Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-12-22
2001-02-27
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06194462
ABSTRACT:
The subject matter of this invention concerns fluid pharmaceutical preparations containing nimesulide active substance for oral and rino-pharyngeal use.
Nimesulide (4-nitro-2-phenoxy-methan-sulfanilide) is a potent non steroidal anti-inflammatory drug, presently used in the treatment of painful inflammatory conditions due to rheumatoid arthritis, which also possesses antipyretic activity (BE 801812). Compared to the other non steroidal anti-inflammatories, Nimesulide has a better therapeutical ratio, low acute gastrotoxicity and generally good tolerability.
Nimesulide differentiates itself chemically from other NSAID's due to the fact that its functional acidic group consists of the sulfanilide fraction.
Nimesulide is a strongly hydrophobic substance that is practically insoluble in water (solubility in water at room temperature: 0.01 mg/ml).
Nimesulide's scarce water solubility and “wettability” represent serious limitations for its use in pharmaceutical presentations since these problems do not allow satisfactory drug release and constant bioavailability. Hence the difficulty to develop acceptable fluid pharmaceutical presentations.
In order to overcome the disadvantages caused by nimesulide's poor solubility and wettability, it is essential to increase its solubility in water.
Numerous investigations have been carried out for this purpose which have lead to a number of patents (WO 94/28031, MI 91 A 001396) that illustrate the possibility of including nimesulide in cyclodextrins by employing various preparation techniques. The products for inclusion in cyclodextrins are usefully employed in the development of solid oral pharmaceutical formulations, but do not satisfactorily resolve the problems connected with the preparation of fluid or liquid forms.
To date the attention has been mainly concentrated on problems connected with the systemic administration of nimesulide, albeit, similarly to other NSAID's, the local use of this molecule has also been evaluated. In fact, there are studies and patents on the local administration of nimesulide dispersions in rheumatology, dermatology and traumatology (WO 96/11002). Anti-inflammatories in the form of liquids, tinctures and mouthwash solutions can be administered locally for the treatment of various pathologies in odontostomatology (local treatment of periodontal inflammation such as gingivitis and periodontitis, stomatitis, glossitis) and otorhinolaryngology (tonsillitis, pharzyngitis, laryngitis).
Due to nimesulide's chemical and physical characteristics, its use in water based fluid or liquid pharmaceutical preparations is subordinated to the dissolution of the substance, achievable by salification of the sulfanilide group. Such salification is obtained by using strong bases such as alkaline or alkaline-earth hydroxides, aminoacids, e.g. lysine, choline, glycine. Such dissolution process occurs directly during the preparation of the finished product and the soluble intermediate compound obtained does not require prior isolation.
The solutions obtained by nimesulide salification have a high pH which cannot be used in pharmaceutics for oral administration because of possible problems related to an increase in gastric pH.
These problems are less important in the case of local treatment of the oral cavity, in view of the fact that the solution is not swallowed and remains in contact with a restricted application area and for a limited amount of time.
Given the fact that nimesulide is partially soluble in ethanol, its dissolution may be facilitated by using varying ratios of pharmaceutically acceptable hydroalcoholic solutions.
The subject matter of this invention is the description of pharmaceutical compositions containing nimesulide for local application in the form of a mouthwash solution, tincture or liquid.
However, dissolution of nimesulide active substance does not resolve the problems related to the development of liquid or fluid pharmaceutical preparations for local use considering the unfavourable organoleptic characteristics of the solutions obtained.
DETAILED DESCRIPTION OF THE INVENTION
The pharmaceutical compositions according to this invention include nimesulide active substance in solution form and in a mixture of traditional vehicles and excipients as liquid or fluid pharmaceutical forms for local use and application to the oral and oropharyngeal cavities.
The pharmaceutical compositions according to this invention consist of liquids, tinctures and mouthwash solutions.
These compositions contain nimesulide active substance in solution form at concentrations ranging between 0.001% and 10%.
The ingredients of the vehicle are powders, liquids or creamy masses that arc soluble in water or in hydroalcoholic solutions, generally used in pharmaceutical and food preparations as solvents, sweeteners, colouring agents, flavouring agents, viscosity enhancers, surfactants, etc.
The pharmaceutical compositions consist of pharmaceutically acceptable vehicle for 90% to 99.999%, prepared according to traditional methods as described, for example, in “Remington's Pharmaceutical Sciences Handbook, Mack. Publ., N.Y., USA”.
The invention concerns in particular a fluid pharmaceutical preparation containing nimesulide active substance (CAS No. 51803-78-2) or one of its active derivatives and is characterized by the fact that in the preparation:
nimesulide is present at concentrations from 0.001 to 10% w/v;
the base of the solution is hydroalcoholic; and
the solution has a pH of 8±2.
Furthermore, the alcohol may have one or more —OH groups, especially ethyl alcohol and/or glycerine.
The above mentioned preparation may also contain carbohydrates with 3 to 6 C, especially sorbitol and xylitol.
The weight ratio between H
2
O and alcohol plus carbohydrates is preferably between 1:25 and 4:1.
If necessary, pH stability is achieved by using a system consisting of acid-salt of the corresponding acid.
The preparation herein is administered in the form of a mouthwash solution or tincture and is indicated for the topical treatment of inflammation of oral and rhinopharyngeal mucosae.
The compositions described herein have shown that it is possible to obtain pharmaceutical forms containing nimesulide in solution form that is acceptable for local application to oral, pharyngeal and laryngeal mucosa, allowing its use in therapeutical areas in which to date there was no possibility of employing an active substance with better pharmacotoxicological characteristics than those of the other antiinflammatory drugs previously used.
REFERENCES:
patent: 5716609 (1998-02-01), Jain et al.
patent: 5998480 (1999-12-01), Giorgetti
patent: 801812 (1974-01-01), None
patent: 4116659 (1991-11-01), None
patent: 0 367 382 (1990-05-01), None
patent: 0532900 (1993-03-01), None
patent: 0 843 998 (1998-05-01), None
patent: 2 662 360 (1991-11-01), None
patent: RM96A0480 (1998-01-01), None
patent: 299 500 (1997-02-01), None
patent: WO 91/17774 (1991-11-01), None
patent: WO 94/28031 (1994-12-01), None
patent: WO 96/11002 (1996-04-01), None
Munhoz M S L et al: “Estudo Comparativo Entre Nimesulide Versus Diclofenaco Potassico Em Afeccoes Otorrinolaringologicas: Comparative Study With Nimesulide V.S. Potassium Diclofenac in ent Disease” Revista Da Sociedade Brasileira de Medicina Tropical, vol. 47, No. 11, Nov. 1, 1990, pp. 591-594, XP000563507.
Susan Buvadari, et al., eds.The Merck Index; (Rahway, New Jersey: Merck & Co., Inc., 1989), 1035.
Dialog Select, The Merick Index Online, CAS Registry No. 51803-78-2 for nimesulide, Dialog File No. 304, Accession No. 006640 (1997).
Analytical Abstracts, Dialog File No. 305, Accession No. 273305 (1997), Abstract for Alvarez-Lueje, A., et al., “Voltammetric Study of Nimesulide and Its Differential Pulse Polarographic Determination in Pharmaceuticals”,Electroanalysis, 9(15), pp. 1209-1213, (New York, Oct. 1997).
Analytical Abstracts, Dialog File No. 305, Accession No. 269327 (1997), Abstract for Chowdary, K.P.R., et al., “A New Spectrophotometric Method for the Determination of Nimesulide”,Indian Drugs, 3
Errekappa Euroterapici S.p.A.
Jarvis William R. A.
Ladas & Parry
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