DK175517B1 - Fixed fast digestible forms of diclofenac - Google Patents

Description

DK 175517 B1 I

The present invention relates to a fixed, fast-aligned H

fragile mode of administration for the preparation of an oral H

applicable aqueous suspension of diclofenac or salts H

thereof, with immediate or delayed release of it H

5 active substances, shower tablets based on the administration form I

as well as pharmaceutical preparations. H

For the treatment of painful inflammatory diseases, e.g. H

rheumatisms, can be used various drugs with H

different structure, especially non-steroidal anti-inflammatory H

drugs (NSAIDs). This group of active substances belongs to H

the water-soluble diclofenac whose H

heavy-soluble sodium salt is traded under the trade name H

"Voltaren". IN

Oral administration forms of NSAIDs, such as tablets, such as H

degradation in the stomach is problematic, since at H

the breakdown may result in local over-concentration of I

due to slow diffusion and unsatisfactory H

20 distribution of the active substance in the gastric juice at risk of H

gastric mucosa irritation and ulcer when administered in H

longer time. Therefore, NSAID tablets should be taken in I

connection with meals, otherwise it only knows H

diffusion caused distribution happens faster and more H

25 uniformly by convection of the active substance. H

New oral administration forms of NSAIDs, such as H, are needed

temporarily independent of the intake of food outside I

the meals cause a uniform distribution of the active H

20 substances in the stomach juice, which can reduce the risk of H

damage to the gastric mucosa at elevated concentrations- H

tions. Such forms of administration should also have an H

more favorable use of diclofenac as an analgesic, with H

ingestion can occur immediately when painful H occurs

25 states, without having to wait for a meal. H

2 DK 175517 B1

For acetylsalicylic acid as a heavily soluble NSAID with a pronounced analgesic effect, a shower formulation, e.g. Alka-Seltzer shower tablets (Bayer AG) with calcium carbonate as an adjuvant. Upon dissolving such effervescent tablets, a taste-neutral, water-soluble calcium salt is formed. The complete distribution of this soluble salt in water, upon ingestion of the solution, causes a rapid onset of analgesic effect in the gastric juice with reduced risk of gastric mucosal damage due to a low concentration in a larger volume of fluid.

For NSAID diclofenac and its salts, there has so far been no suitable analog effervescent formulation and no other fast dissolving formulation, such as e.g. powders 15 or granules, since the active substance, when degraded by such forms of administration, cannot be converted into the therapeutically suitable form of a water-soluble salt with neutral taste properties. In general, the bitter taste of the active substance renders such formulations unsuitable.

In US 4,265,874 A, the claims and examples relate to a pharmaceutical composition based on indomethacin, wherein the active substance protected with polyvinylpyrolidone as a water-soluble binder upon ingestion is released by carbon dioxide-developing components in the acidic physiological environment of the stomach. The specification also mentions other active substances, including diclofenac, and also other water-soluble binders such as polyethylene glycol, gelatin, agar, carboxy-cellulose, ethyl methyl-cellulose, polyvinyl alcohol and water-soluble starch derivative. The older, unpublished DE 38 02 357 A1 discloses preparations containing diclofenac in micronized form.

The present invention has for its object to provide a novel and therapeutically beneficial formulation for the rapidly soluble active substance diclofenac with rapid

DK 175517 B1 I

decomposition and improved taste properties. This form- I

In decomposition, clay must cause a uniform distribution

of the active substance in aqueous phase without the bitter taste I

of which is noticeable. IN

This object is achieved by the present invention which

comprises a solid, rapidly degrading form of administration in Form H

of effervescent tablets for the preparation of an oral appli- I

cereal aqueous suspension containing finely ground I

20 diclofenac with a water permeable, swellable coating I

or a similarly coated pharmaceutically acceptable

salt and pharmaceutically acceptable excipients. H

Preferably, the invention relates to effervescent tablets containing I

15 diclofenac with an average particle size less H

than 100 μηα for auxiliary effervescent formulations, I

suspension auxiliaries and optionally other pharmaceutical H

excipients. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

By adding water to the shower tablet, under I

2

development of CO 2 gas a suspension which within it H

3

required time of approx. 5-10 minutes is stable to I

4

intake without sedimentation of fat and having an I

5

neutral or pleasant taste. With a high I coating

6

permeability, e.g. polyvinylpyrrolidone or H

7

gastric juice-soluble dimethylaminoethylmethacryalt-meth-I

8

acrylic acid ester copolymer of type Eudragit E (R6hm I

9

Pharma) of a suitable thickness may be diclofenac H

10

suspended in water after decomposition of the administration form and H

11

is released in the stomach. · The rapid release of active H

12

drug is important when treating for painful H

13

conditions as soon as these occur, shortly, and H

14

when one wants the effect to occur rapidly with high H

15

dosages while avoiding the risk of H

16

damage to the gastric mucosa. Using an H

low permeability coatings, e.g. acrylic acid ester- I

methacrylic acid ester copolymer of type Eudragit NE and H

possibly thicker coatings, the delivery of the H is delayed

DK 175517 B1 4 active substance in the stomach with corresponding extension of duration of action. The delayed release of the active substance is important for the use of diclofenac as an antirheumatic agent for long-term treatment. Oral suspension pensions, which can be administered orally, with delayed release of diclofenac is an advantageous alternative due to a lighter and more convenient intake to the conventional resistant lacquer tablets.

The terms and terms used in the foregoing and the following are defined in the context of the present invention as follows:

Shower tablets of the present invention are degraded during evolution of CO 2 gas in water within 3 minutes, preferably within 1 minute. A slightly cloudy aqueous drinkable suspension of the active substance is formed with neutral or even pleasant taste. The suspension may be taken immediately after complete degradation of the effervescent tablet.

Diclofenac, o- (2,6-dichloroanilino) phenylacetic acid, is contained in the effervescent tablet as free acid or pharmaceutically useful salt.

25

In particular, a pharmaceutically acceptable salt of diclofenac is an alkali metal salt, for example, the sodium salt, cf. Merck Index 10th Edition, No. 3066, or the potassium salt. 1 2 3 4 5 6 h____ - -1

Finely ground diclofenac has a preferred average 2 particle size of less than 200 microns and is especially 3 micronized with a particle size of less than 100 4 microns. For the preparation of particles with this particle size, common comminution techniques are used, e.g. milling in an air jet, ball or vibrator mill or according to known methods in an ultrasonic integrator, e.g. of the Branson Sonifier type, e.g. as described in J. Pharm. Sci. 53 (9) 1040-45

DK 175517 B1 I

(1965), or by rapid stirring of an I

suspension, e.g. with a stirrer type Homorex from I

Brogli & Co., Basel. IN

The finely ground diclofenac or a pharmaceutical acceptor

tabular salt thereof is provided with a permeable, swellable I

coatings consisting of an elastic film-like material;

which is permeable to water or aqueous body fluid, I

such as gastric or intestinal juices and which are swellable and / or I

10 soluble in these liquids. IN

Elastic film-like materials with water permeability are I

eg. hydrophilic acrylic acid-methacrylic acid ester copolymer I

lysates. IN

15 I

Preferred low alkyl ethers of cellulose are methyl cellulose I

(DP: about 200-1000, MS: about 1.4-2.0), ethyl cellulose (DP: I

ca. 150-1000, MS: approx. 1.2-1.8), e.g. "Aguacoat" ® (FMC I

Corp.), hydroxyethyl cellulose (DP: about 120-1200, MS: about I)

2Q 1.2-2.5), hydroxypropyl cellulose (DP: about 200-3000, MS: I

ca. 1.0-3.0) and methyl hydroxypropyl cellulose (DP: ca.

200-1000, MS: approx. 1.4-2.0), e.g. "Pharraacoat" ® {Shin I

Etsu Corp.). IN

Hydrophilic acrylic acid-methacrylic acid copolymers have an I

average molecular weight of approx. 1.0 x 105 to 1.0 x 10e.

The acid group in acrylic acid and / or methacrylic acid monomers I

is partially or completely esterified with C (1-4) - I

30 alkyl groups, especially methyl and / or ethyl groups, wherein I

these ester groups may be substituted by hydrophilic I

groups, especially trimethylammonium ethyl. IN

Preferred polyacrylates are traded under the registered

35 trademark Eudragit®. Especially preferred is Eudragit-I

the commercial form of rapidly degradable film coatings;

eg. swellable, permeable types on acrylic acid ester I

6 DK 175517 B1 methacrylic acid ester copolymer base, in particular ethyl acrylic acid ester methylmethacrylic acid ester copolymer, for stepwise with an average molecular weight of 800,000, for example Eudragit NE 30 D or gastric soluble types, such as Eudragit E. S, a delayed release can be obtained.

In particular, pharmaceutically acceptable excipients are the viscosity enhancers useful for stabilizing aqueous suspensions which inhibit the sedimentation of the coated active substance diclofenac, e.g. natural macromolecules designated Karaya rubber, e.g. carrageenan or "Viscarin®, guar gum, for example," Meyprogate "galacto-mannan, in particular" standard Meyprogate "30, 60, 90, '120 and 150, gum arabic, sodium alginate or tragacanth , semi-synthetic macromolecules, for example, "Avicel" microcrystalline cellulose, the aforementioned cellulose ethers such as methyl, ethyl, or propyl cellulose, optionally with functional groups such as hydroxy or carboxy groups, or propylene glycol alginate, synthetic macromolecules of the group polyoxyethylene, for example of the type "Polyox" ®, "Carbowax" ® or "Polyglycol" ®, carboxypolymethylene, eg of the type Carbol 25 "polyvinyl alcohol (PVA), e.g. of the type "Polyviol" ® or "Movidl" ®, or polyvinylpyrrolidone (PVP), e.g. of the type "Collidon" ® or "Plasdone" ®, or colloidal silicates, e.g. colloidal silicic acid of the type "Aerosil" ® or "Cab-o-Sil" ®.

30 In shower tablets, in addition to the usual adjuvants used in the manufacture of tablets, there is a CC> 2 release agent as well as an agent which induces the release of CO2. CO 2 ~ Releasable agents are pharmaceutically acceptable mono- or tobacco-based salts of carbonic acid, e.g. alkali metal or alkali metal hydrogen L _ _ _____

I DK 175517 B1 I

I 7 I

In carbonates, e.g. sodium or potassium carbonate or I

In sodium bicarbonate, and alkaline earth metal carbonates, I

In e.g. calcium or magnesium carbonate, or sodium I

In glycine carbonate. Preferred is sodium hydrogen carbonate. IN

I 5 I

The agents which induce the release of CO2 are preferably I

In pharmaceutically acceptable organic acids, their acid influ

In hydrides or acidic salts which are in solid form and I

In which can be formulated outside of early CC> 2 “Development with it H

In 10 coated active substances as well as the other excipients mentioned

I for granules or tablets. In pharmaceutically acceptable acids, e.g. organic acids, fl

I such as tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, I

In ascorbic acid or maleic acid. Preferred is citric acid. IN

In pharmaceutically acceptable acid anhydrides, the corresponding I

In anhydrides of said organic acids, e.g. lemon-I

In acid anhydride or succinic anhydride. fl

I 20 I

In pharmaceutically acceptable acid salts, e.g. salts which you

You are in solid form, of multicasic acids, wherein there is at least one acid function, e.g. sodium hydrogen or fl I disodium hydrogen phosphate. fl

I 25 I

Other interface active substances I may also be added

In or wetting agents, the so-called surfactants, at forward H

In the position of shower tablets, e.g. anionic surfactants of fl

In the type of alkyl sulfate, e.g. sodium, potassium or mag- I

In 30 nesium n-dodecyl sulfate, or nonionic surfactants of I

In the fatty acid polyhydroxy alcohol ester type, such as sorbitan-B

In monostearate or palmitate or sorbitan tristearate. fl In other excipients, e.g. powdered fillers, fl I 35 such as lactose, sucrose, sorbitol, mannitol, starch, fl

I such as potato starch, rice starch, corn starch,

In wheat starch or amylopectin, or cellulose, especially H

In microcrystalline cellulose. IN

DK 175517 B1

ISLAND

w

Additional auxiliaries may improve the appearance or taste characteristics of the aqueous suspensions formed by decomposition of the effervescent tablets, e.g. dyes, sugars or sweeteners.

5

Dyes can be used both to enhance the appearance and to characterize the preparation. Applicable dyes allowed within the pharmacy are e.g. carotenoids, iron oxides or chlorophylls.

10

Sugar and sweeteners are e.g. sucrose, xylitol, D-xylose, D-glucose, sorbitol, mannitol or lactose, as well as saccharin-Na, dulcine, ammonium glycyrrhicinate or sodium cyclamate.

15

Shower tablets are prepared by grinding particles in solid form of diclofenac, providing them with a permeable, swellable coating, and optionally tableting them with the addition of pharmaceutical excipients.

20

The coating of micronized diclofenac with the aforementioned coatings may be accomplished using conventional coating techniques of fine grained material by, e.g. suspending or dissolving the coating substance in the desired proportions in water or an organic solvent or in mixtures thereof, e.g. in ethanol, isopropanol, acetone or methylene chloride, and optionally add adjuvants. This solution or dispersion, preferably 4-6%, is sprayed onto the diclofenac powder or powder mixtures with other excipients, e.g. using known methods such as spray coating in a fluidization layer according to Wurster, e.g. according to the systems of Aeromatic, Glatt or Htittlin (ball coater).

35

By slow and complete removal of the solvent and sieving the residue to a preferred average particle size of from ca. Flow granules 50 to 200 μτα are available which can be mixed with the excipients to promote the release of CO2, such as sodium hydrogen carbonate.

I DK 175517 B1 I

i 9 I

I onate and similar excipients which induce delivery

In the late CO2, such as citric acid. IN

In the granulate of the coated active substance may be present on the I

In the aforementioned manner, mix with those for the preparation of I

In shower tablets necessary and likewise previously mentioned -

In adjuvants and fillers such as lactose and cellulose, I

I and lubricants such as polyethylene glycol and the mixture I

You can compress into shower tablets. , Because of the high I

Tablets contain the following ingredients: 10

Which can be used to make large compressed I

In tablets of up to approx. 3.5 cm in diameter and up to 1 cm I

In thickness. Possible work on the compression below

In the exclusion of humidity or under protective atmos- I

In 15 sphere. The tablets can be individually packaged in foil. IN

In the invention, in particular, shower tablets containing I

In diclofenac with an average particle size of I

In less than 200 μια and a permeable, swellable coating,

In 20 especially on less than 100 shower formulations suitable for adjuvants, suspension adjuvants and optionally other

In pharmaceutical excipients. IN

The invention is further illustrated by the following I

In 25 examples. IN

In Example 1. I

Diclofenac (50 mg) Shower Tablets I

I 30. IN

I Diclofenac 50 mg I

In Galactomannan ("Meyprogat" ® 150) 32 mg I

In Colloidal Silica ("Aerosil" ® 200) 1 mg I

In "Eudragit" ® NE 30 D solid 7 mg I

I 35 I

10 DK 175517 B1

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 mixture of diclofenac, the first portion of "Meyprogat" ® 150 and "Aerosil" ® 200, is sprayed in a fluidization layer with an aqueous "Eudragit" ® NE 30 D dispersion, and the mixture is dried. To the coated active substance is added the outer phase consisting of polyethylene glycol 8000, sodium bicarbonate, citric acid, the second portion of "Meyprogat" ® 150 and microcrystalline cellulose. The homogeneous mixture is compressed on a conventional shower tablet tablet machine (diameter: 19 mm, thickness: 6 mm).

Example 2.

20

Shower tablets for diclofenac (50 mg)

Diclofenac 50 mg

Galactomannan ("Meyprogat" ® 150) 33 mg 25 "Eudragit" ® NE 30 D Solid 7 mg

Lactose, ground 400 mg

Polyvinylpyrrolidone ("PVP" ® K 30) 10 mg, Polyethylene Glycol 8000 50 mg

Sodium bicarbonate 700 mg 30 Citric acid, anhydrous 975 mg

Galactomannan ("Meyprogat" ® 150) 75 mg

Microcrystalline cellulose ("Avicel" ® PH 102) 100 mg 2400 mg 1

I DK 175517 B1 I

I u I

A mixture of diclofenac and the first batch

In "Meyprogat" ® 150, spray with an aqueous "Éudragit" ® NE 30 I

In D dispersion in a fluidization layer, upon which the mixture I

You are dried. The coated active substance is mixed with ground I

In 5 lactose and "PVP" ® K 30, then granulate with water. IN

In the dried kneaded granule, mix with the outer phase · I

In consisting of polyethylene glycol 8000, sodium hydrogencarb

In onat, citric acid, the second batch of "Meyprogat" ® 150 and I

In microcrystalline cellulose, then compressed to I

10 shower tablets. IN

Example 3. I

Diclofenac (50 mg) Shower Tablets I

1 15 I

I Diclofenac 50 mg I

I Galactomannan ("Meyprogat" ® 150) 33 mg I

In "Éudragit" ® NE 30 D solid 7 mg I

In Lactose, ground 400 mg I

I 20 Polyvinylpyrrolidone ("PVP" ® K 30) 10 mg I

I Polyethylene Glycol 8000 50 mg I

I Sodium Hydrogen Carbonate 700 mg I

In Citric Acid, anhydrous 950 mg I

In Microcrystalline Cellulose ("Avicel" ® PH 102) 200 mg I

I 2400 mg I

A mixture of diclofenac and "Meyprogat" ® 150 is sprayed with I

an aqueous "Éudragit" ® NE 30 D dispersion in a fluid I

In a ring, and the mixture is dried. The coated active I

In 30 substance mix with ground lactose and "PVP" ® K 30, then I

Granulated with water. The dried kneaded granulate blends

In the outer phase consisting of polyethylene glycol 8000, I

In sodium hydrogen carbonate, citric acid and microcrystalline alin I

In cellulose, then compressed into effervescent tablets. IN

I 35 I

12 DK 175517 B1

Example 4

Shower tablets for diclofenac sodium 50 mg) Diclofenac sodium 50 mg * Galactomannan ("Meyprogat" ® 150) 32 mg

Colloidal Silica ("Aerosil" ® 200) 1 mg "Eudragit" ® NE 30 D Solid 7 mg

Polyethylene Glycol 8000 50 mg 10 Sodium Hydrogen Carbonate 855 mg

Citric acid, anhydrous 1205 mg

Microcrystalline cellulose ("Avicel" ® PH 102) 200 mg 2400 mg 15 A mixture of diclofenac sodium, "Meyprogat" ® 150 and "Aerosil" ® 200 is sprayed with an aqueous "Eudragit" ® NE 30 D dispersion in a fluidization layer. The outer layer consisting of polyethylene glycol 8000, sodium hydrogen carbonate, citric acid and microcrystalline cellulose is added to the coated active substance.

Example 5

25

Shower tablets for diclofenac (50 mg)

Diclofenac 50 mg

Galactomannan ("Meyprogat" ® 150) 32 mg. 30 Colloidal Silica ("Aerosil" ® 200) 1 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

I DK 175517 B1 I

I 13 I

I Preparation of shower tablets according to Example 1. I

In Example 6. I

5 Diclofenac (50 mg) Shower Tablets I

I I

I Diclofenac 50 mg u

In Galactomannan ("Meyprogat" ® 150) 35 mg I

In Colloidal Silica ("Aerosil" ® 200) 1 mg I

I 10 "Eudragit" ® NE 30 D 50 mg I

I Polyethylene Glycol 8000 50 mg I

I Sodium Hydrogen Carbonate 850 mg I

In Citric Acid, anhydrous 1184 mg I

In Microcrystalline Cellulose ("Avicel" ® PH 102) 200 mg in I

In 15 2400 mg! IN

In the preparation according to Example 4. I

Measuring the dissolution rate I

I 20 I

I Procedure - USP Paddle, 50 rpm I

In Medium - h 60 min. 0.1 n-HCl pH 1.0 µl

I - h 60 min. phosphate buffer pH 6.8 ι I

I i

I 25 Results: I

I% diclofenac I

After 60 min. 4 I

After 120 min. 50 I

For 30 minutes after 240 minutes. 77 I

After 420 min. 93 I

IN

I 35 I

Claims (3)

1. Fixed fast biodegradable administration form for preparing a peronally applicable aqueous suspension of diclofenac 5 with a gastric juice-soluble, permeable and swellable coating as well as any other pharmaceutically acceptable excipients, characterized in that the active substance is in micronized form with an average particle size of less than 200 µm and with a coating of acrylic acid-methacrylic acid ester copolymer. The shower tablet according to the form of administration according to claim 1, characterized in that it contains the coating of ethyl acrylic acid ester methyl methacrylic acid ester copolymer 15 having an average molecular weight of approx. 800,000 and furthermore a pharmaceutically acceptable carbonate salt, an organic acid and a cold water soluble hydrocolloid as a suspension aid. Pharmaceutical composition according to claim 1 or 2, characterized in that the average particle size of the active substance is less than 100 µm. »I 30 1 j