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(19)    Riau    (11) Patent Number: KE 144
    Kenya Indust., Propeny Institute.    (45) Date of grant: 14/03/2002
(12) PATENT
 
(51) Int.CLA:
6 1K 35//74
(21)    Application Number: 1999/000116
(22)    Filing Date: 22/10/1999
(30) Priority data:
9806489-2 27/03/1998 UK
(86) PCT data
PCT/1B98/00445 03/04/1998
WO 99/49875    07/10/1999
 
(73)    Owner:
CADILA PHARMACEUTICALS (E.A) LIMITED. of , P.O. BOX 79642, MOMBASA ROAD, NAIROBI., Kenya
(72) Inventor:
MODI Rajiv Indravadan; BANSAL Yatish Kumar and KHAMAR Bakulesh Mafatlal
(74)    Agent/address for correspondence: Volconsult Ltd, P.o.Box 79130 Nairobi
 
(54) Title:
THE PROCESS FOR THE PREPARATION OF A STABLE FIXED DOSE PHARMACEUTICAL COMPOSITION OF ANTI INFECTIVE AGENT/AGENTS AND MICRO ORGANISMS AS ACTIVE INGREDIENTS.
(57) Abstract:
(EN) Micro organisms are useful in management of diseases including diarrhoea and gastro intestinal diseases like pseudomembranous colitis, megacolon etc. They are also useful in prevention of gastro intestinal disturbances and diseases caused by anti-infective agents like ampicillin, amoxycillin, cloxacillin, clauvanic acid, cefuroxime axetel, cephalixin, erythromycin etc. For prevention micro organisms are to be taken along with anti infective agents. When micro organisms are combined with anti-infective agents for ease of administration and improving compliance and therapeutic effect, the combination is not found to be stable at room temperature as micro organisms are sensitive to anti-infective agents and are destroyed by effect of anti-infective agent in composition. The present invention relates to the process of preparing a stable fixed dose composition of anti-infective agent with micro organism as active ingredient. The process includes preparation of various dosage forms for oral route like capsule, tablet and liquid formulation. The process comprises of providing an appropriate barrier by way of selected coating procedure to one of the active ingredients in such a way that micro organisms are not affected by anti-infective agents. This results in a stable composition. By using an appropriate coating technique composition is made to remain stable over a period of 3-36 months at ambient/room temperature. The ratio of micro organism 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 self life. The micro organisms of the composition were found to be active after variable time period. They also provided therapeutic effect and eliminated gastro intestinal disturbances associated with anti-infective agents when evaluated in humans.
 
DESCRIPTION
THE PROCESS FOR THE PREPARATION OF A STABLE FIXED DOSE PHARMACEUTICAL COMPOSITION OF ANTI INFECTIVE AGENT/AGENTS AND MICRO ORGANISMS AS ACTIVE INGREDItNTS.
The present invention relates to a process of manufacturing a formulation containing arq-
infective agent(s) with viable organisms which are susceptible to anti-infective agents. Micro
organisms are used to prevent adverse effects like diarrhoea caused by anti-infective agents.
The present invention is directed to 'manufacturing of a formulation where in anti-infective agents and susceptible viable organisms are combined in such a way so that micro organisms, through susceptible to anti-infective agent, remain viable for the self life of a forrimlation and/or till they are consumed. Susceptible organisms are usually combined with anti-infective agents to prevent or minimise adverse effects of anti-infective agents like diarrhoea, pseudomembranous colitis, mega colon, etc.
 
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Organisms are classified as pathogens and commonsals. Pathogens are, responsible for various infectious diseases and are not normally present in that part of the body. They ate also known as infectious agents. Conunonsals are normally present in various parts of body and perform useful functions. They provide vitamin K, 1342, Thiamine, Riboflavin etc. to body.' They inhibit the growth of pathogens by variety of mechanisms.' Anti-infective agents are used to treat/prevent infectious diseaSes. They kill organisms by various ways. However they are not always specific for pathogens and also kill commonsats.' Destruction or reduction in number of commonsals results in loss of function of commensals and various effects of these are seen.'.' These effects are known as adverse effects or side effects of anti-infective therapy. Diarrhoea with or without super-infection is one of such effects seen with anti-infective therapy,' .6 Diarrhoea is seen as an adverse reaction to many antibiotics. But they are most commonly seen with broad spectrum antibiotics. The incidence of diarrhoea also depends on level of absorption from G.1. tract: They are less frequent with those getting completely absorbed compared to incompletely absorbed. They also depend on amount of drug used. The antibiotics causing diarrhoea include clindamycin, ampicillin, amoxycillin, cephalosporins (e.g. cefuroxime axetil, cefixitne, cepahlexin ceftriaxoney, amoxycillin clauvanic acid, ampicillin + salbcutam, fluoroquinolens and other combinations of broad spectrum antibiotics, e.g. amoxycillin + cloxacillin.3.,A7.".".1213•" Diarrhoea can be benign and secondary to transient dysfunction of normal colonic lines due to anti-infective agents° or super-infection by pathogens like clostridium difficile following alteration of nonnal flora by anti-ineffective agents.''''''.'" Management in such an event requires cessation of anti-infective (heron?• and use of other therapies. Other therapies which can be used include different kind of anti-infective agents e.g. metronidazole,1vancomycin,3.• iticoplanin and/or use of organisms like lactobacilli, hiofidobacterium,
 
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saccharomyies boulardili, streptococcus thennophilus, enterococcus faceciuth SF 68, L Casei GG ete."•' These can be combined with whole bowel irrigation with good results." Organisms used eradicate or ,help in eradicating pathogens by Variety of mechanisms Which include production of hydrogen peroxide or inhibition or adherence of palbogens to intestinl cells. Anti-infective agents induced diarrhoea prblong treatment, increase cost of therapy by increased number of drugs to be 'used,' dais of hospitalisation and 'consultations.
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Sometimes they create life threatening situation e.g. pseudememberous colitis,""."' toxic megacolon.
The organisms named above can be used to treat diarrhoea when it occurs. They can also be used to prevent diarrhoea.'"•"'" Commercially available preparations include lactobacillus alone (Lactiflora, Lactobacil, Lactocap, Lactovit, Sporlac) or in combination with streptococcus (Lacticyn) or Sacchromyces (Laviest). To prevent diarrhoea organisms are given along with the anti-infective agents. This requires consumption of minimum two different drugs i.e. an anti-infective agent and an organism. This decreases compliance of a patient.
Attempts have been made to put organisms and anti-infective agents into one formulation.

Some of these are commercially available. Lactobacillus is commonly used organism. Anti¬infeCtive agents used in the formulation include ampieillin. (e.g. AlciUM plus from Alpine), amoxicycillin (e.g. Alox plus from Alpine), ampicillin cloxacillin (e.g. Am()Ms from Jagsonpal, Elclox plus from Elder, Penmix plus from Dee Pharma, Pen plus from Systopic, Poxin Plus from Alpine), amoxicycillin 4- cloxacillin (e.g. flicidal plus from Kee Pharma, Piclox from Croford Pharma, Twinelox plus from Alpine). They all are simple admixture
 
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of anti-infective agents and susceptible organisms. However, analysis of commercially available, as well as prepared by us revealed that organisms incorporated into 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 he detected as early as 7 days after putting lactobacilli with various antibiotics like ampiccillin, amoxycillin, ainoxycillin cloxacillin etc. or in commercially available preparation. Though 60 million spores are pm into formulation, none of them could he grown or demonstrated viable on glucose yeast extract agar plate. It also failed to produce lactic acid as evaluated by consumption of NaOH.
 
REFERENCES
1.    Gastrointestinal tracts chapter 65 in Text Book of Medical Physiology ed. Arther C Guyton & John E.Hall
Publishers Prism Books (Pvt.) Ltd., 9th edition 1996
2.    pp. 1042 antimicrobial agents chapter 44 in the Pharmacological Basis of Therapeutics in Goodman & Gillman,
3,    PP-586 antibiotic associated colitis Chapter 14 in Current Medical Diagnosis l&
Treatment 36th edition.
4.    A,P.Ball, Chapter 7, Toxicity in antibiotic and chemotherapy seventh edition.' edit. Francis O'Gerard
5.    Betalactam therapy and intestinal flora Journal of Chemother. 1995 May; 7 suppl 1: 25-31
6.    Diarrhoea caused by antibiotic.therapy. Rev-Prat. 1996 Jan 15; 46(2): 171-6
7.    Antibiotic associated diarrhoea in light of personal observations. Pol-Tyg-Lek, 1995 Sep; 50(36): 45-9
8.    Antibiotic-induced colitis. Semin-Pediatr-Surg. 1995 Nov; (4(4): 215-20
9.    Clostridium difficile acquisition rate and its role in nosocomial diarrhoea at a university hospital in Turkey.
Eur-J-Epiderniol. 1996 Aug; 12(4);391-4 '
10.    Risk factors associated with Clostridium difficile diarrhoea in hospitalized adult patients: a case-control study---sucralfate ingestion is not a negative risk factor. Infect-Control-Hosp-Epidemiol. 1996 Apr; 17(4): 232-5
11.    Clinical comparison of cefuroxime axetil and amoxycillin/clavulanate in the treatment of patients with secondary bacterial infections of acute bronchitis.
Clinical Ther. 1995 Sep-Oct; 17 (5): 861-74
12.    Clinical comparison of cefuroxime axetil suspension and amoxycillinflavulanate suspension in the treatment of paediatric patients with acute otitis media with effusion. Clinical Titer. 1995 Sep-Oct; 17(5) : 838-51
13.    Antibiotic-associated pseudomembranous colitis: retrospective study of 48 cases diagnosed by colonoscopy.
Therapie. 1996 Jan-Feb; 51(1): 81-6
 
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14.    l3iotherapeutic agents. A neglected modality for the treatment and prevention of
selected intestinal and vaginal infections.    .
JAMA 1996 Mar 20; 275(11): 870-6
15.    The pharmacologic principles of medical practice, Krantz & Carr
16.    Prevention of beta-lactam-associated diarrhoea by saccharomyces boulardii compared with placibo.
Ain.J.Gastroenterol. 1995 Mar; 90(3): 439-48
17.    Whole-bowel irrigation as an adjunct to the treatment of chronic, relapsing Clostridium difficile colitis.
J-Clin-Gastroenterol. 1996 Apr; 22(3): 186-9
18.    Prophylaxis against ampiciilin-associated diarrhoea with a lactobacillus preparation. Amillosp.Pharrn. 1979 Jun; 36: 754-757
19.    Clostridium difficile in antibiotic associated pediatric diarrhoea. Indian Pediatr. 1994 Feb; 31(2): 121-6
20.    Side effects and consequences of frequently used antibiotics in clinical practicei Schweiz-Med-Wochenschr. 1996 Mar 30; 126(13): 528-34
 
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The objective of present invention is to combine susceptible organisms into a pharmaceutical composition containing anti-infective agents and keep them viable for the self life of the formulation or till it is consumed.
The further objective of present invention is to minimise side effects of anti-infective agent resulting from destruction/alteration of normal flo• by providing viable organisms along with anti-infective agent(s).
The further objective of present invention is to provide a pharmaceutical composition which is effective after longer period of storage.
The further objective of this present invention is to increase compliance by reduction elimination in side effects of anti-infective agents.
The further objective of the present invention is to improve compliance by providing two drugs in one pharmaceutical composition.
The further objective of present invention is to provide organism at a desired site.
. The following specification particularly describes and ascertain the nature of this invention and manner in which it is to be performed.
The anti-infective agent and organisms are to be identified. Their dosage route of
 
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The susceptible organism are combined into the formulation in such a way that organisms remain viable for the self life of a formulation inspite of being in contact with anti-infee4e agent. To protect susceptible organisms from effect of anti-infective agent a protective barrier is created around organisms or anti-infective agent, in such a way that anti-infective agent cannot have effect on organisms. This result§ in viable organisms in presence of anti-infective agent. The organism remain 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.
The protective barrier is selected depending on route of administration and dosage form of the pharmaceutical composition (anti-infective agent + organism)
The pharmaceutical composition so manufactured is evaluated for stability and efficacy.
The pharmaceutical composition so manufactured is evaluated at different telst conditions of temperature and humidity (45"C, 37"C at 80% relative humidity and ambient temperaturp) for time interval extending upto 12 months.
The.samples of formulation were taken for study at 3 weeks intervals. • Samples were analysed for presence of organisms by quantitative and qualitative microbiological techniques These values were found to he comparable with amount of organisms introduced into formulation.
 
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The samples of formulation were also analysed 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.
Thus findings indicate presence of prganism and anti-infective agent in sane amount When formulation was evaluated at different time interval after it was exposed to different environment.
The formulations so created were found to have improved therapeutic efficacy in term of reduction/elimination of antibiotic induced diarrhoea.
Usually ampicillin causes maximum diarrhoea amongst penicillin. The reported incidence is as high as 20% with atnpicillins. In 40 patients when ampicillin + lactobacilli were given in a pharmaceutical composition prepared as described in this application. none of them developed diarrhoea and everybody could complete the full course of antibiotic
therapy. The non development of diarrhoea suggests efficacy of new pharmaceutical composition prepared according to present invention.
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 ie limited by these examples.
Example I    Example II
Ampicillin    250 mgm    Ampicitlin    500 mgm
Lactobacillus    60 million    Lactobacillus    60 million
 
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Examele III        Example IV   
Amoxycillin    250 mgm    Amoxycillin    500 ingot
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
Sullamicin    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
t
Example XVII        Example XVIII   
Amoxycillin    500 mgm    Amoxycillin    500 mgm
Bromhexine    8 mgm    Carbocisteine    150 mgm
Lactobacillus    60 million    Lactobacillus    60 million
Exarnple_XIX        ExampleLKX   
Cephalexin    250 mgm    Cephalexin     500 ingin
Lactobacillus    . 60 million     Lactobacillus    60 million
Example XXI        Eita. pie XXII   
Cephalexin    250 mgm    Cephalexin    250 mgm
Bromhexine    4 mgm    Probenecid    250 mgm
Lactobacillus    60 million    Lactobacillus    60 million
 
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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.
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 presented by using an organism. The organism can be any which prevents or minimises adverse reactions of anii¬infective agents when taken at same time. For prevention of diarrhoea, pseudomembranous colitis it can be biofidobacterium, sacchormyces streptococcus thermophilus, enterococcus etc. instead of lactobacillus in above examples in their appropriate dosages,
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 1
Capsules :
i)    Organisms can be lumped together and formulated into a tablet. The tablet
coated with a barrier film. The film protected organisms are introduced into the capsule independently. Anti-infective agent is put in the capsule containing organisms protected by a barrier film. It can be vice versa.
 
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ii)    Organisms can be granulated. Granules containing organisms are coated
harrier film. Barrier film coated granules are mixed with anti-infective agent before filling them into capsules.
Exiamole II
Tablets :
i)    Layered tablets :
Organisms are coated and compressed into a layer of tablet. The other layer(s) of tablet contains anti-infective agent.
ii)    Tablet containing mixture
Granules of organisms are coated with barrier film and mixed with granuitted material of anti-infective agents and compressed into a tablet.
iii)    Coated Tablets :
Anti-infective agents are formulated into compressed tablet. They are coated'. During coating stage organisms are introduced in the coati* The coating should be capable of protecting organisms from anti-infective agents. It can he vice versa i.e. anti-infective agent is included in coating.
iv)   
Tablet with a hole is produced containinganti-infective agent. The hole of the tablet is filled with organisms. The tablet so obtained may be coated for final finishing.
 
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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 itt a same tablet. Formulated tablet can be dispersible tablet or simple tablet.
Example 111
Liquid fOrmulations :
i)    The organisms are coated with barrier film mixed with other ingredients (dry
form) of formulation including anti-infective agent.    The product is
reconstituted before use by addition of adequate amount of liquid.
ii)    The organisms are coated with harrier film and suspended in a liquid . containing anti-infective agents or vice versa. The barrier film if stable in liquid formulation but disintegrates in body due to alteration in surrounding, e.g. pH
3.    Following are examples of coating agents which can be used in making stable fixed
dose pharmaceutical composition containing anti-infective agent(si and micro organism. However, it is not intended that the scope of this invention be limited by these examples.
Chemical Name
S.    Cellulose acetate phthalate
2.    Poly(butyl methacrylate, (2-dimethyt aminoethyl)
methacrylate, methyl methacrylatel    Trade_Name
Aquateric
CAP
Cellacelate
Eudragit E 100 Eudragit 15 12.5
 
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Poly(ethyl acrylate, methyl methacrylate) 2:1    Eudragit NE 300
(formerly Eudragit 3015)
 
4.    Poly(methacrylic acid, methyl methaerylate) 1,1
Eudragit L 12.5
Puly(inethacrylic acid, ethyl acrylate) I:1
(1.    Poly(methacrylic acid, methyl melhacrylate) 1:2
Poly(ethyl acrylate, methyl methaerylate, tritnethylammonioethyl methacrylate chloride) 1.2:0.2
B.    Poly(ethyl acrylate, methyl methaerylate,
trimethylanunonioethyl =Maculate chloride) 1:2:0.1
9.    Hydrogenated Castor Oil
10.    Cetyl Alcohol
I L    Diethyl Phthalate
12,    Ethyl cellulose
13.    liydroxypropyl Cellulose
14.    Hydroxypropyl Melhylcellulose Phthalate
15.    Zein
 
Eudragit L 100 Eudragit L 12.5 P
Eudragit L 30 D-515 Eudragit L 100-55
Eudragit S 100 Eudragit S 12.5 Eudragit S 12.5 P
Eudragit RL 100 Eudragit RL PO Eudragit RL 30 D Eudragit RL 12.5
Eudragit RS 100 Eudragit RS PO Eudragit RS SO 1) Eudragit RS 12.5
Castrowax Castrowax MP FO Castrowax MP BO Opalwax
SlumIsol
Crodacol C70
Crodacol C90
Crodaced C95
Kodafley DEP Palatinol A
 
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4,    Following are examples of methods of preparing fixed dose stable pharmaceutkal
composition. However, it is not intended that the scope of this invention be limited by these examples.
Ex_umplg I - Double layered Tablet
A stable fixed ddse' Conthination 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 or 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 process known to those skilled in the art. The separate sets of granules are then compressed on double rotary tablet compression machine having a laying facility at a temperature below 25"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 film coating process known to those skilled in the art.
The relative proportion of anti infective agents and excipients to prepare coating suspension and coating anti-infective agents before granulation Ingredients    'arts by weight
Anti infective agent    77.54%
Ethyl cellulose    2.70%
Isopropyl alcohol    7.42%
Dichloromethane    12.34%
 
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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%
Colour Sunset Yellow Lake    0,45%
Purified water    0,02%
iii)    The relative proportion of excipients to be added to granules containing anti-infective agents as lubricants :
Ingredienll    Parts by weight
Sodium chloride    31.9t%
Polyplasdone XL    14.89%
Microcrystalline cellulose    21.28%
Saccharine sodium    10,64%
Flavour orange    10,64%
Magnesium stearate    5.32%
Purified Talc    5.32%
iv)    The relative proportion of micro organisms and excipients to prepare granules:
Ingredients    Parts by weight
Micro organisms    18.18%
Starch    18.18%
Microcrystalline cellulose    56.67%
Magnesium stearate    0.91%
Polyplasdone XL    3.03%
Sodium chloride    3.03%
 
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The fixed dose layered tablet composition which are prepared' through making use of above described process contain the above active ingredients aktti¬infective agents and viable organisms in their respective therapeutic concentration. The composition provide pharmacological effects which are complementary to the effects produced by (Prior art) each individual ingredient and are stable for a period of atleast 3 - 36 months at ambient molt temperature.
Example II - Capsules
A stable fixed dose combination capsules are prepared using following components of which the active ingredients are anti-infective agents and micro organisms. The remaining components are physiologically acceptable excipients. Granules of one of the active ingredients (e.g. micro organisms) are first prepared by 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 SO% by process known to those skilled in the art. Tablets are transferred to a coating pan for coating to be given by coating process known to those skilled in the art.
The remaining active ingredient is mixed with excipitnts and filled into gelatin capsules by process known to those skilled into the.art. i3efore sealing of capsules the coated tablet containing active ingredients are introduced into capsule by processes known to those skilled in the art.
 
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i)        The relative proportion of anti-infective agent and excipients for filling in
capsule :
Ingredients
Anti-infective agent Pregelatinised starch Magnesium stearate Sodium lauryl sulfate    Parts by weight
91.94% 6,24% 1.44% 0.38%

ii)    The relative proportion of micro organism and excipients to prepare granules as follows
Ingredients    Parts by weight
Micro organism    42.86%
Micro crystalline cellulose    53.93%
Magnesium stearate    1.07%
Colloidal silicone dioxide    0.71%
Cross carmellose sodium    1,43%
iii)    The relative proportion of excipientS to prepare coating suspension for coating of a tablet containing micro organisms to be kept into a capsule
Ingredients    Parts by weight
Hydroxy propyl methyl cellulose    4.37%
pthalate
Titanium dioxide    0.96%
Purified Talc    0.19%
Polyethelene glycol    0.99%
Isopropyl alcohol    34.95%
Dichloroniethane    58.54%
 
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The fixed dose capsule composition 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 composition 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 Ill - Liquid Suspension
A stable fixed dose combination liquid tablet is prepared using the following
,    o.
components of which the active ingredients are anti-infective agent(s) and tnicr) organisms. 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 processes known to those skilled in art. Granules so prepared are suspended into a liquid formulation by processes known to those skilled in the art, The ether 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 micro organisms is 20% of anti infective agent(s).
The relative proportion of anti-infective agent and excipients to prepare coated granules :
ingredients    Parts by weight
Anti infective agent    56.82%
Cellulose acetate pthalate    22.73%
Isopropyl alcohol    5.82%
Dichlorornethane    13.63%
 
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The fixed dose liquid suspension composition which is 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 composition 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 IV - Dry Powder composition to make liquid composition al'Ir reconstitution.
A stable fixed dose combination dry powder for reconstituting liquid formulation before use is prepared using the following components of which the active ingredients are acceptable excipients.
One of the active ingredients is granulated after suspending it in a coating suspension by process known to those skilled in the art. The granules so prepared are dried and inked with dry powder containing another active ingredient by processes knovn to those skilled in the art in such a way that micro organisms are 20% of anti infective agent(s) by weight.
 
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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%
The fixed dose dry powder composition 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 composition 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.
Above composition when reconstituted by adding liquid prior to use remains stable at ambient room temperature for 3 to 7 days.
5.    Following are examples of therapeutic dosage of various anti-infective agents and
micro organisms. However, it is not intended that the scope of this invention be limited by these examples.
 
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A. Anti-infective agents
Anti- infective agents can be penicillin e.g. ampicillin, amoxycillin, cloxacillin, cephalosporins e.g. cephatexin, cefadroxyl, cefuroxime axetil, eefixime, beta tactarnase inhibition like clauvanic acid - macrolide like erythromycin as single ingredient or combination thereof.
Solid dosage forms like capsules• or tablet contains anti infective agents equivalent to 125, 250 or 500 mgm of active component
Liquid dosage forms usually contains anti infective agents equivalent to 125 mgm of active component in 5 ml.
13. Micro organism which can be used for therapeutic purposes and the dosage are as under
1.    2.        Lactobacillus Aciophillus Lactobacillus Spores    10 to 100 million 30 - 60 x 10°
3.        Lactobacillus Lactis    10 - 500 million
4.        Streptococcus thermophilus    10 million
5.        Streptococcus lactis    10 million
6.        Saccrornyces cerevisea    10 million
7.        Lactobacilli GG    10"' units
 
CLAIMS
We claim :
A process to provide a stable fixed dose oral pharmaceuticals composition, composed
of anti-infective agent(s) and micro organisms as active ingredients With their different
•    -•
respective sets of properties, which when taken together as in this invention in a single composition such as a capsuleftablet/liquid preparation made accordihg to a conventional process, result in a cOmposition producing a set of effects complementary to each other, and remaining stable over a period of 3 - 36 months.
2.    A process as claimed in claim 1 to provide a stable pharmaceutical composition consisting essentially of a mixture of i) therapeutic concentration of anti-infective agent and ii) therapeutic concentration of micro organisms, admixed with physiological acceptable excipients selected in nature and amount to provide a solid/liquid oral dosage composition such as a capsule/tablet/liquid preparations with effects complementary to those provided by each separate active ingredient and which is stable for at least 36 months at ambient temperature.
3.    A process as claimed in claim 1 Sr. 2 to make a stable pharmaceutical composition wherein anti-infective agents are selected from various groups of anti-infective agents e.g. Ainpicillin, Amoxycillin, Cloxacillin from Penicillins, Clavulanic acid, Sultamicin from Beta lactamase inhibitors, Cefuroxime axetil, Cefadroxyl, Cephalexin from cepahlosporins, Erythromycin from macrolides, Ciprofloxacin from 8-aminoquinolines alone or in combination and organisms are selected from Lactobacillus aciophillus. Lactobacillus spores, Lactobacillus lactis, Streptococcus
•    theimophilus, Streptococcus lactis, Saecromyces cerevisea, Lactobacilli GG and/or in combination thereof.

 

 

 

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