WO2013135189A1

WO2013135189A1 - Solid dispersion improving absorption performance and preparation of same

Info

Publication number: WO2013135189A1
Application number: PCT/CN2013/072645
Authority: WO
Inventors: 易必慧; 尚晓芳; 陆惠萍; 盛泽林
Original assignee: 苏州泽璟生物制药有限公司
Priority date: 2012-03-15
Filing date: 2013-03-14
Publication date: 2013-09-19
Also published as: CN103301066B; CN103301066A

Abstract

Provided are a solid dispersion improving absorption performance and a method for preparing same. Specifically, a solid dispersion is provided, comprising (A): a compound of Formula A as an active ingredient or a derivant thereof, or a pharmaceutically acceptable salt, a hydrate or a solvate thereof; and (B): a hydrophilic high polymer carrier. A weight ratio of (A) to (B) ranges from 1:1 to 1:40. The solid dispersion according to the present invention can significantly improve a vitro dissolution of the active ingredient and remarkably improve absorption of a mammal for the active ingredient, thereby effectively reducing the dosage thereof in use.

Description

Solid dispersion for improving absorption performance and preparation thereof

Technical field

The present invention is in the field of medicine and relates to a solid dispersion and its preparation, in particular to a solid dispersion for improving absorption properties and its preparation. Background technique

4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureide)-3-fluoro-phenoxy)-2-(Nl,,r,r-triindole Methyl)pyridine amide, i.e., a compound of formula I, which is superior to a phosphate kinase (Kinase) such as raf^ enzyme.

The compound is a colored powder which is odorless and tasteless. Very soluble in dimethyl sulfoxide or dimethylformamide, slightly soluble in tetrahydrofuran, methanol, slightly soluble in acetone, absolute ethanol or glacial acetic acid, but almost insoluble in water.

Because the compound of formula I is extremely poor in water solubility, it is a poorly soluble drug, has a low solubility and dissolution rate in physiological body fluids, and has a low dissolution rate, which ultimately leads to low bioavailability and seriously affects mammalian absorption of the compound of formula I. It is not conducive to giving full play to the therapeutic effects of the compound.

Solid dispersions can increase the bioavailability of poorly soluble drugs, but existing solid dispersions can only increase the area under the curve of the drug (AUC) by a factor of 2-6. For example, CN101632630A in terms of more probucol, probucol, and PVP K ₃ o of the solid dispersion, the bioavailability was only 5.8 fold increased relative dogs.

Therefore, the development of a solid dispersion of a compound of formula I with a markedly improved bioavailability is necessary to address the problem of poor absorption of active ingredients by mammals. Summary of the invention

SUMMARY OF THE INVENTION An object of the present invention is to provide a solid dispersion containing a hydrazine compound or a derivative thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, which is remarkably improved in bioavailability.

Another object of the present invention is to provide a process for the preparation of the solid dispersion of the present invention.

A further object of the invention is to provide a pharmaceutical composition of the solid dispersion.

A first aspect of the invention provides a solid dispersion, including

(A) a compound of the formula A or a derivative thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as an active ingredient, and

Wherein R is CD ₃ or CH _{3 ;}

(B) a hydrophilic polymer carrier;

Wherein the weight ratio of (A) and (B) is 1: 1-1: 40.

In another preferred embodiment, the hydrophilic polymer carrier is povidone or a povidone-containing polymer carrier.

In another preferred embodiment, the hydrophilic polymer carrier is povidone K30 (PVP K30) or a povidone K30-containing polymer carrier, wherein the povidone K30 is contained in an amount of 10 to 100% by weight. Based on the total weight of the polymeric carrier.

In another preferred embodiment, the active ingredient is a compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvent thereof

In another preferred embodiment, the povidone-containing K30-containing polymeric carrier further comprises other water-soluble carriers selected from the group consisting of polyethylene glycols, povidones, celluloses, surfactants, Or a combination thereof;

Wherein the polyethylene glycol is selected from the group consisting of polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000 or a combination thereof;

The povidone is selected from the group consisting of povidone K25, povidone oxime 90, povidone S630, or a combination thereof; the cellulose is selected from the group consisting of hypromellose E5, hyprothenol Cellulose E15, hydroxypropyl cellulose L, or a combination thereof;

The surfactant class is selected from the group consisting of poloxamer 407, poloxamer 188, or a combination thereof. In another preferred embodiment, the povidone-containing K30-containing polymeric carrier comprises a povidone-based carrier selected from the group consisting of povidone K25, povidone 90, povidone S630, or a combination thereof.

In another preferred embodiment, the weight ratio of the povidone-containing K30-containing polymer carrier to the other water-soluble carrier is 1:4-4:1; preferably 1:2-4:1; more preferably For 1: 1-4: 1.

In another preferred embodiment, the weight ratio of the (A) and (B) is 1: 1-1: 20.

In another preferred embodiment, the weight ratio of the (A) and (B) is 1: 2-1: 9.

In another preferred embodiment, the X-ray powder diffraction pattern of the solid dispersion does not have an X-ray diffraction characteristic peak of the active component of the solid dispersion.

In another preferred embodiment, there are one or more of the following features: 1 The area under the drug-time curve of the solid dispersion is 6-20 times, preferably 7-15 times, the area under the drug-time curve when the active ingredient of the solid dispersion is administered alone;

2 The solid dispersion has a cumulative dissolution of more than 70%, preferably 75-95%, at 37 ° C in a pH 4.5 aqueous solution of sodium acetate buffer for 10 minutes;

3 The cumulative dissolution of the solid dispersion at 120 ° C in a pH 4.5 aqueous solution of sodium acetate buffer for 120 minutes is 10-40 times, preferably 15-15, of the cumulative dissolution of the active ingredient of the solid dispersion. 30 times.

In another preferred embodiment, the area under the drug time curve is measured in the following animals: rat, mouse or canine.

A second aspect of the present invention provides a method for preparing a solid dispersion according to the first aspect of the present invention, comprising the method of:

(a) Melting method 1, including steps:

(al) mixing the active ingredient with a hydrophilic polymer carrier to obtain a mixture containing the active ingredient; (a2) heating the molten component (al) to obtain the mixture containing the active ingredient, thereby obtaining a molten mixture;

(a3) cooling the molten mixture obtained in the step (a2) to obtain the solid dispersion according to the first aspect of the invention;

Or

(b) Melting method 2, including steps:

(bl) heating and melting the hydrophilic polymer carrier to obtain a molten carrier;

(b2) mixing the molten carrier obtained in the step (bl) with the active ingredient and melting the mixture to obtain a molten mixture;

(b3) cooling the molten mixture obtained in the step (b2) to obtain the solid dispersion according to the first aspect of the invention;

Or

(c) Solvent method, including steps:

(cl) co-dissolving the active ingredient and the hydrophilic polymer carrier in a solvent to obtain a mixture;

(c2) removing the solvent in the mixture obtained in the step (cl), thereby obtaining the solid dispersion according to the first aspect of the invention;

Wherein the active ingredient is a compound of formula A or a derivative thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

Where R is CD ₃ or CH ₃ ,

The hydrophilic polymer carrier is a hydrophilic polymer carrier containing povidone K30.

The solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, dichloromethane, tetrahydrofuran, or a combination thereof.

In another preferred embodiment, the step (c2) includes the steps of:

The solvent in the mixture obtained in the step (cl) is removed by a rotary evaporator; or

The solvent in the mixture obtained in the step (cl) was removed by drying with a spray dryer.

In another preferred embodiment, the drying process parameters are: inlet air temperature 110 to 120 ° C, fan power 55 % to 65 %, peristaltic pump power 50 % to 55 %.

In another preferred embodiment, the solid dispersion is further treated with at least one additional processing step of grinding, sieving, rolling, milling, screening, mixing, or a combination thereof.

A third aspect of the invention provides a pharmaceutical composition, the composition comprising:

(1) The solid dispersion of the first aspect of the invention; and

(2) A pharmaceutically acceptable excipient.

In another preferred embodiment, the excipient comprises: a filler, a diluent, a sweetener, a flavoring agent, an antioxidant, a coloring agent, a preservative, a lubricant, a binder, a disintegrating agent, or combination.

In another preferred embodiment, the composition is a capsule, a tablet, a pill, a powder, and a granule.

In another preferred embodiment, the pharmaceutical composition is for use in a pharmaceutical composition for inhibiting a phosphokinase such as raft chymase.

In another preferred embodiment, the pharmaceutical composition is for the treatment and prevention of cancer.

According to a fourth aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition according to the third aspect of the present invention, wherein the solid dispersion according to the first aspect of the present invention is mixed with a pharmaceutically acceptable excipient, thereby producing a Said pharmaceutical composition.

A fifth aspect of the invention provides the use of the solid dispersion of the first aspect of the invention for the preparation of a medicament for inhibiting a phosphokinase (e.g., raf^ enzyme); or for the preparation of a medicament for treating a tumor.

A sixth aspect of the invention provides a method of treating (i) the solid dispersion of the first aspect of the invention or (ii) the pharmaceutical composition of the third aspect of the invention for a patient in need of treatment .

It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (e.g., the embodiments) can be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here. DRAWINGS

Figure 1 shows an XRPD pattern of Solid Dispersion 1.

Figure 2 shows an XRPD pattern of Solid Dispersion 2.

Figure 3 shows an XRPD pattern of Solid Dispersion 3. Figure 4 shows an XRPD pattern of Solid Dispersion 4.

Figure 5 shows the dissolution profile of the compound of formula I, the physical mixture of the compound of formula I with PVP K30 and solid dispersion 1.

Figure 6 shows the dissolution profile of the compound of formula I, the physical mixture of the compound of formula I with PVP K30 and solid dispersion 2.

Figure 7 shows an XRPD pattern of solid dispersion 10.

Figure 8 shows the dissolution profile of the solid dispersion 10.

Figure 9 shows a comparison of XRPD of the solid dispersion 1 after 1, 2, and 3 months accelerated stability test, and the results are shown in Figure 9. From the top to the bottom, the compound of the formula I, the newly prepared solid dispersion 1, solid XRPD pattern when Dispersion 1 was left for one month, solid dispersion 1 was placed for two months, and solid dispersion 1 was placed for three months.

Figure 10 shows the XRPD comparison chart of the solid dispersion 2 after 1, 2, 3 months accelerated stability test, and the results are shown in Figure 10: from top to bottom are the compound of formula I, freshly prepared solid dispersion 2, solid XRPD pattern when Dispersion 2 was placed for one month, Solid Dispersion 2 was placed for two months, and Solid Dispersion 2 was placed for three months.

Figure 11 shows the XRPD comparison chart of the solid dispersion 3 after 1, 2, 3 months accelerated stability test, and the results are shown in Figure 11. From the top to the bottom, the compound of the formula I, the newly prepared solid dispersion 3 XRPD pattern when solid dispersion 3 was left for one month, solid dispersion 3 was placed for two months, and solid dispersion 3 was placed for three months.

Figure 12 shows a comparison of XRPD of the solid dispersion 4 after 1, 2, 3 months accelerated stability test, and the results are shown in Figure 12: from top to bottom are the compound of formula I, freshly prepared solid dispersion 4, solid The XRPD pattern at which the dispersion 4 was left for one month, the solid dispersion 4 was left for two months, and the solid dispersion 4 was placed for three months. detailed description

The present inventors have unexpectedly discovered, by long-term and intensive research, a compound of the formula A or a derivative thereof comprising (A) as an active ingredient, or a pharmaceutically acceptable salt, hydrate or solvate thereof and (B) a solid dispersion of a hydrophilic polymer carrier (especially a polymer carrier containing povidone K30), wherein the area under the drug-time curve of the solid dispersion is about 6-20 of the active ingredient relative to the active ingredient The solid dispersion significantly increases the in vitro dissolution of the active ingredient, and significantly improves the absorption of the active ingredient by the mammal, thereby effectively reducing the dosage thereof. In addition, the solid dispersion also has very good stability and is extremely suitable for the preparation of pharmaceutical compositions for related diseases. On this basis, the inventors have completed the present invention. Solid dispersion Solid dispersion refers to a dispersion system in which the active ingredient is highly dispersed in a (solid) support to form a solid form. Active ingredient

The term "active ingredient" as used herein refers to a compound of formula A or a derivative thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R is CD ₃ or CH _{3 ;}

The term also encompasses various crystalline forms, hydrates or solvates of the compounds of formula A or derivatives thereof.

Preferably, the compound of formula A refers to a compound of formula I or a compound of formula II, or a pharmaceutically acceptable salt thereof.

The term "pharmaceutically acceptable salt" as used herein refers to a salt of the compound of the present invention which is formed with an acid or a base and which is suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Suitable acids for forming salts include, but are not limited to: mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

Preferably, the pharmaceutically acceptable salt is p-toluenesulfonate. Carrier

As the carrier for the solid dispersion, the most commonly used are water-soluble carriers, poorly soluble carriers, and enteric carriers.

The "carrier" according to the present invention is a hydrophilic polymer carrier, preferably a povidone or a povidone-containing polymer carrier, or a povidone K30 or a povidone K30-containing polymer carrier, wherein The ketene K30 is contained in an amount of 10 to 100% by weight based on the total weight of the polymer carrier. More preferably, the povidone K30-containing polymer carrier used in the present invention refers to a carrier in which the povidone K30 has a weight content exceeding 20% by weight of the carrier; or the povidone K30 has a weight content exceeding 40% of the total weight of the carrier. The carrier; or the carrier of the povidone K30 in an amount of more than 60% by weight based on the total weight of the carrier.

Of course, other water soluble carriers may also be included, including, for example, but not limited to: polyethylene glycols, povidones, cellulosics, surfactants, mannitol, or combinations thereof.

The polyethylene glycols are selected from the group consisting of polyethylene glycol 4000 (PEG 4000), polyethylene glycol 6000 (PEG 6000), polyethylene glycol 8000 (PEG 8000), or combinations thereof;

The povidone is selected from the group consisting of povidone K90 (PVP K90), povidone K25 (PVP K25), povidone S630, or a combination thereof;

The cellulose is selected from the group consisting of hypromellose E5 (HPMC E5), hypromellose

E15 (HPMC E15), hydroxypropyl cellulose L (HPC-L), or a combination thereof;

The surfactant class is selected from the group consisting of poloxamer 407 (Poloxamer 407), Poloxamer 188 (Poloxamer 188), or a combination thereof. Composition

The solid dispersions provided by the present invention include:

(A) A compound of the formula A or a derivative thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as the active ingredient, wherein the compound of the formula A is as described above. with

(B) a hydrophilic polymer carrier;

Wherein the weight ratio of (A) and (B) is 1: 1-1: 40.

Preferably, the weight ratio of the (A) and (B) is 1:20-1:1. Preferably, the weight ratio of the (A) and (B) is 1:9-1:2.

Preparation

The solid dispersion of the present invention can be obtained by the following method, however, the conditions of the method, such as the carrier, the solvent, the amounts of the respective components, the preparation temperature, the time required for preparation, and the like are not limited to the following explanations. The solid dispersions of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, such combinations being readily made by those skilled in the art to which the present invention pertains. .

Specifically, the preparation method may be a melting method, a solvent method, a solvent-melting method, or a surface dispersion method. Preferably, the preparation method is a melting method, or a solvent method. Melting method

Usually, the melting method is a method in which (A) an active ingredient, and (B) a hydrophilic polymer carrier are uniformly mixed, heated to a melt in a water bath or an oil bath, and then cooled to a solid, and pulverized to obtain a powdery form. A solid dispersion of the active ingredient. Alternatively, the (B) hydrophilic polymer carrier may be heated and melted, and then (A) the active ingredient may be added, and then the molten mixture is rapidly cooled to a solid under vigorous stirring, and pulverized to obtain the active ingredient in a powder form. Solid dispersion. Solvent method

In general, the solvent method is to dissolve the (A) active ingredient and (B) the hydrophilic polymer carrier in a solvent, and after the mixture is uniform, the solvent in the solution is removed, so that the active ingredient and the hydrophilicity are high. The molecular carrier is simultaneously precipitated, and after pulverization, a solid dispersion of the active ingredient in a powder form is obtained.

The solvent used in the solvent method includes: methanol, ethanol, isopropanol, acetone, tetrahydrofuran, or a combination thereof. Structure Identification

Structure identification methods for solid dispersions include differential scanning calorimetry, X-ray powder diffraction, and the like. The solid dispersion prepared by the active ingredient, the carrier and the method of the present invention were subjected to X-ray powder diffraction (XRPD) detection, and the XRPD spectra of the three were compared. Characteristic peak of active ingredient

When the solid dispersion of the present invention is formed, the X-ray diffraction characteristic peak of the active ingredient disappears substantially or completely. In other words, the X-ray powder diffraction pattern of the solid dispersion of the present invention does not have an X-ray diffraction characteristic peak of the active component of the solid dispersion.

a compound of formula I, which is at 7.24±0·, 13·38±0·, 14·53±0·, 14·74±0·, 15.61±0·, 17·23±0·1 ^ο , 18·57±0·1 ^ο , 18·84±0·1 ^ο , 19·81±0·1 ^ο , 20·01±0·1 ^ο , 23·42±0·1 ^ο , 24·24±0 ·1 ^ο , 25·85±0·1. , 26·39±0·1. , 27.43 ± 0. There are strong diffraction peaks.

a compound of formula II, which is at ^7.20 ±0·1 ^ο , 13·34±0·1 ^ο , 14·49±0·1 ^ο , 14·72±0·1 ^ο , 15·55±0·1. , 16·44±0·1 ^ο , 17·17±0·1 ^ο , 18.53±0.1. , 18·81±0·1 ^ο , 19·76±0·1. , 19.97±0·1. , 23.41 ± 0.1 °, 23 · 75 ± 0 · 1. , 24·22±0·1. , 24·75±0·1. , 25·90±0·1. , 26·35±0·1. , 27.42±0·1. , 31·54±0·1. There are strong diffraction peaks. Characteristic peak of the carrier

Some carriers have strong diffraction peaks. For example, PEG4000 and PEG6000 have strong diffraction peaks at 19.20 ± 0.1 ° and 23.30 ± 0.1 °. ? 010 & 11^" 407 has strong diffraction peaks at 19.16 ± 0.1 ° and 23.33 ± 0.1 °. Some carriers have no strong diffraction peaks. For example, PVP K30, HPMC E5, and HPC-L have no strong diffraction peaks. Solid dispersions Characteristic peaks

The strong diffraction peak of the active ingredient disappears in the XRPD spectrum of the solid dispersion prepared by the present invention, thereby confirming the successful preparation of the solid dispersion of the present invention, which is not a simple physical mixing of the active ingredient and the carrier. But in an amorphous or molecular form. Pharmaceutical composition

The term "compound of the invention" refers to a compound of formula A or a derivative thereof, or a pharmaceutically acceptable salt thereof. The term "solid dispersion of the invention" means a solid dispersion of the active ingredient which is a compound of formula A or a derivative thereof, or a pharmaceutically acceptable salt thereof.

Since the compound of the present invention has excellent inhibitory activity against a kinase such as ratase, the solid dispersion of the present invention and a pharmaceutical composition containing the solid dispersion of the present invention as a main component can be used for the treatment, prevention, and alleviation of the phosphoric acid Kinases (Kinase M are listed as raft chymase mediated diseases. According to the prior art, the compounds of the invention are useful in the treatment of the following diseases: cancer, cardiovascular disease, obesity, diabetes and the like.

The pharmaceutical compositions of the present invention comprise a solid dispersion of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in a safe and effective amount. By "safe and effective amount" it is meant that the amount of the solid dispersion of the present invention is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains from 1 to 2000 mg of the solid dispersion/agent of the invention, more preferably from 10 to 200 mg of the solid dispersion/agent of the invention. Preferably, the "one dose" is a capsule or a tablet.

"Pharmaceutically acceptable excipient" means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are compatible with the solid dispersions of the present invention and between them without significantly reducing the efficacy of the solid dispersion. Examples of pharmaceutically acceptable excipients are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as hard Fatty acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®) , wetting agents (such as sodium decyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The mode of administration of the solid dispersion or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical Dosing.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the solid dispersions of the invention are admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) filler or compatibilizer For example, starch, lactose, sucrose, glucose, microcrystalline cellulose, mannitol, and silicic acid; (b) binders, for example, hydroxypropylmethylcellulose, alginate, gelatin, polyvinylpyrrolidone, Sucrose and gum arabic; (c) humectants, for example, glycerin; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, cross-linked carboxymethyl Cellulose sodium and sodium carbonate; (e) slow solvent, such as stone (f) an absorption accelerator, for example, a quaternary amine compound; (g) a wetting agent such as cetyl alcohol, sodium dodecyl sulfate and glyceryl monostearate; (h) an adsorbent, for example, kaolin And (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.

Solid dosage forms such as tablets, troches, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the solid dispersion in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. The solid dispersion may also form a microcapsule form with one or more of the above excipients as necessary.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the solid dispersion, the liquid dosage form may comprise an inert diluent conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.

In addition to these inert diluents, the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.

In addition to the solid dispersion, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar or a mixture of these and the like.

Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyol, and suitable mixtures thereof.

Dosage forms for solid dispersions of the invention for topical administration include ointments, powders, patches, propellants and inhalants. The solid dispersion is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The solid dispersion of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When a pharmaceutical composition is used, a safe and effective amount of the solid dispersion of the present invention is suitably applied to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage for administration to a 60 kg body weight. The daily dose is usually from 1 to 2000 mg, preferably from 20 to 500 mg. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician. The main advantages of the invention are:

(1) Providing a compound of formula A or a derivative thereof, or a pharmaceutically acceptable salt, hydrate thereof or The solvate is a solid dispersion of the active ingredient which significantly improves the in vitro dissolution of the active ingredient and is highly advantageous for mammals to absorb the active ingredient. Moreover, the solid dispersion has significantly superior in vivo pharmacokinetic parameters (especially the area under the curve of the drug) relative to the active ingredient compound itself, and is very stable.

(2) A method of preparing the solid dispersion is provided. The invention will be further elucidated below in conjunction with specific implementations. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in which the specific conditions are not specified in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

As used herein, "API" refers to the active ingredient. Example

Dissolution test method for solid dispersion

According to the "People's Republic of China Pharmacopoeia" 2010 edition of the second appendix XC dissolution method of the second method (paddle method) for testing. The conditions are as follows: Dissolution medium: 0.1% sodium decyl sulfate pH 4.5 acetic acid-sodium acetate buffer 900 mL/dissolution cup; temperature: 37 ± 0.5 ° C; rotation speed: 100 rpm.

Specifically, the samples were divided into three groups, each of which was configured with 3 portions. Among them, the first group of samples is an active ingredient; the second group of samples is a sample obtained by simply mixing the active ingredient with a carrier by a simple physical method such as stirring. The third set of samples was a solid dispersion obtained according to the preparation method in each of the examples. The details are as follows.

Using the dissolution medium, the dissolution rates of the above three groups of samples were respectively measured according to a conventional method, and each sample was tested for 3 samples, and the average value thereof was taken. Compare the test results of the three groups. Example 1 Solid dispersion 1

The compound of formula I and PVP K30, the weight ratio is 1: 9, solvent (anhydrous ethanol) method

Weigh 1 part by weight of the compound of formula I and 9 parts by weight of PVP K30 in the same flask, place the flask in an oil bath at 80 ° C, add absolute ethanol to the flask, and stir the plug under reflux of the condensed water until the compound Both were dissolved in PVP K30 and stirred for another 30 minutes. The dissolved liquid was quickly evaporated to dryness at 80 ° C using a rotary evaporator to give a solid. The solid was dried in a vacuum oven at 50 ° C for 24 hours, and finely ground to obtain a solid dispersion 1. The XRPD test results are shown in Fig. 1. In the solid dispersion 1, the diffraction peaks (characteristic peaks) of the compound of the formula I disappeared completely, and existed in an amorphous or molecular form. Example 2 Solid Dispersion 2

Formula I compound and PVP K30, weight ratio of 1: 4, solvent (anhydrous ethanol) method

The preparation method was the same as in Example 1, except that the weight ratio of the compound of the formula I to the PVP K30 was 1:4. The XRPD test results are shown in Fig. 2. In the solid dispersion 2, the diffraction peaks (characteristic peaks) of the compound of the formula I disappeared completely, and existed in an amorphous or molecular form. Example 3 Solid dispersion 3

Formula I compound and PVP K30, weight ratio of 1: 3, solvent (anhydrous ethanol) method

The preparation method was the same as in Example 1, except that the weight ratio of the compound of the formula I to the PVP K30 was 1:3. The XRPD test results are shown in Fig. 3. In the solid dispersion 3, the diffraction peaks (characteristic peaks) of the compound of the formula I disappeared completely, and existed in an amorphous or molecular form. Example 4 Solid dispersion 4

Formula I compound and PVP K30, weight ratio of 1: 2, solvent (anhydrous ethanol) method

The preparation method was the same as in Example 1, except that the weight ratio of the compound of the formula I to the PVP K30 was 1:2. The XRPD test results are shown in Fig. 4. In the solid dispersion 4, the diffraction peaks (characteristic peaks) of the compound of the formula I disappeared completely, and existed in an amorphous or molecular form. Example 5-9 Solid Dispersion 5-9

The preparation method is the same as that of the example 1, and the specific conditions are shown in Table 1.

Table 1

Example 10 Dissolution Test of Solid Dispersion 1

Refer to the Chinese Pharmacopoeia 2010 edition two appendix XC dissolution test method, measure 0.1% sodium decyl sulfate pH 4.5 acetic acid-sodium acetate buffer 900mL, placed in lOOOOmL dissolution cup, the temperature is maintained at 37 ± 0.5 °C.

A physical mixture of a compound of formula I, a compound of formula I and PVP K30 (compound of formula I and PVP) K30 weighs 50mg and 450mg), solid dispersion l (500mg), paddle speed is 100rpm, sample 5mL at 2min, 5min, 10min, 15min, 20min, 30min, 45min, 60min, 120miri, with 0.45μιη microporous The membrane was filtered, and the clarified filtrate was diluted to determine the drug concentration, and the dissolution of the three was calculated.

The results are shown in Figure 5. The dissolution of the compound of formula I at 10 min is < 2%, the dissolution of the physical mixture of the compound of formula I and PVP K30 is < 5%, and the dissolution of solid dispersion 1 is 78%, with PVP K30. The solid dispersion of the matrix greatly improves the dissolution of the compound of formula I. Example 11 Dissolution test of solid dispersion 2

The dissolution test method was the same as in Example 10.

The test results are shown in Figure 6. At 30 min, the dissolution of the compound of formula I is <2%, the dissolution of the physical mixture of the compound of formula I and PVP K30 is < 5%, and the dissolution of solid dispersion 2 (carrier is PVP K30). It is 78%.

At 120 min, the dissolution of the compound of formula I is ≤ 5%, the physical mixture of the compound of formula I and the carrier is slightly better eluted than the compound of formula I, but ≤ 10%, and the dissolution of the solid dispersion of the compound of formula I with the carrier is about 80%. .

The results show that the dissolution of the solid dispersion is significantly better than the physical mixture of the compound of formula I and the compound of formula I with the carrier. In addition, the solid dispersion of PVP K30 as a carrier greatly improved the dissolution of the compound of formula I, which was significantly better than other commonly used carriers (such as PEG 6000, hypromellose E5) and PVP K90 and K25 (dissolution 65-70% at 30 minutes). Example 12 In vivo pharmacokinetic study of solid dispersion 2

The solid dispersion 2 was selected for in vivo pharmacoassay with the corresponding API (i.e., the compound of formula I).

Eight male 6-week-old Wistar rats weighing approximately 170 g were divided into 2 groups of 4 animals each. Animals were housed in IVC animal rooms and alternated for 12 hours. Hardwood shavings are used as litter. Animals are given feed and sterilized tap water for free diet. Fasting for 16 h before administration and returning to food 2 h after administration. After fasting overnight, 4 mg/kg solid dispersion 1 or 1% CMC suspension of the corresponding API was administered orally, with a drug volume of 10 ml/kg o 0.5, 1.0, 2.0, 4.0, 6.0 after administration. At 8.0, 24, 48 and 72 h, 0.2 ml of venous blood was taken from the posterior venous plexus of rats, placed in heparinized tubes, centrifuged at 3500 rpm for 10 min, and plasma samples were separated and stored at -20 °C.

Plasma samples were quantified for API content using a validated LC-MS/MS analytical method. The pharmacokinetic parameters will be calculated based on the plasma concentration of each rat at different time points. See Table 2 for parameters.

The results are shown in Table 2: Compounds of formula I and PVP K30 1: 4 ratio of weight of the dispersion produced was 9.03 times the solid compound 2 Pharmacokinetics AUC _Q _ _∞ of formula I is about. Table 2

Example 13 Solid Dispersion 10

Compound of formula II and PVP K30 in a weight ratio of 1:4, solvent (anhydrous ethanol)

The preparation method is the same as that in Example 1, except that the compound of the formula II is substituted for the compound of the formula I, and the compound of the formula II is

The PVP K30 has a weight ratio of 1:4.

The XRPD test results are shown in Fig. 7. In the solid dispersion 10, the diffraction peaks (characteristic peaks) of the compound of the formula II disappeared completely, and existed in an amorphous or molecular form. Example 14 Dissolution Test of Solid Dispersion 10

The dissolution test method was the same as in Example 10.

Specifically, the sample was configured in 2 parts (sample 1 and sample 2, respectively). The respective dissolution rates were tested as described above and the average value (i.e., average) was calculated.

The test results are shown in Fig. 8. At 30 minutes, the dissolution rate of the solid dispersion 10 was about 72.5%, and at 120 minutes, the dissolution of the solid dispersion 10 was about 94%. It can be seen that the compound of formula II forms a solid with the carrier PVP K30. The dissolution of the bulk dispersion 10 is good. Example 15 In vivo pharmacokinetic study of solid dispersion 10

The solid dispersion 10 is selected for in vivo pharmacoassay with the corresponding API (i.e., the compound of formula II).

The test method is the same as in the embodiment 12.

The results are shown in Table 3: The solid dispersion 10 of the compound of the formula II and the PVP K30 in a weight ratio of 1:4 was subjected to an AUC _{last of} about 13.5 times that of the compound of the formula II.

table 3

Example 16 Solid dispersion 1 accelerated stability test

The solid dispersion 1 was selected for accelerated stability test (40 ° C, 75% H), and taken out at 1, 2, and 3 months for X-ray powder diffraction.

The XRPD results are shown in Figure 9, which indicates that the solid dispersion 1 is very stable after 1, 2, 3 months accelerated stability test (no X-ray diffraction characteristic peak of API, and the curves are basically the same), and no crystal form is formed. (ie, the original amorphous or molecular state is unchanged), still in the form of a solid dispersion in an amorphous or molecular state.

The results are shown in Fig. 9. From the top to the bottom, the compound of the formula I, the freshly prepared solid dispersion 1, the solid dispersion 1 was left for one month, the solid dispersion 1 was placed for two months, and the solid dispersion 1 was placed three times. XRPD chart at the time of month. Example 17 Solid dispersion 2 accelerated stability test

The solid dispersion 2 was selected for accelerated stability test (40 ° C, 75% H), and taken out at 1, 2, and 3 months for X-ray powder diffraction.

The XRPD results are shown in Figure 10. It shows that the solid dispersion 2 is very stable after 1, 2, 3 months accelerated stability test (no X-ray diffraction characteristic peak of API, and the curves are basically the same), and no crystal form is formed. (ie, the original amorphous or molecular state does not change), still a solid dispersion that exists in an amorphous or molecular state.

The results are shown in Fig. 10: From the top to the bottom, the compound of the formula I, the freshly prepared solid dispersion 2, the solid dispersion 2 are left for one month, the solid dispersion 2 is placed for two months, and the solid dispersion 2 is placed three times. XRPD chart at the time of month. Example 18 Solid dispersion 3 accelerated stability test

The solid dispersion 3 was selected for accelerated stability test (40 ° C, 75% H), and taken out at 1, 2, and 3 months for X-ray powder diffraction.

The XRPD results are shown in Fig. 11. It shows that the solid dispersion 3 is very stable after 1, 2, 3 months accelerated stability test (no X-ray diffraction characteristic peak of API, and the curves are basically the same), and there is no crystal form. The formation (i.e., the original amorphous or molecular state is unchanged) remains a solid dispersion that exists in an amorphous or molecular state.

The results are shown in Fig. 11. From the top to the bottom, the compound of the formula I, the freshly prepared solid dispersion 3, the solid dispersion 3 are left for one month, the solid dispersion 3 is placed for two months, and the solid dispersion 3 is placed three. XRPD chart at the time of month. Example 19 Solid Dispersion 4 Accelerated Stability Test

The solid dispersion 4 was selected for accelerated stability test (40 ° C, 75% H), and taken out at 1, 2, and 3 months for X-ray powder diffraction.

The XRPD results are shown in Figure 12, which indicates that the solid dispersion 4 is very stable after 1, 2, 3 months accelerated stability test (no X-ray diffraction characteristic peak of API, and the curves are basically the same), and no crystal form is formed. (ie, the original amorphous or molecular state does not change), still a solid dispersion that exists in an amorphous or molecular state.

The results are shown in Fig. 12: from the top to the bottom, the compound of the formula I, the freshly prepared solid dispersion 4, the solid dispersion 4 was left for one month, the solid dispersion 4 was left for two months, and the solid dispersion 4 was placed three times. XRPD chart at the time of month. Example 20-24 Solid Dispersion 11-15 Active Ingredient: Compound of Formula I

Vector: Mixed carrier of PVP K30 and other carriers

The preparation method was the same as in Example 1, except that the mixed carrier was subjected to the conditions shown in Table 4.

Table 4

The XRPD test results show that in the solid dispersion, the diffraction peaks (characteristic peaks) of the compound of formula I are all in an amorphous form.

(Before the operation is the same) of a solid dispersion 11-15 Pharmacokinetics test sample showed: solid dispersion of Pharmacokinetics AUC _last about 7-15 times the API.

It can be seen that the solid dispersion comprising the active ingredient and the PVP K30-containing carrier prepared by the present invention is very stable; and the solid dispersion of the present invention has significantly improved dissolution compared to the active ingredient, especially the solid dispersion of the present invention. The area under the curve of the body is 6-20 times, preferably 7-15 times, more preferably 9-14 times the area under the curve of the drug when the active ingredient is administered alone. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it should be understood that various modifications and changes may be made to the present invention, and the scope of the invention is defined by the scope of the appended claims.

Claims

Rights request

A solid dispersion characterized by comprising

Where R is CD ₃ or CH _: and

(B) a hydrophilic polymer carrier;

Among them, the weight ratio of (A) and (B) is 1-1:40.

The solid dispersion according to claim 1, wherein the hydrophilic polymer carrier is povidone or a povidone-containing polymer carrier.

The solid dispersion according to claim 1, wherein the hydrophilic polymer carrier is povidone K30 or a povidone K30-containing polymer carrier, wherein the povidone K30 content It is 10-100% by weight based on the total weight of the polymer carrier.

The solid dispersion according to claim 1, wherein the active ingredient is a compound represented by Formula I, or a pharmaceutical thereof

The solid dispersion according to claim 3, wherein the povidone-containing K30-containing polymer carrier further comprises other water-soluble carriers selected from the group consisting of polyethylene glycols and povidones. , celluloses, surfactants, or combinations thereof;

The surfactant class is selected from the group consisting of poloxamer 407, poloxamer 188, or a combination thereof.

The solid dispersion according to claim 1, wherein the weight ratio of the (A) and (B) is 1:

1-1: 20.

The solid dispersion according to claim 1, wherein the solid dispersion has X-ray powder In the final diffraction pattern, there is no X-ray diffraction characteristic peak of the active component of the solid dispersion.

The solid dispersion according to claim 1, which has one or more of the following features: 1 The area under the drug-time curve of the solid dispersion is when the active ingredient of the solid dispersion is administered alone 6-20 times the area under the drug time curve;

2 The solid dispersion has a cumulative dissolution of more than 70% at 37 ° C in a pH 4.5 aqueous solution of sodium acetate buffer for 10 minutes;

3 The cumulative dispersion of the solid dispersion at 120 ° C in a pH 4.5 aqueous solution of sodium acetate buffer for 120 minutes is 10-40 times the cumulative dissolution of the active ingredient of the solid dispersion.

9. A method of preparing a solid dispersion according to claim 1, comprising the method of: (a) melting method 1, comprising the steps of:

(a3) cooling the molten mixture obtained in the step (a2) to obtain the solid dispersion according to claim 1;

Or

(b) Melting method 2, including steps:

(b3) cooling the molten mixture obtained in the step (b2) to obtain the solid dispersion according to claim 1;

Or

(c) Solvent method, including steps:

(c2) removing the solvent in the mixture obtained in the step (cl), thereby obtaining the solid dispersion according to claim 1;

Where R is CD ₃ or CH _: The hydrophilic polymer carrier is a hydrophilic polymer carrier containing povidone K30, and the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, chloroform, tetrahydrofuran, or a combination thereof. .

10. A pharmaceutical composition, the composition comprising:

(1) The solid dispersion of any one of claims 1-8;

(2) A pharmaceutically acceptable excipient.

A method for producing a pharmaceutical composition according to claim 10, which comprises mixing the solid dispersion according to any one of claims 1 to 8 and a pharmaceutically acceptable excipient. The pharmaceutical composition is described.

12. Use of a solid dispersion according to claim 1 for the preparation of a medicament for inhibiting a phosphokinase (e.g., raf^ enzyme); or for the preparation of a medicament for treating a tumor.

A method of treatment, which comprises applying (i) the solid dispersion according to any one of claims 1 to 8 or (ii) the pharmaceutical composition according to claim 10 to a patient in need of treatment.