GB2323532A - Pharmaceutical compositions containing an anti-infective agent and a micro-organsim as active ingredients - Google Patents

Pharmaceutical compositions containing an anti-infective agent and a micro-organsim as active ingredients Download PDF

Info

Publication number
GB2323532A
GB2323532A GB9806172A GB9806172A GB2323532A GB 2323532 A GB2323532 A GB 2323532A GB 9806172 A GB9806172 A GB 9806172A GB 9806172 A GB9806172 A GB 9806172A GB 2323532 A GB2323532 A GB 2323532A
Authority
GB
United Kingdom
Prior art keywords
infective agent
infective
tablet
coated
active ingredients
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB9806172A
Other versions
GB9806172D0 (en
GB2323532B (en
Inventor
Bakulesh Mafatlal Khamar
Rajiv Indravadan Modi
Yatish Kumar Bansal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to GB9806172A priority Critical patent/GB2323532B/en
Publication of GB9806172D0 publication Critical patent/GB9806172D0/en
Publication of GB2323532A publication Critical patent/GB2323532A/en
Application granted granted Critical
Publication of GB2323532B publication Critical patent/GB2323532B/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/062—Ascomycota
    • A61K36/064—Saccharomycetales, e.g. baker's yeast
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Dispersion Chemistry (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the process of preparing a stable fixed dose composition of anti-infective agent with micro organism as active ingredients. The process includes preparation of various dosage forms for oral route like capsule, tablet and liquid formulation. The process comprises 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 agetns. This results in a stable composition. The ratio of micro organism to anti-infective agents in a composition can be 1:2 to 1:25 by weight. 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 compositions eliminate gastro intestinal disturbances associated with anti-infective agents. The anti-infective agent may be ampicillin, amoxycillin, cloxacillin cephalexin, cefuroxime or cefixime and the micro organism is preferably a Lacto bacillus.

Description

The present invention relates to a process of manufacturing a formulation containing antiinfective 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-intective 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 formulation and/or till they are consumed. Susceptible organisms are usually combined with antiinfective agents to prevent or minimise adverse elects 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 body and perform useful functions. They provide vitamin K, B-12, Thiamine, Riboflavin etc. to body. They iiihibit 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 @@@ patl0ogens and also kill commonsals. Destruction or reduction in number of commonsals results ill 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 antiinfective therapy. Diarrhoea with or without super-infection is one of such effecis seen with anti-infective therapy.3.4.6 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.I. tract. They are less frequent with those getting completely absorbed compared to incompletely absorbed. They also depend on anlount of drug used. The antibiotics causing diarrhoea include clindamycin, ampicillin, amoxycillin, cephalosporins (e.g. cefuroxime axetil, cefixime, cepahiexin ceftriaxone), amoxycillin + clauvanic acid, ampicillin + salbeutam, fluoroquinolens and other combinations of broad spectrum antibiotics, e.g. amoxycillin + cloxacillin. 3.5.6.7.8.9.10.11.12.13.16.18 Diarrhoea can be benign and secondary to transient dysfunction of normal colonic flora due to anti-infective agents6 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 therapy3.7.4 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.'7 Organisms used9 eradicate or help in eradicating pathogens by variety of mechanisms which include production of hydrogen peroxide or inhibition or adherence of pathogens to intestinal cells. Anti-infective agents induced diarrhoea prolong treatment, increase cost of therapy by increased number of' drugs to be used.2 days of hospitalisation and 3consultations.
Sometimes they create life threatening situation e.g. pseudememberous colitis,4.13.20 toxic megacolon.
The organisms named above can be used 10 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 à patient.
Attempts have been made to put organisms and an anti-infective agents into one formulation.
Some of these ore commercially available. Lactobacillus is commonly used organism. Antiinfective 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 simple admixture of anti-infective agents and susceptible organisms. Ilowever, analysis of' cononoercially 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. Through 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 ill Current Medical Diagnosis & Treatment 36th edition.
4. A.P.Ball, Chapter 7, Toxicity in antibiotics 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 antibiotics therapy.
Rev-Prat. 1996 Jan 15; 46(2): 171-6 7. Antibiotic associated diarrhoea in light ol' 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-Epidemiol. 1996 Aug; 12(4): 391-4 10. Risk tractors 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 amoxycillin/lavulanate suspension in tloe treatment of paediatric patients with acute otitis media with effusion.
Clinical Ther. 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 14. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections.
JAMA 1996 Mar20; 275(11): 870-6 15. The pharmacologic principles of medical practice, Krantz & Carr 16. Prevention of beta-lactam-associated diarrhoea by saccllaromyces boulardii compared with placibo.
Am.J.Gastroenterol. 1995 IvIar; 90(3): 439-48 17. Whole-bowel irrigation as 110 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.
Am.J.Hosp.Pharm. 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 lo combine susceptible organisms into a pharmaceutical composition containing anti-infective agents and keep the 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 agents resulting from destruction/alteration of normal flora by provising 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 turther 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 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 administration and dosage fornl is finalised.
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-infective agent. To protect susceptible organisms from effect of anti-infective agent a protective barrier is created around organisins or anti-infective agent, in such a way that anti-infective agent cannot have effect on oräanisnos. This results in viable organisms in presence of antiinfective 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 ot' 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 (45"C, 37"C at 80% relative humidity and ambient temperature) 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 be comparable with amount of organisms introduced into formulation.
The samples ol formulation were also analysed for presence of anti-infective agent by quantitative estimation. The values of anti-infective agents forms wwere found to be comparable to those introduced into the formulation.
Thus findings indicate presence of organism and anti-infective agent in same amount when formulation was evaluated at different time interval after it was exposed to different environment.
The formulations so created were wound 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 ampicillins. 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. Flowever, 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 111 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 Cefuroxine 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 reaction of antiinfective agents alien taken at same time. For prevention ol' 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.
1-lowever, 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) Organisnis can be granulated. Granules colOtaining organisnis iu-e coated barrier film. Barrier film coated granules are mixed with anti-infective agent before filling them into capsules.
Example II Tablets i) Layered tablets Orgtnisms 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 granulated 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 coating. Tlie 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. iv) Tablet with a hole is produced containing anti-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 Inoisture content is controlled and physical separation is maintained in a same tablet. Formulated tablet can be dispersible tablet or simple tablet.
Example III 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 arc coated with barrier film and suspended in a liquid containing anti-infective agents or vice versa. Tlie barrier film is 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 micro organism. Ilowever, 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 : 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) 1.2:0.2 Eudragit RL PO Eudragit RL 3Ú D Eudragit RL 12.5 8. Poly(ethyl acrylate, methyl methacrylate. Eudragit RS 100 trimethylammonioethl methacrylate chloride) 1.2:0.1 Eudragit RS PO 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 II. Diethyl Phihalaic Kodatlex DEP Palatinol A 12. Ethyl cellulose Aquacoat Ethocel Surelease 13. Hydroxypropyl Cellulose Klucel Methocel Nisso HPC 14. Hydroxypropyl Methylcellulose Phthalate -15. Zem - 4. Following are examples of methods of preparing fixed dose stable pharmaceutical composition. However, it is not intended that the scope of this invention be limited by these examples.
Example I - Double layered Tablet A stable fixed dose combination Itycied lablet 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 exc ipients. One of the active ingredients is coated in a coating pan by the coating process known to those skilled in the all. Excipients i IC ll.o used along with one of tile 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. 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% Dichioromethane 12.34% 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 Illureslients 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% iv) The relative proportion of micro organisms and excipients to prepare granules: Ineredients 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% The fixed dose layered tablet composition which are prepared through making use of above described process contain the above active ingredients anti infective agents and viable o%'anisms in their respective therapeutic concentration. The composition provide pharmacological effects which are complementary to the effects produced by (Prior art) each individual ingredient and ure stable for a period of atleast 3 - 36 months at ambient room 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 ploysiologically 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 compresse@ 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 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.
Tile remaining active ingredient is mixed with excipients and filled into gelatin capsules by process known to those skillucl into the art. Be lore sealing of capsules the coated tablet containing active ingredients are introduced into capsule by processes known to those skilled in the art. i) The relative proportion of anti-infective agent 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% ii) The relative proportion of micro organism and excipients to prepare granules as follows : Ingredients~ Parts bv 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 table 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% Dichloromethane 58.54% The fixed dose capsule composition which are prepared through making use of above described process contain tlie 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 III - Liquid Suspension A stable fixed dose combination liquid tablet is prepared using the following components of which the active ingredients are a The fixed dose liquid suspension composition whicli is prepared through making use of above described process coiotaiio 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 temperltule 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 mixed with dry powder containing another active ingredient by processes known to thoSe skilled in the art in such a way that micro organisms are 20% of anti infective agent(s) by weight.
The relative proportion tot' anti infective agents and the excipients to prepare coated granules is as follows Ingredients Parts bv weight Anti infective agent(s) 50% Hydroxy propyl methyl cellulose 45% K-15 M (1,00,000 cps) Purified water 5% Tlle fixed dose dry powdcr composition wliich 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 elTect 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.
Following are examples of therapeutic dosage of various anti-infective agents and micro organisms. However, it is not inteioded that the scope of this invention be limited by these examples.
A. Anti-infective agents Anti infective agents can be penicillins e.g. ampicillin, amoxycillin, cloxacillin, cephalosporins e.g. cephalexin, cefadroxyl, cefurocime axetil, cefixime, beta lactamase inhibition like clauvanic ncid - macrolide like erythromycin as single ingredient or combination tllereof. i. Solid dosage forms like capsules or tablet contains anti infective agents 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. Micro organism 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 106 3. Lactobacillus Lclctis 10 - 500 million 4. Streptococcus thermophilus 10 million 5. Streptococcus lactis 10 million 6. Saccromyces cerevisea 10 million 7. Lactobctcilli GG 10"' units

Claims (17)

We claiiii
1. A process to provide a stable fixed dose oral pharmaceuticals composition, composed of anti-infective agents and micro organislns 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 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 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 io those provided by each separate active ingredient and which is stable for a t least 36 months at ambient temperature.
3. A process as claimed in claim 1 & 2 to make a stable pharmaceutical composition wherein anti-infective agents are selected from various groups of anti-infective agents e.g. Ampicillin, Anaoxycillin, Cloxacillin from Penicillins, Clavulanic acid, Sulfamicin from Beta lactamase inhibitors, Cefuroxime axetil, Cefadroxyl, Cephalexin from cepahlosporins, Erythromycin from macrolides, Ciprotloxacin from 8-aminoquinolines alone or in combination and organisms are selected from Lactobacillus aciophillus. Lactobacillus spores, Lactobacillus lactis, Streptococcus thermophilus, Streptococcus lactis. Saccromyces cerevisea, Lactobacilli GG and/or in combination thereof
4. A process as claimed in claims 1 - 3 to provide a stable pharmaceutical composition wherein the ratio of Anti-infective agent to organism is in the range of 2:1 to 25:1 and preferably in the range of 5:1.
5. A process as claimed in claims 1 - 4 wlticlt process comprises admixing separately anti-infective agent and organism with physiologically acceptable excipients to provide granules, of which at least one is coated, said granules being subsequently compressed into cl layered tablet using a double rotary compression under strict environmental conditions of temperature below 25"C and relative Iiumidity not more than 50%.
6. A process as claimed in claims 1 - 5 one of tile active ingredients comprising the provision ol' the coated anti-infective agent of about 77.54% is coated by suspending coating in a suspension containing about 2.7% of ethyl cellulose dissolved in about
7.42% of isopropyl alcohol and about 12.34% of dichlormethane.
7. A process as claimed in claims t - 5 comprising the provision of granules of coated anti infective agents as claimed in claim 6 admixed with physiologically acceptable exelpient by using a mixture of about 64.08% of anti infective agent about 26.45% of microcrystalline cellulose about 9.0% of starch, about 0.45% of colour sunset yellow lake of about 0.02% of purified water by wight of said mixture, said granules beilog subsequently compressed with granules of micro orgc'tnisms into a layered tablet.
8. A process as claimed in clalnos 1 - 5 comprising the provision of granules of organism admixed with physiologically acceptable salts by using a mixture of about
18.18% of micro organisms, about 18.18% of starch, about 56.67% of microcrystalline cellulose, about 91% of magnesium stearate, about 3.03% of polyplasdone XL and 3.03% of sodium chloride by weight of the mixture, said granules being subsequently compressed with the coated granules of anti-infective agent into a layered tablet.
9. A process as claimed in claim 1 - 4 wherein one of the active ingredients is compressed into a tablet and coated, said coated tablet is put into a capsule containing another active ingredient.
10. A process as claimed in claim 1 - 4 and 9 comprising the provision of a tablet micro organism admixed with physiologically acceptable excipients by using a mixture of about 42.86% of micro organisms, about 53.93% of microcrystalline cellulose, about
1.07% of magnesium stearate, about 10.71% of colloidal silicone dioxide, about
1.43% of cross carmellose sodiullo by weight of said mixture.
11. A process as claimed in claim 1 - 4 and 9 comprising the provision of coating of the tablet is carried out by using a coating suspension comprising about 4.31% of hydroxy propyl methyl cellulose pthalate, about 0.96% of Titanium dioxide, about 0.19% of purified talk, about 0.91% % of poyethelene glycol, about 4.95% of isopropyl alcohol, about 58.54% dichloro methane by weight of suspension.
12. A process as claimed in claim 1 - 4 and 9 comprising the provision anti-infective agents admixed with physiologically acceptable excipients by using a mixture of about
91.94% of anti-infective agent, about 6.24% of pregelatinised starch, about 1.44% of magnesium stearate, about 0.38% of sodium lauryl sulfate by weight of said mixture which is subsequently filled into capsules.
13. A process as claimed in claim 1 - 4 wherein one of the active ingredients is coated and suspended into a solution containing another active ingredient.
14. A process as claimed in claim 1 - 4 and claim 13 comprising of coating of anti infective agent in which coating of about 56.82% of anti-infective agent is carried out by using a coating suspension comprising about 22.73% of cellulose acetate pthalate, about 6.82% of isopropyl alcohol, about 13.63% of dichloromethane by weight, said coated anti-infective agent is suspended in liquid.
15. A process ts Cl;lilllCd ill claim I - 4 and claim 14 COllll)liSilIg the provision of coated anti-infective agent in wliich coating of about 50% of anti-infective agent is carried out by using a coating suspension comprising about 45% of hydroxy propyl methyl cellulose K-15M (1,00,000 cps), about 5% of purified water by weight of said mixture.
16. A process as claimed in claim 1 - 4 wherein liquid preparation having shorter self life has to be dispensed in dry form, said dry form comprising the said two active ingredients wherein one of them is coated and kept in such a way so that when reconstituted it forms a suspension which is stable for 3 to 7 days at ambient temperature.
17. A process for preparation of a stable fixed dose pharmaceutical composition of anti infective agent/agents and micro organism as active ingredients as claimed in claim 1 and subsequehtly herein described in examples 1 to 5 in the accompanying complete specification.
GB9806172A 1997-03-27 1998-03-24 Process for the preparation of a stable fixed dose pharmaceutical composition of anti-infective agent(s) and micro organisms as active ingredients Expired - Fee Related GB2323532B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB9806172A GB2323532B (en) 1997-03-27 1998-03-24 Process for the preparation of a stable fixed dose pharmaceutical composition of anti-infective agent(s) and micro organisms as active ingredients

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN174DE1997 1997-03-27
GB9806172A GB2323532B (en) 1997-03-27 1998-03-24 Process for the preparation of a stable fixed dose pharmaceutical composition of anti-infective agent(s) and micro organisms as active ingredients

Publications (3)

Publication Number Publication Date
GB9806172D0 GB9806172D0 (en) 1998-05-20
GB2323532A true GB2323532A (en) 1998-09-30
GB2323532B GB2323532B (en) 2001-08-22

Family

ID=26313336

Family Applications (1)

Application Number Title Priority Date Filing Date
GB9806172A Expired - Fee Related GB2323532B (en) 1997-03-27 1998-03-24 Process for the preparation of a stable fixed dose pharmaceutical composition of anti-infective agent(s) and micro organisms as active ingredients

Country Status (1)

Country Link
GB (1) GB2323532B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1121940A1 (en) * 2000-01-31 2001-08-08 New Pharma Research Sweden AB Pharmaceutical compositions comprising an antibiotic and bromhexine, and process for their preparation
WO2005063200A2 (en) * 2003-12-24 2005-07-14 Ferrosan A/S Probiotic tablet formulations
EP1744767A2 (en) * 2004-04-20 2007-01-24 The University of Chicago Therapeutic delivery system comprising a high molecular weight peg-like compound
WO2013001541A1 (en) * 2011-06-30 2013-01-03 Aggarwal Kumar Vijay An optimized bilayered tablet dosage form with high rate of bioavailability of two active antibiotics: cefuroxime and clavulanic acid

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306465A1 (en) * 1987-08-31 1989-03-08 Nicasystem Aktiebolag Granular product (III)
WO1996040179A1 (en) * 1995-06-07 1996-12-19 Biogaia Biologics Ab Method of improving animal health

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3658883B2 (en) * 1996-09-06 2005-06-08 株式会社ニコン Lens barrel and its mounting member

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306465A1 (en) * 1987-08-31 1989-03-08 Nicasystem Aktiebolag Granular product (III)
WO1996040179A1 (en) * 1995-06-07 1996-12-19 Biogaia Biologics Ab Method of improving animal health

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Abstract of JP 53052612 A (Biofermin Pharm. Co.) *
Abstracts of JP 01083025 A (F. Hayashi) *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1121940A1 (en) * 2000-01-31 2001-08-08 New Pharma Research Sweden AB Pharmaceutical compositions comprising an antibiotic and bromhexine, and process for their preparation
WO2001056610A1 (en) * 2000-01-31 2001-08-09 New Pharma Research Sweden Ab Stabilised pharmaceutical compositions and process for their preparation comprising an antibiotic and an expectorant
WO2005063200A2 (en) * 2003-12-24 2005-07-14 Ferrosan A/S Probiotic tablet formulations
WO2005063200A3 (en) * 2003-12-24 2005-11-24 Ferrosan As Probiotic tablet formulations
EA011321B1 (en) * 2003-12-24 2009-02-27 Ферросан А/С Probiotic tablet
AU2004308632B2 (en) * 2003-12-24 2010-07-01 Ferrosan Aps Probiotic tablet formulations
NO340908B1 (en) * 2003-12-24 2017-07-10 Ferrosan As Probiotic tablet formulations
US10172793B2 (en) 2003-12-24 2019-01-08 Ferrosan A.S. Probiotic tablet formulations
EP1744767A2 (en) * 2004-04-20 2007-01-24 The University of Chicago Therapeutic delivery system comprising a high molecular weight peg-like compound
JP2007533755A (en) * 2004-04-20 2007-11-22 ザ ユニヴァーシティ オヴ シカゴ Therapeutic drug delivery system comprising high molecular weight PEG-like compounds
EP1744767A4 (en) * 2004-04-20 2008-08-13 Univ Chicago Therapeutic delivery system comprising a high molecular weight peg-like compound
WO2013001541A1 (en) * 2011-06-30 2013-01-03 Aggarwal Kumar Vijay An optimized bilayered tablet dosage form with high rate of bioavailability of two active antibiotics: cefuroxime and clavulanic acid

Also Published As

Publication number Publication date
GB9806172D0 (en) 1998-05-20
GB2323532B (en) 2001-08-22

Similar Documents

Publication Publication Date Title
RU2681315C2 (en) Formulations for oral delivery of adsorbents in intestine
US6306391B1 (en) Preparation of an oral pharmaceutical formulation containing an anti-infective agent and a microorganism
US9649348B2 (en) Compositions and method for treatment and prophylaxis of inflammatory bowel disease
US20160206564A1 (en) Compositions and methods for treatment and prophylaxis of gastrointestinal diseases
JP2019520340A5 (en)
JPS601128A (en) Long-acting cefaclor preparation
GB2189698A (en) Coated omeprazole tablets
MX2010011995A (en) Methods and kits for the treatment of inflammatory bowel disorder conditions.
US20120058936A1 (en) Compositions and methods for elimination of gram negative bacteria
AU2018300075B2 (en) Dual release dosage form capsule and methods, devices and systems for making same
EP3579863A1 (en) Compositions and methods for treating or preventing environmental enteropathy
JP2023546793A (en) Direct delivery of vitamins to inhibit microbial pathogens
US20150202238A1 (en) Compositions and method for treatment and prophylaxis of inflammatory bowel disease
AU770024B2 (en) The process for the preparation of a stable fixed dose pharmaceutical composition of anti infective agent/agents and micro organisms as active ingredients
GB2323532A (en) Pharmaceutical compositions containing an anti-infective agent and a micro-organsim as active ingredients
KR100581967B1 (en) Double pellet formulation of proton pump inhibitors and clarithromycin for the treatment of gastrointestinal ulcer, and method for producing the same
US20020025309A1 (en) Stable oral pharmaceutical formulation containing an anti-infective agent and a microorganism
US20100016333A1 (en) Once-a-day (RNA-Polymerase Inhibiting or phenazine) - dihydropteroate synthase inhibiting - dihydrofolate reductase inhibiting antibiotic pharmaceutical product, formulation thereof, and use thereof in treating infection caused by Methicillin-Resistant Staphylococcus aureus
KR20230097085A (en) Direct delivery of vitamins to rebalance the gut microbiome after exposure to antibiotics
US20100120896A1 (en) Once-A-Day RNA-Polymerase inhibiting and elongation factor G (EF-G) inhibiting antibiotic pharmaceutical product, formulation thereof, and use thereof in treating infection caused by methicillin-resistant staphylococcus aureus
CA3103064A1 (en) Dosage form comprising a live biotherapeutic product
US20230233515A1 (en) Photodynamic anti-gram-positive bacterial activity of pharmaceutical-grade rose bengal
EP2678015B1 (en) Use of nifuratel to treat infections caused by clostridium species
Ouwehand et al. Probiotics resistant to antibiotics
CANANI et al. the evidence for gastroenterology clinical practice in adults and children

Legal Events

Date Code Title Description
732E Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977)
PCNP Patent ceased through non-payment of renewal fee

Effective date: 20110324