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WO1993005785A1 - Compositions pharmaceutiques contenant un anti-inflammatoire non-steroidien et du nocloprost - Google Patents

Compositions pharmaceutiques contenant un anti-inflammatoire non-steroidien et du nocloprost Download PDF

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Publication number
WO1993005785A1
WO1993005785A1 PCT/EP1992/001994 EP9201994W WO9305785A1 WO 1993005785 A1 WO1993005785 A1 WO 1993005785A1 EP 9201994 W EP9201994 W EP 9201994W WO 9305785 A1 WO9305785 A1 WO 9305785A1
Authority
WO
WIPO (PCT)
Prior art keywords
nocloprost
steroidal anti
pharmaceutical preparations
stomach
acetylsalicylic acid
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/EP1992/001994
Other languages
German (de)
English (en)
Inventor
Helmut VORBRÜGGEN
Ulrich Täuber
Johannes Tack
Ingrid Amon
Rudolf Wabnitz
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.)
Bayer Pharma AG
Original Assignee
Schering AG
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 Schering AG filed Critical Schering AG
Publication of WO1993005785A1 publication Critical patent/WO1993005785A1/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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the invention relates to pharmaceutical preparations which are characterized in that they contain a combination of a non-steroidal anti-inflammatory agent with nocloprost as active ingredients.
  • the invention relates to pharmaceutical preparations which contain 10 to 1000 mg of nonsteroidal anti-inflammatories in combination with 20 to 200 ⁇ g of nocloprost.
  • Nonsteroidal anti-inflammatory drugs which are often referred to as nonsteroidal anti-inflammatory substances or as antipyretics and anti-rheumatic drugs, have long been known.
  • Pharmaceutical preparations containing acetylsalicylic acid were already marketed in 1899 by the Wegriken Bayer AG under the name Aspirin ®. Preparations containing acetylsalicylic acid are still the most widely used drugs with anti-inflammatory activity.
  • Non-steroidal anti-inflammatories known to be used in commercial pharmaceutical preparations, such as, for example, acemetacin, acetaminophen (paracetamol), azapropazone, bendazac, bumadizone, cicloprofen, diclofenac, dipyron (metropol) , etofenamate, fenbufen, fenclofenac, fenoprofen, flufenamic acid, flurbiprofen, ibuprofen, indomethacin, indoprofen, ketoprofen, lonazolac, mefenamic acid, mofebutazone, nabumetone, naproxenic acid, N Oxyphenbutazon, Phenylbutazon, Pirazolac, Piroxicam, Pirprofen, Propyphenazon, Suldinac, Suxibuzon, Tenoxicam or Tiaprofen Textre (for the structure of
  • the pharmaceutical preparations according to the invention can be designed as film-coated tablets which contain nocloprost in their core, the non-steroidal anti-inflammatory agents, and in the shell surrounding them.
  • the cyto- Protective Nocloprost released first and can thus protect the gastrointestinal mucosa from contact with the non-steroidal anti-inflammatory.
  • Suitable fillers are, for example, sugar alcohols, such as mannitol, monosaccharides, such as glucose, galactose or fructose, disaccharides, such as sucrose or lactose, polysaccharides, such as amylose, starch or cellulose, chemically modified polysaccharides, such as methyl cellulose, hydroxypropylmethyl cellulose or inorganic fillers, such as magnesium oxide or disperse silica.
  • Suitable auxiliaries are, for example, the usual mold release agents, such as magnesium stearate, stearic acid, calcium behenate, etc.
  • a suspension of nocloprost and the usual film formers and auxiliaries can then be sprayed onto it.
  • auxiliaries include plasticizers, such as polyethylene glycol and / or inorganic pigments, such as titanium dioxide or iron oxide.
  • Enteric-coated preparations are obtained by adding an enteric-film-forming agent, such as hydroxymethyl cellulose phthalate or polyacrylates such as Eudragit Loder S, to the shell. If you insert a casing with an enteric film-forming agent between the nocloprost casing and the anti-inflammatory core, you get preparations whose nocloprost-containing casing quickly dissolves in the stomach, while the core is only dissolved after it has passed into the small intestine.
  • an enteric-film-forming agent such as hydroxymethyl cellulose phthalate or polyacrylates such as Eudragit Loder S
  • the agent according to the invention is also possible to produce as a two-layer tablet, one layer of which contains the non-steroidal anti-inflammatory agent and the other of which contains the nocloprost.
  • the additional swelling substances based on cellulose esters and other auxiliaries can be used, the suitable selection of these substances ensuring that the active substances are each released at the optimum release rate.
  • Preparations according to the invention in the form of capsules are also worth mentioning.
  • a nocloprost clathrate is preferably used for the production of the pharmaceutical preparations according to the invention such as the nocloprost-ß-cyclodextrin clathrate.
  • Formulation 1 film-coated tablets
  • the core is tableted by mixing the auxiliary substances with acetylsalicylic acid and then compressing it.
  • a film coating containing nocloprost clathrate from an aqueous suspension of the components is applied to the tablet cores.
  • the core is tableted by mixing the auxiliary substances with acetylsalicylic acid and then compressing it.
  • a film coating containing nocloprost clathrate from an aqueous suspension of the components is applied to the tablet cores.
  • the core is tableted by mixing the auxiliary substances with acetylsalicylic acid and then compressing it.
  • a film coating containing nocloprost clathrate from an aqueous suspension of the components is applied to the tablet cores.
  • the formulation is enteric-resistant and both active ingredients (acetylsalicylic acid and nocloprost-ß-cyclodextrin clathrate) are released quickly from the stomach into the small intestine.
  • Formulation 4 Enteric-coated tablets
  • the core is tableted by mixing the auxiliary substances with acetylsalicylic acid and then compressing it.
  • a film coating containing nocloprost clathrate from an aqueous suspension of the components is applied to the tablet cores.
  • formulation is enteric-resistant and both active ingredients (acetylsalicylic acid and nocloprost-ß-cyclodextrin clathrate) are released quickly from the stomach into the small intestine.
  • active ingredients acetylsalicylic acid and nocloprost-ß-cyclodextrin clathrate
  • the core is tabletted by mixing the auxiliary substances with acetylsalicylic acid and subsequent pressing.
  • the first shell is applied to the tablet cores as an aqueous suspension.
  • the second shell containing nocloprost clathrate is applied as an aqueous suspension after the first shell has dried.
  • Acetylsalicylic acid 500.00 mg microcrystalline cellulose 196.00 mg magnesium stearate 4.00 mg
  • the core is tabletted by mixing the auxiliary substances with acetylsalicylic acid and subsequent pressing.
  • the first shell is applied to the tablet cores as an aqueous suspension.
  • the second shell containing nocloprost clathrate is applied as an aqueous suspension after the first shell has dried.
  • Titanium dioxide 0.50 mg
  • the stomach-resistant pellets (2.) are produced by mixing the first three components and then granulating, extruding and spheronizing.
  • the enteric coating is applied as an aqueous suspension to the dried pellets of approximately 0.8-1.2 mm.
  • Pellets and the powder mixture (1.) are successively filled into capsules using a suitable capsule filling machine.
  • the stomach-resistant pellets (2.) are produced by mixing the first three components and then granulating, extruding and spheronizing.
  • the enteric coating is applied as an aqueous suspension to the dried pellets of approximately 0.8-1.2 mm.
  • Pellets and the powder mixture (1.) are successively filled into capsules using a suitable capsule filling machine.
  • Active ingredient and excipients of the 1st and 2nd layer are mixed separately and pressed into two-layer tablets using a suitable tablet press.
  • Active ingredient and excipients of the 1st and 2nd layer are mixed separately and pressed into two-layer tablets using a suitable tablet press.
  • Nocloprost-ß-cyclodextrin clathrate 0.35 mg 1 ) hydroxypropylmethyl cellulose 13.65 mg polyethylene glycol 6000 5.50 mg titanium dioxide 0.50 mg
  • the core is tableted by mixing the excipients with indomethacin and subsequent compression.
  • a film coating containing nocloprost clathrate from an aqueous suspension of the components is applied to the tablet cores.
  • the core is tabletted by mixing the auxiliary substances with ketoprofen and subsequent pressing.
  • a film coating containing nocloprost clathrate from an aqueous suspension of the components is applied to the tablet core.
  • formulation is enteric-resistant and both active ingredients (ketoprofen and nocloprost-ß-cyclodextrin clathrate) are quickly released from the stomach into the small intestine.
  • Formulation 13 double-coated film-coated tablets
  • Nocloprost-ß-cyclodextrin clathrate 0.35 mg 1
  • hydroxypropylmethyl cellulose 13.65 mg polyethylene glycol 6000 6.00 mg titanium dioxide 0.50 mg
  • the core is tableted by mixing the excipients with indomethacin and subsequent compression.
  • the first shell is applied to the tablet core as an aqueous suspension.
  • the second shell containing nocloprost clathrate is applied as an aqueous suspension after the first shell has dried.
  • Nocloprost dissolves very quickly and is available in the stomach.
  • the core with indomethacin then disintegrates in the gastrointestinal tract and releases the active ingredient.
  • the stomach-resistant pellets (2.) are produced by mixing the first three components and then granulating, extruding and spheronizing.
  • the enteric coating is applied to the dried pellets of about 0.8-1.2 mm as an aqueous suspension.
  • Pellets and the powder mixture (1.) are successively filled into capsules using a suitable capsule filling machine.
  • Active ingredient and excipients of the 1st and 2nd layer are mixed separately and pressed into two-layer tablets using a suitable tablet molding compound.

Landscapes

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

Abstract

Des compositions pharmaceutiques contiennent en tant que substance active un anti-inflammatoire non-stéroïdien associé à du nocloprost.
PCT/EP1992/001994 1991-09-18 1992-08-28 Compositions pharmaceutiques contenant un anti-inflammatoire non-steroidien et du nocloprost Ceased WO1993005785A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE4131566 1991-09-18
DEP4131566.9 1991-09-18
DEP4220123.3 1992-06-15
DE19924220123 DE4220123A1 (de) 1991-09-18 1992-06-15 Pharmazeutische praeparate

Publications (1)

Publication Number Publication Date
WO1993005785A1 true WO1993005785A1 (fr) 1993-04-01

Family

ID=25907589

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/001994 Ceased WO1993005785A1 (fr) 1991-09-18 1992-08-28 Compositions pharmaceutiques contenant un anti-inflammatoire non-steroidien et du nocloprost

Country Status (2)

Country Link
DE (1) DE4220123A1 (fr)
WO (1) WO1993005785A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2277407A1 (fr) * 1999-07-14 2001-01-14 Bernard Charles Sherman Comprime comprenant un ains et du misoprostol

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3927213A (en) * 1973-07-10 1975-12-16 American Home Prod Prostaglandin E{HD 2 {B and derivatives for reducing the side effects of anti-inflammatory agents
DE3504044A1 (de) * 1985-02-04 1986-08-07 Schering AG, Berlin und Bergkamen, 1000 Berlin 9-halogenprostaglandin-clathrate und ihre verwendung als arzneimittel
US5015481A (en) * 1990-05-03 1991-05-14 G. D. Searle & Co. Stabilized pharmaceutical admixture composition

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3927213A (en) * 1973-07-10 1975-12-16 American Home Prod Prostaglandin E{HD 2 {B and derivatives for reducing the side effects of anti-inflammatory agents
DE3504044A1 (de) * 1985-02-04 1986-08-07 Schering AG, Berlin und Bergkamen, 1000 Berlin 9-halogenprostaglandin-clathrate und ihre verwendung als arzneimittel
US5015481A (en) * 1990-05-03 1991-05-14 G. D. Searle & Co. Stabilized pharmaceutical admixture composition

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Deutsche Gesellschaft für Pharmakologie un Toxikologie Bd. 344, nr. 2, 4-6 /12/1991, Hannover SCHLEUCH E. et al. " Effects of nocloprost on the absorption of diclofenac " Siehe Zusammenfassung *
SCAND. J. GASTROENTEROL. Bd. 26, Nr. 3, 1991, Seiten 231 - 236 KONTUREK S. J. ET AL. 'Gatric protection by nocloprost against apirin' *

Also Published As

Publication number Publication date
DE4220123A1 (de) 1993-04-01

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