Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1999-05-11
2000-06-06
Jordan, Kimberly
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514922, A61K 31195
Patent
active
060719648
DESCRIPTION:
BRIEF SUMMARY
Diclofenac.sodium (chemical name 2-[(2.6-dichlorophenyl)amino]benzeneacetic acid sodium salt) is an effective and widely used non-steroid anti-inflammatory agent marketed as Voltaren.RTM. (Ciba Geigy) in several countries.
Diclofenac is applied in different formulations such as tablet, film tablet, dragee, capsule, retard preparations, injection, suppository, ophthalmic solution, gel.
The most frequently applied tablet formulation--similarly to other poorly soluble, slowly absorbed non-steroid anti-inflammatory drugs--causes local irritation in the stomach especially in case of chronic treatment.
Cyclodextrins are cyclic oligosaccharides consisting of 6, 7 or 8 .alpha.-D-glucopiranose units in which the glucose units are linked by .alpha.,1.fwdarw.4 linkage. The eight-member ring is called .gamma.-cyclodextrin. Cyclodextrins form inclusion complexes with the hydrophobic guest molecules of appropriate size. Cyclodextrins, cyclodextrin derivatives, inclusion complexation process and characterization of complexes are widely discussed by Szejtli (Cyclodextrins and Their Inclusion Complexes, Akademiai kiado, Budapest, 1982. Cyclodextrin Technology, Kluwer Academic Publishers, Dordrecht, 1988) and Fromming and Szejtli (Cyclodextrins in Pharmacy, Kluwer Academic Publishers, Dordrecht/Boston, 1994).
Diclofenac--similarly to other non-steroidal anti-inflammatory drugs--shows toxic side effects; it irritates the gastrointestinal mucosa, bleedings, ulcers and perforations may develop. The development of ulcers is a complex process, involving many factors: damage of the mucosal barrier, inhibition of the mucosal prostanoid synthesis, direct effect on the cellular enzymes, increased acid secretion, slowing down of repair processes etc. Dose of the given drug, route of administration, metabolism etc. may also play a role. The effect of a certain factor may change from drug to drug.
Preparation and pharmaceutical applications of diclofenac/cyclodextrin complexes are described in several patents.
Eye drops containing diclofenac sodium and .beta.-cyclodextrin for enhancement of the solubility of the poorly soluble diclofenac are described in a Japan Kokai 58174310 (Wakamoto Pharm. Co., Ltd. 1982).
The Japan Kokai 590848821 (Teikoku Chemical Industry Co., Ltd. 1982) describes sustained-release analgesics containing diclofenac and .beta.-cyclodextrin.
The Japan Kokai 62289515 (Ishida. K:, 1986) describes lint cloth coated with medicine containing diclofenac and cyclodextrin.
A medical preparation used for treatment of ischaemic brain diseases is discussed in the Japan Kokai 62198616 (Shingijutsu Kaihatsu K.K., 1986), the preparation contains a prostaglandin synthesis inhibitor e.g. diclofenac and cyclodextrin.
Suppositories containing steroid and non-steroid anti-inflammatory drugs--e.g. diclofenac and cyclodextrin are described in the Japan Kokai 87,138.437 (Nakanishi, M. 1987). Cyclodextrin is used as an absorption promoter.
EP 371431 (Vectorpharma International S.p.A., 1988) describes the preparation of supported drugs with increased dissolution rate. The drug and the support material are co-ground in a mill with its grinding chamber saturated with solvent vapour. The solvent solubilizes the drug or promotes its adsorption onto the support material.
This technology decreases the extent of drug crystallinity. The drug can be e.g. diclofenac, the support material may be cyclodextrin polymer or water-soluble cyclodextrin.
The EP 446753 (Vectorpharma International S.p.A., 1990) deals with therapeutic compositions with controlled release of medicaments. The drug is supported on crosslinked polymer matrix which is insoluble but swellable in water.
The drug can be e.g. diclofenac, the polymer matrix is, for example, water-insoluble cyclodextrin polymer.
The WO 92/00725 patent application (Farcon AG, 1990) describes oral topical liquid pharmaceutical compositions of non-steroidal anti-inflammatory drugs e.g. diclofenac. Combining the drugs with cyclodextrins or cyclodextrin derivatives (physical mixture, complex, coprecipitate) i
REFERENCES:
Backensfeld et al., "Interacton of NSA with cyclodextrins and hydroxypropyl cyclodextrin derivatives", International Journal of Pharmaccutics, 74 (1991) pp. 85-93.
Devi et al., "Albumin Microspheres and Betacyclodextrin Inclusion Complex Containing Diclofonac Sodium", Indian Journal of Pharmaceutical Sciences, Nov.-Dec. 1992, pp. 259-261.
Orienti et al., "Availability of NSAIDH .beta.-Cyclodextrin Inclusion Complexes", Arch. Pharm. (Weinheim) 322, 207-211 (1989).
Abstract Printed from the Cyclodextrin News Library Database, CA: 115:239451, "Inclusion complexes between non steroidal antiinflammatory drugs and beta-cyclodextrin" (1991).
Abstract Printed from the Cyclodextrin News Library Database, "Preparation and evaluation of Flurbiprofen and Diclofenac sodium transdermal films" (1993).
Backensfeld, Pharmazeutisches Institut der Christian Albrechts Universitat Kiel., Arch. Pharm. 323, 690 (1990).
Fischer Wilfried
Sendl-Lang Anna
Hexal AG
Jordan Kimberly
LandOfFree
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