CN108403648A - It is a kind of to treat myelodysplastic syndrome pharmaceutical composition and preparation method thereof - Google Patents
It is a kind of to treat myelodysplastic syndrome pharmaceutical composition and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to field of pharmaceutical preparations, specifically discloses and a kind for the treatment of myelodysplastic syndrome pharmaceutical composition and preparation method thereof.The composition includes lenalidomide, octadecenic acid ethyl ester, aerosil, oleic acid LABRAFIL M 1944CS.The selection of above-mentioned auxiliary material reduces hot-melt extruded temperature, easily changes expressing technique, and can get the screw rod shearing effect of sufficient intensity；Simultaneously, moreover it is possible to play solubilization, hot melting temperature can be reduced to 120 140 DEG C, not only reduce energy consumption, and ensure that the stability of drug, improve dissolution rate.Preparation process is simple, and energy consumption is small, and no solvent residue is easy to continuous mass production.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to it is a kind of treat myelodysplastic syndrome pharmaceutical composition and
Preparation method.
Background technology
Myelodysplastic syndrome (MDS), and have title preleukemia, it is one group of acquisition for originating from candidate stem cell
The Clonal disease of property, characteristic pathology physiological change is Clonal hematopoietic stem/progenitor dysplasia and ineffective hematopoiesis, base
This Clinical symptoms is that hematopoietic cell has dysplastic morphologic features and peripheral blood cells to reduce in marrow, and is changed into agent
The danger of type marrow series leukemia is very high.The cause of disease of MDS may with heredity, environment or certain factors as and it is virus hepatitis, swollen
After tumor chemicotherapy and some cytotoxic drugs are related.MDS is mainly seen in the elderly, 90% patient age>60 years old.According to system
It counts, at present global about 300,000 patients of this disease.It is about 3/100000ths in the incidence of China, MDS, and morbidity's age
It is 10 years old or so younger than western countries.With the improvement of people ' s living standards and living-pattern preservation and the industrialization of the country
The generation of the raising of degree, the disease is in rising trend.
The cause of disease of MDS is still not clear, thus it is speculated that is due to biology, chemically or physically etc. factors cause gene mutation, chromosome
Exception makes the cell clonal hyperplasia of some canceration.Generally acknowledged already, mutagens such as virus, some drugs (such as chemotherapeutic), radiation
(radiotherapy), industrial reaction agent (such as benzene, polyethylene) and environmental pollution can cause the rearrangement or gene rearrangement of chromosome, it is also possible to
The change of gene expression is only caused to lead to MDS.
The treatment of MDS is always the intractable area of blood educational circles.Current clinically myelodysplastic syndrome is commonly used
Therapy has supportive treatment (red blood cell transfusion and dispel iron treatment, platelet transfusion, hemopoieticgrowth factor etc.), and immunosupress is controlled
It treats (antithymocyte globulin and antilymphocyte globulin (ALG), cyclosporin A, cortex hormone of aadrenaline), chemotherapy, Hematopoietic Stem is thin
Born of the same parents' transplanting etc..But the inevitable side effect such as also bring along easy infection simultaneously.Molecular mechanism sick MDS is illustrated to MDS
Treatment brings new hope, and initial research show, using survival signaling and genetic integrity as targeted therapy be expected to blocking MDS into
Exhibition.
Huppert's disease (MM) is a kind of malignant tumour leading to osteoclasia and marrow failure originating from bone marrow plasma cells,
Incidence is only second to malignant lymphoma and occupies second in Malignancy.It is about in the annual morbidity of the country such as America and Europe
4/100000, the ratio between male and female patient is 3：2.MM is the Clonal disease of plasma cell dyscrasias proliferation, is still uncurable disease at present
More disease.The patient just controlled can be with use in conjunction melphalan, adriamycin, prednisone, dexamethasone, immunomodulator (such as sand
Sharp degree amine and lenalidomide) and proteasome inhibitor (such as bortezomib) treatment.There is the patient of appropriate donors that can also connect
By stem cell transplantation.
In the past, multiple myeloma patients mostly used greatly interferon therapy, the therapeutic schemes such as chemotherapy such as MP, VAD or DVD,
Or autologous bone marrow, autologous peripheral blood stem cells and simplified marrow transplanting, but the high recurrence rate of such disease, and workable rescue
It is seldom to help treatment.Lenalidomide is a kind of new adjusting immunologic pattern, non-chemical therapy anticancer drug, chemical composition and Sha Lidu
Amine (thalidomide) is similar, but the more remarkable treatment effect in experimental applications, and does not occur taking Thalidomide institute often
Some side effects generated.
Lenalidomide (Lenalidomide/Revlimid), entitled 3- (4- amino -1, the 3- dihydro -1- oxos -2H- of chemistry
Iso-indoles -2- bases) -2,6- piperidine diones, molecular formula C13H 13N 3O 3, molecular weight 259.2606.Its chemical structural formula is such as
Under：
Lenalidomide is the antitumor drug developed by Celgene biopharmaceutical companys of the U.S., is the similar of Thalidomide
Object, but it is more less side effects than Thalidomide, and do not cause newborn teratogenesis.Clinically it is mainly used for myeloproliferative disorder synthesis
The treatment of sign (MDS), Huppert's disease (MM), leukaemia and lymphoma mantle cell etc., on acquisition FDA in 2005 is approved
City.Lenalidomide is the representative drug of immunomodulator of new generation, has dual mechanism of action.
Lenalidomide is a kind of difficult-soluble medicine, and it is poor in some patients' body absorption that the indissoluble property of the drug causes.Thus, increase
It is very necessary to add its dissolution rate and bioavilability from present's view.The common side for improving insoluble drug bioavilability
Method has micronization technology and solid dispersion technology.
The conventional tablet of prior art preparation there are dissolution rates it is low, bioavilability is not high the problems such as, preparation method behaviour
It is long to make step, granulation and it is dry take that longer, energy consumption is higher, the equipment needed is more, preparation efficiency is low, production cost is high；System
Grain porosity, the impacted factor of reproducibility of the properties such as specific surface area are more, to being affected for the stability of drug-eluting.
Patent No. 201610877553.4 provides a kind of pharmaceutical composition of lenalidomide and preparation method thereof, by
The lenalidomide of micronizing and other auxiliary materials form, but after drug micronization, surface free energy is larger, there is becoming for self-assemble
Gesture reduces micronizing effect.And micronization process efficiency is low, expends duration, is unfavorable for producing progress greatly.
Patent No. 201310752093.9 provides a kind of pharmaceutical composition of lenalidomide and preparation method thereof, by
The compositions such as lenalidomide, carrier, solubilizer, disintegrant, lubricant and adhesive, by the way that lenalidomide and carrier grinding to be made
Solid dispersions, to improve product stability and dissolution rate.But solid dispersions drugloading rate prepared by polishing is less, dissolution rate
And bioavilability is all poor.
In recent years, hot-melt extruded method receives domestic and international pharmacy as a kind of novel method for preparing solid dispersions and grinds
The concern for the person of studying carefully.This method is cut by the single screw rod or double screw extruder heated paragraph by paragraph, realizing that the transmission of material conveys
Cut mixing and melt extruded.Relative to traditional solid dispersions preparation method, hot-melt extruded has production efficiency high, without having
Solvent, be suitable for industrialized production the features such as.But the fusing point of lenalidomide is 269-271 DEG C, is had compared with Gao Rong for this
The drug of point, hot-melt extruded method is easy to cause the thermal decomposition of pharmaceutical carrier, to limit the extensive use of the method.
Invention content
The purpose of the present invention is to provide a kind for the treatment of myelodysplastic syndrome medicines for being easy to produce, be easy to dissolution greatly
Object solid dispersions and preparation method thereof.
In order to achieve the above-mentioned object of the invention, inventor has carried out many experiments work, finds to prepare using hot-melt extruded method
Bulk pharmaceutical chemicals, specific auxiliary material are added in extruder by solid dispersions simultaneously, and under in screw rod driving, material realizes melting, row
The operations such as gas, batch mixing, supercharging extrusion, the final lenalidomide solid dispersions for obtaining height mixing and disperseing.
The present invention provides a kind of solid dispersions of lenalidomide.Specifically, the solid dispersions include lenalidomide, ten
Eight olefin(e) acid ethyl esters, aerosil and oleic acid LABRAFIL M 1944CS.The selection of above-mentioned auxiliary material can not only reduce hot melt and squeeze
Go out temperature, easily change expressing technique, and can get the screw rod shearing effect of sufficient intensity, to be effectively improved drug in the carrier
Dispersity, simultaneously, moreover it is possible to play solubilization.
Further, the present invention provides the lenalidomide preparation prepared by the solid dispersions of above-mentioned lenalidomide.Will on
The solid dispersions for stating lenalidomide are further prepared into particle, powder, capsule, tablet, lamination method be wrapped on pellet or
It is coated in preparation outer surface, corresponding solid pharmaceutical preparation is made.
Specifically, a kind of anticancer drug solid dispersion composition, includes the ingredient of following weight ratio：
Preferably comprise the solid dispersion composition of the ingredient of following weight ratio:
It further preferably include the solid dispersion composition of the ingredient of following weight ratio:
Another object of the present invention is to provide a kind of myelodysplastic syndrome solid dispersion compositions for the treatment of
Preparation method.The preparation method of the lenalidomide solid dispersion composition is to use torching mark, including following
Step：
(1) it is weighed by recipe quantity；
(2) lenalidomide, octadecenic acid ethyl ester, aerosil, oleic acid LABRAFIL M 1944CS are mixed with mixing machine
It closes uniformly, and material after mixing is crossed into 60 mesh and is sieved twice；
(3) extrusion temperature of double screw extruder is set as 120-300 DEG C, and temperature starts screw rod after being raised to setting value, will
Mixing sieving in step (2) is added in extruder, by heating melting, is squeezed, is finally squeezed out with ribbon；
(4) bar is placed in 20 DEG C or less coolings and obtains medicine solid dispersion through 80 mesh pulverization process after cooling
Grain or powder；
(5) using gained particle or powder in step (4) as granule or powder direct packaging, or it is processed into capsule
The solid pharmaceutical preparations such as agent, tablet.
The present invention investigates the hot-melt extruded solid dispersions of lenalidomide using Differential scanning calorimetry.Differential is swept
It retouches heat analysis result and shows that lenalidomide endothermic peak disappears.
Compared with traditional handicraft, the present invention has advantageous effect following prominent：
1, the fusing point of lenalidomide is at 269-271 DEG C, and in the present invention, inventor is creative in lenalidomide hot-melt extruded
Be combined oleic acid LABRAFIL M 1944CS and aerosil, as carrier and stabilizer, achieve unexpected effect
Hot melting temperature can be reduced to 120-140 DEG C, not only reduce energy consumption by fruit, and it is difficult to overcome the high technology of lenalidomide fusing point
Topic, and ensure that the stability of drug.
2, in the present invention, inventor is creative in lenalidomide hot-melt extruded to have used octadecenic acid ethyl ester, profit
Sliding effect makes lenalidomide disperse in carrier material more uniformly, meanwhile, the effect of Fast Stripping is played in dissolution medium
Fruit.The bioavilability of insoluble drug is improved, dosage is reduced, reduces adverse drug reaction.By the solid dispersions
The dissolution rates such as capsule obtained, tablet are high, stability is good.
3, apparatus and process provided by the invention is simple, and energy consumption is small, no solvent residue, and whole process will not introduce other miscellaneous
Matter, it is easy to accomplish continuous mass production.
Description of the drawings
Fig. 1：The lenalidomide solid dispersions (extrudate) that are prepared in embodiment 3,4 (physical mixed of comparative example
Object), differential scanning calorimetric analysis (DSC) collection of illustrative plates of lenalidomide bulk pharmaceutical chemicals；
Wherein, 1 is solid dispersions；2 be bulk pharmaceutical chemicals；3 be physical mixture；
Fig. 2：(embodiment 1-5, comparison are implemented for lenalidomide bulk pharmaceutical chemicals, physical mixture and lenalidomide solid dispersions
Example 1-4) drug-eluting curve graph.
Specific implementation mode
The following examples will make the present invention more specifically to explain, but the present invention is not limited only to these implementations
Example, these same embodiments are not also limit the invention in any way.
Embodiment 1
Prepare the lenalidomide hot-melt extruded solid dispersions by forming as following formula：
It is weighed by recipe quantity, lenalidomide, octadecenic acid ethyl ester, aerosil, oleic acid polyethylene glycol is sweet
Grease is uniformly mixed with mixing machine, and material after mixing is crossed 60 mesh and is sieved twice.Set the extrusion temperature of double screw extruder as
120 DEG C, temperature starts screw rod after being raised to setting value, and step, which is mixed sieving, to be added in extruder, is warming up to 120 DEG C completely
Melting squeezes out and obtains bands, cooling at 20 DEG C, crushed 80 mesh sieve, obtains lenalidomide solid dispersion particles or powder
End.
Embodiment 2
It is weighed by recipe quantity, lenalidomide, octadecenic acid ethyl ester, aerosil, oleic acid polyethylene glycol is sweet
Grease is uniformly mixed with mixing machine, and material after mixing is crossed 60 mesh and is sieved twice.Set the extrusion temperature of double screw extruder as
120 DEG C, temperature starts screw rod after being raised to setting value, and step, which is mixed sieving, to be added in extruder, is warming up to 130 DEG C completely
Melting squeezes out and obtains bands, cooling at 20 DEG C, crushed 80 mesh sieve, obtains lenalidomide solid dispersion particles or powder
End.
Embodiment 3
It is weighed by recipe quantity, lenalidomide, octadecenic acid ethyl ester, aerosil, oleic acid polyethylene glycol is sweet
Grease is uniformly mixed with mixing machine, and material after mixing is crossed 60 mesh and is sieved twice.Set the extrusion temperature of double screw extruder as
120 DEG C, temperature starts screw rod after being raised to setting value, and step, which is mixed sieving, to be added in extruder, is warming up to 140 DEG C completely
Melting squeezes out and obtains bands, cooling at 20 DEG C, crushed 80 mesh sieve, obtains lenalidomide solid dispersion particles or powder
End.
Embodiment 4
It is weighed by recipe quantity, lenalidomide, octadecenic acid ethyl ester, aerosil, oleic acid polyethylene glycol is sweet
Grease is uniformly mixed with mixing machine, and material after mixing is crossed 60 mesh and is sieved twice.Set the extrusion temperature of double screw extruder as
120 DEG C, temperature starts screw rod after being raised to setting value, and step, which is mixed sieving, to be added in extruder, is warming up to 120 DEG C completely
Melting squeezes out and obtains bands, cooling at 20 DEG C, crushed 80 mesh sieve, obtains lenalidomide solid dispersion particles or powder
End.
Embodiment 5
It is weighed by recipe quantity, lenalidomide, octadecenic acid ethyl ester, aerosil, oleic acid polyethylene glycol is sweet
Grease is uniformly mixed with mixing machine, and material after mixing is crossed 60 mesh and is sieved twice.Set the extrusion temperature of double screw extruder as
120 DEG C, temperature starts screw rod after being raised to setting value, and step, which is mixed sieving, to be added in extruder, is warming up to 140 DEG C completely
Melting squeezes out and obtains bands, cooling at 20 DEG C, crushed 80 mesh sieve, obtains lenalidomide solid dispersion particles or powder
End.
Comparative example 1
Lenalidomide 100g
Aerosil 400g
Oleic acid LABRAFIL M 1944CS 2500g
It is weighed by recipe quantity, lenalidomide, aerosil, oleic acid LABRAFIL M 1944CS is mixed with mixing machine
It closes uniformly, and material after mixing is crossed into 60 mesh and is sieved twice.The extrusion temperature of double screw extruder is set as 120 DEG C, temperature is raised to
Start screw rod after setting value, step, which is mixed sieving, to be added in extruder, is warming up to 140 DEG C of melting, extrusions completely and is obtained
Bands, it is cooling at 20 DEG C, 80 mesh sieve is crushed, lenalidomide solid dispersion particles or powder are obtained.
Comparative example 2
Lenalidomide 100g
Octadecenic acid ethyl ester 300g
Oleic acid LABRAFIL M 1944CS 2500g
It is weighed by recipe quantity, lenalidomide, octadecenic acid ethyl ester, oleic acid LABRAFIL M 1944CS is mixed with mixing machine
It closes uniformly, and material after mixing is crossed into 60 mesh and is sieved twice.The extrusion temperature of double screw extruder is set as 120 DEG C, temperature is raised to
Start screw rod after setting value, step, which is mixed sieving, to be added in extruder, is warming up to 270 DEG C of melting, extrusions completely and is obtained
Bands, it is cooling at 20 DEG C, 80 mesh sieve is crushed, lenalidomide solid dispersion particles or powder are obtained.
Comparative example 3
It is weighed by recipe quantity, lenalidomide, octadecenic acid ethyl ester, aerosil, Macrogol 6000 is mixed
Conjunction machine is uniformly mixed, and material after mixing is crossed 60 mesh and is sieved twice.The extrusion temperature of double screw extruder is set as 120 DEG C, temperature
Degree starts screw rod after being raised to setting value, and step, which is mixed sieving, to be added in extruder, is warming up to 267 DEG C of meltings completely, squeezes
Go out to obtain bands, cooled down at 20 DEG C, crushed 80 mesh sieve, obtain lenalidomide solid dispersion particles or powder.
Comparative example 4
Lenalidomide 100g
Octadecenic acid ethyl ester 300g
Aerosil 400g
Oleic acid LABRAFIL M 1944CS 2500g
It is uniformly mixed and is prepared into physical mixture.
Verify embodiment 1
By the lenalidomide solid dispersions prepared in embodiment 3,4 gained physical mixture of comparative example and come that
It spends amine bulk pharmaceutical chemicals and carries out differential scanning calorimetric analysis (DSC) experiment, corresponding collection of illustrative plates is shown in Fig. 1；
Differential scanning calorimetric analysis method：10 milligrams of sample is weighed to be placed in aluminium dish, using alumina crucible as reference substance,
Temperature elevating range is 20 DEG C~300 DEG C in nitrogen stream, with 10 DEG C/min-1Rate heating scan.
As shown in Figure 1：There are apparent Pa Boxini endothermic peaks in the spectral line of lenalidomide bulk pharmaceutical chemicals；The peak is real in comparison
It applies and is obviously reduced in 4 gained physical mixture of example, but still exist；The lenalidomide solid dispersions prepared in embodiment 3
The peak completely disappears in spectral line；Drug carrys out that degree in the hot-melt extruded solid dispersions of lenalidomide obtained by technical solution of the present invention
Amine disperses evenly in carrier material.
Verify embodiment 2
Dissolution determination：With reference to dissolution method (two the second methods of annex XC of Chinese Pharmacopoeia version in 2015), rotating speed is
50 turns per minute, 37 DEG C ± 0.5 DEG C of temperature, 0min, 5min, 10min, 15min, 20min, 30min after dispensing take
Sample samples 10ml, immediately mutually synthermal, same volume the dissolution medium of supplement.Sample is filtered through 0.8um water system miillpore filters,
Primary filtrate 3ml is discarded, subsequent filtrate, HPLC is taken to measure content.By lenalidomide bulk pharmaceutical chemicals, physical mixture and Examples 1 to 5,
1~4 gained lenalidomide solid dispersion particles of comparative example carry out dissolution experiment, and corresponding data is shown in Table 1 and Fig. 2.
1 drug-eluting curve data of table
| The title time | 0min | 5min | 10min | 15min | 20min | 30min |
| Embodiment 1 (%) | 0 | 76.6 | 91.0 | 95.2 | 98.2 | 99.5 |
| Embodiment 2 (%) | 0 | 77.9 | 90.1 | 95.5 | 97.3 | 99.3 |
| Embodiment 3 (%) | 0 | 76.2 | 90.1 | 95.2 | 98.2 | 99.4 |
| Embodiment 4 (%) | 0 | 76.8 | 90.1 | 95.8 | 98.4 | 99.6 |
| Embodiment 5 (%) | 0 | 76.2 | 91.1 | 94.8 | 98.4 | 99.4 |
| Comparative example 1 (%) | 0 | 30.2 | 41.5 | 58.3 | 66.2 | 70.5 |
| Comparative example 2 (%) | 0 | 73.3 | 86.3 | 90.1 | 94.1 | 95.8 |
| Comparative example 3 (%) | 0 | 73.7 | 87.1 | 91.5 | 94.6 | 95.8 |
| Comparative example 4 (%) | 0 | 13.4 | 24.8 | 30.0 | 34.7 | 40.6 |
| Lenalidomide raw material (%) | 0.0 | 5.5 | 8.7 | 11.1 | 13.5 | 15.4 |
It can be seen that from table 1 and Fig. 2：1-5 of the embodiment of the present invention, melting temperature is low, and dissolution is rapid；Comparative example 1,
Unused octadecenic acid ethyl ester, melting temperature is low, but dissolution rate is poor；Comparative example 2, unused aerosil, dissolution is fast, but
Melting temperature is high；Comparative example 3 is used Macrogol 6000 instead and is carried as solid dispersions instead of oleic acid LABRAFIL M 1944CS
Body, dissolution is fast, and melting temperature is higher；Comparative example 4, only a physical mixed objects system, do not form solid dispersions, dissolution
Difference；For lenalidomide raw material because of poor solubility, therefore when simple determination of raw material dissolution, dissolution is worst.Dissolution determination result is further
Demonstrating aerosil and the combination of oleic acid LABRAFIL M 1944CS reduces melting temperature, and octadecenic acid ethyl ester improves production
The dissolution rate of product.
Confirmatory experiment example 3
Embodiment 1-5 and comparative example 1-4 resulting compositions is filling at capsule, by 2015《Chinese Pharmacopoeia》Two attached
It records XIXC bulk pharmaceutical chemicals and influence factor is carried out to the lenalidomide pharmaceutical composition with pharmaceutical preparation stability test guideline
Experiment.Hot test：Example and comparative examples are placed 30 days at a temperature of setting 60 DEG C, are sampled in the 15th day and the 30th day,
It is detected by stability high spot reviews project.High humidity test：Example and reference substance are set and are placed under RH92.5% ± RH5%
It 30 days, sampled in the 15th day and the 30th day, is detected by stability high spot reviews project.Strong illumination is tested：Example
And comparative examples are placed in the lighting box equipped with fluorescent lamp, are placed 30 days under conditions of illumination is 4500lx ± 500lx, in
It samples within 15th day and the 30th day, is detected by stability high spot reviews project；Influence factor test result is shown in Table 2.
2 influence factor test result of table
As can be seen from Table 2：Embodiment 1-5 impurity contents are low, and dissolution rate is stablized, and product quality is without bad trend；Comparison
Octadecenic acid ethyl ester is not used in example 1, and product dissolution rate is low, and stability is poor；Aerosil is not used in comparative example 2, melting
Temperature height causes related substance high；Oleic acid LABRAFIL M 1944CS is not used in comparative example 3, and melting temperature height leads to related substance
It is high；Comparative example 4 is non-solid dispersion, and product is unstable, and related substance increases apparent.Further demonstrate the present invention's above
Superiority.
Claims (6)
1. a kind for the treatment of myelodysplastic syndrome pharmaceutical composition, which is characterized in that the composition includes lenalidomide, ten
Eight olefin(e) acid ethyl esters, aerosil, oleic acid LABRAFIL M 1944CS.
2. a kind of as described in claim 1 treat myelodysplastic syndrome pharmaceutical composition, which is characterized in that the combination
Object can be used for preparing tablet, capsule, granule, dry suspensoid agent, powder or micropill preparation.
A kind for the treatment of myelodysplastic syndrome pharmaceutical composition 3. as described in claim 1, which is characterized in that including with
The ingredient of lower weight ratio:
A kind for the treatment of myelodysplastic syndrome pharmaceutical composition 4. as claimed in claim 3, which is characterized in that including with
The ingredient of lower weight ratio:
A kind for the treatment of myelodysplastic syndrome pharmaceutical composition 5. as claimed in claim 4, which is characterized in that including with
The ingredient of lower weight ratio:
6. a kind of system for treating myelodysplastic syndrome pharmaceutical composition as described in claim 1-5 any claims
Preparation Method, which is characterized in that include the following steps：
(1) it is weighed by recipe quantity；
(2) lenalidomide, octadecenic acid ethyl ester, aerosil, oleic acid LABRAFIL M 1944CS mixing machine are mixed equal
It is even, and material after mixing is crossed into 60 mesh and is sieved twice；
(3) extrusion temperature of double screw extruder is set as 120-300 DEG C, and temperature starts screw rod after being raised to setting value, by step
(2) the mixing sieving in is added in extruder, by heating melting, is squeezed, is finally squeezed out with ribbon；
(4) bar is placed in 20 DEG C or less coolings, it is cooling after through 80 mesh pulverization process, obtain medicine solid dispersion particle or
Powder；
(5) using gained particle or powder in step (4) as granule or powder direct packaging, or be processed into capsule,
The solid pharmaceutical preparations such as tablet.
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