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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/4035—Isoindoles, e.g. phthalimide
• • 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
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

• the present invention relates to a solid orodispersible pharmaceutical form for the oral administration of mitiglinide or its pharmaceutically acceptable salts, without simultaneous intake of a glass of water and without swallowing problem.
• Mitllinide can be taken by mouth as a tablet to be swallowed with half a glass of water.
• Mitlinlinide is more particularly in the form of the calcium salt dihydrate or bis- ⁇ (2S) -2-benzyl-4 - [(3ai-, 7aS) -octahydro-2H-isoindol-2-yl] -4- oxobutanoate ⁇ calcium, dihydrate.
• the doses of calcium salt dihydrate of mitlinide used to obtain the desired therapeutic effect generally range from 5 mg to 40 mg per dose, three to four times a day, in the form of an immediate-release tablet.
• the pharmaceutical compositions of the present invention not only make it possible to remedy the known drawbacks of the swallowed tablet form but also to provide a superior medical service which in particular improves the quality of life of the patients.
• the orodispersible pharmaceutical composition of mitiglinide has the advantage of rapidly obtaining high plasma levels of active ingredient.
• the orodispersible pharmaceutical composition according to the invention has the particularity of requiring neither water nor chewing during its administration. It disintegrates very quickly in the mouth, preferably in less than three minutes and even more preferably in less than a minute.
• This disintegrating agent is essential in the formulation of orodispersible tablets and must be used in conjunction with a direct compression excipient.
• the difficulties encountered in the manufacture of such tablets lie in the fact that it is very difficult to obtain tablets having constant and reproducible physical characteristics and compatible with the conventional handling constraints of the tablets.
• oral lyophilisate Other orodispersible forms can be produced by the use of lyophilization, leading to the production of very porous solid forms called "oral lyophilisate". These forms require the use of a very specific industrial process, complicated and time-consuming, giving a medicinal form at high cost price.
• the present invention overcomes these drawbacks. It relates to a solid orodispersible form of mitiglinide containing a simple excipient, of natural origin allowing rapid disintegration, exhibiting taste neutrality and pleasant texture. This excipient plays the role of both a binder and a disintegrant. It makes it possible to obtain a simple mitlinide formulation, having an excellent capacity for direct compression, leading to tablets of low friability and of hardness compatible with conventional handling techniques.
• the invention relates to a solid orodispersible pharmaceutical composition of mitiglinide or of a pharmaceutically acceptable salt thereof, characterized in that it contains:
• the mitlinide is in the form of calcium salt dihydrate.
• composition according to the invention may also contain, for manufacturing reasons, one or more lubricants and a flow agent as well as flavors, colors and sweeteners, conventionally used.
• Mitlinlinide may possibly be associated with excipients such as cyclodextrins or coated with excipients by the use of technologies known to those skilled in the art such as coating fluidized air bed, atomization, coacervation, prilling, spray congealing.
• a subject of the invention is also the use of granules consisting of co-dried lactose and starch for the preparation of solid orodispersible pharmaceutical compositions of mitiglinide.
• orodispersible is understood to mean solid pharmaceutical compositions which disintegrate in the oral cavity in less than 3 minutes, and preferably in less than a minute.
• Said granules included in the solid pharmaceutical compositions according to the invention correspond to the compositions described in patent application EP 00 / 402159.8. These granules are characterized by a spherical structure and an advantageous compressibility and are marketed under the name STARLAC.
• the first is based on the observation that the least water-soluble excipients are the most suitable for the formulation of orodispersible tablets (the solubilization, causing an increase in viscosity of the water, is a brake on its penetration into the tablets. ).
• said granules comprise a large fraction of lactose very soluble in water.
• the starch included in said granules is not a "super disintegrating" agent as used and described in the orodispersible forms of the prior art.
• the second is based on the observation that the disintegration properties of an excipient (used in a tablet) evaluated in water by conventional methods cannot be extrapolated to the behavior of the same tablet in vivo, in saliva. Indeed, the disintegration rates in water are measured (according to the Pharmacopoeia
• compositions according to the invention are preferably characterized in that they contain, relative to the total weight of the tablet:
• lubricating agents such as sodium stearyl fumarate or magnesium stearate, preferably from 0.5% to 1.5%, and from 0.1% to 3 % by weight of a flow agent such as colloidal silica, preferably from 0.5% to 1.5%.
• the tablets are prepared by mixing the constituents followed by direct compression.
• the hardness of the tablets of Examples 1 and 2 is approximately equal to 20 Newtons.
• the orodispersible mitlinide tablets described in examples 1 and 2 were placed in the mouth. During these tests, it turned out that for each of the formulations tested, the disintegration time in the mouth was less than 1 minute.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Diabetes (AREA)
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• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Hematology (AREA)
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• Chemical Kinetics & Catalysis (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
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• Medicinal Preparation (AREA)

Applications Claiming Priority (2)

Publications (1)

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Cited By (2)

Citations (4)

• 2002
  • 2002-01-23 FR FR0200794A patent/FR2834892B1/fr not_active Expired - Fee Related
• 2003
  • 2003-01-22 WO PCT/FR2003/000196 patent/WO2003061650A1/fr not_active Application Discontinuation
  • 2003-01-22 AR ARP030100179A patent/AR038208A1/es unknown

Patent Citations (4)

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