WO1999049875A1 - 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
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- WO1999049875A1 WO1999049875A1 PCT/IB1998/000445 IB9800445W WO9949875A1 WO 1999049875 A1 WO1999049875 A1 WO 1999049875A1 IB 9800445 W IB9800445 W IB 9800445W WO 9949875 A1 WO9949875 A1 WO 9949875A1
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- 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
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- 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
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- 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
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- 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
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- 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
-
- 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
Definitions
- 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 lactobacilh. biofidobacterium. saccharomyies boulardili. streptococcus thermophilus, enterococcus facecium SF 68, L Casei
- Organisms used 9 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 Consultations. Sometimes they create life threatening situation e.g. pseudememberous colitis, 4 13*20 toxic megacolon.
- Antibiotic-associated pseudomembranous colitis retrospective study of 48 cases diagnosed by colonoscopy.
- the further objective of present invention is to minimise 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 objective of present invention is to provide a pharmaceutical composition which is effective after longer period of storage.
- the further objective of the present invention is to improve compliance by providing two drugs in one pharmaceutical composition.
- the anti-infective agent and organisms are to be identified. Their dosage route of administration and dosage form 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.
- 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 anti- infective agent. The organism remain viable as long as the barrier is maintained. This is like applying paint or a film on a substance to prevent corrosion by isolating it from surroundings.
- the protective barrier is selected depending on route of administration and dosage form of the pharmaceutical composition (anti-infective agent + organism)
- the pharmaceutical composition so manufactured is evaluated 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.
- 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
- 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 anti- infective agents when taken at same time.
- pseudomembranous colitis it can be biofidobacterium, sacchormyces streptococcus thermophilus, enterococcus etc. instead of lactobacillus in above examples in their appropriate dosages.
- 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. 12
- Organisms can be granulated. Granules containing organisms are coated
- Organisms are coated and compressed into a layer of tablet.
- the other layer(s) of tablet contains anti-infective agent.
- Granules of organisms are coated with barrier film and mixed with granulated material of anti-infective agents and compressed into a tablet.
- 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.
- 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. 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.
- 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.
- 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
- 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.
- the active ingredients is coated in a coating pan by the coating process known to those skilled in the art. Excipients are also used along with one of the active ingredients (granules) during tablet making for lubrication as required for the purpose.
- Granules of separate active ingredients are first prepared by process known to those skilled in the art. The separate sets of granules are then compressed on double rotary tablet compression machine having a laying facility at a temperature below 25°C and relative humidity not more than 50% by processes known to those skilled in the art and the tablets are transferred to a coating pan for film coating to be given by using film coating process known to those skilled in the art.
- the 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 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 temperamre.
- a stable fixed dose combination capsules are prepared using following components of which the active ingredients are anti-infective agents and micro organisms. The remaining components are physiologically acceptable excipients.
- Granules of one of the active ingredients e.g. micro organisms
- the granules so formed are compressed into a tablet by tablet compression machine heaving a laying facility at a temperamre 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.
- the remaining active ingredient is mixed with excipients and filled into gelatin capsules by process known to those skilled into the art.
- the coated tablet containing active ingredients are introduced into capsule by processes known to those skilled in the art.
- the fixed dose capsule composition which are prepared through making use of above described process contain the above active ingredients, anti infective agents and viable
- 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 temperamre.
- 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 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 temperamre.
- a stable fixed dose combination dry powder for reconstimting 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 propo ⁇ ion of anti infective agents and the excipients to prepare coated granules is as follows :
- 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 an) each individual ingredient and are stable for at least 3 - 36 months at ambient room temperamre.
- composition when reconstituted by adding liquid prior to use remains stable at ambient room temperamre for 3 to 7 days.
- Anti infective agents can be penicillins e.g. ampicillin. amoxycillin. cloxacillin, cephalosporins e.g. cephalexin, cefadroxvl, cefuroxime axetil, cefixime, beta lactamase inhibition like clauvanic acid - macrolide like erythromycin as single ingredient or combination thereof.
- Solid dosage forms like capsules or tablet contains anti infective agents equivalent to 125, 250 or 500 mgm of active component
- Liquid dosage forms usually contains anti infective agents equivalent to 125 mgm of active component in 5 ml.
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Abstract
Micro organisms are useful in management of diseases including diarrhoea and gastro intestinal diseases like pseudomembranous colitis, megacolon etc. They are also useful in prevention of gastro intestinal disturbances and diseases caused by anti-infective agents like ampicillin, amoxycillin, cloxacillin, clauvanic acid, cefuroxime axetel, cephalixin, erythromycin etc. For prevention micro organisms are to be taken along with anti infective agents. When micro organisms are combined with anti-infective agents for ease of administration and improving compliance and therapeutic effect, the combination is not found to be stable at room temperature as micro organisms are sensitive to anti-infective agents and are destroyed by effect of anti-infective agent in composition. The present invention relates to the process of preparing a stable fixed dose composition of anti-infective agent with micro organism as active ingredient. The process includes preparation of various dosage forms for oral route like capsule, tablet and liquid formulation. The process comprises of providing an appropriate barrier by way of selected coating procedure to one of the active ingredients in such a way that micro organisms are not affected by anti-infective agents. This results in a stable composition. By using an appropriate coating technique composition is made to remain stable over a period of 3-36 months at ambient/room temperature. The ratio of micro organism to anti-infective agents in a composition can be 1:2 to 1:25 by weight. The ratio of 1:5 by weight is found to be optimal for the purpose. The amount of coating is dependent on the type of coating technique, dosage form i.e. capsule, tablet or liquid and desired self life. The micro organisms of the composition were found to be active after variable time period. They also provided therapeutic effect and eliminated gastro intestinal disturbances associated with anti-infective agents when evaluated in humans.
Description
DESCRIPTION
THE PROCESS FOR THE PREPARATION OF A STABLE FIXED DOSE PHARMACEUTICAL COMPOSITION OF ANTI INFECTINE AGENT/ AGENTS AND MICRO ORGANISMS AS ACTIVE INGREDIENTS.
The present invention relates to a process of manufacturing a formulation containing anti- infective agent(s) with viable organisms which are susceptible to anti-infective agents. Micro organisms are used to prevent adverse effects like diarrhoea caused by anti-infective agents.
The present invention is directed to manufacturing of a formulation 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 anti- infective agents to prevent or minimise adverse effects of anti-infective agents like diarrhoea, pseudomembranous colitis, mega colon, etc.
Organisms are classified as pathogens and commonsals. Pathogens are responsible for various infectious diseases and are not normally present in that part of the body. They are
also known as infectious agents. Commonsals are normally present in various pans of body and perform useful functions. They provide vitamin K. B-12, Thiamine, Riboflavin etc. to body.1 They inhibit the growth of pathogens by variety of mechanisms.2 Anti- infective agents are used to treat/prevent infectious diseases. They kill organisms by various ways. However they are not always specific for pathogens and also kill commonsals.- Destruction or reduction in number of commonsals results in loss of function of commonsals and various effects of these are seen.2*5 These effects are known as adverse effects or side effects of anti- infective therapy. Diarrhoea with or without super-infection is one of such effects seen with anti-infective therapy.3 4*6 Diarrhoea is seen as an adverse reaction to many antibiotics. But 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 chndamycin. ampicillin. amoxycillin, cephalosporins (e.g. cefuroxime axetil, cefixime. cepahlexin ceftriaxone), amoxycillin + clauvanic acid, ampicillin + salbcutam, fluoroquinolens and other combinations of broad spectrum antibiotics, e.g. amoxycillin + cloxacillin.^ 6 7 8*9 10 11*12*13 16 18 Diarrhoea can be benign and secondary to transient dysfunction ot normal colonic flora due to anti-infective agents0 or super- infection by pathogens like clostridium difficile following alteration of normal flora by anti-ineffective agents.7*4 19 2" 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 lactobacilh. biofidobacterium.
saccharomyies boulardili. streptococcus thermophilus, enterococcus facecium SF 68, L Casei
GG etc.14 15 16 These can be combined with whole bowel irrigation with good results.17 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 Consultations. Sometimes they create life threatening situation e.g. pseudememberous colitis,4 13*20 toxic megacolon.
The organisms named above can be used to treat diarrhoea when it occurs. They can also be used to prevent diarrhoea.14 "-18 Commercially available preparations include lactobacillus alone (Lactiflora, Lactobacil, Lactocap, Lactovit, Sporlac) or in combination with streptococcus (Lacticyn) or Sacchromyces (Laviest). To prevent diarrhoea organisms are given along with the anti-infective agents. This requires consumption of minimum two different drugs i.e. an anti-infective agent and an organism. This decreases compliance of a patient.
Attempts have been made to put organisms and anti-infective agents into one formulation. Some of these are commercially available. Lactobacillus is commonly used organism. Anti- infective agents used in the formulation include ampicillin. (e.g. Alcillin plus from Alpine), amoxicycillin (e.g. Alox plus from Alpine), ampicillin + cloxacillin (e.g. Amplus from Jagsonpal, Elclox plus from Elder. Penmix plus from Dee Pharma. Pen plus from Systopic, Poxin Plus from Alpine), amoxicycillin + cloxacillin (e.g. Bicidal plus from Kee Pharma, Diclox from Croford Pharma. Twinclox plus from Alpine). They all are simple admixture
of anti-infective agents and susceptible organisms. However, analysis of commercially available, as well as prepared by us revealed that organisms incorporated into formulation does not remain viable and did not perform any useful function for which they were to be used. Neither organisms nor their activity could be detected as early as 7 days after putting lactobaciili with various antibiotics like ampicillin. amoxycillin, amoxycillin + cloxacillin etc. or in commercially available preparation. Though 60 million spores are put into formulation, none of them could be grown or demonstrated viable on glucose yeast extract agar plate. It also failed to produce lactic acid as evaluated by consumption of NaOH.
REFERENCES
1. Gastrointestinal tracts chapter 65 in Text Book of Medical Physiology ed. Arther C Guy ton & John E.Hall
Publishers Prism Books (Pvt.) Ltd. , 9th edition 1996
2. pp. 1042 antimicrobial agents chapter 44 in the Pharmacological Basis of Therapeutics in Goodman & Gillman
3. PP-586 antibiotic associated colitis Chapter 14 in Current Medical Diagnosis & Treatment 36th edition.
4. A. P. Ball. Chapter 7, Toxicity in antibiotic and chemotherapy seventh edition, edit. Francis O'Gerard
5. Betalactam therapy and intestinal flora
Journal of Chemother. 1995 May; 7 suppl 1 : 25-31
6. Diarrhoea caused by antibiotic therapy. Rev-Prat. 1996 Jan 15: 46(2): 171-6
7. Antibiotic associated diarrhoea in light of personal observations. Pol-Tyg-Lek. 1995 Sep; 50(36): 45-9
8. Antibiotic-induced colitis. Semin-Pediatr-Surg. 1995 Nov; (4(4): 215-20
9. Clostridium difficile acquisition rate and its role in nosocomial diarrhoea at a university hospital in Turkey.
Eur-J-Epidemiol. 1996 Aug; 12(4): 391-4
10. Risk factors associated with Clostridium difficile diarrhoea in hospitalized adult patients: a case-control study — sucralfate ingestion is not a negative risk factor. Infect-Control-Hosp-Epidemiol. 1996 Apr; 17(4): 232-5
11. Clinical comparison of cefuroxime axetil and amoxycillin/clavulanate in the treatment of patients with secondary bacterial infections of acute bronchitis.
Clinical Ther. 1995 Sep-Oct 17 (5): 861-74
12. Clinical comparison of cefuroxime axetil suspension and 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
14. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections.
JAMA 1996 Mar 20: 275(11 ): 870-6
15. The pharmacologic principles of medical practice, Krantz & Can*
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
20. Side effects and consequences of frequently used antibiotics in clinical practice. Schweiz-Med-Wochenschr. 1996 Mar 30; 126(13): 528-34
7 The objective of present invention is to combine susceptible organisms into a pharmaceutical composition containing anti-infective agents and keep them viable for the self life of the formulation or till it is consumed.
The further objective of present invention is to minimise side effects of anti-infective agents resulting from destruction/alteration of normal flora by providing viable organisms along with anti-infective agent(s).
The further objective of present invention is to provide a pharmaceutical composition which is effective after longer period of storage.
The further objective of this present invention is to increase compliance by reduction / elimination in side effects of anti- infective agents.
The further objective of the present invention is to improve compliance by providing two drugs in one pharmaceutical composition.
The further objective of present invention is to provide organism at a desired site.
The following specification particularly describes and ascertain the nature of this invention and manner in which it is to be performed.
The anti-infective agent and organisms are to be identified. Their dosage route of administration and dosage form 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 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 anti- infective agent. The organism remain viable as long as the barrier is maintained. This is like applying paint or a film on a substance to prevent corrosion by isolating it from surroundings.
The protective barrier is selected depending on route of administration and dosage form of the pharmaceutical composition (anti-infective agent + organism)
The pharmaceutical composition so manufactured is evaluated for stability and efficacy.
The pharmaceutical composition so manufactured is evaluated at different test conditions of temperature and humidity (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.
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 + lactobaciili 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
99/49875 f^ i iiayi
10
Example III 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
ExamDle 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
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 anti- infective agents when taken at same time. For prevention of diarrhoea, pseudomembranous colitis it can be biofidobacterium, sacchormyces streptococcus thermophilus, enterococcus etc. instead of lactobacillus in above examples in their appropriate dosages.
2. Following are examples of providing barrier to organisms for different dosage forms.
However, it is not intended that the scope of this invention be limited by these examples.
Example 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.
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)
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.
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 Cellace ate
2. Poly(butyl methacrylate. (2-dimethyl aminoethyl) Eudragit E 100 meihacrylate. methyl methacrylate) 1 :2: 1 Eudragit E 12.5
99/49875
14
3. Poly(ethyl acrylate. methyl methacrylate) 2: 1 Eudragit NE 30D (formerly Eudragit 30D)
4. Poly(methacrylιc acid, methyl methacrylate) 1.1 Eudragit L 100
Eudragit L 12.5
Eudragit L 12.5 P
5. Poly(methacrylιc acid, ethyl acrylate) 1 : 1 Eudragit L 30 D-55 Eudragit L 100-55
Poly(methacryhc 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 tnmethylammonioethyl methacrylate chloride) 1 :2:0.2 Eudragit RL PO Eudragit RL 30 D Eudragit RL 12.5
Poly(ethyl acrylate. methyl methacrylate, Eudragit RS 100 tnmethylammonioethyl 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
1 1 Diethyl Phthalate Kodaflex DEP Palatmol A
12. Ethyl cellulose Aquacoat
Ethocel
Surelease
13. Hydroxypropyl Cellulose lucel Methocel
Nisso HPC
14. Hydroxypropyl Methylcellulose Phthalate
15 Zein
15 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 bv weight
Anti infective agent 77.54%
Ethyl cellulose 2.70%
Isopropyl alcohol 7.42%
Dichloromethane 12.34%
16
ii) The relative proportion of anti-infective agents and excipients to prepare granules :
Ingredients Parts bv 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 :
Ingredients Parts bv 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 bv weight
Micro organisms 18.18%
Starch 18.18%
Microcrystalline cellulose 56.67%
Magnesium stearate 0.91 %
Polyplasdone XL 3.03 %
Sodium chloride 3.03%
17
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 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 temperamre.
Example II - Capsules
A stable fixed dose combination capsules are prepared using following components of which the active ingredients are anti-infective agents and micro organisms. The remaining components are physiologically acceptable excipients. Granules of one of the active ingredients (e.g. micro organisms) are first prepared by process known to those skilled in the art. The granules so formed are compressed into a tablet by tablet compression machine heaving a laying facility at a temperamre 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.
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.
18
The relative propoπion of anti-infective agent and excipients for filling in capsule :
Ingredients Parts bv 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 tablet containing micro organisms to be kept into a capsule :
Ingredients Parts bv 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%
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 temperamre.
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 %
20
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 temperamre.
Example IV - Dry Powder composition to make liquid composition after reconstitution.
A stable fixed dose combination dry powder for reconstimting 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.
21
The relative propoπion of anti infective agents and the excipients to prepare coated granules is as follows :
Ingredients Pans bv weight
Anti infective agent(s) 50%
Hydroxy propyl methyl cellulose 45% K-15 M (1 ,00,000 cps)
Purified water 5%
The fixed dose dry powder composition which are prepared through making use of above described process contain the above active ingredients, anti infective agents and viable organisms in their respective therapeutic concentrations. The composition provide pharmacological effect which are complementary to the effects produced by (prior an) each individual ingredient and are stable for at least 3 - 36 months at ambient room temperamre.
Above composition when reconstituted by adding liquid prior to use remains stable at ambient room temperamre for 3 to 7 days.
5. Following are examples of therapeutic dosage of various anti-infective agents and micro organisms. However, it is not intended that the scope of this invention be limited by these examples.
22
A. Anti-infective agents
Anti infective agents can be penicillins e.g. ampicillin. amoxycillin. cloxacillin, cephalosporins e.g. cephalexin, cefadroxvl, 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 10"
3. Lactobacillus Lactis 10 - 500 million
4. Streptococcus thermophilus 10 million
5. Streptococcus lactis 10 million
6. Saccromyces cerevisea 10 million
7. Lactobaciili GG 10"' units
Claims
1. A process to provide a stable fixed dose oral pharmaceuticals composition, composed of anti-infective agent(s) and micro organisms as active ingredients with their different respective sets of propeπies. 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 namre and amount to provide a solid/liquid oral dosage composition such as a capsule/tablet/liquid preparations with effects complementary to those provided by each separate active ingredient and which is stable for at least 36 months at ambient temperamre.
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, Amoxycillin, Cloxacillin from Penicillins. Clavulanic acid, Sultamicin from Beta lactamase inhibitors, Cefuroxime axetil, Cefadroxyl, Cephalexin from cepahlosporins. Erythromycin from macrolides. Ciprofloxacin from 8-aminoquinolines alone or in combination and organisms are selected from Lactobacillus aciophillus. Lactobacillus spores. Lactobacillus lactis. Streptococcus thermophilus, Streptococcus lactis, Saccromyces cerevisea. Lactobaciili GG and/or in combination thereof. 24
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 which 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 a layered tablet using a double rotary compression under strict environmental conditions of temperamre below 25┬░C and relative humidity not more than 50%.
6. A process as claimed in claims 1 - 5 one of the active ingredients comprising the provision of 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 1 - 5 comprising the provision of granules of coated anti infective agents as claimed in claim 6 admixed with physiologically acceptable excipient 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 being subsequently compressed with granules of micro organisms into a layered tablet. 25
8. A process as claimed in claims 1 - 5 comprising the provision of granules of organism admixed with physiologically acceptable salts by using a mixmre 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 mixmre, 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 mixmre 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 sodium by weight of said mixmre.
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 polyethelene glycol. about 4.95% of isopropyl alcohol, about 58.54% dichloro methane by weight of suspension. 26
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 mixmre 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 mixmre 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 as claimed in claim 1 - 4 and claim 14 comprising the provision of coated anti-infective agent in which 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 mixmre. 27
16. A process as claimed in claim 1 - 4 wherein liquid preparation having shoπer 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 reconstimted it forms a suspension which is stable for 3 to 7 days at ambient temperamre.
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 subsequently herein described in examples 1 to 5 in the accompanying complete specification.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| UA99116272A UA59394C2 (en) | 1998-03-27 | 1998-03-04 | Process of preparing stable fixed dose composition of anti-infective agent with microorganisms as active ingredients |
| JP54906699A JP2002516616A (en) | 1998-03-27 | 1998-04-03 | Process for the preparation of a stable fixed dose pharmaceutical composition comprising one or more anti-infective drugs and microorganisms as active ingredients |
| CA002291780A CA2291780A1 (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 |
| APAP/P/1999/001724A AP9901724A0 (en) | 1998-03-27 | 1998-04-03 | Process for the preparation of astable fixed dose pharmaceutical composition of anti-infective agent/ agents and microorganisms as active ingredients. |
| EP98909680A EP0998295A1 (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 |
| EA199900938A EA002148B1 (en) | 1998-03-27 | 1998-04-03 | The process for the preparation of a stable fixed dose pharmaceutical compositionof anti infectiveagent/agents and micro organisms as active ingredients |
| IDW991648A ID26341A (en) | 1998-03-27 | 1998-04-03 | PROCESS FOR PROVIDING DOSAGE STABLE COMPOSITION OF ANTI-INFECTION AND MICROORGANISM SUBSTANCE AS ACTIVE DRUG MATERIALS |
| AU64156/98A 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 |
Applications Claiming Priority (4)
| 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 | ||
| LKB16445 | 1998-03-27 | ||
| GB9806489.2 | 1998-03-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999049875A1 true WO1999049875A1 (en) | 1999-10-07 |
Family
ID=26313367
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
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) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011033310A1 (en) * | 2009-09-17 | 2011-03-24 | William John Martin | Encapsulated intestinal flora extracted from feces for use in the treatment of gastrointestinal disorders |
| WO2011086575A2 (en) * | 2010-01-13 | 2011-07-21 | Toyochem Laboratories | A pharmaceutical composition for treatment of respiratory tract infections |
| WO2020164788A1 (en) * | 2019-02-13 | 2020-08-20 | Iterum Therapeutics International Limited | Combinations of beta-lactam compounds and probenecid and uses thereof |
| US11554112B2 (en) | 2018-06-07 | 2023-01-17 | Herum Therapeutics International Limited | Combinations of β-lactam compounds and probenecid and uses thereof |
Families Citing this family (1)
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0306465A1 (en) * | 1987-08-31 | 1989-03-08 | Nicasystem Aktiebolag | Granular product (III) |
-
1998
- 1998-03-04 UA UA99116272A patent/UA59394C2/en unknown
- 1998-04-03 CA CA002291780A patent/CA2291780A1/en not_active Abandoned
- 1998-04-03 EA EA199900938A patent/EA002148B1/en not_active IP Right Cessation
- 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 ID IDW991648A patent/ID26341A/en unknown
- 1998-04-03 JP JP54906699A patent/JP2002516616A/en not_active Ceased
- 1998-04-03 WO PCT/IB1998/000445 patent/WO1999049875A1/en not_active Application Discontinuation
- 1998-04-03 AU AU64156/98A patent/AU770024B2/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0306465A1 (en) * | 1987-08-31 | 1989-03-08 | Nicasystem Aktiebolag | Granular product (III) |
Non-Patent Citations (1)
| Title |
|---|
| PATENT ABSTRACTS OF JAPAN, Vol. 13, No. 286, 29 June 1989; & JP 1083025 A (FUJIO HAYASHI). * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011033310A1 (en) * | 2009-09-17 | 2011-03-24 | William John Martin | Encapsulated intestinal flora extracted from feces for use in the treatment of gastrointestinal disorders |
| WO2011086575A2 (en) * | 2010-01-13 | 2011-07-21 | Toyochem Laboratories | A pharmaceutical composition for treatment of respiratory tract infections |
| WO2011086575A3 (en) * | 2010-01-13 | 2011-09-22 | Toyochem Laboratories | A pharmaceutical composition for treatment 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 |
| WO2020164788A1 (en) * | 2019-02-13 | 2020-08-20 | Iterum Therapeutics International Limited | Combinations of beta-lactam compounds and probenecid and uses thereof |
| US11478428B2 (en) | 2019-02-13 | 2022-10-25 | Iterum Therapeutics International Limited | Combinations of beta-lactam compounds and probenecid and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0998295A1 (en) | 2000-05-10 |
| JP2002516616A (en) | 2002-06-04 |
| AU6415698A (en) | 1999-10-18 |
| ID26341A (en) | 2000-12-14 |
| EA002148B1 (en) | 2001-12-24 |
| AP9901724A0 (en) | 1999-12-31 |
| CA2291780A1 (en) | 1999-10-07 |
| EA199900938A1 (en) | 2000-08-28 |
| AU770024B2 (en) | 2004-02-12 |
| UA59394C2 (en) | 2003-09-15 |
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