WO2024076056A1 - Composition pharmaceutique orale contenant un taxane et son procédé de préparation - Google Patents

Composition pharmaceutique orale contenant un taxane et son procédé de préparation Download PDF

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WO2024076056A1
WO2024076056A1 PCT/KR2023/014343 KR2023014343W WO2024076056A1 WO 2024076056 A1 WO2024076056 A1 WO 2024076056A1 KR 2023014343 W KR2023014343 W KR 2023014343W WO 2024076056 A1 WO2024076056 A1 WO 2024076056A1
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pharmaceutical composition
cholesterol
weight
glycerol
oral administration
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PCT/KR2023/014343
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English (en)
Korean (ko)
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정혜선
방하림
추성남
신봄이
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한국과학기술연구원
대화제약 주식회사
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Publication of WO2024076056A1 publication Critical patent/WO2024076056A1/fr

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention relates to a pharmaceutical composition for oral administration containing a taxane and a method for producing the same.
  • Taxane is a diterpene (C 20 ) compound produced by plants of the genus Taxus. It exerts an anti-proliferative effect by acting on the organization of microtubules in the cellular cytoskeleton system, preventing ovarian cancer, breast cancer, It is widely used as a chemotherapy agent because it has significant cytotoxicity against various cancers such as esophageal cancer, melanoma, and leukemia.
  • Non-limiting examples of taxanes include paclitaxel (Taxol ® ), docetaxel (Taxotere ® ), cabazitaxel, larotaxel, ortataxel, and tesetaxel, and are primarily marketed in parenteral dosage forms.
  • Taxanes are known to have very low solubility in water.
  • Taxol ® a paclitaxel-containing preparation
  • Taxol ® a paclitaxel-containing preparation
  • emulsion preconcentrate a paclitaxel-containing preparation
  • emulsion preconcentrate a paclitaxel-containing preparation
  • Taxanes such as paclitaxel are administered orally, they exhibit low oral bioavailability due to an outward efflux pump action (Walle et al., Drug Metabo. Disp. 26(4): 343 - 346 (1998) ), it has also been reported that paclitaxel is very incompletely absorbed (less than 1%) when administered orally (Eiseman et al., Second NCI Workshop on Taxol and Taxus (sept. 1992), Suffness (ed.) et al., TaxolTM Science and Applications , CRC Press (1995)).
  • the conventional oral solubilized composition of paclitaxel is refrigerated in a semi-solid form, and when used, it is converted to a solution form and orally administered to the patient.
  • the composition which is refrigerated in a semi-solid form, does not convert into a solution at room temperature, and remains in a semi-solid form even if left for a long time.
  • the present inventors developed a pharmaceutical composition for oral administration containing taxane, medium chain triglyceride, oleyl glycerol complex, cholesterol or a derivative thereof, and a surfactant, and the pharmaceutical composition exists in a liquid state at room temperature so that it can be administered to patients.
  • the present invention was completed by confirming that not only can it be easily administered to humans, but also the amount of administered liquid is reduced due to the high oral absorption rate.
  • the object of the present invention is to provide a pharmaceutical composition for oral administration containing a taxane.
  • Another object of the present invention is to provide a method for producing the pharmaceutical composition for oral administration.
  • the present invention provides (a) a taxane; (b) one or more medium chain triglycerides selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprine, and triolein; (c) an oleyl glycerol complex comprising monooleyl glycerol, dioleyl glycerol, and trioleyl glycerol, wherein the monooleyl glycerol content is 30 to 99.9% by weight; (d) cholesterol, cholesterol derivatives, or combinations thereof; and (e) a surfactant; and provides a pharmaceutical composition for oral administration.
  • a taxane selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprine, and triolein
  • an oleyl glycerol complex comprising monooleyl glycerol, dioleyl glycerol, and trioley
  • the cholesterol derivative may be cholesteryl acetate, beta-sitosterol, beta-sitosterol acetate, or a combination thereof. Not limited.
  • the surfactant may be Tween 80, TPGS (D- ⁇ -Tocopherol polyethylene glycol 1000 succinate), and a combination thereof, but is not limited thereto.
  • the pharmaceutical composition contains 0.9 to 7.2% by weight, preferably 2 to 3% by weight, of (d) cholesterol, cholesterol derivatives, or a combination thereof, based on the total weight of the pharmaceutical composition. You can.
  • the pharmaceutical composition may have a weight ratio of (a) taxane and (d) cholesterol, cholesterol derivative, or a combination thereof of 1:1.5 to 1:2, preferably 1:1.8. It can be.
  • the pharmaceutical composition contains (a) 0.5 to 4% by weight of taxane based on the total weight; (b) 15 to 35% by weight of medium chain triglycerides; (c) 40 to 60% by weight of oleyl glycerol complex; (d) 0.9 to 7.2% by weight of cholesterol, cholesterol derivatives, or a combination thereof; and (e) 10 to 30% by weight of a surfactant.
  • a surfactant Preferably, (a) 0.5 to 2% by weight of taxane; (b) 20 to 30% by weight of medium chain triglycerides; (c) 45 to 55% by weight of oleyl glycerol complex; (d) 2 to 3% by weight of cholesterol, cholesterol derivatives, or a combination thereof; and (e) 15 to 25% by weight of a surfactant.
  • the pharmaceutical composition may be a physical mixture of (a) to (e). That is, a covalent or ionic bond may not be formed between (a) to (e) in the pharmaceutical composition.
  • the pharmaceutical composition may be in a liquid phase, preferably an oily liquid, at room temperature conditions. Therefore, manufacturing is possible without separate heating conditions, but a heating step can be added to increase manufacturing efficiency.
  • the present invention provides (a) taxane; (b) one or more medium chain triglycerides selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprine, and triolein; (c) an oleyl glycerol complex comprising monooleyl glycerol, dioleyl glycerol, and trioleyl glycerol, wherein the monooleyl glycerol content is 30 to 99.9% by weight; (d) cholesterol, cholesterol derivatives, or combinations thereof; and (e) a surfactant; providing a method for producing a pharmaceutical composition for oral administration, comprising the step of mixing.
  • the production method may be physically mixing (a) to (e) without a solvent or physically mixing by adding a solvent and then removing the solvent.
  • the solvent is a water-insoluble aprotic solvent such as dichloromethane (DCM, CH 2 Cl 2 ), chloroform (CHCl 3 ), ethanol, and methanol.
  • Protic solvents such as acetone, ethyl acetate, dimethylformamide, acetonitrile (CH 3 CN), tetrahydrofuran (THF, oxolane), etc.
  • It may be a protic solvent (water-soluble aprotic solvent), nucleic acid, benzene, toluene, carbon tetrachloride (CCl 4 ), non-polar solvent such as diethyl ether (Et 2 O), etc., but is not limited thereto.
  • it may be a water-insoluble aprotic solvent or a protic solvent, and more preferably, it may be a water-insoluble aprotic solvent.
  • the production method may further include the steps of heat drying, rotational concentration, or freeze drying.
  • the temperature during heat drying may be 40 to 60°C, preferably 50°C.
  • the present invention provides a method for delivering taxanes into the body, comprising administering the pharmaceutical composition for oral administration to a subject.
  • the present invention provides a composition for preventing or treating cancer, including the pharmaceutical composition for oral administration.
  • the present invention provides a method for preventing or treating cancer comprising administering the pharmaceutical composition for oral administration to a subject.
  • the present invention provides the use of the pharmaceutical composition for oral administration for preparing a drug for preventing or treating cancer.
  • the pharmaceutical composition for oral administration maintains high mucosal adsorption by containing cholesterol, cholesterol derivatives, or a combination thereof, can control membrane fluidity, and contains TPGS in addition to Tween 80 as a surfactant. Oral absorption can be increased by increasing oxidation and physical stability.
  • the pharmaceutical composition for oral administration according to an embodiment of the present invention has high solubility and bioavailability, the patient's convenience in taking it can be improved by administering it using a capsule.
  • the drug shows the same or better efficacy as before, thereby reducing the cost of expensive drugs.
  • the pharmaceutical composition for oral administration according to an embodiment of the present invention can be simply manufactured in a physically mixed form rather than forming a complex by covalent or ionic bonding, and is unlikely to precipitate even if crystalline taxane rather than amorphous taxane is used. It can be minimized.
  • Figure 1 shows the results of dissolving paclitaxel and cholesterol in a composition (eLiporaxel) containing medium chain triglyceride (Captex ® 8000), oleyl glycerol complex (Peceol ® ), and Tween 80 according to weight ratio, observed under optical and polarizing microscopes. It shows one result.
  • (A) in Figure 1 contains 4.0% by weight of paclitaxel, 7.2% by weight of cholesterol, and 88.8% by weight of the composition (eLiporaxel); (B) in Figure 1 contains 5.0% by weight of paclitaxel, 9.0% by weight of cholesterol, and 86.0% by weight of the composition (eLiporaxel); Figure 1 (C) shows the case where paclitaxel is 10.0% by weight, cholesterol is 18.0% by weight, and the composition (eLiporaxel) is 72.0% by weight.
  • Figure 2 shows the results of dissolving 1-10% by weight of cholesterol in a composition (eLiporaxel) containing medium chain triglyceride (Captex ® 8000), oleyl glycerol complex (Peceol ® ), and Tween 80, depending on the weight ratio.
  • a composition eLiporaxel
  • Captex ® 8000 medium chain triglyceride
  • Penceol ® oleyl glycerol complex
  • Tween 80 Tween 80
  • Figure 3 shows the results of dissolving 11-20% by weight of cholesteryl acetate in a composition (eLiporaxel) containing medium chain triglyceride (Captex ® 8000), oleyl glycerol complex (Peceol ® ), and Tween 80, depending on the weight ratio. It is shown.
  • Figure 4 shows the results of dissolving 1-10% by weight of beta-sitosterol in a composition (eLiporaxel) containing medium chain triglyceride (Captex ® 8000), oleyl glycerol complex (Peceol ® ), and Tween 80, depending on the weight ratio. will be.
  • Figure 5 shows the results of dissolving 1-10% by weight of beta-sitosterol acetate in a composition (eLiporaxel) containing medium chain triglyceride (Captex ® 8000), oleyl glycerol complex (Peceol ® ), and Tween 80, depending on the weight ratio. It is shown.
  • Figure 6 shows the results of dissolving 1-10% by weight of TPGS in a composition (eLiporaxel) containing medium chain triglyceride (Captex ® 8000), oleyl glycerol complex (Peceol ® ), and Tween 80, depending on the weight ratio.
  • a composition eLiporaxel
  • Captex ® 8000 medium chain triglyceride
  • Penceol ® oleyl glycerol complex
  • Tween 80 Tween 80
  • Figure 7 shows the concentration of paclitaxel in the blood ( ⁇ g/ml) over time in Comparative Example 1 (liporaxel) and Examples 1-4, 1-5, and 1-6.
  • Figure 8 shows the AUC% of Comparative Example 1 (liporaxel) and Examples 1-4, 1-5, and 1-6.
  • Figure 9 shows the concentration of paclitaxel in blood ( ⁇ g/ml) over time in Comparative Example 1 (liporaxel) and Examples 1-8 and 1-9.
  • Figure 10 shows the AUC% of Comparative Example 1 (liporaxel) and Examples 1-8 and 1-9.
  • Figure 11 shows the AUC% of Comparative Example 1 (liporaxel) and Examples 1-1, 1-2, 1-3, and 1-7.
  • Figure 12 shows the results of differential scanning calorimetry (DSC).
  • Figure 12 (A) shows the DSC results of amorphous paclitaxel
  • Figure 12 (B) shows the DSC results of crystalline paclitaxel.
  • Figure 13 shows the results of differential scanning calorimetry (DSC).
  • Figure 13 (A) shows the DSC results of cholesterol
  • Figure 13 (B) shows the DSC results of a mixture of amorphous paclitaxel and cholesterol.
  • Figure 14 shows the results of differential scanning calorimetry (DSC).
  • Figure 14 (A) is a composition prepared by dissolving amorphous paclitaxel and cholesterol in dichloromethane and then removing the solvent
  • Figure 14 (B) is a composition prepared by dissolving amorphous paclitaxel and cholesterol in dichloromethane and removing the solvent. This shows the DSC results of a composition prepared by dissolving and cholesterol in acetone and removing the solvent.
  • Figure 15 shows the results of differential scanning calorimetry (DSC), where (A) in Figure 15 is amorphous paclitaxel and (B) in Figure 15 is a composition prepared by dissolving amorphous paclitaxel in ethanol and then removing the solvent, Figure 15 (C) shows the DSC results of a composition prepared by dissolving amorphous paclitaxel and cholesterol in ethanol and removing the solvent.
  • DSC differential scanning calorimetry
  • Figures 16a to 16d show the results of This shows the XRD results of a composition prepared by dissolving in methane and removing the solvent.
  • Figures 17a to 17c show the results of This shows the XRD results.
  • Figure 18 shows a scanning electron microscope (SEM) image, where (A) in Figure 18 is a composition prepared by dissolving paclitaxel in dichloromethane and removing the solvent, and (B) in Figure 18 is a composition prepared by dissolving paclitaxel in acetone and removing the solvent. A composition prepared by removing, (C) in Figure 18 is a composition prepared by dissolving paclitaxel and cholesterol in dichloromethane and then removing the solvent, and (D) in Figure 18 is a composition prepared by dissolving paclitaxel and cholesterol in acetone and then removing the solvent.
  • SEM scanning electron microscope
  • the prepared composition, (E) in Figure 18 is a composition prepared by dissolving paclitaxel and cholesteryl acetate in dichloromethane and then removing the solvent, and (F) in Figure 18 is a composition prepared by dissolving paclitaxel and cholesteryl acetate in acetone and then removing the solvent. This shows an SEM image of the composition prepared by removing.
  • the present invention relates to (a) taxane; (b) one or more medium chain triglycerides selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprine, and triolein; (c) an oleyl glycerol complex comprising monooleyl glycerol, dioleyl glycerol, and trioleyl glycerol, wherein the monooleyl glycerol content is 30 to 99.9% by weight; (d) cholesterol, cholesterol derivatives, or combinations thereof; and (e) a surfactant; and provides a pharmaceutical composition for oral administration.
  • the present inventors confirmed that the oral absorption rate increases when cholesterol or a derivative thereof is further included in a composition containing taxane, medium chain triglyceride, oleyl glycerol complex, and surfactant, and used TPGS as a surfactant in addition to Tween 80. It was confirmed that bioavailability improves when more is included.
  • the composition since the composition is liquid at room temperature, it can be administered directly to patients without additional treatment such as heating, and precipitation can be minimized even when crystalline taxanes are used rather than amorphous taxanes.
  • taxane refers to diterpenes (C 20 ) compounds produced by plants of the genus Taxus.
  • the taxane includes paclitaxel, docetaxel ( docetaxel), 7-epipaclitaxel, t-acetylpaclitaxel, 10-desacetylpaclitaxel, 10-desacetyl-7-epipaclitaxel (10-desacetyl-7- epipaclitaxel), 7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel (7-N) ,N-dimethylglycylpaclitaxel), 7-L-alanylpaclitaxel, etc., but is not limited thereto.
  • medium chain triglycerides refers to a substance in which three molecules of saturated or unsaturated C 2 -C 20 fatty acid and one molecule of glycerol are linked by an ester bond.
  • the medium chain triglycerides include triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, and triolein. (triolein), mixtures thereof, etc., but is not limited thereto.
  • oleoyl glycerol complex is obtained by partial glycerolysis of vegetable oil containing mainly triglycerol of oleic acid or by esterification of glycerol and oleic acid. It refers to the obtained complex.
  • the contents of monooleyl glycerol, dioleyl glycerol, and trioleyl glycerol vary depending on partial glycerolysis and/or esterification.
  • the present invention may include an oleyl glycerol complex comprising 30 to 99.9% by weight of monooleyl glycerol, preferably a monooleyl glycerol content of 30 to 65% by weight; It is possible to use oleyl glycerol complexes having a dioleyl glycerol content of 15 to 50% by weight: and trioleyl glycerol content of 2 to 20% by weight.
  • the oleyl glycerol complex has a monooleyl glycerol content of 32 to 52% by weight; Dioleyl glycerol content of 30 to 50% by weight: and trioleyl glycerol content of 5 to 20% by weight.
  • the oleyl glycerol complex has a monooleyl glycerol content of 55 to 65% by weight; Dioleyl glycerol content of 15 to 35% by weight: and trioleyl glycerol content of 2 to 10% by weight.
  • commercially available oleyl glycerol complexes having the above content ratio such as PECEOL ® , Gattefosse or CAPMUL ® , Abitec, can be used.
  • surfactant is a polyoxyethylene-polyoxypropylene copolymer such as Poloxamer ® , a sorbitan ester such as Span ® , a polyoxy surfactant such as Tween ® It may be, but is not limited to, ethylene sorbitan, polyoxyethylene ether such as Brij ® , TPGS, etc.
  • the pharmaceutical composition of the present invention may be in a liquid state at room temperature conditions.
  • room temperature may be 1 to 35°C, and preferably 20 to 35°C, as notified in the Food Code.
  • the production method may be physically mixing (a) to (e) without a solvent or physically mixing by adding a solvent and then removing the solvent.
  • the solvent may be used in an amount capable of dissolving (a) to (e), preferably 5 to 40% of the total composition volume, and more preferably 10 to 25% of the total composition volume. , but is not limited to this.
  • 200 g, or about 150 mL, of methylene chloride can be used as a solvent when preparing 1 L of the composition.
  • the range of solvent usage can sufficiently dissolve taxanes such as paclitaxel while reducing waste due to excessive use of solvent and unnecessary effort in removing organic solvents.
  • the production method may be performed by a conventional method to remove the solvent, preferably by heat drying, rotary concentration, or freeze drying.
  • a solvent as described above, each component in the resulting composition can be uniformly mixed in a solvent state (true solution).
  • the present invention can provide a method for preventing or treating cancer, including the step of administering the pharmaceutical composition for oral administration to a subject.
  • prevention refers to any action that inhibits or delays the occurrence, spread, or recurrence of cancer by administering the composition of the present invention
  • treatment refers to the treatment of symptoms of the disease by administering the composition of the present invention. It means any action that improves or changes beneficially.
  • the term “pharmaceutical composition” refers to a product prepared for the purpose of preventing or treating disease, and can be formulated and used in various forms according to conventional methods.
  • it can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc., and can be formulated and used in the form of external preparations, suppositories, and sterile injection solutions.
  • the composition of the present invention is an oral dosage form that can improve the patient's convenience in taking it.
  • the pharmaceutical composition for oral administration of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the components (a) to (e) described above.
  • the pharmaceutically acceptable carrier may be saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures of one or more of these ingredients, and may include antioxidants, buffers, and bacteriostatic agents as necessary. Other common additives may also be included.
  • diluents such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
  • it may be preferably formulated according to each disease or ingredient using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA).
  • the pharmaceutical composition for oral administration of the present invention can be administered orally in a pharmaceutically effective amount according to the desired method, and the term “pharmaceutically effective amount” in the present invention refers to a disease with a reasonable benefit/risk ratio applicable to medical treatment. It refers to an amount that is sufficient to treat and does not cause side effects.
  • the effective dose level refers to the patient's health status, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and excretion rate, treatment. It may be determined based on factors including duration, combination or drugs used simultaneously, and other factors well known in the medical field.
  • cancer refers to skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, and blood. It may be cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymic cancer, urethral cancer, Kaposi's sarcoma, or bronchial cancer, but is not limited thereto.
  • the term “subject” is not limited to mammals such as livestock or humans that require cancer prevention or treatment, but is preferably a human.
  • the pharmaceutical composition for oral administration of the present invention may further include a known anticancer agent and may be used in combination with other known treatments for the prevention or treatment of cancer.
  • first, second, A, B, (a), and (b) may be used. These terms are only used to distinguish the component from other components, and the nature, sequence, or order of the component is not limited by the term.
  • a component is described as being “connected,” “coupled,” or “connected” to another component, that component may be directly connected or connected to that other component, but there is no need for another component between each component. It should be understood that may be “connected,” “combined,” or “connected.”
  • Examples 1-1 to 1-6 were prepared by mixing amorphous paclitaxel with medium chain triglyceride, oleyl glycerol complex, cholesterol and its derivatives, and surfactant without solvent.
  • Examples 1-7 to 1-9 amorphous, crystalline, or mixed forms of paclitaxel were dissolved in 1 to 5 times the total weight of dichloromethane (DCM, CH 2 Cl 2 ), heated and dried (50° C.), It was prepared by removing the solvent through rotation concentration or freeze drying.
  • DCM dichloromethane
  • Paclitaxel 1.0 1.0 1.4 1.4 1.0 1.4 1.4 medium chain triglycerides Captex8000 27.0 27.0 26.1 26.7 26.0 25.3 27.0 26.0 25.3 Oleyl Glycerol Complex Peceol 54.0 54.0 52.2 53.4 52.0 50.6 54.0 52.0 50.6 Cholesterol and its derivatives cholesterol 1.8 0.0 0.0 2.5 0.0 2.5 0.0 0.0 2.5 cholesteryl acetate 0.0 1.8 0.0 0.0 0.0 0.0 0.0 1.8 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
  • paclitaxel and medium chain triglyceride were dissolved in methylene chloride, and then dried under reduced pressure at 40°C to remove methylene chloride.
  • Oleyl glycerol complex and Tween 80 were added to the obtained mixture, and then stirred at about 40° C. to prepare a pharmaceutical composition in the form of a clear, viscous solution as a comparative example.
  • a composition (eLiporaxel) was prepared containing a medium chain triglyceride (Captex ® 8000), oleyl glycerol complex (Peceol ® ), and Tween 80, and was prepared without paclitaxel, cholesterol, and solvent. Mixed. After leaving it at 37°C for 30 minutes, it was stirred with a vortex mixer, sonicated with a bath sonicator, and the degree of dissolution was observed using optical and polarizing microscopes.
  • a medium chain triglyceride Captex ® 8000
  • oleyl glycerol complex (Peceol ® )
  • Tween 80 oleyl glycerol complex
  • the paclitaxel content was determined to be 0.5 to 4.0% by weight, and the cholesterol content was determined to be 0.9 to 7.2% by weight.
  • composition eLiporaxel
  • -sitosterol acetate and TPGS (D- ⁇ -Tocopherol polyethylene glycol 1000 succinate) were sequentially dissolved to measure solubility, and the results are shown in Table 2 below.
  • beta-sitosterol acetate When the weight ratio of beta-sitosterol acetate:eLiporaxel was 6:94, beta-sitosterol acetate was not sufficiently dissolved, forming a slightly opaque mixture (Figure 5), and the solubility of beta-sitosterol acetate was 5 w/w%. TPGS was confirmed to be very well mixed (miscible) at all weight ratios (FIG. 6).
  • Example 1 The pharmaceutical composition for oral administration prepared in Example 1 and Comparative Example 1 was orally administered to ICR mice (6 weeks old, female, Orient Bio, Korea) using a gastric sonde. After drug administration, blood was collected from the infraorbital vein of the mouse at 0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours, and centrifuged at 8000 x g for 20 minutes to obtain plasma samples; It was stored at -70°C.
  • the plasma sample was left at room temperature to dissolve and then stirred for 1 minute with a vortex mixer.
  • 10.0 ⁇ L of the internal standard solution (paclitaxel- d 5 2.50 ⁇ g/mL, in methanol) was added to 50.0 ⁇ L of the plasma sample, stirred for 3 minutes, and then centrifuged at 4000 xg for about 1 minute.
  • 100 ⁇ L of the supernatant was taken, 100 ⁇ L of distilled water containing 0.1% (v/v) formic acid was added thereto, stirred for 3 minutes, and then centrifuged at 4000 xg for about 1 minute at room temperature.
  • 20.0 ⁇ L of the supernatant was taken and injected into UPLC-MS/MS for analysis. At this time, UPLC-MS/MS analysis conditions are as follows.
  • UPLC UPLC
  • Waters ACQUITY UPLC TM System Waters
  • Examples 1-6, 1-9 showed a higher oral absorption rate compared to the case not containing cholesterol (Examples 1-5, 1-8), and cholesterol, a derivative of cholesterol, It was confirmed that oral absorption rate increased even when steryl acetate was included (Examples 1-2 and 1-7). In addition, as the cholesterol content increased, the oral absorption rate also increased (Examples 1-1 and 1-4). This is because cholesterol and its derivatives maintain mucosal adsorption even when mixed with a large amount of water in the intestines and control the drug release rate by regulating membrane fluidity.
  • TPGS an emulsifier with antioxidant properties, helps form a gel phase with high oxidation and physical stability when mixed with gastric and intestinal fluids in the body.
  • DSC Differential scanning calorimetry
  • Amorphous paclitaxel has a glass transition temperature of 156 °C and a decomposition temperature of 234 °C ( Figure 12 (A)), and crystalline paclitaxel has a melting point of 224 °C and decomposition of 233 °C. The temperature is shown ((B) in Figure 12), and cholesterol has a melting point of 149°C ((A) in Figure 13).
  • the heat flow was measured when amorphous paclitaxel and amorphous paclitaxel were dissolved in ethanol and the solvent was removed, and when amorphous paclitaxel and cholesterol were dissolved in ethanol and the solvent was removed. As a result, it was confirmed that the melting point of cholesterol was lowered like that of dichloromethane, and the corresponding peak was also broadened. This means that a physical mixture is formed between amorphous paclitaxel and cholesterol after removal of ethanol (FIG. 15).
  • Structural information such as chemical composition, crystal structure, crystalline size, and strain of the composition of the present invention was investigated using X-ray diffraction analysis (XRD).
  • a scanning electron microscope (SEM) image was taken to visually confirm the shape of the composition of the present invention (FIG. 18).
  • the pharmaceutical composition for oral administration of the present invention does not form a complex through covalent or ionic bonds, but is physically mixed, and can be manufactured as a simple mixture without a solvent, and various solvents can be used.
  • aprotic solvents including dichloromethane e.g., dichloromethane
  • protic solvents including ethanol e.g., ethanol
  • non-polar solvents e.g., ethanol
  • ethanol is expected to have higher usability as a safe solvent.

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Abstract

La présente invention concerne une composition pharmaceutique orale et son procédé de préparation, la composition comprenant : (a) un taxane ; (b) un ou plusieurs triglycérides à chaîne moyenne choisis dans le groupe constitué par la triacétine, la tributyrine, la tricaproïne, la tricapryline, la tricaprine et la trioléine ; (c) un complexe oléoyl-glycérol comprenant un monooléoyl-glycérol, un dioléoyl-glycérol et un trioléoyl-glycérol, la teneur en monooléoyl-glycérol étant comprise entre 30 et 99,9 % en poids ; (d) du cholestérol, des dérivés de cholestérol, ou une combinaison de ceux-ci ; et (e) un tensioactif.
PCT/KR2023/014343 2022-10-05 2023-09-21 Composition pharmaceutique orale contenant un taxane et son procédé de préparation WO2024076056A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050019386A1 (en) * 2001-11-08 2005-01-27 Regina Reszka Orally administered pharmaceutical preparation comprising liposomically encapsulated paclitaxel
CN102451176A (zh) * 2010-10-28 2012-05-16 中国医学科学院药物研究所 多西紫杉烷/类固醇复合物
CN103357013A (zh) * 2013-04-23 2013-10-23 福建省创欣生物科技有限公司 增强紫杉烷类药物生物利用度的组合物
KR101542364B1 (ko) * 2014-10-31 2015-08-07 대화제약 주식회사 탁산을 포함하는 경구 투여용 약학 조성물
KR20200005110A (ko) * 2018-07-05 2020-01-15 대화제약 주식회사 탁산-함유 약학 조성물을 함유하는 의약품의 안정성 개선방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050019386A1 (en) * 2001-11-08 2005-01-27 Regina Reszka Orally administered pharmaceutical preparation comprising liposomically encapsulated paclitaxel
CN102451176A (zh) * 2010-10-28 2012-05-16 中国医学科学院药物研究所 多西紫杉烷/类固醇复合物
CN103357013A (zh) * 2013-04-23 2013-10-23 福建省创欣生物科技有限公司 增强紫杉烷类药物生物利用度的组合物
KR101542364B1 (ko) * 2014-10-31 2015-08-07 대화제약 주식회사 탁산을 포함하는 경구 투여용 약학 조성물
KR20200005110A (ko) * 2018-07-05 2020-01-15 대화제약 주식회사 탁산-함유 약학 조성물을 함유하는 의약품의 안정성 개선방법

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