NZ569118A

NZ569118A - Agent comprising 5-D-fructose dehydrogenase in combination with one or more other enzymes for reducing the useable calorie content of food and for therapeutic reduction of weight, in particular for use in case of adiposity (obesity)

Info

Publication number: NZ569118A
Application number: NZ569118A
Authority: NZ
Inventors: Daniel Henry Wyrobnik; Isaac Harry Wyrobnik
Original assignee: Pro Natura Ges Fur Gesunde Ernahrung Mbh
Priority date: 2005-11-23
Filing date: 2006-11-23
Publication date: 2011-11-25
Also published as: BRPI0618956A2; BRPI0618956B1; ES2707785T3; BRPI0618956A8; BRPI0618956B8

Abstract

Disclosed is a pharmaceutical composition, a foodstuff, a special foodstuff, a composition of matter or amammalian-ingestable composition of matter comprising 5-D-fructose dehydrogenase in combination with one or more enzyme(s) selected from glucose isomerase, invertase, lactase, maltase, alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and cyclomaltodextrin glucanotransferase.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 5691 18 WO 2007/059955 PCT/EP2006/011231 - 1 - Agent for reducing the useable calorie content of food and for therapeutic reduction of weight, in particular for use in the case of adiposity (obesity) 5 The present invention relates to an agent for reducing the useable calorie content of food. The agent contains a compound that can effect the conversion of fructose to 5-keto-D-fructose. 5-keto-D-fructose cannot be metabolized by the human or animal body and is therefore significantly less caloric than fructose. The present invention also relates to an agent which, in addition to the first 10 compound, contains a compound that can effect the conversion of glucose to fructose. According the invention the term "agent" includes a pharmaceutical composition, a medical device, a foodstuff and a special foodstuff. According to the present invention, the terms "food" and "foodstuff' are used as 15 synonyms. They mean to also include feed in the sense of animal feed. In the context of this application "special foodstuffs" are foodstuffs for particular nutritional uses, foods for special medical purposes, medical foods, food supplements, dietary supplements, dietetic food supplements, health foods, nutraceuti-cals, and food additives. In the context of this application the term foodstuff 20 means to include special foodstuffs as used herein, where applicable. Fructose is a ketohexose and is an important energy providing ingredient of food. It is present as a component of many di- and oligosaccharides, as free fructose or as both in numerous foodstuffs. In contrast to glucose, fructose is 25 assimilated into the mucosa cells of the small intestine by eased carrier-mediated diffusion. The enzymatic degradation starts in the liver by the action of the adenosine triphosphate (ATP) dependent fructokinase, whereby fructose is converted to fructose 1-phosphate. In the liver and in the kidneys, fructose 1-phosphate is cleaved to glycerine aldehyde and dihydroxy acetone phosphate 30 by aldolase B. WO 2007/059955 PCT/EP2006/011231 -2- Food, e.g. fruits and fruit juices, contain a large amount of fructose, but in particular also sucrose, which is cleaved to fructose and glucose in the body. Over the past decades, there has been a dramatic increase in the consumption of 5 free fructose (which is approx. 1.6-fold sweeter than glucose or sucrose) since the cheaper sweetener "high fructose corn syrup" (HFCS) was added to many of our beverages, bakery products and other sweet foodstuffs. Data from the USA show a parallel development between the sharp increase of obesity and the additives of free fructose. In contrast to glucose, fructose is metabolized inde-10 pendently of insulin. Since insulin influences the occurrence of the sensation of satiation indirectly, i.e. fructose does not eliminate the appetite, obesity may easily occur as a result of the extensive use of HFCS as a sweetener. Free fructose in large amounts may also favor hypertension. Large amounts of free fructose also influence the lipid profile (blood lipids) in an unfavorable way, since 15 they promote the synthesis of lipids and thus increase the postprandial serum triglycerides. Patients with metabolic syndrome should not consume beverages that are sweetened with HFCS or sucrose. Fructose is also discussed as a cause of metabolic syndrome. 20 Thus, fructose is an important source of calories for the human body and must be given special consideration in all efforts to reduce the content of calories in the food. In the following, the term "fructose containing" refers to all substances and foodstuffs that either contain fructose in pure form or from which fructose can be released in the digestive tract. The fructose content of substances and 25 foodstuffs refers to all the fructose in a fructose containing food or substance in whatever form (e.g. also as part of sucrose) it is contained in such a food or substance. Departures from normal weight due to an increase in body weight, primarily in 30 the proportion of fat, are referred to as adiposity (obesity), whereby, normally WO 2007/059955 PCT/EP2006/011231 -3- and in the sense of this invention, four grades are differentiated, namely grade 0 = normal weight, grade I = overweight, grade II = adiposity and grade III = extreme adiposity. The individual grades are classified according to the well-known body mass index (BMI). An increase in fatty tissue and thus in body weight 5 above a certain limit leads to an increase in various diseases, such as hypertension, and life expectancy decreases. The number of persons suffering from adiposity grade I to grade III has increased constantly in the industrialized countries over the past decades and amounts to 30 to 50 % of the total population at present, depending on the statistic used and definition of the term overweight or 10 obesity. For example, in the Federal Republic of Germany, every second person is overweight (adiposity grade I) and every sixth person has adiposity grade II or III. The number of adipose children is also increasing as a result of poor nutrition and lack of exercise. To date, therapy has been limited to nutrition therapy and, in extreme cases, surgical measures. It is a well-known fact that there is a very 15 large and constantly increasing number of nutrition therapies and diets that generally do not result in lasting success. Even if there is an initial loss in weight, usually this results in the so-called yoyo effect, i.e. the sufferers initially lose weight, but put it back on again after the end or early termination of the diet. Often, in the end the body weight is even higher than prior to the beginning 20 of the diet. Surgical measures, which are only used in particularly severe cases, have the aim of reducing the supply of nutrients or nutrient utilization, and are associated with high operation risks and long-term negative side effects. Nutrient deficits may thus result, due to impairments of absorption and insufficient supply with the food. These relate to vitamins, minerals and proteins. Up to one 25 third of the surgical patients show a folic acid deficiency. In addition, iron, potassium, magnesium and vitamin A deficiencies may occur. The drug therapies known to date for treating adiposity are controversial. Products have often had to be taken off the market due to severe side effects. All 30 drugs that are still available today also have significant, unpleasant and frequent Received at IPONZ on 22 August 2011 -4- side effects, such as fatty stools, constipation and insomnia. A diet that reliably leads to a sustainable success and/or a broadly applicable therapy for adiposity in its different types without side effects is not known. Of course, the widespread use of surgical measures does not come into question. It remains to be said that those suffering from 5 obesity and the specialists treating them are confronted by a quite hopeless and frustrating situation for all concerned. An agent that does not have an effect on the body, but on the carbohydrates in the food and that would reduce the useable calorie content in the food would satisfy an 10 extremely widespread and pressing need which has existed for decades. Such an agent would also overcome the prejudice widely held in the specialist world and among those suffering from obesity that a lasting weight reduction or the prevention of an increase in weight is not possible without suffering and without a significant change of nutrition habits. It would mean a dramatic improvement in the options available for the 15 treatment of adiposity. Such an agent would also put an end to the as yet fruitless efforts of the specialist world to find an agent to treat adiposity which can be administered broadly, easily, and long-term, without causing side effects. This would apply all the more to an agent which, in addition, has no negative effects on health. 20 There is a need for an agent that significantly reduces the useable calorie content of food, in particular for facilitating the intake of foodstuffs that normally contain fructose also in the case of adiposity, without resulting in an increase in weight. There is also a need to make it possible for persons suffering from adiposity to eat foodstuffs which until now were not allowed to them due to their fructose content or the eating of which 25 was associated with negative effects for the sufferers' health. A need also exists for an agent that, after the intake of fructose, can reduce or prevent the associated negative effects on weight and/or health, in particular in the case of adiposity. There is also a need for an agent that can prevent persons who up to now have not 30 suffered from adiposity from putting on weight as a result of eating fructose containing substances or foodstuffs. There is also a need to allow persons who are not suffering Received at IPONZ on 22 August 2011 -5- from adiposity to eat foodstuffs the intake of which would otherwise lead to the risk of weight gain, with the consequence that these persons might become adipose. The subject matter of the invention is directed to the needs described above. 5 Accordingly, in a first aspect, the invention provides a pharmaceutical composition comprising 5-D-fructose dehydrogenase in combination with one or more enzyme(s) selected from glucose isomerase, invertase, lactase, maltase, alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and 10 cyclomaltodextrin glucanotransferase; but excluding pharmaceutical compositions in which the sole said enzymes present are a combination of 5-D-fructose dehydrogenase and glucose isomerase. In further aspects, the invention provides: 15 A medical device comprising 5-D-fructose dehydrogenase in combination with one or more enzyme(s) selected from glucose isomerase, invertase, lactase, maltase, alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and cyclomaltodextrin glucanotransferase, wherein the medical 20 device is in a form for oral administration; but excluding medical devices in which the sole said enzymes present are a combination of 5-D-fructose dehydrogenase and glucose isomerase. Received at IPONZ on 22 August 2011 -5a- A special foodstuff comprising 5-D-fructose dehydrogenase in combination with one or more enzyme(s) selected from glucose isomerase, invertase, lactase, maltase, alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and cyclomaltodextrin glucanotransferase wherein said special 5 foodstuff is selected from foodstuffs for particular nutritional uses, foods for special medical purposes, medical foods, food supplements, dietary supplements, dietetic food supplements, health foods, nutraceuticals and food additives; but excluding special foodstuffs in which the sole said enzymes present are a combination of 5-D-fructose dehydrogenase and glucose isomerase. 10 A foodstuff comprising 5-D-fructose dehydrogenase, the foodstuff being selected from sweets, fruit preparations (e.g. apple puree), jam, honey, chocolate and chocolate products, baked products (e.g. biscuits and cakes), breads, pastas, vegetable dishes, potato dishes, ice cream, cereals, dairy products (e.g. fruit yoghurt and pudding), 15 glucose containing beverages, glucose containing sauces, tomato ketchup and glucose containing sweeteners, provided that for dishes which are cooked or baked, the 5-D-fructose dehydrogenase has been mixed into or sprinkled onto the foodstuff after cooling down. 20 - The use of 5-D-fructose dehydrogenase, optionally in combination with one or more enzyme(s) selected from glucose isomerase, invertase, lactase, maltase, alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and cyclomaltodextrin glucanotransferase, for the manufacture of a medicament for the curative or prophylactic treatment of adiposity. 25 The use of 5-D-fructose dehydrogenase, in combination with one or more enzyme(s) selected from glucose isomerase, invertase, lactase, maltase, alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and cyclomaltodextrin glucanotransferase for the manufacture of a medicament for (i) 30 lowering the bioavailability of fructose and/or glucose in the human or animal body; or (ii) lowering the content of fructose and/or glucose in a foodstuff; or (iii) for lowering the Received at IPONZ on 22 August 2011 -5b- usable calorie content of food; but excluding the use of a combination consisting of the enzymes 5-D-fructose dehydrogenase and glucose isomerase for use in lowering the bioavailability of fructose and/or glucose in the human or animal body. 5 - A process for the treatment of a foodstuff, comprising the steps of contacting the foodstuff with a 5-D-fructose dehydrogenase in combination with one or more enzyme(s) selected from glucose isomerase, invertase, lactase, maltase, alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and cyclomaltodextrin glucanotransferase, and initiating the reduction of the fructose 10 content and optionally the reduction of the glucose content of the foodstuff. A mammalian-ingestible composition of matter which comprises 5-D-fructose dehydrogenase and one or more members of the group consisting of lactase, alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and 15 cyclomaltodextrin glucantransferase (CGTase); optionally in combination with glucose isomerase and/or invertase and/or maltase. A method for preparing a reduced-total fructose foodstuff, comprising contacting a foodstuff or foodstuff precursor with 5-D-fructose dehydrogenase and with a second 20 enzyme that converts glucose into fructose; and optionally wherein said second enzyme is a glucose isomerase, and completing any additional steps necessary to prepare the foodstuff; and wherein: (a) said reduced-total fructose foodstuff is a reduced-fructose foodstuff; and/or (b) said foodstuff is other than a baked foodstuff; and/or (c) said foodstuff is other than bread; and/or (d) said foodstuff is other than a 25 dough. A method for preparing a foodstuff or foodstuff precursor having a reduced effective fructose content, comprising incorporating into said foodstuff or foodstuff precursor 5-D-fructose dehydrogenase and completing any additional steps necessary 30 to prepare the foodstuff, wherein said 5-D-fructose dehydrogenase is incorporated in such manner that said 5-D-fructose dehydrogenase will convert D-fructose to 5-keto-D- Received at IPONZ on 22 August 2011 - 5c - fructose after ingestion of said foodstuff; and optionally wherein: (a) said foodstuff is other than a baked foodstuff; and/or (b) said foodstuff is other than bread; and/or (c) said foodstuff is other than a dough; and/or (d) said 5-D-fructose dehydrogenase is microencapsulated; and wherein said method optionally further comprises incorporating 5 into said foodstuff or foodstuff precursor a second enzyme in a manner that said additional enzyme will be active in said mammalian body after ingestion therein; and optionally wherein said second enzyme is selected from the group consisting of invertase, maltase, a glucose isomerase, lactase, alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and cyclomaltodextrin 10 glucantransferase (CGTase) or a mixture thereof. A mammalian-ingestible composition of matter which is adapted for oral ingestion and comprises 5-D-fructose dehydrogenase, optionally in combination with a further enzyme or mixture of enzymes selected from invertase, maltase, a glucose 15 isomerase, lactase, alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and cyclomaltodextrin glucantransferase (CGTase) or a mixture thereof; wherein the composition of matter is in the form of: (a) a tablet; or (b) granules; or 20 (c) a powder packaged in single dosage amounts; or (d) a liquid other than a foodstuff, wherein the liquid is in the form of a solution or drops; or (e) a gel. 25 - A composition of matter which is an animal dietary supplement or a veterinary composition comprising 5-D-fructose dehydrogenase. A composition of matter comprising the enzyme 5-D-fructose dehydrogenase admixed with a mammalian-ingestible substance wherein said 5-D-fructose 30 dehydrogenase is microencapsulated. Received at IPONZ on 22 August 2011 - 5d - Further embodiments and aspects of the invention are as set out in the claims or as described below. The agent used in accordance with the invention contains 5-D-fructose dehydrogenase 5 (syn. fructose 5-dehydrogenase). The agent according to the present invention brings about the conversion of fructose in the food into 5-keto-D-fructose by dehydrogenation. Thus, the fructose is changed in such a manner that it is no longer available to the metabolism of the human or animal body. 10 According to one aspect of the invention 5-D-fructose dehydrogenase is used, optionally in combination with glucose isomerase, for treatment of adiposity, for example in the form of a pharmaceutical composition. The treatment of adiposity may be therapeutic or prophylactic. Also, further diseases accompanying adiposity may be treated by making use of the agent according to the invention. 15 According to another aspect of the present invention, the agent is used for lowering the usable calorie content of food. A subject matter of the invention is also an agent that reduces the bioavailability of 20 fructose in the human or animal body with the help of a 5-D-fructose dehydrogenase. WO 2007/059955 PCT/EP2006/011231 -6- A subject matter of the invention is also an agent that reduces the bioavailability of fructose and glucose in the human or animal body with the help of a 5-D-fructose dehydrogenase in combination with a glucose isomerase. 5 A subject matter of the invention is also an agent that reduces the content of fructose in a foodstuff with the help of a 5-D-fructose dehydrogenase. A subject matter of the invention is also an agent that reduces the content of fructose and glucose in a foodstuff with the help of a 5-D-fructose dehydro-10 genase in combination with a glucose isomerase. A subject matter of the present invention is further an agent for reducing the useable calorie content of food which contains a 5-D-fructose dehydrogenase -alone or in combination with a glucose isomerase. 15 The agent according to the invention is suited for the use in the case of adiposity and for the therapeutic or prophylactic treatment of adiposity, possibly accompanied by a further disease usually appearing together with adiposity, including diseases of the cardiovascular system (e.g. hypertension, coronary heart dis-20 ease, venous insufficiency, heart failure, left-ventricular hypertrophy, arteriosclerosis), of metabolic and hormonal function (e.g. diabetes mellitus type II, dyslipi-demias, hyperuricemia, hyperlipoproteinemia), of the respiratory system (e.g. sleep apnea, Pickwickian syndrome), of the hepatobiliary system (e.g. fatty liver, cholecystolithiasis), of the locomotor system (e.g. gonarthrosis, heel spur, ar-25 throsis of the ankle joint), of the skin (e.g. intertrigo, hirsutism, striae) and for use in the case of neoplasias associated with adiposity (e.g. increased risk of endometrial, breast, cervical, gall bladder cancer, etc.), disorders of sexual function (e.g. reduced fertility, complications during birth), psychosocial problems (e.g. reduced self-confidence, social isolation, discrimination, problems 30 with one's partner or at work), and other problems, such as reduced mobility and WO 2007/059955 PCT/EP2006/011231 -7- staying power, increased risk during operations and more difficult examination conditions. All these diseases and health problems are often associated with adiposity. 5 A further subject matter of the invention is the use of a 5-D-fructose dehydrogenase - alone or in combination with a glucose isomerase - in the case of adiposity or in the case of health problems or diseases associated with adiposity (see above). 10 A further subject matter of the invention is the use of 5-D-fructose dehydrogenase - alone or in combination with a further enzyme, preferably together with glucose isomerase - for the manufacture of a medicament (pharmaceutical composition) for the prophylactic or therapeutic treatment of adiposity or dis-15 eases associated with adiposity (see above). According to the present invention, a 5-D-fructose dehydrogenase - alone or in combination with a glucose isomerase - may also be used for reducing the useable calorie content in a foodstuff. 20 A 5-D-fructose dehydrogenase, in the context of this application, is an enzyme that can catalyze the dehydrogenation of fructose to 5-keto-D-fructose. A possible method for the production of a 5-D-fructose dehydrogenase is, for 25 example, described in Ameyama et al., Journal of Bacteriology 1981, 814-823, "D-Fructose Dehydrogenase of Gluconobacter industrius: Purification, Characterization and Application of Enzymatic Microdetermination of D-Fructose", the content of which is incorporated herein by reference. WO 2007/059955 PCT/EP2006/011231 -8- The practical meaning of such an agent for the reduction of the useable calorie content of food becomes clearer if one considers that fructose is used very widely in the foodstuff industry as a sweetener. In the case of foodstuffs which contain sucrose, the content of calories can be reduced by about one half by the 5 use of the agent according to the present invention which contains the enzyme 5-D-fructose dehydrogenase. During digestion, sucrose is enzymatically cleaved to glucose and fructose. The fructose fraction (50 % of the calories contained in sucrose) is then dehydrogenated by said 5-D-fructose dehydrogenase to 5-keto-D-fructose and can therefore no longer be utilized by the body. 10 Glucose is the central carbohydrate of the energy and substrate metabolism. It is the basic component of many polysaccharides (e.g. starch). In the context of this application the term "glucose containing" refers to all substances and foodstuffs that either contain glucose in pure form or from which glucose can be 15 released in the digestive tract. The glucose content of substances and foodstuffs refers to all the glucose in a glucose containing food or substance in whatever form (e.g. also as part of sucrose) it is contained in such a food or substance. Therefore, a further reduction of the calorie content of food may be achieved 20 according to the present invention by an agent that contains glucose isomerase as an additional active ingredient. The invention thus provides compositions and methods that can be used to enable sufferers of Adiposity to ingest fructose-containing foods or fructose- and glucose-containing foods 25 A glucose isomerase in the context of this application is an enzyme that is able to transform glucose into fructose. This conversion can also be brought about, for example, by a xylose isomerase. Thus, such a xylose isomerase is, in the context of this application, also a glucose isomerase. A possible method for the production of a xylose isomerase is, for example, described in Yamanaka, Bio-30 chimica et Biophysika Acta, Volume 151 (3), 1968, 670-680, "Purification, Crys WO 2007/059955 PCT/EP2006/011231 -9- tallization and Properties of the D-Xylose Isomerase from Lactobacillus brevis" and in Yamanaka, Methods in Enzymology, Volume 41, 1971, 466-471, "D-Xylose Isomerase from Lactobacillus brevis", the contents of which are incorporated herein by reference. 5 Such a combination agent can also be used in the form of two separate dose units, e.g. in two separate tablets, one of which contains glucose isomerase and the other 5-D-fructose dehydrogenase. 10 By combining 5-D-fructose dehydrogenase with the enzyme glucose isomerase, ingested glucose as well as the large amounts of glucose released by the degradation of carbohydrates are largely removed from the metabolism of calories by the body. Glucose isomerase has the property of converting glucose into fructose and vice versa with an equilibrium concentration of approximately 50% 15 glucose and 50 % fructose. Such an enzyme combination consisting of 5-D-fructose dehydrogenase and glucose isomerase is ideally suited for considerably reducing the calorie content of, for example starch containing food, such as potatoes. The glucose that is released from starch during digestion is transformed into fructose by said glucose isomerase, which is then converted by said 20 5-D-fructose dehydrogenase into 5-keto-D-fructose which is significantly less bioavailable. Thus, the 5-D-fructose dehydrogenase prevents the above described equilibrium from being established. Therefore, glucose isomerase will convert glucose into fructose, which itself will be dehydrogenated by the 5-D-fructose dehydrogenase to 5-keto-D-fructose, until no further glucose is present 25 in the food and food pulp. Also in the case of sucrose, an increased reduction of calories can be achieved with the combination agent. Fructose, which is released from sucrose during digestion, is converted into 5-keto-D-fructose by 5-D-fructose dehydrogenase, 30 as described above. Therefore the glucose isomerase will attempt to re WO 2007/059955 PCT/EP2006/011231 -10- establish the above described equilibrium by converting glucose into fructose. This conversion process continues until no further glucose is present in the food pulp. In this way, the content of calories of the sucrose containing dishes available to the body is reduced to a greater degree than if 5-D-fructose dehydro-5 genase is used on its own. The combination agent according to the present invention thus leads to a large proportion of the glucose supplied to the body or released in the digestive tract being converted into fructose which in turn is converted into 5-keto-D-fructose, 10 which is of much less value for the metabolism. In a particularly easy way, the invention facilitates the transformation of fructose in a foodstuff into a form that prevents weight gain and enables weight loss. Thus, the invention also facilitates the intake of foodstuffs by persons who suffer 15 from adiposity that had to be avoided by the sufferers up to now because of their content of fructose and glucose. Further, the invention allows the intake of fructose and glucose containing foodstuffs by persons who are not suffering from adiposity, without this leading to negative effects on their weight and/or health. 20 According to the present invention, 5-D-fructose dehydrogenase - alone or in combination with glucose isomerase - is further mentioned for use in medicine (first medical indication), for example as a pharmaceutical composition. Accordingly, a subject matter of the invention is also a product which consists of 5-D-fructose dehydrogenase - alone or in combination with glucose isomerase - or 25 contains 5-D-fructose dehydrogenase - alone or in combination with glucose isomerase - beside one or more other active ingredients for use in a medical method, in particular in a method for the therapeutic treatment of the human or animal body. In the context of this application, a pharmaceutical composition is a product, in particular a substance or a substance mixture, for use in a method 30 for surgical or therapeutic treatment of the human or animal body and in diag WO 2007/059955 PCT/EP2006/011231 - 11 - nostic methods that are performed on the human or animal body. Thus, in the context of this application, pharmaceutical compositions are also products, in particular substances or substance mixtures, that are meant or suitable for curing, alleviating, preventing or determining adiposity. 5 The term "treating" when used in connection with the foregoing disorders includes amelioration, prevention or relief from the symptoms and/or effects associated with these disorders and includes the prophylactic administration of an enzyme or a mixture thereof to diminish the likelihood or seriousness of the 10 conditions. According to a further aspect of the present invention, a foodstuff is provided which contains 5-D-fructose dehydrogenase - alone or in combination - with glucose isomerase. Further, according to the present invention, a foodstuff is 15 provided which contains 5-D-fructose dehydrogenase - alone or in combination with glucose isomerase - in an amount which is sufficient to convert fructose into 5-keto-D-fructose and which, in addition, contains glucose isomerase in an amount which is effective for transforming glucose into fructose. Such a foodstuff may be produced using a method for treating a foodstuff in which the food-20 stuff is placed in contact with a 5-D-fructose dehydrogenase - alone or in combination with glucose isomerase - under such conditions under which the 5-D-fructose dehydrogenase can dehydrogenate fructose to 5-keto-D-fructose and under which the glucose isomerase can convert glucose into fructose. In contrast to otherwise untreated foodstuffs, such a foodstuff has a reduced content 25 of fructose or, if the agent contains both enzymes, a reduced content of fructose and glucose, and therefore, for the first time, is suitable to be consumed by persons who want to control their weight, including adipose persons. Furthermore, a foodstuff can be prepared by a method in which a 5-D-fructose dehydrogenase is added to the foodstuff - alone or in combination with glucose 30 isomerase - in a manner in which the action of the enzyme or both enzymes WO 2007/059955 PCT/EP2006/011231 -12- only starts after the intake of the foodstuff. Such a foodstuff that contains 5-D-fructose dehydrogenase or 5-D-fructose dehydrogenase and glucose isomerase has the same taste as an untreated foodstuff and is, for the first time, suitable to be consumed by persons who want to control their weight including adipose 5 persons due to the reduced content of fructose or fructose and glucose which is established after eating. According to a further aspect, according to the present invention, 5-D-fructose dehydrogenase - alone or in combination with glucose isomerase - is provided 10 as a medical device. The subject matter of the invention is accordingly also a medical device that consists of 5-D-fructose dehydrogenase - alone or in combination with glucose isomerase - or contains the 5-D-fructose dehydrogenase -alone or in combination with glucose isomerase - beside one or more other active ingredients. 15 In the following, the invention will be described further in its various aspects. 5-D-Fructose dehydrogenase is a compound that has been known for nearly 40 years, but has only been used for analytical purposes to date. Glucose isom-20 erase is a compound that has been known for more than 40 years and has only been used for starch saccharification to date. In the industry, it is used for the conversion of glucose into fructose as well as for the conversion of fructose into glucose. 25 5-D-fructose dehydrogenase, in particular in combination with glucose isomerase, has not been used in the medical/pharmaceutical field to date, in particular not in adiposity in humans or animals. Thus, the invention discloses the first medical indication for 5-D-fructose dehydrogenase and the first medical indication for the combination of the two enzymes. Until now, the two enzymes have WO 2007/059955 PCT/EP2006/011231 -13- not been used for the therapeutic treatment of the human or animal body or for diagnostic purposes on the human or animal body. The agent according to the present invention may be taken orally prior to meals, 5 immediately before meals, with meals or immediately after meals, so that it can exert its dehydrogenating effect on fructose and optionally converting effect on glucose in the food pulp. The agent according to the present invention may contain the enzyme(s) without further additives. However, it is preferable that the agent according to the present invention further contains additives that are 10 pharmaceutical^ acceptable and/or acceptable for foodstuffs, such as for example extenders, binders, stabilizers, preservatives, flavourings, etc. Such additives are commonly used and well known for the production of pharmaceutical compositions, medical devices, foodstuffs, and special foodstuffs and the person skilled in the art knows which additives in which amounts are suitable for 15 certain presentation forms. The agents according to the present invention may for example contain as additives dicalcium phosphate, lactose, modified starch, microcrystalline cellulose, maltodextrin and/or fibersol. The agents according to the present invention can also be added to a foodstuff 20 before eating. They may even be added to the foodstuff at the production stage, with the aim of developing their effect only after consuming the foodstuff. This may be achieved by microencapsulation, for example. With this, the useable fructose and/or glucose content of the foodstuff may be reduced, without negatively affecting its taste. Therefore, preparations are particularly useful that 25 contain 5-D-fructose dehydrogenase - alone or in combination with glucose isomerase - and which release these enzymes only in the digestive tract of a human or animal or let them become effective in another way, in particular in the stomach or small intestine. Therefore, the invention can be used for example in the production of sweets, fruit preparations (e.g. apple sauce), jam, honey, 30 chocolate and chocolate products, bakery products (e.g. biscuits and cakes), WO 2007/059955 PCT/EP2006/011231 - 14- breads, pastas, vegetable dishes, potato dishes, ice cream, cereals, dairy products (e.g. fruit yogurt and pudding), fructose- and/or glucose-containing beverages, fructose- and/or glucose-containing sauces (e.g. tomato ketchup) and fructose- and/or glucose-containing sweeteners. For dishes that are boiled or 5 baked, the agents according to the present invention could e.g. be mixed into or sprinkled onto them after cooling. Since fructose is widely used as a sweetener in foodstuffs that are especially produced for diabetics, the addition of the agents according to the present in-10 vention to diabetic food before eating or the addition of the agents according to the present invention during the production of diabetic food allows diabetics who suffer from adiposity to eat diabetic food, such as the above mentioned foodstuffs in their respective form as diabetic foods. 15 The agent according to the present invention may also be added to a foodstuff, to exert its effect on the fructose originating from another foodstuff and in the case of an agent containing both enzymes also on the glucose originating from another foodstuff after their consumption. An example of this would be the addition of the agent according to the present invention to a spread so that the re-20 duction of the calories that are contained in the bread and that can be utilized by the body occurs after the intake of the bread, without an impairment of taste of the bread. Another example would be mixed spices and mayonnaise, among other things for use with french fries. 25 5-D-fructose dehydrogenase and the combination agent may also be used in immobilized form. This is useful for the treatment of liquid foodstuffs. For example, 5-D-fructose dehydrogenase can be embedded in a matrix which is permeable for fructose. If a fructose containing liquid foodstuff is allowed to flow along the enzyme containing matrix, then fructose is extracted from the foodstuff by 30 the action of the enzyme and converted into 5-keto-D-fructose. WO 2007/059955 PCT/EP2006/011231 -15- A subject matter of the present invention are also agents that in addition to other active ingredients also contain 5-D-fructose dehydrogenase, either alone or in combination with glucose isomerase. 5 The agent may be formulated in any form which is suitable for the intended route of administration. A preferred route of administration is oral administration. For oral administration, the agent may be formulated for example in the form of capsules (coated or non-coated) containing powder, coated or non-coated pel-10 lets, granules or micro-/mini-tablets or in the form of tablets (coated or non-coated) pressed from powder, coated or non-coated pellets, dragees or micro-/mini-tablets. The agent may also be formulated for example in the form of gel caps or in liquid form as solution, drops, suspension or gel. The agent may also be formulated e.g. as dried or moist oral supplement. The formulation of the 15 agent according to the present invention as powder is particularly suitable for admixing with foodstuff. The powder may be sprinkled onto a meal or mixed into a pulp or beverage. It is particularly beneficial, if the agent offered as bulk powder is packaged in single dosage amounts, such as in single bags or capsules, or if it is provided in a dosing dispenser. 20 For oral administration, the 5-D-fructose dehydrogenase - alone or in combination with glucose isomerase - may be used with acceptable excipients and/or carriers. 25 The total amount of the carrier and/or excipient of an agent containing 5-D-fructose dehydrogenase or 5-D-fructose dehydrogenase and glucose isomerase is preferably between 5 and 99.9 % by weight, more preferably between 10 and 80 % by weight and even more preferably between 25 and 60 % by weight of the composition. 30 WO 2007/059955 PCT/EP2006/011231 -16- Suitable excipients and/or carriers include maltodextrin, calcium carbonate, dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose, dextrose, rice flour, magnesium stearate, stearic acid, croscarmellose sodium, sodium starch glycolate, crospovidone, sucrose, vegetable gums, lactose, methylcellu-5 lose, povidone, carboxymethyl cellulose, corn starch, modified starch, fibersol, gelatine, hydroxypropylmethyl cellulose and the like (including mixtures thereof). Preferable carriers include calcium carbonate, magnesium stearate, maltodextrin, dicalcium phosphate, modified starch, microcrystalline cellulose, fibersol, 10 gelatine, hydroxypropylmethyl cellulose and mixtures thereof. The various ingredients and the excipient and/or carrier may be mixed and formed into the desired form using common methods well known to the skilled person. The administration form according to the present invention which is 15 suited for the oral route, such as e.g. tablet or capsule, may be coated with a coating which is resistant against low pH values (approximately pH 1 to 2.5) and which dissolves at a pH value of approximately 3.0 to 8.0, preferably at a pH value of 3.0 to 6.5 and particularly preferable at a pH value of 4.0 to 6.0. An optionally used coating should be in accordance with the pH optimum of the 20 enzyme used and its stability at pH values to which the formulation will be exposed. Also a coating may be used which is not resistant to low pH values but which delays the release of the enzyme at low pH values. It is also possible to prepare the agent according to the present invention as coated (see above) pellets, granules or micro-/mini-tablets which can be filled into coated or non-25 coated capsules or which can be pressed into coated or non-coated tablets. Suitable coatings are, for example, cellulose acetate phthalate, cellulose deri-vates, shellac, polyvinylpyrrolidone derivates, acrylic acid, polyacrylic acid deri-vates and polymethyl methacrylate (PMMA), such as e.g. Eudragit® (from Rohm GmbH, Darmstadt, Germany), in particular Eudragit® L30D-55. The coating 30 Eudragit® L30D-55 is dissolved, for example, at a pH value of 5.5 and higher. If WO 2007/059955 PCT/EP2006/011231 -17- it is desired to release the enzyme already at a lower pH value, this may be achieved e.g. by the addition of sodium hydroxide solution to the coating agent Eudragit® L30D-55, because in this case carboxyl groups of the methacrylate would be neutralised. Therefore, this coating will be dissolved, for example, 5 already at a pH value of 4.0 provided that 5 % of the carboxyl groups are neutralised. The addition of about 100 g of 4 % sodium hydroxide solution to 1 kg of Eudragit® L30D-55 would result in a neutralisation of about 6 % of the carboxyl groups. Further details about formulation methods and administration methods can be found in the 21st edition of "Remington: The Science & Practice of 10 Pharmacy", published 2005 by Lippincott, Williams & Wilkins, Baltimore, USA, in the Encyclopedia of Pharmaceutical Technology (Editor James Swarbrick) and in Prof. Bauer "Lehrbuch der Pharmazeutischen Technologie", 18th edition, published 2006 by Wissenschaftliche Verlagsgesellschaft (ISBN 3804-72222-9). The contents of these documents are incorporated herein by reference. 15 Other suitable acceptable carriers or adjuvants for use in the present invention include, but are not restricted to water, mineral oil, ethylene glycol, propylene glycol, lanolin, glyceryl stearate, sorbitan stearate, isopropyl myristate, isopropyl palmitate, acetone, glycerine, phosphatidylcholine, sodium cholate or ethanol. 20 The compositions for use in the present invention may also comprise at least one co-emulsifying agent which includes but is not limited to oxyethylenated sorbitan monostearate, fatty alcohols, such as stearyl alcohol or cetyl alcohol, or esters of fatty acids and polyols, such as glyceryl stearate. 25 The agents according to the present invention may be provided in a stabilized form. Generally, stabilization methods and procedures which may be used according to the present invention include any and all methods for the stabilization of chemical or biological material which are known in the art, comprising e.g. the 30 addition of chemical agents, methods which are based on temperature modula WO 2007/059955 PCT/EP2006/011231 -18- tion, methods which are based on irradiation or combinations thereof. Chemical agents that may be used according to the present invention include, among others, preservatives, acids, bases, salts, antioxidants, viscosity enhancers, emulsifying agents, gelatinizers, and mixtures thereof. 5 Usually, the industrial production of enzymes is performed in a technical fermentation way using suitable microorganisms (bacteria, moulds, fungi). Usually the strains are recovered from natural ecosystems according to a special screening protocol, isolated as pure cultures as well as improved in their properties with 10 respect to the enzyme spectrum and biosynthesis performance (volume/time yield). Enzyme production may also be carried out by methods developed in the future. 5-D-fructose dehydrogenase is commercially available (e.g. Sigma-Aldrich or 15 Toyobo Enzymes, Japan) and is usually prepared in a microbiological way with the help of the microorganism Gluconobacter industrius. Glucose isomerase is also commercially available (e.g. Sigma-Aldrich or Novozymes A/S, Denmark) and usually prepared in a microbiological way with the help of the microorganism Streptomyces murinus. However, the invention is not limited to the enzymes 20 that are commercially available at the moment, but generally relates to enzymes that can catalyze the conversion of fructose - specifically or non-specifically - to 5-keto-D-fructose, and of glucose - specifically or non-specifically - to fructose. A person skilled in the art can prepare suitable further enzymes by conventional methods, for example by mutagenesis of the gene encoding 5-D-fructose dehy-25 drogenase which is present in Gluconobacter industrius or by mutagenesis of the gene encoding glucose isomerase in streptomyces murinus. The enzymes may also be prepared with the help of other microorganisms, such as fungi, in sufficient amounts and the required purities, also by the use of the genetic engineering methods which are presently known or may be developed in the future. 30 For example, if it is desired to produce the enzymes with other microorganisms, WO 2007/059955 PCT/EP2006/011231 -19- then the genetic information of a microorganism which has been found initially by extensive screening and which has been proven to be a suitable source of the enzyme with the desired properties can be transferred to a microorganism ° which is normally used for the production of enzymes. Also the modification of 5 the enzyme(s) and the production of the enzyme(s) by means of methods which are presently known or may be developed in the future in the area of industrial enzyme development and enzyme production, such as genetic engineering, is possible. The use and the manner of performing all these methods for developing and producing the enzyme(s) with the desired purities and activities and with 10 the desired properties, in particular with respect to the stability of the enzyme(s) at various pH values, regarding the optimum of the pH value, the stability at various temperatures and temperature optimum, are well known to a person skilled in the art. The explanations in chapter 2 (page 82 to page 130) of the textbook "Lebensmittel-Biotechnologie und Ernahrung" of Heinz Ruttloff, Jiirgen 15 Proll and Andreas Leuchtenberger, published by Springer Verlag 1997 (ISBN 3-540-61135-5) describe these methods in detail. These methods are also described in "Advances in Fungal Biotechnology for Industry, Agriculture, and Medicine" by Jan S. Tkacz, Lene Langeand (published in 2004, ISBN 0-306-47866-8), in "Enzymes in Industry: Production and Applications" by Wolfgang 20 Aehle (Editor), published in 2004, ISBN 3527295925 and in "Microbial Enzymes and Biotransformations" by Jose-Luis Barredo (Humana Press 2005, ISBN 1588292533). These documents are herewith incorporated into the patent application by reference. All this also applies to the enzymes mentioned below that can optionally be added to the agent according to the present invention. 25 The activity of 5-D-fructose dehydrogenase is defined in units (assay available e.g. from Sigma-Aldrich), whereby one unit is the amount of 5-D-fructose dehydrogenase that converts one micromole of D-fructose to 5-keto-D-fructose per minute at pH 4.5 and 37°C. Generally, the activity of 5-D-fructose dehydro-30 genase per dose unit should be between 10 and 5 million units, preferably be WO 2007/059955 PCT/EP2006/011231 -20- tween 25 and 2.5 million units and particularly preferably between 50 and 1 million units. In the case of the combination agent according to the present invention which 5 also contains glucose isomerase, the composition should contain glucose isomerase in an amount of 0.01 to 100,000 GIU, preferably of 0.05 to 10,000 GIU and particularly preferably of 0.1 to 1,000 GIU per dose unit. One unit of this enzyme is defined as a glucose isomerase unit (GIU). One GIU converts 1 g of glucose into fructose at a pH value of 6.0 and at a temperature of 37°C from a 10 solution of initially 10 % (percent by weight, i.e. 10 g of glucose + 90 g of water) in 5 minutes. The wide range of the above mentioned dosages may be explained by the fact that the agent according to the present invention can be applied for many uses, 15 such as the different categories of adiposity and its accompanying and resulting diseases, or simply the effort of persons of normal weight to limit the intake of calories for preventing weight gain. Furthermore, the different dosages also result from the fact that strongly varying amounts of fructose and glucose are administered to the body, depending on the respective food. 20 The agent according to the present invention may comprise one or more additional enzymes, such as invertase (syn. beta-fructofuranosidase or beta-fructosidase), lactase (syn. beta-galactosidase), maltase (syn. alpha-glucosidase), alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamy-25 lase, amyloglucosidase, cyclomaltodextrin glucantransferase (CGTase). These enzymes have the property of releasing fructose and/or glucose from fructose and/or glucose containing substances and foodstuffs - alone or in combination with one or more of these enzymes -, whereby the enzymes pullulanase and isoamylase also increase the efficiency of glucoamylase and beta-amylase. All 30 these enzymes are commercially available (e.g. BioCat Inc., Troy, USA or No- WO 2007/059955 PCT/EP2006/011231 -21 - vozymes A/S, Denmark or Amano Enzymes Inc., Japan or Sigma-Aldrich) and, up to now, have never been used in combination with 5-D-fructose dehydrogenase - alone or in combination with glucose isomerase - in the medical/pharmaceutical field, in particular not in the case of adiposity. Thus this 5 application discloses the first medical indication for 5-D-fructose dehydrogenase - alone or in combination with glucose isomerase - in combination with any or all of these enzymes. Examples for agents according to the present invention include: 5-D-fructose dehydrogenase in combination with invertase, or 5-D-fructose 10 dehydrogenase in combination with glucose isomerase and invertase, or 5-D-fructose dehydrogenase in combination with glucose isomerase and lactase and invertase, still further 5-D-fructose dehydrogenase in combination with glucose isomerase, Invertase, alpha amylase, beta amylase, glucoamylase, maltase, iso-amylase and pullulanase (combination of 9 enzymes), or 5-D-fructose dehy-15 drogenase in combination with glucose isomerase, alpha amylase, beta amylase, glucoamylase, maltase, iso-amylase and pullulanase as well as invertase and lactase (combination of 10 enzymes). For example, said invertase can release glucose and fructose from e.g. sucrose 20 and said lactase can release glucose from lactose. Beta-amylase breaks down e.g. 1,4-alpha bonds in starch, starting at the non-reducing end of the polysaccharide chain with cleaving of maltose, and glucose is released by the action of maltase on maltose. By the addition of one or more of these enzymes to the agent according to the present invention, the endogenic release of fructose 25 and/or glucose from fructose- and/or glucose-containing substances or foodstuffs, in particular from sucrose and starch, may also be promoted and accelerated, so that the conversion of fructose into 5-keto-D-fructose which is catalyzed by 5-D-fructose dehydrogenase and/or the conversion of glucose to fructose, which is effected by glucose isomerase, may occur earlier. Therefore, the addi-30 tion of one or more of these enzymes to the agent according to the present WO 2007/059955 PCT/EP2006/011231 -22- invention may have the benefit of reducing the required amount of 5-D-fructose dehydrogenase and glucose isomerase. The activity of invertase is measured in Sumner units (SU, assay available e.g. 5 from Bio-Cat Inc., Troy, Virginia, USA). An SU is defined as the amount of the enzyme which converts 1 mg of sucrose into glucose and fructose under standard test conditions within 5 minutes at 20°C and a pH value of 4.5. If the agent according to the present invention also contains invertase, the activity of the invertase per dose unit should be between 50 and 250,000 SU, preferably be-10 tween 100 and 150.000 SU and particularly preferably between 150 and 100,000 SU per dose unit. The activity of lactase is given in Food Chemical Codex (FCC) units (assay is published in the Food Chemical Codex, fifth edition, and also available e.g. from 15 Bio Cat Inc. Troy, Virginia or Amano Enzymes, Japan or from Sigma Aldrich). If the agent according to the present invention also contains lactase, the activity of the lactase per dose unit should be between 50 and 200,000 FCC units, preferably between 100 and 100,000 FFC units and particularly preferably between 150 and 50,000 FCC units. 20 The activity of maltase is defined in units, wherein one unit is the amount of maltase which will convert maltose to D-glucose at a rate of one milligram per minute at 37°C and a pH of 4.0 in a 10% maltose solution by weight. 25 Where the agent according to the present invention also contains maltase, the activity per dose unit should be between 100 and 100,000 units, preferably between 200 and 50,000 units and particularly preferably between 500 and 20,000 units. WO 2007/059955 PCT/EP2006/011231 -23- Also for the other enzymes mentioned, the standard test conditions and the way in which the enzyme activities are to be determined are known and can be read up by specialists in the field. 5 Insofar as one or more of the optional enzymes are added to the agent according to the present invention, they - as is the case for the 5-D-fructose dehydrogenase and the glucose isomerase - should be used in sufficient amounts so that they can develop a sufficient enzyme activity for the intended purpose, e.g. sufficient invertase, so that an amount of sucrose usually ingested with a normal 10 meal (e.g. 15 g) can be cleaved, and/or lactase, so that an amount of lactose usually ingested with a normal meal (e.g. 10 g) can be cleaved. The enzymes used can be for example in solid form, e.g. as crystalline or amorphous granules or powders, as a paste or as a liquid, as well as in other forms. 15 In some embodiments, the enzyme is a free enzyme. In other embodiments, the enzyme may e.g. be immobilized on substrate, which can be powderized if necessary before the enzyme is used in accordance with the invention. If the agent according to the present invention is added to a foodstuff before 20 eating or during production, the activity of 5-D-fructose dehydrogenase should be between 10 and 250,000 units, preferably between 25 and 150,000 units and particularly preferably between 50 and 100,000 units per gram fructose in the foodstuff. If the agent also contains glucose isomerase and the agent according to the present invention is added to a foodstuff before eating or during produc-25 tion, the activity of glucose isomerase should be between 0.01 and 20,000 units, preferably between 0.05 and 10,000 units and particularly preferably between 0.1 and 1000 units per gram glucose in the foodstuff. If the agent according to the present invention is added to a foodstuff before 30 eating or during production and if the agent contains 5-D-fructose dehydro- WO 2007/059955 PCT/EP2006/011231 -24- genase and glucose isomerase, the activity of 5-D-fructose dehydrogenase should be between 10 and 250,000 units, preferably between 25 and 150,000 units and particularly preferably between 50 and 100,000 units per gram of fructose and glucose combined contained in the foodstuff. 5 It may be advantageous to add an electron acceptor to the agent according to the present invention at e.g. a ratio (acceptor : substrate) of 1:1 to 1:1,000, preferably at a ratio of 1:2 to 1:200, particularly preferably at a ratio of 1:10 to 1:50. Examples of suitable acceptors which may be used include NAD+, 10 NADP+, FAD+, vitamins, such as vitamin C, vitamin E or vitamin A, ferricyanide, ketones, aldehydes, 2,6-dichlorophenolindophenol, phenazine methosulfate, nitroblue tetrazolium (including mixtures thereof), but are not limited thereto. The physiologically present electrolytes should be sufficient for the function of 15 the glucose isomerase. But it may also be advantageous to add electrolytes to the agent according to the present invention, e.g. in an amount of 0.0001 % to 0.1 % of the substrate (glucose). Examples of the electrolytes include, but are not limited to, MgS04, Na2C03, NaHC03, NaOH, Na2S04, MgC03, H2S04, NaS203, NaS205 (including 20 mixtures thereof). It may also be advantageous to add metal ions, in particular cations, such as Mn2+, Mg2+, Ca2+, Zn2+, Fe2+, Co2+ or Cu2+, including mixtures thereof, to the agent according to the present invention, namely preferably in a molar ratio of 25 10~6 to 10"2. For the above mentioned (xylose) glucose isomerase which is described by Yamanaka, in particular Mn2+ is a suitable cation. Capsule sizes mentioned below refer to the size definitions used by Capsugel Belgium BVBA, Bornem, Belgium. The size of the capsules should be chosen 30 according to the specific formulation of the agent. WO 2007/059955 PCT/EP2006/011231 -25- A composition according to the present invention for the production of capsules (for example of size 00) may consist of 370 mg of 5-D-fructose dehydrogenase with an activity of 90 units/mg and 100 mg of dicalcium phosphate per capsule. 5 Another example for a dosage form according to the present invention consists of capsules (size 1) that contain 110 mg of 5-D-fructose dehydrogenase with an activity of 500 units/mg as well as 50 mg of invertase with an activity of 200 SU units/mg as well as 50 mg of maltase with an activity of 200 units/mg and 90 mg 10 of maltodextrin. Another example for the dosage form according to the present invention consists of capsules of size 00 which contain 200 mg of 5-D-fructose dehydrogenase with an activity of 500 units/mg as well as 100 mg of invertase with an 15 activity of 200 SU units/mg as well as 150 mg of dicalcium phosphate. In the case of a combination agent in which 5-D-fructose dehydrogenase and glucose isomerase are used, a capsule of size 0 may contain 250 mg of 5-D-fructose dehydrogenase with an activity of 90 units/mg and 20 mg of glucose 20 isomerase with an activity of 1 GlU/mg and 50 mg dicalcium phosphate. A further example of a combination preparation with 5-D-fructose dehydrogenase and glucose isomerase for the production of capsules of size 00 may contain 370 mg of 5-D-fructose dehydrogenase with an activity of 90 units/mg, 25 30 mg of glucose isomerase with an activity of 1 GlU/mg and 70 mg of dicalcium phosphate. A further example of a combination preparation with 5-D-fructose dehydrogenase and glucose isomerase for the production of capsules of size 00 may 30 contain 110 mg of 5-D-fructose dehydrogenase with an activity of 500 units/g, WO 2007/059955 PCT/EP2006/011231 -26- 50 mg of glucose isomerase with an activity of 1 GlU/mg, 100 mg of invertase with an activity of 200 SU units/mg, 90 mg of lactase with an activity of 100 FCC units/mg and 120 mg of dicalcium phosphate. 5 A further example of a combination preparation with 5-D-fructose dehydrogenase and glucose isomerase for the production of capsules (e.g. of size 3) may consist of 55 mg of 5-D-fructose dehydrogenase with an activity of 1000 units/mg, 50 mg of glucose isomerase with an activity 1 GlU/mg and 55 mg of dicalcium phosphate per capsule. 10 A further example for a dosage form according to the present invention consists of capsules (size 00) that contain 165 mg of 5-D-Fructose dehydrogenase with an activity of 1000 units/mg, 150 mg of glucose isomerase with an activity of 1 GlU/mg and 155 mg of dicalcium phosphate per capsule. 15 The invention may for example contain between 10 and 5 million units of 5-D-fructose dehydrogenase per dose unit. In addition, suitable additives in the required amount may be used. The invention may, in addition, contain glucose isomerase, for example between 0.01 and 100,000 GIU (= glucose isomerase 20 units) per dose unit. The invention may be provided for medical purposes and non-medical purposes, e.g. as a pharmaceutical composition, medical device, foodstuff or special foodstuff. 25 With the agents according to the present invention the content of calories of carbohydrate containing food that can be utilized by the body can be reduced to such a degree that a marked weight loss can be achieved or a weight gain can be prevented despite the intake of carbohydrate rich food. The agents according 30 to the present invention are thus suitable for use in methods for the therapeutic WO 2007/059955 PCT/EP2006/011231 -27- treatment of the human or animal body in which a limitation or reduction of the intake of food calories originating from carbohydrates is intended, e.g. in the case of the therapy of diseases of the cardiovascular system (e.g. hypertension, coronary heart disease, venous insufficiency, heart failure, left-ventricular hyper-5 trophy, arteriosclerosis), of metabolic and hormonal function (e.g. diabetes mellitus type II, dyslipidemias, hyperuricemia, hyperlipoproteinemia), of the respiratory system (e.g. sleep apnea, Pickwickian syndrome), of the hepatobiliary system (e.g. fatty liver, cholecystolithiasis), of the locomotor system (e.g. gonarthrosis, heel spur, arthrosis of the ankle joint), of the skin (e.g. intertrigo, 10 hirsutism, striae), in the therapy of neoplasias (e.g. increased risk of endometrial, breast, cervical, gall bladder cancer, etc.), in the therapy of disorders of sexual function (e.g. reduced fertility, complications during birth), in the therapy of psychosocial problems (e.g. reduced self-confidence, social isolation, discrimination, problems with one's partner or at work) and other problems, such as 15 reduced mobility and staying power, increased risk during operations and more difficult examination conditions. All these diseases and health problems are often associated with adiposity. The agents according to the present invention are in particular suitable for use in 20 the case of adiposity and for the therapeutic treatment of adiposity. In the following claims, the term 'fructose equivalent-containing" refers to all substances and foodstuffs that contain fructose (a) as fructose per se, (b) in a form from which fructose can be released in the digestive tract (e.g. by cleavage 25 as fructose from a saccharide chain containing at least two saccharide monomers), (c) in a form that can be converted to fructose, e.g. as glucose per se, or (d) in a form that can be released in the digestive tract and converted to fructose, e.g. as a saccharide chain containing at least two saccharide monomers, at least one of which can be cleaved from the saccharide chain as glucose. 30 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> Received at IPONZ on 22 August 2011 -28- ln the following claims, the term "total fructose" refers to the total content of fructose in a foodstuff (a) as fructose per se, (b) in a form from which fructose can be released in the digestive tract (e.g. by cleavage as fructose from a saccharide chain containing at least two saccharide monomers), (c) in a form that can be converted to fructose, e.g. as 5 glucose per se, or (d) in a form that can be released in the digestive tract and converted to fructose, e.g. a saccharide chain containing at least two saccharide monomers, at least one of which can be cleaved from the saccharide chain as glucose. In the following claims, the term "effective fructose content" of an item refers to the 10 effective amount of total fructose in that item, taking into account the prior action of fructose converting enzymes that have been added to the item or the future action of fructose converting enzymes that have been added to the item. Thus, for example, a foodstuff having a given fructose content and having microencapsulated 5-D-fructose dehydrogenase incorporated therein will have a lower effective fructose content than a 15 foodstuff which lacks the microencapsulated 5-D-fructose dehydrogenase but is otherwise identical, since release of the 5-D-fructose dehydrogenase after ingestion will result in at least a portion of the fructose in the foodstuff being converted to 5-keto D-fructose. 20 Uses of 5-D-fructose dehydrogenase and compositions of matter containing 5-D-fructose dehydrogenase are also disclosed and claimed in our co-pending New Zealand patent application No 569117. Received at IPONZ on 18 October 2011 -29- Claims 1. A pharmaceutical composition comprising 5-D-fructose dehydrogenase in combination with one or more enzyme(s) selected from glucose isomerase. invertase, lactase, maltase. alpha-amylase, beta-amylase. glucoamylase. 5 pullulanase, isoamylase. amyloglucosidase and cyclomaltodextrin glucanotransferase: but excluding pharmaceutical compositions in which the sole said enzymes present are a combination of 5-D-fructose dehydrogenase and glucose isomerase. 2. A pharmaceutical composition according to claim 1 including one or more 10 enzyme(s) protected by a coating to be stable at pH values of less than 4. 3. A pharmaceutical composition according to claim 1 or claim 2 rm for oral administration. 4. A special foodstuff comprising 5-D-fructose dehydrogenase in combination with one or more enzyme(s) selected from glucose isomerase, invertase, 15 lactase, maltase. alpha-amylase. beta-amylase, glucoamylase. pullulanase, isoamylase. amyloglucosidase and cyclomaltodextrin glucanotransferase wherein said special foodstuff is selected from foodstuffs for particular nutritional uses, foods for special medical purposes, medical foods, food supplements, dietary supplements, dietetic food supplements, health foods, 20 nutraceuticals and food additives; but excluding special foodstuffs in which the sole said enzymes present are a combination of 5-D-fructose dehydrogenase and glucose isomerase. 5. The special foodstuff according to claim 4 including one or more enzyme(s) protected by a coating to be stable at pH values of less than 4. 25 6 The special foodstuff according to claim 4 or claim 5 in a form for oral administration. Received at IPONZ on 18 October 2011 — 3D— 7. A foodstuff comprising 5-D-fructose dehydrogenase, the foodstuff being selected from sweets, fruit preparations, jam, honey, chocolate and chocolate products, baked products, breads, pastas, vegetable dishes, potato dishes, ice cream, cereals, dairy products, glucose containing beverages, glucose 5 containing sauces, tomato ketchup and glucose containing sweeteners, provided that for dishes which are cooked or baked, the 5-D-fructose dehydrogenase has been mixed into or sprinkled onto the foodstuff after cooling down. 8. The foodstuff according to claim 7 comprising 5-D-fructose dehydrogenase in 10 combination with glucose isomerase, 9. The use of 5-D-fructose dehydrogenase, optionally in combination with one or more enzyme(s) selected from glucose isomerase. invertase, lactase. maltase, alpha-amylase, beta-amylase, glucoamylase. pullulanase. isoamylase, amyloglucosidase and cyclomaltodextrin glucanotransferase, for 15 the manufacture of a medicament for the curative or prophylactic treatment of adiposity. 10. The use according to claim 9, wherein adiposity is accompanied by disturbances of the cardiovascular system and/or of the metabolic and hormone based function and/or of the respiratory system and/or of the 20 hepatobiliary system and/or disturbances of the locomotor system and/or diseases of the skin and/or neoplasias and/or disorders of the sexual function and/or psychosocial problems and/or reduced mobility and staying power and/or an increased operation risk and/or more difficult examination conditions 25 11. The use according to claim 10. wherein: (a) the disturbances of the cardiovascular system are hypertension, coronary heart disease, venous insufficiency, heart failure, left-ventricular hypertrophy and/or arteriosclerosis; or Received at IPONZ on 18 October 2011 - 31- (b) the disturbances of the metabolic or hormonal function are diabetes mellitus type II, dyslipidemias, hyperuricemia and/or hyperlipoproteinemia; or (c) the disturbances of the respiratory system are sleep apnea and/or the Pickwickan syndrome; or (d) the disturbances of the hepatobiliary system are fatty liver and/or cholecystolithiasis, or (e) the disturbances of the locomotor system are gonarthrosis. heel spur and/or arthrosis of the ankle joint; or (f) the disturbances of the skin are intertrigo, hirsutism and/or striae; or (g) in the case of neoplasias these are endometrial, mama, cervix and/or gall bladder carcinoma, or (h) the disorders of the sexual function are reduced fertility and/or an increased risk of complications in the case of birth; or (i) the psychosocial problems are reduced self-confidence, social isolation, discrimination and/or, problems with the partner and/or at the job. The use of 5-D-fructose dehydrogenase, in combination with one or more enzyme(s) selected from glucose isomerase, invertase, lactase, maltase. alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and cyclomaltodextrin glucanotransferase for the manufacture of a medicament for (i) lowering the bioavailability of fructose and/or glucose in the human or animal body; or (ii) lowering the content of fructose and/or glucose in a foodstuff: or (iii) for lowering the usable calorie content of food; but excluding the use of a combination consisting of the enzymes 5-D-fructose dehydrogenase and glucose isomerase for use in lowering the bioavailability of fructose and/or glucose in the human or animal body Received at IPONZ on 18 October 2011 -32- 13. The use according to one or more of claims 9 to 12. wherein the medicament is in a form for oral administration; and optionally wherein the enzymes are protected by a coating to be stable at pH values of less than 4 14. The use according to claim 13, wherein the enzymes are protected by a 5 coating to be stable at pH values of less than 3. 15. The use according to one or more of claims 9 to 14, according to which at least the two enzymes 5-D-fructose dehydrogenase and glucose isomerase are present. 16. A mammalian-ingestible composition of matter which comprises 5-D-fructose 10 dehydrogenase and one or more members of the group consisting of lactase, alpha-amylase, beta-amylase, glucoamylase. pullulanase, isoamylase, amyloglucosidase and cyclomaltodextrin glucantransferase (CGTase); optionally in combination with glucose isomerase and/or invertase and/or maltase. 15 17. A mammalian-ingestible composition of matter according to claim 16, wherein (a) said mammalian-ingestible composition of matter is a human ingestible composition of matter; or (b) said mammalian-ingestible composition of matter is a non-human ingestible composition of matter. 18. A composition of matter according to claim 16 or claim 17 which i: 20 human dietary supplement or a pharmaceutical composition; or (b) an animal dietary supplement or a veterinary composition; and wherein said composition of matter optionally further comprises at least one pharmaceutically or dietarily or veterinarily acceptable carrier or excipient. 19. A composition of matter according to claim 16 or claim 17 which is a special 25 foodstuff, wherein said special foodstuff is selected from foodstuffs for particular nutritional uses, foods for special medical purposes, medical foods, food supplements, dietary supplements dietetic food supplements, health foods, nutraceutical and food additives, and wherein said composition of Received at IPONZ on 18 October 2011 — 33— matter optionally further comprises at least one pharmaceutically or dietarily acceptable carrier or excipient. 20 A composition of matter according to claim 18 or claim 19, wherein said composition of matter is in the form of (a) a capsule or tablet; or (b) a gelcap. 5 21. A composition of matter according to claim 18 or claim 19, wherein said composition of matter is selected from fa) granules or pellets; (b) a solution; (c) a gel or suspension; (d) a liquid (e! a powder; (e) a gel; or (f) a suspension; or (g) a powder. 22. A composition of matter according to claim 20 which is in the form of a 10 capsule or tablet 23. A composition of matter according to any of claii to 22, wherein said 5-D-fructose-dehydrogenase is not contained in an inorganic-based sol-gel biocompatible matrix. 24. A mammalian-ingestible composition of matter according to any one of 15 claims 16 to 23, wherein said member is lactase, and said composition of matter is in unit dosage form and; (a) each dosage unit contains 50 to 200,000 FCC units of lactase activity per dose unit; or (b) each dosage unit contains 100 to 100,000 FCC units of lactase activity per dose unit; or (c) each dosage unit contains 150 to 50,000 units of lactase activity per dose unit. 20 25. A composition of matter according to any of claims 16 to 24, wherein: (a) the fructose dehydrogenase constitutes between 5 and 99.9% by weight of the composition of matter; or (b) the fructose dehydrogenase constitutes between 10 and 80% by weight of the composition of matter; or (c) the fructose dehydrogenase constitutes between 25 and 60% by weight of the composition 25 of matter. Received at IPONZ on 18 October 2011 -34- 26. A composition of matter according to any of claims 16 to 25, wherein said composition of matter is in unit dosage form and said unit dosage contains: (a) between 10 and 5 million units of 5-D-fructose dehydrogenase activity; or (b) between 25 and 2 b million units of 5-D-fructose dehydrogenase activity: or (c) 5 between 50 and 1 million units of 5-D-fructose dehydrogenase activity. 27. A composition of matter according to any of claims 16 to 26. wherein said composition of matter comprises a coating which dissolves in an aqueous medium at a pH of between 3.0 and 8.0; and optionally: id coating does not dissolve in an aqueous medium at a pH of below 3.0; or (b) said coating 10 does not dissolve in an aqueous medium at a pH below 4.0: and/or (c) said coating does not dissolve in an aqueous medium at a pH above 6.5; and/or (d) said coating does not dissolve in an aqueous medium at a pH above 6.0. 28 A composition of matter according to any of claims 16 to 26. wherein said composition of matter is a slow-release or extended-release formulation; and 15 optionally wherein said slow-release or extended-release formulation comprises a slow-release or extended-release coating 29. A composition of matter according to any of claims 16 to 28. wherein said composition of matter further comprises a further enzyme which is capable of cleaving fructose or glucose from a sugar that contains at least two 20 saccharide monomers 30. A composition of matter according to claim 29. wherein said further enzyme is invertase or maltase. 31. A composition of matter according to claim 29, wherein: (a) said further enzyme is invertase, said composition of matter is in unit dosage form, and (i) 25 each unit dosage contains between 50 and 250.000 Sumner units of invertase activity, or (ii) each unit dosage contains between 100 and 150,000 Sumner units of invertase activity, or (iii) each unit dosage contains between 150 and 100,000 Sumner units of invertase activity; or (b) said further enzyme is maltase. said composition of matter is in unit dosage form, and (i) each unit Received at IPONZ on 18 October 2011 -35— dosage contains between 100 and 100,000 units of maltase activity or (ii) each unit dosage contains between 200 and 50,000 units of maltase activity, or (iii) each unit dosage contains between 500 and 20,000 units of maltase activity 5 32. A composition of matter according to claim 30 or claim 31, wherein said composition of matter comprises both invertase and maltase. 33. A composition of matter according to any one of claims 16 to 32. wherein said composition of matter further comprises a glucose isomerase; and optionally wherein said composition of matter is in unit dosage form and; (a) each 10 dosage unit contains 0.01 to 100,000 units of glucose isomerase activity per dose unit; or (b) each dosage unit contains 0.05 to 10,000 units of glucose isomerase activity per dose unit; or (c) each dosage unit contains 0.1 to 1.000 units of glucose isomerase activity per dose unit; and further optionally wherein said glucose isomerase is a xylose isomerase. 15 34. A composition of matter according to claim 16 which is a foodstuff; and optionally wherein the amount or concentration of the fructose dehydrogenase in said foodstuff is greater than the naturally occurring concentration or amount of the fructose dehydrogenase in said foodstuff. A composition of matter according to claim 34, wherein: tid foodstuff is a foodstuff which has been baked; or (b) said foodstuff is a foodstuff which has been cooked; or (c) said foodstuff is a liquid, paste or broth; and/or (d) the fructose dehydrogenase is present in microencapsulated form. 36. A mammalian-ingestible composition of matter which is adapted for oral ingestion and comprises 5-D-fructose dehydrogenase, optionally in 25 combination with a further enzyme or mixture of enzymes selected from invertase, maltase, a glucose isomerase, lactase, alpha-amylase. beta-amylase, glucoamylase, pullulanase. isoamylase. amyloglucosidase and cyclomaltodextrin glucantransferase (CGTase) or a mixture thereof; wherein the composition of matter is in the form of: 35. 20 Received at IPONZ on 18 October 2011 -36- (a) a tablet, or (b) granules; or (c) a powder packaged in single dosage amounts; or (d) a liquid other than a foodstuff, wherein the liquid is in the form of a 5 solution or drops; or (e) a gel. 37. - A mammalian-ingestible composition of matter according to claim 36 which is in liquid form and wherein the liquid form is a solution 38. A mammalian-ingestible composition of matter according to claim 36 which is 10 in liquid form and wherein the liquid form is in the form of drops. 39. A mammalian-ingestible composition of matter according to claim 36 which is in powder form and is packaged in single dosage amounts. 40. A mammalian-ingestible composition of matter according to claim 37, wherein the single dosage amount is packaged in single bags. 15 41 A mammalian-ingestible composition of matter according to claim 36 which is in powder form and is provided in a dosing dispenser. 42. A composition of matter which is an animal dietary supplement or a veterinary composition comprising 5-D-fructose dehydrogenase. 43. A composition of matter according to claim 42 which further comprises at least 20 one veterinarily acceptable carrier or excipient. 44. A composition of matter according to claim 42 or 43, wherein said composition of matter contains said enzyme in microencapsulated form. Received at IPONZ on 18 October 2011 - 37- 45. A composition of matter according to any of claims 42 to 44. wherein said composition of matter is in the form of (a) a capsule or tablet; or (b) granules or pellets; or (c) a solution; or (d) a liquid; or (e) a gel or suspension; or (f) a gelcap; or (g) a powder 5 46 A composition of matter according to any of claims 42 to 45, wherein the 5-D-fructose dehydrogenase constitutes (a) between 5 and 99.9% by weight of the composition of matter; or (b) between 10 and 80% by weight of the composition of matter; or (c) between 25 and 60% by weight of the composition of matter. 10 47. A composition of matter according to any of claims 42 to 45, wherein said composition of matter is in unit dosage form and said unit dosage contains (a) between 10 and 5 million units of 5-D-fructose dehydrogenase activity: or (b) between 25 and 2.5 million units of 5-D-fructose dehydrogenase activity; or (c) between 50 and 1 million units of 5-D-fructose dehydrogenase activity. 15 48. A composition of matter according to any of claims 42 to 47 wherein said composition of matter comprises a coating which dissolves in an aqueous medium at a pH of between 3.0 and 8.0. 49. A composition of matter according to claim 48, wherein: (a) said coating does not dissolve in an aqueous medium at a pH of 20 below 3.0: or (b) said coating does not dissolve in an aqueous medium at a pH below 4.0; or (c) said coating does not dissolve in an aqueous medium ; above 6.5; or 25 (d) said coating does not dissolve in an aqueous medium at a pH above 6.0. Received at IPONZ on 18 October 2011 -38- 50. A composition of matter according to any of claims 42 to 49. wherein said composition of matter is a slow-release or extended release formulation. 51. A composition of matter according to claim 50, wherein said slow-release or extended-release formulation comprises a slow-release or extended-release 5 coating 52. A composition of matter according to any of claims 42 to 51, wherein said composition of matter further comprises a second enzyme. 53. A composition of matter according to claim 42, wherein said second enzyme is capable of cleaving fructose or glucose from a sugar that contains at least two 10 saccharide monomers. 54. A composition of matter according to claim 53, wherein said second enzyme is invertase or maltase. 55. A composition of matter according to any of claims 42 to 54. wherein said composition of matter further comprises an additional enzyme that converts 15 D-glucose to D-fructose, and said additional enzyme is a glucose isomerase 56. A composition of matter according to claim 55, wherein said glucose isomerase is a xylose isomerase. 57. A composition of matter according to any of claims 42 to 56, wherein said composition further comprises one or more members of the group consisting 20 of lactase, alpha-amylase, beta-amylase, glucoamylase, pullulanase, isoamylase, amyloglucosidase and cyclomaltodextrin glucantransferase (CGTase). 58. A composition of matter comprising the enzyme 5-D-fructose dehydrogenase admixed with a mammalian-ingestible substance wherein said 5-D-fructose 25 dehydrogenase is microencapsulated. 59 A composition of matter according to claim 58 which is human ingestible Received at IPONZ on 18 October 2011 - 39- 60. A pharmaceutical composition according to claim 2, or a foodstuff according to claim 5, including one or more enzymes protected by a coating which is stable at pH values of less than 3 61. A foodstuff according to claim 7 or 9 wherein the fruit preparation is apple puree, the baked products are biscuits and cakes, and the dairy products are fruit yoghurt and pudding. 10 Pro Nature! Gesellschaft fur Gesunde Ernahrung MBH By the attorneys for the Applicant Aliens Arthur Robinson Patent & Trade Marks Attorneys Per: X 15 Reference has been directed, in pursuance of section I6<11 of the Patents Act 1953, to patent no 569117. </div>