CN102743354A - Repaglinide tablet and preparation method thereof - Google Patents
Repaglinide tablet and preparation method thereof Download PDFInfo
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- CN102743354A CN102743354A CN2012102665208A CN201210266520A CN102743354A CN 102743354 A CN102743354 A CN 102743354A CN 2012102665208 A CN2012102665208 A CN 2012102665208A CN 201210266520 A CN201210266520 A CN 201210266520A CN 102743354 A CN102743354 A CN 102743354A
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Abstract
The invention discloses a repaglinide tablet and a preparation method thereof, belonging to the new technical field of medicines. The repaglinide tablet mainly contains repaglinide and is prepared by a solid self-emulsifying technology, wherein the tablet further contains a diluent, an emulsifier, an assistant emulsifier, an adsorbent, filler, a disintegrating agent and a lubricant. The repaglinide tablet overcomes the instability of repaglinide, has the advantages of improved dissolution rate of repaglinide and enhanced treatment effect and has ideal treatment effect.
Description
Technical field
The invention belongs to medical manufacturing field, relate to a kind of new technique of repaglinide, be specifically related to a kind of repaglinide sheet and preparation method thereof.
Background technology
Repaglinide (Repaglinide) is the non-sulfonylurea blood sugar lowering, and by the development of Boehringer Ingelheim. company, nineteen ninety licenses to Novo Nordisk company the earliest.1997 obtain the FDA approval is used to treat type 2 diabetes mellitus
1. pharmacological toxicology
36KDA protein-specific on the potassium-channel of the outer dependency ATP of these article and beta Cell of islet film combines, and potassium channel is closed, the β cell depolarization; Calcium channel is open, and flow of calcium ions promotes insulin secretion; Its effect is faster than sulfonylurea, so hypoglycemic activity is very fast after the meal.
2. pharmacokinetics
The repaglinide sheet through the gastrointestinal tract fast Absorption, cause plasma drug level to raise rapidly.The plasma drug level peaking in back 1 hour of taking medicine.PC descends rapidly then, is eliminated in 4～6 hours.Plasma half-life is about 1 hour.The repaglinide sheet combines greater than 98% with human plasma protein fraction.The repaglinide sheet is almost all by metabolism, and metabolite is not seen the hypoglycemic activity that any clinical meaning is arranged.Repaglinide sheet and metabolite thereof are mainly from bile excretion, and very fraction (less than 8%) metabolite is discharged from urine.Original shape medicine in the feces is less than 1%.
3. indication
Be used for diet control and motion exercise and can not effectively control type 2 diabetes mellitus (non-insulin-dependent) patient of hyperglycemia.The repaglinide sheet can with the metformin contract.Compare with using separately separately, the two share has synergism to blood sugar control.
Usage and dosage repaglinide sheet should be taken (promptly taking before the meal) before dinner.The insulin secretion accelerating reaction promptly appears in 30 minutes at oral repaglinide sheet.Usually in 15 minutes before the meal, take this medicine.Also can grasp in 0～30 minute before the meal medicine time.Please follow the doctor's advice and take the repaglinide sheet.Dosage varies with each individual, and decides with individual blood glucose.Recommending initial dose is 0.5 milligram, can weekly or adjust in per two weeks as needing later on.The patient who accepts the treatment of other oral hypoglycemic repaglinide sheet treatment of can directly migrating.It recommends initial dose is 0.5mg.Maximum recommendation single dose is 4mg, takes during dining.But maximum daily dose should not surpass 16mg.For weak and underfed patient, should careful adjustment dosage.If share, should reduce the dosage of repaglinide sheet with metformin.Although repaglinide is mainly by bile excretion, the patient of renal insufficiency must carefully use.
4. untoward reaction
(1) these reactions of hypoglycemia are slighter usually, are prone to correct through giving carbohydrate.If more serious, but input glucose.(2) change of the known blood sugar level of visual abnormality can cause temporary visual abnormality, especially when the treatment beginning.When having only only a few case report repaglinide sheet treatment beginning above-mentioned visual abnormality taking place, but in clinical trial, does not have so and the case of the repaglinide sheet of stopping using.(3) have report that gastrointestinal reaction takes place in the gastrointestinal tract clinical trial, like stomachache, diarrhoea, feel sick, vomiting and constipation.Compare frequency and the equal indifference of the order of severity that these symptoms occur with other oral hypoglycemic thing.(4) liver function enzyme index raise during the indivedual case reports of liver enzyme system were treated with the repaglinide sheet.Most cases be slight and temporary, because of the patient that the rising of enzyme index stops to treat few.(5) skin allergy can take place in anaphylaxis, like pruritus, rubescent, urticaria.Because chemical constitution is different, have no reason to suspect possibly take place and sulfonylurea drugs between the cross allergy reaction.
5. contraindication
Known to the patient hypersensitive of any excipients in repaglinide or these article; Diabetes mellitus type (insulin-dependent, IDDM); Follow or do not accompany the diabetic ketoacidosis patient of stupor; Gestation or nursing women; Child below 8 years old; The patient of severe renal function or hepatic insufficiency; During with CYP3A4 inhibitor or derivant combined treatment.
6. points for attention
The careful usefulness of the bad patient of renal function, the malnutrition patient should adjust dosage; The same with other most of oral insulin secretion accelerating hypoglycemic drugs, the repaglinide sheet also can cause hypoglycemia; Share and hypoglycemic danger to take place increase with metformin.If still take place behind the drug combination to continue hyperglycemia, then should not continue to use the OHA blood sugar control, and need use insulinize instead; When stress takes place, like heating, wound, infection or operation, remarkable hyperglycemia may appear; The repaglinide sheet did not carry out research as yet in the patient of hepatic insufficiency.In under-18s or the patient more than 75 years old, do not carry out research yet.So examining, the patient of hepatic insufficiency uses; The necessary careful usefulness of patient is not had meal and is not taken medicine, and hypoglycemia takes place when avoiding driving simultaneously.
7. drug interaction
Following medicine can strengthen the hypoglycemic activity of repaglinide sheet: oxidase inhibitor (MAOI), non-selective beta-blocker, ACE inhibitor, NSAID, Salicylate, octreotide, ethanol and excito-anabolic hormone.Beta-blocker may be covered the hypoglycemia symptom.Ethanol may increase the weight of or prolong by the hypoglycemia symptom due to the repaglinide sheet.Following medicine can weaken the hypoglycemic activity of repaglinide sheet: oral contraceptive, thiazide medicine, 17-hydroxy-11-dehydrocorticosterone, danazol, thyroxin and sympathomimetic.The repaglinide sheet does not influence the pharmacokinetic properties of digoxin, theophylline and Fa Hua order, and sago does not influence the pharmacokinetic properties of repaglinide sheet yet for western fourth.Results of in vitro studies shows that the repaglinide sheet is mainly by the metabolism of P450 (CYP3A4) derivant.So CYP3A4 inhibitor such as ketoconazole, itraconazole, erythromycin, fluconazol, rice be your repaglinide sheet blood plasma level that possibly raise than method ground.And can induce chemical compound such as the rifampicin of CYP3A4 or phenytoin possibly reduce repaglinide sheet blood plasma level.Because of not understanding the degree that it is induced or restrains, should avoid said medicine and repaglinide sheet and merge use.
Repaglinide is white or off-white color crystalline powder; Odorless.These article are prone to dissolve in chloroform, dissolve at ethanol or acetone part omitted, and are almost insoluble in water, slightly soluble in the 0.1mol/L hydrochloric acid solution; The relatively poor dissolubility of repaglinide is the key factor that influences clinical efficacy difference.The ether fracture can take place to oxygen, damp and hot equal instability in repaglinide with this understanding, and catabolite increases, thus further toxigenicity impurity.External polacrilin potassium and the repaglinide of adopting carries out compatibility, utilize the intermolecular network of polacrilin potassium and repaglinide and, increased the stability of repaglinide; The domestic degraded of all adopting control production and condition of storage to delay repaglinide, but two kinds of methods all fail fundamentally to solve the difficult problem that repaglinide is degraded.Therefore developing a kind of dissolution in vitro repaglinide sheet good and steady in a long-term is imminent.
Summary of the invention:
The object of the present invention is to provide a kind of good stability, dissolution is high, and is evident in efficacy, repaglinide sheet that untoward reaction is little and preparation method thereof.The present invention adopts the solid self-emulsifying technology earlier repaglinide to be dissolved in diluent, emulsifying agent and the co-emulsifier; The reuse adsorbent adsorbs; The repaglinide that is dissolved in diluent, emulsifying agent and the co-emulsifier runs into the moisture in the adsorbent, form the Emulsion of oil-in-water type automatically, thereby has blocked contacting of oxygen in repaglinide and the air; Avoided the ether fracture, be convenient to long term storage thereby repaglinide is stablized.After repaglinide is adsorbed agent absorption, again with adjuvant compacting such as filler in flakes, further blocked contacting of oxygen in repaglinide and the air, thereby the repaglinide sheet that adopts the present invention to process is stablized.
Repaglinide sheet disintegrate fast in water of adopting the present invention to process; Be adsorbed on adsorbent repaglinide Emulsion; Under the help of emulsifying agent and co-emulsifier; Form the nano-emulsion of diameter fast, improved the dissolubility of repaglinide sheet in water greatly, improved the curative effect of medicine less than 10nm.
Repaglinide sheet of the present invention is made up of the component of the following content that accounts for composition total weight: repaglinide is 0.5-5%; Diluent is 1-10%; Emulsifying agent is 1-5%; Co-emulsifier is 1-5%; Adsorbent is 20-40%; Filler is 40-70%; Disintegrating agent is 2-10%; Lubricant is 0.1-2%; A kind of repaglinide sheet of the present invention is realized through following Technology: the repaglinide, diluent, emulsifying agent, the co-emulsifier mix homogeneously that take by weighing recipe quantity; Be heated to 60 ℃ of stirring and dissolving and become solution; Add adsorbent, stir, 60 ℃ of dryings 2 hours; Pulverized 80 mesh sieves, subsequent use as intermediate (1); Take by weighing the filler and intermediate (1) mix homogeneously of recipe quantity, dry method 20 orders are granulated, 18 order granulate, and disintegrating agent, the lubricant of adding recipe quantity, mix homogeneously is pressed into the tablet that hardness is 5-8kg.
Description of drawings
Fig. 1 is that embodiment 1, embodiment 2 and repaglinide sheet (NovoNorm) stripping curve are measured figure (dissolution medium: pH5.0 Fructus Citri Limoniae hydrochloric acid buffer solution).
Fig. 2 is that embodiment 1, embodiment 2 and repaglinide sheet (NovoNorm) long-time stability related substance are investigated the mensuration trendgram.
The specific embodiment
The repaglinide sheet that the present invention obtains has simple, the good stability of method, and dissolution is high, characteristics evident in efficacy.Below implement explanation the present invention, but do not limit the present invention in any way.
Embodiment 1:
Prescription:
Method for making: with repaglinide, ethyl oleate, polyoxyethylene hydrogenated Oleum Ricini, gather diethanol 4000 mix homogeneously, be heated to 60 ℃ of stirring and dissolving and become solution, add starch, stir, 60 ℃ of dryings 2 hours were pulverized 80 mesh sieves, and were subsequent use as intermediate (1); Take by weighing the microcrystalline Cellulose and intermediate (1) mix homogeneously of recipe quantity, dry method 20 orders are granulated, 18 order granulate, and cross-linking sodium carboxymethyl cellulose, the magnesium stearate of adding recipe quantity, mix homogeneously is pressed into the tablet that hardness is 5-8kg.
Embodiment 2:
Prescription:
Method for making: with repaglinide, ethyl oleate, Polyethylene Glycol 15 hydroxy stearic acid esters, meglumine, gather diethanol 6000 mix homogeneously, be heated to 60 ℃ of stirring and dissolving and become solution, add calcium hydrogen phosphate; Stir; 60 ℃ of dryings 2 hours were pulverized 80 mesh sieves, and were subsequent use as intermediate (1); Take by weighing the microcrystalline Cellulose and intermediate (1) mix homogeneously of recipe quantity, dry method 20 orders are granulated, 18 order granulate, and carboxymethyl starch sodium, the magnesium stearate of adding recipe quantity, mix homogeneously is pressed into the tablet that hardness is 5-8kg.
Embodiment 3: carry out dissolution determination and long-time stability investigation to adopting embodiment 1, repaglinide sheet and commercially available repaglinide sheet (NovoNorm) that embodiment 2 processes.
Dissolution determination: get the repaglinide sheet, adopt 2010 editions two appendix XD drug release determinations of Chinese Pharmacopoeia method, second method, 900ml is a solvent with Fructus Citri Limoniae hydrochloric acid buffer solution (pH value is 5.0); Rotating speed is that per minute 75 changes, and operation is got solution 10ml respectively at 5min, 15min, 30min, 45min, 60min in accordance with the law; Add the dissolution medium of equality of temperature homogeneity simultaneously; Institute's sample thief filters immediately, gets subsequent filtrate as need testing solution, measures according to HPLC (two appendix VD of Chinese Pharmacopoeia version in 2010); Use octadecylsilane chemically bonded silica to be filler: (to get ammonium acetate 3.85g with ammonium acetate buffer; Add water 1000ml, make dissolving, regulate pH value to 4.0 with glacial acetic acid)-methanol (20: 80) is mobile phase; The detection wavelength is 243nm, and number of theoretical plate is pressed the repaglinide peak and calculated, and should be not less than 2000.Precision is measured need testing solution 20 μ l, injects chromatograph of liquid, the record chromatogram; Other the learn from else's experience repaglinide reference substance of 80 ℃ of drying under reduced pressure to constant weights is an amount of, accurately claims surely, adds Fructus Citri Limoniae hydrochloric acid buffer solution (pH value is 5.0) and dissolves and process the solution that contains 1 μ g among every 1ml, measures with method,, promptly gets with calculated by peak area by external standard method.Measure the result and see table 1, Fig. 1.
Table 1 repaglinide sheet dissolution determination table (dissolution medium: pH5.0 Fructus Citri Limoniae hydrochloric acid buffer solution)
| 5min | 15min | 30min | 45min | 60min | |
| Embodiment 1 | 86.2％ | 98.5％ | 97.8％ | 98.9％ | 98.3％ |
| Embodiment 2 | 88.4％ | 97.1％ | 98.3％ | 98.7％ | 98.9％ |
| Repaglinide sheet (NovoNorm) | 48.7％ | 72.1％ | 88.2％ | 92.1％ | 93.7％ |
Long-time stability are investigated: get by embodiment 1, repaglinide sheet that embodiment 2 processes and commercially available repaglinide sheet (NovoNorm) and carry out (40 ℃ of accelerated tests; RH60%); Respectively at 0,1,2,3, June sample analysis, related substance situation of change in the working sample.Use octadecylsilane chemically bonded silica to be filler: (get ammonium acetate 3.85g, add water 1000ml, make dissolving, regulate pH value to 4.0 with glacial acetic acid)-methanol (20: 80) is mobile phase with ammonium acetate buffer; The detection wavelength is 243nm, and number of theoretical plate is pressed the repaglinide peak and calculated, and should be not less than 2000.Get the fine powder an amount of (containing repaglinide 0.01g approximately) of repaglinide sheet, stable precision is put in the volumetric flask of 10ml, adds the mobile phase supersound process and makes dissolving in 10 minutes, puts coldly, adds mobile phase and is diluted to scale, shakes up, and filter membrane filters, as need testing solution; Precision is measured in need testing solution 1.0ml to the 100ml volumetric flask, is diluted to scale with mobile phase, shakes up, as contrast solution; According to above-mentioned chromatographic condition, measure contrast solution 20 μ l injecting chromatographs, regulate sensitivity, make the peak height of main constituent chromatographic peak be about 20% of full scale; Measure each 20 μ l of need testing solution and contrast solution again, inject chromatograph of liquid respectively, 4 times of record chromatogram to test sample main peak retention times.Calculate the impurity summation with Self-control method.Measure the result and see table 2, Fig. 2.
The long-term study on the stability of table 2 repaglinide sheet is measured table
| 0 day | Quicken January | Quicken February | Quicken March | Quicken June | |
| Embodiment 1 | 0.11％ | 0.12％ | 0.14％ | 0.17％ | 0.19％ |
| Embodiment 2 | 0.12％ | 0.12％ | 0.14％ | 0.16％ | 0.20％ |
| Repaglinide sheet (NovoNorm) | 0.12％ | 0.17％ | 0.24％ | 0.32％ | 0.46％ |
Claims (10)
1. repaglinide sheet and preparation method thereof, it is characterized in that: this repaglinide sheet is made up of the component of the following content that accounts for the tablet total weight amount:
1) repaglinide: 0.5-5%;
2) diluent: 1-10%;
3) emulsifying agent: 1-5%;
4) co-emulsifier: 1-5%;
5) adsorbent: 20-40%
6) filler: 40-70%;
7) disintegrating agent: 2-10%;
8) lubricant: 0.1-2%.
2. repaglinide sheet according to claim 1 and preparation method thereof is characterized in that: the specification of repaglinide is 0.5mg～5mg.
3. repaglinide sheet according to claim 1 and preparation method thereof is characterized in that: described diluent is one or more mixture in oleic acid, the ethyl oleate.
4. repaglinide sheet according to claim 1 and preparation method thereof is characterized in that: described emulsifying agent is one or more mixture in tween, polyoxyethylene hydrogenated Oleum Ricini, Polyethylene Glycol 15 hydroxy stearic acid esters.
5. repaglinide sheet according to claim 1 and preparation method thereof is characterized in that: described to help emulsifying be one or more mixture in Macrogol 4000, polyethylene glycol 6000, meglumine, the poloxamer.
6. repaglinide sheet according to claim 1 and preparation method thereof is characterized in that: described adsorbent is one or more mixture in micropowder silica gel, microcrystalline Cellulose, calcium hydrogen phosphate, the starch.
7. repaglinide sheet according to claim 1 and preparation method thereof is characterized in that: described filler is one or more mixture in microcrystalline Cellulose, lactose, starch, the calcium hydrogen phosphate.
8. repaglinide sheet according to claim 1 and preparation method thereof is characterized in that: described disintegrating agent is cross-linked carboxymethyl fiber sodium, carboxymethyl starch sodium, polyvinylpolypyrrolidone, hangs down and get one or more mixture in the hydroxy methocel.
9. repaglinide sheet according to claim 1 and preparation method thereof is characterized in that: described lubricant is a magnesium stearate.
10. repaglinide sheet according to claim 1 and preparation method thereof; It is characterized in that: described repaglinide piece preparation method is repaglinide, diluent, emulsifying agent, the co-emulsifier mix homogeneously that takes by weighing recipe quantity, is heated to 60 ℃ of stirring and dissolving and becomes solution, adds adsorbent; Stir; 60 ℃ of dryings 2 hours were pulverized 80 mesh sieves, and were subsequent use as intermediate (1); Take by weighing the filler and intermediate (1) mix homogeneously of recipe quantity, dry method 20 orders are granulated, 18 order granulate, and disintegrating agent, the lubricant of adding recipe quantity, mix homogeneously is pressed into the tablet that hardness is 5-8kg.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103142476A (en) * | 2013-03-21 | 2013-06-12 | 青岛正大海尔制药有限公司 | Calcitriol suspension and preparation method thereof |
| CN104840437A (en) * | 2014-02-13 | 2015-08-19 | 长春海悦药业有限公司 | Pharmaceutical composition containing repaglinide |
| CN113116892A (en) * | 2021-05-24 | 2021-07-16 | 杭州华东医药集团新药研究院有限公司 | Pharmaceutical composition containing repaglinide and preparation method thereof |
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Application publication date: 20121024 |