WO2017036390A1 - Composition of palbociclib or pharmaceutically acceptable salt thereof and pharmaceutical excipient, and preparation method therefor - Google Patents

Abstract

A composition of Palbociclib or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient, and a preparation method therefor. Palbociclib or the pharmaceutically acceptable salt thereof is amorphous. The present invention further relates to a pharmaceutical composition containing a Palbociclib solid dispersion, comprising a solid dispersion formed by Palbociclib and an organic carrier and at least one pharmaceutical excipient, wherein Palbociclib is amorphous. The pharmaceutical composition of the present invention increases the dissolution rate of Palbociclib, and helps improve the bioavailability of medicine.

Description

Composition of paclocillin or a pharmaceutically acceptable salt thereof and medicinal adjuvant and preparation method thereof Technical field

The invention belongs to the field of pharmaceutical preparations, in particular to a composition of paclicillin or a pharmaceutically acceptable salt thereof and a medicinal adjuvant, and a preparation method thereof, and to a medicinal preparation containing an amorphous dispersion of paclicillin solid dispersion. A composition, a method of its preparation, and the use of the composition for treating cancer.

Background technique

Palbociclib, chemical name 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(1-piperazinyl)pyridin-2-ylamino]-8H-pyridine [2,3-d]pyrimidin-7-one, trade name Ibrance, is a new drug developed by Pfizer for the treatment of metastatic breast cancer. Paclocillin is a cyclin-dependent kinase 4,6 inhibition. The drug, mainly by inhibiting CDK4/6 activity, prevents cells from G1 to S phase and thereby inhibits DNA synthesis. Clinical trials have found that paclicillin plus letrozole is very effective in postmenopausal patients with locally invasive breast cancer or newly diagnosed estrogen receptor (ER), and HER-2 negative patients. Pabsilin was approved by the US Food and Drug Administration (FDA) on February 3, 2015. The US Food and Drug Administration (FDA) says the drug is a breakthrough drug that provides longer-lasting efficacy than drugs on the market today.

Although the efficacy of paclicillin has been widely recognized, there are still some shortcomings. Patent WO2014128588 discloses two crystal forms of paclicillin free base: Form A and Form B, but no amorphous reports have been reported. The drug is used for preparation of the free base crystal form Form A. Although Form A is a thermodynamically stable crystal form and has a stable stability, the solubility of the crystal form in water is extremely low, and the solubility is only 19 under near neutral conditions. Mg/L. Therefore, the drug is a poorly soluble drug, and its extremely low water solubility seriously affects the bioavailability of the drug. In addition, the difference in efficacy between patients is relatively large, 13% of patients have very low absorption of the original drug, and can be slightly increased after taking the meal. Eating low-fat food equivalent to 3 grams of peanut oil can increase absorption by 12%. Eating high-fat food equivalent to 67 grams of peanut oil can increase absorption by 21%, but high-fat foods also have considerable harm to the health of patients.

The solid form of the drug directly affects the dissolution rate of the drug substance, the dissolution rate of the drug, and the bioavailability. In order to improve the bioavailability of the drug, reduce the dosage, and reduce the side effects, a new solid form of the drug is usually developed. Solid forms with better drug solubility and higher bioavailability are necessary.

In addition to the crystalline state, the solid form of the drug has an amorphous state. The amorphous state of the drug, as a special form of solid matter, has an important use in drug preparation. Amorphous drugs can be widely used not only in pharmaceutical preparations, but also in a variety of technical means and methods to improve the stability of amorphous drugs, making them a good quality drug.

Due to the lack of bioavailability of paclocillin and the active ingredients of amorphous drugs in pharmaceutical preparations The good application prospects, it is necessary to find a new amorphous form of Pabcillin and its preparation method.

Summary of the invention

An object of the present invention is to provide a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, and a process for the preparation thereof, which provide an amorphous form of paclocillin or a pharmaceutically thereof thereof which is excellent in stability and dispersibility. The composition of the acceptable salt and the medicinal adjuvant increases the dissolution rate of paboxirin or a salt thereof, and the preparation method is not limited by the drying process, and is not limited by the kind of the solvent and the amount of the solvent, and is easy to operate and cost. Low cost, easy to implement, and industrial production.

In order to achieve the above object, the technical solution of the present invention is as follows:

A composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, the composition comprising paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in a weight ratio of 1:0.1 ～100, wherein the paclicillin or a pharmaceutically acceptable salt thereof is in an amorphous state, and in the X-ray powder diffraction spectrum of the composition, there is no paclicillin after subtracting the background peak of the medicinal excipient a characteristic peak of a crystal of a salt thereof.

Further, the medicinal adjuvant is selected from the group consisting of an excipient, a propellant, a solubilizer, a cosolvent, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, Stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release retardant At least one.

Preferably, the medicinal adjuvant is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymer, polyacetic acid Ethylene, carboxymethylethylcellulose, carboxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin , carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan At least one of chitosan, ion exchange resin and collagen.

Further, the present invention provides a pharmaceutical composition comprising a solid dispersion of paclicillin, which is a composition of paboxirillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, wherein the pharmaceutical excipient is Including an organic vehicle and a pharmaceutical preparation auxiliary, the pablocillin forms a solid dispersion with the organic carrier, and then forms a composition with the pharmaceutical preparation auxiliary, wherein the weight of the paclicillin is 20% to 80% of the total weight of the solid dispersion. The weight of the auxiliary material is 0.1% to 80% by weight of the solid dispersion, wherein the paclocillin is in an amorphous state, and the X-ray powder diffraction spectrum of the composition is deducted from the carrier and the medicinal auxiliary material. There are no characteristic peaks of pabsilin crystals after the background peak.

Further, the organic vehicle is selected from the group consisting of polymers or copolymers.

Preferably, the organic vehicle is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymer, polyvinyl acetate. , carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate Peric acid ester, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polycyclic At least one of oxyethane, chitosan, chitosan, ion exchange resin, and collagen.

Further, the pharmaceutical preparation auxiliary is selected from the group consisting of an excipient, a propellant, a solubilizer, a solubilizer, an emulsifier, a colorant, a binder, a disintegrator, a filler, a lubricant, a wetting agent, and an osmotic pressure adjustment. Agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, Surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release retarder At least one of them.

A method for preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant of the present invention, comprising the steps of:

1) mixing paclocillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, and heating to melt the medicinal adjuvant; wherein the weight ratio of paboxirin or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable excipient is 1: 0.1 to 100;

2) After mixing and cooling, the mixture is pulverized to obtain an amorphous form of a combination of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.

Further, the medicinal adjuvant is selected from the group consisting of an excipient, a propellant, a solubilizer, a cosolvent, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, Stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release retardant At least one.

Preferably, the pharmaceutical excipient described in step 1) is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymerization. , polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate , polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide At least one of chitosan, chitosan, and collagen.

The present invention provides a method for preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, comprising the steps of:

1) mixing paclocillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant in a solvent at a mixing temperature of -50 to 150 ° C to form a solution or suspension containing paboxirin or a salt thereof and a pharmaceutically acceptable excipient. Wherein the weight ratio of paclocillin or a pharmaceutically acceptable salt thereof to the solvent is from 0.001 to 100:1, and the weight ratio of paboxirillin or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable excipient is from 1:0.1 to 100;

2) The solvent in the solution or suspension obtained in the step 1) is removed to obtain a composition of the amorphous form of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.

Further, the medicinal adjuvant is selected from the group consisting of an excipient, a propellant, a solubilizer, a cosolvent, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, Stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release retardant At least one.

Preferably, the pharmaceutical excipient described in step 1) is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymerization. , polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate , polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide At least one of chitosan, chitosan, ion exchange resin, and collagen.

Further, the solvent of the step 1) is selected from the group consisting of alcohols having a carbon number of 12 or less, phenols, ethers, halogenated hydrocarbons, ketones, aldehydes, nitriles, amides, sulfones, sulfoxides, carboxylic acids, and water. At least one of the steps 2) removing the solvent includes evaporation, vacuum evaporation, spray drying, freeze drying, hot melt extrusion, filtration, centrifugation or stirring film drying.

The preparation method of the pharmaceutical composition containing the paboxirillin solid dispersion of the invention comprises the following steps:

1) heating a mixture of paboxirin, at least one organic vehicle and at least one pharmaceutical preparation auxiliary, wherein the weight of the paclicillin is 20% to 80% of the total weight of the solid dispersion, the auxiliary material The weight is from 0.1% to 80% by weight of the solid dispersion;

2) After mixing and cooling, the obtained mixture was pulverized to obtain a pharmaceutical composition containing a solid dispersion of paclicillin in an amorphous state.

Further, the organic vehicle described in the step 1) is selected from a polymer or a copolymer.

Preferably, the organic vehicle described in the step 1) is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymer , polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, Polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, At least one of chitosan, chitosan, and collagen.

Further, the pharmaceutical preparation auxiliary agent described in the step 1) is selected from the group consisting of an excipient, a propellant, a solubilizer, a solubilizer, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, and a wetting agent. , osmotic pressure regulator, stabilizer, glidant, flavoring agent, preservative, suspending agent, coating material, fragrance, anti-adhesive agent, integrator, penetration enhancer, pH adjuster, buffer, Plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, antioxidants, adsorbents, filter aids, At least one of releasing a retarder.

The invention provides a preparation method of another pharmaceutical composition containing a solid dispersion of paboxirin, comprising the following steps:

1) mixing paboxirin, at least one organic vehicle and at least one pharmaceutical preparation auxiliary in a solvent at a mixing temperature of -50 to 150 ° C to form a solution containing paboxirin, an organic vehicle and a pharmaceutical preparation auxiliary or a suspension wherein the weight ratio of paboxirin to solvent is from 0.001 to 100:1, the weight of paboxirin is from 20% to 80% by weight based on the total weight of the solid dispersion, and the weight of the excipient is 0.1 by weight of the solid dispersion. %~80%;

2) The solvent in the solution or suspension obtained in the step 1) is removed to obtain a pharmaceutical composition containing a solid dispersion of the paclicillin in an amorphous state.

Further, the organic vehicle described in the step 1) is selected from a polymer or a copolymer.

Preferably, the organic vehicle described in the step 1) is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymer , polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, Polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, At least one of chitosan, chitosan, ion exchange resin, and collagen.

Further, the pharmaceutical preparation auxiliary agent described in the step 1) is selected from the group consisting of an excipient, a propellant, a solubilizer, a solubilizer, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, and a wetting agent. , osmotic pressure regulator, stabilizer, glidant, flavoring agent, preservative, suspending agent, coating material, fragrance, anti-adhesive agent, integrator, penetration enhancer, pH adjuster, buffer, Plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, antioxidants, adsorbents, filter aids, At least one of releasing a retarder.

Further, the solvent of the step 1) is selected from the group consisting of alcohols having a carbon number of 12 or less, phenols, ethers, halogenated hydrocarbons, ketones, aldehydes, nitriles, amides, sulfones, sulfoxides, carboxylic acids and water. At least one of the steps 2) removing the solvent includes evaporation, vacuum evaporation, spray drying, freeze drying, hot melt extrusion, filtration, centrifugation or stirring film drying.

The composition in the present invention means a mixture, a composite, a copolymer, a coprecipitate, a eutectic, a solid dispersion, a solvate, and a hydrate.

The pharmaceutically acceptable pharmaceutical excipients and pharmaceutical preparation excipients in the present invention refer to excipients and additives used in the production of pharmaceuticals and formulation formulations, including excipients, propellants, solubilizers, solubilizers, emulsifiers, Colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, Anti-adhesive, integrator, penetration enhancer, pH adjuster, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, thinner , flocculants and deflocculants, antioxidants, adsorbents, filter aids, release retarders, etc.

The present invention also provides a pharmaceutical composition comprising amorphous form of paclicillin for use in the treatment of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, esophageal cancer, Gastric cancer, Skin cancer, lung cancer, bone cancer, colon cancer, pancreatic cancer, thyroid cancer, biliary tract cancer, oral vestibular and pharyngeal cancer (oral), lip cancer, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colon-rectal cancer, large intestine Cancer, rectal cancer, brain and central nervous system cancer, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, Sperm cell carcinoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphoid disorders, Hodgkin's disease, skin cell carcinoma, and leukemia.

The composition of the paclicillin of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, using Cu-Kα radiation, deducting the background peak of the medicinal excipient from the X-ray powder diffraction spectrum expressed by degree 2θ A characteristic peak of the crystalline form of Xilin indicates that paclicillin or a pharmaceutically acceptable salt thereof is in an amorphous state. The crystalline state of paclicillin is generally used in the prior art, and no report of its amorphous state has been reported. Generally, due to the ordered and periodic arrangement of crystalline material molecules, the energy of the intermolecular interaction is reduced, and the energy is low, while the paclicillin of the present invention or a pharmaceutically acceptable salt thereof is in an amorphous state, and the molecule is Highly disordered, the surface free energy of the material is larger, the molecules in the solid matter have higher energy than the molecules in the crystalline solid matter, are more likely to disperse, increase their dissolution, and improve the biosynthesis of paboxirin or its salts. Utilization.

The present invention mixes paclocillin or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable adjuvant, and then uses a "solid dispersant" method to block the drug molecules through the polymer network structure of the medicinal adjuvant to inhibit the occurrence of crystallization. To keep it in a dispersed and amorphous state. The invention adopts the medicinal excipients which are widely used, low in price and good in solubility, and the medicinal excipients are mixed with paboxirin or its pharmaceutically acceptable salt, and combined with evaporation, spray drying, freeze drying and hot melt extrusion. An amorphous form of paclicillin or a pharmaceutically acceptable salt thereof may be obtained, which increases the absence of paclicillin or a pharmaceutically acceptable salt thereof in the composition of the paclicillin or a pharmaceutically acceptable salt thereof of the present invention. The stability of the stereotype.

The invention selects a pharmaceutically widely used and low-cost auxiliary material, and obtains a composition of paclicillin or a pharmaceutically acceptable salt thereof and a medicinal auxiliary material, and is easy to develop a formulation of the preparation, and the preparation method of the invention is not affected by the drying process. The limitation is also not limited by the type of solvent and the amount of solvent, and the operation is simple, the cost is low, the realization is easy, and industrial production can be realized.

Compared with the prior art, the beneficial effects of the present invention are:

1) The composition of the amorphous form of paclocillin or a pharmaceutically acceptable salt thereof prepared from the present invention and a pharmaceutically acceptable adjuvant has high dispersibility and stability, and after disintegration into a solid preparation, dispersion of the drug particles can be achieved. The degree is better, the dispersion and dissolution rate are faster, which is beneficial to the absorption of drugs. Therefore, the dissolution rate of the drug in the amorphous state is significantly increased, which is more conducive to the absorption of the drug by the body, and the bioavailability of the drug is improved, so that the drug can better exert the therapeutic effect of the clinical disease.

2) The preparation method of the composition of the paclicillin or the pharmaceutically acceptable salt thereof and the pharmaceutically acceptable adjuvant in the amorphous state of the present invention is not limited by the drying process, and is not limited by the kind of the solvent and the amount of the solvent, and is easy to operate. Low cost, easy to implement, and industrial production.

3) The composition of the amorphous form of paclocillin or a pharmaceutically acceptable salt thereof and the pharmaceutically acceptable excipient prepared by the present invention can be maintained under accelerated test conditions (40 ± 2 ° C, humidity: 75% ± 5%). Physical stability and chemistry stability. Therefore, the present invention will have broad application prospects.

DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray powder diffraction pattern of a composition of amorphous form of paclicillin and povidone K30 of Example 1 of the present invention.

2 is an X-ray powder diffraction pattern of a composition of amorphous paclicillin and polyacrylic resin L100 of Example 12 of the present invention.

Figure 3 is an X-ray powder diffraction pattern of a composition of an amorphous form of paclicillin solid dispersion and microcrystalline cellulose according to Example 56 of the present invention.

Figure 4 is an X-ray powder diffraction pattern of microcrystalline cellulose used in Example 56 of the present invention.

Figure 5 is an X-ray powder diffraction pattern of a composition of an amorphous paboxirillin solid dispersion and colloidal silica Aerosil 200 of Example 76 of the present invention.

detailed description

The invention is further illustrated by the following specific examples, but the scope of the invention is not limited by the following examples.

The X-ray powder diffraction pattern of the present invention was collected on a Ultima IV X-ray diffractometer. The method parameters of the X-ray powder diffraction according to the present invention are as follows:

X-ray powder parameters: Cu-Kα

：1.5418Kα

:1.5418

Voltage: 40 kV

Current: 40 mA

Divergence slit: automatic

Scan mode: continuous

Scan range: from 2.0 to 60.0 degrees

Sampling step size: 0.0200 degrees

Scan rate: 60 degrees / minute

Any physical form of paclicillin can be used to prepare the composition of the amorphous form of paclicillin of the present invention.

The loading rate of paboxirin in the pharmaceutical composition is calculated as follows:

Loading ratio = content of paboxirin in the pharmaceutical composition / weight of the paclicilin.

Example 1

Papacillin (50 mg) and povidone K30 (100 mg) were dissolved in n-butanol (600 μl), anisole (900 μl) and methanol (600 μL) and heated to 60 ° C for stirring. Dissolve. Drop the above solution quickly The temperature was raised to -10 ° C, a yellow solid was precipitated, filtered, and dried to obtain a composition of amorphous paboxirin and povidone K30. The X-ray powder diffraction pattern of the composition is shown in Fig. 1, X-ray powder diffraction. There is no characteristic peak of the paclicillin crystal form after subtracting the background peak of the medicinal excipient.

Example 2

Paclocillin hydrochloride (50 mg) and polyethylene glycol 4000 (200 mg) were dissolved in ethanol (600 μL) and water (600 μl), and stirred and mixed at -40 ° C. The above solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, which gave a composition of amorphous paboxirin and polyethylene glycol 4000. The X-ray powder diffraction pattern of the composition was deducted from the excipients. There is no characteristic peak of the paclicillin hydrochloride crystal form after the background peak.

Example 3

Paclocillin hydrochloride (5 g) and polyethylene glycol 8000 (10 g) were added to water (300 ml), and heated to 60 ° C to stir and dissolve. The above solution was dried with JISL micro spray dryer LSD-48, and the inlet temperature was maintained at 60 ° C and the outlet temperature was 50 ° C. The outlet material was collected to obtain a yellow solid, which was further dried by vacuum to obtain a combination of amorphous papacillin and polyethylene glycol 8000. In the X-ray powder diffraction pattern of the composition, there is no characteristic peak of the paclicillin hydrochloride crystal form after subtracting the background peak of the pharmaceutical excipient.

Example 4

Paclocillin hydrochloride (1 g) and hydroxypropylmethylcellulose E50 (0.2 g) were added to water (10 ml), and the mixture was heated to 40 ° C and stirred to dissolve. The above solution was freeze-dried to obtain a yellow solid, that is, a composition of amorphous paclicillin and hydroxypropylmethylcellulose E50. The X-ray powder diffraction pattern of the composition was subtracted from the background peak of the medicinal adjuvant. Characteristic peak of the crystal form of bosiline hydroxyethanesulfonate.

Example 5

Paclocillin (1 g) and polyethylene glycol 8000 (50 g) were heated to melt, and rapidly cooled to room temperature with stirring to give a yellow solid. The solid was pulverized to obtain a yellow powdery solid, that is, a composition of amorphous paboxirin and polyethylene glycol 8000. In the X-ray powder diffraction pattern of the composition, there was no Pabbo after subtracting the background peak of the medicinal adjuvant. The characteristic peak of the Xilin crystal form.

Example 6

Paclocillin (1 g), anisole (0.1 g) and polyethylene glycol 10000 (100 g) were heated to 240 ° C, mixed well and rapidly cooled to room temperature to give a yellow solid. The solid is pulverized to obtain a yellow powdery solid, that is, a composition of amorphous paboxirin and polyethylene glycol 10000. In the X-ray powder diffraction pattern of the composition, there is no Pabbo after subtracting the background peak of the medicinal adjuvant. The characteristic peak of the Xilin crystal form.

Example 7

Mix a mixture of pabocillin (1 g), anisole (10 g), n-butanol (20 g) and liposome (4 g) to 90 ° C, stir, mix well, remove the solvent by evaporation in vacuo, and cool A yellow solid, i.e., a combination of amorphous paclocillin and liposomes, was obtained at room temperature. In the X-ray powder diffraction pattern of the composition, there was no characteristic peak of the paclicillin crystal form after subtracting the background peak of the pharmaceutical excipient.

Example 8

A mixture of paclocillin hydrobromide (1 g), methanol (20 g) and methacrylic acid copolymer type A (4 g) was heated to 50 ° C, stirred, dissolved, evaporated in vacuo, and cooled to room temperature. Obtaining a yellow solid, a composition of amorphous paboxirin and methacrylic acid copolymer type A. In the X-ray powder diffraction pattern of the composition, there is no paclicillin hydrobromide after subtracting the background peak of the medicinal adjuvant. Characteristic peak of the crystal form.

Example 9

A mixture of pabocillin (1 g), n-butanol (20 g), anisole (10 g) and ethyl cellulose (2 g) was heated to 30 ° C, stirred, uniformly mixed, and the solvent was evaporated in vacuo. Cooling to room temperature gives a yellow solid, a combination of amorphous paclicillin and ethylcellulose, the X-ray powder diffraction pattern of the composition, without the background peak of the medicinal excipients, without the characteristics of the paclicillin crystal form peak.

Example 10

A mixture of pabocillin hydrochloride (1 g), methanol (20 g) and hydroxypropylcellulose SSL (4 g) was heated to 30 ° C, stirred and evaporated, evaporated in vacuo. , that is, a composition of amorphous papacillin and hydroxypropyl cellulose SSL, in the X-ray powder diffraction pattern of the composition, after deducting the background peak of the medicinal adjuvant, there is no characteristic peak of the paclicillin hydrochloride crystal form .

Example 11

A mixture of paboxirin hydroxyethanesulfonate (1 g), methanol (20 g), water (10 g) and polyvinyl acetate (4 g) was heated to 30 ° C, stirred to dissolve, and the solvent was evaporated in vacuo to cool. A yellow solid is obtained at room temperature, that is, a composition of amorphous paboxirin and polyvinyl acetate. In the X-ray powder diffraction pattern of the composition, there is no paclicillin hydroxyethanesulfonate crystal after subtracting the background peak of the medicinal adjuvant. Characteristic peak of the type.

Example 12

Paclocillin (50 mg) and polyacrylic resin Eudragit L100 (100 mg) were added to methanol (750 μl) and stirred to dissolve at room temperature. The above solution was slowly concentrated to dryness in a rotary evaporator to obtain a yellow solid, that is, a composition of amorphous paboxirin and polyacrylic resin Eudragit L100, the X-ray powder diffraction pattern of the composition is shown in Fig. 2, X In the -ray powder diffraction pattern, after subtracting the background peak of the medicinal excipient, there is no paclicillin crystal form. Characteristic peaks.

Example 13

Paclocillin (50 mg) and polyacrylic resin Eudragit S100 (5 mg) were added to methanol (4 ml) and ethyl acetate (1 ml), and the mixture was stirred at -30 °C. The above solution was slowly concentrated to dryness in a rotary evaporator to obtain a yellow solid, and a yellow solid was precipitated under stirring, that is, a composition of amorphous paboxirin and polyacrylic resin Eudragit S100, in the X-ray powder diffraction pattern of the composition After deducting the background peak of the medicinal excipients, there is no characteristic peak of the paclicillin crystal form.

Example 14

Paclocillin (50 mg) and Carbopol Carbomer 940 (50 mg) were added to methanol (4 ml) and tetrahydrofuran (1 ml), and the mixture was stirred and mixed at -30 °C. The above solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, which was precipitated with a yellow solid, that is, a combination of amorphous papacillin and carbopolized carbomer 940, in the X-ray powder diffraction pattern of the composition, There is no characteristic peak of the paclicillin crystal form after deducting the background peak of the medicinal excipient.

Example 15

Paclocillin (50 mg) and pregelatinized starch Pharma-Gel (100 mg) were added to methanol (4 ml) and water (1 ml) and mixed well at room temperature. The solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid. A yellow solid was precipitated with stirring, i.e., a combination of amorphous papacillin and Pharma-Gel pregelatinized starch, X-ray powder diffraction of the composition. In the figure, there is no characteristic peak of the paclicillin crystal form after subtracting the background peak of the medicinal excipient.

Example 16

Paclocillin (50 mg) and high-branched cross-linked starch (50 mg) were added to methanol (4 ml) and water (1 ml), and the solution was dissolved by stirring at room temperature, and the solution was slowly concentrated to dryness in a rotary evaporator. Obtaining a yellow solid, and a yellow solid is precipitated under stirring, that is, a composition of amorphous paboxirin and high-branched crosslinked starch. In the X-ray powder diffraction pattern of the composition, there is no Pabsilin crystal after subtracting the background peak of the medicinal adjuvant. Characteristic peak of the type.

Example 17

Paclocillin (50 mg) and sodium carboxymethylcellulose SCMC (500 mg) were added to dimethyl sulfoxide (5 ml), and the solution was dissolved by stirring at room temperature. The solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, that is, a combination of amorphous papacillin and sodium carboxymethylcellulose SCMC, the composition was deducted from the X-ray powder diffraction pattern. There is no characteristic peak of the Pabsilin crystal form after the background peak of the excipient.

Example 18

Paclocillin (50 mg) and chitosan (500 mg) were added to ethanol (5 ml), and the solution was dissolved by stirring at room temperature, and the solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid. A composition of phenotype of paclicillin and chitosan, in which the characteristic peak of the paclicillin crystal form is absent after subtracting the background peak of the medicinal excipient from the X-ray powder diffraction pattern of the composition.

Example 19

Paclocillin (50 mg) and sodium carboxymethyl starch Explotab (500 mg) were added to ethanol (5 ml), and the mixture was stirred and stirred at room temperature, and the solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid. That is, a composition of amorphous papacillin and sodium carboxymethyl starch Explotab, in which the characteristic peak of the paclicillin crystal form is absent after subtracting the background peak of the medicinal adjuvant in the X-ray powder diffraction pattern of the composition.

Example 20

Paclocillin (50 mg) and alginate E401 (500 mg) were added to ethanol (5 ml), and the mixture was stirred and stirred at room temperature. The solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, that is, a combination of amorphous papacillin and alginate E401. The X-ray powder diffraction pattern of the composition was subtracted from the background of the pharmaceutical excipient. There is no characteristic peak of the Pabsilin crystal form after the peak.

Example 21

Paclocillin (50 mg) and carboxymethylcellulose phthalate Agucoat CPD (5 g) were suspended in methanol (30 ml), heated to 50 ° C and stirred to homogenize. The above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered and dried to give a yellow solid, that is, a composition of amorphous paboxirin and carboxymethylcellulose phthalate Agucoat CPD, the composition In the X-ray powder diffraction pattern, there is no characteristic peak of the paclicillin crystal form after subtracting the background peak of the medicinal adjuvant.

Example 22

Paclocillin (50 mg) and carrageenan E407 (500 mg) were suspended in methanol (30 ml), heated to 50 ° C, stirred and mixed well. The solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered and dried. A yellow solid, i.e., a combination of amorphous papacillin and carrageenan E407, was obtained. In the X-ray powder diffraction pattern of the composition, there was no characteristic peak of the paclicillin crystal form after subtracting the background peak of the pharmaceutical excipient.

Example 23

Paclocillin (50 mg) and chitosan (5 g) were suspended in methanol (50 ml), heated to 50 ° C and stirred to mix well. The above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered and dried to give a yellow solid, i.e., a combination of amorphous paboxirin and chitosan, X-ray powder diffraction pattern of the composition. In the absence of the background peak of the medicinal excipients, there is no characteristic peak of the paclicillin crystal form.

Example 24

Papacillin (30 mg) and polyacrylic resin Eudragit E100 (30 mg) were dissolved in n-butanol (600 μl), anisole (900 μl) and N,N-dimethylformamide (600 μm). In liter), the mixture was heated to 50 ° C to be stirred and dissolved, and the solution was cooled to 10 ° C to precipitate a yellow solid, which was filtered and dried to obtain a composition of amorphous paclicillin and polyacrylic resin Eudragit E100, X- of the composition In the ray powder diffraction pattern, there is no characteristic peak of the paclicillin crystal form after subtracting the background peak of the medicinal adjuvant.

Example 25

Papacillin (30 mg) and collagen Peptan (300 mg) were dissolved in n-butanol (600 μL), anisole (900 μl) and acetonitrile (600 μL) and heated to 50 ° C to dissolve. clear. The solution was cooled to 10 ° C, a yellow solid was precipitated, filtered, and dried to obtain a composition of amorphous paboxirin and collagen Peptan. The X-ray powder diffraction pattern of the composition was subtracted from the background peak of the medicinal excipient. There are no characteristic peaks of the Pabsilin crystal form.

Example 26

Papacillin (30 mg) and gum Galactosol (300 mg) were dissolved in n-butanol (600 μl), anisole (900 μl) and methanol (600 μL), heated to 50 ° C and stirred to dissolve. . The solution was cooled to 10 ° C, a yellow solid was precipitated, filtered, and dried to obtain a composition of amorphous paboxirin and gum Galactosol. The X-ray powder diffraction pattern of the composition was subtracted from the background peak of the medicinal excipient. The characteristic peak of the Pabsilin crystal form.

Example 27

Add paclicillin hydroxyethanesulfonate (30 mg) and hydroxypropylmethylcellulose phthalate HPMCP (30 mg) to ethanol (750 μl) and water (750 μl) and heat to 80 Stir and mix well at °C. The solution was slowly concentrated in a rotary evaporator to remove the solvent to give a yellow solid, that is, a combination of amorphous paclicillin hydroxyethanesulfonate and hydroxypropylmethylcellulose phthalate HPMCP, the composition of which In the X-ray powder diffraction pattern, there is no characteristic peak of the paclicillin hydroxyethanesulfonate crystal form after subtracting the background peak of the medicinal adjuvant.

Example 28

Paclocillin hydrobromide (30 mg) and ion exchange resin Amberlite IR-120 (300 mg) were added to ethanol (750 μl) and water (750 μl), and heated to 80 ° C to stir and mix well. The solution was slowly concentrated in a rotary evaporator to remove the solvent to give a brown solid, that is, a combination of amorphous paclicillin hydrobromide and ion exchange resin Amberlite IR-120, in the X-ray powder diffraction pattern of the composition. , minus medicinal There is no characteristic peak of the paclicillin hydrobromide crystal form after the background peak of the excipient.

Example 29

Paclocillin (30 mg) and carboxyacetolactone (300 mg) were added to ethanol (750 μl) and water (750 μl), and heated to 80 ° C to stir and mix well. The solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a brown solid, that is, a combination of amorphous paclicillin and carboxyacetolactone. The X-ray powder diffraction pattern of the composition was subtracted from the background of the medicinal excipient. There is no characteristic peak of the Pabsilin crystal form after the peak.

Example 30

Paclocillin (30 mg) and dextrin Maltrin M100 (300 mg) were added to ethanol (750 μl) and water (750 μl), and heated to 80 ° C to stir and mix well. The solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a brown solid, a composition of amorphous papacillin and dextrin Maltrin M100. The X-ray powder diffraction pattern of the composition was subtracted from the background of the medicinal excipient. There is no characteristic peak of the Pabsilin crystal form after the peak.

Example 31

Paclocillin hydrochloride (30 mg) and sodium carboxymethylcellulose SCMS (3 mg) were added to water (30 ml), and the mixture was heated to 100 ° C and stirred to homogenize. The solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a yellow solid, that is, a combination of amorphous paclicillin hydrochloride and sodium carboxymethylcellulose SCMC, in the X-ray powder diffraction pattern of the composition, There is no characteristic peak of the paclicillin hydrochloride crystal form after subtracting the background peak of the medicinal excipient.

Example 32

Paclocillin dihydrochloride (30 mg) and β-cyclodextrin (30 mg) were added to methanol (300 μl) and water (300 μl), and the mixture was stirred at room temperature. The above solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a yellow solid, that is, a composition of amorphous paclicillin dihydrochloride and β-cyclodextrin, which was deducted from the X-ray powder diffraction pattern of the composition. There is no characteristic peak of the paclicillin dihydrochloride crystal form after the background peak of the medicinal adjuvant.

Example 33

Paclocillin (30 mg) and sodium carboxymethylcellulose SCMC (30 mg) were added to methanol (300 μl) and water (60 μl), and the mixture was stirred and homogenized at 60 °C. The above solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a yellow solid, that is, a composition of amorphous paclicillin and sodium carboxymethylcellulose SCMC, the composition was deducted from the X-ray powder diffraction pattern. There is no characteristic peak of the Pabsilin crystal form after the background peak of the excipient.

Example 34

Add paclicillin (5 mg) and polyethylene oxide Polyox WSR301 (60 mg) to methanol (300) Microliters) and water (60 μl) were stirred and mixed at 60 °C. The above solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a yellow solid, that is, a composition of amorphous paboxirin and polyethylene oxide Polyox WSR301, which was deducted from the X-ray powder diffraction pattern of the composition. There is no characteristic peak of the Pabsilin crystal form after the background peak of the excipient.

Example 35

Add paclocillin (30 mg) and polyvinyl alcohol EG-40 (60 mg) to methanol (300 μl) and water (60 μl), stir at 60 ° C, and dissolve the solution in a rotary evaporator. The solvent was slowly concentrated to give a yellow solid, that is, a combination of amorphous paclicillin and polyvinyl alcohol EG-40. In the X-ray powder diffraction pattern of the composition, there was no paclicillin after subtracting the background peak of the medicinal adjuvant. Characteristic peak of the crystal form.

Example 36

Add paclicillin (50 mg) and hydroxypropylmethylcellulose acetate succinate Agoat MG (2 g) to ethanol (10 ml) and water (2 ml), mix well at 80 ° C, and dissolve the above solution. Slowly concentrated to dryness in a rotary evaporator to give a yellow solid, that is, a combination of amorphous paclicillin and hydroxypropylmethylcellulose acetate succinate Agoat MG, in the X-ray powder diffraction pattern of the composition, There is no characteristic peak of the paclicillin crystal form after deducting the background peak of the medicinal excipient.

Example 37

Add paclocillin (50 mg) and carboxymethylethylcellulose (2 g) to ethanol (10 ml) and water (1 ml), mix well at 80 ° C, and slowly dissolve the above solution in a rotary evaporator. Concentrated to dryness to give a yellow solid, a combination of amorphous paclicillin and carboxymethylethylcellulose. In the X-ray powder diffraction pattern of the composition, there was no paclicillin after subtracting the background peak of the pharmaceutical excipient. Characteristic peak of the crystal form.

Example 38

Paclocillin (50 mg) and polyacrylic resin Eudragit L100 (100 mg) were added to methanol (100 μl) and dichloromethane (200 μl), and the mixture was stirred at room temperature. The above solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, a combination of amorphous papacillin and polyacrylic resin Eudragit L100, the background of which was subtracted from the X-ray powder diffraction pattern of the pharmaceutical excipient. There is no characteristic peak of the Pabsilin crystal form after the peak.

Example 39

Paclocillin (50 mg) and polyacrylic resin Eudragit S100 (50 mg) were added to methanol (100 μL) and dichloromethane (200 μL), and the mixture was stirred at room temperature. The solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, that is, a combination of amorphous paclocillin and polyacrylic resin Eudragit S100, the background of which was deducted from the X-ray powder diffraction pattern of the pharmaceutical excipient There is no characteristic peak of the Pabsilin crystal form after the peak.

Example 40: Influential factors test of amorphous paclocillin and povidone K30 compositions

Materials: The composition of the amorphous form of paclocillin and povidone K30 obtained in Example 1.

Table 1:

Table 1 shows that the amorphous epichlorophene and povidone K30 compositions were allowed to stand for 10 days under high temperature and high humidity conditions, and there was no significant change in related substances, and no crystals of paboxirin were precipitated.

Example 41: Influential factors test of amorphous paclocillin and povidone K30 compositions

Materials: The composition of the amorphous form of paclocillin and povidone K30 obtained in Example 1.

Experimental conditions: temperature 40 ° C ± 2 ° C, humidity 75% ± 5%.

Table 2:

Table 2 shows that the amorphous paclicillin and povidone K30 compositions were placed under accelerated test conditions for 6 months, and there was no significant change in the relevant substances, and no crystals of paclicillin were precipitated.

Example 42: Influencing factors of amorphous paboxirin and polyacrylic resin Eudragit L100 composition Test

Materials: The composition of the amorphous form of Pabcillin obtained in Example 12 and the polyacrylic resin Eudragit L1000.

table 3:

Table 3 shows that the amorphous form of paclocillin and povidone K30 was allowed to stand under high temperature and high humidity conditions for 10 days, and there was no significant change in related substances, and no crystals of paboxirin were precipitated.

Example 43: Influential factors test of a combination of amorphous paclocillin and polyacrylic resin Eudragit L100

Materials: The composition of the amorphous form of Pabcillin and the polyacrylic resin Eudragit L100 obtained in Example 12.

Experimental conditions: temperature 40 ° C ± 2 ° C, humidity 75% ± 5%.

Table 4:

Table 4 shows that the composition of amorphous paclicillin and polyacrylic resin Eudragit L100 was placed under accelerated test conditions for 6 months, and there was no significant change in related substances, and no crystals of paboxirin were precipitated.

Example 44: Determination of Apparent Solubility

The apparent solubility of the composition of the invention with the paclicillin crystal form mixture was compared.

The measurement objects were respectively: the composition obtained in Example 12 of the present invention; the mixture of the paboxirin crystal form (Form A) and the polyacrylic resin Eudragit L100 were physically mixed at a weight ratio of 1:2. , Pabsilin Form (Form A) was prepared according to the method of Example 5 of Patent WO2014/128588).

Determination of Apparent Solubility: A sufficient amount of the composition obtained in Example 12 of the present invention and a mixture of the paboxirin crystal form were weighed and placed in two stoppered Erlenmeyer flasks, and a diluent of a specified pH was added to prepare Become a saturated solution and seal tightly. Three samples were prepared in parallel for each pH dilution. It was shaken in a constant temperature water bath shaker at 37 ° C ± 0.5 ° C for 12 h to fully dissolve to achieve saturation. The supernatant was filtered with a 0.45 μm microporous membrane, diluted appropriately, shaken, and injected into the liquid chromatograph. The apparent solubility of the three parallel samples in this pH buffer was calculated by external standard method and averaged.

Preparation of various pH dilutions:

(1) Diluent of pH = 1.0: 9 ml of concentrated hydrochloric acid was diluted with water to 1000 ml.

(2) Diluent of pH=2.0: Liquid A: Take 16.6 ml of phosphoric acid, and add water to 100 ml to shake. Solution B: Take 71.63 g of disodium hydrogen phosphate and dissolve it into 1000 ml with water. Take 72.5 ml of the above liquid A and 27.5 ml of the liquid B, and shake well to obtain.

(3) Diluent of pH=3.0: 50 ml of glacial acetic acid, 800 ml of water was added, and the pH was adjusted to 3.0 with lithium hydroxide, and then diluted with water to 1000 ml.

(4) Diluent of pH=4.5: Take 7.7 g of ammonium acetate, add 50 ml of water to dissolve, add 6 ml of glacial acetic acid and make an appropriate amount of water to make 100 ml.

(5) Dilution solution with pH=5.6: Take 10 g of potassium hydrogen phthalate, add 900 ml of water, stir to dissolve, adjust the pH to 5.6 with sodium hydroxide test solution (diluted hydrochloric acid if necessary), dilute with water until 1000 ml, mix well, that is.

(6) Dilution solution of pH=6.8: Take 250 ml of a 0.2 mol/L potassium dihydrogen phosphate solution, add 118 ml of a 0.2 mol/L sodium hydroxide solution, dilute to 1000 ml with water, and shake well.

(7) Diluent of pH=7.4: Take 1.36 g of potassium dihydrogen phosphate, add 79 ml of 0.1 mol/L sodium hydroxide solution, and dilute to 200 ml with water to obtain.

The experimental results are shown in Table 5:

Table 5 shows that the apparent solubility of the composition of the amorphous form of Paclocillin and the polyacrylic resin Eudragit L100 of the present invention is significantly higher than that of the Paboxirin crystal form (Form A) and the polyacrylic resin Eudragit L100 at various pH values. The apparent solubility of the mixture.

Example 45

Papacillin (50 mg) and povidone K30 (100 mg) were dissolved in n-butanol (600 μl), anisole (900 μl) and methanol (600 μL) and heated to 60 ° C for stirring. The solution was dissolved and microcrystalline cellulose (50 mg) was added. The solution was rapidly cooled to -10 ° C, a yellow solid was precipitated, filtered, and dried in vacuo to obtain a composition of an amorphous form of paclocillin solid dispersion and microcrystalline cellulose, which was deducted from the X-ray powder diffraction pattern of the composition. There are no characteristic peaks of the paclicillin crystal form after the background peak of the medicinal excipients.

Example 46

Dispatch paclicillin (50 mg) and polyethylene glycol 4000 (200 mg) in ethanol (600 μl) and water (600 μl), mix well at -40 ° C, then add microcrystalline cellulose (50 mg). The above solution was slowly concentrated to dryness in a rotary evaporator to obtain a yellow solid, a composition of amorphous paboxirin and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition was subtracted from the carrier and the medicinal excipient. There is no characteristic peak of the Pabsilin crystal form after the background peak.

Example 47

Paclocillin (5 g) and polyethylene glycol 8000 (10 g) were added to methanol (300 ml), heated to 60 ° C to stir and dissolve, and then croscarmellose sodium (0.1 g) was added. The above solution was dried with JISL micro spray dryer LSD-48, the inlet temperature was maintained at 60 ° C, the outlet temperature was 50 ° C, and the outlet material was collected to obtain a yellow solid, which was further dried under vacuum to obtain an amorphous epichlorohydrin solid dispersion and crosslinked carboxymethyl group. Combination of sodium cellulose In the X-ray powder diffraction pattern of the composition, there is no characteristic peak of the paclicillin crystal form after subtracting the background peak of the carrier and the pharmaceutically acceptable excipient.

Example 48

Paclocillin (1 g) and hydroxypropylmethylcellulose E50 (0.2 g) were added to water (10 ml), heated to 40 ° C, stirred and mixed well, and crospovidone (0.2 g) was added. The above solution is freeze-dried to obtain a yellow solid, that is, a composition of an amorphous paboxirin solid dispersion and crospovidone, in which the background peak of the carrier and the pharmaceutically acceptable excipient is subtracted in the X-ray powder diffraction pattern of the composition. There is no characteristic peak of the Pabsilin crystal form.

Example 49

Paclocillin (1 g), mannitol (5 g) and polyethylene glycol 8000 (5 g) were heated to melt, and rapidly cooled to room temperature with stirring to give a yellow solid. The solid is pulverized to obtain a yellow powdery solid, that is, a composition of an amorphous form of paclocillin solid dispersion and mannitol, in which the X-ray powder diffraction pattern of the composition is subtracted from the background peak of the carrier and the pharmaceutically acceptable excipient The characteristic peak of the Pabsilin crystal form.

Example 50

Paclocillin (1 g), mannitol (0.1 g) and polyethylene glycol 10000 (10 g) were heated to 240 ° C, mixed well and rapidly cooled to room temperature to give a yellow solid. The solid is pulverized to obtain a yellow powdery solid, that is, a composition of an amorphous form of paclocillin solid dispersion and mannitol, in which the X-ray powder diffraction pattern of the composition is deducted from the background peak of the carrier and the pharmaceutically acceptable excipient The characteristic peak of the Pabsilin crystal form.

Example 51

A mixture of paboxirin (1 g), anisole (10 g), n-butanol (20 g) and liposome (4 g) was heated to 90 ° C and mixed well with stirring. Further adding microcrystalline cellulose (2 g), stirring uniformly, and evaporating the solvent in vacuo to obtain a yellow solid, that is, a composition of an amorphous paboxirin solid dispersion and microcrystalline cellulose, the X-ray powder diffraction of the composition In the figure, there is no characteristic peak of the paclicillin crystal form after subtracting the background peak of the carrier and the medicinal adjuvant.

Example 52

A mixture of paclicillin (1 g), methanol (20 g) and methacrylic acid copolymer type A (4 g) was heated to 50 ° C, dissolved under stirring, and then crospovidone (1 g) was added. The solvent was removed by evaporation in vacuo, and cooled to room temperature to give a yellow solid, that is, a combination of amorphous and a mixture of a mixture of a mixture and a mixture of There is no characteristic peak of the paclicillin hydrobromide crystal form after the background peak.

Example 53

Mix a mixture of paboxirin (1 g), n-butanol (20 g), anisole (10 g) and ethyl cellulose (2 g) to 30 ° C, stir, mix well, then add stearic acid Magnesium (0.1 g), the solvent was evaporated in vacuo, and cooled to room temperature to give a yellow solid, that is, a combination of amorphous PABSILIN solid dispersion and magnesium stearate. In the X-ray powder diffraction pattern of the composition, the carrier was deducted. There are no characteristic peaks of the paclicillin crystal form after the background peak of the medicinal excipients.

Example 54

A mixture of pabocillin (1 g), methanol (10 g), dichloromethane (10 g) and hydroxypropyl cellulose SSL (4 g) was heated to 30 ° C, stirred and dissolved, and then microcrystalline cellulose was added. (0.5 g), the solvent was evaporated in vacuo, and cooled to room temperature to give a yellow solid, that is, a combination of amorphous PABSILIN solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition was deducted from the carrier and There is no characteristic peak of the paclicillin crystal form after the background peak of the medicinal excipient.

Example 55

A mixture of pabocillin (1 g), methanol (20 g), dichloromethane (10 g) and polyvinyl acetate (4 g) was heated to 30 ° C, stirred and dissolved, and then microcrystalline cellulose (0.5 g) was added. The solvent is removed by evaporation in vacuo and cooled to room temperature to give a yellow solid, that is, a combination of an amorphous PABSILIN solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition is deducted from the carrier and the pharmaceutically acceptable excipient. There is no characteristic peak of the paboxirin crystal form after the background peak.

Example 56

Paclocillin (50 mg) and polyacrylic resin Eudragit L100 (100 mg) were added to methanol (750 μl), stirred and dissolved at 60 ° C, and microcrystalline cellulose (100 mg) was added. The suspension was rapidly cooled to 20 ° C to precipitate a yellow solid. Filtration, vacuum drying, to obtain a yellow solid, that is, a combination of an amorphous paboxirin solid dispersion and microcrystalline cellulose, the X-ray powder diffraction pattern of the composition is shown in Figure 3, in the X-ray powder diffraction pattern There is no characteristic peak of the paclicillin crystal form after subtracting the background peak of the carrier and the medicinal adjuvant. The X-ray powder diffraction pattern of microcrystalline cellulose is shown in Fig. 4.

Example 57

Paclocillin (50 mg) and polyacrylic resin Eudragit S100 (5 mg) were added to methanol (4 ml) and ethyl acetate (1 ml), and the mixture was stirred at -30 °C. Add sodium carboxymethyl starch (100 mg). The solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, that is, a combination of an amorphous form of paclocillin solid dispersion and sodium carboxymethyl starch. The X-ray powder diffraction pattern of the composition was subtracted from the carrier. There are no characteristic peaks of the paclicillin crystal form after the background peak of the medicinal excipients.

Example 58

Paclocillin (50 mg) and Carbopol Carbomer 940 (50 mg) were added to methanol (4 ml) and tetrahydrofuran (1 ml), and the mixture was uniformly stirred at 30 ° C, and then microcrystalline cellulose (50 mg) was added. The above solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, a combination of an amorphous form of paboxirin solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition was subtracted from the carrier and There is no characteristic peak of the paclicillin crystal form after the background peak of the medicinal excipient.

Example 59

Add paclicillin (50 mg) and pregelatinized starch Pharma-Gel (100 mg) to methanol (4 ml) and water (1 ml), mix well at room temperature, and add croscarmellose sodium ( 100 mg). The solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, that is, a combination of an amorphous PABSILIN solid dispersion and croscarmellose sodium, in an X-ray powder diffraction pattern of the composition. After deducting the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the paclicillin crystal form.

Example 60

Add paclicillin (50 mg) and high-branched cross-linked starch (50 mg) to methanol (4 ml) and water (1 ml), stir at room temperature, and add croscarmellose sodium (100 mg) ). The above solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, i.e., a composition free of amorphous PABSILIN solid dispersion and croscarmellose sodium, X-ray powder diffraction pattern of the composition In the absence of the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the paclicillin crystal form.

Example 61

Paclocillin (50 mg) and sodium carboxymethylcellulose SCMC (500 mg) were added to dimethyl sulfoxide (5 ml), stirred at room temperature, and then croscarmellose sodium (100) was added. Mg). The solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, that is, a combination of an amorphous PABSILIN solid dispersion and croscarmellose sodium, in an X-ray powder diffraction pattern of the composition. After deducting the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the paclicillin crystal form.

Example 62

Paclocillin (50 mg) and chitosan (500 mg) were added to ethanol (5 ml), and the solution was dissolved by stirring at room temperature, followed by addition of microcrystalline cellulose (50 mg). The above solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, a combination of an amorphous form of paboxirin solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition was subtracted from the carrier and There is no characteristic peak of the paclicillin crystal form after the background peak of the medicinal excipient.

Example 63

Paclocillin (50 mg) and sodium carboxymethyl starch Explotab (500 mg) were added to ethanol (5 ml), stirred at room temperature, and then added with lactose (100 mg). The solution is slowly concentrated to dryness in a rotary evaporator to give a yellow solid, a combination of an amorphous form of paclocillin solid dispersion and lactose, in which the carrier and excipients are deducted from the X-ray powder diffraction pattern. There is no characteristic peak of the Pabsilin crystal form after the background peak.

Example 64

Paclocillin (50 mg) and alginate E401 (500 mg) were added to ethanol (5 ml), and the mixture was stirred and stirred at room temperature, and lactose (10 mg) was added. The solution is slowly concentrated to dryness in a rotary evaporator to give a yellow solid, a combination of an amorphous form of paclocillin solid dispersion and lactose, in which the carrier and excipients are deducted from the X-ray powder diffraction pattern. There is no characteristic peak of the Pabsilin crystal form after the background peak.

Example 65

Paclocillin (50 mg) and carboxymethylcellulose phthalate Agucoat CPD (0.5 g) were suspended in methanol (30 ml), heated to 50 ° C, stirred and mixed, and then lactose (50 mg) was added. The above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered, and dried to give a yellow solid, that is, a composition of an amorphous form of paclocillin solid dispersion and lactose, in the X-ray powder diffraction pattern of the composition, There is no characteristic peak of the paclicillin crystal form after subtracting the background peak of the carrier and the medicinal adjuvant.

Example 66

Paclocillin (50 mg) and carrageenan E407 (500 mg) were suspended in methanol (30 ml), heated to 50 ° C, stirred and mixed, and then microcrystalline cellulose (50 mg) was added. The above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered, and dried to give a yellow solid, that is, a combination of an amorphous epichlorohydrin solid dispersion and microcrystalline cellulose, X-ray powder diffraction of the composition. In the figure, there is no characteristic peak of the paclicillin crystal form after subtracting the background peak of the carrier and the medicinal adjuvant.

Example 67

Paclocillin (50 mg) and chitosan (5 g) were suspended in methanol (50 ml), heated to 50 ° C, stirred and mixed, and then lactose (100 mg) was added. The above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered, and dried to give a yellow solid, that is, a composition of an amorphous form of paclocillin solid dispersion and lactose, in the X-ray powder diffraction pattern of the composition, There is no characteristic peak of the paclicillin crystal form after subtracting the background peak of the carrier and the medicinal adjuvant.

Example 68

Papacillin (30 mg) and polyacrylic resin Eudragit E100 (30 mg) were dissolved in n-butanol (600 μl), anisole (900 μl) and N,N-dimethylformamide (600 μm). In liter), the mixture was heated to 50 ° C, stirred and dissolved, and then lactose (30 mg) was added. The solution was cooled to 10 ° C, a yellow solid was precipitated, filtered, and dried to obtain a composition of an amorphous form of paclocillin solid dispersion and lactose. The X-ray powder diffraction pattern of the composition was deducted from the carrier and the medicinal excipient. There is no characteristic peak of the paboxirin crystal form after the background peak.

Example 69

Papacillin (30 mg) and collagen Peptan (300 mg) were dissolved in n-butanol (600 μL), anisole (900 μl) and acetonitrile (600 μL) and heated to 50 ° C to dissolve. Clear, then add microcrystalline cellulose (30 mg). The solution was cooled to 10 ° C, a yellow solid was precipitated, filtered, and dried to obtain a composition of amorphous paboxirin and collagen Peptan. The X-ray powder diffraction pattern of the composition was deducted from the background of the carrier and the medicinal excipient. There is no characteristic peak of the Pabsilin crystal form after the peak.

Example 70

Papacillin (30 mg) and gum Galactosol (300 mg) were dissolved in n-butanol (600 μl), anisole (900 μl) and methanol (600 μL), heated to 50 ° C and stirred to dissolve. Then add microcrystalline cellulose (30 mg). The solution was cooled to 10 ° C, a yellow solid was precipitated, filtered, and dried to obtain a composition of an amorphous form of paclocillin solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition was deducted from the carrier and the drug. There is no characteristic peak of the Pabsilin crystal form after the background peak of the auxiliary material.

Example 71

Add paclicillin (30 mg) and hydroxypropylmethylcellulose phthalate HPMCP (30 mg) to ethanol (750 μl) and water (750 μl), heat to 80 ° C and mix well. Sodium carboxymethylcellulose (30 mg) was added. The solution is slowly concentrated in a rotary evaporator to remove the solvent to obtain a yellow solid, that is, a composition of amorphous paboxirin and sodium carboxymethylcellulose. The X-ray powder diffraction pattern of the composition is deducted from the carrier and the drug. There is no characteristic peak of the Pabsilin crystal form after the background peak of the auxiliary material.

Example 72

Paclocillin (30 mg) and carboxyacetolactone (300 mg) were added to ethanol (750 μl) and water (750 μl), heated to 80 ° C, stirred and mixed, and then lactose (200 mg) was added. The solution is slowly concentrated in a rotary evaporator to remove the solvent to obtain a yellow solid, that is, a combination of an amorphous form of paclocillin solid dispersion and lactose, in which the carrier and the excipients are deducted from the X-ray powder diffraction pattern. There is no characteristic peak of the Pabsilin crystal form after the background peak.

Example 73

Paclocillin (30 mg) and dextrin Maltrin M100 (300 mg) were added to ethanol (750 μl) and water (750 μl), heated to 80 ° C, stirred and mixed, and then lactose (200 mg) was added. The solution is slowly concentrated in a rotary evaporator to remove the solvent to obtain a yellow solid, that is, a combination of an amorphous form of paclocillin solid dispersion and lactose, in which the carrier and the excipients are deducted from the X-ray powder diffraction pattern. There is no characteristic peak of the Pabsilin crystal form after the background peak.

Example 74

Paclocillin (30 mg) and sodium carboxymethylcellulose SCMS (3 mg) were added to water (30 ml), heated to 100 ° C, stirred and mixed, and then microcrystalline cellulose (30 mg) was added. The solution is slowly concentrated in a rotary evaporator to remove the solvent to obtain a yellow solid, that is, a composition of an amorphous paboxirin solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition is deducted from the carrier and There is no characteristic peak of the paclicillin hydrochloride crystal form after the background peak of the medicinal adjuvant.

Example 75

Add paclicillin (30 mg) and sodium carboxymethylcellulose SCMC (30 mg) to methanol (300 μl) and water (60 μl), mix well at 60 ° C, and add microcrystalline cellulose ( 60 mg). The solution is slowly concentrated in a rotary evaporator to remove the solvent to obtain a yellow solid, that is, a composition of an amorphous paboxirin solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition is deducted from the carrier and There is no characteristic peak of the paclicillin crystal form after the background peak of the medicinal excipient.

Example 76

Add paclocillin (5 mg) and polyethylene oxide Polyox WSR301 (30 mg) to methanol (300 μl) and water (60 μl), mix well at 60 ° C, add colloidal silica Aerosil 200 (20 mg). The above solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a yellow solid, that is, a composition of an amorphous form of Pabsilill solid dispersion and colloidal silica Aerosil 200, the X-ray powder diffraction pattern of the composition is shown in the figure As shown in Fig. 5, there is no characteristic peak of the paboxirin crystal form after subtracting the background peak of the carrier and the medicinal excipient from the X-ray powder diffraction pattern.

Example 77

Add paclocillin (30 mg) and polyvinyl alcohol EG-40 (60 mg) to methanol (300 μl) and water (60 μl), stir at 60 ° C, add lactose (30 mg) The solution is slowly concentrated in a rotary evaporator to remove the solvent to obtain a yellow solid, that is, a composition of an amorphous form of paclocillin solid dispersion and lactose. The X-ray powder diffraction pattern of the composition is deducted from the carrier and the pharmaceutically acceptable excipient. There is no characteristic peak of the paboxirin crystal form after the background peak.

Example 78

Add paclicillin (50 mg) and hydroxypropylmethylcellulose acetate succinate Agoat MG (2 g) to ethanol (10 ml) and water (2 ml), mix well at 80 ° C, then add micro Crystalline cellulose (50 mg). The above solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, a combination of an amorphous form of paboxirin solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition was subtracted from the carrier and There is no characteristic peak of the paclicillin crystal form after the background peak of the medicinal excipient.

Example 79

Add paclocillin (50 mg) and carboxymethylethylcellulose (2 g) to ethanol (10 ml) and water (1 ml), mix well at 80 ° C, and add croscarmellose Sodium (50 mg). The solution was slowly concentrated to dryness in a rotary evaporator to give a yellow solid, that is, a combination of an amorphous PABSILIN solid dispersion and croscarmellose sodium, in an X-ray powder diffraction pattern of the composition. After deducting the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the paclicillin crystal form.

Example 80

Paclocillin (10 g) and polyacrylic resin Eudragit L100 (20 g) were added to methanol (20 ml) and dichloromethane (40 ml), and the mixture was stirred at room temperature. The above mixture was spray dried in a fluidized bed and loaded onto microcrystalline cellulose (20 g) to obtain 47.3 g of a yellow solid, that is, a composition of amorphous paboxirin, polyacrylic resin Eudragit L100 and microcrystalline cellulose. The loading ratio of the active ingredient was 20.7%. The X-ray powder diffraction pattern of the composition lacked the characteristic peak of the paclicillin crystal form after subtracting the background peak of the pharmaceutical excipient.

Example 81

Paclocillin (10 g) and polyacrylic resin Eudragit L100 (10 g) were added to methanol (20 ml) and dichloromethane (40 ml), and the mixture was stirred at room temperature, followed by the addition of colloidal silica Aerosil 200 ( 5 grams). The above mixture was spray-dried in a fluidized bed and loaded onto microcrystalline cellulose (10 g) to obtain 32.9 g of a yellow solid, i.e., amorphous paboxirin, polyacrylic resin Eudragit L100, colloidal silica Aerosil 200 and micro In the composition of crystalline cellulose, the loading ratio of the active ingredient was 29.1%. The X-ray powder diffraction pattern of the composition lacked the characteristic peak of the paclicillin crystal form after subtracting the background peak of the pharmaceutical excipient.

Example 82

Paclocillin (10 g) and polyacrylic resin Eudragit S100 (20 g) were added to methanol (20 ml) and dichloromethane (60 ml), and the mixture was stirred at room temperature. The above mixture was spray dried in a fluidized bed and loaded onto microcrystalline cellulose (20 g) to obtain 47.3 g of a yellow solid, that is, a combination of amorphous paclocillin, polyacrylic resin Eudragit S100 and microcrystalline cellulose. The loading ratio of the active ingredient was 20.7%. The X-ray powder diffraction pattern of the composition lacked the characteristic peak of the paclicillin crystal form after subtracting the background peak of the pharmaceutical excipient.

Example 83

Paclocillin (10 g) and polyacrylic resin Eudragit S100 (10 g) were added to methanol (20 ml) and dichloromethane (40 ml), and the mixture was stirred at room temperature, and then silica Syloid 244 FP (8) was added. Gram). The above mixture was spray dried in a fluidized bed and loaded onto microcrystalline cellulose (10 g) to obtain 36.5 g of a yellow solid, i.e., amorphous paclocillin, polyacrylic resin Eudragit S100, silica Syloid 244 FP and micro In the composition of crystalline cellulose, the loading ratio of the active ingredient was 25.8%. The X-ray powder diffraction pattern of the composition lacked the characteristic peak of the paclicillin crystal form after subtracting the background peak of the pharmaceutical excipient.

Example 84: Influential factors test of a combination of amorphous paclicillin solid dispersion and microcrystalline cellulose

Materials: A composition of the amorphous form of paclocillin solid dispersion obtained in Example 56 and microcrystalline cellulose.

Table 6:

Table 6 shows that the composition of the amorphous paboxirin solid dispersion and the microcrystalline cellulose was allowed to stand under high temperature and high humidity conditions for 10 days, and the related substances were not significantly changed, and no crystals of paboxirin were precipitated.

Example 85: Accelerated Stability Experiment of Composition of Amorphous Pabuscillin Solid Dispersion and Microcrystalline Cellulose

Materials: A composition of the amorphous form of paclocillin solid dispersion obtained in Example 56 and microcrystalline cellulose.

Experimental conditions: temperature 40 ° C ± 2 ° C, humidity 75% ± 5%.

Table 7:

Table 7 shows that the composition of the amorphous form of the paclicillin solid dispersion and the microcrystalline cellulose was allowed to stand for 6 months under accelerated test conditions, and the related substances were not significantly changed, and no crystals of paboxirin were precipitated.

Example 86: Determination of apparent solubility

The apparent solubility of the solid dispersion-containing composition of the present invention and the paboxirin crystal form mixture was compared.

The measurement objects were respectively: the composition obtained in Example 56 of the present invention; the mixture of the paboxirin crystal form (Form A, the polyacryl resin Eudragit L100, and the microcrystalline cellulose were physically mixed, and the weight The ratio is 1:2:2, and the Formosa is prepared according to the method of Example 5 of the patent WO2014/128588).

Determination of Apparent Solubility: A sufficient amount of the composition obtained in Example 56 of the present invention and the above-mentioned mixture of the paboxirin crystal form were weighed and placed in two stoppered Erlenmeyer flasks, and a dilution solution of a specified pH was added. Formulated as a supersaturated solution with a tight seal. Three samples were prepared in parallel for each pH dilution. It was shaken in a constant temperature water bath shaker at 37 ° C ± 0.5 ° C for 12 h to fully dissolve to achieve saturation. The supernatant was filtered with a 0.45 μm microporous membrane, diluted appropriately, shaken, and injected into a liquid chromatograph. The apparent solubility of the three parallel samples in this pH buffer was calculated by external standard method and averaged.

Preparation of various pH dilutions:

(1) Diluent of pH = 1.0: 9 ml of concentrated hydrochloric acid was diluted with water to 1000 ml.

(2) Diluent of pH=2.0: Liquid A: Take 16.6 ml of phosphoric acid, and add water to 100 ml to shake. Solution B: Take 71.63 g of disodium hydrogen phosphate and dissolve it into 1000 ml with water. Take 72.5 ml of the above liquid A and 27.5 ml of the liquid B, and shake well to obtain.

(3) Diluent of pH=3.0: 50 ml of glacial acetic acid, 800 ml of water was added, and the pH was adjusted to 3.0 with lithium hydroxide, and then diluted with water to 1000 ml.

(4) Diluent of pH=4.5: Take 7.7 g of ammonium acetate, add 50 ml of water to dissolve, add 6 ml of glacial acetic acid and make an appropriate amount of water to make 100 ml.

(5) Dilution solution with pH=5.6: Take 10 g of potassium hydrogen phthalate, add 900 ml of water, stir to dissolve, adjust the pH to 5.6 with sodium hydroxide test solution (diluted hydrochloric acid if necessary), dilute with water until 1000 ml, mix well, that is.

(6) Dilution solution of pH=6.8: Take 250 ml of a 0.2 mol/L potassium dihydrogen phosphate solution, add 118 ml of a 0.2 mol/L sodium hydroxide solution, dilute to 1000 ml with water, and shake well.

(7) Diluent of pH=7.4: Take 1.36 g of potassium dihydrogen phosphate, add 0.1 mol/L sodium hydroxide solution 79 ML, diluted to 200 ml with water, that is.

The experimental results are shown in Table 8:

Table 8:

Table 8 shows that at each pH value, the apparent solubility of the composition of the amorphous paboxirin solid dispersion and the microcrystalline cellulose is significantly higher than that of the crystalline form (Form A) and the polyacrylic resin Eudragit L100. The apparent solubility of a mixture of microcrystalline cellulose.

The paclicillin of the invention or the pharmaceutically acceptable salt thereof and the medicinal auxiliary material are amorphous compositions, and the dissolution rate thereof is obviously increased, which is more favorable for improving the bioavailability of the medicine, so that the medicine can better exert the clinical disease treatment. The amorphous material maintains good physical and chemical stability under accelerated test conditions (40 ± 2 ° C, humidity 75% ± 5%).

Claims (24)

A composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, characterized in that the composition comprises paboxirin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, the weight of both The ratio is 1:0.1 to 100, wherein the paclicillin or a pharmaceutically acceptable salt thereof is in an amorphous state, and the background peak of the pharmaceutical excipient is subtracted from the X-ray powder diffraction spectrum of the composition. There is no characteristic peak of paboxirin or its salt crystals. The composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of an excipient, a propellant, a solubilizer, a cosolvent, Emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, Aromatic agent, anti-adhesive agent, integrator, penetration enhancer, pH adjuster, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent At least one of a diluent, a flocculating agent and a deflocculating agent, an antioxidant, an adsorbent, a filter aid, and a release retarder. The composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 1, wherein the pharmaceutically acceptable adjuvant is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, Povidone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl Methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pre- At least one of gelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, ion exchange resin, and collagen. The composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 1, wherein the pharmaceutical excipient comprises an organic vehicle and a medicinal preparation auxiliary, Pabsilin first The organic vehicle forms a solid dispersion, and the solid dispersion is further combined with a pharmaceutical preparation auxiliary composition, wherein the weight of the paclicillin is 20% to 80% by weight based on the total weight of the solid dispersion, and the pharmaceutical preparation auxiliary material The weight is from 0.1% to 80% by weight of the solid dispersion. A composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 4, wherein the organic vehicle is selected from pharmaceutically acceptable polymers or copolymers. The composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 4 or 5, wherein the organic vehicle is selected from the group consisting of hydroxypropylmethylcellulose and hydroxypropylcellulose. , povidone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxy Propylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, At least one of pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, ion exchange resin, and collagen. A composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 4, The pharmaceutical excipient is selected from the group consisting of excipients, propellants, solubilizers, solubilizers, emulsifiers, colorants, binders, disintegrators, fillers, lubricants, wetting agents, osmotic pressure regulators. , stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfaces Active agent, foaming agent, defoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release retardant At least one of them. A method of preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 1, comprising the steps of: 1) mixing paclocillin or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable adjuvant, and heating to melt the medicinal adjuvant; wherein the weight ratio of paboxirin or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable excipient is 1: 0.1 to 100; 2) After mixing and cooling, the obtained mixture is pulverized to obtain a composition of an amorphous form of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant. The method for preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 8, wherein the pharmaceutically acceptable excipient is selected from the group consisting of an excipient, a propellant, a solubilizing agent, Cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, bags Clothing materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants At least one of an absorbent, a diluent, a flocculating agent and a deflocculating agent, an antioxidant, an adsorbent, a filter aid, and a release retarder. The method for preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 7, wherein the pharmaceutically acceptable adjuvant is selected from the group consisting of hydroxypropylmethylcellulose and hydroxypropyl Cellulose, povidone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalic acid Ester, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, poly At least one of vinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, and collagen. A method of preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 1, comprising the steps of: 1) mixing paclocillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant in a solvent at a mixing temperature of -50 to 150 ° C to form a paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. a solution or suspension wherein the weight ratio of paboxirin or a pharmaceutically acceptable salt thereof to the solvent is from 0.001 to 100:1, and the weight ratio of paclocillin or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable excipient is 1 :0.1～100; 2) The solvent in the solution or suspension obtained in the step 1) is removed to obtain a composition of the amorphous form of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant. The composition of the composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 11. The preparation method is characterized in that the pharmaceutical auxiliary is selected from the group consisting of an excipient, a propellant, a solubilizer, a co-solvent, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, Osmotic pressure regulator, stabilizer, glidant, flavoring agent, preservative, suspending agent, coating material, fragrance, anti-adhesive agent, integrator, penetration enhancer, pH adjuster, buffer, increase Plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release At least one of the retarders. The method for preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 11, wherein the pharmaceutically acceptable adjuvant is selected from the group consisting of hydroxypropylmethylcellulose and hydroxypropyl Cellulose, povidone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalic acid Ester, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, poly At least one of vinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, ion exchange resin, and collagen. The method for preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 11, wherein the solvent in the step 1) is selected from the group consisting of alcohols having 12 or less carbon atoms At least one of a phenol, an ether, a halogenated hydrocarbon, a ketone, an aldehyde, a nitrile, an amide, a sulfone, a sulfoxide, a carboxylic acid, and water; and the step 2) the solvent is removed by evaporation, vacuum evaporation, Spray drying, freeze drying, hot melt extrusion, filtration, centrifugation or stirring film drying. A method of preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 4, comprising the steps of: 1) mixing paboxirin, at least one organic vehicle and at least one pharmaceutical preparation auxiliary, and heating to melt, wherein the weight of the paclicillin is 20% to 80% of the total weight of the solid dispersion, the pharmaceutical preparation The weight of the auxiliary material is 0.1% to 80% by weight of the solid dispersion; 2) After mixing and cooling, the obtained mixture was pulverized to obtain a pharmaceutical composition containing a solid dispersion of paclicillin in an amorphous state. A method of preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 15, wherein the organic vehicle is selected from a pharmaceutically acceptable polymer or copolymer . The method for producing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 15 or 16, wherein the organic carrier is selected from the group consisting of hydroxypropylmethylcellulose and hydroxy Propyl cellulose, povidone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate Acid ester, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, At least one of polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, and collagen. The composition of the composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 15. The preparation method is characterized in that the pharmaceutical preparation auxiliary is selected from the group consisting of an excipient, a propellant, a solubilizer, a solubilizer, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, and a wetting agent. Agent, osmotic pressure regulator, stabilizer, glidant, flavoring agent, preservative, suspending agent, coating material, fragrance, anti-adhesive agent, integrator, penetration enhancer, pH adjuster, buffer , plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid And releasing at least one of the retarders. A method of preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 4, comprising the steps of: 1) mixing paboxirin, at least one organic vehicle and at least one pharmaceutical preparation auxiliary in a solvent at a mixing temperature of -50 to 150 ° C to form a solution containing paboxirin, an organic vehicle and a pharmaceutical preparation auxiliary or a suspension wherein the weight ratio of paboxirin to solvent is from 0.001 to 100:1, the weight of paclicillin is from 20% to 80% by weight based on the total weight of the solid dispersion, and the weight of the pharmaceutical preparation excipient is solid dispersion. 0.1% to 80% by weight; 2) The solvent in the solution or suspension obtained in the step 1) is removed. The method for producing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 19, wherein the organic vehicle is selected from a pharmaceutically acceptable polymer or copolymer . The method for preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 19 or 20, wherein the organic carrier is selected from the group consisting of hydroxypropylmethylcellulose and hydroxy Propyl cellulose, povidone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate Acid ester, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, At least one of polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, ion exchange resin, and collagen. The method for preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 19, wherein the medicinal preparation excipient is selected from the group consisting of an excipient, a propellant, and an increase Solvents, solubilizers, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents , coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, At least one of a humectant, an absorbent, a diluent, a flocculating agent and a deflocculating agent, an antioxidant, an adsorbent, a filter aid, and a release retarder. The method for preparing a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 19, wherein the solvent of the step 1) is selected from the group consisting of alcohols having a carbon number of 12 or less At least one of a class, a phenol, an ether, a halogenated hydrocarbon, a ketone, an aldehyde, a nitrile, an amide, a sulfone, a sulfoxide, a carboxylic acid, and water; and the step 2) removing the solvent includes: evaporation, vacuum evaporation , spray drying, freeze drying, hot melt extrusion, filtration, centrifugation or stirring film drying. The use of a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant according to claim 1 or 4 for the preparation of a medicament for treating cancer comprising: breast cancer, ovarian cancer, cervical cancer, prostate Cancer, testicular cancer, esophageal cancer, gastric cancer, skin cancer, lung cancer, bone cancer, colon cancer, pancreatic cancer, thyroid cancer, biliary tract cancer, oral vestibular and pharyngeal cancer, lip cancer, tongue cancer, oral cancer, pharyngeal cancer, small bowel cancer , colon-rectal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, follicular carcinoma, Differentiated cancer, papillary carcinoma, sperm cell carcinoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's disease, skin cell carcinoma, and leukemia.

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