DK175752B1 - Liquid oral pharmaceutical diclofenac preparation and process for its preparation - Google Patents

Abstract

The invention relates to an aqueous oral pharmaceutical formulation of diclofenac, which can be used for treating pain and inflammatory processes, and also to the preparation of such a formulation.

Description

DK 175752 B1

The present invention relates to an aqueous oral pharmaceutical diclofenac composition and to a process for its preparation.

> 5 Diclofenac with the chemical designation o- (2,6-dichloro-1ino) phenylacetic acid is a known potent analgesic and anti-rheumatic agent and is described, for example, in U.S. Patent No. 3,558,690.

Many attempts have been made to develop an aqueous, individually dosed oral administration form for this active substance. The desired form of administration must have a neutral or pleasant taste and, moreover, have a satisfactory storage stability, so that physicians as well as patients are given the opportunity to use an appropriate alternative to other oral preparations.

It is known that diclofenac has a bitter taste and produces a throbbing sensation in the throat. In addition, it is a disadvantage that by forming the usual aqueous oral solutions, heavily soluble hydrates are formed which cause precipitation. In addition, it is known that diclofenac cycles, especially in acidic solution, to 1- (2,6-dichlorophenyl) -indolin-2-one. Similarly aqueous pharmaceutical diclofenac-.

Therefore, 25 formulations do not have sufficient storage stability and would therefore not meet the criteria for registration as a drug.

It is the object of the present invention to provide an aqueous oral pharmaceutical diclofenac composition which does not have the disadvantages mentioned above.

This is achieved with the composition according to the invention, characterized in that diclofenac is present in a pH-35 range of 2-3.5.

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Using such aqueous formulations or

Surprisingly, in preparations it has been found that not particularly I

You find some prohibitive indolinone formation. Furthermore, I

such preparations have a pleasant taste and induce I

5 no scratching sensation in the throat. IN

The preferred concentration of active substance in composition I

according to the invention is between 0.5 and 10% by weight, especially I

At between 1 and 5% by weight, first of all at 1% by weight; IN

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The pH range at issue is between 2 and 3.5 I

Preferably between 2.5 and 3.5, and it is set by means of I

of known pharmaceutically usable acids or buffer I

systems. As pharmaceutically useful acids, you can

For example, carboxylic acids such as acetic acid are mentioned

malonic acid, furmic acid, maleic acid, succinic acid, lactic acid, I

tartaric acid or primarily citric acid. As examples of I

buffer systems may be mentioned sodium citrate / HCl buffer or I

citric acid / phosphate buffer. IN

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Corresponding application forms for the suspension according to I

The invention is drops, mixtures, juices or syrups, which I

can also be used in dosage unit form. IN

The present compositions may further comprise pharmaceuticals

In auxiliary additives and additives, example I

In pelvic preservatives, antioxidants, flavorings, I

H dyes, sweeteners, suspension stabilizers I

In and / or wetting agents. IN

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As preservatives that protect against microorganism- I

In attack, benzoic acid or salts thereof may be used, such as I

In sodium, potassium or calcium salts, 4-hydroxybenzoic acid I

1 esters such as 4-hydroxybenzoic acid methyl, ethyl or I

-Propyl ester (PHB ester), phenols such as tert-butyl-4-I

methoxy or 2,6-di-tert-butyl-4-methyl-phenol, phenyl-I

B1 low alkanols, benzyl alcohol, 4-chloro or 2,4-dichlorobenzyl alcohol, 2-phenylethanol or 3-phenylpropanol, chlorhexidine diacetate or digluconate, thiabendazole, bromide, phenododecinium bromide or cetylpyridinium chloride, or primarily sorbic acid, e.g. in an amount of from approx. 0.01 to approx. 0.1% by weight.

Suitable antioxidants which are intended to inhibit the oxidative processes are, for example, sulfites, such as alkali metal sulfites, hydrogen sulfites or pyrosulfites, e.g. the corresponding sodium or potassium salts, thiodipropionic acid, thioglycol, thiolactic acid, glutathione, preferably however cysteine, ascorbic acid and esters thereof, e.g. ascorbic acid myristate, palmitate or stearate, or gallic acid esters such as gallus propyl, octyl or dodecyl ester, e.g. in an amount of from approx. 0.01 to approx. 0.1% by weight. Alternatively, synergists such as citric acid, citraconic acid, phosphoric acid or tartaric acid may also be used.

For flavor enhancement, for example, flavorings can be used, for example, essential oils, especially oils from fruits such as orange, pomeran, mandarin or lemon oil, and furthermore sugar color.

Suitable dyes are, for example, indigotine I (blue), amaranth (red), yellow orange S (orange), tartrazine XX (yellow) or chlorophyll (green).

As sweeteners which e.g. in syrups present in high concentration, for example, sugars such as 30 mono- or disaccharides, e.g. D-glucose, D-fructose, D-xylose, maltose or sucrose, polyols such as glycerol, dulcitol, mannitol, sorbitol or xylitol, or artificial sweeteners such as saccharin or the corresponding sodium, potassium or calcium salt, cyclamate

I DK 175752 B1 I

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or the corresponding sodium or calcium salt, aspartame I

or acesulfame or its potassium salt, furthermore dulcln I

or ammonium glycyrrhlzlnat. IN

The purpose of the stabilizer addition to the suspensions

is to ensure that the single doses taken have a constant I

In concentration of active substance. Corresponding stabilizers I

H is e.g. inorganic stabilizers for suspensions, I

eg. colloidal silicates with large aluminum and magnetic I

Calcium content, such as bentonites, veegum or gel white, I

In colloidal silica, e.g. "Aerosil" ® (Degussa), I

In "Cabosil" ® (Cabot), organic stabilizers, e.g. IN

I. suffocating agents such as alginates, e.g. sodium alginate, I

potassium alginate or propylene glycol alginate, gum arabic, I

I tragacanth, karaya gum, sterculia gum, carageenan, I

In guar gum or agar, synthetic or semi-synthetic I

In quelters, e.g. 1,2-epoxide polymers, especially ethylene-I

In oxide homopolymers with a degree of polymerization of approx. 2000 I

to approx. 100,000, for example, which is negotiated under the name I

Polyox® (Union Carbide), preferably swellable cellulose

seethers, e.g. methyl or ethyl cellulose, hydroxy-I

ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl-I

methyl cellulose, methyl or ethyl hydroxyethyl cellulose, I

carboxymethyl cellulose or an alkali metal salt thereof I

Or microcrystalline cellulose, or water-soluble I

polyvinyl compounds such as polyvinyl acetate, polyvinyl I

alcohol or polyvinylpyrrolidone.

The stabilizers may advantageously be added to wetting agents. IN

Suitable wetting agents are, for example, sulfosuccinates such as I

Dihexyl, dioctyl or diamyl succinate, sulfonates or I

sulfates, e.g. Na-alkylnaphthalenesulfonate, fatty alcohol I

sulphonates or fatty alcohol polyglycol ether sulphates, I

fatty acid polyglycol esters, e.g. polyethylene glycol stearate, I

polyglycol esters of C (8-18) fatty acids, fatty alcohol poly-I

35 glycol ethers, e.g. lauryl, cetyl, stearyl or oleyl I

alcohol polyglycol ether or cetylstearyl alcohol polygly- I

5 DK 175752 B1 colether, poly fatty acid ester polyglycol ethers ,. eg. polyethylene glycol sorbitan monolaurate, monopalmitate, monostearate or monooleate, glycerol fatty acid ester polyglycol ethers or pentaerythritol fatty acid polyglycol ethers, sucrose esters, e.g. sucrose mono- or distearate or sucrose monopalmitate, ethoxylated vegetable oils, e.g. ethoxylated castor oil or hydrogenated or ethoxylated castor oil, or block polymers such as polyoxyethylene-polyoxypropylene polymers.

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The present aqueous oral pharmaceutical diclofenac preparations are prepared depending on the form of application, for example, as described below.

The process of the invention is characterized by suspending diclofenac in water, adjusting the pH by acid or buffer system and optionally admitting pharmaceutically useful auxiliaries and additives 20

For example, you can start by incorporating the auxiliaries and additives in the water, possibly during heating, e.g. in a temperature range of approx. 20 to approx. 100 ° C. In this basis, the active substance is then suspended. However, the mixing order of the components of the composition of the invention is not critical.

For example, to make syrups, the suspending agent and the corresponding suspension stabilizer are added to the 2Q water. Subsequently, sweetening agent and any preservative, antioxidants, flavorings and / or j dyes are incorporated, optionally during heating, e.g. in a temperature range from approx. 50 to about 100 ° C. The active substance is then suspended in the medium.

The present aqueous oral pharmaceutical composition may be used, for example, to treat pain states and inflammatory processes.

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In particular, the invention relates to the I described in the Examples

preparations and modes of manufacture. IN

The invention will be further elucidated by means of the following I

H 5 Examples I

Example 1 I

Syrup containing 1% by weight of diclofenac. IN

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Employment I

B Diclofenac (free acid) 1.00 g I

B Hydroxyethyl cellulose ("Natrosol®" 250G) 0.50 g I

Cellulose and sodium carboxymethyl cellulose I

B ("Avicel®" RC591) 1.20 g I

Sorbitol Solution 25.00 g I

In Sorbic Acid 0.05 g I

In Vitamin C 0.10 g I

Citric acid 0.20 g I

Saccharin sodium 0.06 g I

In Water demineralized 71.89 g I

100.00 g I

In pH: 2.9 I

I I

In Manufacture. IN

X the water is suspended "Avicel" ® by a quick walk

In the end mixer, and during mixing I is added

30 "Natrosol®" and the mixture is allowed to swell for about 1 L

For hours. Sorbitol solution and sorbic acid are added and I

with stirring is heated to approx. 85cc. After cooling to I

at room temperature, vitamin C, citric acid and saccharin I are dissolved

in that order in the mixture with stirring. Using I

35 of the mixer, the active substance is suspended, upon which I

the mixture is finally deaerated. : I

Example 2 DK 175752 B1 7

Syrup containing 1% diclofenac.

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Diclofenac (free acid) 1.0 g

Sucrose 40.0 g

Agar powder 0.3 g

Sorbic acid 0.1 g 2Q Vitamin C 0.1 g

Citric Acid 1 AQ 0.2 g

Disodium phosphate 2 AQ 0.08 g

Lemon flavor 0.1 g

Water demineralized 58.12 g 15.00 g pH: 3.2

Preparation 2o The water is heated to approx. 90 ° C, whereupon the sorbic acid is dissolved therein. Then agar powder is sprayed onto the solution during dispersion with a fast-moving mixer. The mixture is then left for approx. 30 minutes at 90 ° C for swelling. Then the sucrose which is dissolved under stirring is added. After cooling to approx. 40 ° C is added and dissolved in citric acid, disodium phosphate and vitamin C in that order. After addition of the flavoring, the active substance is expelled with a small amount of the base, after which this mixture is distributed to the rest of the base.

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I DK 175752 B1 I

Example 3 I

Mixture containing 1% diclofenac. IN

Diclofenac (free acid) 1.0 g I

Hydroxyethyl cellulose ("Natrosol®" 250G) 0.5 g I

Cellulose and sodium carboxymethyl cellulose I

i ("Avicel®" RC591) 1.2 g I

! Sorbic acid 0.1 g I

Vitamin C 0.1 g I

Citric Acid 1 AQ 0.2 g I

Saccharin sodium 0.05 g I

Disodium phosphate 2 AQ 0.08 g I

Lemon flavor 0.1 g I

Water demineralized 97.16 g I

100.00 g I

pH: 3.2 L

Preparation I

In 50 g of water, "Avicel" ® is dispersed by means of a rapid I

walking mixer, to which, during mixing, I is added

"Natrosol" ® and the mixture is left for approx. 1 hour until evening

25. The rest of the water (47.16 g) is heated to ca. 60 ° C and I

the sorbic acid is dissolved therein. After cooling to 40 ° C I

add and dissolve saccharin sodium, citric acid, I

disodium phosphate and vitamin C in that order. This one

solution is mixed with the "Aviel" ® dispersion. After I

After addition of the flavoring, the active substance is expelled with an I

small part of the basis on which this mixture is distributed in I

the rest of the foundation. IN

DK 175752 B1 9

Example 4

Drops containing 1% diclofenac.

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Diclofenac (free acid) 1.0 g "Meyprogate" 150 (guar gum) 0.5 g

Sorbitol Solution 50.0 g

Sorbic acid 0.1 g Vitamin C 0.1 g

Citric Acid 1 AQ 0.2 g

Disodium phosphate 1 AQ 0.08 g

Lemon flavor 0.1 g

Water demineralized 47.92 g 15.00 g pH: 3.1 Preparation 20 The water is heated to approx. 90 ° C, whereupon the sorbic acid is dissolved therein. Then "Mayprogat" is sprinkled and dispersed with a fast-moving mixer. The mixture is then left for approx. 30 minutes at 90 ° C to swell and then add the sorbitol solution. After cooling to 25 approx. 40g C are added 6g dissolved citric acid, disodium phosphate and vitamin C with stirring. After adding the flavoring, the active substance is released in a small portion of! base and this mixture is then distributed to the rest of the foundation.

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H Example 5 I

In Syrup containing 1% by weight Diclofenac. IN

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In Diclofenac (free acid) 1.00 g I

In Hydroxyethylcellulose ("Natrosol®" 250G) 0.50 g -I

I Cellulose and sodium carboxymethyl cellulose I

I ("Avicel®" RC591) 1.20 g I

I 10 Sorbitol Solution 25.00 g I

Sorbic Acid 0.05 g I

In Vitamin C 0.60 g I

In Citric Acid 1.00 g I

In Saccharin sodium 0.06 g I

Hi 15 Water demineralized 70.59 g I

I I 100.00 g I

Η in pH: 2.3 I

H Preparation I

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"In the water," Avicel "® is suspended with a fast-moving I

H mixer, then adding "Natrosol" ®, I, while mixing

H and the mixture is left for approx. 1 hour for swelling. Then you

add sorbitol solution and sorbic acid and heat I

25 with stirring to ca. 85 ° C. After cooling to room temp

rature is dissolved with stirring vitamin C, citric acid and I

saccharin in said order. With the mixer, I suspend

the active substance therein, upon which the mixture is finally I

de-aerated. IN

IN

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DK 175752 B1 11

Example 6

Syrup containing 1% by weight of diclofenac.

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Diclofenac (free acid) 1.00 g

Hydroxyethyl cellulose ("Natrosol®" 250G) 0.50 g

Cellulose and Sodium Carboxymethyl Cellulose ("Avicel®" RC591) 1.20 g 10 Sorbitol Solution 25.00 g

Vitamin C 0.60 g In Citric Acid 1.00 g

Methylparaben 0.12 g

Propylparaben 0.05 g in Saccharin Sodium 0.06 g

Water demineralized 70.49 g I

100,00 g pH: 3.0 20 Preparation i - In the water, "Avicel" ® is suspended with a fast-moving mixer, then "Natrosol" ® is added to the mixture and the mixture is left for approx. 1 hour for swelling. Then, sorbitol solution and sorbic acid are added and the mixture is heated with stirring to ca. B5 ° C. After cooling to room temperature, vitamin C, citric acid and saccharin are added and dissolved with stirring. With the mixer, the active substance is suspended and the mixture is finally deaerated.

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Claims (17)

1. An aqueous oral pharmaceutical diclofenac preparation, characterized in that diclofenac is present in suspended form I I 5 in a pH range of 2 to 3.5. IN Composition according to claim 1, characterized in that the concentration of active substance is from 0.5 to 10% by weight. Composition according to Claim 1 or 2, characterized in that the pH-I range is between 2.5 and approx. 3.5. IN Composition according to claim 3, characterized in that the pH-value I 15 is adjusted with citric acid. IN Composition according to claim 3, characterized in that the pH value I is adjusted with citric acid / phosphate buffer. I I 20 Composition according to one of claims 1 to 5, characterized in that it contains pharmaceutically usable auxiliaries and I additives selected from preservatives, antioxidants, flavorings, dyes, sweeteners, in suspending agents and wetting agents. I I: I Composition according to claim 6, characterized in that, as a preservative, it contains benzoic acid or salts thereof, 4-hydroxybenzoic acid esters, phenols, phenyllavalcanols, quaternary ammonium halides or sorbic acid. I I 30 I Composition according to claim 7, characterized in that it contains sorbic acid. IN Composition according to claim 6, characterized in that it contains as an antioxidant cysteine, ascorbic acid or esters 1 H thereof or a gallic acid ester. In DK 175752 B1 Composition according to claim 9, characterized in that it contains ascorbic acid. Composition according to claim 6, characterized in that it contains as a sweetening agent a mono- or disaccharide, a polyol or an artificial sweetener. in Composition according to claim 6, characterized in that it contains as a suspension stabilizer colloidal silicates with high aluminum and magnesium content, colloidal silicic acid, swelling agents, swellable cellulose ethers, carboxymethyl cellulose or an alkali metal salt thereof, microcrystalline cellulose or water soluble . 15 Composition according to claim 12, characterized in that it contains hydroxyethyl cellulose and / or cellulose and sodium carboxymethyl cellulose or agar or guar gum. A composition according to any one of claims 1-13 in the form of drops, mixtures, juices or syrups. The composition of claim 14, in dosage unit form. Process for the preparation of an aqueous oral pharmaceutical diclofenac preparation according to one of claims 1-15, characterized in that diclofenac is suspended in water, the pH is adjusted by means of acid or a buffer system and optionally admits pharmaceutically useful auxiliaries and additives. . A process for the preparation of an aqueous oral pharmaceutical diclofenac composition characterized by suspending diclofenac at a pH range of 2-3.5 and optionally admitting pharmaceutically useful excipients and additives.