CN104971046B

CN104971046B - A kind of immediate-release granules and its quick releasing formulation containing Lurasidone HCl

Info

Publication number: CN104971046B
Application number: CN201410139224.0A
Authority: CN
Inventors: 柯尊洪; 郑强; 秦应飞
Original assignee: CHENGDU KANGHONG PHARMACEUTICALS GROUP Co Ltd
Current assignee: CHENGDU KANGHONG PHARMACEUTICALS GROUP Co Ltd
Priority date: 2014-04-08
Filing date: 2014-04-08
Publication date: 2018-01-09
Anticipated expiration: 2034-04-08
Also published as: CN104971046A

Abstract

The present invention provides a kind of immediate-release granules of the Lurasidone HCl containing insoluble drug, and it includes Lurasidone HCl and poloxamer, and the weight proportion of the Lurasidone HCl and poloxamer is 1：0.25‑1:1, it, which can also add different auxiliary materials and prepare, turns into quick releasing formulation, the immediate-release granules and quick releasing formulation disintegration time limited are short, can Fast Stripping and dissolution it is complete, 5min dissolution rates are up to more than 70%, substantially increase the bioavilability of medicine, and prescription and preparation technology are simple, direct powder compression can be used, production cost is low, suitable for industrial production.

Description

A kind of immediate-release granules and its quick releasing formulation containing Lurasidone HCl

Technical field

The present invention relates to field of pharmaceutical preparations, and in particular to a kind of immediate-release granules and its quick-release containing Lurasidone HCl Preparation.

Background technology

Lurasidone HCl (lurasidone hydrochloride, trade name Latuda) is by SUMITOMO CHEMICAL pharmacy Company (Dainippon Sumitomo) exploitation the antipsychotic agent with double action, it to 5-HT2A acceptors with D2 dopamine receptor is respectively provided with high affinity, and significant curative effect is respectively provided with to the positive and negative symptoms of mental patient.Its in October 28 in 2010, Nikkei FDA (Food and Drug Adminstration) (FDA) approval listed the schizophrenia for treating adult in the U.S. Disease, Chinese chemical name：(3aR, 4S, 7R, 7aS) -2- { (1R, 2R) -2- [4- (1,2- benzisothiazole -3- bases) piperazine -1- Ylmethyl] cyclohexylmethyl } hexahydro -1H-4,7- methyl iso-indoles -1,3- dione hydrochlorides；Molecular formula：C₂₈H₃₆N₄O₂S.HCL, Molecular weight：529.14 its structural formula is：

Compared with other antipsychotic drugs, Lurasidone HCl has advantages below：1st, it is to d2 dopamine receptor, 5- Hydroxytryptamine (5-HT7,5-HT2A, 5-HT1A) and adrenaline α 2c acceptors are respectively provided with high affinity, to the sun of mental patient Property and negative symptoms are respectively provided with significant curative effect；2nd, Lurasidone to the above-mentioned acceptor that can improve memory defects except having height Outside affinity, nor affecting on acetylcholinergic receptor, histamine H1-receptor, both are believed to destroy learning and memory function Acceptor, therefore also made moderate progress for the cognitive disorder of schizophreniac, in clinical research, by with other anti-spirit The comparative study of medicine, the mental patient that find Lurasidone has cognition dysfunction for treatment have extraordinary treatment Effect；3rd, the adverse reaction (extrapyramidal symptom) of Lurasidone HCl is weaker, is not easy to cause the adverse reactions such as weightening, hyperlipemia [Feng Yufei, the pharmacology and clinical progress of antipsychotic new drug Lurasidone, Chinese Journal of New Drugs 2011 year volume 20 the 10th Phase, 853-856 pages], therefore Lurasidone HCl is that most one of product of advantage, market are applied in current antipsychotics Have a extensive future.

At present, the formulation that Lurasidone HCl has listed is conventional tablet, there is tetra- kinds of rule of 20mg, 40mg, 80mg and 120mg Lattice, its insoluble drug release is slower, and disintegration rate is slow, is not suitable for having the clothes for patients of dysphagia or special circumstances use.Quick releasing formulation Refer to after taking to be capable of fater disintegration or Fast Stripping, in oral cavity or the gastrointestinal tract mucous rapid preparation for discharging and absorbing, It possesses many advantages compared with ordinary preparation in clinical practice：1st, speed collapses, is instant, is rapid-action；2nd, abundant, biology profit is absorbed Expenditure is high；3rd, enteron aisle residual less, adverse reaction it is small；4th, it is convenient to take；Therefore a kind of disintegration of exploitation is rapid, dissolution rate is high, produces Technique is simple, is adapted to industrial Lurasidone HCl quick releasing formulation to have very for expanding its clinical application range Great meaning.

However, in the fater disintegration absorption process of quick releasing formulation, the rate-limiting step of drug absorption is often the molten of medicine Speed is solved, for insoluble drug, dissolution velocity may result in bioavilability and reduces slowly [Shen Lan etc., orally to be consolidated The progress of body quick releasing formulation, CHINA JOURNAL OF CHINESE MATERIA MEDICA, the 2nd phase of volume 30 in 2005,89-92 pages], and national medicine examines center pair In the technical requirements of oral disnitegration tablet for insoluble drug, except establishing suitable disintegration time mensuration method and limit Outside inclusive criteria, suitable dissolution determination method and limit and inclusive criteria should be also established.However, Lurasidone HCl is not By its dissolubility all extreme differences in which kind of solvent, its is atomic to be dissolved in water, is slightly soluble in ethanol, is insoluble in methanol, is practically insoluble in first Benzene and atomic it is dissolved in acetone, its preparation dissolution rate of this dissolution properties strong influence of Lurasidone HCl, so as to influence it The bioavilability of preparation, therefore, how to cause medicine Fast Stripping is to prepare to need solution badly during Lurasidone quick releasing formulation Certainly the problem of.Dainippon Sumitomo Pharma Co., Ltd of Yuan Yan companies disclosed in patent (CN101184489B) a kind of dissolution compared with Good Lurasidone HCl tablet, its 10min dissolution rate can reach about 70-80%, and 15min dissolution rates can reach about 80- 90%, but it can be seen that 5min dissolution rates only 50% or so, are unable to reach Fast Stripping, now from its stripping curve figure Have and a kind of Lurasidone HCl Orally disintegrating tablet (CN103054824A) is also reported in technology, it is by bulk drug and hydrophily Auxiliary material uses wet granulation technique after carrying out ultramicro grinding, and to reach the purpose of Fast Stripping, but this method operating process is answered It is miscellaneous, cost height is prepared, and 15min dissolution rates can reach more than 90%, can not obtain rapid dissolution.Another patented technology (CN103006661A) a kind of Lurasidone HCl preparation with very fast dissolution characteristic is reported in, it discloses using grinding Method prepares its solid dispersions, it is therefore an objective to allows medicine to be dispersed in dispersible carrier to improve the dissolution rate of its preparation and dissolution Degree, but can be seen that its 5min dissolution rate by its preparation stripping curve disclosed in patent is only 40% or so.

The content of the invention

To solve the problems, such as the fater disintegration of insoluble drug and Fast Stripping, the present invention provides one kind and is disintegrated rapid, release Hurry up, dissolution rate is high, preparation technology is simple, production cost is low contain Lurasidone HCl immediate-release granules, it includes the drawing of hydrochloric acid Shandong Western ketone and poloxamer, the weight proportion of the Lurasidone HCl and poloxamer is 1:0.25~1:2.

In the immediate-release granules of above-mentioned Lurasidone HCl, the weight proportion of the Lurasidone HCl and poloxamer is preferred For 1:0.25~1:1, more preferably 1:0.5.

In the immediate-release granules of above-mentioned Lurasidone HCl, the average grain diameter of the Lurasidone HCl is less than or equal to 20 μm, The average grain diameter, which is preferably less than, is equal to 10 μm, further preferably less than equal to 5 μm.

The preparation method of the immediate-release granules of above-mentioned Lurasidone HCl is：At the Lurasidone HCl micronizing of recipe quantity Reason, after being mixed with recipe quantity poloxamer, resulting mixture is fully dried and removes second alcohol and water, dried 50 mesh sieve is whole Grain produces.

The drying means can be to crush or be spray-dried after solidifying under cryogenic conditions.

The present invention further provides a kind of Lurasidone HCl quick releasing formulation, and it includes above-mentioned Lurasidone HCl quick-release Grain, diluent, filler, disintegrant, lubricant, glidant.

Wherein described Lurasidone HCl immediate-release granules weight proportion is preferably 10%-30%, and more preferably 15%, The diluent is selected from lactose, starch, starch milk saccharide complex, preferably pregelatinized starch, starch milk saccharide complex, described dilute The weight proportion for releasing agent is preferably 55%-65%, and more preferably 60%；The filler is selected from：Microcrystalline cellulose, sorb Alcohol, mannitol, preferably microcrystalline cellulose；Its weight proportion is preferably 10%-20%, and more preferably 14%；It is described to collapse Solve agent and be selected from carmethose, PVPP, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose pyce, preferably the poly- dimension of crosslinking Ketone；Its weight proportion is preferably 1%-4%, and more preferably 3%；The lubricant is selected from magnesium stearate and its metal salt Class, talcum powder, preferably aliphatic acid lipid, magnesium stearate, its weight proportion are preferably 1%-3%, and more preferably 2%； The glidant is superfine silica gel powder；Its weight proportion is preferably 1%-3%, and more preferably 2%.

In the quick releasing formulation of above-mentioned Lurasidone HCl, flavouring can also be further included.

The flavouring is selected from acesulfame potassium, Sucralose, aspartame, steviol glycoside, menthol, orange bitter taste and covered Agent, Mint Essence, more preferably aspartame, the flavouring weight proportion is preferably 3%-5%, further preferably For 4%.

The quick releasing formulation of the Lurasidone HCl, its prescription are preferably to be made up of the component of following weight proportioning：Hydrochloric acid Lurasidone immediate-release granules 15%, starch milk saccharide complex 55%-65%, microcrystalline cellulose 10%-20%, PVPP 1%-4%, magnesium stearate 1%-3%, silica 1 %-3%, aspartame 3%-5%.

The preparation prescription is preferably：Lurasidone HCl immediate-release granules 15%, starch milk saccharide complex 60%, crystallite are fine Dimension element 14%, PVPP 3%, magnesium stearate 2%, silica 2%, aspartame 4%.

The present invention further provides a kind of preparation method of the quick releasing formulation of Lurasidone HCl, its step is after crushing Lurasidone HCl immediate-release granules carry out mixing 50 mesh sieves with other auxiliary materials in prescription, and direct powder compression produces.

The quick releasing formulation of the Lurasidone HCl, its formulation are oral disnitegration tablet, are freeze-dried piece, ordinary tablet, preferably For oral disnitegration tablet.

Compared with prior art, following advantage be present in Lurasidone HCl pharmaceutical composition provided by the present invention：

1st, insoluble drug Lurasidone HCl immediate release drug formulations provided by the invention, convenient to take, disintegration time limited is short, Can Fast Stripping and dissolution it is complete, 5min dissolution rates are up to more than 70%, substantially increase the bioavilability of medicine.

2nd, Lurasidone HCl quick-release medicinal composition prescription provided by the invention and preparation technology are simple, can use powder Direct tablet compressing, production cost is low, is suitable for industrial production.

Below by specific embodiment, the present invention is described further：

In embodiment of the present invention or embodiment, to quick releasing formulation disintegration time limited, dissolution rate, mouthfeel detection side Method and evaluation index are as follows：

Disintegration time limited detection method and evaluation：20 eye mesh screens are encapsulated in both ends open glass-tube (diameter 1.5cm), one end；Input Tablet, it is put into 25ml graduated cylinders, adds 37 DEG C of water 2ml, stand, observes disintegration situation；Add 3ml water after 1min to rinse, Ying Wu Residual particles.

1st, sentence and do not pass through with the presence of the particle more than mesh or block non-disintegration solids on screen cloth；

2nd, the solid without the particle for being more than mesh or block non-disintegration on screen cloth is present, that is, sentences and pass through.

Same sample follow-on test 6, if having 5 or more than 5 test by, it is qualified that this batch of sample is judged to, if Have it is a piece of more than not by, then separately take 6 and retest, still have more than 1 not by, then this batch of sample is judged to unqualified, if There are 5 or more than 5 to test by the way that then this batch of sample is judged to qualified.

Dissolution detection method and evaluation：

1st, the particle dissolution detection method containing Lurasidone HCl：Medicine-containing particle 100mg is taken, in optical fiber dissolution instrument Tabletting on subsidiary tablet press machine, pressure 50kg, time 2min；Then drug containing rotor is put into the stripping rotor of optical fiber dissolution instrument Detect 5min dissolution rates.

2nd, Lurasidone HCl quick releasing formulation dissolution detection method：

It is prepared by need testing solution：Using Macllvaiane cushioning liquid (PH=3.8) 900ml as dissolution medium, rotating speed is 50r/min, take 6 to weigh, then put into respectively in stripping rotor, 10ml dissolution mediums are taken out respectively at 5,10,15,20,30min (while adding isometric blank medium), rapid filtration, takes filtrate as need testing solution.

The configuration of standard liquid：Lurasidone HCl reference substance about 11mg is taken, it is accurately weighed, put in 250ml volumetric flasks, add 5ml methanol makes dissolving, then is diluted to scale with dissolution medium, shakes up, as reference substance solution.

Assay method：Take above two solution, according to UV-VIS spectrophotometry (《Chinese Pharmacopoeia》2010 editions two attached Record IV A), absorbance is determined at 315nm wavelength, calculates the dissolution rate of every.

In above-mentioned dissolution rate testing result, it is qualified that 5min dissolution rates are considered as more than 70%.

In embodiment of the present invention or embodiment, used medicine, reagent and instrument are as follows：

Lurasidone HCl (self-control, lot number：121030)；It is mannitol, lactose, starch, pregelatinized starch, sorbierite, micro- Crystalline cellulose 101, polyvinyl alcohol 1788, Macrogol 4000, Macrogol 6000, sodium carboxymethylcellulose, PVP K30 and PVPP；Starch milk saccharide complex (, ROQUETTE)；PLURONICS F87 (BASF)；Acesulfame potassium, trichlorine Sucrose, aspartame, steviol glycoside, menthol, cherry essence, strawberry essence, corn essence, lemon extract, Mint Essence (), medicinal alcohol.

Single-punch tablet press (the vertical science and technology of Beijing traditional Chinese medicines dragon), ultraviolet spectrometry degree meter (Shimadzu UV-1800), airslide disintegrating mill (MORGEC MACHINERY MAS-01), optical fiber dissolution instrument (rich Coase FODT-101).

Contrast experiment 1 uses its disclosed wet granulation according to the prescription (embodiment 1) disclosed in patent CN103006661 Preparation method and powder direct pressure closing prepare Lurasidone HCl quick releasing formulation, and detect its 5min dissolution rate, wherein wet granulation Preparation method is：It is standby that each supplementary material is crossed into 40 mesh sieves, weighs recipe quantity Lurasidone HCl and mannitol, is well mixed；Powder It is broken to obtain microsome particle A, 5% cmc soln is configured, obtains solution B；In microsome particle A, crystallite is added Cellulose, PVPP are well mixed, and obtain mixture C；Solution B being added in mixture C softwood is made, 14 mesh are pelletized, 55 DEG C of dryings 14 mesh whole grains, obtain particle D to weightless 1-3% (wt/wt)；In particle D, silica, stearic acid are added Magnesium, it is well mixed, tabletting；12% Opadry is configured, is coated；Powder direct pressure closing preparation method is：Each supplementary material is crossed into 40 mesh sieves It is standby, recipe quantity Lurasidone HCl and mannitol are weighed, is well mixed；Crushing obtains microsome particle A, by carboxymethyl cellulose Element, microcrystalline cellulose, PVPP, silica, magnesium stearate cross 40 mesh sieves respectively, then by microsome particle A and its Its auxiliary material fully mixes, tabletting；12% Opadry is configured, is coated.

Specific prescription dosage is shown in Table 4, and dissolution results are shown in Table 5.

Prescription matches in the contrast experiment of table 4

Prescription 1

Prescription 2

Prescription 3

Prescription 4

Prescription 5

Prescription 6

Lurasidone HCl

120mg

Mannitol

120mg

/

120mg

/

120mg

/

Poloxamer

/

120mg

/

120mg

/

120mg

Microcrystalline cellulose

195mg

Sodium carboxymethyl starch

24mg

/

PVPP

/

24mg

Silica

9mg

Magnesium stearate

9mg

Opadry

15mg

Wet granulation

Powder vertical compression

Wet granulation

The dissolution rate testing result of table 5

	5min	10min	15min	20min	30min
						Prescription 1	43%	77%	82%	87%	95%

Prescription 2	47%	80%	84%	89%	97%
						Prescription 3	37%	67%	72%	76%	79%
Prescription 4	41%	71%	76%	82%	87%
						Prescription 5	35%	56%	63%	68%	76%
Prescription 6	48%	61%	75%	80%	82%

(1) auxiliary material selects：Applicant selects a large amount of different auxiliary materials to prepare the immediate-release granules containing Lurasidone HCl, and Dissolution rate when detecting its 5min using method 1 in dissolution detection method and evaluation, part of test results are shown in Table 1, wherein medicine The preparation method of composition is：Lurasidone HCl (average grain diameter≤20 μm) is well mixed by prescription, added at 100 DEG C or so Heat fusing, crushed after cooling.

Table 1 is using Lurasidone HCl quick-release medicinal composition dissolution results during different auxiliary material

Prescription	Component (ratio 1:1)	5min dissolution rates
			1	Lurasidone HCl：Poloxamer	65%
2	Lurasidone HCl：Macrogol 4000	46%
			3	Lurasidone HCl：Macrogol 6000	42%
4	Lurasidone HCl：Polyvinyl alcohol 1788	41%
			5	Lurasidone HCl：Xylitol	52%
6	Lurasidone HCl：Antierythrite	51%
			7	Lurasidone HCl：PVP K30	48%

It can be seen from the results above that when auxiliary material uses poloxamer, the dissolution rate of resulting pharmaceutical composition is excellent In other auxiliary materials.

(2) selection of preparation method：More excellent prescription (the Lurasidone HCl that will be obtained in above-mentioned experiment：Poloxamer= 1：1, Lurasidone HCl average grain diameter≤20 micron) according to different preparation methods the particle containing Lurasidone HCl is prepared, And dissolution rate when detecting its 5min using method 1 in dissolution detection method and evaluation, which part preparation method are as follows：Prepare Method 1：By the Lurasidone HCl of recipe quantity, after being mixed with recipe quantity poloxamer, appropriate 95% ethanol infiltration is added, will Resulting mixture is fully dried and removes second alcohol and water, is taken out after solidifying under cryogenic conditions and crushed 50 mesh sieves and obtain.

Preparation method 2：Spray drying process, the Lurasidone HCl of recipe quantity after being mixed with recipe quantity poloxamer, adds Enter appropriate 95% ethanol infiltration, solid content 30%, resulting mixed solution is spray-dried to obtain.

Preparation method 3：Polishing, the Lurasidone HCl of above-mentioned recipe quantity and poloxamer are put into high speed ball mill Grinding obtains, and crushed material average grain diameter is less than 10 μm.

Preparation method 4：Fusion method, the Lurasidone HCl of above-mentioned recipe quantity is well mixed with poloxamer, at 100 DEG C Left and right heating melting, crushed 50 mesh sieves and obtains after cooling.

Preparation method 5：Comminuting method altogether, after the Lurasidone HCl of above-mentioned recipe quantity is well mixed with poloxamer, enters Row air-flow crushing obtains, and crushed material average grain diameter is less than 10 μm.

Dissolution rate testing result is shown in Table 2.

The pharmaceutical composition dissolution results that 2 different preparation methods of table are prepared

Preparation method	1	2	3	4	5
						Dissolution rate (5min)	81%	82%	55%	52%	54%

It is can be seen that according to above-mentioned dissolution rate testing result when poloxamer content is reduced, the dissolution rate of method 4 substantially drops Low, the pharmaceutical composition dissolution rate being prepared using method 1 and method 2 is significantly larger than remaining method, and dissolution is rapid, wherein just Method 1 approaches with the dissolution rate of method 2, method 1 operate it is more easy, it is low for equipment requirements.

(3) diameter of aspirin particle, prescription, proportioning selection：Using different auxiliary materials, different Lurasidone HCl particle diameters, and not Same proportioning, different pharmaceutical compositions is prepared according to preparation method 1, and using method 1 in dissolution detection method and evaluation Its 5min dissolution rate is detected, art pharmaceutical compositions prescription and testing result are shown in Table 3, and the particle diameter is average grain diameter.

The medicine-containing particle dissolution results of 3 different prescriptions of table and proportioning

Prescription	Component	Ratio	5min dissolution rates
				1	(≤40 μm) Lurasidone HCl：Poloxamer	1:0.5	50%
2	(≤40 μm) Lurasidone HCl：Poloxamer	1:1	56%
				3	(≤40 μm) Lurasidone HCl：Poloxamer	1:2	60%
4	(≤20 μm) Lurasidone HCl：Poloxamer	1:0.25	71%
				5	(≤20 μm) Lurasidone HCl：Poloxamer	1:0.5	78%
6	(≤20 μm) Lurasidone HCl：Poloxamer	1:1	81%
				7	(≤20 μm) Lurasidone HCl：Poloxamer	1:2	87%
8	(≤10 μm) Lurasidone HCl：Poloxamer	1:0.25	74%
				9	(≤10 μm) Lurasidone HCl：Poloxamer	1:0.5	77%
10	(≤10 μm) Lurasidone HCl：Poloxamer	1:1	82%
				11	(≤10 μm) Lurasidone HCl：Poloxamer	1:2	87%
12	(≤5 μm) Lurasidone HCl：Poloxamer	1:0.25	75%
				13	(≤5 μm) Lurasidone HCl：Poloxamer	1:0.5	80%
14	(≤5 μm) Lurasidone HCl：Poloxamer	1:1	88%
				15	(≤5 μm) Lurasidone HCl：Poloxamer	1:1.5	90%
16	(≤5 μm) Lurasidone HCl：Poloxamer	1:2	94%
				17	(≤5 μm) Lurasidone HCl：Macrogol 4000	1:2	48%
18	(≤5 μm) Lurasidone HCl：Macrogol 6000	1:2	45%
				19	(≤5 μm) Lurasidone HCl：Polyvinyl alcohol 1788	1:2	42%

20

(≤5 μm) Lurasidone HCl：PVP K30

1:2

47%

When result can be seen that auxiliary material and select poloxamer from table 3, dissolution rate is significantly larger than other auxiliary materials；Hydrochloric acid Shandong When drawing the western ketone average grain diameter to be less than or equal to 20 μm, the pharmaceutical composition dissolution rate of Lurasidone HCl and poloxamer composition compared with Height, when Lurasidone average grain diameter is less than or equal to 5 μm, dissolution rate is more excellent.The wherein ratio of Lurasidone HCl and poloxamer Preferably 1:0.25~1:2, more preferably 1:2.

Optimal Lurasidone HCl average grain diameter (≤5 μm), supplementary product kind and the two proportioning obtained according to the above results, Different Lurasidone HCl quick releasing formulations is prepared, observes its dissolution rate and disintegration time limited, which part prescription is shown in Table 4, dissolution Degree the results are shown in Table 5, and disintegration time limited the results are shown in Table 6, and wherein preparation method is：By the Lurasidone HCl of recipe quantity, with recipe quantity After poloxamer mixing, appropriate 95% ethanol infiltration is added, resulting mixture is fully dried and removes second alcohol and water, then Taking-up crushed 50 mesh sieves and obtain particle after solidifying under cryogenic conditions, particle be mixed with the auxiliary material of other recipe quantities, directly Tabletting obtains.

The Lurasidone HCl quick releasing formulation prescription of table 4

The Lurasidone HCl quick releasing formulation dissolution results of table 5

The Lurasidone HCl quick-release disintegration time limited inspection result of table 6

Prescription	Prescription 1	Prescription 2	Prescription 3	Prescription 4
					Disintegration time limited	19s	23s	57s	3min

Lurasidone HCl quick releasing formulation dissolution results and the immediate-release granules containing Lurasidone HCl in table 3 in table 5 Dissolution results show that its change is consistent, and disintegration time limited result can be seen that as Lurasidone HCl and pool Lip river are husky from table 6 The increase of nurse ratio, especially proportioning are 1:When 2, disintegration time limited is elongated rapidly, does not meet the requirement of quick releasing formulation, therefore comprehensive The ratio of dissolution rate and disintegration time limited result, Lurasidone HCl and poloxamer is preferably 1:0.25~1:1, further preferably For 1:0.5.

Brief description of the drawings

Fig. 1 is the stripping curve figure of Lurasidone HCl preparation in embodiment 16

Embodiment

Below by embodiment, the present invention is further described, but can not limit the scope of the invention.

The Lurasidone HCl quick releasing formulation of embodiment one prepares and evaluation

Prescription：Lurasidone HCl 10mg, poloxamer 5mg,65mg, MCC 10mg, PVPP 4mg, magnesium stearate 0.5mg, silica 3.5mg, aspartame 2mg

Preparation method：By the Lurasidone HCl (average grain diameter≤20 μm) of recipe quantity, mixed with recipe quantity poloxamer Afterwards, appropriate 95% ethanol infiltration is added, resulting mixture is fully dried and removes second alcohol and water, under cryogenic conditions Taking-up crushed 50 mesh sieves and obtain after solidification；It is standby that other auxiliary materials are crossed to 50 mesh sieves respectively, then Lurasidone HCl will be contained Particle is well mixed with other auxiliary materials of recipe quantity, then with prescription piece weight, hardness 50N tablettings on single-punch tablet press.

Testing result disintegration time 21s, powder fluidity angle of repose θ=37.5 °, release is as follows in PH3.8

Evaluation：Dissolution is rapid and dissolution is complete, and 5min dissolutions reach 81%.

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	81%	91%	98%	98%	99%

The Lurasidone HCl quick releasing formulation of embodiment two prepares and evaluation

Prescription：Lurasidone HCl 20mg (average grain diameter≤20 μm), poloxamer 10mg,106mg、 MCC 40mg, PVPP 6mg, magnesium stearate 3mg, silica 3mg, aspartame 12mg

Preparation method：With embodiment one

Testing result disintegration time 26s, powder fluidity angle of repose θ=35.0 °, release is as follows in PH3.8

Evaluation：Dissolution is rapid and dissolution is complete, and 5min dissolutions reach 82%.

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	82%	92%	97%	98%	100%

The Lurasidone HCl quick releasing formulation of embodiment three prepares and evaluation

Prescription：Lurasidone HCl 30mg (average grain diameter≤10 μm), poloxamer 15mg,It is 120mg, micro- The 99mg of crystalline cellulose 101, PVPP 15mg, magnesium stearate 6mg, silica 6mg, aspartame 9mg

Preparation method：With embodiment one

Testing result disintegration time 19s, powder fluidity angle of repose θ=36.4 °, release is as follows in PH3.8

Evaluation：Dissolution is rapid and dissolution is complete, and 5min dissolutions reach 85%.

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	85%	91%	95%	97%	99%

Example IV Lurasidone HCl quick releasing formulation prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤5 μm), poloxamer 20mg,It is 240mg, micro- The 56mg of crystalline cellulose 101, PVPP 12mg, magnesium stearate 8mg, silica 8mg, aspartame 16mg

Preparation method：With embodiment one

Testing result disintegration time 23s, powder fluidity angle of repose θ=32.4 °, release is as follows in PH3.8

Evaluation：Dissolution is rapid and dissolution is complete, and 5min dissolutions reach 87%.

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	87%	93%	97%	99%	100%

The Lurasidone HCl quick releasing formulation of embodiment five prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤10 μm), poloxamer 20mg,It is 280mg, micro- The 20mg of crystalline cellulose 101, PVPP 12mg, magnesium stearate 12mg, silica 4mg, aspartame 12mg

Preparation method：With embodiment one

Testing result disintegration time 21s, powder fluidity angle of repose θ=38.6 °, release is as follows in PH3.8

Evaluation：Dissolution is rapid and dissolution is complete, and 5min dissolutions reach 80%.

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	80%	89%	94%	98%	100%

The Lurasidone HCl quick releasing formulation of embodiment six prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤10 μm), poloxamer 20mg,It is 80mg, micro- The 220mg of crystalline cellulose 101, PVPP 8mg, magnesium stearate 4mg, silica 1 2mg, aspartame 16mg

Preparation method：With embodiment one

Testing result disintegration time 19s, powder fluidity angle of repose θ=34.1 °, release is as follows in PH3.8

Evaluation：Dissolution is rapid and dissolution is complete, and 5min dissolutions reach 83%.

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	83%	87%	93%	96%	100%

The Lurasidone HCl quick releasing formulation of embodiment seven prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤20 μm), poloxamer 20mg,240mg、 MCC 60mg, PVPP 4mg, magnesium stearate 14mg, silica 2mg, aspartame 20mg

Preparation method：With embodiment one

Testing result disintegration time 36s, powder fluidity angle of repose θ=37.6 °, release is as follows in PH3.8

Evaluation：Dissolution is rapid and dissolution is complete, and 5min dissolutions reach 79%.

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	79%	85%	92%	97%	100%

The Lurasidone HCl quick releasing formulation of embodiment eight prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤5 μm), poloxamer 20mg,It is 220mg, micro- The 60mg of crystalline cellulose 101, PVPP 24mg, magnesium stearate 8mg, silica 8mg, aspartame 20mg

Preparation method：With embodiment one

Testing result disintegration time 35s, powder fluidity angle of repose θ=36.2 °, release is as follows in PH3.8

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	82%	88%	95%	98%	99%

The Lurasidone HCl quick releasing formulation of embodiment nine prepares and evaluation

Prescription：Lurasidone HCl 80mg (average grain diameter≤5 μm), poloxamer 40mg,It is 100mg, micro- The 200mg of crystalline cellulose 101, PVPP 40mg, magnesium stearate 10mg, silica 1 0mg, aspartame 20mg

Preparation method：With embodiment one

Testing result disintegration time 34s, powder fluidity angle of repose θ=38.1 °, release is as follows in PH3.8

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	80%	88%	94%	97%	100%

The Lurasidone HCl quick releasing formulation of embodiment ten prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤5 μm), poloxamer 40mg,It is 165mg, micro- The 180mg of crystalline cellulose 101, PVPP 35mg, magnesium stearate 10mg, silica 1 0mg, aspartame 20mg

Preparation method：With embodiment one

Testing result disintegration time 36s, powder fluidity angle of repose θ=35.4 °, release is as follows in PH3.8

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	79%	85%	91%	95%	98%

The Lurasidone HCl quick releasing formulation of embodiment 11 prepares and evaluation

Prescription：Lurasidone HCl 120mg (average grain diameter≤5 μm), poloxamer 60mg,120mg、 MCC 180mg, PVPP 72mg, magnesium stearate 12mg, silica 1 2mg, aspartame 24mg

Preparation method：With embodiment one

Testing result disintegration time 38s, powder fluidity angle of repose θ=39.2 °, release is as follows in PH3.8

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	83%	88%	95%	97%	101%

The Lurasidone HCl quick releasing formulation of embodiment 12 prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤5 μm), poloxamer 20mg, lactose 200mg, mannitol 160mg, PVPP 40mg, magnesium stearate 10mg, silica 1 0mg, aspartame 15mg

Preparation method：With embodiment one

Testing result disintegration time 29s, powder fluidity angle of repose θ=36.1 °, release is as follows in PH3.8

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	80%	86%	94%	95%	99%

The Lurasidone HCl quick releasing formulation of embodiment 13 prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤5 μm), poloxamer 20mg, lactose 170mg, mannitol 100mg, PVPP 30mg, magnesium stearate 8mg, silica 8mg, aspartame 16mg

Preparation method：With embodiment one

Testing result disintegration time 24s, powder fluidity angle of repose θ=39.1 °, release is as follows in PH3.8

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	79%	82%	89%	94%	98%

The Lurasidone HCl quick releasing formulation of embodiment 14 prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤5 μm), poloxamer 20mg, lactose 180mg, mannitol 120mg, PVPP 30mg, magnesium stearate 10mg, silica 1 0mg, aspartame 15mg

Preparation method：With embodiment one

Testing result disintegration time 27s, powder fluidity angle of repose θ=37.1 °, release is as follows in PH3.8

Evaluation：Dissolution is rapid and dissolution is complete, and 5min dissolutions reach 78%.

Time (min)

5

10

15

20

30

Accumulate dissolution rate

78%

81%

87%

94%

100%

The Lurasidone HCl quick releasing formulation of embodiment 15 prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤5 μm), poloxamer 20mg, lactose 150mg, mannitol 200mg, PVPP 35mg, magnesium stearate 8mg, silica 8mg, aspartame 20mg

Preparation method：With embodiment one

Testing result disintegration time 21s, powder fluidity angle of repose θ=37.1 °, release is as follows in PH3.8

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	81%	87%	90%	97%	100%

The Lurasidone HCl quick releasing formulation of embodiment 16 prepares and evaluation

Prescription：Lurasidone HCl 30mg (average grain diameter≤10 μm), poloxamer 15mg,120mg、 MCC 99mg, PVPP 15mg, magnesium stearate 6mg, silica 6mg, aspartame 9mg preparation sides Method：Spray drying process, by the Lurasidone HCl of recipe quantity, after being mixed with recipe quantity poloxamer, add 95% appropriate second Alcohol is infiltrated, and resulting mixed solution is spray-dried, then by the other of the particle containing Lurasidone HCl and recipe quantity Auxiliary material is well mixed, then with prescription piece weight, hardness 50N tablettings on single-punch tablet press.

Testing result disintegration time 21s, powder fluidity angle of repose θ=36.0 °, release is as follows in PH3.8

Evaluation：Dissolution is rapid and dissolution is complete, and 5min dissolutions reach 86%.

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	86%	91%	94%	97%	98%

The Lurasidone HCl quick releasing formulation of embodiment 17 prepares and evaluation

Preparation method：With embodiment 16

Testing result disintegration time 25s, powder fluidity angle of repose θ=34.3 °, release is as follows in PH3.8

Evaluation：Dissolution is rapid and dissolution is complete, and 5min dissolutions reach 88%.

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	88%	93%	96%	99%	100%

The Lurasidone HCl quick releasing formulation of embodiment 18 prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤10 μm), poloxamer 20mg,280mg、 MCC 20mg, PVPP 12mg, magnesium stearate 12mg, silica 4mg, aspartame 12mg

Preparation method：With embodiment 16

Testing result disintegration time 23s, powder fluidity angle of repose θ=37.5 °, release is as follows in PH3.8

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	81%	86%	93%	96%	100%

The Lurasidone HCl quick releasing formulation of embodiment 19 prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤10 μm), poloxamer 20mg,It is 80mg, micro- Crystalline cellulose 101220mg, PVPP 8mg, magnesium stearate 4mg, silica 1 2mg, aspartame 16mg

Preparation method：With embodiment 16

Testing result disintegration time 20s, powder fluidity angle of repose θ=35.1 °, release is as follows in PH3.8

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	82%	89%	94%	97%	100%

The Lurasidone HCl quick releasing formulation of embodiment 20 prepares and evaluation

Prescription：Lurasidone HCl 40mg (average grain diameter≤20 μm), poloxamer 20mg,It is 240mg, micro- Crystalline cellulose 10160mg, PVPP 4mg, magnesium stearate 14mg, silica 2mg, aspartame 20mg

Preparation method：With embodiment 16

Testing result disintegration time 32s, powder fluidity angle of repose θ=37.5 °, release is as follows in PH3.8

Time (min)	5	10	15	20	30
						Accumulate dissolution rate	80%	83%	94%	98%	100%

Lurasidone HCl quick releasing formulation prescription is shown in Table 6 (wherein Lurasidone HCl average grain diameter≤5 μm), dissolution rate knot Fruit is shown in Table 7, and stripping curve figure is shown in Fig. 1, and the preparation method of Lurasidone HCl oral disnitegration tablet is the same as embodiment one.

The Lurasidone HCl quick releasing formulation prescription of table 6

The Lurasidone HCl quick releasing formulation dissolution results of table 7 are evaluated

Time (min)	Prescription 1	Prescription 2	Prescription 3	Prescription 4	Commercial samples
						5	85%	87%	84%	82%	57%
10	91%	93%	92%	93%	92%
						15	95%	97%	96%	97%	96%
20	98%	99%	98%	99%	98%
						30	100%	100%	99%	100%	100%

Claims

A kind of 1. Lurasidone HCl immediate-release granules, it is characterised in that comprising Lurasidone HCl and poloxamer, the hydrochloric acid The weight proportion of Lurasidone and poloxamer is 1:0.25-1:1, its preparation method is：By the hydrochloric acid Lu Laxi of recipe quantity Micropowderization processing, after being mixed with recipe quantity poloxamer, adds ethanol in proper amount infiltration, and resulting mixture is fully dried Second alcohol and water is removed, crushes, sieves after solidifying under cryogenic conditions；Or its preparation method is：By the Lurasidone HCl of recipe quantity Micronization processes, after being mixed with recipe quantity poloxamer, ethanol in proper amount infiltration is added, is spray-dried, sieving；Wherein described hydrochloric acid The average grain diameter of Lurasidone is less than or equal to 20 μm.
2. the immediate-release granules of Lurasidone HCl according to claim 1, it is characterised in that the Lurasidone HCl and The weight proportion of poloxamer is 1: 0.5.
3. the immediate-release granules of Lurasidone HCl according to claim 1, it is characterised in that the Lurasidone HCl Average grain diameter is less than or equal to 10 μm.
4. the immediate-release granules of Lurasidone HCl according to claim 3, it is characterised in that the Lurasidone HCl Average grain diameter is less than or equal to 5 μm.
5. a kind of quick releasing formulation of Lurasidone HCl, it is characterised in that wherein comprising described in any one in claim 1-4 Lurasidone HCl immediate-release granules, diluent, filler, disintegrant, lubricant or glidant；Wherein described diluent choosing From lactose, starch, starch milk saccharide complex, pregelatinized starch；Wherein described filler be selected from MCC, sorbierite, Mannitol.
6. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that the Lurasidone HCl speed It is 10%-30% to release particle weight proportioning.
7. the quick releasing formulation of the Lurasidone HCl according to claim 6, it is characterised in that the Lurasidone HCl speed It is 15% to release particle weight proportioning.
8. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that the diluent is starch milk Saccharide complex.
9. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that the weight of the diluent is matched somebody with somebody Than for 20%-70%.
10. the quick releasing formulation of the Lurasidone HCl according to claim 9, it is characterised in that the weight of the diluent is matched somebody with somebody Than for 55%-65%.
11. the quick releasing formulation of the Lurasidone HCl according to claim 10, it is characterised in that the weight of the diluent Match as 60%.
12. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that the filler is that crystallite is fine Dimension element 101.
13. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that the weight of the filler is matched somebody with somebody Than for 5%-55%.
14. the quick releasing formulation of the Lurasidone HCl according to claim 13, it is characterised in that the weight of the filler Match as 10%-20%.
15. the quick releasing formulation of the Lurasidone HCl according to claim 14, it is characterised in that the weight of the filler Match as 14%.
16. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that the disintegrant is selected from carboxylic first Sodium cellulosate, PVPP, low-substituted hydroxypropyl cellulose.
17. the quick releasing formulation of the Lurasidone HCl according to claim 16, it is characterised in that the disintegrant is crosslinking PVP.
18. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that the weight of the disintegrant is matched somebody with somebody Than for 1%-5%.
19. the quick releasing formulation of the Lurasidone HCl according to claim 18, it is characterised in that the weight of the disintegrant Match as 1%-4%.
20. the quick releasing formulation of the Lurasidone HCl according to claim 19, it is characterised in that the weight of the disintegrant Match as 3%.
21. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that the lubricant is selected from tristearin Sour magnesium, talcum powder, aliphatic acid lipid.
22. the quick releasing formulation of the Lurasidone HCl according to claim 21, it is characterised in that the lubricant is tristearin Sour magnesium.
23. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that the lubricant weight proportioning For 0.5%-3.5%.
24. the quick releasing formulation of the Lurasidone HCl according to claim 23, it is characterised in that the lubricant weight is matched somebody with somebody Than for 1%-3%.
25. the quick releasing formulation of the Lurasidone HCl according to claim 24, it is characterised in that the lubricant weight is matched somebody with somebody Than for 2%.
26. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that the glidant is micro mist silicon Glue.
27. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that the glidant weight proportion For 0.5%-3.5%.
28. the quick releasing formulation of the Lurasidone HCl according to claim 27, it is characterised in that the glidant weight is matched somebody with somebody Than for 1%-3%.
29. the quick releasing formulation of the Lurasidone HCl according to claim 28, it is characterised in that the glidant weight is matched somebody with somebody Than for 2%.
30. the quick releasing formulation of the Lurasidone HCl according to claim 5, it is characterised in that wherein also include flavouring.
31. the quick releasing formulation of Lurasidone HCl according to claim 30, it is characterised in that the flavouring is selected from peace Match honey, Sucralose, aspartame, steviol glycoside, menthol, orange bitter taste masking agent, Mint Essence.
32. the quick releasing formulation of Lurasidone HCl according to claim 31, it is characterised in that the flavouring is Ah Si Pa Tan.
33. the quick releasing formulation of Lurasidone HCl according to claim 30, it is characterised in that the flavouring weight is matched somebody with somebody Than for 2%-6%.
34. the quick releasing formulation of Lurasidone HCl according to claim 33, it is characterised in that the flavouring weight is matched somebody with somebody Than for 3%-5%.
35. the quick releasing formulation of Lurasidone HCl according to claim 34, it is characterised in that the flavouring weight is matched somebody with somebody Than for 4%.
36. according to the quick releasing formulation of Lurasidone HCl any one of claim 30-32, it is characterised in that at preparation Side is made up of the component of following weight proportioning：Lurasidone HCl immediate-release granules 15%, starch milk saccharide complex 55%-65% are micro- Crystalline cellulose 10%-20%, PVPP 1%-4%, magnesium stearate 1%-3%, silica 1 %-3%, aspartame 3%- 5%。
37. the quick releasing formulation of Lurasidone HCl according to claim 36, it is characterised in that the preparation prescription is：Salt Sour Lurasidone immediate-release granules 15%, starch milk saccharide complex 60%, microcrystalline cellulose 14%, PVPP 3%, magnesium stearate 2%, silica 2%, aspartame 4%.
38. the quick releasing formulation of Lurasidone HCl according to claim 5, it is characterised in that its preparation method includes：Will Lurasidone HCl immediate-release granules after crushing carry out mixing 50 mesh sieves with other auxiliary materials in prescription, and direct powder compression is .
39. according to the quick releasing formulation of the Lurasidone HCl described in claim 38, it is characterised in that the preparation is oral cavity Disintegrated tablet.
40. the Lurasidone HCl quick releasing formulation according to claim 39, it is characterised in that the oral disnitegration tablet is cold Freeze drying sheet.