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WO2013001542A1 - Comprimé bicouches optimisé comprenant deux antibiotiques actifs : le céfadroxil et l'acide clavulanique - Google Patents

Comprimé bicouches optimisé comprenant deux antibiotiques actifs : le céfadroxil et l'acide clavulanique Download PDF

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Publication number
WO2013001542A1
WO2013001542A1 PCT/IN2011/000686 IN2011000686W WO2013001542A1 WO 2013001542 A1 WO2013001542 A1 WO 2013001542A1 IN 2011000686 W IN2011000686 W IN 2011000686W WO 2013001542 A1 WO2013001542 A1 WO 2013001542A1
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WO
WIPO (PCT)
Prior art keywords
bilayer tablet
pharmaceutical composition
clavulanic acid
cefadroxil
layer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2011/000686
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English (en)
Inventor
Kumar Vijay AGGARWAL
Sanjeev GOEL
Umakant MISHRA
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Individual
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Individual
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Filing date
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Application filed by Individual filed Critical Individual
Publication of WO2013001542A1 publication Critical patent/WO2013001542A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates to a stable, bioavailability bilayer tablet which contains antibiotic agents Cefadroxil and Clavulanic acid with less reconstitution time.
  • This medication is a cephalosporin-type antibiotic used to treat a wide variety of bacterial infections.
  • This invention exhibits a slow dissolution rate of the antibiotic formulations.
  • the chemical stabilities is major desire characteristic in the case of antibiotic tablet obtained after reconstitution.
  • Bilayer tablet is a formulation of two or more active ingredients combined in a single dosage form available in certain fixed doses.
  • the invention is therefore advantageous in that it allows the formation of a stable bilayer tablet containing two active pharmaceutical agents.
  • Other advantages include the ability of the pharmaceutical formulation to be antibiotic .and stored suitable to be reconstituted as an aqueous solution, which solution is suitable to be administered to a patient in need thereof.
  • Batch of tablet made in accordance with given formula were stored in blister strip/sealed container together with commercially available tablets with similar levels of actives storage was at 40 degree C. and relative humidity 75%. After 4week storage, it was evident that there was marked discoloration and bulging in the reference tablets where as that of the invention tablets remain unchanged (as it is) the brown discoloration are due to potassium clavulanate inactivation. This indicated that the stability of potassium clavulanate in the invention tablets has been markedly enhanced.
  • Enhanced chemical stability of the pharmaceutical formulation means the pharmaceutical formulation is stable, Enhanced chemical stability of the both active ingredients means the bilayer tablet is suitable for storage from 20..degree C. to about 30..degree. C. preferably for about 18 months or more.
  • Extended pharmaceutical shelf life offers significant economic advantages.
  • the present invention discloses stable pharmaceutical formulations comprising two active pharmaceutical ingredients and at least one dissolution enhancing agent sufficient to substantially dissolve both ingredients in at least one aqueous diluent.
  • Cefadroxil is a semi synthetic cephalosporin antibiotic intended for oral administration. It is a white to yellowish- white crystalline powder. It is chemically designated as 5-Thia-l-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid, 7-[[amino(4-hydroxyphenyl)acetyl]amino]-3-methyl-8- oxo-, monohydrate, [6R-[6a,7p'(R*)]]-. It has the molecular formula C16H17N3O5S » H20 and the molecular weight of 381.40.
  • Cefadroxil is a broad spectrum antibiotic of the cephalosporin type, effective in gram- positive and gram- negative bacterial infections. It is a bactericidal antibiotic.
  • Cefadroxil is a first generation cephalosporin antibacterial drugs that is the para-hydroxy derivative of cefalexin and is used similarly in the treatment of mild to moderate susceptible infections, such as the bacterium streptococcus pyogenes,cousing the disease popularly called strepthroat or streptococcal tonsillitis, urinary tract infection(UTI) reproductive tract infection (RTI) and skin infections.
  • mild to moderate susceptible infections such as the bacterium streptococcus pyogenes,cousing the disease popularly called strepthroat or streptococcal tonsillitis, urinary tract infection(UTI) reproductive tract infection (RTI) and skin infections.
  • Cephalosporins are bactericidal because of their inhibition of cell-wall synthesis. Cefadroxil has been shown to be active against the following organisms both in vitro and in clinical infections for example Beta-hemolytic streptococci, Staphylococci, including penicillinase- producing strains,Streptococcus (Diplococcus) pneumoniae, Escherichia coli ,Proteus mirabilis ,Klebsiella species ,Moraxella (Branhamella) catarrhalis thereof.
  • Cefadroxil is almost completely absorbed from the gastrointestinal tract. After doses of 500 mg and 1 g by mouth, peak plasma concentrations of about 16 and 30 micrograms/mL respectively are obtained after 1.5 to 2 hours. Although peak concentrations are similar to those of cefalexin, plasma concentrations are more sustained. Dosage with food does not appear to affect the absorption of cefadroxil.
  • cefadroxil About 20% of cefadroxil is reported to be bound to plasma proteins.
  • the plasma half-life of cefadroxil is about 1.5 hours and is prolonged in patients with renal impairment.
  • Cefadroxil is widely distributed to body tissues and fluids. It crosses the placenta and appears in breast milk.
  • Cefadroxil More than 90% of a dose of cefadroxil may be excreted unchanged in the urine within 24 hours by glomerular filtration and tubular secretion; peak urinary concentrations of 1.8 mg/mL have been reported after a dose of 500 mg.
  • Cefadroxil is removed by haemodialysis. Cefadroxil is given by mouth in the form of tablet, capsule, and oral suspension, and doses are expressed in terms of the anhydrous substances. Cefadroxil is used as an antibiotic prophylaxis before dental procedure in case of penicillin allergy.
  • Cefadroxil is a bactericidal and acts by inhibition of bacterial cell wall synthesis. It passes through porin channels in the bacterial cell wall and binds to the penicillin binding proteins,(PBPs) in the cell membrane this leads to reduced synthesis of peptidoglycan and results in damages of cell wall. Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity.
  • PBPs penicillin-binding proteins
  • Clavulanic acid is a beta-lactamase inhibitor Combined with a class of beta-lactam group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete beta-lactamase, which otherwise inactivates most beta-lactam group antibiotics by breaking of beta lactam ring The bioavailability is "well absorbed”.
  • a beta-lactamase inhibitor is a drug given in conjunction with a beta-lactam antibiotic. Although the inhibitor does not usually have significant antibiotic activity on its own, it inhibits activity
  • Beta- lactamase inhibitors in clinical use include clavulanic acid and its potassium salt. In its most common form the potassium salt potassium clavulanate is combined with beta-lactam antibiotic .
  • Potassium clavulanate diluted is a dry mixture of potassium clavulanate and MCC or silica
  • colloidal anhydrous silica are colloidal hydrated silica, more hygroscopic moisture and temperature sensitive having pH 4.8 to 8 water not more than 2.5 %. It can be freely soluble in water, slightly soluble in ethanol 95%.
  • Clavulanic acid has small basic antimicrobial activity, despite sharing the beta-lactam ring that is characteristic of beta-lactam antibiotics. However, the similarity in chemical structure allows the molecule to interact with the enzyme beta-lactamase secreted by certain bacteria to confer resistance to beta-lactam antibiotics. Clavulanic acid is a suicide inhibitor, its covalently bonding to a serine residue in the active site of the beta-lactamase.
  • Cefadroxil is a first generations Cephalosporin antibiotic, effective against a wide spectrum of sensitive gram positive, Gram negative and anaerobic bacterial pathogens including beta- lactamase producing strains. It has high affinity for penicillin binding proteins with varying site of activity. It acts by inhibition of bacterial cell wall synthesis. The elimination half-life is about 2-3 hours, with little variation over the usual therapeutic dosage range.
  • Clavulanic acid is a naturally derived beta lactamase inhibitor produced by streptomyces clavuligerus. Clavulanic acid is an irreversible inhibitor of intracellular and extra cellular beta- lactamases, demonstrating concentration-dependent and competitive inhibition. It has a high affinity for the class A beta-lactamases.
  • beta-lactamases which includes the plasmid-mediated TEM and SHV enzymes is found frequently in members of the Enterobacteriaceae, Heamophilus influenzae and Neisseria gonorrhoeae.
  • the chromosomally mediated beta-lactamases of Klebsiella pneumoniae, Proteus mirabilis, proteus vulgaris, Bacteroides fragilis and Moraxella catarrhalis are also inhibited, as are the extended-spectrum beta-lactamases.
  • the frequency of beta- lactamases mediated resistance ha continued to rise over the years, but the majority of clinically significant beta-lactamases are inhibited by potassium clavulanate.
  • Beta-lactam antibiotics such as the penicillin's and cephalosporins, act by disrupting the development of bacterial cells walls thus causing the disintegration of the bacteria.
  • some bacteria acquire the genes to produce enzymes which inactivate this mode of action. So called beta-lactamases- drastically reducing the efficacy of this class of antibiotics.
  • Clavulanic acid has a similar structure to the beta-lactam antibiotics but binds irreversibly to the beta-lactamase enzymes as suicide inhibitor. Used in combination with the beta-lactam antibiotics. It has become one of the most prescribed antibiotics prolonging the effective life of antibiotics. Cefadroxil is found to be ineffective against bacteria which produces ESBL (Extended- Spectrum Beta-Lactamases) enzyme and resistance is seen in such types of bacteria. The combination of Cefadroxil and clavulanic acid (Beta-Lactamaes inhibitor) provides a solution for treatment of bacterial infections caused by beta lactam resistant pathogens.
  • ESBL Extended- Spectrum Beta-Lactamases
  • cefadroxil and clavulanic acid provide a solution for treatment of bacterial infections caused by beta lactam resistant pathogens.
  • Cefadroxil is used to treat multiple bacterial infections in different parts of the body.
  • Cefadroxil and clavulanic acid can be used as a second line therapy where cefadroxil alone is not able to show its bactericidal activity.
  • Clavulanic acid acts as beta-lactamase inhibitor thus making cefadroxil effective against resistant bacteria.
  • Cefadroxil is generally well tolerated; well absorbed following oral administration and absorption is not affect by the presence of food. Presence of food increases the absorption of drugs.
  • the pharmaceutical formulation of the invention comprises diluents, binder and disintigrants, lubricant, antiadherent, Film forming agents, moisture barrier agent, glidants and pharmaceutically acceptable salt thereof.
  • the pharmaceutical formulation further comprises Diluent which is important in the pharmaceutical industry. They are inactive ingredients that are added to tablets and capsules in addition to the active drug. These additives may be used as binders, disintegrants (help the tablet break apart in the digestive system), or flavor enhancers. Some very common diluents in tablets include starch, cellulose derivatives, magnesium stearate and Micro crystalline cellulose powder (MCCP) thereof. In a preferred embodiment, the diluent agent in the pharmaceutical formulation is MCCP.
  • the pharmaceutical formulation further comprises lubricant which is a substance introduced between two moving surfaces to reduce the friction between them, improving efficiency.
  • lubricant is a substance introduced between two moving surfaces to reduce the friction between them, improving efficiency.
  • TALC TALC
  • AEROSIL AEROSIL
  • the pharmaceutical formulation further comprises Anti-adherent which Prevents sticking to punch faces or in the case of encapsulation, lubricants prevent sticking to machine dosators, tamping pins.
  • Anti-adherent which Prevents sticking to punch faces or in the case of encapsulation, lubricants prevent sticking to machine dosators, tamping pins.
  • MAGNESIUM STEARATE/Sodium steryl fumarate more preferably Magnesium Stearate.
  • the pharmaceutical formulation further comprises Glidant which is enhancing product flow by reducing interparticulate friction.
  • Glidant which is enhancing product flow by reducing interparticulate friction.
  • Glidant Preferably MAGNESIUM STEARATE, TALC and AEROSIL.
  • the pharmaceutical formulation further comprises binder which preferably HPMC. It does not interact with drugs due to non ionic character has superior stability provide variety of function (water retention, thickening, reduce surface tension and improve solubility of drugs.
  • the pharmaceutical formulation further comprises Film forming agents, moisture barrier agents which preferably Ethylcellulose.
  • the pharmaceutical formulation further comprises plastisizer for film coating which preferably dibutylpthalate, PEG 6000 and triacetin more preferably dibutylpthalate.
  • the pharmaceutical formulation further comprises white pigment and opacifying agents in film coating mixes for tablet preferably titanium dioxide.
  • the pharmaceutical formulation further comprises super disintigrants in tablet for improving release of active substances, used as solubility enhancer. It rapidly exhibits high capillary activity and pronounced hydration capacity with little tendency to form gel which is preferably 1 venyl 2 pyrrolidinone (CLPVP).
  • CLPVP 1 venyl 2 pyrrolidinone
  • the pharmaceutical formulation further comprises super disintigrants in tablet for improving release of active substances.
  • active substances which preferably cross carmilose sodium.
  • the concentration of Cefadroxil in individual layer will be 56.25% to 68.75% preferably 62.5% for adult. Accordingly both layer tablet weight% will be36%to 44% preferably 40%. It can be available in various concentration for example 31.25%, 15.6% and 7.8% thereof.
  • the concentration of Clavulanic acid in individual layer will be 25% to 50% preferably 27.80% and 13.5% thereof. Accordingly both layer tablet weight clavulanic acid % will be 9%to 11% preferably 10%.
  • Dry Granulation This process of granulation is commonly used when the tablet ingredients are sensitive to moisture or are unable to withstand elevated temperature during drying. Under such conditions dry granulation is the method of choice provided the tablet ingredients have sufficient inherent binding or cohesive properties.
  • the essential steps are weighing, mixing, slugging, dry screening, lubrication and compression.
  • the present bilayer tablet aims at formulating bilayer tablet of cefadroxil with potassium clavulanate both layer as fast release.
  • the present invention relates to an improvement in bilayer tableting technology and provides a method of producing a bilayer pharmaceutical tablet.
  • the flowing examples illustrate the invention in further detail.
  • Core tablet composition - (cefadroxil layer) cefadroxil monohydrate 540mg eq.to cefadroxil 500mg (quantity based on assay)
  • Potassium clavulanate (second layer) composition - potassium clavulanate diluted 308mg eq. to clavulanic acid 125mg (based on assay) , Microcrystalline cellulose (PH 200) 61mg, Microcrystalline cellulose 40mg, talc 2mg, 1-venyl 2-pyrrolidinone 20mg, Aerosil 3.334mg, Magnesium stearate 5 mg, HPMC (hydroxypropyl methyl cellulose) 10.666 mg Total weight : 450mg .
  • Compression - compressed the tablet using suitable compression machine, introducing the first or the second layer composition in a tablets press compressing said tablet layer composition to form a tablet layer, introducing the other tablet layer composition into the tablets press and compressing both tablets layer composition to form a bilayer tablet check the physical parameters such as hardness, friability, thickness, weight variation and disintegration test.
  • Coating formula - film forming composition (protective coat ) HPMC E5 2.5mg, ethyl cellulose 2.5mg, dibutylpthalate 0.83mg, talc 0.43mg, titanium dioxide 0.83mg, isopropyl alcohol 41.66mg, methylene chloride 83.33mg, the protective film forming composition were prepared by dispersing the ingredients in solvent mixture. It was then applied by spray coating over tablet in a coating pan target weight gain 0.35-0.55%
  • film forming composition HPMC E15 12.5mg, dibutylpthalate 3.33mg, talc 0.93 mg, titanium dioxide 5mg, isopropyl alcohol 116.66mg, methylene chloride 350mg, the film forming composition were prepared by dispersing the ingredients in solvent mixture and filtered. The filtered solution was sprayed over previously coated tablet in a coating pan. Target weight gain 1.5-2.0%
  • RTI Reproductive tract infection

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique optimisée pour une forme galénique de type comprimé bicouches comprenant au moins un antibiotique ou un sel pharmaceutiquement acceptable de celui-ci, et au moins un agent améliorant la dissolution en quantité suffisante pour sensiblement dissoudre ledit agent diluant aqueux, un liant, des agents délitants, des agents formant un film, des agents barrières contre l'humidité. L'invention concerne ainsi les deux principes actifs dans des formes galéniques unitaires présentant, en même temps, une solubilité et une stabilité élevées en éliminant les interactions croisées ou les incompatibilités chimiques entre deux molécules médicamenteuses physiques, chimiques et physicochimiques différentes grâce à une séparation physique, et en permettant le développement de profils de libération différents pour les médicaments à la fois pour une libération immédiate et pour une libération immédiate ajoutée à une libération prolongée et en favorisant le confort et l'observance du patient.
PCT/IN2011/000686 2011-06-30 2011-10-03 Comprimé bicouches optimisé comprenant deux antibiotiques actifs : le céfadroxil et l'acide clavulanique Ceased WO2013001542A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1853/DEL/2011 2011-06-30
IN1853DE2011 2011-06-30

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WO2013001542A1 true WO2013001542A1 (fr) 2013-01-03

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PCT/IN2011/000686 Ceased WO2013001542A1 (fr) 2011-06-30 2011-10-03 Comprimé bicouches optimisé comprenant deux antibiotiques actifs : le céfadroxil et l'acide clavulanique

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH501436A (de) * 1969-04-18 1971-01-15 Buerkle & Co Robert Giesskopf an Flüssigkeitsgiessmaschine
US20060024368A1 (en) * 2004-07-30 2006-02-02 Reza Fassihi Compressed composite delivery system for release-rate modulation of bioactives
CN1729983A (zh) * 2005-06-20 2006-02-08 四川大学 头孢羟氨苄和β－内酰胺酶抑制剂的药物组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH501436A (de) * 1969-04-18 1971-01-15 Buerkle & Co Robert Giesskopf an Flüssigkeitsgiessmaschine
US20060024368A1 (en) * 2004-07-30 2006-02-02 Reza Fassihi Compressed composite delivery system for release-rate modulation of bioactives
CN1729983A (zh) * 2005-06-20 2006-02-08 四川大学 头孢羟氨苄和β－内酰胺酶抑制剂的药物组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 200806, Derwent World Patents Index; AN 2008-A87209, XP002683499 *

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