CN1218054A - Preparation of chromium methionine and its composition as Jiangtangyikang tablets (capsules) series - Google Patents
Preparation of chromium methionine and its composition as Jiangtangyikang tablets (capsules) series Download PDFInfo
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Abstract
The chromium methionine as an organic coordination compound is prepared from 3-valence chromium and methionine, and then combined with the hypoglycemic that is compatible with the chromium methionine and has different action mode and position to obtain a new medicine in the form of tablet or capsule. Said chromium methionine can serve as the synergistic of insulin and to remove free radicals, and features its targetability to pancreas, so it can be used to treat diabetes.
Description
The preparation of chromium methionine and composition Jiangtangyikang tablet (capsule) thereof [being called for short Jiangtangyikang tablet (capsule)] series, being the chromium methionine that will have Regular Insulin stiffeners and an effect of pancreas function rehabilitation agent becomes tablet or capsule with the definite diabetes oral antidiabetic drug compatible combination of clinical efficacy, relates to clinical pharmacology and drug preparation techniques such as the technology of preparing of chromium methionine and pharmacokinetics, compatibility.The invention belongs to the new drug development technical field.
At present, though the medicine of many treatment non insulin dependent diabetess (NIDDM, II type) is arranged, not having a kind of is the ideal medicine; And insulin-dependent diabetes mellitus (IDDM, I type), though Regular Insulin is arranged, because the limitation of using method, the long term injections administration has brought painful and inconvenient to the patient.Therefore, when excavating new treatment diabetes medicament, the medicine that existing clinical efficacy is definite through optimization, compatibility, be combined into a whole tablet or capsule, ofhypoglycemic medicine with different binding modes and different site of action is combined into has complementary action and synergy, the Different types of etiopathogenises that diabetes are still not clear is carried out polynary pharmacological agent, satisfy needs and the requirement clinical and treatment of extensive patients enforcement drug combination.
The objective of the invention is:
First purpose is, is developed into the chromium methionine coordination compound with pancreas target, as the stiffeners of Regular Insulin and the rehabilitation agent of pancreas function, treats at the corresponding cause of disease of diabetes;
Second purpose is, to have the drug regimen that promotes insulin secretion, improves insulin action, slows down carbohydrate absorption, promotes islet function to recover and become whole tablet or capsule, realize the drug combination for the treatment of diabetes, the complementary and synergy of performance medicine, medicament curative effect enhancement;
The 3rd purpose be, to numerous medicines be optimized, compatibility, combination reach and reduce or avoid Side effects of pharmaceutical drugs, improves the security of medication;
The 4th purpose is that Jiangtangyikang tablet (capsule) not only provides new scheme for clinical drug combination and the polynary curing that carries out Different types of etiopathogenises, and has saved dosage and manufacturing expense, has reduced expense/effect ratio, has tangible economic benefit;
The 5th purpose is, according to experimental study and clinical observation, it is that the radical damage pancreatic tissue causes the unusual diabetes etiology of islet function that the contriver proposes one of onset diabetes reason, is developed into the chromium methionine coordination compound with promotion pancreas rehabilitative action and Regular Insulin booster action and carries out the specific aim treatment;
The 6th purpose be, replaces clinical injection of insulin agent with oral insulin, alleviates the painful and inconvenient of patient's medication;
Pursuing purpose for the 7th is, for the treatment Glucovance developed and associating, the compatibility of hypoglycemic patent drugs provide new prospect design;
Below invention is described in detail.
One, the preparation of chromium methionine
Chromium methionine is by the coordination compound of trivalent chromium (Cr (III)) with the methionine(Met) chemosynthesis.Its main biological function shows as the Regular Insulin stiffeners of diabetes and the rehabilitation agent of pancreas function, it is the specific aim medicine of " one of diabetes cause of disease is that the radical damage pancreatic tissue causes the islet function unusual " theory of proposing of contriver, have the effect that two-way adjustment blood sugar and prevention type II diabetes take place, be expected one of standard care medicine that becomes diabetes.
(1) trivalent chromium (Cr (III))
1. the character of trivalent chromium (Cr (III)):
Chromium is a kind of element with multiple valence, and Cr (III) is an essential life metal trace element in the human body, has vital role in normal carbohydrate metabolism and lipid metabolism, also has enhancing to the removing of free radical and the effect of inhibition free-radical generating.Cr (III) is the most stable a kind of form, and the intravital chromium of people is the coordination compound of Cr (III) substantially.The biological dative bond of the coordination compound of Cr (III) is chromium dissolves, absorbs, brings into play physiological function under the physiological pH condition a prerequisite.Cr (III) forms the very capable of coordination compound, mainly is the compound that forms hexa-coordinate, and the sterie configuration of its mononuclear coordination compound is octahedra, and Cr (III) ion provides 6 unoccupied orbitals, forms 6 d
2Sp
3Hybridized orbital.In vivo, it is that methionine(Met) under physiological condition, can suppress the olation effect of Cr (III) as part because it can form diffluent title complex with more weak organic ligand or inorganic part that chromium can work, can prevent even reverse the olation effect, keep the biologic activity of Cr (III).
2. the content and the distribution of trivalent chromium (Cr (III)) in the body:
The intravital chromium of people mainly concentrates in liver, spleen, soft tissue and bone, is difficult to enter pancreas, and the chromium content in insulin-dependent diabetes mellitus (IDDM, I type) and non insulin dependent diabetes (NIDDM, II type) patient's pancreas and the hepatic tissue all is lower than healthy people.But the compound of general chromium does not influence chromium in the intravital distribution of people, and Cr (III) mainly is strapped in liver, spleen and the kidney.Therefore, target is an important topic of preventing and treating diabetes to pancreas for chromium.
The biochemical function of (3.Cr III):
Chromium is the essential life metal trace element of animal and human's body, is the integral part in a series of enzymes and proteic active centre, and its biochemical function mainly is as the stiffeners of Regular Insulin and the rehabilitation agent of pancreas function.Aspect the effect relevant with Regular Insulin, for example from glucose intake, glucose oxidase to carbonic acid gas and conversion of glucose to fat etc., chromium potentiating insulin action.For Regular Insulin, be not substituent, but chromium combine with protein, nucleic acid and various low molecular part in the body as it, participate in the sugar and the metabolism of fat of body; Aspect the effect relevant with free radical, observed the biological effect of chromium, Cr (III) not only has enhancing to measured by esr technique, and suppresses the effect of free-radical generating in addition, and the biochemical function of Cr (III) has been had new understanding and discovery.
The human phenomenon that lacks chromium exists, and lacks chromium phenomenon serious area, the sickness rate height of diabetes, and the diabetic subject merges other lethal disease easily.Therefore, replenish scarce chromium and can prevent and treat diabetes and atherosclerosis.Per day for adults is supplied with 20～50 μ g can satisfy physiological requirements, and lacking chromium patient safety and suitable cr intake is 50～200 μ g/ days.
(2) methionine(Met)
Methionine(Met) (methionine(Met)) Methioninum (Methionine)
Molecular formula and molecular weight: C
2H
11NO
2S:149.21
Structural formula
1. general aspects:
This product extensively is present in the animal proteinum, can make by proteolysis, also can make by synthesizing, and is white sexangle crystallization, contains the neutral amino acids of amino and carboxyl, is essential amino acid.1% pH value of solution is 5.6～6.1, is 33.1 during 25 ℃ of solubleness in water (g/L), and solubility with temperature raises to be increased.Nontoxic, It is generally accepted it is safe.
2. biologic activity and clinical application:
Be sulfur-containing amino acid, synthetic choline needs to supply with methyl by methionine(Met) in the body, is the substrate of methionyl transfer RNA (tRNA) synthetic enzyme.Choline is the integral part of Yelkin TTS, and choline and the fat effect of accumulating in the liver become the Yelkin TTS of easy absorption, remove the deposition fat in the liver, the clinical treatment that is used for hepatitis, liver cirrhosis, fatty liver.Methionine(Met) is supplied with sulphur in vivo with synthetic non-exogenous amino acid cystine, and the latter has detoxification, as alcohol, sulfonamides poisoning adjuvant therapy medicaments.
Methionine(Met) is a kind of oxidation inhibitor, is effective free-radical scavengers.
3. special biochemical function:
1) the natural ligand of chromium: from the result of completed metalloprotein, metalloenzyme crystal structure analysis, the sulphur on the methionine residue (S) atom is the most common most important coordinating group of metallic ion coordination.
The coordination compound that methionine(Met) and chromium form, under physiological condition, they suppress the olation effect of Cr (III), guarantee the biologic activity of chromium and methionine(Met).
2) targeting vector of pancreas: experimental study confirms that methionine(Met) combines with chromium has tangible target, oral back 25～30 minutes, and the amount of chromium methionine in pancreas is than high 7～8 times in liver.For Cr (III) and methionine(Met) are entered pancreas as treating, diagnose radiography that new approaches and methods is provided.
3) free-radical scavengers: Cr (III) has the effect of the free radical of removing with methionine(Met), suppresses the effect of free-radical generating in addition, has strengthened the synergy of the two behind the formation coordination compound.Because chromium methionine can be delivered to pancreas by target, and the gland pancreas is had therapeutic action.
(3) the chromium methionine coordination compound is synthetic
Chromium methionine is a kind of coordination compound, be by the methionine(Met) neutral molecule ligand that provides electron pair or a plurality of delocalized electronses and have the central ion three price Cr (III) in the room of accepting arc electron pair or a plurality of delocalized electronses that formed to be arranged in individuality of being formed around it be the compound of feature by certain composition sterie configuration.
1. chemosynthesis principle:
1) when forming complex ion, combines with coordinate bond between ligand and the central ion.Methionine(Met) electron donor always wherein, central ion chromium is electron pair acceptor(FPA) always.Methionine(Met) is octahedron at the dimensional orientation that central ion Cr (III) arranges on every side, and Cr (III) is at octahedral center, and ligand is on six summits.
2) in the methionine(Met) neutral molecule, there are S, O, N and C to contain " lone pair electron ", promptly can become key and be not used for into the electron pair of key as yet.Generally speaking, no matter on the methionine(Met) ligating atom several arc electron pairs are arranged, when forming coordinate bond, all only use wherein a pair of and form a coordinate bond.
3) Cr (III) central ion has the unoccupied orbital of valence electron to accept the electron pair that methionine(Met) gives and enough strong magnetism is arranged.Cr (III) generally can accept 6 electron pairs, forms 6 ligancies.
The most important bio-ligand of Cr (III) has three classes, and protein, polynucleotide and carbohydrate are macromolecular compound.
2, chromium methionine is synthetic:
Cr (III) ion-conductance sublayer structure is 3d
34S
04P
3, therefore can provide 6 tracks that energy is close, and Gr
3+Ionic radius is little, and positive charge is higher, thus Cr (III) to be easy to form ligancy be 6 d
2SP
3The type title complex.Methionine(Met) and chromic coordination situation, owing to there are two class Cr (III) combining sites on the methionine(Met), it is S, N and O that strong bonded is joined atom, and then the feature ligancy of Cr (III) is 6, and therefore, methionine(Met) and Cr (III) form octahedral structure.
From the result of completed metalloprotein, metalloenzyme crystal structure analysis, methionine(Met) side chain hydrophobic group sulfur-bearing (S) atom is the most common most important coordinating group of metallic ion coordination, is the key that combines with coordination with Cr (III).
1) electrocatalysis is synthetic:
2) transfer transport:
3) substitution reaction: chromium can be synthetic by following method for methionine(Met).
(4) biological function of chromium methionine
1. to the provide protection of pancreas:
Chromium methionine is the organic coordination compounds that contains chromium, has the bioactive synergy of trivalent chromium Cr (III) and methionine(Met), mainly shows following three aspects.
1) the target medicament of pancreas: behind oral synthetic chromium methionine 25～30 minutes, the amount of chromium methionine in pancreas is than high 7～8 times in liver, because ordinary method is difficult to the diagnosis and treatment medicine is brought into pancreas, especially Cr (III) is delivered in the pancreas that lacks chromium.Experimental study proves that chromium methionine is the effective target medicament of present pancreas, can be used for the angiographic diagnosis and the treatment of pancreas.
2) promote pancreas function: pancreas needs a large amount of amino acid and chromium when synthesizing digestive ferment, the susceptibility of the secreting function of the pancreas islet of promotion pancreas and raising Regular Insulin.
3) remove and suppress the damage of radical pair pancreas: experimental study proves that chromium methionine can not only be removed the free radical of pancreas, and can suppress the generation of free radical, and it is stronger than independent Cr (III) and independent methionine(Met) that it removes free radical effect.
2. to sugar and lipometabolic effect:
1) chromium methionine is the stiffeners of Regular Insulin: Regular Insulin one of the most significant function is the effect with lowering blood glucose, and chromium is then with the coordination compound chromium methionine of Cr (III) a kind of " the collaborative hormone " as Regular Insulin.It is to assist sugar to enter cytolemma that Regular Insulin is regulated glycometabolic mechanism, and chromium methionine can promote Regular Insulin and tissue bond, and the effect of Regular Insulin is given full play to.
The glucose oxidase decomposition gives off energy, and also needs Regular Insulin and chromium to participate in.Need a kind of phosphoglucomutase to carry out catalysis in the glucose glycolysis process in vivo, even when not having magnesium to exist, it can keep this kind of enzyme works better.Because chromium and pancreas islet have a kind of mutual synergy, chromium can make the insulin molecule Stability Analysis of Structures.
2) the fat effect that becomes of chromium methionine: chromium methionine participates in lipid metabolism and accelerate fat oxidation, helps the transportation and the removing of lipid in the arterial wall.Scarce chromium may be an atherosclerotic paathogenic factor, and chromium methionine has strengthened the lipid metabolism effect of Cr (III) and the acid of egg peace.Synthetic choline needs to supply with methyl by methionine(Met) in the body, and the Yelkin TTS of being made up of choline etc. is the indispensable material of fat transportation and removing fatty deposits.Therefore, the lipid metabolism effect of chromium methionine is prevention and treatment atherosclerosis and the active drug that protects the liver.
(5) etiology of the diabetes of radical damage pancreas
At present, cause that the cause of disease of diabetes is still not too clear.Number of research projects concentrates on the research to inherited genetic factors, and less to environmental factors research.But from many-sided synthetic studies such as epidemiological study and clinical observations, the contriver thinks: it is the important factor that causes maturity-onset diabetes unusually that radical damage causes pancreas function.Therefore, the contriver proposes the etiology of the diabetes of radical damage pancreas.
1. the performance of radical damage pancreas:
1) the islet secretion function reduces, the performance hypoinsulinism;
2) insulin sensitivity reduces;
3) oxidation inhibitor and trace element deficiency in the pancreas islet, experimental study proves that Cr (III) is a kind of free-radical scavengers, but also is the active substance that suppresses free-radical generating, has the effect that prevents that type II diabetes from taking place;
2. the reaction of diagnostic treatment:
Give and oxidation inhibitor, especially target chromium methionine to the recovery of impaired pancreas function, the obvious treatment effect is arranged; Equally, give and scavenger SOD, can strengthen the susceptibility of Regular Insulin.Therefore, the contriver thinks that chromium methionine of the present invention also is at one of etiological treatment medicine of the etiology of the radical damage pancreas of diabetes.
Two, combinatorial principle and method
Combination is two or more compatibility of drugs tissues to be become whole preparation use for clinical and patient.Pharmacological action be can strengthen after the drug regimen, side effect and medicine irritation etc. alleviated.It is prerequisite that its combinatorial principle does not react mutually with compatibe drug, select that route of administration is identical, time of administration at interval and medicine have complementary action in the intravital metabolic process of people, compatibe drug must be to have different binding modes to make it produce the identical medicine of synergistic clinical pharmacology with different site of action.
Combined method is, the antidiabetic drug compatibility prescription and the suitable auxiliary material that can not directly be employed are made whole tablet or capsule is used for clinical and patient by preparation technique.
Three, with the ofhypoglycemic medicine of chromium methionine combination
(1) sulfonylurea hypoglycemic agent
The sulfonylurea oral antidiabetic drug have the first-generation (1) tolbutamide (Tolbutamide, D860), (2) P-607 (Chlorpropamide); The oral antidiabetic drug of the s-generation comprises: (1) Glyburide (Glyburide, glyburide), (2) glipizide (Glipizide), (3) diamicron (Gliclazide), (4) Glibornuride (Glibor-nuride, gram sugar is sharp), (5) quinoline sulphur ring is urea (Gliquidone, and may become new drug (6) glimepiride (Glimepiride) of treatment etc. Glurenor).
1. the mechanism of hypoglycemic:
1) stimulate the beta Cell of islet more Regular Insulin of secretion in time: using this type of medicine plasma insulin can raise, and also can stimulate the beta Cell of islet hyperplasia.
2) increase the susceptibility of bodily tissue: increase the insulin receptor quantity on the bodily tissue cell, and strengthen avidity between the two, promote the physiological action of Regular Insulin to Regular Insulin.
3) other effects: suppress the secretion of high sugar element and Somatostatin; Suppressing liver insulinase activity lowers Regular Insulin katabolism in liver; Suppress liver starch heteroplasia and liver starch and decompose, liver glucose output is reduced, liver starch increases.
2. indication:
The sulfonylurea medicine is mainly used in following patient:
1) at the non insulin dependent diabetes (NIDDM, II type) of the onset above middle age of non-obesity, still controls bad person through dietetic treatment, sports therapy blood sugar.
2) use Regular Insulin only to need 20～40 units to get final product controlling blood sugar person, the often alternative Regular Insulin of sulfonylureas.
3) person that makes the insulinize can unite the 2nd generation the sulfonylurea medicine, to reduce insulin dosage, heighten the effect of a treatment.
4) course of disease though there is blood sugar obviously to raise, also can be tried out in 10 years.
3. the contraindication of sulfonylureas has following several:
1) insulin-dependent diabetes mellitus (IDDM, I type) and II type companion ketoacidosis, hyperosmolar coma person's forbidding;
2), the tangible heart, brain, liver, kidney, ocular complications person's forbidding have been arranged for II type patient;
3) plasma insulin and the low I of C peptide level type person avoid usefulness;
4) for hemopoietic system be subjected to suppress, the oligoleukocythemia person is unsuitable;
5) use amount of insulin every day and surpass the above person's forbidding of 20 units;
4. the side effect of sulfonylureas:
Hypoglycemia is the major side effects of sulfonylurea derivative, and especially to the elderly, the side effect of the easier generation hypoglycemia of P-607 and glyburide to excessive drinking, poor, the impaired renal function of food and can strengthen the pharmaceutically-active medicine of this class received, more can increase risk of hypoglycemia.
(2) biguanides antidiabetic drug
Biguanides antidiabetic drug commonly used has (1) phenformin (Phenethyliguanide, phenformin) and (2) N1,N1-Dimethylbiguanide (Metformin, Siofor).
1. the mechanism of hypoglycemic:
1) avidity of insulin receptor number in the increase target cell, the susceptibility and the physiological action of enhancing Regular Insulin.
2) suppress gluconeogenesis in the liver, increase the anaerobic glycolysis of intramuscular glucose.
3) suppress glucose from intestinal absorption.
4) increase the utilization of surrounding tissue to glucose.
2. indication and contraindication:
The indication of biguanides comprises:
1) is used for the endomorphy type non insulin dependent diabetes,, can plays antiobesity action in the hypoglycemic while.
2) take the not good enough person of sulfonylureas effect, but the coupling biguanides, and can lose weight.
3) for insulin-dependent diabetes mellitus Regular Insulin coupling in case of necessity biguanides antidiabetic drug, can obtain better curative effect.
The contraindication of biguanides antidiabetic drug is identical with sulfonylurea, diabetes acute and chronic complication particularly occurs, as severe brain, the heart, liver, eye and the biguanideses of all should stopping using such as severe infection are arranged, uses Regular Insulin instead in case lactic acidosis.
3. the side effect of biguanides: gastrointestinal discomfort is arranged, and as nauseating, appetite decline, apocleisis, diarrhoea etc., Most patients is along with the time can disappear more.
(3) glucosidase inhibitor
What the glucosidase inhibitor was used for clinical treatment has acarbose (Acarbose) and a ripple lattice array wave sugar (Bo-glybose).
1. blood sugar reducing function mechanism:
After the glucosidase inhibitor enters enteron aisle, can be competitively and dose-dependently ground inhibition enteron aisle α-glucosidase, the carbohydrate of taking in the intestines can't be combined with the latter, thereby various carbohydrates just slow down absorption, cause postprandial blood sugar and insulin level slowly and a small amount of the rising, can improve dietetic treatment, oral antidiabetic drug or with Regular Insulin patient's glucostasis index.Therefore, this medicine is that the incoming road from glucose raises obstacles, rather than promotes its utilization.
2. indication and contraindication:
Be applicable to non insulin dependent diabetes patient with slight symptoms and the elderly, this medicine is preferable to the control postprandial hyperglycemia.
3. the side effect of glucosidase inhibitor
Its major side effects is GI intolerance, and is main relevant with dosage, and is a property crossed, and takes place in the first few weeks of treatment.Therefore, dosage should slowly increase, and adjusts gradually.
(4) oral insulin millimicro ball
Regular Insulin (Insulin, INS) injection is clinical treatment insulin-dependent diabetes mellitus (IDDM, the I type) indispensable medicine and conventional dosage forms, the patient need stand repeatedly hypodermic trouble and misery for a long time, thereby places hope on oral absorption and other insulin administration method.But the difficult point that oral insulin absorbs mainly is that medicine is easily decomposed inactivation by acid catalysis degraded and proteolytic ferment in gi tract; Next is the polymerization trend between insulin molecule, and molecular weight is greater than 6000, and first pass metabolism etc. also destroys the activity of Regular Insulin when diffusing through the epithelium layer of gastrointestinal wall and entering liver.
Domestic in the development of insulin oral preparation, the Zhang Qiang of College of Pharmaceuticals, Beijing Medical University etc. be that the bioavailability of material preparation is higher with Polyalkylcyanoacrylanano, and short oral insulin millimicro ball of hypoglycemic activity time have had tangible progress.Abroad, the Regular Insulin capsule of the special macromolecular material of a kind of outsourcing has been studied by Ohio, USA medical college, can prevent that Regular Insulin is degraded in stomach and small intestine, adds 5-methyl salicylic acid in the preparation, can promote its absorption.This medicine has tried out in 1994 that (Scrip 1990. (1478): 30 in insulin-dependent diabetes mellitus; (1501): 23; 1990, (1504): 26.)
Sulfonylurea medicine treatment non insulin dependent diabetes is invalid, and is normal because due to the further minimizing of insulin secretion.Therefore, need supplemented with exogenous Regular Insulin.The primary and foremost purpose of insulinize type II diabetes is to suppress clinical symptom, and final purpose is to prevent complication.Therefore, patient IDDM and patient NIDDM there are the hope and the requirement of urgent employing oral insulin.
The new drug of the treatment diabetes of (five) developing
1. the medicine that stimulates insulin secretion: (1) new sulfonyl urea compound glimepiride (Glimepiride) is the new drug that is better than glyburide, can reduce and cause hypoglycemic side effect; (2) non-sulfonylurea insulin secretion accelerating medicine repaglinide (Repaglinide) helps the bad patient of renal function; (3) α
2-suprarenin antagonist can increase the insulin secretion that glucose brings out; (4) glucagon-like peptide-I (GLP-1).
2. the new drug that reduces the preparation of insulin resistant has: (1) thiazolidinedione, pioglitazone (Pioglita-zone), darglitazone (Darglitazone) and can improve the obesity patient and the troglitazone of type II diabetes patient's insulin resistant and glucose tolerance (Troglitazone), can avoid severe side effect; (2) lipid agent interfering; (3) glucagon antagonists; (4) vanadium compound etc.
3. the preparation of the carbohydrate absorption that slows down has: (1) 1-deoxynojirimycin derivative miglitol (Migilitol) has (2) amylopectin analogue (Pramlintide) to the medicine of type II diabetes assisting therapy.
Recently, by the above-mentioned application that may treat the new drug of glycosuria is recommended, with α-glucosidase inhibitor acarbose and thiazolidinedione, especially troglitazone, situation changes, the increase of medication amount helps carrying out the drug combination treatment, but also needs further to confirm, any actually drug combination treatment is better.Can believe that the some of them new drug can have the complementary synergy with the antidiabetic drug of standard.
The advantage of Jiangtangyikang tablet (capsule) is:
1. the present invention has realized the life metal trace element trivalent chromium of needed by human and the methionine(Met) of essential amino acid are made the coordination compound chromium methionine;
Chromium methionine can target arrival pancreas organ, for the treatment of pancreas and angiographic diagnosis have opened approach newly out-of-the-way;
3. chromium methionine has the stiffeners effect to Regular Insulin, and impaired pancreas is had the rehabilitation agent effect, for the control of diabetes has proposed new scenario;
4. the diabetes antidiabetic drug that chromium methionine and clinical efficacy is definite is combined into tablet (or capsule) by preparation technique, makes the different the medicines different with site of action realization of binding mode drug combination;
5. the antidiabetic drug that combines has complementation and synergy, reduces the generation of life-time service single medicine and induces inhibition, improves the clinical drug curative effect;
6. the etiology of the diabetes of Jiangtangyikang tablet (or capsule) radical damage pancreas that the present invention is proposed is treated targetedly, implement multiple diabetes because of polynary pharmacological agent;
7. medicinal composition dosage of the present invention is accurate, steady quality, and it is convenient to use;
8. Jiangtangyikang tablet (or capsule) volume is little, and storage and easy to carry has enlarged clinical application;
9. production technique mechanize, level of automation height are convenient to large-scale industrial production;
10. composition has reduced drug dose, has reduced Financial cost, has reduced expense/effect ratio;
11. replace injection with oral insulin, alleviate patient's misery and inconvenient.
Embodiment:
Embodiment one: No. one, Jiangtangyikang tablet (capsule) (Hypoglycemic Pancreas RecoveryTablets (Capsule) No.1, HPRT 1)
Every of this product contains chromium methionine and should be 2mg (wherein containing Cr (III) 100 μ g), contains glyburide and should be 1.25mg, contains N1,N1-Dimethylbiguanide 250mg.
(prescription)
Chromium methionine 2.00g
Glyburide 1.25g
N1,N1-Dimethylbiguanide 250.00g
Vehicle is an amount of
Make 1000
(method for making) gets glyburide 1.25g crystalline powder; the fine powder mixing of N1,N1-Dimethylbiguanide 250g powder and starch adds 10% starch slurry, mixes granulation thoroughly; in oven dry below 60 ℃, processing, mixing; be pressed into sheet with weight, fragmentation is sieved then, makes whole grain; add chromium methionine solution and dry granular mixing again; the talcum powder of adding 3%, mixing, compressing tablet are promptly.
(effect and purposes) has lowering blood glucose and promotes the pancreas function restitution, is used for the preferred option that type II diabetes begins pharmacological agent.
(usage and consumption) is oral, every day 2 times, each 1, clothes before having meal.
(storage) sealing, dry place preserves.
(prescription analysis)
1. chromium methionine is by life essential metal trace element trivalent chromium and essential amino acid methionine(Met) synthetic coordination compound.Have the function that target is delivered to pancreas, 25～30 minutes amounts in pancreas in oral back can be transmitted chromium and oxidation inhibitor methionine(Met) to pancreas than high 7～8 times in liver.Its effect mainly is to promote that the susceptibility of secretion of insulin and raising Regular Insulin is the stiffeners of Regular Insulin, chromium methionine still is the scavenging agent of free radical, its effect is similar with SOD, and can suppress the generation of free radical, therefore, can promote to be subjected to the recovery of pancreas function of radical damage and the activity of improving the pancreas enzyme is the rehabilitation agent of pancreas function.
Chromium methionine is still methyl donor in vivo, promote choline synthetic and with the fat effect of accumulating in the liver, become the Yelkin TTS of easy absorption, can prevent and treat the liver lipopexia, clinically be used for poisonings such as hepatitis, liver cirrhosis, fatty liver, alcohol and sulfanilamide (SN).
2. glyburide: this product is a white crystalline powder, and odorless, tasteless is a sulfonylurea s-generation oral antidiabetic drug.Pharmacological action is, in the initial period is to stimulate the beta Cell of islet excreting insulin with function, though stimulate the islet secretion effect to reduce gradually when non insulin dependent diabetes is taken for a long time, but hypoglycemic activity still can continue, have beyond the beta Cell of islet and pancreas acts on outward, it also has slight diuretic properties.
The side effect of glyburide mainly is a hypoglycemia, especially to the elderly and excessive drinking, impaired renal function and with can strengthen its pharmaceutically-active medicine compatibility, more can increase risk of hypoglycemia.
3. N1,N1-Dimethylbiguanide: be the biguanides oral antidiabetic drug, invalid to insulinopenic patient.Main effect is the output that reduces liver starch, strengthens the picked-up of surrounding tissue to glucose, reduces to refer to the fat acid oxidase and increase glucose transport carrier GLUT
4Quantity.N1,N1-Dimethylbiguanide is not put on weight, can reduce plasma insulin level, can be used as the non-line medicine of obesity person according to the plain dependent diabetes in island, to non-obese person with high triglyceride, low hdl, high Profibrinolysin activates the horizontal person of supressor, and N1,N1-Dimethylbiguanide is also helpful.Studies show that recently, can make glycerine oxyphorase (HbAlc) level further reduce by 1.7% to 1.8% with N1,N1-Dimethylbiguanide.
That side effect has is nauseating, flatulence, diarrhoea and stomachache convulsion are twin etc., but Most patients is along with the time can disappear.It should be avoided liver, ephrosis, heart trouble and respiratory function deficiency person by renal excretion, and the medication age limit is below 70 years old.
4. vehicle, except that main ingredient, all auxiliary materials that react with main ingredient are not referred to as vehicle, comprise that this medical instrument has the starch slurry of sorption and diluting effect and the dry starch of good disintegration is arranged, also have the talcum powder tool lubricated, anti-stick, help effects such as stream, absorption.
(note)
1. the chromium methionine fearness is damp and hot, need directly enter sheeting process, perhaps adopts Alpha-starch and other main ingredient direct to piece together compressing tablet.
2. the consumption of starch making beating should increase or reduce by the quality weight of main ingredient when this product was granulated.
3. the main ingredient glyburide of this product can replace with new antidiabetic drug, and that introduces in the document has new sulfonylurea glimepiride (Drugs, 1997; 54 (3); 355～368), good effect, side effect is little.
4. the tablet of this medicine can replace with capsule, selects suitable capsule for use according to clinical needs.
Embodiment two: No. two, Jiangtangyikang tablet (capsule) (Hypoglycemic Pancreas RecoveryTablets (Capsule) No.2, HPRT 1)
Every of this product contains chromium methionine and should be 2mg (wherein containing Cr (III) 100 μ g), contains N1,N1-Dimethylbiguanide and should be 250mg, contains acarbose and should be 10mg.
(prescription)
Chromium methionine 2g
N1,N1-Dimethylbiguanide 250g
Acarbose 100g
Vehicle is an amount of
Make 1000
(method for making) gets N1,N1-Dimethylbiguanide 250g crystalline powder, and the fine powder mixing of acarbose powder 100g and starch adds 10% starch slurry; mix granulation thoroughly; in oven dry below 60 ℃, processing, mixing is pressed into sheet with weight; fragmentation is sieved then; make whole grain, add chromium methionine solution and dried particle mixing again, add 3% talcum powder; mixing, compressing tablet are promptly.
(effect and purposes) promotes pancreas function to recover and strengthen the physiological action of Regular Insulin, and the speed of intestinal absorption glucose is slowed down, and prevents blood sugar increasing.Also have the fat of inhibition, amino acid and cholate absorption and suppress the liver starch heteroplasia and liver starch output.
Be applicable to the non insulin dependent diabetes obese person, have antiobesity action.
(usage and consumption) is oral, every day 3 times, each 1, obeys during dining.
(storage) sealing, dry place preserves
(prescription analysis)
1. chromium methionine is the coordination compound of the methionine(Met) of a kind of life essential metal trace element Cr (III) and needed by human, this product is a white crystalline powder, have off-odor, little sweet, be slightly soluble in water, it is the target medicament of pancreas, oral after intestinal absorption is more than 97%, amount in pancreas is than high 7～8 times in liver, having additional human body lacks chromium and promotes the effect that impaired pancreas function recovers, also can promote the susceptibility of the secreting function and the raising Regular Insulin of pancreas islet, reduce insulin resistant; Chromium methionine also is a kind of oxidation inhibitor, can not only strengthen the removing to free radical of Cr (III) and methionine(Met), also suppresses the generation of free radical, has the activity of improving the pancreas enzyme, recovers the effect of impaired pancreas function; Chromium methionine is the donor of methyl, and the fat of becoming effect and detoxification are arranged, for fatty liver and good with curative effects such as the chronic hepatitis of fatty infiltration, liver cirrhosis.
2. N1,N1-Dimethylbiguanide: be the biguanides oral antidiabetic drug, invalid to insulinopenic patient.This medicine does not stimulate insulin secretion, but can strengthen the physiological action of Regular Insulin, and the speed of intestinal absorption glucose is slowed down, and prevents that blood sugar from raising rapidly, can also reduce the liver starch heteroplasia, reduces the output of liver starch, strengthens the picked-up of surrounding tissue to glucose; Reduce Fatty Acid Oxidation and increase glucose transport carrier GLUT
4Quantity.Because this medicine depress appetite so be commonly used for diet pill, is particularly useful for the non insulin dependent diabetes obese patient, to non-obese patient, activate supressor person with high glyceryl ester, low hdl, high Profibrinolysin, also helpful.Can make glycerine oxyphorase (HbAl with N1,N1-Dimethylbiguanide
c) level further reduces by 1.7%～1.8%.
That the common side effect of this medicine has is nauseating, flatulence, diarrhoea and spasmodic colic etc., but Most patients can disappear in time.Orally discharge through kidney, should avoid liver, kidney, heart trouble and respiratory function deficiency person are arranged, age limit is below 70 years old.
3. acarbose: this medicine is α-glucosidase inhibitor, this medicine enters behind the enteron aisle can be competitively and dose-dependently ground inhibition enteron aisle α-glucosidase, glucose can't be combined with it, thereby various carbohydrates just can not further be processed and be absorbed, cause postprandial blood sugar and insulin level slowly and a small amount of the rising, can improve dietetic treatment, oral antidiabetic drug or with Regular Insulin patient's glucostasis index.Can make glycerine oxyphorase (HbAlc) level reduce 0.5%～3%.The mechanism of action of this medicine can be summarized as, and raises obstacles from the incoming road of glucose, rather than promotes its utilization.
Side effect is GI intolerance, and is main relevant with dosage, and is a property crossed, and how to find that therefore, dosage should slowly increase in the first few weeks of treatment, adjusts gradually.
4. vehicle: remove not all additional materials that react with main ingredient and comprise, have the starch slurry of sorption and diluting effect and the dry starch of good disintegration is arranged, reach the talcum powder that tool is lubricated, anti-stick, help stream, absorption etc. to act on, and help the auxiliary material that tablet is made.
(note)
1. chromium methionine is to damp and hot instability and the less medicine of dosage is selected blank particle method for use.
2. the consumption of starch making beating should increase or reduce by the quality weight of main ingredient when this product was granulated.
3. the tablet of this product can replace with capsule, selects suitable capsule for use according to the clinical pharmacology needs.
Embodiment three: and No. three, Jiangtangyikang tablet (capsule) (Hypoglycemic Pancreas RecoveryTablets (Capsule) No.3, HPRT-3)
Every of this product contains chromium methionine and should be 2mg (wherein containing Cr (III) 100 μ g), contains Glurenor and should be 15mg.
(prescription)
Chromium methionine 2g
Glurenor 15g
Vehicle is an amount of
Make 1000
(method for making) gets chromium methionine crystal powder 2g (wherein containing Cr (III) 100 μ g), Glurenor powder 15g, and mixing adds Alpha-starch 75g, and the well-established law direct compression is promptly.
(effect and purposes) chromium methionine and Glurenor synergy are improved the beta Cell of islet function and are promoted the endogenous insulin secretion, recover impaired pancreas function, eliminate insulin resistant, increase the susceptibility of Regular Insulin.
This medicine is rapid from the gi tract intracellular metabolite, and its meta-bolites non-activity has only 5% be the maximum characteristics of this medicine by discharging in the urine, is used for non-insulin-depending type the old and new diabetic subject of existing certain renal insufficiency.
(usage and consumption) oral every day 2 times, each 2
(storage) sealing, shady and cool dry place preserves
(prescription analysis)
1. chromium methionine is by the organic coordination compounds of life essential metal trace element chromium Cr (III) and essential amino acid, and this product is a white powder, little frowziness, little sweet, be slightly soluble in water.Be the medicament of pancreas target, the amount of oral back in pancreas is than high 7～8 times in liver.Lack chromium by replenishing human body, especially replenish the susceptibility that chromium promotes the islet secretion function and improves Regular Insulin, lower insulin resistant performance insulin physiological function to pancreas; The antioxidant effect of chromium methionine is stronger, can target arrival pancreas, can not only remove the free radical of pancreas, suppress the generation effect of free radical in addition, improve the activity of pancreas enzyme, promote the recovery of impaired pancreas function; Chromium methionine still is the donor of methyl, and the steatolysis toxic action of dispelling is for fatty liver and good with curative effects such as the chronic hepatitis of fatty infiltration, liver cirrhosis.
2. Glurenor: be sulfonylurea s-generation oral antidiabetic drug, pharmacokinetics shows as can be rapidly by gastrointestinal absorption after oral, the concentration that in 2～3 hours, promptly peaks, after beginning descends rapidly slowly to 8～10 hours.With other sulfonylurea difference be that its non-activity metabolite is discharged through gi tract again, have only 5% to discharge, for existing certain renal insufficiency and the good diabetic subject of liver function can use this medicine through kidney.
Pharmacological action is similar to other sulfonylureas, all is to promote the endogenous insulin secretion to realize blood sugar reducing function by improving the beta Cell of islet function.
3. vehicle: adopt the Alpha-starch direct compression, can keep its stability, prolonged the time limit of service of medicament to the chromium methionine of damp and hot sensitivity.
(note)
1. chromium methionine adopts the Alpha-starch direct compression to damp and hot instability, can avoid causing that content and drug effect descend.
2. adding Magnesium Stearate in the direct compression prescription can not be above 0.5%, in order to avoid produce softening effect as the amount of lubricant.
3. the tablet of this product can replace with capsule, selects capsule for use by clinical pharmacology as required.
Embodiment four: No. four, Jiangtangyikang tablet (capsule) (Hypoglycemic Pancreas RecoveryTablets (Capsule) No.4, HPRT-4)
Every of this product contains chromium methionine and should be 2mg, wherein contains Cr (III) 100 μ g, contains oral insulin and should be 15 units.
(prescription)
Regular Insulin 400g
Chromium methionine 2g
Vehicle is an amount of
Make 1000
(method for making) gets 400 gram insulin crystals powder, with the solid support material alkyl cyanoacrylate, by polyreaction, with the Regular Insulin parcel, forms the insulin microsphere of microparticulate system in polymerization process, and particle diameter is at 0.2～0.6 μ m.Through dialysis tubing (aperture is 0.2 μ m) dialysis, with super absorbent pregelatinized starch (Alpha-starch), the moisture in the Alpha-starch is taken off driedly in advance Regular Insulin millimicro ball, add methionine(Met) 2g crystalline powder, mixing is pressed the well-established law direct compression promptly.
(effect and purposes) supplementation with insulin deficiency is kept the eubolism of body tissue.No matter the patient of insulin-dependent diabetes mellitus has or not ketoacidosis and other complication, must adhere to making insulinize and even lifelong; Decline is unsatisfied with the person, should uses Regular Insulin control treatment with complication and gerontal patient to non insulin dependent diabetes oral antidiabetic drug blood sugar.
(usage and consumption) is oral, every day 2 times, early, evening each 1 time, each 1-2 sheet.
(storage) sealing, 10 ℃ of dry places preserve.
(prescription analysis)
1. Regular Insulin: the protein hormone of forming by 51 amino acid.According to the length difference of time that plays a role and acting duration, be divided into three types of Semilente Insulin (regular insulin), intermediate-acting insulins (low smart protamine zinc insulin(PZI)), protamine zine insulins (protamine zinc insulin(PZI)) etc.
The pharmacodynamics of Regular Insulin is, the deficiency of supplementation with insulin is kept the eubolism of body tissue, can suppress liver starch and decompose and glyconeogenesis, reduces liver output glucose, impels the synthetic of liver ingestion of glucose and liver starch; Impel muscle and fatty tissue ingestion of glucose and amino acid, impel the synthetic and storage of fat; Impelling liver to generate vldl increases, and suppresses fat and proteinic decomposition, suppresses the utilization of ketoboidies.Intensive insulin therapy can also prevent the microvascular complication of type II diabetes people.
2. chromium methionine is the medicament with pancreas target, can replenish human body and lack chromium and methionine(Met) deficiency, promotes the susceptibility of the secreting function and the raising Regular Insulin of pancreas islet, reduces the resistance of Regular Insulin; The antioxidant effect of chromium methionine is very strong, can not only remove free radical, suppresses the effect of free-radical generating in addition, therefore, has the recovery that promotes impaired pancreas function, improves the activity of pancreas enzyme; Chromium methionine is the donor of methyl, has the fat of dispelling and detoxification, for fatty liver and good with curative effects such as the chronic hepatitis of fatty infiltration, liver cirrhosis.
3. vehicle: select for use Alpha-starch to have the disintegrating agent effect of weighting agent, tackiness agent and direct compression, removed from wet, heat sensitive Regular Insulin, chromium methionine etc. are caused degradation destruction under protein denaturation, content and the drug effect with wet granulation.
(note)
1. Regular Insulin is protein, to damp and hot instability, is that proteolytic ferment destroys at gi tract, for keeping its pharmacodynamic stability, be that carrier is made the millimicro ball with alkyl cyanoacrylate, again water is granulated through the drying of dialysing, cross 20 mesh sieves, with the chromium methionine mixed pressuring plate.
The carrier of Regular Insulin millimicro ball can also have microballoon (Luo Mingsheng, Gao Tianhui chief editor of one's own with carboxymethylation crosslinked dextran and Regular Insulin.The pharmaceutical necessities complete works, the 1995:p.135 of Sichuan science tech publishing house～142), through dialysis Alpha-starch compressing tablet.
2. chromium methionine is to damp and hot instability, and dosage is less, adopts crystalline powder Alpha-starch direct compression.
3. prepare the mixing Regular Insulin of the preparation selection of Regular Insulin millimicro ball, the ratio of its protamine zine insulin and Semilente Insulin can be 1: 2,1: 3, or 1: 4.
4. the tablet of this product can replace with capsule, selects capsule for use by clinical pharmacology as required.
Claims (10)
1. by life metal trace element three prices of needed by human and the methionine(Met) synthetic organic coordination compounds chromium methionine of needed by human, with the definite diabetes ofhypoglycemic medicine of clinical efficacy through optimizing, compatibility, the inventive features of the preparation of the chromium methionine that is combined into and composition Jiangtangyikang tablet (capsule) series (being called for short Jiangtangyikang tablet (capsule)) thereof is, the methionine(Met) and central ion trivalent chromium that will have electron donor with electron pair receptor, by electrocatalysis or transfer transport or substitution reaction, make contained the most common most important coordinating group sulphur (S) atom and other bonded nitrogen (N) of combining with metal ion on the methionine(Met) side chain hydrophobic group, the coordinate bond of oxygen (O) and carbon (C) atom and trivalent chromium synthetic methionine chromium coordination compound, different but diabetes antidiabetic drugs that clinical pharmacology effect identical different of chromium methionine with pancreas target and binding mode definite and directly the Regular Insulin millimicro ball compatibility prescription of oral application and the auxiliary material that suits are combined into oral tablet or capsule by preparation technique with site of action with clinical efficacy, make the complementary and synergy of combination of traditional Chinese medicine deposits yields, medicament curative effect enhancement, reduce side effect, become increase insulin sensitivity with treatment diabetes and reduce resistivity the effect of Regular Insulin stiffeners, have again and remove free radical and suppress the medicinal composition that free-radical generating promotes the effect of impaired pancreas function rehabilitation agent.Series of the present invention is used for the adjustment blood sugar treatment of diabetes, and wherein the radical damage pancreas function that also proposes at the contriver of chromium methionine is that the etiology of non insulin dependent diabetes carries out etiological treatment.
2. the preparation of chromium methionine according to claim 1 and composition Jiangtangyikang tablet (capsule) series thereof is characterized in that, the methionine(Met) of described chromium methionine coordination compound is as electron donor, with the chromic strong combining site of metal ion except that sulphur (S) atom of side chain hydrophobic group, also have nitrogen (N), oxygen (O) and carbon (C) atom, synthetic method can be the electrocatalysis method, also can be the transfer transport method, can also be the multiple chromium methionine coordination compoundes of formation such as substitution reaction method.
3. the preparation of chromium methionine according to claim 1 and composition Jiangtangyikang tablet (capsule) series thereof is characterized in that, described methionine(Met) as part under the physiological pH condition, can suppress chromic olation effect, keep chromic reinforcement insulin physiological function, participate in distinctive biologic activity such as body sugar and metabolism of fat and removing free radical.
4. the preparation of chromium methionine according to claim 1 and composition Jiangtangyikang tablet (capsule) series thereof is characterized in that, described chromium methionine has the characteristic to arrival of pancreas target and distribution, can be with trivalent chromium and methionine(Met) targeted delivery to the pancreas position that is difficult to enter, have the characteristic carrier that the target medicine of treatment and diagnosis pancreatic disease transmits.
5. the preparation of chromium methionine according to claim 1 and composition Jiangtangyikang tablet (capsule) series thereof is characterized in that, described diabetes ofhypoglycemic medicine with the chromium methionine combination comprises the medicine of adjustment blood sugar such as sulfonylurea, biguanides, glucosidase inhibitor and oral insulin millimicro ball, developing the new drug that may be used for treating diabetes in addition, with two or more pharmacokinetics wherein is identical and binding mode different and the site of action difference can produce complementary action and becomes integral body with synergistic drug regimen.
6. the preparation of chromium methionine according to claim 1 and composition Jiangtangyikang tablet (capsule) series thereof is characterized in that, described Jiangtangyikang tablet (capsule), according to the clinical application needs and the market requirement, the compatibility prescription drug of tablet is made particle be divided in and be combined into oral capsule in the suitable capsule and replace tablet for clinical and patient's use.
7. the preparation of chromium methionine according to claim 1 and composition Jiangtangyikang tablet (capsule) series thereof is characterized in that, described Jiangtangyikang tablet (capsule) series, be meant No. four, No., the described Jiangtangyikang tablet of embodiment (capsule), No. two, Jiangtangyikang tablet (capsule), No. three, Jiangtangyikang tablet (capsule) and Jiangtangyikang tablet (capsule), also comprise the new drug that may be used for the treatment of diabetes and the composition Jiangtangyikang tablet (capsule) of patent drugs and existing antidiabetic drug.
8. the preparation of chromium methionine according to claim 1 and composition Jiangtangyikang tablet (capsule) series thereof is characterized in that, the dosage of the main ingredient compatibility in described tablet or the capsule increases or reduces according to the dose titration that clinical needs carry out in the safety range, and diabetes antidiabetic drug and chromium methionine all are the main ingredients in the preparation.
9. the preparation of chromium methionine according to claim 1 and composition Jiangtangyikang tablet (capsule) series thereof is characterized in that, described oral insulin is that Semilente Insulin and protamine zine insulin were made into mixing Regular Insulin in 2: 1 by a certain percentage or 3: 1, aggregate into the insulin microsphere dispersion system with alkyl cyanoacrylate, can be that carrier and Regular Insulin have microballoon of one's own also with the crosslinked dextran of carboxymethylation, through dialysis tubing dialysis make particle with Alpha-starch, with the chromium methionine direct compression or be sub-packed in and make oral capsule in the capsule.
10. the preparation of chromium methionine according to claim 1 and composition Jiangtangyikang tablet (capsule) series thereof is characterized in that, the etiology of the diabetes of described radical damage pancreas function, be according to many-sided synthetic studies such as epidemiology and clinical observations, the contriver has proposed radical damage, and to cause pancreas function be to cause that maturity-onset diabetes is the etiology of non insulin dependent diabetes unusually, be an important factor in the still not clear Different types of etiopathogenises of present diabetes, chromium methionine is the etiological treatment medicine at the radical damage pancreas function.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 98120143 CN1218054A (en) | 1998-10-09 | 1998-10-09 | Preparation of chromium methionine and its composition as Jiangtangyikang tablets (capsules) series |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 98120143 CN1218054A (en) | 1998-10-09 | 1998-10-09 | Preparation of chromium methionine and its composition as Jiangtangyikang tablets (capsules) series |
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|---|---|
| CN1218054A true CN1218054A (en) | 1999-06-02 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002072078A3 (en) * | 2001-03-13 | 2002-12-12 | Erich Eigenbrodt | Use of sugar phosphates, amino acids, amino acid analogs, e.g. carbomethoxypropionyl cyanide for reducing weight or diabetes complications |
| WO2007121312A3 (en) * | 2006-04-12 | 2008-05-15 | Interhealth Nutraceuticals Inc | Trivalent chromium compounds, compositions and methods of use |
| CN102552290A (en) * | 2012-02-23 | 2012-07-11 | 重庆康刻尔制药有限公司 | Glimepiride medicinal composition tablets and preparation method and application thereof |
| CN102631433A (en) * | 2012-04-07 | 2012-08-15 | 恩施尚灵生物医药科技有限公司 | Capsule for treating diabetes |
-
1998
- 1998-10-09 CN CN 98120143 patent/CN1218054A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002072078A3 (en) * | 2001-03-13 | 2002-12-12 | Erich Eigenbrodt | Use of sugar phosphates, amino acids, amino acid analogs, e.g. carbomethoxypropionyl cyanide for reducing weight or diabetes complications |
| WO2007121312A3 (en) * | 2006-04-12 | 2008-05-15 | Interhealth Nutraceuticals Inc | Trivalent chromium compounds, compositions and methods of use |
| US9700546B2 (en) | 2006-04-12 | 2017-07-11 | Interhealth Nutraceuticals, Inc. | Trivalent chromium compounds, compositions and methods of use |
| CN102552290A (en) * | 2012-02-23 | 2012-07-11 | 重庆康刻尔制药有限公司 | Glimepiride medicinal composition tablets and preparation method and application thereof |
| CN102631433A (en) * | 2012-04-07 | 2012-08-15 | 恩施尚灵生物医药科技有限公司 | Capsule for treating diabetes |
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