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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • 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 present invention relates to a pharmaceutical composition for the programmed release of dexfenfiuramine by the oral route.
• Dexfenfiuramine is an active ingredient used in the treatment of obesity.
• This active ingredient has so far been administered orally, twice a day, in the form of an immediate-release capsule, dosed at 15 mg dexfenfiuramine hydrochloride.
• the Applicant has currently developed an extended-release form of dexfenfiuramine which has the advantage for the patient of being administered only once a day.
• the new pharmaceutical composition which is the subject of the present invention has the advantage not only of prolonging the release of the active ingredient. but still to delay this release. This makes it possible to modulate the release of the active principle as a function of the hours of the day and thus to obtain two peaks of plasma concentration, which, depending on the percentage of the constituents of this pharmaceutical composition, can be adapted to the requirements of the treatment.
• the active principle is administered chronobiologically: a first part of the active principle is released instantly, the other part is released after a few hours, which makes it possible to obtain two peaks of plasma concentration staggered in the time.
• the pharmaceutical composition according to the invention consists of: - quick-release minigranules, - slow-release minigranules. All of these minigranules are then put in a pharmaceutically acceptable form.
• These pharmaceutically acceptable forms are preferably capsules or tablets.
• the quick-release minigranules consist of neutral supports on which the active principle is deposited. These minigranules can then optionally be coated with a polymer allowing rapid release of the active principle.
• the slow-release minigranules consist of neutral supports on which the active principle and talc are deposited. These minigranules are then coated with a polymer allowing the release of the active principle to be controlled and with a surfactant. This coating may also contain other excipients such as plasticizers or stabilizing agents.
• the neutral supports used in the minigranules are more particularly neutral microgranules and preferably of sucrose-starch microgranules.
• binders can be used such as, for example, methylhydroxypropylcellulose.
• the preferred polymer is a low viscosity methyl hydroxypropyl cellulose.
• water-insoluble cellulose derivatives such as, for example, ethylcellulose or cellulose acetate or acrylic copolymers such as Eudragits.
• the preferred polymer is ethylcellulose.
• the surfactants used for coating the slow-release minigranules there may be mentioned the fatty alcohol ester salts or the polysorbates.
• the preferred surfactant is sodium lauryl sulfate.
• the plasticizers optionally used for coating the slow-release minigranules there may be mentioned the esters of citric acid or the sebacates.
• the preferred plasticizer is acetyltributylcitrate.
• stabilizing agents optionally used for coating the slow-release minigranules, mention may preferably be made of cetyl alcohol.
• minigranules can also contain excipients conventionally used as colorants, flavoring agents, bulking agents ... and can contain anti-sticking agents making it possible to avoid sticking of the minigranules together when their preparation.
• Slow or fast minigranules are produced either by extrusion and spheronization, whether or not followed by coating, or by assembly and coating.
• the preferred manufacturing process for these minigranules is mounting followed by coating.
• the rapid minigranules are prepared by mounting, that is to say by spraying an aqueous solution of the active principle which can contain a binder, for example methyl hydroxypropylcellulose, on a neutral support, for example neutral sucrose-starch microgranules.
• the minigranules are dried as they are assembled, either by using a coating or film-coating turbine equipped with a blower and a hot air suction, or by using a fluidized air bed apparatus.
• a protective coating is optionally applied, using the same equipment.
• the polymer used to protect the minigranules must allow rapid release of the active principle.
• Slow minigranules are prepared according to the same mounting principle, talc being added to the mounting solution.
• the coating of these minigranules is applied using the same apparatus.
• talc in the mounting suspension as well as the use of a surfactant such as sodium lauryl sulfate made it possible to obtain a delayed release of the active principle. This release can be delayed by 4 hours or more and modulated over time depending on the percentages of constituents used. Rapid minigranules contain 10 to 80% dexfenfiuramine. Slow minigranules contain 10 to 80% dexfenfiuramine. The percentage of talc contained in the slow-release minigranules is between 10 and 80% of the mass of active principle.
• the percentage of surfactant contained in the slow-release minigranules is between 0.05% and 3% of the total mass of the minigranules before coating.
• the percentage of the polymer used for coating the slow-release minigranules is between 3 and 20% of the total mass of the minigranules before coating.
• a suspension of active ingredient is sprayed onto neutral sucrose-starch microgranules (Micro granules 710-850 ⁇ m).
• the suspension contains methylhydroxypropylcellulose in an amount of 2% relative to the amount of active ingredient and of talc, in an amount of 40% relative to the amount of active ingredient.
• the assembly is carried out in a fluidized air bed.
• a 5% (m / v) solution of ethylcellulose in alcohol is then sprayed onto the minigranules loaded with active ingredient.
• This solution contains acetyltributyl citrate at a rate of 10% of the mass of ethylcellulose, sodium lauryl sulfate at a rate of 0.3% (m / v) and cetyl alcohol at a rate of 0.7% (m / v).
• the coating is carried out in the same device as during assembly.
• the kinetics of release of the active principle is measured using the rotary vane technique described in the European Pharmacopoeia.
• the flasks are filled with 500 ml of phosphate buffer maintained at 37 ° C. The speed of the blades is 50 rpm.
• the coating is carried out so as to obtain a coating containing 7, 8, 9 and 10% of ethylcellulose, percentage expressed relative to the mass of minigranules mounted.
• the release kinetics obtained are shown in Figure 1 (in the appendix). A standby time of 2 to 4 hours is observed depending on the amount of polymer sprayed.
• the minigranules described in this example were prepared according to the method described in Example 1 but do not contain talc.
• the coatings correspond to amounts of ethylcellulose of 9, 12 and 14% of ethylcellulose.
• the release kinetics obtained are shown in Figure 2 (in the appendix).
• Minigranules mounted with talc are coated with an ethylcellulose solution containing acetyltributylcitrate without sodium lauryl sulfate.
• the quantity of ethylcellulose sprayed corresponds for each test to 9%.
• the results are presented in FIG. 3 (in the appendix), compared to the corresponding formula of example 1 and to that corresponding of example 2 (without talc). It appears that a combination of talc in the mounting suspension and sodium lauryl sulfate in the coating solution is required to obtain a latency of at least 2 h.
• a suspension of active ingredient is sprayed onto neutral sucrose-starch microgranules.
• the suspension contains methylhydroxypropylcellulose at a rate of 2% relative to the amount of active ingredient.
• a 5% solution (m / v) of methylhydroxypropylcellulose in alcohol is then sprayed onto the minigranules loaded with active ingredient.
• the coating is carried out in the same device as the assembly.
• capsules containing quick-release minigranules and slow-release minigranules are examples of capsules containing quick-release minigranules and slow-release minigranules.
• Formulation A contains two types of minigranules: rapid release minigranules obtained according to the process described in Example 4. These minigranules are coated with a standard suspension of methyl hydroxypropylcellulose containing a red dye. Slow-release minigranules obtained according to the process described in Example 1 but do not containing neither talc, nor ethyl alcohol, nor sodium lauryl sulphate and with an amount of ethyl cellulose of 9%. The quantities of these minigranules are such that they make it possible to obtain 10 mg of dexfenfiuramine released immediately and 20 mg of dexfenfiuramine released in a delayed or prolonged manner. These slow and fast minigranules are put in capsules.
• Formulation B is identical to formulation A but the slow release minigranules contain talc, ethyl alcohol and sodium lauryl sulfate.
• Figure 4 presented in the appendix compares the kinetics of dissolution of the two formulations. There is a plateau on the profile of formulation B, plateau corresponding to the latency time of the minigranules with sustained release. Formulation A does not present this plateau.
• These capsules were used for a pharmacokinetic study comparing the capsules of formulation A and B with an immediate-release formulation dosed at 15 mg of active principle in 9 healthy male volunteers. The plasma concentrations obtained are shown in FIG. 5.
• the profile of formulation B shows two peaks of plasma concentration; the first corresponds to the Cmax of the immediate release form (2.5 to 3 h), the other is around 8 h.
• Formulation C is identical to formulation B but the immediate-release minigranules are coated with a dye-free suspension of hydroxypropylmethylcellulose.
• the unit formula of formulation C is presented in the following table:

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

Applications Claiming Priority (3)

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Family Cites Families (19)

• 1997
  • 1997-02-28 FR FR9702446A patent/FR2760190B1/fr not_active Expired - Fee Related
• 1998
  • 1998-02-17 US US09/024,364 patent/US5980952A/en not_active Expired - Fee Related
  • 1998-02-26 BR BR9807278-1A patent/BR9807278A/pt not_active IP Right Cessation
  • 1998-02-26 NZ NZ337208A patent/NZ337208A/xx unknown
  • 1998-02-26 WO PCT/FR1998/000377 patent/WO1998037876A1/fr not_active Application Discontinuation
  • 1998-02-26 PL PL98335374A patent/PL335374A1/xx unknown
  • 1998-02-26 CA CA002280980A patent/CA2280980A1/fr not_active Abandoned
  • 1998-02-26 JP JP53738198A patent/JP2001513100A/ja active Pending
  • 1998-02-26 HU HU0001234A patent/HUP0001234A3/hu unknown
  • 1998-02-26 EP EP98912553A patent/EP0975339A1/de not_active Withdrawn
  • 1998-02-26 CN CN98802919A patent/CN1248913A/zh active Pending
  • 1998-02-26 AU AU67346/98A patent/AU727614B2/en not_active Ceased
  • 1998-02-27 ZA ZA981679A patent/ZA981679B/xx unknown
• 1999
  • 1999-08-26 NO NO994140A patent/NO994140L/no not_active Application Discontinuation

Non-Patent Citations (1)

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