PHARMACEUTICAL COMPOSITIONS BASED ON DICLOFENAC

Abstract: New pharmaceutical compositions for oral use containing diclofenac together with alkali metal carbonates and bicarbonates and particular flavouring substances are described. These compositions are entirely palatable and free from any unpleasant taste or other side effects.

Description: Pharmaceutical compositions based on diclofenac The present invention relates to new pharmaceutical compositions containing [(2,6-dichloro-anilino)-2-phenyl]-2-acetic acid (more commonly known as diclofenac) in acid and/or salt form. Diclofenac is a non-steroidal drug which is widely dispensed and used owing to its well-known analgesic, anti-pyretic, anti-arthritic, anti-phlogistic and anti- rheumatic properties; its structural formula is indicated below. Diclofenac is generally taken orally in the form of normal tablets or tablets covered with coatings resistant to gastric juices, or rectally, or by injection, or topically. The possibility of taking it in the form of sweets, tablets dissolving in the mouth, drages, chewing gum or other similar pharmaceutical forms or in formulations for the extemporary preparation of diclofenac-based aqueous solutions and/or suspensions would represent a different mode of administration which is definitely more suitable, especially for children and elderly persons. Owing to its poor solubility in water, diclofenac is normally used in salt form; the salts of diclofenac customarily used are those of sodium, potassium or other alkali and alkaline earth metals, together with salts of organic nature, such as the salts of basic amino acids, such as lysine, arginine and oraithine, or other pharmacologically acceptable organic bases which have the ability to render the resulting salt soluble in water. The pharmaceutical compositions of the diclofenac salts for oral use are generally accompanied by side effects of not inconsiderable consequence. Diclofenac salts are characterised by a particularly unpleasant and bitter taste and by the fact that they produce a sensation of strong astringency and cause an especially intense form of irritation in the buccal cavity, especially in the area of the larynx. Although the first problem has been partly solved by using flavourings which are able in some manner to mask the taste, satisfactory solutions have still not been proposed for the two remaining problems. Therefore, the pharmaceutical compositions containing diclofenac salts still have a poor palatability which limits their adoption and possible fields of application, despite the excellent therapeutic effect with which they are associated. The subject of the present invention is that it has now surprisingly been found that, by adding alkali metal carbonates and bicarbonates or mixtures thereof to the diclofenac salts, together with customary excipients and adjuvants, pharmaceutical compositions can be obtained which are for the most part free from the side effects mentioned above and especially from the astringent sensation in the area of the larynx. The amount of such inorganic salts added to the compositions containing diclofenac is from 20 to 80 % by weight, based on the weight of the acid-form diclofenac. In the preferred embodiment of the present invention, the inorganic salts are selected from sodium and potassium carbonates and bicarbonates. It has also been found, and forms a second subject of the present invention, that the addition of flavouring substances selected from mint, aniseed, ammonium glycyrrhizinate and mixtures thereof to the compositions containing the diclofenac salts and alkali metal carbonates and/or bicarbonates produces a synergistic effect which completely eliminates all the above-mentioned side effects, providing pharmaceutical compositions which are entirely palatable (and/or drinkable in the case of those used for the preparation of solutions and/or suspensions) and free from aftertaste. It has now surprisingly been found that the use of alkali metal carbonates and/or bicarbonates for the preparation of the compositions of the present invention permit constant, reproducible and foreseeable blood levels of the active ingredient, as it will be clear from example 5, with the consequent indisputable advantages from the therapeutic point of view. Finally, it has also surprisingly been found that the combined use of alkali metal carbonates and/or bicarbonates and the above-mentioned flavouring substances yields diclofenac-based pharmaceutical compositions in which the active ingredient is released more rapidly compared with normal formulations, bringing about higher blood levels and therefore a more immediate therapeutic effect. The flavouring substances may be used as such or supported on inert materials, for example maltodextrin, in order to obtain a better distribution of the granulates and to facilitate excellent dispersibility of the flavouring in solution. Preferably, they are absorbed on maltodextrin with a power of 1 to 2000 and 1 to 1000. The amount of flavouring substances in its pure form is also preferably from 1/5 to 3 times the weight of the acid-form diclofenac. These flavouring substances are used in the implementation of the present invention without altering their organoleptic properties and without depriving them of their intrinsic qualities of flavourings which are liposoluble and generally oily in the pure state. The following Examples are given purely by way of non-limiting illustration. Example 1 - Composition dissolving instantly in water - Active ingredients 1) Diclofenac potassium salt* : 50 mg 2) Potassium bicarbonate: 22 mg 3) Mint flavouring on maltodextrin(l :2000)**: 60 mg 4) Aniseed flavouring on maltodextrin (1 :1000)** * : 104 mg - Excipients and adjuvants 5) Saccharin: 4 mg 6) Aspartame: lO mg 7) Mannitol: 50 mg 8) Saccharose*** *q.s.: 2 g * If it is desired to prepare compositions based on diclofenac sodium salt, it is advantageous to use sodium bicarbonate in a quantity of approximately 38% by weight based on the weight of the diclofenac sodium salt present Sodium carbonate may also be added to the sodium bicarbonate, maintaining the following optimum proportions 27 % of sodium bicarbonate and 4-5 % of sodium carbonate, always based on the amount by weight of diclofenac sodium salt present ** The title of the pure mint essence, as obtained according to the Dean-Stark method, is of 18% by weight, the related amount is therefore in this case of 10 8 mg *** The title of the pure anise essence, as obtained according to the Dean-Stark method, is of 14 5% by weight, the related amount is therefore in this case of 16 mg **** j ne p resence 0 f saccharose is not strictly necessary, in its absence, a composition having a very limited granulate content is obtained which is perfectly soluble in contact with water In that case, nothing is changed from the point of view of tolerability in contact with the mucosa and from the point of view of the palatability of the drinkable solution - Preparation Components 1, 2, 5, 6 and 7 are mixed in a suitable mixer, and the mixture so obtained is wetted with 95% ethanol Granulation is carried out with a 66 mm mesh and the granulate is preferably dried in a current of air Components 3, 4 and 8, which have already been granulated using a mesh of the same granulometry, are then added and the whole is mixed The mixture is then introduced into a metering machine filling packets or similar containers Example 2 - Effervescent composition - Active ingredients 1 ) Diclofenac potassium salt* 50 mg 2) Potassium bicarbonate 24 mg 3) Mint flavouring on maltodextrin (1 2000)** 50 mg 4) Aniseed flavouring on maltodextrin (1 1000)*** 120 mg - Excipients and adjuvants 5) Potassium bicarbonate 780 mg 6) Sacchaπn 5 mg 7) Mannitol 65 mg 8) Citric acid 500 mg 9) Aspartame 9 mg 10) Saccharose**** q s 3 g * to**** see Example 1 - Preparation Components 1, 2, 5, 6, 7 and 9 are mixed in a suitable mixer, and the mixture so obtained is wetted with 95 % ethanol Granulation is carried out using a 66 mm mesh and the granulate is preferably dried in a current of air Components 3, 4, 8 and 10, which have already been granulated using a mesh of the same granulometry, are then added and the whole is mixed The mixture is then introduced into a metering machine filling packets or similar containers in a dehumidified chamber Example 3 - Tablet for dissolving in the mouth - Active ingredients 1) Diclofenac potassium salt* 50 mg 2) Potassium bicarbonate 35 mg 3) Mint flavouring on maltodextrin** ( 1.2000) + gum arable (E 414)- 50 mg 4) Aniseed flavouring (1 1000) on maltodextrin*** + silicon dioxide (E 551) 120 mg - Excipients and adjuvants 5) Saccharin 50 mg 6) Aspartame 12 mg 7) Mannitol 20 mg 8) Saccharose**** 300 mg * to**** see Example 1 Example 4 - Gum tablet - Active ingredients 1) Diclofenac potassium salt* 50 mg 2) Potassium bicarbonate 35 mg 3) Mint flavouring on maltodextrin** 30 mg 4) Aniseed flavouring on maltodextrin*** 80 mg - Excipients and adjuvants 5) Mannitol- 30 mg 6) Menthol 0 010 mg 7) Gum base 600 mg 8) Sorbitol 700 mg 9) Saccharin. 3 mg 10) Hydroxypropylmethylcellulose' 33 mg 1 1 ) Colouring agent 7 mg * to*** see Example 1 Example 5 - Comparative test The packaged composition containing 50 mg of diclofenac potassium of Example 1 (formulation C) was subjected to a pharmacokinetic test for comparison with a similar composition not containing alkali metal carbonates and bicarbonates (formulation B), and with a second composition in tablet form (formulation A) produced by Ciba-Geigy (Voltaren Rapid ®), also in this case not containing alkali metal carbonates and bicarbonates, both formulations A and B containing 50 mg of diclofenac potassium This comparative evaluation was carried out on the same 6 healthy volunteers in accordance with the experimental plan described hereinafter - Experimental scheme Single-dose study using three methods in randomised cross- over with a wash-out of three days - Sampling times Oh (before administration), 5 min, 10 min, 30 min, 45 min, lh, 1 5h, 2h, 3h, 4h, 6h, 8h, after each administration - Blood sample treatment' 8MI in heparinised test tubes, centrifugation for 15 min at 1500 rev/min, subdivided into two fractions and subsequently frozen at -20°C - Times wash-out of two days between treatments - Determination method HPLC, with internal standard, sensitivity 10 ng/ml. Analysis method - Column. Nova Pak C18, 3.9x150 mm, 4 μm Waters S.p.A - Vimodrone, Italy - Eluant NaH2PO4 0.01 M + 0.1 % TEA, pH 3 0 (H3PO4)/acetonitrile, 60/40 - Flow 1.2 ml/min - Detection UV/275 nm - Temperature 30°C - Injection 50 al - Analysis time' 16 min Sample preparation 10 al of the internal standard methanolic solution, and flufenamic acid (corresponding to 1320 ng) are added to 1 ml of defrosted plasma in 10 ml glass test tubes The tubes are agitated in a Vortex mixer for 1 minute 0 5 ml of a 0.5N HCl/ IN NaCl solution is added The whole is agitated in a Vortex mixer for 1 minute 6 ml of a 95/5 n-hexane/isopropanol solution are added The mixture is then agitated in the Vortex mixer for a further 15 minutes Centrifugation is carried out at 3000 rev/min for 15 minutes and the organic phase is transferred to fresh 10 ml glass test tubes and evaporated to dryness in a centrifugal evaporator under vacuum at ambient temperature The whole is taken up in 200 al of a 70/30 acetonitrile/water solution, and the precipitate is dissolved under ultrasound for 2 minutes Figures 1 , 2 and 3 show the concentrations of diclofenac in the blood of the six volunteers as regards formulations A, B (Ciba-Geigy comparative formulations) and C (formulation corresponding to the composition of Example 1), respectively As will be appreciated, the blood concentration of the formulation of the present invention has, compared with the comparative formulations, a more constant and uniform pattern. This characteristic is also found in Figures 4, 5 and 6 which show the average values corresponding to the blood levels of the six volunteers together with the corresponding standard deviation. The result is clear and surprising: compared with the sample compositions, the compositions of the present invention permit constant, reproducible and foreseeable blood levels of the active ingredient, irrespective of the characteristics of the volunteer (weight, age, etc), with the consequent indisputable advantages from the therapeutic point of view. Finally, Figure 7 shows, by comparison, the graphs relating to the average values of the six volunteers (that is to say, the preceding Figures 4, 5 and 6); as will be noted, the formulation of the present invention permits, in addition to the advantages already mentioned, the attainment of a blood peak higher than that of the other formulations. Example 6 - Two layered tablet (fast and slow release) Fast release layer 1) Diclofenac potassium salt: 30 mg 2) Potassium bicarbonate: 30 mg 3) Lactose: 13.2 mg 4) Maize starch (intragranular): 6 mg 5) Methyl cellulose: 0.12 mg 6) Sodium laurylsulfate: 0.06 mg 7) Maize starch (extragranular): 9 mg 8) Crospovidone: 0.6 mg 9) Sodium carboxtmethylstarch: 1 5 mg 10) Magnesium stearate: 2.7 mg 1 1) Colloidal silicon dioxide: 0.6 mg Slow release layer 1) Diclofenac potassium salt: 70 mg 2) Potassium bicarbonate 30 8 mg 3) Lactose 32 2 mg 4) Polyvinylpyrrolidone 1 16 mg 5) Hydrpxypropylmethylcellulose 70 mg 6) Magnesium stearate 0 84 mg 7) Colloidal silicon dioxide 0 21 mg 8) Talc 3 92 mg 9) Polyethylene glycol 0 56 mg Example 7 - Drops 1 ) Diclofenac potassium salt 75 g 2) Methyl p-oxybenzoate 2 7 g 3) Propyl p-oxybenzoate 0 3 g 4) Aspartame 37 5 g 5) Potassium bicarbonate 37 5 g 6) Glycerol 300 g 7) Ethyl alcool 450 g 8) Water q s 1500 g Possible modifications a) Addition of sodium metabisulfite (0 06%) b) Addition of sodium metabisulfite (0 06%) Mint flavouring (1 25%) Strawberry flavouring (0 75%) Example 8 - Drops 1) Diclofenac potassium salt 37 5 g 2) Methyl p-oxybenzoate 2 7 g 3) Propyl p-oxybenzoate 0 3 g 4) Aspartame 37 5 g 5) Potassium bicarbonate 18 75 g 6) Saccharin 6 0 g 7) Glycerol 300 g 8) Ethyl alcool: 450 g 9) Water q.s. : 1500 g Possible modifications. a) Addition of sodium metabisulfite (0. 03%) b) Addition of sodium metabisulfite (0. 03%) Mint flavouring (1.25%) Strawberry flavouring (0.75%) Example 9 - Mouthwash 1) Diclofenac potassium salt: 0.75 g 2) Glycerol: 50 g 3) Sorbitol: 12 g 4) Saccharin: 0.5 g 5) Aspartame: l .O g 6) Methyl p-oxybenzoate: 0.5 g 7) Propyl p-oxybenzoate: 0.1 g 8) Mint flavouring: 1 0 g 9) Ethyl alcool: 100 g 10) Potassium bicarbonate: 0.33 g 1 1) Water q.s.: 500 ml Example 10 - Gum-paste 1) Diclofenac potassium salt: 5.0 g 2) Glycerol: 630 g 3) Sodium benzoate: 5.0 g 4) Silica (Wessalon S® - Degussa): 120 g 5) Silica (Siddent 9® - Degussa): 80 g 6) Cellulose gum: 3.0 g 7) Polyethylenglycol 600: 30 g 8) Sodium lauroyl sarcosinate (or sodium lauryl sulfate): 60 g 9) Mint flavouring: lO g 10) Sodium saccharin. 1 0 g 11) Aspartame 30g 12) Potassium bicarbonate 22g 13) Water qs 1kg Example 11 - Tooth-paste 1) Diclofenac potassium salt 50g 2) Glycerol 630 g 3) Sodium benzoate 5.0 g 4) Silica (Wessalon S® - Degussa ι) 20 g 5) Silica (Siddent 9® - Degussa) 80 g 6) Cellulose gum 30g 7) Polyethylenglycol 600 30 g 8) Sodium lauroyl sarcosinate (or sodium lauryl sulfate) 60 g 9) Mint flavouring lOg 10) Sodium saccharin 10g 11 ) Aspartame 30g 12)NaF 10g 13)Na 2 FPO 3 40g 14) Potassium bicarbonate 2.2 g 15) Water qs 1kg Example 12 - Tablet 1) Diclofenac potassium salt 50 mg 2) Mannitol 50 mg 3) Potassium bicarbonate 22 mg 4) Maize starch (intragranular) 10 mg 5) Methyl cellulose 02mg 6) Sodium laurylsulfate. 01 mg 7) Maize starch (extragranular). 15 mg 8) Crospovidone 1 Omg 9) Sodium carboxymethylstarch 25mg 10) Magnesium stearate 45 mg ) Colloidal silicon dioxide: 10 mg

Claims: CLAIMS 1 Pharmaceutical compositions for oral use containing diclofenac in acid and/or salt form, together with customary excipients and adjuvants, characterised in that they contain alkali metal carbonates and bicarbonates or mixtures thereof in an amount of at least 20% by weight, based on the weight of acid-form diclofenac 2 Pharmaceutical compositions according to Claim 1, characterised in that the alkali metals are sodium and potassium 3 Pharmaceutical compositions according to Claim 1, characterised in that the alkali metal carbonates and bicarbonates or their mixtures are present in an amount of from 20 to 80 % by weight, based on the weight of acid-form diclofenac 4 Pharmaceutical compositions according to Claim 1, characterised in that they contain at least one flavouring substance selected from mint, aniseed and ammonium glycyrrhizinate. 5 Pharmaceutical compositions according to Claim 4, characterised in that the at least one flavouring substance is present in pure form in an amount of from 1/5 to 3 times the weight of the acid-form diclofenac 6 Use of alkali metal carbonates and bicarbonates or mixtures in various ratios of these salts, together with customary excipients and adjuvants, for the preparation of pharmaceutical compositions for oral use containing diclofenac in acid and/or salt form 7 Use according to Claim 6, characterised in that the alkali metals are sodium and potassium 8 Use according to Claim 6, characterised in that the alkali metal carbonates and bicarbonates or mixtures thereof are present in an amount of from 20 to 80 % by weight, based on the weight of the acid-form diclofenac. 9 Use according to Claim 6, characterised in that at least one flavouring substance selected from mint, aniseed and ammonium glycyrrhizinate is used in combination with the alkali metal carbonates and bicarbonates or mixtures in various ratios of these salts. 10. Use according to Claim 9, characterised in that the at least one flavouring substance is present in pure form in an amount of from 1/5 to 3 times by weight, based on the weight of the acid-form diclofenac.

Inventors: REINER ALBERTO, REINER GIORGIO, REINER, ALBERTO, REINER, GIORGIO
Applicants: APR PATENT HOLDER S A, REINER ALBERTO, REINER GIORGIO, APR PATENT HOLDER S.A., REINER, ALBERTO, REINER, GIORGIO
Application year: 1997
Main classification: A61K31
IPC codes: A61K8, A61K9, A61K31, A61K47, A61P19, A61Q11