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
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir

Definitions

• the invention relates to a process for the manufacture of prolonged-release tablets of active principle (s) as well as to the tablets thus obtained.
• the expression “prolonged release tablet of active principle” means a tablet capable of increasing the therapeutic effect of the active principle in the tissues or in the blood for an extended period of time.
• the documents FR-A-2417982 and HU-A-9960 describe a process for the production of delayed-action tablets by wet granulation. More specifically, the powder mixture comprising the active principle and the various adjuvants is mixed with a granulation liquid consisting of an aqueous emulsion based on a hydrophobic component such as stearic acid and nonionic hydrophilic components such as polysorbates. The resulting wet mass is then dried and then passed through a sieve, the granules obtained then being pelletized so as to obtain tablets. The steps of kneading, sieving, drying and pelletizing the powder mixture make it a long and expensive process.
• document WO 94/06416 describes tablets consisting of a core coated with a double layer, respectively a first layer containing at least one active principle with immediate or modulated release, a second layer with delayed release of active principle and an additional layer of low permeability. There is therefore obtained, by a relatively long process, a tablet having a complex structure, the kinetics of release of the active principle is predetermined during manufacture.
• document WO 87/04070 describes a process for spraying onto tablets an aqueous dispersion prepared by re-dissolving in water a dried lipid emulsion, based on wax or hydrogenated oils.
• the document JP-A-53062821 describes a process consisting in emulsifying a lipophilic substance in fusion in an aqueous phase then in coating a pharmaceutical preparation by spraying this emulsion at high temperature, higher than the melting point of the lipophilic substance ( so-called dry-spraying technique). Besides the fact that nothing is indicated concerning the nature of the coated pharmaceutical preparation. This technique has the drawback of leading, during the spraying, to an evaporation of the aqueous phase and thus of modifying the coating conditions.
• the problem that the invention proposes to solve is therefore to develop prolonged-release tablets of active principle (s), the manufacturing process of which is simple to implement, potentially shorter and consequently less expensive. than the methods proposed in the state of the art.
• the invention provides a process for the manufacture of prolonged-release tablets of active principle (s) according to which:
• the emulsion obtained is sprayed on a powder mixture comprising at least the active principle
• the powder mixture comprises not only the active principle, but also the formulation excipients.
• formulation excipient is meant the excipients necessary for the formulation of the dosage form envisaged.
• the compression step can be carried out using any known excipient intended to promote said compression.
• the spray air temperature is between 20 and 60 ° C, advantageously 25 ° C, the temperature of the emulsion being fixed between 20 and 25 ° C.
• the initial powder mixture is subjected beforehand to a granulation step in order to obtain granules.
• said emulsion is advantageously produced in phase inversion, so as to modify the particle size distribution, thus making it possible to reduce the size of the particles and therefore the viscosity of the emulsion.
• the fluid oil-in-water emulsion comprises from 5 to 35% by weight of fatty substances.
• concentration of fatty substance is not sufficient to ensure the prolonged release of the active principle.
• the viscosity is too high to obtain a fluid emulsion.
• the compression step is difficult.
• said particles are coated in an amount of 3 to 100% by weight of fluid emulsion, advantageously from 10 to 60%.
• the tablet becomes too bulky to constitute an appropriate dosage form.
• the fatty substances are chosen from the group comprising fatty acids, hydrogenated oils, fatty acid esters with glycerin or polyols and natural waxes.
• the chosen fatty substance is glycerol behenate marketed by the Applicant under the trade name COMPRITOL ® 888 ATO.
• the fatty substance is glycerol palmitostearate marketed by the Applicant under the trade mark ® Precirol® Ato 5.
• the emulsion also contains an emulsifier or surfactant.
• the surfactant used is chosen from nonionic and / or ionic surfactants. More specifically, the emulsifying agent will be chosen so as to ensure the fluidity of the emulsion, its stability and the absence of foaming. In addition, the emulsifier must be pharmaceutically acceptable.
• the emulsifying agent chosen is polyethylene glycol 4000 palmitostearate.
• the emulsifying agent is sodium lauryl sulfate used in an amount of 0.5 to 1% by weight of the emulsion. Beyond 10 1%, no improvement in the emulsion is obtained and foaming is observed.
• the viscosity of the oil-in-water fluid emulsion is chosen between 10 and 15 70 centipoise.
• the invention also relates to the prolonged-release tablet of active principle (s) capable of being obtained by the process described above.
• Figure 1 is a representation of the release profile of a tablet with kinetics of dissolution of the active principle of order 0.
• Figure 2 is a representation of the release profile of a tablet with kinetics of dissolution of the active principle of order 1.
• FIG. 3 shows the release profile of theophylline granules at a spray air temperature 25 ° C of an emulsion based COMPRITOL ® 888 ATO.
• Figure 4 shows the release profile of theophylline granules at a spray air temperature of 60 ° C of an emulsion based COMPRITOL ® 888 ATO.
• FIG. 5 shows the theophylline granules release profile at a spraying air temperature of 25 ° C of an emulsion based on 35 Precirol® ATO 5 ®.
• FIG. 6 represents the release profile of theophylline granules at a spray air temperature of 60 ° C. from an emulsion based on
• FIG. 7 shows the release profile of theophylline tablets a spraying air temperature of 25 ° C of an emulsion based COMPRITOL ® 888 ATO.
• FIG. 8 shows the release profile of theophylline tablets a spraying air temperature of 60 ° C of an emulsion based COMPRITOL ® 888 ATO.
• 9 shows Diclofenac tablets release profile made from an emulsion-based COMPRITOL ® 888 ATO or PRECIROL ® ATO 5 to a spray temperature of 25 ° C.
• Figure 10 shows the release profile of the same batch of tablets of Diclofenac made from an emulsion-based COMPRITOL ® 888 ATO or PRECIROL ® ATO 5 before and after stability at 40 ° C.
• Diclofenac tablets release profile made from a PRECIROL based emulsion ® ATO 5 at a spraying air temperature of 25 ° C.
• kinetics of order 1 correspond to a release proportional to the quantity remaining in the dosage form envisaged and which decreases over time exponentially (see FIG. 2).
• Example 1 the kinetics of in vitro release of the active ingredients is carried out in a dissolumeter (conventional SOTAX) in accordance with European and American pharmacopoeias at pH 1.2.
• the blade rotation speed is 100 revolutions per minute.
• Example 1 we compare the theophylline granules coated release profile according to the method of the invention before and after compression with two different fats, namely Compritol ® 888 ® and Precirol® Ato 5 by setting the temperature atomizing air at 25 ° C or 60 ° C.
• Granules are prepared corresponding to the following formula:
• the granules are produced by wet granulation in a Guedu type mixer with rotating blades by implementing the following steps:
• a lipid emulsion comprising:
• COMPRITOL ® 888 or PRECIROL ® is used as a fatty substance
• the fatty substance and the surfactant are heated until complete fusion. Distilled water, heated to the same temperature, is added slowly with stirring. The addition of water gradually transforms the initial water-in-oil emulsion into an oil-in-water emulsion. The emulsion is then homogenized with a homogenizer of the POLYTRON type for three minutes in order to reduce and homogenize the size of the oil droplets.
• sodium lauryl sulfate when sodium lauryl sulfate is used as a surfactant, it is dissolved hot in the aqueous phase.
• a fluidized air flow device is used, the fluidizing air temperature of which is chosen at 25 ° C. or 60 ° C.
• the fluidization pressure is chosen to be of the order of 1.5 bar.
• the spray rate is set at 10 grams per minute.
• FIGS. 3 and 4 appended show the release profile of theophylline granules coated with a lipid emulsion based on
• COMPRITOL® 888 for spray air temperatures of 25 ° C ( Figure 3) or 60 ° C ( Figure 4).
• the proportion of COMPRITOL® 888 varies between 10 and 30% relative to the mass of dry matter used.
• Figures 5 and 6 show immediate release profiles when the emulsion used is based on PRECIROL ® Ato 5.
• the method of the invention has the advantage of being able to be implemented at a spraying air temperature of the order of only 25 ° C., which not only facilitates the various operations but also reduces the manufacturing cost, particularly in terms of energy consumed.
• Diclofenac particles are produced under the same conditions as in Example 1, starting from a diclofenac / bicalcium phosphate mixture in proportions of 50/50.
• Figure 10 depicts the release profiles of diclofenac tablets coated with lipid emulsions comprising 20% COMPRITOL ® 888 ATO or 20% Precirol® ® Ato 5, before and after twelve months of stability at 40 ° C and 75% relative humidity (accelerated stability).
• Example 2 does not carry out prior wet granulation of the active principle.
• the powder mixture consisting of a diclofenac / dicalcium phosphate mixture is then coated in the proportions of 50/50 in order to obtain coated particles having good compressibility properties.
• the spraying of the emulsion on the particles is carried out under the same conditions as in Example 1 at a spraying air temperature of around 25 ° C.
• the coated particles are then compressed on an industrial rotary press.
• the compression characteristics and tablets obtained are as follows:
• FIG. 11 shows the release profile of diclofenac tablets, the proportion of PRECIROL® ATO 5 relative to the mass of dry matter used is 20%.
• the kinetics of in vitro release of diclofenac is evaluated in a dissolumeter in accordance with the European, American and Japanese pharmacopoeias at pH 6.8 according to the provisions of the American Pharmacopoeia edition XXIII.
• the rotation speed of the blades is 50 rotations per minute.
• the two tests carried out on the same batch show a profile of prolonged release over 12 hours of the active principle.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)

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• 1998
  • 1998-06-16 FR FR9807725A patent/FR2779651B1/fr not_active Expired - Fee Related
• 1999
  • 1999-06-16 JP JP2000554351A patent/JP2002518320A/ja not_active Withdrawn
  • 1999-06-16 EP EP99925111A patent/EP1087757A1/de not_active Withdrawn
  • 1999-06-16 WO PCT/FR1999/001443 patent/WO1999065471A1/fr not_active Ceased
• 2000
  • 2000-12-08 US US09/733,668 patent/US6379700B2/en not_active Expired - Fee Related

Non-Patent Citations (1)

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