CN104208034A - Glimepiride pharmaceutical composition tablet and its preparation method and use - Google Patents
Glimepiride pharmaceutical composition tablet and its preparation method and use Download PDFInfo
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- CN104208034A CN104208034A CN201310673693.6A CN201310673693A CN104208034A CN 104208034 A CN104208034 A CN 104208034A CN 201310673693 A CN201310673693 A CN 201310673693A CN 104208034 A CN104208034 A CN 104208034A
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Abstract
The invention discloses a glimepiride pharmaceutical composition tablet and its preparation method and use. The invention provides the glimepiride pharmaceutical composition for solving problems of the existing glimepiride tablet. The glimepiride pharmaceutical composition comprises glimepiride and sorbitol. The glimepiride pharmaceutical composition tablet has a long release period in the human body and has a plasma concentration more stable than that of the common glimepiride tablet. The glimepiride pharmaceutical composition is suitable for treating diabetic nephropathy and has the insulin secretion promoting effect better than that of the common glimepiride pharmaceutical tablet.
Description
Technical field
The present invention relates to a kind of medicine composition, relate to a kind of Glimepiride medicinal composition tablets, preparation method and application thereof in particular.
Technical background
Glimepiride is third generation sulfonyl urea antidiabetic medicine, has and suppresses hepatic glucose synthesis, promotion muscular tissue to the picked-up of periphery glucose and the effect promoting insulin secretion.This product is applicable to diet-treated only and tempers the type 2 diabetes mellitus patient failing to control blood glucose.
Clinical research is reported; After oral administration, glimepiride 100% is in gastrointestinal absorption.Within 2-3 hour, blood drug level reaches peak value (C
max), protein binding rate is greater than 99.5%.Glimepiride is by the complete metabolism of oxidative biotransformation effect, and main metabolites is cyclohexyl hydroxymethyl derivative (M
1) and carboxylation derivant (M
2), M
1through one or several cytosol enzyme effect, further metabolism is M
2, M
1animal model has the pharmacologically active of about 1/3 compared with its parent.And M
2do not have this active, but about M
1whether hypoglycemic activity is meaningful also clear at present clinically.
Summary of the invention
For solving the problems referred to above that glimepiride tablet exists, the present patent application provides a kind of Glimepiride medicinal composition, and described pharmaceutical composition is become to be grouped into by glimepiride and sorbitol two kinds.
The weight ratio of described glimepiride and sorbitol is 1-20:1-20.
The weight ratio of described glimepiride and sorbitol is 2-10:1-2.
The weight ratio of described glimepiride and sorbitol is 2:1.
A kind of Glimepiride medicinal composition double-layer sustained release tablets, described tablet is made up of the release layer containing the Glimepiride medicinal composition described in claim 1-4 and slow release layer respectively.
In described release layer and slow release layer, the content ratio of Glimepiride medicinal composition is 2 ~ 4:6 ~ 8.
The formula of described slow release layer is Glimepiride medicinal composition, PEG, cyclodextrin, HPMC K4M, magnesium stearate.
The consumption of described HPMC K4M is 15% ~ 45% of slow release layer gross mass.
The formula of described release layer is starch, calcium carbonate, HPC.
Glimepiride medicinal composition described above and the application of double-layer sustained release tablets in preparation treatment medicine for treating diabetic nephropathy thereof.
Advantageous Effects of the present invention is: Glimepiride medicinal composition tablets provided by the invention, longer in the release time of human body, and blood drug level comparatively ordinary tablet is more steady; Composition of medicine provided by the invention is suitable for and diabetic nephropathy, promotes insulin secretion better effects if than common glimepiride medicine sheet simultaneously.
Accompanying drawing explanation
Fig. 1 blood concentration-time curve.
Detailed description of the invention
The preparation method of embodiment 1 Glimepiride medicinal composition double-layer sustained release tablets
Take glimepiride and sorbitol monomer medicine according to the proportion of weight ratio 1:1, Homogeneous phase mixing of milling, obtain removing the peel Glimepiride medicinal composition.
The preliminary election of slow release layer adjuvant is with HPMC K4M(HPMC K4M) for framework material, by Glimepiride medicinal composition and PEG(Polyethylene Glycol), the adjuvant such as cyclodextrin, HPMC K4M with solvent-dissolve legal system for solid dispersion, granulate, tabletting; Investigate the impact of adjuvant on mouldability and slow-releasing.
In Vitro Dissolution assay method is: by Chinese Pharmacopoeia 2010 editions two dissolution determination second methods, measures dissolution medium (simulated gastric fluid of the 10% isopropyl alcohol) 900ml through degassed process, injects each stripping rotor, temperature (37 ± 0.5) DEG C, rotating speed 50rmin
-1the Glimepiride medicinal composition double-layer sustained release tablets 2 of precise weighing is dropped in each cup, clock immediately, 2h is replaced by enteric medium (the pH7.2 phosphate buffer of 10% isopropyl alcohol), dissolution fluid (namely supplementing same volume medium after sampling) is drawn, every sub-sampling 10ml, in tool plug in vitro by certain hour, add ethyl acetate 10ml, jolting.Treat stratification, draw upper solution 9ml, heating in water bath evaporate to dryness, with 70% ethanol 0.5ml, residue is dissolved as test solution.Separately get same batch sample to grind, precision takes about 2 amounts, with simulated gastric fluid 900ml backflow 4h, make abundant stripping, leave standstill, treat that temperature is down to (37 ± 0.5) DEG C, supply the solvent of loss, accurate absorption dissolution fluid 10ml, by the process of test solution same procedure, solution in contrast, adds chromogenic reagent respectively, and measure trap, calculate the accumulation dissolution of diterpenic lactone:
As a result, pharmaceutical composition: PEG6000: cyclodextrin: HPMC-K4M(0.2:5:15:3, w/w) be applicable to pulverizing, granulation, tabletting, tablet is complete corrosion about 7.5 ~ 10.0h in simulated gastric fluid, enteric medium.
Release layer adjuvant selects to investigate the impact on mouldability and disintegrative of the supplementary product kind such as diluent, disintegrating agent, adhesive and consumption, result, with starch-calcium carbonate be diluent, disintegrating agent (calcium carbonate consumption 10mg/ sheet) pharmaceutical composition with the weight ratio of adjuvant for 1:90,3%HPC makes adhesive, is applicable to granulation, tabletting.Tablet in 1 ~ 3min disintegrate, in Powdered.
Orthogonal experiment optimization formulation composition and technique
(1) Dissolution Evaluation standard.Reach 30% respectively with 2,5,10h drug-eluting, 50%, 95% is the perfect solution out-degree of double-layer tablet, works out standards of grading and is:
(2) setting of factor level.Plan passes through L
9(3
4) orthogonal test, investigation slow release and immediate release section drug ratios, slow-released part HPMC-K4M consumption and film-making pressure are on the impact of drug dissolution, and factor level is as shown in table 1.
Table 1 experimental factor level
(3) orthogonal test and interpretation of result result as shown in table 2.
Table 2 orthogonal experiments and calculating
Selection process is A
2b
2c
1, namely slow release and immediate release drug ratio are 7:3, slow-released part pharmaceutical composition and HPMC K4M(1:0.30, w/w), compression force 3 ~ 5kgcm
-2.
The dosage such as double-layer tablet and ordinary tablet beasle dog gastric infusion, glimepiride blood drug level after the medication of isotope method mensuration.Blood concentration-time curve as shown in Figure 1.As seen from Figure 1, double-layer tablet peak time extends, and peak concentration reduces, and blood drug level is steady, reaches the basic demand of slow releasing preparation.
Glimepiride medicinal composition double-layer sustained release tablets immediate release section is with starch and calcium carbonate for adjuvant, and HPC is that release layer granule prepared by adhesive; Slow-released part is prepared into granule with PEG6000, cyclodextrin, HPMC K4M; Slow release and release layer drug ratios 7:3, HPMC-K4M consumption 10.5g, film-making pressure 3 ~ 5kgcm
-2; The conditions such as the heavy 0.1g of sheet, are suitable for the preparation of Glimepiride medicinal composition double-layer sustained release tablets.Double-layer tablet release layer acid medium can collapse fast loose, discharge medicine under one's belt, slow release layer is then in the slow corrosion of intestinal.Pharmacology, toxicological test, medicine dynamic test and clinical verification show, the double-layer tablet of development has prolong drug release time, and increase medicinal effectiveness, reduce untoward reaction and reduce, medication is safer, easily feature.This experiment can overcome with the new method of cyclodextrin instead Icing Sugar and dry, pulverize, and granulates and problem in the moulding process such as tabletting.
The preparation of embodiment 2 laboratory sample
Take glimepiride and sorbitol monomer component by weight 20:1,10:1,5:1,3:1,2:1,1:1,1:10,1:20 respectively, and fully mixing is milled, and by the best practice in embodiment 1, prepares Glimepiride medicinal composition tablets; Called after respectively: group I, II, III, IV, V, VI, VII, VIII.Weigh glimepiride list composition as medicine, adopt commercially available glimepiride tablet (glimepiride 1mg/ sheet, every sheet 0.1g), as glimepiride matched group; Weigh sorbitol monomer component as medicine, adopt method optimum in embodiment 1 to prepare tablet, as sorbitol matched group.When zoopery by above-mentioned each pack agent, pulverize, become outstanding muddy liquid with distilled water by solid-to-liquid ratio 1:5 dilution.
Embodiment 3 Glimepiride medicinal composition sheet is to the investigation of early diabetic nephropathy activity
Select type 2 diabetes mellitus patient by the diagnostic criteria of WHO diabetes, 24h urinary albumin excretion ratio (UAER), all at 2O ~ 200/min, meets the III phase diagnostic criteria of diabetic nephropathy.All cases all gets rid of primary glomerulopathy, renal arteriosclerosis and the secondary glomerulopathy using nephrotoxic drugs etc. to cause in the recent period.Be divided into matched group and treatment group at random.Glimepiride matched group 31 example, wherein man 16 example, female 15 example, 51 ~ 70 years old age, average (54.5 scholar 8.5) year; Sorbitol matched group 31 example, wherein man 17 example, female 14 example, 50 ~ 70 years old age, average (53.5 ± 10.5) year.There are no significant for 5 groups of sexes, age and course of disease differences; Group I 31 example, wherein man 15 example, female 16 example, 50 ~ 70 years old age, average (55.5 ± 9.5) year; Experimental group V 31 example, wherein man 16 example, female 15 example, 50 ~ 70 years old age, average (55.5 ± 8.5) year; Experimental group VIII 31 example, wherein man 17 example, female 14 example, 50 ~ 70 years old age, average (55.5 ± 8.5) year; There are no significant for 5 groups of sexes, age and course of disease differences.
All patients all give oral hypoglycaemic medicine and control blood glucose, some patients is subcutaneous insulin injections simultaneously, and give blood lipid-lowering medicine treatment for merging hyperlipemic patients, complicated hypertension patient is controlled blood pressure simultaneously, general calcium channel blocker, beta-blocker; Low protein diet, every day albumin intake moon 1.0g/kg.2 groups all give conventional therapy, and matched group is oral commercially available Glimepiride medicinal composition sheet simultaneously, and dosage is Glimepiride medicinal composition 2mg/d.The oral Glimepiride medicinal composition tablets provided by the invention for the treatment of group, dosage is Glimepiride medicinal composition 2mg/d, and 2 groups of patients all treat 6 months, observes the change of each parameter after 6 months.
Data represent with mean ± standard deviation, and comparitive study paired t-test analysis before and after treatment, P<O.05 is that difference has significance.5 groups of patients rear glycolated hemoglobin (HbAlc), Ccr, serum potassium concentration (cK+) before the treatment, the more equal not statistically significant of blood lipid level (P ﹥ 0.05), ordinary circumstance is in table 3; Before and after 5 groups of patient treatments, UAER compares, in table 4.
Before and after table 35 group patient treatment, ordinary circumstance compares
UAER change before and after table 45 group patient treatment
Note: compared with before treatment,
*p ﹤ 0.05,
*p ﹤ 0.05
Modern medicine study proves that sugared microalbuminuria is the index of diagnosis early diabetic nephropathy, is also the important indicator of judging prognosis and curative effect, urinaryalbumin is reduced and even recovers to be normally the key delaying 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 independent of outside hypotensive effect, with the direct regulating action of blood vessel in kidney, suppress the pro-inflammatory of Angiotensin II, to suppress TGF-B to raise relevant.
The UAER detecting type 2 diabetes mellitus patient can be used as diagnosing diabetes nephropathy and judges its index be in progress, after treatment group case-finding uses Glimepiride medicinal composition tablet preparation provided by the invention, UAER obviously reduces, and has significant difference (P ﹤ 0.05).This result of study shows, the more traditional glimepiride medicine marketed tablet of Glimepiride medicinal composition tablets provided by the invention not only have reduce urine protein effect and delay diabetics renal function injury all more remarkable.This result shows sorbitol itself in the bright medicine of the present invention and has diuresis; with Glimepiride medicinal composition, there is Synergistic Hypotensive Effects in vivo; enhance the curative effect of product; take the UAER of Glimepiride medicinal composition provided by the invention to early diabetic nephropathy patient obviously to decline, have Renoprotective Effect.Patient's routine uses this medicine, can delay being in progress of diabetic nephropathy.
Embodiment 3 Glimepiride medicinal composition tablets blood sugar reducing function is investigated
6 the monthly age Health China suslik 200, weight (128 ± 16.5) g.Before experiment, survey blood glucose with enzymatic measurement, select blood glucose higher than the animal 132 of 6.661mmoL/L.The single cage of animal is raised, and freely drinks water, 12h illumination.Fasting 12h before Chinese hamster experiment, but can't help water, orbital venous plexus is got blood enzymatic measurement and is measured blood glucose, by document claims, blood glucose is selected to test higher than the animal of 6.661mmoL/L, by the layering of animal blood glucose height, animal is divided into 11 groups, often organizes 12, give agents respectively: the 1st group as a control group (0.1% tween); Glimepiride matched group prepared by the 2nd group of administration embodiment 2, sorbitol matched group prepared by the 3rd group of administration embodiment 2, the Glimepiride medicinal composition tablets (group I, II, III, IV, V, VI, VII, VIII) of 4-11 group respectively described in administration group I; Dosage is active component (glimepiride monomer or sorbitol monomer and composition thereof) 5mg/kg gastric infusion, and gavage volume is continuous 7d, and every day 1 time, after secondary last administration, 2h gets blood.
Measure blood glucose with enzymatic measurement, and calculate blood glucose decreasing value and reduce percentage rate.Use serum measured by radioimmunoassay insulin.Software SPSS13.0 is used to analyze the inspection of group difference application t method.As shown in Table 5,6.
Table 5 Glimepiride medicinal composition sheet is on the impact of spontaneous hyperglycemia Chinese hamster
Note: compare with before administration
*p ﹤ 0.05,
*p ﹤ 0.01; Compare with matched group
△p ﹤ 0.01.
Table 6 Glimepiride medicinal composition sheet is on the impact of spontaneous hyperglycemia Chinese hamster serum insulin
Note: compare with matched group
*p ﹥ 0.05;
△ △p ﹤ 0.01; Compare with glimepiride dosage group
#p ﹥ 0.05.
From the data display table 5,6, Glimepiride medicinal composition sheet is for falling hypoglycemic effect and simple commercially available glimepiride tablet does not have significant difference, the insulin level but Glimepiride medicinal composition sheet does not increase significantly.
Claims (10)
1. a Glimepiride medicinal composition, is characterized in that: described pharmaceutical composition is become to be grouped into by glimepiride and sorbitol two kinds.
2. Glimepiride medicinal composition according to claim 1, is characterized in that: the weight ratio of described glimepiride and sorbitol is 1-20:1-20.
3. Glimepiride medicinal composition according to claim 1, is characterized in that: the weight ratio of described glimepiride and sorbitol is 2-10:1-2.
4. Glimepiride medicinal composition according to claim 1, is characterized in that: the weight ratio of described glimepiride and sorbitol is 2:1.
5. a Glimepiride medicinal composition double-layer sustained release tablets, is characterized in that: described tablet is made up of the release layer containing the Glimepiride medicinal composition described in claim 1-4 and slow release layer respectively.
6. Glimepiride medicinal composition double-layer sustained release tablets according to claim 5, is characterized in that: in described release layer and slow release layer, the content ratio of Glimepiride medicinal composition is 2 ~ 4:6 ~ 8.
7. Glimepiride medicinal composition double-layer sustained release tablets according to claim 6, is characterized in that: the formula of described slow release layer is Glimepiride medicinal composition, PEG, cyclodextrin, HPMC K4M, magnesium stearate.
8. Glimepiride medicinal composition double-layer sustained release tablets according to claim 7, is characterized in that: the consumption of described HPMC K4M is 15% ~ 45% of slow release layer gross mass.
9. Glimepiride medicinal composition double-layer sustained release tablets according to claim 6, is characterized in that: the formula of described release layer is starch, calcium carbonate, HPC.
10. the arbitrary described Glimepiride medicinal composition of claim 1-9 and the application of double-layer sustained release tablets in preparation treatment medicine for treating diabetic nephropathy thereof.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109432031A (en) * | 2018-12-24 | 2019-03-08 | 扬子江药业集团广州海瑞药业有限公司 | A kind of determination of glimepiride in tablet and preparation method thereof |
| TWI765157B (en) * | 2018-05-31 | 2022-05-21 | 大陸商華領醫藥技術（上海）有限公司 | Pharmaceutical combination containing glucokinase promoter and α-glucosidase inhibitor, preparation method and use thereof |
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| WO2006104401A1 (en) * | 2005-03-26 | 2006-10-05 | Protemix Corporation Limited | Copper antagonist compositions |
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| CN101804056A (en) * | 2010-04-16 | 2010-08-18 | 山东新华制药股份有限公司 | Compound tablet of pioglitazone hydrochloride, glimepiride and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1729005A (en) * | 2002-11-15 | 2006-02-01 | 兰贝克赛实验室有限公司 | Pharmaceutical dosage forms of biguanide-sulfonylurea combinations |
| WO2006104401A1 (en) * | 2005-03-26 | 2006-10-05 | Protemix Corporation Limited | Copper antagonist compositions |
| CN101168059A (en) * | 2007-10-12 | 2008-04-30 | 重庆医药工业研究院有限责任公司 | Stable medicinal composition containing biguanide, sulfonylurea and thiazolidinedione and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| TWI765157B (en) * | 2018-05-31 | 2022-05-21 | 大陸商華領醫藥技術（上海）有限公司 | Pharmaceutical combination containing glucokinase promoter and α-glucosidase inhibitor, preparation method and use thereof |
| CN109432031A (en) * | 2018-12-24 | 2019-03-08 | 扬子江药业集团广州海瑞药业有限公司 | A kind of determination of glimepiride in tablet and preparation method thereof |
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