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WO2012060788A1 - Formulations de céphalosporines avec teneur en humidité contrôlée - Google Patents

Formulations de céphalosporines avec teneur en humidité contrôlée Download PDF

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Publication number
WO2012060788A1
WO2012060788A1 PCT/TR2011/000253 TR2011000253W WO2012060788A1 WO 2012060788 A1 WO2012060788 A1 WO 2012060788A1 TR 2011000253 W TR2011000253 W TR 2011000253W WO 2012060788 A1 WO2012060788 A1 WO 2012060788A1
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WIPO (PCT)
Prior art keywords
granules
group
granule
cephalosporin
active agent
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/TR2011/000253
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English (en)
Inventor
Mahmut Bilgic
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Individual
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Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO2012060788A1 publication Critical patent/WO2012060788A1/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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to granules comprising cephalosporin molecules as active agent; pharmaceutical compositions comprising said granules and a production method for preparation of said compositions.
  • Cephalosporins were first isolated in 1948 and first generation cephalosporins were produced and released in 1960.
  • Cephem derivative 7- amino-cephalosporinic acid constitutes the basic core of cephalosporins. Cephalosporins are classified into different generations according to a classification method which is chronological and practical in terms of reflecting the improvement in antibacterial spectrum.
  • Antibiotics belonging to cephalosporin group are characterised by the lactam ring in their chemical structure. Since lactam rings are not durable to water, such molecules disintegrate when they come into contact with water and undesirable by products emerge. As water is a frequently used solvent in chemical processes, this problem is observed in pharmaceutical compositions prepared by using water. This situation causes lower active substance amount in the final product than expected and this consequently causes lower dose. Therefore, different methods should be developed for preparation of stabile cepholosporin group of products.
  • the present invention relates to granules which have a maximum moisture content of 1% and comprise cepholosporin group molecules as the active agent.
  • cepholosporin group molecules stated in the text comprises cepholosporin group molecules such as cefpodoxime, cefditoren, cefdinir, cefixime, cefuroxime, cefaclor, ceftibuten, cefprozil, cefepime and cefetamet.
  • Cefpodoxime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
  • cefpodoxime proxetil is used.
  • Cefditoren can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
  • cefditoren pivoxil is used.
  • Cefdinir can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
  • Cefixime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Cefixime can be in monohydrate, dihydrate or trihydrate form before granulation.
  • Cefuroxime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
  • cefuroxime axetil is used.
  • Cefaclor can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
  • Ceftibuten can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Ceftibuten can be in monohydrate, dihydrate or trihydrate form before granulation.
  • Cefprozil can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
  • Cefetamet can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
  • cefetamet pivoxil is used.
  • the said granules which have a maximum moisture content of 1% and comprise cephalosporin group molecules as active agent can comprise various excipients such as binders, diluents, disintegrants, sweeteners, lubricants, effervescent couples, glidants along with the active agent.
  • the present invention relates to pharmaceutical compositions comprising granules which have a maximum moisture content of 1% and comprise cephalosporin group molecules as the active agent.
  • compositions comprising granules which have a maximum moisture content of 1% and comprise cephalosporin group molecules as the active agent can comprise various excipients such as binders, diluents, disintegrants, lubricants, glidants, effervescent couple and sweetener in addition to said granules.
  • the disintegrant that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminum silicate and starch or combinations thereof.
  • the binder that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methylcellulose, polyvinylpyrrolidone.
  • the lubricant that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate and sodium benzoate.
  • the diluent that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch and xylitol or combinations thereof.
  • the glidant that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from a group comprising magnesium silicate, silicone dioxide, starch, talc, tribasic calcium phosphate or the combination thereof.
  • the sweetener that can be used in the granules of the present invention and in the formulations comprising these granules 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 effervescent couple that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid etc. and from basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate etc.
  • the formulations comprising the granules of the present invention can be in different dosage forms, for instance; tablet, capsule, film-coated tablet, sachet, suspension, effervescent tablet, orodispersible tablet, prolonged-release tablet, modified-release tablet.
  • these formulations comprising the granules of the present invention are in the form of tablet or film- coated tablet.
  • the granules of the present invention and the formulations comprising these granules can comprise 1 -4000 mg cephalosporin or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equivalent amount.
  • compositions comprising granules of the present invention which have a maximum moisture content of %1 and comprise cephalosporin group molecules as the active agent can further comprise an active agent along with the said granules and the excipients specified above.
  • the second active substance can be selected from cephalosporins or beta-lactamases.
  • clavulanic acid is used or derivatives thereof.
  • the clavulanic acid that can be used optionally in the pharmaceutical composition comprising granules 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 in free form and/or the combination thereof.
  • potassium clavulanate is used.
  • said composition 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 is preferably used with a humectant in the ratio of 1 : 1 in the pharmaceutical composition of the present invention.
  • a humectant in the ratio of 1 : 1 in the pharmaceutical composition of the present invention.
  • One or more of the substances comprising silica; colloidal silica, for instance colloidal silica anhydrous, for instance Aerosil® 200, magnesium trisilicate, cellulose powder, Cabosil® magnesium oxide, calcium silicate, Syloid®, starch, microcrystalline cellulose, talc can be used as the humectant.
  • potassium clavulanate is preferably used with syloid in the ratio of 1 : 1.
  • the pharmaceutical composition comprising granules of the present invention comprises 10- 90%, preferably 40-80% of cephalosporin or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms, and 0,1-10% binder; 0,1-10%, lubricant; 0-5% sweetener; 0,1-30%) diluent; 6-15%) disintegrant; 0-85% effervescent couple; 0,1-5% glidant; 0-90% clavulanic acid or an equivalent amount of its pharmaceutically acceptable salts, hydrates, solvates or the combination thereof in proportion to the total weight of unit dose amount.
  • the present invention relates to a process that shall be used for preparation of granules which have a moisture content less than 1% and comprise cephalosporin as the active agent.
  • the process for preparation of said granules is composed of the following steps;
  • Granulation solution is prepared by solving the binder in water
  • Obtained granules are dried at 40 °C such that they have a maximum moisture content of 1%.
  • the present invention relates to processes that can be used for preparation of pharmaceutical compositions comprising said granules.
  • the process for preparation of pharmaceutical compositions comprising said granules is composed of the following steps;
  • Granules are blended with diluent, disintegrant, glidant and the second active agent -if available- and effervescent couple,
  • the granules are sieved with a sieve, mesh size of which is in the range of 0,5-5 mm, preferably in the range of 1-3 mm.
  • the pharmaceutical composition obtained is stored in a required dosage form. It is preferably compressed in tablet form and optionally packed with commercially available coating agents by using the techniques in the prior art.
  • Tablet hardness should be at desired level in order to compress the pharmaceutical composition in tablet form.
  • the inventors have found that 96%- 100% diluent and disintegrant in proportion to the diluent and disintegrant amount used for preparation of the granules should be added to the pharmaceutical composition comprising said granules and the other excipients so as to obtain desired tablet hardness for preparation of the pharmaceutical compositions comprising granules which have a maximum moisture content of 1% and comprise cephalosporin as the active agent.
  • another aspect of the present invention is to use 96% - 100% diluent and disintegrant in proportion to the diluent and disintegrant amount used for obtaining granules for preparation of the pharmaceutical composition comprising granules which have a maximum moisture content of 1% and comprise cephalosporin as the active agent.
  • the pharmaceutical composition comprising granules of the present invention can be used in treatment of upper respiratory infections, such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections, such as pneumonia, acute bronchitis and acute exacerbation of acute bronchitis; genitourinary infections, such as pyelonephritis, cystitis, urethritis; skin and soft tissue infections, such as furuncle, pyoderma, impetigo; and such diseases as community-acquired pneumonia, acute maxillary sinus infection.
  • upper respiratory infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis
  • lower respiratory tract infections such as pneumonia, acute bronchitis and acute exacerbation of acute bronchitis
  • genitourinary infections such as pyelonephritis, cystitis
  • Example 1 Formulation and process for preparation of film-coated tablet comprising cefdinir.
  • Cefdinir is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C such that they have a maximum moisture content of 1% and sieved with a 1-3 mm mesh sieve. Obtained granules are mixed with the diluent and disintegrant, glidant and the other excipients. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and then tablets are coated with an appropriate coating agent.
  • Example 2 Formulation and process for preparation of tablet comprising cefdinir and potassium clavulanate.
  • Cefdinir is mixed with a part of the diluent and a part of the disintegrant and granulated with granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C such that they have a maximum moisture content of 1%; and sieved with a 1-3 mm mesh sieve. Then potassium clavulanate, diluent, and the rest of the disintegrant, glidant and the other excipients are added and said granules are mixed. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and then 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)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

La présente invention concerne des granules comprenant des molécules du groupe des céphalosporines en tant qu'agent actif ; les compositions pharmaceutiques comprenant lesdits granules et un procédé de production qui doit être utilisé pour la préparation desdites compositions.
PCT/TR2011/000253 2010-11-05 2011-11-03 Formulations de céphalosporines avec teneur en humidité contrôlée Ceased WO2012060788A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2010/09167A TR201009167A2 (tr) 2010-11-05 2010-11-05 Sefalosporin içeren farmasötik granüller.
TR2010/09167 2010-11-05

Publications (1)

Publication Number Publication Date
WO2012060788A1 true WO2012060788A1 (fr) 2012-05-10

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PCT/TR2011/000253 Ceased WO2012060788A1 (fr) 2010-11-05 2011-11-03 Formulations de céphalosporines avec teneur en humidité contrôlée
PCT/TR2011/000250 Ceased WO2012060785A1 (fr) 2010-11-05 2011-11-03 Procédé de production de formulations comprenant de la céphalosporine

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PCT/TR2011/000250 Ceased WO2012060785A1 (fr) 2010-11-05 2011-11-03 Procédé de production de formulations comprenant de la céphalosporine

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TR (1) TR201009167A2 (fr)
WO (2) WO2012060788A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103405387A (zh) * 2013-08-13 2013-11-27 江苏正大清江制药有限公司 一种新的头孢克肟干混悬剂及其制备方法
US10624899B2 (en) 2016-07-14 2020-04-21 Achaogen, Inc. Combination products for the treatment of bacterial infections and methods of producing or dosing of same

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013109203A1 (fr) * 2012-01-18 2013-07-25 Mahmut Bilgic Formulations en comprimés comprenant du cefditoren pivoxil
WO2013109225A1 (fr) * 2012-01-18 2013-07-25 Mahmut Bilgic Formulations pharmaceutiques en comprimés comprenant du ceftibutène
CN105168147A (zh) * 2015-09-11 2015-12-23 青岛蓝盛洋医药生物科技有限责任公司 一种治疗细菌感染的药物盐酸头孢他美酯组合物颗粒剂
WO2018071810A1 (fr) 2016-10-13 2018-04-19 RhinoNase, Inc. Compositions antibiotiques pour irrigation nasale et procédés
CN108743548B (zh) * 2018-06-28 2021-08-06 苏州盛达药业有限公司 一种头孢丙烯颗粒剂及其制备方法

Citations (2)

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WO2007017895A2 (fr) * 2005-05-05 2007-02-15 Lupin Limited Compositions pharmaceutiques stabilisees de cephalosporines
WO2011152806A1 (fr) * 2010-06-03 2011-12-08 Mahmut Bilgic Méthode de production de formulation effervescente comprenant du céphalosporine et du clavulanate de potassium

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ES2061623T3 (es) * 1987-03-02 1994-12-16 Brocades Pharma Bv Procedimiento para la obtencion de una composicion farmaceutica y un granulado farmaceutico.
KR20050062514A (ko) * 2002-07-16 2005-06-23 랜박시 래보러터리스 리미티드 경구 투여용 분산성 정제
CA2393614C (fr) * 2002-07-19 2003-09-30 Abbott Laboratories Compositions antibacteriennes de clarithromycine et processus de preparation connexe
WO2005115347A1 (fr) * 2004-05-31 2005-12-08 Sam-A Pharmaceuticals Co., Ltd. Comprime dispersible comprenant des antibiotiques beta-lactame et procede de preparation dudit comprime
WO2007058397A1 (fr) * 2005-11-17 2007-05-24 Gl Pharmtech Corp. Comprime dispersible comportant le melange d'amoxicilline et d'acide clavulanique ou ses sels et son procede de preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007017895A2 (fr) * 2005-05-05 2007-02-15 Lupin Limited Compositions pharmaceutiques stabilisees de cephalosporines
WO2011152806A1 (fr) * 2010-06-03 2011-12-08 Mahmut Bilgic Méthode de production de formulation effervescente comprenant du céphalosporine et du clavulanate de potassium

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103405387A (zh) * 2013-08-13 2013-11-27 江苏正大清江制药有限公司 一种新的头孢克肟干混悬剂及其制备方法
CN103405387B (zh) * 2013-08-13 2015-11-04 江苏正大清江制药有限公司 一种新的头孢克肟干混悬剂及其制备方法
US10624899B2 (en) 2016-07-14 2020-04-21 Achaogen, Inc. Combination products for the treatment of bacterial infections and methods of producing or dosing of same

Also Published As

Publication number Publication date
TR201009167A2 (tr) 2012-05-21
WO2012060785A1 (fr) 2012-05-10

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