EP1608370A1 - Use of cuminum cyminum extract and piperine for potention of bioeffiacy of anti infectives - Google Patents

Use of cuminum cyminum extract and piperine for potention of bioeffiacy of anti infectives

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Publication number
EP1608370A1
EP1608370A1 EP03719082A EP03719082A EP1608370A1 EP 1608370 A1 EP1608370 A1 EP 1608370A1 EP 03719082 A EP03719082 A EP 03719082A EP 03719082 A EP03719082 A EP 03719082A EP 1608370 A1 EP1608370 A1 EP 1608370A1
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EP
European Patent Office
Prior art keywords
composition
infective
bioenhancer
formula
group
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.)
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Application number
EP03719082A
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German (de)
French (fr)
Inventor
Ghulam Nabi Qazi
Om Parkash Suri
Kasturi Lal Bedi
Inshad Ali Khan
Vijeshwar Verma
Rakesh Kamal Johri
Krishan Avtar Suri
Bishan Datt
Naresh Kumar Satti
Manoj Kumar Tikoo
Subhash Chander Sharma
Ashok Kumar Tikoo
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Council of Scientific and Industrial Research CSIR
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Council of Scientific and Industrial Research CSIR
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Classifications

    • 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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • A61P31/10—Antimycotics
    • 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
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to the field of chemotherapeutics, particularly to their formulation as of oral pharmaceutical compositions containing bioenhancers for increasing bioefficacy of anti-infectives and thereby requiring lower doses and/or decreased frequency of dosing of such anti-infectives while mamtaining the therapeutic efficacy of standard doses of such drugs. Background of the invention.
  • pathogenic microorgnisms which include bacteria, virus and fungi.
  • pathogenic microorgnisms lead to septicaemia, serious infections of upper and lower respiratory tract, CNS, meningitis, intra- abdominal including peritoneum, genito-urinary tract, skin, and soft tissue, and variety of other infections like systemic mycosis, candidiasis including infections caused by dermatophytes.
  • antimicrobials include aminoglycosides, penicillins, cephalosporins, macrolides, glycopeptides, fluoroquinolones, tetracyclins, first and second line anti-TB drags, anti- leprosy, antivirals, polyene, triazole, and imidazole anti-fungals, combinations like pyrimidine derivatives and trimethoprim and sulphamethoxizole.
  • Trimethoprim-sulfamethoxazole also known as co-trimoxazole or TMP-SMX, which was introduced in 1968 as a broad-spectrum antimicrobial agent.
  • Tri ethoprim was specially developed as a potentiator of sulphonamide to act synergistically against bacteria and delay the development of bacterial resistance.
  • the 1:5 ratio of trimethoprim to sulfamethoxazole achieves an approximate 1:20 ratio of peak serum concentrations which is the optimal synergistic ratio of serum concentrations against most susceptible bacteria (Gutman LT, Pediatr Infect Dis 1984;3 :349-57, Olin BR, Facts and Comparisons, Inc. 1998; 408b-409d, Cockerill FR, Edson RS, Mayo Clin Proc 1991;66:1260-9)
  • the combination can also be between one antiinfective agent and another chemical agent which by itself is not antiinfective in nature but when combined with the antiinfective, enhances the effectiveness of this antiinfective.
  • the example of such combination is Amoxicillin + Clavulanic acid, more commonly known as Augmentin.
  • Amoxicillin is an antibiotic of the penicillin type. It is effective against different bacteria such as H. influenzae, N. gonorrhea, E. coli, Pneumococci, Streptococci, and certain strains of Staphylococci. Chemically, it is closely related to penicillin and ampicillin.
  • Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a ⁇ -lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of ⁇ -lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasimd mediated ⁇ -lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins.
  • Ayurveda One of the most notable features that has been associated with the traditional Indian medicine and amply described in Ayurveda is the use of compositions which offer additive, synergistic and potentiating effect of one medicament when used in combination with the other.
  • Ayurveda there are several natural products, which have been used as an essential ingredient of many formulations used against wide range of diseases. The most prominent of these being 'Trikatu' comprising black pepper, long pepper and dry ginger.
  • 'Trikatu' comprising black pepper, long pepper and dry ginger.
  • Detailed and systematic studies have shown that one of the active ingredients of peppers i.e., piperine is a potent bioavailability and/ or bioeffacicay enhancer of several drugs and nutrients.
  • the main object of the invention is to provide a oral pharmaceutical compositions containing bioenhancers for increasing bioefficacy of anti-infectives and thereby requiring lower doses and/or decreased frequency of dosing of such anti-infectives while maintaining the therapeutic efficacy of standard doses of such drugs.
  • the present invention deals with one such combinations, where piperine and other bioenhancers are used as potentiators when combined with various anti-infective agents in vitro using bacteria, viruses and yeast and in vivo using mice and guinea pig infection models.
  • the present invention is aimed to overcome or avoid problems faced in the prior art.
  • the use of products of the present invention offer a low dose regimen that produces enhanced therapeutic action comparable to that of standard dose alone.
  • the present invention provides a composition useful for enhanced therapeutic effect at reduced doses of the anti infectives against infection caused bya microorganism comprising a mixture of an anti-infective agent and a bioenhancer selected from piperine of formula 1 and 3',5-Dihydroxy flavone 7-O- ⁇ -D-galacturonide-4'-O- ⁇ -D- glucopyranoside of formula 2 or a mixture thereof.
  • the anti infective agent is selected from the group consisting of penicillins including semi synthetic, cephalosporins, aminoglycosides, glycopeptides, fluroquinolones, macrolides, tetracyclines, first and second line anti-TB drugs, antileprosy drugs, oxazolidelones, antifungal agents, antiviral agents and pyrimidine derivatives - sulphonamides combination.
  • the anti-fungal agent is selected from the group consisting of polyenes, imidazoles and triazoles.
  • the antiviral agent is selected from the group consisting of Zidovudines, idouridine, acyclovir and ribavarine.
  • the 3',5-Dihydroxy flavone 7-O- ⁇ -D- galacturonide-4'-0- ⁇ -D-glucopyranoside is used in pure form or in the form of a HPLC fingerprinted fraction of 3',5-Dihydroxy flavone 7-O- ⁇ -D-galacturonide-4'-O- ⁇ -D- glucopyranoside from Cuminum cyminum or a sub fraction.
  • the concentration of the anti infective is two to eight times lesser than when such anti infective is used without the bioenhancer.
  • the composition includes one or more pharmaceutically acceptable additives and excipients.
  • the additives/excipients are selected from the group consisting of nutrients comprising proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, starch-gelatin paste, and/ or pharmaceutically acceptable carriers, diluents and solvents.
  • the composition is in oral administration form.
  • the ratio of the anti-infective to the bioenhancer is in the range of 1 : 1 to 1:5.
  • the additives have no effect on the anti- infective property of the said composition.
  • the present invention also provides a process for the preparation of a composition useful for enhanced therapeutic effect at reduced doses of the anti infectives against infection caused bya microorganism comprising a mixture of an anti-infective agent and a bioenhancer selected from piperine of formula 1 and 3',5-Dihydroxy flavone 7-O- ⁇ -D- galacturonide-4'-O- ⁇ -D-glucopyranoside of formula 2 or a mixture thereof, said process comprising a physical admixing technique.
  • a bioenhancer selected from piperine of formula 1 and 3',5-Dihydroxy flavone 7-O- ⁇ -D- galacturonide-4'-O- ⁇ -D-glucopyranoside of formula 2 or a mixture thereof, said process comprising a physical admixing technique.
  • the physical admixing technique is selected from dialysis, molecular sieving and by membranes.
  • the process of preparation of the bioenhancer comprises use of water, alcohol, combinations of water and alcohol, hydrocarbons, ketones and ethers.
  • the anti infective agent is selected from the group consisting of penicillins including semi synthetic, cephalosporins, aminoglycosides, glycopeptides, fluroquinolones, macrolides, tetracyclines, first and second line anti-TB drugs, antileprosy drugs, oxazolidelones, antifungal agents, antiviral agents and pyrimidine derivatives - sulphonamides combination.
  • the anti-fungal agent is selected from the group consisting of polyenes, imidazoles and triazoles.
  • the antiviral agent is selected from the group consisting of Zidovudines, idouridine, acyclovir and ribavarine.
  • the 3',5-Dihydroxy flavone 7-O- ⁇ -D- galacturonide-4'-O- ⁇ -D-glucopyranoside is used in pure form or in the form of a HPLC fingerprinted fraction of 3',5-Dihydroxy flavone 7-O- ⁇ -D-galacturonide-4'-O- ⁇ -D- glucopyranoside from Cuminum cyminum or a sub fraction.
  • the concentration of the anti infective is two to eight times lesser than when such anti infective is used without the bioenhancer.
  • the composition includes one or more pharmaceutically acceptable additives and excipients.
  • the additives/excipients are selected from the group consisting of nutrients comprising proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, starch-gelatin paste, and/ or pharmaceutically acceptable carriers, diluents and solvents.
  • the composition is in oral administration form.
  • the ratio of the anti-infective to the bioenhancer is in the range of 1 : 1 to 1:5.
  • Figure 2 is a graph showing the effect of rifampicin alone and in combination with piperine in an in vivo mice infection model.
  • Figure 3 is a graph showing the effect of rifampicin alone and in combination with 3',5-Dihydroxy flavone 7-O- ⁇ -D-galacturonide-4'-O- ⁇ -D-glucopyranoside of formula 2 in in vivo mice infection model.
  • Bioefficacy/bioavailability
  • Chemoresistance is a major problem in drag therapy.
  • the mechanisms underlying the clinical phenomena of de novo and acquired drag resistance may arise from alterations at any step in the cell-killing pathway. These include drug transport, drag metabolism, drag targets, cellular repair mechanisms and the ability of cells to recognize a harmful toxin or pathogen.
  • a common mechanism of reduced cellular drag accumulation is the increased expression of P-glycoprotein, a membrane transporter that efficiently removes drugs from these cells.
  • Another limiting factor is the high activity of cytochrome P 450 dependent proteins. Both these proteins P-gp and CYP 450 have been shown to regulate the oral bioavailability of a majority of drags.
  • P-gp is considered to be associated with MDR caused by the levels of its expression in tumors and after drug therapy.
  • the overall permeability changes may affect (i) specific ion transporter channels, and (ii) also lead to bulk movement of lipophilic solutes along the paracellular pathway.
  • Such membrane changes have also been evidenced in the action of several polyene antibiotics (Milhaud J et al, Biochimica et Biophysica Acta, 1988; 943:315-325).
  • the changes caused by piperine in membrane fluidity are, as already stated, short living, completely reversible but more than any thing is selective.
  • the products of the present invention are novel mechanism based pharmaceutical entities acting through synergism and or additive effect so that drags contained in the formulation are more bioefficaceous as a result of one or more of the mechanism as revealed above and thereby increasing the sensitivity of the target cell to an anti-infective.
  • the 'drag' in the present invention refers to a chemical entity capable of affecting organism's patho-physiology and used for the treatment or prevention of disease.
  • Drags include a number of classes of compounds, but not limited to aminoglycoside, penicillins, cephalosporins and other ⁇ -lactam agents, macrolides, glycopeptides, fluoroquinolones, tetracyclines, first and second line anti-TB drags, anti-leprosy, antivirals, polyene, triazole, and imidazoles and combinations like pyrimidines, sulphamethoxazole.
  • Drags may be a pro- drag, activated or metabolised form, consisting of charged, uncharged, hydrophilic, hydrophobic or zwitter-ion species which make their entry by simple diffusion, carrier mediated transport dependent and not dependent on energy requirements, through ion and/ or voltage gated channels.
  • the 'bioenhancer' refers to piperine (formula 1) or other such molecules, characterised fractions and / or extracts as a chemical entity.
  • the process of obtaining piperine as more than 98 % pure chemicaly characterized form has been disclosed in LP 172689, IP 172690, IP 176433, US 5439891 and a co-pending US patent application No 60/306917/2001.
  • the processes for preparation of a characterised fraction (HPLC profile enclosed) and a pure chemically characterised molecule (Fig.2) from Cuminum cyminum have been disclosed in co-pending patent application No.
  • the ratio of those two bioenhancers to drugs may vary from 1 to 50% for the fraction and from 0.1 to 30% for the pure molecule to obtain desired reduction in MIC values anti infectives.
  • the ratios of the drag and the bioenhancers and / or in composite bioenhancers are governed by amounts sufficient to produce enhanced therapeutic efficacy as measured by MIC of the formulation being lesser than the drug alone.
  • a pharmaceutical carrier is generally an inert bulk agent added to make the ingredients achieve superior admixing and can be solid or liquid.
  • the inert parts of standard pharmaceutical compositions used in this process are also part of the present invention. Study design The checkerboard method:
  • checkerboard refers to the pattern (of tubes or microtiter plate wells) formed by multiple dilutions of two drags being tested (Eliopoulos GM, Moellering RC. Antimicrobila Combinations. In: Antibiotics in Laboratory Medicine: USA: Williams & Wilkins).
  • the checkerboard consisted of columns in which each tube (or well) contains the same amount of the standard drug (antibacterial/antifbngal/anti- TB/antiviral) being diluted along the x-axis and rows in which each tube (or well) contains the same amount of the bioenhancer being diluted on the y-axis (Fig.3).
  • each square in the checkerboard (which represents one tube/ well or plate) contained a unique combination of the standard drag and bioenhancer.
  • the concentration range of standard drag in the present study was 64 ⁇ g/ml to 0.03 ⁇ g/ml, whereas the bioenhancer was tested in the range of 500 ⁇ g/ml to 0.2 ⁇ g/ml.
  • This checkerboard technique can be performed with liquid or semisolid (agar) media.
  • the agar (Mueller Hinton agar, Middlebrook 7H10 agar) was autoclaved and allowed to cool to 50°C to 55°C.
  • the combination of the standard drag and the bioenhancer was added to the agar.
  • Serial two fold dilutions of each of standard drag and the bioenhancer were prepared in appropriate solvents.
  • the volume of solvent (containing standard drag or bioenhancer) added to agar was kept small (i.e ⁇ 5% of the total volume).
  • Methicillin Resistant Staphylococcus aureus ++++ No inhibition, +++ 20% inhibition, ++ 50% inhibition
  • Example 2 Decrease in the MICs of rifampicin against M.tuberculosis, M. avium and M. intracellure when used in combination with piperine and fraction of Cuminum cyminum.
  • MIC Minimum Inhibitory Concentration
  • Example 3 Reduction in the dose requirement of rifampicin when used in combination with piperine and fraction of Cuminum cyminum in systemic infection model of mice.
  • the study was conducted to see the in vivo response of rifampicin in combination with piperine.
  • the Swiss albino mice were infected intravenously with M.tuberculosis H 3 Rv (10 6 CFU/mouse). The infected mice were divided in groups and each group consisted of 6 mice.
  • Example 4 Decrease in the MICs of Ciprofloxacin against Staphylococcus aureus, MRSA and Staphylococcus hemolyticus when used in combination with piperine.
  • MIC Minimum Inhibitory Concentration
  • Example 5 Decrease in the MICs of fluconazole against Candida albicans, Candida parapsilosis and Candida glabrata when used in combination with piperine.
  • Minimum Inhibitory Concentration (MIC) of fluconazole alone and in combination with piperine was performed against fungal species, using method described in the study design Two to eight fold reductions in MIC of fluconazole was observed in combination wffli piperine. (Table -6)
  • Example 6 List of drugs cited in accompanying Table 7 as some of the examples for the purpose of the present invention.

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Abstract

The present invention relates to the use of bioenhancers to decrease the resistance of microbial strains to anti-infective such as antibiotics and antifungals by potentiating the activities of anti-infective. This may be useful to reduce resistance in bacteria and yeast to aid in the treatment of certain infections and diseases and to lower the concentration of anti-infectives necessary to inhibit the growth of microbial strains.

Description

USE OF CUMI UM CYMINUM EXTRACT AND PIPERINE FOR POTENTION OF BIOEFFIACY OF ANTI INFECTIVES
The present invention relates to the field of chemotherapeutics, particularly to their formulation as of oral pharmaceutical compositions containing bioenhancers for increasing bioefficacy of anti-infectives and thereby requiring lower doses and/or decreased frequency of dosing of such anti-infectives while mamtaining the therapeutic efficacy of standard doses of such drugs. Background of the invention.
A variety of human ailments owe their origin to pathogenic microorgnisms, which include bacteria, virus and fungi. The presence of such pathogenic microorgnisms lead to septicaemia, serious infections of upper and lower respiratory tract, CNS, meningitis, intra- abdominal including peritoneum, genito-urinary tract, skin, and soft tissue, and variety of other infections like systemic mycosis, candidiasis including infections caused by dermatophytes. During the last 100 years, significant progress has been made to combat the diseases caused by such a large family of microbes with innumerable therapeutic agents of diverse chemical and biological nature that have become available as a short and long -term cure. Such antimicrobials include aminoglycosides, penicillins, cephalosporins, macrolides, glycopeptides, fluoroquinolones, tetracyclins, first and second line anti-TB drags, anti- leprosy, antivirals, polyene, triazole, and imidazole anti-fungals, combinations like pyrimidine derivatives and trimethoprim and sulphamethoxizole.
While such agents are effective against pathogenic bacteria and fungi and therefore useful in the treatment of disease conditions associated with the presence of such pathogens, there is increasing evidence that use of such agents has certain limitations and led to clinical concern. There are several such factors responsible for such a concern: (a) certain strains of bacteria and fungi become increasingly resistant to one or more of the known anti-infectives and therefore the usual or standard therapeutic doses lead to less beneficial effect, (b) higher doses that are required to combat this cause undesirable side effects and toxicity, and (c) high-cost of treatment and patient-non-compliance. The emergence of drug-resistant pathogenic organisms has also been attributed to uncontrolled antibiotic overuse and under use and even under dosing, irrational frequency of administration. The prolonged and high dose therapy is also a matter of serious concern particularly in pregnant women, geriatrics and children.
While an approach embodying rational use of antibiotics use may help slow the problem of microbial drug resistance, new antimicrobial agents must be discovered to combat those strains that are now resistant to most, if not all, currently available antibiotics. As such, there is a continued interest in the identification of novel antimicrobial agents, which can be used to further supplement the medical practitioner's armamentarium against pathogenic microorganisms In another approach, two anti-infectives are combined in such a way that the combination produces synergy i.e. one of the anti-infective acts as the potentiator of the other antiinfective. The example of such combination is Trimethoprim-sulfamethoxazole also known as co-trimoxazole or TMP-SMX, which was introduced in 1968 as a broad-spectrum antimicrobial agent. Tri ethoprim was specially developed as a potentiator of sulphonamide to act synergistically against bacteria and delay the development of bacterial resistance. The 1:5 ratio of trimethoprim to sulfamethoxazole achieves an approximate 1:20 ratio of peak serum concentrations which is the optimal synergistic ratio of serum concentrations against most susceptible bacteria (Gutman LT, Pediatr Infect Dis 1984;3 :349-57, Olin BR, Facts and Comparisons, Inc. 1998; 408b-409d, Cockerill FR, Edson RS, Mayo Clin Proc 1991;66:1260-9)
The combination can also be between one antiinfective agent and another chemical agent which by itself is not antiinfective in nature but when combined with the antiinfective, enhances the effectiveness of this antiinfective. The example of such combination is Amoxicillin + Clavulanic acid, more commonly known as Augmentin. Amoxicillin is an antibiotic of the penicillin type. It is effective against different bacteria such as H. influenzae, N. gonorrhea, E. coli, Pneumococci, Streptococci, and certain strains of Staphylococci. Chemically, it is closely related to penicillin and ampicillin. Addition of clavulanic acid to amoxicillin in Augmentin enhances the effectiveness of this antibiotic against many other bacteria that are ordinarily resistant to amoxicillin. Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasimd mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. One of the most notable features that has been associated with the traditional Indian medicine and amply described in Ayurveda is the use of compositions which offer additive, synergistic and potentiating effect of one medicament when used in combination with the other. In Ayurveda there are several natural products, which have been used as an essential ingredient of many formulations used against wide range of diseases. The most prominent of these being 'Trikatu' comprising black pepper, long pepper and dry ginger. Detailed and systematic studies have shown that one of the active ingredients of peppers i.e., piperine is a potent bioavailability and/ or bioeffacicay enhancer of several drugs and nutrients. The process of obtaining piperine and piperine containing formulations including anti-TB antibiotics with enhanced bioavailability / bioefficacy at lower doses of active drugs has been disclosed in earlier patents (IP 172684,; IP 172690,; IP 176433; US 5439891). Objects of the invention
The main object of the invention is to provide a oral pharmaceutical compositions containing bioenhancers for increasing bioefficacy of anti-infectives and thereby requiring lower doses and/or decreased frequency of dosing of such anti-infectives while maintaining the therapeutic efficacy of standard doses of such drugs. Summary of the invention
The present invention deals with one such combinations, where piperine and other bioenhancers are used as potentiators when combined with various anti-infective agents in vitro using bacteria, viruses and yeast and in vivo using mice and guinea pig infection models. The present invention is aimed to overcome or avoid problems faced in the prior art. The use of products of the present invention offer a low dose regimen that produces enhanced therapeutic action comparable to that of standard dose alone.
Accordingly, the present invention provides a composition useful for enhanced therapeutic effect at reduced doses of the anti infectives against infection caused bya microorganism comprising a mixture of an anti-infective agent and a bioenhancer selected from piperine of formula 1 and 3',5-Dihydroxy flavone 7-O-β-D-galacturonide-4'-O- β-D- glucopyranoside of formula 2 or a mixture thereof.
Formula 1
Cri,OH
Formula 2 In one embodiment of the invention, the anti infective agent is selected from the group consisting of penicillins including semi synthetic, cephalosporins, aminoglycosides, glycopeptides, fluroquinolones, macrolides, tetracyclines, first and second line anti-TB drugs, antileprosy drugs, oxazolidelones, antifungal agents, antiviral agents and pyrimidine derivatives - sulphonamides combination.
In a further embodiment of the invention, the anti-fungal agent is selected from the group consisting of polyenes, imidazoles and triazoles.
In yet another embodiment of the invention, the antiviral agent is selected from the group consisting of Zidovudines, idouridine, acyclovir and ribavarine. In another embodiment of the invention, the 3',5-Dihydroxy flavone 7-O-β-D- galacturonide-4'-0- β-D-glucopyranoside is used in pure form or in the form of a HPLC fingerprinted fraction of 3',5-Dihydroxy flavone 7-O-β-D-galacturonide-4'-O- β-D- glucopyranoside from Cuminum cyminum or a sub fraction.
In another embodiment of the invention, the concentration of the anti infective is two to eight times lesser than when such anti infective is used without the bioenhancer.
In another embodiment of the invention, the composition includes one or more pharmaceutically acceptable additives and excipients.
In another embodiment of the invention, the additives/excipients are selected from the group consisting of nutrients comprising proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, starch-gelatin paste, and/ or pharmaceutically acceptable carriers, diluents and solvents.
In another embodiment of the invention, the composition is in oral administration form.
In a further embodiment of the invention, the ratio of the anti-infective to the bioenhancer is in the range of 1 : 1 to 1:5.
In yet another embodiment of the invention, the additives have no effect on the anti- infective property of the said composition.
The present invention also provides a process for the preparation of a composition useful for enhanced therapeutic effect at reduced doses of the anti infectives against infection caused bya microorganism comprising a mixture of an anti-infective agent and a bioenhancer selected from piperine of formula 1 and 3',5-Dihydroxy flavone 7-O-β-D- galacturonide-4'-O- β-D-glucopyranoside of formula 2 or a mixture thereof, said process comprising a physical admixing technique. Formula 1
Formula 2 In one embodiment of the invention, the physical admixing technique is selected from dialysis, molecular sieving and by membranes.
In another embodiment of the invention, the process of preparation of the bioenhancer comprises use of water, alcohol, combinations of water and alcohol, hydrocarbons, ketones and ethers.
In one embodiment of the invention, the anti infective agent is selected from the group consisting of penicillins including semi synthetic, cephalosporins, aminoglycosides, glycopeptides, fluroquinolones, macrolides, tetracyclines, first and second line anti-TB drugs, antileprosy drugs, oxazolidelones, antifungal agents, antiviral agents and pyrimidine derivatives - sulphonamides combination.
In a further embodiment of the invention, the anti-fungal agent is selected from the group consisting of polyenes, imidazoles and triazoles.
In yet another embodiment of the invention, the antiviral agent is selected from the group consisting of Zidovudines, idouridine, acyclovir and ribavarine.
In another embodiment of the invention, the 3',5-Dihydroxy flavone 7-O-β-D- galacturonide-4'-O- β-D-glucopyranoside is used in pure form or in the form of a HPLC fingerprinted fraction of 3',5-Dihydroxy flavone 7-O-β-D-galacturonide-4'-O- β-D- glucopyranoside from Cuminum cyminum or a sub fraction.
In another embodiment of the invention, the concentration of the anti infective is two to eight times lesser than when such anti infective is used without the bioenhancer.
In another embodiment of the invention, the composition includes one or more pharmaceutically acceptable additives and excipients.
In another embodiment of the invention, the additives/excipients are selected from the group consisting of nutrients comprising proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, starch-gelatin paste, and/ or pharmaceutically acceptable carriers, diluents and solvents.
In another embodiment of the invention, the composition is in oral administration form. In a further embodiment of the invention, the ratio of the anti-infective to the bioenhancer is in the range of 1 : 1 to 1:5.
In yet another embodiment of the invention, the additives have no effect on the anti- infective property of the said composition. Brief description of the accompanying drawings Figure 1 is antimicrobial composition of the invention according to the checker board method.
Figure 2 is a graph showing the effect of rifampicin alone and in combination with piperine in an in vivo mice infection model.
Figure 3 is a graph showing the effect of rifampicin alone and in combination with 3',5-Dihydroxy flavone 7-O-β-D-galacturonide-4'-O- β-D-glucopyranoside of formula 2 in in vivo mice infection model. Detailed description of the invention Bioefficacy/bioavailability
Studies originating from the laboratory of the inventors resulted in conceptualisation of 'bioenhancers' wherein such agents, which by themselves are not therapeutic entities but when combined with an active drug lead to the potentiation of the pharmacologic effect of the drug. Such formulations have been found to increase the bioavailability/bioefficacy of a number of drugs even when reduced doses of drugs are present in such formulations. Evidence have been obtained for such classes of drugs which are (a) poorly bioavailable and / or efficacious, (b) require prolonged therapy, and (c) are highly toxic and expensive. For example, Patent nos. LP 172690, IP 176433 and US 5744161 disclose such art. Further studies carried out in the laboratory of the inventors have shown that such bioenhancers are not only capable of increasing bioavailability of a wide variety of therapeutic agents but are also capable of enhancing bioefficacy through a variety of mechanisms underscored in serial nos (a) to (g) below. As a result newer understanding has emerged about the factors involved in decreased cellular concentrations of drugs at which they fail to attain therapeutic levels and the strategies that make it possible to enhance the bioavailability and /or bioefficacy of these active drugs even at lower concentrations compared to standard high dosing. Some of these factors are: (a) Increasing the penetration or entry of the active drag into the pathogen even where they become persistors, besides inhibiting the capability of pathogens and abnormal tissues to reject the drag. This would eventually ensure the enhanced killing of the pathogenic microorganisms, which are otherwise inaccessible to the active drag. (b) Chemoresistance is a major problem in drag therapy. The mechanisms underlying the clinical phenomena of de novo and acquired drag resistance may arise from alterations at any step in the cell-killing pathway. These include drug transport, drag metabolism, drag targets, cellular repair mechanisms and the ability of cells to recognize a harmful toxin or pathogen. A common mechanism of reduced cellular drag accumulation is the increased expression of P-glycoprotein, a membrane transporter that efficiently removes drugs from these cells. Another limiting factor is the high activity of cytochrome P 450 dependent proteins. Both these proteins P-gp and CYP 450 have been shown to regulate the oral bioavailability of a majority of drags. P-gp is considered to be associated with MDR caused by the levels of its expression in tumors and after drug therapy.
(c) Modifying the signalling process to ensure increased accessibility of drags to the pathogens. Considerable evidence is accumulating to suggest that calcium signalling plays a major role in the therapeutic action of several drags, which are effluxed by P- gp independent pathways. (Vilpo et al, Haematologica 2000:85:806-813). cAMP mediated signal pathways on the other hand are associated with an alteration in membrane fluidity ( Friedlander G et al, Biochimica et Biophysica Acta 1990; 1022:1-
7).
(d) Immunological intervention through NO production, CMI and /or humoral immune potentiation with favourable influence on the Th 1/ Th 2 balance. (e) Sensitization of specific receptors like proteins, DNA, RNA etc thus potentiating and prolonging the effect leading to enhanced antibiotic activity against pathogens, and disorders Adequate experimental evidences have been gained in respect of several of these mechanisms. For example, piperine has been shown to intercalate deeply into the phospholipids of the cell membrane,(Ray et al, Ind. J Biochem. Biophys 1999; 36: 248-251) modulating the membrane fluidity, which may alter the activity of membrane bound transporter proteins. The overall permeability changes may affect (i) specific ion transporter channels, and (ii) also lead to bulk movement of lipophilic solutes along the paracellular pathway. Such membrane changes have also been evidenced in the action of several polyene antibiotics (Milhaud J et al, Biochimica et Biophysica Acta, 1988; 943:315-325). However, the changes caused by piperine in membrane fluidity are, as already stated, short living, completely reversible but more than any thing is selective. Had it not been so, serious side effects and toxicity should have manifested themselves during phase II and phase III clinical trials of reduced dose formulation of anti-TB drags wherein piperine was admisistered daily for six months at lOmg dose vis-a-vis standard dose anti-TB drags without piperine. The black pepper containing piperine is a part of food practically all over the world. The average amount of pepper consumed per capita will account for piperine content much more than the amount used in these formulations of present invention.
(f) Potentiating the mechanism of action of drugs and thus increasing their efficacy at lower doses e.g. inhibition of RNA polymerase transcription leading to potentiation of the effect of rifampicin at less than half the standard dose.
(g) Enhancing the absorption and/or inhibiting biotransformation of drags thereby increasing bioavailability of drags.
The products of the present invention are novel mechanism based pharmaceutical entities acting through synergism and or additive effect so that drags contained in the formulation are more bioefficaceous as a result of one or more of the mechanism as revealed above and thereby increasing the sensitivity of the target cell to an anti-infective. Description of the formulations containing bioenhancer.
The 'drag' in the present invention refers to a chemical entity capable of affecting organism's patho-physiology and used for the treatment or prevention of disease. Drags include a number of classes of compounds, but not limited to aminoglycoside, penicillins, cephalosporins and other β-lactam agents, macrolides, glycopeptides, fluoroquinolones, tetracyclines, first and second line anti-TB drags, anti-leprosy, antivirals, polyene, triazole, and imidazoles and combinations like pyrimidines, sulphamethoxazole. Drags may be a pro- drag, activated or metabolised form, consisting of charged, uncharged, hydrophilic, hydrophobic or zwitter-ion species which make their entry by simple diffusion, carrier mediated transport dependent and not dependent on energy requirements, through ion and/ or voltage gated channels.
The 'bioenhancer' refers to piperine (formula 1) or other such molecules, characterised fractions and / or extracts as a chemical entity. The process of obtaining piperine as more than 98 % pure chemicaly characterized form has been disclosed in LP 172689, IP 172690, IP 176433, US 5439891 and a co-pending US patent application No 60/306917/2001. The processes for preparation of a characterised fraction (HPLC profile enclosed) and a pure chemically characterised molecule (Fig.2) from Cuminum cyminum have been disclosed in co-pending patent application No. NF 515/2001, The ratio of those two bioenhancers to drugs may vary from 1 to 50% for the fraction and from 0.1 to 30% for the pure molecule to obtain desired reduction in MIC values anti infectives. The ratios of the drag and the bioenhancers and / or in composite bioenhancers are governed by amounts sufficient to produce enhanced therapeutic efficacy as measured by MIC of the formulation being lesser than the drug alone. A pharmaceutical carrier is generally an inert bulk agent added to make the ingredients achieve superior admixing and can be solid or liquid. The inert parts of standard pharmaceutical compositions used in this process are also part of the present invention. Study design The checkerboard method:
This is the most frequently used method to access the antimicrobial combinations in vitro. The term "checkerboard" refers to the pattern (of tubes or microtiter plate wells) formed by multiple dilutions of two drags being tested (Eliopoulos GM, Moellering RC. Antimicrobila Combinations. In: Antibiotics in Laboratory Medicine: USA: Williams & Wilkins). In the present study the checkerboard consisted of columns in which each tube (or well) contains the same amount of the standard drug (antibacterial/antifbngal/anti- TB/antiviral) being diluted along the x-axis and rows in which each tube (or well) contains the same amount of the bioenhancer being diluted on the y-axis (Fig.3). As a result each square in the checkerboard (which represents one tube/ well or plate) contained a unique combination of the standard drag and bioenhancer. The concentration range of standard drag in the present study was 64μg/ml to 0.03 μg/ml, whereas the bioenhancer was tested in the range of 500μg/ml to 0.2μg/ml. This checkerboard technique can be performed with liquid or semisolid (agar) media. Agar Method:
In this method the agar (Mueller Hinton agar, Middlebrook 7H10 agar) was autoclaved and allowed to cool to 50°C to 55°C. The combination of the standard drag and the bioenhancer was added to the agar. Serial two fold dilutions of each of standard drag and the bioenhancer were prepared in appropriate solvents. In order to maintain the desired concentrations of both agar and drags, and to rale out the effect of solvent, the volume of solvent (containing standard drag or bioenhancer) added to agar was kept small (i.e < 5% of the total volume). After the agar plates have been poured and allowed to dry, the bacteria to be tested were applied to the surface of agar with a replicating device designed to dehver a standard inoculum (approx 104 cfu|spot). The plates were incubated at 37°C for 24hrs (3 weeks in case of Mycobacterium tuberculosis) Broth Method:
The above-mentioned checkerboard was also performed with liquid media in a microtiter plate format. This method was used to study the combination of antibacterial/ antifungal/antiviral drugs with bioenhancer. Inhibitory effect of bioenhancers
All bioenhancers were evaluated for their own inhibitory effect, if any, at a concentration range of 500μg/ml to 0.2μg/ml. (Table 1, 2 & 3) Table-1: Effect of Piperine on Microorganisms
Methicillin Resistant Staphylococcus aureus
++++ No inhibition, +++ 20% inhibition, ++ 50% inhibition Table-2: Effect of fraction of Cuminum cyminum on Micro organisms
Methicillin Resistant Staphylococcus aureus ++++ No inhibition, +++ 20% inhibition, ++ 50% inhibition
Methicillin Resistant Staphylococcus aureus
++++ No inhibition, +++ 20% inhibition, ++ 50% inhibition
Examples:
The following examples are intended to demonstrate some of the preferred embodiments but in no way be constraed so as to limit the scope of the invention. Any person skilled in the art can design more formulations, which may be considered as part of the present invention. Example 1. Preparation of colourless, non-pungent 99 % pure piperine
This was done by the process claimed in Indian Patents 1726891 and IP 172690 and US Patent 5439891 and US Apphcation No. 60/306917/2001, which is incorporated herein by reference. Example 2 Decrease in the MICs of rifampicin against M.tuberculosis, M. avium and M. intracellure when used in combination with piperine and fraction of Cuminum cyminum.
Minimum Inhibitory Concentration (MIC) of rifampicin alone and in combination with piperine was performed against Mycobacterial species, using method described in the study design.
Two-fold reduction in MIC of rifampicin was observed in combination with piperine and fraction of Cuminum cyminum (Table 4-a, 4-b)
Example 3 Reduction in the dose requirement of rifampicin when used in combination with piperine and fraction of Cuminum cyminum in systemic infection model of mice. The study was conducted to see the in vivo response of rifampicin in combination with piperine. The Swiss albino mice were infected intravenously with M.tuberculosis H3 Rv (106 CFU/mouse). The infected mice were divided in groups and each group consisted of 6 mice.
The treatment started 24hrs post infection and continued for 4 weeks in once a day for 5 days in a week dosing schedule. The mice were sacrificed after 4 weeks and the CFU was enumerated from the lungs and the spleen. Rifampicin alone at 20mg/kg was able to bring about 2-log deduction in log 10 CFU. Same effect was observed with rifampicin at lOmg/kg when given in combination with piperine at 20mg/kg. Whereas fraction of Cuminum cyminum was more effective as it yielded the same reduction in log 10 CFU at 5mg/kg dose of rifampicin. (Figure 4-a, 4-b)
Table-4-a MICs of Rifampicin alone and in combination with piperine
TabIe-4-b MICs of Rifampicin alone and in combination with fraction of Cuminum cyminum.
Example 4 Decrease in the MICs of Ciprofloxacin against Staphylococcus aureus, MRSA and Staphylococcus hemolyticus when used in combination with piperine.
Minimum Inhibitory Concentration (MIC) of ciprofloxacin alone and in combination with piperine was performed against bacterial species, using method described in the study design. Two to more than eight fold reductions in MIC of ciprofloxacin was observed in combination with piperine. (Table -5)
Table- 5. MICs of Ciprofloxacin alone and in combination with piperine.
Example 5 Decrease in the MICs of fluconazole against Candida albicans, Candida parapsilosis and Candida glabrata when used in combination with piperine. Minimum Inhibitory Concentration (MIC) of fluconazole alone and in combination with piperine was performed against fungal species, using method described in the study design Two to eight fold reductions in MIC of fluconazole was observed in combination wffli piperine. (Table -6)
Table- 6 MICs of Fluconazole alone and in combination with piperine (P)
Example 6 List of drugs cited in accompanying Table 7 as some of the examples for the purpose of the present invention.
REFERENCES
1. Gutman LT. The use of TMP-SMX in children: a review of adverse reactions and indications. Pediatr Infect Dis 1984;3 : 349-57.
2. Bushby SRM. Synergy of trimethoprim and sulfonamides: History and current status. In: Antibiotics and Antibiosis in Agriculture, London: Butterworths. 1977;64-81.
3. Olin BR, ed. Drag Facts and Comparisons. St. Louis, Facts and Comparisons, Inc.; 1998: 408b-409d.
4. Cockerill FR, Edson RS. TMP-SMX. Mayo Clin Proc 1991;66: 1260-9. Table 7
NF/158/03

Claims

We claim:
1. A composition useful for enhanced therapeutic effect at reduced doses of the anti infectives against infection caused bya microorganism comprising a mixture of an anti- infective agent and a bioenhancer selected from piperine of formula 1 and 3',5-Dihydroxy flavone 7-O-β-D-galacturonide-4'-0- β-D-glucopyranoside of formula 2 or a mixture thereof.
Formula 1
CH-OH
Formula 2
2. A composition as claimed in claim 1 wherein the anti infective agent is selected from the group consisting of penicillins including semi synthetic, cephalosporins, aminoglycosides, glycopeptides, fluroquinolones, macrolides, tetracyclines, first and second line anti-TB drags, antileprosy drags, oxazolidelones, antifungal agents, antiviral agents and pyrimidine derivatives - sulphonamides combination.
3. A composition as claimed in claim 2 wherein the anti-fungal agent is selected from the group consisting of polyenes, imidazoles and triazoles.
4. A composition as claimed in claim 2 wherein the antiviral agent is selected from the group consisting of Zidovudines, idouridine, acyclovir and ribavarine.
5. A composition as claimed in claim 1 wherein the 3',5-Dihydroxy flavone 7-O-β-D- galacturonide-4'-O- β-D-glucopyranoside is used in pure form or in the form of a HPLC fingerprinted fraction of 3',5-Dihydroxy flavone 7-O-β-D-galacturonide-4'-O- β-D- glucopyranoside from Cuminum cyminum or a sub fraction.
6. A composition as claimed in claim 1 wherein concentration of the anti infective is two to eight times lesser than when such anti infective is used without the bioenhancer.
7. A composition as claimed in claim 1 wherein the composition includes one or more pharmaceutically acceptable additives and excipients.
8. A composition as claimed in claim 7 wherein the additives/excipients are selected from the group consisting of nutrients comprising proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, starch-gelatin paste, and/ or pharmaceutically acceptable carriers, diluents and solvents.
9. A composition as claimed in claim 1 wherein the composition is in oral administration form.
10. A composition as claimed in claim 1 wherein the ratio of the anti-infective to the bioenhancer is in the range of 1 : 1 to 1:5.
11. A composition as claimed in claim 7 wherein the additives have no effect on the anti- infective property of the said composition.
12. A process for the preparation of a composition useful for enhanced therapeutic effect at reduced doses of the anti infectives against infection caused by a microorganism comprising a mixture of an anti-infective agent and a bioenhancer selected from piperine of formula 1 and 3',5-Dihydroxy flavone 7-O-β-D-galacturonide-4'-O- β-D-glucopyranoside of formula 2 or a mixture thereof, said process comprising a physical admixing technique.
Formula 1
Formula 2 13. A process as claimed in claim 12 wherein the physical admixing technique is selected from dialysis, molecular sieving and by membranes.
14. A process as claimed in claim 12 wherein the process of preparation of the bioenhancer comprises use of water, alcohol, combinations of water and alcohol, hydrocarbons, ketones and ethers.
15. A process as claimed in claim 12 wherein the anti infective agent is selected from the group consisting of penicillins including semi synthetic, cephalosporins, aminoglycosides, glycopeptides, fluroquinolones, macrolides, tetracyclines, first and second line anti-TB drags, antileprosy drags, oxazolidelones, antifungal agents, antiviral agents and pyrimidine derivatives - sulphonamides combination.
16. A process as claimed in claim 15 wherein the anti-fungal agent is selected from the group consisting of polyenes, imidazoles and triazoles.
17. A process as claimed in claim 15 wherein the antiviral agent is selected from the group consisting of Zidovudines, idouridine, acyclovir and ribavarine.
18. A process as claimed in claim 12 wherein the 3',5-Dihydroxy flavone 7-O-β-D- galacturonide-4'-O- β-D-glucopyranoside is used in pure form or in the form of a HPLC fingerprinted fraction of 3',5-Dihydroxy flavone 7-O-β-D-galacturonide-4'-O- β-D- glucopyranoside from Cuminum cyminum or a sub fraction.
19. A process as claimed in claim 12 wherein the concentration of the anti infective is two to eight times lesser than when such anti infective is used without the bioenhancer.
20. A process as claimed in claim 12 wherein the composition includes one or more pharmaceutically acceptable additives and excipients.
21. A process as claimed in claim 20 wherein the additives/excipients are selected from the group consisting of nutrients comprising proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, starch-gelatin paste, and/ or pharmaceutically acceptable carriers, diluents and solvents.
22. A process as claimed in claim 12 wherein the composition is in oral administration form.
23. A process as claimed in claim 12 wherein the ratio of the anti-infective to the bioenhancer is in the range of 1 : 1 to 1 :5.
24. A process as claimed in claim 20 wherein the additives have no effect on the anti- infective property of the said composition.
EP03719082A 2003-03-31 2003-03-31 Use of cuminum cyminum extract and piperine for potention of bioeffiacy of anti infectives Withdrawn EP1608370A1 (en)

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US5744161A (en) 1995-02-24 1998-04-28 Sabinsa Corporation Use of piperine as a bioavailability enhancer
US5908650A (en) * 1995-10-20 1999-06-01 Hauser, Inc. Pigment composition containing anthocyanins stabilized by plant extracts
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