阅读说明：本技术 一种含恩替卡韦的药物组合物及其制备方法 (Pharmaceutical composition containing entecavir and preparation method thereof ) 是由 魏建民 赵智勇 张国恩 于 2020-11-30 设计创作，主要内容包括：本发明涉及一种口服的恩替卡韦药物组合物,包含恩替卡韦0.4-0.6、填充剂180-200、粘合剂4-6、崩解剂7-9、润滑剂0.5-3,通过筛选合适的填充剂以及粘合剂,制备所得的组合物具有较好的溶出效果。(The invention relates to an oral entecavir pharmaceutical composition, which comprises 0.4-0.6 of entecavir, 180-200 of a filling agent, 4-6 of a binding agent, 7-9 of a disintegrating agent and 0.5-3 of a lubricating agent, wherein the composition prepared by screening the appropriate filling agent and the binding agent has a good dissolution effect.)

1. An entecavir pharmaceutical composition comprises the following components in parts by weight: 0.4-0.6 part of entecavir, 180 parts of filler, 4-6 parts of adhesive, 7-9 parts of disintegrant and 0.5-3 parts of lubricant.

2. The pharmaceutical composition of claim 1, wherein the binder is selected from one or more of povidone, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hypromellose, hydroxyethyl cellulose, starch slurry, dextrin, sugar powder, syrup, mucilage, sodium carboxymethyl cellulose, sodium alginate, polyethylene glycol, and magnesium aluminum silicate.

3. The pharmaceutical composition of claim 1, wherein the binder is preferably povidone.

4. The pharmaceutical composition of claim 1, 2 or 3, wherein the filler is one or more of microcrystalline cellulose, calcium phosphate, dextrin, glucose, dextrates, mannitol, sorbitol and sucrose.

5. A pharmaceutical composition according to claim 4, wherein the filler is preferably a combination of microcrystalline cellulose and lactose in a weight ratio of 1: 1.5-3.

6. The pharmaceutical composition according to claim 1, wherein the disintegrant is selected from one or more of sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose, and croscarmellose sodium.

7. The pharmaceutical composition of claim 1, wherein the lubricant is selected from one or more of aerosil, talc, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.

8. The pharmaceutical composition of claim 8, wherein the lubricant is selected from magnesium stearate.

9. An entecavir pharmaceutical composition comprises 0.4-0.6 of entecavir, 50-70 of microcrystalline cellulose, 100 of lactose, 150 of povidone, 4-6 of crospovidone, 7-9 of magnesium stearate and 0.5-3 of magnesium stearate.

10. An entecavir pharmaceutical composition is prepared from the following components: .

Composition (I) mg/tablet Entecavir 0.5 Lactose 120.5 Microcrystalline cellulose 65 Cross-linked polyvidone 8 Povidone 5 Magnesium stearate 1 50% ethanol solution 95 Film coating premix 6 Purified water 44

。

11. A process for preparing a composition according to claim 10, which process comprises:

preparing an adhesive: taking povidone with the prescription amount, adding a proper amount of 50% ethanol solution: medicinal alcohol and purified water 10: 9 (V: V)

Swelling completely, and preparing into adhesive solution with required concentration;

② premixing

Dissolving entecavir

Fourthly, granulating

Dry

Preparing granules

Seventhly total mixing

And eighthly, tabletting.

Technical Field

The invention relates to the field of medicaments, in particular to a medicinal composition of entecavir and a preparation method thereof.

Background

Entecavir (Entecavir) is an oral antiviral drug originally developed by behcet schrobo corporation under the chemical name [1S- (1 α, 3 α, 4 β) ] -2-amino-1, 9-dihydro-9- [ 4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentyl ] -6H-purin-6-one, sparingly soluble in water and having a solubility of 2.4 mg/mL.

The entecavir can be prepared into capsule, tablet, dripping pill, etc. Therefore, the entecavir pharmaceutical composition which has uniform content, extremely small batch difference and stable quality and is suitable for industrial production has great significance. Wherein the batch difference not only comprises the difference between different batches, but also comprises the difference between single doses in the same batch.

Disclosure of Invention

The invention aims to provide an entecavir oral pharmaceutical composition with high content uniformity, extremely small batch difference and stable quality.

The invention provides an entecavir pharmaceutical composition, which comprises 0.4-0.6 part of entecavir, 180-200 parts of filling agent, 4-6 parts of adhesive, 7-9 parts of disintegrating agent and 0.5-3 parts of lubricating agent. Wherein the binder is selected from one or more of polyvidone, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hypromellose, hydroxyethyl cellulose, starch slurry, dextrin, sugar powder, syrup, mucilage, sodium carboxymethylcellulose, sodium alginate, polyethylene glycol or magnesium aluminum silicate. The binder is preferably povidone.

The filler in the invention is one or more of microcrystalline cellulose, calcium phosphate, dextrin, glucose, dextrates, mannitol, sorbitol and sucrose. Preferably microcrystalline cellulose in combination with lactose.

The disintegrant in the composition is selected from one or more of sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose and croscarmellose sodium. Wherein the lubricant is selected from one or more of superfine silica powder, pulvis Talci, sodium dodecyl sulfate, colloidal silicon dioxide, and magnesium stearate. Wherein the lubricant is preferably magnesium stearate.

The invention is preferably an oral entecavir pharmaceutical composition, which comprises 0.4-0.6 of entecavir, 50-70 of microcrystalline cellulose, 100-150 of lactose, 4-6 of polyvidone 7-9 and 0.5-3 of magnesium stearate.

Examples

1. Filler (diluent) proportion screening optimization process

Lactose, microcrystalline cellulose, mannitol and the like are commonly used fillers in the field, wherein the lactose and the microcrystalline cellulose are widely used as fillers of tablets and capsules, and the proportion of the fillers can influence the density, compressibility, flowability and dissolution rate of the preparation.

Composition (I)	(example 1) mg/tablet	2	3
				Entecavir	0.5	0.5	0.5
Lactose	120.5	140	92.75
				Microcrystalline cellulose	65	45	92.75
Cross-linked polyvidone	8	8	8
				Povidone	4.48	4.48	4.48
50% ethanol solution	85	85	85
				Magnesium stearate	1	1	1
Film coating premix	6	6	6
				Purified water	44	44	44
Batch (sheet)	500 pieces	500 pieces	500 pieces

Composition (I)	(example 1) mg/tablet	2	3	4
					Lactose	120.5	140	92.75	92
Microcrystalline cellulose	65	45	92.75	120
					Bulk density	0.37	0.38	0.41	0.41
Tap density	0.44	0.46	0.52	0.56
					Karl index	15.91	17.39	19.15	23
Angle of repose	38.67	37.9	39.08	39.82
					Hardness of	8-14	8-14	8-14	8-14
Dissolution rate of-5 min	98.08	99.13	96.3	84.13
					Dissolution rate-10 min	98.7	99.62	101.87	92.25

And (4) conclusion: the ratio of lactose to microcrystalline cellulose in the filler is 3: 1-1: 1, the Carr index is less than 21%, the compressibility is good, the preparation can be dissolved out rapidly in the range, and the dissolution rate in 5min is more than 85%; finally, the dosage of the lactose is selected to be closer to the dosage of the analytic lactose of the commercial product according to the proportion of the filler, namely the ratio of the lactose to the microcrystalline cellulose is approximately equal to 2: 1.

2. Binder (hydroxypropyl cellulose, povidone) screening optimization

The adhesive is a viscous solid powder or a viscous solution which is formed by aggregating powder materials without viscosity or insufficient viscosity into granules or by compression molding. Binders are dissolved or dispersed in the granulating solution, some binders being dry powders. With the volatilization of the granulating solution, the binding agent makes various properties of the granules (such as the particle size and the distribution, the form, the content uniformity and the like) meet the requirements.

Hydroxypropyl cellulose and povidone are widely used as binders of tablets, and the binders are screened and optimized.

And (4) conclusion: the adhesive is prepared by adopting 2% of HPC 50% ethanol solution and 5% of PVP 50% ethanol solution for wet granulation, the bulk density, the tap density, the tablet hardness, the dissolution rate and the like are not obviously influenced, but the prepared 2% of HPC 50% ethanol solution has slow swelling speed and is not completely swelled after more than 1 hour, the complete swelling time of 5% of PVP 50% ethanol solution only needs 5-10min, and 5% of PVP 50% ethanol is preferably selected as the adhesive.

The most preferable formula of the application is determined by the formula screening: comprises

Composition (I)	mg/tablet
		Entecavir	0.5
Lactose	120.5
		Microcrystalline cellulose	65
Cross-linked polyvidone	8
		Povidone	5
Magnesium stearate	1
		50% ethanol solution	95
Film coating premix	6
		Purified water	44

The preparation method comprises the following steps:

preparing an adhesive: taking povidone with the prescription amount, adding a proper amount of 50% ethanol solution (medicinal alcohol: purified water is 10: 9 (V: V)) to completely swell, and preparing into adhesive solution with the required concentration.

② premixing

Weighing lactose, microcrystalline cellulose and crospovidone according to the proportion of the prescription, putting the lactose, the microcrystalline cellulose and the crospovidone into a wet mixing granulator, setting mixing parameters, and uniformly mixing.

The entecavir tablets are premixed as auxiliary materials, the influence on the mixing uniformity of main drugs is low, and the common premixing parameters of the equipment are adopted according to experience: the stirring speed is 8r/s, the chopping speed is 15r/s, and the premixing time is 2-5 min.

Dissolving entecavir

Taking entecavir with the prescription amount, adding the entecavir into a proper amount of adhesive solution, and heating in a water bath at 60 ℃ to completely dissolve the entecavir.

Fourthly, granulating

The entecavir tablets are prepared by a wet granulation process, the granulation process at the screening stage of the small prescription adopts empirical parameters, namely setting the stirring speed to be 8r/s and the chopping speed to be 15r/s, slowly adding the adhesive containing the entecavir into the premixed powder while the adhesive is hot, and adding the slurry for the following time: continuously adding a proper amount of adhesive (at room temperature) for 50-240 s, wherein the adding time is as follows: and (3) 30-120 s, setting the stirring rotation speed to be 8r/s, the chopping rotation speed to be 30r/s, granulating for 2min, and carrying out wet granulation by using a 18-mesh screen of a swing type granulator.

Dry

Preparing granules

Seventhly total mixing

And eighthly, tabletting.

The above-listed detailed description is only a specific description of a possible embodiment of the present invention, and they are not intended to limit the scope of the present invention, and equivalent embodiments or modifications made without departing from the technical spirit of the present invention should be included in the scope of the present invention. Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.