CN101757627A - Combined drug and drug combination for treating diabetes - Google Patents
Combined drug and drug combination for treating diabetes Download PDFInfo
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- CN101757627A CN101757627A CN200910235596A CN200910235596A CN101757627A CN 101757627 A CN101757627 A CN 101757627A CN 200910235596 A CN200910235596 A CN 200910235596A CN 200910235596 A CN200910235596 A CN 200910235596A CN 101757627 A CN101757627 A CN 101757627A
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Abstract
The invention provides applications of a thiazolidinediones insulin sensitizer and a bile acid chelating agent in preparing drugs for treating diabetes, diabetic complication and diseases related to diabetes, and also provides a drug composition containing the thiazolidinediones insulin sensitizer and the bile acid chelating agent. The thiazolidinediones insulin sensitizer is preferably pioglitazone, and the bile acid chelating agent is preferably non-absorbing type bile acid, and further preferably colesevelam.
Description
Technical field
The present invention relates to the purposes of two kinds of chemicals therapeutic alliance diabetes and complication thereof, and, belong to the chemicals field by these two kinds of pharmaceutical compositions that medicine is formed.
Background technology
The diabetes branch be mainly type 1 diabetes, type 2 diabetes mellitus (noninsulindependent diabetes, NIDDM) and the diabetes that cause of other reasons such as gestation.Wherein type 2 diabetes mellitus accounts for more than 90% of patient's sum.Type 2 diabetes mellitus is because of insulin resistant is main, the absolute or relative deficiency of companion's insulin secretion and what cause is the endocrine metabolism disease of feature with hyperglycemia and multiple complication and depositing etc., and insulin resistant is the main pathology and the physiological feature of type 2 diabetes mellitus.
According to The World Health Organization (WHO) statistics, present global diabetics is about 1.94 hundred million, also will double to the year two thousand thirty.The diabetics of China has reached about 4,000 ten thousand, is only second to India and occupies the second place of the world.The type 2 diabetes mellitus patient accounts for 90%～95% of diabetics sum in the diabetic population of China.Type 2 diabetes mellitus has become one of principal disease that threatens China's national health.The up-to-date Chinese Diabetes Epidemiological Investigation of finishing of diabetology branch of Chinese Medical Association shows: at present, in China's urban population, diabetics probably has 4,100 ten thousand people, and prevalence has reached 3.2%, and annual average rate of increase is near 10%.In the flourishing relatively big cities such as Beijing and Shanghai of economy, the sickness rate of diabetes reaches about 8% especially.
Be still the main force of treatment diabetes from present overall clinical application situation chemicals.
The characteristics of thiazolidinediones medicine are that obviously the enhancing body tissue improves the beta Cell of islet function to the sensitivity of insulin, realize the long-term control to blood glucose, reduce the danger that diabetic complication takes place.Because it has good tolerability and safety simultaneously, therefore has the effect that delays the diabetes progress.As euglycemic agent, increase the sensitivity of body clinically, alleviate insulin resistant insulin.The thiazolidinediones medicine can directly reduce insulin resistant, significantly improve the β cell function, realize the long-term control of blood glucose, lower the risk that diabetic complication takes place with this, have good tolerability and safety simultaneously, therefore have the effect that delays the diabetes progress.
The thiazolidinediones medicine alleviates insulin resistant because of it, improves simultaneously and protects the β cell function, improves sugar, lipid metabolism, thereby has the effect that reduces cardiovascular risk factors and delay disease process.Therefore, in clinic diagnosis, for fat or overweight type 2 diabetes mellitus patient, and not fat but with the type 2 diabetes mellitus patient of metabolism syndrome, should be preferentially and give the thiazolidinediones medicine as early as possible.The early stage thiazolidinediones medicine that uses; never only mean the decline of blood glucose, glycolated hemoglobin level and blood lipid level and up to standard; prior potential benefit is protection and the improvement to the β cell function; and then delay the diabetics disease progression; improve many cardiovascular risk factors; the generation and the development of prevention chronic complicating diseases and cardiovascular event improve patient's life quality, reduce patient's disability rate and fatality rate.
Pioglitazone, English name Pioglitazone, chemistry (±) 5-[4-[2-(5-ethyl-2-pyridine) ethyoxyl by name] benzyl]-2, the 4-thiazolidinedione.Pioglitazone is the thiazolidinediones antidiabetic medicine, belongs to euglycemic agent, and mechanism of action is relevant with the existence of insulin, can reduce the insulin resistant of peripheral tissues and liver, increases the processing of the glucose that relies on insulin, and reduces the output of glycogen.Different with sulfonylurea, pioglitazone does not promote insulin secretion, its mechanism of action is the exciting microperoxisome growth factor activation receptor-gamma [PPAR-γ] of high selectivity, the transcribing of the insulin related gene of many control glucoses of the activation scalable of PPAR-γ and lipid metabolism.
Zoopery shows, pioglitazone can reduce the hyperglycemia, hyperinsulinism of insulin resistant because of disease and high triglyceride.The increase that the metabolic alterations that pioglitazone causes has caused the tissue of dependence insulin to be replied.Clinical research shows that pioglitazone can improve insulin resistant patient's insulin sensitivity, improves the reactivity of insulin pair cell, and improves glucose metabolism obstacle in the body.
Bile acid chelating agent is the resinae material, is not absorbed but at intestinal to be irreversible with cholic acid and to combine and discharge with feces, makes the intestinal bile acid heavily absorb minimizing.Quicken to utilize in the liver cholesterol degradation to become more bile acid on the one hand, reduced body inner cholesterol level thereby the intestinal absorption cholesterol is reduced; Strengthened surface of hepatocytes ldl receptor activity by feedback regulation like this, absorbed more LDL and carry out catabolism.This class medicine can make serum TC reduce 20%-30%, and HDL-C also has the rising that does not wait degree, is suitable for the hypercholesterolemiapatients patients of any kind except that homozygote familial high-cholesterol disease.The instantiation of bile acid chelating agent is colestyramine, colesevelam.
Colesevelam, English name Colesevelam, colesevelam hydrochlorlde, trade name WelChol, chemical name N, N, the polymer of N-trimethyl-6-(2-acrylic amino)-own ammonium of 1-and (chloromethyl) oxirane, 2-propylene-1-amine and N-2-acrylic-1-decyl amine hydrochlorate, it is a non-absorptive-type bile acid chelating agent of U.S. GelTex Pharmaceuticals Inc Centre company exploitation, FDA approval in 2000 is used for the treatment of hypercholesterolemia, and in JIUYUE, 2000 is in U.S.'s Initial Public Offering.Colesevelam is and epichlorohydrin cross-linked, and presses alkylating poly-(allylamine hydrochloride) with 1-bromo-decane and bromination (6 bromine hexyl) front three.Possess hydrophilic property, but be not dissolved in water, can be used for reducing elevated cholesterol in the blood, help to prevent the obstruction of cholesterol in the blood vessel.Colesevelam is not absorbed only by draining behind the human body by human body.
Clinical studies show, the increase of T-CHOL, LDL-C and apolipoprotein B (APoB) is relevant with the increase of human body artery sclerosis danger.Equally, the reduction of HDL-C (HDL-C) is relevant with the hardened progress of arteria coronaria.Studies show that the M ﹠ M of cardiovascular system and T-CHOL, HDL-C level are directly related, are negative correlation with the HDL-C level.
The inside and outside studies show that colesevelam can combine with bile acid and main component glycocholic acid thereof.Cholesterol is unique precursor of bile acid, and in the normal stool process, bile acid secretion is to intestinal, and a large amount of bile acids are from intestinal absorption, and after the liver sausage circulation reenters liver.Colesevelam is non-absorbent polymer, be oral fat-reducing medicament, can combine with the bile acid in the intestinal is a large amount of, block its heavy absorption, in case bile acid is exhausted, liver cholesterol 7ALPHA-hydroxylase promptly raises, thereby increase the conversion of cholesterol to bile acid, make the increase in demand of cholesterol in the hepatocyte, the final dual function that produces, promptly both increase conversion, improved the activity of the biosynthetic enzyme (through the methylglutaric acid CoA-reductase) of cholesterol again, increased liver low density lipoprotein, LDL (LDL) receptor.These compensatory effects can increase the clearance rate of LDL cholesterol in the blood, reduce serum LDL-C level.
Colesevelam tool lipotropy is water-insoluble polymer, and is not the digestive enzyme hydrolysis, is not absorption of human body.Colesevelam is oral effectively, can combine with bile acid, for the nonabsorbable polyalcohol hydrogel of human body, as fat-reducing medicament, as the former auxiliary treatment that mails to hypercholesterolemia invalid diet and motion, with low-density lipoprotein cholesterol (LDL-C) level that reduces its rising.
FDA approval in 2008 is used for the treatment of type 2 diabetes mellitus.Its mechanism of action is that medicine passes through the chelating bile acid at digestive system, reduces the metabolism and the absorption of fat, thereby reaches the purpose of blood fat reducing and blood sugar lowering.WO9427620, WO2085377, WO0038664, WO9933452, WO9922721, WO9857652, WO9829107, WO9639449, WO9534585, WO9534588 relate to colesevelam in blood fat reducing, the application of blood sugar lowering aspect.
Summary of the invention
The inventor is by the surprised discovery of big quantity research, and thiazolidinediones euglycemic agent and bile acid chelating agent combination medicine form can provide useful especially blood pressure and blood lipoid control effect, and do not find side reaction.This combination medicine form can be good especially be applied to treat diabetes, especially type 2 diabetes mellitus and the disease relevant with diabetes, reach blood sugar lowering, blood fat improves the purpose of diabetes, its effect significantly is better than any single component.
Wherein, the combination medicine form of preferred especially pioglitazone and colesevelam.
The invention provides a kind of thiazolidinediones euglycemic agent and bile acid chelating agent preparation be used for the treatment of diabetes, diabetic complication, with the medicine of diabetes diseases associated in purposes.
Wherein the thiazolidinediones euglycemic agent is selected from following compounds or its pharmaceutically acceptable salt: ciglitazone (Ciglitazone), englitazone (Englitazone), troglitazone (Troglitazone), rosiglitazone (Rosiglitazone), pioglitazone (Pioglitazone), Fa Gelie ketone (Farglitazar), darglitazone (Darglitazoan).
Be preferably rosiglitazone, pioglitazone.The rosiglitazone class is for example: rosiglitazone maleate, Rosiglitazone sodium, rosiglitazone, Luogelie ketone hydrochloride.The pioglitazone class is for example: pioglitazone hydrochloride.
Pioglitazone more preferably, or its pharmaceutically acceptable salt, for example hydrochlorate.
Bile acid chelating agent is selected from colestyramine, colesevelam.
The preferred non-absorption-type bile acid chelating agent of bile acid chelating agent, colesevelam more preferably, or its pharmaceutically acceptable salt, for example hydrochlorate.
Further, the invention provides a kind of thiazolidinediones euglycemic agent and colesevelam preparation be used for the treatment of diabetes, diabetic complication, with the medicine of diabetes diseases associated in purposes.
Further, the invention provides pioglitazone and colesevelam preparation be used for the treatment of diabetes, diabetic complication, with the medicine of diabetes diseases associated in purposes.
Described purposes comprises euglycemic agent such as pioglitazone and the administration simultaneously of colesevelam class hyperglycemia high blood cholesterol drug or the two order administration.
Administration simultaneously comprises that administration simultaneously comprises and gives a kind of euglycemic agent such as pioglitazone and colesevelam class hyperglycemia hyperlipidemia preparation of comprising, perhaps with the independent preparation administration simultaneously basically of every kind of activating agent.
The present invention also provide a kind of treat diabetes, diabetic complication, with the pharmaceutical composition of diabetes diseases associated, wherein contain thiazolidinediones euglycemic agent, bile acid chelating agent in the said composition.As required, also contain an amount of acceptable accessories in the said composition.
Thiazolidinediones euglycemic agent in the said composition is selected from following compounds or its pharmaceutically acceptable salt: ciglitazone (Ciglitazone), englitazone (Englitazone), troglitazone (Troglitazone), rosiglitazone (Rosiglitazone), pioglitazone (Pioglitazone), Fa Gelie ketone (Farglitazar), darglitazone (Darglitazoan).Be preferably rosiglitazone, pioglitazone.Pioglitazone more preferably, or its pharmaceutically acceptable salt, for example hydrochlorate.
Bile acid chelating agent is selected from colestyramine, colesevelam.
The preferred non-absorption-type bile acid chelating agent of bile acid chelating agent, colesevelam more preferably, or its pharmaceutically acceptable salt, for example hydrochlorate.
Further, the invention provides a kind of treat diabetes, diabetic complication, with the pharmaceutical composition of diabetes diseases associated, wherein contain thiazolidinediones euglycemic agent, bile acid chelating agent.
Further, the invention provides a kind of treat diabetes, diabetic complication, with the pharmaceutical composition of diabetes diseases associated, wherein contain thiazolidinediones euglycemic agent, non-absorption-type bile acid chelating agent.
Further, the invention provides a kind of treat diabetes, diabetic complication, with the pharmaceutical composition of diabetes diseases associated, wherein contain thiazolidinediones euglycemic agent, colesevelam.
Further, the invention provides a kind of treat diabetes, diabetic complication, with the pharmaceutical composition of diabetes diseases associated, wherein contain pioglitazone, colesevelam.
The inventor is by a large amount of discovering, thiazolidinediones euglycemic agent and bile acid chelating agent combination medicine form can provide useful especially blood pressure and blood lipoid control effect, and do not find side reaction.This combination medicine form can be good especially be applied to treat diabetes, especially type 2 diabetes mellitus and the disease relevant with diabetes, reach blood sugar lowering, blood fat improves the purpose of diabetes, its effect significantly is better than any single component.
Wherein, the combination medicine form of preferred especially pioglitazone and colesevelam.Especially preferably contain the pharmaceutical composition that pioglitazone, colesevelam are formed as effective ingredient and an amount of acceptable accessories.
Drug combination form of the present invention and pharmaceutical composition utilize thiazolidinediones (TZDs) class medicine to improve type ii diabetes patient's insulin resistant on the one hand, thereby improve hyperinsulinemia and hyperglycemia metabolism disorder.Utilize bile acid chelating agent and cholic acid to be irreversible on the other hand and combine, intestinal bile acid resorption is received reduced, quicken to utilize cholesterol in the liver, thereby reduced body inner cholesterol level.Both combine, and by reducing fat absorption, improve the effect that insulin resistant reaches hypoglycemic.Drug combination absorbs from reducing, and strengthens metabolism two aspects and works, and drug effect significantly is better than single medicine.
Pharmaceutical composition of the present invention is owing to contain pioglitazone; so the hypoglycemic while does not change the insulin secretion state; do not influence the absorption of saccharide yet; can protect the life-span of pancreas β cell fully; examine polyvinyl can reduce the absorption of fat owing to containing simultaneously; utilize the metabolic interaction of saccharide and lipid, reached the purpose of the Synergistic of reducing blood sugar and blood fat.
The drug combination of pharmaceutical composition of the present invention can reduce the pioglitazone consumption, has reduced because the excessive hypoglycemia odds that causes of pioglitazone consumption.
Pioglitazone itself has certain cardiac side effects; pioglitazone can increase the blood plasma volume; cause the cardiac preload increase and induce cardiac hypertrophy; when examining polyvinyl to reduce low density fat in the pharmaceutical composition of the present invention; can also increase hdl concentration, thereby be of value to Cardioprotective.Therefore pharmaceutical composition of the present invention can significantly improve the heart side reaction of pioglitazone.
The diabetes patient is in hyperglycemia, mostly with hyperlipidemia, obesity.Pharmaceutical composition of the present invention can blood sugar lowering, again can blood fat reducing, thus more effective, and be the long-acting lasting diabetes of improving.
An advantage of the present invention is when using according to the inventive method, used various active dose levels will less than reach add merely and the blood pressure and blood lipoid control action dosage that may need.
Also have index to show, with respect to individual independent component, Therapeutic Method of the present invention will improve serum lipids and comprise that T-CHOL, HDL-cholesterol, LDL-cholesterol level comprise and improve its ratio.
The present composition is applicable to the treatment diabetes, and especially type 2 diabetes mellitus further is specially adapted to treat the type 2 diabetes mellitus of following hyperlipidemia.
Pharmaceutical composition of the present invention according to the ratio of weight, contains the pioglitazone and the 1875-4375 weight portion colesevelam of 15-45 weight portion.
Scope 15-45 weight portion comprises the 15-30 weight portion, 20-35 weight portion, or 30-45 weight portion.
Scope 1875-4375 weight portion comprises the 1875-3750 weight portion, 2200-4100 weight portion, or 3750-4375 weight portion.
The given dose of preferred pioglitazone is 15 weight portions or 30 weight portions or 45 weight portions.
The given dose of preferred colesevelam is 1875 weight portions or 3750 weight portions or 4375 weight portions.
The inventor finds that following embodiment is particularly preferred: according to the ratio of weight, contain the pioglitazone and the 3750 weight portion colesevelams of 30 weight portions.
According to patient's individual demand, other preferred embodiment comprises: according to the ratio of weight, contain the pioglitazone and the 1875 weight portion colesevelams of 15 weight portions.
According to the ratio of weight, contain the pioglitazone and the 1875 weight portion colesevelams of 30 weight portions.
According to the ratio of weight, contain the pioglitazone and the 1875 weight portion colesevelams of 45 weight portions.
According to the ratio of weight, contain the pioglitazone and the 3750 weight portion colesevelams of 15 weight portions.
According to the ratio of weight, contain the pioglitazone and the 3750 weight portion colesevelams of 45 weight portions.
According to the ratio of weight, contain the pioglitazone and the 4375 weight portion colesevelams of 15 weight portions.
According to the ratio of weight, contain the pioglitazone and the 4375 weight portion colesevelams of 30 weight portions.
According to the ratio of weight, contain the pioglitazone and the 4375 weight portion colesevelams of 45 weight portions.
These compositionss are preferably to make unit dosage forms with the amount that relevant daily dose suits.For example 5mg pioglitazone and 625mg colesevelam are made 1 unit dosage forms.
Compositions of the present invention can the administration every day 1-7 time, preferred administration every day 1 or 2 times, and most preferably administration every day is 2 times.Each administration 1-10 unit dose, preferred 1-7 unit dose.
The present composition is suitable for oral administration usually.But they also are fit to other administering mode, as parenteral, sublingual administration or percutaneous dosing.
Said composition can be tablet, capsule, powder, granule, suppository, oral cavity disintegration tablet, dispersible tablet, or such as liquid preparation forms such as oral or aseptic parenteral solution or suspensions.
In order to reach the concordance of administration, the present composition is preferably single agent form.
The single agent representation that is used for oral administration can be tablet and capsule, and can contain conventional excipients such as binding agent, for example syrup, arabic gum, gelatin, sorbitol or polyvinylpyrrolidone; Filler, for example lactose, corn starch, calcium phosphate, glycine; Tabletting lubricant, for example magnesium stearate; Disintegrating agent, for example starch starch sodium glycollate; Or pharmaceutically acceptable wetting agent, as dodecyl sodium sulfate.
Solid oral composition can prepare with conventional mixing, filling or pressed disc method.Repeating married operation can be used for activating agent fully is distributed to the compositions of using a large amount of filleies.Well-known method coating during tablet can prepare according to conventional medicine, particularly enteric coated.
Oral liquid can make example emulsion, syrupy form, or can be used as dry products exists, and water or other suitable carriers reconstitute again before the use.This liquid can have conventional additives, such as suspending agent, and for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel, hydrogenation edible fat; Emulsifying agent, for example lecithin or arabic gum; Anhydrous carrier is as almond oil, slideization Oleum Cocois, propylene glycol.Can also add conventional flavoring agent or coloring agent if desired.
For parenteral, can utilize this chemical compound and sterile carrier to prepare the liquid unit dosage forms, and, can suspend or be dissolved in the carrier according to used concentration.When preparation solution, can be filled into sealing in bottle or the peace bottle afterwards with this compound dissolution in water for injection and filtration sterilization.For enhanced stability, be filled in the bottle after can be with said composition freezing, and under vacuum, remove moisture.The parenteral suspension uses the identical mode of essence to prepare, and just chemical compound is not to be dissolved in the carrier, but is suspended in the carrier, and sterilization is not accomplished by filtration.Can comprise surfactant or wetting agent in the said composition and distribution all be arranged to promote this chemical compound.
Can contain 0.1% to 99% weight, be preferably the active substance of 10-60% weight according to different medication compositionss.
These compositionss are prepared according to conventional method, such as in the canonical reference book, and those disclosed in Britain and American Pharmacopeia, Remington ' s pharmaceutical science, Extra Pharmacopoeia Martindale and Harry ' s cosmetic conduct and learning for example.
Term used herein " disease relevant with diabetes " comprises those diseases relevant with the prediabetes state, with diabetes self diseases associated and with diabetes relevant complication; Comprise such as the insulin resistance disease, comprise heritability insulin resistance, glucose tolerance weakening and hyperinsulinemia; Comprise hyperglycemia, insulin resistance comprises insulin resistance and obesity and the hyperlipidemia day after tomorrow; Other and diabetes self diseases associated comprise hypertension and cardiovascular disease, especially atherosclerosis and hyperlipidemia.
Term used herein " " comprises kidney disease, especially relevant with type ii diabetes kidney disease, neuropathy and retinopathy with the diabetes complications associated with arterial system.
Term herein " pharmaceutically acceptable " comprises people and veterinary purpose, and for example term " pharmaceutically acceptable " comprises the still acceptable chemical compound of veterinary.
In the present invention, active medicine is preferably the form administration of a pharmaceutical composition, and for example pharmaceutical composition comprises pioglitazone and colesevelam and pharmaceutically acceptable carrier thereof, derivant simultaneously.
Provide the blood pressure and blood lipoid control action of having a mind to especially to be designated as with respect to the synergism that contrasts by treatment of the present invention, this contrast is contemplated to the effect summation of independent active agents.
Glycemic control can utilize conventional method to describe its feature, for example by measuring glycemic control index commonly used, for example fasting plasma glucose or glycolated hemoglobin (HbA1c).These indexs can utilize standard method to measure.
Blood fat control can utilize conventional method to describe its feature, for example by measuring blood fat control characteristic commonly used, as low density lipoprotein, LDL LDL content in the blood plasma.These indexs can utilize standard method to measure.
Pioglitazone or its pharmaceutically acceptable salt or ester, or its pharmaceutically acceptable solvate can utilize the known method preparation, for example those disclosed among EP0306228, WO9405659, the CN1114404.EP0306228, WO9405659, CN1114404 combination are therewith as a reference.
Chemical compound colesevelam or its pharmaceutically acceptable salt or ester, or its pharmaceutically acceptable solvate can utilize the known method preparation, for example publication those disclosed such as WO9534588, WO9427620, WO9534585.WO9534588, WO9427620, WO9534585 combination are therewith as a reference.
For avoiding query, the chemical compound scalar that provides herein comprises g, mg amount, provides about chemical compound itself.Chemical compound as 1mg maleate form is meant: the maleate that contains this chemical compound of 1mg.
The preferred for preparation method of pharmaceutical preparation of the present invention is:
Prescription:
Label prescription: pioglitazone 2.5-7.5 weight portion, colesevelam 312.5-730.0 weight portion, lactose 30-70 weight portion, starch 10-30 weight portion, microcrystalline Cellulose 30-70 weight portion, the L-HPC3-10 weight portion, the 5%PVP aqueous solution is an amount of, magnesium stearate 2-5 weight portion, micropowder silica gel 3-10 weight portion.Coated formula: HPMC10-30 weight portion, acetylated monoglyceride 3-5 weight portion.
Further preferred prescription:
The label prescription: pioglitazone hydrochloride 5.0g, colesevelam 625.0g, lactose 55.0g, starch 16.0g, microcrystalline Cellulose 56.0g, L-HPC4.60g, magnesium stearate 3.80g, micropowder silica gel 6.10g, the 5%PVP aqueous solution is an amount of; Coated formula: HPMC 23.1g, acetylated monoglyceride 2.31g; Make 1000 units.
Preparation method (pioglitazone wet granulation, colesevelam dry granulation):
It is standby that pioglitazone hydrochloride, colesevelam and adjuvant are crossed 80 mesh sieves respectively, takes by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5%PVP aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60-65 ℃ of drying, cross 24 mesh sieve granulate; With colesevelam and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, direct packaging is made granule; Perhaps incapsulate, make capsule; Perhaps tabletting behind the tabletting, is a solvent with 20% ethanol, prepares HPMC and acetylated monoglyceride solution as coating solution, coating, coating weightening finish 3%-5%.
Below, foregoing of the present invention is described in further detail by the specific embodiment:
The specific embodiment
Embodiment 1: granule
Prescription:
Pioglitazone hydrochloride 5.0g
Colesevelam 625.0g
Lactose 55.0g
Starch 16.0g
Microcrystalline Cellulose 56.0g
L-HPC???????????4.60g
Magnesium stearate 3.80g
Micropowder silica gel 6.10g
The 5%PVP aqueous solution is an amount of
Preparation method:
It is standby that pioglitazone hydrochloride, colesevelam and adjuvant are crossed 80 mesh sieves respectively.Take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5%PVP aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60-65 ℃ of drying, cross 24 mesh sieve granulate.With colesevelam and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, direct packaging is made granule.
Embodiment 2: granule
Prescription:
Pioglitazone hydrochloride 2.5g
Colesevelam 312.5g
Lactose 55.0g
Starch 16.0g
Microcrystalline Cellulose 56.0g
L-HPC???????????4.60g
Magnesium stearate 3.80g
Micropowder silica gel 6.10g
The 5%PVP aqueous solution is an amount of
Preparation method:
It is standby that pioglitazone hydrochloride, colesevelam and adjuvant are crossed 80 mesh sieves respectively.Take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5%PVP aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60-65 ℃ of drying, cross 24 mesh sieve granulate.With colesevelam and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, direct packaging is made granule.
Embodiment 3: tablet
The label prescription:
Pioglitazone hydrochloride 5.0g
Colesevelam 312.5g
Lactose 55.0g
Starch 16.0g
Microcrystalline Cellulose 56.0g
L-HPC???????????????4.60g
Magnesium stearate 3.80g
Micropowder silica gel 6.10g
The 5%PVP aqueous solution is an amount of
Coated formula:
HPMC????????????????23.1g
Acetylated monoglyceride 2.31g
Preparation method:
It is standby that pioglitazone hydrochloride, colesevelam and adjuvant are crossed 80 mesh sieves respectively.Take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5%PVP aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60-65 ℃ of drying, cross 24 mesh sieve granulate.With colesevelam and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, make granule, tabletting behind the tabletting, is a solvent with 20% ethanol, according to above prescription preparation HPMC and acetylated monoglyceride solution, coating, coating weightening finish 3%-5%.
Embodiment 4: tablet
The label prescription:
Pioglitazone hydrochloride 7.5g
Colesevelam 312.5g
Lactose 55.0g
Starch 16.0g
Microcrystalline Cellulose 56.0g
L-HPC???????????????4.60g
Magnesium stearate 3.80g
Micropowder silica gel 6.10g
The 5%PVP aqueous solution is an amount of
Coated formula:
HPMC????????????????23.1g
Acetylated monoglyceride 2.31g
Preparation method:
It is standby that pioglitazone hydrochloride, colesevelam and adjuvant are crossed 80 mesh sieves respectively.Take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5%PVP aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60-65 ℃ of drying, cross 24 mesh sieve granulate.With colesevelam and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, make granule, tabletting behind the tabletting, is a solvent with 20% ethanol, according to above prescription preparation HPMC and acetylated monoglyceride solution, coating, coating weightening finish 3%-5%.
Embodiment 5: capsule
Prescription:
Pioglitazone hydrochloride 2.5g
Colesevelam 625.0g
Lactose 55.0g
Starch 16.0g
Microcrystalline Cellulose 56.0g
L-HPC???????????????4.60g
Magnesium stearate 3.80g
Micropowder silica gel 6.10g
The 5%PVP aqueous solution is an amount of
Preparation method:
It is standby that pioglitazone hydrochloride, colesevelam and adjuvant are crossed 80 mesh sieves respectively.Take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5%PVP aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60-65 ℃ of drying, cross 24 mesh sieve granulate.With colesevelam and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, make granule, incapsulate, make capsule.
Embodiment 6: capsule
Prescription:
Pioglitazone hydrochloride 7.5g
Colesevelam 625.0g
Lactose 55.0g
Starch 16.0g
Microcrystalline Cellulose 56.0g
L-HPC???????????4.60g
Magnesium stearate 3.80g
Micropowder silica gel 6.10g
The 5%PVP aqueous solution is an amount of
Preparation method:
It is standby that pioglitazone hydrochloride, colesevelam and adjuvant are crossed 80 mesh sieves respectively.Take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5%PVP aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60-65 ℃ of drying, cross 24 mesh sieve granulate.With colesevelam and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, make granule, incapsulate, make capsule.
Embodiment 7: tablet
The label prescription:
Pioglitazone hydrochloride 2.5g
Colesevelam 730.0g
Lactose 55.0g
Starch 16.0g
Microcrystalline Cellulose 56.0g
L-HPC???????????????4.60g
Magnesium stearate 3.80g
Micropowder silica gel 6.10g
The 5%PVP aqueous solution is an amount of
Coated formula:
HPMC????????????????23.1g
Acetylated monoglyceride 2.31g
Preparation method:
It is standby that pioglitazone hydrochloride, colesevelam and adjuvant are crossed 80 mesh sieves respectively.Take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5%PVP aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60-65 ℃ of drying, cross 24 mesh sieve granulate.With colesevelam and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, make granule, tabletting behind the tabletting, is a solvent with 20% ethanol, according to above prescription preparation HPMC and acetylated monoglyceride solution, coating, coating weightening finish 3%-5%.
Embodiment 8: capsule
Prescription:
Pioglitazone hydrochloride 5.0g
Colesevelam 730.0g
Lactose 55.0g
Starch 16.0g
Microcrystalline Cellulose 56.0g
L-HPC???????????????4.60g
Magnesium stearate 3.80g
Micropowder silica gel 6.10g
The 5%PVP aqueous solution is an amount of
Preparation method:
It is standby that pioglitazone hydrochloride, colesevelam and adjuvant are crossed 80 mesh sieves respectively.Take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5%PVP aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60-65 ℃ of drying, cross 24 mesh sieve granulate.With colesevelam and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, make granule, incapsulate, make capsule.
Embodiment 9: capsule
Prescription:
Pioglitazone hydrochloride 7.5g
Colesevelam 730.0g
Lactose 55.0g
Starch 16.0g
Microcrystalline Cellulose 56.0g
L-HPC???????????????4.60g
Magnesium stearate 3.80g
Micropowder silica gel 6.10g
The 5%PVP aqueous solution is an amount of
Preparation method:
It is standby that pioglitazone hydrochloride, colesevelam and adjuvant are crossed 80 mesh sieves respectively.Take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5%PVP aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60-65 ℃ of drying, cross 24 mesh sieve granulate.With colesevelam and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, make granule, incapsulate, make capsule.
Further set forth the beneficial effect of medicine of the present invention by following experiment:
The pharmacodynamic experiment of pioglitazone, colesevelam compositions:
1, animal model: high fat diet adds low dose of streptozotocin (STZ) and sets up type 2 diabetes mellitus merging hyperlipidemia rats model.Male SD rat, body weight (180 ± 25) g, the cleaning level, 60 of quantity are divided into normal control group (10) and modeling group (50) at random.The normal control group gives normal feedstuff, and the modeling group gives high-sugar-fat-diet (containing sucrose 20%, Adeps Sus domestica 10%, cholesterol 2.5%, cholate 0.25%, normal feedstuff 67.25%).After raising for 5 weeks, fasting 12h, the model group rat is by 40mg/kg body weight lumbar injection STZ (be mixed with preceding citric acid-sodium citrate buffer with 0.1mol/L, pH4.2 1% solution), and the normal control group is only injected equivalent citric acid-sodium citrate buffer.STZ is after one week in injection, and docking is got blood and surveyed fasting glucose (FBG) and blood fat.With fasting glucose＞11mmol/L, TG, LDL-C exist significant difference (P＜0.05) for becoming the mould standard with the normal control group.STZ is after one week for the injection of modeling group rat, and 43 reach into the mould standard, and the fasting glucose average is (18.5 ± 4.02) mmol/L, and becoming the mould rate is 90%.
2, grouping: the rat that will meet into the mould standard is divided at random: model group, medicine group of the present invention ((0.5mg pioglitazone+62.5mg colesevelam)/kg), pioglitazone group (0.5mg/kg) and colesevelam group (62.5mg/kg), every group each 10.
3, experimental procedure: each high-sugar-fat-diet group all continues to give high-sugar-fat-diet and feeds, each medicine group is irritated stomach and is given corresponding medicine, the normal control group continues to give normal feedstuff, normal control group and model group give isopyknic D-hank ' S liquid and irritate stomach, every morning administration 1 time, be total to 25d, every 3d weighs 1 time, satellite recanalization dosage.Fasting 12h after the last administration, pentobarbital sodium anesthesia, abdominal aortic blood, centrifugal back separation of serum; The content of oxidation enzymatic assays serum FBG, LDL-C, HDL-C.
4, result of the test
The result draws with every group of (n=6) meansigma methods ± SD and with Dunnett ' s check analysis.
4.1 respectively organize the influence of medicine to blood glucose:
| Group | ??FBGmmol/L |
| The pioglitazone hydrochloride group | ??17.7±1.9 |
| The colesevelam group | ??18.3±2.5 |
| Medicine group of the present invention | ??14.8±2.2* |
| Model group | ??21.9±3.8 |
| The normal control group | ??5.1±0.95 |
Compare with pioglitazone hydrochloride group, colesevelam group, model group, normal control group: * p＜0.01.
Interpretation of result: from experimental result, pioglitazone hydrochloride group, colesevelam group, and medicine group of the present invention with respect to model group, blood sugar lowering that can both be to a certain degree.Wherein best with medicine group hypoglycemic effect of the present invention, and obviously be better than pioglitazone hydrochloride group, colesevelam group (p＜0.01).
4.2 respectively organize the influence of medicine to blood fat:
| Group | ??HDL-Cmmol/L | ??LDL-Cmmol/L |
| The pioglitazone hydrochloride group | ??0.55±0.13 | ??1.40±0.58 |
| The colesevelam group | ??0.68±0.15 | ??1.07±0.35 |
| Medicine group of the present invention | ??0.78±0.16* | ??0.81±0.26# |
| Model group | ??0.19±0.12 | ??2.61±0.60 |
| The normal control group | ??0.82±0.15 | ??0.31±0.09 |
Compare with pioglitazone hydrochloride group, colesevelam group, model group, normal control group: * p＜0.05; #p＜0.05; Compare * p＜0.01 with model group, normal control group; #p＜0.01.
Interpretation of result: from experimental result, pioglitazone hydrochloride group, colesevelam group, and medicine group of the present invention with respect to model group, blood fat reducing that can both be to a certain degree.Wherein best with medicine group lipid-lowering effect of the present invention, and obviously be better than pioglitazone hydrochloride group, colesevelam group (p＜0.01).
Experiment conclusion: experimental result shows, medicine of the present invention has the effect of blood sugar lowering, the effect that has blood fat reducing simultaneously, reach equal hypoglycemic effect, the amount of required pioglitazone is than using the amount of pioglitazone to lack separately, the reducing blood sugar and blood fat effect of medicine of the present invention is better than using separately its arbitrary component, and medicine of the present invention can be treated diabetes, the patient of especially diabetes complicated hyperlipidemia safely and effectively.
Claims (28)
- Thiazolidinediones euglycemic agent and bile acid chelating agent preparation be used for the treatment of diabetes, diabetic complication, with the medicine of diabetes diseases associated in purposes.
- 2. according to the purposes of claim 1, wherein the thiazolidinediones euglycemic agent is selected from following compounds or its pharmaceutically acceptable salt: ciglitazone, englitazone, troglitazone, rosiglitazone, pioglitazone, Fa Gelie ketone, darglitazone.
- 3. according to the purposes of claim 1, wherein the thiazolidinediones euglycemic agent is selected from following compounds or its pharmaceutically acceptable salt: rosiglitazone, pioglitazone.
- 4. according to the purposes of claim 1, wherein the thiazolidinediones euglycemic agent is pioglitazone or its pharmaceutically acceptable salt.
- 5. according to the purposes of claim 1, wherein bile acid chelating agent is non-absorption-type bile acid chelating agent.
- 6. according to the purposes of claim 5, wherein non-absorption-type bile acid chelating agent is colesevelam or its pharmaceutically acceptable salt.
- One kind treat diabetes, diabetic complication, with the pharmaceutical composition of diabetes diseases associated, wherein contain thiazolidinediones euglycemic agent, bile acid chelating agent.
- 8. according to the pharmaceutical composition of claim 7, wherein the thiazolidinediones euglycemic agent is selected from following compounds or its pharmaceutically acceptable salt: ciglitazone, englitazone, troglitazone, rosiglitazone, pioglitazone, Fa Gelie ketone, darglitazone.
- 9. according to the pharmaceutical composition of claim 7, wherein the thiazolidinediones euglycemic agent is selected from following compounds or its pharmaceutically acceptable salt: rosiglitazone, pioglitazone.
- 10. according to the pharmaceutical composition of claim 7, wherein the thiazolidinediones euglycemic agent is pioglitazone or its pharmaceutically acceptable salt.
- 11. according to the pharmaceutical composition of claim 7, wherein bile acid chelating agent is non-absorption-type bile acid chelating agent.
- 12. according to the pharmaceutical composition of claim 11, wherein non-absorption-type bile acid chelating agent is colesevelam or its pharmaceutically acceptable salt.
- 13.,, contain the pioglitazone and the 1875-4375 weight portion colesevelam of 15-45 weight portion according to part by weight according to the pharmaceutical composition of claim 7.
- 14. according to the pharmaceutical composition of claim 13, wherein the given dose of pioglitazone is 15 weight portions or 30 weight portions or 45 weight portions.
- 15. according to the pharmaceutical composition of claim 13, wherein the given dose of colesevelam is 1875 weight portions or 3750 weight portions or 4375 weight portions.
- 16.,, contain the pioglitazone and the 1875 weight portion colesevelams of 15 weight portions according to part by weight according to the pharmaceutical composition of claim 13.
- 17.,, contain the pioglitazone and the 1875 weight portion colesevelams of 30 weight portions according to part by weight according to the pharmaceutical composition of claim 13.
- 18.,, contain the pioglitazone and the 1875 weight portion colesevelams of 45 weight portions according to part by weight according to the pharmaceutical composition of claim 13.
- 19.,, contain the pioglitazone and the 3750 weight portion colesevelams of 15 weight portions according to part by weight according to the pharmaceutical composition of claim 13.
- 20.,, contain the pioglitazone and the 3750 weight portion colesevelams of 30 weight portions according to part by weight according to the pharmaceutical composition of claim 13.
- 21.,, contain the pioglitazone and the 3750 weight portion colesevelams of 45 weight portions according to part by weight according to the pharmaceutical composition of claim 13.
- 22.,, contain the pioglitazone and 4375 colesevelams of 15 weight portions according to part by weight according to the pharmaceutical composition of claim 13.
- 23.,, contain the pioglitazone and the 4375 weight portion colesevelams of 30 weight portions according to part by weight according to the pharmaceutical composition of claim 13.
- 24.,, contain the pioglitazone and the 4375 weight portion colesevelams of 45 weight portions according to part by weight according to the pharmaceutical composition of claim 13.
- 25. any described pharmaceutical composition among the claim 7-24, wherein, pioglitazone is a hydrochloride form.
- 26. any described pharmaceutical composition among the claim 7-24, wherein, colesevelam is a hydrochloride form.
- 27. any described pharmaceutical composition among the claim 7-24, comprise pioglitazone 5.0 weight portions, colesevelam 625.0 weight portions, lactose 55.0 weight portions, starch 16.0 weight portions, microcrystalline Cellulose 56.0 weight portions, L-HPC4.60 weight portion, magnesium stearate 3.80 weight portions, micropowder silica gel 6.10 weight portions.
- 28. any described preparation of drug combination method among the claim 7-24: it is standby that pioglitazone, colesevelam and adjuvant are crossed 80 mesh sieves respectively, take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC, behind equivalent incremental method mixing, add 5%PVP aqueous solution system soft material, crossing 24 mesh sieves granulates, after 60-65 ℃ of drying, cross 24 mesh sieve granulate; With colesevelam and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate; Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, direct packaging is made granule; Perhaps incapsulate, make capsule; Perhaps tabletting behind the tabletting, is a solvent with 20% ethanol, and preparation HPMC and acetylated monoglyceride solution are as coating solution, and coating is made coated tablet.
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| CN200910235596A CN101757627A (en) | 2009-09-29 | 2009-09-29 | Combined drug and drug combination for treating diabetes |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104434952A (en) * | 2014-12-08 | 2015-03-25 | 成都恒瑞制药有限公司 | Pharmaceutical composition for treating diabetes and preparation method thereof |
| WO2017029094A1 (en) * | 2015-08-19 | 2017-02-23 | Alpex Pharma S.A. | Granular composition for oral administration |
| CN106880643A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | Drug combination and pharmaceutical composition for treating diabetes |
| CN111110647A (en) * | 2018-10-31 | 2020-05-08 | 浙江京新药业股份有限公司 | Pharmaceutical composition containing colesevelam hydrochloride and preparation method thereof |
-
2009
- 2009-09-29 CN CN200910235596A patent/CN101757627A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104434952A (en) * | 2014-12-08 | 2015-03-25 | 成都恒瑞制药有限公司 | Pharmaceutical composition for treating diabetes and preparation method thereof |
| WO2017029094A1 (en) * | 2015-08-19 | 2017-02-23 | Alpex Pharma S.A. | Granular composition for oral administration |
| US10245284B2 (en) | 2015-08-19 | 2019-04-02 | Alpex Pharma S.A. | Granular composition for oral administration |
| US10688121B2 (en) | 2015-08-19 | 2020-06-23 | Alpex Pharma S.A. | Granular composition for oral administration |
| CN106880643A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | Drug combination and pharmaceutical composition for treating diabetes |
| CN111110647A (en) * | 2018-10-31 | 2020-05-08 | 浙江京新药业股份有限公司 | Pharmaceutical composition containing colesevelam hydrochloride and preparation method thereof |
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