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WO2017036390A1 - Composition à base de palbociclib ou de son sel de qualité pharmaceutique et d'un excipient pharmaceutique, et son procédé de préparation - Google Patents

Composition à base de palbociclib ou de son sel de qualité pharmaceutique et d'un excipient pharmaceutique, et son procédé de préparation Download PDF

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Publication number
WO2017036390A1
WO2017036390A1 PCT/CN2016/097412 CN2016097412W WO2017036390A1 WO 2017036390 A1 WO2017036390 A1 WO 2017036390A1 CN 2016097412 W CN2016097412 W CN 2016097412W WO 2017036390 A1 WO2017036390 A1 WO 2017036390A1
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Prior art keywords
pharmaceutically acceptable
composition
paclicillin
acceptable salt
cancer
Prior art date
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Ceased
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PCT/CN2016/097412
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English (en)
Chinese (zh)
Inventor
张席妮
熊志刚
资春鹏
胡涛
周涛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alnova Pharmaceuticals Ltd
Changzhou Fangnan Pharmaceuticals Ltd
Original Assignee
Alnova Pharmaceuticals Ltd
Changzhou Fangnan Pharmaceuticals Ltd
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Priority claimed from CN201510551018.5A external-priority patent/CN106474129A/zh
Priority claimed from CN201610432284.0A external-priority patent/CN107510847A/zh
Application filed by Alnova Pharmaceuticals Ltd, Changzhou Fangnan Pharmaceuticals Ltd filed Critical Alnova Pharmaceuticals Ltd
Publication of WO2017036390A1 publication Critical patent/WO2017036390A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • the solid form of the drug directly affects the dissolution rate of the drug substance, the dissolution rate of the drug, and the bioavailability.
  • a new solid form of the drug is usually developed. Solid forms with better drug solubility and higher bioavailability are necessary.
  • 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.
  • 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.
  • a composition of paclicillin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient 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.
  • 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.
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • organic vehicle is selected from the group consisting of polymers or copolymers.
  • the organic vehicle is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymer, polyvinyl acetate.
  • 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:
  • 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.
  • 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:
  • 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.
  • 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.
  • 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:
  • the organic vehicle described in the step 1) is selected from a polymer or a copolymer.
  • 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.
  • 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:
  • the organic vehicle described in the step 1) is selected from a polymer or a copolymer.
  • 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.
  • 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 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.
  • 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
  • composition of the paclicillin of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient using Cu-K ⁇ radiation, deducting the background peak of the medicinal excipient from the X-ray powder diffraction spectrum expressed by degree 2 ⁇
  • 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.
  • 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 is not limited to, but not limited to, but not limited to, but not limited to, but not limited to, but not limited to, but not limited to, but not limited to, but not limited to paclicillin or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 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.
  • 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:
  • Scan range: from 2.0 to 60.0 degrees
  • 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.
  • Papacillin (50 mg) and povidone K30 (100 mg) were dissolved in n-butanol (600 ⁇ l), anisole (900 ⁇ l) and methanol (600 ⁇ L) 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.
  • Paclocillin hydrochloride 50 mg and polyethylene glycol 4000 (200 mg) were dissolved in ethanol (600 ⁇ L) and water (600 ⁇ l), 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.
  • 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.
  • 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.
  • 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.
  • a yellow powdery solid that is, a composition of amorphous paboxirin and polyethylene glycol 8000.
  • 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.
  • a yellow powdery solid that is, a composition of amorphous paboxirin and polyethylene glycol 10000.
  • the characteristic peak of the Xilin crystal form 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.
  • 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.
  • 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 .
  • 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.
  • the composition there is no paclicillin hydroxyethanesulfonate crystal after subtracting the background peak of the medicinal adjuvant. Characteristic peak of the type.
  • Paclocillin (50 mg) and polyacrylic resin Eudragit L100 (100 mg) were added to methanol (750 ⁇ l) 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Paclocillin 50 mg
  • sodium carboxymethylcellulose SCMC 500 mg
  • dimethyl sulfoxide 5 ml
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Papacillin (30 mg) and polyacrylic resin Eudragit E100 (30 mg) were dissolved in n-butanol (600 ⁇ l), anisole (900 ⁇ l) and N,N-dimethylformamide (600 ⁇ m). 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.
  • Papacillin (30 mg) and collagen Peptan (300 mg) were dissolved in n-butanol (600 ⁇ L), anisole (900 ⁇ l) and acetonitrile (600 ⁇ L) 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.
  • Papacillin (30 mg) and gum Galactosol (300 mg) were dissolved in n-butanol (600 ⁇ l), anisole (900 ⁇ l) and methanol (600 ⁇ L), 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.
  • paclicillin hydroxyethanesulfonate (30 mg) and hydroxypropylmethylcellulose phthalate HPMCP (30 mg) to ethanol (750 ⁇ l) and water (750 ⁇ l) 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.
  • Paclocillin hydrobromide (30 mg) and ion exchange resin Amberlite IR-120 (300 mg) were added to ethanol (750 ⁇ l) and water (750 ⁇ l), 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.
  • Paclocillin (30 mg) and carboxyacetolactone (300 mg) were added to ethanol (750 ⁇ l) and water (750 ⁇ l), 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.
  • Paclocillin (30 mg) and dextrin Maltrin M100 (300 mg) were added to ethanol (750 ⁇ l) and water (750 ⁇ l), 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.
  • 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.
  • Paclocillin dihydrochloride (30 mg) and ⁇ -cyclodextrin (30 mg) were added to methanol (300 ⁇ l) and water (300 ⁇ l), 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 ⁇ -cyclodextrin, which was deducted from the X-ray powder diffraction pattern of the composition.
  • a composition of amorphous paclicillin dihydrochloride and ⁇ -cyclodextrin which was deducted from the X-ray powder diffraction pattern of the composition.
  • Paclocillin (30 mg) and sodium carboxymethylcellulose SCMC (30 mg) were added to methanol (300 ⁇ l) and water (60 ⁇ l), 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.
  • Paclocillin (50 mg) and polyacrylic resin Eudragit L100 (100 mg) were added to methanol (100 ⁇ l) and dichloromethane (200 ⁇ l), 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.
  • Paclocillin (50 mg) and polyacrylic resin Eudragit S100 (50 mg) were added to methanol (100 ⁇ L) and dichloromethane (200 ⁇ L), 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
  • 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
  • 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
  • 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
  • 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.
  • 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).
  • Example 12 of the present invention 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 ⁇ m 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.
  • 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 is significantly higher than that of the Paboxirin crystal form (Form A) and the polyacrylic resin Eudragit L100 at various pH values.
  • Papacillin (50 mg) and povidone K30 (100 mg) were dissolved in n-butanol (600 ⁇ l), anisole (900 ⁇ l) and methanol (600 ⁇ L) 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Paclocillin (50 mg) and polyacrylic resin Eudragit L100 (100 mg) were added to methanol (750 ⁇ l), 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.
  • Paclocillin 50 mg
  • polyacrylic resin Eudragit S100 5 mg
  • methanol 4 ml
  • ethyl acetate 1 ml
  • 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.
  • 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.
  • paclicillin 50 mg
  • pregelatinized starch Pharma-Gel 100 mg
  • methanol 4 ml
  • water 1 ml
  • 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.
  • Paclocillin 50 mg
  • sodium carboxymethylcellulose SCMC 500 mg
  • 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.
  • 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.
  • Paclocillin 50 mg
  • sodium carboxymethyl starch Explotab 500 mg
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Papacillin (30 mg) and polyacrylic resin Eudragit E100 (30 mg) were dissolved in n-butanol (600 ⁇ l), anisole (900 ⁇ l) and N,N-dimethylformamide (600 ⁇ m). 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.
  • Papacillin (30 mg) and collagen Peptan (300 mg) were dissolved in n-butanol (600 ⁇ L), anisole (900 ⁇ l) and acetonitrile (600 ⁇ L) 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.
  • Papacillin (30 mg) and gum Galactosol (300 mg) were dissolved in n-butanol (600 ⁇ l), anisole (900 ⁇ l) and methanol (600 ⁇ L), 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.
  • paclicillin (30 mg) and hydroxypropylmethylcellulose phthalate HPMCP (30 mg) to ethanol (750 ⁇ l) and water (750 ⁇ l), 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.
  • Paclocillin (30 mg) and carboxyacetolactone (300 mg) were added to ethanol (750 ⁇ l) and water (750 ⁇ l), 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.
  • Paclocillin (30 mg) and dextrin Maltrin M100 (300 mg) were added to ethanol (750 ⁇ l) and water (750 ⁇ l), 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.
  • 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.
  • paclicillin (30 mg) and sodium carboxymethylcellulose SCMC (30 mg) to methanol (300 ⁇ l) and water (60 ⁇ l), 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.
  • paclocillin (30 mg) and polyvinyl alcohol EG-40 (60 mg) to methanol (300 ⁇ l) and water (60 ⁇ l), stir at 60 ° C, add lactose (30 mg)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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).
  • Example 56 of the present invention 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 ⁇ m 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.
  • 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%).

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Abstract

L'invention concerne une composition à base de palbociclib ou de son sel de qualité pharmaceutique et d'un excipient pharmaceutique, ainsi que son procédé de préparation. Le palbociclib ou son sel de qualité pharmaceutique est amorphe. La présente invention concerne, en outre, une composition pharmaceutique comprenant une dispersion solide de palbociclib, comprenant une dispersion solide formée de palbociclib et d'un support organique, ainsi qu'au moins un excipient pharmaceutique, dans lequel le palbociclib est amorphe. La composition pharmaceutique selon la présente invention accélère la vitesse de dissolution du palbociclib et contribue à améliorer la biodisponibilité de ce médicament.
PCT/CN2016/097412 2015-09-01 2016-08-30 Composition à base de palbociclib ou de son sel de qualité pharmaceutique et d'un excipient pharmaceutique, et son procédé de préparation Ceased WO2017036390A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201510551018.5 2015-09-01
CN201510551018.5A CN106474129A (zh) 2015-09-01 2015-09-01 一种帕博西林或其药学上可接受的盐与药用辅料的组合物及其制备方法
CN201610432284.0A CN107510847A (zh) 2016-06-16 2016-06-16 一种含有无定型帕博西林固体分散体的药用组合物及其制备方法
CN201610432284.0 2016-06-16

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10813937B2 (en) * 2016-03-29 2020-10-27 Shenzhen Pharmacin Co., Ltd. Pharmaceutical formulation of palbociclib and a preparation method thereof
GB2583425A (en) * 2016-03-29 2020-10-28 Shenzhen Pharmacin Co Ltd A pharmaceutical formulation of palbociclib and a preparation method thereof
US11471418B2 (en) 2020-09-29 2022-10-18 Shenzhen Pharmacin Co., Ltd. Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101511829A (zh) * 2006-09-08 2009-08-19 辉瑞产品公司 2-（吡啶-2-基氨基）-吡啶并[2,3-d]嘧啶-7-酮的合成

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101511829A (zh) * 2006-09-08 2009-08-19 辉瑞产品公司 2-（吡啶-2-基氨基）-吡啶并[2,3-d]嘧啶-7-酮的合成

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10813937B2 (en) * 2016-03-29 2020-10-27 Shenzhen Pharmacin Co., Ltd. Pharmaceutical formulation of palbociclib and a preparation method thereof
GB2583425A (en) * 2016-03-29 2020-10-28 Shenzhen Pharmacin Co Ltd A pharmaceutical formulation of palbociclib and a preparation method thereof
GB2583425B (en) * 2016-03-29 2021-01-13 Shenzhen Pharmacin Co Ltd A pharmaceutical formulation of palbociclib and a preparation method thereof
US10894049B2 (en) * 2016-03-29 2021-01-19 Shenzhen Pharmacin Co., Ltd. Pharmaceutical formulation of palbociclib and a preparation method thereof
US11464779B2 (en) 2016-03-29 2022-10-11 Shenzhen Pharmacin Co., Ltd. Pharmaceutical formulation of palbociclib and a preparation method thereof
US11471418B2 (en) 2020-09-29 2022-10-18 Shenzhen Pharmacin Co., Ltd. Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof

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