WO2017036390A1 - 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 - Google Patents

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 Download PDF

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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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pharmaceutically acceptable
composition
paclicillin
acceptable salt
cancer
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PCT/CN2016/097412
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English (en)
French (fr)
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张席妮
熊志刚
资春鹏
胡涛
周涛
Original Assignee
上海方楠生物科技有限公司
常州方楠医药技术有限公司
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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 上海方楠生物科技有限公司, 常州方楠医药技术有限公司 filed Critical 上海方楠生物科技有限公司
Publication of WO2017036390A1 publication Critical patent/WO2017036390A1/zh

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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%).

Abstract

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，其中，帕博西林或其药学上可接受的盐为无定型态。本发明还涉及一种含有帕博西林固体分散体的药用组合物，包含帕博西林与有机载体形成的固体分散体以及至少一种药用制剂辅料，其中帕博西林为无定型态。本发明药物组合物增加了帕博西林的溶出度，有利于提高药物的生物利用度。

Description

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 技术领域
本发明属于药物制剂领域，具体涉及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，还涉及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，以及该组合物治疗癌症的用途。
背景技术
帕博西林(Palbociclib)，化学名为6-乙酰基-8-环戊基-5-甲基-2-[5-(1-哌嗪基)吡啶-2-基氨基]-8H-吡啶并[2,3-d]嘧啶-7-酮，商品名为Ibrance，是辉瑞公司开发的一种口服的治疗转移性乳腺癌的新药，帕博西林是细胞周期素依赖性激酶4、6的抑制药物，主要通过抑制CDK4/6活性来阻止细胞由G1期到S期进而抑制DNA的合成。临床试验研究发现，帕博西林联合来曲唑对绝经后的局部浸润性乳腺癌患者或新近诊断的***受体(ER)阳性，HER-2阴性的患者非常有效。帕博西林已于2015年2月3日获得了美国食品和药物管理局(FDA)批准上市。美国食品药监局(FDA)称该药是一种突破性药物，能够提供比现在市场上的药物更加持久的药效。
虽然帕博西林的疗效已获得广泛认可，但仍然存在一些缺陷。专利WO2014128588公开了帕博西林游离碱的两种晶型：Form A和Form B，但并未见无定型的报道。该药物用于制剂的是游离碱晶型Form A，虽然Form A是热力学稳定的晶型，稳定型良好，但从该晶型在水中的溶解度极低，近中性条件下，溶解度仅为19毫克/升。因此，该药物为难溶性药物，其极低的水溶性严重影响了药物的生物利用度。此外，患者之间药效差异较大，有13％的患者对原研药物吸收极低，餐后服用可稍稍提高药物的吸收，食用相当于3克花生油的低脂食物可提高吸收12％，而食用相当于67克花生油的高脂食物可提高吸收21％，但高脂食物对病人的健康也有相当大的危害。
药物的固体形态直接影响原料药的溶解速率、制剂的溶出度和生物利用度，为了提高药物的生物利用度，降低用量、降低毒副作用，通常会开发药物的新的固体形态，因此，开发该药物溶解性更好、生物利用度更高的固体形式就显得很有必要。
药物的固体形态除晶态外，还有无定型状态，药物的无定型状态作为固体物质的一种特殊形态，在药物制备中有着重要的用途。无定型态药物不仅可以广泛应用于药物制剂中，而且可以通过多种技术手段和方法提高无定型态药物的稳定性，使之成为具有优良品质的药物。
由于帕博西林在生物利用度方面的不足和无定型药物活性成分在药物制剂方面 的良好的应用前景，寻找新的无定型帕博西林及其制备方法就显得十分必要。
发明内容
本发明的目的是提供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，得到稳定性及分散性良好的无定型态的帕博西林或其药学上可接受的盐与药用辅料的组合物，增加了帕博西林或其盐的溶出度，该制备方法不受干燥过程的限制，也不受溶剂种类和溶剂量的限制，操作简便，成本低廉，易于实现，可实现工业化生产。
为了达到上述目的，本发明的技术方案如下：
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，该组合物包含帕博西林或其药学上可接受的盐与药用辅料，两者的重量比为1:0.1～100，其中，所述的帕博西林或其药学上可接受的盐为无定型态，所述组合物的X-射线粉末衍射光谱中，扣除药用辅料的背景峰后无帕博西林或其盐的晶体的特征峰。
进一步，所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
优选地，所述的药用辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
进一步，本发明还提供了一种含有帕博西林固体分散体的药用组合物，其为帕博西林或其药学上可接受的盐与药用辅料的组合物中，所述药用辅料中包含有机载体和药用制剂辅料，帕博西林与有机载体形成固体分散体，再与药用制剂辅料形成组合物，其中，帕博西林的重量为固体分散体的总重量的20％～80％，辅料的重量为固体分散体的重量的0.1％～80％，其中，所述的帕博西林为无定型态，所述组合物的X-射线粉末衍射光谱中，扣除载体和药用辅料的背景峰后无帕博西林晶体的特征峰。
进一步，所述的有机载体选自聚合物或共聚物。
优选地，所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥 珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
又，所述的药用制剂辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
本发明的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，包括如下步骤：
1)将帕博西林或其药学上可接受的盐和药用辅料混合，加热至药用辅料熔融；其中，帕博西林或其药学上可接受的盐与药用辅料的重量比为1:0.1～100；
2)混合均匀后冷却，将混合物粉碎，得到无定型态的帕博西林或其药学上可接受的盐与药用辅料的组合物。
进一步，所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
优选地，步骤1)中所述的药用辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白中的至少一种。
本发明提供另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的制备方法，包括如下步骤：
1)将帕博西林或其药学上可接受的盐和药用辅料在溶剂中混合，混合温度为-50～150℃，形成含帕博西林或其盐和药用辅料的溶液或悬浮液，其中，帕博西林或其药学上可接受的盐与溶剂的重量比为0.001～100:1，帕博西林或其药学上可接受的盐与药用辅料的重量比为1:0.1～100；
2)除去步骤1)得到的溶液或悬浮液中的溶剂，得到无定型态的帕博西林或其药学上可接受的盐与药用辅料的组合物。
进一步，所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
优选地，步骤1)中所述的药用辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
又，步骤1)所述溶剂选自碳原子数在12以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种，步骤2)除去溶剂的方法包括：蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
本发明的含有帕博西林固体分散体的药用组合物的制备方法，包括如下步骤：
1)将帕博西林、至少一种有机载体和至少一种药用制剂辅料混物，加热至熔融，其中，帕博西林的重量为固体分散体的总重量的20％～80％，辅料的重量为固体分散体的重量的0.1％～80％；
2)混合均匀后冷却，将得到的混合物粉碎，得到含无定型态的帕博西林固体分散体的药用组合物。
进一步，步骤1)中所述的有机载体选自聚合物或共聚物。
优选地，步骤1)中所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白中的至少一种。
又，步骤1)中所述的药用制剂辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
本发明提供另一种含有帕博西林固体分散体的药用组合物的制备方法，包括如下步骤：
1)将帕博西林、至少一种有机载体和至少一种药用制剂辅料在溶剂中混合，混合温度为-50～150℃，形成含帕博西林、有机载体和药用制剂辅料的溶液或悬浮液，其中，帕博西林与溶剂的重量比为0.001～100:1，帕博西林的重量为固体分散体的总重量的20％～80％，辅料的重量为固体分散体的重量的0.1％～80％；
2)除去步骤1)得到的溶液或悬浮液中的溶剂，得到含无定型态的帕博西林固体分散体的药用组合物。
进一步，步骤1)中所述的有机载体选自聚合物或共聚物。
优选地，步骤1)中所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
又，步骤1)中所述的药用制剂辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
再，步骤1)所述溶剂选自碳原子数在12以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种，步骤2)除去溶剂的方法包括：蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
本发明中的组合物是指混合物、复合物、共聚物、共沉淀物、共晶、固体分散体、溶剂合物和水合物。
本发明中药学上可接受的药用辅料和药用制剂辅料是指生产药品和调配处方时使用的赋形剂和附加剂，包括赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂等。
本发明还提供了一种含有无定型帕博西林的药用组合物用于治疗以下疾病的用途：所述疾病包括：乳腺癌、卵巢癌、子***、***癌、睾丸癌、食道癌、胃癌、 皮肤癌、肺癌、骨癌、结肠癌、胰腺癌、甲状腺癌、胆道癌、口腔前庭和咽癌(口腔)、唇癌、舌癌、口癌、咽癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑和中枢神经***癌、胶质母细胞癌、神经母细胞癌、角化棘皮癌、表皮样癌、大细胞癌、腺癌、卵泡癌、未分化癌、***状癌、精元细胞癌、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓失调症、淋巴失调症、霍奇金氏症、皮肤细胞癌和白血病。
本发明的帕博西林或其药学上可接受的盐与药用辅料的组合物，使用Cu-Kα辐射，以度2θ表示的X-射线粉末衍射光谱中扣除药用辅料的背景峰无帕博西林结晶态的特征峰，表明帕博西林或其药学上可接受的盐为无定型状态。现有技术中一般使用帕博西林的结晶态，未见其无定型态的报道。一般由于晶态物质分子的有序和周期性排列，降低了分子间相互作用的能量，能量较低，而本发明的帕博西林或其药学上可接受的盐为无定型态，分子处于高度无序状态，物质的表面自由能更大，固体物质中的分子较晶态固体物质中的分子有更高的能量，更容易分散，增加其溶出度，提高帕博西林或其盐的生物利用度。
本发明将帕博西林或其药学上可接受的盐和药用辅料混合均匀后，使用“固体分散剂”法，通过药用辅料的多聚体网状结构将药物分子阻隔，抑制结晶的发生，使其保持分散和无定型状态。本发明采用应用广泛、价格低廉、溶解性好的药用辅料，这些药用辅料与帕博西林或其药学上可接受的盐混合，配合蒸发、喷雾干燥、冷冻干燥和热熔挤出等技术可以得到帕博西林或其药学上可接受的盐的无定型形式，增加本发明帕博西林或其药学上可接受的盐的组合物中的帕博西林或其药学上可接受的盐的无定型态的稳定性。
本发明选用在药学上应用广泛的、价格低廉的辅料，得到帕博西林或其药学上可接受的盐与药用辅料的组合物，易于开发制剂配方，本发明的制备方法不受干燥过程的限制，也不受溶剂种类和溶剂量的限制，操作简便，成本低廉，易于实现，可实现工业化生产。
与现有技术相比，本发明的有益效果是：
1)本发明制备的无定型帕博西林或其药学上可接受的盐与药用辅料的组合物具有高度分散性及稳定性，在制成固体制剂后，经过崩解可使药物粒子的分散程度更好，分散及溶出速度更快，有利于药物的吸收。因此，无定型状态药物的溶出度明显增加，更有利于机体对药物的吸收，提高药物的生物利用度，使药物能够更好地发挥临床疾病治疗作用。
2)本发明无定型状态的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法不受干燥过程的限制，也不受溶剂种类和溶剂量的限制，操作简便，成本低廉，易于实现，可实现工业化生产。
3)本发明制备的无定型状态的帕博西林或其药学上可接受的盐与药用辅料的组合物在加速试验条件下(40±2℃，湿度75％±5％)，能保持良好的物理稳定性和化学 稳定性。因此，本发明将会有广阔的应用前景。
附图说明
图1为本发明实施例1的无定型帕博西林和聚维酮K30的组合物的X-射线粉末衍射图。
图2为本发明实施例12的无定型帕博西林和聚丙烯酸树脂L100的组合物的X-射线粉末衍射图。
图3为本发明实施例56的无定型帕博西林固体分散体和微晶纤维素的组合物的X-射线粉末衍射图。
图4为本发明实施例56中使用的微晶纤维素的X-射线粉末衍射图。
图5为本发明实施例76的无定型帕博西林固体分散体与胶态二氧化硅Aerosil 200的组合物的X-射线粉末衍射图。
具体实施方式
以下结合具体实施例对本发明作进一步说明，但本发明的保护范围不受以下实施例的限制。
本发明所述的X-射线粉末衍射图在Ultima IV X-射线衍射仪上采集。本发明所述的X-射线粉末衍射的方法参数如下：
X-射线粉末参数：Cu-Kα
Kα
Figure PCTCN2016097412-appb-000001
：1.5418
电压：40千伏
电流：40毫安
发散狭缝：自动
扫描模式：连续
扫描范围：自2.0至60.0度
取样步长：0.0200度
扫描速率：60度/分钟
任何物理形式的帕博西林都可以用于制备本发明中无定型帕博西林的组合物。
帕博西林在所述药用组合物中的负载率的计算方式如下：
负载率＝药用组合物中帕博西林的含量/帕博西林的投料重量。
实施例1
将帕博西林(50毫克)和聚维酮K30(100毫克)溶于正丁醇(600微升)、苯甲醚(900微升)和甲醇(600微升)中，加热到60℃搅拌溶清。将上述溶液迅速降 温到-10℃，析出黄色固体，过滤，干燥，得到无定型帕博西林与聚维酮K30的组合物，该组合物的X-射线粉末衍射图如图1所示，X-射线粉末衍射图中扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例2
将帕博西林盐酸盐(50毫克)和聚乙二醇4000(200毫克)溶于乙醇(600微升)和水(600微升)中，在-40℃下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，得到无定型帕博西林与聚乙二醇4000的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林盐酸盐晶型的特征峰。
实施例3
将帕博西林盐酸盐(5克)和聚乙二醇8000(10克)加入水(300毫升)中，加热到60℃搅拌溶清。将上述溶液用JISL微型喷雾干燥机LSD-48干燥，维持进口温度60℃、出口温度50℃，收集出口物料，得到黄色固体，进一步真空干燥得到无定型帕博西林与聚乙二醇8000的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林盐酸盐晶型的特征峰。
实施例4
将帕博西林羟基乙磺酸盐(1克)和羟丙甲基纤维素E50(0.2克)加到水(10毫升)中，加热到40℃搅拌溶清。将上述溶液冷冻干燥，得到黄色固体，即无定型帕博西林与羟丙甲基纤维素E50的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林羟基乙磺酸盐晶型的特征峰。
实施例5
将帕博西林(1克)和聚乙二醇8000(50克)加热到熔融，搅拌下迅速冷却到室温，得到黄色固体。将上述固体粉碎，得到黄色粉末状固体，即无定型帕博西林与聚乙二醇8000的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例6
将帕博西林(1克)、苯甲醚(0.1克)和聚乙二醇10000(100克)加热到240℃，混合均匀，迅速冷却到室温，得到黄色固体。将上述固体粉碎，得到黄色粉末状固体，即无定型帕博西林与聚乙二醇10000的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例7
将帕博西林(1克)、苯甲醚(10克)、正丁醇(20克)和脂质体(4克)的混合物加热到90℃，搅拌，混合均匀，真空蒸发除去溶剂，冷却到室温得到黄色固体，即无定型帕博西林与脂质体的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例8
将帕博西林氢溴酸盐(1克)、甲醇(20克)和甲基丙烯酸共聚物A型(4克)的混合物加热到50℃，搅拌，溶清，真空蒸发除去溶剂，冷却到室温得到黄色固体，即无定型帕博西林与甲基丙烯酸共聚物A型的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林氢溴酸盐晶型的特征峰。
实施例9
将帕博西林(1克)、正丁醇(20克)、苯甲醚(10克)和乙基纤维素(2克)的混合物加热到30℃，搅拌，混合均匀，真空蒸发除去溶剂，冷却到室温得到黄色固体，即无定型帕博西林与乙基纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例10
将帕博西林盐酸盐(1克)、甲醇(20克)和羟丙基纤维素SSL(4克)的混合物加热到30℃，搅拌溶清，真空蒸发除去溶剂，冷却到室温得到黄色固体，即无定型帕博西林与羟丙基纤维素SSL的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林盐酸盐晶型的特征峰。
实施例11
将帕博西林羟基乙磺酸盐(1克)、甲醇(20克)、水(10克)和聚醋酸乙烯(4克)的混合物加热到30℃，搅拌溶清，真空蒸发除去溶剂，冷却到室温得到黄色固体，即无定型帕博西林与聚醋酸乙烯的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林羟基乙磺酸盐晶型的特征峰。
实施例12
将帕博西林(50毫克)和聚丙烯酸树脂Eudragit L100(100毫克)加入到甲醇(750微升)，室温下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林与聚丙烯酸树脂Eudragit L100的组合物，该组合物的X-射线粉末衍射图如图2所示，X-射线粉末衍射图中扣除药用辅料的背景峰后无帕博西林晶型的 特征峰。
实施例13
将帕博西林(50毫克)和聚丙烯酸树脂Eudragit S100(5毫克)加入到甲醇(4毫升)和乙酸乙酯(1毫升)，-30℃下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，搅拌下析出黄色固体，即无定型帕博西林与聚丙烯酸树脂Eudragit S100的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例14
将帕博西林(50毫克)和聚羧乙烯Carbomer 940(50毫克)加入到甲醇(4毫升)和四氢呋喃(1毫升)，-30℃下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，搅拌下析出黄色固体，即无定型帕博西林与聚羧乙烯Carbomer940的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例15
将帕博西林(50毫克)和预胶化淀粉Pharma-Gel(100毫克)加入到甲醇(4毫升)和水(1毫升)，室温下混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，搅拌下析出黄色固体，即无定型帕博西林与Pharma-Gel预胶化淀粉的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例16
将帕博西林(50毫克)和高支链交联淀粉(50毫克)加入到甲醇(4毫升)和水(1毫升)，室温下搅拌溶清，将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，搅拌下析出黄色固体，即无定型帕博西林与高支链交联淀粉的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例17
将帕博西林(50毫克)和羧甲基纤维素钠SCMC(500毫克)加入到二甲基亚砜(5毫升)，室温下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林与羧甲基纤维素钠SCMC的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例18
将帕博西林(50毫克)和几丁聚糖(500毫克)加入到乙醇(5毫升)，室温下搅拌溶清，将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林与几丁聚糖的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例19
将帕博西林(50毫克)和羧甲基淀粉钠Explotab(500毫克)加入到乙醇(5毫升)，室温下搅拌混合均匀，将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林与羧甲基淀粉钠Explotab的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例20
将帕博西林(50毫克)和藻酸盐E401(500毫克)加入到乙醇(5毫升)，室温下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林与藻酸盐E401的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例21
将帕博西林(50毫克)和羧甲基纤维素邻苯二甲酸酯Agucoat CPD(5克)悬浮于甲醇(30毫升)，加热到50℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂，过滤，干燥，得到黄色固体，即无定型帕博西林与羧甲基纤维素邻苯二甲酸酯Agucoat CPD的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例22
将帕博西林(50毫克)和卡拉胶E407(500毫克)悬浮于甲醇(30毫升)，加热到50℃搅拌混合均匀，将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂，过滤，干燥，得到黄色固体，即无定型帕博西林与卡拉胶E407的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例23
将帕博西林(50毫克)和壳聚糖(5克)悬浮于甲醇(50毫升)，加热到50℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂，过滤，干燥，得到黄色固体，即无定型帕博西林与壳聚糖的组合物，该组合物的X-射线粉末衍射图 中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例24
将帕博西林(30毫克)和聚丙烯酸树脂Eudragit E100(30毫克)溶于正丁醇(600微升)、苯甲醚(900微升)和N,N-二甲基甲酰胺(600微升)中，加热到50℃搅拌溶清，将上述溶液降温到10℃，析出黄色固体，过滤，干燥，得到无定型帕博西林与聚丙烯酸树脂Eudragit E100的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例25
将帕博西林(30毫克)和胶原蛋白Peptan(300毫克)溶于正丁醇(600微升)、苯甲醚(900微升)和乙腈(600微升)中，加热到50℃搅拌溶清。将上述溶液降温到10℃，析出黄色固体，过滤，干燥，得到无定型帕博西林与胶原蛋白Peptan的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例26
将帕博西林(30毫克)和树胶Galactosol(300毫克)溶于正丁醇(600微升)、苯甲醚(900微升)和甲醇(600微升)中，加热到50℃搅拌溶清。将上述溶液降温到10℃，析出黄色固体，过滤，干燥，得到无定型帕博西林与树胶Galactosol的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例27
将帕博西林羟基乙磺酸盐(30毫克)和羟丙甲基纤维素邻苯二甲酸酯HPMCP(30毫克)加入到乙醇(750微升)和水(750微升)，加热到80℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林羟基乙磺酸盐与羟丙甲基纤维素邻苯二甲酸酯HPMCP的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林羟基乙磺酸盐晶型的特征峰。
实施例28
将帕博西林氢溴酸盐(30毫克)和离子交换树脂Amberlite IR-120(300毫克)加入到乙醇(750微升)和水(750微升)，加热到80℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到棕色固体，即无定型帕博西林氢溴酸盐与离子交换树脂Amberlite IR-120的组合物，该组合物的X-射线粉末衍射图中，扣除药用 辅料的背景峰后无帕博西林氢溴酸盐晶型的特征峰。
实施例29
将帕博西林(30毫克)和羧基乙酸内酯(300毫克)加入到乙醇(750微升)和水(750微升)，加热到80℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到棕色固体，即无定型帕博西林与羧基乙酸内酯的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例30
将帕博西林(30毫克)和糊精Maltrin M100(300毫克)加入到乙醇(750微升)和水(750微升)，加热到80℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到棕色固体，即无定型帕博西林与糊精Maltrin M100的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例31
将帕博西林盐酸盐(30毫克)和羧甲基纤维素钠SCMS(3毫克)加入到水(30毫升)，加热到100℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林盐酸盐与羧甲基纤维素钠SCMC的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林盐酸盐晶型的特征峰。
实施例32
将帕博西林二盐酸盐(30毫克)和β-环糊精(30毫克)加入到甲醇(300微升)和水(300微升)，室温下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林二盐酸盐与β-环糊精的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林二盐酸盐晶型的特征峰。
实施例33
将帕博西林(30毫克)和羧甲基纤维素钠SCMC(30毫克)加入到甲醇(300微升)和水(60微升)，60℃下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林与羧甲基纤维素钠SCMC的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例34
将帕博西林(5毫克)和聚环氧乙烷Polyox WSR301(60毫克)加入到甲醇(300 微升)和水(60微升)，60℃下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林与聚环氧乙烷Polyox WSR301的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例35
将帕博西林(30毫克)和聚乙烯醇EG-40(60毫克)加入到甲醇(300微升)和水(60微升)，60℃下搅拌溶清，将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林与聚乙烯醇EG-40的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例36
将帕博西林(50毫克)和羟丙甲基纤维素醋酸酯琥珀酸酯Agoat MG(2克)加入到乙醇(10毫升)和水(2毫升)，80℃下搅拌混合均匀，将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林与羟丙甲基纤维素醋酸酯琥珀酸酯Agoat MG的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例37
将帕博西林(50毫克)和羧甲基乙基纤维素(2克)加入到乙醇(10毫升)和水(1毫升)，80℃下搅拌混合均匀，将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林与羧甲基乙基纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例38
将帕博西林(50毫克)和聚丙烯酸树脂Eudragit L100(100毫克)加入到甲醇(100微升)和二氯甲烷(200微升)，室温下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林与聚丙烯酸树脂Eudragit L100的组合物，该组合物的X-射线粉末衍射图中扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例39
将帕博西林(50毫克)和聚丙烯酸树脂Eudragit S100(50毫克)加入到甲醇(100微升)和二氯甲烷(200微升)，室温下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林与聚丙烯酸树脂Eudragit S100的组合物，该组合物的X-射线粉末衍射图中扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例40：无定型帕博西林与聚维酮K30组合物的影响因素试验
材料：实施例1所得无定型帕博西林与聚维酮K30的组合物。
表1：
Figure PCTCN2016097412-appb-000002
表1说明：无定型帕博西林与聚维酮K30组合物在高温、高湿条件下，放置10天，有关物质无显著改变，无帕博西林结晶析出。
实施例41：无定型帕博西林与聚维酮K30组合物的影响因素试验
材料：实施例1所得无定型帕博西林与聚维酮K30的组合物。
实验条件：温度40℃±2℃，湿度75％±5％。
表2：
Figure PCTCN2016097412-appb-000003
表2说明：无定型帕博西林与聚维酮K30组合物在加速试验条件下，放置6个月，有关物质无显著改变，无帕博西林结晶析出。
实施例42：无定型帕博西林与聚丙烯酸树脂Eudragit L100组合物的影响因素试 验
材料：实施例12所得无定型帕博西林与聚丙烯酸树脂Eudragit L1000的组合物。
表3：
Figure PCTCN2016097412-appb-000004
表3说明：无定型帕博西林与聚维酮K30组合物在高温、高湿条件下，放置10天，有关物质无显著改变，无帕博西林结晶析出。
实施例43：无定型帕博西林与聚丙烯酸树脂Eudragit L100的组合物的影响因素试验
材料：实施例12所得无定型帕博西林与聚丙烯酸树脂Eudragit L100的组合物。
实验条件：温度40℃±2℃，湿度75％±5％。
表4：
Figure PCTCN2016097412-appb-000005
表4说明：无定型帕博西林与聚丙烯酸树脂Eudragit L100的组合物在加速试验条件下，放置6个月，有关物质无显著改变，无帕博西林结晶析出。
实施例44：测定表观溶解度
比较本发明组合物与帕博西林晶型物混合物的表观溶解度。
测定对象分别为：本发明实施例12得到的组合物；帕博西林晶型物的混合物(帕博西林晶型物(Form A)与聚丙烯酸树脂Eudragit L100经过物理混合，重量比为1:2，帕博西林晶型物(Form A)根据专利WO2014/128588实施例5的方法制备得到)。
表观溶解度的测定：分别称取足量本发明实施例12获得的组合物及帕博西林晶型物的混合物，置于两个具塞锥形瓶中，加入指定pH值的稀释液，配制成过饱和溶液，密封盖紧。每个pH稀释液中平行制备三份样品。置于37℃±0.5℃的恒温水浴摇床中振荡12h，使其充分溶解以达到饱和。取上清液用0.45微米的微孔滤膜趁热过滤，并适当稀释，摇匀，分别注入液相色谱仪。以外标法计算三份平行样品在此pH缓冲液中的表观溶解度，取平均值。
各种pH值稀释液的配制：
(1)pH＝1.0的稀释液：9毫升浓盐酸加水稀释至1000毫升。
(2)pH＝2.0的稀释液：甲液：取磷酸16.6毫升，加水至100毫升摇匀。乙液：取磷酸氢二钠71.63克,加水使溶解成1000毫升。取上述甲液72.5毫升与乙液27.5毫升混合，摇匀，即得。
(3)pH＝3.0的稀释液：取冰醋酸50毫升，加水800毫升混合后，用氢氧化锂调节pH值至3.0，再加水稀释至1000毫升，即得。
(4)pH＝4.5的稀释液：取醋酸铵7.7克，加水50毫升溶解后，加冰醋酸6毫升与适量的水使成100毫升，即得。
(5)pH＝5.6的稀释液：取邻苯二甲酸氢钾10克，加水900毫升，搅拌使溶解，用氢氧化钠试液(必要时用稀盐酸)调节pH值至5.6,加水稀释至1000毫升，混匀，即得。
(6)pH＝6.8的稀释液：取0.2摩尔/升的磷酸二氢钾溶液250毫升,加0.2摩尔/升的氢氧化钠溶液118毫升，用水稀释至1000毫升，摇匀，即得。
(7)pH＝7.4的稀释液：取磷酸二氢钾1.36克,加0.l摩尔/升的氢氧化钠溶液79毫升，用水稀释至200毫升，即得。
实验结果如表5所示：
Figure PCTCN2016097412-appb-000006
表5表明：在各个pH值下，本发明的无定型帕博西林与聚丙烯酸树脂Eudragit L100的组合物的表观溶解度明显高于帕博西林晶型物(Form A)与聚丙烯酸树脂Eudragit L100的混合物的表观溶解度。
实施例45
将帕博西林(50毫克)和聚维酮K30(100毫克)溶于正丁醇(600微升)、苯甲醚(900微升)和甲醇(600微升)中，加热到60℃搅拌溶清，再加入微晶纤维素(50毫克)。将上述溶液迅速降温到-10℃，析出黄色固体，过滤，真空干燥，得到无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例46
将帕博西林(50毫克)和聚乙二醇4000(200毫克)溶于乙醇(600微升)和水(600微升)中，在-40℃下搅拌混合均匀，再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例47
将帕博西林(5克)和聚乙二醇8000(10克)加入甲醇(300毫升)中，加热到60℃搅拌溶清，再加入交联羧甲基纤维素钠(0.1克)。将上述溶液用JISL微型喷雾干燥机LSD-48干燥，维持进口温度60℃、出口温度50℃，收集出口物料，得到黄色固体，进一步真空干燥得到无定型帕博西林固体分散体与交联羧甲基纤维素钠的组合 物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例48
将帕博西林(1克)和羟丙甲基纤维素E50(0.2克)加到水(10毫升)中，加热到40℃搅拌混合均匀，再加入交联聚维酮(0.2克)。将上述溶液冷冻干燥，得到黄色固体，即无定型帕博西林固体分散体与交联聚维酮的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例49
将帕博西林(1克)、甘露醇(5克)和聚乙二醇8000(5克)加热到熔融，搅拌下迅速冷却到室温，得到黄色固体。将上述固体粉碎，得到黄色粉末状固体，即无定型帕博西林固体分散体和甘露醇的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例50
将帕博西林(1克)、甘露醇(0.1克)和聚乙二醇10000(10克)加热到240℃，混合均匀，迅速冷却到室温，得到黄色固体。将上述固体粉碎，得到黄色粉末状固体，即无定型帕博西林固体分散体与甘露醇的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例51
将帕博西林(1克)、苯甲醚(10克)、正丁醇(20克)和脂质体(4克)的混合物加热到90℃，搅拌下混合均匀。再加入微晶纤维素(2克)，搅拌均匀，真空蒸发除去溶剂，得到黄色固体，即无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例52
将帕博西林(1克)、甲醇(20克)和甲基丙烯酸共聚物A型(4克)的混合物加热到50℃，搅拌下溶清，再加入交联聚维酮(1克)，真空蒸发除去溶剂，冷却到室温得到黄色固体，即无定型帕博西林固体分散体与交联聚维酮的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林氢溴酸盐晶型的特征峰。
实施例53
将帕博西林(1克)、正丁醇(20克)、苯甲醚(10克)和乙基纤维素(2克)的混合物加热到30℃，搅拌，混合均匀，再加入硬脂酸镁(0.1克)，真空蒸发除去溶剂，冷却到室温得到黄色固体，即无定型帕博西林固体分散体与硬脂酸镁的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例54
将帕博西林(1克)、甲醇(10克)、二氯甲烷(10克)和羟丙基纤维素SSL(4克)的混合物加热到30℃，搅拌溶清，再加入微晶纤维素(0.5克)，真空蒸发除去溶剂，冷却到室温得到黄色固体，即无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例55
将帕博西林(1克)、甲醇(20克)、二氯甲烷(10克)和聚醋酸乙烯(4克)的混合物加热到30℃，搅拌溶清，再加入微晶纤维素(0.5克)真空蒸发除去溶剂，冷却到室温得到黄色固体，即无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例56
将帕博西林(50毫克)和聚丙烯酸树脂Eudragit L100(100毫克)加入到甲醇(750微升)，60℃下搅拌溶清，再加入微晶纤维素(100毫克)。将上述悬浮液迅速冷却至20℃，析出黄色固体。过滤、真空干燥，得到黄色固体，即无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图如图3所示，X-射线粉末衍射图中扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。微晶纤维素的X-射线粉末衍射图如图4所示。
实施例57
将帕博西林(50毫克)和聚丙烯酸树脂Eudragit S100(5毫克)加入到甲醇(4毫升)和乙酸乙酯(1毫升)，-30℃下搅拌溶清。在加入羧甲基淀粉钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林固体分散体与羧甲基淀粉钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例58
将帕博西林(50毫克)和聚羧乙烯Carbomer 940(50毫克)加入到甲醇(4毫升)和四氢呋喃(1毫升)，30℃下搅拌混合均匀，再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例59
将帕博西林(50毫克)和预胶化淀粉Pharma-Gel(100毫克)加入到甲醇(4毫升)和水(1毫升)，室温下混合均匀，再加入交联羧甲基纤维素钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林固体分散体与交联羧甲基纤维素钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例60
将帕博西林(50毫克)和高支链交联淀粉(50毫克)加入到甲醇(4毫升)和水(1毫升)，室温下搅拌溶清，再加入交联羧甲基纤维素钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无无定型帕博西林固体分散体与交联羧甲基纤维素钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例61
将帕博西林(50毫克)和羧甲基纤维素钠SCMC(500毫克)加入到二甲基亚砜(5毫升)，室温下搅拌溶清，再加入交联羧甲基纤维素钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林固体分散体与交联羧甲基纤维素钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例62
将帕博西林(50毫克)和几丁聚糖(500毫克)加入到乙醇(5毫升)，室温下搅拌溶清，再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例63
将帕博西林(50毫克)和羧甲基淀粉钠Explotab(500毫克)加入到乙醇(5毫升)，室温下搅拌混合均匀，再加入乳糖(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例64
将帕博西林(50毫克)和藻酸盐E401(500毫克)加入到乙醇(5毫升)，室温下搅拌混合均匀，在加入乳糖(10毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例65
将帕博西林(50毫克)和羧甲基纤维素邻苯二甲酸酯Agucoat CPD(0.5克)悬浮于甲醇(30毫升)，加热到50℃搅拌混合均匀，再加入乳糖(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂，过滤，干燥，得到黄色固体，即无定型帕博西林固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例66
将帕博西林(50毫克)和卡拉胶E407(500毫克)悬浮于甲醇(30毫升)，加热到50℃搅拌混合均匀，再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂，过滤，干燥，得到黄色固体，即无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例67
将帕博西林(50毫克)和壳聚糖(5克)悬浮于甲醇(50毫升)，加热到50℃搅拌混合均匀，再加入乳糖(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂，过滤，干燥，得到黄色固体，即无定型帕博西林固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例68
将帕博西林(30毫克)和聚丙烯酸树脂Eudragit E100(30毫克)溶于正丁醇(600微升)、苯甲醚(900微升)和N,N-二甲基甲酰胺(600微升)中，加热到50℃搅拌溶清，再加入乳糖(30毫克)。将上述溶液降温到10℃，析出黄色固体，过滤，干燥，得到无定型帕博西林固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例69
将帕博西林(30毫克)和胶原蛋白Peptan(300毫克)溶于正丁醇(600微升)、苯甲醚(900微升)和乙腈(600微升)中，加热到50℃搅拌溶清，再加入微晶纤维素(30毫克)。将上述溶液降温到10℃，析出黄色固体，过滤，干燥，得到无定型帕博西林与胶原蛋白Peptan的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例70
将帕博西林(30毫克)和树胶Galactosol(300毫克)溶于正丁醇(600微升)、苯甲醚(900微升)和甲醇(600微升)中，加热到50℃搅拌溶清，再加入微晶纤维素(30毫克)。将上述溶液降温到10℃，析出黄色固体，过滤，干燥，得到无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例71
将帕博西林(30毫克)和羟丙甲基纤维素邻苯二甲酸酯HPMCP(30毫克)加入到乙醇(750微升)和水(750微升)，加热到80℃搅拌混合均匀，加入羧甲基纤维素钠(30毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林与羧甲基纤维素钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例72
将帕博西林(30毫克)和羧基乙酸内酯(300毫克)加入到乙醇(750微升)和水(750微升)，加热到80℃搅拌混合均匀，再加入乳糖(200毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例73
将帕博西林(30毫克)和糊精Maltrin M100(300毫克)加入到乙醇(750微升)和水(750微升)，加热到80℃搅拌混合均匀，再加入乳糖(200毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例74
将帕博西林(30毫克)和羧甲基纤维素钠SCMS(3毫克)加入到水(30毫升)，加热到100℃搅拌混合均匀，再加入微晶纤维素(30毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林盐酸盐晶型的特征峰。
实施例75
将帕博西林(30毫克)和羧甲基纤维素钠SCMC(30毫克)加入到甲醇(300微升)和水(60微升)，60℃下搅拌混合均匀，再加入微晶纤维素(60毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例76
将帕博西林(5毫克)和聚环氧乙烷Polyox WSR301(30毫克)加入到甲醇(300微升)和水(60微升)，60℃下搅拌混合均匀，加入胶态二氧化硅Aerosil 200(20毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林固体分散体与胶态二氧化硅Aerosil 200的组合物，该组合物的X-射线粉末衍射图如图5所示，X-射线粉末衍射图中扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例77
将帕博西林(30毫克)和聚乙烯醇EG-40(60毫克)加入到甲醇(300微升)和水(60微升)，60℃下搅拌溶清，再加入乳糖(30毫克)将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到黄色固体，即无定型帕博西林固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例78
将帕博西林(50毫克)和羟丙甲基纤维素醋酸酯琥珀酸酯Agoat MG(2克)加入到乙醇(10毫升)和水(2毫升)，80℃下搅拌混合均匀，再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例79
将帕博西林(50毫克)和羧甲基乙基纤维素(2克)加入到乙醇(10毫升)和水(1毫升)，80℃下搅拌混合均匀，再加入交联羧甲基纤维素钠(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到黄色固体，即无定型帕博西林固体分散体与交联羧甲基纤维素钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例80
将帕博西林(10克)和聚丙烯酸树脂Eudragit L100(20克)加入到甲醇(20毫升)和二氯甲烷(40毫升)，室温下搅拌溶清。将上述混合物在流化床中喷雾干燥，负载到微晶纤维素(20克)上，得到黄色固体47.3克，即无定型帕博西林、聚丙烯酸树脂Eudragit L100与微晶纤维素的组合物，活性成分的负载率为20.7％。该组合物的X-射线粉末衍射图中扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例81
将帕博西林(10克)和聚丙烯酸树脂Eudragit L100(10克)加入到甲醇(20毫升)和二氯甲烷(40毫升)，室温下搅拌溶清，再加入胶态二氧化硅Aerosil 200(5克)。将上述混合物在流化床中喷雾干燥，负载到微晶纤维素(10克)上，得到黄色固体32.9克，即无定型帕博西林、聚丙烯酸树脂Eudragit L100、胶态二氧化硅Aerosil200与微晶纤维素的组合物，活性成分的负载率为29.1％。该组合物的X-射线粉末衍射图中扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例82
将帕博西林(10克)和聚丙烯酸树脂Eudragit S100(20克)加入到甲醇(20毫升)和二氯甲烷(60毫升)，室温下搅拌溶清。将上述混合物在流化床中喷雾干燥，负载到微晶纤维素(20克)上，得到黄色固体47.3克，即无定型帕博西林、聚丙烯酸树脂Eudragit S100与微晶纤维素的组合物，活性成分的负载率为20.7％。该组合物的X-射线粉末衍射图中扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例83
将帕博西林(10克)和聚丙烯酸树脂Eudragit S100(10克)加入到甲醇(20毫升)和二氯甲烷(40毫升)，室温下搅拌溶清，再加入二氧化硅Syloid 244 FP(8克)。将上述混合物在流化床中喷雾干燥，负载到微晶纤维素(10克)上，得到黄色固体36.5克，即无定型帕博西林、聚丙烯酸树脂Eudragit S100、二氧化硅Syloid 244 FP与微晶纤维素的组合物，活性成分的负载率为25.8％。该组合物的X-射线粉末衍射图中扣除药用辅料的背景峰后无帕博西林晶型的特征峰。
实施例84：无定型帕博西林固体分散体与微晶纤维素的组合物的影响因素试验
材料：实施例56所得无定型帕博西林固体分散体与微晶纤维素的组合物。
表6：
Figure PCTCN2016097412-appb-000007
表6说明：无定型帕博西林固体分散体与微晶纤维素的组合物在高温、高湿条件下，放置10天，有关物质无显著改变，无帕博西林结晶析出。
实施例85：无定型帕博西林固体分散体与微晶纤维素的组合物的加速稳定性实验
材料：实施例56所得无定型帕博西林固体分散体与微晶纤维素的组合物。
实验条件：温度40℃±2℃，湿度75％±5％。
表7：
Figure PCTCN2016097412-appb-000008
Figure PCTCN2016097412-appb-000009
表7说明：无定型帕博西林固体分散体与微晶纤维素的组合物在加速试验条件下，放置6个月，有关物质无显著改变，无帕博西林结晶析出。
实施例86：测定表观溶解度
比较本发明含固体分散体的组合物与帕博西林晶型物混合物的表观溶解度。
测定对象分别为：本发明实施例56得到的组合物；帕博西林晶型物的混合物(帕博西林晶型物(Form A)、聚丙烯酸树脂Eudragit L100和微晶纤维素经过物理混合，重量比为1:2:2，帕博西林晶型物(Form A)根据专利WO2014/128588实施例5的方法制备得到)。
表观溶解度的测定：分别称取足量本发明实施例56获得的组合物及上述帕博西林晶型物的混合物，置于两个具塞锥形瓶中，加入指定pH值的稀释液，配制成过饱和溶液，密封盖紧。每个pH稀释液中平行制备三份样品。置于37℃±0.5℃的恒温水浴摇床中振荡12h，使其充分溶解以达到饱和。取上清液用0.45um的微孔滤膜趁热过滤，并适当稀释，摇匀，分别注入液相色谱仪。以外标法计算三份平行样品在此pH缓冲液中的表观溶解度，取平均值。
各种pH值稀释液的配制：
(1)pH＝1.0的稀释液：9毫升浓盐酸加水稀释至1000毫升。
(2)pH＝2.0的稀释液：甲液：取磷酸16.6毫升，加水至100毫升摇匀。乙液：取磷酸氢二钠71.63克,加水使溶解成1000毫升。取上述甲液72.5毫升与乙液27.5毫升混合，摇匀，即得。
(3)pH＝3.0的稀释液：取冰醋酸50毫升，加水800毫升混合后，用氢氧化锂调节pH值至3.0，再加水稀释至1000毫升，即得。
(4)pH＝4.5的稀释液：取醋酸铵7.7克，加水50毫升溶解后，加冰醋酸6毫升与适量的水使成100毫升，即得。
(5)pH＝5.6的稀释液：取邻苯二甲酸氢钾10克，加水900毫升，搅拌使溶解，用氢氧化钠试液(必要时用稀盐酸)调节pH值至5.6,加水稀释至1000毫升，混匀，即得。
(6)pH＝6.8的稀释液：取0.2摩尔/升的磷酸二氢钾溶液250毫升,加0.2摩尔/升的氢氧化钠溶液118毫升，用水稀释至1000毫升，摇匀，即得。
(7)pH＝7.4的稀释液：取磷酸二氢钾1.36克,加0.l摩尔/升的氢氧化钠溶液79 毫升，用水稀释至200毫升，即得。
实验结果如表8所示：
表8：
Figure PCTCN2016097412-appb-000010
表8表明：在各个pH值下，无定型帕博西林固体分散体与微晶纤维素的组合物的表观溶解度的表观溶解度明显高于晶型物(Form A)与聚丙烯酸树脂Eudragit L100、微晶纤维素的混合物的表观溶解度。
本发明的帕博西林或其药学上可接受的盐与药用辅料为无定型组合物，其溶出度明显增加，更有利于提高药物的生物利用度，使药物能够更好地发挥临床疾病治疗作用，该无定型物在加速试验条件下(40±2℃，湿度75％±5％)，能保持良好的物理稳定性和化学稳定性。

Claims (24)

  1. 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，其特征在于，所述组合物包含帕博西林或其药学上可接受的盐与药用辅料，两者的重量比为1:0.1～100，其中，所述的帕博西林或其药学上可接受的盐为无定型态，所述组合物的X-射线粉末衍射光谱中，扣除药用辅料的背景峰后无帕博西林或其盐晶体的特征峰。
  2. 根据权利要求1所述的帕博西林或其药学上可接受的盐与药用辅料的组合物，其特征在于，所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  3. 根据权利要求1所述的帕博西林或其药学上可接受的盐与药用辅料的组合物，其特征在于，所述药用辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
  4. 根据权利要求1所述的帕博西林或其药学上可接受的盐与药用辅料的组合物，其特征在于，所述药用辅料中包含有机载体和药用制剂辅料，帕博西林先与有机载体形成固体分散体，所述的固体分散体再与药用制剂辅料形成组合物，其中，帕博西林的重量为固体分散体的总重量的20％～80％，所述药用制剂辅料的重量为固体分散体的重量的0.1％～80％。
  5. 根据权利要求4所述的帕博西林或其药学上可接受的盐与药用辅料的组合物，其特征在于，所述的有机载体选自药学上可接受的聚合物或共聚物。
  6. 根据权利要求4或5所述的帕博西林或其药学上可接受的盐与药用辅料的组合物，其特征在于，所述有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
  7. 根据权利要求4所述的帕博西林或其药学上可接受的盐与药用辅料的组合物，其特 征在于，所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  8. 如权利要求1所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，包括如下步骤：
    1)将帕博西林或其药学上可接受的盐与药用辅料混合，加热至药用辅料熔融；其中，帕博西林或其药学上可接受的盐与药用辅料的重量比为1:0.1～100；
    2)混合均匀后冷却，将得到的混合物粉碎，得到无定型态的帕博西林或其药学上可接受的盐与药用辅料的组合物。
  9. 根据权利要求8所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，其特征在于，所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  10. 根据权利要求7所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，其特征在于，所述的药用辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白中的至少一种。
  11. 如权利要求1所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，包括如下步骤：
    1)将帕博西林或其药学上可接受的盐和药用辅料在溶剂中混合，混合温度为-50～150℃，形成含帕博西林或其药学上可接受的盐和药用辅料的溶液或悬浮液，其中，帕博西林或其药学上可接受的盐与溶剂的重量比为0.001～100:1，帕博西林或其药学上可接受的盐与药用辅料的重量比为1:0.1～100；
    2)除去步骤1)得到的溶液或悬浮液中的溶剂，得到无定型态的帕博西林或其药学上可接受的盐与药用辅料的组合物。
  12. 根据权利要求11所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制 备方法，其特征在于，所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  13. 根据权利要求11所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，其特征在于，所述的药用辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
  14. 根据权利要求11所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，其特征在于，步骤1)所述溶剂选自碳原子数在12以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种；步骤2)除去溶剂的方法包括：蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
  15. 如权利要求4所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，包括如下步骤：
    1)将帕博西林、至少一种有机载体和至少一种药用制剂辅料混合，加热至熔融，其中，帕博西林的重量为固体分散体的总重量的20％～80％，药用制剂辅料的重量为固体分散体的重量的0.1％～80％；
    2)混合均匀后冷却，将得到的混合物粉碎，得到含无定型态的帕博西林固体分散体的药用组合物。
  16. 根据权利要求15所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，其特征在于，所述的有机载体选自药学上可接受的聚合物或共聚物。
  17. 根据权利要求15或16所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，其特征在于，所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白中的至少一种。
  18. 根据权利要求15所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制 备方法，其特征在于，所述的药用制剂辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  19. 如权利要求4所述帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，包括如下步骤：
    1)将帕博西林、至少一种有机载体和至少一种药用制剂辅料在溶剂中混合，混合温度为-50～150℃，形成含帕博西林、有机载体和药用制剂辅料的溶液或悬浮液，其中，帕博西林与溶剂的重量比为0.001～100:1，帕博西林的重量为固体分散体的总重量的20％～80％，药用制剂辅料的重量为固体分散体的重量的0.1％～80％；
    2)除去步骤1)得到的溶液或悬浮液中的溶剂，即得。
  20. 根据权利要求19所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，其特征在于，所述的有机载体选自药学上可接受的聚合物或共聚物。
  21. 根据权利要求19或20所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，其特征在于，所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
  22. 根据权利要求19所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，其特征在于，所述的药用制剂辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  23. 根据权利要求19所述的帕博西林或其药学上可接受的盐与药用辅料的组合物的制备方法，其特征在于，步骤1)所述溶剂选自含碳原子数在12以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种；步骤2)除去溶剂的方法包括：蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
  24. 如权利要求1或4的帕博西林或其药学上可接受的盐与药用辅料的组合物在制备治疗癌症药物中的用途，所述癌症包括：乳腺癌、卵巢癌、子***、***癌、睾丸癌、食道癌、胃癌、皮肤癌、肺癌、骨癌、结肠癌、胰腺癌、甲状腺癌、胆道癌、口腔前庭和咽癌、唇癌、舌癌、口癌、咽癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑和中枢神经***癌、胶质母细胞癌、神经母细胞癌、角化棘皮癌、表皮样癌、大细胞癌、腺癌、卵泡癌、未分化癌、***状癌、精元细胞癌、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓失调症、淋巴失调症、霍奇金氏症、皮肤细胞癌和白血病。
PCT/CN2016/097412 2015-09-01 2016-08-30 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 WO2017036390A1 (zh)

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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
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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
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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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