MX2008006327A - Agent for use in the case of fructose intolerance - Google Patents
Agent for use in the case of fructose intoleranceInfo
- Publication number
- MX2008006327A MX2008006327A MXMX/A/2008/006327A MX2008006327A MX2008006327A MX 2008006327 A MX2008006327 A MX 2008006327A MX 2008006327 A MX2008006327 A MX 2008006327A MX 2008006327 A MX2008006327 A MX 2008006327A
- Authority
- MX
- Mexico
- Prior art keywords
- composition
- fructose
- technique according
- enzyme
- technique
- Prior art date
Links
- 206010072104 Fructose intolerance Diseases 0.000 title claims abstract description 45
- 239000003795 chemical substances by application Substances 0.000 title abstract description 63
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 claims abstract description 295
- 239000000203 mixture Substances 0.000 claims abstract description 183
- 239000005715 Fructose Substances 0.000 claims abstract description 131
- 102000004190 Enzymes Human genes 0.000 claims abstract description 104
- 108090000790 Enzymes Proteins 0.000 claims abstract description 104
- 108090000854 Oxidoreductases Proteins 0.000 claims abstract description 76
- 102000004316 Oxidoreductases Human genes 0.000 claims abstract description 76
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 65
- 239000008103 glucose Substances 0.000 claims abstract description 64
- 108010051210 beta-Fructofuranosidase Proteins 0.000 claims abstract description 41
- 235000011073 invertase Nutrition 0.000 claims abstract description 41
- 108090000769 Isomerases Proteins 0.000 claims abstract description 40
- 102000004195 Isomerases Human genes 0.000 claims abstract description 40
- 239000001573 invertase Substances 0.000 claims abstract description 39
- 102100008175 MGAM Human genes 0.000 claims abstract description 35
- 101700023572 AGL Proteins 0.000 claims abstract description 34
- 101710012512 CPM1 Proteins 0.000 claims abstract description 34
- 101700010794 MAL12 Proteins 0.000 claims abstract description 34
- 101700025925 MAL32 Proteins 0.000 claims abstract description 34
- 101700012066 MAL62 Proteins 0.000 claims abstract description 34
- 101710026950 MGAM Proteins 0.000 claims abstract description 34
- 101710011129 Mal-B1 Proteins 0.000 claims abstract description 34
- 101700023638 aglA Proteins 0.000 claims abstract description 34
- 101700009216 malA Proteins 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 239000000126 substance Substances 0.000 claims abstract description 15
- 210000001035 Gastrointestinal Tract Anatomy 0.000 claims abstract description 11
- 235000013305 food Nutrition 0.000 claims description 112
- 238000000034 method Methods 0.000 claims description 100
- 229960001031 Glucose Drugs 0.000 claims description 65
- 230000000694 effects Effects 0.000 claims description 36
- 238000004519 manufacturing process Methods 0.000 claims description 25
- AWQIYVPBMVSGCL-PHDIDXHHSA-N 5-dehydro-D-fructose Chemical compound OCC(=O)[C@@H](O)[C@H](O)C(=O)CO AWQIYVPBMVSGCL-PHDIDXHHSA-N 0.000 claims description 18
- 239000002775 capsule Substances 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 14
- 239000011248 coating agent Substances 0.000 claims description 13
- 238000000576 coating method Methods 0.000 claims description 12
- 235000005911 diet Nutrition 0.000 claims description 12
- 230000037406 food intake Effects 0.000 claims description 12
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- 230000004060 metabolic process Effects 0.000 claims description 9
- 230000035786 metabolism Effects 0.000 claims description 9
- 229960000304 Folic Acid Drugs 0.000 claims description 7
- 241000282412 Homo Species 0.000 claims description 7
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- 235000019152 folic acid Nutrition 0.000 claims description 7
- 239000011724 folic acid Substances 0.000 claims description 7
- 210000000936 Intestines Anatomy 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 102000027721 Fructose-Bisphosphatase Human genes 0.000 claims description 5
- 108010017464 Fructose-Bisphosphatase Proteins 0.000 claims description 5
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- 150000002500 ions Chemical class 0.000 claims description 5
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- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- BAWFJGJZGIEFAR-NNYOXOHSSA-N Nicotinamide adenine dinucleotide Chemical group NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 claims description 4
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- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
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- YAGKRVSRTSUGEY-UHFFFAOYSA-N Ferricyanide Chemical compound [Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] YAGKRVSRTSUGEY-UHFFFAOYSA-N 0.000 claims description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Chemical compound C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 2
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- ZKJOXOJMGXFSPF-QYZPTAICSA-N [[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate;hydrate Chemical compound O.NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 ZKJOXOJMGXFSPF-QYZPTAICSA-N 0.000 claims description 2
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- 239000011719 vitamin A Substances 0.000 claims description 2
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- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 3
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Abstract
The present invention refers to an agent for use in the case of fructose intolerance and any form of impairment and affliction of health and well being which is caused by the administration of fructose or fructose containing foodstuffs or by the release of fructose in the digestive tract of humans or animals from other substances, such as e.g. sucrose. The agent according to the invention comprises 5-D-fructose dehydrogenase, optionally in combination with invertase and/or maltase and/or glucose isomerase, which enzyme or combination of enzymes is/are used in the medical field for the first time. Preferably the agent is in the form of a pharmaceutical composition which is useful for treatment of fructose intolerance.
Description
AGENT FOR USE IN CASE OF INTOLERANCE TO FRUCTOSE
Description of the Invention The present invention relates to an agent for use in the case of fructose intolerance. In the sense of this patent application, fructose intolerance means not only fructose intolerance and medically defined fructose metabolism disorders (additional details below), but any form of impairment and affliction of health and well-being that is caused by the administration of fructose or food products containing fructose or by the release of fructose in the digestive tract of humans or animals of other substances, such as for example sucrose. In the context of this patent application, the terms food and food products are used as synonyms. They mean that they also include food in the sense of the animal food product. The term "special food product" is defined below and has a particular meaning according to the invention. Fructose is a ketohexose and an important ingredient of the food that provides energy. It is present as a component of many di- and oligosaccharides, but also as free fructose, or as both in numerous food products. Fructose is contained in the product
food, such as fruits and fruit juices in high amounts, but in particular also in sucrose which is divided into fructose and glucose in the body. Next, the 'fructose content' should mean all substances and food products that either contain fructose in pure form or from which fructose can be released into the digestive tract. In contrast to glucose, fructose is assimilated into the cells of the mucosa of the small intestine by diffusion facilitated by the carrier. Enzymatic degradation begins in the liver by the action of adenosine triphosphate-dependent fructo-kinase (ATP), where fructose reacts with fructose 1-phosphate. In the liver and kidneys, fructos¾ 1-phosphate is separated into glycerin aldehyde and dihydroxyacetone phosphate by aldolase B. Three different disorders of fructose metabolism are known, mainly hereditary fructose intolerance, intolerance to intestinal fructose and lack of fructose 1,6 diphosphatase. In addition, fructosuria is known, so it does not need to be treated according to the present knowledge. Hereditary fructose intolerance (HFI) is caused by a lack of aldolase B, an enzyme that is present in the intestinal mucosa, in the liver, in the lymphocytes and in the kidneys. Normally, this enzyme degrades the intermediate fructose fructose 1-phosphate to fructose 1,6-bisphosphate. In
the case of absence of aldolase B, results in an accumulation of fructose 1-phosphate, and due to the inhibition of glycogen degradation and hypoglycemia of severe gluconeogenesis appears, associated with the manifestation of sweat, tremor, vomiting and cramps after the absorption of fructose. In an unknown way, acidosis, kidney lesions and aminoaciduria can occur. In infants, there is the danger of hemorrhaging to sudden death. Intestinal fructose intolerance exhibits other symptoms. It is widespread and occurs more frequently, particularly in Western industrialized nations. Intestinal fructose intolerance is caused by a disorder of fructose resorption as a result of the weakening of transport processes in the mucosa of the small intestine. The patient shows pain / confused abdominal symptoms and as a result of the bacterial degradation of the carbohydrates which have been transferred in the colon increased the production of intestinal gas. The discomfort includes, for example, feeling bloated, flatulence, stomach pain such as cramps, watery diarrhea and noises in the intestines. Frequently, an incorrect diagnosis of irritable bowel is made. The lack of fructose 1, 6-diphosphatase is a deficiency of this dominant enzyme in the path of gluconeogenesis. This deficiency causes an increase in the level of lactate in the blood after the ingestion of fructose, and hypoglycemia in the case
of an empty stomach with lactacidosis, cramps of muscular hypotonia and coma. Through an adiposis of the liver, hepatomegaly can also occur. Not every fructose metabolism disorder necessarily results in severe fructose intolerance. However, even in the case of mild fructose metabolism disorders, health or wellness conditions can often be observed, which until now could only be influenced by a change in diet. Also, an excessive intake of food containing fructose can result in a health condition. Until now, the symptoms and conditions mentioned above could be avoided only by adhering to a diet free of fructose-, sucrose-, sorbitol-. However, maintaining such a diet is very difficult for patients, since fructose is contained in all fruits and many vegetables and is used extensively in the food industry as a sweetener. Also all food products that contain, for example, sucrose (house sugar) have to be avoided. It is not only difficult to stick to a corresponding diet - in the case of hereditary fructose intolerance, even a very strict diet - it is also extremely unfavorable with respect to the physiology of nutrition and significantly affects the quality of life of patients. Patients and experts in the art (eg doctors, medical specialists,
nutrition scientists, nutrition consultants, special journalists, etc.) have assumed for decades that there is no alternative but to stick to a diet. Research aimed at finding an alternative to maintain a diet has not been successful. An agent that would allow this to be possible to avoid maintaining a diet, allowing the intake of fructose contained in the food, would thus solve the urgent need of many patients that has existed for decades. A strong prejudice in the technique and by the patients would be overcome, leading to a dramatic improvement of the possibilities of therapy and nutrition in the case of fructose intolerance, since there is, with the exception of the diet, simply available therapy. Such an agent would also stop the unsuccessful efforts so far of persons skilled in the art of allowing patients to enjoy a normal diet, including foods containing fructose, without discomfort. The importance of such an agent becomes evident if the most severe and dangerous consequences for the health of patients with hereditary fructose intolerance are considered in the event that they, for example, ingest fructose without knowledge, inadvertently or unintentionally. This would be even more valid for an agent that also has no negative side effects for health. Thus, it is an object of the present invention to provide an effective agent for use in the case of mild conditions of fructose metabolism as well as in cases of intolerance
to hereditary and intestinal fructose and to the lack of fructose 1,6-diphosphatase, especially to allow the ingestion of food products containing fructose even in the case of fructose intolerance. Furthermore, it is an object of the invention to allow patients of fructose intolerance to eat foods that they had to avoid until now due to their fructose content. In addition, an agent will be provided, which can reduce or eliminate the occurrence of symptoms of fructose intolerance after the ingestion of fructose. These objects are solved by the subject matter as described in claims 1 to 139. The object of the invention is an agent that can solve all the problems described above. The agent comprising 5-D-fructose dehydrogenase (without fructose 5-dehydrogenase). The agent according to the present invention can facilitate the conversion of fructose in the feed into 5-keto-D-fructose via dehydrogenation. In this way, it has changed in such a way that it is not available for bacterial metabolism, which is characterized by fermentation in the intestine, nor can an accumulation of fructose 1-phosphate in the liver or elsewhere occur. Thus, an increase in the level of lactate in the blood can be avoided, too. The invention thus provides compositions and methods that can be used to allow patients of fructose intolerance to ingest fructose-containing food products.
Another additional objective of the present invention is an agent that reduces the bioavailability of fructose in the human or animal body with the help of 5-D-fructose dehydrogenase.
In addition, an object of the invention is an agent for use in the case of metabolism of the affected fructose, including fructose intolerance, which contains a compound that effects the dehydrogenation of fructose to 5-keto-D-fructose. This conversion can be achieved, for example, enzymatically by a 5-D-fructose dehydrogenase. Preferably, the agent according to the invention comprises a 5-D-fructose dehydrogenase. Therefore, an object of the invention is in particular an agent for use in the case of fructose intolerance comprising a 5-D-fructose dehydrogenase. Another objective of the invention is the use of 5-D-fructose dehydrogenase in the case of an affected fructose metabolism, including fructose intolerance. According to the present invention, a 5-D-fructose dehydrogenase can also be used to lower the fructose content in a food product. In the context of this application a 5-D-fructose dehydrogenase is an enzyme that can catalyze the dehydrogenation of fructose to 5-keto-D-fructose. A possible production method for a 5-D-fructose dehydrogenase for example is 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. In the context of this application food products are food products for particular nutritional uses, foods for special medical purposes, food supplements, dietary supplements, dietary food supplements, health foods, natural foods and additives. In the context of this application the term "food product" means that it includes special food products as used herein1; where applicable. The invention allows the easy conversion of fructose into a food product in a form that can avoid the problems associated with fructose intolerance. Thus, the invention also allows patients of fructose intolerance to eat foods that they have to avoid until this time due to the fructose content of these foods. According to the present invention, 5-D-fructose dehydrogenase is further described for use in medicine, for example as a pharmaceutical composition. Accordingly, the subject of the invention includes a product that can be 5-D-fructose dehydrogenase or can comprise this enzyme for use in a medical treatment. In particular, a method for the therapeutic treatment of the human or animal body is
treaty. In the context of this invention, a pharmaceutical composition is a product, in particular a substance or mixture of substances, suitable for use in the surgical or therapeutic treatment of the human or animal body and for diagnostic methods that are performed on the body human or animal In the context of this application the pharmaceutical compositions therefore means to include, for example, products, in particular substances or mixtures of substances, which are meant or suitable for curing, alleviating, preventing or detecting fructose intolerance. The term "treating" when used in connection with the foregoing disorders includes the improvement, prevention or alleviation of symptoms and / or effects associated with these disorders and includes the prophylactic administration of an enzyme or a mixture thereof to decrease the probability or seriousness of the condition. According to another aspect, the present invention provides a food product comprising 5-D-fructose dehydrogenase. Still further, the present invention provides a food containing a sufficient amount of 5-D-fructose dehydrogenase to convert fructose to 5-keto-D-fructose. Such a food product can advantageously be produced for example by a process for treating a food product where the food product is contacted with the 5-D-fructose dehydrogenase under such
conditions, that the enzyme is capable of converting fructose into 5-keto-D-fructose. Such a food product has a reduced fructose content compared to the untreated food product and is therefore for the first time suitable for consumption in case of fructose intolerance. A food product can be produced for example by a method where a 5-D-fructose dehydrogenase is added to the food product in such a way that the dehydrogenation effect of 5-D-fructose dehydrogenase begins only after the food is ingested. Such a food product containing 5-D-fructose dehydrogenase has the same taste as an untreated food. Therefore, for the first time such foods are suitable for consumption in the case of fructose intolerance due to the reduction of the fructose content that occurs after ingestion. According to another aspect of the present invention, a medical device comprising 5-D-fructose dehydrogenase is provided. Still further, a medical device comprising 5-D-fructose dehydrogenase is provided in an amount that is effective for the conversion of fructose to 5-keto-D-fructose. The invention will now be described with respect to different aspects thereof in more detail. With respect to the meaning of the term "agent", in the following it should be understood to include a food product, a product
special food, a medical device or a pharmaceutical composition. 5-D-Fructose Dehydrogenase is a substance that has been known for almost 40 years without being used for anything other than analytical purposes. Accordingly, it was never used in the medical / pharmaceutical field, particularly not for the therapeutic treatment of the human or animal body or for diagnostic purposes in the human or animal body and very particularly not in the case of disorders of fructose metabolism in humans or animals. Thus, the present invention directs the first medical indication for 5-D-fructose dehydrogenase. The agent according to the present invention can be taken orally before the foods, preferably immediately before the food, together with a food or immediately after the food so that it can exert its dehydrogenation effect on the fructose in the pulp of the food. The agent can contain the enzyme without other additives. However, it is preferable that the agent according to the present invention also contains the additives which are, for example, pharmaceutically acceptable ingredients and / or acceptable ingredients for food products, such as, for example, supplements, binders, stabilizers, preservatives, flavorings, etc. . Such additives are conventional and well known for the production of
pharmaceutical compositions, medical devices, food products, and special food products, and those skilled in the art know which additives are in which quantities are suitable for certain dosage forms. Particularly preferable, the agent according to the present invention may contain additives, such as dicalcium phosphate, lactose, modified starch, microcrystalline cellulose, maltodextrin and / or fibersol. It may be advantageous to add to the agent according to the invention an electron acceptor, for example in an amount of 1: 1 to 1: 1000 (proportion of the acceptor: substrate), preferably 1: 2 to 1: 200, more preferred in one amount from 1:10 to 1:50. Examples of suitable acceptors are, but are not limited to, NAD +, NADP +, FAD +, vitamins, such as for example vitamin C, E or A, ferricyanide, ketones, aldehydes, 2,6-di-chloro-phenolindophenol, Phenazine metasulfate, nitroblue tetrazolium and mixtures of such acceptors. The agent according to the present invention can also be added to a food product before ingestion. It can even be added to the food product in the production stage for the purpose of developing its effect after the ingestion of the food product. This can be achieved, for example, by microencapsulation. With this, the content of the usable fructose of the food product can be reduced without altering the flavor of the food product in an unfavorable manner. Therefore, the agents according to this
invention may comprise the 5-D-fructose dehydrogenase which will be released, or will be rendered effective by other means, only in the digestive tract of a human or animal, in particular in the stomach or small intestine. Therefore, the invention can be used, for example, in the production of sweets, fruit preparations (for example applesauce), jelly, honey, chocolate and chocolate products, baked goods (for example cookies and cakes), breads , pastas, vegetable dishes, potato dishes, ice cream, cereals, dairy products (for example fruit yogurt and pudding), fructose-containing beverages, sauces containing fructose (for example tomato sauce) and sweeteners containing fructose. For the dishes that are cooked or baked, the agent according to the present invention could for example be mixed in or sprinkled on these after cooling. Since fructose is used as a sweetener in high amounts in food products for diabetics, it is beneficial to add the agent according to the present invention to such a food before eating or already in the production stage. This allows diabetics intolerant to fructose the intake of diabetic foods, such as the aforementioned food products in a convenient form for diabetics (diabetes food). The agent according to the present invention can also be added to a food product to exert its effect on the
fructose that originates from another food after ingestion. The agent may for example be added to a spreads meal so that the reduction of the fructose contained in the bread occurs after eating the bread with the food spread on it without affecting the taste of the bread. Another example would be mixtures of species. The agent according to the present invention can also be used in immobilized form. This is particularly useful for the treatment of liquid food products. For example, 5-D-fructose dehydrogenase can be embedded in a matrix that is permeable to fructose: When a liquid food product containing fructose flows past the matrix containing the enzyme, then the fructose is extracted from the food product by the action of the enzyme and converted to 5-keto-D-fructose. The subject of the present invention are also the agents containing 5-D-fructose dehydrogenase in addition to other active ingredients. The agent can be formulated in any way that is convenient for the desired administration route. A preferred route of administration is oral administration. For oral administration, the agent can be formulated, for example, in the form of capsules (coated or uncoated) containing powder, coated or non-coated granules, granules or micro- / mini-tablets or in the form of tablets (coated or uncoated). -dressed)
Pressed with powder, coated or non-coated granules, dragees or micro- / mini-tablets. The agent can also be formulated, for example, in the form of gel capsules or in liquid form as a solution, drops, suspension or gel. The agent can also be formulated, for example, as a wet or dry oral supplement. The formulation of the agent according to the present invention as a powder is particularly convenient for mixing with the food product. The powder can be sprinkled in a meal or mixed in a pulp or drink. It is particularly beneficial if the agent offered as bulk powder is packaged in amounts of a single dose, for example, in capsules or single bags, or if it is provided in a dose dispenser. For oral administration, 5-D-fructose dehydrogenase may be used with acceptable excipients and / or carriers. The term "acceptable carrier" refers to a carrier for pharmaceutical use, which delivers the active ingredient to its site of marked activity without causing significant damage to the treated human or animal. However, the exact form of the carrier is not of substantial importance. The total content of the carrier within an agent containing the 5-D-fructose dehydrogenase is preferably between 5 and 99.9% by weight of the composition, more preferably between 10 and 80%, more preferably between 25 and 60%. Suitable excipients and / or carriers include but
are not limited to 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, methylcellulose, povidone, carboxymethyl cellulose, corn starch, modified starch, fibersol, gelatin, hydroxypropylmethylcellulose and the like (including mixtures thereof). Preferred carriers include calcium carbonate, magnesium stearate, maltodextrin, dicalcium phosphate, modified starch, microcrystalline cellulose, fibersol, gelatin, hydroxypropylmethyl cellulose and mixtures thereof. The different ingredients and the excipient and / or carrier can be mixed and formed into the desired form using common methods well known to the person skilled in the art. The administration form according to the present invention which is suitable for the oral route, such as for example tablet or capsule, can 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 about 3.0 to 8.0, preferably at a pH value of 3.0 to 6.5 and particularly preferably at a pH value of 4.0 to 6.0. An optionally used coating must be in accordance with the optimum pH of the enzyme used and its stability at the pH values at which the formulation will be exposed. Also a
Coating can be used that is not resistant to low pH values but that delays the release of the enzyme at low pH values. It is also possible to prepare the agent according to the present invention as (see above) granules, granules or micro- / mini-tablets which can be filled into coated or non-coated capsules or which can be compressed into coated or uncoated tablets. Suitable coatings are, for example, cellulose acetate phthalate, cellulose derivatives, shellac, polyvinylpyrrolidone derivatives, acrylic acid, polyacrylic acid derivatives and polymethyl methacrylate (PMMA), such as, for example, Eudragit® (from Rohm GmbH , Darmstadt, Germany), in particular Eudragit® L30D-55. The Eudragit® L30D-55 coating is dissolved, for example, at a pH value of 5.5 and higher. If it is desired to release the enzyme at a lower pH value, this can be achieved, for example, by the addition of the sodium hydroxide solution to the coating agent Eudragit® L30D-55, because in this case the carboxyl groups of the methacrylate would be neutralized . Therefore, this coating will be dissolved, for example, at a pH value of 4.0 provided that 5% of the carboxyl groups are neutralized. Addition of about 100 g of the 4% solution of sodium hydroxide to 1 kg of Eudragit® L30D-55 would result in a neutralization of about 6% of the carboxyl groups. Additional details about the methods of formulation and methods of
Administration can be found in issue 21 of "Remington: The Science &Practice of Pharmacy," published in 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 in 2006 by Wissenschaftliche Verlagsgesellschaft (ISBN 3804-72222-9). The content of these documents is incorporated herein by reference. Other acceptable pharmaceutically acceptable carriers for use in the present invention include, but are not limited to water, mineral oil, ethylene glycol, propylene glycol, lanolin, glyceryl stearate, sorbitan stearate, isopropyl myristate, isopropyl palmitate, acetone, glycerin, phosphatidylcholine. , sodium cholate or ethanol. 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 fatty acid esters and polyols, such as glyceryl stearate. The agents that will be used in accordance with the present invention can be provided in a stabilized form. Generally, stabilization methods and procedures that can be used include any and all methods
for the stabilization of chemical or biological material which are known in the art and which are suitable for the particular purpose, comprising, for example, the addition of chemical agents, methods which are based on temperature modulation, methods which are based on the irradiation or combinations thereof. Chemical agents that can be used according to the present invention include, among others, preservatives, acids, bases, salts, antioxidants, viscosity builders, emulsifying agents, gelatinizers, and mixtures thereof. Generally, the industrial production of enzymes is carried out in a technical fermentation process using suitable microorganisms (bacteria, molds, fungi). Generally, the strains are recovered from natural ecosystems according to a special selection protocol, isolated as pure cultures as well as improved in their properties with respect to the functioning of the spectrum and biosynthesis of the enzyme (volume / time yield). The production of the enzyme can also be done by methods developed in the future. 5-D-fructose dehydrogenase is commercially available (for example from Sigma-Aldrich and Toyobo Enzymes) and is generally prepared in a microbiological manner with the aid of the microorganism Gluconobacter industrius. However, the invention is not limited to enzymes that are
currently available commercially, but is generally related to enzymes that can catalyze the conversion of fructose - specifically or not specifically - to 5-keto-D-fructose. A person skilled in the art can further prepare suitable enzymes by methods currently known in the art or by methods that can be developed in the future, for example by mutagenesis of the 5-D-fructose dehydrogenase gene that is present in Gluconobacter industrius . The enzyme can also be prepared with the help of other microorganisms, such as fungi, in sufficient quantities and purities required, also by the use of genetic engineering methods that are currently known or can be developed in the future. For example, if it is desired to produce the enzyme with another microorganism, then the genetic information of a microorganism that has been found initially by extensive selection and that has been proven to be a convenient source of the enzyme with the desired characteristics can be transferred to a microorganism which is normally used for the production of enzymes. Also, the modification of the enzyme by itself and the production of the enzyme by means of methods that are currently known or that may be developed in the future in the area of enzyme development and industrial enzyme production, such as genetic engineering, it's possible. The use and manner of execution of all these methods to develop and produce the
enzyme with the purities and the desired activities and with the desired properties, in particular with respect to the stability of the enzyme with respect to the pH value, with respect to the optimum pH value, the stability of temperature and optimum temperature, are well known for those skilled in the art. The explanations in chapter 2 (page 82 to page 130) of the textbook "Lebensmittel-Biotechnologie und Ernahrung" by Heinz Ruttloff, Jürgen Proll and Andreas Leuchtenberger, published by Springer Verlag 1997 (ISBN 3-540-61135-5) describe these methods in detail. Additional information, can also be found. These methods are also described in "Advances in Fungal Biotechnology for Industry, Agriculture, and Medicine" by Jan S. Tkacz, Lene Langeand (published 2004, ISBN 0-306-47866-8), in "Enzymes in Industry: Production and Applications "by Wolfgang Aehle (Editor), published in 2004, ISBN 3527295925 and in" Microbial Enzymes and Biotransformations "by José Luis Barredo (Humana Press 2005, ISBN 1588292533). These documents herein are incorporated in 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. The 5-D-fructose dehydrogenase activity is defined in units (analysis available for example from Sigma-Aldrich), wherein one unit is the amount of 5-D-fructose dehydrogenase
which converts a micromole of D-fructose to 5-keto-D-fructose per minute at pH 4.5 and 37 ° C. The assay is available from Sigma-Aldrich. Generally, the activity of 5-D-fructose dehydrogenase per dose unit should be between 10 and 5 million units, preferably between 25 and 2.5 million units and particularly preferable between 50 and 1 million units. The wide range of the above doses can be explained by the fact that the agent according to the present invention is applicable to three different types of fructose intolerance, namely hereditary fructose intolerance, intolerance to intestinal fructose and the lack of fructose 1,6-diphosphatase, each at different degrees of severity, as well as mild fructose metabolism disorders. In addition, the different doses also result from the fact that they depend on the specific food intake that varies widely in the amounts of fructose that enter the body. The agent according to the present invention may comprise one or more additional enzymes, such as invertase (synonymous with beta-fructofuranosidase or beta-fructosidase). The invertase can split the fructose of chemical compounds from the fructose side and can thus release the fructose from such compounds. For example, you can separate sucrose (homemade sugar) into glucose and fructose. In another embodiment, the agent according to the present invention also comprises the maltase of
the enzyme (without alpha-glucosidase) alone or in combination with nvertasa. This enzyme can also release fructose by separating the glucose from for example sucrose. By the addition of invertase and / or maltase to the agent according to the present invention, the endogenous release of fructose, fructose containing substances or foodstuffs, in particular of sucrose, can both be promoted and accelerated, so that the conversion of fructose to 5-keto-D-fructose which is catalyzed by D-fructose dehydrogenase 5 can occur before. Therefore, the addition of invertase and / or maltase to the agent according to the present invention may have the benefit of reducing the required amount of 5-D-fructose dehydrogenase. Such combinations have never been used in the therapeutic treatment of the human or animal body or for diagnostic purposes of the human or animal body. In another embodiment, the agent according to the present invention also comprises the enzyme glucose isomerase. A glucose isomerase in the context of this application is an enzyme that is capable of catalyzing a conversion of fructose to glucose. This conversion can also bring, for example, a xylose isomerase. Thus, such xylose isomerase is, in the sense of this invention, also a glucose isomerase. A possible method for the production of a xylose isomerase is, for example, described in Yamanaka, Biochimica et Biophysika, Acta, Volume 151 (3), 1968, 670-680, "Purification, Crystallization 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. "Glucose isomerase has the property of converting glucose into fructose and vice versa with a glucose equilibrium concentration of approximately 50% and 50% fructose.The glucose isomerase is therefore ideally suited to support the action of dehydrogenase 5-D-fructose: Fructose is a monosaccharide that is only slowly absorbed from In contrast, glucose is a monosaccharide that is rapidly absorbed from the intestine into the bloodstream and that does not pose a problem for people with fructose intolerance, if a person intolerant to fructose ingests for example. Apple juice glucose isomerase will try to establish the balance mentioned above.Therefore the glucose isomerase will begin to convert the fructose in glucose. The glucose that results from this conversion process will be absorbed in the intestine. This prevents the consequence of the aforementioned balance. Thus, glucose isomerase will continue to convert fructose to glucose in the pulp of the food until the aforementioned balance is reached or until the fructose has left. Thus, it may be beneficial to combine 5-D-fructose dehydrogenase not only with invertase and / or maltase but also with glucose
isomerase In this mode, while 5-D-f-dehydrogenase dehydrogenase converts fructose to 5 keto-D-fructose, at the same time glucose isomerase converts fructose to glucose, which is also harmless for people with fructose intolerance.
Therefore, the addition of glucose isomerase to the agent according to the present invention can reduce the required amount of 5-D-fructose dehydrogenase. The combination of 5-D-fructose dehydrogenase with glucose isomerase and optionally with invertase and / or maltase have never been used in the therapeutic treatment of the human or animal body or for the diagnostic purposes of the human or animal body. Invertase and maltase are compounds that have been known for decades and are commercially available (for example BioCat Inc., Troy, USA, Novozymes A / S, Denmark, Sigma Aldrich or Toyobo Enzymes, Japan). Until now, invertase has been used almost exclusively in the production of inverted sugar, inverted honey and chocolate dishes, such as for example chocolate candies. It has never been used before in combination with 5-D-fructose dehydrogenase in the medical / pharmaceutical field, and in particular in the case of disorders of fructose metabolism in humans or animals. Until now, this enzyme combination has never been used in the therapeutic treatment of the human or animal body or for diagnostic purposes. Thus, the first medical indication for the combination of dehydrogenase is described herein.
-D-fructose and invertase. The same applies to the combination of dehydrogenase 5-D-fructose with maltase and to the combination of 5-D-fructose dehydrogenase with invertase and maltase. The invertase activity is measured in Sumner Units (SU, assay available for example from Bio-Cat Inc., Troy, Virginia, USA). A SU is defined as the amount of the enzyme that converts 1 mg of sucrose to 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 between 100 and 150,000 SU and particularly preferably between 150 and 100,000 SU per dose unit. Maltase activity is defined in units, where one unit is the amount of maltose that will convert maltose to glucose-D at a rate of one milligram per minute at 37 ° C and a pH of 4.0 in a 10% solution of maltose by weight. Where the agent according to the present invention also contains maltase, the activity per unit dose should be between 100 and 100,000 units, preferably between 200 and 50,000 units and particularly preferably between 500 and 20,000 units. Glucose isomerase is a compound that has been known for more than 40 years and has been used only for saccharification of starch to date. In the industry, it
commonly used in immobilized form for the conversion of glucose to fructose as well as for the conversion of fructose to glucose. Glucose isomerase is commercially available (for example from Sigma-Aldrich or Novozymes A / S, Denmark) and generally prepared in a microbiological manner with the aid of the microorganism Streptomyces murinus, where the agent according to the present invention also contains glucose isomerase, the composition should contain glucose isomerase in an amount of 0.01 to 100,000 GIU, preferably 0.05 to 10,000 GIU and particularly preferable 0.1 to 1,000 GIU per unit dose. One unit of this enzyme is defined as a glucose isomerase unit (GIU) which converts 1 g of glucose into fructose at a pH value of 6.0 and at a temperature of 37 ° C of an initial solution of 10% (weight percent, ie 10 g of glucose + 90 g of water) in 5 minutes. If the agent according to the present invention comprises one or more of the optional enzymes already mentioned, then it should be used in sufficient quantities - as in the case of 5-D-fructose dehydrogenase so that they can develop sufficient enzyme activity for the desired purpose, for example sufficient invertase, so that an amount of sucrose ingested generally with a normal food (for example 15 g) can be separated. The physiological electrolytes present will usually be
sufficient for the function of glucose isomerase. But it can also be advantageous to add electrolytes to the agent according to the present invention, preferably in an amount of 0.0001% to 0.1% substrate (glucose). Examples of the electrolytes include, but are not limited to, MgSO4, Na2CO3, NaHCOg, NaOH, Na2SO4, MgCO3, H2SO4, NaS203, NaS205 (including 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, ie preferably in a molar ratio of 10 ~ 6 to 10"2. For the aforementioned glucose isomerase (xylose) which is described by Yamanaka, Mn2 + is a convenient cation in particular.In the case of intolerance to intestinal fructose it is particularly preferred that the agent according to the present invention may contain - in addition to 5-D-fructose dehydrogenase and optionally invertase and / or maltase and / or glucose isomerase - also glucose in an amount of 50 mg to 50,000 mg, preferably 500 mg to 25,000 mg and more preferably 1, 000 mg to 15,000 per unit dose.This is because glucose accelerates the resorption of fructose in the intestine.In the case of hereditary fructose intolerance it is particularly preferable that the agent according to the present invention may contain - in addition to 5-D dehydrogenase
fructose and optionally invertase and / or maltase and / or glucose; shallow- also folic acid in an amount of 1 mg to 100 mg, preferably 2 mg to 50 mg and particularly preferably 3 mg to 10 mg per unit dose. This is because folic acid increases the activity of aldolase B. In case the agent according to the present invention is added to a food product before ingestion or already in the production stage, the activity of dehydrogenase 5 -D-fructose should be between 10 and 150,000 units, preferably between 25 and 100,000 units and particularly preferably between 50 and 50,000 units per gram of fructose in the food product. In addition, the present invention provides methods for diagnosing fructose intolerance, for example by administering to a person exhibiting the symptoms of fructose intolerance a capsule or other formulation comprising 5-D-fructose dehydrogenase or other convenient enzyme that converts fructose to a form that is biologically inactive in humans, or administering to a person known to exhibit the symptoms of fructose intolerance in an amount of fructose and a capsule or other formulation comprising a sufficient amount of 5-D dehydrogenase fructose or another convenient enzyme that converts fructose to a form that is biologically inactive in humans to convert at least a portion of the
fructose administered to a form that is at least one of (a) biologically inactive in the human body, (b) non-digestible in the human digestive tract and (c) non-metabolizable in the human body, and determining the results of administration of the enzyme. In some embodiments, the portion is at least 50% of the fructose administered. In other embodiments, the portion is at least 75% of the fructose administered. In other embodiments, the portion is at least 90% of the fructose administered. In other embodiments, the portion is at least 100% of the fructose administered. The sizes of the capsule mentioned below refer to the size of the definitions used by Capsugel Belgium BVBA, Bornem, Belgium. The size of the capsules should be chosen according to the specific formulation of the agent. An example for the formulation of the agent according to the present invention is the formulation in capsule form with capsules size 3 containing 75 mg of dehydrogenase 5-D-fructose with an activity of 90 units / mg and 85 mg of dicalcium phosphate. Another example for a dosage form according to the present invention consists of capsules of size 1 containing 150 mg of 5-D-fructose dehydrogenase with an activity of 90 units / mg, of folic acid and 150 mg of maltodextrin. Another form of dose according to the present invention
it can consist of capsules (size 3) containing 55 mg dehydrogenase 5-D-fructose with an activity of 500 units / mg, 50 mg of invertase with an activity of 200 SU units / mg and 65 mg of dicalcium phosphate. An additional dosage form according to the present invention consists of capsules (size 3) containing 55 mg of 5-D-fructose dehydrogenase with an activity of 500 units / mg, as well as 50 mg of maltase with an activity of 200 units / mg and 65 mg of dicalcium phosphate. Another dosage form according to the present invention consists of capsules (size 1) containing 110 mg of 5-D-fructose dehydrogenase with an activity of 500 units / mg as well as 100 mg of invertase with an activity of 200 SU units / mg and 90 mg of maltodextrin. The invention may for example contain between 10 and 5 million units of 5-D-fructose dehydrogenase, between 50 and 250,000 units of invertase, between 100 and 100,000 units of maltase, between 0.01 and 100,000 GIU, between 50 mg and 50 g of glucose and / or between 1 mg and 100 mg of folic acid per dose unit. In addition, suitable additives in useful amounts can be used. The invention can be provided for medical purposes and non-medical purposes, for example as a pharmaceutical composition, a medical device, food products or special food products.
In summary, dehydrogenase 5-D-fructose is convenient in an excellent manner for use in the case of fructose intolerance or any disturbance of fructose metabolism.
Claims (139)
1. Dehydrogenase 5-D-fructose, optionally in combination with invertase and / or maltase and / or glucose isomerase, for use in medicine, preferably in the form of a pharmaceutical composition.
2. Pharmaceutical composition comprising 5-D-fructose dehydrogenase, optionally in combination with invertase and / or maltase and / or glucose isomerase.
3. Pharmaceutical composition according to claims 1 and / or 2, which includes one or more enzyme (s) protected by a coating to be stable at pH values of less than 4, preferably less than 3.
4. Pharmaceutical composition of according to one or more of claims 1 to 3, in a form for oral administration.
5. Pharmaceutical composition according to one or more of claims 1 to 4, in a convenient form to be added to the food in the production stage thereof and / or before eating it.
6. Medical device comprising 5-D-fructose dehydrogenase, optionally in combination with invertase and / or maltase and / or glucose isomerase.
The medical device according to claim 6, which includes one or more enzyme (s) protected by a coating to be stable at pH values of less than 4, preferably less than 3.
8. Medical device according to claims 6 and / or 7, in a form for oral administration.
9. Medical device according to one or more of claims 6 to 8, in a convenient form to be added to the food in the production stage thereof and / or before eating it.
10. Food comprising 5-D-fructose dehydrogenase together with invertase and / or maltase.
11. Special food comprising 5-D-fructose dehydrogenase, optionally in combination with invertase and / or maltase and / or glucose isomerase.
12. Food product according to claim 10 and / or 11, which includes one or more enzyme (s) protected by a coating to be stable at pH values of less than 4, preferably less than 3.
13. Food products of according to claims 11 and / or 12, in a convenient form to be added to the food in the production stage thereof and / or before eating it.
14. Use of 5-D-fructose dehydrogenase alone or optionally in combination with invertase and / or maltase and / or glucose isomerase for the production of a product, preferably a pharmaceutical composition, for use in therapy or diagnosis of disorders of fructose metabolism, which includes fructose intolerance.
15. Use of 5-D-fructose dehydrogenase alone or optionally in combination with invertase and / or maltase and / or glucose isomerase for the production of a product, preferably for the production of a pharmaceutical composition, to lower the bioavailability of fructose in the human or animal body.
16. Use of 5-D-fructose dehydrogenase alone or optionally in combination with invertase and / or maltase and / or glucose isomerase for the production of a product, preferably for the production of a pharmaceutical composition, to lower the content of fructose in foods.
17. Use of 5-D-fructose dehydrogenase alone or optionally in combination with invertase and / or maltase and / or glucose isomerase for the production of a product, preferably for the production of a pharmaceutical composition, to lower the amount of fructose available to the human body or animal and / or intestinal bacteria of the human or animal body.
18. Use according to one or more of claims 14 to 17, wherein the product comprises any pharmaceutical composition, a medical device, a food product or a special food product.
19. Use in accordance with one or more of the claims 14 to 18, wherein the product is coated in such a way that one or more enzyme (s) are protected against pH values of less than 4, preferably less than 3.
20. Use in accordance with one or more of the claims 14 to 19, wherein the product is in a form for oral use.
21. Use according to one or more of claims 14 to 20, wherein the product is convenient to be added to the food in the production stage thereof and / or earlier. to eat it
22. Use according to one or more of claims 14 to 19, wherein the product is in a form for use in immobilized form.
23. Process for the treatment of a food product, comprising the steps of contacting the food with a 5-D-fructose dehydrogenase, optionally in combination with invertase and / or maltase, and initiating the reaction of fructose to 5-keto -D-fructose
24. Process for the treatment of a food product, comprising the steps of contacting the food with a 5-D-fructose dehydrogenase, optionally in combination with invertase and / or maltase and / or glucose isomerase, and initiating the reaction of the fructose to 5-keto-D-fructose and optionally the reaction of fructose to glucose.
25. Process according to claim 23 and / or 24, where as an additional stage prior to the occurrence of the ingestion reaction of the food.
26. Ingestable human composition of the technique comprising an enzyme that converts D-fructose to a form that is biologically inactive in the human body or a mixture of these enzymes.
27. Ingestable human composition of the technique comprising an enzyme that converts D-fructose to a form that can not be digested in the human digestive tract
28. Ingestable human composition of the technique comprising an enzyme that converts D-fructose to a form that is not metabolizable in the human body.
29. Composition of the technique according to any of claims 26 to 28, wherein the form is 5-keto-D-fructose.
30. Composition of the technique according to any of claims 26 to 29, wherein the enzyme is 5-D-fructose dehydrogenase.
31. Composition of the technique according to any of claims 26 to 30, which is a dietary supplement or a pharmaceutical composition.
32. Composition of the technique according to any of claims 26 to 30, which is a special food product.
33. Composition of the technique in accordance with claim 31 or 32, which further comprises at least one pharmaceutically or dietetically acceptable carrier or excipient.
34. Composition of the technique according to any of claims 31 to 33, wherein the composition of the technique contains the enzyme in the form of my capsule.
35. Composition of the technique according to any of claims 31-34, wherein the composition of the art is in the form of a capsule or tablet.
36. Composition of the technique according to any of claims 31-34, wherein the composition of the art is in the form of granules or granules.
37. Composition of the technique according to any of claims 31-33, wherein the composition of the art is in the form of a solution.
38. Composition of the technique according to any of claims 31-34, wherein the composition of the art is in the form of a gel or suspension.
39. Composition of the technique according to claim 38, wherein the composition of the art is in the form of a gel capsule.
40. Composition of the technique which is dehydrogenase 5-D-fructose microencapsulated.
41. Composition of the technique comprising 5-D-fructose dehydrogenase mixed with a substance ingestible by humans.
42. Composition of the technique according to claim 41, wherein the substance ingested by humans is a pharmaceutical or dietetic acceptable carrier or excipient.
43. Composition of the technique according to claim 41 or 42, wherein the dehydrogenase 5-D-fructose is microencapsulated.
44. Composition of the technique according to any of claims 26-43, wherein the enzyme constitutes between 5 and 99.9% by weight of the composition of the art.
45. Composition of the technique according to claim 44, wherein the enzyme constitutes between 10 and 80% by weight of the composition of the art.
46. Composition of the technique according to claim 44, wherein the enzyme constitutes between 25 and 60% by weight of the composition of the art.
47. Composition of the technique according to any of claims 26-46, wherein the composition of the art is in the form of a dose unit and the dose unit contains between 10 and 5 million units of activity of dehydrogenase 5. -D-fructose
48. Composition of the technique according to claim 47, wherein the dose unit contains between 25 and 2.5 million units of 5-D-dehydrogenase activity fruitful
49. Composition of the technique according to claim 47, wherein the dose unit contains between 50 and 1 million units of 5-D-fructose dehydrogenase activity.
50. Composition of the technique according to any of claims 26-49, wherein the composition of the art comprises a coating that dissolves in an aqueous medium at a pH of between 3.0 and 8.0.
51. Composition of the technique according to claim 50, wherein the layer does not dissolve in an aqueous medium at a pH below 3.0.
52. Composition of the technique according to claim 50, wherein the layer is not dissolved in an aqueous medium at a pH below 4.0,
53. Composition of the technique according to any of claims 50-52, wherein the coating does not dissolve in an aqueous medium at a pH above 6.5.
54. Composition of the technique according to claim 53, wherein the coating does not dissolve in an aqueous medium at a pH above 6.0.
55. Composition of the technique according to any of claims 26-49, wherein the composition of the art is a slow release or release formulation prolonged
56. Composition of the technique according to claim 55, wherein the sustained release or sustained release formulation comprises a slow release or prolonged release coating.
57. Composition of the technique according to any of claims 26-56, wherein the composition of the technique further comprises a second enzyme.
58. Composition of the technique according to claim 57, wherein the second enzyme is capable of separating fructose from a more complex sugar.
59. Composition of the technique according to claim 58, wherein the second enzyme is invertase or maltase.
60. Composition of the technique according to claim 59, wherein the second enzyme is invertase, the composition of the art is in the form of a dosage unit, and each dosage unit contains between 50 and 250,000 units of activity Sumner. invertase.
61. Composition of the technique according to claim 60, wherein each dosage unit contains between 100 and 150,000 Sumner units of invertase activity.
62. Composition of the technique according to claim 60, wherein each dosage unit contains between 150 and 100,000 Sumner units of invertase activity.
63. Composition of the technique according to claim 59, wherein the second enzyme is maltase, the composition of the art is in the form of a dose unit, and each dose unit contains between 100 and 100,000 units of maltase activity.
64. Composition of the technique according to claim 63, wherein each dose unit contains between 200 and 50,000 units of maltase activity.
65. Composition of the technique according to claim 63, wherein each dose unit contains between 500 and 20,000 units of maltase activity.
66. Composition of the technique according to any of claims 59-65, wherein the composition of the art comprises both invertase and maltase.
67. Composition of the technique according to any of claims 26-66, wherein the composition of the art also comprises an additional enzyme that converts the D-fructose into a molecule that is absorbed more quickly than the D-fructose of the intestine in the bloodstream.
68. Composition of the technique according to claim 67, wherein the molecule is D-glucose.
69. Composition of the technique in accordance with the claim 67 or 68, wherein the additional enzyme is a glucose isomerase.
70. Composition of the technique according to claim 69, wherein the composition of the technique is in the form of a dose unit and each dose unit contains 0.01 to 100,000 units of glucose isomerase activity per unit dose.
71. Composition of the technique according to claim 70, wherein each dose unit contains 0.05 to 10,000 units of glucose isomerase activity per unit dose.
72. Composition of the technique according to claim 70, wherein each dose unit contains 0.1 to 1,000 units of glucose isomerase activity per unit dose.
73. Composition of the technique according to any of claims 69-72, wherein the glucose isomerase is a xylose isomerase.
74. Composition of the technique according to any of claims 67-73, wherein the composition further comprises at least one of an electrolyte and a metal ion
75. Composition of the technique according to claim 74, in where the electrolyte is selected from the group consisting of MgSO4, Na2CO3, NaHCO3, NaOH, Na2SO4, MgC03, H2S04l NaS203, NaS205 and mixtures thereof.
76. Composition of the technique according to claim 74 or 75, wherein the metal ion is selected from the group consisting of Mn2 +, Mg2 +, Ca2 +, Zn2 +, Fe2 +, Co2 +, Cu2 + and mixtures thereof.
77. Composition of the technique according to any preceding claim which is in the form of a dosage unit, wherein each dose unit further comprises from 50 to 50,000 mg of glucose.
78. Composition of the technique according to claim 77, wherein each dose unit comprises from 500 to 25,000 mg of glucose.
79. Composition of the technique according to claim 77, wherein each dose unit comprises from 1,000 to 15,000 mg of glucose.
80. Composition of the technique according to any preceding claim which is in dosage unit form, wherein each dose unit further comprises from 1 to 100 mg of folic acid.
81. Composition of the technique according to claim 80, wherein each dose unit comprises from 2 to 50 mg of folic acid.
82. Composition of the technique according to claim 80, wherein each dose unit comprises from 3 to 10 mg of folic acid.
83. Composition of the technique according to any of claims 26-30, which is a food product, and the enzyme is in active form.
84. Composition of the technique according to claim 83, wherein the amount or concentration of the enzyme in the food product is greater than the concentration or naturally occurring amount of the enzyme in the food product.
85. Composition according to claim 83, wherein the food product is a food product that contains fructose.
86. Composition of the technique according to claim 83 or 85, wherein the food product is a food product that has been baked.
87. Composition of the technique according to claim 83 or 85, wherein the food product is a food product that has been cooked.
88. Composition of the technique according to claim 83 or 85, wherein the food product is a liquid, paste or broth.
89. Composition of the technique according to any of claims 83-88, wherein the enzyme is present in microencapsulated form.
90. Composition of the technique according to any of claims 83-89, wherein the enzyme is 5-D-fructose dehydrogenase.
91. Composition of the technique according to any of claims 83-90, wherein the food product further contains a second enzyme in active form.
92. Composition of the technique according to claim 91, wherein the concentration or amount of the second enzyme in the food product is greater than the concentration or naturally occurring amount of the second enzyme in the food product.
93. Composition of the technique according to claim 92, wherein the second enzyme is invertase.
94. Composition of the technique according to claim 92, wherein the second enzyme is maltase.
95. Composition of the technique according to claim 92, wherein the second enzyme is a glucose isomerase.
96. Composition of the technique according to claim 95, wherein the glucose isomerase is a xylose isomerase.
97. Composition of the technique according to claim 95 or 96, wherein the composition further comprises at least one of an electrolyte and a metal ion.
98. Composition of the technique according to claim 97, wherein the electrolyte is selected from the group consisting of MgSO4, Na2CO3, NaHCO3, NaOH, Na2SO4, MgC03, H2SO4, NaS203, NaS205 and mixtures thereof.
99. Composition of the technique according to claim 97 or 98, wherein the metal ion is selected from the group consisting of Mn2 +, Mg2 +, Ca2 +, Zn2 +, Fe2 +, Co2 +, Cu + and mixtures thereof.
100. Composition of the technique according to any of claims 92-99, wherein the second enzyme is a mixture of at least two of the group of invertase, maltase and glucose isomerase.
101. Composition of the technique according to any of claims 92-100, wherein the second enzyme is in microencapsulated form.
102. Composition of the technique according to any of claims 26-101, comprising a mixture of enzymes that convert D-fructose in a form that is at least one of (a) biologically inactive in the human body, (b) ) not digestible in the human digestive tract and (c) not metabolizable in the human body.
103. Composition of the technique according to any of claims 83-102, wherein the food product is not a paste.
104. Composition of the technique according to any of claims 26-103, wherein the enzyme that converts D-fructose to a form that is at least one (a) biologically inactive in the human body, (b) non-digestible in the human digestive tract and (c) non-metabolizable in the human body is not contained in a biocompatible matrix of inorganic-based solid-gel.
105. Composition of the technique according to any of claims 26-104, wherein the composition is substantially free of substances that are not approved for oral human ingestion.
106. Composition of the technique according to any of claims 26-105, wherein the composition of the art is adapted for oral ingestion.
107. Composition of the technique according to any of claims 26-106, wherein the composition comprises an electron acceptor.
108. Composition of the technique according to claim 107, wherein the electron acceptor is selected from the group consisting of nicotinamide adenine dinucleotide + (NAD +), nicotinamide adenine dinucleotide + phosphate (NADP +), dinucleotide of flavin adenine +, vitamin C, E or A, ferricyanide, ketones, aldehydes, 2,6-di-chloro-phenolindophenol, phenazine metasulfate and mixtures thereof.
109. Composition according to claim 107 or 108, wherein the molar ratio of the electron acceptor to fructose is from 1: 1 to 1: 1000.
110. Composition according to claim 109, wherein the molar ratio of the electron acceptor to fructose is from 1: 2 to 1: 200.
111. Composition according to claim 109, wherein the molar ratio of the electron acceptor to fructose is from 1:10 to 1: 50.
112. Method for treating fructose intolerance or impaired fructose metabolism, comprising administering to a human or animal subject an effective amount of an enzyme or a mixture of enzymes that converts D-fructose to a form that is at least one of (a) biologically inactive in the subject's body, (b) non-digestible in the digestive tract of the subject and (c) non-metabolizable in the subject's body.
113. Method according to claim 112, wherein the subject is a human subject.
114. Method according to claim 112 or 113, wherein the administration comprises administering a human ingestible composition of the technique according to any of claims 26-111.
115. Method according to any of claims 112-114, wherein the fructose intolerance is intolerance to hereditary fructose.
116. Method according to any of claims 112-114, wherein the intolerance to fructose is intolerance to intestinal fructose.
117. Method according to any of claims 112-114, wherein the fructose intolerance is due to the lack of fructose 1,6-diphosphatase.
118. Method according to any of claims 104 to 117, wherein the composition of the technique is administered immediately before eating.
119. Method according to any of claims 104 to 117, wherein the composition of the technique is administered concurrently with a meal.
120. Method according to any of claims 104 to 117, wherein the composition of the technique is administered immediately after eating.
121. Method according to any of claims 104 to 117, wherein the form is 5-keto-D-fructose.
122. Method for diagnosing fructose intolerance, which comprises administering to a human or animal subject exhibiting the symptoms of fructose intolerance a composition of the technique according to any of claims 26 to 111, and observing whether the administration partially or completely improves the symptoms.
123. Method according to claim 122, wherein the subject is a human subject.
124. Method for diagnosing fructose intolerance, which comprises administering to a known human or animal subject which exhibits the symptoms of fructose intolerance of both (a) an amount of fructose effective to induce such symptoms and (b) a composition of the technique according to any of claims 26-111, comprising the enzyme that converts fructose, or mixture of such enzymes, in an amount that is sufficient to convert at least 50% of the amount of fructose, and which determines the results of the administration of the enzyme or mixture thereof.
125. Method according to claim 124, wherein the composition comprises the enzyme that converts the fructose, or the mixture of these enzymes, in an amount that is sufficient to convert at least 75% of the amount of fructose.
126. Method according to claim 124, wherein the composition comprises the enzyme that converts the fructose, or the mixture of these enzymes, in an amount that is sufficient to convert at least 90% of the amount of fructose.
127. Method according to claim 124, wherein the composition comprises the enzyme that converts the fructose, or the mixture of these enzymes, in an amount that is sufficient to substantially convert the entire amount of fructose.
128. Method according to any of claims 124-127, wherein the enzyme or the mixture of enzymes converts D-fructose to 5-keto-D-fructose.
129. Method according to any of claims 124-128, wherein the subject is a human subject.
130. An assembly comprising an enzyme that converts D-fructose to a form that is at least one of (a) biologically inactive in the human body, (b) non-digestible in the human digestive tract and (c) not metabolizable in the human body, or a mixture of such enzymes, and the instructions that explain how to use the enzyme or the mixture thereof to diagnose or treat fructose intolerance.
131. The assembly according to claim 130, wherein the enzyme or mixture thereof is present as a composition of the art according to any of claims 26-111.
132. The kit according to claim 130 or 131, wherein the enzyme or mixture of enzymes converts D-fructose to 5-keto-D-fructose.
133. Food product reduced in fructose.
134. Method for preparing a reduced fructose food product, which comprises contacting a food product or a precursor of the food product with an enzyme that converts the D-fructose to a form that is at least one of (a) biologically inactive in the human body, (b) not digestible in the human digestive tract and (c) not metabolizable in the body human, and that completes any of the additional steps necessary to prepare the food product.
135. Method according to claim 134, wherein the enzyme is 5-D-fructose dehydrogenase.
136. Method according to claim 134 or 135, wherein the food product is not a baked food product.
137. Method according to claim 134 or 135, wherein the food product is not bread.
138. Method according to claim 134 or 135, wherein the food product is not a paste.
139. Method according to any of claims 134-138, wherein the enzyme converts D-fructose to 5-keto-D-fructose.
Applications Claiming Priority (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005055081.9 | 2005-11-16 | ||
| DE102005056169.1 | 2005-11-23 | ||
| DE102005060768.3 | 2005-12-16 | ||
| DE102005060769.1 | 2005-12-16 | ||
| DE102006000881.2 | 2006-01-04 | ||
| DE102006000873.1 | 2006-01-04 | ||
| DE102006001015.9 | 2006-01-05 | ||
| US60/757,414 | 2006-01-10 | ||
| US60/757,424 | 2006-01-10 | ||
| DE102006012244.5 | 2006-03-15 | ||
| DE102006013624.1 | 2006-03-22 | ||
| DE102006014423.6 | 2006-03-27 | ||
| US60/831,050 | 2006-07-17 | ||
| US60/831,174 | 2006-07-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2008006327A true MX2008006327A (en) | 2008-10-03 |
Family
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