WO1999062559A1 - Pharmaceutical tablets comprising cefuroxime axetil - Google Patents

Pharmaceutical tablets comprising cefuroxime axetil Download PDF

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Publication number
WO1999062559A1
WO1999062559A1 PCT/CA1999/000446 CA9900446W WO9962559A1 WO 1999062559 A1 WO1999062559 A1 WO 1999062559A1 CA 9900446 W CA9900446 W CA 9900446W WO 9962559 A1 WO9962559 A1 WO 9962559A1
Authority
WO
WIPO (PCT)
Prior art keywords
cefuroxime axetil
carbonate
tablet
bicarbonate
tablets
Prior art date
Application number
PCT/CA1999/000446
Other languages
French (fr)
Inventor
Bernard Charles Sherman
Original Assignee
Bernard Charles Sherman
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bernard Charles Sherman filed Critical Bernard Charles Sherman
Priority to AU38074/99A priority Critical patent/AU3807499A/en
Publication of WO1999062559A1 publication Critical patent/WO1999062559A1/en

Links

Classifications

    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • Cefuroxime axetil is an antibiotic effective against a wide spectrum of microorganisms.
  • Antibiotics for oral administration should be in a form which provides high bioavailability, whereby absorption into the bloodstream from the gastro-intestinal tract is maximized.
  • Pure cefuroxime axetil can be produced in crystalline form or amorphous form.
  • U.S. patent 4820833 discloses that the pure amorphous form is more soluble in water than the pure crystalline form and gives higher bioavailability upon oral administration.
  • U.S. patent 4897270 further discloses that film coated tablets comprising cefuroxime axetil (even in amorphous form) give low levels of absorption into the blood stream unless the tablets are formulated such that, when the tablet is ingested, the film coating ruptures very rapidly and the core then disintegrates immediately.
  • U.S. patent 5677433 discloses a new ⁇ crystalline form which purports to have good bioavailability characteristics.
  • U.S. patents 4820833 and 4897270 teach that good absorption from tablets comprising cefuroxime axetil can be achieved only if the cefuroxime axetil used in the formulation is in pure amorphous form and the tablets contain sufficient disintegrant to cause them to disintegrate immediately in gastro-intestinal fluid.
  • Copending Canadian patent application 2,209,868 discloses that the need to use cefuroxime axetil in pure amorphous form can be overcome by making a co-precipitate of cefuroxime axetil and a water-soluble excipient.
  • prior art tablets have required inclusion of a relatively large amount of disintegrant to cause the tablets to disintegrate sufficiently rapidly to enable satisfactory absorption after ingestion.
  • the disintegrant is an ingredient which absorbs water and swells to cause the tablet to disintegrate when immersed in gastro-intestinal fluid.
  • Preferred disintegrants are water-insoluble cross-linked polymers, including, for example, croscarmellose sodium, sodium starch glycolate, and crospovidone.
  • the carbonate and bicarbonate that may be used within the scope of the invention may be any carbonate or bicarbonate that is sufficiently non-toxic to be suitable for use as a pharmaceutical excipient, including for example sodium bicarbonate, sodium carbonate, calcium carbonate, potassium carbonate, and magnesium carbonate.
  • Preferred carbonates and bicarbonates are sodium bicarbonate, sodium carbonate and calcium carbonate.
  • Gastric fluid is acidic.
  • the acid in the gastric fluid will react with the carbonate or bicarbonate.
  • the reaction causes release of carbon dioxide, and thus effervescence.
  • compositions within the scope of the present invention are thus pharmaceutical tablets that comprise cefuroxime axetil and a carbonate or bicarbonate.
  • each tablet contained of about 627 mg of cefuroxime axetil, which in turn is equivalent to about 500 mg of cefuroxime.
  • the tablets were also tested for dissolution as set out in the United States Pharmacoepia, 23rd edition, page 316.
  • the result was over 75% in 45 minutes, which exceeds the lower limit set in the United States Pharmacoepia, and is sufficient to ensure good absorption.

Abstract

A pharmaceutical tablet comprising cefuroxime axetil and a carbonate or bicarbonate.

Description

PHARMACEUTICAL TABLETS COMPRISING CEFUROXIME AXETIL
BACKGROUND
Cefuroxime axetil is an antibiotic effective against a wide spectrum of microorganisms. Antibiotics for oral administration should be in a form which provides high bioavailability, whereby absorption into the bloodstream from the gastro-intestinal tract is maximized.
For cefuroxime axetil, the prior art discloses substantial difficulties in making compositions for oral administration providing high bioavailability.
Pure cefuroxime axetil can be produced in crystalline form or amorphous form. U.S. patent 4820833 discloses that the pure amorphous form is more soluble in water than the pure crystalline form and gives higher bioavailability upon oral administration.
U.S. patent 4897270 further discloses that film coated tablets comprising cefuroxime axetil (even in amorphous form) give low levels of absorption into the blood stream unless the tablets are formulated such that, when the tablet is ingested, the film coating ruptures very rapidly and the core then disintegrates immediately.
U.S. patent 5677433 discloses a new β crystalline form which purports to have good bioavailability characteristics.
Taken together, U.S. patents 4820833 and 4897270 teach that good absorption from tablets comprising cefuroxime axetil can be achieved only if the cefuroxime axetil used in the formulation is in pure amorphous form and the tablets contain sufficient disintegrant to cause them to disintegrate immediately in gastro-intestinal fluid.
Copending Canadian patent application 2,209,868 discloses that the need to use cefuroxime axetil in pure amorphous form can be overcome by making a co-precipitate of cefuroxime axetil and a water-soluble excipient.
However, even when a co-precipitate is used, because of the tendency of cefuroxime axetil to form a gel in water, even when the cefuroxime axetil is in a co-precipitate, the tablets still must contain a substantial amount of disintegrant to cause them to disintegrate sufficiently rapidly to enable satisfactory absorption after ingestion.
It is the object of the present invention to overcome this limitation disclosed in the prior art; that is to say, to enable satisfactory absorption with a lesser amount of disintegrant in the tablet than required in prior art formulations.
BRIEF SUMMARY OF THE INVENTION
It has been found that the rate of disintegration of the tablets in gastric fluid can be enhanced by including in the tablet a carbonate or bicarbonate.
DETAILED DESCRIPTION OF THE INVENTION
As aforesaid, because of the tendency of cefuroxime axetil to form a gel in water, prior art tablets have required inclusion of a relatively large amount of disintegrant to cause the tablets to disintegrate sufficiently rapidly to enable satisfactory absorption after ingestion. The disintegrant is an ingredient which absorbs water and swells to cause the tablet to disintegrate when immersed in gastro-intestinal fluid. Preferred disintegrants are water-insoluble cross-linked polymers, including, for example, croscarmellose sodium, sodium starch glycolate, and crospovidone.
It has now been found that, for tablets containing cefuroxime axetil, the tendency to form a gel in water can be alleviated and the required quantity of disintegrant that is needed can thus be reduced by including in the tablet a carbonate or bicarbonate.
The carbonate and bicarbonate that may be used within the scope of the invention may be any carbonate or bicarbonate that is sufficiently non-toxic to be suitable for use as a pharmaceutical excipient, including for example sodium bicarbonate, sodium carbonate, calcium carbonate, potassium carbonate, and magnesium carbonate.
Preferred carbonates and bicarbonates are sodium bicarbonate, sodium carbonate and calcium carbonate.
Gastric fluid is acidic. Hence, when a tablet containing a carbonate or bicarbonate is ingested and immersed in gastric fluid, the acid in the gastric fluid will react with the carbonate or bicarbonate. The reaction causes release of carbon dioxide, and thus effervescence.
In the case of cefuroxime axetil tablets, it has been found that this effervescence helps inhibit gel formation and thus enables disintegration of the tablet with less disintegrant than otherwise required to achieve the desired rate of disintegration, and have the consequent desired dissolution and absorption. Compositions within the scope of the present invention are thus pharmaceutical tablets that comprise cefuroxime axetil and a carbonate or bicarbonate. The invention will be further illustrated by the following example, which is intended to be illustrative but not limiting of the scope of the invention.
EXAMPLE
4.5 kg of cefuroxime axetil together with 0.5 kg of sorbitol were dissolved in a mixture of 20.0 kg of acetone and 5.0 kg of water. The solution was spray- dried to obtain a co-precipitate comprising by weight 90% cefuroxime axetil and 10% sorbitol. About 0.4% by weight magnesium stearate, as a lubricant, and 0.1% by weight colloidal silicon dioxide, as glidant, were added to this Co-precipitate and the mixture was then compacted to increase its density and then ground up into granules. The following were then mixed together:
granules 3500 g crospovidone 1470 g sodium bicarbonate 700 g magnesium stearate 20 g colloidal silicon dioxide 10 g
Total : 5700 g
This mixture was then compressed into tablets of weight 1140 mg.
In view of the proportions of ingredients as aforesaid, each tablet contained of about 627 mg of cefuroxime axetil, which in turn is equivalent to about 500 mg of cefuroxime.
The tablets were also tested for dissolution as set out in the United States Pharmacoepia, 23rd edition, page 316. The result was over 75% in 45 minutes, which exceeds the lower limit set in the United States Pharmacoepia, and is sufficient to ensure good absorption.

Claims

CLAIMS:
1. A pharmaceutical tablet comprising cefuroxime axetil and a carbonate or bicarbonate.
2. A tablet as in Claim 1 further comprising a disintegrant.
3. A tablet as in Claim 1 or 2 wherein the carbonate or bicarbonate is selected from the group consisting of sodium bicarbonate, sodium carbonate, calcium carbonate, potassium carbonate and magnesium carbonate.
4. A tablet as in Claim 2 wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, and crospovidone.
5. A tablet as in any Claims 1 to 4 which comprises a co-precipitate of cefuroxime axetil and a water-soluble excipient.
PCT/CA1999/000446 1998-05-29 1999-05-18 Pharmaceutical tablets comprising cefuroxime axetil WO1999062559A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38074/99A AU3807499A (en) 1998-05-29 1999-05-18 Pharmaceutical tablets comprising cefuroxime axetil

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA 2239331 CA2239331C (en) 1998-05-29 1998-05-29 Pharmaceutical tablets comprising cefuroxime axetil
CA2,239,331 1998-05-29

Publications (1)

Publication Number Publication Date
WO1999062559A1 true WO1999062559A1 (en) 1999-12-09

Family

ID=4162505

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA1999/000446 WO1999062559A1 (en) 1998-05-29 1999-05-18 Pharmaceutical tablets comprising cefuroxime axetil

Country Status (3)

Country Link
AU (1) AU3807499A (en)
CA (1) CA2239331C (en)
WO (1) WO1999062559A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000030647A1 (en) * 1998-11-26 2000-06-02 Biochemie Gesellschaft M.B.H. Compositions comprising cefuroxime axetil
EP1342470A1 (en) * 2002-03-04 2003-09-10 Pharmathen S.A. Fast release cefuroxime axetil compositions
WO2005002540A2 (en) * 2003-07-01 2005-01-13 Ranbaxy Laboratories Limited Dry powder pharmaceutical suspension compositions of cefuroxime axetil
WO2005018618A1 (en) * 2003-08-23 2005-03-03 Korea United Pharm, Inc Formulation of stable for moisture absorption and quickly dissolved tablet containing cefuroxime axetil and it's manufacturing process
WO2005067895A1 (en) * 2004-01-16 2005-07-28 Sandoz Ag Controlled release pharmaceutical compositions
CN104230957A (en) * 2013-06-09 2014-12-24 广东立国制药有限公司 Preparing method of cefuroxime acid and method of removing DCC lactone in preparation process of the cefuroxime acid
CN106109433A (en) * 2016-08-10 2016-11-16 瑞阳制药有限公司 CEFUROXIME AXETIL Film coated tablets and preparation method thereof
CN114191375A (en) * 2021-12-20 2022-03-18 广东金城金素制药有限公司 Cefuroxime sodium for injection and preparation method thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2126479A (en) * 1982-09-10 1984-03-28 Glaxo Group Ltd Pharmaceutical-compositions in inert carbon dioxide atmosphere
US4820833A (en) * 1982-07-30 1989-04-11 Glaxo Group Limited Preparation of a highly pure, substantially amorphous form of cefuroxime axetil
US4897270A (en) * 1985-09-30 1990-01-30 Glaxo Group Limited Pharmaceutical compositions
WO1999008683A1 (en) * 1997-08-15 1999-02-25 Bernard Charles Sherman Pharmaceutical compositions comprising cefuroxime axetil

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820833A (en) * 1982-07-30 1989-04-11 Glaxo Group Limited Preparation of a highly pure, substantially amorphous form of cefuroxime axetil
GB2126479A (en) * 1982-09-10 1984-03-28 Glaxo Group Ltd Pharmaceutical-compositions in inert carbon dioxide atmosphere
US4897270A (en) * 1985-09-30 1990-01-30 Glaxo Group Limited Pharmaceutical compositions
WO1999008683A1 (en) * 1997-08-15 1999-02-25 Bernard Charles Sherman Pharmaceutical compositions comprising cefuroxime axetil

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000030647A1 (en) * 1998-11-26 2000-06-02 Biochemie Gesellschaft M.B.H. Compositions comprising cefuroxime axetil
US6727243B1 (en) 1998-11-26 2004-04-27 Biochemie Gesellschaft M.B.H. Compositions comprising cefuroxime axetil
EP1342470A1 (en) * 2002-03-04 2003-09-10 Pharmathen S.A. Fast release cefuroxime axetil compositions
WO2005002540A2 (en) * 2003-07-01 2005-01-13 Ranbaxy Laboratories Limited Dry powder pharmaceutical suspension compositions of cefuroxime axetil
WO2005002540A3 (en) * 2003-07-01 2005-02-17 Ranbaxy Lab Ltd Dry powder pharmaceutical suspension compositions of cefuroxime axetil
WO2005018618A1 (en) * 2003-08-23 2005-03-03 Korea United Pharm, Inc Formulation of stable for moisture absorption and quickly dissolved tablet containing cefuroxime axetil and it's manufacturing process
WO2005067895A1 (en) * 2004-01-16 2005-07-28 Sandoz Ag Controlled release pharmaceutical compositions
CN104230957A (en) * 2013-06-09 2014-12-24 广东立国制药有限公司 Preparing method of cefuroxime acid and method of removing DCC lactone in preparation process of the cefuroxime acid
CN104230957B (en) * 2013-06-09 2017-02-08 广东立国制药有限公司 Preparing method of cefuroxime acid and method of removing DCC lactone in preparation process of the cefuroxime acid
CN106109433A (en) * 2016-08-10 2016-11-16 瑞阳制药有限公司 CEFUROXIME AXETIL Film coated tablets and preparation method thereof
CN114191375A (en) * 2021-12-20 2022-03-18 广东金城金素制药有限公司 Cefuroxime sodium for injection and preparation method thereof

Also Published As

Publication number Publication date
CA2239331C (en) 1999-11-30
AU3807499A (en) 1999-12-20

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