WO2006085517A1 - Ointment preparation or suppository for pdt based on chlorin or porphyrin derivative - Google Patents

Ointment preparation or suppository for pdt based on chlorin or porphyrin derivative Download PDF

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WO2006085517A1
WO2006085517A1 PCT/JP2006/302031 JP2006302031W WO2006085517A1 WO 2006085517 A1 WO2006085517 A1 WO 2006085517A1 JP 2006302031 W JP2006302031 W JP 2006302031W WO 2006085517 A1 WO2006085517 A1 WO 2006085517A1
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ointment
base
suppository
derivative
pdt
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PCT/JP2006/302031
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French (fr)
Japanese (ja)
Inventor
Yoshinori Nakae
Isao Sakata
Susumu Nakajima
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Photochemical Co., Ltd.
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Priority to JP2007502601A priority Critical patent/JPWO2006085517A1/en
Publication of WO2006085517A1 publication Critical patent/WO2006085517A1/en

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • 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
    • A61P17/06—Antipsoriatics
    • 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
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an ointment preparation and a suppository for a chlorin derivative or a porphyrin derivative used as photodynamic therapy (PDT).
  • PDT photodynamic therapy
  • PDT photodynamic therapy
  • certain porphyrin derivatives are administered by intravenous injection, etc., and these porphyrin derivatives are selectively accumulated in cancer cells and then irradiated with laser light to destroy only the cancer cells. It is a therapy that utilizes the two properties of porphyrin derivatives: selectivity for cancer cells and photosensitization.
  • porphyrin derivative used clinically for this PDT is porfimer sodium.
  • Non-Patent Document 1 Sales name: Photofrin Note
  • Porfimer sodium which first appeared, is a mixture of 2- to 6-mer polymers consisting of ether and Z or ester of a hematoporphyrin derivative. Porfimer sodium is known to cause temporary photosensitivity as a side effect when administered to the human body. In addition, the selective accumulation of porfimer sodium in cancer cells was still not sufficient, but it was confirmed that it was accumulated in normal cells.
  • NPe6 which has recently appeared, is a chlorin derivative and has attracted attention as a therapeutic agent for PDT that has solved the above-mentioned problems.
  • the present inventors have also described the above porfimana.
  • Various porphyrin derivatives have been proposed to solve the problems of thorium.
  • chlorin derivatives or porphyrin derivatives that have been used in the PDT proposed so far are administered to a living body by intravenous administration and then receive a single laser irradiation. It is effective for the treatment of cancer in some parts.
  • these chlorin derivatives or Borfilin compounds are absorbed through the skin. Therefore, it is desirable to selectively accumulate only in the affected area.
  • the present inventors should obtain accumulation by transdermal absorption for diseases formed in the skin epidermis such as actinic keratosis, inflammatory keratosis, V, ivy, and epidermis cancer.
  • diseases formed in the skin epidermis such as actinic keratosis, inflammatory keratosis, V, ivy, and epidermis cancer.
  • the application of an ointment preparation or suppository of a chlorin derivative or a porphyrin derivative was considered. Therefore, we investigated ointments based on the hydrophilic ointment base listed in the Japanese Pharmacopoeia, but the chlorin derivative or porphyrin derivative, which is an active ingredient contained in the base, decomposed over time, I could't get the desired result.
  • Non-patent document 1 Susumu Nakajima et al .: New drugs and clinical practice, 48 (1): 26 (1999)
  • Non-Patent Document 2 Saito K., et al: Jpn. J. Cancer Res., 91: 560, 2000
  • the present invention provides an ointment preparation and a suppository for a chlorin derivative or a porphyrin derivative used for PDT that can be applied to skin diseases such as actinic keratosis, inflammatory keratosis, warts, and epidermis cancer.
  • the task is to do.
  • the present invention for solving the problem to be solved is, as a basic aspect thereof, a non-aqueous solution for PDT containing 0.01 to 10.0% by weight of a chlorin derivative or a porphyrin derivative as an active ingredient. Ointment formulation or suppository.
  • the chlorin derivative or porphyrin derivative may be 13, 17-bis [( 1, 2 dicarboxyethyl) rubamoylethyl] 8 etyr-2-hydroxy 3 hydroxyiminoethylidene 1, 7, 12, 18-tetramethylchlorine tetrasodium [hereinafter abbreviated as ATX-S10 ⁇ Na ( ⁇ ) MOR], (2S, 3S) —18 Carboxy-20—Carboxymethyl-13 Ethyl 3, 7, 12, 17—Tetramethyl-8 Vinylchlorin — 2— [N— (1S)-(1, 2-Dicarboxy ) Ethyl] propionamide tetrasodium [hereinafter sometimes referred to as NPe6 or talaporphyrin sodium], protoporphyrin IX, hematoporphyrinka is a nonaqueous ointment or suppository for PDT as described above. .
  • the non-aqueous ointment base is FAPG (H) ointment base, FA PG (K) ointment base, PEG ointment base, PEG-PG ointment base, Vaseline ointment base, SR ⁇ serine ointment base, SR petrolatum IPM ointment base, plastibase ointment base force The nonaqueous ointment for PDT as described above.
  • the suppository base is a hydrophobic (lipophilic) base or a hydrophilic base, preferably cocoa butter, wittebuzole or macrogol. Suppository.
  • a non-aqueous ointment preparation and a suppository for PDT which contains a chlorin derivative or a porphyrin derivative having excellent pharmacological stability and good skin permeability as an active ingredient.
  • the ointment preparation provided by the present invention has an extremely good skin permeability (percutaneous absorbability), so that it is effective for cancer cells when applied to a diseased site such as epidermis cancer, for example, squamous cell carcinoma.
  • chlorin derivatives or voruline derivatives are accumulated, and by irradiating with laser light, only cancer cells can be selectively destroyed. Therefore, the present invention has great medical value in that it provides an ointment for use in a treatment method based on the concept of a single DDS (drug 'delivery' system).
  • chlorin derivatives or porphyrin derivatives used in the ointments and suppositories provided in the present invention include various derivatives that have been used in PDT so far. wear.
  • these chlorin derivatives or porphyrin derivatives include 13, 17-bis [(1, 2 dicarboxyethyl) force rubermoylethyl] 8 etyl 2 hydroxyl 3 hydroxyiminoethylidene 1, 2, 12 , 18-Tetramethylchlorine tetrasodium [ATX— S10'Na (II)], (2S, 3S) — 18-carboxy-20-carboxymethyl — 13 ethyl 3, 7, 12, 17-tetramethyl mono 8
  • Examples include bulchlorine 1- [N— (1S)-(1,2 dicarboxy) ethyl] propionamide tetrasodium [NPe6], protoporphyrin IX or hematoporphyrin.
  • ATX-SlO-Na (ll) is a chlorin derivative proposed by the present inventors, which reduces temporary photosensitivity as a side effect of porfimer sodium. It is a chlorin derivative for PDT that does not show accumulation in normal cells compared to Mer sodium and is excellent in selection and accumulation only in cancer cells.
  • NPe6 (Talaporphyrin Sodium) is a chlorin derivative and is a compound that has recently attracted attention as a therapeutic agent for PDT following Porfimanatrium. It is clinically known as Meiji Seika Co., Ltd. under the name of Rezafilin. More provided!
  • protoporphyrin IX or hematoporphyrin is a porphyrin derivative and is not very effective as a therapeutic agent for PDT.
  • the treatment based on the DDS theory of the present invention has a certain effect. It is a compound that can.
  • aminolevulinic acid (ALA) which is a protoporphyrin precursor, which is not limited to these chlorin derivatives or porphyrin derivatives, and benzoborphyrin as a new chlorin derivative whose structure has been converted from porphyrin derived from hemoglobin.
  • Derivatives (BPD) and metatetrahydroxyphenol chloride (m-THPC) can also be mentioned.
  • ATX-SlO'Na (II) or NPe6 can be preferably used.
  • non-aqueous ointment base can be a very good ointment.
  • non-aqueous ointment bases include FAPG (H) ointment base, FAPG (K) ointment base, PEG ointment base, PEG-PG ointment base, petrolatum ointment base, SR Vaseline ointment base, SR petrolatum IPM ointment base, and plastibase ointment base.
  • the FAPG (H) ointment base is an ointment base that also has stearyl alcohol, stearic acid, and propylene glycol.
  • the FAPG (K) ointment base is an ointment base composed of stearic alcohol, stearic acid and polyethylene glycol 400.
  • the PEG ointment base is an ointment base made of polyethylene glycol 400 and polyethylene glycol 4000
  • the PEG-PG ointment base is an ointment base made of propylene glycol and polyethylene glycol 4000.
  • Vaseline ointment base is an ointment base with petrolatum and liquid paraffin
  • SR petrolatum ointment base is an ointment base with SR petrolatum (5% salicylic acid-petrolatum) and liquid paraffin
  • SR petrolatum — IP M ointment base is an ointment base with SR petrolatum and isopropyl myristate
  • plastibase ointment base is an ointment base that also has a plastibase (95% liquid paraffin and 5% polyethylene oil) strength.
  • non-aqueous ointment base used in the present invention is not limited to those described above, and it goes without saying that an ointment base used pharmaceutically as a non-aqueous ointment can be used. Absent . It is also acceptable to add other stabilizers or transdermal absorption enhancers pharmacologically or pharmacologically.
  • the chlorin derivative or Borf contained in these non-aqueous ointment bases The chlorin derivative or the porphyrin derivative, which is a compounded active ingredient, is absorbed percutaneously and accumulates at the diseased site, and if the compound is added in an amount sufficient to kill the target cell by laser irradiation. Good. According to the study by the present inventors, it was found that a sufficient effect can be obtained if the blending amount is 0.01 to LO weight% based on the formulation weight.
  • the blending amount is less than 0.01% by weight, the intended therapeutic effect cannot be improved, and even if it is blended more than 10.0% by weight, no further effect can be obtained.
  • the compounding amount cannot be specified in general depending on the type of active ingredient to be contained, and the stability of the active ingredient to be contained is not greatly affected by the concentration of the active ingredient and the ointment base to be used. It is possible to make various changes according to the application within the range of the amount. Among them, when ATX-SlO'Na (II) is used as an active ingredient, a particularly preferable preparation with good pharmacological stability can be obtained by adding about 0.5% by weight. There was found.
  • a chlorin derivative or a porphyrin derivative which is an active ingredient, may be uniformly mixed in an ointment base.
  • the ointment preparation of the present invention obtained as described above is used for PDT therapy, skin diseases such as actinic keratosis, inflammatory keratosis, warts, epidermis cancer, for example, squamous epithelium
  • skin diseases such as actinic keratosis, inflammatory keratosis, warts, epidermis cancer, for example, squamous epithelium
  • the chlorin derivative or porphyrin derivative is effectively accumulated, and then the site can be effectively treated by light irradiation with a laser beam or the like.
  • Various laser lights, LEDs, and lamps can be used for light irradiation at a diseased site after the ointment of the present invention is applied.
  • a titanium sapphire laser, a semiconductor laser, an OPO-YAG laser, a xenon lamp, a halogen lamp, a methanolenolide lamp, or the like can be used.
  • the absorption wavelength is around 670 nm. It is more effective to use a semiconductor laser or LED for the chlorin derivative.
  • suppository bases that are widely used in pharmaceutics, preferably hydrophobic (lipophilic) bases, hydrophilic
  • a suppository can be prepared by applying a general suppository preparation using, for example, cacao butter, wittebuzole, or macrogol, such as a base.
  • Thea 25.0 g Thea 250 0 g Stearate 5-0 g Stearate 5 0 g Propylene glycol 69.5 g PEG 4 0 0 69 5 g Active ingredient 0.5 g Active ingredient 0 5 g Total 100. Og Total Amount 100 g
  • Example 2 Stable test of ointment preparation
  • the ointment preparation obtained above was sealed in an aluminum tube, stored at 40 ° CZ for 2 weeks, and the purity of the active ingredient was measured by HPLC to evaluate its stability.
  • the purity was determined by the area percentage by HPLC, and the purity before the start of storage and the purity after storage at 40 ° CZ for 2 weeks were determined. The results are shown in Tables 2 to 5 below.
  • Table 2 shows the purity of ATX-S10 ⁇ Na ( ⁇ ) stored at 40 ° CZ for 2 weeks
  • Table 3 shows the purity of NPe6 stored at 40 ° CZ for 2 weeks
  • Table 4 shows the protocol for storage at 40 ° CZ for 2 weeks.
  • the purity of porphyrin IX was shown
  • Table 5 shows the purity of hematoporphyrin stored at 40 ° CZ for 2 weeks.
  • Example 3 Long-term stability test of ointment preparation
  • Table 6 shows the results at room temperature and constant temperature (25 ° C), and Table 7 shows the results in a cold place (4 ° CZ refrigerator).
  • ointment preparations [Prescription 103 (PEG ointment) and Prescription 104 (PEG-PG ointment)] were applied to the injured and normal areas of the skin, and the application site was kept sealed for 4 hours. The ointment on the back surface was wiped off. A frozen skin section of the site was prepared and observed with fluorescence (excitation wavelength: 400 nm, fluorescence wavelength: 670 nm).
  • Fig. 1 is a fluorescence photograph of a frozen section of the skin when prescription 103 (PEG ointment) is applied at the injury site
  • Fig. 2 is the skin when prescription 104 (PEG-PG ointment) is applied at the injury site. It is a fluorescence photograph of a frozen section.
  • Fig. 3 is a fluorescent photograph of a frozen section of the skin when prescription 103 (PEG ointment) is applied at the normal site
  • Fig. 4 is a case when prescription 104 (PEG-PG ointment) is applied at the normal site. It is a fluorescence photograph of a skin frozen section.
  • the ointment preparation containing ATX—SlO—Na (II) as an active ingredient was tested for skin permeability in the ointment of Formula 103 (PE G ointment).
  • UV-B (apparatus: DMR—1, Toshiba—Eizai, fluorescent lamp: FL—20—SE—30, Toshiba) is irradiated 3 times in Z week for 1 month for 1 month on the hairless mouse.
  • Actinic keratosis model: Fig. 5 An image similar to actinic keratosis was observed (Actinic keratosis model: Fig. 5).
  • SCC model Fig. 6
  • squamous cell carcinoma develops (Fig. 7).
  • TPA (12-O-tetradecanol phorbol 13-acetate) was applied to the back of hairless mice to cause inflammation (psoriasis model).
  • An ointment of Formula 103 (PEG ointment) was applied to the affected area of these model animals in a red bean size, the application site was kept sealed for 4 hours, and then the surface ointment was wiped off. A frozen section of the skin at the site was prepared and observed with fluorescence (excitation wavelength: 400 nm, fluorescence wavelength: 670 nm).
  • Fig. 8 is a fluorescence photograph of a frozen skin section of the affected area of an Actinic keratosis model animal when prescription 103 (PEG ointment) is applied
  • Fig. 9 is a prescription 103 (PEG ointment) of an affected area of an SCC model animal.
  • FIG. 10 is a fluorescent photograph of a frozen skin section when a preparation of Formula 103 (PEG ointment) is applied in an affected area of a psoriasis model animal.
  • fe5ATX-S10'Na (II) is an active ingredient of the present invention in any model animal, that is, in the affected area of the Actinic ke ratosis model, the SCC model, and the psoriasis model. ) Permeates to the dermis.
  • the SCC model mouse prepared in Example 5 was used, and an ointment of prescription 103 (PEG ointment) was applied to the affected area in a red bean size, and the application site was kept sealed for 4 hours. Next, the ointment on the affected surface was wiped off, and a semiconductor laser (wavelength: 670 nm; energy: lOOjZcm 2) was irradiated from above.
  • PEG ointment prescription 103
  • Fig. 11 shows an SCC model animal before the semiconductor laser irradiation
  • Fig. 12 shows the state one day after the semiconductor laser irradiation
  • Fig. 13 shows the state three days after the semiconductor laser irradiation
  • Figs. This shows the situation after 6 days of semiconductor laser irradiation.
  • the arrow in the figure indicates the affected area of SCC, but it seems that the tumor area of the affected area disappears over time after irradiation. It is understood that the tumor site disappears completely 6 days after irradiation.
  • the present invention provides an ointment preparation for a chlorin derivative or a porphyrin derivative used as photodynamic therapy (PDT), and the ointment preparation provided by the present invention is a skin permeation preparation.
  • the property (percutaneous absorption) is very good. Therefore, chlorin derivatives or porphyrin derivatives can be effectively applied to cancer cells by applying to skin diseases such as actinic keratosis, inflammatory keratosis, warts, epidermoid cancer, eg squamous cell carcinoma. Are accumulated.
  • the chlorin derivative or porphyrin derivative accumulated at the tumor site can selectively destroy only cancer cells by light irradiation. Therefore, the present invention has great medical value in that it provides an ointment for use in a treatment method based on the concept of a single DDS (Drug 'Delivery System).
  • FIG. 1 is a fluorescence photograph of a frozen skin section when a preparation of Formula 103 (PEG ointment) is applied to an injury site in Example 4.
  • Formula 103 PEG ointment
  • FIG. 2 is a fluorescence photograph of a frozen skin section when a preparation of Formula 104 (PEG-PG ointment) is applied to an injury site in Example 4.
  • a preparation of Formula 104 PEG-PG ointment
  • FIG. 3 is a fluorescence photograph of a frozen skin section when a preparation of Formula 103 (PEG ointment) is applied to a normal site in Example 4.
  • Formula 103 PEG ointment
  • FIG. 4 is a fluorescence photograph of a frozen skin section when a preparation of Formula 104 (PEG-PG ointment) is applied to a normal site in Example 4.
  • FIG. 5 is a photograph of an actinic keratosis model animal in Example 5.
  • FIG. 6 is a photograph of an SCC model animal in Example 5.
  • FIG. 7 is a photograph of a squamous cell carcinoma model animal in Example 5.
  • FIG. 9 is a fluorescence photograph of a frozen skin section when a preparation of Formula 103 (PEG ointment) is applied to an affected area of an SCC model animal in Example 5.
  • a preparation of Formula 103 PEG ointment
  • Example 5 In Example 5, the formulation 103 (PEG ointment) was applied to the affected area of psoriasis model animals. It is the fluorescence photograph of the skin frozen section at the time of applying.
  • FIG. 11 is a photograph of an SCC model animal before irradiation with a semiconductor laser in Example 6.
  • FIG. 12 is a photograph of an SCC model animal one day after irradiation with a semiconductor laser in Example 6.
  • FIG. 13 is a photograph of an SCC model animal 3 days after irradiation with a semiconductor laser in Example 6.
  • FIG. 14 is a photograph of an SCC model animal 6 days after irradiation with a semiconductor laser in Example 6.

Abstract

Ointment preparations based on a chlorin derivative or porphyrin derivative, for use in photodynamic therapy (PDT) applicable to skin diseases, such as solar keratosis, inflammatory keratosis, wart and epidermal cancer. There are provided nonaqueous ointment preparations for PDT, comprising 0.01 to 10.0 wt.% of chlorin derivative or porphyrin derivative as an active ingredient. In particular, there is provided an ointment or suppository wherein the contained chlorin derivative or porphyrin derivative is ATX-S10 ⋅ Na (II), Npe6, protoporphyrin IX or hematoporphyrin.

Description

明 細 書  Specification
クロリン類及びポルフィリン類の PDT用軟膏製剤及び坐剤  Ophthalmic preparations and suppositories for PDT of chlorins and porphyrins
技術分野  Technical field
[0001] 本発明は、光線力学的療法（PDT:photodynamic therapy)として使用するクロ リン誘導体又はポルフィリン誘導体についての軟膏製剤及び坐剤に関する。  [0001] The present invention relates to an ointment preparation and a suppository for a chlorin derivative or a porphyrin derivative used as photodynamic therapy (PDT).
背景技術  Background art
[0002] 癌の新しい治療法として、最近光線力学的療法 (以下、 PDTと略記する場合もある )が脚光を浴びてきている。これは、ある種のポルフィリン誘導体を静脈注射などによ り投与し、癌細胞にこれらポルフィリン誘導体を選択的に集積させた後、レーザー光 を照射することにより、癌細胞のみを破壊するというものであり、ポルフィリン誘導体が 有する癌細胞への選択性と光増感作用という二つの性質を利用した療法である。  Recently, photodynamic therapy (hereinafter sometimes abbreviated as PDT) has been in the spotlight as a new treatment for cancer. This is because certain porphyrin derivatives are administered by intravenous injection, etc., and these porphyrin derivatives are selectively accumulated in cancer cells and then irradiated with laser light to destroy only the cancer cells. It is a therapy that utilizes the two properties of porphyrin derivatives: selectivity for cancer cells and photosensitization.
[0003] この PDTに臨床的に使用されているポルフィリン誘導体は、ポルフィマーナトリウム  [0003] The porphyrin derivative used clinically for this PDT is porfimer sodium.
(販売名：フォトフリン注）が唯一のものであった (非特許文献 1)が、最近に至り、 NPe 6 (タラポルフィリンナトリウム;販売名：レザフィリン)が登場するに至った (非特許文献 2)。  (Sales name: Photofrin Note) was the only one (Non-Patent Document 1), but recently NPe 6 (Talaporphyrin sodium; Sales name: Rezaphyrin) has appeared (Non-Patent Document 2). ).
[0004] 最初に登場したポルフィマーナトリウムは、へマトポルフィリン誘導体のエーテル体 及び Z又はエステル体からなる 2〜6量体のポリマーとしての混合物である。ポルフィ マーナトリウムは、人体に投与した場合に、副作用として一時的な光過敏症を引き起 こすことが知られている。また、ポルフィマーナトリウムの癌細胞への選択'集積性は 未だ十分なものとは 、えず、正常細胞への集積性も認められて 、た。  [0004] Porfimer sodium, which first appeared, is a mixture of 2- to 6-mer polymers consisting of ether and Z or ester of a hematoporphyrin derivative. Porfimer sodium is known to cause temporary photosensitivity as a side effect when administered to the human body. In addition, the selective accumulation of porfimer sodium in cancer cells was still not sufficient, but it was confirmed that it was accumulated in normal cells.
[0005] したがって、ポルフィマーナトリウムの投与を受けた患者は、正常細胞に集積したポ ルフィマーナトリウムによる光増感作用で、正常細胞が破壊されないように、ポルフィ マーナトリウムが体内から完全に***されるまで、長時間にわたって暗室に留まること が必要であった。また、ポルフィマーナトリウムの正常細胞力 の排出速度が遅ぐ時 として、 6週間以上にわたって光過敏症が残ることがあった。  [0005] Therefore, patients who receive porfimer sodium are completely excreted from the body so that normal cells are not destroyed by photosensitization by porfimer sodium accumulated in normal cells. Until then, it was necessary to stay in the darkroom for a long time. In addition, photosensitivity sometimes remained for more than 6 weeks when the normal cellular force excretion rate of porfimer sodium was slow.
[0006] 最近になって登場した NPe6は、クロリン誘導体であり、上記した問題点を解決した PDT用の治療剤として注目されている。また、本発明者らも上記したポルフィマーナ トリウムの問題点を解決するポルフィリン誘導体を種々提案してきて 、る。 [0006] NPe6, which has recently appeared, is a chlorin derivative and has attracted attention as a therapeutic agent for PDT that has solved the above-mentioned problems. In addition, the present inventors have also described the above porfimana. Various porphyrin derivatives have been proposed to solve the problems of thorium.
[0007] ところで、これまで提案されている PDTに使用されてきているクロリン誘導体あるい はポルフィリン誘導体は、いずれも静脈投与により生体内に投与された後に、レーザ 一照射を受けるものであり、深層部の癌の治療に対し有効なものである。しかしなが ら、日光角化症、炎症性角化症、いぼ、表皮癌等の皮膚表皮に形成される疾患に対 しては、これらのクロリン誘導体あるいはボルフイリンィ匕合物は、経皮吸収させることに より当該患部にのみ選択的に集積させるのが望ましい。 [0007] By the way, all of the chlorin derivatives or porphyrin derivatives that have been used in the PDT proposed so far are administered to a living body by intravenous administration and then receive a single laser irradiation. It is effective for the treatment of cancer in some parts. However, for diseases formed in the skin epidermis such as actinic keratosis, inflammatory keratosis, warts, and epidermoid cancer, these chlorin derivatives or Borfilin compounds are absorbed through the skin. Therefore, it is desirable to selectively accumulate only in the affected area.
[0008] 本発明者らは、かかる観点から、日光角化症、炎症性角化症、 V、ぼ、表皮癌等の 皮膚表皮に形成される疾患に対する経皮吸収による集積性を得るベぐクロリン誘導 体あるいはポルフィリン誘導体の軟膏製剤又は坐剤の適用を考えた。そのため、日 本薬局方に収載される親水軟膏基剤による軟膏剤の検討を行ったが、基剤中に含 有される有効成分であるクロリン誘導体あるいはポルフィリン誘導体が経時的に分解 してしまい、目的とする結果を得ることができな力つた。 [0008] From this viewpoint, the present inventors should obtain accumulation by transdermal absorption for diseases formed in the skin epidermis such as actinic keratosis, inflammatory keratosis, V, ivy, and epidermis cancer. The application of an ointment preparation or suppository of a chlorin derivative or a porphyrin derivative was considered. Therefore, we investigated ointments based on the hydrophilic ointment base listed in the Japanese Pharmacopoeia, but the chlorin derivative or porphyrin derivative, which is an active ingredient contained in the base, decomposed over time, I couldn't get the desired result.
[0009] そこで、軟膏基剤について種々検討をおこなった結果、非水性軟膏基剤を用いる ことにより、効果的に優れ、安定性のよい軟膏剤を得ることに成功し、本発明を完成さ せるに至った。 [0009] Thus, as a result of various investigations on the ointment base, by using a non-aqueous ointment base, the present invention succeeded in obtaining an effective and stable ointment, thereby completing the present invention. It came to.
非特許文献 1：中島 進ほか:新薬と臨床、 48(1):26(1999)  Non-patent document 1: Susumu Nakajima et al .: New drugs and clinical practice, 48 (1): 26 (1999)
非特許文献 2 : Saito K., et al: Jpn. J. Cancer Res., 91:560, 2000  Non-Patent Document 2: Saito K., et al: Jpn. J. Cancer Res., 91: 560, 2000
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0010] すなわち本発明は、日光角化症、炎症性角化症、いぼ、表皮癌等の皮膚疾患に適 用しうる PDTに使用するクロリン誘導体又はポルフィリン誘導体についての軟膏製剤 及び坐剤を提供することを課題とする。 That is, the present invention provides an ointment preparation and a suppository for a chlorin derivative or a porphyrin derivative used for PDT that can be applied to skin diseases such as actinic keratosis, inflammatory keratosis, warts, and epidermis cancer. The task is to do.
課題を解決するための手段  Means for solving the problem
[0011] カゝかる課題を解決するための本発明は、その基本的態様として、クロリン誘導体又 はポルフィリン誘導体を有効成分として 0. 01〜10. 0重量％含有してなる PDT用の 非水性軟膏製剤又は坐剤である。 [0011] The present invention for solving the problem to be solved is, as a basic aspect thereof, a non-aqueous solution for PDT containing 0.01 to 10.0% by weight of a chlorin derivative or a porphyrin derivative as an active ingredient. Ointment formulation or suppository.
[0012] より具体的な本発明は、クロリン誘導体又はポルフィリン誘導体が、 13, 17—ビス [ ( 1, 2 ジカルボキシェチル）力ルバモイルェチル] 8 ェテュル - 2-ヒドロキシ 3 ヒドロキシイミノエチリデン一 2, 7, 12, 18—テトラメチルクロリン四ナトリウム [以下 、ATX—S10·Na (Π)と略記する場合もぁる]、 (2S, 3S)— 18 カルボキシ—20— カルボキシメチルー 13 ェチルー 3, 7, 12, 17—テトラメチルー 8 ビニルクロリン — 2— [N— (1S) - (1, 2—ジカルボキシ)ェチル]プロピオナミド四ナトリウム [以下、 NPe6またはタラポルフィリンナトリウムと記載する場合もある]、プロトポルフィリン IX、 へマトポルフィリンカ 選択されるものである上記に記載の PDT用非水性軟膏又は 坐剤である。 [0012] In a more specific aspect of the present invention, the chlorin derivative or porphyrin derivative may be 13, 17-bis [( 1, 2 dicarboxyethyl) rubamoylethyl] 8 etyr-2-hydroxy 3 hydroxyiminoethylidene 1, 7, 12, 18-tetramethylchlorine tetrasodium [hereinafter abbreviated as ATX-S10 · Na (Π) MOR], (2S, 3S) —18 Carboxy-20—Carboxymethyl-13 Ethyl 3, 7, 12, 17—Tetramethyl-8 Vinylchlorin — 2— [N— (1S)-(1, 2-Dicarboxy ) Ethyl] propionamide tetrasodium [hereinafter sometimes referred to as NPe6 or talaporphyrin sodium], protoporphyrin IX, hematoporphyrinka is a nonaqueous ointment or suppository for PDT as described above. .
[0013] さらに本発明は、より具体的には、非水性軟膏基剤が、 FAPG (H)軟膏基剤、 FA PG (K)軟膏基剤、 PEG軟膏基剤、 PEG— PG軟膏基剤、ワセリン軟膏基剤、 SRヮ セリン軟膏基剤、 SRワセリン IPM軟膏基剤、プラスチベース軟膏基剤力 選択さ れるものである上記に記載の PDT用非水性軟膏である。  [0013] Further, the present invention more specifically, the non-aqueous ointment base is FAPG (H) ointment base, FA PG (K) ointment base, PEG ointment base, PEG-PG ointment base, Vaseline ointment base, SR ヮ serine ointment base, SR petrolatum IPM ointment base, plastibase ointment base force The nonaqueous ointment for PDT as described above.
[0014] また本発明は、さらに具体的には、坐剤の基剤が、疎水性 (親油性)基剤又は親水 性基剤であり、好ましくは、カカオ脂、ウイテツブゾール又はマクロゴールである PDT 用坐剤である。  [0014] Further, in the present invention, more specifically, the suppository base is a hydrophobic (lipophilic) base or a hydrophilic base, preferably cocoa butter, wittebuzole or macrogol. Suppository.
発明の効果  The invention's effect
[0015] 本発明により、製剤学的に安定性に優れ、かつ皮膚浸透性が良好であるクロリン誘 導体又はポルフィリン誘導体を有効成分として含有してなる PDT用の非水性軟膏製 剤及び坐剤が提供される。特に、本発明が提供する軟膏製剤は、皮膚透過性 (経皮 吸収性）が極めて良好であることより、表皮癌、例えば扁平上皮癌等の疾患部位に塗 布することにより、癌細胞に効果的にクロリン誘導体又はボルフイリン誘導体が集積さ れ、レーザー光を照射することにより、癌細胞のみを選択的に破壊することができる。 したがって、本発明は、一つの DDS (ドラッグ 'デリバリー 'システム）の概念に基づく 治療方法に使用する軟膏剤を提供する点で、その医療上の価値は多大なものであ る。  [0015] According to the present invention, there is provided a non-aqueous ointment preparation and a suppository for PDT, which contains a chlorin derivative or a porphyrin derivative having excellent pharmacological stability and good skin permeability as an active ingredient. Provided. In particular, the ointment preparation provided by the present invention has an extremely good skin permeability (percutaneous absorbability), so that it is effective for cancer cells when applied to a diseased site such as epidermis cancer, for example, squamous cell carcinoma. In particular, chlorin derivatives or voruline derivatives are accumulated, and by irradiating with laser light, only cancer cells can be selectively destroyed. Therefore, the present invention has great medical value in that it provides an ointment for use in a treatment method based on the concept of a single DDS (drug 'delivery' system).
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0016] 本発明で提供する軟膏剤及び坐剤にお!ヽて使用するクロリン誘導体又はポルフィ リン誘導体としては、これまで PDTに使用されている各種の誘導体を挙げることがで きる。具体的には、これらのクロリン誘導体又はポルフィリン誘導体としては、 13, 17 —ビス [ ( 1 , 2 ジカルボキシェチル）力ルバモイルェチル] 8 ェテュル 2 ヒド 口キシ一 3 ヒドロキシイミノエチリデン一 2, 7, 12, 18—テトラメチルクロリン四ナトリ ゥム [ATX— S10'Na (II) ]、 (2S, 3S)— 18—カルボキシ— 20—カルボキシメチル — 13 ェチル 3, 7, 12, 17—テトラメチル一 8 ビュルクロリン一 2— [N—(1S) - (1, 2 ジカルボキシ）ェチル]プロピオナミド四ナトリウム [NPe6]、プロトポルフィ リン IXあるいはへマトポルフィリンを挙げることができる。 [0016] Examples of chlorin derivatives or porphyrin derivatives used in the ointments and suppositories provided in the present invention include various derivatives that have been used in PDT so far. wear. Specifically, these chlorin derivatives or porphyrin derivatives include 13, 17-bis [(1, 2 dicarboxyethyl) force rubermoylethyl] 8 etyl 2 hydroxyl 3 hydroxyiminoethylidene 1, 2, 12 , 18-Tetramethylchlorine tetrasodium [ATX— S10'Na (II)], (2S, 3S) — 18-carboxy-20-carboxymethyl — 13 ethyl 3, 7, 12, 17-tetramethyl mono 8 Examples include bulchlorine 1- [N— (1S)-(1,2 dicarboxy) ethyl] propionamide tetrasodium [NPe6], protoporphyrin IX or hematoporphyrin.
[0017] そのなかで、 ATX-SlO-Na (ll)は本発明者らにより提案されているクロリン誘導 体であり、ポルフィマーナトリウムの副作用としての一時的な光過敏症を軽減し、ポル フィマーナトリウムに比較して正常細胞への集積性が認められず、癌細胞のみへの 選択 ·集積性に優れた PDT用クロリン誘導体である。  [0017] Among them, ATX-SlO-Na (ll) is a chlorin derivative proposed by the present inventors, which reduces temporary photosensitivity as a side effect of porfimer sodium. It is a chlorin derivative for PDT that does not show accumulation in normal cells compared to Mer sodium and is excellent in selection and accumulation only in cancer cells.
また、 NPe6 (タラポルフィリンナトリウム）はクロリン誘導体であり、ポルフィマーナトリ ゥムに続く PDT用の治療剤として最近注目されている化合物であり、臨床的にレザフ ィリンの販売名で明治製菓 (株)より提供されて!、る。  NPe6 (Talaporphyrin Sodium) is a chlorin derivative and is a compound that has recently attracted attention as a therapeutic agent for PDT following Porfimanatrium. It is clinically known as Meiji Seika Co., Ltd. under the name of Rezafilin. More provided!
[0018] さらに、プロトポルフィリン IXあるいはへマトポルフィリンは、ポルフィリン誘導体であ り、 PDT用治療剤としてはそれほど効果的なものではないが、本発明の DDS理論に 基づく治療では、ある程度の効果を上げることができる化合物である。本発明にあつ ては、これらのクロリン誘導体又はポルフィリン誘導体に限定されるものではなぐプロ トポルフィリン前駆体であるアミノレブリン酸 (ALA)、血色素由来のポルフィリンから 構造変換された新規クロリン誘導体としてのベンゾボルフィリン誘導体 (BPD)、メタテ トラヒドロキシフエ-ルクロリン (m—THPC)なども挙げることができる。  [0018] Furthermore, protoporphyrin IX or hematoporphyrin is a porphyrin derivative and is not very effective as a therapeutic agent for PDT. However, the treatment based on the DDS theory of the present invention has a certain effect. It is a compound that can. In the present invention, aminolevulinic acid (ALA) which is a protoporphyrin precursor, which is not limited to these chlorin derivatives or porphyrin derivatives, and benzoborphyrin as a new chlorin derivative whose structure has been converted from porphyrin derived from hemoglobin. Derivatives (BPD) and metatetrahydroxyphenol chloride (m-THPC) can also be mentioned.
[0019] さらに本発明者らが提案してぃるATX—S10·Na (Π)にぉぃて、 3位のヒドロキシィ ミノエチリデン基をアルコキシィミノ化、特にエトキシィミノ化したポルフィリン誘導体も 使用することができる。  [0019] Further, according to ATX-S10 · Na (Π) proposed by the present inventors, a porphyrin derivative in which the hydroxyiminoethylidene group at the 3-position is alkoxylimated, particularly ethoxyiminized, is also used. be able to.
[0020] 本発明にあっては、これらのクロリン誘導体又はポルフィリン誘導体のなかでも、 AT X— SlO'Na (II)あるいは NPe6を好適に使用することができる。  [0020] In the present invention, among these chlorin derivatives or porphyrin derivatives, ATX-SlO'Na (II) or NPe6 can be preferably used.
[0021] 本発明者らは、これらのクロリン誘導体又はポルフィリン誘導体を軟膏剤とするにあ つたって、最初に ATX—S10'Na (II)を含有させる有効成分として選択し、 日本薬 局方記載の親水軟膏と同じ軟膏基剤を用いて軟膏製剤を調製し、その製剤学的な 安定性を検討した。 [0021] In order to use these chlorin derivatives or porphyrin derivatives as an ointment, the present inventors first selected them as an active ingredient containing ATX-S10'Na (II). An ointment preparation was prepared using the same ointment base as the hydrophilic ointment described in the pharmacopoeia, and its pharmaceutical stability was examined.
[0022] しかしながら、得られた軟膏製剤の保存安定性を検討したところ、有効成分である ATX-SlO-Na (ll)が経時的に分解することが判明した。この経時的な分解は、他 のクロリン誘導体またはポルフィリン誘導体にも認められるものであって、この原因は However, when the storage stability of the obtained ointment preparation was examined, it was found that ATX-SlO-Na (ll), which is an active ingredient, was degraded over time. This degradation over time is also observed in other chlorin derivatives or porphyrin derivatives.
、軟膏基剤としての親水性に起因して 、るものと考えられた。 This was thought to be due to the hydrophilicity of the ointment base.
[0023] そこで、経時的な製剤の安定性を確保しうる軟膏製剤の処方につ!、て検討したとこ ろ、非水性軟膏基剤が極めて良好な軟膏剤となり得ることを見出したのである。 このような非水性軟膏基剤としては、具体的には、 FAPG (H)軟膏基剤、 FAPG ( K)軟膏基剤、 PEG軟膏基剤、 PEG— PG軟膏基剤、ワセリン軟膏基剤、 SRワセリン 軟膏基剤、 SRワセリン IPM軟膏基剤、プラスチベース軟膏基剤を挙げることがで きる。 [0023] Thus, as a result of studies on the formulation of an ointment preparation that can ensure the stability of the preparation over time, it was found that a non-aqueous ointment base can be a very good ointment. Specific examples of such non-aqueous ointment bases include FAPG (H) ointment base, FAPG (K) ointment base, PEG ointment base, PEG-PG ointment base, petrolatum ointment base, SR Vaseline ointment base, SR petrolatum IPM ointment base, and plastibase ointment base.
[0024] 具体的には、 FAPG (H)軟膏基剤とはステアリルアルコール、ステアリン酸ならびに プロピレングリコール力もなる軟膏基剤である。また、 FAPG (K)軟膏基剤とはステア リルアルコール、ステアリン酸及びポリエチレングリコール 400からなる軟膏基剤であ る。 PEG軟膏基剤とはポリエチレングリコール 400及びポリエチレングリコール 4000 力 なる軟膏基剤であり、 PEG— PG軟膏基剤とはプロピレングリコール及びポリェチ レンダリコール 4000からなる軟膏基剤である。また、ワセリン軟膏基剤とはワセリン及 び流動パラフィン力 なる軟膏基剤であり、 SRワセリン軟膏基剤とは SRワセリン（5% サリチル酸—ワセリン)及び流動パラフィン力もなる軟膏基剤であり、 SRワセリン— IP M軟膏基剤とは SRワセリン及びミリスチン酸イソプロピル力もなる軟膏基剤である。さ らに、プラスチベース軟膏基剤とはプラスチベース（95%の流動パラフィンと 5%のポ リエチレン榭脂)力もなる軟膏基剤である。  [0024] Specifically, the FAPG (H) ointment base is an ointment base that also has stearyl alcohol, stearic acid, and propylene glycol. The FAPG (K) ointment base is an ointment base composed of stearic alcohol, stearic acid and polyethylene glycol 400. The PEG ointment base is an ointment base made of polyethylene glycol 400 and polyethylene glycol 4000, and the PEG-PG ointment base is an ointment base made of propylene glycol and polyethylene glycol 4000. Vaseline ointment base is an ointment base with petrolatum and liquid paraffin, and SR petrolatum ointment base is an ointment base with SR petrolatum (5% salicylic acid-petrolatum) and liquid paraffin. SR petrolatum — IP M ointment base is an ointment base with SR petrolatum and isopropyl myristate. In addition, plastibase ointment base is an ointment base that also has a plastibase (95% liquid paraffin and 5% polyethylene oil) strength.
[0025] なお、本発明で使用する非水性軟膏基剤としては上記のものに限定されず、非水 性軟膏として製剤学的に使用されている軟膏基剤を使用し得ることはいうまでもない 。また、薬剤学的もしくは製剤学的に他の安定剤や経皮吸収促進剤を加えることも許 容される。  [0025] It should be noted that the non-aqueous ointment base used in the present invention is not limited to those described above, and it goes without saying that an ointment base used pharmaceutically as a non-aqueous ointment can be used. Absent . It is also acceptable to add other stabilizers or transdermal absorption enhancers pharmacologically or pharmacologically.
[0026] 本発明にお 、て、これらの非水性軟膏基剤に含有させるクロリン誘導体又はボルフ ィリン誘導体の配合量は、配合された有効成分であるクロリン誘導体又はポルフィリン 誘導体が経皮吸収され、疾患部位に蓄積され、レーザー光線の照射により標的細胞 を死滅させるのに十分な量が配合されればよい。本発明者らの検討によれば、その 配合量は、製剤重量をベースとして 0. 01〜： LO重量％であれば、十分な効果が得ら れることが判明した。 [0026] In the present invention, the chlorin derivative or Borf contained in these non-aqueous ointment bases The chlorin derivative or the porphyrin derivative, which is a compounded active ingredient, is absorbed percutaneously and accumulates at the diseased site, and if the compound is added in an amount sufficient to kill the target cell by laser irradiation. Good. According to the study by the present inventors, it was found that a sufficient effect can be obtained if the blending amount is 0.01 to LO weight% based on the formulation weight.
[0027] 配合量が 0. 01重量％未満であると目的とする治療効果を上げることができず、ま た 10. 0重量％以上配合させてもそれ以上の効果は得られな力つた。  [0027] If the blending amount is less than 0.01% by weight, the intended therapeutic effect cannot be improved, and even if it is blended more than 10.0% by weight, no further effect can be obtained.
なお、配合量は含有させる有効成分の種類により一概に特定することはできず、ま た、含有させる有効成分の安定性は有効成分の濃度、用いる軟膏基剤に大きく影響 されないため、上記の含有量の範囲内で、用途に合わせ種々変更させることが可能 である。そのなかでも、有効成分として ATX— SlO'Na (II)を使用する場合には、 0 . 5重量％程度含有させることで、製剤学的な安定性も良好な、特に好ましい製剤が 得られることが判明した。  The compounding amount cannot be specified in general depending on the type of active ingredient to be contained, and the stability of the active ingredient to be contained is not greatly affected by the concentration of the active ingredient and the ointment base to be used. It is possible to make various changes according to the application within the range of the amount. Among them, when ATX-SlO'Na (II) is used as an active ingredient, a particularly preferable preparation with good pharmacological stability can be obtained by adding about 0.5% by weight. There was found.
[0028] 本発明の軟膏製剤を製造するには、汎用されている軟膏製剤の調製法が用いられ 、軟膏基剤中に有効成分であるクロリン誘導体又はポルフィリン誘導体を、均一に混 練すればよい。  [0028] In order to produce the ointment preparation of the present invention, a widely used method for preparing an ointment preparation is used, and a chlorin derivative or a porphyrin derivative, which is an active ingredient, may be uniformly mixed in an ointment base. .
[0029] 以上のようにして得られた本発明の軟膏製剤を PDT療法に使用する場合には、日 光角化症、炎症性角化症、いぼ、表皮癌等の皮膚疾患、例えば扁平上皮癌等の疾 患部位に塗布することにより、効果的にクロリン誘導体又はポルフィリン誘導体が集 積され、その後、その部位をレーザー光線等による光照射により、当該疾患を効果的 に治療することができる。  [0029] When the ointment preparation of the present invention obtained as described above is used for PDT therapy, skin diseases such as actinic keratosis, inflammatory keratosis, warts, epidermis cancer, for example, squamous epithelium By applying to a disease site such as cancer, the chlorin derivative or porphyrin derivative is effectively accumulated, and then the site can be effectively treated by light irradiation with a laser beam or the like.
なお、軟膏の塗布に当たっては、 ODT効果 (密封包帯効果： occlusive dressing tec hnique)を得るために、塗布部位を密閉状態に保つことがより効果的であることが判 明した。  In applying ointment, it was found that it is more effective to keep the application site sealed in order to obtain the ODT effect (occlusive dressing effect).
[0030] 本発明の軟膏剤を塗布した後の疾患部位における光照射に際しては、種々のレー ザ一光、 LED、ランプを使用することができる。例えば、チタンサフアイャレーザー、 半導体レーザー、 OPO—YAGレーザー、キセノンランプ、ハロゲンランプ、メタノレノヽ ライドランプ等を使用することができる。そのなかでも、 670nm付近に吸収波長を持 つクロリン誘導体には半導体レーザーや LEDを用いることがより効果的である。 [0030] Various laser lights, LEDs, and lamps can be used for light irradiation at a diseased site after the ointment of the present invention is applied. For example, a titanium sapphire laser, a semiconductor laser, an OPO-YAG laser, a xenon lamp, a halogen lamp, a methanolenolide lamp, or the like can be used. Among them, the absorption wavelength is around 670 nm. It is more effective to use a semiconductor laser or LED for the chlorin derivative.
[0031] カゝくして、本発明の軟膏製剤を疾患部位に塗布し、有効成分を経皮吸収させた後 、当該疾患部位を光照射することにより、当該疾患を効果的に治療することができる [0031] It is possible to effectively treat the disease by applying the ointment preparation of the present invention to the diseased site and absorbing the active ingredient percutaneously and then irradiating the diseased site with light. it can
[0032] また、本発明の坐剤に関しても、上記した軟膏製剤の調製例を参照にして、製剤学 的に汎用されている坐薬基剤、好ましくは疎水性 (親油性)基剤、親水性基剤等、具 体的にはカカオ脂、ウイテツブゾール、マクロゴールを用い、一般的な坐剤の調製を 適用して、坐剤を調製することができる。 [0032] Also for the suppository of the present invention, referring to the above-mentioned preparation examples of ointment preparations, suppository bases that are widely used in pharmaceutics, preferably hydrophobic (lipophilic) bases, hydrophilic A suppository can be prepared by applying a general suppository preparation using, for example, cacao butter, wittebuzole, or macrogol, such as a base.
実施例  Example
[0033] 以下に本発明を、具体的実施例を説明することよりさらに詳細に説明するが、本発 明はこれら実施例に限定されるものではない。  [0033] The present invention will be described in more detail below by describing specific examples, but the present invention is not limited to these examples.
¾施例 ί :非水敕膏製剤の調製  ¾ Example ί: Preparation of non-aqueous plaster formulation
有効成分として、 ATX— S10'Na (II)、 NPe6、プロトポルフィリン IX及びへマトポ ルフィリンを用い、下記表 1に記載の各種軟膏製剤を常法に従って、調製した。  Using ATX-S10′Na (II), NPe6, protoporphyrin IX and hematoporphyrin as active ingredients, various ointment formulations shown in Table 1 below were prepared according to conventional methods.
[0034] [表 1] [0034] [Table 1]
処方 1 0 1 処方 1 0 2 Formula 1 0 1 Formula 1 0 2
F A P G ( H ) 軟膏 F A P G ( ) 軟膏  F A P G (H) Ointment F A P G () Ointment
テア 25.0 g テア 25 0 g ステア リ ン酸 5 -0g ステア リ ン酸 5 0 g プロ ピ レンダ リ コ一 69.5g P E G 4 0 0 69 5g 有効成分 0.5g 有効成分 0 5 g 全 量 100. Og 全 量 100 ■ g  Thea 25.0 g Thea 250 0 g Stearate 5-0 g Stearate 5 0 g Propylene glycol 69.5 g PEG 4 0 0 69 5 g Active ingredient 0.5 g Active ingredient 0 5 g Total 100. Og Total Amount 100 g
処方 1 0 3 処方 1 0 4  Formula 1 0 3 Formula 1 0 4
P E G軟膏 P E G— P G軟膏  P E G ointment P E G— P G ointment
P E G 4 0 0 69.5 g プロ ピ レンダ リ コ一 69 5g P E G 4 0 0 69.5 g
P E G 4 0 0 0 30. Og P E G 4 0 0 0 30 0g 有効成分 0.5g 有効成分 0 5 g 全 量 100. Og 全 量 100 ■Og P E G 4 0 0 0 30. Og P E G 4 0 0 0 30 0g Active ingredient 0.5g Active ingredient 0 5 g Total amount 100. Og Total amount 100 ■ Og
処方 1 0 5 処方 1 0 6  Formula 1 0 5 Formula 1 0 6
ヮセ リ ン軟膏 S R ワセ リ ン軟膏  ヮ Selin ointment S R Wasselin ointment
ワセ リ ン 69.5 g S R ワセ リ ン 69 5 g 流動パラフィ ン 30. Og 流動パラフィ ン 30 0g 有効成分 0.5g 有効成分 0 5 g 全 量 100. Og 全 量 100 ■Og  Vaseline 69.5 g S R Vaseline 69 5 g Fluid paraffin 30. Og Fluid paraffin 30 0 g Active ingredient 0.5 g Active ingredient 0 5 g Total amount 100. Og Total amount 100 ■ Og
処方 1 0 7 処方 1 0 8  Formula 1 0 7 Formula 1 0 8
S R ワセ リ ン I P M軟膏 プラスチベース軟膏  S R Vaseline I P M Ointment Plastic Base Ointment
S R ヮセ リ ン 69.5 g プラスチベース 99 5 g ミ リ スチン酸イ ソプロ ピル 30. Og 有効成分 0 5 g 有効成分 0.5g  S R ヮ Serine 69.5 g Plastic base 99 5 g Isopropyl myristate 30. Og Active ingredient 0 5 g Active ingredient 0.5 g
全 量 100. Og 全 量 100 ■ 0g  Total amount 100. Og Total amount 100 ■ 0g
[0035] 実施例 2：軟膏製剤の安定件試験 [0035] Example 2: Stable test of ointment preparation
上記で得られた軟膏製剤を、アルミチューブに封入し、 40°CZ2週間保存し、有効 成分の純度を HPLCにより測定し、その安定性を評価した。純度は、 HPLCによる面 積百分率により求め、保存開始前の純度と、 40°CZ2週間保存後の純度を求めた。 それらの結果を下記表 2〜表 5にそれぞれ示した。  The ointment preparation obtained above was sealed in an aluminum tube, stored at 40 ° CZ for 2 weeks, and the purity of the active ingredient was measured by HPLC to evaluate its stability. The purity was determined by the area percentage by HPLC, and the purity before the start of storage and the purity after storage at 40 ° CZ for 2 weeks were determined. The results are shown in Tables 2 to 5 below.
表 2は、 40°CZ2週間保存のATX—S10·Na(Π)の純度を示し、表 3は、 40°CZ2 週間保存の NPe6の純度を示し、表 4は、 40°CZ2週間保存のプロトポルフィリン IX の純度を示し、表 5は、 40°CZ2週間保存のへマトポルフィリンの純度を示した。  Table 2 shows the purity of ATX-S10 · Na (Π) stored at 40 ° CZ for 2 weeks, Table 3 shows the purity of NPe6 stored at 40 ° CZ for 2 weeks, and Table 4 shows the protocol for storage at 40 ° CZ for 2 weeks. The purity of porphyrin IX was shown, and Table 5 shows the purity of hematoporphyrin stored at 40 ° CZ for 2 weeks.
[0036] [表 2] 処方 軟膏製剤処方 保存前の純度 （％ ) 保存後 の 純度 ( % ) 〇 ) 軟膏 [0036] [Table 2] Formulation Ointment Formulation Purity before storage (%) Purity after storage (%) 〇) Ointment
) 軟膏  ) Ointment
軟膏  Ointment
〇 軟膏  ○ Ointment
ワ セ リ ン軟膏  Waslin ointment
〇 ワ セ リ ン軟膏  〇 Vaseline ointment
ワ セ リ ン 軟膏  Waslin ointment
プラ ス チぺ一 ス軟膏  Plastic tip ointment
[0037] 軟膏製剤における ATX—S10'Na (II)の安定性に関しては、処方 103〜108の 軟膏製剤において安定性に優れたものであることが判明した。 [0037] Regarding the stability of ATX-S10'Na (II) in ointment preparations, it was found that the ointment preparations of formulas 103 to 108 were excellent in stability.
[0038] [表 3]  [0038] [Table 3]
Figure imgf000011_0001
Figure imgf000011_0001
[0039] 軟膏製剤における NPe6の安定性に関しては、処方 101〜108の軟膏製剤におい て高 、安定性が確認された。 [0039] Regarding the stability of NPe6 in the ointment preparation, high stability was confirmed in the ointment preparations of formulations 101 to 108.
[0040] [表 4] [0040] [Table 4]
Figure imgf000011_0002
Figure imgf000011_0002
[0041] 軟膏製剤におけるプロトポルフィリン IXの安定性に関しては、処方 101〜108の軟 膏製剤にお!、て高!、安定性が確認された。 [0041] Concerning the stability of protoporphyrin IX in the ointment preparation, it was confirmed that the ointment preparations of formulas 101 to 108 were very high and stable.
[0042] [表 5] 処方 軟膏製剤処方 保存前の純度 （％ ) 保存後 の 純度 ( % ) 軟膏 [0042] [Table 5] Formulation Ointment Formulation Purity before storage (%) Purity after storage (%) Ointment
軟膏  Ointment
軟膏  Ointment
軟膏  Ointment
ワ セ リ ン軟膏  Waslin ointment
ワ セ リ ン軟膏  Waslin ointment
ワ セ リ ン 軟膏  Waslin ointment
プ ラ ス チ ぺ 一 ス 軟膏  Plastic stripe ointment
[0043] 軟膏製剤におけるへマトポルフィリンの安定性に関しては、処方 101〜108の軟膏 製剤にお 1、て高 \、安定性が確認された。 [0043] With regard to the stability of hematoporphyrin in the ointment preparation, it was confirmed that the ointment preparations of formulas 101 to 108 were highly stable.
[0044] 実施例 3：軟膏製剤の長期安定件試験 [0044] Example 3: Long-term stability test of ointment preparation
有効成分として ATX— SlO-Na (II)を含有する軟膏製剤にお!/、て、処方 103 (PE G軟膏)及び処方 104 (PEG— PG軟膏）について、室温恒温下（25°C)及び冷所 (4 °CZ冷蔵庫)に 6ヶ月間保存し、保存開始前、保存後 1ヶ月、 3ヶ月及び 6ヶ月後 (冷 所保存は、保存後 3及び 6ヶ月後）の安定性 (純度）を、実施例 2と同様に HPLCによ る面積百分率により求めた。  For ointment preparations containing ATX—SlO—Na (II) as an active ingredient! /, For Formula 103 (PE G ointment) and Formula 104 (PEG—PG ointment), at room temperature (25 ° C.) and Store in a cold place (4 ° CZ refrigerator) for 6 months, before start of storage, after storage for 1 month, 3 months and 6 months (stored in cold place after storage after 3 and 6 months) (purity) Was obtained by area percentage by HPLC in the same manner as in Example 2.
その結果を下記表 6及び表 7に示した。  The results are shown in Table 6 and Table 7 below.
表 6は室温恒温下（25°C)における結果を、表 7は冷所 (4°CZ冷蔵庫）における結 果を示した。  Table 6 shows the results at room temperature and constant temperature (25 ° C), and Table 7 shows the results in a cold place (4 ° CZ refrigerator).
[0045] [表 6] [0045] [Table 6]
Figure imgf000012_0001
Figure imgf000012_0001
[0047] 上記の結果力らも判明するように、 2種の軟膏処方にぉ 、て、有効成分である ATX [0047] As shown in the above results, the two types of ointment formulation, ATX which is the active ingredient
-SlO-Na (II)の長期安定性が確認された。 [0048] 実施例 4：皮膚浔诱件試験 (その 1) The long-term stability of -SlO-Na (II) was confirmed. [0048] Example 4: Skin condition test (Part 1)
有効成分として ATX— S10-Na (II)を含有する軟膏製剤にお!/、て、処方 103 (PE G軟膏)及び処方 104 (PEG— PG軟膏)の 2種類について、皮膚浸透性を試験した  In an ointment formulation containing ATX—S10-Na (II) as an active ingredient! /, Skin penetration was tested on two types of formulation 103 (PE G ointment) and formulation 104 (PEG—PG ointment)
[0049] (方法） [0049] (Method)
ヘアレスマウスの背部皮膚にデープを貼付して剥がし取る方法で、傷害を加えた。 皮膚の傷害部及び正常部に 2種の軟膏製剤 [処方 103 (PEG軟膏)及び処方 104 ( PEG— PG軟膏) ]を、小豆大状程度を塗布し、塗布部位を 4時間密閉状態に保った 後表面の軟膏を拭き取った。当該部位の皮膚凍結切片を作成し、蛍光観察 (励起波 長： 400nm、蛍光波長: 670nm)した。  Injury was applied by applying a tape to the back skin of a hairless mouse and peeling it off. Two ointment preparations [Prescription 103 (PEG ointment) and Prescription 104 (PEG-PG ointment)] were applied to the injured and normal areas of the skin, and the application site was kept sealed for 4 hours. The ointment on the back surface was wiped off. A frozen skin section of the site was prepared and observed with fluorescence (excitation wavelength: 400 nm, fluorescence wavelength: 670 nm).
[0050] (結果） [0050] (Result)
その結果を図 1〜図 3に示した。  The results are shown in Figs.
図 1は傷害部位における処方 103 (PEG軟膏)の製剤を塗布した場合の皮膚凍結 切片の蛍光写真であり、図 2は傷害部位における処方 104 (PEG— PG軟膏)の製剤 を塗布した場合の皮膚凍結切片の蛍光写真である。  Fig. 1 is a fluorescence photograph of a frozen section of the skin when prescription 103 (PEG ointment) is applied at the injury site, and Fig. 2 is the skin when prescription 104 (PEG-PG ointment) is applied at the injury site. It is a fluorescence photograph of a frozen section.
また、図 3は正常部位における処方 103 (PEG軟膏)の製剤を塗布した場合の皮膚 凍結切片の蛍光写真であり、図 4は正常部位における処方 104 (PEG— PG軟膏)の 製剤を塗布した場合の皮膚凍結切片の蛍光写真である。  Fig. 3 is a fluorescent photograph of a frozen section of the skin when prescription 103 (PEG ointment) is applied at the normal site, and Fig. 4 is a case when prescription 104 (PEG-PG ointment) is applied at the normal site. It is a fluorescence photograph of a skin frozen section.
[0051] 2種類の処方においては、傷害部位及び正常部位共に有効成分の皮膚浸透性は ほぼ同等であつたが、傷害部位では真皮まで浸透しており、正常部位では角質層ま で浸透し、若干皮膚の表皮に軟膏が残存するが、真皮までは到達していな力つた。 [0051] In the two types of prescriptions, the skin penetration of the active ingredient was almost the same at the injury site and the normal site, but it penetrated to the dermis at the injury site and penetrated to the stratum corneum at the normal site, Some ointment remained in the epidermis of the skin, but it did not reach the dermis.
[0052] 実施例 5：皮膚浔诱件試験 (その 2) [0052] Example 5: Skin condition test (2)
有効成分として ATX— SlO-Na (II)を含有する軟膏製剤にお!/、て、処方 103 (PE G軟膏)の軟膏につ 、て皮膚浸透性を試験した。  The ointment preparation containing ATX—SlO—Na (II) as an active ingredient was tested for skin permeability in the ointment of Formula 103 (PE G ointment).
(方法）  (Method)
ヘアレスマウスの背部に UV—B (装置： DMR—1、 Toshiba— Eizai、蛍光ランプ： FL— 20— SE— 30、東芝）を 3回 Z週で 1力月間照射することにより、皮膚が厚くかさ 力さの日光角化症に近い像が認められた（Actinic keratosisモデル：図 5)。 この方法により、 3ヶ月後で腫瘍が発生し (SCCモデル：図 6)、 4ヶ月後では扁平上 皮癌を発症（図 7)する。 UV-B (apparatus: DMR—1, Toshiba—Eizai, fluorescent lamp: FL—20—SE—30, Toshiba) is irradiated 3 times in Z week for 1 month for 1 month on the hairless mouse. An image similar to actinic keratosis was observed (Actinic keratosis model: Fig. 5). By this method, a tumor develops after 3 months (SCC model: Fig. 6), and after 4 months, squamous cell carcinoma develops (Fig. 7).
一方、ヘアレスマウスの背部に TPA ( 12— O—テトラデカノィルフオルボール 13 —アセテート）を塗布し、炎症を発症させた（乾癬モデル)。  On the other hand, TPA (12-O-tetradecanol phorbol 13-acetate) was applied to the back of hairless mice to cause inflammation (psoriasis model).
これらのモデル動物の患部に、処方 103 (PEG軟膏)の軟膏を小豆大状に塗布し、 塗布部位を 4時間密閉状態に保った後、表面の軟膏を拭き取った。当該部位の皮膚 凍結切片を作成し、蛍光観察 (励起波長: 400nm、蛍光波長: 670nm)した。  An ointment of Formula 103 (PEG ointment) was applied to the affected area of these model animals in a red bean size, the application site was kept sealed for 4 hours, and then the surface ointment was wiped off. A frozen section of the skin at the site was prepared and observed with fluorescence (excitation wavelength: 400 nm, fluorescence wavelength: 670 nm).
[0053] (結果） [0053] (Result)
その結果を図 8〜図 10に示した。  The results are shown in FIGS.
図 8は Actinic keratosisモデル動物の患部における、処方 103 (PEG軟膏）の製剤 を塗布した場合の皮膚凍結切片の蛍光写真であり、図 9は SCCモデル動物の患部 における、処方 103 (PEG軟膏)の製剤を塗布した場合の皮膚凍結切片の蛍光写真 であり、図 10は乾癬モデル動物の患部における、処方 103 (PEG軟膏)の製剤を塗 布した場合の皮膚凍結切片の蛍光写真である。  Fig. 8 is a fluorescence photograph of a frozen skin section of the affected area of an Actinic keratosis model animal when prescription 103 (PEG ointment) is applied, and Fig. 9 is a prescription 103 (PEG ointment) of an affected area of an SCC model animal. FIG. 10 is a fluorescent photograph of a frozen skin section when a preparation of Formula 103 (PEG ointment) is applied in an affected area of a psoriasis model animal.
[0054] 図に示した結果からも判明するように、いずれのモデル動物、すなわち、 Actinic ke ratosisモデル、 SCCモデル、乾癬モデルの患部においても、本発明の有効成分で fe5ATX—S10'Na (II)が真皮まで浸透しているのが理解される。 [0054] As can be seen from the results shown in the figure, fe5ATX-S10'Na (II) is an active ingredient of the present invention in any model animal, that is, in the affected area of the Actinic ke ratosis model, the SCC model, and the psoriasis model. ) Permeates to the dermis.
[0055] me 軟膏製剤の憨効試験  [0055] Efficacy test of me ointment formulation
実施例 5で作成した SCCモデルマウスを使用し、その患部に処方 103 (PEG軟膏） の軟膏を小豆大状に塗布し、塗布部位を 4時間密閉状態に保った。次いで患部表面 の軟膏を拭き取り、上部より半導体レーザー（波長： 670nm;エネルギー： lOOjZcm 2)を照射した。  The SCC model mouse prepared in Example 5 was used, and an ointment of prescription 103 (PEG ointment) was applied to the affected area in a red bean size, and the application site was kept sealed for 4 hours. Next, the ointment on the affected surface was wiped off, and a semiconductor laser (wavelength: 670 nm; energy: lOOjZcm 2) was irradiated from above.
その結果、照射 6日後で、腫瘍部位を消失させることができた。その経緯を図 11〜 図 14に示した。  As a result, the tumor site was able to disappear 6 days after irradiation. The history is shown in Figs.
[0056] 図 11は半導体レーザーの照射前の SCCモデル動物であり、図 12は半導体レーザ 一の照射 1日後の様子を、図 13は半導体レーザーの照射 3日後の様子を、また図 1 4は半導体レーザーの照射 6日後の様子を示したものである。図中矢印は SCCの発 症患部を示すものであるが、患部の腫瘍部が照射後経時的に消失していく様子が理 解され、照射 6日後では、腫瘍部位が完全に消失している様子が判明する。 [0056] Fig. 11 shows an SCC model animal before the semiconductor laser irradiation, Fig. 12 shows the state one day after the semiconductor laser irradiation, Fig. 13 shows the state three days after the semiconductor laser irradiation, and Figs. This shows the situation after 6 days of semiconductor laser irradiation. The arrow in the figure indicates the affected area of SCC, but it seems that the tumor area of the affected area disappears over time after irradiation. It is understood that the tumor site disappears completely 6 days after irradiation.
産業上の利用可能性  Industrial applicability
[0057] 以上記載のように、本発明は光線力学的療法 (PDT)として使用するクロリン誘導 体又はポルフィリン誘導体についての軟膏製剤を提供するものであり、本発明が提 供する軟膏製剤は、皮膚透過性 (経皮吸収性）が極めて良好である。したがって、日 光角化症、炎症性角化症、いぼ、表皮癌等の皮膚疾患、例えば扁平上皮癌等の疾 患部位に塗布することにより、癌細胞に効果的にクロリン誘導体又はポルフィリン誘 導体が集積される。腫瘍部位に集積されたクロリン誘導体又はポルフィリン誘導体は 、光照射により、癌細胞のみを選択的に破壊することができる。したがって、本発明は 、一つの DDS (ドラッグ 'デリバリー ·システム）の概念に基づく治療方法に使用する 軟膏剤を提供する点で、その医療上の価値は多大なものである [0057] As described above, the present invention provides an ointment preparation for a chlorin derivative or a porphyrin derivative used as photodynamic therapy (PDT), and the ointment preparation provided by the present invention is a skin permeation preparation. The property (percutaneous absorption) is very good. Therefore, chlorin derivatives or porphyrin derivatives can be effectively applied to cancer cells by applying to skin diseases such as actinic keratosis, inflammatory keratosis, warts, epidermoid cancer, eg squamous cell carcinoma. Are accumulated. The chlorin derivative or porphyrin derivative accumulated at the tumor site can selectively destroy only cancer cells by light irradiation. Therefore, the present invention has great medical value in that it provides an ointment for use in a treatment method based on the concept of a single DDS (Drug 'Delivery System).
図面の簡単な説明  Brief Description of Drawings
[0058] [図 1]実施例 4における、傷害部位へ処方 103 (PEG軟膏)の製剤を塗布した場合の 皮膚凍結切片の蛍光写真である。  FIG. 1 is a fluorescence photograph of a frozen skin section when a preparation of Formula 103 (PEG ointment) is applied to an injury site in Example 4.
[図 2]実施例 4における、傷害部位へ処方 104 (PEG— PG軟膏)の製剤を塗布した 場合の皮膚凍結切片の蛍光写真である。  FIG. 2 is a fluorescence photograph of a frozen skin section when a preparation of Formula 104 (PEG-PG ointment) is applied to an injury site in Example 4.
[図 3]実施例 4における、正常部位へ処方 103 (PEG軟膏)の製剤を塗布した場合の 皮膚凍結切片の蛍光写真である。  FIG. 3 is a fluorescence photograph of a frozen skin section when a preparation of Formula 103 (PEG ointment) is applied to a normal site in Example 4.
[図 4]実施例 4における、正常部位へ処方 104 (PEG— PG軟膏)の製剤を塗布した 場合の皮膚凍結切片の蛍光写真である。  FIG. 4 is a fluorescence photograph of a frozen skin section when a preparation of Formula 104 (PEG-PG ointment) is applied to a normal site in Example 4.
[図 5]実施例 5における、 Actinic keratosisモデル動物の写真である。  FIG. 5 is a photograph of an actinic keratosis model animal in Example 5.
[図 6]実施例 5における、 SCCモデル動物の写真である。  FIG. 6 is a photograph of an SCC model animal in Example 5.
[図 7]実施例 5における、扁平上皮癌モデル動物の写真である。  FIG. 7 is a photograph of a squamous cell carcinoma model animal in Example 5.
[図 8]実施例 5における、 Actinic keratosisモデル動物の患部へ処方 103 (PEG軟膏 [Fig. 8] Formulation 103 (PEG ointment) to the affected area of an actinic keratosis model animal in Example 5
)の製剤を塗布した場合の皮膚凍結切片の蛍光写真である。 ) Is a fluorescence photograph of a frozen section of skin when the preparation (1) is applied.
[図 9]実施例 5における、 SCCモデル動物の患部へ処方 103 (PEG軟膏)の製剤を 塗布した場合の皮膚凍結切片の蛍光写真である。  FIG. 9 is a fluorescence photograph of a frozen skin section when a preparation of Formula 103 (PEG ointment) is applied to an affected area of an SCC model animal in Example 5.
[図 10]実施例 5における、乾癬モデル動物の患部へ処方 103 (PEG軟膏)の製剤を 塗布した場合の皮膚凍結切片の蛍光写真である。 [FIG. 10] In Example 5, the formulation 103 (PEG ointment) was applied to the affected area of psoriasis model animals. It is the fluorescence photograph of the skin frozen section at the time of applying.
[図 11]実施例 6における、半導体レーザーを照射する前の SCCモデル動物の写真 である。 FIG. 11 is a photograph of an SCC model animal before irradiation with a semiconductor laser in Example 6.
[図 12]実施例 6における、半導体レーザーの照射 1日後における SCCモデル動物の 写真である。  FIG. 12 is a photograph of an SCC model animal one day after irradiation with a semiconductor laser in Example 6.
[図 13]実施例 6における、半導体レーザーの照射 3日後における SCCモデル動物の 写真である。  FIG. 13 is a photograph of an SCC model animal 3 days after irradiation with a semiconductor laser in Example 6.
[図 14]実施例 6における、半導体レーザーの照射 6日後における SCCモデル動物の 写真である。  FIG. 14 is a photograph of an SCC model animal 6 days after irradiation with a semiconductor laser in Example 6.

Claims

請求の範囲 The scope of the claims
[1] クロリン誘導体又はポルフィリン誘導体を有効成分として 0. 01〜： LO. 0重量％含有 してなる光線力学療法用（PDT用）の非水性軟膏製剤又は坐剤。  [1] A non-aqueous ointment formulation or suppository for photodynamic therapy (for PDT) containing 0.01% by weight of LO.
[2] クロリン誘導体またはポルフィリン誘導体が 13, 17 ビス [ (1, 2 ジカルボキシェ チル）力ルバモイルェチル] 8 ェテニル 2 ヒドロキシ一 3 ヒドロキシイミノエチ リデン 2, 7, 12, 18—テトラメチルクロリン四ナトリウム [ATX— S10'Na (II) ]、 (2 S, 3S)— 18—カルボキシ— 20—カルボキシメチル— 13 ェチル—3, 7, 12, 17 —テトラメチル— 8 ビュルクロリン— 2— [N— (1S) - (1, 2 ジカルボキシ）ェチル ]プロピオナミド四ナトリウム [NPe6]、プロトポルフィリン IX、又はへマトポルフィリンか ら選択されるものである請求項 1に記載の PDT用非水性軟膏又は坐剤。  [2] Chlorine derivative or porphyrin derivative is 13, 17 bis [(1,2 dicarboxyethyl) rubamoylethyl] 8 ethenyl 2 hydroxy 1-3 hydroxyiminoethylidene 2, 7, 12, 18-tetramethylchlorine tetrasodium [ATX— S10'Na (II)], (2 S, 3S) — 18-Carboxy-20-Carboxymethyl—13 Ethyl-3, 7, 12, 17 —Tetramethyl—8 Burchlorin— 2— [N— (1S) The nonaqueous ointment or suppository for PDT according to claim 1, which is selected from-(1, 2 dicarboxy) ethyl] propionamide tetrasodium [NPe6], protoporphyrin IX, or hematoporphyrin.
[3] 非水性軟膏基剤が、 FAPG (H)軟膏基剤、 FAPG (K)軟膏基剤、 PEG軟膏基剤 、 PEG— PG軟膏基剤、ワセリン軟膏基剤、 SRワセリン軟膏基剤、 SRワセリン IPM 軟膏基剤又はプラスチベース軟膏基剤力 選択させるものである請求項 1に記載の PDT用非水性軟膏。  [3] Non-aqueous ointment base is FAPG (H) ointment base, FAPG (K) ointment base, PEG ointment base, PEG-PG ointment base, petrolatum ointment base, SR petrolatum ointment base, SR The nonaqueous ointment for PDT according to claim 1, which is selected from petrolatum IPM ointment base or plastic base ointment base power.
[4] 坐剤の基剤が、疎水性 (親油性)基剤又は親水性基剤である請求項 1又は 2に記 載の PDT用坐剤。  [4] The suppository for PDT according to claim 1 or 2, wherein the suppository base is a hydrophobic (lipophilic) base or a hydrophilic base.
[5] 坐剤の基剤が、カカオ脂、ウイテツブゾール又はマクロゴールである請求項 4に記載 の PDT用坐剤。  [5] The suppository for PDT according to claim 4, wherein the base of the suppository is cacao butter, witetbuzole or macrogol.
PCT/JP2006/302031 2005-02-08 2006-02-07 Ointment preparation or suppository for pdt based on chlorin or porphyrin derivative WO2006085517A1 (en)

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Cited By (2)

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EP2702030A1 (en) * 2011-04-27 2014-03-05 Northshore University Healthsystem Compositions and methods
KR101623553B1 (en) 2013-07-23 2016-05-23 동성제약주식회사 Chlorin e6 for the treatment, prevention or improvement of acne

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WO1998014453A1 (en) * 1996-10-01 1998-04-09 Wyeth Lederle Japan, Ltd. Iminochlorinaspartic acid derivatives
JP2004026717A (en) * 2002-06-25 2004-01-29 Photochemical Co Photo-physicochemical diagnostic/therapeutic agent for vascular disease

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014453A1 (en) * 1996-10-01 1998-04-09 Wyeth Lederle Japan, Ltd. Iminochlorinaspartic acid derivatives
JP2004026717A (en) * 2002-06-25 2004-01-29 Photochemical Co Photo-physicochemical diagnostic/therapeutic agent for vascular disease

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2702030A1 (en) * 2011-04-27 2014-03-05 Northshore University Healthsystem Compositions and methods
EP2702030A4 (en) * 2011-04-27 2014-09-10 Univ Northshore Healthsystem Compositions and methods
KR101623553B1 (en) 2013-07-23 2016-05-23 동성제약주식회사 Chlorin e6 for the treatment, prevention or improvement of acne

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