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WO2012060787A1 - Comprimés contenant du cefdinir - Google Patents

Comprimés contenant du cefdinir Download PDF

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Publication number
WO2012060787A1
WO2012060787A1 PCT/TR2011/000252 TR2011000252W WO2012060787A1 WO 2012060787 A1 WO2012060787 A1 WO 2012060787A1 TR 2011000252 W TR2011000252 W TR 2011000252W WO 2012060787 A1 WO2012060787 A1 WO 2012060787A1
Authority
WO
WIPO (PCT)
Prior art keywords
cefdinir
formulation
formulation according
pharmaceutical composition
range
Prior art date
Application number
PCT/TR2011/000252
Other languages
English (en)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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
Priority claimed from TR2010/09165A external-priority patent/TR201009165A2/xx
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2012060787A1 publication Critical patent/WO2012060787A1/fr

Links

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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • 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
    • A61K31/546—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 containing further heterocyclic rings, e.g. cephalothin
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to compositions comprising cefdinir as the active agent and a production method that can be used for preparation of these compositions.
  • Cefdinir chemical name of which is (6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(hydroxyimino) acetyl]amino]-3-ethynyl-8-oxo-5-thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, was first disclosed in the patent numbered BE897864.
  • the chemical structure of cefdinir is seen in Formula 1. This third generation cephalosporin molecule is indicated for the treatment of infections caused by gram positive and gram negative bacteria.
  • cefdinir Physically appearing as a white powder, cefdinir has quite low solubility in common organic solvents such as methanol, ethanol, acetonitrile and in water. Due to this property, some problems are observed while developing formulations comprising this molecule.
  • Solubility problem of the active agent influences dissolution time of the finished product and this poses problems for bioavailability and duration of action of the product.
  • cefdinir formulations having desired water solubility in order to provide effective and easy treatment for patients receiving cefdinir treatment.
  • the present invention relates to cefdinir formulations. Surprisingly, it has been seen that dissolution of the dosage forms prepared with the pharmaceutical composition obtained in the case that the amount of carboxymethyl cellulose calcium used as disintegrant in the formulation comprising cefdinir is minimum 6%, preferably in the range of 6%-15%, more preferably in the range of 8%-13% by weight and the amount of microcrystalline cellulose used as diluent is maximum 25%, preferably in the range of 20%-25%, more preferably in the range of 21%-24% by weight.
  • cefdinir formulations comprising minimum 6%, preferably in the range of 6%-15%, more preferably in the range of 8%-13% of carboxymethyl cellulose calcium, and maximum 25%, preferably in the range of 20%-25%, more preferably in the range of 21%-24% of microcrystalline cellulose in proportion to the total weight of unit dose.
  • Said formulations can be formulated in a pharmaceutically acceptable dosage form, for instance in solid oral dosage forms such as tablet, film-coated tablet, capsule, prolonged- release tablet, modified-released tablet, effervescent tablet, orodispersible tablet, sachet, dry powder to form suspension; and/or liquid dosage forms such as suspension.
  • the formulation is in the form of tablet, more preferably in the form of film-coated tablet.
  • Cefdinir used in the formulations prepared according to the present invention can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or the combination thereof.
  • cefdinir having average particle size (d50) smaller than 20 ⁇ , preferably in the range of 5-15 ⁇ is used as active agent, the pharmaceutical composition comprising cefdinir has a high dissolution rate and desired dose uniformity resulting in a high bioavailability of cefdinir.
  • the present invention is related to the formulations comprising cefdinir as active agent having average particle size smaller than 20 ⁇ , preferably in the range of 5-15 ⁇ .
  • the present invention relates to cefdinir formulations comprising minimum 6% of carboxymethyl cellulose calcium and tablet forms comprising this formulation.
  • Tablet hardness should also be taken into consideration in terms of the bioavailability of active agent and thus the efficiency of the treatment. Because, tablets with high hardness value leads to a slow dispersion and dissolution. Therefore, sufficient active agent can not be dissolved and thus bioavailibility of cefdinir decreases. Based on the studies, the inventors have seen that the particle size of the excipient is an important parameter on optimizing the tablet hardness and achieving high bioavailibity of cefdinir.
  • cefdinir formulations which comprise carboxymethyl cellulose calcium having an average particle size in the range of 15-100 ⁇ , preferably 20-90 ⁇ and more preferably 25-75 ⁇ can disperse rapidly and thus high bioavailibility of cefdinir can be obtained.
  • the present invention is related to the formulations comprising carboxymetyl cellulose calcium as disintegrant having average particle size in the range of 15- 100 ⁇ , preferably 20-90 ⁇ and more preferably 25-75 ⁇ .
  • the present invention relates to cefdinir formulations comprising maximum 25% of microcrystalline cellulose and tablet forms comprising this formulation.
  • cefdinir formulations which comprise microcrystalline cellulose having an average particle size in the range of 30-200 ⁇ , preferably 40-170 ⁇ and more preferably 50-150 ⁇ have a short dispersion time and thus using microcrystalline cellulose having the abovementioned average particle size helps to increase bioavailability of cefdinir.
  • the present invention is related to the formulations comprising microcrystalline cellulose as diluent having average particle size which is in the range of 30- 200 ⁇ , preferably 40-170 ⁇ and more preferably 50-150 ⁇ .
  • the pharmaceutical composition of the present invention comprises at least one pharmaceutically acceptable excipient along with cefdinir and disintegrant.
  • the excipients of said composition can be selected from a group comprising humectants, binders, lubricants, sweeteners and/or glidant.
  • the binder that can be used in the cefdinir formulation of the present invention can be selected from a group comprising ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methylcellulose, polyvinylpyrrolidone.
  • Polyvinylpyrrolidone is preferably used in the pharmaceutical composition of the invention.
  • the lubricant that can be used in the cefdinir formulation of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
  • Magnesium stearate is preferably used in the present invention.
  • the humectant that can be used in the cefdinir formulation of the present invention can be selected from a group comprising anhydrous sodium sulphate, silica gel and potassium carbonate.
  • the sweetener that can be used in the cefdinir formulation of the present invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharine, saccharine sodium, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof.
  • the glidant that can be used in the cefdinir formulation of the present invention can be selected from a group comprising magnesium silicate, silicon dioxide, starch, talc, tribasic calcium phosphate or the combination thereof.
  • silicon dioxide is used as glidant in formulation of the invention.
  • cefdinir formulation to be prepared according to the process of the invention can comprise 1-4000 mg of cefdinir or its pharmaceutically acceptable salts, hydrates, solvates or the combination thereof in an equivalent amount.
  • the formulation of the present invention can comprise;
  • cefdinir or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms,
  • a second active agent can optionally be used in the cefdinir formulation of the present invention.
  • the second active agent can be selected from cephalosporins, beta-lactamases.
  • clavulanic acid or its derivatives are used .
  • Clavulanic acid that can optionally be used in the pharmaceutical composition of the present invention can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or the combination thereof.
  • potassium clavulanate is used in the present invention.
  • the pharmaceutical composition of the present invention can comprise clavulanic acid in the range of 50-500 mg or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equivalent amount.
  • Clavulanic acid and its derivatives are extremely susceptible to moisture.
  • potassium clavulanate in the pharmaceutical composition of the present invention is preferably used with a humectant in the ratio of 1 : 1.
  • colloidal silica for instance colloidal silica anhydrous, for example Aerosil® 200, magnesium trisilicate, cellulose powder, Cabosil®, magnesium oxide, calcium silicate, Syloid®, starch, microcrystalline cellulose, talc
  • syloid in the ratio of 1 : 1.
  • water solubility of potassium clavulanate in water is quite good, addition of this active agent to the formulation has not required to change the amount of the excipients used.
  • the present invention relates to pharmaceutical compositions comprising minimum 6% of carboxymethyl cellulose calcium; maximum 25% of microcrystalline cellulose; cefdinir and potassium clavulanate as the active agent and tablet forms comprising these compositions.
  • the pharmaceutical composition of the present invention can comprise 5-90%, preferably 10- 80% of clavulanic acid in proportion to total weight of unit dose amount or pharmaceutically acceptable salts, hydrates, solvates or the combination thereof in an equivalent amount.
  • the present invention relates to processes that can be used for preparation of formulations comprising pharmaceutically acceptable excipients along with cefdinir as the active agent.
  • the process of the present invention comprises granulation of the active agent cefdinir by conventional wet and/or dry granulation methods; or powdering cefdinir and the other excipients after mixing them by dry blending method and optionally compressing tablets or filling the sachets and capsules.
  • the formulation is formulated by adding the second active agent and using the methods specified above.
  • the pharmaceutical composition prepared according to said invention is used in treatment of diseases related with infections caused by gram negative and gram positive bacteria.
  • the pharmaceutical formulation prepared according to said invention is used for production of a drug to be used in treatment and prophylaxis of upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as, pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.
  • upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis
  • lower respiratory tract infections such as, pyelonephritis, cystitis and urethritis
  • skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorr
  • EXAMPLE 1 Formulation and process for preparation of film-coated tablet comprising cefdinir.
  • Cefdinir a part of microcrystalline cellulose, a part of the carboxymethyl cellulose calcium are mixed and granulated with the granulation solution composed of the aqueous solution of the binder. Obtained granules are dried and mixed with the rest of the microcrystalline cellulose and carboxymethyl cellulose calcium, glidant and the other excipients. Then, lubricant is added and mixed again. Obtained composition is loaded to the tablet compression machine and then the tablets are coated with an appropriate coating agent.
  • Example 2 Formulation and process for preparation of capsule comprising cefdinir and potassium clavulanate.
  • Cefdinir a part of microcrystalline cellulose, a part of carboxymethyl cellulose are mixed and granulated with the granulation solution composed of the aqueous solution of the binder. Obtained granules are dried and potassium clavulanate, the rest of microcrystalline cellulose and carboxymethyl cellulose calcium, glidant and the other excipients added and mixed. Then, lubricant is added and mixed again. Obtained composition is loaded to the tablet compression machine and then the tablets are coated with an appropriate coating agent.

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

Abstract

L'invention concerne des compositions pharmaceutiques comprenant du cefdinir comme principe actif, et un procédé de production à utiliser pour la préparation de ces compositions.
PCT/TR2011/000252 2010-11-05 2011-11-03 Comprimés contenant du cefdinir WO2012060787A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
TR2010/09165 2010-11-05
TR2010/09165A TR201009165A2 (tr) 2010-11-05 2010-11-05 Sefdinir içeren tabletler
TR2010/10859A TR201010859A2 (tr) 2010-11-05 2010-12-24 Sefdinir içeren tablet formları.
TR2010/10859 2010-12-24

Publications (1)

Publication Number Publication Date
WO2012060787A1 true WO2012060787A1 (fr) 2012-05-10

Family

ID=45607338

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2011/000252 WO2012060787A1 (fr) 2010-11-05 2011-11-03 Comprimés contenant du cefdinir

Country Status (2)

Country Link
TR (1) TR201010859A2 (fr)
WO (1) WO2012060787A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014051532A1 (fr) * 2012-09-28 2014-04-03 Bilgic Mahmut Formulations en comprimé pharmaceutique comprenant du cefdinir
CN114681414A (zh) * 2020-12-28 2022-07-01 北京新领先医药科技发展有限公司 一种头孢地尼分散片药物组合物及其制备工艺

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE897864A (fr) 1982-09-30 1984-03-29 Fujisawa Pharmaceutical Co Procede de production de composes de 3-vinyl-3-cephem 7-substitues et nouveaux produits ainsi obtenus
US20050131079A1 (en) * 2003-12-10 2005-06-16 Pujara Chetan P. Cefdinir oral suspension
US20070160675A1 (en) * 1998-11-02 2007-07-12 Elan Corporation, Plc Nanoparticulate and controlled release compositions comprising a cephalosporin
WO2011078822A1 (fr) * 2009-12-25 2011-06-30 Mahmut Bilgic Compositions pharmaceutiques comprenant cefdinir comme principe
WO2011078830A1 (fr) * 2009-12-25 2011-06-30 Bilgic Mahmut Formulation effervescente à dispersion rapide
EP2366379A1 (fr) * 2010-02-25 2011-09-21 Sanovel Ilac Sanayi ve Ticaret A.S. Forme de cefdinir avec taux de dissolution amélioré

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE897864A (fr) 1982-09-30 1984-03-29 Fujisawa Pharmaceutical Co Procede de production de composes de 3-vinyl-3-cephem 7-substitues et nouveaux produits ainsi obtenus
US20070160675A1 (en) * 1998-11-02 2007-07-12 Elan Corporation, Plc Nanoparticulate and controlled release compositions comprising a cephalosporin
US20050131079A1 (en) * 2003-12-10 2005-06-16 Pujara Chetan P. Cefdinir oral suspension
WO2011078822A1 (fr) * 2009-12-25 2011-06-30 Mahmut Bilgic Compositions pharmaceutiques comprenant cefdinir comme principe
WO2011078830A1 (fr) * 2009-12-25 2011-06-30 Bilgic Mahmut Formulation effervescente à dispersion rapide
EP2366379A1 (fr) * 2010-02-25 2011-09-21 Sanovel Ilac Sanayi ve Ticaret A.S. Forme de cefdinir avec taux de dissolution amélioré

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JAIN ET AL: "Voltammetric behavior of cefdinir in solubilized system", JOURNAL OF COLLOID AND INTERFACE SCIENCE, ACADEMIC PRESS, NEW YORK, NY, US, vol. 318, no. 2, 1 November 2007 (2007-11-01), pages 296 - 301, XP022402558, ISSN: 0021-9797, DOI: 10.1016/J.JCIS.2007.10.037 *
ZHANG R ET AL: "Effervescent cefdinir prepn and its preparation process consists cefdinir disintegrating agent including acid and alkali and other components which are stuffing, adhesive, moistener, lubricant, sweetener and aromatic", WPI / THOMSON,, 14 December 2005 (2005-12-14), XP002620814 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014051532A1 (fr) * 2012-09-28 2014-04-03 Bilgic Mahmut Formulations en comprimé pharmaceutique comprenant du cefdinir
CN114681414A (zh) * 2020-12-28 2022-07-01 北京新领先医药科技发展有限公司 一种头孢地尼分散片药物组合物及其制备工艺

Also Published As

Publication number Publication date
TR201010859A2 (tr) 2012-05-21

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