CN102885790A - Entecavir dispersing tablet and preparation method thereof - Google Patents
Entecavir dispersing tablet and preparation method thereof Download PDFInfo
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- CN102885790A CN102885790A CN2012103528994A CN201210352899A CN102885790A CN 102885790 A CN102885790 A CN 102885790A CN 2012103528994 A CN2012103528994 A CN 2012103528994A CN 201210352899 A CN201210352899 A CN 201210352899A CN 102885790 A CN102885790 A CN 102885790A
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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 142
- 229960000980 entecavir Drugs 0.000 title claims abstract description 139
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 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 18
- 229920000168 Microcrystalline cellulose Polymers 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
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 18
- 239000008101 lactose Substances 0.000 claims abstract description 17
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
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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 are C
12H
15N
5O
3H
2O, molecular weight are 295.3, and 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 the pharmacopeia disintegrate of dispersible tablet being dispersed with and explicitly calling for, how to make as soon as possible disintegrate of dispersible tablet, stripping, is people's problems of concerns thereby make human body absorb quickly the performance drug effect.For Entecavir formulation, its content in single dose is smaller, only be 0.5mg or 1mg, so low dosage usually so that various preparations especially in the dispersible tablet content of effective ingredient between each single dose, be difficult to keep constant, so the oral solid formulation for low dose requires to check its uniformity of dosage units in the 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 comprises the steps:
(1), takes by weighing raw material 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 per 1000 entecavir dispersible tablets;
(2), take by weighing the PVP K30 of described amount, it is 10% povidone solution that the alcoholic solution with 50% is made into concentration; Take by weighing the Entecavir of described amount, join in the above-mentioned povidone solution, and dissolving is for subsequent use in 50-70 ℃ of water-bath;
(3), take by weighing lactose and the microcrystalline Cellulose of described amount, mix homogeneously; The solution made from 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 the prescription, mix homogeneously, the interline body burden of going forward side by side mensuration;
(6), according to intermediate content tabletting; Make entecavir dispersible tablet, wherein containing anhydrous Entecavir in the entecavir dispersible tablet is 90.0%～110.0% of labelled amount.
Entecavir dispersible tablet, wherein, the composition that contains 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, and wherein containing anhydrous Entecavir in the entecavir dispersible tablet is 90.0%～110.0% of labelled amount.
The described entecavir dispersible tablet of technique scheme, wherein, single impurity must not cross 0.5% in the described entecavir dispersible tablet, 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 more than 80% of labelled amount.
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, adopt the dispersible tablet of method preparation of the present invention to have 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, adopt dispersible tablet and the taking convenience, easy to carry of method preparation of the present invention, both can be used as ordinary tablet and taken, can put into again and take after water disperses rapidly, 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 comprises the steps:
(1), takes by weighing raw material 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;
(2), take by weighing the PVP K30 of described amount, it is 10% povidone solution that the alcoholic solution with 50% is made into concentration; Take by weighing the Entecavir of described amount, join in the above-mentioned povidone solution, and dissolving is for subsequent use in 50-70 ℃ of water-bath;
(3), take by weighing lactose and the microcrystalline Cellulose of described amount, mix homogeneously; The solution made from step (2) prepares soft material (with an amount of 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 the prescription, mix homogeneously, the interline body burden of going forward side by side mensuration;
(6), according to intermediate content tabletting; Make entecavir dispersible tablet, wherein containing anhydrous Entecavir in the entecavir dispersible tablet is 90.0%～110.0% of labelled amount.
Prescription 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 that needs has filler, disintegrating agent, binding agent, lubricant and correctives, all kinds of adjuvants specifically as described in the 5.2.3.2.The conventional amount used of type adjuvant is in each: filler 70-90%, and disintegrating agent 3-10%, binding agent 1-3%, lubricant 0.5-2%, correctives are 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 the 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 the 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 ℃ dries.Because of the content of this product very little, adopt conventional mixed method that raw material is uniformly dispersed in material, mixed method is time-consuming and equivalent is progressively increased, on large production, can't realize again, in order to meet large production requirement, intend to use 50% alcoholic solution to be dissolved in soft material process processed and add, and this product need to add binding agent, dissolve therefore at last this product is added in the binder solution that 50% alcoholic solution configures.
This part will be screened all kinds of alternative adjuvants, 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, do not add raw material first, light screens with blank adjuvant.Considering simultaneously the cost of filler, is the filler that has therefore select microcrystalline Cellulose, 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, with the disintegrating agent mix homogeneously, add suitable amount of adhesive 30 orders and granulate, 60 ℃ of dryings, 30 order granulate add disintegrating agent and an amount of 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, so that tablet surface produces 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 the tablet that contains mannitol not only hardness is also longer not as lactose but also disintegration time, therefore reject, remaining adjuvant is at last: lactose, microcrystalline Cellulose, carboxymethylstach sodium, magnesium stearate, aspartame and orange flavor.
The adjustment of prescription and definite
In the dispersible tablet preparation is affected mainly from filler, disintegrating agent and binding agent, and binding agent not only has consumption but also the selection of adding method is arranged, above 4 influence factors are arranged respectively three levels be optimized, concrete level is as shown in table 2, optimizes orthogonal table as shown in table 3:
Table 2 factor level table
Annotate: add in the what is called, for adding in the part and partly adding.Be the inside and outside added-time such as disintegrating agent, Nei Jia and Extra Section respectively are 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 part in the adding disintegrating agent, and 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, best factor level is that filler is lactose 70g behind the orthogonal optimization, and MCC is 20g, and binder dosage is 15ml, and the disintegrating agent consumption is 7g, and disintegrating agent adding mode is for adding;
Take dispersing uniformity as index, 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 disintegrating agent adding mode is for adding;
Therefore according to these two indexs, determined that tentatively the consumption of each factor and method are: lactose 70g, MCC are 20g, and binder dosage is 15ml, and the disintegrating agent consumption is 7g, and disintegrating agent adding mode is for adding.
Through above quadrature, preliminary definite prescription is as follows:
Preliminary definite technique is:
(1), take by weighing the PVP K30 of recipe quantity, be 10% povidone solution be made into concentration with 50% alcoholic solution; Take by weighing the Entecavir of recipe quantity, join in the above-mentioned povidone solution, and dissolving is for subsequent use in 50-70 ℃ of water-bath;
(2), take by weighing lactose and the microcrystalline Cellulose of recipe quantity, mix homogeneously; Prepare soft material (with an amount of 50% 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 the 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 the lab scale of 5000 sample sizes, and the preliminary prescription of determining and technique being carried out simple authentication repeat, the 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 influence factor's test, influence factor's result of the test such as table 5:
Table 5 influence factor result of the test
Entecavir dispersible tablet was 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, determine that at last formulation and technology is as follows:
Prescription:
Preparation technology:
(1), take by weighing the PVP K30 of recipe quantity, be 10% povidone solution be made into concentration with 50% alcoholic solution; Take by weighing the Entecavir of recipe quantity, join in the above-mentioned povidone solution, and dissolving is for subsequent use in 50-70 ℃ of water-bath;
(2), take by weighing lactose and the microcrystalline Cellulose of recipe quantity, mix homogeneously; Prepare soft material (with an amount of 50% 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 the 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 by concrete test example the beneficial effect that has of entecavir dispersible tablet of preparation method of the present invention and preparation gained is described:
Test example 1:The mensuration of related substance:
(1), chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Take water-acetonitrile-trifluoroacetic acid (990:10:1) as mobile phase A, take water-acetonitrile-trifluoroacetic acid (700:300:1) as Mobile phase B, carry out gradient degree eluting by table 6, the detection wavelength is 254nm.Tailing factor is pressed the calculating of Entecavir peak between 0.8～1.5 in the chromatogram, and number of theoretical plate calculates by the Entecavir peak should be not less than 3000.
Table 6 gradient elution table
(2), algoscopy gets the entecavir dispersible tablet fine powder an amount of (being equivalent to Entecavir 3.5mg) of embodiment 1 preparation gained, and is accurately weighed, put in the 100ml measuring bottle, add the 0.01mol/L hydrochloric acid solution an amount of, jolting made dissolving, and put to room temperature in ultrasonic 30 minutes, be diluted to scale with the 0.01mol/L hydrochloric acid solution, shake up, get solution and left the heart 10 minutes with per minute 3000 in right amount, get supernatant, filter, as need testing solution; Other gets approximately 22mg of Entecavir reference substance, and is accurately weighed, puts in the 50ml measuring bottle, adds methanol 25ml, ultrasonicly make dissolving, add the 0.01mol/L hydrochloric acid solution to scale, shake 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, in contrast product solution.Get contrast solution 20 μ l, the injection liquid chromatography is regulated 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); Each impurity peak area and must not be greater than 2 times (2.0%) of contrast solution main constituent peak area.
(3), three batch samples and commercially available product related substance check
Determination of related substances method according to this step is carried out the related substance inspection to three batch samples and market sale product (abbreviation commercially available product) Bo Luding (Entecavir sheet) that the present invention prepares gained, and measurement result sees Table 7; Bo Luding (Entecavir sheet) executes expensive precious pharmaceutical Co. Ltd by Shanghai and produces 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 all less than 1%, this product is through 4500Lx illumination, 60 ℃ of high temperature, investigate 10 days under the high humidity 90%RH condition, 40 ℃, 75% RH condition was accelerated 6 months and 25 ℃, 60%RH kept 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, in the investigation in later stage, do not increase new catabolite, show constant product quality, but for strict control product quality, we list " related substance " in the quality standard in, and 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 to measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Take water-acetonitrile-trifluoroacetic acid (990:10:1) as mobile phase A, take water-acetonitrile-trifluoroacetic acid (700:300:1) as Mobile phase B, carry out gradient degree eluting by table 1, flow velocity is 1.0ml/min, the detection wavelength is 254nm, 30 ℃ of column temperatures.Tailing factor is pressed the calculating of Entecavir peak between 0.8～1.5 in the chromatogram, and number of theoretical plate calculates by the Entecavir peak should be not less than 3000.
(2), Determination of Content Uniformity method
Get 1 of the entecavir dispersible tablet of embodiment 1 preparation gained, in the impouring 20ml measuring bottle, add approximately 80% diluent 0.01mol/l hydrochloric acid solution, shake well made dissolving, and put to room temperature in ultrasonic 30 minutes, 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, the record chromatogram.
(3), the mensuration of three batch sample uniformity of dosage units
Get three batches of the entecavir dispersible tablets of embodiment 1 preparation 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 the quality standard, limit is 20%, should be up to specification.
Test example 3: dissolution determination:
(1), inspection method:
Get the entecavir dispersible tablet of embodiment 1 preparation gained, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C three therapeutic methods of traditional Chinese medicine), take 0.05mol/L potassium dihydrogen phosphate (regulating pH value as 6.8 with the sodium hydroxide solution of 1mol/L) 200ml as solvent, rotating speed is that per minute 50 turns, operation in the time of 30 minutes, is got solution an amount of in accordance with the law, filter, get subsequent filtrate as need testing solution; It is an amount of that other precision takes by weighing the Entecavir reference substance, adds the 0.05mol/L potassium dihydrogen phosphate and make the solution that approximately contains 2.5 μ g among every 1ml, in contrast product solution.Measuring according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005), is filler with octadecylsilane chemically bonded silica, and take water-acetonitrile (92:8) as mobile phase, flow velocity is 1.0ml/min, detects wavelength 254nm.Precision measures need testing solution and each 20 μ l of reference substance solution respectively, the injection liquid chromatography, and the record chromatogram, by the stripping quantity of external standard method with every dispersible tablet of calculated by peak area, limit is 80% of labelled amount, should be up to specification.
(2), sample dissolution test
Get three batches of the entecavir dispersible tablets of embodiment 1 preparation 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 |
The result shows: 30 minutes stripping quantities of this product are all at more than 80% of labelled amount, are 75% to the General Requirements of dissolution limit in the pharmacopeia, consider the stripping situation of this product, are 80% of labelled amount therefore the dissolution limit of this product ordered.
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 need check " dispersing uniformity ", by the pharmacopeia predetermined operation.
Method: get 2 of the entecavir dispersible tablets of embodiment 1 preparation gained, put in 20 ℃ ± 1 ℃ the water of 100ml, jolting 3 minutes, all disintegrate and sieve by No. two.
The result: three batch samples are all up to specification, see Table 10.
Table 10 dispersing uniformity check result
| Lot number | The 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 the 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; Take water-acetonitrile-trifluoroacetic acid (990:10:1) as mobile phase A, take water-acetonitrile-trifluoroacetic acid (700:300:1) as Mobile phase B, carry out gradient degree eluting by table 11, the detection wavelength is 254nm.Tailing factor is pressed the calculating of Entecavir peak between 0.8～1.5 in the chromatogram, and number of theoretical plate calculates by the Entecavir peak should be not less than 3000.
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 an amount of (being equivalent to Entecavir 3.5mg) of embodiment 1 preparation gained, and is accurately weighed, puts in the 100ml measuring bottle, add the 0.01mol/L hydrochloric acid solution an amount of, jolting made dissolving 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 left the heart 10 minutes with per minute 3000 in right amount, get supernatant, filter, precision measures subsequent filtrate 20 μ l injection liquid chromatographies, the record chromatogram.Other gets approximately 22mg of Entecavir reference substance, and is accurately weighed, puts in the 50ml measuring bottle, add methanol 25ml, ultrasonicly make dissolving, add the 0.01mol/L hydrochloric acid solution to scale, shake 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, measure with method, press external standard method with calculated by peak area, and get final product.
(2), assay result: get the entecavir dispersible tablet of embodiment 1 preparation gained, measure according to the method for assay, the results are shown in Table 12.
The measurement result of table 12 three batch samples
The result: three batch samples are all up to specification.
Studies show that by above-mentioned, 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, the result is all up to specification, and system suitability all can be up to specification, and this content is listed in the 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:Extracorporeal antivirus effect is active:
Press EC
50(reducing the outer virion 50% required drug level of HepG2 2.2.15 cell line cell) calculated, and Entecavir is present the most effective anti-HBV nucleoside analog.And the CC of Entecavir
50(50% cell is produced 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
50Be 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 chemical compounds that comprise Entecavir in wild type and 5 plant mutant HBV, and the result shows that only Entecavir and adefovirdipivoxil (Adefovir) are all effective to all 5 strain HBV mutants.
With the model of HepG2 2.2.15 cell line as hbv replication, the HBV dna content of generation level, HBV dna polymerase activity level and the endocellular liberation of detection HBV DNA etc. are as the observation index of anti-HBV effect.The people such as Price confirm Entecavir to the suppression ratio of HBV greater than 95%, but be transcribed into the then not impact of process of RNA for the HBV DNA that has integrated.Study with radiolabeled Entecavir, find that this medicine can directly carry out phosphorylation modification in 2.2.15 cell line, and penetrate among the HBV DNA, opposite, radiolabeled deoxyguanosine, the metabolism by a kind of " rescue " approach is incorporated among 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 the 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 human 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), well below the EC of adefovirdipivoxil to the HBV wild strain
50Value; To the 1 type HIV (human immunodeficiency virus) (HIV) of in cell culture fluid, growing without clinical related activity (EC
5010 μ M).Entecavir is stronger 30 ~ 60 times than lamivudine to the inhibitory action of hbv replication in the 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 experiment in vitro, 5 μ M were hatched three days jointly with isotope-labeled Entecavir and HepG2 2.2.15 people liver cell, and the concentration of triphosphoric acid Entecavir is 65.8% in the cell, 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 metabolite of Entecavir is the Entecavir of diphosphonic acid and triphosphoric acid form, take the latter as main.The run-up in cell of the Entecavir of triphosphoric acid form reaches 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 efficient 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 easier to be 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 the 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 all is lower than wild strain to the sensitivity of LVD drug resistance variant, the decline degree is different in different cell lines: Entecavir descends the most obvious (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, and is different to the antiviral activity reduction degree of Different Variation Strain.
Test example 7:Zoopery:
1, marmot model:
Method: Entecavir 0.5mgkg
-1Oral, every day 1 time; Animal: America marmot
The result: behind the administration 5wk in the animal serum viral DNA level be reduced to the level that do not measure of inspection.But drug withdrawal 1～8wk behind administration 8wk, bounce-back has appearred in the viral DNA level in the animal serum.
If continue to keep administration, namely behind every day 1 administration 8wk, use same dosage instead and continue weekly administration 1 time, then in 6 animals of keeping administration 34mo, having the serum-virus dna levels of 4 animals can remain on the lowest detectable limit level reaches more than the 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, main antiviral drugs such as the interferon used at present, lamivudine etc., its action target spot all under the cccDNA level, therefore can not reduce cccDNA level in the 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 the animal serum.
Give Entecavir 0.1 or 0.5mgkg
-1, behind the 4wk, endogenous contaminating virus polymerase level is approximately than reducing by 1000 times before the administration in the animal serum.Behind the administration 3mo, the viral DNA in the animal serum is down to the level that 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
The result: the antiviral activity of Entecavir is dose dependent, even 0.01mgkg
-1Lowest dose level, its antiviral activity also is 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 the 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 used dosage range Entecavir has no significant effect the body weight gain of animal.
3, woodchuck:
Method: oral Entecavir (0.05mgkg
-1D
-1) treated 21 months; Animal: woodchuck.
The result: after 4 weeks for the treatment of, serum-virus DNA amount is existing obviously to descend, and the DNA amount has reduced by 8 log10 during to 32 week, 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 the serum after 21 months, this shows that Entecavir can not only suppress copying of virus, and cccDNA is also had 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
The result: Entecavir can significantly reduce the HBV dna content in the Mouse Liver, the HBV DNA in the every microgram cell DNA of female mice is reduced to less than 0.82pg from original 5.9pg, and male mice is from original 8.3pg μ g
-1Be reduced to the g less than 1.1pg μ
-1In the research of 10d, animal is the well tolerable Entecavir of energy all, has no dying or the death condition generation.
The above, it only is preferred embodiment of the present invention, be not that the present invention is done 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 can utilizing the disclosed above technology contents, and a little change of making, modify the equivalent variations with differentiation, be 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, modify 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 comprises the steps:
(1), takes by weighing raw material 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 per 1000 entecavir dispersible tablets;
(2), take by weighing the PVP K30 of described amount, it is 10% povidone solution that the alcoholic solution with 50% is made into concentration; Take by weighing the Entecavir of described amount, join in the above-mentioned povidone solution, and dissolving is for subsequent use in 50-70 ℃ of water-bath;
(3), take by weighing lactose and the microcrystalline Cellulose of described amount, mix homogeneously; The solution made from 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 the prescription, mix homogeneously, the interline body burden of going forward side by side mensuration.
(6), according to intermediate content tabletting; Make entecavir dispersible tablet, wherein containing anhydrous Entecavir in the entecavir dispersible tablet is 90.0%～110.0% of labelled amount.
2. entecavir dispersible tablet, it is characterized in that: the composition that contains 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; Wherein containing anhydrous Entecavir in the entecavir dispersible tablet is 90.0%～110.0% of labelled amount.
3. entecavir dispersible tablet according to claim 2, it is characterized in that: single impurity must not cross 0.5% in the described entecavir dispersible tablet, and total impurities must not cross 2.0%.
4. entecavir dispersible tablet according to claim 2, it is characterized in that: the dissolution of described entecavir dispersible tablet is more than 80% of labelled amount.
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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| US20110217342A1 (en) * | 2000-04-12 | 2011-09-08 | Bristol-Myers Squibb Company | Flashmelt oral dosage formulation |
| CN101244044A (en) * | 2008-03-24 | 2008-08-20 | 杭州盛友医药技术开发有限公司 | Entecavir dispersible tablet and preparation thereof |
| CN102144983A (en) * | 2011-04-06 | 2011-08-10 | 福建广生堂药业有限公司 | Entecavir dispersible tablets and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105287419A (en) * | 2015-12-01 | 2016-02-03 | 李正梅 | Anti-hepatitis B entecavir dispersible tablet |
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| CN102885790B (en) | 2013-12-25 |
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