IE63482B1

IE63482B1 - Liquid oral formulation

Info

Publication number: IE63482B1
Application number: IE361189A
Authority: IE
Inventors: Heidi Affolter
Original assignee: Ciba Geigy Ag
Priority date: 1988-11-10
Filing date: 1989-11-09
Publication date: 1995-05-03
Also published as: NZ231320A; DK561589D0; IE893611L; PT92228B; IL92190A; JPH02178224A; PT92228A; ES2054089T3; CA2002472C; DK175752B1; KR0152983B1; IL92190A0; AU624190B2; CA2002472A1; DE58903964D1; SA90100152B1; GR3007995T3; DK561589A; AU4434389A; EP0373103B1

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

The invention relates to an aqueous oral pharmaceutical preparation of diclofenac, and to its use and preparation.

Diclofenac, chemical name o-(2,6-dichloroanilino)phenylacetic acid, is known as a potent analgesic and antirheumatic and is described, for example, in US Patent No. 3,558,690.

Much effort has been directed toward developing for this active ingredient an aqueous, individually dosable oral form of administration which has a neutral or pleasant taste and, in addition, has a satisfactory shelf life so as to make available to doctors and patients θ an appropriate alternative to other oral preparations.

It is known that diclofenac has a bitter taste and causes a scratching sensation in the throat. In addition, it has proven disadvantageous that, when customary aqueous oral solutions are used, water*insoluble hydrates are formed which result in precipitations. It is furthermore known that diclofenac cyclizes, in particular in acid solution, to form 1-(2,6-dichlorophenyl)indolin-2-one. Thus, corresponding aqueous pharmaceutical formulations of diclofenac do not have an adequate shelf life and, as a consequence, would not meet the criteria for registration as a medicament.

The present invention had the object of developing an aqueous oral pharmaceutical preparation of diclofenac which does not have the disadvantages mentioned.

This object is achieved by the preparation according to the invention. This has the feature that diclofenac is present in a pH range from 2 to 3.5.

Surprisingly, when aqueous formulations of this type are used, absolutely no prohibitive formation of indolinone, in particular, is observed. In addition, preparations of this type have a pleasant taste and do not cause a scratching sensation in the throat.

The preferred active ingredient concentration of the preparation according to the invention is 0.5 to 10X by weight, in particular 1 to 5X by weight, primarily about IX by weight.

The pH range according to the invention is, in particular, between 2 and 3.5, preferably between 2.5 and 3.5, and is established by means of pharmaceutically acceptable acids or buffer systems which are known per se. Suitable pharmaceutically acceptable acids are preferably carboxylic acids, such as acetic acid, malonic acid, fumaric acid, maleic acid, succinic acid, lactic acid, tartaric acid or primarily citric acid. Examples of buffer systems of this type are sodium citrate/HCl or citric acid/phosphate buffer.

'« Appropriate forms of administration of the suspension according to the invention are drops, mixtures, juices or syrups, which may also be used in dose-unit forms.

The composition according to the invention may contain further pharmaceutically acceptable adjuncts and additives, for example preservatives, antioxidants, fragrances, dyes, sweeteners, suspension stabilizers and/or wetting agents.

Suitable preservatives, which protect against infestation by microorganisms, are benzoic acid or salts thereof, such as sodium, potassium or calcium salts, 4-hydroxybenzoic acid esters, such as methyl, ethyl or propyl 4-hydroxybenzoate (PHB esters), phenols, such as tert-butyl-4-methoxy- or 2,6-ditert-butyl-4-methylphenol, phenyl (lower alkanols), benzyl alcohol, 4-chloro- or 2,4-dichlorobenzyl alcohol, 2phenylethanol or 3-phenylpropanol, chlorohexidine diacetate or digluconate, thiabendazole, furthermore nitrofural, quaternary ammonium halides, such as alkonium bromide, benzalkonium chloride, cetrimonium bromide, phenododecinium bromide or cetylpyridinium chloride, or primarily sorbic acid, for example in a proportion of 0.01 to 0.1X by weight.

Suitable antioxidants, which are intended to inhibit oxidative processes, are, for example, sulfites, such as alkali metal sulfites, alkali metal bisulfites or alkali metal pyrosulfites, for example the corresponding sodium or potassium salts, thiodipropionic acid, thioglycol, thiolactic acid, glutathione, but preferably cystein, ascorbic acid and esters thereof, for example ascorbic acid myristate, palmitate or stearate, or esters of gallic acid, such as propyl, octyl or dodecyl esters, for example in a proportion of 0.01 to 0.1Z by weight. Synergists, such as citric acid, citraconic acid, phosphoric acid or tartaric acid, may be admixed.

To improve the flavour, suitable fragrances are, for example, etherial oils, in particular those derived from fruits, such as oranges, and oils from Seville oranges, mandarines or lemons, and furthermore caramel.

Examples of suitable dyes are Indigo Tin I(blue), Amaranth (red), Yellow orange S (orange), Tartrazine XX (yellow) or chlorophyll (green).

Examples of suitable sweeteners, which are present in high concentration, in for example, syrups, are sugar such as monosaccharides or disaccharides, for example D-glucose, D-fructose, D-xylose, maltose or sucrose, polyols, such as glycerol, dulcitol, mannitol, sorbitol or xylitol, or artificial sweeteners, such as saccharine or the corresponding sodium, potassium or calcium salt, cyclamate or the corresponding sodium or calcium salt, aspartam or acesulfam or the potassium salt thereof, furthermore Dulcin or ammonium glycyrrhizinate.

The suspension stabilizers are intended to ensure that the individual doses removed have a constant active ingredient content. Examples of appropriate stabilizers are inorganic suspension stabilizers, for example colloidal silicates having a high aluminium and magnesium content, such as bentonite, Veegum or Gel White, colloidal silica, for example Aerosil® (Degussa), Cabosil® (Cabot), organic stabilizers, for example swelling agents, such as alginates, for sodium alginate, calcium alginate or propylene glycol alginate, gum arabic, tragasanth, karaya gum, sterculia gum, carrageen, guar gum or agar, synthetic or semisynthetic swelling agents, for example 1,2-epoxide polymers, in particular ethylene oxide homopolymers having a degree of polymerization of about 2,000-100,000, which are known, for example, under the trade name Polyox® (Union Carbide), preferably swellable cellulose ethers, for example methyl- or ethyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl- or ethylhydroxyethyl cellulose, carboxymethyl cellulose or an alkali metal salt thereof, or microcrystalline cellulose, or water-soluble polyvinyl compounds, such as polyvinyl acetate, polyvinyl alcohol or polyvinylpyrrolidone.

Wetting agents may advantageously be added to the stabilizers. Examples of suitable wetting agents are sulfosuccinates, such as dihexyl sulfosuccinate, dioctyl sulfosuccinate or diamyl sulfosuccinate, sulfonates or sulfates, ‘for example Na alkylnaphthalenesulfonates, fatty alcohol sulfonates or fatty alcohol polyglycol ether sulfates, fatty acid polyglycol esters, for example polyethylene glycol stearates, polyglycol esters of C8-C18 fatty acids, fatty alcohol polyglycol ethers, for example lauryl, cetyl, stearyl or oleyl alcohol polyglycol ether or cetylstearyl alcohol polyglycol ether, poly(fatty acid) ester polyglycol ethers, for example polyethylene glycol sorbitan monolaurate, monopalmitate, monostearate or monooleate, glycerol fatty acid ester polyglycol ether or pentaerythritol fatty acid polyglycol ether, sucrose esters, for example sucrose monostearate or distearate or sucrose monopalmitate, ethoxylated vegetable oils, for example ethoxylated castor oil or hydrogenated and ethoxylated castor oil, or block polymers, such as polyoxyethylene-polyoxypropylene polymers.

The aqueous oral pharmaceutical preparations of diclofenac according to the Invention are prepared, for example, as follows depending on the nature of the form of administration.

Thus, for example, the adjuncts and additives are incorporated into the water with or without warming, for example in a temperature range of from 20° to 100eC. The active ingredient is then suspended in this base. However, the sequence of mixing the components of the preparation according to the invention is not important.

To prepare syrups, for example, the suspension agent and the appropriate suspension stabilizer are added to the water. A sweetener and, if desired, preservatives, antioxidants, fragrances and/or dyes are incorporated with or without wanning, for example in a temperature range of from 50° to 100eC. The active ingredient is then suspended in the medium.

The aqueous oral pharmaceutical preparation according to the invention can be used, for example, for treating pain and inflammatory processes.

The invention also relates, in particular, to the preparations and preparation processes described in the Examples.

The Examples below serve merely to illustrate the above-described invention; however they are not intended to represent a limitation.

Example 1: Syrup containing IX by weight of diclofenac.

Composition: Diclofenac (free acid) 1.00 g Hydroxyethyl cellulose (Natrosol® 250 G) 0.50 g Cellulose and sodium carboxymethyl cellulose (Avicel® RC 591) 1.20 g Sorbitol solution 25.00 g Sorbic acid 0.05 g Vitamin C 0.10 g Citric acid 0.20 g Saccharine sodium 0.06 g Demineralized water 71.89 g 100.00 g pH: 2.9 Preparation: Avicel® is suspended in the water using a high-speed mixer, Natrosol® is admixed, and the mixture is left to swell for about 1 hour. Sorbitol solution and sorbic acid are added, and the mixture is heated to about 85® with stirring. After the mixture has been cooled to room temperature, vitamin C, citric acid and saccharine are dissolved consecutively therein with stirring. The active ingredient is suspended in the mixture with the aid of the mixer, and the mixture is subsequently deaerated.

Example 2: Syrup containing 1% of diclofenac: Diclofenac (free acid) 1.0 g Sucrose 40.0 g Agar powder 0.3 g Sorbic acid 0.1 g Vitamin C 0.1 g Citric acid 1 AQ 0.2 g Disodium phosphate 2 AQ 0.08 g Lemon aroma 0.1 g Demineralized water 58.12 g 100.00 g pH: 3.2 Preparation: The water is warmed to about 90®C and sorbic acid is dissolved therein. Agar powder is subsequently scattered into the mixture and dispersed using a high-speed mixer. The mixture is then left to swell at 90’C for about 30 minutes. The sucrose is added and dissolved with stirring. After the mixture has cooled to about 40’C, citric acid, disodium phosphate and vitamin C are added consecutively and dissolved. After the fragrance has been added, the active ingredient is ground with a small amount of the base and then distributed in the remainder of the base.

Example 3 Mixture containing IX of diclofenac.

Diclofenac (free acid) Hydroxyethylcellulose (Natrosol® 250 G) Cellulose and sodium carboxymethylcellulose (Avicel® RC 591) 1.0 g 0.5 g 1.2 Sorbic acid 0.1 g Vitamin C 0.1 g Citric acid 1 AQ 0.2 g Saccharine sodium 0.06 g Disodium phosphate 2 AQ 0.08 g Lemon aroma 0.1 g Demineralized water 97.16 g 100.00 g pH 3.2 Preparation: Avicel® is dispersed in 50 g of water using a high-speed mixer, Natrosol® is admixed, and the mixture is left to swell for about 1 hour. The remainder of the water (47.16 g) is heated to about 60eC and sorbic acid is dissolved therein. After the latter mixture has cooled to 40°C, saccharin, citric acid, disodium phosphate and vitamin C are added consecutively and dissolved. This solution is mixed with the Avicel® dispersion. After the fragrance has been added, the active ingredient is ground with a small amount of the base and then distributed in the remainder of the base.

Example 4: Drops containing 1Z of diclofenac: Diclofenac (free acid) 1.0 g Meyprogat® 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 aroma 0.1 g Demineralized water 47.92 g 100.00 g pH: 3.1 Preparation: The water is warmed to about 90’C and sorbic acid is dissolved therein. Meyprogat® is scattered into the mixture and dispersed using a high-speed mixer. The mixture is then left to swell at 90°C for about 30 minutes. Sorbitol solution is then added. After the mixture has cooled to about 40’C, citric acid, disodium phosphate and vitamin C are added consecutively and dissolved with stirring. After the fragrance has been added, the active ingredient is ground with a small amount of the base and then distributed in the remainder of the base.

Example 5: Syrup containing IX by weight of diclofenac.

Diclofenac (free acid) 1.00 g Hydroxyethyl cellulose (Natrosol® 250 G) 0.50 g Cellulose and sodium carboxymethylcellulose (Avicel® RC 591) 1.20 g Sorbitol solution 25.00 g Sorbic acid 0.05 g Vitamin C 0.60 g Citric acid 1.00 g Saccharine sodium 0.06 g Demineralized water 70.59 g 100.00 g pH: 2.3 Preparation: Avicel® is suspended in the water using a high-speed mixer, Natrosol® is admixed and the mixture is left to swell for about 1 hour. Sorbitol solution and sorbic acid are added, and the mixture is heated to about 85’ with stirring. After the mixture has cooled to room temperature, vitamin C, citric acid and saccharine are dissolved consecutively therein with stirring. The active ingredient is then suspended therein using the mixer, and the mixture is subsequently deaerated.

Example 6: Syrup containing IX by weight of diclofenac.

Diclofenac (free acid) Hydroxyethylcellulose (Natrosol® 250 G) 1.00 g 0.50 g 1.20 g 25.00 g Cellulose and sodium carboxymethylcellulose (Avicel® RC 591) Sorbitol solution 5 Vitamin C 0.60 g Citric acid 1.00 g Methylparaben 0.12 g Propylparaben 0.05 g Saccharine sodium 0.06 g 1 0 Demineralized water 70.49 g 100.00 g pH: 3.0 « Preparation: Avicel® is suspended in the water using a high-speed mixer, Natrosol® is admixed, and the mixture is left to swell for about 1 hour. Sorbitol solution and sorbic acid are added, and the mixture is heated to about 85° with stirring. After the mixture has cooled to room temperature, vitamin C, citric acid and saccharine are dissolved consecutively therein with stirring. The active ingredient is suspended therein using the mixer, and the mixture is subsequently deaerated.

Claims

1. An aqueous oral pharmaceutical preparation of diclofenac, wherein diclofenac is present in suspended form in a pH range from 2 to 3.5. 2. 5 described and exemplified.

2. A preparation according to claim 1, wherein the active ingredient

3. A preparation according to claim 1 or 2, wherein the pH range is between 2.5 and 3.5.

4. A preparation according to claim 3, wherein the pH is set using « citric acid.

5. Cellulose or water-soluble polyvinyl compounds. t 5 concentration is from 0.5 to 10Z by weight.

6. A preparation according to one of claims 1-5, which contains pharmaceutically utilizable adjuncts and additives selected from the group of preservatives, antioxidants, fragrances, dyes, sweeteners,

7. A preparation according to claim 6, which contains, as preservative, benzoic acid or salts thereof, 4-hydroxybenzoic acid esters, phenols, phenyl-lower alkanols, quaternary ammonium halides or sorbic acid.

8. A preparation according to claim 7, which contains sorbic acid. 2q

9. A preparation according to claim 6, which contains, as antioxidant, cystein, ascorbic acid or esters thereof, or an ester of gallic acid. 10. Mixture, juice or syrup. <

10. A preparation according to claim 9, which contains ascorbic acid. 10 5. A preparation according to claim 3, wherein the pH is set using citric acid/phosphate buffer.

11. A preparation according to claim 6, which contains, as sweetener, a monosaccharide, disaccharide, polyol or artificial sweetener.

12. A preparation according to claim 6, which contains, as suspension stabilizer,* colloidal silicates having a high aluminum and magnesium content, colloidal silica, swelling agents, swellable cellulose ethers, carboxymethylcellulose or an alkali metal salt thereof, microcrystalline

13. A preparation according to claim 12, which contains hydroxyethylcellulose and/or cellulose and sodium carboxymethylcellulose or agar or guar gum.

14. A preparation according to one of claims 1-13 in the form of drops, 15. And, optionally, pharmaceutically utilizable adjuncts and additives are admixed.

15. A preparation according to claim 14 in dose-unit form. < 15 suspension agents and wetting agents.

16. A method of preparing an aqueous oral pharmaceutical preparation of diclofenac according to one of claims 1-15, wherein diclofenac is suspended in water and the pH is set using acid and/or a buffer system

17. A method of preparing an aqueous oral pharmaceutical preparation of diclofenac, wherein diclofenac is suspended in a pH range from 2 to 3.5 and, optionally, pharmaceutically utilizable adjuncts and additives are 20 admixed.

18. An aqueous oral pharmaceutical preparation of diclofenac according to claim 1, substantially as hereinbefore described and exemplified.

19. A method of preparing an aqueous oral pharmaceutical preparation of diclofenac according to claim 1, substantially as hereinbefore

20. An aqueous oral pharmaceutical preparation of diclofenac according to claim 1, whenever prepared by a method claimed in a preceding claim.