WO2001062231A1 - Antibiotic composition with inhibitor - Google Patents
Antibiotic composition with inhibitor Download PDFInfo
- Publication number
- WO2001062231A1 WO2001062231A1 PCT/US2001/005984 US0105984W WO0162231A1 WO 2001062231 A1 WO2001062231 A1 WO 2001062231A1 US 0105984 W US0105984 W US 0105984W WO 0162231 A1 WO0162231 A1 WO 0162231A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antibiotic
- dosage form
- patient
- inhibitor
- treating
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K9/48—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
Definitions
- This invention relates to antibiotics that contain beta-lactam rings that are subject to attack by beta-lactamases in combination with beta-lactamase inhibitors.
- beta-lactam rings for example, pencillins and cephalosporins
- beta-lactamases sometimes called penicillinases
- Clavulanic acid, and its derivatives, as well as sulbactam are generally used to bind irreversibly to the beta- lactamase to prevent its activity against such an antibiotic.
- an antibiotic composition that includes the inhibitor with such combinations generally being delivered as an immediate release dosage form.
- the present invention relates to an improved, antibiotic composition that is comprised of at least four different dosage forms, two of which include at least one antibiotic with a beta-lactam ring ( or any portions of such a ring) and two of which include at least one beta-lactamase inhibitor, with the four different dosage forms having release profiles such that there is a first dosage form that releases said at least one antibiotic, a second dosage form that releases at least one beta-lactamase inhibitor, a third dosage form that releases said at least one antibiotic, and a fourth dosage form that releases said at least one inhibitor, with the release profile of the first and second dosage forms being such that the maximum serum concentration of the inhibitor is reached at a time no sooner and preferably after the time at which the maximum serum concentration of the antibiotic released from the first dosage form is achieved, with the third dosage form having a release profile such that the second antibiotic achieves a maximum serum concentration at a time no sooner than and preferably after the time at which the inhibitor released from the second dosage form reaches a maximum serum concentration, and with the fourth dosage form having a
- the initiation of release from the second, third and fourth dosage form occurs at least one hour after initiation of release from the first, second and third form, respectively.
- a maximum serum concentration for the antibiotic released from the first dosage form is achieved in no more than about three hours; the maximum serum concentration for the inhibitor released from the second dosage form is reached in a time of from about three to six hours; the maximum serum concentration of the antibiotic released from the third dosage form is reached in from about six to nine hours, and the maximum serum concentration released from the fourth dosage form is achieved in no more than twelve hours, with such times being measured from the time of administration of the antibiotic composition that is comprised of the at least four different dosage forms.
- the at least four dosage forms are provided with release profiles such that the inhibitor is released from the second dosage form after the maximum serum concentration is achieved for antibiotic released from the first dosage form; antibiotic is released from the third dosage form after the maximum serum concentration is reached for the inhibitor released from the second dosage form, and inhibitor is released from the fourth dosage form after the maximum serum concentration is reached for the antibiotic released from the third dosage form.
- each inhibitor release achieves a serum concentration maximum no sooner than and preferably after the serum concentration maximum of the immediately preceding antibiotic released, and the next antibiotic released reaches a serum concentration maximum no sooner than and preferably after the serum concentration maximum is achieved for the immediately preceding inhibitor dosage form.
- each of the dosage forms that contains an inhibitor includes such inhibitor in an amount that is effective to inhibit chemical inactivation of the antibiotic by beta-lactamase.
- the dosage forms that contain the inhibitor contain such an inhibitor in an amount from about 20 percent to about 80 percent.
- the dosage forms that contain the antibiotic generally include the antibiotic in an amount from about 30 percent to about 80 percent.
- Each of the dosage forms that deliver antibiotics include from 30% to 70% of the dosage of the antibiotic to be delivered by the composition.
- the first dosage form that releases antibiotic is an immediate release dosage form.
- the second, third, and fourth dosage forms are delayed release dosage forms, which may be pH independent or pH dependent (enteric) dosage forms.
- the second, third and fourth dosage forms are formulated in a matter to provide the release profiles as hereinabove described.
- each of the dosage forms may be in the form of a pellet or a particle, with pellet particles being formed into the overall composition, in the form, for example, of the pellet particles in a capsule, or the pellet particles embedded in a tablet or suspended in a liquid suspension.
- the antibiotic composition of the prevent invention may be administered, for example, by any of the following routes of administration: sublingual, transmucosal, transdermal, parenteral, and preferably are administered orally.
- the composition includes a therapeutically effective amount of the antibiotic, which amount will vary with the antibiotic to be used, the disease or infection to be treated, and the number of times that the composition is to be delivered in a day.
- the antibiotic product of the present invention as hereinabove described, may be formulated for administration by a variety of routes of administration.
- the antibiotic product may be formulated in a way that is suitable for topical administration; administration in the eye or the ear; rectal or vaginal administration; as nose drops; by inhalation; as an injectable; or for oral administration.
- the antibiotic product is formulated in a manner such that it is suitable for oral administration.
- the antibiotic in formulating the antibiotic product for topical administration, such as by application to the skin, may be formulated for topical administration by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion.
- the immediate release dosage forms are in the continuous phase
- the delayed release dosage form is in a discontinuous phase.
- an antibiotic product in the form of a patch which includes different antibiotic and inhibitor dosage forms having different release profiles, as hereinabove described.
- the antibiotic product with different dosage forms with different release profiles may be formulated for rectal or vaginal administration, as known in the art. This may take the form of a cream or emulsion, or other dissolvable dosage forms similar to those used for topical administration.
- the antibiotic product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation.
- the antibiotic product is formulated in a manner suitable for oral administration.
- each of the dosage forms may be used as a pellet or a particle, with a pellet or particle then being formed into a unitary pharmaceutical product, for example, in a capsule, or embedded in a tablet, or suspended in a liquid for oral administration.
- each of the dosage forms of the product may be formulated as a tablet, with each of the tablets being put into a capsule to produce a unitary antibiotic product.
- antibiotic products may include a first dosage form in the form of a tablet that is an immediate release tablet, and may also include three additional tablets, each of which provides for a delayed release of the antibiotic and inhibitor, as hereinabove described.
- the antibiotics that are employed in the present invention are ones that include a beta-lactam ring or a portion thereof such as for example, penicillin derivatives, such as penicillin V, penicillin G, penicillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, piperacillin, nafcillin, cloxacillin, dicloxacillin, monobactams such as aztreonam, carbapenems such as imipenem, cephalosporins such as cefoxitan, cephalexin, ceferiaxone, cefuroxime, cefpodoxime, and others.
- penicillin derivatives such as penicillin V, penicillin G, penicillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, piperacillin, nafcillin, cloxacillin, dicloxacillin
- monobactams such as aztreonam
- carbapenems such as imipenem
- the beta-lactamase inhibitors maybe any one of a wide variety that are effective to inhibit the action of beta-lactamases on a beta-lactam ring, such as clavulanic acid and its derivatives, sulbactam.
- the product contains sufficient antibiotic for a twenty- four hour period whereby the product is administered once a day.
- the immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the antibiotic. This can take the form of either a discrete pellet or granule that is mixed in with, or compressed with, the other three components.
- the materials to be added to the antibiotics for the immediate release component can be, but are not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000- 10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons.
- ingredients in this system may be useful to have other ingredients in this system to aid in the dissolution of the drug, or the breakdown of the component after ingestion or administration.
- These ingredients can be surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non- ionic surfactants such as the Pluronic line of surfactants, or any other material with surface active properties, or any combination of the above.
- surfactants such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non- ionic surfactants such as the Pluronic line of surfactants, or
- These materials may be present in the rate of 0.05-15% (W/W).
- compositions in this composition are the same immediate release unit, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
- Materials that can be used to obtain a delay in release suitable for this component of the invention can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit), propylene glycol, and ethylcellulose.
- PEG polyethylene glycol
- Carbowax, Polyox polyethylene glycol
- waxes such as white wax or bees wax
- paraffin acrylic acid derivatives
- acrylic acid derivatives Eudragit
- propylene glycol and ethylcellulose
- compositions in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
- the kind of materials useful for this purpose can be, but are not limited to, cellulose acetate pthalate, Eudragit L, and other pthalate salts of cellulose derivatives.
- These materials can be present in concentrations from 4-20% (WAV).
- Clarithromycin 65% (WAV)
- Clarithromycin 75 % (WAV)
- composition of the antibiotic or inhibitor matrix pellets provided in Table 1.
- Table 1 Composition of Antibiotic Pellets
- composition of the aqueous Eudragit L30D-55 dispersion applied to the antibiotic matrix pellets and to the inhibitor matrix pellets is provided below in Table 2.
- the TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
- composition of the aqueous Eudragit® S 100 dispersion applied to the inhibitor matrix pellets is provided below in Table 3.
- Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
- Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and S100 coated pellets respectively.
- the capsule is filled with the four different pellets to achieve the desired dosage.
- the immediate release pellets contain the antibiotic; the L30 D-55 12% weight gain coated pellets contain the inhibitor; the L30 D-55 30% weight gain coated pellets contain the antibiotic and the SI 00 coated pellets contain the inhibitor.
- the present invention is advantageous in that the beta-lactamase inhibitor will be dosed at a lower peak concentration, giving rise to fewer side effects.
- the alternative dosing of the antibiotic and the inhibitor will alternate the exposure to the bacteria in such a way as to make the antibiotic more effective than if they were co- administered, and thereby competing with each other for sites on the bacterial cell wall receptors.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002399856A CA2399856C (en) | 2000-02-24 | 2001-02-23 | Antibiotic composition with inhibitor |
JP2001561298A JP2003531115A (en) | 2000-02-24 | 2001-02-23 | Antibiotic compositions with inhibitors |
AU2001239869A AU2001239869B2 (en) | 2000-02-24 | 2001-02-23 | Antibiotic composition with inhibitor |
EP01914484A EP1265599A4 (en) | 2000-02-24 | 2001-02-23 | Antibiotic composition with inhibitor |
AU3986901A AU3986901A (en) | 2000-02-24 | 2001-02-23 | Antibiotic composition with inhibitor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14258200P | 2000-02-24 | 2000-02-24 | |
US60/142,582 | 2000-02-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001062231A1 true WO2001062231A1 (en) | 2001-08-30 |
Family
ID=22500418
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/005984 WO2001062231A1 (en) | 2000-02-24 | 2001-02-23 | Antibiotic composition with inhibitor |
Country Status (4)
Country | Link |
---|---|
JP (1) | JP2003531115A (en) |
AU (2) | AU3986901A (en) |
CA (1) | CA2399856C (en) |
WO (1) | WO2001062231A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6660299B2 (en) | 1999-04-13 | 2003-12-09 | Beecham Pharmaceuticals Limited | Modified release pharmaceutical formulation comprising amoxycillin |
US6746692B2 (en) | 1999-04-13 | 2004-06-08 | Beecham Pharmaceuticals (Pte) Limited | Modified release pharmaceutical formulation comprising amoxycillin |
US6756057B2 (en) | 2000-10-12 | 2004-06-29 | Beecham Pharmaceuticals (Pte) Limited | Amoxicillin and potassium clavulanate dosage form |
US6783773B1 (en) | 1999-04-13 | 2004-08-31 | Beecham Pharmaceuticals (Pte) Limited | Composition comprising amoxicillin and potassium clavulanate |
WO2011139253A3 (en) * | 2010-05-04 | 2012-05-31 | Mahmut Bilgic | Pharmaceutical compositions comprising ceftibuten |
US8303988B2 (en) | 2000-10-13 | 2012-11-06 | Shionogi Inc. | Antifungal once-a-day product, use and formulation thereof |
US8889187B2 (en) | 2000-02-24 | 2014-11-18 | Shionogi Inc. | Once a day amoxicillin product comprising immediate and delayed release dosage forms |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1996004908A1 (en) * | 1994-08-17 | 1996-02-22 | Smithkline Beecham Plc | Pharmaceutical formulation containing amoxycillin and potassium clavulanate |
WO1998022091A1 (en) * | 1996-11-17 | 1998-05-28 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | PHARMACEUTICAL PREPARATIONS FOR THE CONTROLLED RELEASE OF β-LACTAM ANTIBIOTICS |
US6027748A (en) * | 1997-01-08 | 2000-02-22 | Jagotec Ag | Pharmaceutical tablet, completely coated, for controlled release of active principles that present problems of bio-availability linked to gastro-intestinal absorption |
Family Cites Families (12)
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JPS601128A (en) * | 1983-06-15 | 1985-01-07 | Shionogi & Co Ltd | Long-acting cefaclor preparation |
JPS61210025A (en) * | 1985-03-14 | 1986-09-18 | Teisan Seiyaku Kk | Stabilized antibioitc complex granule preparation |
US4794001A (en) * | 1986-03-04 | 1988-12-27 | American Home Products Corporation | Formulations providing three distinct releases |
US5326570A (en) * | 1991-07-23 | 1994-07-05 | Pharmavene, Inc. | Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine |
US5260068A (en) * | 1992-05-04 | 1993-11-09 | Anda Sr Pharmaceuticals Inc. | Multiparticulate pulsatile drug delivery system |
US5260069A (en) * | 1992-11-27 | 1993-11-09 | Anda Sr Pharmaceuticals Inc. | Pulsatile particles drug delivery system |
IL109770A0 (en) * | 1993-05-29 | 1994-11-28 | Smithkline Beecham Corp | Thermal infusion process for preparing controlled release solid dosage forms of medicaments for oral administration and controlled release solid dosage forms of medicaments prepared thereby |
WO1996010996A1 (en) * | 1993-07-21 | 1996-04-18 | The University Of Kentucky Research Foundation | A multicompartment hard capsule with control release properties |
GB9407386D0 (en) * | 1994-04-14 | 1994-06-08 | Smithkline Beecham Plc | Pharmaceutical formulation |
US6090985A (en) * | 1996-07-26 | 2000-07-18 | The Trustees Of The University Of Pennsylvania | Chiral polyanilines and the synthesis thereof |
DE19718012C1 (en) * | 1997-04-29 | 1998-10-08 | Jenapharm Gmbh | Process for the production of orally applicable solid pharmaceutical forms with controlled release of active substances |
US5840329A (en) * | 1997-05-15 | 1998-11-24 | Bioadvances Llc | Pulsatile drug delivery system |
-
2001
- 2001-02-23 AU AU3986901A patent/AU3986901A/en active Pending
- 2001-02-23 JP JP2001561298A patent/JP2003531115A/en active Pending
- 2001-02-23 AU AU2001239869A patent/AU2001239869B2/en not_active Expired
- 2001-02-23 CA CA002399856A patent/CA2399856C/en not_active Expired - Lifetime
- 2001-02-23 WO PCT/US2001/005984 patent/WO2001062231A1/en active Search and Examination
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996004908A1 (en) * | 1994-08-17 | 1996-02-22 | Smithkline Beecham Plc | Pharmaceutical formulation containing amoxycillin and potassium clavulanate |
WO1998022091A1 (en) * | 1996-11-17 | 1998-05-28 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | PHARMACEUTICAL PREPARATIONS FOR THE CONTROLLED RELEASE OF β-LACTAM ANTIBIOTICS |
US6027748A (en) * | 1997-01-08 | 2000-02-22 | Jagotec Ag | Pharmaceutical tablet, completely coated, for controlled release of active principles that present problems of bio-availability linked to gastro-intestinal absorption |
Non-Patent Citations (1)
Title |
---|
See also references of EP1265599A4 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6660299B2 (en) | 1999-04-13 | 2003-12-09 | Beecham Pharmaceuticals Limited | Modified release pharmaceutical formulation comprising amoxycillin |
US6746692B2 (en) | 1999-04-13 | 2004-06-08 | Beecham Pharmaceuticals (Pte) Limited | Modified release pharmaceutical formulation comprising amoxycillin |
US6783773B1 (en) | 1999-04-13 | 2004-08-31 | Beecham Pharmaceuticals (Pte) Limited | Composition comprising amoxicillin and potassium clavulanate |
US6878386B1 (en) | 1999-04-13 | 2005-04-12 | Beecham Pharmaceuticals (Pte) Limited | Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate |
US8889187B2 (en) | 2000-02-24 | 2014-11-18 | Shionogi Inc. | Once a day amoxicillin product comprising immediate and delayed release dosage forms |
US6756057B2 (en) | 2000-10-12 | 2004-06-29 | Beecham Pharmaceuticals (Pte) Limited | Amoxicillin and potassium clavulanate dosage form |
US8303988B2 (en) | 2000-10-13 | 2012-11-06 | Shionogi Inc. | Antifungal once-a-day product, use and formulation thereof |
WO2011139253A3 (en) * | 2010-05-04 | 2012-05-31 | Mahmut Bilgic | Pharmaceutical compositions comprising ceftibuten |
Also Published As
Publication number | Publication date |
---|---|
CA2399856A1 (en) | 2001-08-30 |
CA2399856C (en) | 2009-01-27 |
AU2001239869B2 (en) | 2005-12-15 |
AU3986901A (en) | 2001-09-03 |
JP2003531115A (en) | 2003-10-21 |
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