CN102885790B - Entecavir dispersing tablet and preparation method thereof - Google Patents
Entecavir dispersing tablet and preparation method thereof Download PDFInfo
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- CN102885790B CN102885790B CN 201210352899 CN201210352899A CN102885790B CN 102885790 B CN102885790 B CN 102885790B CN 201210352899 CN201210352899 CN 201210352899 CN 201210352899 A CN201210352899 A CN 201210352899A CN 102885790 B CN102885790 B CN 102885790B
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- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 title claims abstract description 145
- 229960000980 entecavir Drugs 0.000 title claims abstract description 142
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 19
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 19
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 19
- 239000008101 lactose Substances 0.000 claims abstract description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 18
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 15
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses an entecavir dispersing tablet and a preparation method thereof, which belong to the technical field of medicament preparations. Every 100 entecavir dispersing tablets contain 0.5g of entecavir, 70g of lactose, 20g of microcrystalline cellulose, 1.5g of polyvidone K30, 7g of carboxyrnethyl starch sodium, 0.5g of orange flavor, 0.5g of aspartame and 0.5g of magnesium stearate, wherein the anhydrous entecavir in the entecavir dispersing tablet is 90.0-110.0 percent of the labeled amount. The dispersing tablet prepared with the method disclosed by the invention has the advantages of rapid disintegration, high dissolution rate, high dispersion uniformity, high content uniformity and high entecavir content, and further has the advantages of convenience in taking and carrying, capability of serving as an ordinary tablet for taking, rapid dispersion into water for taking, and great improvement on the compliance of clinical administration.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to entecavir dispersible tablet and preparation method thereof.
Background technology
Entecavir, molecular formula is C
12h
15n
5o
3h
2o, molecular weight is 295.3, its structural formula is:
Entecavir is a kind of efficient antiviral agent, clinical research has shown has good inhibitory action to hepatitis B virus, because the activity of Entecavir anti-hepatitis virus is very high, therefore adopt low-down dosage just to be enough to reach the therapeutic effect of expectation, generally be grown up every day oral 0.5mg or the 1mg Entecavir just can reach good therapeutical effect.
The peroral dosage form of Entecavir comprises capsule, dispersible tablet, drop pill etc., and Chinese patent CN1732943A, CN1732944A, CN1732945A disclose respectively the dosage form of its soft capsule, dispersible tablet and drop pill.In pharmacopeia, the disintegrate of dispersible tablet being dispersed with and explicitly calling for, how to make dispersible tablet disintegrate as soon as possible, stripping, is the problem that people pay close attention to thereby make human body absorb quickly the performance drug effect.For Entecavir formulation, its content in single dose is smaller, be only 0.5mg or 1mg, so low dosage usually make various preparations especially in dispersible tablet the content of effective ingredient be difficult to keep constant between each single dose, so require to check its uniformity of dosage units for low dose of oral solid formulation in Chinese Pharmacopoeia.In addition, in when prescription design, also need to investigate selected non-active ingredient whether to factors such as the stability of preparation impact.
Summary of the invention
The object of the invention is to disclose that a kind of disintegrate meets the requirements, dissolution rate is good, content is even, stay-in-grade entecavir dispersible tablet.
Another object of the present invention has been to disclose the preparation method of this entecavir dispersible tablet.
The objective of the invention is to be achieved through the following technical solutions:
The preparation method of entecavir dispersible tablet, comprise the steps:
(1), according to the amount that contains Entecavir 0.5g, lactose 70g, microcrystalline Cellulose 20g, PVP K30 1.5g, carboxymethylstach sodium 7g, orange flavor 0.5g, aspartame 0.5g and magnesium stearate 0.5g in every 1000 entecavir dispersible tablets, take raw material;
(2), take the PVP K30 of described amount, the alcoholic solution with 50% is made into the povidone solution that concentration is 10%; Take the Entecavir of described amount, join in above-mentioned povidone solution, and dissolve standby in 50-70 ℃ of water-bath;
(3), take lactose and the microcrystalline Cellulose of described amount, mix homogeneously; The solution of making by step (2) prepares soft material, with 50% alcoholic solution washing binding agent placing container, granulates;
(4), wet granular is in 60 ± 2 ℃ of oven dry; 30 order granulate;
(5), add remaining adjuvant in prescription, mix homogeneously, the interline body burden of going forward side by side mensuration;
(6), according to intermediate content tabletting; Making entecavir dispersible tablet, is wherein labelled amount 90.0%～110.0% containing anhydrous Entecavir in entecavir dispersible tablet.
Entecavir dispersible tablet, wherein, the composition contained in described 1000 entecavir dispersible tablets is Entecavir 0.5g, lactose 70g, microcrystalline Cellulose 20g, PVP K30 1.5g, carboxymethylstach sodium 7g, orange flavor 0.5g, aspartame 0.5g and magnesium stearate 0.5g, in entecavir dispersible tablet, containing anhydrous Entecavir, is wherein labelled amount 90.0%～110.0%.
The described entecavir dispersible tablet of technique scheme, wherein, in described entecavir dispersible tablet, single impurity must not cross 0.5%, and total impurities must not cross 2.0%.
The described entecavir dispersible tablet of technique scheme, wherein, the dissolution of described entecavir dispersible tablet is labelled amount more than 80%.
The described entecavir dispersible tablet of technique scheme, wherein, the dispersing uniformity of described entecavir dispersible tablet is by No. two sieves after whole disintegrates.
The present invention has following beneficial effect:
1, the dispersible tablet that adopts method of the present invention to prepare has advantages of that disintegrate is fast, dissolution is high, dispersing uniformity is good, uniformity of dosage units is good and Entecavir content is high.
2, the dispersible tablet that adopts method of the present invention to prepare and taking convenience, easy to carry, both can be used as ordinary tablet and taken, and can put into again after water disperses rapidly and take, and greatly improved the compliance of clinical application.
The specific embodiment:
For making technical scheme of the present invention be convenient to understand, below in conjunction with specific embodiment, entecavir dispersible tablet of the present invention and preparation method thereof is further described.
embodiment 1:the preparation of entecavir dispersible tablet:
The preparation method of entecavir dispersible tablet, comprise the steps:
(1), according to the amount that contains Entecavir 0.5g, lactose 70g, microcrystalline Cellulose 20g, PVP K30 1.5g, carboxymethylstach sodium 7g, orange flavor 0.5g, aspartame 0.5g and magnesium stearate 0.5g in 1000 entecavir dispersible tablets, take raw material;
(2), take the PVP K30 of described amount, the alcoholic solution with 50% is made into the povidone solution that concentration is 10%; Take the Entecavir of described amount, join in above-mentioned povidone solution, and dissolve standby in 50-70 ℃ of water-bath;
(3), take lactose and the microcrystalline Cellulose of described amount, mix homogeneously; The solution of making by step (2) prepares soft material (with 50% appropriate alcoholic solution washing binding agent placing container), granulates;
(4), wet granular is in 60 ± 2 ℃ of oven dry; 30 order granulate;
(5), add remaining adjuvant in prescription, mix homogeneously, the interline body burden of going forward side by side mensuration;
(6), according to intermediate content tabletting; Making entecavir dispersible tablet, is wherein labelled amount 90.0%～110.0% containing anhydrous Entecavir in entecavir dispersible tablet.
Formula of the present invention and preparation method are determined by following method:
Determining of formulation and technology:
The present invention's standby entecavir dispersible tablet of drawing up, according to the characteristics of dispersible tablet, the supplementary product kind needed has filler, disintegrating agent, binding agent, lubricant and correctives, all kinds of adjuvants specifically as described in 5.2.3.2.In each, the conventional amount used of type adjuvant is: filler 70-90%, and disintegrating agent 3-10%, binding agent 1-3%, lubricant 0.5-2%, correctives is 0.5-1%.Although Entecavir is insoluble drug, the dissolubility in water is 2.4mg/ml, and the specification of this product is the 0.5mg/ sheet, so need not add solubilizing agent in preparation.
The present invention adopts the wet particle method pelletizing press sheet, and the technique of general wet granular pelletizing press sheet is mixing of materials, soft material processed, wet granular processed, oven dry, granulate, total mixed tabletting.Because dispersible tablet requires the granule after disintegrate to sieve (24 order) by No. 2 to dispersing uniformity, the specification and the sheet that add this product are heavy smaller, and granule too slightly can affect tablet weight variation, thereby affects uniformity of dosage units, therefore, this product intends gathering and processing into the granule between the 30-60 order; This product intends adopting 60 ℃ is dried.Because of the content of this product very little, adopt conventional mixed method can't make raw material be uniformly dispersed in material, and equivalent is progressively increased, mixed method is time-consuming, on large production, can't realize again, in order to meet large production requirement, the alcoholic solution of intending use 50% is dissolved in soft material process processed to add, and this product need to add binding agent, therefore dissolve in the binder solution that finally this product is added 50% alcoholic solution to configure.
This part will be screened all kinds of alternative adjuvants, and because the Entecavir specification is little, the content in sheet is also fewer, and this raw material is more valuable in addition, therefore, to the selection supplementary product kind time, first do not add raw material, light is screened with blank adjuvant.Consider the cost of filler, be total filler therefore select microcrystalline Cellulose simultaneously, and different filleies and disintegrating agent are screened:
The blank adjuvant screening of table 1
Technique: according to the prescription ratio of 5.2.3.3, by the disintegrating agent mix homogeneously, add suitable amount of adhesive 30 orders and granulate, 60 ℃ of dryings, 30 order granulate, add disintegrating agent and appropriate magnesium stearate mix homogeneously, tabletting, outward appearance, hardness, friability and the dispersing uniformity of examination tablet.(wherein MCC content is 20%)
Because PVPP has stronger water absorption, make tablet surface produce pit, therefore the use of PVPP has higher requirement to the ambient humidity of production process, for production is made troubles, therefore reject this adjuvant; And containing the tablet of mannitol not only hardness not as lactose and also disintegration time also longer, therefore reject, finally remaining adjuvant is: lactose, microcrystalline Cellulose, carboxymethylstach sodium, magnesium stearate, aspartame and orange flavor.
The adjustment of prescription and definite
In dispersible tablet, preparation is affected mainly from filler, disintegrating agent and binding agent, and binding agent not only has consumption but also the selection that adds method is arranged, above 4 influence factors are arranged respectively to three levels and be optimized, concrete level is as shown in table 2, optimizes orthogonal table as shown in table 3:
Table 2 factor level table
Annotate: additional in so-called, additional for adding in part with part.As disintegrating agent is the inside and outside added-time, Nei Jia and Extra Section are respectively half of total disintegrate dosage.
Table 3 orthogonal array
Prescription: the consumption of lactose, MCC, binding agent disintegrating agent is as shown in table 3, and remaining adjuvant is aspartame (0.5g), orange flavor (0.5g) and magnesium stearate (0.5), and in all tests, this adjuvant addition of three is identical.
Technique: the filler mix homogeneously, or add in disintegrating agent and add part, mix homogeneously, the PVP solution with 10% is soft material processed in right amount, granulates, 60 ± 2 ℃ of oven dry, 30 order granulate, tabletting.
Checking item: related substance, dispersing uniformity, dissolution and hardness.
Projects result of Orthogonal Optimization Test is as follows:
Table 4 formulation optimization orthogonal experiments
Take dissolution as index, and after orthogonal optimization, best factor level is that filler is lactose 70g, and MCC is 20g, and binder dosage is 15ml, and the disintegrating agent consumption is 7g, and the disintegrating agent mode that adds is additional;
Take dispersing uniformity as index, and best factor level is lactose 70g, and MCC is 20g, and 10% PVP solution usage is 15ml, and the disintegrating agent consumption is 7g, and the disintegrating agent mode that adds is additional;
Therefore according to these two indexs, tentatively determined that the consumption of each factor and method are: lactose 70g, MCC is 20g, and binder dosage is 15ml, and the disintegrating agent consumption is 7g, and the disintegrating agent mode that adds is additional.
Through above quadrature, preliminary definite prescription is as follows:
Preliminary definite technique is:
(1), take the PVP K30 of recipe quantity, be made into the alcoholic solution with 50% povidone solution that concentration is 10%; Take the Entecavir of recipe quantity, join in above-mentioned povidone solution, and dissolve standby in 50-70 ℃ of water-bath;
(2), take lactose and the microcrystalline Cellulose of recipe quantity, mix homogeneously; Prepare soft material (with 50% appropriate alcoholic solution washing binding agent placing container) with the solution of 2. making, granulate;
(3), wet granular is in 60 ± 2 ℃ of oven dry; 30 order granulate;
(4), add remaining adjuvant in prescription, mix homogeneously, the interline body burden of going forward side by side mensuration;
(5), according to intermediate content tabletting;
(6), finished product carries out quality and entirely examines;
(7), qualified products packing.
And this formulation and technology is carried out to the lab scale of 5000 sample sizes, and preliminary definite prescription and technique is carried out to the simple authentication repetition, result is as follows:
Content: 99.07%
Related substance: single maximum contaminant 0.07%, total impurities 0.13%
98.77%, 98.09%, 102.60%, 98.56%, 100.47% 99.12% dissolution:
Uniformity of dosage units: meet the dispersible tablet regulation
Dispersing uniformity: meet the dispersible tablet regulation
Above each index all meets the requirements, and subsequently sample is carried out to influence factor's test, and influence factor's result of the test is as table 5:
Table 5 influence factor result of the test
Entecavir dispersible tablet is placed 10 days under 4500Lx illumination, 60 ℃ and high humidity RH92.5% condition, with 0 day relatively, except high humidity 5 days and 10 days, because of outside tablet moisture absorption character changes, all other indexs all, without obviously changing, illustrate this product steady quality, but need sealed damp-proof.
According to above primary stability examination result, finally determine that formulation and technology is as follows:
Prescription:
Preparation technology:
(1), take the PVP K30 of recipe quantity, be made into the alcoholic solution with 50% povidone solution that concentration is 10%; Take the Entecavir of recipe quantity, join in above-mentioned povidone solution, and dissolve standby in 50-70 ℃ of water-bath;
(2), take lactose and the microcrystalline Cellulose of recipe quantity, mix homogeneously; Prepare soft material (with 50% appropriate alcoholic solution washing binding agent placing container) with the solution of 2. making, granulate;
(3), wet granular is in 60 ± 2 ℃ of oven dry; 30 order granulate;
(4), add remaining adjuvant in prescription, mix homogeneously, the interline body burden of going forward side by side mensuration;
(5), according to intermediate content tabletting;
(6), finished product carries out quality and entirely examines;
(7), qualified products packing.
Below preparation method of the present invention is described and prepares the beneficial effect that the entecavir dispersible tablet of gained has by concrete test example:
test example 1:the mensuration of related substance:
(1), chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Water-acetonitrile-the trifluoroacetic acid (990:10:1) of take is mobile phase A, and the water-acetonitrile-trifluoroacetic acid (700:300:1) of take is Mobile phase B, by table 6, carries out gradient degree eluting, and the detection wavelength is 254nm.In chromatogram, tailing factor is pressed the calculating of Entecavir peak between 0.8～1.5, and number of theoretical plate calculates and should be not less than 3000 by the Entecavir peak.
Table 6 gradient elution table
(2), algoscopy gets the entecavir dispersible tablet fine powder appropriate (being equivalent to Entecavir 3.5mg) that embodiment 1 prepares gained, accurately weighed, put in the 100ml measuring bottle, add the 0.01mol/L hydrochloric acid solution appropriate, jolting, make to dissolve in ultrasonic 30 minutes, puts to room temperature, be diluted to scale with the 0.01mol/L hydrochloric acid solution, shake up, get solution and leave the heart 10 minutes with per minute 3000 in right amount, get supernatant, filter, as need testing solution; Separately get the about 22mg of Entecavir reference substance, accurately weighed, put in the 50ml measuring bottle, add methanol 25ml, ultrasonic making dissolved, and adds the 0.01mol/L hydrochloric acid solution to scale, shakes up, and gets this solution 2.0ml, put in the 25ml measuring bottle, add the 0.01mol/L hydrochloric acid solution and be diluted to scale, in contrast product solution.Get contrast solution 20 μ l, the injection liquid chromatography, regulate detection sensitivity, makes the peak height of main constituent chromatographic peak be about 10% of full scale; Precision measures need testing solution and each 20 μ l of contrast solution, difference injection liquid chromatography, the chromatogram of record.In the need testing solution chromatogram, as aobvious impurity peaks, the single contaminant peak area must not be greater than the 1/2(0.5% of contrast solution main constituent peak area); 2 times (2.0%) each impurity peak area and that must not be greater than contrast solution main constituent peak area.
(3), three batch samples and commercially available product related substance check
Three batch samples and market sale product (abbreviation commercially available product) Bo Luding (Entecavir sheet) that the present invention are prepared to gained according to the determination of related substances method of this step carry out the related substance inspection, and measurement result is in Table 7; Bo Luding (Entecavir sheet) is produced by Shanghai Shi Guibao pharmaceutical Co. Ltd, lot number: LT0607682(specification: 0.5mg).
Table 7 entecavir dispersible tablet related substance checks
| Lot number | The 1st batch | The 2nd batch | The 3rd batch | Bo Luding |
| Maximum single impurity (%) | 0.08 | 0.20 | 0.25 | 0.39 |
| Total impurities (%) | 0.22 | 0.28 | 0.33 | 0.65 |
(4), the conclusion of related substance
Three crowdes of the present invention prepare the Drug-related measurement result and all are less than 1%, this product is through 4500Lx illumination, 60 ℃ of high temperature, investigate 10 days under high humidity 90%RH condition, 40 ℃, 75% RH condition is accelerated 6 months and 25 ℃, 60%RH keeps sample 9 months, related substance and 0 month are relatively all without obviously increasing, illustrate that this product is stable under these conditions, amount of impurities and total amount are without obvious increase, do not increase new catabolite in the investigation in later stage, show constant product quality, but for the strict product quality of controlling, we list " related substance " in quality standard in, limit is: single impurity must not cross 0.5%, total impurities must not cross 2.0%, should be up to specification.
test example 2:determination of Content Uniformity:
(1), chromatographic condition
Adopt the HPLC method to measure uniformity of dosage units, chromatographic condition, compound method, mensuration concentration and sample size are all identical with assay.Specific as follows: as according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005), to measure.
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Water-acetonitrile-the trifluoroacetic acid (990:10:1) of take is mobile phase A, and the water-acetonitrile-trifluoroacetic acid (700:300:1) of take is Mobile phase B, by table 1, carries out gradient degree eluting, and flow velocity is 1.0ml/min, and the detection wavelength is 254nm, 30 ℃ of column temperatures.In chromatogram, tailing factor is pressed the calculating of Entecavir peak between 0.8～1.5, and number of theoretical plate calculates and should be not less than 3000 by the Entecavir peak.
(2), Determination of Content Uniformity method
Get 1 of the entecavir dispersible tablet that embodiment 1 prepares gained, in impouring 20ml measuring bottle, add approximately 80% diluent 0.01mol/l hydrochloric acid solution, shake well, make to dissolve in ultrasonic 30 minutes, puts to room temperature, be diluted to scale with diluent, shake up, get solution under 3000 rev/mins of conditions centrifugal 10 minutes, get supernatant, filter, get subsequent filtrate as need testing solution, measure according to the chromatographic condition under the assay item, precision measures 20 μ l injection liquid chromatographies, records chromatogram.
(3), the mensuration of three batch sample uniformity of dosage units
Get three batches of the entecavir dispersible tablets that embodiment 1 prepares gained, measure uniformity of dosage units in accordance with the law, the results are shown in Table 8.
Table 8 entecavir dispersible tablet uniformity test result
Conclusion: above test data shows, the uniformity of dosage units of HPLC method mensuration this product, and method is feasible.Because this product specification is 0.5mg, consider that dosage is too little, therefore, according to Chinese Pharmacopoeia version requirement in 2005, the Content uniformity test of this product is listed in quality standard, limit is 20%, should be up to specification.
Test example 3: dissolution determination:
(1), inspection method:
Get the entecavir dispersible tablet that embodiment 1 prepares gained, according to dissolution method (two appendix X C three therapeutic methods of traditional Chinese medicine of Chinese Pharmacopoeia version in 2005), 0.05mol/L potassium dihydrogen phosphate (regulating pH value with the sodium hydroxide solution of 1mol/L the is 6.8) 200ml of take is solvent, rotating speed is per minute 50 to turn, operation, in the time of 30 minutes, get solution appropriate in accordance with the law, filter, get subsequent filtrate as need testing solution; It is appropriate that another precision takes the Entecavir reference substance, adds the 0.05mol/L potassium dihydrogen phosphate and make the solution that approximately contains 2.5 μ g in every 1ml, product solution in contrast.According to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005), measuring, is filler with octadecylsilane chemically bonded silica, and the water-acetonitrile (92:8) of take is mobile phase, and flow velocity is 1.0ml/min, detects wavelength 254nm.Precision measures each 20 μ l of need testing solution and reference substance solution respectively, and the injection liquid chromatography, record chromatogram, the stripping quantity by external standard method with every dispersible tablet of calculated by peak area, and limit is labelled amount 80%, should be up to specification.
(2), sample dissolution test
Get three batches of the entecavir dispersible tablets that embodiment 1 prepares gained, measure according to above-mentioned dissolution method, the results are shown in Table 9.
Table 9 entecavir dispersible tablet three batch sample stripping results
| Lot number | The 1st batch | The 2nd batch | The 3rd batch | Bo Luding |
| Stripping quantity (%) | 100.77 | 101.69 | 100.76 | 92.9 |
Result shows: 30 minutes stripping quantities of this product, all at more than 80% of labelled amount, are 75% to the General Requirements of dissolution limit in pharmacopeia, consider the stripping situation of this product, therefore the dissolution limit of this product is ordered as 80% of labelled amount.
test example 4:dispersing uniformity
This product is dispersible tablet, and according to the general rule regulation under " tablet " item in two appendix of Chinese Pharmacopoeia version in 2005, dispersible tablet needs to check " dispersing uniformity ", by the pharmacopeia predetermined operation.
Method: get 2 of the entecavir dispersible tablets that embodiment 1 prepares gained, put in the water of 100ml of 20 ℃ ± 1 ℃, jolting 3 minutes, all disintegrate by No. two sieves.
Result: three batch samples are all up to specification, in Table 10.
Table 10 dispersing uniformity check result
| Lot number | Result |
| The 1st batch | All sieve is also crossed in disintegrate No. two |
| The 2nd batch | All sieve is also crossed in disintegrate No. two |
| The 3rd batch | All sieve is also crossed in disintegrate No. two |
test example 5:entecavir assay in entecavir dispersible tablet:
(1), method: measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability test octadecylsilane chemically bonded silica are filler; Water-acetonitrile-the trifluoroacetic acid (990:10:1) of take is mobile phase A, and the water-acetonitrile-trifluoroacetic acid (700:300:1) of take is Mobile phase B, by table 11, carries out gradient degree eluting, and the detection wavelength is 254nm.In chromatogram, tailing factor is pressed the calculating of Entecavir peak between 0.8～1.5, and number of theoretical plate calculates and should be not less than 3000 by the Entecavir peak.
Table 11 gradient elution table
Time (min) mobile phase composition
| A（%） | B（%） | |
| 0～3.5 | 100 | 0 |
| 3.5～21 | 100～69 | 0～31 |
| 21～24 | 69～51 | 31～49 |
| 24～27 | 51～0 | 49～100 |
| 27～28 | 0～100 | 100～0 |
| 28～35 | 100 | 0 |
Algoscopy is got the entecavir dispersible tablet fine powder appropriate (being equivalent to Entecavir 3.5mg) that embodiment 1 prepares gained, accurately weighed, puts in the 100ml measuring bottle, add the 0.01mol/L hydrochloric acid solution appropriate, jolting, make to dissolve in ultrasonic 30 minutes, put to room temperature, be diluted to scale with the 0.01mol/L hydrochloric acid solution, shake up, get solution and leave the heart 10 minutes with per minute 3000 in right amount, get supernatant, filter, precision measures subsequent filtrate 20 μ l injection liquid chromatographies, records chromatogram.Separately get the about 22mg of Entecavir reference substance, accurately weighed, put in the 50ml measuring bottle, add methanol 25ml, ultrasonic making dissolved, and adds the 0.01mol/L hydrochloric acid solution to scale, shakes up, get this solution 2.0ml, put in the 25ml measuring bottle, add the 0.01mol/L hydrochloric acid solution and be diluted to scale, be measured in the same method, by external standard method, with calculated by peak area, obtain.
(2), assay result: get the entecavir dispersible tablet that embodiment 1 prepares gained, measure according to the method for assay, the results are shown in Table 12.
The measurement result of table 12 three batch samples
Result: three batch samples are all up to specification.
Show by above-mentioned research, but, with the Entecavir content of the high-efficient liquid phase technique Accurate Determining this product under this chromatographic condition, survey 3 batch sample content, result is all up to specification, and system suitability all can be up to specification, and this content is listed in quality standard.
Below illustrate that by pharmacodynamic experiment the inventive method prepares the therapeutic effect that the entecavir dispersible tablet of gained has:
test example 6:the extracorporeal antivirus effect activity:
Press EC
50(reducing the outer required drug level of virion 50% of HepG2 2.2.15 cell line cell) calculated, and Entecavir is the most effective anti-HBV nucleoside analog at present.And the CC of Entecavir
50(50% cell is produced to toxic action concentration) is EC
508000 times (30 μ mol/L are to 0.004 μ moL/L).In the primary duck hepatocyte model, the EC of Entecavir
50for 0.13nmol/L.
Under antiviral drugs and immunity of organisms effect, hepatitis B virus is usually undergone mutation, thereby causes hepatitis B virus drug resistance to occur.After using Lamivudine treatment of chronic hepatitis B 3a, patient's 67%-75% HBV polymerase B functional areas L528M, C functional areas M552I or M552VB produce sudden change.In order to estimate the impact of these sudden change enantiopathy cytotoxic drug sensitivity, ONO etc. are studied 11 compounds that comprise Entecavir in wild type and 5 plant mutant HBV, and result shows that only Entecavir and adefovirdipivoxil (Adefovir) are all effective to all 5 strain HBV mutants.
Using HepG2 2.2.15 cell line as the model of hbv replication, detect the HBV DNA content etc. of generation level, HBV DNA polymerase activity level and the endocellular liberation of HBV DNA, as the observation index of anti-HBV effect.The people such as Price confirm that Entecavir is greater than 95% to the suppression ratio of HBV, but are transcribed into the not impact of process of RNA for the HBV DNA integrated.With radiolabeled Entecavir, studied, find that this medicine can directly carry out phosphorylation modification in 2.2.15 cell line, and penetrate in HBV DNA, contrary, radiolabeled deoxyguanosine, the metabolism by a kind of " rescue " approach is incorporated in the DNA of cell.This nucleoside analog has more than 90% can be incorporated into the DNA site, and the terminator that is not a kind of DNA is described.Km and the Ki value of analyzing dGTP and carbocyclic ring 2 '-deoxyguanosine 5 '-triphosphate show, the latter just has significant inhibitory action to the HBV archaeal dna polymerase under low-level condition in cell
[2].
Entecavir is to the selective inhibitory action of HBV DNA polymerase, and Ki is 0.0012 μ M.In transfection in the mankind HepG2 cell of wild type HBV, Entecavir suppresses the synthetic desired concn (EC of 50% viral DNA
50) be 0.004 μ M; EC to lamivudine resistance Strain (rtL 180M, rtM204V)
50median is 0.026 μ M (0.01 ~ 0.059 μ M), the EC well below adefovirdipivoxil to the HBV wild strain
50value; To the 1 type HIV (human immunodeficiency virus) (HIV) of growing in cell culture fluid without clinical related activity (EC
5010 μ M).Entecavir is stronger 30 ~ 60 times than lamivudine to the inhibitory action of hbv replication in cell culture.Every day or use weekly Entecavir can make the hepatitis virus DNA level of woodchuck and duck reduce by 4 ~ 8 log10.
In the experiment, 5 μ M are hatched three days jointly with isotope-labeled Entecavir and HepG2 2.2.15 people liver cell in vitro, and in cell, the concentration of triphosphoric acid Entecavir is 65.8%, and recording triphosphoric acid lamivudine concentration under the same terms is 11.6%.Entecavir suppresses the medium effective concentration (EC of the interior HBV DNA replication dna of HepG2 2.2.15 cell of transfection
50) be 3.75nM, and lamivudine is 116nM, lower more than 30 times than the former.
Cellular metabolism
The enzyme system of cell is responsible for picked-up and the metabolism of Entecavir.After entering cell, the Entecavir that the metabolite of Entecavir is diphosphonic acid and triphosphoric acid form, take the latter as main.The run-up in cell of the Entecavir of triphosphoric acid form, reach EC
502000 times, it is 15h in the intracellular half-life.Although the enzyme system of Entecavir phosphorylation be it be unclear that, the phosphorylation efficiency of Entecavir is high than other nucleoside analogs.
Antiviral mechanism
Experiment in vitro proves, the mainly guiding by suppressing varial polymerases of the Entecavir of triphosphoric acid form, genome is synthetic to reverse transcription and the DNA normal chain of minus strand in the past.The more natural dGTP of the Entecavir of triphosphoric acid form is more easily identified and mixes nucleotide chain by the HBV polymerase, makes the synthetic termination of nucleotide chain.It is many in continuous two deoxyguanylic acids or a plurality of discontinuous deoxyguanylic acids downstream that the nucleotide chain that Entecavir causes is ended position.These are different from LVD and adefovirdipivoxil, and both can cause nucleotide chain to be ended at once afterwards.The Entecavir of triphosphoric acid form can suppress copying of the strain of anti-LVD, but requires Entecavir concentration higher (approximately 30 times).This concentration is easy to reach in the patient body.
Crossing drug resistant with LVD
With can stably express HBV wild strain and LVD drug resistance variant (comprise four kinds of variation mode: L180M+M204V, V173L+IJl80M+M204V, five kinds of cell lines of M2041 and L180M+M204U are carried out experiment in vitro and are shown, Entecavir to the sensitivity of LVD drug resistance variant all lower than wild strain, the decline degree is different in different cell line: Entecavir descends the most obviously (471 times) to the sensitivity of M2041 variant viral strain, to the sensitivity decline degree of other variant viral strains between 37 to 164 times.Therefore, Entecavir reduces the antiviral activity of LVD drug resistance variant, to the antiviral activity reduction degree difference of Different Variation Strain.
test example 7:zoopery:
1, marmot model:
Method: Entecavir 0.5mgkg
-1oral, every day 1 time; Animal: America marmot
Result: after administration 5wk in animal serum the viral DNA level be reduced to the level that do not measure of inspection.But drug withdrawal 1～8wk after administration 8wk, in animal serum, bounce-back has appearred in the viral DNA level.
If continue to maintain administration, after every day 1 administration 8wk, use same dosage instead and continue administration weekly 1 time, in 6 animals that maintain administration 34mo, there is the serum-virus DNA levels of 4 animals can remain on more than the lowest detectable limit level reaches 2a, and the virus antigen in all animal liver (surface and cAg) and cccDNA all significantly reduce, and the existence of cccDNA is the main cause of hepatocyte persistent infection (chronic hepatitis) and recurrent HBV, the main antiviral drugs of application is as interferon at present, lamivudine etc., its action target spot is all under the cccDNA level, therefore can not reduce cccDNA level in body.
Give the animal Entecavir 0.02～0.5mgkg
-1, 1～3mo can effectively reduce viral DNA level and endogenous hepatitis B virus polymerase activity in animal serum.
Give Entecavir 0.1 or 0.5mgkg
-1, after 4wk, in animal serum, endogenous contaminating virus polymerase level is approximately than before administration, reducing by 1000 times.After administration 3mo, the viral DNA in animal serum is down to the level can't detect.
2, duck model:
Method: gavage gives Entecavir 0.01,0.1 or 1mgkg
-1, every day 1 time, successive administration 21d.Animal: Beijing duck
Result: the antiviral activity of Entecavir is dose dependent, even 0.01mgkg
-1lowest dose level, its antiviral activity is also higher than 25mgkg
-1the positive control drug lamivudine.
Entecavir group 0.01,0.1 and 1mgkg
-1and lamivudine group 25mgkg
-1the serum-virus DNA level is the average lg 3.1 that reduces respectively, and lg 2.1, lg 0.97 and lg 0.66.Aspect DHBV DNA level in reducing duck liver, Entecavir is also more effective than lamivudine.Compare Entecavir group 1mgkg with negative control group
-1in virus covalently closed circular viral DNA (cccDNA) level reduce.
Weight gain value and clinical symptoms by animal during the monitoring administration are found, all administration treated animals are the well tolerable Entecavir of energy all, weight gain value between administration group and matched group is without significant difference, shows that in dosage range used Entecavir has no significant effect the body weight gain of animal.
3, woodchuck:
Method: oral Entecavir (0.05mgkg
-1d
-1) treat 21 months; Animal: woodchuck.
Result: after treatment 4 weeks, serum-virus DNA amount is existing obviously to descend, and during to 32 weeks, the DNA amount has reduced by 8 log10, even than low dosage (0.02mgkg
-1d
-1), positive effect is also arranged.After treatment 14 months, get liver puncture Samples detection cAg and cccDNA all negative.Drug withdrawal does not still measure viral DNA in serum after 21 months, this shows that Entecavir can not only suppress copying of virus, and cccDNA is also had to direct impact.PRELIMINARY RESULTS shows, Entecavir also can reduce or postpone the generation of woodchuck hepatocellular carcinoma.
4, transgenic mice
Method: gavage gives animal 3.2mgkg
-1the Entecavir of dosage or sterile saline, every day 1 time, successive administration 10d.Animal: the transgenic mice of hepatitis B virus
Result: Entecavir can significantly reduce the HBV DNA content in Mouse Liver, make the HBV DNA in the every microgram cell DNA of female mice be reduced to and be less than 0.82pg from original 5.9pg, and male mice is from original 8.3pg μ g
-1be reduced to and be less than 1.1pg μ g
-1.In the research of 10d, animal is the well tolerable Entecavir of energy all, has no dying or death condition generation.
The above, it is only preferred embodiment of the present invention, not the present invention is done to any formal and substantial restriction, all those skilled in the art, within not breaking away from the technical solution of the present invention scope, when utilizing the disclosed above technology contents, and the equivalent variations of a little change of making, modification and differentiation is equivalent embodiment of the present invention; Simultaneously, the change of any equivalent variations that all foundations essence technology of the present invention is done above embodiment, modification and differentiation, all still belong in the scope of technical scheme of the present invention.
Claims (5)
1. the preparation method of entecavir dispersible tablet, comprise the steps:
(1), according to the amount that contains Entecavir 0.5g, lactose 70g, microcrystalline Cellulose 20g, PVP K30 1.5g, carboxymethylstach sodium 7g, orange flavor 0.5g, aspartame 0.5g and magnesium stearate 0.5g in every 1000 entecavir dispersible tablets, take raw material;
(2), take the PVP K30 of described amount, the alcoholic solution with 50% is made into the povidone solution that concentration is 10%; Take the Entecavir of described amount, join in above-mentioned povidone solution, and dissolve standby in 50-70 ℃ of water-bath;
(3), take lactose and the microcrystalline Cellulose of described amount, mix homogeneously; The solution of making by step (2) prepares soft material, with 50% alcoholic solution washing binding agent placing container, granulates;
(4), wet granular is in 60 ± 2 ℃ of oven dry; 30 order granulate;
(5), add remaining adjuvant in prescription, mix homogeneously, the interline body burden of going forward side by side mensuration;
(6), according to intermediate content tabletting; Making entecavir dispersible tablet, is wherein labelled amount 90.0%～110.0% containing anhydrous Entecavir in entecavir dispersible tablet.
2. entecavir dispersible tablet, is characterized in that, described entecavir dispersible tablet is to prepare gained by following step:
(1), according to the amount that contains Entecavir 0.5g, lactose 70g, microcrystalline Cellulose 20g, PVP K30 1.5g, carboxymethylstach sodium 7g, orange flavor 0.5g, aspartame 0.5g and magnesium stearate 0.5g in every 1000 entecavir dispersible tablets, take raw material;
(2), take the PVP K30 of described amount, the alcoholic solution with 50% is made into the povidone solution that concentration is 10%; Take the Entecavir of described amount, join in above-mentioned povidone solution, and dissolve standby in 50-70 ℃ of water-bath;
(3), take lactose and the microcrystalline Cellulose of described amount, mix homogeneously; The solution of making by step (2) prepares soft material, with 50% alcoholic solution washing binding agent placing container, granulates;
(4), wet granular is in 60 ± 2 ℃ of oven dry; 30 order granulate;
(5), add remaining adjuvant in prescription, mix homogeneously, the interline body burden of going forward side by side mensuration;
(6), according to intermediate content tabletting; Making entecavir dispersible tablet, is wherein labelled amount 90.0%～110.0% containing anhydrous Entecavir in entecavir dispersible tablet.
3. entecavir dispersible tablet according to claim 2, it is characterized in that: in described entecavir dispersible tablet, single impurity must not cross 0.5%, and total impurities must not cross 2.0%.
4. entecavir dispersible tablet according to claim 2 is characterized in that: the dissolution of described entecavir dispersible tablet is labelled amount more than 80%.
5. entecavir dispersible tablet according to claim 2 is characterized in that: the dispersing uniformity of described entecavir dispersible tablet is by No. two sieves after whole disintegrates.
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