Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2000-10-27
2002-10-29
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S422000, C424S425000, C424S484000, C514S002600, C514S784000, C514S786000, C514S944000, C514S900000
Reexamination Certificate
active
06471970
ABSTRACT:
The present invention relates to pharmaceutical compositions which allow the sustained release of at least one active substance, to methods for preparing these compositions, as well as to their use for treating periodontitis, gingivitis, dental abscesses, mouth ulcers and mycoses.
Periodontitis is a disease which is revealed by the destruction of the supporting tissues of teeth subsequent to an inflammation which is caused by the anaerobic microorganisms of dental plaque. Without treatment, the disease inevitably develops and increasing numbers of bacterial populations continuously maintain the immune reaction which triggers the phenomena of periodontal disease and periodontoclasia. As soon as it reaches a depth greater than 3 mm, the gingivo-dental crevice is considered to be a periodontal pocket. Periodontitis is also accompanied by the resorption of the alveolar bone. Its development finally leads to tooth loss.
Periodontitis is a disease which more greatly affects the adult population over forty years old. Periodontitis is not, however, a disease of elderly people; it quite frequently affects even the young.
It is possible to distinguish acute infections (superficial gingivitis or deep periodontal abscesses); “rapidly evolving” infections (adolescent and young-adult periodontitis); and finally, chronic infections which evolve in stages (chronic periodontal disease).
The methods for treating periodontitis comprise in particular daily hygiene and mechanical means (cleaning, descaling, surfacing of roots, etc.), as well as local and systemic antiseptic and antibiotic means.
Antiseptics can be administered locally in the form of mouthwashes, toothpastes or creams. However, this mode of local administration does not allow the antiseptics to diffuse all the way to the bottom of the periodontal pockets. The function of this mode of administration cannot go beyond the stage of prophylaxis.
With regard to antibiotics, they are no more active by topical administration for the same reason, since they do not manage to reach the depth of the bacterial biofilms (or plaque). When the severity of the case makes it necessary, antibiotics are thus generally administered systemically, relying on their diffusion as far as the periodontal pockets through the gingival fluid which continually flows into them.
Another method consists in using pharmaceutical compositions which allow the controlled release of antiseptic or antibiotic agents, and which are inserted directly at the bottom of the periodontal pocket. Sustained-release compositions exist which are deposited on solid devices such as soaked threads, gelatin chips, etc. Such devices can leave insoluble frameworks in place which must, of course, be removed at the end of treatment.
The literature also mentions fluid pharmaceutical compositions, such as more or less viscous emulsions or suspensions, which are administered into the periodontal pocket generally with the aid of syringes.
International patent application WO 95/34287 describes biodegradable lipid compositions in the form of L2 crystalline phases which allow the controlled release of active substances and which comprise, besides the active substance, at least one unsaturated fatty acid diacylglycerol which has 16 to 22 carbon atoms or saturated fatty acid diacylglycerol which has 14 to 22 carbon atoms, at least one phospholipid chosen from glycerophosphatides and sphingophosphatides, and, optionally, at least one polar liquid chosen from water, glycerol, ethylene glycol and propylene glycol. These compositions have the characteristic of transforming into cubic liquid crystal phases upon contact with water, which makes it possible to “mould” the active substance in the site where it is desired for the action to take place. The said document mentions, among other uses, the possibility of using such compositions for treating periodontitis. However, the effectiveness of such compositions in the treatment of periodontitis is not illustrated in that document.
European patent 429224 describes compositions which are in the form of gels containing from 1 to 99% by weight of monoolein and from 1 to 90% by weight of active substance, which are placed in the periodontal cavity. In the presence of the surrounding water, these compositions become more viscous and keep the active substance close to its site of action. The active substance is released slowly in controlled fashion.
U.S. Pat. No. 5,230,895 describes the use of compositions which are in the form of solutions or pastes which are capable of transforming into gel when they have been placed in the periodontal pocket. These compositions are biodegradable and allow the controlled release of the active substance in the site of action. They contain a mixture of glycerides and of an active substance chosen such that it is capable of forming a gel in the environment of the periodontal pocket. The compositions illustrated in the said document contain at least 70% of Myverol™ 18-92, which is a composition of sunflower monoglycerides which has a monoglyceride content of at least 90%.
U.S. Pat. No. 5,143,934 describes compositions which allow the administration, by controlled release, of an active substance in a periodontal pocket, and which comprise at least one monoglyceride and at least one plant oil in proportions which are sufficient to form a liquid crystal phase upon contact with the water present in the periodontal pocket. These compositions are solid at room temperature, but they have a melting point which is lower than body temperature.
In that document, the results obtained for several compositions of this type are compared with the results obtained with a conventional mechanical treatment. It is noted that the compositions which are described therein make it possible to obtain a reduction in the size of the periodontal pockets and a decrease in bleeding during three months of treatment. However, the effect obtained by applying the compositions is no better, and is even slightly worse, than the result which may be obtained with the reference mechanical treatment.
In addition, since the compositions described in U.S. Pat. No. 5,143,934 are solid at room temperature, they must be liquefied at the moment of insertion into the periodontal pocket.
The applicant has now just discovered novel pharmaceutical compositions which can be easily applied into the periodontal pocket and which allow the sustained release of active substances in this pocket. The applicant has in particular just discovered that these novel compositions are very well suited to the treatment of periodontitis, due to both their effectiveness and their ease of use. In addition, these compositions are obtained by an extremely simple preparation method.
Consequently, the present invention relates to fluid pharmaceutical compositions which allow the controlled release of at least one active substance and which comprise
a) a therapeutically effective amount of at least one active substance,
b) from 3 to 55% by weight of phospholipid,
c) from 16 to 72% by weight of pharmaceutically acceptable solvent, and
d) from 4 to 52% by weight of fatty acid, these compositions having the property of gelling instantaneously in the presence of an aqueous phase.
According to another aspect, the invention relates to methods for preparing these compositions.
According to a third aspect, the invention relates to the use of these compositions for treating periodontitis, gingivitis, dental abscesses, mouth ulcers and mycoses.
The compositions according to the present invention comprise a therapeutically effective amount of at least one active substance. The latter can be lipid-soluble or water-soluble. By way of example, mention will be made of antibiotics, in particular antibiotics which are active against anaerobic bacteria, such as doxycycline or minocycline, and the pharmaceutically acceptable salts thereof, anti-infectious agents such as metronidazole, chlorhexidine, benzalkonium chloride, p-chloro-m-cresol, 2,4-dichlorobenzyl alcohol, hexamidine or chlorofen, and the pharmaceutically acceptab
Deleers Michel
Fanara Domenico
Grognet Pierre
Vranckx Henri
Russel Jeffrey E.
UCB S.A.
Wenderoth , Lind & Ponack, L.L.P.
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