acute bronchitis. Clinical Ther. 1995 September-October; 17 (5): 861-74  
           [0018]    12. Clinical comparison of cefuroxime axetil suspension and amoxycillin/lavulanate suspension in the treatment of pediatric patients with acute otitis media with effusion. Clinical Ther. 1995 September-October: 17 (5): 838-51  
           [0019]    13. Antibiotic-associated pseudomembranous colitis: retrospective study of 48 cases diagnosed by colonoscopy. Therapy. 1996 January-February; 51 (1): 81-6  
           [0020]    14. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996 March20; 275 (11): 870-6  
           [0021]    15. The pharmacologic principles of medical practice, Krantz &amp; Carr  
           [0022]    16. Prevention of beta-lactam-associated diarrhea by saccharomyces boulardii compared with placibo. Am. J. Gastroenterol. 1995 March; 90 (3): 439-48  
           [0023]    17. Whole-bowel irrigation as an adjunct to the treatment of chronic, relapsing Clostridium difficile colitis. J-Clin-Gastroenterol. 1996 April; 22 (3): 186-9  
           [0024]    18. Prophylaxis against ampicillin-associated diarrhea with a lactobacillus preparation. Am. J. Hosp. Pharm. 1979 June; 36: 754-757  
           [0025]    19. Clostridium difficile in antibiotic associated pediatric diarrhea. Indian Pediatr. 1994 February; 31 (2): 121-6  
           [0026]    20. Side effects and consequences of frequently used antibiotics in clinical practice. Schweiz-Med-Wochenschr. 1996 March 30; 126 (13): 528-34  
         BRIEF SUMMARY OF THE INVENTION  
         [0027]    An object of the present invention is to combine susceptible organisms into a pharmaceutical composition containing anti-infective agents and keep them viable for the shelf life of the formulation or until it is consumed.  
           [0028]    A further object of the present invention is to minimize side effects of anti-infective agents resulting from destruction/alteration of normal flora by providing viable organisms along with anti-infective agent(s).  
           [0029]    A further object of the present invention is to provide a pharmaceutical composition which is effective after a longer period of storage.  
           [0030]    A further object of the present invention is to increase compliance by reduction or elimination in side effects of anti-infective agents.  
           [0031]    A further object of the present invention is to improve compliance by providing two drugs in one pharmaceutical composition.  
           [0032]    A further object of the present invention is to provide an organism at a desired site.  
           [0033]    The following specification particularly describes and ascertains the nature of this invention and manner in which it is to be performed.  
           [0034]    The susceptible organisms are combined into the formulation in such a way that the organisms remain viable for the shelf life of a formulation in spite of being in contact with the anti-infective agent. To protect susceptible organisms from the effect of anti-infective agents, a protective barrier is created around the organisms or anti-infective agents, in such a way that the anti-infective agents cannot have an effect on the organisms. This results in viable organisms in the presence of anti-infective agents. The organism remains viable as long as the barrier is maintained. This is like applying paint or a film on a substance to prevent corrosion by isolating it from surroundings.  
           [0035]    The present invention provides an appropriate barrier by way of a selected coating 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, the composition is made to remain stable over a period of 3-36 months at ambient/room temperature. The ratio of a 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 a variable time period. They also provided a therapeutic effect and eliminated gastro intestinal disturbances associated with anti-infective agents when evaluated in humans.  
           [0036]    The protective barrier is selected depending on the route of administration and the dosage form of the pharmaceutical composition (anti-infective agent+organism).  
           [0037]    The pharmaceutical composition so manufactured is evaluated for stability and efficacy.  
           [0038]    The pharmaceutical composition so manufactured is evaluated at different test conditions of temperature and humidity (45° C., 37° C. at 80% relative humidity and ambient temperature) for time interval extending up to 12 months.  
           [0039]    The samples of formulation were taken for study at 3-week intervals. Samples were analyzed for presence of organisms by quantitative and qualitative microbiological techniques. These values were found to be comparable with the amount of organisms introduced into the formulation.  
           [0040]    The samples of formulation were also analyzed for presence of anti-infective agent by quantitative estimation. The values of anti-infective agents forms were found to be comparable to those introduced into the formulation.  
           [0041]    Thus, findings indicate the presence of organisms and anti-infective agents in the same amount when the formulation was evaluated at different time interval after it was exposed to different environments.  
           [0042]    The formulations so created were found to have improved therapeutic efficacy in term of reduction/elimination of antibiotic induced diarrhea.  
         DETAILED DESCRIPTION OF THE INVENTION  
         [0043]    Usually ampicillin causes maximum diarrhea amongst penicillin. The reported incidence is as high as 20% with ampicillins. In 40 patients when ampicillin+lactobacilli were given in a pharmaceutical composition prepared as described in this application, none of them developed diarrhea and everybody could complete the full course of antibiotic therapy. The non-development of diarrhea suggests efficacy of a new pharmaceutical composition prepared according to present invention.  
         DESCRIPTION OF THE PREFERRED EMBODIMENTS  
         [0044]    1. Following are examples of formulations containing various anti-infective agents and susceptible organisms. However, it is not intended that the scope of this invention be limited by these examples.  
                                                       Example I   Example II           Ampicillin 250 mgm   Ampicillin 500 mgm           Lactobacillus 60 million   Lactobacillus 60 million           Example III   Example IV           Amoxycillin 250 mgm   Amoxycillin 500 mgm           Lactobacillus 60 million   Lactobacillus 60 million           Example V   Example VI           Cloxacillin 250 mgm   Cloxacillin 500 mgm           Lactobacillus 60 million   Lactobacillus 60 million           Example VII   Example VIII           Ampicillin 250 mgm   Ampicillin 125 mgm           Cloxacillin 250 mgm   Cloxacillin 125 mgm           Lactobacillus 60 million   Lactobacillus 30 million           Example IX   Example X           Amoxycillin 250 mgm   Amoxycillin 125 mgm           Cloxacillin 250 mgm   Cloxacillin 125 mgm           Lactobacillus 60 million   Lactobacillus 30 million           Example XI   Example XII           Ampicillin 1000 mgm   Ampicillin 250 mgm           Sultamicin 500 mgm   Probenecid 250 mgm           Lactobacillus 60 million   Lactobacillus 60 million           Example XIII   Example XIV           Amoxycillin 250 mgm   Amoxycillin 500 mgm           Clavulanic acid 125 mgm   Probenecid 500 mgm           Lactobacillus 60 million   Lactobacillus 60 million           Example XV   Example XVI           Amoxycillin 250 mgm   Amoxycillin 250 mgm           Bromhexine 8 mgm   Carbocisteine 150 mgm           Lactobacillus 60 million   Lactobacillus 60 million           Example XVII   Example XVIII           Amoxycillin 500 mgm   Amoxycillin 500 mgm           Bromhexine 8 mgm   Carbocisteine 150 mgm           Lactobacillus 60 million   Lactobacillus 60 million           Example XIX   Example XX           Cephalexin 250 mgm   Cephalexin 500 mgm           Lactobacillus 60 million   Lactobacillus 60 million           Example XXI   Example XXII           Cephalexin 250 mgm   Cephalexin 250 mgm           Bromhexine 4 mgm   Probenecid 250 mgm           Lactobacillus 60 million   Lactobacillus 60 million           Example XXIII   Example XXIV           Cephalexin 500 mgm   Cefuroxime Axetil 125 mgm           Probenecid 500 mgm   Lactobacillus 60 million           Lactobacillus 60 million           Example XXV   Example XXVI           Cefuroxime Axetil 250 mgm   Cefuroxime Axetil 500 mgm           Lactobacillus 60 million   Lactobacillus 60 million           Example XXVII   Example XXVIII           Cefixime 200 mgm   Cefixime 400 mgm           Lactobacillus 60 million   Lactobacillus 60 million                      
 
           [0045]    In above examples anti-infective agents can be used for any therapeutic purpose, which in a therapeutic dosage causes significant adverse effects, which can be prevented by using an organism. The organism can be any which prevents or minimizes adverse reactions of anti-infective agents when taken at the same time. For prevention of diarrhea, pseudomembranous colitis it can be biofidobacterium, sacchormyces streptococcus thermophilus, enterococcus etc. instead of lactobacillus in above examples in their appropriate dosages.  
           [0046]    2. Following are examples of providing barrier to organisms for different dosage forms. However, it is not intended that the scope of this invention be limited by these examples.  
         Example I  
         [0047]    Capsules:  
           [0048]    i) Organisms can be lumped together and formulated into a tablet. The tablet is coated with a barrier film. The film-protected organisms are introduced into the capsule independently. An anti-infective agent is put in the capsule containing organisms protected by a barrier film. It can be vice versa.  
           [0049]    ii) Organisms can be granulated. Granules containing organisms are coated with a barrier film. Barrier film coated granules are mixed with anti-infective agent before filling them into capsules.  
         Example II  
         [0050]    Tablets:  
           [0051]    i) Layered Tablets:  
           [0052]    Organisms are coated and compressed into layers of a tablet. The other layers of a tablet contains an anti-infective agent.  
           [0053]    ii) Tablet Containing Mixture:  
           [0054]    Granules of organisms are coated with barrier film and mixed with granulated material of anti-infective agents and compressed into a tablet.  
           [0055]    iii) Coated Tablets:  
           [0056]    Anti-infective agents are formulated into compressed tablets. They are coated. During coating stage organisms are introduced into the coating. The coating should be capable of protecting organisms from anti-infective agents. It can be vice versa i.e. anti-infective agent is included in coating.  
           [0057]    iv) Composite Tablet  
           [0058]    A tablet with a hole is produced containing anti-infective agents. The hole of the tablet is filled with organisms. The tablet so obtained may be coated for final finishing. Coating/barrier protection is not so much necessary as it is in a capsule form as long as moisture content is controlled and physical separation is maintained in a same tablet. A formulated tablet can be a dispersible tablet or a simple tablet.  
         Example III  
         [0059]    Liquid Formulations:  
           [0060]    i) The organisms are coated with a barrier film mixed with other ingredients (dry form) of the formulation including anti-infective agents. The product is reconstituted before use by the addition of an adequate amount of liquid.  
           [0061]    ii) The organisms are coated with barrier film and suspended in a liquid containing anti-infective agents or vice versa. The barrier film is stable in liquid formulation but disintegrates in the body due to alteration in surrounding, e.g. pH.  
           [0062]    3. Following are examples of coating agents, which can be used in making a stable fixed dose of pharmaceutical composition containing anti-infective agent(s) and micro-organisms. However, it is not intended that the scope of this invention be limited by these examples.  
                                                                 Chemical Name   Trade Name                                    1.   Cellulose acetate phthalate   Aquateric               CAP               Cellacefate       2.   Poly (butyl methacrylate, (2-dimethyl aminoethyl)   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 12.5 P       5.   Poly (methacrylic acid, ethyl acrylate) 1:1   Eudragit L 30               D-55               Eudragit L               100-55       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     —                  
 
           [0063]    4. Following are examples of methods of preparing fixed doses of stable pharmaceutical compositions. However, it is not intended that the scope of this invention be limited by these examples. 
       
    
    
     EXAMPLE I  
       [0064]    Double layered Tablet  
         [0065]    A stable fixed dose combination layered tablet is prepared using the following components of which the active ingredients are anti-infective agent (s) and micro organisms. The remaining components are physiologically acceptable excipients. One of the active ingredients is coated in a coating pan by the coating process known to those skilled in the art. Excipients are also used along with one of the active ingredients (granules) during tablet making for lubrication as required for the purpose. Granules of separate active ingredients are first prepared by a process known to those skilled in the art. The separate sets of granules are then compressed on a double rotary tablet compression machine having a laying facility at a temperature below 250 C and relative humidity not more than 50% by processes known to those skilled in the art and the tablets are transferred to a coating pan for film coating to be given by using a film coating process known to those skilled in the art.  
         [0066]    i) The relative proportion of anti-infective agents and excipients to prepare coating suspension and coating anti-infective agents before granulation:  
                                                   Ingredients   Parts by weight                           Anti infective agent   77.54%           Ethyl cellulose    2.70%           Isopropyl alcohol    7.42%           Dichloromethane   12.34%                      
 
         [0067]    ii) The relative proportion of anti-infective agents and excipients to prepare granules:  
                                                   Ingredients   Parts by weight                           Anti-infective agent   64.08%            Microcrystalline cellulose   26.45%            Starch   9.00%           Color Sunset Yellow Lake   0.45%           Purified water   0.02%                      
 
         [0068]    iii) The relative proportion of excipients to be added to granules containing anti-infective agents as lubricants:  
                                                                 Ingredients   Parts by weight                                        Sodium chloride   31.91%           Polyplasdone XL   14.89%           Microcrystalline cellulose   21.28%           Saccharine sodium   10.64%           Flavour orange   10.64%           Magnesium stearate   5.32%           Purified Talc   5.32%                      
 
         [0069]    iv) The relative proportion of microorganisms and excipients to prepare granules:  
                                                   Ingredients   Parts by weight                           Microorganisms   18.18%           Starch   18.18%           Microcrystalline cellulose   56.67%           Magnesium stearate    0.91%           Polyplasdone XL    3.03%           Sodium chloride    3.03%                      
 
         [0070]    The fixed dose layered tablet compositions, which are prepared through making use of the above described process contains the above active ingredients anti-infective agents and viable organisms in their respective therapeutic concentration. The compositions provide pharmacological effects which are complementary to the effects produced by (Prior art) each individual ingredient and are stable for a period of at least 3-36 months at ambient room temperature.  
       EXAMPLE II  
       [0071]    Capsules  
         [0072]    Stable fixed dose combination capsules are prepared using following components of which the active ingredients are anti-infective agents and microorganisms. The remaining components are physiologically acceptable excipients. Granules of one of the active ingredients (e.g. microorganisms) are first prepared by a process known to those skilled in the art. The granules so formed are compressed into a tablet-by-tablet compression machine heaving a laying facility at a temperature below 25° C. and relative humidity not more than 50% by a process known to those skilled in the art. Tablets are transferred to a coating pan for coating to be given by a coating process known to those skilled in the art.  
         [0073]    The remaining active ingredient is mixed with excipients and filled into gelatin capsules by a process known to those skilled in the art. Before sealing of the capsules, the coated tablet containing active ingredients is introduced into the capsules by a process known to those skilled in the art.  
         [0074]    i) The relative proportions of anti-infective agents and excipients for filling in capsule:  
                                                   Ingredients   Parts by weight                           Anti-infective agent   91.94%            Pregelatinised starch   6.24%           Magnesium stearate   1.44%           Sodium lauryl sulfate   0.38%                      
 
         [0075]    ii) The. relative proportion of microorganisms and excipients to prepare granules is as follows:  
                                                                 Ingredients   Parts by weight                                        Microorganism   42.86%           Microcrystalline cellulose   53.93%           Magnesium stearate   1.07%           Colloidal silicone dioxide   0.71%           Cross carmellose sodium   1.43%                      
 
         [0076]    iii) The relative proportion of excipients to prepare coating suspension for coating of a tablet containing microorganisms to be kept into a capsule:  
                                                   Ingredients   Parts by weight                           Hydroxy propyl methyl cellulose pthalate   4.37%           Titanium dioxide   0.96%           Purified Talc   0.19%           Polyethelene glycol   0.99%           Isopropyl alcohol   34.95%            Dichloromethane   58.54%                       
 
         [0077]    The fixed dose capsule compositions, which are prepared through making use of above described process contain the above active ingredients, anti infective agents, and viable organisms in their respective therapeutic concentrations. The compositions provide pharmacological effect, which are complementary to the effects produced by (prior art) each individual ingredient and are stable for at least 3-36 months at ambient room temperature.  
       EXAMPLE III  
       [0078]    Liquid Suspension  
         [0079]    A stable fixed dose combination liquid tablet is prepared using the following components of which the active ingredients are anti-infective agent (s) and microorganisms. One of the active ingredients is granulated after suspending it in a coating suspension to provide granules of 100 micron or less in size by a processes known to those skilled in the art. Granules so prepared are suspended into a liquid formulation by processes known to those skilled in the art. The other active ingredient is introduced into the suspension by the process known to those skilled in the art in such a way that final concentration of microorganisms is 20% of anti-infective agent(s).  
         [0080]    The relative proportion of anti-infective agents and excipients to prepare coated granules:  
                                                   Ingredients   Parts by weight                           Anti infective agent   56.82%           Cellulose acetate pthalate   22.73%           Isopropyl alcohol    6.82%           Dichloromethane   13.63%                      
 
         [0081]    The fixed dose liquid suspension composition, which is prepared through making use of the above described process contains the above active ingredients, anti-infective agents, and viable organisms in their respective therapeutic concentrations. The composition provides pharmacological effects, which are complementary to the effects produced by (prior art) each individual ingredient and are stable for at least 3-36 months at ambient room temperature.  
       EXAMPLE IV  
       [0082]    Dry Powder Composition to Make Liquid Composition after Reconstitution  
         [0083]    A stable fixed dose combination of dry powder for reconstituting the liquid formulation before use is prepared using the following components of which the active ingredients are anti-infective agent(s) and micro organisms. The remaining components are physiologically acceptable excipients.  
         [0084]    One of the active ingredients is granulated after suspending it in a coating suspension by a process known to those skilled in the art. The granules so prepared are dried and mixed with a dry powder containing another active ingredient by processes known to those skilled in the art in such a way that microorganisms are 20% of anti infective agent(s) by weight.  
         [0085]    The relative proportion of anti infective agents and the excipients to prepare coated granules is as follows:  
                                                   Ingredients   Parts by weight                           Anti infective agent(s)   50%           Hydroxy propyl methyl cellulose   45%           K-15 M (1,00,000 cps)           Purified water    5%                      
 
         [0086]    The fixed doses of dry powder compositions, which are prepared through making use of the above described process contains the above active ingredients, anti infective agents and viable organisms in their respective therapeutic concentrations. The compositions provide pharmacological effects, which are complementary to the effects produced by (prior art) each individual ingredient and are stable for at least 3-36 months at ambient room temperature. The above composition when reconstituted by adding liquid prior to use remains stable at ambient room temperature for 3 to 7 days.  
         [0087]    5. Following are examples of therapeutic dosages of various anti-infective agents and microorganisms. However, it is not intended that the scope of this invention be limited by these examples.  
         [0088]    A. Anti-infective Agents  
         [0089]    Anti infective agents can be penicillins e.g. ampicillin. amoxycillin. cloxacillin, cephalosporins e.g. cephalexin, cefadroxyl, cefuroxime axetil, cefixime, beta lactamase inhibition like clauvanic acid-macrolide like erythromycin as single ingredient or combination thereof.  
         [0090]    i). Solid dosage forms like capsules or tablet contains anti infective agents equivalent to 125,250 or 500 mgm of the active component  
         [0091]    ii. Liquid dosage forms usually contain anti infective agents equivalent to 125 mgm of active component in 5 ml.  
         [0092]    B. Microorganisms, which can be used for therapeutic purposes and the dosages are as under:  
                                                           1.     Lactobacillus Aciophillus     10 to 100 million           2.     Lactobacillus Spores     30-60 × 10 6             3.     Lactobacillus Lactis     10-500 million           4.     Streptococcus thermophilus     10 million           5.     Streptococcus lactis     10 million           6.     Saccromyces cerevisea     10 million           7.     Lactobacilli GG     10 10  units