Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-09-21
2003-12-02
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06656921
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to pharmaceutical compositions with activity against peptic ulcer containing a zinc associate (complex) of hyaluronic acid as well as a process for the preparation thereof.
The invention furthermore relates to the use of the zinc associate (complex) of hyaluronic acid, i.e. zinc hyaluronate for the preparation of pharmaceutical compositions of activity against peptic ulcer and a method for the treatment and prevention of peptic ulcer. The invention also relates to the use of zinc hyaluronate for the prevention of reinfection after the healing of peptic ulcer.
BACKGROUND OF THE INVENTION
The macromolecule known as hyaluronic acid usually occurring in the form of its sodium salt, is a compound known for more than 50 years. It had first been described by Meyer et al [J. Biol. Chem. 107, 629 (1934)]. Hyaluronic acid is a highly viscous native glucosaminoglycan containing alternating &bgr;1-3 glucuronic acid and &bgr;1-4 glucosamine moieties, its molecular weight is between 50000 and several millions. Hyaluronic acid is found in the connective tissues of all mammals; it occurs in higher levels in the skin, vitreous body of the eye, synovial fluid, umbilical cord as well as cartilaginous tissue.
Up to recently, hyaluronic acid has been employed as the sodium salt in therapy—mainly in ophthalmology, dermatology, surgery, articular therapy—and cosmetics. The salts of hyaluronic acid formed with alkali, alkaline earth, magnesium, aluminum, ammonium and substituted ammonium ions may serve as carriers for promoting the absorption of drugs (see the Belgian patent specification No. 904,547). Heavy metal salts of hyaluronic acid, among these the silver salt, are employed as fungicides; whereas the gold salt is useful for the treatment of rheumatoid arthritis (see the patent specification No. WO 87/05517). However, severe adverse effects of silver and gold compounds are known, i.e. their effects on the immune system, hematopoietic organs and nervous system [M. Shinogi, S. Maeizumi: “Effect of preinduction of metallothionein on tissue distribution of silver and hepatic lipid peroxidation”, Biol. Pharm. Bull. (Japan), April 1993 16 (4), p. 372-374; C. Masson et al.: Rev. Med. Interne (France) May-June 1992, 13 (3) p. 225-232 (1992)].
Associates (complexes) of deprotonated hyaluronic acid with 3d metal ions of 4th period of the Periodic Table such as zinc and cobalt hyaluronates with a curative effect especially on crural ulcer, decubitus ulcer or the like are discussed in the Hungarian patent specification No. 203,372, with confirmations by external use.
Now, it has been found that the zinc associate (complex) of hyaluronic acid, i.e. zinc hyaluronate possesses significant gastroprotective activity so it can be used in the prophylaxis and treatment of peptic ulcers including Helicobacter pylori-induced ulcers.
There are known structurally similar gastroprotective compounds in the literature. The anti-gastric ulcer effect of zinc salts of acidic polysaccharides and within these, of mucopolysaccharides is described in the published Japanese patent application No. 60-48950, giving a list of alga-derived agar agaropectin of marine origin, carrageenin, alginic acid as acid polysaccharides; hyaluronic acid, heparin, chondroitin sulfate as mucopolysaccharides; as well as other compounds such as dextran sulfate, carboxymethylcellulose and the like and pectinic acid of plant origin. However, according to this application, the molecular weights of acidic polysaccharides are about a few thousands, preferably about 20 thousand. The zinc salt of hyaluronic acid and its pharmacological activity are not published in the examples at all.
The U.S. Pat. No. 5,514,660 describes the antiulcer effect of pharmaceutical compositions containing an oligosaccharide type active ingredient, together with examples of investigations on the effects of the compounds on the Helicobacter pylori-induced ulcer. Neither hyaluronic acid nor its zinc associate are involved in this specification and no wound-healing effect is mentioned.
Peptic ulcer disease is a complex and multifactorial disease which concerns a great part of civilized population. Many questions still remain in relation to the exact pathogenesis of this disease. In the last five years a new approach has emerged due to the “re-discovery” of Helicobacter pylori. It is generally accepted that the development of peptic ulcer disease in humans is associated with the infection of Helicobacter pylori, but on the other hand H. pylori can not be held responsible for all causes of peptic ulcer. Up to now the peptic ulcer therapy has not changed essentially: still H
2
blockers and proton pump inhibitors are the most important requisites of the therapeutic arsenal, whilst the possible therapeutical methods for killing the H. Pylori bacteria are now disclosed in the literature. In addition, the treatment of gastro-duodenal damage caused by nonsteroidal anti-inflammatory drugs has become the center of interest.
A peptic ulcer, developed by any mechanism, may be characterized by an upset of that balance, which exists under healthy conditions between aggressive factors—which induce development of ulcers—and defensive factors—which protect the stomach against induction of ulcers. Thus, an ulcer develops in each case when the aggressive factors are enhanced beyond certain limits and/or the defensive factors become weaker. Defensive factors include the resistance of gastric mucosa, sufficient blood supply of gastric mucosa, and mucus formation [H. Shay: Etiology of peptic ulcer, Am. J. Dig. Dis. 6, 29-49 (1961)]. Among the aggressive factors, the leading ones are the secretion of hydrochloric acid and pepsin as well as all factors stimulating the secretion of any of both substances. The secretion of acid may be enhanced also by a pathological vagal stimulus or increased gastrin formation, by an autoimmune mechanism and in some cases by hormonal effect. In addition, the balance between aggressive and defensive factors may be disturbed also by injuries affecting the whole body. Thus, peptic ulcer is a multifactorial disease. Agents used in ulcer therapy are intended to reduce the role of aggressive factors and/or to enhance the role of defensive factors. Up to recently, the pharmacological investigations have sought ways to weaken the effects of aggressive factors so the primary target was to moderate the acid-pepsin activity. Drugs used in the treatment of ulcer were targeted first to neutralize the acid (antacids such as sodium hydrogen carbonate, or aluminum hydroxide) or to inhibit its secretion (H
2
blockers, e.g. cimetidine, famotidine, proton pump inhibitors, e.g. omeprazole); only recently research into those agents which enhance the role of defensive factors became important, beyond the development of a monotherapy useful for killing Helicobacter pylori.
However, compositions strengthening the defensive factors are available only in a limited number and they show some side effects. Such compositions are colloidal bismuth subcitrate (CBS, DeNol), sucralfate and misoprostol. CBS contains bismuth, which is responsible for toxicological problems. Sucralfate a basic aluminum salt of sulphated sucrose possesses some adverse effects, e.g. nausea, vomiting, aluminum intoxication, etc., and the misoprostol, a synthetic prostaglandin analogue, induces an enhanced intestinal activity or nausea.
It can be seen from the above that there is a further need for effective and safe drugs to treat ulcers not accompanied with an increased acid secretion. Such compositions could be employed with success in cases where the aim is to prevent the gastric lesions from the gastric irritative, damaging effect of e.g. nonsteroidal anti-inflammatory drugs such as indomethacin, aspirin by strengthening the mucosal protective mechanism. The number of patients having peptic ulcers due to NSAID (nonsteroidal anti inflammatory drug) consumption might grow in the future if we take into consideration the data showing that more than ten
Forrai Gaborne
Illes Janos
Matuz Judit
Neszmelyi Erzsabet
Saghy Katalin
Delacroix-Muirheid C.
Dubno Herbert
Jones Dwayne C.
Myers Jonathan
Richter Gedeon Vegyeszeti Gyar RT.
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