Preparation of an oral pharmaceutical formulation containing...

Details Preparation of an oral pharmaceutical formulation containing... Preparation of an oral pharmaceutical formulation containing...

1998-03-23

2001-10-23

Naff, David M. (Department: 1651)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Bacteria or actinomycetales

C424S093460, C435S252900, C435S253400

Reexamination Certificate

active

06306391

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATIONS
Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
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. 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 wherein anti-infective agents and susceptible viable organisms are combined in that micro organisms, though susceptible to anti-infective agent, remain viable for the shelf life of a formulation or until 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.
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 are also known as infectious agents. Commonsals are normally present in various parts of the body and perform useful functions. They provide vitamin K, B-12, Thiamine, Riboflavin etc. to the body.
1
They inhibit the growth of pathogens by variety of mechanisms.
2
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 commonsals.
2
Destruction or reduction in the number of commonsals results in loss of function of commonsals and various effects of these are seen.
2,5
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.
3,4,6
Diarrhoea is seen as an adverse reaction to many antibiotics, but it is most commonly seen with broad spectrum antibiotics. The incidence of diarrhoea also depends on level of absorption from G.I. It is less frequent with those getting completely absorbed compared to incompletely absorbed. It also depend on the amount of drug used. The antibiotics causing diarrhoea 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.
3,5,6,7,8,9,10,11,12,13,14,15,16,18
Diarrhoea 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 kind 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 diarrhoea prolongs-treatment and increases the cost of therapy by increased number of
1
drugs to be used,
2
days of hospitalisation and
3
consultations. Sometimes it creates a life threatening situation e.g. pseudememberous colitis,
4,13,20
toxic megacolon.
The organisms named above can be used to treat diarrhoea when it occurs. They can also be used to prevent diarrhoea.
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 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), 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 trom 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 be detected as early as 7 days after putting lactobacilli with various antibiotics like ampicillin, amoxycillin, amoxycillin+cloxacillin etc. or in 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
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 & 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. May 1995; 7 suppl 1: 25-31
6. Diarrhoea caused by antibiotic therapy. Rev-Prat. Jan. 15, 1996; 46(2): 171-6
7. Antibiotic associated diarrhoea in light of personal observations. Pol-Tyg-Lek. September 1995; 50(36): 45-9
8. Antibiotic-induced colitis. Semin-Pediatr-Surg. November 1995; (4(4): 215-20
9. Clostridium difficile acquisition rate and its role in nosocomial diarrhoea at a university hospital in Turkey. Eur-J-Epidemiol. August 1996; 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. April 1996; 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. September-October 1995; 17 (5): 861-74
12. Clinical comparison of cefuroxime axetil suspension and amoxycillin/lavulanate suspension in the treatment of paediatric patients with acute otitis media with effusion. Clinical Ther. September-October 1995; 17(5): 838-51
13. Antibiotic-associated pseudomembranous colitis: retrospective study of 48 cases diagnosed by colonoscopy. Therapie. January-February 1996; 51(1): 81-6
14. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA Mar. 20, 1996; 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. Am.J.Gastroenterol. March 1995; 90(3): 439-48
17. Whole-bowel irrigation as an adjunct to the treatment of chronic, relapsing Clostridium difficile colitis. J-Clin-Gastroenterol. April 1996; 22(3): 186-9
18. Prophylaxis against ampicillin-associated diarrhoea with

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