CN106880643A - Drug combination and pharmaceutical composition for treating diabetes - Google Patents
Drug combination and pharmaceutical composition for treating diabetes Download PDFInfo
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- CN106880643A CN106880643A CN201510930891.5A CN201510930891A CN106880643A CN 106880643 A CN106880643 A CN 106880643A CN 201510930891 A CN201510930891 A CN 201510930891A CN 106880643 A CN106880643 A CN 106880643A
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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
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
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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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
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Abstract
Drug combination and pharmaceutical composition for treating diabetes.The invention discloses the purposes of Rosiglitazone and sevelamer in the medicine for being used for treating diabetes, the diabetic complication disease relevant with diabetes is prepared.
Description
Technical field
The present invention relates to two kinds of chemicals therapeutic alliance diabetes and its purposes of complication, and be made up of both medicines
Pharmaceutical composition, belongs to chemical medicine field.
Background technology
Diabetes point predominantly type 1 diabetes, diabetes B (adult-onset diabetes, NIDDM) and it is pregnant etc. its
The diabetes that his reason causes.Wherein diabetes B accounts for more than the 90% of patient populations.Diabetes B is because insulin resistance is
It is main, with insulin secretion definitely or relative deficiency and cause with hyperglycaemia and multiple complication and the endocrine generation being characterized such as deposit
Thanking property disease, insulin resistance is the main pathology and physiological feature of diabetes B.
Counted according to the World Health Organization (WHO), whole world diabetic is about 1.94 hundred million at present, will also be doubled to the year two thousand thirty.
The diabetic of China is only second to India and occupies second place of the world up to 40,000,000 or so.2 types sugar in the diabetic population of China
Urine patient accounts for the 90%~95% of diabetic's sum.Diabetes B turned into threaten China national health principal disease it
One.The diabetes mellitus in China epidemiology survey of the newest completion of diabetology branch of Chinese Medical Association shows：At present, in China cities and towns
In population, diabetic probably has 41,000,000 people, and, up to 3.2%, annual average rate of increase is close to 10% for illness rate.In economy
The big cities such as relatively flourishing Beijing and Shanghai, the incidence of disease of diabetes is even more and reaches 8% or so.
It is still the main force for treating diabetes from chemicals from the point of view of current overall clinical medicining condition.
The characteristics of Thiazolidinediones is the sensitiveness that can be remarkably reinforced body tissue to insulin, improves beta Cell of islet work(
Can, the long-term control to blood sugar is realized, reduce the danger that diabetic complication occurs.There is good tolerance simultaneously due to it
With security, therefore with delaying the effect of diabetes development.Clinically as insulin sensitizer, increase body to insulin
Sensitiveness, mitigate insulin resistance.Thiazolidinediones can directly reduce insulin resistance, significantly improve β cell work(
Can, the long-term control of blood sugar is realized, the risk of diabetic complication generation is lowered with this, while there is good tolerance with peace
Quan Xing, therefore with delaying the effect of diabetes development.
Thiazolidinediones mitigate insulin resistance because of it, while improving and protecting β cell functions, improve glucose-lipid metabolism,
Thus there is the effect for reducing cardiovascular risk factors and delaying disease process.Therefore, in clinic diagnosis, for fat or super
The diabetes B patient of weight, and diabetes B patient not fat but with metabolic syndrome, should give preferentially and as early as possible
Thiazolidinediones.Early application Thiazolidinediones, never merely mean that blood sugar, glycated hemoglobin levels
With the decline of blood lipid level and up to standard, the prior potential protection and improvement haveing an advantage that to β cell functions, and then delay sugar
Urine patient's disease progression, many cardiovascular risk factors of improvement, the generation and development of preventing chronic complication and cardiovascular event,
Life in patients is improved, the disability rate and fatal rate of patient is reduced.
Rosiglitazone, English name Rosiglitazone.Rosiglitazone is thiazolidinediones antidiabetic medicine, belongs to insulin
Sensitizer, mechanism of action is relevant with the presence of insulin, can reduce the insulin resistance of peripheral tissues and liver, increases and relies on pancreas
The treatment of the glucose of island element, and reduce the output of glycogen.Different from sulfonylurea, Rosiglitazone does not promote insulin secretion,
Its mechanism of action is the exciting microperoxisome growth factor activation receptor-gamma [PPAR- γ] of high selectivity, PPAR- γ's
The transcription of the adjustable many control glucose of activation and the insulin related gene of lipid metabolism.
Zoopery shows that Rosiglitazone can reduce the hyperglycaemia of insulin resistance, hyperinsulinism because of disease and high triglyceride.Sieve
The metabolic alterations that lattice row ketone causes result in the increase of the tissue response for relying on insulin.Clinical research shows that Rosiglitazone can change
The insulin sensitivity of kind Patients with Insulin Resistance, improves reactivity of the insulin to cell, and improve internal glucose metabolism barrier
Hinder.
Bile acid sequestrant is resinous matter, is not absorbed in enteron aisle and is but discharged in irreversible combination and with excrement with cholic acid,
Reduce intestinal bile acid reabsorption.On the one hand accelerate in liver using cholesterol degradation into more bile acids, on the other hand also make
Intestinal absorption cholesterol is reduced so as to reduce internal cholesterol levels；Surface of hepatocytes LDL is so enhanced by feedback regulation
Receptor active, absorbing more LDL carries out catabolism.This kind of medicine can make serum TC reduction 20%-30%, and HDL-C also has
Not etc. the rising of degree, is not suitable for any kind of hypercholesterolemiapatients patients in addition to homozygote familial hypercholesterolemia.Courage
The instantiation of juice acid sequestering agent is Cholestyramine, sevelamer.
Sevelamer is phosphate binders, and foreign countries list the serium inorganic phosphorus content for controlling dialysis Chronic Renal Failure Patients, with non-suction
The property received, can avoid the characteristics of gastrointestinal absorption and degraded；Entrained multiple amidos are positively charged in small intestine inner proton,
Combined with the phosphate radical in small intestine by ion exchange and hydrogen bond, excretion phosphorus increases in causing excrement, so as to reduce serium inorganic phosphorus and first shape
The high level in gland side.
We have found that give renal insufficiency rat model by sevelamer gavage, it is same that rat serium inorganic phosphorus is reduced in zoopery
When, cholic acid, triglycerides, LDL-C, liposoluble vitamin level are also reduced, and enlighten us, oral to fill
Stomach is given rat sevelamer and can be lost weight with lipid-loweringing, but liposoluble vitamin level simultaneously needed by human declines.For this
Experiment finds that we devise various dose, the sevelamer of different ratio and vitamin and orally give rat again, observe its body
Weight, apparent condition, behavior and blood fat, vitamin level etc. change.It has been found through experiments that sevelamer is most preferably matched somebody with somebody with vitamin
The composition of ratio can reduce rat appetite, suppress rat body weight growth, reduction rat fat and its liposoluble vitamin level
It is held essentially constant, rat spirit is good, and behavior is normal.
Sevelamer purposes aspect has numerous patents, except applying and must treat outside hyperphosphatemia now, United States Patent (USP)
US2002187120A, illustrates that sevelamer hydrochloride and Kao Lai polyvinyls have the possibility for reducing uric acid or treatment gout；United States Patent (USP)
US2002187121A illustrates that sevelamer hydrochloride and Kao Lai polyvinyls have the possibility for reducing glucose or having treatment hyperglycaemia.
Compound preparation formula science designed by the present invention, sevelamer is swelling after orally reaching in vivo, has both reached satiety reduction
Appetite, while fat-reducing effect can be reached by adsorbing the cholic acid and grease of enteron aisle and reduction blood fat again, coordinates vitamin to take,
Replenishing vitamins, play antioxidation, can prevent unrighted acid peroxidating, prevent the formation of lipofuscin from reaching reinforcement
Matter, the effect of anti-aging.
The content of the invention
The present inventor has surprisingly found that Study of Thiazolidinedione derivatives as Insulin Sensitizer and bile acid sequestrant combine medicine by numerous studies
Thing form can provide particularly advantageous blood pressure and blood lipoid control effect, and without discovery side reaction.This combination medicine form can be special
Not good is applied to treatment diabetes, especially diabetes B and the disease related to diabetes, reaches reduction blood sugar, blood fat,
Improve the purpose of diabetes, its effect is significant is better than any single component.
Wherein, the combination medicine form of particularly preferred Rosiglitazone and sevelamer.
The present invention provides a kind of Study of Thiazolidinedione derivatives as Insulin Sensitizer and bile acid sequestrant and is preparing for treating diabetes, sugar
Purposes in the medicine of the sick complication of the urine disease relevant with diabetes.
Wherein Study of Thiazolidinedione derivatives as Insulin Sensitizer 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)。
Rosiglitazone class is for example：Rosiglitazone Maleate, Rosiglitazone sodium, Rosiglitazone, Luogelie ketone hydrochloride.
More preferably Rosiglitazone, or its pharmaceutically acceptable salt, such as hydrochloride.
Bile acid sequestrant is selected from Cholestyramine, sevelamer.
The preferred non-absorbing type bile acid sequestrant of bile acid sequestrant, more preferably sevelamer, or its is pharmaceutically acceptable
Salt, such as hydrochloride.
Further, the present invention provides a kind of Study of Thiazolidinedione derivatives as Insulin Sensitizer and is being prepared for treating glycosuria with sevelamer
Purposes in the medicine of disease, the diabetic complication disease relevant with diabetes.
Further, the present invention provide Rosiglitazone and sevelamer prepare for treat diabetes, diabetic complication,
Purposes in the medicine of the disease relevant with diabetes.
The purposes is included and is administered simultaneously insulin sensitizer such as Rosiglitazone, and sevelamer class antihyperglycemic high blood cholesterol drug
Or the two order of administration.
It is administered simultaneously including giving one kind comprising insulin sensitizer such as Rosiglitazone, and sevelamer class antihyperglycemic high fat of blood system
Agent, or the independent preparation of every kind of activating agent is substantially simultaneously administered.
The present invention also provides a kind of pharmaceutical composition for treating diabetes, the diabetic complication disease relevant with diabetes, its
Contain Study of Thiazolidinedione derivatives as Insulin Sensitizer, bile acid sequestrant in middle said composition.As needed, also contain in said composition
There is appropriate pharmaceutically acceptable auxiliary material.
Study of Thiazolidinedione derivatives as Insulin Sensitizer in said composition is selected from following compounds or its pharmaceutically acceptable salt：Ring lattice
Row ketone (Ciglitazone), Englitazone (Englitazone), troglitazone (Troglitazone), Rosiglitazone
(Rosiglitazone), Pioglitazone (Pioglitazone), Fa Gelie ketone (Farglitazar), Darglitazone
(Darglitazoan).Preferably Rosiglitazone, or its pharmaceutically acceptable salt, such as hydrochloride.
Bile acid sequestrant is selected from Cholestyramine, sevelamer
The preferred non-absorbing type bile acid sequestrant of bile acid sequestrant, more preferably sevelamer, or its is pharmaceutically acceptable
Salt, such as hydrochloride.
Further, the present invention provides a kind of medicine group for treating diabetes, the diabetic complication disease relevant with diabetes
Compound, wherein containing Study of Thiazolidinedione derivatives as Insulin Sensitizer, bile acid sequestrant.
Further, the present invention provides a kind of medicine group for treating diabetes, the diabetic complication disease relevant with diabetes
Compound, wherein containing Study of Thiazolidinedione derivatives as Insulin Sensitizer, non-absorbing type bile acid sequestrant.
Further, the present invention provides a kind of medicine for treating diabetes, the diabetic complication disease relevant with diabetes
Composition, wherein containing Study of Thiazolidinedione derivatives as Insulin Sensitizer, sevelamer.
Further, the present invention provides a kind of medicine for treating diabetes, the diabetic complication disease relevant with diabetes
Composition, wherein containing Rosiglitazone, sevelamer.
The present inventor is by substantial amounts of research discovery, Study of Thiazolidinedione derivatives as Insulin Sensitizer and bile acid sequestrant combination medicine shape
Formula can provide particularly advantageous blood pressure and blood lipoid control effect, and without discovery side reaction.This combination medicine form can be especially good
Be applied to treat diabetes, especially diabetes B and the disease related to diabetes, reach reduce blood sugar, blood fat, change
The purpose of kind diabetes, its effect is significant is better than any single component.
Wherein, the combination medicine form of particularly preferred Rosiglitazone and sevelamer.Particularly preferably contain Rosiglitazone, department's Wella
Nurse is used as active ingredient, and the pharmaceutical composition that appropriate pharmaceutically acceptable auxiliary material is constituted.
On the one hand drug combination form of the present invention and pharmaceutical composition improve II type glycosuria using thiazolidinediones (TZDs) class medicine
The insulin resistance of patient, so as to improve hyperinsulinemia and hyperglycemia metabolic disorder；On the other hand bile acid chela is utilized
Mixture is in irreversible combination with cholic acid, receives intestinal bile acid resorption and reduces, and accelerates to utilize cholesterol in liver, so as to reduce
Internal cholesterol levels.Both are combined together, and by reducing fat absorption, improve the effect that insulin resistance reaches hypoglycemic
Really.Drug combination is strengthened the aspect of metabolism two and is worked from absorption is reduced, and drug effect is significantly stronger than single medicine.
Pharmaceutical composition of the present invention is due to containing Rosiglitazone, so do not change insulin secretion state while hypoglycemic, also not
The absorption of carbohydrate is influenceed, the life-span of pancreatic β cell can be sufficiently protected, simultaneously because fat can be reduced containing sevelamer
Absorb, make use of the interaction of the metabolism of carbohydrate 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 Rosiglitazone consumption, reduce and draw because Rosiglitazone consumption is excessive
The hypoglycemia odds for rising.
Rosiglitazone has certain cardiac side effects in itself, and Rosiglitazone can increase plasma volume, cause cardiac preload to increase
And inducing heart is loose, while sevelamer reduces low density fat in pharmaceutical composition of the present invention, high density can also be increased
Lipoprotein content, so as to be beneficial to Cardioprotective.Therefore pharmaceutical composition of the present invention can significantly improve the heart pair of Rosiglitazone
Reaction.
Diabetes patient while hyperglycaemia, mostly with high fat of blood, obesity.Pharmaceutical composition of the present invention can hypoglycemic, and energy
Lipid-loweringing, so that more effectively, and be long-acting lasting improvement diabetes.
An advantage of the present invention is that, when being used according to the inventive method, various active dose levels used will be less than reaching
The dosage that the blood pressure and blood lipoid control action of single pure addition may need.
Also index shows, relative to individual independent component, treatment method of the invention will improve serum lipids include T-CHOL,
The level of HDL- cholesterol, LDL- cholesterol, including improve its ratio.
The present composition is applied to treatment diabetes, especially diabetes B, is further particularly well-suited to treatment with blood high
The diabetes B of fat.
Pharmaceutical composition of the invention, according to the ratio of weight, the Rosiglitazone containing 15-45 weight portions and 1875-4375 are heavy
Amount part sevelamer.
Scope 15-45 weight portions include 15-30 weight portions, 20-35 weight portions, or 30-45 weight portions.
Scope 1875-4375 weight portions include 1875-3750 weight portions, 2200-4100 weight portions, or 3750-4375 weight
Part.
It is preferred that the given dose of Rosiglitazone is 15 weight portions or 30 weight portions or 45 weight portions.
It is preferred that the given dose of sevelamer is 1875 weight portions or 3750 weight portions or 4375 weight portions.
The inventors discovered that, embodiment disclosed below is particularly preferred：According to the ratio of weight, the Roger containing 30 weight portions
Row ketone and 3750 weight portion sevelamers.
According to the individual demand of patient, other preferred embodiment include：According to the ratio of weight, sieve containing 15 weight portions
Lattice row ketone and 1875 weight portion sevelamers.
According to the ratio of weight, the Rosiglitazone containing 30 weight portions and 1875 weight portion sevelamers.
According to the ratio of weight, the Rosiglitazone containing 45 weight portions and 1875 weight portion sevelamers.
According to the ratio of weight, the Rosiglitazone containing 15 weight portions and 3750 weight portion sevelamers.
According to the ratio of weight, the Rosiglitazone containing 45 weight portions and 3750 weight portion sevelamers.
According to the ratio of weight, the Rosiglitazone containing 15 weight portions and 4375 weight portion sevelamers.
According to the ratio of weight, the Rosiglitazone containing 30 weight portions and 4375 weight portion sevelamers.
According to the ratio of weight, the Rosiglitazone containing 45 weight portions and 4375 weight portion sevelamers.
These compositions are preferably made unit dosage forms, such as 5mg Rosiglitazones and 625mg departments with the amount with relevant date appropriate dosage
Wella nurse is made 1 unit dosage forms.
Composition of the invention can be administered 1-7 times daily, preferably administration 1 or 2 time daily, most preferably administration 2 times daily.
1-10 UD, preferably 1-7 UD are administered every time.
The present composition is typically suitable for being administered orally, but, they also are adapted for other administering modes, such as parenteral,
Sublingual administration or percutaneous dosing.
Said composition can be tablet, capsule, pulvis, particle, suppository, oral disnitegration tablet, dispersible tablet, or it is such as oral or
The liquid forms such as sterile parenteral solutions or suspension.
In order to reach the uniformity of administration, the present composition is preferably unit dose form.
Single dose representation for being administered orally can be tablet and capsule, and can contain conventional excipients such as adhesive, example
Such as syrup, Arabic gum, gelatin, sorbierite or polyvinylpyrrolidone；Filler, such as lactose, cornstarch, phosphoric acid
Calcium, glycine；Tableting lubricant, such as magnesium stearate；Disintegrant, such as starch starch sodium glycollate；Or can pharmaceutically connect
The wetting agent received, such as dodecyl sodium sulfate.
Solid oral composition can be prepared with conventional mixing, filling or pressed disc method.Married operation is repeated to can be used for activity
Agent is fully distributed in the composition using a large amount of fillers.Tablet can be according to well-known method bag in conventional medicine preparation
Clothing, it is particularly enteric coated.
Oral liquid can be the form of such as emulsion, syrup, or can exist as dry products, be used again using preceding
Water or other suitable carriers reconstitute.This liquid can have conventional additives, such as suspending agent, such as sorbierite, sugar
Slurry, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethylcellulose calcium, aluminium stearate gel, hydrogenated edible fats；Emulsification
Agent, such as lecithin or Arabic gum；Anhydrous carrier, such as apricot kernel oil, slipping coconut oil, propane diols.If desired can be with
Add conventional flavourings or colouring agent.
For parenteral, fluid unit dosage form is prepared using the compound and sterile carrier, and according to concentration used,
Can be suspended or dissolved in carrier.When solution is prepared, the compound can be dissolved in water for injection and filtration sterilization, it
After be filled into bottle or ampulla and seal.In order to strengthen stability, it is filled into bottle after can said composition be freezed, and
Moisture is removed under vacuum.Parenteral suspension is prepared using substantially identical mode, and simply compound is not dissolved in carrier, and
It is suspended in carrier, and sterilizing is not accomplished by filtration.Can include surfactant or wetting agent to promote in said composition
The compound is distributed.
According to different medication compositions can containing 0.1% to 99% weight, be preferably 10-60% weight active material.
These compositions are conventionally prepared, such as in standard reference, for example Britain and American Pharmacopeia,
Those disclosed in Remington ' s pharmaceutical sciences, Extra Pharmacopoeia Martindale and Harry ' s cosmeceuticals.
Term " disease related with diabetes " used herein includes those diseases relevant with prediabetic conditions, with
The relevant disease of diabetes itself and the complication related to diabetes；Including such as insulin resistance disease, including heredity pancreas
The plain resistance in island, glucose tolerance weaken and hyperinsulinemia；Including hyperglycaemia, insulin resistance, including the day after tomorrow, insulin resisted
Property and fat and high fat of blood；The relevant disease of other and diabetes itself includes hypertension and angiocardiopathy, especially artery congee
Sample is hardened and high fat of blood.
Term used herein " complication relevant with diabetes " including kidney trouble, it is especially relevant with type ii diabetes
Kidney trouble, neuropathy and retinopathy.
Term herein is " pharmaceutically acceptable " to include people and veterinary purpose, " pharmaceutically acceptable " bag of such as term
Containing the still acceptable compound of veterinary science.
In the present invention, active medicine is preferably the form administration of a pharmaceutical composition, and such as pharmaceutical composition includes Roger simultaneously
Row ketone and sevelamer and its pharmaceutically acceptable carrier, derivative.
Especially intentional blood pressure and blood lipoid control action is provided by treatment of the invention to be designated as relative to the synergy for compareing, should
Control is contemplated to the effect summation of single active agents.
Glycemic control can describe its feature using conventional method, such as by the glycemic control index that measurement is conventional, for example, prohibit
Food plasma glucose or glycosylated hemoglobin (HbA1c).These indexs can be determined using standard method.
Blood fat control can describe its feature using conventional method, such as by the blood fat control characteristic that measurement is conventional, such as blood plasma
Middle low-density lipoprotein LDL contents.These indexs can be determined using standard method.
Rosiglitazone or its pharmaceutically acceptable salt or ester, or its pharmaceutically acceptable solvate, it is possible to use known formula
Prepared by method, such as those disclosed in EP0306228, WO9405659, CN1114404.EP0306228、WO9405659、
CN1114404 is combined with this as reference.
Compound sevelamer or its pharmaceutically acceptable salt or ester, or its pharmaceutically acceptable solvate, it is possible to use
Prepared by known method, the publication those disclosed such as such as WO9534588, WO9427620, WO9534585.WO9534588、
WO9427620, WO9534585 are combined with this as reference.
To avoid query, the compound scalar being presented herein, including g, mg amount, be given in itself on compound.Such as
The compound of 1mg maleate forms refers to：Maleate containing the 1mg compounds.
The preferred preparation method of pharmaceutical preparation of the present invention is：
Formula：
Core tablet formula：Rosiglitazone 2.5-7.5 weight portions, sevelamer 312.5-730.0 weight portions, lactose 30-70 weight
Part, starch 10-30 weight portions, microcrystalline cellulose 30-70 weight portions, L-HPC 3-10 weight portions, the 5%PVP aqueous solution is appropriate,
Magnesium stearate 2-5 weight portions, superfine silica gel powder 3-10 weight portions.Coated formula：HPMC 10-30 weight portions, acetyl mono-acid are sweet
Oily ethyl ester 3-5 weight portions.
Further preferred formula：
Core tablet formula：Luogelie ketone hydrochloride 5.0g, sevelamer 625.0g, lactose 55.0g, starch 16.0g, crystallite are fine
Dimension element 56.0g, L-HPC4.60g, magnesium stearate 3.80g, superfine silica gel powder 6.10g, the 5%PVP aqueous solution is appropriate；Coated formula：
HPMC 23.1g, acetylated monoglyceride 2.31g；It is made 1000 units.
Preparation method (Rosiglitazone wet granulation, sevelamer dry granulation)：
By Luogelie ketone hydrochloride, sevelamer and auxiliary material respectively cross 80 mesh sieves it is standby, according to formula weigh Luogelie ketone hydrochloride, lactose,
Starch, L-HPC, after being mixed with equal increments method, add 5%PVP aqueous solution softwoods, the granulation of 24 mesh sieves are crossed, in 60-65 DEG C
After drying, 24 mesh sieve whole grains are crossed；Sevelamer is well mixed with microcrystalline cellulose, using dry granulation, 24 mesh sieve series is crossed
Grain.After both the above particle is well mixed with magnesium stearate, superfine silica gel powder, direct packaging is made granule；Or load
Capsule, is made capsule；Or compressing tablet, it is solvent with 20% ethanol after compressing tablet, prepare HPMC and acetylated monoglyceride
Solution is coated, coating weight gain 3%-5% as Coating Solution.
Specific embodiment
Below by way of specific embodiment, the above of the invention is described in further detail：
Embodiment 1：Granule
Formula：
Preparation method：
Luogelie ketone hydrochloride, sevelamer and auxiliary material are crossed 80 mesh sieves respectively standby.According to prescription weigh Luogelie ketone hydrochloride, lactose,
Starch, L-HPC, after being mixed with equal increments method, add 5%PVP aqueous solution softwoods, the granulation of 24 mesh sieves are crossed, in 60-65 DEG C
After drying, 24 mesh sieve whole grains are crossed.Sevelamer is well mixed with microcrystalline cellulose, using dry granulation, 24 mesh sieve series is crossed
Grain.After both the above particle is well mixed with magnesium stearate, superfine silica gel powder, direct packaging is made granule.
Embodiment 2：Granule
Formula：
Preparation method：
Luogelie ketone hydrochloride, sevelamer and auxiliary material are crossed 80 mesh sieves respectively standby.According to prescription weigh Luogelie ketone hydrochloride, lactose,
Starch, L-HPC, after being mixed with equal increments method, add 5%PVP aqueous solution softwoods, the granulation of 24 mesh sieves are crossed, in 60-65 DEG C
After drying, 24 mesh sieve whole grains are crossed.Sevelamer is well mixed with microcrystalline cellulose, using dry granulation, 24 mesh sieve series is crossed
Grain.After both the above particle is well mixed with magnesium stearate, superfine silica gel powder, direct packaging is made granule.
Embodiment 3：Tablet
Core tablet formula：
Coated formula：
HPMC 23.1g
Acetylated monoglyceride 2.31g
Preparation method：
Luogelie ketone hydrochloride, sevelamer and auxiliary material are crossed 80 mesh sieves respectively standby.According to prescription weigh Luogelie ketone hydrochloride, lactose,
Starch, L-HPC, after being mixed with equal increments method, add 5%PVP aqueous solution softwoods, the granulation of 24 mesh sieves are crossed, in 60-65 DEG C
After drying, 24 mesh sieve whole grains are crossed.Sevelamer is well mixed with microcrystalline cellulose, using dry granulation, 24 mesh sieve series is crossed
Grain.After both the above particle is well mixed with magnesium stearate, superfine silica gel powder, particle, compressing tablet, after compressing tablet, with 20% are made
Ethanol is solvent, and HPMC and acetylated monoglyceride solution are prepared according to above prescription, is coated, coating weight gain 3%-5%.
Embodiment 4：Tablet
Core tablet formula：
Coated formula：
HPMC 23.1g
Acetylated monoglyceride 2.31g
Preparation method：
Luogelie ketone hydrochloride, sevelamer and auxiliary material are crossed 80 mesh sieves respectively standby.According to prescription weigh Luogelie ketone hydrochloride, lactose,
Starch, L-HPC, after being mixed with equal increments method, add 5%PVP aqueous solution softwoods, the granulation of 24 mesh sieves are crossed, in 60-65 DEG C
After drying, 24 mesh sieve whole grains are crossed.Sevelamer is well mixed with microcrystalline cellulose, using dry granulation, 24 mesh sieve series is crossed
Grain.After both the above particle is well mixed with magnesium stearate, superfine silica gel powder, particle, compressing tablet, after compressing tablet, with 20% are made
Ethanol is solvent, and HPMC and acetylated monoglyceride solution are prepared according to above prescription, is coated, coating weight gain 3%-5%.
Embodiment 5：Capsule
Formula：
Preparation method：
Luogelie ketone hydrochloride, sevelamer and auxiliary material are crossed 80 mesh sieves respectively standby.According to prescription weigh Luogelie ketone hydrochloride, lactose,
Starch, L-HPC, after being mixed with equal increments method, add 5%PVP aqueous solution softwoods, the granulation of 24 mesh sieves are crossed, in 60-65 DEG C
After drying, 24 mesh sieve whole grains are crossed.Sevelamer is well mixed with microcrystalline cellulose, using dry granulation, 24 mesh sieve series is crossed
Grain.After both the above particle is well mixed with magnesium stearate, superfine silica gel powder, particle is made, loads capsule, be made capsule.
Embodiment 6：Capsule
Formula：
Preparation method：
Luogelie ketone hydrochloride, sevelamer and auxiliary material are crossed 80 mesh sieves respectively standby.According to prescription weigh Luogelie ketone hydrochloride, lactose,
Starch, L-HPC, after being mixed with equal increments method, add 5%PVP aqueous solution softwoods, the granulation of 24 mesh sieves are crossed, in 60-65 DEG C
After drying, 24 mesh sieve whole grains are crossed.Sevelamer is well mixed with microcrystalline cellulose, using dry granulation, 24 mesh sieve series is crossed
Grain.After both the above particle is well mixed with magnesium stearate, superfine silica gel powder, particle is made, loads capsule, be made capsule.
Embodiment 7：Tablet
Core tablet formula：
Coated formula：
Preparation method：
Luogelie ketone hydrochloride, sevelamer and auxiliary material are crossed 80 mesh sieves respectively standby.According to prescription weigh Luogelie ketone hydrochloride, lactose,
Starch, L-HPC, after being mixed with equal increments method, add 5%PVP aqueous solution softwoods, the granulation of 24 mesh sieves are crossed, in 60-65 DEG C
After drying, 24 mesh sieve whole grains are crossed.Sevelamer is well mixed with microcrystalline cellulose, using dry granulation, 24 mesh sieve series is crossed
Grain.After both the above particle is well mixed with magnesium stearate, superfine silica gel powder, particle, compressing tablet, after compressing tablet, with 20% are made
Ethanol is solvent, and HPMC and acetylated monoglyceride solution are prepared according to above prescription, is coated, coating weight gain 3%-5%.
Embodiment 8：Capsule
Formula：
Preparation method：
Luogelie ketone hydrochloride, sevelamer and auxiliary material are crossed 80 mesh sieves respectively standby.According to prescription weigh Luogelie ketone hydrochloride, lactose,
Starch, L-HPC, after being mixed with equal increments method, add 5%PVP aqueous solution softwoods, the granulation of 24 mesh sieves are crossed, in 60-65 DEG C
After drying, 24 mesh sieve whole grains are crossed.Sevelamer is well mixed with microcrystalline cellulose, using dry granulation, 24 mesh sieve series is crossed
Grain.After both the above particle is well mixed with magnesium stearate, superfine silica gel powder, particle is made, loads capsule, be made capsule.
Embodiment 9：Capsule
Formula：
Preparation method：
Luogelie ketone hydrochloride, sevelamer and auxiliary material are crossed 80 mesh sieves respectively standby.According to prescription weigh Luogelie ketone hydrochloride, lactose,
Starch, L-HPC, after being mixed with equal increments method, add 5%PVP aqueous solution softwoods, the granulation of 24 mesh sieves are crossed, in 60-65 DEG C
After drying, 24 mesh sieve whole grains are crossed.Sevelamer is well mixed with microcrystalline cellulose, using dry granulation, 24 mesh sieve series is crossed
Grain.After both the above particle is well mixed with magnesium stearate, superfine silica gel powder, particle is made, loads capsule, be made capsule.
Claims (9)
1. Rosiglitazone and sevelamer or its pharmaceutically acceptable salt prepare for treat diabetes, diabetic complication,
Purposes in the medicine of the disease relevant with diabetes.
2. a kind of pharmaceutical composition, according to part by weight, the Rosiglitazone containing 15-45 weight portions and 1875-4375 weight portions
Sevelamer.
3. pharmaceutical composition according to claim 2, it is characterised in that the given dose of Rosiglitazone be 15 weight portions,
Or 30 weight portion or 45 weight portions.
4. pharmaceutical composition according to claim 2, it is characterised in that the given dose of sevelamer is 1875 weight
Part or 3750 weight portions or 4375 weight portions.
5. pharmaceutical composition according to claim 2, according to part by weight, the Roger containing 15,30 or 45 weight portions
Row ketone and 1875 weight portion sevelamers.
6. pharmaceutical composition according to claim 2, according to part by weight, the Roger containing 15,30 or 45 weight portions
Row ketone and 3750 weight portion sevelamers.
7. pharmaceutical composition according to claim 2, according to part by weight, the Roger containing 15,30 or 45 weight portions
Row ketone and 4375 sevelamers.
8. the weight portion of pharmaceutical composition according to claim 2, including Rosiglitazone 5.0, the weight of sevelamer 625.0
Part, the weight portion of lactose 55.0, the weight portion of starch 16.0, the weight portion of microcrystalline cellulose 56.0, L-HPC4.60 weight portions, firmly
The weight portion of fatty acid magnesium 3.80, the weight portion of superfine silica gel powder 6.10.
9. the preparation method of the pharmaceutical composition in claim 2-8 described in any one：By Rosiglitazone, sevelamer and auxiliary
80 mesh sieves excessively are standby respectively for material, weigh Luogelie ketone hydrochloride, lactose, starch, L-HPC, after being mixed with equal increments method, add
5%PVP aqueous solution softwoods, cross the granulation of 24 mesh sieves, in after 60-65 DEG C of drying, cross 24 mesh sieve whole grains；By sevelamer with it is micro-
Crystalline cellulose is well mixed, and using dry granulation, crosses the granulation of 24 mesh sieves；By both the above particle and magnesium stearate, superfine silica gel powder
After well mixed, direct packaging is made granule；Or load capsule, it is made capsule；Or compressing tablet, after compressing tablet, with
20% ethanol is solvent, prepares HPMC and acetylated monoglyceride solution as Coating Solution, is coated, and is made coated tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510930891.5A CN106880643A (en) | 2015-12-15 | 2015-12-15 | Drug combination and pharmaceutical composition for treating diabetes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510930891.5A CN106880643A (en) | 2015-12-15 | 2015-12-15 | Drug combination and pharmaceutical composition for treating diabetes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106880643A true CN106880643A (en) | 2017-06-23 |
Family
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510930891.5A Pending CN106880643A (en) | 2015-12-15 | 2015-12-15 | Drug combination and pharmaceutical composition for treating diabetes |
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| Country | Link |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101237870A (en) * | 2005-06-03 | 2008-08-06 | 田边三菱制药株式会社 | Concomitant pharmaceutical agents and use thereof |
| CN101757627A (en) * | 2009-09-29 | 2010-06-30 | 北大方正集团有限公司 | Combined drug and drug combination for treating diabetes |
-
2015
- 2015-12-15 CN CN201510930891.5A patent/CN106880643A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101237870A (en) * | 2005-06-03 | 2008-08-06 | 田边三菱制药株式会社 | Concomitant pharmaceutical agents and use thereof |
| CN101757627A (en) * | 2009-09-29 | 2010-06-30 | 北大方正集团有限公司 | Combined drug and drug combination for treating diabetes |
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Application publication date: 20170623 |