CN1806796B - Pharmaceutical composition containing valibose, its preparation method and application - Google Patents
Pharmaceutical composition containing valibose, its preparation method and application Download PDFInfo
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- CN1806796B CN1806796B CN 200510002327 CN200510002327A CN1806796B CN 1806796 B CN1806796 B CN 1806796B CN 200510002327 CN200510002327 CN 200510002327 CN 200510002327 A CN200510002327 A CN 200510002327A CN 1806796 B CN1806796 B CN 1806796B
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Abstract
The invention relates to a pharmaceutical composition containing Weilibo sugar and its preparing process, wherein the composition comprises 0.5-50mg of pharmaceutically acceptable Weilibo sugar and optional carrying agent. The invention also provides the use of the pharmaceutical composition in the preparation of medicament for the treatment or prevention of diabetes and diabetes-related diseases.
Description
Technical field
The present invention relates to contain the compositions of kind of alpha glycosidase inhibitor, relate in particular to the pharmaceutical composition that contains kind of alpha glycosidase inhibitor.
The invention still further relates to this preparation of drug combination method.
The invention still further relates to the application of this pharmaceutical composition in field of medicaments.
Background technology
Kind of alpha glycosidase inhibitor (valibose) (chemical name: (+)-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-N-2-(1, the 3-dihydroxypropyl)-2,3,4-phloroglucite) in U.S. Pat 4,701, be disclosed in 559 and US4,777,294, its structural formula [I] is:
Kind of alpha glycosidase inhibitor is a kind of alpha-glucosidase inhibitor, can compete antagonism ground after oral and suppress disaccharidase class hydrolytic enzyme (alpha-glucosidase) in the intestinal, thereby delay the digestion and the absorption of saccharide, and then improve postprandial hyperglycemia.Postprandial hyperglycemia can make the effect of secretion of insulin and insulin obstacle occur, and carbohydrate metabolism is further worsened, and therefore correcting postprandial hyperglycemia is very important for the development that prevents diabetes and complication thereof.
Diabetes are a kind of carrying out property of chronic whole body incretion metabolism diseases, comprise insulin dependent diabetes mellitus (IDDM) (IDDM, I type) and non-insulin-dependent diabetes mellitus (NIDDM, II type).Because insulin is relative or absolute not enough in the body, form the hyperglycemia of persistence, cause some histoorgan Developmental and Metabolic Disorder, cause that then their dysfunction and form change, the easiest what endangered is that retina, kidney, blood vessel and nervous system etc. are unusual.
The relevant diabetologist statistics of World Health Organization (WHO): because of losing one's sight that diabetes cause than common people's many 10～23 times; Diabetic gangrene and amputation are than common people's many 20 times; Diabetes complicated coronary heart disease and apoplexy are than 2～3 times of common people's increases; The renal failure that diabetes cause is Duoed 7 times than general nephropathy; The diabetes genetic ring is 1.90%～8.33%.At present, the mortality rate that diabetic complication caused is only second to the mortality rate of cardiovascular diseases, cerebrovascular and tumor.The middle and elderly diabetic patient often dies from coronary heart disease, myocardial infarction, apoplexy; The concurrent renal failure of juvenile diabetes patient Chang Yin and death.In addition, diabetes complicated severe infection, acidosis, hyperosmolar coma etc. also are main fatal reasons.
At present still there is not document to show that kind of alpha glycosidase inhibitor single, particular day dosage has useful especially effect to glycemic control, and therefore particularly useful to treatment diabetes and the disease relevant with diabetes, also less than this is single about containing, the report of the pharmaceutical composition of the kind of alpha glycosidase inhibitor of particular day dosage and preparation method thereof.
Summary of the invention
One object of the present invention is to provide the pharmaceutical composition that contains kind of alpha glycosidase inhibitor.
Another object of the present invention is to provide the preparation method of said composition.
A further object of the present invention be to provide said composition preparation treat and/or prevent diabetes and with the medicine of diabetes diseases associated in application.
According to an aspect of the present invention, the invention provides the pharmaceutical composition that contains kind of alpha glycosidase inhibitor, said composition contains the kind of alpha glycosidase inhibitor and the optional pharmaceutically acceptable carrier of the pharmaceutically acceptable form of 0.5～50mg.Preferably, this pharmaceutical composition is the compositions of unit dose.
Unit dose of the present invention is meant the dosage of single administration.For example, when adopting kind of alpha glycosidase inhibitor treatment diabetes and diseases associated thereof, each administration 2.5mg, be administered three times every day, and then the unit dose of kind of alpha glycosidase inhibitor pharmaceutical composition is 2.5mg.
The kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form that is fit to comprises pharmaceutically acceptable salt form and pharmaceutically acceptable solvate forms, the pharmaceutically acceptable solvate forms that also comprises pharmaceutically acceptable salt, wherein said kind of alpha glycosidase inhibitor are pharmaceutically acceptable amorphous state or crystal habit.
Suitable compositions contains 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,15,20,25,30,35,40,45, the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 50mg.
Concrete compositions contains the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 0.5～2.5mg.
Concrete compositions contains the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 2.5～5mg.
Concrete compositions contains the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 5～10mg.
Concrete compositions contains the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 10～15mg.
Concrete compositions contains the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 15～50mg.
Preferred compositions contains the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 2.5mg.
Preferred compositions contains the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 5mg.
Preferred compositions contains the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 7.5mg.
Preferred compositions contains the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 10mg.
Preferred compositions contains the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 15mg.
Particularly preferred compositions contains the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 2.5mg.
The suitable pharmaceutically acceptable form of kind of alpha glycosidase inhibitor is included in US4, and the amorphous state of describing in 701,559 also comprises crystal habit.The form of preferred pharmaceutical compositions is the kind of alpha glycosidase inhibitor of crystal habit.
The suitable pharmaceutically acceptable salt form of kind of alpha glycosidase inhibitor comprises hydrochlorate, sulfate, maleate, phosphate etc., and the salt form of preferred pharmaceutical compositions is a hydrochlorate.
The suitable pharmaceutically acceptable solvate forms preferred water compound of kind of alpha glycosidase inhibitor.
According at US 4,701,559 and US 4,777,294 in disclosed method, can prepare the kind of alpha glycosidase inhibitor and the hydrochlorate thereof of amorphous state; According to the method that those skilled in the art knew, can prepare other pharmaceutically acceptable salt or the solvate of kind of alpha glycosidase inhibitor; In addition, preparation method described later can prepare the kind of alpha glycosidase inhibitor and the hydrochlorate thereof of crystal habit according to the present invention.
Kind of alpha glycosidase inhibitor can exist with one of several tautomeric forms, and term " kind of alpha glycosidase inhibitor " comprises used these independent tautomeric forms or their mixture.
Therefore kind of alpha glycosidase inhibitor contains chiral carbon atom, can exist with two kinds of stereoisomer forms of as many as, and term " kind of alpha glycosidase inhibitor " comprises the isomer that these are independent or the isomeric forms of mixture of isomers, comprises racemate.
" pharmaceutically acceptable " of the present invention comprises human and two kinds of purposes for animals, promptly comprises acceptable chemical compound and acceptable chemical compound for animals on the human.
For avoiding query, when providing the scalar of pharmaceutically acceptable kind of alpha glycosidase inhibitor when (comprising mg amount and weight % amount) in the present invention, the scalar of indication is with reference to the amount of kind of alpha glycosidase inhibitor itself, and for example the kind of alpha glycosidase inhibitor of 2.5mg hydrochloride form is the amount that contains the hydrochlorate of 2.5mg kind of alpha glycosidase inhibitor.
In the present invention, preferred kind of alpha glycosidase inhibitor pharmaceutical composition is the compositions of unit dose.When unit dose during less than 0.5mg, do not reach effective blood drug level because dosage is too for a short time, do not have therapeutical effect; When unit dose when 0.5mg is increased to 2.5mg, preferable therapeutic effect can appear; When unit dose surpassed 2.5mg, in present animal experiment, blood drug level reached capacity; In addition, acute toxicity test shows that kind of alpha glycosidase inhibitor has very high drug safety.Therefore, when the unit dose of kind of alpha glycosidase inhibitor pharmaceutical composition in this scope of 2.5～50mg, all can show better therapeutic effect, when clinical practice, can select as required.The unit dose of the preferred kind of alpha glycosidase inhibitor pharmaceutical composition of the present invention is 2.5mg, to save drug cost.Yet, those skilled in the art will appreciate that other dosage that is included in 2.5～50mg also should be within the scope of the present invention.
Same medicine, the dosage form difference, its used dosage is also inequality.If when kind of alpha glycosidase inhibitor preparation of pharmaceutical compositions of the present invention is become sustained-release preparation, then the unit dose of said composition can increase along with the minimizing of medication every day number of times accordingly.For example, when the kind of alpha glycosidase inhibitor pharmaceutical composition was made unit dose and is the common oral preparation of 2.5mg, be administered three times every day, each administration 2.5mg; When the kind of alpha glycosidase inhibitor pharmaceutical composition was made once sustained-release preparation of oral administration every day, the unit dose of said composition should be about 7.5mg.Those skilled in the art will appreciate that the above-mentioned dose titration that change is done according to dosage form should be within the scope of the present invention.
According to another aspect of the present invention, the invention provides the kind of alpha glycosidase inhibitor that contains the pharmaceutically acceptable form of 0.5～50mg and the preparation of drug combination method of pharmaceutically acceptable carrier, this method comprises that the kind of alpha glycosidase inhibitor with the pharmaceutically acceptable form of 0.5～50mg mixes with pharmaceutically acceptable carrier, and optional subsequently the compositions that produces is formulated as the form that can supply with medicine.
The medicine the supplied with form of the pharmaceutical composition of preferred kind of alpha glycosidase inhibitor is the compositions of unit dose.
Except that specializing, the unit dose that is fit to contains as many as 50mg, as the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 0.5～50mg.
Other unit dose comprises those mentioned in this manual dosage.
Method of the present invention can provide any pharmaceutical composition that makes things convenient for the kind of alpha glycosidase inhibitor of form of medication, comprises per os or parenteral form.They are particularly suitable for being prepared as the tablet of the kind of alpha glycosidase inhibitor of oral administration form, particularly pharmaceutically acceptable form.
In a specific embodiments of the present invention, the kind of alpha glycosidase inhibitor pharmaceutical composition contains kind of alpha glycosidase inhibitor, disintegrating agent, binding agent, diluent and the lubricant of pharmaceutically acceptable form.Suitable disintegrating agent is a crospovidone; Suitable adhesive is the hydroxypropyl emthylcellulose binding agent; The suitable dilution agent is a lactose; Suitable lubricant is a magnesium stearate.
It is the conventional formulation method that compositions of the present invention is formulated as the method that can supply with the medicine form, as pressed disc method.
The compositions that preferred the present invention can supply with medicine is fit to oral administration.Yet they also are suitable for other route of administration, as parenteral, Sublingual or transdermal administration.
The compositions that can supply with medicine can be tablet, capsule, powder, granule, lozenge, suppository, reconstitutable powders or liquid preparation (as oral or aseptic parenteral solution or suspension).
For obtaining the concordance of administration, preferred compositions of the present invention is a unit dosage forms.
The unit dosage forms of oral administration can be tablet and capsule, and they can contain conventional excipients such as binding agent as syrup, dextrin, starch slurry, arabic gum, gelatin, sorbitol, Tragacanth, hydroxypropyl emthylcellulose or polyvinylpyrrolidone; Filler such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, mannitol, microcrystalline Cellulose, calcium sulfate or glycine; Tabletting lubricant such as magnesium stearate; Disintegrating agent such as cross-linking sodium carboxymethyl cellulose, starch, polyvinylpyrrolidone, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose or microcrystalline Cellulose or pharmaceutically acceptable wetting agent such as sodium lauryl sulphate, water, ethanol.
Except that specializing, preferred compositions of the present invention is the unit dosage forms as the appropriate amount of corresponding daily dose, and suitable unit dosage forms contains 0.1,0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,15,20,25,30,35,40,45 or the kind of alpha glycosidase inhibitor of the pharmaceutically acceptable form of 50mg.
The pharmaceutical composition of unit dose of the present invention (as previously mentioned, being the dosage of single administration) can be mixed with one or more unit dosage forms as required.For example, when unit dose is 2.5mg, can be formulated as a tablet that contains the 2.5mg kind of alpha glycosidase inhibitor, also can be formulated as 5 tablets that contain the 0.5mg kind of alpha glycosidase inhibitor, can also be formulated as 25 tablets that contain the 0.1mg kind of alpha glycosidase inhibitor.Those skilled in the art will appreciate that under the prerequisite that the unit dose of compositions is not done to change, the adjustment of unit dosage forms number can cause the change of kind of alpha glycosidase inhibitor content in the unit dosage forms, this change should be within the scope of the present invention.
Can mix by conventional method, filling or tabletting prepare solid composite (as Orally administered composition).If desired, can repeat the married operation step described active component is scattered in the compositions of using a large amount of filleies.This type of operating procedure is this area routine.Can carry out coating to tablet according to the method for knowing in the pharmacy practice, particularly carry out coating with film coating thing aqueous solution.
Fluid composition (as liquid oral compositions) can be prepared as emulsion, syrup or elixir form, perhaps they is prepared as the desciccate form, water or other suitable solvent dissolving before use.This type of liquid preparation can contain conventional additive, as suspending agent as sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel, hydrogenation edible fat; Emulsifying agent such as lecithin, Arlacel-80 or arabic gum; Water-insoluble solvent (can comprise edible oil) is as almond oil, fractionated coconut oil, oily ester such as glycerol, propylene glycol or alcoholic acid ester; Antiseptic such as methyl parahydroxybenzoate or propyl ester or sorbitol; And can contain conventional correctives or coloring agent if desired.
Reactive compound and aseptic solvent as described in parenteral compositions (comprising that the parenteral compositions is as units dosage composition) can contain, according to the concentration of using, described reactive compound can be suspended in or be dissolved in this solvent.When preparing the solution of parenteral, compositions of the present invention can be dissolved in the water for injection filtration sterilization, fill also sealing in suitable glass tube vial or ampoule then.As described in preferably adjuvant being dissolved in as local anesthetic, antiseptic and buffer agent in the solvent.For increasing stability, freezing after the said composition fill is in glass tube vial and vacuum can be removed moisture.Can prepare the parenteral suspension with essentially identical method, but described reactive compound is to be suspended in the solvent rather than to be dissolved in the solvent, and degerming can not be undertaken by filtration.Described chemical compound can be sterilized by being exposed in the oxirane, then it is suspended in the aseptic solvent.Preferably contain surfactant or wetting agent in the said composition to help the uniform distribution of kind of alpha glycosidase inhibitor.
Except that specializing, according to the difference of medication, compositions of the present invention can contain the active substance of 0.1 to 99% (weight), preferred 10% to 60% (weight).
If desired, described compositions can be for having the packaged form of operation instruction.
According to a further aspect of the invention, the pharmaceutical composition that the invention provides the above-mentioned kind of alpha glycosidase inhibitor that contains the pharmaceutically acceptable form of 0.5～50mg treats and/or prevents application in the medicine of diabetes and the disease relevant with diabetes in preparation.
In the present invention, " diabetes " comprise type i diabetes and type ii diabetes.
" disease relevant with diabetes " comprises the disease relevant with prediabetes, disease and the diabetic complication relevant with diabetes itself.
" disease relevant with prediabetes " comprises as insulin resistance (comprising the heritability insulin resistance) disease, infringement property glucose tolerance and hyperinsulinemia.
" disease relevant with diabetes itself " comprises the insulin resistance hyperglycemia, comprises acquired insulin resistance and obesity.Other disease relevant with diabetes itself comprises hypertension; Cardiovascular disease, particularly atherosclerosis; Some eating disorder, particularly those need the disease of modulation of appetite and food intake, as with the very few relevant disease of feed as anorexia nervosa, and with the too much relevant disease of feed, as obesity and bulimia nerovsa (bulimia).Other disease relevant with diabetes itself comprises polycystic ovary syndrome and inductive insulin resistance of steroid and gestational diabetes.
Further, the described disease relevant with diabetes is obesity and/or bulimia nerovsa.
Further, the described disease relevant with diabetes is diabetic complication.
" diabetic complication " comprises acute complications and chronic complicating diseases.Acute complications comprises: various actute infection, hypoglycemia, diabetic ketoacidosis, diabetic lactoacidosis, diabetic hyperosmolar coma.Chronic complicating diseases means trunk, blood capillary and neuropathy.Chronic complicating diseases of diabetes comprises: the hyperlipemia of coronary heart disease, hypertension, cerebrovascular, nephropathy, ocular complications (retinopathy, cataract, ametropia, diabetic eye muscular nerve pathological changes etc.), neuropathy (peripheral neuropathy, vegetative nerve pathological changes and central neuropathy), diabetic foot, diabetic dermopathy, diabetic impotence, diabetics etc.Diabetic nephropathy comprises diabetic nephropathy, glomerulonephritis, glomerulosclerosis, the nephrotic syndrome, hypertensive nephrosclerosis and end-stage renal disease.
Further, diabetic complication of the present invention is a chronic complicating diseases.
Further again, diabetic complication of the present invention comprises the hyperlipemia and the diabetictrunk angiopathy of diabetic microvascular complication, diabetics, and wherein diabetic microvascular complication comprises diabetic retina microangiopathies and diabetic nephropathy etc.
Because kind of alpha glycosidase inhibitor is a kind of alpha-glucosidase inhibitor, can compete antagonism ground after oral and suppress disaccharidase class hydrolytic enzyme (alpha-glucosidase) in the intestinal, thereby the digestion and the absorption of saccharide have been delayed, and then improve postprandial hyperglycemia, therefore the pharmaceutical composition that contains kind of alpha glycosidase inhibitor of the present invention should every day just before the meal or with the meal administration, usually administration every day is 1～6 time, preferred administration every day 2～3 times.
Results of pharmacodynamic test shows that in the selected dosage range of the present invention, (1) kind of alpha glycosidase inhibitor is obviously alleviated the symptom more than three of diabetic animal, has reduced food-intake, illustrates that kind of alpha glycosidase inhibitor can be used for the treatment of the obesity that feed is too much and caused; (2) kind of alpha glycosidase inhibitor has obviously reduced fasting serum glucose, non-fasting serum glucose, serum fructosamine, glucose in urine, illustrates that kind of alpha glycosidase inhibitor has improved the carbohydrate metabolism of hyperglycemia animal, can be used for prevention or treatment diabetes; (3) kind of alpha glycosidase inhibitor has obviously improved the feature of change of diabetes early nephropathies such as serum N AG enzymatic activity, serum urea nitrogen content, kidney hypertrophy and renal cells glycogen deposition or retinal microvascular pathological changes, illustrates that kind of alpha glycosidase inhibitor can prevent or treat diseases such as diabetic microvascular complication; (4) kind of alpha glycosidase inhibitor has obviously reduced blood triglyceride and cholesterol level and cardiac index, illustrates that kind of alpha glycosidase inhibitor has to improve the unusual effect of diabetic lipid metabolism, can be used for prevention or diseases such as treatment diabetictrunk angiopathy and hyperlipemia.In sum, the pharmaceutical composition that contains kind of alpha glycosidase inhibitor of the present invention can prevent and/or treat diabetes and the disease relevant with diabetes.
The acute toxicity tests shows that kind of alpha glycosidase inhibitor has good drug safety in the selected dosage range of the present invention.
As mentioned above, the present invention has found, and kind of alpha glycosidase inhibitor single, particular day dosage has useful especially effect to glycemic control, and therefore particularly useful to treatment diabetes and the disease relevant with diabetes.
In order to understand essence of the present invention better,,, describe in detail but do not limit the present invention by description to better embodiment of the present invention below in conjunction with accompanying drawing.
Brief description of drawings
Fig. 1 is the influence of kind of alpha glycosidase inhibitor to STZ diabetes rat glucose in urine
Nor is the normal rat group, Con is a STZ diabetes rat matched group, kind of alpha glycosidase inhibitor (0.4mg), kind of alpha glycosidase inhibitor (0.9mg), kind of alpha glycosidase inhibitor (1.6mg) are kind of alpha glycosidase inhibitor administration group, and dosage is respectively 0.4mg/kg body weight, 0.9mg/kg body weight and 1.6mg/kg body weight; Compare with matched group Con,
*P＜0.05,
* *P＜0.001; N=8-10
Fig. 2 is the influence of kind of alpha glycosidase inhibitor to STZ diabetes rat kidney, cardiac index
Nor is the normal rat group, Con is a STZ diabetes rat matched group, kind of alpha glycosidase inhibitor (0.4mg), kind of alpha glycosidase inhibitor (0.9mg), kind of alpha glycosidase inhibitor (1.6mg) are kind of alpha glycosidase inhibitor administration group, and dosage is respectively 0.4mg/kg body weight, 0.9mg/kg body weight and 1.6mg/kg body weight; Compare with matched group Con,
*P＜0.05,
*P＜0.01,
* *P＜0.001; N=8-10
Fig. 3 is a normal rat group rat kidney pathological section light microscopic photo
The light microscopic photo shows that normal rat group rat kidney structure is normal, does not see pathological changes.
Fig. 4 is a STZ diabetes rat control rats kidney pathological section light microscopic photo
The light microscopic photo shows that the most of glomerular capsule fiber-like of hyperglycemia control rats is oozed out, epithelial cell slurry dissolving of the nearly straight portion of curved tube or vacuolar degeneration.
Fig. 5 is a kind of alpha glycosidase inhibitor 0.4mg/kg body weight administration group rat kidney pathological section light microscopic photo
The light microscopic photo shows that kind of alpha glycosidase inhibitor 0.4mg/kg body weight administration group rat small part glomerular capsule fiber-like is oozed out, epithelial cell slurry dissolving of the nearly straight portion of curved tube or vacuolar degeneration.
Fig. 6 is a kind of alpha glycosidase inhibitor 0.9mg/kg body weight administration group rat kidney pathological section light microscopic photo
The light microscopic photo shows that kind of alpha glycosidase inhibitor 0.9mg/kg body weight administration group kidney of rats bead is not seen significant change, and epithelial cell vacuolar degeneration situation reduces.
Fig. 7 is a kind of alpha glycosidase inhibitor 1.6mg/kg body weight administration group rat kidney pathological section light microscopic photo
The light microscopic photo shows that kind of alpha glycosidase inhibitor 1.6mg/kg body weight administration group kidney of rats bead is not seen significant change, and epithelial cell vacuolar degeneration situation reduces.
The specific embodiment
The equal crystal habit kind of alpha glycosidase inhibitor for being provided by Shenzhen Taitai Pharmaceutical Industry Co. Ltd. of employed kind of alpha glycosidase inhibitor in following pharmacodynamics test and acute toxicity test, other test material is commercially available purchase product if no special instructions.The concrete preparation method of this crystal habit kind of alpha glycosidase inhibitor and hydrochlorate thereof and the determination of physical appearance result of crystal habit kind of alpha glycosidase inhibitor are as follows:
I, preparation method
1, the preparation of raw material Validamine
Raw material Validamine can be by disclosed method preparation in the prior art document, for example: .J.Antibiotics24:57-58,1971 and Chem.Lctt., 1989,725-728 (Harii, s.j.T.Iwasa﹠amp; Y.Kameda) method of describing in, among the preparation technology of the present invention, the preparation of raw material Validamine be by by jinggangmycin A (available from Zhejiang Qian Jiang biochemistry corporation,Ltd., content 60%) obtain validoxylamineA through hydrolysis, by validoxylamineA and N-bromo-succinimide (NBS) reaction, obtain validamine again.Reaction equation is as follows:
With product CG-50NH
4 +The weak-type cationic resin column, the separation of 0.1N ammonia eluting obtains pure Validamine and Valienamine.
2, the preparation of crystal habit kind of alpha glycosidase inhibitor
Reaction equation is as follows:
In 2600 milliliters of absolute methanols (analytical pure), add Validamine104 gram (587 mM), 1,3 dihydroxy acetones, 82.3 gram (FRUKA97%, 886 mMs), (chemical industry company limited 97% is levied in Yingkou three to 10.4 milliliters in glacial acetic acid, sodium cyanoborohydride 76.5 grams, 1.18 back flow reaction 6 hours mole).After reaction finishes, steam and remove methanol, add 500 milliliters in water, be acidified to pH1.5 with 2N HCl, reuse NaOH is neutralized to pH6.Pass through PURLITEC100H respectively
+Type strong acid type cationic resin post (water/0.5N ammonia), YD CG-50NH
4 +Weak-type cationic resin column (0.1N ammonia), HZ-202OH-strong base resin anion (R.A.) post (H
2O), TLC follows the tracks of and detects (developing solvent: n-butyl alcohol: methanol: chloroform: ammonia=5: 4: 2: 5; Developer: 0.2% ethanol solution of ninhydrin; Rf=0.46 (validamine); Rf=0.52 (valibose)).Merge 1,2,3-indantrione monohydrate and be positive and the identical component of Valibose reference substance Rf value, be evaporated to driedly, use dissolve with ethanol, add the crystal seed crystallize, 93 restrain.Yield: 63.1%, mp:88-89 ℃.
3, the preparation method of the hydrochlorate of crystal habit kind of alpha glycosidase inhibitor
Get the kind of alpha glycosidase inhibitor (according to the preceding method preparation) of 2 gram crystal habits, be dissolved in water, stir and drip 2N HCl solution down,, continue to stir 2 hours to pH3, through the activated carbon chromatography post, H
2The O eluting is collected eluent (TLC trackings), and the sample concentration that obtains to doing, use recrystallizing methanol, filters, drying, gets the a kind of alpha glycosidase inhibitor hydrochlorate that restrains crystal habit.
II, crystal habit kind of alpha glycosidase inhibitor determination of physical appearance
Carry out nuclear magnetic resonance spectroscopy and elementary analysis discovery by the crystal habit kind of alpha glycosidase inhibitor that above-mentioned preparation method is obtained, crystal habit kind of alpha glycosidase inhibitor that is obtained and amorphous kind of alpha glycosidase inhibitor powder have obtained identical result, show kind of alpha glycosidase inhibitor and U.S. Pat 4 that this test obtains, 701, the kind of alpha glycosidase inhibitor that has been disclosed in 559 has identical chemical constitution, structural formula is (+)-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-N-2-(1, the 3-dihydroxypropyl)-2,3, the 4-phloroglucite).
1, nuclear magnetic resonance spectroscopy
Instrument: Varian500
The result:
1H-NMR (D
2O, 500MHZ) δ
1.32(1H，ddt，J＝3，1.5，15)，1.80-1.87(1H，m)，1.92(1H，dt，J＝3，15)，2.78(1H，m，J＝5.5)，3.15(1H，dd，J＝3.5)，3.25(1H，dd，J＝10.5).3.50-3.55(2H，m)，3.57(2H，t，J＝4.5)，3.62(2H，t，J＝5.5)，3.65(1H，dd，J＝5，11.5)，3.72(1H，dd，J＝3.5，11)；
13C-NMR(D
2O，75MHZ)δ
28.61，38.97，55.63，59.28，61.31，62.70，63.19，73.91，74.21，75.34
2, elementary analysis (C
10H
21NO
6)
Instrument: the German ELEMENTAR vario EL of company elemental analyser
Value of calculation: (%) C, 47.80; H, 8.42; N, 5.57
Measured value (twice): (%) C, 47.90/47.84; H, 8.56/8.57; N, 5.41/5.45
Pharmacodynamics test
[embodiment 1]
With the kind of alpha glycosidase inhibitor is trial drug, has investigated the influence of the kind of alpha glycosidase inhibitor of different daily doses to the general situation of streptozotocin diabetes rat, blood glucose, fructosamine, glucose in urine, blood NAG enzymatic activity, serum urea nitrogen and creatinine content, kidney pathological change and blood fat (comprising triglyceride, cholesterol and free fatty) and cardiac index.
In the long-term experiment of streptozotocin (STZ) diabetes rat feeding high sugar feed (5 week), when the daily dose of rat 〉=0.4mg/kg body weight, (1) kind of alpha glycosidase inhibitor is obviously alleviated the symptom more than three of diabetic animal, reduced food-intake, illustrated that kind of alpha glycosidase inhibitor can be used for the treatment of the obesity that feed is too much and caused; (2) kind of alpha glycosidase inhibitor has obviously reduced fasting serum glucose, non-fasting serum glucose, serum fructosamine, glucose in urine, illustrates that kind of alpha glycosidase inhibitor has improved the carbohydrate metabolism of hyperglycemia animal, can be used for prevention or treatment diabetes; (3) kind of alpha glycosidase inhibitor has obviously improved the feature of change of diabetes early nephropathies such as serum N AG enzymatic activity, serum urea nitrogen content, kidney hypertrophy and renal cells glycogen deposition or retinal microvascular pathological changes, illustrates that kind of alpha glycosidase inhibitor can prevent or treat diseases such as diabetic microvascular complication; (4) kind of alpha glycosidase inhibitor has obviously reduced blood triglyceride and cholesterol level and cardiac index, illustrates that kind of alpha glycosidase inhibitor has to improve the unusual effect of diabetic lipid metabolism, can be used for prevention or diseases such as treatment diabetictrunk angiopathy and hyperlipemia.
As mentioned above, prompting is when the daily dose of rat 〉=0.4mg/kg body weight, and kind of alpha glycosidase inhibitor has the prevention of being beneficial to and the treatment diabetes reach the disease relevant with diabetes.
One, test material
(1) trial drug
1, kind of alpha glycosidase inhibitor
The chemical compound of chemosynthesis provides (preparation method as mentioned above) by Shenzhen Taitai Pharmaceutical Industry Co. Ltd..Lot number is 20030801, molecular weight 251, and the outward appearance powder that is white in color, purity is 99.8%, is mixed with desired concn with deionized water during experiment.
(2) experimental animal
1, streptozotocin (streptozotocin is called for short STZ) diabetes rat
Normal SD rats lumbar injection streptozotocin 58mg/kg (with pH4.0 citrate buffer solution preparation) predicted blood glucose after 72 hours, selected for use blood glucose in the grouping that experimentizes of the rat of 250-450mg/dl.
2, normal rat
Normal male SD rat, 140-160g, available from Beijing Vital River Experimental Animals Technology Co., Ltd., licence numbering SCXK (capital) 2002-0003 raises in institute of Materia Medica,Chinese Academy of Medical Sciences secondary Animal House.
Two, test method
According to the mechanism of action characteristics of alpha-glucosidase inhibitor, and, choose four groups of streptozotocins (STZ) diabetes rat, 10 every group in conjunction with kind of alpha glycosidase inhibitor trial test result of study.Matched group is with high-sucrose feedstuff (sucrose: normal feedstuff=1:1) feed, its excess-three group is raised respectively to contain various dose kind of alpha glycosidase inhibitor (0.4mg/kg body weight, 0.9mg/kg body weight, 1.6mg/kg body weight, calculate gained for experiment finishes the back according to this group average food ration every day) high-sucrose feedstuff (0.4mg/100g material, the 1mg/100g material, 2.5mg/100g material), establishing one group of normal rat (n=10) simultaneously raises with normal feedstuff and organizes as the intact animal, below respectively organize the equal drinking-water of freely ingesting, observe the general situation of animal every day, record food ration and amount of drinking water, get blood after one week and survey blood glucose, get blood survey blood fat after three weeks and (comprise triglyceride, cholesterol and free fatty), fructosamine, blood N-acetyl-(NAG enzyme) activity, biochemical indicator such as serum urea nitrogen and creatinine content, the back is collected urine with metabolic cage and is surveyed 6 hours glucose in urine content all around, when experiment finishes, the sacrificed by decapitation animal, weigh, kidney and cardiac weight, kidney 10% formalin fixed, paraffin embedding, conventional section, the kidney pathological change is observed in the dyeing of haematoxylin Yihong, light microscopic down.
Three, result of the test
1, the variation of food ration and amount of drinking water
The results are shown in Table 1.The result shows that the symptom that the diabetes rat food ration of kind of alpha glycosidase inhibitor administration group and amount of drinking water are many all alleviates extremely significantly.
Table a kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat food ration, amount of drinking water (X ± SD)
Compare with Con,
* *P＜0.001; N=9-10; Nor is the normal rat group, and Con is a STZ diabetes rat matched group, and other are kind of alpha glycosidase inhibitor administration group
2, kind of alpha glycosidase inhibitor is to the influence of STZ blood glucose in diabetic rats
The results are shown in Table 2.The result shows that administration is in the time of 18 days, and the not fasting serum glucose content of kind of alpha glycosidase inhibitor administration group all is lower than matched group extremely significantly, and fasting serum glucose content also reduces in various degree.
Table 2 kind of alpha glycosidase inhibitor is to the influence of STZ blood glucose in diabetic rats (X ± SD)
Compare with Con,
*P＜0.05,
*P＜0.01,
* *P＜0.001; N=9-10; Nor is the normal rat group, and Con is a STZ diabetes rat matched group, and other are kind of alpha glycosidase inhibitor administration group
3, kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat serum fructosamine
Fructosamine is the aldehyde-ketone condensate that plasma albumin and glucose molecule form through molecular rearrangement in the nonenzymatic glycosylation process.Since albumin concentration stability in vivo, so serum fructosamine level is also more stable, the influence of not ingested, the variation of the blood sugar level in its reflection 1-2 week.Test kit builds up bio-engineering research institute available from Nanjing.
The results are shown in Table 3.The result shows that the serum fructosamine level of kind of alpha glycosidase inhibitor 0.9mg/kg body weight and 1.6mg/kg body weight administration group all significantly is lower than matched group.
Table 3 kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat fructosamine (X ± SD)
Compare with Con,
*P＜0.05,
*P＜0.01; N=9-10; Nor is the normal rat group, and Con is a STZ diabetes rat matched group, and other are kind of alpha glycosidase inhibitor administration group
4, kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat glucose in urine content
The results are shown in Figure 1.The result shows that the glucose in urine content of kind of alpha glycosidase inhibitor administration group all is lower than matched group extremely significantly.
5, kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat serum N AG enzymatic activity
NAG enzyme (N-acetyl-) is a kind of lysosomal enzyme that extensively is present in excess of the kidney matter, and is in close relations with urine albumin discharge capacity and retinal microvascular lesion degree, is the sensitive indicator of reflection microangiopathies.Along with microangiopathies increases the weight of, the NAG enzymatic activity increases (end-point method mensuration).
The results are shown in Table 4.The result shows that kind of alpha glycosidase inhibitor 0.9mg/kg body weight and 1.6mg/kg body weight administration group rat NAG enzymatic activity reduce, and the degree that the NAG enzymatic activity reduces increases along with the increase of dosage.
Table 4 kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat serum N AG enzymatic activity (X ± SD)
Compare with Con,
*P＜0.05,
* *P＜0.001; N=9-10; Nor is the normal rat group, and Con is a STZ diabetes rat matched group, and other are kind of alpha glycosidase inhibitor administration group
6, kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat kidney exponential sum cardiac index
The results are shown in Figure 2.The result shows, the animal kidney index of kind of alpha glycosidase inhibitor administration group all reduces extremely significantly, cardiac index also in various degree be lower than matched group.
7, kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat serum urea nitrogen and creatinine content
Measure blood urea nitrogen and creatinine content and can understand the variation of renal function.Serum urea nitrogen, creatinine content raise, and then represent renal dysfunction.Mensuration is carried out according to the kit method of giving birth to biotechnology company in Beijing.
The results are shown in Table 5.The result shows that the animal serum urea nitrogen levels of kind of alpha glycosidase inhibitor administration group all reduces in various degree.
Table 5 kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat serum urea nitrogen and creatinine content (X ± SD)
Compare with matched group Con,
*P＜0.05,
*P＜0.01; N=9-10; Nor is the normal rat group, and Con is a STZ diabetes rat group, and other are kind of alpha glycosidase inhibitor administration group
8, kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat kidney pathological change
Rat kidney 10% formalin fixed is respectively organized in experiment, paraffin embedding, conventional section, the dyeing of haematoxylin Yihong, om observation.
The results are shown in Figure 3～7.The result shows that normal rat kidney structure is normal, does not see pathological changes; The most of glomerular capsule fiber-like of hyperglycemia control rats is oozed out, epithelial cell slurry dissolving of the nearly straight portion of curved tube or vacuolar degeneration; Kind of alpha glycosidase inhibitor 0.4mg/kg body weight administration group rat small part glomerular capsule fiber-like is oozed out, epithelial cell slurry dissolving of the nearly straight portion of curved tube or vacuolar degeneration; Kind of alpha glycosidase inhibitor 0.9mg/kg body weight and 1.6mg/kg body weight administration group glomerule are not seen significant change, and epithelial cell vacuolar degeneration situation reduces.Illustrate that kind of alpha glycosidase inhibitor brings out the diabetes rat nephropathy to STZ and has the certain protection effect.
9, kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat blood fat
Hyperglycemia animal shows as unusual rising such as cholesterol, triglyceride and free fatty often with abnormalities of sugar/lipid metabolism.Blood fat is measured with enzyme method, and cholesterol and triglyceride test kit are available from giving birth to biotechnology company in Beijing, and the free fatty test kit is available from Tokyo Daiichi Pure Chemicals Co., Ltd..
The results are shown in Table 6.The result shows that kind of alpha glycosidase inhibitor all has the reduction effect to blood triglyceride levels under three dosages, and the blood triglyceride levels of kind of alpha glycosidase inhibitor 1.6mg/kg body weight administration group is lower than matched group extremely significantly; The blood cholesterol levels of kind of alpha glycosidase inhibitor 0.9mg/kg body weight administration group is lower than matched group simultaneously; And kind of alpha glycosidase inhibitor does not all influence the blood free fatty acid levels under three dosage.
Table 6 kind of alpha glycosidase inhibitor is to the influence of STZ diabetes rat blood fat (X ± SD)
Compare with Con,
*P＜0.05; N=9-10; Nor is the normal rat group, and Con is a STZ diabetes rat matched group, and other are kind of alpha glycosidase inhibitor administration group
Four, conclusion (of pressure testing):
STZ diabetes rat long-term experiment (5 week) is the result show, when daily dose 〉=0.4mg/kg body weight, kind of alpha glycosidase inhibitor makes diabetes rat symptom more than three obviously alleviate (table 1); Fasting serum glucose, non-fasting serum glucose, serum fructosamine level and glucose in urine content etc. all are starkly lower than matched group, and (table 2,3 Fig. 1), illustrates that kind of alpha glycosidase inhibitor helps the glycometabolic improvement of hyperglycemia animal, and helps improving the too much symptom of feed.The blood glucose that the serum fructosamine concentration of kind of alpha glycosidase inhibitor 0.9mg/kg body weight and 1.6mg/kg body weight administration group reduces the explanation animal has obtained more stable control.
STZ diabetes rat feeding high sugar feed can quicken the generation and the development of diabetes rat and diabetes diseases associated such as diabetic complication, showing as matched group serum N AG enzymatic activity increases, the kidney hypertrophy, the level rising of renal cells glycogen deposition and cholesterolemia and triglyceride etc., and kind of alpha glycosidase inhibitor administration treated animal NAG enzymatic activity reduces (table 4), kidney exponential sum cardiac index obviously reduces (Fig. 2), the serum urea nitrogen level reduces (table 5), glomerule pathological changes and renal cells vacuolar degeneration are improved (Fig. 3～7), cholesterolemia and triglyceride levels reduce (table 6), illustrate when daily dose 〉=0.4mg/kg body weight, kind of alpha glycosidase inhibitor helps delaying disease relevant with diabetes such as diabetic microvascular complication when improving hyperglycemia animal abnormal carbohydrate metabolism, nephropathy becomes, the generation of hyperlipemia and macroangiopathy etc. and development.
Above-mentioned result of the test also shows, when the dosage of kind of alpha glycosidase inhibitor is the 0.4mg/kg body weight/day, can show certain curative effect; In the dosage range (0.4～1.6mg/kg body weight/day) that test is adopted, kind of alpha glycosidase inhibitor improves streptozotocin (STZ) diabetes rat diabetes and strengthens with the increasing of diabetes diseases associated with dosage; And when daily dose during greater than the 0.9mg/kg body weight, the drug effect of kind of alpha glycosidase inhibitor increases not obvious.
The acute toxicity test of kind of alpha glycosidase inhibitor
With the kind of alpha glycosidase inhibitor is trial drug, has carried out large and small Mus acute toxicity test.In test, observe the kind of alpha glycosidase inhibitor single and given acute toxic reaction and the death condition that rat, mice produce, drawn the maximum tolerated dose of rat, its mouse oral gastric infusion and intraperitoneal injection respectively.The result shows: healthy cleaning level SD rat and ICR mice difference single oral filling stomach (po) and lumbar injection (ip) give kind of alpha glycosidase inhibitor, and large and small Mus is all Non Apparent Abnormality reactions during whole test.The maximum tolerated dose that per os filling stomach (po) gives kind of alpha glycosidase inhibitor is: rat〉5g/kg; Mice〉7.5g/kg.The maximum tolerated dose that lumbar injection gives kind of alpha glycosidase inhibitor is: rat〉3g/kg; Mice〉4.5g/kg.
The unit dose that contains the kind of alpha glycosidase inhibitor pharmaceutical composition is determined foundation
In this research, determine the dosage of kind of alpha glycosidase inhibitor according to the conventional method known to those skilled in the art.At first explore the toxic dose or the fatal dose of kind of alpha glycosidase inhibitor roughly, use dosage less than toxic dose then, determine that thus the minimum effective dose of mice is about 2mg/kg as application dose with mice; By above-mentioned The acute toxicity tests as can be known, the maximum tolerated dose that rat, mice difference single oral filling stomach (po) give kind of alpha glycosidase inhibitor is: rat〉5g/kg, mice〉7.5g/kg, the maximum tolerated dose that rat, mice difference single intraperitoneal injection (ip) give kind of alpha glycosidase inhibitor is: rat〉3g/kg, mice〉4.5g/kg, can infer thus the dosage range that kind of alpha glycosidase inhibitor is used for human body can be very wide, have very high drug safety; Again as can be known by above-mentioned results of pharmacodynamic test, when the dosage of kind of alpha glycosidase inhibitor is the 0.4mg/kg body weight/day, can show certain curative effect, in the dosage range (0.4～1.6mg/kg body weight/day) that test is adopted, kind of alpha glycosidase inhibitor improves streptozotocin (STZ) diabetes rat diabetes and strengthens with the increasing of diabetes diseases associated with dosage, and when daily dose during greater than the 0.9mg/kg body weight, blood drug level reaches capacity, and the drug effect of kind of alpha glycosidase inhibitor increases not obvious.
The medicine of determining also to consider kind of alpha glycosidase inhibitor of dosage is for result of the test, and this medicine is with AUC
0-tMean value calculation is at 1.0mg.kg
-1Absolute bioavailability average out to 15.26% under the dosage after the rat oral gavage administration; With AUC
0-tMean value calculation is at 0.297mgkg
-1Absolute bioavailability under the dosage behind the dog gastric infusion is 26.27%, therefore estimates that kind of alpha glycosidase inhibitor has blood plasma combination and the absorption about 20% in vivo, and theoretical consumption will increase about 20%.
Take all factors into consideration above result of the test, per kilogram of body weight dosage conversion factor table (medical experimental zoology with reference to the animals and human beings body, Shi Xinyou writes, Xi'an, Shaanxi science tech publishing house, 1989) convert the compliance when also considering patient's clinical application when determining kind of alpha glycosidase inhibitor human body oral medication dosage range according to formula " dosage (mg/kg) of the dosage of human body (mg/kg)=0.16 * rat ".
Determine that thus kind of alpha glycosidase inhibitor human body oral medication dosage is 1mg～150mg/60kg body weight/day, preferred 5mg～30mg/60kg body weight/day, preferred especially 7.5mg～15mg/60kg body weight/day.
Because administration every day is 1～3 time usually, so the unit dose scope that contains the pharmaceutical composition of kind of alpha glycosidase inhibitor of the present invention is 0.5～50mg, preferred 1mg～15mg, preferred especially 2.5mg～7.5mg, most preferably 2.5mg.
The preparation of drug combination that contains kind of alpha glycosidase inhibitor
[embodiment 2]
The I prescription
The crude drug kind of alpha glycosidase inhibitor prepares according to above-described method, and other adjuvants are commercially available purchase commodity.
The II method for making
Be prepared according to following steps:
1, prepares 4% Gonak with 75% ethanol.
2, in appropriate vessel kind of alpha glycosidase inhibitor and 1/4th is measured the lactose mix homogeneously, cross 80 mesh sieves, put in the High Speed Stirring Machine, add surplus lactose, crospovidone, mix homogeneously adds Gonak, opens the granulating cutter granulation.
3, the granule that makes is dry in heated-air circulation oven, dry good granule oscillating granulator 20 mesh sieve granulate.With the granule that makes, magnesium stearate is put in the three-dimensional mixer and is mixed.
4, the granule that mixes is pressed into tablet with tablet machine, for contain 0.5,2.5,5 and the tablet weight of 10mg active component be 120mg, be 250mg for the tablet weight that contains the 50mg active component.
5, above-mentioned label is put into the high-efficiency coating machine coating, 40 ℃～45 ℃ of retention tab bed tempertaures, coating weightening finish 2.0%～4.0%.
More than the description of better embodiment of the present invention is not limited the present invention, those skilled in the art can make various changes or distortion according to the present invention, only otherwise break away from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (5)
1. pharmaceutical composition that contains kind of alpha glycosidase inhibitor, it is characterized in that, described pharmaceutical composition is a coated tablet, every label prescription consists of: 2.5mg kind of alpha glycosidase inhibitor, lactose 113.42mg, hydroxypropyl emthylcellulose 0.48mg, crospovidone 2.4mg, magnesium stearate 1.2mg, 75% ethanol 11.52mg is prepared into the label that gross weight is 120.0mg; Use coating materials aqueous solution 20mg coating, be prepared into the coated tablet of 123.6mg.
2. the described compositions of claim 1 is characterized in that, said composition contains the kind of alpha glycosidase inhibitor of crystal habit.
3. one kind prepares claim 1 or 2 described method for compositions, and this method may further comprise the steps:
(1) prepares 4% Gonak with 75% ethanol;
(2) in appropriate vessel kind of alpha glycosidase inhibitor and 1/4th is measured the lactose mix homogeneously, cross 80 mesh sieves, put in the High Speed Stirring Machine, add surplus lactose, crospovidone, mix homogeneously adds Gonak, opens the granulating cutter granulation;
(3) granule that makes is dry in heated-air circulation oven, dry good granule oscillating granulator 20 mesh sieve granulate; With the granule that makes, magnesium stearate is put in the three-dimensional mixer and is mixed;
(4) granule that mixes being pressed into tablet with tablet machine, is 120mg for the tablet weight that contains the 2.5mg active component;
(5) above-mentioned label is put into the high-efficiency coating machine coating, 40 ℃～45 ℃ of retention tab bed tempertaures, coating weightening finish 2.0%～4.0%.
4. method according to claim 3 is characterized in that, the compositions of described preparation is a unit dosage forms.
5. claim 1 or 2 described compositionss treat and/or prevent application in the medicine of diabetes and the disease relevant with diabetes in preparation, and the described disease relevant with diabetes is diabetic complication, obesity and/or bulimia nerovsa.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4701559A (en) * | 1981-01-05 | 1987-10-20 | Takeda Chemical Industries, Inc. | N-substituted pseudo-aminosugars, their production and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4701559A (en) * | 1981-01-05 | 1987-10-20 | Takeda Chemical Industries, Inc. | N-substituted pseudo-aminosugars, their production and use |
| US4777294A (en) * | 1981-01-05 | 1988-10-11 | Takeda Chemical Industries, Ltd. | N-substituted pseudo-aminosugars, their production and use |
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