CN102657626A - Medicinal composite tablet of pioglitazone medicine - Google Patents
Medicinal composite tablet of pioglitazone medicine Download PDFInfo
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Abstract
The invention discloses a medicinal composite tablet of a pioglitazone medicine. The medicinal composite tablet comprises a self-emulsifying medicine release part and a water-soluble carrier part, wherein the self-emulsifying medicine release part comprises pioglitazone, an oil phase, an emulsifier and a promotion emulsifier in the mass ratio of 1:(2-25):(1-10): (1-5). The self-emulsifying tablet can increase the total area of dissolution of the pioglitazone medicine. Compared with the traditional preparation, the medicine is relatively long in retention time in a human body and more facilitates the absorption of the human body. The self-emulsifying preparation provided by the invention can reduce the drug metabolism from kidneys, and the relapse of bladder cancer is reduced to a certain extent. In addition, phosphatidylcholine in the preparation also has the activity of repairing diabetic complications, such as liver impairment, caused by diseases, such as diabetic hypertension and primary hypertension, so that the treatment effect of the preparation is improved.
Description
Technical field
The present invention relates to a kind of medicine preparation, relate to a kind of pioglitazone hydrochloride composition tablet more specifically.
Technical background
Diabetes are to be the syndrome of basic biochemical character to continue hyperglycemia.Cause insulin to be enough to relatively or anything but and in various degree insulin resistant by a variety of causes, make carbohydrate, fat and protein metabolism disorder, clinical manifestation is diabetes.Along with the prolongation of the course of disease, blood capillary and macroangiopathy widely can appear, cause losing the sight of both eyes, renal failure, acromelic gangrene, myocardial infarction and cerebrovascular disease serious threat patient's life.Wherein type 2 diabetes mellitus accounts for 90%～95%, and the pathogenesis basis of type 2 diabetes mellitus is insulin resistant and β cell dysfunction.Discovering so-called " type 2 diabetes mellitus ", is under the effect of various paathogenic factors, forms through very long pathological process.Because the existence of virulence factor, normal blood constitutional balance is destroyed, and insulin is renderd a service and weakened relatively in the blood, through the startup of body internal feedback system, at first involves islets of langerhans, makes it long-term overwork and loses compensatory capacity.Be main feature clinically with the hyperglycemia; The secular blood sugar increasing of diabetics can quicken the beta Cell of islet apoptosis; Cause blood capillary, trunk and neuropathy widely, cause the functional lesion even the depletion of vitals such as the heart, brain, kidney, serious threat patient's life.Controlling needs strict blood sugar control, the protection target organ.The type 2 diabetes mellitus patient is tending towards more early, more being prone to take place cardiovascular complication.Except that hyperglycemia, dyslipidemia, the disorder of fibrinolytic balance all are the key factors that promotes that cardiovascular event takes place.Pioglitazone hydrochloride belongs to the thiazolidinedione oral antidiabetic drug, can improve cell to glucose and utilization through strengthening the sensitivity of tissue to insulin, and obvious the reduction on an empty stomach and post-prandial glycemia.Its mechanism of action is relevant with two receptors (ppary) of specificity peroxide activator enzyme paraphyte factor activator; Have the insulin of adjusting effector and transcribe and control the glucose generation; The effect of rotating and utilizing; Can increase the sensitivity of insulin, thereby play blood sugar reducing function liver, muscle insulin tissue.Glimepiride is a third generation sulfonylurea antidiabetic drug, has the inhibition hepatic glucose and synthesizes, promotes muscular tissue to the picked-up of periphery glucose and the effect of promotion insulin secretion.
But, discover that pioglitazone hydrochloride is dissolved in N, the N-dimethyl imide is slightly soluble in ethanol, is dissolved in acetone and acetonitrile hardly, water insoluble and ether, blood drug level maximum in human body is 30-50%, total bioavailability is 20-25%.Mainly be to improve the dissolution velocity of preparation to the research that improves biological pioglitazone hydrochloride bioavailability at present at human body.Chinese patent (publication number: CN101269040A) disclose a kind of pioglitazone hydrochloride sustained-release micropill and preparation method thereof; Utilize hydrophilic framework material and hydrophobicity framework material as substrate; Process dispersant with pioglitazone hydrochloride; Make medicine be molecule, colloid or microcrystalline state and be scattered in the substrate, the total surface area of medicine strengthens, and improves bioavailability.
Summary of the invention
The present invention is directed to the pioglitazone hydrochloride bad water-solubility for addressing the above problem; A kind of self emulsifying tablet is provided; From increasing medicine at the intravital time of staying of people, raising drug solubility; Three aspects such as total surface area that increase medicine solve the not high problem of pioglitazone hydrochloride bioavailability, make the drug effect cycle elongated; Self-emulsifier can increase the absorption of liver to medicine simultaneously, has certain targeting, reduces the injury of medicine to kidney; More helping medicine plays a role.Phosphatidylcholine not only can play the effect of emulsifying agent simultaneously, and simultaneously, phosphatidylcholine has the effect that cuts grease; Can promote blood circulation, improve serum lipids, remove peroxide; Make cholesterol and the reduction of neutral fat content in the blood; Reduce fat in the holdup time of blood vessel, promote the dissipation of atherosis speckle, prevent the tunica intima damage that causes by cholesterol.Take phosphatidylcholine hyperlipidemia and hypercholesterolemia are had obvious effect, thereby can prevent and treat arteriosclerosiss such as hypertension, myocardial infarction, cerebral hemorrhage.In addition, phosphatidylcholine not only can prevent fatty liver, can also promote liver cell regeneration, and simultaneously, phosphatidylcholine can reduce serum cholesterol content, prevents liver cirrhosis and helps liver and the recovery of renal function.This drug regimen is lowering blood pressure, in the time of diseases such as treatment diabetic hypertension, essential hypertension, can also repair the hepar damnification that causes because of diseases such as diabetic hypertension and essential hypertensions.
A kind of pioglitazone hydrochloride drug regimen tablet; Comprise self-emulsifying drug delivery part and water-soluble solid carrier part; Said self-emulsifying drug delivery partly comprises pioglitazone hydrochloride, oil phase, emulsifying agent and short emulsifying agent; Wherein, the mass ratio of pioglitazone hydrochloride, oil phase, emulsifying agent and short emulsifying agent is 1:2-25:1-10:1-5.
Comprised phosphatidylcholine in the said emulsifying agent.
The mixture that except phosphatidylcholine, also comprises any one or two kinds in ethyoxyl polyoxyethylene glyceride, polyoxyethylene oleate and the tween 80 of liquid or solid in the said emulsifying agent.
Said emulsifying agent is the mixture of phosphatidylcholine and tween 80.
The weight ratio of said phosphatidylcholine and tween 80 is 1-2:1-2.
The weight ratio of said phosphatidylcholine and tween 80 is 1:1.
Said water-soluble solid carrier portion is the combination of any one or two kinds in microcrystalline Cellulose (MCC), lactose, cellulose acetate, ethyl cellulose, polyacrylic resin, silicone rubber, gelatin, Hydroxypropyl Methyl Cellulose Phthalate (I-IPMCAS-LG), cellulose acetate phthalate ester (CAP), dichloromethane and aerosil, hydroxypropyl emthylcellulose (HPMC) and the Ka Baibo resin (carbopol).
Said water-soluble solid carrier partly is the combination of hydroxypropyl emthylcellulose and Ka Baibo resin.
Said oil phase is any one or the two or more mixture in Oleum Ricini, soybean oil, Oleum Arachidis hypogaeae semen, olive oil, butyl oleate, Ethyl linoleate, isopropyl myristate, medium-chain fatty acid triacylglycerol, sad, capric acid triacylglycerol, oleic acid, linoleic acid, the linolenic acid triacylglycerol.
Said short emulsifying agent is a kind of in ethanol or the butanediol.
Useful technique effect of the present invention is: adopt the self emulsifying tablet not only can increase the gross area of pioglitazone hydrochloride medicine dissolution, and the relative conventional formulation of time that medicine is detained human body had than leap ahead, more helped absorption of human body; Self-emulsifiable preparation provided by the invention can reduce the metabolism of medicine from kidney, has reduced the morbidity of bladder cancer to a certain extent; The intermediary phosphatidylcholine of preparation also has the activity that can also repair the diabetic complications such as hepar damnification that cause because of diseases such as diabetic hypertension and essential hypertensions in addition, has improved the curative effect of preparation according to the invention.
Description of drawings
The emulsion droplet particle diameter of Fig. 1 different formulations;
The release profiles of Fig. 2 pioglitazone hydrochloride tablet medicine.
The specific embodiment
The research of embodiment 1 pioglitazone hydrochloride tablet drug release behavior
Pioglitazone hydrochloride (Pioglitazone hydrochloride; PGH) be Thiazolidine ketone antidiabetic drug; Act on peroxisome proliferation activated receptor-(PPAR-), increase the sensitivity of Insulin receptor INSR, be mainly used in the treatment type 2 diabetes mellitus; Its drug effect and dosage are dependency, have the characteristics of administration once a day.PGH not only untoward reaction is less, and can not cause hypoglycemic reaction.With tween 80 and phosphatidylcholine is emulsifying agent, is framework material with hydroxypropyl emthylcellulose (HPMC) and Ka Baibo resin (carbopol), optimizes prescription and has prepared the self emulsifying hydrophilic gel slow releasing tablet that meets the 24h release request, to improve bioavailability.
Precision takes by weighing quantitative pioglitazone hydrochloride raw material and adds in the quantitative buffer salt solution, 37 ℃ of water-baths, and electronic stirring, rotating speed is 50r/min, oil droplet presents situation in solution of every separated 30min observation.The preliminary pH value of confirming slow releasing tablet.
The consumption of emulsifying agent is chosen tween 80 and the phosphatidylcholine and the buffer salt of different proportion, and pioglitazone hydrochloride is granulated jointly, and get quantitative (amount that is equivalent to a slice) granule and be dissolved in the quantitative distilled water, electromagnetic agitation, rotating speed is 50r/min.Get the emulsion smear, observe emulsion droplet particle diameter and quantity down in 1600 power microscopes.Confirm the consumption of emulsifying agent with this.
The consumption of framework material is chosen the HPMC and the carbopol of different proportion, with medicine and the abundant mix homogeneously of adjuvant on the basis that emulsifying agent and buffer salt are confirmed; With dehydrated alcohol system soft material, 24 order stainless steel sifts are granulated, 45 ℃ of dryings; 8.5mm the scrobicula stamping, hardness 7 ± 0.5kg.
Precision takes by weighing the about 20mg of pioglitazone hydrochloride, puts in the 100ml volumetric flask, adds simulated gastric fluid dissolving standardize solution, makes storing solution.Accurate this liquid 0.5,1,2,3 of drawing; 4,5ml adds simulated gastric fluid dilution standardize solution in the 10ml volumetric flask, and the 269nm place measures trap (A); Make linear regression with corresponding concentration (c), get standard curve equation: c (μ g/ml)=0.1671A+0.00175, r=0.9999.
According to 2010 editions appendix dissolution determination first methods of Chinese Pharmacopoeia, release medium (simulated gastric fluid) 900ml, 37 ± 0.5 ℃ of temperature, rotating speed is 50r/min; In 1,4,8,10; 12,16,20, the 24h 5ml (adding the equivalent medium simultaneously) that respectively takes a sample; Discharge liquid through filtering with microporous membrane, measure absorption value in the 260nm place, calculating cumulative discharges percentage rate.
The situation of pioglitazone hydrochloride in different medium observed
Discover that along with increasing of buffer pH value, the oil droplet time of occurrence in advance.When pH value is respectively 7.6,7.8,8.0 o'clock, the oil droplet time of occurrence was respectively 4.2,2.5,0.2h, and self-emulsifying drug delivery partly is transformed into the quantity showed increased of oily molecular state.But consider that the hypertensive patient needs the characteristics of long-term prescription, the prescription pH value again can not be too high, and therefore when pH=8.0, oil droplet 0.2h occurs, and meets requirement of experiment.
The emulsion droplet particle diameter is seen table 1 with shown in Figure 1, can know that Fg prescription particle diameter is minimum.
The composition of table 1 emulsifying agent
A, b, c, d: emulsifying agent/tablet (g/g) A, B, C: phosphatidylcholine/tween 80 (g/g)
Experiment showed, that the size of emulsion droplet particle diameter and the total amount and the ratio of the two of phosphatidylcholine and tween 80 all have relation, is not The more the better.When the total amount of emulsifying agent was 10%, gained prescription size ratio was less.Further optimize, the ratio of phosphatidylcholine and tween is transferred to 2:1 from 1:2 respectively, the result is with the prescription particle diameter minimum of 1:1.
On the basis of above-mentioned research, be aided with the hydrophilic blocker as framework material, consumption and ratio through the adjustment framework material obtain 9 prescriptions, and as shown in table 2, its release curve is shown in accompanying drawing 2.The blocker total amount is many more, and release is slow more.In certain scope, HPMC is many more, and release is slow more.With the Higuchi equation of statement Fick ' s first law and the single index equation of reaction diffusion and the comprehensive function of skeleton swelling the release parameter of 9 prescriptions is carried out regression treatment respectively, it is more reasonable that the result shows with the higuchi equation model.Try to achieve the release parameter T of each prescription according to regression equation
15, T
50, T
90As shown in table 3.Can be known by the result, contain blocker 30%, HPMC and carbopol are the prescription F of 1:3
5, discharging 15% dose needs about 1h, and discharging 50% dose needs about 8h, 23h release 90%.
The composition of table 2 framework material
The Higuish fit equation of 9 prescriptions is following:
F1：Q%=0.20l4t
1/2+0.1073，r=0.9469
F2：Q%=0.2179t
1/2-0.0025，r=0.9695
F3：Q%=0.2015t
1/2-0.0671，r=0.9873
F4：Q%=0.2106t
1/2+0.0257，r=0.9590
F5：Q%=0.2145t
1/2-0.0145，r=0.9709
F6：Q%=0.1904t
1/2-0.0957，r=0.9879
F7：Q%=0.1999t
1/2-0.0114，r=0.9671
F8：Q%=0.2062t
1/2-0.0404，r=0.9695
F9：Q%=0.1811t
1/2-0.0894，r=0.1862
The drug parameters that table 3 pioglitazone hydrochloride tablet discharges
Comprehensive above-mentioned research can be found after the drug oral, usually about Entogastric lingering 2h; In this section process, gastric juice can only see through tablet surface on a small quantity, fails to arrive label; Therefore tablet still can not form complete gel layer, and the gastric acid buffer salt with tablet surface of merely hitting does not change the label pH value.Take medicine behind the 2h, tablet arrives near the pylorus, and this position pH value has reached 5～6, and the buffer salt in the tablet is enough to overcome weak acidic medium, and remains on pH 8.0.In dosage form, add blocker, can slow down the change of gastric acid on the one hand, thereby guarantee the needed pH value of emulsifying the tablet pH value; Emulsion droplet is swum out of lentamente, to reach long lasting purpose from skeleton.
The preparation of embodiment 2 pioglitazone hydrochloride tablets
The mass ratio of pioglitazone hydrochloride, oil phase, emulsifying agent and short emulsifying agent is 1:2-25:1-10:0.2-5.
According to embodiment 1 described research conclusion, preparation pioglitazone hydrochloride tablet takes by weighing pioglitazone hydrochloride 15g, Oleum Ricini 30g, and phosphatidylcholine 10g, soil temperature-80 5g, ethanol 3g is prepared into the self-emulsifying drug delivery part; Take by weighing HPMC 2.72g, carbopol10.88g.With medicine and the abundant mix homogeneously of adjuvant, with dehydrated alcohol system soft material, 24 order stainless steel sifts are granulated, 45 ℃ of dryings, the stamping of 8.5mm scrobicula, hardness 7 ± 0.5kg.Obtain pioglitazone hydrochloride tablet medicine group I.
Adopt above-mentioned same procedure, take by weighing pioglitazone hydrochloride 15g, Oleum Ricini 45g, phosphatidylcholine 30g, soil temperature-80 30g, ethanol 15g, HPMC 8.1g, carbopol 24.3g.Obtain pioglitazone hydrochloride tablet medicine group II.
Adopt above-mentioned same procedure, take by weighing pioglitazone hydrochloride 15g, Oleum Ricini 375g, phosphatidylcholine 50g, soil temperature-80 100g, ethanol 75g, HPMC 82g, carbopol 164g.Obtain pioglitazone hydrochloride tablet medicine group III.
The tissue distribution research of embodiment 3 pioglitazone hydrochloride self-emulsifying drug deliveries part in liver, kidney
1. test material
Pioglitazone hydrochloride self-emulsifying drug delivery part (the drug group I for preparing according to the method for the embodiment of the invention 2; Adopt the normal saline dilution according to desired concn during test; Every bottle of hydrochloric pioglitazone 2.5g of 100ml), oral administration gavage pioglitazone hydrochloride solution (adopting 5% alcoholic solution that pioglitazone hydrochloride is configured to 6mg/ml solution).The SD rat (male, quality 200 ± 20g).
2. instrument and chromatographic condition
The Waters2695 high performance liquid chromatograph, the Waters2996 UV-detector; Symmetry shield C18 chromatographic column (4.6mm * 250mm, 5 μ m); Mobile phase acetonitrile: water (35:65); Flow velocity 0.5ml/min, 30 ℃ of column temperatures, ultraviolet detection wavelength 269nm, sample size are 20 μ l.
3. method and result
3.1 sample collecting and processing
Get 18 of rats, be divided into 2 groups at random, 9 every group, fasting 12h before the experiment; 60mg/kg according to dosage, one group of oral administration gavage pioglitazone hydrochloride solution, another group oral administration gavage pioglitazone hydrochloride self-emulsifying drug delivery part, after the administration in different time points; Get 3 mice cervical vertebra dislocation execution for each every group, get mouse liver and kidney, blot, prepare homogenate liquid with normal saline after precision is weighed with filter paper after the normal saline rinsing; Get equal serosity 0.1g, add methanol 0.5ml, vortex; Vortex vibration 1min, centrifugal 10min (12000r/min), supernatant dries up with nitrogen current; Residue adds 0.1ml methanol ultrasonic dissolution, and centrifugal 10min (12000r/min) gets supernatant and carries out the HPLC analysis.
3.2 standard solution preparation
Precision takes by weighing pioglitazone hydrochloride reference substance 11.36mg, adopts dissolve with methanol, and standardize solution is 10ml, and fully mixing is processed the 1.136mg/ml stock solution.
3.3 standard curve preparation
With an amount of equal serosity of blank liver, nephridial tissue the standard stock solution is diluted to series standard solution respectively; Measure by 2 following chromatographic conditions; The record peak area is an abscissa with the concentration C, and peak area A is a vertical coordinate; Get the standard curve of pioglitazone hydrochloride in liver, kidney respectively, as shown in table 4.
The standard curve of table 4 pioglitazone hydrochloride in liver and kidney
3.4 mouse stomach and injection back tissue distribution
Behind dosage such as mouse stomach and intravenous injection (the 60 μ g/ml) pioglitazone hydrochloride, the distribution results of different time points medicine in liver and kidney is as shown in table 5.Can find out by table 5; The concentration of different time points medicine in liver all is higher than gastric infusion behind the intravenous injection pioglitazone hydrochloride fat milk, and the concentration in kidney all is lower than gastric infusion, explains that thus the pioglitazone hydrochloride self-emulsifying drug delivery partly has certain targeting property; Can make medicine more accumulate in liver after the intravenous injection; Reduce the drug level in the kidney, reach the raising therapeutic effect, reduce the effect of Toxicity of Kidney with this.
The concentration of pioglitazone hydrochloride in table 5 different time points liver and the kidney
The tissue distribution research 2 of embodiment 4 pioglitazone hydrochloride self-emulsifying drug deliveries part in liver, kidney
Hydrochloride for injection pioglitazone self-emulsifying drug delivery part ((the drug group II for preparing according to the method for the embodiment of the invention 2; Adopt the normal saline dilution according to desired concn during test; Every bottle of hydrochloric pioglitazone 2.5g of 100ml); Test method is identical with embodiment 3, investigates the tissue distribution research of pioglitazone hydrochloride self-emulsifying drug delivery part in liver, kidney.
With an amount of equal serosity of blank liver, nephridial tissue the standard stock solution is diluted to series standard solution respectively; Measure by 2 following chromatographic conditions; The record peak area is an abscissa with the concentration C, and peak area A is a vertical coordinate; Get the standard curve of pioglitazone hydrochloride in liver, kidney respectively, as shown in table 6.
The standard curve of table 6 pioglitazone hydrochloride in liver and kidney
Behind dosage such as mouse stomach and intravenous injection (the 60 μ g/ml) pioglitazone hydrochloride, the distribution results of different time points medicine in liver and kidney is as shown in table 7.Can find out by table 7; The concentration of different time points medicine in liver all is higher than gastric infusion behind the intravenous injection pioglitazone hydrochloride fat milk, and the concentration in kidney all is lower than gastric infusion, explains that thus the pioglitazone hydrochloride self-emulsifying drug delivery partly has certain targeting property; Can make medicine more accumulate in liver after the intravenous injection; Reduce the drug level in the kidney, reach the raising therapeutic effect, reduce the effect of Toxicity of Kidney with this.
The concentration of pioglitazone hydrochloride in table 7 different time points liver and the kidney
The tissue distribution research 3 of embodiment 5 pioglitazone hydrochloride self-emulsifying drug deliveries part in liver, kidney
Hydrochloride for injection pioglitazone self-emulsifying drug delivery part ((the drug group III for preparing according to the method for the embodiment of the invention 2; Adopt the normal saline dilution according to desired concn during test; Every bottle of hydrochloric pioglitazone 2.5g of 100ml); Test method is identical with embodiment 3, investigates the tissue distribution research of pioglitazone hydrochloride self-emulsifying drug delivery part in liver, kidney.
With an amount of equal serosity of blank liver, nephridial tissue the standard stock solution is diluted to series standard solution respectively; Measure by 2 following chromatographic conditions; The record peak area is an abscissa with the concentration C, and peak area A is a vertical coordinate; Get the standard curve of pioglitazone hydrochloride in liver, kidney respectively, as shown in table 8.
The standard curve of table 8 pioglitazone hydrochloride in liver and kidney
Behind dosage such as mouse stomach and intravenous injection (the 60 μ g/ml) pioglitazone hydrochloride, the distribution results of different time points medicine in liver and kidney is as shown in table 9.Can find out by table 9; The concentration of different time points medicine in liver all is higher than gastric infusion behind the intravenous injection pioglitazone hydrochloride fat milk, and the concentration in kidney all is lower than gastric infusion, explains that thus the pioglitazone hydrochloride self-emulsifying drug delivery partly has certain targeting property; Can make medicine more accumulate in liver after the intravenous injection; Reduce the drug level in the kidney, reach the raising therapeutic effect, reduce the effect of Toxicity of Kidney with this.
The concentration of pioglitazone hydrochloride in table 9 different time points liver and the kidney
Embodiment 6 pioglitazone hydrochloride tablets are investigated the activity of early diabetic nephropathy
Press WHO diagnosis of diabetes Standard Selection type 2 diabetes mellitus patient, 24h urinary albumin excretion rate (UAER) meets the III phase diagnostic criteria of diabetic nephropathy all at 20～200/min.All cases are all got rid of primary glomerulopathy, renal arteriosclerosis and the secondary glomerulopathy that uses nephrotoxicity medicine etc. to cause in the recent period.Be divided into matched group and drug group I, drug group II and drug group III at random.Matched group 31 examples, wherein male 16 examples, women 15 examples, 51～70 years old age, average (54.5 ± 8.5) year; Drug group I 31 examples, wherein male 17 examples, women 14 examples, 50～70 years old age, average (53.5 ± 10.5) year.Drug group II 31 examples, wherein male 16 examples, women 15 examples, 50～70 years old age, average (54.1 ± 10.8) year.Drug group III 31 examples, wherein male 15 examples, women 16 examples, 50～70 years old age, average (53.4 ± 10.4) year.There are no significant for 4 groups of sexes, age and course of disease differences.
All patients all give oral hypoglycemic thing blood sugar control; Part patient is the subcutaneous injection insulin simultaneously, gives the blood lipid-lowering medicine treatment simultaneously for merging hyperlipemic patients, and the complicated hypertension patient gives controlling blood pressure; The general calcium channel blocker, beta-blocker used; Low protein diet, every day albumin intake moon 1.0g/Kg.2 groups all give conventional therapy, and matched group is oral commercially available pioglitazone hydrochloride sheet simultaneously, and dosage is pioglitazone hydrochloride tablet 40mg/d.Pioglitazone hydrochloride tablet medicine group I, drug group II and drug group III that the oral embodiment of the invention 2 of drug group I, drug group II and drug group III provides; Dosage is pioglitazone hydrochloride 43mg/d; 2 groups of patients all treated 6 months, observed the variation of each parameter after 6 months.
Data represent with mean ± standard deviation, and curative effect is relatively used the paired t-test analysis before and after the treatment, and < 0.05 has significance for difference to P.2 groups of patients glycolated hemoglobin (HbAlc), Ccr, serum potassium concentration (cK) before and after treatment, blood lipid level is not statistically significant (P＞0.05) relatively all, and ordinary circumstance is seen shown in the table 10; UAER compares before and after 2 groups of patient treatments, and is as shown in table 11.
Ordinary circumstance compares
before and after 2 groups of patient treatments of table 10
UAER changes
before and after 2 groups of patient treatments of table 11
Annotate: with compare P＜0.05 before the treatment
Modern medicine study proves that sugared microalbuminuria is the index of diagnosis early diabetic nephropathy, also is the important indicator of judging prognosis and curative effect, and making urinaryalbumin reduce even recover normally is the key that delays and reverse DN.Albuminuretic control confirms that angiotensin ii receptor antagonist (ARB) can play a protective role to the renal function of early stage DN; This protective effect is to be independent of outside the hypotensive effect, raises relevant with the direct regulating action of blood vessel in the kidney, the pro-inflammatory that suppresses Angiotensin II, inhibition TGF-B.
Detection type 2 diabetes mellitus patient's UAER can be used as the diagnosing diabetes nephropathy and judges the index of its progress, and UAER obviously reduced after drug group I case-finding used pioglitazone hydrochloride sheet provided by the invention, and significant difference (P＜0.05) is arranged.This result of study shows that the more traditional pioglitazone hydrochloride tablet of pioglitazone hydrochloride sheet provided by the invention not only has the urine protein effect of reduction and delay the diabetics renal function injury all more remarkable.Phosphatidylcholine can reduce serum cholesterol content, prevents liver cirrhosis and helps liver and the recovery of renal function; Have collaborative hypoglycemic activity with pioglitazone hydrochloride in vivo, strengthened the curative effect of product, take pioglitazone hydrochloride tablet provided by the invention diabetes early nephropathy patient's UAER is obviously descended, the kidney protection effect is arranged.Conventional this medicine that uses of patient can delay making progress of diabetic nephropathy.
Claims (10)
1. pioglitazone hydrochloride drug regimen tablet; It is characterized in that: comprise self-emulsifying drug delivery part and water-soluble solid carrier part; Said self-emulsifying drug delivery partly comprises pioglitazone hydrochloride, oil phase, emulsifying agent and short emulsifying agent; Wherein, the mass ratio of pioglitazone hydrochloride, oil phase, emulsifying agent and short emulsifying agent is 1:2-25:1-10:0.2-5.
2. pioglitazone hydrochloride tablet according to claim 1 is characterized in that: comprised phosphatidylcholine in the said emulsifying agent.
3. pioglitazone hydrochloride tablet according to claim 2 is characterized in that: the mixture that except phosphatidylcholine, also comprises any one or two kinds in ethyoxyl polyoxyethylene glyceride, polyoxyethylene oleate and the tween 80 of liquid or solid in the said emulsifying agent.
4. pioglitazone hydrochloride tablet according to claim 3 is characterized in that: said emulsifying agent is the mixture of phosphatidylcholine and tween 80.
5. pioglitazone hydrochloride tablet according to claim 4 is characterized in that: the weight ratio of said phosphatidylcholine and tween 80 is 1-2:1-2.
6. pioglitazone hydrochloride tablet according to claim 5 is characterized in that: the weight ratio of said phosphatidylcholine and tween 80 is 1:1.
7. pioglitazone hydrochloride tablet according to claim 1 is characterized in that: said water-soluble solid carrier portion is for dividing the combination of any one or two kinds in a microcrystalline Cellulose, lactose, cellulose acetate, ethyl cellulose, polyacrylic resin, silicone rubber, gelatin, Hydroxypropyl Methyl Cellulose Phthalate, cellulose acetate phthalate ester, dichloromethane and aerosil, hydroxypropyl emthylcellulose and the Ka Baibo resin.
8. pioglitazone hydrochloride tablet according to claim 7 is characterized in that: said water-soluble solid carrier partly is the combination of hydroxypropyl emthylcellulose and Ka Baibo resin.
9. pioglitazone hydrochloride tablet according to claim 1 is characterized in that: said oil phase is any one or the two or more mixture in Oleum Ricini, soybean oil, Oleum Arachidis hypogaeae semen, olive oil, butyl oleate, Ethyl linoleate, isopropyl myristate, medium-chain fatty acid triacylglycerol, sad, capric acid triacylglycerol, oleic acid, linoleic acid, the linolenic acid triacylglycerol.
10. pioglitazone hydrochloride tablet according to claim 1 is characterized in that: said short emulsifying agent is a kind of in ethanol or the butanediol.
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| CN107823151A (en) * | 2017-11-06 | 2018-03-23 | 广州市桐晖药业有限公司 | A kind of Rates of Pioglitazone Hydrochloride Tablets Preparation |
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| WO2001037808A1 (en) * | 1999-11-23 | 2001-05-31 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
| CN1709249A (en) * | 2005-07-04 | 2005-12-21 | 宛六一 | Pioglitazone soft capsule and its preparing method |
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| WO2001037808A1 (en) * | 1999-11-23 | 2001-05-31 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
| WO2006135693A2 (en) * | 2005-06-10 | 2006-12-21 | Novartis Ag | Direct compression formulation of dpp-iv inhibitors and glitazones, and process |
| CN1709249A (en) * | 2005-07-04 | 2005-12-21 | 宛六一 | Pioglitazone soft capsule and its preparing method |
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| CN107823151A (en) * | 2017-11-06 | 2018-03-23 | 广州市桐晖药业有限公司 | A kind of Rates of Pioglitazone Hydrochloride Tablets Preparation |
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| CN102657626B (en) | 2013-07-17 |
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