WO2013135187A1

WO2013135187A1 - Solid dispersion of improved adsorption performance and preparation thereof

Info

Publication number: WO2013135187A1
Application number: PCT/CN2013/072643
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: CN103301067B; CN103301067A

Abstract

A solid dispersion of improved adsorption performance and preparation thereof. Specifically, provided in the present invention is the solid dispersion. The solid dispersion comprises (A) serving as an active ingredient and represented by formula A, a compound or a derivative thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and, (B) a hydrophilic macromolecule carrier, where the weight ratio between (A) and (B) is between 1:1 and 1:40. The solid dispersion provided in the present invention significantly increases in vitro dissolution of active ingredients, and greatly increases adsorption of the active ingredients for mammals, thus effectively reducing dosage.

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, and in particular to a solid dispersion for improving absorption properties and preparation thereof. Background technique

The compound of formula II is a novel multi-targeted oral drug for the treatment of tumors. Its primary development goal is to treat gastrointestinal stromal tumors and metastatic renal cell carcinoma that are not responsive or intolerant to standard therapies.

The compound shown by formula 极 is extremely poor in water solubility and is a poorly soluble drug. It has a low solubility and dissolution rate in physiological body fluids, and a low dissolution rate, which ultimately leads to low bioavailability and seriously affects the absorption of active ingredients by the human body. 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, in CN101632630A, the relative bioavailability of probucol and PVP K30 solids is only 5.8 times higher than that of probucol.

Therefore, the development of a solid dispersion of a compound of formula II with significantly improved bioavailability is highly important in addressing the problem of poor absorption of active ingredients by mammals. Summary of the invention

SUMMARY OF THE INVENTION One object of the present invention is to provide a solid dispersion of a compound of the formula A or a derivative thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, having a significant increase in bioavailability as an active ingredient.

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 comprising:

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

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 II, or a pharmaceutically acceptable salt, hydrate or solvate thereof

In another preferred embodiment, the active ingredient is a p-toluenesulfonate of a compound of formula II.

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: 5.

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 is cumulatively dissolved in a sodium acetate buffered aqueous solution at 37 ° C, pH 4.5 for 10 minutes. Degree greater than 70%, preferably 75-95%;

3 The cumulative dissolution of the solid dispersion at 37 ° C, pH 4.5 in an 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, chloroform, tetrahydrofuran, or Combination.

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 an XRPD pattern of solid dispersion 5.

Figure 6 shows an XRPD pattern of solid dispersion 6. Figure 7 shows an XRPD pattern of solid dispersion 7.

Figure 8 shows an XRPD pattern of solid dispersion 8.

Figure 9 shows an XRPD pattern of Solid Dispersion 9.

Figure 10 shows an XRPD pattern of solid dispersion 10.

Figure 1 1 shows an XRPD pattern of the solid dispersion 1 1 .

Figure 12 shows the physical mixture of the compound of the formula II, the compound of the formula II and the PVP K30 and the dissolution profile of the solid dispersion 1.

Figure 13 shows an XRPD pattern of solid dispersion 12.

Figure 14 shows a comparison of XRPD of the solid dispersion 4 after 1, 2, and 3 months accelerated stability test. The results are shown in Figure 14: From top to bottom, the compound of formula II is p-toluenesulfonate, new The prepared solid dispersion 4, the XRPD pattern when the solid dispersion 4 was left for one month, the solid dispersion 4 was left for two months, and the solid dispersion 4 was left for three months.

Figure 15 shows a comparison of XRPD of the solid dispersion 5 after 1, 2, and 3 months accelerated stability test. The results are shown in Figure 15: From top to bottom, the compound of formula II is p-toluenesulfonate, new The prepared solid dispersion 5, the XRPD pattern when the solid dispersion 5 was left for one month, the solid dispersion 5 was left for two months, and the solid dispersion 5 was left for three months.

Figure 16 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 16: From the top to the bottom, the compound of the formula II, the newly prepared solid dispersion 1, The XRPD pattern of the solid dispersion 1 when it was left for one month, when the solid dispersion 1 was left for two months, and when the solid dispersion 1 was left for three months.

Figure 17 shows a comparison of XRPD of the solid dispersion 3 after 1, 2, and 3 months accelerated stability test. The results are shown in Figure 17: From the top to the bottom, the compound of the formula II, the newly prepared solid dispersion 3, The XRPD pattern when the solid dispersion 3 was left for one month, when the solid dispersion 3 was left for two months, and when the solid dispersion 3 was left 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 very 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 thereof, as an active ingredient,

The term also encompasses various crystalline forms, hydrates or solvates of a compound of formula A or a derivative thereof, preferably:

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

The carrier used for the solid dispersion, the most commonly used water-soluble carrier, poorly soluble carrier and enteric carrier. The "carrier" of the present invention is a hydrophilic polymer carrier, preferably povidone or povidone-containing. A molecular carrier, or povidone K30 or a polymeric carrier containing povidone K30, wherein the povidone 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 the weight of povidone K30. A carrier having a weight exceeding 20% by weight of the carrier; or a carrier having a weight content of povidone K30 of more than 40% by weight based on the total weight of the carrier; or a carrier having a weight content of povidone K30 of more than 60% by weight based on the total weight of the carrier.

Of course, the hydrophilic polymeric carrier may also contain other water soluble carriers such as, but not limited to, polyethylene glycols, povidones, cellulosics, surfactants, 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 a combination 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), hydroxypropylcellulose 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: 5-1: 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, a spray drying method, or a surface dispersion method. Preferably, the preparation method is a melt method or a solvent method. Melting method

Usually, in the melting method, the (A) active ingredient and (B) the hydrophilic polymer carrier are uniformly mixed, heated to melt in a water bath or an oil bath, and then cooled to a solid, and pulverized to obtain the active substance in a powder form. A solid dispersion of the ingredients.

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 after pulverization, a solid dispersion of the active ingredient in a powder form is obtained. Solvent method

In general, the solvent method is a method in which (A) an active ingredient and (B) a hydrophilic polymer carrier are co-dissolved in a solvent, and after the mixture is homogeneous, the solvent in the solution is removed to obtain an active ingredient and a hydrophilic polymer. The 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.

The typical diffraction peak (characteristic peak) of the active ingredient when measured by XRPD is as follows;

A compound of formula I, which is at 14.58±0·, 18·71±0·, 21·08±0·1. , 23·35±0·, 29.44±0. Strong diffraction peaks.

A compound of formula II which is at 12.49 ± 0.1. , 22·40±0·, 22·83±0·, 24.69±0.1. 25.11±0.1° has strong diffraction peaks.

a p-toluenesulfonate of the compound of formula II, which is at 4.40 ± 0., 13.18 ± 0., 14.74 ± 0.1 °,

16·64±0·1 ^ο , 17·82±0·1 ^ο , 20·01±0·1 ^ο , 20·41±0·1 ^ο , 20·78±0·1 ^ο , 21·47±0 ·1 ^ο , 22·83±0·1 ^ο Strong diffraction peaks. Characteristic peak of the carrier

Some carriers have strong diffraction peaks. For example, PEG4000 and PEG6000 have strong diffraction peaks at 19.19±0. and 23.30±0.1°. ? 01 ₀ & 111⁄2 407 has strong diffraction peaks at 19.16 ± 0.1 ° and 23.32 ± 0.1 °. Some carriers do not have strong diffraction peaks. For example, strong diffraction peaks are not detected in PVP K30, HPMC E5, and HPC-L. Characteristic peak of solid dispersion

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 formula A (or a derivative thereof, or a salt thereof) has excellent inhibitory activity against phosphokinase (Kinase M column such as raft敫 enzyme, the solid dispersion of the present invention and the pharmaceutical composition containing the solid dispersion of the present invention as a main component The compounds are useful for the treatment, prevention, and alleviation of diseases mediated by phosphokinase (Kinase M, such as raft敫 enzyme. According to the prior art, the compounds of the present invention are useful for treating diseases such as cancer, cardiovascular disease, obesity, diabetes, etc. .

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" is meant: The amount of solid dispersion is sufficient to significantly improve the condition without causing serious side effects. In general, 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.), starches, monosaccharides or polysaccharides, gelatin , talc, solid lubricants (such as stearic 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 dispersion is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) 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 (a) humectants, for example, glycerin; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, croscarmellose Sodium and sodium carbonate; (e) a slow solvent such as paraffin; (f) aspiration Accelerator, for example, a quaternary amine compound; (g) a wetting agent such as cetyl alcohol, sodium dodecyl sulfate, glyceryl monostearate; (h) an adsorbent, for example, kaolin; and (i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures 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, lozenges 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 dispersions of the present invention are 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

Formula II compound and PVP K30, weight ratio of 1: 4, solvent (methanol) method

Weigh 1 part by weight of the compound of formula II and 4 parts by weight of PVP K30 in the same flask, place the flask in an oil bath at 80 ° C, add methanol to the flask, and stir the plug under reflux of the condensed water until the compound and PVP K30 was dissolved 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, pulverized or 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 II disappeared completely, and existed in an amorphous or molecular form. Example 2 Solid Dispersion 2

Formula II compound and PVP K30, weight ratio of 1: 3, solvent (methanol) method

The preparation method was the same as in Example 1, except that the weight ratio of the compound of the formula II to the PVP K30 was 1:3. 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 II disappeared completely, and existed in an amorphous or molecular form. Example 3 Solid dispersion 3

Formula II compound and PVP K30, weight ratio of 1: 2, solvent (methanol) method

The preparation method was the same as in Example 1, except that the weight ratio of the compound of the formula II to the PVP K30 was 1:2. 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 II disappeared completely, and existed in an amorphous or molecular form. Example 4 Solid dispersion 4

The p-toluenesulfonate of the compound of the formula II and the PVP K30 are in a weight ratio of 1:4, and the solvent (methanol) method is the same as in the first embodiment except that the p-toluenesulfonate of the compound of the formula II is used instead. a compound of formula II.

The XRPD test results are shown in Fig. 4. In the solid dispersion 4, the diffraction peaks (characteristic peaks) of the p-toluenesulfonate of the compound of the formula II disappeared, and existed in an amorphous or molecular form. Example 5 Solid dispersion 5

The p-toluenesulfonate of the compound of the formula II and the PVP K30 are in a weight ratio of 1:3, and the solvent (methanol) method is the same as in the example 4 except that the p-toluenesulfonate of the compound of the formula II is used. PVP

The weight ratio of K30 is 1:3.

The XRPD test results are shown in Fig. 5. In the solid dispersion 5, the diffraction peaks (characteristic peaks) of the p-toluenesulfonate of the compound of the formula II disappeared, and existed in an amorphous or molecular form. Example 6 Solid dispersion 6

Formula II 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 solvent was absolute ethanol.

The XRPD test results are shown in Fig. 6. In the solid dispersion 6, the diffraction peaks (characteristic peaks) of the compound of the formula II disappeared completely, and existed in an amorphous or molecular form. Example 7 Solid Dispersion 7 The compound of formula II has p-toluenesulfonate and PVP K30 in a weight ratio of 1:4, solvent (anhydrous ethanol) method

The preparation method is the same as that of Example 1, except that the p-toluenesulfonate of the compound of the formula II is used instead of the compound of the formula II, and the solvent is anhydrous ethanol.

The XRPD test results are shown in Fig. 7. In the solid dispersion 7, the diffraction peaks (characteristic peaks) of the p-toluenesulfonate of the compound of the formula II disappeared, and existed in an amorphous or molecular form. Example 8 Solid dispersion 8

The compound of formula II has p-toluenesulfonate and PVP K30 in a weight ratio of 1:4, solvent (isopropyl alcohol) method

The preparation method is the same as in Example 1, except that the p-toluenesulfonate of the compound of the formula II is used instead of the compound of the formula II, and the solvent is isopropanol.

The XRPD test results are shown in Fig. 8. In the solid dispersion 8, the diffraction peaks (characteristic peaks) of the p-toluenesulfonate of the compound of the formula II disappeared, and existed in an amorphous or molecular form. Example 9 Solid Dispersion 9 (spray drying)

The compound of formula II has p-toluenesulfonate and PVP K30 in a weight ratio of 1:4, solvent (anhydrous ethanol) method

1 part by weight of p-toluenesulfonate of the compound of the formula II and 4 parts by weight of the carrier PVP K30 were mixed into a three-necked flask, and the flask was added with a quantitative amount (p-toluenesulfonate of the compound of the formula II: solvent = lg: 400ml) of solvent (anhydrous ethanol), the flask is placed in a 80 ° C oil bath, stirred under condensed water reflux conditions, and the mixture is stirred until the p-toluenesulfonate and the carrier of the compound of formula II are completely dissolved. Stir for 30 minutes.

The lysed solution was spray dried with a Swiss-made Buchi Model 209 spray dryer. The process parameters are as follows: inlet air temperature 1 10 ° C ~ 120 ° C, fan power 55% ~ 65%, peristaltic pump power 50% ~ 55%. A white fine powder was obtained. The obtained powder was vacuum dried in a vacuum oven at 50 ° C for 24 hours to obtain a solid dispersion 9 powder.

The XRPD test results are shown in Fig. 9. In the solid dispersion 9, the diffraction peaks (characteristic peaks) of the p-toluenesulfonate of the compound of the formula II disappeared and existed in an amorphous or molecular form. Example 10 Solid Dispersion 10 (spray drying)

The preparation method was the same as in Example 9, except that the solvent was isopropyl alcohol.

The XRPD test results are shown in Fig. 10. In the solid dispersion 10, the diffraction peaks (characteristic peaks) of the p-toluenesulfonate of the compound of the formula II disappeared and existed in an amorphous or molecular form. Example 11 Solid Dispersion 11 (spray drying)

The compound of formula II has p-toluenesulfonate and PVP K30 in a weight ratio of 1:2, solvent (isopropyl alcohol) method

The preparation method is the same as that of Example 9, except that p-toluenesulfonate and PVP of the compound of formula II are used.

The weight ratio of K30 is 1:2, and the solvent is isopropyl alcohol.

The XRPD test results are shown in Fig. 11. In the solid dispersion 1, the diffraction peaks (characteristic peaks) of the p-toluenesulfonate of the compound of the formula II disappeared and existed in an amorphous or molecular form. The solid dispersion prepared in Examples 9-11 was tested and found to:

In the solid dispersion of the active ingredient to the carrier in a weight ratio of 1: 2, the percentage of API is 33.97%;

The percentage of API in the solid dispersion in which the active ingredient to carrier weight ratio was 1:4 was 20.61-21.50%, indicating that there was no loss in API during the preparation of the solid dispersion by spray drying. Example 12 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.

The physical mixture of the compound of the formula II, the compound of the formula II and the PVP K30 (the weight of the compound of the formula II and the PVP K30 are 50 mg and 200 mg, respectively) and the solid dispersion 1 (250 mg) are respectively added, and the paddle speed is 100 rpm, respectively. 5 mL was sampled at 2 min, 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 120 min, filtered through a 0.45 μιη microporous membrane filter, 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 12. The dissolution of the compound of formula II at 10 min was < 1%, the dissolution of the physical mixture of the compound of formula II and PVP K30 was < 3%, and the dissolution of solid dispersion 1 was 76%, with PVP K30. The solid dispersion of the carrier greatly improves the dissolution of the compound of formula II. Example 13 In vivo pharmacokinetic test of solid dispersion 1

The solid dispersion 1 was selected for in vivo pharmacoassay with the corresponding API (i.e., the compound of formula II).

Six male 6-week-old Wistar rats weighing approximately 170 g were divided into 2 groups of 3 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 was separated. Sample, 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. The parameters are shown in Table 1.

The results are shown in Table 1: AUC _INF of the in vivo pharmacogen of solid dispersion 1. _Bs is about 13.9 times that of the API.

Table 1

Example 14 Solid Dispersion 12

Formula I compound and PVPK30, weight ratio 1: 4, solvent (anhydrous ethanol) method

The preparation method was the same as in Example 1, except that the compound of the formula I was used instead of the compound of the formula II, and the solvent was anhydrous ethanol.

The XRPD test results are shown in Fig. 13. In the solid dispersion 12, the diffraction peaks (characteristic peaks) of the compound of the formula I disappeared and existed in an amorphous or molecular form. Example 15 Solid dispersion 13

Formula I compound and PVPK25, weight ratio 1: 4, solvent (anhydrous ethanol) method

The preparation method was the same as that of Example 14, except that the carrier PVPK25 was used instead of the carrier PVPK30. Example 16 Solid Dispersion 14

Formula I compound and PVPK90, weight ratio 1: 4, solvent (anhydrous ethanol) method

The preparation method was the same as that of Example 14, except that the carrier PVPK90 was used instead of the carrier PVPK30. Example 17 Comparative Test of Dissolution of Solid Dispersion 12

The test method was the same as in Example 12, and the dissolution rate of the solid dispersion 12 (250 mg) was tested. The results show that the solid dispersion 12 has a dissolution rate of 80% at 30 minutes, and the solid dispersion of PVP K30 as a carrier greatly improves the dissolution of the compound of formula I, which is significantly better than other commonly used carriers (such as PEG 6000). Hypromellose E5) is also superior to PVP K90 and K25. Example 18 In vivo pharmacokinetic test of solid dispersion 12

The solid dispersion 12 was selected for in vivo pharmacoassay with the corresponding API (i.e., the compound of formula I) in the same manner as in Example 13.

The results are shown in Table 2: AUC _INF of the in vivo pharmacogen of solid dispersion 12. _Bs is about 7.3 times that of the API.

Table 2

Example 19 Solid dispersion 4 amorphous stability test

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

The XRPD results are shown in Figure 14, which indicates that the solid dispersion 4 is very stable after 1, 2, and 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. 14. From the top to the bottom, the compound of the formula II is p-toluenesulfonate, the freshly prepared solid dispersion 4, the solid dispersion 4 is left for one month, and the solid dispersion 4 is placed for two months. The solid dispersion 4 was placed in an XRPD pattern at three months. Example 20 Solid dispersion 5 amorphous stability test

Solid dispersion 5 was selected for accelerated stability test (40 ° C, 75% H): 1, 2, 3 months The X-ray powder diffraction was taken out.

The XRPD results are shown in Figure 15, which indicates that the solid dispersion 5 is very stable after 1, 2, and 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. 15 : from top to bottom, the compound of formula II is p-toluenesulfonate, freshly prepared solid dispersion 5, solid dispersion 5 is left for one month, and solid dispersion 5 is placed for two months. , XRPD pattern of solid dispersion 5 placed for three months. Example 21 Solid Dispersion 1 Amorphous Stability Test

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

The XRPD results are shown in Fig. 16, which indicates that the solid dispersion 1 is very stable after the 1, 2, and 3 months accelerated stability test (no X-ray diffraction characteristic peak of the 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. 16: From the top to the bottom, the compound of the formula II, the freshly prepared solid dispersion 1, the solid dispersion 1 was left for one month, the solid dispersion 1 was left for two months, and the solid dispersion 1 was placed three. XRPD chart at the time of month. Example 22 Solid dispersion 3 amorphous stability test

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

The XRPD results are shown in Figure 17, which indicates 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 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. 17. From the top to the bottom, the compound of the formula II, the freshly prepared solid dispersion 3, the solid dispersion 3 were left for one month, the solid dispersion 3 was left for two months, and the solid dispersion 3 was placed three. XRPD chart at the time of month. Example 23-27 Solid Dispersion 15-19

API is a compound of formula II;

The carrier is a mixed carrier of PVP K30 and other water-soluble carriers (see Table 3 for mixed carriers).

The preparation method was the same as that in Example 1, except that the mixed carrier was subjected to the conditions shown in Table 3, and the solvent was Anhydrous ethanol.

table 3

The XRPD test results show that the diffraction peaks (characteristic peaks) of the compound of formula II disappear completely, and exist in an amorphous or molecular form.

The in vivo pharmacokinetic test of solid dispersions 15-19 (in turn, corresponding to Examples 23-27) (operation as before) indicates: AUC _INF of the in vivo pharmacophore of the solid dispersion. _Bs is about 7-15 times the API. in conclusion:

1. The solid dispersion comprising the active ingredient and the PVP K30-containing carrier prepared according to the present invention is very stable.

2. Compared with the active ingredient, the solid dispersion prepared by the invention has significantly improved dissolution and good in vivo pharmacokinetic parameters, especially the area under the drug-time curve of the solid dispersion of the invention is its active ingredient alone. The area under the curve of the drug at the time of administration is 6-20 times, preferably 7-15 times.

3. The solids dispersion of the compound of formula II has a more pronounced improvement in area under the drug time curve than the solid dispersion of the compound of formula I. The solids dispersion of the solid dispersion of the compound of formula II is 13.9 times the area of the active ingredient of the compound of formula II, and the solid dispersion of the solid dispersion of the compound of formula I is 7.3 times the area of the active ingredient of the compound of formula I. 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:

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:

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 II, or a drug 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, pH 4.5 in a sodium acetate buffered aqueous solution for 10 minutes;

3 The cumulative dispersion of the solid dispersion at 37 ° 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 ₃ ,

The solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, dichloromethane, 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. Said pharmaceutical composition.

12. Use of a solid dispersion according to claim 1 for the preparation of a medicament for inhibiting a phosphokinase (e.g., rafase); 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.