CN103006605A - Bendazac lysine sustained release preparation as well as preparation method and application of preparation - Google Patents

Abstract

The invention discloses a bendazac lysine sustained release oral preparation for treating diabetic complications. The sustained release preparation is prepared from bendazac lysine, a hydrophilic gel matrix, a diluting agent, a binding agent, a lubricant/flow aid and a wetting agent according to certain weight proportions. The preparation is a tablet or a capsule; the diabetic complications can be diabetic nephropathy, diabetic neuropathy and diabetic cataract. Compared with the common bendazac lysine tablet, the bendazac lysine sustained release oral preparation has the advantages that the preparation slowly releases and enters into a human body, has small fluctuation of blood concentration 'peak valley', small toxic and side effects and long half-life period, the number of times of taking medicines by patients is reduced and the preparation is safer in use, effective and economic and is an effective ideal medicine for treating the diabetic complications.

Description

Bendazac lysine slow releasing preparation and preparation method and application thereof

One, technical field

The present invention relates to bendazac lysine oral slow-releasing preparation and preparation and relate to the application of bendazac lysine oral slow-releasing preparation in the treatment diabetic complication.

Two, background technology

Bendazac lysine (bendazac lysine, BDL) is the anti-cataract new drug, is aldose reductase (aldose reductase, AR) inhibitor, has antiinflammatory concurrently, anti-albuminous degeneration, the effects such as free radical resisting.List of references: Drug.39(4) 576-961990,

The chemical name of bendazac lysine: 1B [1-benzyl-1H-Yin rattle away azoles-3-oxygen base] acetate L-lysine-mono[[[(1-phenylmethyl)-1H-indazol-3-yl] oxy] acetat]

Its chemical structural formula:

Molecular formula: C ₁₆H ₁₄N ₂O ₃C ₆H ₁₄N ₂O ₂

Molecular weight: 428.49

Nineteen eighty-three, this product at first going on the market in Italy, had eye drop and tablet form by Angelini pharmacy group, and is not only effective to sugared cataract,

Also polytype early-stage senile cataract is had preventive and therapeutic action, and untoward reaction is slight.List of references is the same.

Find also that in recent years bendazac lysine can effectively be prevented and treated diabetic nephropathy (DN) Acta PharmacolSin.2005Jun; 26 (6): 721-8. and diabetic neuropathy (DPN), Clinical and Experimental Physiology and Pharmacology.2006; 33:1231-38. the pathogeny of these two kinds of complication and diabetic cataract complication has many common parts, its mechanism of action of curing the disease is all relevant with the activity that suppresses aldose reductase.

Bendazac lysine is prevented and treated cataractous usage clinically: abroad be each 500mg, and one day three times, be used in conjunction 3-6 month, and even 1 year; Domestic is each 400mg, one day three times, is used in conjunction 6 months.This usage year in year out affects the compliance that the patient takes medicine.

Bendazac lysine common oral preparation lot number: 070402, the 200mg/ sheet, its technological process: get bendazac lysine (BDL) powder 200g and starch 32g mixing by 80 mesh sieves, add 50% ethanol 50ml and make wetting agent, stir into the soft material of appropriateness, cross the 18-24 mesh sieve, make the granule of degree of tightness appropriateness, 60-70 ℃ of drying, dry granular is through 16 mesh sieve granulate, adding magnesium stearate 3.5g mixing gets final product the fill capsule behind the mensuration content or tabletting becomes 0.2//sheet of bendazac lysine.Its Dissolution Rate Testing result is i.e. all strippings in 1 hour.

Slow releasing preparation means with ordinary preparation and compares that the Drug therapy effect is lasting, toxic and side effects is low, per 24 hours medication number of times should be reduced to 1～2 time preparation from 3～4 times.Press slow release, controlled release preparation designing requirement, medicine can discharge in the body lentamente, blood drug level " peak valley " fluctuation is little, can avoid surpassing the toxic and side effects for the treatment of blood drug level scope, can remain on again within the valid density scope (treatment window) to keep curative effect.Usually the technique of slow releasing preparation is complicated.In order to obtain the again unlikely danger that causes sudden outburst (prominent release) toxic and side effects of bringing of reliable therapeutic effect, must avoid or reduce prominent releasing or excessive slow release in links such as design, trial-production, productions.Slow releasing preparation and corresponding ordinary preparation relatively, to slow releasing preparation usually always take the dissolution in vitro of this slow releasing preparation as quality control index,

Three, summary of the invention:

(1) goal of the invention: the object of the invention is to provide a kind of bendazac lysine oral slow-releasing preparation of preventing and treating diabetic complication to reach the slow releasing preparation that the Drug therapy effect is lasting, toxic and side effects is low, the medication number of times reduces and lays a solid foundation for its application.。

(2) technical scheme:

A kind of bendazac lysine oral slow-releasing preparation for the treatment of diabetic complication is characterized in that this slow releasing preparation is made by the raw material of following weight proportion, with thousand or a restatement:

Described bendazac lysine oral slow-releasing preparation is characterized in that described hydrogel matrix is: hypromellose, carbomer, polyvinyl alcohol or ethyl cellulose.

Described bendazac lysine oral slow-releasing preparation is characterized in that described diluent is pregelatinized Starch, lactose, microcrystalline Cellulose, mannitol or L-arginine.

Described bendazac lysine oral slow-releasing preparation is characterized in that described binding agent is starch, microcrystalline Cellulose, polyvidone, methylcellulose or hydroxypropyl methylcellulose.

Described bendazac lysine oral slow-releasing preparation system is characterized in that described lubricant or fluidizer are silicon dioxide, magnesium stearate, stearic acid or Polyethylene Glycol.

Described bendazac lysine oral slow-releasing preparation is characterized in that described wetting agent is ethanol or water.

Described bendazac lysine oral slow-releasing preparation is characterized in that said preparation is tablet or capsule.

Described bendazac lysine oral slow-releasing preparation is characterized in that described diabetic complication is diabetic nephropathy, diabetic neuropathy and diabetic cataract.

(3) beneficial effect

According to the prepared bendazac lysine slow releasing preparation of such scheme and common bendazac lysine sheet relatively, the former is by discharging into lentamente in the body, and blood drug level " peak valley " fluctuation is little, can avoid surpassing treatment blood drug level scope and cause toxic and side effects; Again because of slow releasing preparation the apparent half-life long, it is longer to make the valid density scope namely treat within the window retention time, can reach like this medication number of times and reduce, increase patient's Compliance, it is safer, effective and economical to make the bendazac lysine slow releasing preparation be used for the treatment of diabetic complication.

Four. description of drawings:

Fig. 1: 25mg bendazac lysine Dissolution of Sustained Release Tablet curve

Fig. 2: 50mg bendazac lysine Dissolution of Sustained Release Tablet curve

Fig. 3: 100mg bendazac lysine Dissolution of Sustained Release Tablet curve

Fig. 4: 200mg bendazac lysine slow releasing capsule stripping curve

Fig. 5: 250mg bendazac lysine Dissolution of Sustained Release Tablet curve

Fig. 6: 300mg bendazac lysine Dissolution of Sustained Release Tablet curve

Fig. 7: serum level time graph

Fig. 8: beagle dog time front of blood concentration

Five. the specific embodiment

Embodiment 1:

Bendazac lysine slow releasing tablet (25mg)

Preparation technology:

(1) solvent preparation: 80% ethanol 80ml, add hypromellose, stir;

(2) get the bendazac lysine raw material, add microcrystalline Cellulose, silicon dioxide, pregelatinized Starch, the solvent 80ml that slowly adds above-mentioned preparation makes soft material, 24 mesh sieves are granulated, the hot air drying oven drying: 50 ℃-60 ℃, and oven dry, cross 24 mesh sieve granulate, 100 mesh sieves remove fine powder, get the bendazac lysine granule, add the magnesium stearate mixing;

(3) get the bendazac lysine granule, tabletting, usefulness coating material film coating (Ka Lekang Opadry II, lower same) gets final product.

The dissolution in vitro test;

Specification	The 25mg/ sheet	1 of every stripping rotor	Amount to 6
				Rotating speed	50r/min	Temperature	37℃±0.5℃

25mg Dissolution of Sustained Release Tablet record

Embodiment 2:

Bendazac lysine slow releasing tablet (50mg)

Prescription:

Preparation technology:

Get the bendazac lysine of 80 mesh sieves, added hypromellose, carbomer, L-arginine, mixing, 150ml makes soft material with dehydrated alcohol, and 24 mesh sieves are granulated, 50 ℃ of oven dry, 24 mesh sieve granulate add the stearic acid mixing, tabletting.Use the coating material film coating, get final product.

The dissolution in vitro test:

Specification	The 50mg/ sheet	1 of every stripping rotor	Amount to 6
				Rotating speed	50r/min	Temperature	37℃±0.5℃

50mg Dissolution of Sustained Release Tablet record

Embodiment 3:

Bendazac lysine slow releasing tablet (100mg) prescription:

Preparation technology:

Get bendazac lysine fine powder (crossing 80 mesh sieves), with methylcellulose, hypromellose mixes inhomogeneous with lactose, uses polyvidone k ₃₀5.0g be dissolved in soft material processed in the 50% ethanol 250ml solution, 24 mesh sieves are granulated, 60 ℃ of oven dryings are crossed 24 mesh sieve granulate, and 100 mesh sieves remove fine powder; Add starch, the magnesium stearate mixing, tabletting is used the coating material film coating, gets final product.Starch

The dissolution in vitro test:

Specification	1OO mg/ sheet	1 of every stripping rotor	Amount to 6
				Rotating speed	50r/min	Temperature	37℃±0.5℃

100mg Dissolution of Sustained Release Tablet record

Embodiment 4:

Bendazac lysine slow releasing capsule 200mg ∕ grain

Prescription:

Preparation technology:

Get 80 mesh sieve bendazac lysine and polyvinyl alcohol, added the microcrystalline Cellulose mixing, and added 50% ethanol 300ml and stir evenly and make soft material, crossed 20 mesh sieves, 60～70 ℃ of dryings, 20 mesh sieve granulate add starch, magnesium stearate mixing, and fill gets final product.

Dissolution Rate Testing:

Specification	The 200mg/ grain	1 of every stripping rotor	Amount to 6
				Rotating speed	50r/min	Temperature	37℃±0.5℃

200mg Dissolution of Sustained Release Tablet record

Embodiment 5:

Bendazac lysine slow releasing tablet (250mg ∕ sheet)

Technique:

Got 80 mesh sieve bendazac lysine and mix with microcrystalline Cellulose, and added L-arginine and carbomer, mix homogeneously is with 75% ethanol polyvidone k ₃₀Solution 300ml soft material processed, 24 mesh sieves are granulated, 60 ℃ of hot air drying oven dryings, 24 mesh sieve granulate add the stearic acid mix homogeneously, and tabletting is used the coating material film coating, gets final product.

The Dissolution Rate Testing result:

Specification	The 250mg/ sheet	1 of every stripping rotor	Amount to 6
				Rotating speed	50r/min	Temperature	37℃±0.5℃

250mg Dissolution of Sustained Release Tablet record

Embodiment 6:

Bendazac lysine slow releasing tablet (300mg)

Prescription:

Technique:

Got 80 mesh sieve bendazac lysine, add respectively hypromellose, microcrystalline Cellulose, adding mannitol and polyvinyl alcohol, mix homogeneously, with 80% ethanol 800ml soft material processed, 24 mesh sieves are granulated, 60 ℃ of dryings of hot air drying baking oven, cross 24 mesh sieve granulate, add magnesium stearate, silicon dioxide mixing tabletting, film coating gets final product.

The Dissolution Rate Testing result:

Specification	The 300mg/ sheet	1 of every stripping rotor	Amount to 6
				Rotating speed	50r/min	Temperature	37℃±0.5℃

300mg/ Dissolution of Sustained Release Tablet record

Embodiment 7:

The pharmacokinetics in rats comparative test material of bendazac lysine sustained-release tablet preparation and bendazac lysine ordinary tablet

1.1 instrument Japan Shimadzu LC-10A HPLC instrument, SPD-10Avp UV-detector, 1N-180 column oven, the high-precision microanalytical balance of METTMER, Shimadzu chromatographic work station.

1.2 medicine is subjected to test preparation: the bendazac lysine slow releasing tablet, the 25mg/ sheet, lot number 080306, content 108.08%, BDL Pharmaceutical limited company in Pinghu, Zhejiang provides; Reference preparation: bendazac lysine ordinary tablet 25mg/ sheet, lot number 080318, content 95.04%, BDL Pharmaceutical limited company in Pinghu, Zhejiang provides, bendazac lysine chemical reference substance content 90.5%, BDL Pharmaceutical limited company in Pinghu, Zhejiang provides.

1.3 chromatographic condition chromatographic column: Gemin C ₁₈(250 * 4.6mm, ￠ 5 μ m), 35 ℃ of column temperatures, ultraviolet wavelength 307nm, mobile phase: acetonitrile: 0.1molL ^-1(56:44), flow velocity 1ml/min, sample introduction 40 μ l.

1.4 10 of the healthy Wistar rats of animal subject, male and female half and half, body weight 256-327g is provided by Nanjing Medical University's animal center, the quality certification number: SCXK (Soviet Union) 2008-0004 breeding observing two weeks, the front fasting 15h of blood drawing freely drinks water.

2. assay method

2.1 administration and sample collecting are divided into 2 groups at random with 10 of healthy Wistar rats, male and female all have, and femoral artery is got blood, all through the intestines and stomach administration, dosage is 25mg for BDL slow release and ordinary tablet, and ordinary tablet is after administration 0.083,0.25,0.5,1.0,1.5,2.0,4.0,6.0,8.0 12.0h gets respectively 0.25ml blood; Slow releasing tablet after administration 0.25,0.5,1.0,2.0,4.0,6.0,8.0,12.0,24.0h.Get respectively 0.25ml blood, blood sample is all put in the anticoagulant heparin pipe, and centrifugal separation plasma is put under 40 ℃ of conditions and preserved immediately.

2.2 plasma sample is processed with mensuration and is got blood plasma 50 μ l, adds acetonitrile 450 μ l, mixed whirlpool 1min, and high speed centrifugation (16000r/min) 5min gets supernatant 40 μ l injection liquid chromatographies, and the external standard method peak area quantification is measured.The result: without endogenic Interference Peaks, specificity is good in the chromatogram.

3. result

The preparation of blood plasma standard curve and the mensuration of lower limit of quantitation, precision test, extraction recovery, accuracy test (relative recovery), retinue blood plasma standard curve and Quality Control, Almost Sure Sample Stability is investigated dark the grade and is all conformed to requirement

4. blood drug level and pharmacokinetic parameter calculate

4.1 blood drug level as a result table 1 is the blood drug level results of 5 tested Mus after to the BDL ordinary tablet;

Table 2 is the blood drug level results of 5 tested Mus after to the BDL slow releasing tablet

The blood drug level of table 1 rat after to the BDL ordinary tablet

Time (h)	1	3	5	7	9	x±SD
							0.083	69.49	65.16	52.94	52.45	52.32	58.47±8.23
0.25	124.18	145.45	103.33	104.68	126.33	120.79±17.43
							0.5	202.74	197.98	202.15	226.36	209.24	207.69±11.19
1.0	196.65	157.16	186.04	156.33	139.88	167.21±23.39
							1.5	111.93	111.91	154.84	96.08	105.77	116.11±22.60
2.0	92.48	82.69	102.48	66.16	51.66	79.09±20.37
							4.0	47.04	27.58	49.23	40.98	29.93	38.95±9.82
6.0	29.14	13.26	19.7	21.41	19.48	20.60±5.69
							8.0	19.48	7.82	10.39	9.99	13.07	12.15±4.50
12.0	7.37	4.81	4.95	6.99	7.80	6.38±1.40

The blood drug level of table 2 rat after to the BDL slow releasing tablet

Time (h)	2	4	6	8	10	x±SD
							0.25	32.98	45.86	59.29	87.20	47.0	54.47±20.53
0.5	39.30	88.97	68.18	98.31	74.91	73.90±22.63
							1.0	42.45	141.22	75.19	104.52	104.21	93.52±36.93

2.0	92.69	150.88	76.91	117.58	141.35	115.85±31.33
							4.0	65.36	59.16	91.56	78.93	77.09	74.42±12.61
6.0	34.92	24.39	41.05	44.83	35.68	36.17±7.73
							8.0	19.30	13.06	19.46	23.02	20.25	19.02±3.65
12.0	8.34	12.69	10.91	15.23	7.50	10.93±3.16
							24.0	4.02	6.77	6.54	6.50	4.26	5.62±1.36

Table 3BDL(25mg) slow releasing tablet and ordinary tablet main pharmacokinetic parameters in the rat body compares

Annotate: with the ordinary tablet ratio, both have utmost point significant difference, p＜0.001

4.2 the blood drug level time data result that pharmacokinetic parameter records according to 10 tested Mus,

1) asks calculation area under curve (AUC with trapezoidal method _0-t), C _MaxAnd T _MaxBe measured value.

AUC _0-∝=C _tn/λ+AUC _0-t.

2) ask calculation MRT with statistical moment

3) blood drug level---time graph all meets oral one compartment open model in BDL slow releasing tablet and its common lamellar body, and available residual error method is estimated Ke, t _1/2, Ka, cl/F, the parameter initial value such as Vd also utilizes iterative method to be optimized.

4.). the bioavailability evaluation method

Bendazac lysine (BDL) slow releasing tablet area under curve AUC with measuring _0-tBe the relative bioavailability of (T), take the bendazac lysine ordinary tablet as contrast (S), ask its relative bioavailability, formula is:

$F_1={\left({\mathrm{AUC}}_{0-t}\right)}_T/{\left({\mathrm{AUC}}_{0-t}\right)}_S\×100\%$

${\mathrm{<figure-callout\; id="2"\; label="F"\; filenames="DEST\_PATH\_121122153245.png,DEST\_PATH\_RE-RE-121122153227.png"\; state="\{\{state\}\}">F</figure-callout>}}_2=\frac{{\left({\mathrm{AUC}}_{0-t}\right)}_T\&times;\mathrm{SD}}{{\left({\mathrm{AUC}}_{0-t}\right)}_S\&times;\mathrm{TD}}\&times;100\%$

Above-mentioned calculating can (the Chinese Journal of Clinical Pharmacology 1990 carries out on S1:15-16) at the CAPP software kit.Pharmacokinetic parameter with the estimation of CAPP program the results are shown in Table 3.Curve chart is seen Fig. 7 during both medicine

The result: blood drug level---time graph all meets one compartment open model in BDL slow releasing tablet and its common lamellar body, and its main pharmacokinetic parameter is respectively: ordinary tablet T(1/2) 3.12 ± 0.41, and Cmax(mgL ^-1) 207.69 ± 11.19; Tmax(h) 0.5 ± 0; MRT(h) 3.49 ± 0.42; AUC 0-12(mgh ^-1L ^-1) 518.09 ± 69.13; AUC 0-∞ (mgh ^-1L ^-1) 546.76 ± 65.31, slow releasing tablet T(1/2) .4.63 ± 0.46; Cmax(mgL ^-1) 118.81 ± 27.22; Tmax(h) 2.40 ± 0.87; MRT(h) 6.84 ± 0.74; AUC 0-24(mgh ^-1L ^-1) 671.02 ± 80.97; AUC 0-∞ (mgh ^-1L ^-1) 707.81 ± 84.62.

Conclusion: the BDL slow releasing tablet is 113.80% to conventional tablet relative bioavailability for (0--∞) (through dose titration).The slow releasing preparation that conforms to the pharmacopeia requirement should be in the scope of this 80-120% to the relative bioavailability of ordinary preparation.

Embodiment 8:

The beagle dog pharmacokinetics comparative test of bendazac lysine (BDL) sustained-release tablet preparation and bendazac lysine ordinary tablet

Medicine is subjected to test preparation: bendazac lysine slow releasing tablet, 100mg(50mg/ sheet * 2 slice), lot number 070611, content 102.18%, BDL Pharmaceutical limited company in Pinghu, Zhejiang provides; Reference preparation: bendazac lysine ordinary tablet 50mg/ sheet, lot number 0070612, content 97.24%, BDL Pharmaceutical limited company in Pinghu, Zhejiang provides, bendazac lysine chemical reference substance content 90.5%, BDL Pharmaceutical limited company in Pinghu, Zhejiang provides.

2 of the healthy beagle dogs of animal subject, dog 1 female kg, 6.5kg, dog 2 male body weight 7.0kg, each one, the quality certification number is provided by Nanjing Medical University's animal center: in SCXK (Soviet Union) 2008-0004 one week of breeding observing, the front fasting 12h of blood drawing freely drinks water.Through the intestines and stomach administration, dog 1 gives first BDL slow releasing tablet and dog 2 first to the BDL ordinary tablet, and dosage is 100mg(50mg/ sheet * 2 slice) venous blood collection, anticoagulant heparin.Two dogs intersection medication after two weeks.

Blood sampling time sees the following form

Condition determination, methodology (except with the dog plasma) and pharmacokinetic parameter calculate with embodiment 7. blood drug level as a result table 1 be that 2 tested dogs are intersected to the blood drug level result after BDL ordinary tablet and the slow releasing tablet; Curve is that a chamber is touched type during with CAPP program estimation BDL medicine, and the pharmacokinetic parameter of calculating the results are shown in Table 2.

Curve chart is seen Fig. 8 during both medicine

Table 1Beagle dog to BDL slow releasing tablet and ordinary tablet after the blood drug level (ug/ml) of (100mg)

Table 2BDL(100mg) slow releasing tablet and ordinary tablet main pharmacokinetic parameters in beaglequan dog body compares

The result: blood drug level---time graph all meets one compartment open model in BDL slow releasing tablet and its common lamellar body, and its main pharmacokinetic parameter is respectively: ordinary tablet T(1/2) 42.61, and Cmax(mgL ^-1) 231.02; Tmax(h) 1.5; MRT(h) 56.44; AUC 0-190(mgh ^-1L ^-1) 13093.58; AUC 0-∞ (mgh ^-1L ^-1) 13964.26, slow releasing tablet T(1/2) .55.46; Cmax(mgL ^-1) 158.09; Tmax (h) 10.0; MRT (h) 79.64; AUC 0-240 (mgh ^-1L ^-1) 14184.28; AUC 0-∞ (mgh ^-1L ^-1) 14841.67.

Conclusion: the BDL slow releasing tablet is 101.20% for (0--∞) through dose titration to conventional tablet relative bioavailability.The slow releasing preparation that conforms to the pharmacopeia requirement should be in the scope of this 80-120% to the relative bioavailability of ordinary preparation.

Claims (8)

1. bendazac lysine oral slow-releasing preparation for the treatment of diabetic complication, it is characterized in that this slow releasing preparation by

The raw material of following weight proportion is made, with thousand or a restatement:

Bendazac lysine 25～300g

Hydrogel matrix 4～170g

Diluent 20～250g

Binding agent 20～150g

Lubricants/glidants 1～20g

Wetting agent 80～800ml

1000 slices/.

2. bendazac lysine oral slow-releasing preparation according to claim 1 is characterized in that described hydrogel matrix is: hypromellose, carbomer, polyvinyl alcohol or ethyl cellulose.

3. bendazac lysine oral slow-releasing preparation according to claim 1 is characterized in that described diluent is pregelatinized Starch, lactose, microcrystalline Cellulose, mannitol or L-arginine.

4. bendazac lysine oral slow-releasing preparation according to claim 1 is characterized in that described binding agent is starch, microcrystalline Cellulose, polyvidone, methylcellulose or hydroxypropyl methylcellulose.

5. bendazac lysine oral slow-releasing preparation system according to claim 1 is characterized in that described lubricant or fluidizer are silicon dioxide, magnesium stearate, stearic acid or Polyethylene Glycol.

6. bendazac lysine oral slow-releasing preparation according to claim 1 is characterized in that described wetting agent is ethanol or water.

7. bendazac lysine oral slow-releasing preparation according to claim 1 is characterized in that said preparation is tablet or capsule.

8. bendazac lysine oral slow-releasing preparation according to claim 1 is characterized in that described diabetic complication is diabetic nephropathy, diabetic neuropathy and diabetic cataract.

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