CN107441497A - A kind of A Lishatan esters solid dispersions and preparation method thereof and the preparation containing the solid dispersions - Google Patents
A kind of A Lishatan esters solid dispersions and preparation method thereof and the preparation containing the solid dispersions Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
The invention provides a kind of improved A Lishatan esters solid dispersions, by Formulation to realize hot-melt extruded preparation technology, and realize that hot-melt extrusion process prepares the technical advantages such as easy, the used time is shorter, ensure the dissolving out capability of solid dispersions, and a kind of A Lishatan ester formulations further developed based on this.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, more particularly to a kind of A Lishatan esters solid dispersions and preparation method thereof and
Preparation containing the solid dispersions.
Background technology
Hypertension is the clinical syndrome for increasing mainly to show with body circulation arterial hypertension, is most common cardiovascular disease
Disease.It is reported that the whole world has nearly 1,000,000,000 people to suffer from hypertension, and lasting hypertension is the caused heart, brain, kidney, angiocarpy etc.
The main reason for organ injury.
A Lishatan esters (CAS：947331-05-7), entitled -4 chloro- 1- of 2- butyl of chemistry [2 '-(1H-TETRAZOLE -5- bases) -
1,1 '-diphenyl-methyl]-imidazole-5-carboxylic acid, 1- [(isopropoxy)-carbonyloxy group]-methyl esters, is a kind of new vasotonia
Plain II receptor antagonists, A Lishatan ester small toxicities, antihypertensive effect are better than similar-type products (such as Losartan).A Lishatan esters lead to
Cross metabolism generation active metabolite EXP-3174 (EXP3174) in vivo and play antihypertensive effect, Chinese patent
CN200680000397.8 makes public for the first time the structural formula of A Lishatan esters.
A Lishatan esters it is water-soluble poor, after oral, intestines and stomach dissolution is slow, absorbs poor, and bioavilability is low.Will
A Lishatan esters are prepared into solid dispersions, are the current important means for improving A Lishatan ester oral formulations dissolving out capability.Pass
The solid dispersions preparation method of system has：Fusion method, solvent method, polishing, spray drying process etc., prior art is mainly using spray
Mist seasoning prepares A Lishatan ester solid dispersions.
Chinese patent CN200880001668.0 discloses a series of preparations containing A Lishatan esters, wherein embodiment D1
~D6 discloses a kind of A Lishatan esters solid dispersions and preparation method thereof, using fluid bed top spray Fa Zhi Bei A Lishatan esters
Solid dispersions.This method complex process, to avoid organic solvent residual exceeded, it usually needs relatively long drying time,
It is not the optimised process for preparing solid dispersions.
Chinese patent CN201510254020.6 and Chinese patent CN201510334498.X are in patent
CN200880001668.0 bases are further optimized to preparation prescription, there is provided two kinds of improved A Lishatan esters solids point
Granular media, but its technological improvement is not directed to the change of preparation technology, therefore fluid bed top spray method still be present in this method technique
Complex process, the defects of process time is relatively long.
Therefore, a kind of improved A Lishatan esters solid dispersions are found, make its corresponding easy, efficient solid dispersions
Preparation technology (such as hot-melt extrusion process) is the unsolved technical problem of prior art.
The content of the invention
The shortcomings that it is an object of the invention to overcome prior art to prepare A Lishatan ester solid dispersions, there is provided a kind of
Improved A Lishatan esters solid dispersions, by Formulation to realize hot-melt extruded preparation technology, and realize hot-melt extruded
Technique prepares the technical advantages such as easy, the used time is shorter, ensures the dissolving out capability of solid dispersions.
The above-mentioned purpose of the present invention is achieved by the following technical programs：
A kind of A Lishatan esters solid dispersions, comprising A Lishatan esters, carrier material, plasticizer, the A Lishatan
Ester solid dispersions are prepared using hot-melt extrusion process, and the carrier material is copolyvidone, PVP, PEO
(PEO), rilanit special, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polymethacrylate resin, ethylene glycol-
The mixture of gained more than one or both of vinyl alcohol graft copolymer is mixed with arbitrary proportion, the plasticizer is pool Lip river
One kind in Sha Mu, tween, lauryl sulfate, cetyl sulfate, octadecyl sulfate, glycerin monostearate
It is or two or more with arbitrary proportion mixing gained mixture, when the mass parts of A Lishatan esters are 1, the mass parts of carrier material
For 0.8~2.5, the mass parts of plasticizer are 0.01~0.1.
Hot-melt extruded method is to be applied to a new solid dispersions technique of field of pharmaceutical preparations in recent years, and it is by raw material
The auxiliary materials such as medicine, carrier material are added in extruder simultaneously, make material through three phases such as Solid Conveying and Melting, melting, melt conveyings,
Under the extruding of the strength of kneading device and screw element, shear action, obtain height and mix scattered shaped article.Hot-melt extruded work
Skill is not related to the use of solvent, and operating method is simple, therefore, the preparation for A Lishatan ester solid dispersions, using heat
Molten expressing technique can effectively simplify A Lishatan ester preparation technologies, and shorten the process time.
Realize that the key problem in technology of first purpose of the invention is the selection to carrier material species and its dosage, specifically
, the targeted active ingredient A Lishatan esters of the present invention, the carrier material mainly used is copolyvidone, PVP, polycyclic
Oxidative ethane (PEO), rilanit special, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polymethacrylate resin, second
More than one or both of glycol-vinyl alcohol graft copolymer etc. gained mixture is mixed with arbitrary proportion.Wherein copolymerization dimension
Ketone is the linear copolymer of a series of NVPs (NVP) and vinylacetate (VA), commercially available conventional copolymerization dimension
Ketone has：PVP-VA64, Kollidon VA64, Plasdone S-630 etc.；PVP is a series of water-soluble N- vinyl pyrroles
The homopolymer of alkanone (NVP), conventional PVP have PVP-K30, PVP-K90 etc.；Rilanit special is made after being hydrogenated by castor oil
, commonly using commercially available kind has：Cremophor RH40、Sterotex K、Castwax MP-70、Castwax MP-80、
Catina, Cerit 3H etc., the selection in hot-melt extrusion process for kind of carrier need to consider the simultaneous of carrier and raw material
The factors such as capacitive, solubilizing effect, technological operation feasibility, the preferred copolyvidone of the dispersion carrier material, PVP, polycyclic
More than one or both of oxidative ethane (PEO), rilanit special gained mixture is mixed with arbitrary proportion.
In addition, also exist and select for the dosage of carrier material, specifically, for active ingredient A Lishatan esters, excessively
The use of carrier material can not correspond to significantly improving for preparation dissolving out capability, and the load efficiency of its carrier is also corresponded to and reduced, and
The use of very few carrier material can not then realize the preparation of solid dispersions, and then can not reach target dissolving out capability, therefore, when
When the mass parts of A Lishatan esters are 1 in the A Lishatan esters solid dispersions, the mass parts of the carrier material for 0.8~
2.5；Preferably, when the mass parts of A Lishatan esters in the A Lishatan esters solid dispersions are 1, the carrier material
Mass parts are 1~2.
Plasticizer of the present invention refers to a series of auxiliary materials that can change polymer property, reduce extrusion pressure.Increase
The addition of modeling agent advantageously reduces material melting temperature, in order to which molten mixture is smoothly extruded.The plasticizer is selected from pool Lip river
One in Sha Mu, tween, lauryl sulfate, cetyl sulfate, octadecyl sulfate, glycerin monostearate etc.
Kind is two or more with arbitrary proportion mixing gained mixture；When A Lishatan esters in the A Lishatan esters solid dispersions
When mass parts are 1, the mass parts of the plasticizer are 0.01~0.1；Wherein conventional poloxamer has：F68, poloxamer
124th, PLURONICS F87, poloxamer 237, Pluronic/Lutrol F 108, poloxamer188 etc., conventional tween has：Polysorbas20, tell
Temperature 40, polysorbate60, Tween 80 etc., conventional lauryl sulfate, cetyl sulfate, octadecyl sulfate have：Sodium
Salt, sylvite, magnesium salts etc.；Preferably, when the mass parts of A Lishatan esters in the A Lishatan esters solid dispersions are 1, institute
The mass parts for stating plasticizer are 0.03~0.08.
The prescription of the solid dispersions can further include glidant, it will be understood to those skilled in the art that
Glidant reference of the present invention is a series of to have improvement powder fluidity to realize normal machines feed, and realizes that easyization is squeezed
The auxiliary material gone out, the glidant are selected from more than one or both of magnesium stearate, aerosil, talcum powder etc. with any
The mixture of ratio mixing gained, it is described when the mass parts of A Lishatan esters in the A Lishatan esters solid dispersions are 1
The mass parts of glidant are 0.01~0.1；Preferably, when the quality of A Lishatan esters in the A Lishatan esters solid dispersions
When part is 1, the mass parts of the glidant are 0.02~0.05.
In a preferable scheme, the A Lishatan esters solid dispersions prescription is as follows：
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K30 | 2 |
| Poloxamer | 0.06 |
| Magnesium stearate | 0.03 |
In a preferable scheme, the A Lishatan esters solid dispersions prescription is as follows：
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K30 | 1 |
| Poloxamer | 0.06 |
| Magnesium stearate | 0.03 |
In a preferable scheme, the A Lishatan esters solid dispersions prescription is as follows：
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K30 | 0.8 |
| PEO | 0.7 |
| Poloxamer | 0.06 |
| Talcum powder | 0.03 |
In a preferable scheme, the A Lishatan esters solid dispersions prescription is as follows：
In a preferable scheme, the A Lishatan esters solid dispersions prescription is as follows：
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-VA64 | 2 |
| Poloxamer | 0.06 |
| Aerosil | 0.03 |
In a preferable scheme, the A Lishatan esters solid dispersions prescription is as follows：
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-VA64 | 2 |
| Lauryl sodium sulfate | 0.03 |
| Talcum powder | 0.03 |
In a preferable scheme, the A Lishatan esters solid dispersions prescription is as follows：
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP VA64 | 0.85 |
| Cremophor RH40 | 0.15 |
| Glycerin monostearate | 0.08 |
| Aerosil | 0.03 |
In a preferable scheme, the A Lishatan esters solid dispersions prescription is as follows：
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K30 | 2 |
| Poloxamer | 0.03 |
| Lauryl sodium sulfate | 0.03 |
| Aerosil | 0.03 |
In a preferable scheme, the A Lishatan esters solid dispersions prescription is as follows：
| Species | Dosage |
| A Lishatan esters | 1 |
| PEO | 1.5 |
| Poloxamer | 0.03 |
| Lauryl sodium sulfate | 0.03 |
| Aerosil | 0.03 |
In a preferable scheme, the A Lishatan esters solid dispersions prescription is as follows：
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K90 | 2 |
| Tween-80 | 0.08 |
| Aerosil | 0.03 |
Second object of the present invention is to provide a kind of preparation method of A Lishatan esters solid dispersions, the preparation
Method uses hot-melt extrusion process, and the technique is not related to the use of solvent, and operating method is simple；Can using hot-melt extrusion process
Effectively to simplify A Lishatan ester preparation technologies, and shorten the process time.
Second object of the present invention is achieved through the following technical solutions：
A kind of hot-melt extruded Fa Zhi Beis the methods of A Lishatan ester solid dispersions, it is characterised in that methods described includes such as
Lower step：
(1) A Lishatan esters and auxiliary material are well mixed, physical mixture is made；
(2) physical mixture in step (1) is added in hot-melt extruded machine, by melting, extruding ribbon product；
(3) by pulverization process after ribbon product cooling obtained by step (2), get A Lishatan ester medicine solid dispersions.
Wherein, the original in step (1), auxiliary material can be pre-processed before combination, such as cross 60~100 mesh sieves；Step (2)
In hot-melt extruded extrusion temperature by can realize melt and smoothly extrusion be defined, i.e., can realize melting at 100~200 DEG C
And smoothly extrude；
Active ingredient A Lishatan esters height in the form of approximation is unbodied in described A Lishatan ester solid dispersions
It is scattered in hot melt auxiliary material, the XRD spectra for showing as the solid dispersion powder is different from bulk drug, supplementary material physical mixture
And the XRD spectra of blank auxiliary mixture.Specifically, A Lishatan esters solid dispersion powder XRD spectra of the present invention
It is middle without obvious and sharp diffraction maximum, more specifically, A Lishatan esters solid dispersion powder XRD spectra of the present invention exists
The θ angles of scanning angle 2 are 3-45 ° without sharp and obvious absworption peak.
Third object of the present invention is to provide a kind of impurity content low A Lishatan ester solid dispersions, passes through place
Side's design and key process parameter are set, and (0 day) total impurities contains at the beginning of the solid dispersions are made using melting extrusion technique
Below 1.5%, single miscellaneous content control can especially contain important degradation impurity (EXP3174) below 0.5% for amount control
Amount control is below 0.3%.
Third object of the present invention is achieved by following：
A kind of A Lishatan esters solid dispersions, include A Lishatan esters, carrier material, plasticizer, it is characterised in that institute
State A Lishatan esters solid dispersions to prepare using hot-melt extrusion process, the carrier material is copolyvidone, PVP, polycyclic
Oxidative ethane (PEO), rilanit special, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polymethacrylate resin, second
The mixture of gained, the plasticizer more than one or both of glycol-vinyl alcohol graft copolymer are mixed with arbitrary proportion
Selected from poloxamer, tween, lauryl sulfate, cetyl sulfate, octadecyl sulfate, glycerin monostearate
Deng one or both of more than gained mixture mixed with arbitrary proportion, the A Lishatan esters solid dispersions are using hot melt
Prepared by expressing technique, the extrusion temperature of the hot-melt extrusion process is 100 DEG C~130 DEG C.
Realize that the key problem in technology of the 3rd purpose of the invention is the selection of solubilization carrier and plasticiser species, and extrusion
The selection of temperature.First, former, auxiliary material compatibility is the impurity content key factor influenceed, but inventor is had found by studying：
For A Lishatan ester hot-melt extrusion process prescriptions, influence of the auxiliary material to impurity content is limited, solubilization carrier and plasticiser species
Selection be more to have to influence on the dissolving out capability of the feasibility of hot-melt extrusion process and solid dispersions, solubilising carries herein
The selection of body species and its preferably all follow described in first purpose；Specifically, the active ingredient A Lisha that the present invention is targeted
Smooth ester, the dispersible carrier material mainly used is copolyvidone, PVP, PEO (PEO), rilanit special, hydroxypropyl
In base cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polymethacrylate resin, ethylene glycol-vinyl alcohol graft copolymer etc.
It is one or more kinds of that gained mixture is mixed with arbitrary proportion；Preferably, the dispersion carrier material be selected from copolyvidone,
More than one or both of PVP, PEO (PEO), rilanit special etc. gained is mixed with arbitrary proportion to mix
Thing.Likewise, the selection of plasticiser species herein and its preferably also follow described in first purpose, further, the increasing
Molten carrier, the dosage of plasticiser and its preferably also follow described in first purpose.
The extrusion temperature of hot-melt extrusion process is an important factor for influenceing impurity content, specifically, inventor passes through research
It was found that：For specific solubilization carrier and plasticiser, too low extrusion temperature can not be extruded because supplementary material can not be realized co-melting
Or extrusion is ineffective, and too high extrusion temperature is although melting extrusion can be realized, and active ingredient dissolving out capability meets
Clinical application requirement, but the drastically rise of impurity content particularly degradation impurity (EXP3174) content can be caused, and then influence solid
Body dispersion quality, inventor are had found by studying：When using specific solubilization carrier and plasticiser, the hot-melt extruded work
While the extrusion temperature of skill can realize hot-melt extruded for 100 DEG C~130 DEG C, realize to solid dispersions impurity content
Effectively control, below 1.5%, single miscellaneous content control exists the control of (0 day) total impurities content at the beginning of the solid dispersions are made
Less than 0.5%, important degradation impurity (EXP3174) content can be especially controlled below 0.3%.
Further, the A Lishatan esters solid dispersions can also further include glidant, specific glidant
The selection of species, dosage is followed described in first purpose of the invention.
4th purpose of the invention be to provide a kind of A Lishatan ester formulations, and the A Lishatan ester formulations include this hair
Bright described A Lishatan ester solid dispersions, the beneficial effect of the A Lishatan ester formulations mostly come from A Lishatan esters
There is technique to prepare the technical advantages such as easy, the used time is shorter for solid dispersions, i.e., described A Lishatan ester formulations, also have stable
Property the high, technical advantage such as dissolving out capability is good.
The formulation of the A Lishatan ester formulations includes but is not limited to tablet, capsule, granule, powder, powder-injection etc.,
Preferred tablet.
When the formulation of the A Lishatan ester formulations is tablet, the tablet first purpose of the invention or the 3rd mesh
The A Lishatan esters solid dispersions, and include at least one of filler, disintegrant, adhesive, the filler
Selected from lactose, mannitol, dextrin, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, calcium phosphate, calcium monohydrogen phosphate, starch milk
The mixture of gained, preferably lactose, mannitol, microcrystalline cellulose, shallow lake more than one or both of sugar are mixed with arbitrary proportion
The mixture of gained more than one or both of powder is mixed with arbitrary proportion；In the A Lishatan ester formulations, when Ah
When the mass parts of Li Shatan ester solid dispersions are 1, the mass parts of the filler are 0~1.0, preferably 0.4~0.8；It is described
Disintegrant be selected from Ac-Di-Sol, PVPP, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch,
The mixture of gained more than one or both of pregelatinized starch, cross-linked carboxymethyl cellulose calcium is mixed with arbitrary proportion, it is excellent
Select one or both of low-substituted hydroxypropyl cellulose, PVPP, Ac-Di-Sol, sodium carboxymethyl starch
The mixture of gained is mixed with arbitrary proportion above, in the A Lishatan ester formulations, when the A Lishatan esters solid disperses
When the mass parts of body are 1, the mass parts of the disintegrant are 0~1.0, preferably 0.4~0.8；Described adhesive is selected from described viscous
Mixture is selected from HPMC, Hydroxypropylcelliloxe, sodium carboxymethylcellulose, PVP, starch slurry, gelatin etc.
One or both of more than the mixture of gained is mixed with arbitrary proportion, in the A Lishatan ester formulations, as the A Li
When the mass parts of husky smooth ester solid dispersions are 1, the mass parts of described adhesive are 0~0.05.
The tablet can also further include lubricant, and the lubricant is selected from stearic acid, magnesium stearate, micro mist silicon
Mixture more than one or both of glue, talcum powder, polyethylene glycol etc., amount with lubricator with energy well known in the art
Realize that the amount of lubricant effect is defined, it is preferred that when the mass parts of the A Lishatan esters solid dispersions are 1, the lubrication
The mass parts of agent are 0.01~0.03.
Above-mentioned one preferable scheme of A Lishatan esters tablet, prescription are as follows：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Mannitol | 0.74 |
| PVPP | 0.22 |
| Ac-Di-Sol | 0.22 |
| Aerosil | 0.01 |
| Magnesium stearate | 0.01 |
Above-mentioned one preferable scheme of A Lishatan esters tablet, prescription are as follows：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Lactose | 0.74 |
| PVPP | 0.23 |
| Ac-Di-Sol | 0.22 |
| Magnesium stearate | 0.01 |
Above-mentioned one preferable scheme of A Lishatan esters tablet, prescription are as follows：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Starch | 0.58 |
| PVPP | 0.22 |
| Ac-Di-Sol | 0.22 |
| Low-substituted hydroxypropyl cellulose | 0.16 |
| Aerosil | 0.01 |
| Magnesium stearate | 0.01 |
Above-mentioned one preferable scheme of A Lishatan esters tablet, prescription are as follows：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Microcrystalline cellulose | 0.47 |
| PVPP | 0.18 |
| Ac-Di-Sol | 0.18 |
| Sodium carboxymethyl starch | 0.16 |
| Magnesium stearate | 0.01 |
Above-mentioned one preferable scheme of A Lishatan esters tablet, prescription are as follows：
Above-mentioned one preferable scheme of A Lishatan esters tablet, prescription are as follows：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Microcrystalline cellulose | 0.58 |
| PVPP | 0.22 |
| Ac-Di-Sol | 0.22 |
| Low-substituted hydroxypropyl methylcellulose | 0.16 |
| Aerosil | 0.01 |
| Magnesium stearate | 0.01 |
5th purpose of the invention is to provide a kind of preparation method of A Lishatan esters tablet, suitable in the 4th purpose
The large-scale production of the A Lishatan esters tablet, is comprised the following steps：
(1) by solid dispersions obtained by hot-melt extruded and additional auxiliary materials and mixing, vertical compression powder is obtained；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan ester tablets.
Vertical compression powder obtained by above-mentioned steps (1) can preferably be pre-processed, the step with screened pretreatment through 60~80 mesh sieves
Suddenly tabletting specification preferred 20mg, 30mg, 40mg, 60mg, 80mg, 120mg, 240mg in (2).
If it is desired, gained A Lishatan esters tablet can be further coated using common process and conventional coating material
Obtain coated tablet.
The present invention is had the following advantages relative to prior art and beneficial effect：
1st, a kind of improved A Lishatan esters solid dispersions are provided, by Formulation with realize hot-melt extruded prepare
Technique, and realize that hot-melt extrusion process prepares the technical advantages such as easy, the used time is shorter, ensure the dissolving out capability of solid dispersions；
2nd, a kind of preparation method of A Lishatan esters solid dispersions is provided, the preparation method uses hot-melt extruded work
Skill, the technique is not related to the use of solvent, and operating method is simple, can effectively simplify A Lishatan using hot-melt extrusion process
Ester preparation technology, and shorten the process time；
3rd, a kind of low A Lishatan ester solid dispersions of impurity content are provided, are joined by Formulation and critical process
Number is set, and (0 day) total impurities content is controlled below 1.5% at the beginning of the solid dispersions are made using melting extrusion technique,
Single miscellaneous content control below 0.5%, especially can by important degraded singly miscellaneous (EXP3174) content control below 0.3%；
4th, a kind of A Lishatan ester formulations are provided, the A Lishatan ester formulations include A Lishatan of the present invention
Ester solid dispersions, there is technique to prepare the technical advantages such as easy, the used time is shorter, it is good etc. also with stability height, dissolving out capability
Technical advantage；
5th, a kind of preparation method of A Lishatan esters tablet is provided, suitable for the big of A Lishatan esters tablet of the present invention
Large-scale production.
Brief description of the drawings
The gained solid dispersions of Fig. 1 embodiments 1, bulk drug, the XRD spectra comparison diagram of pure auxiliary material and physical mixture
Embodiment
With reference to embodiment and accompanying drawing, the present invention is described in further detail, but the embodiment invented is not limited to
This.
It is prepared by the solid dispersions of embodiment 1
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K30 | 2 |
| Poloxamer | 0.06 |
| Magnesium stearate | 0.03 |
(1) A Lishatan esters and auxiliary material are well mixed, physical mixture is made；
(2) it is 130 DEG C to set extrusion temperature, is at the uniform velocity added to the physical mixture in step (1) after temperature stabilization
In hot-melt extruded machine, ribbon extrudate is extruded；
(3) 60 mesh sieves, get A Lishatan esters medical solid point will be crushed after ribbon extrudate cooling obtained by step (2)
Granular media.
The XRD spectra of gained solid dispersions is compared with the XRD spectra of bulk drug, pure auxiliary material and physical mixture
(comparison diagram is as shown in Figure 1), by the contrast of XRD powder diagrams, A Lishatan esters are in solid dispersions with approximation
Unbodied form is present, it is known that the melting extrusion technique prepares the success of A Lishatan esters solid dispersions.
It is prepared by the solid dispersions of embodiment 2
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K30 | 1 |
| Poloxamer | 0.06 |
| Magnesium stearate | 0.03 |
(1) A Lishatan esters and auxiliary material are well mixed, physical mixture is made；
(2) it is 115 DEG C to set extrusion temperature, is at the uniform velocity added to the physical mixture in step (1) after temperature stabilization
In hot-melt extruded machine, ribbon extrudate is extruded；
(3) 60 mesh sieves, get A Lishatan esters medical solid point will be crushed after ribbon extrudate cooling obtained by step (2)
Granular media.
The presence in the form of approximation is unbodied in solid dispersions of A Lishatan esters is found by detecting, it is known that the melting
Expressing technique prepares the success of A Lishatan esters solid dispersions.
It is prepared by the solid dispersions of embodiment 3
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K30 | 0.8 |
| PEO | 0.7 |
| Poloxamer | 0.06 |
| Talcum powder | 0.03 |
(1) A Lishatan esters and auxiliary material are well mixed, and physical mixture is made；
(2) it is 100 DEG C to set extrusion temperature, is at the uniform velocity added to the physical mixture in step (1) after temperature stabilization
In hot-melt extruded machine, ribbon extrudate is extruded；
(3) 60 mesh sieves, get A Lishatan esters medical solid point will be crushed after ribbon extrudate cooling obtained by step (2)
Granular media.
The presence in the form of approximation is unbodied in solid dispersions of A Lishatan esters is found by detecting, it is known that the melting
Expressing technique prepares the success of A Lishatan esters solid dispersions.
It is prepared by the solid dispersions of embodiment 4
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-VA64 | 1 |
| Poloxamer | 0.05 |
| Aerosil | 0.03 |
(1) A Lishatan esters and auxiliary material are well mixed, and physical mixture is made；
(2) it is 120 DEG C to set extrusion temperature, is at the uniform velocity added to the physical mixture in step (1) after temperature stabilization
In hot-melt extruded machine, ribbon extrudate is extruded；
(3) 60 mesh sieves, get A Lishatan esters medical solid point will be crushed after ribbon extrudate cooling obtained by step (2)
Granular media.
The presence in the form of approximation is unbodied in solid dispersions of A Lishatan esters is found by detecting, it is known that the melting
Expressing technique prepares the success of A Lishatan esters solid dispersions.
It is prepared by the solid dispersions of embodiment 5
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-VA64 | 2 |
| Poloxamer | 0.06 |
| Aerosil | 0.03 |
(1) A Lishatan esters and auxiliary material are well mixed, and physical mixture is made；
(2) it is 120 DEG C to set extrusion temperature, is at the uniform velocity added to the physical mixture in step (1) after temperature stabilization
In hot-melt extruded machine, ribbon extrudate is extruded；
(3) 60 mesh sieves, get A Lishatan esters medical solid point will be crushed after ribbon extrudate cooling obtained by step (2)
Granular media.
The presence in the form of approximation is unbodied in solid dispersions of A Lishatan esters is found by detecting, it is known that the melting
Expressing technique prepares the success of A Lishatan esters solid dispersions.
It is prepared by the solid dispersions of embodiment 6
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-VA64 | 2 |
| Lauryl sodium sulfate | 0.03 |
| Talcum powder | 0.03 |
(1) A Lishatan esters and auxiliary material are well mixed, and physical mixture is made；
(2) it is 130 DEG C to set extrusion temperature, is at the uniform velocity added to the physical mixture in step (1) after temperature stabilization
In hot-melt extruded machine, ribbon extrudate is extruded；
(3) 60 mesh sieves, get A Lishatan esters medical solid point will be crushed after ribbon extrudate cooling obtained by step (2)
Granular media.
The presence in the form of approximation is unbodied in solid dispersions of A Lishatan esters is found by detecting, it is known that the melting
Expressing technique prepares the success of A Lishatan esters solid dispersions.
It is prepared by the solid dispersions of embodiment 7
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP VA64 | 0.85 |
| Cremophor RH40 | 0.15 |
| Glycerin monostearate | 0.08 |
| Aerosil | 0.03 |
(1) A Lishatan esters and auxiliary material are well mixed, and physical mixture is made；
(2) it is 120 DEG C to set extrusion temperature, is at the uniform velocity added to the physical mixture in step (1) after temperature stabilization
In hot-melt extruded machine, ribbon extrudate is extruded；
(3) 60 mesh sieves, get A Lishatan esters medical solid point will be crushed after ribbon extrudate cooling obtained by step (2)
Granular media.
The presence in the form of approximation is unbodied in solid dispersions of A Lishatan esters is found by detecting, it is known that the melting
Expressing technique prepares the success of A Lishatan esters solid dispersions.
It is prepared by the solid dispersions of embodiment 8
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K30 | 2 |
| Poloxamer | 0.03 |
| Lauryl sodium sulfate | 0.03 |
| Aerosil | 0.03 |
(1) A Lishatan esters and auxiliary material are well mixed, and physical mixture is made；
(2) it is 120 DEG C to set extrusion temperature, is at the uniform velocity added to the physical mixture in step (1) after temperature stabilization
In hot-melt extruded machine, ribbon extrudate is extruded；
(3) 60 mesh sieves, get A Lishatan esters medical solid point will be crushed after ribbon extrudate cooling obtained by step (2)
Granular media.
The presence in the form of approximation is unbodied in solid dispersions of A Lishatan esters is found by detecting, it is known that the melting
Expressing technique prepares the success of A Lishatan esters solid dispersions.
It is prepared by the solid dispersions of embodiment 9
| Species | Dosage |
| A Lishatan esters | 1 |
| PEO | 1.5 |
| Poloxamer | 0.03 |
| Lauryl sodium sulfate | 0.03 |
| Aerosil | 0.03 |
(1) A Lishatan esters and auxiliary material are well mixed, and physical mixture is made；
(2) it is 130 DEG C to set extrusion temperature, is at the uniform velocity added to the physical mixture in step (1) after temperature stabilization
In hot-melt extruded machine, ribbon extrudate is extruded；
(3) 60 mesh sieves, get A Lishatan esters medical solid point will be crushed after ribbon extrudate cooling obtained by step (2)
Granular media.
The presence in the form of approximation is unbodied in solid dispersions of A Lishatan esters is found by detecting, it is known that the melting
Expressing technique prepares the success of A Lishatan esters solid dispersions.
It is prepared by the solid dispersions of embodiment 10
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K90 | 2 |
| Tween-80 | 0.08 |
| Aerosil | 0.03 |
(1) A Lishatan esters and auxiliary material are well mixed, and physical mixture is made；
(2) it is 110 DEG C to set extrusion temperature, is at the uniform velocity added to the physical mixture in step (1) after temperature stabilization
In hot-melt extruded machine, ribbon extrudate is extruded；
(3) 60 mesh sieves, get A Lishatan esters medical solid point will be crushed after ribbon extrudate cooling obtained by step (2)
Granular media.
The presence in the form of approximation is unbodied in solid dispersions of A Lishatan esters is found by detecting, it is known that the melting
Expressing technique prepares the success of A Lishatan esters solid dispersions.
It is prepared by the solid dispersions of comparative example 1
Carrier material in the prescription of embodiment 1 is replaced with into one of hot-melt extrusion process common carrier materialIt is (poly-
Vinyl caprolactam-polyvinyl acetate-polyethyleneglycol-graft copolymer),
Solid dispersions are prepared using technique same as Example 1.
It is prepared by the solid dispersions of comparative example 2
Carrier material dosage in the prescription of embodiment 1 is reduced to 0.5 mass parts,
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K30 | 0.5 |
| Poloxamer | 0.06 |
| Magnesium stearate | 0.03 |
Solid dispersions are prepared using technique same as Example 1.
It is prepared by the solid dispersions of comparative example 3
Using prescription same as Example 1, adjustment extrusion temperature obtains solid dispersions to 180 DEG C.
| Species | Dosage |
| A Lishatan esters | 1 |
| PVP-K30 | 2 |
| Poloxamer | 0.06 |
| Magnesium stearate | 0.03 |
The solid dispersions dissolving out capability of embodiment 11 detects
It is molten in pH6.8 phosphate buffers to detect solid dispersions and comparative example 1~3 obtained by embodiment 1-10
Artificial situation, and acquired results are as follows：
| Embodiment | 15min (%) |
| Embodiment 1 | 88 |
| Embodiment 2 | 82 |
| Embodiment 3 | 85 |
| Embodiment 4 | 86 |
| Embodiment 5 | 88 |
| Embodiment 6 | 89 |
| Embodiment 7 | 86 |
| Embodiment 8 | 88 |
| Embodiment 9 | 82 |
| Embodiment 10 | 85 |
| Comparative example 1 | 55 |
| Comparative example 2 | 71 |
| Comparative example 3 | 84 |
By analysis, the dissolution of embodiment 1-10 and the gained solid dispersions of comparative example 3 in 15min exists
More than 80%, meet A Lishatan ester solid pharmaceutical preparation clinical application requirements；And comparative example 1~2 is reviewed, wherein contrast is implemented
Because it does not use claimed carrier material, its dissolution of gained solid dispersions in 15min is only example 1
55%, far below solid dispersions obtained by embodiment 1-10, and do not meet A Lishatan ester solid pharmaceutical preparation clinical application requirements；And
Comparative example 2 is then because used carrier material is very few so that active ingredient is not dispersed in carrier enough with target morphology
In material, show as gained solid dispersions 15min dissolution do not meet yet the clinical application of A Lishatan ester solid pharmaceutical preparations will
Ask.
Further experiment finds that embodiment 1-10 and the gained solid dispersions of comparative example 3 are in other dissolution mediums
In dissolution rate also correspond to A Lishatan ester solid pharmaceutical preparation clinical application requirements.
The solid dispersions dissolving out capability of embodiment 11 detects
The impurity situation of solid dispersions and comparative example 1~3 obtained by embodiment 1-10 is detected, acquired results are as follows：
| Embodiment | Extrusion temperature (DEG C) | EXP3174 (%) | Total miscellaneous (%) |
| Embodiment 1 | 120 | 0.049 | 0.352 |
| Embodiment 2 | 115 | 0.042 | 0.311 |
| Embodiment 3 | 125 | 0.047 | 0.345 |
| Embodiment 4 | 120 | 0.045 | 0.361 |
| Embodiment 5 | 120 | 0.057 | 0.377 |
| Embodiment 6 | 130 | 0.053 | 0.362 |
| Embodiment 7 | 120 | 0.043 | 0.358 |
| Embodiment 8 | 120 | 0.057 | 0.377 |
| Embodiment 9 | 130 | 0.051 | 0.372 |
| Embodiment 10 | 110 | 0.047 | 0.355 |
| Comparative example 1 | 120 | 0.066 | 0.417 |
| Comparative example 2 | 120 | 0.061 | 0.402 |
| Comparative example 3 | 180 | 0.980 | 3.057 |
Understand that hot-melt extruded temperature is for solid dispersions dissolution by the result of comprehensive analysis embodiment 11,12
The influence of degree is smaller, and the solid dispersions (comparative example 3) being prepared at a temperature of 180 DEG C of hot-melt extruded remain to realize
Satisfactory dissolving out capability；And hot-melt extruded temperature has considerable influence to the impurity content of solid dispersions, specifically, working as
Embodiment 1-10 and comparative example 1-2 due to by hot-melt extruded temperature control at 110~130 DEG C, can will total miscellaneous content
In the range of far below 1.5%, important miscellaneous (EXP3174) the content control of list is worked as in the range of far below 0.3% for control
When hot-melt extruded temperature is more than 130 DEG C, impurity content steeply rises, so that gained solid dispersions are although solve dissolution
Technical problem, but without solve impurity content technical problem.
The preparation of the A Lishatan ester tablets of embodiment 12
Using the A Lishatan ester solid dispersions of the gained of embodiment 1, A Lishatan ester formulations are prepared using following prescription：
(1) solid dispersions obtained by hot-melt extruded are obtained into vertical compression powder with being handled after additional auxiliary materials and mixing through 60 mesh sieves；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan esters tablet (80mg).
The preparation of the A Lishatan ester tablets of embodiment 13
Using the A Lishatan ester solid dispersions of the gained of embodiment 1, A Lishatan ester formulations are prepared using following prescription：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Lactose | 0.74 |
| PVPP | 0.23 |
| Ac-Di-Sol | 0.22 |
| Magnesium stearate | 0.01 |
(1) solid dispersions obtained by hot-melt extruded are obtained into vertical compression powder with being handled after additional auxiliary materials and mixing through 60 mesh sieves；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan esters tablet (80mg).
The preparation of the A Lishatan ester tablets of embodiment 14
Using the A Lishatan ester solid dispersions of the gained of embodiment 1, A Lishatan ester formulations are prepared using following prescription：
(1) solid dispersions obtained by hot-melt extruded are obtained into vertical compression powder with being handled after additional auxiliary materials and mixing through 60 mesh sieves；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan esters tablet (80mg).
The preparation of the A Lishatan ester tablets of embodiment 15
Using the A Lishatan ester solid dispersions of the gained of embodiment 1, A Lishatan ester formulations are prepared using following prescription：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Microcrystalline cellulose | 0.47 |
| PVPP | 0.18 |
| Ac-Di-Sol | 0.18 |
| Sodium carboxymethyl starch | 0.16 |
| Magnesium stearate | 0.01 |
(1) solid dispersions obtained by hot-melt extruded are obtained into vertical compression powder with being handled after additional auxiliary materials and mixing through 60 mesh sieves；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan esters tablet (80mg).
The preparation of the A Lishatan ester tablets of embodiment 16
Using the A Lishatan ester solid dispersions of the gained of embodiment 1, A Lishatan ester formulations are prepared using following prescription：
(1) solid dispersions obtained by hot-melt extruded are obtained into vertical compression powder with being handled after additional auxiliary materials and mixing through 60 mesh sieves；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan esters tablet (80mg).
WhereinIt is lactose/PVP/Crospovidone vertical compression excipient.
The preparation of the A Lishatan ester tablets of embodiment 17
Using the A Lishatan ester solid dispersions of the gained of embodiment 1, A Lishatan ester formulations are prepared using following prescription：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Microcrystalline cellulose | 0.58 |
| PVPP | 0.22 |
| Ac-Di-Sol | 0.22 |
| Low-substituted hydroxypropyl methylcellulose | 0.16 |
| Aerosil | 0.01 |
| Magnesium stearate | 0.01 |
(1) solid dispersions obtained by hot-melt extruded are obtained into vertical compression powder with being handled after additional auxiliary materials and mixing through 60 mesh sieves；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan esters tablet (80mg).
The preparation of the A Lishatan ester tablets of embodiment 18
Using the A Lishatan ester solid dispersions of the gained of embodiment 1, A Lishatan ester formulations are prepared using following prescription：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Lactose | 0.74 |
| PVPP | 0.22 |
| Cross-linked carboxymethyl cellulose calcium | 0.14 |
| Starch | 0.08 |
| Aerosil | 0.01 |
| Magnesium stearate | 0.01 |
(1) solid dispersions obtained by hot-melt extruded are obtained into vertical compression powder with being handled after additional auxiliary materials and mixing through 60 mesh sieves；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan esters tablet (80mg).
The preparation of the A Lishatan ester tablets of embodiment 19
Using the A Lishatan ester solid dispersions of the gained of embodiment 1, A Lishatan ester formulations are prepared using following prescription：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Mannitol | 0.74 |
| PVPP | 0.22 |
| Sodium carboxymethyl starch | 0.14 |
| Pregelatinized starch | 0.08 |
| Aerosil | 0.01 |
| Magnesium stearate | 0.01 |
(1) solid dispersions obtained by hot-melt extruded are obtained into vertical compression powder with being handled after additional auxiliary materials and mixing through 60 mesh sieves；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan esters tablet (80mg).
The preparation of the A Lishatan ester tablets of embodiment 20
Using the A Lishatan ester solid dispersions of the gained of embodiment 1, A Lishatan ester formulations are prepared using following prescription：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Microcrystalline cellulose | 0.74 |
| Starch | 0.22 |
| Ac-Di-Sol | 0.22 |
| Aerosil | 0.01 |
| Magnesium stearate | 0.01 |
(1) solid dispersions obtained by hot-melt extruded are obtained into vertical compression powder with being handled after additional auxiliary materials and mixing through 60 mesh sieves；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan esters tablet (80mg).
The preparation of the A Lishatan ester tablets of embodiment 21
Using the A Lishatan ester solid dispersions of the gained of embodiment 1, A Lishatan ester formulations are prepared using following prescription：
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Mannitol | 0.74 |
| PVPP | 0.22 |
| Ac-Di-Sol | 0.18 |
| Sodium carboxymethylcellulose | 0.04 |
| Aerosil | 0.01 |
| Magnesium stearate | 0.01 |
(1) solid dispersions obtained by hot-melt extruded are obtained into vertical compression powder with being handled after additional auxiliary materials and mixing through 60 mesh sieves；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan esters tablet (80mg).
The preparation of the A Lishatan ester tablets of comparative example 4
Using the formulation and technology of embodiment 12, PVPP is changed to sodium alginate, A Lishatan ester pieces are prepared
Agent.
| Species | Dosage |
| A Lishatan ester solid dispersions | 1 |
| Mannitol | 0.74 |
| Sodium alginate | 0.22 |
| Ac-Di-Sol | 0.22 |
| Aerosil | 0.01 |
| Magnesium stearate | 0.01 |
The disintegration rate of embodiment 22 is tested
Embodiment 12~21, the gained A Lishatan ester disintegration of tablet speed of comparative example 4 are detected, is measured in 37 DEG C of water
Disintegration time is as follows：
| Embodiment | Disintegration time (min) |
| Embodiment 12 | 2.7 |
| Embodiment 13 | 3 |
| Embodiment 14 | 2 |
| Embodiment 15 | 2 |
| Embodiment 16 | 1 |
| Embodiment 17 | 1 |
| Embodiment 18 | 4.2 |
| Embodiment 19 | 5.0 |
| Embodiment 20 | 4.7 |
| Embodiment 21 | 4.0 |
| Comparative example 4 | 8.5 |
As can be seen that the original, auxiliary material in the prescription of embodiment 12~21 be in the scope of protection of present invention, gained
A Lishatan esters tablet can realize fater disintegration in 5 minutes, and then the smooth dissolution of real active ingredient, and then ensure clinical
Medication effect, wherein embodiment 12-17 more can be achieved on to be disintegrated in 3 minutes；
And for comparative example 4, because it does not use claimed adhesive, therefore its disintegration time mistake
It is long, it is unfavorable for realizing the dissolution for meeting clinical application.
Further stability experiment shows that every stability indicator of preparation is far above phase obtained by embodiment 12-21
Close drug registration rules and regulations.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any Spirit Essences without departing from the present invention with made under principle change, modification, replacement, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (10)
1. a kind of A Lishatan esters solid dispersions, comprising A Lishatan esters, carrier material, plasticizer, the A Lishatan esters
Solid dispersions are prepared using hot-melt extrusion process, the carrier material be copolyvidone, PVP, PEO,
Rilanit special, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polymethacrylate resin, ethylene glycol-vinyl alcohol
More than one or both of graft copolymer mix the mixture of gained with arbitrary proportion, the plasticizer be poloxamer,
One kind in tween, lauryl sulfate, cetyl sulfate, octadecyl sulfate, glycerin monostearate or two
Gained mixture, the lauryl sulfate, cetyl sulfate, octadecyl sulfuric acid are mixed with arbitrary proportion more than kind
Salt particular certain cancers, sylvite, magnesium salts, when the mass parts of A Lishatan esters are 1, the mass parts of carrier material are 0.8~2.5, excellent
1~2 is selected, the mass parts of plasticizer are 0.01~0.1, preferably 0.03~0.08.
2. A Lishatan esters solid dispersions according to claim 1, it is characterised in that when the A Lishatan esters solid
Dispersion further includes glidant, the one kind or two of the glidant in magnesium stearate, aerosil, talcum powder
The mixture of gained is mixed more than kind with arbitrary proportion, when the quality of A Lishatan esters in the A Lishatan esters solid dispersions
When part is 1, the mass parts of the glidant are 0.01~0.1, preferably 0.02~0.05.
A kind of 3. A Lishatan ester solid dispersions according to any one of claim 1 or 2, it is characterised in that the heat
The extrusion temperature of molten expressing technique is 100~200 DEG C, preferably 100~130 DEG C.
4. A Lishatan esters solid dispersions according to claim 1, it is characterised in that the A Lishatan esters solid point
The prescription of granular media is any one in following prescription 1-10：
Prescription 1
Prescription 2
Prescription 3
Prescription 4
Prescription 5
Prescription 6
Prescription 7
Prescription 8
Prescription 9
Prescription 10
5. a kind of method that hot-melt extruded method prepares the A Lishatan ester solid dispersions as described in claim 1-4 any one,
It is characterized in that methods described comprises the following steps：
(1) A Lishatan esters and auxiliary material are well mixed, physical mixture is made；
(2) physical mixture in step (1) is added in hot-melt extruded machine, by melting, extruding ribbon product；
(3) by pulverization process after ribbon product cooling obtained by step (2), get A Lishatan ester medicine solid dispersions.
Original, auxiliary material in the step (1) cross 60~100 mesh sieves before combination；The extrusion of hot-melt extruded in the step (2)
Temperature is 100~200 DEG C, preferably 100~130 DEG C.
6. a kind of A Lishatan esters solid dispersions, include A Lishatan esters, carrier material, plasticizer, it is characterised in that described
A Lishatan esters solid dispersions are prepared using hot-melt extrusion process, and the carrier material is copolyvidone, PVP, polycyclic oxygen
Ethane, rilanit special, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polymethacrylate resin, ethylene glycol-second
The mixture of gained more than one or both of enol graft copolymer is mixed with arbitrary proportion, the plasticizer is selected from pool Lip river
One kind in Sha Mu, tween, lauryl sulfate, cetyl sulfate, octadecyl sulfate, glycerin monostearate
It is or two or more with arbitrary proportion mixing gained mixture, the lauryl sulfate, cetyl sulfate, octadecyl
Sulfate particular certain cancers, sylvite, magnesium salts, the extrusion temperature of the hot-melt extrusion process is 100 DEG C~130 DEG C.
7. a kind of A Lishatan esters tablet, the tablet is consolidated comprising the A Lishatan esters as described in claim 1-4,6 any one
Body dispersion, and include at least one of filler, disintegrant, adhesive, it is characterised in that the filler be selected from lactose,
One in mannitol, dextrin, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, calcium phosphate, calcium monohydrogen phosphate, starch lactose
Kind or the two or more mixtures that gained is mixed with arbitrary proportion, preferably one in lactose, mannitol, microcrystalline cellulose, starch
Kind or the two or more mixtures that gained is mixed with arbitrary proportion；In the A Lishatan ester formulations, when the A Lishatan esters
When the mass parts of solid dispersions are 1, the mass parts of the filler are 0~1.0；It is fine that the disintegrant is selected from cross-linked carboxymethyl
Tie up plain sodium, PVPP, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, cross-linked carboxymethyl
More than one or both of cellulose calcium mix the mixture of gained with arbitrary proportion, in the A Lishatan ester formulations, when
When the mass parts of the A Lishatan esters solid dispersions are 1, the mass parts of the disintegrant are 0~1.0；Described adhesive is selected
HPMC, Hydroxypropylcelliloxe, sodium carboxymethylcellulose, PVP, starch are selected from from described adhesive
More than slurry, one or both of gelatin mix the mixture of gained with arbitrary proportion, in the A Lishatan ester formulations, work as institute
When the mass parts for stating A Lishatan ester solid dispersions are 1, the mass parts of described adhesive are 0~0.05.
8. A Lishatan esters tablet according to claim 7, it is characterised in that A Lisha in the A Lishatan esters tablet
When the mass parts of smooth ester solid dispersions are 1, the mass parts of the filler are 0.4~0.8, and the mass parts of the disintegrant are
0.4~0.8.
9. according to the A Lishatan ester tablets described in any one of claim 7 or 8, it is characterised in that the A Lishatan esters piece
Lubricant is further included in agent, the lubricant is in stearic acid, magnesium stearate, superfine silica gel powder, talcum powder, polyethylene glycol
One or more kinds of mixtures, when the A Lishatan esters solid dispersions mass parts be 1 when, the lubricant
Mass parts are 0.01~0.03.
10. a kind of preparation method of the A Lishatan ester tablets as described in claim 7-9 any one, is comprised the following steps：
(1) by solid dispersions obtained by hot-melt extruded and additional auxiliary materials and mixing, vertical compression powder is obtained；
(2) vertical compression pressed powder obtained by step (1) is produced into A Lishatan ester tablets.
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