CN1895250A - Gliquilone slow-releasing preparation - Google Patents
Gliquilone slow-releasing preparation Download PDFInfo
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- CN1895250A CN1895250A CN 200510014483 CN200510014483A CN1895250A CN 1895250 A CN1895250 A CN 1895250A CN 200510014483 CN200510014483 CN 200510014483 CN 200510014483 A CN200510014483 A CN 200510014483A CN 1895250 A CN1895250 A CN 1895250A
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Abstract
A slow-releasing medicine of gliquidone contains gliquidone, slow-releasing matrix and pharmacologically acceptable carrier. Its peak time of blood concentration is 3-8 hr.
Description
Technical field
The present invention relates to a kind of medical slow releasing preparation, particularly, the prescription of gliquidone oral slow-releasing preparation and preparation technology.
Background information
Diabetic nephropathy is one of modal chronic microvascular complication of diabetes.Statistics are arranged, and in middle aged diabetics, the sickness rate of diabetic nephropathy is 20%, and the gerontal patient can reach 65.5%.The course of disease average out to of diabetic nephropathy patient 16.9.Therefore, but diabetics especially diabetic nephropathy patient be badly in need of that a kind of hypoglycemic effect is good, the oral antidiabetic drug of the low long-term prescription of side effect.
The medicine of treatment insulin non-insulin dependent diabetes commonly used has clinically at present: sulfonylurea, biguanides, the sweet enzyme inhibitor class of phlorose, euglycemic agent and Chinese patent medicine etc.The sulfonylurea oral antidiabetic drug mainly comprises: glibenclamide, glipizide, gliquidone and gliclazide.Wherein, gliquidone (preparation method is with reference to U.S.Patent 3708486) is unique non-main through the fugitive sulfonylurea oral antidiabetic drug of the second filial generation of renal excretion, only 5% through renal excretion, its metabolic pathway uniqueness, be specially adapted to the diabetics of poor kidney, when glomerular filtration rate was reduced to 30～60ml/min, this medicine was the oral antidiabetic drug drug of first choice.That uses clinically at present be the normal release tablet formulations of gliquidone, and specification is 30mg, and according to the state of an illness, day clothes dosage is taken between 15～180mg before the meal, and day obeys 2～3 times.Because gliquidone (Gliquidone) belongs to fugitive oral antidiabetic drug, mainly there is following shortcoming in common normal release formulation:
1. blood drug level peak in the body-paddy fluctuation is big, and the hypoglycemia phenomenon may appear in the effective blood drug concentration that surpasses far away during peak concentration;
2. because day obeys often, and the situation of missing appears in regular meeting, compliance is poor, makes glycemic control ineffective;
3. after the post-prandial glycemia peak, still have higher blood drug level, stimulate insulin secretion, if things go on like this, cause the insulin secretion ability drop, body insulin sensitivity degree descends.
Therefore, develop slow releasing preparation of this medicine day clothes and will bring great convenience, help the steady control of blood glucose in the body simultaneously, reduce side effect to the patient.By literature search, the slow releasing preparation of gliquidone of the present invention has not yet to see any literature research report.
Summary of the invention
The objective of the invention is to obtain a kind of solid preparation of gliquidone, said preparation has high bioavailability, and continuing absorbent properties with gastrointestinal combines, thereby reach take every day once after, in human body or animal body, reach continuous release, the effect that blood sugar level is steadily controlled.
The present invention also aims to provide a kind of gliquidone slow releasing preparation, the slow release of gliquidone is provided in can 24 hours, its body giving drugs into nose for dynamic characteristic was: reached the blood drug level peak value behind the oral administration at 3.0 hours to 8.0 hours.
Gliquidone slow releasing preparation of the present invention, the effective ingredient gliquidone that contains therapeutic dose, medicament sustained-release matrix and/or medicine acceptable carrier, for gliquidone slow releasing preparation once-a-day, it is 30～180mg that each preparation unit contains gliquidone.
Each preparation unit of therapeutic dose of the present invention is meant the unit of each dosage form, as every of tablet, and each capsules of capsule or the like.
Gliquidone slow releasing preparation of the present invention can be pharmaceutical formulation forms such as tablet, capsule, preferred tablet.
Gliquidone slow releasing preparation of the present invention comprises the gliquidone of therapeutic dose and an amount of hydroxypropyl emthylcellulose and filler.Wherein, the weight ratio of gliquidone and hydroxypropyl emthylcellulose is 1: 1～1: 5; The weight ratio of gliquidone and filler is 1: 1～5: 1.
Has more short-decayed gliquidone for picture, dosed administration once a day, need slower rate of release, so that obtain the effective blood drug level in 24 hours, the release of control gliquidone was desirable during 12～18 hours, and its pharmacokinetics feature shows as: reached the blood drug level peak value behind the oral administration at 3.0 hours to 8.0 hours.
Usually, controlled delivery of pharmaceutical agents is to reach by different dosage form control medicine dissolution and/or diffusion with postponing release.Some materials have been used for this purpose, such as wax, fatty material, polymer, natural resin, synthetic resin and semi-synthetic resin.Sustained-release matrix of the present invention is selected from hydroxypropyl emthylcellulose, sodium alginate, chitosan, polyvinyl alcohol, ethyl cellulose, polymethyl methacrylate or the like.Wherein, because the pH independence performance of hydroxypropyl emthylcellulose (HPMC) and its semi-synthetic source, so in resin, it constitutes an important class.
When using this hydrophilic matrix of hydroxypropyl emthylcellulose, with after gastrointestinal tract or saliva contact, soluble polymer forms a kind of tablet gel layer on every side that is enclosed at tablet.The release of medicine is subject to speed, the speed of drug diffusion and the speed that forms gel that water infiltrates.Hydroxypropyl emthylcellulose has this character, and the hydroxypropyl methylcellulose of different molecular weight (representing with viscosity) is united use, forms the different purposes that reach sustained release speed of gelation rate thereby make.The hydroxypropyl emthylcellulose viscosity that is adopted can be 50～100000mPas, and viscosity commonly used is 10000mPas, 15000mPas, and 4000mPas and 50mPas etc., multiple viscosity is used so that obtain optimum drug release rate.
Gliquidone raw material involved in the present invention is comparatively loose, compressibility is relatively poor, so can add the adjuvant that improves the tablet compressibility in the prescription, can select cellulose family and starch based for use, use as filler as one or more mixing in pregelatinized Starch, corn starch, microcrystalline Cellulose, the low-substituted hydroxypropyl cellulose, improve compressibility.Simultaneously, add a certain amount of filler, make to form certain infiltration lane after the gel aquation, make the moistening dissolving of medicine, be discharged in the environment, play the purpose of regulating drug release.Because said preparation is used for blood sugar lowering, so do not use saccharide filleies such as sucrose, lactose, mannitol.
When the compacting slow releasing tablet, can select for use stearic acid, magnesium stearate as lubricant, select for use micropowder silica gel, Pulvis Talci etc. to increase mobility of particle.
The inventor invents following method in secular practice, the different proportionings by compositions can prepare the slow releasing preparation with pharmacokinetics feature that preamble mentions.
The preparation method of gliquidone slow releasing preparation of the present invention is characterized in that: the slow releasing preparation of each preparation unit is grouped into by following one-tenth:
Gliquidone 30-180mg
Hydroxypropyl emthylcellulose 30-900mg
Filler 6-180mg
According to the weight difference of the diabetic state of an illness, gliquidone content is 30～180mg in each preparation unit.The hydroxypropyl emthylcellulose viscosity that is adopted can be 50～100000mPas, viscosity commonly used is 10000mPas, 15000mPas, 4000mPas and 50mPas etc., 15000mPas wherein, the slow release effect of 4000mPas viscosity is more excellent, is used a certain amount of 10000mPas, 50mPas can obtain optimum drug release rate.Filler comprises one or more in pregelatinized Starch, corn starch, microcrystalline Cellulose, the low-substituted hydroxypropyl cellulose.
The present invention's gliquidone slow releasing tablet or capsular production technology comprise the steps:
(1) 80～120 mesh sieves are standby excessively gliquidone, hydroxypropyl emthylcellulose, filler all to be pulverized the back;
(2) in the prescription ratio with adjuvants such as gliquidone and HPMC, filleies by behind the abundant mixing of equivalent incremental method, add suitable binding agent system granule;
(3) tabletting behind adding fluidizer and the lubricant mixing.
The binding agent that the preparation granule is used can be 40～80% alcoholic solution commonly used on the preparation process, 80% alcoholic solution of 2% ethyl cellulose, 5% polyvinylpyrrolidone, 70% alcoholic solution or the like.
Fluidizer and lubricant are stearic acid commonly used on the preparation process, magnesium stearate, Pulvis Talci etc.
Slow releasing preparation of the present invention is taken once every day, each a slice
Release in vitro degree research: according to Pharmacopoeia of the People's Republic of China version dissolution method second method in 2000, with 0.5% sodium dodecyl sulfate solution 1000mL is medium, 75rpm, under 37 ℃ of conditions gliquidone slow releasing preparation related among the present invention is carried out the release test, shows following release profiles result:
Time (hour)
The cumulative release amount
2 0～30％
4 30～50％
8 50～70％
More than 12 70%
More than 16 80%
More than 24 90%
In vivo, the slow releasing preparation degree of absorption height and the favorable reproducibility of the present invention's preparation.The oral one day intravital T of gliquidone preparation that is administered once that relates among the present invention
MaxBe 3～8 hours, and the T after the administration of common quick release gliquidone preparation oral
MaxIt is 1.5～2.5 hours.
Gliquidone slow releasing tablet of the present invention is compared with common quick release gliquidone preparation has following advantage:
(1) gliquidone slow releasing tablet technology of the present invention is the preparation method of conventional tablet, and is simple and easy to do, need not increase equipment and investment, can large batch of suitability for industrialized production.
(2) gliquidone slow releasing preparation of the present invention reduces maximum blood medicine peak value effectively; Reduced the hypoglycemia incidence rate simultaneously; In addition, slow releasing preparation has reduced medicining times, has improved patient's compliance.
(3) slow releasing preparation stable blood concentration can not cause the damage to organs such as islets of langerhans, liver, kidneys owing to too high blood drug level long-term prescription, reduces the generation of complication and increases the weight of, thereby effectively reduced toxic and side effects, has improved patient's drug safety.
(4) slow releasing preparation can reach the effect of the control post-prandial glycemia identical with ordinary tablet, the two bioequivalence;
The insulin secretion pattern that above advantage can make the patient rebuild more to meet psychological need, and do not control the post-prandial glycemia peak merely.
Description of drawings
Fig. 1 is the release in vitro curve of gliquidone slow releasing tablet in the example 1;
Fig. 2 is blood drug level-time graph (AUC in example 5 gliquidone slow releasing tablet and the conventional sheet single-dose body
0-t).
The specific embodiment
The present invention will be further described below in conjunction with embodiment and pharmacodynamic experiment data
Embodiment 1:
Form
Recipe quantity (mg/ sheet)
Gliquidone 60
Hydroxypropyl emthylcellulose 4000mPas 125
Hydroxypropyl emthylcellulose 50mPas 65
Carboxymethyl starch sodium 2.0
Magnesium stearate 1.5
Pulvis Talci 1.5
This method for preparing tablet thereof is as follows:
(1) gliquidone crude drug, adjuvant are all pulverized the back and crossed 100 mesh sieves, standby;
(2) in above-mentioned prescription ratio each adjuvant is mixed, press the abundant mixing of equivalent incremental method with gliquidone again, 80% alcoholic solution that adds an amount of 2% ethyl cellulose is made soft material;
(3) granulate with 20 mesh sieves, 50 ℃ of dryings were taken out in 3 hours;
(4) with 20 mesh sieve granulate, tabletting behind adding fluidizer and the lubricant mixing;
Above gliquidone slow releasing tablet release conditions sees Table 1, Fig. 1:
Table 1 gliquidone slow releasing tablet release in vitro degree (Q%)
| t(h) | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 14 | 16 | 20 | 24 |
| | 5 | 15 | 30 | 45 | 62 | 74 | 85 | 94 | 99 | 101 | 101 |
Embodiment 2:
Form
Recipe quantity (mg/ sheet)
Hydroxypropyl emthylcellulose 15000mPas 60
Hydroxypropyl emthylcellulose 50mPas 10
Corn starch 1.2
Magnesium stearate 0.5
Pulvis Talci 0.6
This method for preparing tablet thereof is as follows:
(1) gliquidone crude drug, adjuvant are all pulverized the back and crossed 100 mesh sieves, and be standby;
(2) in above-mentioned prescription ratio each adjuvant is mixed, press the abundant mixing of equivalent incremental method with gliquidone again, add an amount of 70% alcoholic solution and make soft material;
(3) granulate with 20 mesh sieves, 50 ℃ of dryings were taken out in 2.5 hours;
(4) with 20 mesh sieve granulate, tabletting behind adding fluidizer and the lubricant mixing;
Above gliquidone slow releasing tablet release conditions sees Table 2:
Table 2 gliquidone slow releasing tablet release in vitro degree
| t(h) | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 14 | 16 | 20 | 24 |
| |
4 | 11 | 25 | 39 | 53 | 65 | 76 | 85 | 91 | 94 | 96 |
Embodiment 3:
Form
Recipe quantity (mg/ sheet)
Hydroxypropyl emthylcellulose 4000mPas 360
Hydroxypropyl emthylcellulose 50mPas 113
Microcrystalline Cellulose 45
Low-substituted hydroxypropyl cellulose 35
Magnesium stearate 2.5
Pulvis Talci 2.5
This method for preparing tablet thereof is as follows:
(1) gliquidone crude drug, adjuvant are all pulverized the back and crossed 100 mesh sieves, and be standby;
(2) in above-mentioned prescription ratio each adjuvant is mixed, press the abundant mixing of equivalent incremental method with gliquidone again, add an amount of 5% polyvinylpyrrolidone, 70% alcoholic solution and make soft material;
(3) granulate with 20 mesh sieves, 50 ℃ of dryings were taken out in 3.5 hours;
(4) with 20 mesh sieve granulate, tabletting behind adding fluidizer and the lubricant mixing;
Above gliquidone slow releasing tablet release conditions sees Table 3:
Table 3 gliquidone slow releasing tablet release in vitro degree
| t(h) | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 14 | 16 | 20 | 24 |
| | 5 | 15 | 30 | 45 | 62 | 74 | 85 | 94 | 99 | 101 | 101 |
Embodiment 4:
Form
Recipe quantity (mg/ sheet)
Gliquidone 180
Hydroxypropyl emthylcellulose 4000mPas 300
Hydroxypropyl emthylcellulose 10000mPas 165
Microcrystalline Cellulose 70
Carboxymethyl starch sodium 5.5
Magnesium stearate 4.2
This method for preparing tablet thereof is as follows:
(1) gliquidone crude drug, adjuvant are all pulverized the back and crossed 100 mesh sieves, and be standby;
(2) in above-mentioned prescription ratio each adjuvant is mixed, press the abundant mixing of equivalent incremental method with gliquidone again, 80% alcoholic solution that adds an amount of 2% ethyl cellulose is made soft material;
(3) granulate with 20 mesh sieves, 50 ℃ of dryings were taken out in 4 hours;
(4) with 20 mesh sieve granulate, tabletting behind adding fluidizer and the lubricant mixing;
Above gliquidone slow releasing tablet release conditions sees Table 4:
Table 4 gliquidone slow releasing tablet release in vitro degree
| t(h) | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 14 | 16 | 20 | 24 |
| | 7 | 16 | 32 | 51 | 66 | 82 | 92 | 96 | 99 | 101 | 103 |
Following reference example is described the release in vitro situation of the conventional sheet of gliquidone.
Reference example:
The conventional sheet that gliquidone is 60 milligrams sees Table 5 at external dissolution:
The external dissolution of the conventional sheet of table 5 gliquidone
| t(min) | 5 | 15 | 30 | 45 | 60 |
| Q％ | 27 | 66 | 85 | 92 | 99 |
Following data declaration good effect of the present invention by experiment:
Embodiment 5: the body giving drugs into nose is for dynamics research
The animal body giving drugs into nose is as follows for dynamics research: the slow releasing tablet that conventional sheet (specification 60mg) of gliquidone and embodiment 1 make is distinguished administration, observes drug absorption and metabolism situation behind the oral single-dose.
6 of beasle dogs are divided into two groups at random, and three every group, the male and female dual-purpose, fasting is after 16 hours, and oral gliquidone slow releasing tablet of difference and conventional sheet, dosage only are 60mg/, and taking medicine gives suitable quantity of water simultaneously.The slow release group was got blood 2ml in 1,2,3,4,6,8,10,12,15 and 24 hour after administration, and got blood after common group of administration in 0.5,1,1.5,2,3,4,6,8,10 and 12 hour.After room temperature is placed and is treated blood clotting, with 10000rpm centrifugalize serum, the freezing mensuration that is saved to.Intersect after a week and take medicine, blood-sampling method is the same.The concentration of gliquidone is measured with the HPLC method in the blood sample.Average blood plasma drug level-time data sees Table 6,7,8 curves and sees Fig. 2.
The serum prototype drug level (unit: μ g/ml) of each time point of table 6 beasle dog oral slow-releasing preparation
| t(h) | 1 | 2 | 3 | 4 | 6 | 8 | 10 | 12 | 15 | 24 |
| mean S.d. | 0.31 0.42 | 1.79 1.82 | 2.28 1.10 | 2.14 0.64 | 2.05 0.85 | 2.24 1.21 | 1.42 0.86 | 1.33 0.56 | 1.70 1.20 | 0.65 0.64 |
The serum prototype drug level (unit: μ g/ml) of oral each time point of ordinary preparation of table 7 beasle dog
| t(h) | 0.5 | 1 | 1.5 | 2 | 3 | 4 | 6 | 8 | 10 | 12 |
| mean S.d. | 0.40 0.24 | 2.14 1.08 | 5.96 2.24 | 7.39 2.47 | 4.10 1.90 | 3.05 1.58 | 1.35 0.69 | 0.97 0.50 | 0.65 0.40 | 0.35 0.28 |
Calculate medicine for parameter with the blood drug level of individuality-time graph, slow releasing tablet and conventional sheet the results are shown in Table 8.
The gliquidone medicine is for the parametric statistics result behind table 8 beasle dog oral sustained release and the conventional sheet
| Slow releasing preparation | Ordinary preparation | The P value | |
| T max(h) C max(μg/ml) Ke(l/h) T 1/2(h) Vd(L) AUC 0-t(μg h/ml) CL(L/h) | 5.67±2.09 3.51±0.55 0.207±0.175 5.22±3.03 9.88±3.99 35.43±7.12 1.54±0.50 | 1.92±0.20 7.53±2.27 0.275±0.055 2.61±0.56 5.35±1.85 43.53±12.36 1.45±0.48 | ＜0.01 ＜0.01 ＜0.05 ＞0.05 ＜0.05 ＞0.05 ＞0.05 |
The release property that all shows the delay of gliquidone in testing in vitro tests and body according to preparation of the present invention.Because sulfonylurea hypoglycemic agent easily causes hypoglycemia in treatment, reduce C
MaxBe to reduce the main method that side effect takes place.The C of oral gliquidone conventional formulation
MaxAbout 7.5 μ g/ml, slow releasing tablet then is 3.51 μ g/ml, has both reduced blood medicine peak value, far above minimum effective blood drug concentration 80ng/ml, has guaranteed hypoglycemic effect again.Above-mentioned test data is compared with conventional sheet situation, is significantly according to prescription advantage of the present invention, and in addition, bioavailability reaches (the area under the drug-time curve AUC more than 80% of conventional sheet in the body of slow releasing tablet
0-tRatio), hypoglycemic effect equivalence.
After the preferred embodiment that describes in detail, being familiar with this technology personage can clearly understand, can carry out various variations and modification not breaking away under above-mentioned claim and the spirit, all foundations technical spirit of the present invention all belongs in the scope of technical solution of the present invention any simple modification, equivalent variations and modification that above embodiment did.And the present invention also is not subject to the embodiment of illustrated embodiment in the description.
Claims (9)
1, a kind of gliquidone slow releasing preparation is characterized in that, contains the gliquidone for the treatment of effective dose, medicament sustained-release matrix and/or medicine acceptable carrier.
2, slow releasing preparation according to claim 1 is characterized in that, the release of gliquidone can be provided after the administration in 24 hours, and the body giving drugs into nose is 3～8 hours for the average peak reaching time of blood concentration of kinetics.
3, slow releasing preparation according to claim 1 is characterized in that, the amount that gliquidone is contained in each preparation unit of treatment effective dose is 30～180mg.
4, slow releasing preparation according to claim 1, sustained-release matrix wherein is selected from hydroxypropyl emthylcellulose, sodium alginate, chitosan, polyvinyl alcohol, ethyl cellulose, polymethyl methacrylate.
5, slow releasing preparation as claimed in claim 1 is tablet, capsule.
6, slow releasing preparation as claimed in claim 5 is tablet.
7, slow releasing preparation as claimed in claim 6 wherein, comprises the gliquidone for the treatment of effective dose, an amount of hydroxypropyl emthylcellulose and filler, and wherein, the weight ratio of gliquidone and hydroxypropyl emthylcellulose is 1: 1～1: 5; The weight ratio of gliquidone and filler is 1: 1～5: 1.
8, slow releasing preparation as claimed in claim 7, wherein filler comprises one or more in pregelatinized Starch, corn starch, microcrystalline Cellulose, the low-substituted hydroxypropyl cellulose.
9, the preparation method of the described gliquidone slow releasing preparation of claim 6 is characterized in that: made by following raw material and adjuvant for every:
Gliquidone 30-180mg
Hydroxypropyl emthylcellulose 30-900mg
Filler 6-180mg
(1) gliquidone crude drug, adjuvant are all pulverized the back and crossed 100 mesh sieves, standby;
(2) in above-mentioned prescription ratio each adjuvant is mixed, again with gliquidone by behind the abundant mixing of equivalent incremental method, add suitable binding agent system granule;
(3) tabletting behind adding fluidizer and the lubricant mixing.
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| CNB2005100144831A CN100490808C (en) | 2005-07-15 | 2005-07-15 | Gliquilone slow-releasing preparation |
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| CNB2005100144831A CN100490808C (en) | 2005-07-15 | 2005-07-15 | Gliquilone slow-releasing preparation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104127423A (en) * | 2014-07-30 | 2014-11-05 | 沈阳药科大学 | Gliquidone derivative, preparation method and application thereof |
| CN104127424A (en) * | 2014-07-30 | 2014-11-05 | 沈阳药科大学 | Glibenclamide derivative, preparation method and application thereof |
| CN104688670A (en) * | 2015-01-29 | 2015-06-10 | 成都恒瑞制药有限公司 | Invokana sustained release preparation and preparation method thereof |
-
2005
- 2005-07-15 CN CNB2005100144831A patent/CN100490808C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104127423A (en) * | 2014-07-30 | 2014-11-05 | 沈阳药科大学 | Gliquidone derivative, preparation method and application thereof |
| CN104127424A (en) * | 2014-07-30 | 2014-11-05 | 沈阳药科大学 | Glibenclamide derivative, preparation method and application thereof |
| CN104688670A (en) * | 2015-01-29 | 2015-06-10 | 成都恒瑞制药有限公司 | Invokana sustained release preparation and preparation method thereof |
| CN104688670B (en) * | 2015-01-29 | 2017-10-24 | 成都恒瑞制药有限公司 | A kind of canagliflozin sustained release preparation and preparation method thereof |
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| CN100490808C (en) | 2009-05-27 |
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