LIQUID ORAL PHARMACEUTICAL COMPOSITIONS HAVING ANTI-INFLAMMATORY ACTIVITY

Abstract: Liquid pharmaceutical compositions for the oral topical treatment, containing as the active ingredients non steroidal anti-inflammatory drugs, characterized in that they contain dimethyl isosorbide as the carrier.

Description: LIQUID ORAL PHARMACEUTICAL COMPOSITIONS HAVING ANTI-IN¬ FLAMMATORY ACTIVITY The present invention relates to liquid pharmaceu¬ tical compositions for the oral topical treatment, containing non steroidal anti-inflammatory drugs as the active ingredients. Therapeutical treatment of inflammations of the oral cavity, such as aspecific odontostomatologic af¬ fections, gingivitis, glossitis, stomatitis and the like, is particularly complex and, until the specific pathogenic agent has precisely been determined, treat- ment can be restricted to the use of disinfectants of the general type. Moreover, even when the pathogenic agent has cer¬ tainly been determined, administration of antibiotics such as tetracyclines and the like, generally by the parenteral or systemic routes, must be carried out in most cases. Said drugs, besides showing negative characteri¬ stics (remarkable side-effects) can cause severe and diffused allergy phenomena, so as to compel to immedia- tely interrupt treatment and to take suitable restora¬ tion measures. Now it has been found, and it is the object of the present invention, that pharmaceutical compositions comprising non steroidal anti-inflammatory drugs (FANS) in form of solutions intended for the oral topical tre¬ atment (collutories) , allow to obtain very good thera¬ peutical results without causing sensitization pheno¬ mena. The compositions of the invention are characteri¬ zed by the presence of a specific excipient, dimethyl isosorbide, giving them advantageous antiseptic proper¬ ties together with an antiplaque action which is parti- cularly desired in this kind of preparations. Anti-in¬ flammatory properties of the active ingredients also turn out to be surprisingly enhanced through a synerge- tic interaction with dimethyl isosorbide. The compositions of the present invention can con- tain the active ingredient in amounts ranging from 0.001 to 20% by weight, whereas dimethyl isosorbide can be present in amounts ranging from 1 to 40% by weight. Of course, the compositions of the invention can also contain other excipients and/or coadjuvants, such as surfactants, flavouring and sweetening agents, in order to give the preparation suitable organoleptic characteristics. Examples of said excipients and/or co¬ adjuvants conventionally used for the preparation of collutories are described in "Remington's Pharm. Scien- ces Handbook", Mack Pub. Co., NY. The compositions of the invention will preferably contain natural and/or synthetic sweetening agents such as saccharine, ammo¬ nium glycyrrhizinate, cycla ate or, more preferably, not cariogenic carbohydrates such as xylitol and sorbi- tol. All the up to now known non steroidal anti- inflammatory drugs such as ketoprofen, ibuprofen, ibu- profen lysine salt, naproxen, suprofen, diclofenac, al- clofenac, indomethacin, acemethacin, benzidamine, flur- biprofen, piroxicam and the like, can be used as active ingredients, either in the free form or salified, in order to improve the solubility thereof. According to a particularly preferred embodiment, the active ingredients are present in combination with cyclodextrins or derivatives thereof, for example in form of physical admixtures, inclusion products or co- precipitates. Cyclodextrins or derivatives thereof, such as hydroxypropyl beta-cyclodextrins, involve fa¬ vourable pharmacokinetic effects and, moreover, are useful to increase solubility and stability, or to im- prove the organoleptic characteristics of the medica¬ ment. Cyclodextrin contents can range from 0.5 to 50% by weight of the finished composition, but equimolecular ratios of active ingredient to cyclodextrin are prefe- rably used. Besides the commonly available cyclodex¬ trins (o , β, -) and the already cited hydroxypropyl β- cyclodextriπ, dimethylcyclodextrins or other derivati¬ ves, possibly in a mixture thereof, can also be used. The techniques for the preparation of both inclu-* sion complexes with cyclodextrins and co-precipitates are well-known. In principle, the active ingredient is added to an aqueous solution of cyclodextrin or hy¬ droxypropyl β-cyclodextrin, keeping the mixture under stirring for 40-80 hours at a temperature from the room one to 80 e C. The desired compound is obtained upon eva¬ poration of the solvent under vacuum. Another particularly preferred embodiment of the invention is provided by formulations in which polymers having an adhesive power towards ucosae are used as excipients. Examples of said polymers are provided by carboxyvinyl polymers, ethyle e oxide - propylene oxide copolymers, cellulose derivatives such as carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxy- propylethyl cellulose, hydroxyethyl cellulose, hydroxy¬ propyl cellulose, carrageenan, dextrins, natural or synthetic gums and the like. Said excipients, which can be def ned bioadhesive polymers, can be present in per¬ centages ranging from 0.5 to 30%, preferably from 1 to 5%. The use of said excipients allows to obtain sli¬ ghtly viscous solutions having adhesiveness towards mu- cosae, so as to achieve a better persistence of the preparation in contact with the area to be treated, thus obtaining a more effective and lasting action. Whenever said bioadhesive polymers are present, the compositions can also contain no dimethyl isosor- bide : said compositions also fall within the scope of the present invention. The following examples further illustrate the in¬ vention. EXAMPLE 1 Collutory containing ketoprofen (in form of solution) 100 ml of collutory contain i% composition) Active ingredient: ketoprofen 0.0133 to 0.133 Excipients: Tween 60 0.5 alpine herb flavor 52,503 T 0.100 dimethyl isosorbide 10 90% ethanol 15 sodium saccharinate 0.1 Sodium benzoate 0.2 ? sorbitol solution 10 distilled water q.s. to ml 100 Each 15 ml ampoule contains: Active ingredient: ketoprofen Excipients: Tween 60 alpine herb flavor 52,503 T dimethyl isosorbide 90% ethanol sodium saccharinate Sodium benzoate 70% sorbitol solution distilled water q.s. to ml Ketoprofen is dissolved in an ethanol solution containing dimethyl isosorbide and Tween 60, the solu¬ tion is heated to 35 C C under stirring, to obtain a clear solution which is added with the other components. After filtration, a clear homogeneous solution (collutory) is obtained. EXAMPLE 2 Collutory containing ketoprofen - β-cyclodextrins (so¬ lution) 100 ml of collutory contain (% composition): Active ingredient: ketoprofen 0,25 Excipients: β-cyclodextrin 1.14 dimethyl isosorbie 10.00 ethanol 15.0 sodium saccharinate 0.1 sodium benzoate 0.2 70% sorbitol solution 10.0 distilled water q.s. to ml 100 Ketoprofen is added to a β-cyclodextrin aqueous solution (about 50 ml), which is heated to 30-40 e C for 30 hours. A solution is obtained which is added with dimethyl isosorbide and the other components, then fil¬ tered. EXAMPLE 3 Collutory containing ketoprofen and bioadhesive poly- mers (solution) 100 ml of collutory contain (% composition): Active ingredient: ketoprofen 0.05 Excipients: Ethylene oxide-propylene oxide copolymer (Poloxamer 188) 1.2 ethanol 95 e 5.0 sodium benzoate 0.1 sodium saccharinate 0.3 benzoic acid 0.05 natural flavor 0.05 depurated water q.s. to ml 100 EXAMPLE 4 Collutory containing ketoprofen, dimethyl isosorbide and bioadhesive polymers (in form of solution) 100 ml of collutory contain (% composition): Active ingredient: ketoprofen 0.05 Excipients: Ethylene oxide-propylene oxide copolymer (Poloxamer 188) 1.2 dimethyl isosorbide 5.0 ethanol 95 5.0 sodium benzoate 0.1 sodium saccharinate 0.3 benzoic acid 0.05 natural flavor 0.05 depurated water q.s. to ml 100 Ketoprofen is dissolved in ethanol, dimethyl iso¬ sorbide and Poloxamer 188 are added, then about 50 ml depurated water and the other components. The mixture is filtered to obtain a clear light solution. EXAMPLE 5 Collutory containing benzidamine (in form of solution) 100 ml of collutory contain (% composition): Active inσredient: Benzidamine 0.0133 to 0,133 Excipients: Tween 60 0.5 alpine herb flavor 52,503 T 0.100 dimethyl isosorbide 10 90% ethanol 15 sodium saccharinate 0.1 sodium benzoate 0.2 xylitol 10 distillated water q.s. to ml 100 Each 15 ml ampoule contains : Active ingredient: Benzidamine 2 to 20 mg ExciDients: Tween 60 5 mg alpine herb flavor 52,503 T 15 mg dimethyl isosorbide 1500 mg 90% ethanol 2250 mg sodium saccharinate 15 mg sodium benzoate 30 mg xyilitol 1500 mg distillated water q.s. to ml 100 EXAMPLE 6 Collutory containing ibuprofen lysinate (in form of so¬ lution) 100 ml of collutory contain (% composition) : Active ingredient: Ibuprofen lisinate 0.0266 to 0,266 Excipients: Tween 60 0.5 alpine herb flavor 52,503 T 0.100 dimethyl isosorbide 10 90% ethanol 15 sodium saccharinate 0.1 sodium benzoate 0.2 70% sorbitol solution 10 distillated water q.s. to ml 100 Each 15 ml ampoule contains : Active ingredient: Ibuprofen lisinate 4 to 40 mg Excipients: Tween 60 5 mg alpine herb flavor 52,503 T 15 mg dimethyl isosorbide 1500 mg 90% ethanol 2250 mg sodium saccharinate 15 mg sodium benzoate 30 mg 70% sorbitol solution 1500 mg distillated water q.s. to ml 100 EXAMPLE 7 Collutory containing piroxicam (in form of solution) 100 ml of collutory contain (% composition) : Active ingredient: Piroxicam 0.001 to 0,01% Excipients: Tween 60 0.5 alpine herb flavor 52,503 T 0.100 dimethyl isosorbide 10 90% ethanol 15 sodium saccharinate 0.1 sodium benzoate 0.2 70% sorbitol solution 10 distillated water q.s. to ml 100 Each 15 ml ampoule contains: Active ingredient: Piroxicam Excipients: Tween 60 alpine herb flavor 52,503 T dimethyl isosorbide 90% ethanol sodium saccharinate sodium benzoate 70% sorbitol solution distillated water q.s. to ml

Claims: CLAIMS 1. Liquid pharmaceutical compositions for the oral topical treatment, containing as the active ingredients non steroidal anti-inflammatory drugs, characterized in that they contain dimethyl isosorbide as the carrier. 2. Compositions according to claim 1, wherein di¬ methyl isosorbide is present in percentages from 1 to 40% by weight. 3. Compositions according to claim 1 or 2, wherein the active ingredient is present in percentages from 0.001 to 20% by weight. 4. Compositions according to any one of the preceding claims, wherein the active ingredient is selected from ketoprofen, ibuprofen, ibuprofen lysinate, suprofen, flurbiprofen, naproxen, diclofenac, alclofenac, benzi¬ damine, piroxicam, acemethacin, indomethacin. 5. Compositions according to claim 4, wherein the ac¬ tive ingredient is ketoprofen. 6. Compositions according to any one of the preceding claims, wherein the active ingredient is combined with cyclodextrins or derivatives thereof, in form of mixtu¬ res, inclusion complexes or co-precipitates. 7. Compositions according to claim 6, wherein combi- nations with &(. , β or g" cyclodextrins or hydroxypropyl β-cyclodextrins are used in almost equimolecular ratios to the active ingredient. 8. Compositions according to any one of the preceding claims, further containing bioadhesive polymers. 9. Liquid pharmaceutical compositions for the oral topical treatment, containing as the active ingredients non steroidal anti-inflammatory drugs, characterized in that they contain a bioadhesive polymer as an exci- pient. 10. Compositions according to claim 9, wherein the bioadhesive polymer is selected from carboxyvinyl poly¬ mers, ethylene oxide - propylene oxide copolymers, cel¬ lulose derivatives, carrageenan, dextrins, natural or synthetic gums.

Inventors: CONTE UBALDO, CONTE, UBALDO
Applicants: FARCON AG
Application year: 1991
Main classification: A61K47
IPC codes: A61K9, A61K47