EP2173320A1 - Composition pharmaceutique flottante à libération prolongée contenant du métronidazole - Google Patents

Composition pharmaceutique flottante à libération prolongée contenant du métronidazole

Info

Publication number
EP2173320A1
EP2173320A1 EP08776247A EP08776247A EP2173320A1 EP 2173320 A1 EP2173320 A1 EP 2173320A1 EP 08776247 A EP08776247 A EP 08776247A EP 08776247 A EP08776247 A EP 08776247A EP 2173320 A1 EP2173320 A1 EP 2173320A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
composition according
metronidazole
excipients
low density
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.)
Withdrawn
Application number
EP08776247A
Other languages
German (de)
English (en)
Inventor
Dorottya Kiss
Romána ZELKÓ
István ANTAL
Imre Klebovich
Béla NOSZÁL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Nyrt
Original Assignee
Richter Gedeon Nyrt
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 Richter Gedeon Nyrt filed Critical Richter Gedeon Nyrt
Publication of EP2173320A1 publication Critical patent/EP2173320A1/fr
Withdrawn legal-status Critical Current

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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent

Definitions

  • the present invention relates to a metronidazole containing gastroretentive, extended release, floating dosage form which comprises a matrix-forming polymer, gas generating excipients and/or low density foam powder and other pharmaceutically acceptable excipients.
  • the dosage form according to the present invention contains all components as a homogeneous mixture tableting by direct compression or filling into a capsule.
  • Gastroretentive dosage forms are drug delivery systems which remain in the stomach for an extended period of time, and allow both spatial and time control of drug liberation. Their application can be advantageous in the case of drugs that are absorbed better from the stomach or the upper part of the gastrointestinal tract than from the distal intestinal regions. This selective absorption can be arisen from the existence of a local selective transporter or from the better solubility of the active ingredients in the gastric juice.
  • Such pharmaceutical compositions can be employed in the administration of drugs which are unstable in distal intestinal regions or are harmful. They can also be used beneficially in the local therapy of the stomach. The continuous release of the active ingredient results a higher local concentration for a longer period of time so that the dose to be administered and/or the number of administration can be reduced, the side effects are better avoided and the therapeutic effect is increased. These can result a better compliance of the patients.
  • the so called floating systems have low density and are able to float on the surface of the gastric juice as they are far from the pylorus so that they can avoid evacuation from the stomach.
  • High density systems can also avoid evacuation as they are located the bottom of the stomach under the pylorus.
  • Expandable systems are able to grow by bulking or unfolding so that they can't get through the pylorus until becoming smaller because of the erosion. Besides the size of the dosage form the special shape of it can also hinder getting through the pylorus. There are other possibilities to extend the residence time of the drugs. Bioadhesive systems are also gastroretentive as they can stick to the gastric wall.
  • the dosage form can be fixed with an incorporated and an outer magnet. hi our case the floating dosage form with bioadhesive character seems to be the most advantageous solution. Because in the case of using the high density systems gastric contractions can make the dosage form get into the small intestine, using the bulking and modified shape systems increase the risk of obstruction and using an outer magnet makes the administration difficult.
  • EP 307904 discloses a covered, solid retard form which in the case of oral administration remains in the stomach ensuring continuous release.
  • One layer of the dosage form expands on contact with body fluid as it comprises gas (CO 2 , N 2 ) generating excipients and hydrophilic bulkable polymer (cellulose ether, vinyl alcohol etc.) beside the active ingredients.
  • This layer is covered by a hydrophilic membrane which is permeable to gastric juice.
  • the form is film-coated tablet or capsule which disintegrates in the stomach immediately.
  • US 5360793 relates to an antacid composition capable of forming a floating gelatinous mass when contacted with aqueous acid. It comprises xanthan gum, hexitol stabilized aluminium hydroxide and a gas generating material (alkaline or alkaline earth metal carbonate or bicarbonate salt) capable of producing a non-toxic gas when contacted with gastric juice.
  • xanthan gum hexitol stabilized aluminium hydroxide
  • a gas generating material alkaline or alkaline earth metal carbonate or bicarbonate salt
  • the dosage form can be powder, tablet or suspension.
  • WO 98/47506 describes floating pharmaceutical compositions (capsule, granule, tablet) comprise benzamide derivatives.
  • the bioavailability of the active ingredients is improved by formulating them in the form of a floating system because this system let the active ingredients release in the upper part of the small intestine.
  • the low density of the composition is provided by a gas generating excipient which comprises sodium bicarbonate or calcium carbonate and weak, organic acid or salt thereof.
  • the addition of the acid provides the immediate lift of the dosage form and avoids the problems caused by pH-changing in the stomach.
  • a polymer keeps the generated gas in the composition; in the working example this polymer is hydroxypropyl methyl cellulose.
  • the dosage forms further comprise other pharmaceutical excipients e. g. magnesium stearate, polyethylene glycol.
  • EP 1014952 discloses pellets or tablets where the SiO 2 core is covered by the active ingredients then it is coated by a gas generating and a barrier layer which encloses the generated gas.
  • US 1990/0629918 describes an extended release capsule comprises non compressed, two-layer systems. One layer provides the release of the active ingredients and the other one provides the floating of the system. The system remains in the stomach until almost all of the active ingredients release. Its diameter is big compared to its size; its beginning density is under 1 g/cm 3 . Both layers contain bulkable polymer (hydroxypropyl methyl cellulose) which provide low density and extended release in the composition. The system is able to float for about 13 hours.
  • EP 1138320 presents an excipient-system.
  • the dosage form made of it is able to float in the stomach without adding any gas generating excipients or low density wax or fat.
  • the appropriate ratio of polyvinyl acetate and polyvinyl pirrolidon provides proper stability of the composition and at the same time the tablet remains enough porous to be able to float even applying quite low compressing pressure.
  • Metronidazole is an antibiotic against anaerobe bacteria. It is effective against
  • Helicobacter pylori so that an extended release form would be useful in the local therapy of gastric ulcer.
  • the doses are 250-400 mg 3 times a day.
  • the dose can be reduced.
  • the possibility to reduce the dose and the number of administrations is advantageous considering the side effects and the co-operation of the patients.
  • the first layer comprises metronidazole, tetracycline and release-controller polymers
  • the second layer comprises gas generating excipients which provide the low density
  • the third layer comprises bismuth salts.
  • the disadvantage of the system is that the preparation of a three-layer composition is quite difficult.
  • Metronidazole was incorporated into alginate gel beads by Murata et al. They prepared two types of alginate gel beads. The first type contains vegetable oil in order to provide low density; the second type containing citosan can stick to gastric mucosa.
  • Sriamornsak et al. prepared metronidazole-loaded emulsion gel beads of calcium pectinate. The preparation of the beads is time-consuming because it contains long drying phases. (Sriamornsak P, Thirawong N, Puttipipatkhachorn S: Eur. J. Pharm. Sci. 24(4):363- 373, 2005).
  • Hongquin et al. produced gastroretentive tablets comprising metronidazole.
  • the base ingredients of the tablets are polyvinyl pirrolidon, carbopol, microcrystalline cellulose.
  • the composition contains less metronidazole than its single dose which results a better floating character but it is unbeneficial for the therapeutic effect especially in the case of the extended release form.
  • CN 2005/1009758 discloses an extended release dosage form comprising an antibacterial component (gentamicin, clarithromycin, metronidazole or tinidazol) used in the treatment of chronic gastritis, gastric ulcer and intestinal infections. Beside the active ingredients it also comprises extended release providing excipients, floating excipients and bioadhesive component. Extended release providing excipients can be stearyl alcohol, glycerine monostearate, carbomer, glycerine behenate or a mixture thereof. Bioadhesive components are dextrin, microcrystalline cellulose polyethylene glycol or a mixture thereof. Using additional excipients to provide bioadhesive character is disadvantageous as there are many matrix-forming and extended release providing polymer having such character. Applying as few excipients as possible is one of the most important principles of the drug formulation.
  • an antibacterial component gentamicin, clarithromycin, metronidazole or tinidazol
  • Cedillo-Ramirez et al. prepared matrix tablets containing metronidazole using methocel K4M, carbopol and sodium bicarbonate; however these compositions comprise only 150 mg of the active ingredients which is less than the single dose. It can be misleading evaluating the hydrodynamic properties of the tablets. (Cedillo-Ramirez E, Villafuerte-Robles
  • a sustained release pharmaceutical composition comprising metronidazole which comprises matrix-forming polymer, gas-generating excipients, low density foam powder, pharmaceutically acceptable excipients.
  • the matrix-forming polymer can be a cellulose derivative (ethyl cellulose, hydroxyethylcellulose, carboxymethyl cellulose sodium, methylcellulose), xanthan gum, polyacrylic acid derivative, polyvinyl derivative, polyethylene oxide.
  • the gas generating excipients are metal-ion carbonate salts and/or hydrogen carbonate salts.
  • the low density foam powder is spongy structure polypropylene.
  • the pharmaceutical composition according to the present invention could further comprise a weak organic acid beside gas generating excipients.
  • the weak organic acid is tartaric acid or citric acid.
  • the pharmaceutical composition according to the present invention contains the components as a homogeneous mixture compressing into a tablet form or filling into a capsule.
  • the advantage of the dosage form according to the invention is that this form provides the extended dissolution of metronidazole by almost zeroth-order kinetics.
  • the release of metronidazole during 1 hour is 5-15 %, during 2 hours is 15-25%, during 3 hours is 25-35%, during 4 hours is 35-45 %, during 5 hours is 45-55 %, during 6 hours is 55-65 %, during 7 hours is 65-75 %, and during 8 hours is 75-85 %.
  • the time-controlled drug release is associated with a local specific dissolution due to the extended residence of the dosage form in the stomach which is caused by form's low density.
  • the low density of the pharmaceutical composition is provided by the developed CO 2 in the polymer-matrix.
  • the CO 2 is generated from foam powder or gas generating excipients on contact with gastric acid.
  • Figure 1 illustrates the dissolution profile of metronidazole from the tablet prepared according to the Example 1
  • Figure 2 illustrates the dissolution profile of metronidazole from the tablet prepared according to the Example 2
  • Figure 3 illustrates the dissolution profile of metronidazole from the tablet prepared according to the Example 3
  • Figure 4 illustrates the dissolution profile of metronidazole from the capsule prepared according to the Example 4
  • Figure 5 illustrates the dissolution profile of metronidazole from the capsule prepared according to the Example 5
  • Figure 6 illustrates the dissolution profile of metronidazole from the capsule prepared according to the Example 6
  • Figure 7 illustrates the dissolution profile of metronidazole from the tablet prepared according to the Example 7
  • Figure 8 illustrates the dissolution profile of metronidazole from the tablet prepared according to the Example 8.
  • Figure 9 illustrates the dissolution profile of metronidazole from the tablet prepared according to the Example 9
  • the above described pharmaceutical composition is a capsule.
  • the listed ingredients were homogenized then filled into a hard gelatine capsule.
  • the incorporated carbonates generate carbon dioxide on contact with gastric acid.
  • the expanding gas stays in the polymer matrix and results the low density of the extended release floating capsule.
  • the dissolution of metronidazole from the capsule is shown in Figure 4.
  • Example 5 1000 capsules:
  • the above described pharmaceutical composition is a capsule.
  • the listed ingredients were homogenized then filled into a hard gelatine capsule.
  • the incorporated carbonates generate carbon dioxide on contact with gastric acid.
  • the expanding gas stays in the polymer matrix and results the low density of the extended release floating capsule.
  • Example 6 1000 capsules:
  • the above described pharmaceutical composition is a capsule.
  • the listed ingredients were homogenized then filled into a hard gelatine capsule.
  • the incorporated carbonates generate carbon dioxide on contact with gastric acid.
  • the expanding gas stays in the polymer matrix and results the low density of the extended release floating capsule.
  • the above listed ingredients were homogenized then tablets were produced by direct compression thereof.
  • the low density of the extended release floating tablet is provided by the spongy structure polypropylene foam powder.
  • HPMC based matrix effects two phase in the dissolution profile. It means that with using
  • HPMC in the first hour of drug release the quantity of the dissolved drug compared to polyethylene oxide containing dosage forms can be increased.

Landscapes

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

Abstract

La présente invention concerne une composition pharmaceutique à libération prolongée comprenant du métronidazole, ladite forme à libération prolongée comprenant des excipients produisant du gaz et/ou une mousse génératrice de mousse de faible densité. La composition pharmaceutique comprend également d'autres excipients acceptables sur le plan pharmaceutique. En outre, l'invention concerne un procédé de fabrication de ladite composition pharmaceutique.
EP08776247A 2007-07-09 2008-07-09 Composition pharmaceutique flottante à libération prolongée contenant du métronidazole Withdrawn EP2173320A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU0700469A HUP0700469A2 (en) 2007-07-09 2007-07-09 Floating pharmaceutical composition of sustained release containing metronidazol
PCT/HU2008/000081 WO2009007762A1 (fr) 2007-07-09 2008-07-09 Composition pharmaceutique flottante à libération prolongée contenant du métronidazole

Publications (1)

Publication Number Publication Date
EP2173320A1 true EP2173320A1 (fr) 2010-04-14

Family

ID=89987633

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08776247A Withdrawn EP2173320A1 (fr) 2007-07-09 2008-07-09 Composition pharmaceutique flottante à libération prolongée contenant du métronidazole

Country Status (4)

Country Link
EP (1) EP2173320A1 (fr)
EA (1) EA201070106A1 (fr)
HU (1) HUP0700469A2 (fr)
WO (1) WO2009007762A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103191432B (zh) * 2013-04-27 2014-09-17 中国药科大学 一种水溶性药物骨架缓释片及其制备方法
WO2019069108A1 (fr) * 2017-10-04 2019-04-11 Debreceni Egyetem Forme galénique solide, moulée, à rétention gastrique et à libération prolongée et procédé de préparation de celle-ci

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9702533D0 (sv) * 1997-07-01 1997-07-01 Astra Ab New oral formulation
BR0211317A (pt) * 2001-07-04 2004-12-14 Sun Pharmaceutical Ind Ltd Sistema para a liberação controlada de uma droga por meio de retenção gástrica

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009007762A1 *

Also Published As

Publication number Publication date
HUP0700469A2 (en) 2009-04-28
WO2009007762A1 (fr) 2009-01-15
EA201070106A1 (ru) 2010-06-30
HU0700469D0 (en) 2007-08-28

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