WO2020184131A1 - Préparation externe à action systémique contenant du sirolimus ou son dérivé - Google Patents

Préparation externe à action systémique contenant du sirolimus ou son dérivé Download PDF

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Publication number
WO2020184131A1
WO2020184131A1 PCT/JP2020/006722 JP2020006722W WO2020184131A1 WO 2020184131 A1 WO2020184131 A1 WO 2020184131A1 JP 2020006722 W JP2020006722 W JP 2020006722W WO 2020184131 A1 WO2020184131 A1 WO 2020184131A1
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sirolimus
external preparation
blood
preparation
weight
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PCT/JP2020/006722
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English (en)
Japanese (ja)
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眞理 金田
一朗 片山
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国立大学法人大阪大学
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention relates to an external preparation containing at least one selected from the group consisting of sirolimus and sirolimus derivatives.
  • Sirolimus and sirolimus derivatives have mTOR inhibitory activity, immunosuppressive activity, antiproliferative activity and the like.
  • Oral preparation containing sirolimus for lymphangioleiomyomatosis, topical sirolimus-containing preparation for skin lesions associated with tuberous sclerosis, and everolimus for tuberous sclerosis and some tumors Oral formulations are currently in use.
  • the present inventor has found that an external preparation containing sirolimus can treat skin lesions associated with tuberous sclerosis (Patent Document 1), and succeeded in developing and selling a safe external preparation with few side effects. ..
  • Sirolimus or sirolimus derivatives must be absorbed into the blood for treatment of lesions other than the skin and mucous membranes, but long-term administration by oral administration has caused side effects.
  • An object of the present invention is to provide an external preparation in which sirolimus or a sirolimus derivative is percutaneously or transmucosally absorbed into blood and exerts an action and effect on the whole body.
  • an external preparation containing at least one active ingredient selected from the group consisting of sirolimus and sirolimus derivatives and vegetable oil transfers the active ingredient into the blood. We found that we could do this, and completed the present invention.
  • the external preparation of the present invention can treat systemic lesions by rapidly transferring sirolimus or a sirolimus derivative into the blood.
  • the sirolimus or sirolimus derivative which is the active ingredient of the external preparation of the present invention, efficiently permeates the epidermis, passes through the dermis, and translocates into the blood.
  • the external preparation of the present invention can avoid the first pass effect and reduce the burden on the liver as compared with the oral preparation. It can also be administered to patients with dysphagia, patients who cannot take oral preparations temporarily or continuously due to impaired consciousness, convulsions, etc., and infants. It can be administered to elderly people with weak swallowing ability without causing aspiration.
  • the external preparation of the present invention can administer sirolimus or a sirolimus derivative into blood without pain like injection, and does not require administration technique.
  • the blood concentration rises within a few hours after administration and then falls, but in the case of an external preparation, a stable blood concentration can be maintained for a long time by the formulation design.
  • the external preparation of the present invention expands the application of sirolimus and sirolimus derivatives by developing a continuous preparation, optimizing the administration form according to the pathological condition, and the like.
  • FIG. 1 shows the sirolimus concentration in the dermis and blood at each time after a single transdermal administration of 0.4% sirolimus-containing liniment agent (SLN), which is an embodiment of the external preparation of the present invention, to mice. It is a graph.
  • SSN sirolimus-containing liniment agent
  • (A) indicates the concentration in the dermis (ng / mg) and
  • (b) indicates the concentration in the blood (ng / ml).
  • the insertion graph in (a) is an enlarged graph on the y-axis.
  • N 6, ** P ⁇ 0.01, * P ⁇ 0.05
  • FIG. 2 is a graph showing the sirolimus concentration in the dermis and blood at each time after a single transdermal administration of 0.8% sirolimus-containing gel (SG), which is a comparative preparation, to mice.
  • SG sirolimus-containing gel
  • (A) indicates the concentration in the dermis (ng / mg) and (b) indicates the concentration in the blood (ng / ml).
  • (N 6-9, ** P ⁇ 0.01)
  • FIG. 3 is a graph showing the sirolimus concentration in the dermis and blood at each time after oral administration of the comparative preparation sirolimus-containing oral preparation (Oral S) to mice.
  • (A) indicates the concentration in the dermis (ng / mg) and (b) indicates the concentration in the blood (ng / ml).
  • FIG. 4 is a graph showing the efficiency of delivery of sirolimus to the dermis and blood of a liniment agent (SLN), a gel agent (SG) and an oral preparation (Oral S) containing sirolimus.
  • SN liniment agent
  • SG gel agent
  • Oral S oral preparation
  • the external preparation according to the present invention contains at least one selected from the group consisting of sirolimus and sirolimus derivatives as an active ingredient.
  • the sirolimus derivative is not particularly limited, and examples thereof include everolimus, temsirolimus, lidaphorolimus, and zotarolimus. These have almost the same basic skeleton as the basic skeleton of sirolimus, and are known to have the same physiological activity as sirolimus. Therefore, these sirolimus derivatives can also be used as the active ingredient according to the embodiment of the present invention, like sirolimus.
  • Sirolimus and everolimus have already been used as therapeutic agents and have been confirmed to be clinically safe. Therefore, preferred active ingredients include sirolimus and everolimus. Sirolimus has already been used as an external preparation for the treatment of skin lesions associated with tuberous sclerosis, and a more preferable active ingredient is sirolimus.
  • the external preparation of the present invention is a preparation for transdermal or transmucosal administration, preferably a preparation for transdermal administration.
  • the dosage form of the external preparation of the present invention is not particularly limited. Examples thereof include liniments, ointments, patches, poultices, creams, gels, lotions, and suppositories. A liniment agent is preferred.
  • transdermal preparation which is a preferred embodiment of the external preparation of the present invention, can also be referred to as a transdermal preparation.
  • the transdermal preparation includes not only patches and poultices but also all external dosage forms such as liniments, ointments, creams, gels, lotions, and suppositories.
  • the amount of sirolimus or sirolimus derivative as an active ingredient contained in the external preparation of the present invention is not particularly limited.
  • the following concentrations are suitable from the viewpoint of rapidly migrating into the blood and obtaining a therapeutic effect.
  • the lower limit of the concentration of the active ingredient is 0.01% by weight or more, 0.02% by weight or more, 0.03% by weight or more, 0.04% by weight or more, 0.05% by weight based on the total weight of the external preparation. % Or more, 0.06% by weight or more, 0.07% by weight or more, 0.08% by weight or more, 0.09% by weight or more, 0.1% by weight or more.
  • the upper limit of the concentration of the active ingredient is 2.0% by weight or less, 1.5% by weight or less, 1.0% by weight or less, 0.9% by weight or less, 0.8% by weight based on the total weight of the external preparation. % Or less, 0.7% by weight or less, 0.6% by weight or less, 0.5% by weight or less, 0.4% by weight or less, 0.3% by weight or less, 0.25% by weight or less, 0.2% by weight It can be:
  • the concentration of the active ingredient is, for example, preferably 0.01 to 2.0% by weight, more preferably 0.03 to 1.0% by weight, and 0.04 to 0.8, based on the total weight of the external preparation. By weight% is more preferable, and 0.05 to 0.4% by weight is more preferable.
  • the daily dose of sirolimus or sirolimus derivative per unit surface area in a living body is not particularly limited.
  • the lower limit of the dosage per day 0.0001 mg / cm 2 or more, 0.0002 mg / cm 2 or more, 0.0005 mg / cm 2 or more, 0.001 mg / cm 2 or more, 0.002 mg / cm 2 As mentioned above, it can be 0.003 mg / cm 2 or more.
  • the upper limit of the dose is 2 mg / cm 2 or less, 1 mg / cm 2 or less, 0.5 mg / cm 2 or less, 0.1 mg / cm 2 or less, 0.05 mg / cm 2 or less, 0. 04mg / cm 2 or less, it may be 0.03 mg / cm 2 or less.
  • the dose is, for example, 0.0001 to 2 mg / cm 2 , preferably 0.0002 to 1 mg / cm 2 , more preferably 0.0005 to 0.5 mg / cm 2 , and more preferably 0.001 to 0. It is 1 mg / cm 2 .
  • the above-mentioned amount of sirolimus or sirolimus derivative may be administered once a day by application or the like, or may be administered in a plurality of times. In other words, it is preferable that the external preparation according to the present invention can realize the above-mentioned dose.
  • the external preparation of the present invention contains vegetable oil.
  • the vegetable oil is not particularly limited, but a preferable vegetable oil is edible oil.
  • the edible oil is not particularly limited, but preferred edible oils include sesame oil, olive oil, soybean oil, camellia oil and the like. From the viewpoint of skin permeability, sesame oil is most preferable. Further, edible oil heat-treated at 80 to 100 ° C. for 1 to 120 minutes is preferable, and sesame oil heat-treated at 80 to 100 ° C. for 1 to 120 minutes is more preferable.
  • the content of the vegetable oil contained in the external preparation of the present invention is, for example, preferably 10 to 99% by weight, more preferably 30 to 97% by weight, and even more preferably 50 to 95% by weight, based on the total weight of the external preparation. , 60-93% by weight is more preferable.
  • the external preparation of the present invention preferably contains alkanols C 2 ⁇ C 4.
  • Sirolimus may be admixed with a vegetable oil from dissolved in alkanol C 2 ⁇ C 4.
  • the alkanol C 2 ⁇ C 4 ethanol, isopropanol, n- propanol, butan-1-ol and butan-2-ol, and the like. Ethanol and isopropanol are preferred, and ethanol is most preferred. It may be a mixture of these C 2 to C 4 alkanols.
  • the amount of C 2 to C 4 alkanol contained in the external preparation of the present invention may be an amount capable of dissolving sirolimus or a sirolimus derivative.
  • 1 to 40% by weight is preferable, 2 to 30% by weight is more preferable, and 5 to 25% by weight is more preferable.
  • a liniment agent can be prepared by mixing a solution containing sirolimus or a sirolimus derivative with a vegetable oil.
  • An ointment can be prepared by mixing a solution containing sirolimus or a sirolimus derivative with a vegetable oil and then mixing with an ointment base.
  • Patches, poultices, lotions, gels and creams can be prepared according to well-known methods after mixing a solution containing sirolimus or a sirolimus derivative with vegetable oil.
  • Examples of the base and additives for the external preparation of the present invention include various components.
  • oily components oily components, aqueous components, surfactants, preservatives, pH adjusters, antioxidants and the like can be mentioned.
  • examples of the oily component include hydrocarbons, fatty acid esters, waxes, higher fatty acids, higher alcohols and the like.
  • it may contain a medicinal ingredient different from that of sirolimus or a sirolimus derivative.
  • compositions of the external preparation of the present invention include, for example, the following compositions based on the total weight of the external preparation.
  • Sirolimus or sirolimus derivative 0.01-2.0 wt%, vegetable oil 50-95 wt%, C 2 alkanol 5 ⁇ C 4 ⁇ 25 wt%
  • the external preparation of the present invention is an external preparation in which at least one selected from the group consisting of the active ingredients sirolimus and sirolimus derivatives is transferred into blood.
  • An external preparation that transfers into the blood is a preparation in which most of the active ingredients administered on the skin or mucous membrane pass through not only the skin or mucous membrane tissue but also into the blood in blood vessels. That is, the external preparation of the present invention is a preparation having excellent delivery efficiency of the active ingredient into blood.
  • the amount of the active ingredient present in the blood is 2 or more with respect to the amount of the active ingredient in the dermis under the applied region in 6 to 12 hours after administration. It is preferably 3 or more, more preferably 4 or more, and more preferably 5 or more, 6 or more, 7 or more, and 8 or more.
  • the external preparation of the present invention is an external preparation whose delivery efficiency of the active ingredient into blood is almost the same as that of an oral preparation.
  • AUC area under the blood drug concentration time curve
  • the AUC of the external preparation of the present invention is 0.1 or more, preferably 0.5 or more. , More preferably 0.8 or more, still more preferably 1 or more.
  • the external preparation of the present invention is administered to the affected area, for example, daily or once every 2 to 3 days.
  • Daily application is preferable, application 1 to 3 times a day is preferable, and application 2 to 3 times a day is more preferable.
  • an external preparation having a concentration of 0.05 to 0.2% may be applied 1 to 3 times a day.
  • 0.2 to 0.8% of an external preparation may be applied to the palm, footpad, etc. once or twice a day.
  • a liniment agent containing 0.4% by weight of sirolimus was prepared as follows.
  • Sirolimus powder was obtained from Fujian Kerui Pharmaceutical Co., Ltd.
  • Pretreated sesame oil was prepared by heating sesame oil at 95 ° C. for 5 minutes and then allowing it to cool to room temperature.
  • Sirolimus powder was added to ethanol to dissolve it and mixed with pretreated sesame oil to obtain a liniment agent.
  • the specific composition is shown below.
  • Example 2 A liniment agent containing 0.2% by weight of sirolimus was prepared in the same manner as in Example 1 except that the composition was changed to the following. The specific composition is shown below. Sirolimus 0.2g Ethanol 10g Sesame oil 89.8g (Total amount 100g)
  • Sirolimus-containing gel agent Sirolimus was added to ethanol to dissolve it, and then mixed with a pH-adjusted carboxyvinyl polymer to prepare a gel agent (SG) containing 0.8% of sirolimus.
  • the specific composition is shown below.
  • Sirolimus 0.8g Ethanol 48g Water for injection 49g Carbomer® 934P NF 1.6g Trishydroxymethylaminomethane 0.6g (Total amount 100g)
  • Oral preparation containing sirolimus A 1.25% sirolimus solution obtained by adding sirolimus to ethanol and dissolving it is mixed with a 9-fold amount of a physiological saline solution containing 0.1% Tween 20, and 1.25 mg of sirolimus in 1 ml. An oral preparation containing the above was obtained.
  • mice were injected intraperitoneally with an anesthetic (a combination of medetomidine 0.3 mg / kg, midazolam 4.0 mg / kg and butorphanol 5.0 mg / kg).
  • an E color (Natsume Seisakusho) was attached to the mouse to prevent grooming. The E-color was worn for up to 24 hours after administration of sirolimus.
  • Dermis and blood sampling Sampling was performed 1 hour, 3 hours, 6 hours, 12 hours, and 24 hours after the administration of sirolimus. Sampling was performed under sevoflurane anesthesia. The liniment or gel was removed by stripping with scotch tape several times. Blood was drawn from the inferior vena cava, internal jugular vein or cardiac puncture using an EDTA-coated syringe. Whole blood was inverted and mixed in a storage tube and stored at ⁇ 80 ° C. until measurement. After blood collection, the mice were sacrificed, the locally administered back skin was cut off, and the dermis was obtained with tweezers. Dermal tissue samples were snap frozen in liquid nitrogen and stored at -80 ° C until measurement.
  • sirolimus concentration in dermis and blood by LC-MS / MS was measured by the LC-MS / MS method using Waters ultra-high performance liquid chromatography (UPLC) and a tandem quadrupole mass spectrometer (TQD).
  • UPLC Waters ultra-high performance liquid chromatography
  • TQD tandem quadrupole mass spectrometer
  • the mass-to-charge ratio of silolimus used for quantification was m / z 931.7 (precursor ion) ⁇ 864.6 (product ion), and the mass-to-charge ratio of internal standard asomycin was m / z 809.7 (precursor ion) ⁇ 756.5 (product ion). Results were calculated using Waters' MassLynx 4.1 software. Tissue and blood sirolimus concentrations were calculated based on the tissue weight and blood volume used for quantification.
  • FIG. 1 (a) shows the sirolimus concentration in the dermis
  • FIG. 1 (b) shows the sirolimus concentration in the blood.
  • the concentration of sirolimus in the dermis was low and constant until after 12 hours, and became undetectable after 24 hours. Blood levels increased after 3 hours and increased after 6 and 12 hours.
  • FIG. 2 shows the sirolimus concentration in the dermis and the sirolimus concentration in the blood up to 24 hours after the single administration of the comparative preparation 0.8% sirolimus gel (SG) for external use.
  • FIG. 2A shows the sirolimus concentration in the dermis
  • FIG. 2B shows the sirolimus concentration in the blood.
  • FIG. 3 shows the sirolimus concentration in the dermis and the sirolimus concentration in the blood up to 24 hours after a single oral administration of the comparative oral preparation (Oral S).
  • FIG. 3 (a) shows the sirolimus concentration in the dermis
  • FIG. 3 (b) shows the sirolimus concentration in the blood. It hardly migrated into the dermis, and the concentration in blood decreased after 1 to 3 hours after the concentration increased.
  • Ds 50Cd / 10Sd
  • Ds Delivery efficiency of sirolimus to the dermis
  • Cd Median sirolimus concentration in the dermis (ng / mg)
  • Sd Dosing sirolimus amount ( ⁇ g)
  • Bs 2Cb / 10Sd
  • Bs Efficiency of delivery of sirolimus to blood
  • Cb Median blood sirolimus concentration (ng / mL)
  • Sd Dosing sirolimus amount ( ⁇ g) The results are shown in FIG.
  • the external preparation of the present invention is a preparation in which sirolimus efficiently permeates the epidermis and then transfers to the blood, not only in the dermis, and it has been shown that the efficiency of delivering sirolimus to the blood is equivalent to that of the oral preparation.
  • the external preparation of the present invention is a preparation that can be efficiently delivered into blood.
  • the external preparation of the present invention does not require administration technique, does not cause pain like injection, does not cause aspiration even in infants and elderly people with weak swallowing ability, and sirolimus or sirolimus derivative in blood. It can be administered to the patient and will greatly contribute to future medical care.

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Abstract

Le problème décrit par la présente invention est de fournir une préparation externe moyennant quoi du sirolimus ou un dérivé de sirolimus est absorbé par voie transdermique ou transmucosale dans le sang et exerce un effet sur le corps entier. La solution selon l'invention porte sur une préparation externe contenant au moins l'un sélectionné dans le groupe constitué par le sirolimus et des dérivés de sirolimus, et de l'huile végétale. Cette préparation externe possède un ingrédient actif qui passe à travers la peau ou la muqueuse et qui migre efficacement dans le sang, et le taux de libération de l'ingrédient actif dans le sang est sensiblement équivalent à celui d'une formulation orale.
PCT/JP2020/006722 2019-03-08 2020-02-20 Préparation externe à action systémique contenant du sirolimus ou son dérivé WO2020184131A1 (fr)

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JP2019-042981 2019-03-08
JP2019042981A JP2022065224A (ja) 2019-03-08 2019-03-08 経皮吸収型外用剤

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1919194A (zh) * 2006-08-17 2007-02-28 刘瑜玲 西罗莫司的液体组合物
WO2012105521A1 (fr) * 2011-01-31 2012-08-09 国立大学法人大阪大学 Médicament à usage externe pour traiter un trouble cutané et procédé pour produire celui-ci
CN105663027A (zh) * 2016-04-01 2016-06-15 中国人民解放军广州军区武汉总医院 西罗莫司外用制剂、其制备方法及用途
WO2016114216A1 (fr) * 2015-01-13 2016-07-21 テルモ株式会社 Stent biodégradable

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1919194A (zh) * 2006-08-17 2007-02-28 刘瑜玲 西罗莫司的液体组合物
WO2012105521A1 (fr) * 2011-01-31 2012-08-09 国立大学法人大阪大学 Médicament à usage externe pour traiter un trouble cutané et procédé pour produire celui-ci
WO2016114216A1 (fr) * 2015-01-13 2016-07-21 テルモ株式会社 Stent biodégradable
CN105663027A (zh) * 2016-04-01 2016-06-15 中国人民解放军广州军区武汉总医院 西罗莫司外用制剂、其制备方法及用途

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