AU770024B2 - The process for the preparation of a stable fixed dose pharmaceutical composition of anti infective agent/agents and micro organisms as active ingredients - Google Patents
The process for the preparation of a stable fixed dose pharmaceutical composition of anti infective agent/agents and micro organisms as active ingredients Download PDFInfo
- Publication number
- AU770024B2 AU770024B2 AU64156/98A AU6415698A AU770024B2 AU 770024 B2 AU770024 B2 AU 770024B2 AU 64156/98 A AU64156/98 A AU 64156/98A AU 6415698 A AU6415698 A AU 6415698A AU 770024 B2 AU770024 B2 AU 770024B2
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- Australia
- Prior art keywords
- infective agent
- micro
- organism
- granules
- organisms
- 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.)
- Ceased
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- DDTDNCYHLGRFBM-YZEKDTGTSA-N chembl2367892 Chemical compound CC(=O)N[C@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1O[C@@H]([C@H]1C(N[C@@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(O)C=C(C=4)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@H](CC=4C=C(Cl)C(O5)=CC=4)C(=O)N3)C(=O)N1)C(O)=O)=O)C(C=C1Cl)=CC=C1OC1=C(O[C@H]3[C@H]([C@@H](O)[C@H](O)[C@H](CO)O3)NC(C)=O)C5=CC2=C1 DDTDNCYHLGRFBM-YZEKDTGTSA-N 0.000 description 1
- MYPYJXKWCTUITO-KIIOPKALSA-N chembl3301825 Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)C(O)[C@H](C)O1 MYPYJXKWCTUITO-KIIOPKALSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940090805 clavulanate Drugs 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 238000002052 colonoscopy Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000000214 effect on organisms Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 208000004840 megacolon Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229960002181 saccharomyces boulardii Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960004291 sucralfate Drugs 0.000 description 1
- 229960001608 teicoplanin Drugs 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 201000002516 toxic megacolon Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- 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
- 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
- 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
- A61K9/20—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
- A61K9/48—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- Animal Behavior & Ethology (AREA)
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- Oncology (AREA)
- Communicable Diseases (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
WO 99/49875 PCT/IB98/00445
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 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-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 formulation and/or till they are consumed. Susceptible organisms are usually combined with antiinfective agents to prevent or minimise adverse effects of anti-infective agents like diarrhoea, pseudomembranous colitis, mega colon, etc.
SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 Organisms are classified as pathogens and commonsals. Pathogens are responsible for various infectious diseases and are not rmally 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 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 number of commonsals results in loss of function of commonsals and various effects of these are seen.
2 s' These effects are known as adverse effects or side effects of antiinfective 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 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 amount of drug used. The antibiotics causing diarrhoea include clindamycin. ampicillin. amoxycillin.
cephalosporins cefuroxime axetil, cefixime. cepahlexin ceftriaxone), amoxycillin clauvanic acid. ampicillin salbcutam, fluoroquinolens and other combinations of broad spectrum antibiotics, e.g. amoxycillin cloxacillin. Diarrhoea can be benign and secondary to transient dysfunction of normal colonic flora due to anti-infective agents' or super-infection by pathogens like clostridium difficile following alteration of normal flora by anti-ineffective agents.7.
4 l v 2' Management in such an.event requires cessation of anti-infective therapy' 7 and use of other therapies. Other therapies which can be used include different kind of anti-infective agents e.g. metronidazole. vancomycin. 13 teicoplanin and/or use of organisms like lactobacilli. biofidobacterium.
SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 3 saccharomyies boulardili. streptococcus thermophilus, enterococcus facecium SF68. L Casei GG etc.'4!5"16 These can be combined with whole bowel irrigation with good results.
1 7 Organisms used' 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 3 consultations.
Sometimes they create life threatening situation e.g. pseudememberous colitis,4.1 3 2 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. Antiinfective agents used in the formulation include ampicillin. Alcillin plus from Alpine), amoxicycillin Alox plus from Alpine), ampicillin cloxacillin Amplus from Jagsonpal, Elclox plus from Elder. Penmix plus from Dee Pharma. Pen plus from Systopic.
Poxin Plus from Alpine). amoxicycillin cloxacillin Bicidal plus from Kee Pharma, Diclox from Croford Pharma. Twinclox plus from Alpine). They all are simple admixture SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 4 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.
SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445
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 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; 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 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: 17 861-74 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. 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 SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 6 14. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections.
JAMA 1996 Mar 20: 275(1):.870-6 The pharmacologic principles of medical practice, Krantz Cart 16. Prevention of beta-lactam-associated diarrhoea by saccharomyces boulardii compared with placibo.
Am.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.
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 Side effects and consequences of frequently used antibiotics in clinical practice.
Schweiz-Med-Wochenschr. 1996 Mar 30; 126(13): 528-34 SUBSTITUTE SHEET (RULE 26) The object of present invention is to provide a process which enables susceptible organisms to be combined into a pharmaceutical composition containing anti-infective agents and keep them viable for a period of at least 3 months.
In accordance with a first aspect of the present invention there is disclosed a process to provide a stable fixed dose oral pharmaceutical formulation comprising at least one anti-infective agent as a first active ingredient and at least one micro-organism susceptible to said anti-infective agent as a second active ingredient, the process comprising a step of coating at least one of the first and second active ingredients to provide a protective barrier around the active ingredient, and thereafter a step of combining the active ingredients into a single pharmaceutical formulation selected from the group consisting of a tablet and a capsule wherein said tablet or capsule contains both said anti-infective agent and said micro-organism, the protective barrier protects the susceptible micro-organism from the effect of the anti-infective agent to maintain the susceptible micro-organism in a viable form for a period of at least three months, said anti-infective agent is selected from the group consisting of Ampicillin, Amoxycillin, Cloxacillin, Clavulanic acid, Sultamicin, Cefuroxime axetil, Cefadroxyl, Cephalexin, Cefixime, Erythromycin, Ciprofloxacin, and combinations thereof, and said micro organism is selected from the group consisting of Lactobacillus acidophilus, Lactobacillus spores, Lactobacillus lactis, Streptococcus thermophilus, Streptococcus lactis, Saccromyces cerevisea, Lactobacilli GG, and combinations thereof.
A composition made by the process is also disclosed.
A preferred feature of present invention is to minimize side effects of anti-infective agents resulting from destruction/alteration of normal flora by providing viable organisms along with anti-infective agent(s).
The further preferred feature of present invention is to provide a pharmaceutical composition which is effective after a longer period of storage.
3196 7A The further preferred feature of this present invention is to increase compliance by reduction/elimination in side effects of anti-infective agents.
The further preferred feature of the present invention is to improve compliance by providing two drugs in one pharmaceutical composition.
The further preferred feature of present invention is to provide organism at a desired site.
The following describes embodiments of the invention and describes the manner in which they are to be performed. In this specification the term "comprising" (and its grammatical variations) as used herein is used in the inclusive sense of "having" or "including" and not in the exclusive sense of "consisting only of'.
The anti-infective agent and organisms are to be identified. Their dosage route of administration and dosage form is finalised.
o .o oo o* o *o ooooo o:.oo oooo.
3196 WO 99/49875 PCT/IB98/00445 8 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 organisms or anti-infective agent, in such a way that anti-infective agent cannot have effect on organisms. 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 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 (45"C. 37 0 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.
SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 9 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 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 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 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. However, it is not intended that the scope of this invention be limited by these examples.
Example I Example II Ampicillin 250 mgm Ampicillin 500 mgm Lactobacillus 60 million Lactobacillus 60 million SUBSTITUTE SHEET (RULE 26) WO 99/49875 WO 9949875PCTIIB98/00445 Examnle III Amoxycillin Lactobacillus Exam~leV Cloxacillin Lactobacillus 250 mgm 60 million 250 mgm 60 million Example IV Amnoxycillin Lactobac illus Example VI Cloxacillin La ctob acillI I.us 500 mgm 60 million.
500 mgm .60 million Examnie V I Ampicillin Cloxacillin Lactobacillus Example IX Amnoxycillin Cloxacillin Lacctobacillus, Exanle X1 Ampicillin Sultamnicin Lactobacillus Examnle XII Amnoxycillin Clavulanic acid Lactobacillus Exanie XV.
.Amoxycillin.
Bromhexine Lactobacillus Exam~ie XVIT Amnoxycillin Bromhexine Lactobacillus Example XIX Cephalexin Lactobacillus E xamvple X X1 Cephalexin Bromhexine Lactobacillus.
250 mgm 25.0 mgm 60 million 250 mgm 250 mgm 60. million...
Example VIII Ampicillin Cloxacillin Lactobacillus Exampl& X Amnoxycillin Cloxacillin Lactobacillus.
1000 mgm 500 mgm 60 million 250 mgm 125 mgm 60 million 250 mgm 8 mgm 60. million 500 mgm 8 mgm 60 million 250 mgm 60 million 250 rngm 4 mgm 60 million, *Ex .amlle .XI .II Ampicillin Probenecid Lactobacillus Example XIV Amoxycillin Probenecid Lactobacillus Example. XVI *Aioxycillin Carbocisteine Lactobacillus.
ExamnIe XVIII Amnoxycillin Carbocisteine Lactobac illus Example XX Cephalexin Lactobacillus Example XXII Cephalexin Probenecid Lactobacillus.
125 mgm 125 mgm.
30 million 125 mgm 125 mgm 30 million 250 mgm 250 mgm 60 million 500 mgm.
500 mgm.
60 million 250 mgm 150 mgm 60 million 500 mgm 150 mgm 60 million 500 mgm 60 million 250 mgm 250 mgm 60 million SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 11 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 antiinfective 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 I 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.
SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 12 ii) Organisms can be granulated. Granules containing organisms are coated barrier 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 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. The coating should be capable of protecting organisms from anti-infective agents. It can be vice versa i.e. anti-infective agent is included in coating.
iv 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.
SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 13 Coating/barrier protection is not so much necessary as it is in a capsule form as long as moisture content is controlled and physical separation is maintained in a same tablet. 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 are coated with barrier film and suspended in a liquid containing anti-infective agents or vice versa. The barrier film is stable in liquid formulation but disintegrates in 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. However, it is not intended that the scope of this invention be limited by these examples.
Chemical Name Trade Name 1. Cellulose acetate phthalate Aquateric
CAP
Cellacefate 2. Poly(butyl methacrylate. (2-dimethyl aminoethyl). Eudragit E 100 methacrylate. methyl methacrylate) 1:2:1 Eudragit E 12.5 SUBSTITUTE SHEET (RULE 26) *6 00/49875 WO 999875PCT/1B398/00445 3. Poly(ethyl acrylate. methyl methacrvlate) 2:1 4. Poly(methacrylic acid, methyl methacrylate) 1:1 Eudragit L 12.5 Poly(methacrylic acid,. ethyl acrylate) 1:1- .o..eharyi acid. methy mehar.ae.I 7. Poly(ethactylcae, methyl methacrylate 1, trimechylammnonioethyl methacrylate chloride) 1:2:0.2 8. Poly(ethyl acrylate. methyl merhacrvlate.
trimethylamunonioethyl methacrylate chloride) 1 :2:0.1 Hydrogenated Castor Oil Cetyl Alcohol...
Eudragit NE (fortneiv Eudragit Eudragit: L 100 Eudragit L '12.5 *P Eudragit L 30 Eudragit L 100-M5 Eudragit S. 100 Eudragit S 12.5 Eudragit S 12.5 P Eudragit RL 100 Eudragit RL P0 Eudragit RL 30 D Eudragit RL 12.5 Eudragit RS 100 Eudragit RS P0 Eudragit RS 30 D Eudragit RS 12.5 Castrowax Castrowax MP Castrowax MP Opalwax Simulsol Crodacol Crodacol Crodacol II. Diethyl .Phthalate 12. Ethyl cellulose Kodatlex DEP Palatinol A Aquacoat Ethocel Surelease 13. Hydroxypropyl Cellulose Klucel Methocel Nisso HPC 14. Hydroxypropyl Methylcellulose Phthalate Zein SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 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 layered tablet is prepared using the following components of which the active ingredients are anti-infective agent(s) and micro organisms. The remaining components are physiologically acceptable excipients. One of the active ingredients is coated in a coating pan by the coating process known to those skilled in the art. Excipients are also used along with one of the active ingredients (granules) during tablet making for lubrication as required for the purpose.
Granules of separate active ingredients are first prepared by 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% Dichloromethane 12.34% SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 16 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 antiinfective agents as lubricants Ingredients Parts by weight Sodium chloride 31.91% Polyplasdone XL 14.89% Microcrystalline cellulose 21.28% Saccharine sodium 10.64% Flavour orange 10.64% Magnesium stearate 5.32% Purified Talc 5.32% 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% SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 17 I The fixed dose layered tablet composition which are prepared through making use of above described process contain the above active ingredients antiinfective 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 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 physiologically acceptable excipients. Granules of one of the active ingredients 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 0 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.
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.
SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 18 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 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% Dichloromethane 58.54% SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 19 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 III 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 micro 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 other active ingredient is introduced into the suspension by the process known to those skilled in the art in such a way that final concentration of micro organisms is 20% of anti infective agent(s).
The relative proportion of anti-infective agent and excipients to prepare coated granules Ingredients Parts bv weight Anti infective agent 56.82% Cellulose acetate pthalate 22.73% Isopropyl alcohol 6.82% Dichloromethane 13.63% SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 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 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.
SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 21 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) Hydroxy propyl methyl cellulose M (1,00,000 cps) Purified water 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.
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.
SUBSTITUTE SHEET (RULE 26) WO 99/49875 PCT/IB98/00445 22 A. Anti-infective agents Anti infective agents can be penicillins e.g. ampicillin. amoxycillin. cloxacillin, cephalosporins e.g. cephalexin, cefadroxyl, cefuroxime axetil. cefixime, beta lactamase inhibition like clauvanic acid macrolide like erythromycin as single ingredient or combination thereof.
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 Lactobacillus Lactis 10 500 million 4. Streptococcus thermophilus 10 million Streptococcus lactis 10 million 6. Saccromyces cerevisea 10 million 7. Lactobacilli GG 10 1 units SUBSTITUTE SHEET (RULE 26)
Claims (18)
1-1 Dee 2003 13:2G FRASER OLD SOHN 61 2 9955 2700 p. 3 23 The claims defining the invention are as follows: 1. A process to provide a stable fixed dose oral pharmaceutical formulation comprising at least one anti-infective agent as a first active ingredient and at least one micro-organism susceptible to said anti-infective agent as a second active ingredient, the process comprising a step of coating at least one of the first and second active ingredients to provide a protective barrier around the active ingredient, and thereafter a step of combining the active ingredients into a single pharmaceutical formulation selected from the group consisting of a tablet and a capsule wherein said tablet or capsule contains both said anti-infective agent and said micro-organism, the protective barrier protects the susceptible micro-organism from the effect of the anti-infective agent to maintain the susceptible micro-organism in a viable form for a period of at least three months, said anti-infective agent is selected from the group consisting of Ampicillin, Amoxycillin, Cloxacillin, Clavulanic acid, Sultamicin, Cefuroxime axetil, Cefadroxyl, Cephalexin, Cefixime, Erythromycin, Ciprofloxacin, and combinations thereof, and said micro organism is selected from the group consisting of Lactobacillus acidophilus, Lactobacillus spores, Lactobacillus lactis, Streptococcus thermophilus, Streptococcus lactis, Saccromyces cerevisea, Lactobacilli GG, and combinations thereof.
2. A process as claimed in claim 1 wherein the anti-infective agent and the micro-organisms are separately admixed with physiologically acceptable excipients.
3. A process as claimed in claim 1 which process comprises admixing separately the anti-infective agent and the micro-organism with a physiologically acceptable 25 excipient to provide granules of the anti-infective agent and the micro-organism, and coating at least one of the anti-infective agent granules and the micro-organism granules, and subsequently compressing said anti-infective agent granules and said 1 micro-organism granules into a layered tablet such that one layer contains the anti- infective agent and the other layer contains the micro organism. i 4. A process as claimed in claim 3 wherein the excipient is ethyl cellulose and said coating is performed by suspending the granules to be coated in a suspension **containing ethyl cellulose dissolved in isopropyl alcohol and dichloromethane. 3196 COMS ID No: SMBI-00531547 Received by IP Australia: Time 14:34 Date 2003-12-11 11 Dec 2003 13:27 FRASER OLD SOHN 61 2 9955 2700 p.4 24 A process as claimed in claim 4 wherein the excipient is a mixture of microcrystalline cellulose, and starch.
6. A process as claimed in claim 3 wherein the excipient is a mixture of magnesium stearate, polyplasdone XL and sodium chloride.
7. A process as claimed in claim 1 wherein one of the active ingredients is compressed into a tablet and coated, and said coated tablet is put into a capsule containing the other active ingredient.
8. A process as claimed in claim 7 wherein said tablet contains said micro- organism admixed with physiologically acceptable excipients.
9. A process as claimed in claim 7 wherein coating to produce the coated tablet is carried out by using a coating suspension comprising hydroxy propyl methyl cellulose phthalate, titanium dioxide, talc, polyethelene glycol, isopropyl alcohol and dichloromethane. A process as claimed in claim 1 wherein a mixture is formed containing the anti-infective agent and a mixture of physiological acceptable excipients containing pregelatinised starch, magnesium stearate, and sodium lauryl sulphate, and the mixture containing the anti-infective agent and the excipients is subsequently filled into capsules. 25 11. A process as claimed in claim 1 wherein coating of the anti-infective agent is carried out by using a coating suspension comprising cellulose acetate phthalate, isopropyl alcohol, and dichloromethane.
12. A process as claimed in claim 1 wherein the anti-infective agent is coated in a coating suspension comprising hydroxy propyl methyl cellulose and purified water.
13. A process as claimed in claim 1 wherein one of the active ingredients is coated and suspended in a solution containing another active ingredient. 3196 COMS ID No: SMBI-00531547 Received by IP Australia: Time 14:34 Date 2003-12-11 1.1 Dec 2003 13:27 FRRSER OLD SOHN 61 2 9955 2700
14. A stable fixed-dose oral pharmaceutical composition prepared by the process as claimed in any one of claims 1-13. The stable pharmaceutical composition of claim 13 wherein the ratio of anti- infective agent to micro organism is in the range of 2:1 to 25:1.
16. The stable pharmaceutical composition of claim 14 wherein the ratio of anti- infective agent to micro organism is about 5:1.
17. A stable pharmaceutical composition as claimed in claim 14 when dependent upon claim 3 wherein said layer containing the anti-infective agent comprises anti- infective agent, microcrystalline cellulose, colour sunset yellow lake and purified water, and wherein the granules comprising the anti-infective agent are coated.
18. A stable pharmaceutical composition as claimed in claim 14 when dependent upon claim 3 wherein said layer containing the micro-organisms comprises micro- organisms, starch, microcrystalline cellulose, magnesium stearate, polyplasdone XL and sodium chloride, and wherein the granules comprising the anti-infective agent are coated.
19. The stable pharmaceutical composition of claim 14 wherein the coating comprises a compound selected from the group consisting of cellulose acetate phthalate; poly(butylmethacrylate, (2-dimethyl aminoethyl) methacrylate, methyl methacrylate); poly(ethyl acrylate, methyl methacrylate); poly(methacrylic acid, 25 methyl methacrylate); poly(methacrylic acid, ethyl acrylate); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride), hydrogenated Castor oil; Cetyl alcohol; diethyl phthalate; ethyl cellulose; hydroxypropyl cellulose; hydroxypropyl methylcellulose phthalate; and zein.
20. A process to provide a stable fixed dose oral pharmaceutical formulation, said process being substantially as herein described with reference to any one of the Examples. 3* COMS ID No: SMBI-00531547 Received by IP Australia: Time 14:34 Date 2003-12-11 11 Dec 2003 13:27 11 Dc 203 1:27 FRASER OLD SOHN G 9520 GI 2 9955 2700 p. G
21. A stable, fixed dose, oral pharmaceutical composition substantially as herein described with reference to any one of the Examples.
22. A method of treatment of a patient comprising the step of administration of a composition as claimed in any one of claims 14-19 and 21 or as prepared in accordance with the process as claimed in any one of claims 1- 13 and Dated this 1 1 "h day of December 2003 CADILA PHARMACEUTICALS LID FRASER OLD SOHN Patent Attorneys for the Applicant S S S S S *5*S S S S S
55.555 0 3196 COMS ID No: SMBI-00531547 Received by IP Australia: Time 14:34 Date 2003-12-11
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9806489.2A GB9806489D0 (en) | 1998-03-27 | 1998-03-27 | The process for the preparation of a stable fixed dose pharmaceutical composition of anti-infective agent/agents and micro organisms as active ingredients |
| LK1644598 | 1998-03-27 | ||
| PCT/IB1998/000445 WO1999049875A1 (en) | 1998-03-27 | 1998-04-03 | The process for the preparation of a stable fixed dose pharmaceutical composition of anti infective agent/agents and micro organisms as active ingredients |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6415698A AU6415698A (en) | 1999-10-18 |
| AU770024B2 true AU770024B2 (en) | 2004-02-12 |
Family
ID=26313367
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU64156/98A Ceased AU770024B2 (en) | 1998-03-27 | 1998-04-03 | The process for the preparation of a stable fixed dose pharmaceutical composition of anti infective agent/agents and micro organisms as active ingredients |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0998295A1 (en) |
| JP (1) | JP2002516616A (en) |
| AP (1) | AP9901724A0 (en) |
| AU (1) | AU770024B2 (en) |
| CA (1) | CA2291780A1 (en) |
| EA (1) | EA002148B1 (en) |
| ID (1) | ID26341A (en) |
| UA (1) | UA59394C2 (en) |
| WO (1) | WO1999049875A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8227235B2 (en) * | 2008-12-10 | 2012-07-24 | Alpharma, Llc | Compositions and methods for controlling diseases in animals |
| GB0916335D0 (en) * | 2009-09-17 | 2009-10-28 | Martin W J | Medicaments |
| US20130131033A1 (en) * | 2010-01-13 | 2013-05-23 | Toyochem Laboratories | Pharmaceutical composition for treatment of respiratory tract infections |
| US11554112B2 (en) | 2018-06-07 | 2023-01-17 | Herum Therapeutics International Limited | Combinations of β-lactam compounds and probenecid and uses thereof |
| EP3790535A1 (en) | 2019-02-13 | 2021-03-17 | Iterum Therapeutics International Limited | Combinations of beta-lactam compounds and probenecid and uses thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8703360L (en) * | 1987-08-31 | 1989-03-01 | Lejus Medical Ab | GRANULATED PRODUCTS (III) |
-
1998
- 1998-03-04 UA UA99116272A patent/UA59394C2/en unknown
- 1998-04-03 AP APAP/P/1999/001724A patent/AP9901724A0/en unknown
- 1998-04-03 EP EP98909680A patent/EP0998295A1/en not_active Withdrawn
- 1998-04-03 AU AU64156/98A patent/AU770024B2/en not_active Ceased
- 1998-04-03 EA EA199900938A patent/EA002148B1/en not_active IP Right Cessation
- 1998-04-03 JP JP54906699A patent/JP2002516616A/en not_active Ceased
- 1998-04-03 CA CA002291780A patent/CA2291780A1/en not_active Abandoned
- 1998-04-03 WO PCT/IB1998/000445 patent/WO1999049875A1/en not_active Ceased
- 1998-04-03 ID IDW991648A patent/ID26341A/en unknown
Non-Patent Citations (3)
| Title |
|---|
| BLACK ET AL., (1991) SCAND J INFECT DES. V23(2) PP247-254 * |
| GOTZ ET. AL., (1979) AM.J.HOSP. PHARM V36(6) PP754-757 * |
| RIJHISINGHANI ET. AL., AM. J. PERINATOL V12(5) PP322-324 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AP9901724A0 (en) | 1999-12-31 |
| WO1999049875A1 (en) | 1999-10-07 |
| ID26341A (en) | 2000-12-14 |
| CA2291780A1 (en) | 1999-10-07 |
| EA199900938A1 (en) | 2000-08-28 |
| AU6415698A (en) | 1999-10-18 |
| JP2002516616A (en) | 2002-06-04 |
| EA002148B1 (en) | 2001-12-24 |
| EP0998295A1 (en) | 2000-05-10 |
| UA59394C2 (en) | 2003-09-15 |
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