CN1274282A - Treatment of diabetes with thiazolidinedione and Alpha-glucosidase inhibitor - Google Patents
Treatment of diabetes with thiazolidinedione and Alpha-glucosidase inhibitor Download PDFInfo
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- CN1274282A CN1274282A CN98806319A CN98806319A CN1274282A CN 1274282 A CN1274282 A CN 1274282A CN 98806319 A CN98806319 A CN 98806319A CN 98806319 A CN98806319 A CN 98806319A CN 1274282 A CN1274282 A CN 1274282A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Abstract
A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser and an alpha-glucosidase inhibitor antihyperglycaemic agent, to a mammal in need thereof.
Description
The present invention relates to Therapeutic Method, especially treat the method for diabetes, particularly non-insulin-dependent diabetes mellitus (NIDDM) or type ii diabetes and the indication relevant with diabetes.
The Alpha-glucosidase inhibitor blood sugar lowering, for example acarbose, emiglitate and miglitol are normally used for treating NIDDM (or type ii diabetes).
The open EP0306228 of european patent application relates to the thiazolidine diketone derivative that some have blood sugar lowering and hypolipidemic activity.The disclosed concrete thiazolidinedione of EP0306228 is 5-[4-[2-(N-methyl-N-(2-pyridine radicals) amino) ethyoxyl] benzyl] thiazolidine-2,4-diketone (hereinafter referred to as " chemical compound (I) ").WO94/05659 discloses the salt of some chemical compounds (I), is included in the maleate of describing in the embodiment 1.
Chemical compound (I) is the example that a class is called the blood sugar lowering of " insulin sensitizers ".Chemical compound (I) is the thiazolidinedione insulin sensitizers especially.
European patent application publication No.: 0008203,0139421,0032128,0428312,0489663,0155845,0257781,0208420,0177353,0319189,0332331,0332332,0528734,0508740; International Patent Application Publication No. 92/18501,93/02079,93/22445 and United States Patent (USP) 5104888 and 5478852 some thiazolidinedione insulin sensitizers are also disclosed.
The another kind of active chemical compound of insulin sensitizers that is considered to have usually is by the chemical compound that discloses the chemical compound representative of describing among WO93/21166 and the WO94/01420 at international patent application.Hereinafter these chemical compounds are called " acyclic insulin sensitizers ".Other example of acyclic insulin sensitizers is a disclosed chemical compound in United States Patent (USP) 5232945 and open WO92/03425 of international patent application and WO91/19702.
The example of other insulin sensitizers is a disclosed chemical compound in european patent application open EP0533933, Japanese Patent Application Publication 05271204 and United States Patent (USP) 5264451.
Above-mentioned publication is listed the present invention in for your guidance.
Be surprised to find now, chemical compound (I) can provide good especially glycemic control effect with Alpha-glucosidase inhibitor blood sugar lowering use in conjunction, and disadvantageous side effect is very little, so this use in conjunction can be used in particular for treating diabetes, especially type ii diabetes and the indication relevant with diabetes.
Therefore, the invention provides the method for for example treating diabetes, especially type ii diabetes and the indication relevant mammal among the people with diabetes, described method comprise with the insulin sensitizers of effective non-toxicity and pharmaceutically acceptable amount for example chemical compound (I) and Alpha-glucosidase inhibitor blood sugar lowering to the mammal administration of this treatment of needs.
On the other hand, the invention provides in the method for treatment diabetes, especially type ii diabetes and the indication relevant and use insulin sensitizers for example chemical compound (I) and Alpha-glucosidase inhibitor blood sugar lowering together with diabetes.
The inventive method comprises for example chemical compound (I) and Alpha-glucosidase inhibitor blood sugar lowering administration or with its order administration together of insulin sensitizers.
Administration comprises together, will not only contain for example chemical compound (I) but also contain the preparation administration of biguanide blood sugar lowering of insulin sensitizers, or with the independent preparation administration simultaneously basically of every kind of activating agent.
On the other hand, for example chemical compound (I) and Alpha-glucosidase inhibitor blood sugar lowering are used for the treatment of application in the compositions of diabetes, especially type ii diabetes and the indication relevant with diabetes in preparation to the invention provides insulin sensitizers.
Suitable thiazolidinedione insulin sensitizers is chemical compound (I).
Other suitable thiazolidinedione insulin sensitizers comprises (+)-5-[[4-[(3,4-dihydro-6-hydroxyl-2,5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-2-yl) methoxyl group] phenyl] methyl]-2,4-thiazolidinedione (or troglitazone), the 5-[4-[(1-methylcyclohexyl) methoxyl group] benzyl] thiazolidine-2,4-diketone (or ciglitazone), 5-[4-[2-(5-ethylpyridine-2-yl) ethyoxyl] benzyl] thiazolidine-2,4-diketone (or pioglitazone), or 5-[(2-benzyl-2, the 3-dihydrobenzopyrans)-and the 5-ylmethyl] thiazolidine-2,4-diketone (or anthracene lattice row ketone).
Suitable Alpha-glucosidase inhibitor blood sugar lowering is an acarbose.
Other suitable Alpha-glucosidase inhibitor blood sugar lowering is emiglitate and miglitol.
One special aspect in, the inventive method comprises, especially when the every day administration with 2-12mg chemical compound (I) administration.
The inventive method comprises that especially every day is with 2-4,4-8 or for example chemical compound (I) administration of 8-12mg insulin sensitizers.
The inventive method especially comprises, particularly when the every day administration with 2-4mg chemical compound (I) administration.
The inventive method especially comprises, particularly when the every day administration with 4-8mg chemical compound (I) administration.
The inventive method especially comprises, particularly when the every day administration with 8-12mg chemical compound (I) administration.
The inventive method preferably includes, particularly when the every day administration with 2mg chemical compound (I) administration.
The inventive method preferably includes, particularly when the every day administration with 4mg chemical compound (I) administration.
The inventive method preferably includes, particularly when the every day administration with 8mg chemical compound (I) administration.
Be to be understood that, insulin sensitizers for example chemical compound (I) and Alpha-glucosidase inhibitor blood sugar lowering respectively with its pharmaceutically acceptable form as suitable related drugs active agent delivery, its pharmaceutically acceptable form comprises pharmaceutically acceptable derivant, for example its officinal salt, ester and solvate.In some examples of this description, be used to represent that the title of relevant Alpha-glucosidase inhibitor can relate to the certain drug form of this related activity agent: all pharmaceutically acceptable forms that should be appreciated that this activating agent all are included in the scope of the present invention.
The suitable pharmaceutically acceptable form of insulin sensitizers is included in the pharmaceutically acceptable form of describing in the above-mentioned publication.
The suitable pharmaceutical acceptable salt of chemical compound (I) is included in its officinal salt of describing among EP0306228 and the WO94/05659.Preferred officinal salt is a maleate.
The suitable acceptable solvent thing form of chemical compound (I) is included in its solvate, the especially hydras of describing among EP0306228 and the WO94/05659.
The suitable pharmaceutically acceptable form of Alpha-glucosidase inhibitor blood sugar lowering depends on used concrete activating agent, but comprises the known pharmaceutically acceptable form of selected particular compound.This analog derivative can be consulted or reference standard list of references index, for example Britain and American Pharmacopeia, Remington ' sPharmaceutical Sciences (Mack Publishing Co.) and Martindale TheExtra Pharmacopoeia (London, The Pharma-ceutical Press) (for example referring to the 31st edition the 341st page and its referer).
Insulin sensitizers can make with known method, for example disclosed method in the above-mentioned publication of listing list of references of the present invention in.
Chemical compound (I) or its officinal salt or its acceptable solvent thing can make with known method, for example disclosed method in EP0306228 and WO94/05659.The publication of EP0306228 and WO94/05659 is listed the present invention in for your guidance.
A kind of existence of chemical compound (I) in can several tautomeric forms, all tautomeric forms such as single tautomeric form or its form of mixtures all are included in term chemical compound (I) scope.Chemical compound (I) has chiral carbon atom, therefore can be as high as two kinds of stereoisomer forms exists, no matter chemical compound (I) is to exist with the single isomer or the form of isomer mixture, and term chemical compound (I) comprises the isomeric forms that all these comprise raceme.
Selected Alpha-glucosidase inhibitor blood sugar lowering makes according to known method, these class methods can be consulted or reference standard list of references index, for example Britain and American Pharmacopeia, Remington ' s Pharmaceu-tical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The PharmaceuticalPress) (for example referring to the 31st edition the 341st page and its referer).
Term among the present invention " indication relevant " with diabetes comprise the indication relevant, the indication relevant with diabetes itself with the prediabetes state and with the diabetes complications associated with arterial system.
Term among the present invention " indication relevant with the prediabetes state " comprises symptom, and for example insulin resistance comprises the heritability glucagon, and glucose tolerance descends, obesity and hyperinsulinemia.
Term " indication relevant with diabetes itself " comprises hyperglycemia, and insulin resistance comprises acquired insulin resistance and obesity.Other indication relevant with diabetes itself comprises hypertension and cardiovascular diseases, especially atherosclerosis and the indication relevant with insulin resistance.The indication relevant with insulin resistance comprises polycystic ovary syndrome and inductive insulin resistance of steroid and gestational diabetes mellitus.
" with the diabetes complications associated with arterial system " comprises nephropathy, especially relevant with type ii diabetes nephropathy, neuropathy and retinopathy.
The nephropathy relevant with type ii diabetes comprises nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end-stage renal disease.
Term used herein " pharmaceutically acceptable " but both comprised that the people was pharmaceutical, but comprise that also veterinary drug uses: for example term " pharmaceutically acceptable " but comprise the veterinary drug chemical compound.
For fear of query, when the present invention used the labelled amount of mg amount of the chemical compound (I) comprise pharmaceutically acceptable form, labelled amount refers to the amount of chemical compound (I) itself: for example the chemical compound of 2mg maleate form (I) was meant the maleate that contains 2mg chemical compound (I).
Diabetes are preferably type ii diabetes.
The good especially glycemic control effect that the present invention treatment is provided is meant, for each single activating agent effect of the contrast of expection add and, the synergism that is equivalent to contrast.
Glycemic control can be used conventional method, and for example plasma glucose concentration or glycosylated hemoglobin (Hb A1 c) concentration are carried out feature description when measuring glycemic control index commonly used such as fasting.This class index is measured with standard method, for example at Tuescher A, Richterich, P., Schweiz.Med.Wschr.101 (1971), 345 and 390 and Frank P., " measure glycosylated hemoglobin and monitor diabetics ", the method that " clinical product " (ClinicalProducts) described in 1988.
One preferred aspect, when using when foundation the present invention treatment, it is low that the dosage level of various activating agents will be compared adding purely with the required dosage of effect of glycemic control.
Also need point out, with respect to single activating agent, the present invention's treatment will make advanced glycosylation end product (AGEs), leptin and serum lipids comprise T-CHOL, HDL-cholesterol, the improvement of LDL-cholesterol level, comprise its ratio is improved, especially make serum lipids comprise that T-CHOL, HDL-cholesterol, LDL-cholesterol improve, comprise its ratio is improved.
In the methods of the invention, active medicine is preferably with the pharmaceutical compositions administration.As mentioned above, this based composition both can contain two kinds of medicines, also can only contain wherein a kind of medicine.
Therefore, in one aspect of the invention, the invention provides and contain for example chemical compound (I) pharmaceutical composition of 2-12mg, Alpha-glucosidase inhibitor blood sugar lowering and pharmaceutically suitable carrier especially of insulin sensitizers.
This based composition can by with insulin sensitizers for example chemical compound (I) especially 2-12mg, Alpha-glucosidase inhibitor blood sugar lowering and pharmaceutically suitable carrier are mixed.
Compositions normally is suitable for oral compositions.Yet compositions also can be suitable for other administering mode administration, for example with parenterai administration, sublingual administration or the administration of transdermal administration mode.
Compositions can be made into tablet, capsule, powder, granule, lozenge, suppository, the powder that can reformulate or liquid preparation, for example oral or aseptic parenterai administration solution or suspension.
In order to reach the concordance of administration, the present composition is preferably made unit dosage form.
The oral dosage dosage form can be tablet or capsule, and can contain for example binding agent of conventional excipients, for example syrup, arabic gum, gelatin, sorbitol, Tragacanth or polyvinylpyrrolidone; Filler, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Tabletting lubricant, for example magnesium stearate; Disintegrating agent, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline Cellulose; Or pharmaceutically acceptable wetting agent sodium lauryl sulphate for example.
Compositions is preferably made the unit dose formulations that contains suitably relevant daily dose.
The suitable dosage that comprises the chemical compound (I) of unit dose comprises 1,2,3,4,5,6,7,8,9,10,11 or the chemical compound (I) of 12mg.
In treatment, but medicine of the present invention administration every day 1-6 time, but every day 1-2 time most preferably.
The concrete dosage of chemical compound (I) has 2mg/ day; 4mg/ day comprises administration every day 2 times, each 2mg; 8mg/ day comprises administration every day 2 times, each 4mg.
The suitable dosage that comprises the insulin sensitizers of unit dose and Alpha-glucosidase inhibitor blood sugar lowering comprises the known dose and the unit dose of these chemical compounds, these known dose were described at list of references, for example Britain and American Pharmacopeia, Remington ' s Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example referring to the 31st edition the 341st page and its referer) or above-mentioned publication.
Therefore, the daily dose of acarbose is generally 50-600mg, for example 100mg/ day or 200mg/ day.
Solid oral composition can make by mixing, filling or the pressed disc method of routine.Can adopt the repetition married operation so that activating agent is distributed in the compositions of having used a large amount of filleies fully.Certain this operation also is this area routine techniques.But well-known method is tablet coating in the establishing criteria pharmaceutical manufacturing, especially enteric coating on the coating.
Oral liquid can be example emulsion, syrup or elixir, water or the blended again dry products of other suitable carrier before maybe can being to use.This class I liquid I preparation can contain for example suspending agent of typical additives, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel, hydrogenation edible fat; Emulsifying agent, for example lecithin, anhydro sorbitol monooleate or arabic gum; Nonaqueous carrier (can comprise edible oil), for example for example glyceride, propylene glycol or ethanol of almond oil, fractionated Oleum Cocois, oily ester; Antiseptic, for example methyl parahydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid; And the flavoring agent or the coloring agent that can contain when needing.
For parenterai administration, the liquid unit doses dosage form can make with chemical compound and sterile carrier, and according to used concentration, can suspend or be dissolved in the carrier.In preparation solution process, chemical compound may be dissolved in the water for injection, and filtration sterilization, is contained in suitable bottle or the ampoule then and sealing.With adjuvant for example local anesthetic, antiseptic and buffer agent to be dissolved in the carrier be favourable.For enhanced stability, freezing after compositions is in installing to bottle and vacuum can be removed moisture.Except chemical compound (I) is to suspend rather than be dissolved in the carrier, and beyond sterilization do not reach by filtration, non-intestinal suspending agent can substantially the same method make.Can be by placing ethylene oxide to sterilize with before chemical compound is in being suspended in sterile carrier.Contain surfactant or humidizer in the compositions to promote that the chemical compound uniform distribution is favourable.
According to the medication that is adopted, compositions can contain the activating agent of 0.1%-99%, preferred 10%-60% weight.
If necessary, compositions can be packaged into have written or the printing operation instruction packing box.
Compositions can be prepared according to conventional method, for example at the canonical reference document, the method of describing among Britain and American Pharmacopeia, Remington ' s Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The PharmaceuticalPress) (for example referring to the 31st edition the 341st page and its referer) and the Harry ' sCosmeticology (Leonard Hill Books) for example.
On the other hand, the present invention also provides and has contained chemical compound (I) the especially pharmaceutical composition of 2-12mg, Alpha-glucosidase inhibitor blood sugar lowering and pharmaceutically suitable carrier as the active treatment material.
Especially, the invention provides be used for the treatment of diabetes, especially type ii diabetes and the indication relevant with diabetes contain the especially pharmaceutical composition of 2-12mg, Alpha-glucosidase inhibitor blood sugar lowering and pharmaceutically suitable carrier of chemical compound (I).
2-4mg comprises 2.1-4,2.2-4,2.3-4,2.4-4,2.5-4,2.6-4,2.7-4,2.8-4,2.9-4 or 3-4mg.
4-8mg comprises 4.1-8,4.2-8,4.3-8,4.4-8,4.5-8,4.6-8,4.7-8,4.8-8,4.9-8,5-8,6-8 or 7-8mg.
8-12mg comprises 8.1-12,8.2-12,8.3-12,8.4-12,8.5-12,8.6-12,8.7-12,8.8-12,8.9-12,9-12,10-12 or 11-12mg.
In above-mentioned dosage range, the present composition or method are not brought any disadvantageous toxicology effect.
Following embodiment is in order to set forth the present invention, but is not limitation of the present invention by any way.
Embodiment
This test is to study the PK whether administration of acarbose (A) can change the chemical compound (I) of administration together.At first day, the chemical compound (I) that 16 healthy volunteers take single port clothes dosage (8mg) next repeated to take A (100mg, takes with food at every day three times) in 7 days.At the 8th day, the chemical compound (I) of single port clothes dosage was taken with the A of dosage in morning.Compare the PK feature after taking chemical compound (I) in the 1st day and the 8th day.Chemical compound (I) and A administration are together tolerated well.The PK data of chemical compound (I)+A and point estimation (95% confidence interval): analysis of compounds (I) only.
| Chemical compound (I) chemical compound (I)+A that parameter [unit] is independent |
| AUC (0-infinity) [ng.h/mL] 2793 (581) 2502 (755) Cmax[ng/mL] 428 (86) 451 (141) Tmax*[hour] 1.48 (0.97-5.95) 1.24 (0.95-3.98) T1/2[hour] 4.93 (0.78) 3.79 (0.78) |
* data are intermediate value (scope)
The absorption of chemical compound (I) (Cmax and Tmax) is not subjected to the influence of administration altogether with A, but during chemical compound (I)+A is total to administration, the area under curve of chemical compound (I) (AUC[0-infinity]) has on average descended 12% (PE 0.88[0.79,0.98]), and T1/2 has reduced about 1 hour.Therefore, look that acarbose makes the clearance rate of chemical compound (I) that slight increase be arranged, yet this variation is very little and it is clinical relevant not to be.Therefore, chemical compound (I) can be total to administration and can not cause adverse effect to pharmacokinetics and/or its potential clinical effectiveness of chemical compound (I) with acarbose.
The compositions that contains chemical compound (I)
A prepares the granule concentrate
The sieve that lactose monohydrate with about 2/3rds is suitable excessively, and mix with the maleate of levigated chemical compound (I).The sieve that sodium starch glycolate, hydroxypropyl emthylcellulose, microcrystalline Cellulose and residue lactose is suitable excessively also is added in the mixture.Continue then to mix.With purified water the gained mixture is made wet granular then.Wet granular is sieved, dry on fluidized bed dryer, again the gained dried particles is sieved, make it even at last.
The % of granule concentrate forms
Constituent content (%)
The maleate 13.25 of levigated chemical compound (I) (pure maleate)
Sodium starch glycolate 5.00
Hydroxypropyl methylcellulose 2910 5.00
Microcrystalline Cellulose 20.0
Lactose monohydrate (typical stage) adds to 100
Purified water *
* be removed in the preparation process
B makes tablet with the granule concentrate
The above-mentioned granule that makes is placed the upset blender.About 2/3rds lactose are sieved and be added in the blender.Microcrystalline Cellulose, sodium starch glycolate, magnesium stearate and residue lactose are sieved and be added in the blender, mixture is mixed.Then on rotary tablet machine with gained mixture tabletting, be 1,2 and the tablet of 4mg for active agent content, target weight is set to 150mg, is the tablet of 8mg for active agent content, target weight is set to 300mg.
Then tablet core is placed the tablet coating machine of using warm air preheating (about 65 ℃), give tablet peplos till tablet weight increases 2.0%-3.5%.
| Content (mg/ sheet) |
| Active agent content 1.0mg 2.0mg 4.0mg 8.0mg in the tablet |
| Active component: maleate concentrated granular 10.00 20.00 40.00 80.00 other components of compound (I): sodium starch glycolate 6.96 6.46 5.46 10.92 microcrystalline celluloses 27.85 25.85 21.85 43.70 lactose monohydrates 104.44 96.94 81.94 163.88 dolomols 0.75 0.75 0.75 1.50 |
| Tablet cores gross weight 150.0 150.0 150.0 300.0 |
| The tablet total weight amount 154.5 154.5 154.5 309.0 of water-solubility membrane coating material 4.5 4.5 4.5 9.0 film coatings |
Claims (21)
1. the method for treatment mammal diabetes and the indication relevant with diabetes comprises the mammal administration to this treatment of needs of the insulin sensitizers of effective non-toxicity and pharmaceutically acceptable amount and Alpha-glucosidase inhibitor blood sugar lowering.
2. the process of claim 1 wherein that described Alpha-glucosidase inhibitor blood sugar lowering is acarbose, emiglitate or miglitol.
3. the process of claim 1 wherein that described Alpha-glucosidase inhibitor blood sugar lowering is an acarbose.
4. each method of claim 1-3, wherein said insulin sensitizers is 5-[4-[2-(N-methyl-N-(2-pyridine radicals) amino) ethyoxyl] benzyl] thiazolidine-2,4-diketone (Compound I).
5. each method of claim 1-4 is comprising with 2-12mg chemical compound (I) administration.
6. each method of claim 1-5 is comprising with 2-4,4-8 or 8-12mg chemical compound (I) administration.
7. each method of claim 1-6 is comprising with 2-4mg chemical compound (I) administration.
8. each method of claim 1-6 is comprising with 4-8mg chemical compound (I) administration.
9. each method of claim 1-6 is comprising with 8-12mg chemical compound (I) administration.
10. each method of claim 1-6 is comprising with 2mg chemical compound (I) administration.
11. each method of claim 1-6 is comprising with 4mg chemical compound (I) administration.
12. each method of claim 1-6 is comprising 8mg chemical compound (I) administration.
13. the method for claim 1, wherein said insulin sensitizers is (+)-5-[[4-[(3,4-dihydro-6-hydroxyl-2,5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-2-yl) methoxyl group] phenyl] methyl]-2,4-thiazolidinedione (or troglitazone), 5-[4-(1-methylcyclohexyl) methoxyl group] benzyl] thiazolidine-2,4-diketone (or ciglitazone), 5-[4-[2-(5-ethylpyridine-2-yl) ethyoxyl] benzyl] thiazolidine-2,4-diketone (or pioglitazone), or 5-[(2-benzyl-2, the 3-dihydrobenzopyrans)-and the 5-ylmethyl] thiazolidine-2,4-diketone (or anthracene lattice row ketone); Or their officinal salts.
14. contain the pharmaceutical composition of insulin sensitizers, Alpha-glucosidase inhibitor blood sugar lowering and pharmaceutically suitable carrier.
15. the compositions of claim 14, wherein said Alpha-glucosidase inhibitor blood sugar lowering is acarbose, emiglitate or miglitol.
16. the compositions of claim 14 or 15, wherein said Alpha-glucosidase inhibitor blood sugar lowering is an acarbose.
17. each compositions of claim 14-16, wherein said insulin sensitizers is chemical compound (I).
18. each compositions of claim 14-17 wherein contains 2-12mg chemical compound (I).
19. the pharmaceutical composition that contains insulin sensitizers, Alpha-glucosidase inhibitor blood sugar lowering and pharmaceutically suitable carrier as the active treatment material.
20. be used for the treatment of the pharmaceutical composition that contains insulin sensitizers, Alpha-glucosidase inhibitor blood sugar lowering and pharmaceutically suitable carrier of diabetes and the indication relevant with diabetes.
21. claim 14, each compositions in 20 or 21, wherein said insulin sensitizers is (+)-5-[[4-[(3,4-dihydro-6-hydroxyl-2,5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-2-yl) methoxyl group] phenyl] methyl]-2,4-thiazolidinedione (or troglitazone), the 5-[4-[(1-methylcyclohexyl) methoxyl group] benzyl] thiazolidine-2,4-diketone (or ciglitazone), 5-[4-[2-(5-ethylpyridine-2-yl) ethyoxyl] benzyl] thiazolidine-2,4-diketone (or pioglitazone), or 5-[(2-benzyl-2, the 3-dihydrobenzopyrans)-and the 5-ylmethyl] thiazolidine-2,4-diketone (or anthracene lattice row ketone); Or their officinal salts.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9712865.6 | 1997-06-18 | ||
| GBGB9712865.6A GB9712865D0 (en) | 1997-06-18 | 1997-06-18 | Novel method of treatment |
| GBGB9806708.5A GB9806708D0 (en) | 1998-03-27 | 1998-03-27 | Novel method |
| GB9806708.5 | 1998-03-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1274282A true CN1274282A (en) | 2000-11-22 |
Family
ID=26311746
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98806319A Pending CN1274282A (en) | 1997-06-18 | 1998-06-15 | Treatment of diabetes with thiazolidinedione and Alpha-glucosidase inhibitor |
Country Status (24)
| Country | Link |
|---|---|
| EP (1) | EP0975343A1 (en) |
| JP (1) | JP2001523271A (en) |
| KR (1) | KR20010013845A (en) |
| CN (1) | CN1274282A (en) |
| AP (1) | AP9901720A0 (en) |
| AR (2) | AR014881A1 (en) |
| AU (1) | AU8799998A (en) |
| BG (1) | BG103966A (en) |
| BR (1) | BR9810186A (en) |
| CA (1) | CA2294134A1 (en) |
| CO (1) | CO4940453A1 (en) |
| DZ (1) | DZ2519A1 (en) |
| EA (1) | EA200000040A1 (en) |
| IL (1) | IL133138A0 (en) |
| MA (1) | MA26510A1 (en) |
| NO (1) | NO996270D0 (en) |
| NZ (1) | NZ501345A (en) |
| OA (1) | OA11631A (en) |
| PE (1) | PE89199A1 (en) |
| PL (1) | PL337577A1 (en) |
| SK (1) | SK179499A3 (en) |
| TR (1) | TR199903072T2 (en) |
| UY (1) | UY25051A1 (en) |
| WO (1) | WO1998057635A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101121004B (en) * | 2006-08-08 | 2010-07-21 | 鲁南制药集团股份有限公司 | Medicine composition containing insulin intensifier and miglitol |
| CN101584705B (en) * | 2008-05-24 | 2010-10-27 | 鲁南制药集团股份有限公司 | Medicament composition for treating diabetes and complications of diabetes |
| CN101584688B (en) * | 2008-05-24 | 2010-11-10 | 鲁南制药集团股份有限公司 | Medicament composition for treating diabetes and complications of diabetes |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DZ3155A1 (en) | 1999-04-23 | 2000-11-02 | Smithkline Beecham Plc | New pharmaceutical composition. |
| JP4590159B2 (en) | 2001-04-04 | 2010-12-01 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | Combination therapy comprising a glucose reabsorption inhibitor and a PPAR modulator |
| WO2002080935A1 (en) | 2001-04-04 | 2002-10-17 | Ortho Mcneil Pharmaceutical, Inc. | Combination therapy comprising glucose reabsorption inhibitors and retinoid-x receptor modulators |
| FR2832930A1 (en) * | 2001-12-03 | 2003-06-06 | Lipha | PHARMACEUTICAL COMPOSITION COMPRISING AN ALPHA-GLUCOSIDASE INHIBITOR AND A THIAZOLIDINEDIONE DERIVATIVE AND USE THEREOF FOR THE PREPARATION OF MEDICINES FOR TREATING DIABETES |
| JP2004067575A (en) * | 2002-08-06 | 2004-03-04 | Yaizu Suisankagaku Industry Co Ltd | Promoter for effect of therapeutic agent for diabetes |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0601001T3 (en) * | 1991-08-26 | 1997-10-20 | Upjohn Co | Liquid food product containing 3-guanidinopropionic acid. |
| US5917052A (en) * | 1994-09-28 | 1999-06-29 | Shaman Pharmaceuticals, Inc. | Hypoglycemic agent from cryptolepis |
| TWI238064B (en) * | 1995-06-20 | 2005-08-21 | Takeda Chemical Industries Ltd | A pharmaceutical composition for prophylaxis and treatment of diabetes |
-
1998
- 1998-06-15 EA EA200000040A patent/EA200000040A1/en unknown
- 1998-06-15 WO PCT/EP1998/003691 patent/WO1998057635A1/en not_active Application Discontinuation
- 1998-06-15 CN CN98806319A patent/CN1274282A/en active Pending
- 1998-06-15 CA CA002294134A patent/CA2294134A1/en not_active Abandoned
- 1998-06-15 EP EP98939513A patent/EP0975343A1/en not_active Withdrawn
- 1998-06-15 IL IL13313898A patent/IL133138A0/en unknown
- 1998-06-15 SK SK1794-99A patent/SK179499A3/en unknown
- 1998-06-15 PL PL98337577A patent/PL337577A1/en unknown
- 1998-06-15 TR TR1999/03072T patent/TR199903072T2/en unknown
- 1998-06-15 BR BR9810186-2A patent/BR9810186A/en not_active IP Right Cessation
- 1998-06-15 KR KR1019997011866A patent/KR20010013845A/en not_active Application Discontinuation
- 1998-06-15 AU AU87999/98A patent/AU8799998A/en not_active Abandoned
- 1998-06-15 AP APAP/P/1999/001720A patent/AP9901720A0/en unknown
- 1998-06-15 JP JP50375699A patent/JP2001523271A/en not_active Ceased
- 1998-06-17 AR ARP980102885A patent/AR014881A1/en unknown
- 1998-06-17 MA MA25121A patent/MA26510A1/en unknown
- 1998-06-17 AR ARP980102882A patent/AR013352A1/en unknown
- 1998-06-17 DZ DZ980129A patent/DZ2519A1/en active
- 1998-06-18 UY UY25051A patent/UY25051A1/en not_active Application Discontinuation
- 1998-06-18 CO CO98034648A patent/CO4940453A1/en unknown
- 1998-06-18 PE PE1998000536A patent/PE89199A1/en not_active Application Discontinuation
- 1998-07-15 NZ NZ501345A patent/NZ501345A/en unknown
-
1999
- 1999-12-08 BG BG103966A patent/BG103966A/en unknown
- 1999-12-17 OA OA9900295A patent/OA11631A/en unknown
- 1999-12-17 NO NO996270A patent/NO996270D0/en not_active Application Discontinuation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101121004B (en) * | 2006-08-08 | 2010-07-21 | 鲁南制药集团股份有限公司 | Medicine composition containing insulin intensifier and miglitol |
| CN101584705B (en) * | 2008-05-24 | 2010-10-27 | 鲁南制药集团股份有限公司 | Medicament composition for treating diabetes and complications of diabetes |
| CN101584688B (en) * | 2008-05-24 | 2010-11-10 | 鲁南制药集团股份有限公司 | Medicament composition for treating diabetes and complications of diabetes |
Also Published As
| Publication number | Publication date |
|---|---|
| BG103966A (en) | 2000-07-31 |
| TR199903072T2 (en) | 2000-07-21 |
| JP2001523271A (en) | 2001-11-20 |
| MA26510A1 (en) | 2004-12-20 |
| AU8799998A (en) | 1999-01-04 |
| DZ2519A1 (en) | 2003-02-01 |
| BR9810186A (en) | 2000-08-08 |
| AP9901720A0 (en) | 1999-12-31 |
| PE89199A1 (en) | 1999-10-23 |
| AR014881A1 (en) | 2001-04-11 |
| WO1998057635A1 (en) | 1998-12-23 |
| EP0975343A1 (en) | 2000-02-02 |
| CA2294134A1 (en) | 1998-12-23 |
| IL133138A0 (en) | 2001-03-19 |
| AR013352A1 (en) | 2000-12-27 |
| PL337577A1 (en) | 2000-08-28 |
| NO996270L (en) | 1999-12-17 |
| KR20010013845A (en) | 2001-02-26 |
| NO996270D0 (en) | 1999-12-17 |
| NZ501345A (en) | 2001-10-26 |
| EA200000040A1 (en) | 2000-08-28 |
| SK179499A3 (en) | 2000-11-07 |
| OA11631A (en) | 2004-11-22 |
| UY25051A1 (en) | 2000-09-29 |
| CO4940453A1 (en) | 2000-07-24 |
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| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |