FR2628971A1 - SOLID ADMINISTRATION FORM WITH FAST DISAGGREGATION OF DICLOFENAC - Google Patents

Abstract

Rapidly breaking solid dosage form of the known anti-inflammatory drug Diclofenac. These are effervescent tablets themselves used for the preparation of an aqueous suspension for peroral administration. The effervescent tablets contain Diclofenac in a finely ground state and bearing a water-permeable and swellable coating, together with usual pharmaceutical auxiliaries.

Description

(FRENCH REPUBLIC Publication No. 2,628,971 (to be used only

  for the NATIONAL INSTITUTE reproduction orders

OF INDUSTRIAL PROPERTY

  OF INDUSTRIAL PROPERTY N of national registration: 89 03820 PARIS

  INT CI: A 61 K 9/46.

  APPLICATION FOR PATENT OF INVENTION A1

  (Filing date: 23 March 1989) Q Applicant (s): CIBA-GEIGYAG - CH.

  ) Priority: EC, 25 March 1988, No. 1138 / 88-7.

  Inventor (s): Ruth Hagemann; Dagmar Wirth: Henri-

Julien Bronner.

  Date of the public availability of the

  application: BOPI "Patents" No. 39 of 29 September 1989.

  0 References to other national documents appearing

  () Holder (s): (Agent (s): Cabinet Regimbeau, Martin, Schrimpf,

Warcoin and Ahner.

  Fast-disintegrating solid form of administration of diclofenac.

  (Fast-disintegrating solid form of administration

  known anti-inflammatory drug Diclofenac.

  These are effervescent tablets themselves for the preparation of an aqueous suspension for peroral administration. The effervescent tablets contain Diclofenac in a finely ground state and bearing a permeable and water-swellable coating, with usual pharmaceutical auxiliaries. cc IO N TO oe D Sale of booklets to NATIONAL PRINTING, 27. rue de la Convention - 75732 PARIS CEDEX 15 -1 -

  The invention relates to effervescent tablets

  intended for the preparation of an aqueous suspension for the peroral administration of Diclofenac or salts thereof and for the immediate or delayed release of the active substance; the suspension

  obtained by disaggregation of this form of

  aqueous phase; Diclofenac or one of its salts in a finely ground state and bearing a permeable and swellable coating, which is contained in the effervescent tablet or in the aqueous suspension prepared from this tablet; processes for the preparation of

  effervescent tablets and their use.

  For the treatment of painful inflammatory diseases, for example rheumatism, there are now various drugs of various natures, and in particular non-steroidal anti-inflammatory drugs (NSAID). In this group of active substances, we find

  Diclofenac, poorly soluble in water, and its salt of

  dium, also slightly soluble, under the trademark

VOLTAREN (from the firm Ciba-Geigy).

  Peroral administration forms of the anti-

  non-steroidal inflammatory drugs, such as

  which break up in the stomach, pose problems

  because, during the disaggregation, it can occur

  local overconcentration resulting from a diffusion of

-2 -

  slow release and incomplete dispersion of the

  active in gastric juice, with the risk of irritation of the gastric mucosa and ulcers during prolonged administration. Tablets containing these drugs should therefore be absorbed at meals so that the distribution of the active substance, which otherwise only results from diffusion, occurs.

  faster and more regularly by convection.

  There is a need for new forms of admi-

  Oral administration of non-steroidal anti-inflammatory drugs ensuring, regardless of the time of absorption, even in the case of absorption outside

  meals, a regular distribution of the substance

  in the gastric juice, and thus reduce the risk of gastric mucosal

  too much concentration. These forms of administration

  In addition, they should allow a more advantageous use of Diclofenac as an analgesic in that they allow absorption exactly when the pain states appear without waiting for a meal. In the case of acetylsalicylic acid, which is a poorly soluble non-steroidal anti-inflammatory

  with marked analgesic activity,

  time of effervescent compositions, for example Alka-Seltzer effervescent tablets (from Bayer

  AG) containing calcium carbonate as a

  auxiliary duit. When these tablets are dissolved

  fervescents, it forms the calcium salt soluble in water and neutral taste. The perfect distribution of this water-soluble salt causes, after dispersion of the solution in the gastric juice, an analgesic effect

  fast with little risk of gastric mucosal attack.

  because of the low concentration of the drug

  in a large volume of liquid.

  In the case of the non-steroidal anti-inflammatory drug Diclofenac and also its salts, up to now no suitable effervescent composition or any other fast disintegrating composition, for example powder, has been available. or granules, because upon disintegration of these forms of administration, the active substance can not be converted into the appropriate therapeutic form of

  water-soluble salt with a neutral taste. In a general way

  neral, the bitter taste of the active substance contained

  in these compositions is poorly accepted by the patient.

  The present invention aims to the development of a new composition, more advantageous from the therapeutic point of view, for the active substance poorly soluble in water Diclofenac, composition which would fall apart

  quickly and have improved taste properties.

  Rees. On disintegration, this composition should

  to achieve a uniform distribution of the active substance

  aqueous phase, without its bitter taste being perceived.

  This object has been achieved according to the invention in a solid form of administration, disintegrating

  rapidly, consisting of effervescent tablets

  to prepare an aqueous suspension for the administration

  administered perorally, these tablets containing Diclofe-

  finely milled nac and having an inflatable, water-permeable coating, or a corresponding salt acceptable for pharmaceutical use also coated, as well as

  auxiliary products acceptable for phar-

ceutical.

  The invention preferably relates to

  effervescent salts containing Diclofenac at a

  average particle size less than 200 μm, plus

  especially less than 100 pm, auxiliary products

  Suitable for effervescent compositions, suspension auxiliaries and where appropriate

  other pharmaceutical auxiliary products.

  When water is added to the effervescent tablets

  On the other hand, with evolution of gaseous CO 2, a stable suspension without sedimentation of the solid material is obtained in the course of about 5 to 10 minutes necessary for the absorption of the suspension, and which has a neutral or pleasant taste. A high permeability coating, for example of polyvinylpyrrolidone or dimethylaminoethyl methacrylate / methacrylic ester copolymer soluble in gastric juice, of the type of commercial product EUDRAGIT E (from the firm Rbhm Pharma) at an appropriate layer thickness, makes that Diclofenac, after disintegration of the form of administration, passes

  suspended in water and is released in the stomach.

  Rapid release of the active substance is important when treating painful conditions

  in a short time after their appearance and that we

  hates the rapid onset of high dose activity avoiding as much as possible the risk of gastric mucosal attack. By choosing a low permeability coating, for example an acrylic ester / methacrylic ester copolymer of the type of the commercial product EUDRAGIT NE, with, if necessary, a higher

  thick layer, we can delay the release

  the active substance in the stomach and prolong the duration of action accordingly. Delayed release of the active substance is of interest when Diclofenac is used as an antirheumatic agent in long-term therapy. Suspensions

  aqueous orally administrable, releasable

  Diclofeilac, offer, because of an absorp-

  easier and more convenient, an alternative

  to the usual tablets with resistant varnish

  aunt. The expressions used above and below -5-

  must be understood as part of the description

  of the invention, as follows: The effervescent tablets according to the invention are disintegrated with release of CO 2 gas in water over a period of 3 minutes and preferably 1 minute. A slightly cloudy, drinkable aqueous suspension of the active, neutral-tasting substance is formed.

  or even nice. The suspension must be absorbed immediately

  diatement after complete disintegration of tablets

Effervescent.

  Diclofenac, o- (2,6-dichloroanilino) acid

  phenylacetic acid is contained in effervescent tablets.

  cents in the state of free acid or salt acceptable for

pharmaceutical use.

  An acceptable salt for the pharmaceutical use of Diclofenac consists in particular of an alkali metal salt, for example the sodium salt: cf. Merck Index,

  th edition, No. 3066, or potassium salt.

  The finely ground Diclofenac preferably has a mean particle size of less than 200 μm;

  in fact, it is more specifically micronized at one

  particle size less than 100 μm. To get

  particles of this size, the technologies

  crushing techniques, for example grinding in

  an air jet mill, a ball mill or a broach

  It is possible to use the method known per se of the ultrasonic disintegrator, for example of the Branson Sonifier type, as described for example in J. Pharm. Sci. 53, (9) 1040-45 (1965), or a suspension is stirred using a high speed stirrer, for example a Homorex type agitator of the firm.

Brogli and Company, Basel, Switzerland.

  On Diclofenac or one of its acceptable salts

  tables for pharmaceutical use, in the finely ground state, a permeable and inflatable coating is applied -6-

  which consists of a permeable elastic film-forming

  water or aqueous body fluids such as

  gastric juice or intestinal juice, and which is gon-

  flable and / or soluble in these liquids.

  The water-permeable elastic film-forming materials consist, for example, of hydrophilic mixtures

  of polyvinylpyrrolidone or a copolymer of vinyl

  pyrrolidone and vinyl acetate with hydroxypropyl

  propylmethylcellulose, in mixtures of polyvinylpyrrolidine

  done and a polysorbate, for example the product of the com-

  Polysorbat 60, in mixtures of shellac and hy-

  hydroxypropyl methylcellulose, polyvinyl acetate or

  of copolymers of vinyl acetate with poly-

  vinylpyrrolidone, or in mixtures of cellulose derivatives

  soluble in water such as hydroxypropylmethyl-

  cellulose, and ethylcellulose insoluble in water. These

  coating products can be used if desired

  mixed with other auxiliary products such as

  talc, wetting agents, for example

  bates (used for example to facilitate the application).

  Elastic film-forming materials can

  especially in a polyvinylpyrrolidone hydro-

  phile (PVP-Povidons, with an average molecular weight of

  10,000 to 700,000), in partial cellulosic derivatives

  etherified and hydrophilic and in polyacrylates hy-

  drophiles, for example polymers of acrylic acid

  or acrylic acid / methacrylate ester copolymers

lic.

  The partially ethereal cellulosic derivatives

  hydrophilic compounds consist, for example, of ethers

  kylics of cellulose to a degree of substitution

  average molar ratio (MS) greater than 1 and less than 3, and an average degree of polymerization of about 100 to 5000. The degree of substitution is a measure of the number of hydroxy groups per glucose unit which

  are. placed with lower alkoxy groups. Of the-

  average molar substitution (MS) is a value

  average and therefore gives the number of lower alkoxy groups

  by glucose unit of the polymer.

  The average degree of polymerisation (DP) is also

  an average value and indicates the average number of

  glucose units in the cellulosic polymer.

  The lower alkyl ethers of cellulose

  are, for example, derivatives of cellulose which

  are substituted on the hydroxymethyl group (hydroxyl group

  primary droxy) of the glucose unit forming the cellulose chains and, if appropriate, on the second and the

  third group of secondary hydroxyl groups

  C 1 -C 4 alkyl, in particular methyl or ethyl, or substituted C 1 -C 4 alkyl groups, for example

  2-hydroxyethyl, 3-hydroxy-n-propyl, carboxy-

methyl or 2-carboxyethyl.

  The lower alkyl ethers of cellulose

  are preferably derivatives

  of cellulose which are substituted on the hydro-

  xymethyl (primary hydroxy group) of the glucose unit

  C 1 -C 4 alkyl or C 1 -C 4 alkyl groups.

  in question and on the second hydroxy group se-

  condaire and possibly the third by groups

methyl or ethyl.

  Suitable lower alkyl ethers of cellulose include, in particular,

  methylcellulose, ethylcellulose, methylhydroxyethyl-

  cellulose, methylhydroxypropylcellulose, ethyl-

  hydroxyethylcellulose, hydroxyethylcellulose, hydro-

  xypropylcellulose, carboxymethylcellulose (as it is

  salt, for example sodium salt) or methylcarbo

  xymethylcellulose (also in the form of salt, for example

in the form of sodium salt).

-8-

  The lower alkyl ethers of cellulose

  which are preferred are methylcellulose (DP:

  about 200 to 1000, S: about 1.4 to 2.0), ethyl

  cellulose (DP: about 150 to 1000, MS: about 1.2 to 1.8), for example the commercial product Aquacoat (from

  FMC Corp.), hydroxyethylcellulose (DP: approx.

  120 to 1200, IIS: about 1.2 to 2.5), hydroxypropyl-

  cellulose (DP: about 200 to 3000, MS: about 1.0 to 3.0) and methylhydroxypropylcellulose (DP: about 200 to 1000, MS: about 1.4 to 2.0), e.g. the product

  Pharmacoat (from Shin Etsu Corp.).

  The hydrophilic polyacrylates have a molecular weight of

  average of approximately 1.0 x 105 to 1.0 x 10O6 and

  are made of polymers of acrylic acid or copoly-

  acrylic acid / methacrylic acid mothers. The groups

  acids of acrylic and / or methacrylic acid mono-

  mothers are esterified in whole or in part by

  C 1 -C 4 alkyl groups, in particular metal groups

  and / or ethyl, and these ester groups may also

  be replaced by hydrophilic groups, in particular

  especially trimethylammonium-ethyl groups.

  The preferred polyacrylates are the commercial products sold under the generic brand EUDRLGI2 from the firm Rbhm Pharma Weiterstadt, FRG. Particularly preferred are the commercially available forms of EUDRAGIT for rapidly disintegrating coating films, for example permeable and swellable types based on acrylic ester / methacrylic ester copolymers, particularly ethyl acrylate / methyl methacrylate copolymer, preferably at the average molecular weight of 800,000, such as the EUDRAGIT NE 30 D brand product, or the soluble types in gastric juice such as the EUDRAGIT E brand product. When using gastric juice resistant types such as EUDRAGIT L or his

  causes a delay in the release.

-5-

  Auxiliary products acceptable for use

  pharmaceutical medicines are in particular substances

  increasing the viscosity and which are suitable for the

  bilization of aqueous suspensions by preventing

  of the coated active substance, Diclofe-

  nac, for example natural macromolecules which are

  sign under the name karaya gums, for example of the carragheen gum type, or the Viscarin trade product of the firm Marine Colloid, guar gums, for example galactomannans of the Meyprogat commercial product type from Meyhall Chemical, in particular "Meyprogat" of the standard types 30, 60, 90, 120 and, gum arabic, sodium alginate or gum tragacanth, semi-synthetic macromolecules, by

  example of microcrystalline cellulose of the type of

  Avicel from the company FMC Corp., the cellulosic ethers mentioned above, such as methyl-, ethyl- or propyl-cellulose, optionally bearing functional groups such as hydroxy or carboxy groups, or alginate of propylene glycol,

  macromolecules of the polyoxyethylene groups

  such as the trade products Polyox from Union Carbide, Carbowax from Goodrich or

  Polyglycol from Dow Chemical, carboxypoly-

  methylenes, for example the commercial product Carbopol from the firm Goodrich, polyvinyl alcohol (PVA), for example the commercial product Polyviol from the firm

  Wacker or Mowiol from Hoechst, or polyvinyl-

  pyrrolidone (PVP), for example the commercial product Kollidon from the firm BASF or Plasdone from the firm GAF,

  or colloidal silicates, for example a silica

  loidal such as the commercial product Aerosil of the

  Firm Degussa or Cab-o-sil Cabot firm.

  In addition to the auxiliary products used

  For the preparation of tablets,

  -10- award-winning effervescent contain an agent capable of

  release CO 2 as well as a product causing the release

  CO2. Products capable of releasing CO2 are mono and di-basic salts of carbonic acid acceptable for pharmaceutical use, for example alkali metal bicarbonates or carbonates such as sodium or potassium carbonate or bicarbonate

  of sodium or alkali metal carbonates

  earthy, for example calcium carbonate or magnesium

  sium, or glycine-sodium carbonate. We prefer

sodium bicarbonate.

  The products causing the evolution of CO2 are preferably organic acids acceptable for pharmaceutical use, their anhydrides or their salts

  acids, which are in the solid state and can be introduced

  with the coated active substance and the other

  auxiliary fats mentioned in granules or

  tablets without causing premature release of CO2.

  Acids acceptable for pharmaceutical use

  are, for example, organic acids such as

  tartaric, malic, fumaric, adipic, sucrose

  cinic, ascorbic or maleic. The acid

cudgel.

  Anhydrides acceptable for pharmaceutical use

  are the anhydrides corresponding to the acids

  organic substances just mentioned, for example, the

  citric hydride or succinic anhydride.

  Acidic salts acceptable for pharmaceutical use

  for example, consist of solid salts of

  polybasic acids in which there is at least one acid function, for example monosodium phosphate

or disodium phosphate.

  We can add to the preparation of

  effervescent tablets of other surface-active substances

  active agents or wetting agents, that is to say surfactants, for example anionic surfactants of the alkyl sulphate type, for example sodium, potassium or magnesium n-dodecyl sulphate,

  or nonionic surfactants of the type of

  fatty acids and polyalcohols such as monostearate or sorbitan monopalmitate or tristearate

of sorbitan.

  Among the other ancillary products, mention is made of

  for example, pulverulent fillers such as lactose, sucrose, sorbitol, mannitol, starch, for example potato starch, rice starch, corn starch, starch of wheat or amylopectin or cellulose, especially

microcrystalline cellulose.

  Other auxiliary products make it possible to

* improve the appearance and taste properties of the sus-

  aqueous solution obtained on the disintegration of the effervescent tablets, for example dyes, sugars or

sweetening agents.

  The dyes can serve both to improve

  look and characterize a composition. Among the suitable dyes that are authorized for use in pharmacy are, for example,

  carotenoids, iron oxides and chlorophyll.

  Sugars and sweetening agents consist for example of sucrose, xylitol, D-xylose, D-glucose, sorbitol, mannitol or lactose, and respectively

  sodium saccharin, dulcin, ammonium glycyrrhizinate

nium or sodium cyclamate.

  For the preparation of the effervescent tablets, the solid particles of Diclofenac are finely ground, a permeable and inflatable coating is applied and tableted, optionally by adding

  pharmaceutical auxiliary products.

  The coating of micronised Diclofenac with the aforementioned coating products can be carried out by conventional coating techniques for fine particulate materials: for example, the coating product is dissolved or suspended. the desired proportion, in water or an organic solvent or a mixture of water and an organic solvent, for example in ethanol, isopropanol, acetone or methylene chloride, and the where appropriate auxiliary products. This solution or dispersion, preferably at a concentration of 4 to 6%, is sprayed onto the powder of Diclofenac or onto

  powdered mixtures containing also

  for example according to known methods such as Wurster fluidized bed atomization coating, for example according to Aeromatic, Glatt systems.

or HUttlin (ball coating).

  By slow and complete removal of the solvent and sieving the residue to a preferred average particle size of about 50 to 200 I / um, granules are obtained.

  that flow well, that can be mixed with

  auxiliary fuels capable of releasing CO2, such as

  sodium bicarbonate, and with the corresponding products

  causing the release of CO2, for example, the

citric acid.

  The granules consisting of the coated active substance can be mixed as described above with

  the ancillary products necessary for their preparation

  and other auxiliary products such as

  above, as well as fillers such as lactose and cellulose, lubricating agents such as polyethylene glycol, and the mixture may be

  put to the press in the form of effervescent tablets.

  Due to the high content of auxiliary products,

  uses tablet machines suitable for the manufacture of

  large tablets, up to

  -3.3 cm and a thickness of up to about 1 cm. If necessary, it is compressed in the absence of moisture or inert gas atmosphere. Tablets can

  be wrapped individually in leaves.

  ; The invention preferably relates to

  effervescent salts containing Diclofenac at a

  average particle size of less than 200 μm, bearing a permeable and inflatable coating, particularly

  a particle size of less than 100 μm,

  auxiliaries suitable for the compositions

  vescentes, auxiliary products of suspension and the

  where appropriate other auxiliary products

  c. The following examples illustrate the invention

without limiting its scope.

  Exemole 1 Effervescent tablet containing 50 mg of Diclofenac Diclofenac 50 mg galactomannan (Meyprogat 150) 32 mg colloidal silica (Aerosil 200) 1 mg Eudragit LIE 30 D solid 7 mg polyethylene glycol 8000 50 mg sodium bicarbonate 825 mg citric acid anhydrous 1160 mg galactomannan (Meyprogat 150) 75 mg microcrystalline cellulose (Avicel PH 102) 200 mg 2400 mg A fluidized mixture is sprayed with a mixture of Diclofenac, the first portion of Meyprogat 150 and

  Aerosil 200 with an aqueous dispersion of Eudra

  git NE 30 D then dry. Mix with the substance

  active ingredient coated the outer phase consisting of poly-

  ethylene glycol 8000, sodium bicarbonate, acid

  the second portion of Meyprogat 150 and the -14-

  microcrystalline cellulose and the homogeneous mixture is

  gene in the form of effervescent tablets (diameter 19 mm, thickness 6 mm) on a tablet machine

usual trade.

  Example 2 Effervescent tablet containing 50 mg Diclofenac Diclofenac 50 mg Galactomannan (Meyprogat 150) 33 mg Eudragit NE 30 D Solid 7 mg Crushed lactose 400 mg Polyvinylpyrrolidone (PVP K 30) 10 mg Polyethylene glycol 8000 50 mg Sodium bicarbonate 700 mg Citric acid anhydrous 975 mg galactomannan (Heyprogat 150) 75 mg microcrystalline cellulose (Avicel PH 102) 100 mg 2400 mg A fluidized layer is sprayed with a mixture of Diclofenac and the first portion of Meyprogat 150 with an aqueous dispersion of Eudragit NE 30 D and then dried. The coated active substance is mixed with the ground lactose and the PVP K 30 and granulated by the addition of water. The dried kneading granules are mixed with the outer phase consisting of

  polyethylene glycol 8000, sodium bicarbonate

  dium, citric acid, second portion of Ileyprogat and microcrystalline cellulose and released to the press

  in the form of effervescent tablets.

  Example 3 Effervescent tablet containing 50 mg of Diclofenac Diclofenac 50 mg galactomannan (Meyprogat 150) 3355 mg Eudragit NE 30 D solid 7 mg milled lactose 400 mg -15- polyvinylpyrrolidone (PVP K 30) 10 mg polyethylene glycol 8000 50 mg sodium bicarbonate 700 mg citric acid anhydrous 900 mg microcrystalline cellulose (Avicel PH 102) 200 mg 2400 mg A fluid mixture is sprayed in a fluidized bed.

  Diclofenac and Meyprogat 150 by aqueous dispersion of Eudragit NE 30 D and then dried. The active substance is mixed

  coated with ground lactose and PVP K 30 and granulated with addition of water. The dried kneading granules are mixed with the outer phase consisting of polyethylene glycol 8000, sodium bicarbonate, citric acid and

  microcrystalline cellulose and the press is

state of effervescent tablets.

Example 4

  Effervescent tablet containing 50 mg of Diclofenac-

  sodium Diclofenac-sodium 50 mg-galactomannan (Meyprogat 150) 32 mg colloidal silica (Aerosil 200) I mg Eudragit NE 30 D solid 7 mg polyethylene glycol 8000 50 mg sodium bicarbonate 855 mg citric acid anhydrous 1205 mg microcrystalline cellulose (Avicel PH 102) 200 mg 2400 mg A fluidized layer of a mixture of Diclofenac sodium, IMeyprogat 150 and Aerosil 200 is sprayed with an aqueous dispersion of Eudragit NE 30 D and then dried. The coated active substance is mixed with the external phase consisting of polyethylene glycol-8000, sodium bicarbonate, citric acid and

  microcrystalline cellulose and the homogeneous mixture is

  gene in the state of effervescent tablet tablet machine. Example 5 Coated Tablet Containing 50 mg Diclofenac Diclofenac 50 mg Galactomannan (Meyprogat 150) 32 mg Colloidal Silica (Aerosil 200) I mg Eudragit NE 30 D Solid 25 mg Polyethylene Glycol 8000 50 mg Sodium Bicarbonate 825 mg Citric Acid Anhydrous 1142 mg galactomannan (Meyprogat 150) 75 mg microcrystalline cellulose (Avicel PH 102) 200 mg 2400 mg

  The coated tablets are prepared as

scream in example 1.

  Example 6 Effervescent tablet containing 50 mg of Diclofenac Diclofenac 50 mg galactomannan (Meyprogat 150) 33 mg colloidal silica (Aerosil 200) 1 mg Aquacoat solid ECD 20 mg polyethylene glycol 8000 50 mg sodium bicarbonate 850 mg citric acid anhydrous 1196 mg microcrystalline cellulose (Avicel PH 102) 200 mg 2400 mg A fluidized layer is sprayed with a mixture of Diclofenac, Meyprogat 150 and Aerosil 200 by

  aqueous dispersion of Aquacoat ECD 30 and then dried.

  The outer phase consisting of polyethylene glycol 8000 is mixed with the coated active substance,

  sodium bicarbonate, citric acid and cellulose

  microcrystalline lose and the homogeneous mixture is put into the state of effervescent tablets on a tablet machine.

Example 7

  Effervescent tablet containing 50 mg of Diclofenac Diclofenac 50 mg galactomannan (Meyprogat 150) 36.7 mg Colloidal silica (Aerosil 200) 1, 1 mg Cellulose-HPH-603 (Pharmacoat) 5.5 mg Polyethylene glycol 8000 50 mg Sodium bicarbonate 850 mg anhydrous citric acid 1206.7 mg microcrystalline cellulose Avicel PH 102 200 mg 2400 mg A fluidized layer is sprayed with a mixture of Diclofenac, Meyprogat 150 and Aerosil 200 with an aqueous solution of the Pharmacoat and then dried. We

  mixture with the coated active ingredient-the outer phase

  consisting of polyethylene glycol 8000,

  sodium carbonate, citric acid and microcrystalline cellulose and the homogeneous mixture is

  from effervescent tablets to the tablet machine.

Example 8

  Effervescent tablet containing 50 mg of Diclofenac Diclofenac 50 mg galactomannan (Meyprogat 150) 35 mg Colloidal silica (Aerosil 200) I mg Eudragit NE 30 D 50 mg Polyethylene glycol 8000 50 mg Sodium bicarbonate 830 mg Citric acid anhydrous 1184 mg -18- microcrystalline cellulose (Avicel PH 102) 200 mg 2400 mg The effervescent tablets are prepared as described in Example 4. Measurement of the dissolution rate USP method at the blade, 50 rpm Medium-t 60 minutes, 0.1 HCl N, pH 1.0 - t 60 minutes, phosphate buffer pH 6.8 Results:% of Diclofenac after 60 minutes 4 after 120 minutes 50 after 240 minutes 77 after 420 minutes 93

Example 9

  Effervescent tablet containing 46.5 mg of Diclofenac Diclofenac 46.5 mg galactomannan (Meyprogat 160) 37 mg colloidal silica (Aerosil 200) I mg polyvinylpyrrolidone K 30 10 mg zolysorbate 80 0.8 mg polyethylene glycol 8000 powder 60 mg bicarbonate sodium 700 mg citric acid anhydrous 1344.7 mg HIalbit 200 mg 2400 mg A fluidized layer is sprayed with a mixture of Diclofenac, Meyprogat 150 and Aerosil 200 with an aqueous solution of polyvinylpyrrolidone K 30 and Polysorbate 80, and then dried. With the coated active substance, the outer phase consisting of

  polyethylene glycol 8000, sodium bicarbonate, the

  citric acid and Malbit and put the mixture homogeneous

  in the form of effervescent tablets on a tablet machine.

-19-

- iEVENDIC.TIONS -

  I - Solid form of administration with disaggregation

  rapid preparation, consisting of effervescent tablets for preparing an aqueous suspension to be administered orally, of Diclofenac, characterized in that it

  contains finely ground Diclofenac with

  permeable and water-swellable, or a corresponding salt.

  acceptable for pharmaceutical use and

  such a coating, and auxiliary products acceptable

for pharmaceutical use.

  2 - Form of administration according to the claim

  1, characterized in that it contains Diclofe-

  micronized nac at a mean particle size of less than

  than 200, m, bearing a polyvinylpyridine

  rolidone, a lower alkyl ether of cellulose or an acrylic ester / methacrylic ester copolymer

  permeable and inflatable, auxiliary products

  for solid effervescent compositions, suspension auxiliaries and, as the case may

  other pharmaceutical auxiliary products.

  3 - Form of administration according to the claim

  2, characterized in that it contains micronized Diclofenac with a lower average particle size

at 100 μm.

  4 - Form of administration according to the claim

  2 or 3, characterized in that it contains Diclo

  micronized fenac bearing a permeable coating of ethyl-

  cellulose or methylhydroxypropylcellulose, a co-

  polymer ethyl acrylate / methyl methacrylate

  and inflatable, suitable auxiliary products

  for solid effervescent compositions,

  suspension auxiliaries and, where appropriate,

very auxiliary products.

  Form of administration according to claim 4, characterized in that it contains Diclofenac.

  finely ground to an average particle size

  less than 200 μm, bearing a coating of a permeable and inflatable methyl acrylate / methyl methacrylate copolymer at an average molecular weight of about 800,000, a salt of carbonic acid acceptable for

  pharmaceutical use and an organic acid, a hydro-

  colloidal soluble in cold water as a product

  suspension aid and, where appropriate, other

auxiliary feeds.

  6 - Aqueous suspension for the peroral administration of Diclofenac, characterized in that it was obtained by disintegration in the aqueous phase of a fast disintegrating solid administration form according to

claim 1.

  7 - Micronized Diclofenac, characterized in that

  that it bears a coating of an acrylate copolymer of

  methyl and methyl methacrylate permeable and inflatable, or

  of permeable and inflatable polyvinylpyrrolidone.

  8 - Process for preparing the form of administration

  solid administration with rapid disaggregation according to the

  1, characterized in that the solid particles of Diclofenac are finely ground, a permeable and inflatable coating is applied thereto and the tablets are added with the addition of auxiliary products.

pharmaceuticals.

  9 - Use of a rapid disintegrating solid administration form according to claim 1

  for the preparation of an aqueous suspension for ad-

  Peroral administration of Diclofenac.

  10 - The therapeutic use of the form of ad-

  solid administration with rapid disaggregation according to

  I in human and veterinary medicine.

  11 - The use according to claim 10

  for the treatment of painful states.