CN105496979A

CN105496979A - Rasagiline tablet

Info

Publication number: CN105496979A
Application number: CN201610037015.4A
Authority: CN
Inventors: 张壹; 沈浩; 王茂; 游洪涛; 刘小英; 王道权; 魏洪刚; 吴科
Original assignee: CHONGQING HUASEN PHARMACEUTICAL Co Ltd
Current assignee: CHONGQING HUASEN PHARMACEUTICAL Co Ltd
Priority date: 2015-12-08
Filing date: 2016-01-20
Publication date: 2016-04-20
Anticipated expiration: 2036-01-20
Also published as: CN105496979B

Abstract

The invention discloses a rasagiline tablet. The rasagiline tablet comprises 1-3% of rasagiline mesylate, 1.5-3% of hydroxypropyl methylcellulose, 0.3-3% of EDTA (ethylenediaminetetraacetic acid)-2Na and 50-75% of microcrystalline cellulose by weight. The tablet is prepared by adopting wet granulation and is obtained by dissolving the main drug and EDTA-2Na in part of a hydroxypropyl methylcellulose solution, stirring and mixing suspension formed by the solution and part of microcrystalline cellulose, then mixing the suspension with the remaining microcrystalline cellulose and the residual hydroxypropyl methylcellulose solution to carry out wet granulation and carrying out tabletting. The rasagiline tablet has the advantages of simple prescription, easiness in operation of each process, low production cost and suitability for large-scale industrial production. The obtained product has good long-term stability.

Description

A kind of rasagiline tablet

Technical field

The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of rasagiline tablet.

Background technology

Parkinson disease (PD), also known as Parkinsonism, are the Alzheimer second largest neurodegenerative diseases after being ill that continues.Parkinsonian morbidity mainly due to dopaminergic neuron Progressive symmetric erythrokeratodermia degeneration in brain nigro-striatal system, caused by the exhaustion causing neurotransmitter dopamine in striatal main movement region.Its two large characteristic pathological marks---the existence of Lewy corpusculum in the dead and remaining neuron of substantia nigra of midbrain compact part a large amount of dopaminergic neuron selectivity, the root place of clinical symptoms, its important physiological foundation be due to dopamine reduce relative with acetylcholine increase between the central neurotransmitter that causes unbalance.The Parkinsonian cause of disease may relate to age ageing, genetic and environmental factor etc.

The Parkinsonian medicine of current treatment has levodopa, DA receptor stimulating agent, MAO-B inhibitor, COMT inhibitor.Since the sixties in 20th century, levodopa is the Parkinsonian main force for the treatment of all the time, although the superiority that levodopa has it not replace, is only carry out supplementary DA content as the precursor of DA, easily occurs serious complication.Relative to levodopa, rasagiline has better safety, can improve motion and cognitive function, can separately for the treatment of Early Parkinson's disease patient.

The chemical name of rasagiline: (1R)-2,3-dihydro-N-2-propinyl-1H-indenes-1-amine, effectively can treat Early Parkinson's disease separately, better tolerance, length of holding time, can slow down the progress of primary disease in the medication of parkinson disease commitment.When rasagiline and levodopa share, significantly shorten the time of "Off" state, and show good toleration.

The application of the open rasagiline of EP0436492 disease in treatment parkinson disease, dysmnesia etc., discloses rasagiline and all plays a role with dosage administration such as oral solid formulation, liquid preparation, emulsifiable paste, preparation capable of permeating skin.

CN101152153 discloses the medicinal compositions of a kind of oral administration solid, the rasagiline mesilate containing 0.5% ~ 3% weight portion, is not less than 40% and lower than the pentabasis alcohol of 60% weight portion and/or the organic acid of hexahydroxylic alcohols and 0.5% ~ 3% weight portion.Containing more pentabasis alcohol and/or hexahydroxylic alcohols in this invention, comprise mannitol, xylitol, sorbitol, maltose alcohol, although the product of this invention has good stability, its cost is higher.

CN102333442 discloses a kind of delayed release rasagiline formulation, by mixing rasagiline, citric acid and/or malic acid, can accept adjuvant and prepare core, then utilize acidproof coating by coated for this core with pharmacy.This invention needs rasagiline to be prepared into medicated core, and then utilizes acid resisting material coating, its complex manufacturing, and process control is strict, adds the difficulty of industrialized great production.

CN103315983 discloses a kind of rasagiline formulations and preparation method thereof, and containing as the stabilizing agent of acidulant, it is right that acidulant comprises the buffering that organic monoacid and its conjugate base form, and the buffering that organic monoacid and strong base-weak acid salt form is right.This invention solves the stability problem of product by adding acidulant, thus prescription is complicated, production cost is higher.

Rasagiline tablet has played important effect in treatment parkinson disease.But the quality of said preparation still has problems, pharmaceutical industry is carrying out the research and development rasagiline novel formulation improving the quality of the pharmaceutical preparations always.

In disclosed various prior art, some prescriptions are complicated, and some production processes are many, and process control is strict, and some costs are higher, are necessary the formulation and technology improving this product further, make it be more suitable for industrialized great production.The present inventor is in this product development process, and by large quantifier elimination, surprised discovery, adopts specific binding agent and technique can produce stay-in-grade rasagiline mesilate tablet.

Summary of the invention

The object of this invention is to provide a kind of rasagiline tablet, this tablet have prescription simple, be easy to operation, production cost is low, is easy to industrialized great production, and the advantage that long-time stability are good.

The present inventor is in the research of rasagiline tablet, by a large amount of contrast test, find that following prescription and the stability of technological factor on this rasagiline tablet have impact: binding agent selects hypromellose, EDTA-2Na, microcrystalline Cellulose, wherein, the segmentation in tablet producing technology process of binding agent and microcrystalline Cellulose adds, and principal agent rasagiline is first dissolved in binder solution, the suspension formed with portions microcrystalline cellulose again mixes, then adds filler, disintegrating agent and microcrystalline Cellulose and binder solution mixing granulation.The combination of these prescriptions and technological factor obtains stable rasagiline tablet.

In one embodiment, rasagiline tablet of the present invention, comprise: rasagiline mesilate 1% ~ 3%, hypromellose 1.5% ~ 3%, EDTA-2Na0.1% ~ 3%, microcrystalline Cellulose 50% ~ 75%, surplus is other pharmaceutic adjuvants, all by weight percentage, other pharmaceutic adjuvants described comprise filler, disintegrating agent and lubricant, and described tablet is obtained by following methods, and the method comprises following process:

(1) hypromellose water dissolution is become hypromellose cellulose solution, get portions microcrystalline cellulose aqueous dispersion and form microcrystalline Cellulose suspension;

(2) get part hypromellose solubilize rasagiline and EDTA-2Na, then add microcrystalline Cellulose suspension, stir and obtain mixed liquor;

(3) after being mixed with the mixed liquor of upper step by the microcrystalline Cellulose of filler, disintegrating agent and remainder, then the hypromellose cellulose solution adding remainder carries out wet granulation;

(4) by granule obtained for upper step and mix lubricant tabletting.

Preferably, rasagiline tablet of the present invention, described filler is selected from starch, pre-paying starch and lactose, described lubricant, its consumption account for sheet heavy 0.8% ~ 3%, described lubricant is selected from stearic acid, Pulvis Talci and micropowder silica gel, described disintegrating agent, its consumption account for sheet heavy 2% ~ 8%, described disintegrating agent is selected from carboxymethylstach sodium, polyvinylpolypyrrolidone and cross-linked carboxymethyl cellulose sodium.

Preferably, rasagiline tablet of the present invention, the portions microcrystalline fiber of step (1) account for sheet heavy 3% ~ 7%,

The concentration of the hypromellose cellulose solution in step (1) is 5-10%, and the part hypromellose cellulose solution in step (1) accounts for the 30-35% of hypromellose total solution weight.

Preferably, rasagiline tablet of the present invention, the percentage by weight of EDTA-2Na is 0.5% ~ 1.5%, and the percentage by weight of microcrystalline Cellulose is 50% ~ 65%, and the percentage by weight of lubricant is 0.8% ~ 3%, lubricant is preferably stearic acid, micropowder silica gel, the percentage by weight of disintegrating agent is 2% ~ 8%, and be preferably 3% ~ 5%, disintegrating agent is preferably carboxymethylstach sodium, the consumption of filler is the 8-38% of tablet formulation amount, is preferably starch.

The preparation method of rasagiline sheet of the present invention, the various step adopting this area to belong to wet granulation is carried out with condition, as fast Speed mixer, waves and extrudes granulation, fluidized-bed spray granulation etc.The key of preparation method of the present invention is: principal agent rasagiline and EDTA-2Na are dissolved in part hypromellose cellulose solution, the suspension that this solution and portions microcrystalline cellulose are formed is uniformly mixed, and carries out wet granulation with this mixed liquor and remaining microcrystalline Cellulose and hypromellose cellulose solution.

Further, hypromellose solution with water is prepared.After preparing, get a part of solution, add rasagiline mesilate and EDTA-2Na, stirring and dissolving.Get the microcrystalline cellulose of recipe quantity 3% ~ 7%, use aqueous dispersion.Mix being added with rasagiline with the suspension containing portions microcrystalline cellulose with the binder solution of EDTA-2Na, dispersed with stirring, mixing time more than 30 minutes, preferably 30 minutes to 60 minutes.During dispersed with stirring, suspension temperature should remain on 30 DEG C to 40 DEG C, and this can be realized by simple heating or natural cooling mode.The amount of taking of hypromellose cellulose solution, and the water yield of preparation microcrystalline Cellulose suspension, to be enough to make mixed mixed liquor, can all for wet granulation, to avoid causing principal agent rasagiline to lose with water excess, therefore, the water yield those skilled in the art preparing microcrystalline Cellulose suspension can determine with Conventional wisdom.

The advantage of tablet of the present invention and good effect:

1. tablet stability of the present invention is very good, and when its key is to granulate, in prescription, the suspension of portions microcrystalline cellulose needs to be uniformly mixed with principal agent rasagiline, EDTA-2Na and hypromellose cellulose solution, thus solves the stability problem of tablet.By test of many times, this people finds that EDTA-2Na, hypromellose have certain effect to the stability improving rasagiline formulations, but this is for solving the stability of this product not enough.Microcrystalline Cellulose, as a kind of conventional solid preparation filler, in the production of solid preparation, generally adds as solid form.In the development process of this product, found by lot of experiments, principal agent rasagiline and EDTA-2Na are dissolved in part hypromellose cellulose solution, then be uniformly mixed with the suspension containing portions microcrystalline cellulose, obtain the mixed liquor containing principal agent rasagiline, EDTA-2Na, part hypromellose, portions microcrystalline cellulose.This mixed liquor all mixes with remaining microcrystalline Cellulose, other filleies and disintegrating agent as the binding agent first used, then adds remaining hypromellose cellulose solution, and then wet granulation routinely carries out granulating.In the preparation process of tablet of the present invention, and the microcrystalline Cellulose of not all adds all in solid form, and part adds with the form of suspension, and need be uniformly mixed with principal agent rasagiline, EDTA-2Na, hypromellose.This is different from the change of routine operation, and tablet of the present invention can be made to have good long-time stability.

2. tablet of the present invention adopts conventional wet lay granulating process, simple to operate, and process is easy to control, and is more suitable for suitability for industrialized production.

3. tablet of the present invention adopts common, conventional pharmaceutic adjuvant, and be mainly microcrystalline Cellulose, other filleies comprise starch, pre-paying starch, lactose.These are all cheap pharmaceutic adjuvants, and therefore, the present invention has cost advantage.

Detailed description of the invention

The following examples for illustration of with understand essence of the present invention, but the scope do not limited the present invention in any way.

The amount of the rasagiline mesilate adopted in following examples is by rasagiline, and 1.56mg rasagiline mesilate is about equivalent to 1mg rasagiline.

Embodiment 1: the heavy 100mg of sheet

Prescription:

Supplementary material title	Percentage by weight %
		Rasagiline mesilate	1.56
Hypromellose	2
		Carboxymethylstach sodium	8
EDTA-2Na	0.1
		Microcrystalline Cellulose	50
Starch	37.54
		Stearic acid	0.4
Micropowder silica gel	0.4
		Add up to	100

Technique:

1. prepare binder solution: the hypromellose cellulose solution of preparation 5%, get about 30% amount, add EDTA-2Na, rasagiline mesilate, stirring and dissolving.Get the microcrystalline cellulose of recipe quantity 5%, use aqueous dispersion.Mix being added with principal agent with microcrystalline Cellulose suspension with the binder solution of EDTA-2Na, controlling mixeding liquid temperature is 30 DEG C to 40 DEG C, dispersed with stirring 30 minutes.

2. surplus microcrystalline Cellulose, carboxymethylstach sodium, starch mix homogeneously, first use the mixed solution of step 1, then with remaining hypromellose cellulose solution, carry out wet granulation.Wet grain drying, granulate.

3. add tabletting after stearic acid, micropowder silica gel mix homogeneously.

Embodiment 2: the heavy 156mg of sheet

(distinguishing that to be that the microcrystalline cellulose of recipe quantity 3% adds form different from comparative example 1)

Prescription:

Supplementary material title	Percentage ratio %
		Rasagiline mesilate	1
Hypromellose	2.5
		Polyvinylpolypyrrolidone	2
EDTA-2Na	0.5
		Microcrystalline Cellulose	60
Pre-paying starch	32
		Stearic acid	1
Pulvis Talci	1
		Add up to	100

Technique:

1. prepare binder solution: the hypromellose cellulose solution of preparation 8%, get about 35% amount, add EDTA-2Na, rasagiline mesilate, stirring and dissolving.Get the microcrystalline cellulose of recipe quantity 3%, use aqueous dispersion.Mix being added with principal agent with microcrystalline Cellulose suspension with the binder solution of EDTA-2Na, controlling mixeding liquid temperature is 30 DEG C to 40 DEG C, dispersed with stirring 60 minutes.

2. surplus microcrystalline Cellulose, polyvinylpolypyrrolidone, pre-paying starch mix homogeneously, first use the mixed solution of step 1, then with remaining hypromellose cellulose solution, carry out wet granulation.Wet grain drying, granulate.

3. add tabletting after stearic acid, Pulvis Talci mix homogeneously.

Embodiment 3: the heavy 78mg of sheet

Prescription:

Supplementary material title	Percentage ratio %
		Rasagiline mesilate	2
Hypromellose	1.5
		Cross-linked carboxymethyl cellulose sodium	3
EDTA-2Na	1.5
		Microcrystalline Cellulose	65
Lactose	25.2
		Pulvis Talci	1
Micropowder silica gel	0.8
		Add up to	100

Technique:

1. prepare binder solution: the hypromellose cellulose solution of preparation 10%, get about 25% amount, add EDTA-2Na, rasagiline mesilate, stirring and dissolving.Get the microcrystalline cellulose of recipe quantity 7%, use aqueous dispersion.Mix being added with principal agent with microcrystalline Cellulose suspension with the binder solution of EDTA-2Na, controlling mixeding liquid temperature is 30 DEG C to 40 DEG C, dispersed with stirring 40 minutes.

2. surplus microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium, lactose mix homogeneously, first use the mixed solution of step 1, then with remaining hypromellose cellulose solution, carry out wet granulation.Wet grain drying, granulate.

3. add tabletting after Pulvis Talci, micropowder silica gel mix homogeneously.

Embodiment 4: the heavy 52mg of sheet

Prescription:

Technique:

1. prepare binder solution: the hypromellose cellulose solution of preparation 8%, get about 30% amount, add EDTA-2Na, rasagiline mesilate, stirring and dissolving.Get the microcrystalline cellulose of recipe quantity 4%, use aqueous dispersion.Mix being added with principal agent with microcrystalline Cellulose suspension with the binder solution of EDTA-2Na, controlling mixeding liquid temperature is 30 DEG C to 40 DEG C, dispersed with stirring 50 minutes.

3. add tabletting after sliding stearic acid mix homogeneously.

Comparative example 1: the heavy 156mg of sheet

Prescription:

Technique:

1. prepare binder solution: the hypromellose cellulose solution of preparation 8%, get about 35% amount, add EDTA-2Na, rasagiline mesilate, stirring and dissolving is for subsequent use.

2. microcrystalline Cellulose, polyvinylpolypyrrolidone, pre-paying starch mix homogeneously, first uses the binder solution of step 1, then with remaining hypromellose cellulose solution, carries out wet granulation.Wet grain drying, granulate.

3. add tabletting after stearic acid, Pulvis Talci mix homogeneously.

Comparative example 2: the heavy 78mg of sheet

Prescription:

Technique:

1. prepare binder solution: the hypromellose cellulose solution of preparation 10%, get about 25% amount, add EDTA-2Na, rasagiline mesilate, stirring and dissolving is for subsequent use.

2. microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium, lactose mix homogeneously, first use the binder solution of step 1, then with remaining hypromellose cellulose solution, carry out wet granulation.Wet grain drying, granulate.

3. add tabletting after Pulvis Talci, micropowder silica gel mix homogeneously.

Comparative example embodiment 3

Hypromellose polyvidone in embodiment 1 prescription is substituted, other prescription and technique constant.

Comparative example embodiment 4

Microcrystalline Cellulose lactose in embodiment 1 prescription is substituted, other prescription and technique constant.

Experimental example

Accelerated stability is investigated

Sample adopts common aluminum-plastic packaged, under the condition of temperature 40 ± 2 DEG C, relative humidity RH75% ± 5%, carries out accelerated stability investigation.Result of the test shows, in probation, and the rasagiline sheet that comparative example 1 and comparative example 2 produce, its S-isomer, single impurity, total impurities have certain growth, the results are shown in Table 1 and table 2; , comparative example 3 produce the S-isomer of rasagiline sheet, single impurity, total impurities is at the content 0.21,0.26,0.35 of 6th month.The S-isomer of rasagiline sheet that comparative example 4 produces, single impurity, total impurities were at the content 0.25,0.31,0.38 of 6th month.Rasagiline sheet prepared by the present invention and the tablet of embodiment 1 ~ embodiment 4, indices, without significant change, constant product quality, the results are shown in Table 3-6.

Table 1 comparative example 1 accelerated stability investigates result:

Table 2 comparative example 2 accelerated stability investigates result:

Table 3 embodiment 1 accelerated stability investigates result:

Table 4 embodiment 2 accelerated stability investigates result:

Table 5 embodiment 3 accelerated stability investigates result:

Table 6 embodiment 4 accelerated stability investigates result:

Long-time stability investigate result:

Sample adopts common aluminum-plastic packaged, under the condition of temperature 25 ± 2 DEG C, relative humidity RH60% ± 10%, carries out long-time stability investigation.Result shows, in probation, rasagiline sheet prepared by the present invention, indices is without significant change, constant product quality.

Table 7 embodiment 1 long-time stability investigate result:

Table 8 embodiment 2 long-time stability investigate result:

Table 9 embodiment 3 long-time stability investigate result:

Table 10 embodiment 4 long-time stability investigate result:

The result more than showing 1-10 shows, rasagiline tablet of the present invention, owing to adopting hypromellose to be binding agent and microcrystalline Cellulose, and adopting the technique that segmentation adds, rasagiline dissolves in binder solution in advance, and the tablet of acquisition is highly stable, impurity is few, and quality is good.And not with the prescription adopting hypromellose and microcrystalline Cellulose, and the rasagiline tablet long term storage rear impurity content that the technique not adopting segmentation to add obtains increases, poor stability.

The suitable increase and decrease making simple change and adjuvant in spirit of the present invention also belongs to scope of the present invention.

Claims

1. a rasagiline tablet, comprise: the rasagiline mesilate of 1 ~ 3%, the hypromellose of 1.5 ~ 3%, the EDTA-2Na of 0.1 ~ 3%, the microcrystalline Cellulose of 50 ~ 75%, surplus is other pharmaceutic adjuvants, all by weight percentage, other pharmaceutic adjuvants described comprise filler, disintegrating agent and lubricant, described tablet is obtained by following methods, and the method comprises following process:

(1) hypromellose water dissolution is become hypromellose cellulose solution, get part hypromellose solubilize rasagiline and EDTA-2Na, then add portions microcrystalline cellulose, stir and obtain mixed liquor;

(2) after being mixed with the mixed liquor of upper step by the microcrystalline Cellulose of filler, disintegrating agent and remainder, then the hypromellose cellulose solution adding step remainder carries out wet granulation;

(3) by obtained granule and mix lubricant tabletting.

2. tablet as claimed in claim 1, described filler is selected from starch, pre-paying starch and lactose.

3. tablet as claimed in claim 1, described lubricant, its consumption account for sheet heavy 0.8 ~ 3%.

4. tablet as claimed in claim 3, described lubricant is selected from stearic acid, Pulvis Talci and micropowder silica gel.

5. tablet as claimed in claim 1, described disintegrating agent, its consumption account for sheet heavy 2 ~ 8%.

6. tablet as claimed in claim 5, described disintegrating agent is selected from carboxymethylstach sodium, polyvinylpolypyrrolidone and cross-linked carboxymethyl cellulose sodium.

7. tablet as claimed in claim 1, the portions microcrystalline fiber of step (1) account for sheet heavy 3 ~ 7%.

8. tablet as claimed in claim 1, the concentration of the hypromellose cellulose solution in step (1) is 5-10%.

9. tablet as claimed in claim 1, the part hypromellose cellulose solution in step (1) accounts for the 30-35% of hypromellose total solution weight.

10. tablet as claimed in claim 1, described filler, its consumption account for sheet heavy 8% ~ 38%.