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(11) Patent Number: KE 144
(45) Date of grant: 14/03/2002
(12) PATENT
 
(51) Int.CI.A: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) Microorganisms are useful in management of diseases including diarrhea and gastro intestinal diseases like pseudomembranous colitis, mega-colon etc. They are also useful in prevention of gastro intestinal disturbances and diseases caused by anti-infective agents like ampicillin, amoxicillin, cloxacillin, clauvanic acid, cefuroxime axetel, cephalixin, erythromycin etc. For prevention microorganisms are to be taken along with anti-infective agents. When microorganisms are combined with anti-infective agents for ease of administration and improving compliance and therapeutic effect, the combination is not found to be stable at room temperature as microorganisms are sensitive to anti-infective agents and are destroyed by effect of anti-infective agent in composition. The present invention relates to the process of preparing a stable fixed dose composition of anti-infective agent with microorganism as active ingredient. The process includes preparation of various dosage forms for oral route like capsule, tablet and liquid formulation. The process comprises of providing an appropriate barrier by way of selected coating procedure to one of the active ingredients in such a way that microorganisms are not affected by anti-infective agents. This results in a stable composition. By using an appropriate coating technique composition is made to remain stable over a period of 3-36 months at ambient/room temperature. The ratio of microorganism to anti-infective agents in a composition can be 1:2 to 1:25 by weight. The ratio of 1:5 by weight is found to be optimal for the purpose. The amount of coating is dependent on the type of coating technique, dosage form i.e. capsule, tablet or liquid and desired self-life. The microorganisms 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 INGREDIENTS.
The present invention relates to a process of manufacturing a formulation containing ant 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.
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 microorganisms, through susceptible to anti-infective agent, remain viable for the self-life of a formulation and/or till 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.
 
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. Commonsats 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. Diarrhea with or without super-infection is one of such effects seen with anti-infective therapy,' .6 Diarrhea is seen as an adverse reaction to many antibiotics. But they are most commonly seen with broad spectrum antibiotics. The incidence of diarrhea 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 diarrhea include clindamycin, ampicillin, amoxicillin, cephalosporin’s (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•" Diarrhea 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 nominal 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, 3iticoplanin and/or use of organisms like lactobacilli, hiofidobacterium, saccharomyces 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 halogens to intestinal cells. Anti-infective agents induced diarrheaprolong treatment, increase cost of therapy by increased number of drugs to be 'used,' dais of hospitalization and 'consultations.
Sometimes they create life threatening situation e.g. pseudememberous colitis,""."' toxic mega colon.
The organisms named above can be used to treat diarrhea when it occurs. They can also be used to prevent diarrhea. Commercially available preparations include lactobacillus alone (Lactiflora, Lactobacilli, 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 ampicillin. (E.g. Alcillin plus from Alpine), amoxicillin (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 4- cloxacillin (e.g. flicidal plus from Kee Pharma, Piclox from Croford Pharma, Twinelox plus from Alpine). They all are simple admixture 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 ampicillin, 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.Hal Publishers Prism Books (Pvt.) Ltd., 9th edition 1996

2. pp. 1042 antimicrobial agent’s 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. Beta lactam therapy and intestinal flora Journal of Chemother. 1995 May; 7 supply 1: 25-31
6. Diarrhoea caused by antibiotic. Therapy. Rev-Part. 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-Pediatric-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 Epidemiologic. 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. Therapies. 1996 Jan-Feb; 51(1): 81-6
 
14. Biotherapeutic 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 place. 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 ampicillin-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 practice Schweiz-Med-Wochenschr. 1996 Mar 30; 126(13): 528-34
 
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 minimize side effects of anti-infective agent resulting from destruction/alteration of normal flow 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 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 test conditions of temperature and humidity (45OC, 37OC at 80% relative humidity and ambient temperature) for time interval extending up to 12 months.
The samples of formulation were taken for study at 3 weeks intervals. Samples were analyzed for presence of organisms by quantitative and qualitative microbiological techniques these values were found to the comparable with amount of organisms introduced into formulation.
 
The samples of formulation were also analyzed for presence of anti-infective agent by quantitative estimation. The values of anti-infective agent’s forms were found to! Be comparable to those introduced into the formulation.
Thus findings indicate presence of organism 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 lactobacilli’. 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     Ampicillin    500 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.
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 minimizes adverse reactions of anti-infective agents when taken at same time. For prevention of diarrhoea, pseudomembranous colitis it can be biofidobacterium, saccharomyces streptococcus thermophiles, 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.
 
(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.
Example 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 granulite 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.
 
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 it 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(s) and microorganism. However, it is not intended that the scope of this invention be limited by these examples.
Chemical Name
1. Cellulose acetate phthalate
2. Poly (butyl methacrylate, (2-dimethyt amino ethyl)
methacrylate, methyl methacrylate    Trade Name
Aquateric
 

The fixed dose layered tablet composition which are prepared' through making use of above described process contain the above active ingredients ant 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 at least 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 microorganisms. 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 excipients and filled into gelatin capsules by process known to those skilled into the art. Before sealing of capsules the coated tablet containing active ingredients are introduced into capsule by processes known to those skilled in the art.
  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 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 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 microorganisms 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 phthalate    22.73%
Isopropyl alcohol                                         5.82%
Dichloromethane                                         13.63%
 
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 after 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 known to those skilled in the art in such a way that microorganisms are 20% of anti-infective agent(s) by weight.
 
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
microorganisms. However, it is not intended that the scope of this invention be limited by these examples.
 
A. Anti-infective agents
Anti- infective agents can be penicillin e.g. ampicillin, amoxycillin, cloxacillin, cephalosporin’s e.g. cephalexin, cefadroxyl, cefuroxime axetil, cefixime, beta tactarnase inhibition like clauvanic acid - macrolide like erythromycin as single ingredient or combination thereof.

i. Solid dosage forms like capsules or tablet contains anti-infectiveagent’s equivalent to 125, 250 or 500 mgm of active component
ii. Liquid dosage forms usually contains anti-infective agents equivalent to 125 mgm of active component in 5 ml.
B. Microorganism which can be used for therapeutic purposes and the dosage are as under
1.     Lactobacillus Aciophillus 10 to 100 million
2.Lactobacillus Spores   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 microorganisms as active ingredients With their differen
respective sets of properties, which when taken together as in this invention in a single composition such as a capsule tablet/liquid preparation made according 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 microorganisms, 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 Penicillin’s, Clavulanic acid, Sultamicin from Beta lactamase inhibitors, Cefuroxime axetil, Cefadroxyl, Cephalexin from cephalosporin’s, Erythromycin from macrolides, Ciprofloxacin from 8-aminoquinolines alone or in combination and organisms are selected from Lactobacillus acidophilus. Lactobacillus spores, Lactobacillus lactis, Streptococcus
theimophilus, Streptococcus lactis, Saecromyces cerevisea, Lactobacilli GG and/or in combination thereof.

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