EP3958845A1 - Composition pharmaceutique comprenant du sunitinib amorphe - Google Patents

Composition pharmaceutique comprenant du sunitinib amorphe

Info

Publication number
EP3958845A1
EP3958845A1 EP19719886.4A EP19719886A EP3958845A1 EP 3958845 A1 EP3958845 A1 EP 3958845A1 EP 19719886 A EP19719886 A EP 19719886A EP 3958845 A1 EP3958845 A1 EP 3958845A1
Authority
EP
European Patent Office
Prior art keywords
sunitinib
composition according
malate
present
amorphous
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19719886.4A
Other languages
German (de)
English (en)
Inventor
Sonia GARCIA JIMENEZ
Luis Nogueiras Nieto
Lisardo Alvarez Fernandez
Rohit Kumar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthon BV
Original Assignee
Synthon BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthon BV filed Critical Synthon BV
Publication of EP3958845A1 publication Critical patent/EP3958845A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol

Definitions

  • sunitinib L-malate which is the active ingredient in the medicinal product sold under the brand name Sutent ® by Pfizer.
  • Sunitinib L- malate exhibits polymorphism.
  • WO03016305 discloses form I and II of sunitinib L-malate, processes for their preparation and compositions comprising these forms. Form I is the most stable form and is present in the marketed capsules. Form II is more soluble, but hygroscopic and less stable. Other polymorphic forms of sunitinib L-malate are disclosed in
  • W02009067686 W02009104021, W02010010454, W02010055082, W02010076805, WO2011092664 and CN 104693187.
  • Amorphous drugs show in general better solubility and bioavailability than the crystalline forms. It might therefore be an advantage to develop a pharmaceutical
  • composition comprising amorphous sunitinib L-malate.
  • W02009156837 discloses amorphous sunitinib L-malate.
  • Amorphous compositions comprising sunitinib and its acid addition salt are disclosed in W02009100929 and
  • W02010039798 (paragraph [0045]) mentions that many experiments performed by the inventors attempting to prepare amorphous sunitinib malate were unsuccessful, i.e., the sunitinib L-malate obtained was not amorphous. In our laboratory, it was confirmed that sunitinib L-malate crystallizes very easily.
  • W02009100929, W02010039798, W02013160916 and CN106974890 disclose ways to stabilize amorphous sunitinib L-malate by preparing solid dispersions with a polymer.
  • W02009100929 provides capsule formulations comprising the solid dispersions disclosed.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a solid dispersion of sunitinib L-malate and polyvinylpyrrolidone in a primary packaging comprising means to absorb water.
  • Said pharmaceutical composition may be used as a medicament, particularly in the treatment of tyrosine kinase -related disorder.
  • Sutent ® capsules contain sunitinib L-malate form I. This polymorphic form is the most stable form at ambient conditions. Sunitinib L-malate form II is more soluble, but less stable and hygroscopic. Other forms of sunitinib L-malate have been disclosed in the prior art.
  • amorphous drugs are in general more soluble and exhibit better bioavailability than the crystalline forms, it would be desirable to have sunitinib L-malate in amorphous form.
  • drugs that can exist in either amorphous or crystalline form tend to crystallize over time when present in amorphous state because the crystalline form of the drug is a lower-energy state than the amorphous form.
  • solid dispersion has been defined as a dispersion of one or more Active Pharmaceutical Ingredients (APIs) in an inert carrier or matrix at the solid state, prepared by a solvent or melting process or a combination of the two.
  • APIs Active Pharmaceutical Ingredients
  • the solid dispersions are divided into crystalline solid dispersions and amorphous solid dispersions respectively.
  • Amorphous carriers used are mostly polymers.
  • the API is dispersed in very small size and exists in supersaturated state in amorphous carriers because of forced degradation.
  • the amorphous carriers can increase the wettability and dispersibility of drugs as well as inhibit the precipitation process of drugs when amorphous solid dispersions are dissolved in water. These properties along with the fast dissolution rate of amorphous carriers due to the low thermodynamic stability of amorphous state carriers enhance the drug solubility and release rate.
  • the number of marketed products arising from solid dispersion approaches is still low. This low number is mainly due to scale-up problems and physicochemical instability in the manufacturing process or during storage leading to phase separation and crystallization (Vo et. al, Eur. J. Pharm. Biopharm., 85 (2013) 799-813).
  • the process selected to prepare the pharmaceutical compositions of the present invention is the solvent evaporation method, because in this method problems related to decomposition, as observed when applying the melting method, are prevented.
  • An important prerequisite of the solvent evaporation method is the sufficient solubility of the drug and the carrier in the solvent system. Finding a suitable non-toxic solvent is sometimes difficult because carriers are hydrophilic whereas drugs may tend to be hydrophobic.
  • compositions comprising a solid dispersion of sunitinib F-malate and a polymer, exhibiting adequate dissolution and excellent long term stability, which are suitable for production on commercial scale, the use of several, commonly used, polymers has been studied.
  • the polymers investigated are polyvinyl pyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, PVA, polyethylene glycol, poloxamer and Eudragit E-100.
  • polyvinylpyrrolidone also known as PVP or povidone
  • PVP polyvinylpyrrolidone
  • PVP povidone
  • Use of this polymer results in solid dispersions wherein sunitinib L-malate is present in fully amorphous form and wherein, even after storage under stressed conditions, no conversion into crystalline material occurs.
  • PVP with various molecular weights can be obtained.
  • the person skilled in the art will be able to select the grade of PVP with a specific molecular weight to be used in accordance with the present invention.
  • PVP grades with molecular weights of 20.000 to 100.000 are particularly preferred.
  • Even more preferred to be used in accordance with the present invention is PVP with a molecular weight ranging from 30.000 to 60.000.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a solid dispersion of sunitinib L-malate and polyvinylpyrrolidone in a primary packaging comprising means to absorb water.
  • WVTR water vapor transmission rate
  • MVTR moisture vapor transmission rate
  • Three different blister pack materials with films having different WVTR’s were studied.
  • Triplex a PVC/PE/PVDC film
  • Aclar which is a PTFE film
  • CFF Cold Form Foil
  • Alu-Alu foil has a WVTR value of ⁇ 0.01 g/m 2 /day at 23°C/100% RH. It was noted that the amount of impurities in the composition after 3 months storage at 40°C/75% RH decreased with decreasing WVTR value.
  • Alu-Alu blister packs gave the best results, the required purity levels as demanded for this pharmaceutical product is not reached.
  • hydroxytoluene (BHT) as additive to the pharmaceutical composition and their effect on the impurity profile was studied.
  • BHT hydroxytoluene
  • Polyvinylpyrrolidone is the polymer used in accordance with the present invention to form a solid dispersion with sunitinib F-malate. It is known that PVP contains peroxides and these components may promote oxidative degradation. Therefore, two different grades of PVP with different content of peroxides were used to prepare the solid dispersions of the present invention. The first type of PVP used, contains ⁇ 400 ppm of peroxides.
  • PlasdoneTM K29/32 is a typical example of such grade of PVP.
  • the peroxide content of the second type of PVP used is significantly lower: ⁇ 150 ppm.
  • a typical example of such low peroxide content grade of PVP is Kollidon ® 30 LP. Both polymers were used to prepare solid dispersions with sunitinib L-malate which were further processed into the pharmaceutical compositions in accordance with the present invention. The impurity profiles after storage at 40°C/75% RH in bottles and blisters seem to indicate that only slightly better results are obtained with the low peroxide content PVP.
  • compositions comprising a solid dispersion of sunitinib L-malate and polyvinylpyrrolidone displaying acceptable purity levels upon long term storage.
  • formation of impurities in the pharmaceutical composition comprising a solid dispersion of sunitinib L-malate and polyvinylpyrrolidone can be very effectively suppressed by using primary packaging comprising means to absorb water. In this way, compositions with purity levels as demanded for pharmaceutical products are obtained.
  • Primary packaging materials are those that are in direct contact with the product.
  • Typical examples are blisters and bottles. These primary packaging materials may comprise means to absorb water. This can be achieved by e.g. inclusion of a desiccant.
  • the primary packaging comprising means to absorb water is a blister pack having a water absorption capacity of at least 2.0 g/m 2 at 40°C/90% RH.
  • the water absorption capacity is determined by gravimetric measurement over 24 hours.
  • the primary packaging material is a blister pack having a water absorption capacity of at least 3.5 g/m 2 at 40°C/90% RH.
  • the primary packaging material is a blister pack having a water absorption capacity of at least 5 g/m 2 at 40°C/90% RH.
  • the primary packaging material is a blister pack having a water absorption capacity of at least 6.1 g/m 2 at 40°C/90% RH.
  • a laminated cold forming blister pack comprising desiccant is a specifically preferred blister pack to be used in accordance with the present invention.
  • Typical examples of commercially available desiccated Alu-Alu blisters are known under the name DessiflexTM.
  • DessiflexTM 2.0 is for example a laminated cold forming blister pack comprising desiccant having a guaranteed water absorption capacity of at least 2.0 g/m 2 at 40°C/90% RH
  • DessiflexTM Plus and DessiflexTM Ultra are dessicated Alu-Alu blisters having a water absorption capacity of at least 3.6 and 6.1 g/m 2 at 40°C/90% RH respectively.
  • the primary packaging comprising means to absorb water is a capped bottle having a water absorption capacity of at least 5.3 g/dm 3 at 23°C/40% RH. More preferably, the water absorption capacity of the capped bottle is at least 10 g/dm 3 at 23°C/40% RH. Most preferably, the water absorption capacity of the capped bottle is at least 15 g/dm 3 at 23°C/40% RH.
  • Examples of such capped bottles comprising means to absorb water are bottles having a cap containing desiccant, e.g. silica gel.
  • Typical examples of commercially available caps containing silica gel are the Duma® Twist-Off Caps wherein different quantities of silica gel are integrated, resulting in varying water absorption capacity values.
  • the capped bottle is a HDPE bottle and the cap comprises desiccant.
  • sunitinib L-malate in the pharmaceutical composition is amorphous.
  • the term“a major portion” of sunitinib L-malate means that at least 60% of the drug is in amorphous form, rather than a crystalline form.
  • sunitinib L-malate in the pharmaceutical composition is at least 80% in amorphous form.
  • sunitinib L-malate in the composition is“almost completely amorphous” meaning that the amount of sunitinib L-malate in the amorphous form is at least 90% as measured by powder X-ray diffraction or any other standard quantitative measurement.
  • sunitinib L-malate in the pharmaceutical composition is in a completely amorphous form within the detection limits of the techniques used for characterization.
  • the weight ratio of sunitinib L-malate to polyvinylpyrrolidone in the solid dispersion ranges from 1:1 to 1:2. At lower ratios of sunitinib L-malate to pyrrolidone, e.g. 1:0.5, amorphous product is obtained, but upon storage conversion into crystalline sunitinib L- malate occurs. Ratios of sunitinib L-malate to polyvinylpyrrolidone above 1:2 will provide stable amorphous compositions, but are accompanied with an unacceptable increase in capsule size.
  • the pharmaceutical composition of the present invention is very suitable for production on commercial scale.
  • the solid dispersion comprising sunitinib L-malate is obtained by applying the process of wet granulation.
  • This conventional technique can be carried out with equipment commonly used in pharmaceutical industry, which is a big advantage over other known techniques to prepare solid dispersions, like hot melt extrusion, freeze drying and spray-drying. These techniques do require specific, expensive equipment.
  • the pharmaceutical composition of the present invention is obtained by dissolving, in the first step of the process, sunitinib L-malate and polyvinylpyrrolidone in a solvent mixture.
  • the non-toxic solvent mixture in accordance with the present invention is an aqueous acidic solution.
  • the solvent mixture is a solution of water comprising a mineral acid. More preferably, the mineral acid is hydrochloric acid. Even more preferably, a solution comprising of a mixture of water and IN hydrochloric acid is used.
  • the amount of acid present in the solvent mixture may range.
  • the solvent system used in accordance with the present invention is consisting of water and IN hydrochloric acid in a ratio of 81.5:18.5 (w/w). Both sunitinib L-malate and polyvinylpyrrolidone dissolve well in the solvent mixture upon heating at a temperature ranging from 35 to 85°C. At low
  • the temperature of the solvent system is ranging from 45 to 55°C.
  • the resulting solution is mixed with a diluent.
  • the diluent to be used in accordance with the present invention may be any diluent known to a person of ordinary skill in the art.
  • the diluent to be used in accordance with the present invention is an inorganic diluent, polysaccharide, mono- or disaccharide or sugar alcohol.
  • Microcrystalline cellulose is a particularly preferred diluent.
  • the solvent is evaporated.
  • the evaporation is carried out by techniques known to a person of ordinary skill in the art.
  • the solution comprising sunitinib L-malate and polyvinylpyrrolidone in the solvent mixture, is sprayed over the diluent in a fluid bed reactor and the resulting mixture is subsequently dried.
  • the solvent mixture used is an aqueous acidic solvent system and the diluent used is microcrystalline cellulose.
  • the resulting blend is then mixed with further excipients.
  • the pharmaceutical composition of the present invention comprising the solid dispersion of sunitinib L-malate and polyvinylpyrrolidone, further comprises, besides the diluent in the intragranular phase, one or more extragranular pharmaceutically acceptable excipients.
  • the excipients to be used in accordance with the present invention are well-known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients.
  • the dosage form is an immediate release hard shell capsule and the pharmaceutically acceptable excipients are chosen from one or more diluents, disintegrants or lubricants.
  • the diluent to be used in accordance with the present invention may be any diluent known to a person of ordinary skill in the art.
  • the diluent to be used in accordance with the present invention is an inorganic diluent, polysaccharide, mono- or disaccharide or sugar alcohol.
  • Microcrystalline cellulose is a particularly preferred diluent.
  • the disintegrant to be used in accordance with the present invention may be any disintegrant known to a person of ordinary skill in the art. Suitable disintegrants to be used in accordance with the present invention are selected from the group consisting of croscarmellose sodium, crospovidone or sodium starch glycolate. Croscarmellose sodium is a particularly preferred disintegrant.
  • the lubricant to be used in accordance with the present invention may be any lubricant known to a person of ordinary skill in the art.
  • Magnesium stearate is a particularly preferred lubricant.
  • microcrystalline cellulose, croscarmellose sodium and magnesium stearate are present as extragranular excipients.
  • the final blend is compressed into tablets, or filled into capsules, using equipment and methods well-known in the art.
  • the pharmaceutical composition of the present invention exhibits excellent long term stability. Even after 6 months at 40°C/75% RH, no conversion into any crystalline form of sunitinib L-malate was observed. Moreover, the composition of the present invention fulfills the required purity levels as demanded for pharmaceutical products even after long term storage under accelerated conditions.
  • the pharmaceutical composition of the present invention displays dissolution behavior typical for immediate-release formulations.
  • the composition of the present invention exhibits a dissolution rate of at least 85% in 15 minutes when tested in 900 ml 0.1 N hydrochloric acid pH 1.0 at 37°C, 75 rpm in a USP apparatus II.
  • the pharmaceutical composition in accordance with the present invention may be used as a medicament.
  • the pharmaceutical composition typically may be used in the treatment of a tyrosine kinase-related disorder, preferably for the treatment of gastrointestinal stromal tumors (GIST), metastatic renal cell carcinoma (MRCC) and pancreatic neuroendocrine tumors (pNET).
  • GIST gastrointestinal stromal tumors
  • MRCC metastatic renal cell carcinoma
  • pNET pancreatic neuroendocrine tumors
  • Example 1 preparation of capsule compositions comprising a solid dispersion of sunitinib L-malate and PVP in different ratios (1:1, 1:1.5, 1:2)
  • Polyvinylpyrrolidone and sunitinib L-malate were dissolved in a solution of hydro- chloric acid in water under heating and stirring. The solution was sprayed and dried under heating and stirring over the sieved microcrystalline cellulose (intragranular part) in a fluid bed reactor. The obtained granules were milled. Microcrystalline cellulose (extragranular part) and croscarmellose sodium were sieved to deagglomerate and mixed with the sieved granulate in a tumbling mixer. Magnesium stearate was sieved and added to the tumbling mixer and the resulting mixture was mixed. The homogeneous blend was encapsulated using a dosator filling machine into capsules.
  • the capsules were packed in suitable packaging material.
  • Example 2 stability results for 50 mg capsules with different ratios of sunitinib L- malate to PVP (1:1, 1:1.5, 1:2)
  • the capsules have the compositions as given in example 1 and are prepared by the process given in that example.
  • Example 3 stability results for 50 mg capsules (sunitinib L-malate:PVP 1:1.5) stored in several type of blister pack materials with different Water Vapour Transmission Rates (WVTR), determined at 23°C/100% RH
  • the capsules have the composition as given in example 1 and are prepared by the process given in that example.
  • Example 4 stability results for 50 mg capsules (sunitinib L-malate:PVP 1:1.5) without and with different type of antioxidants
  • the capsules have the composition as given in example 1 and are prepared by the process given in that example.
  • the antioxidants are added intragranularly.
  • Example 5 stability results for 50 mg capsules (sunitinib L-malate:PVP 1:1.5) comprising different grades (peroxide content) of PVP
  • the capsules have the composition as given in example 1 and are prepared by the process given in that example.
  • the capsules have the composition as given in example 1 and are prepared by the process given in that example.
  • Example 7 stability results for 50 mg capsules (sunitinib L-malate:PVP 1:1.5) stored in different sizes of bottles (headspace volume)
  • the capsules have the composition as given in example 1 and are prepared by the process given in that example.
  • the PVP used is Kollidon ® 30 LP
  • Example 8 stability results for slugs (sunitinib L-malate:PVP 1:1.5) comprising different type of lubricants
  • the slugs have the composition as given in example 1 and are prepared by the process given in that example. Magnesium stearate is in two of the compositions replaced by other lubricants.
  • Example 9 stability results for 50 mg capsules (sunitinib L-malate:PVP 1:1.5) stored in different type of Alu/Alu blister pack materials (with and without desiccant)
  • the capsules have the composition as given in example 1 and are prepared by the process given in that example.
  • DessiflexTM Ultra dessicated alu/alu blister having a water absorption capacity of at least 6.1 g/m 2 at 40°C/90% RH.
  • the water absorption capacity of the blister is determined by gravimetric measurement. A 100 cm 2 sample is exposed in a climate chamber (40°C/90% RH) for 24 hr. The weight increase is the humidity absorption capacity per 100 cm 2 which can be expressed (multiplying with 100) into water absorption capacity in g/m 2 .
  • Example 10 stability results for 50 mg capsules (sunitinib L-malate:PVP 1:1.5) stored in capped HDPE bottles with different amounts of desiccant (2 g, 6 g) or oxygen scavenger (1 g, 2.15g) in the caps
  • the capsules have the composition as given in example 1 and are prepared by the process given in that example.

Abstract

La présente invention concerne une composition pharmaceutique comprenant une dispersion solide de L-malate de sunitinib et de polyvinylpyrrolidone dans un emballage primaire comprenant des moyens pour absorber L'eau. L'invention concerne en outre l'utilisation de ladite composition en tant que médicament, en particulier dans le traitement d'un trouble lié à la tyrosine kinase.
EP19719886.4A 2019-04-25 2019-04-25 Composition pharmaceutique comprenant du sunitinib amorphe Pending EP3958845A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2019/060682 WO2020216450A1 (fr) 2019-04-25 2019-04-25 Composition pharmaceutique comprenant du sunitinib amorphe

Publications (1)

Publication Number Publication Date
EP3958845A1 true EP3958845A1 (fr) 2022-03-02

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ID=66290468

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EP19719886.4A Pending EP3958845A1 (fr) 2019-04-25 2019-04-25 Composition pharmaceutique comprenant du sunitinib amorphe

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EP (1) EP3958845A1 (fr)
WO (1) WO2020216450A1 (fr)

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AR034118A1 (es) 2000-02-15 2004-02-04 Sugen Inc Compuestos de 2-indolinonas sustituidas con pirroles inhibidoras de proteinquinasas; sus composiciones farmaceuticas e intermediarios de sintesis
DK3168218T3 (en) 2001-08-15 2019-01-14 Pharmacia & Upjohn Co Llc Crystalline comprising an L-malic acid salt of N- [2- (DIETHYLAMINO) ETHYL] -5 - [(5-FLUOR-1,2-DIHYDRO-2-OXO-3H-INDOL-3-YLIDE) METHYL] -2,4 -DIMETHYL-1H-PYRROL-3-CARBOXAMIDE FOR USE AS A MEDICINE
CA2699306A1 (fr) 2007-11-21 2009-05-28 Teva Pharmaceutical Industries Ltd. Hemi-l-malate de sunitinib, polymorphes et leur preparation, polymorphes de malate de sunitinib racemique, compositions contenant une base de sunitinib et de l'acide malique et leur preparation
US20100310668A1 (en) 2008-02-13 2010-12-09 Ratiopharm Gmbh Pharmaceutical compositions comprising n-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide
WO2009104021A2 (fr) 2008-02-21 2009-08-27 Generics [Uk] Limited Nouveaux polymorphes et procédés de préparation
WO2009156837A2 (fr) 2008-06-26 2009-12-30 Medichem, S.A. Forme amorphe d'un sel de malate de 2-indolinone à substitution 3-pyrrole
EP2342195B1 (fr) 2008-07-24 2014-09-10 Medichem, S.A. Formes cristallines d un sel de malate de 2-indolinone à substitution 3-pyrrole
KR20100051769A (ko) 2008-09-30 2010-05-18 테바 파마슈티컬 인더스트리즈 리미티드 수니티닙 베이스 및 ｌ-말산의 비정질 조성물
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WO2013160916A1 (fr) 2012-04-25 2013-10-31 Hetero Research Foundation Dispersion solide de malate de sunitinib
CN104693187A (zh) 2013-12-10 2015-06-10 安杰世纪生物科技（北京）有限公司 一种舒尼替尼L-苹果酸盐晶型λ及其制备方法
CN106974890A (zh) 2016-01-15 2017-07-25 常州方楠医药技术有限公司 一种无定型舒尼替尼l-苹果酸盐与药用辅料的固体分散体及其制备方法

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