WO1993021918A1 - Emulsion de matieres grasses contenant un ester d'acide gras de rhizoxine - Google Patents

Emulsion de matieres grasses contenant un ester d'acide gras de rhizoxine Download PDF

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Publication number
WO1993021918A1
WO1993021918A1 PCT/JP1993/000505 JP9300505W WO9321918A1 WO 1993021918 A1 WO1993021918 A1 WO 1993021918A1 JP 9300505 W JP9300505 W JP 9300505W WO 9321918 A1 WO9321918 A1 WO 9321918A1
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WO
WIPO (PCT)
Prior art keywords
fat emulsion
fatty acid
average particle
emulsifier
medium
Prior art date
Application number
PCT/JP1993/000505
Other languages
English (en)
Japanese (ja)
Inventor
Masafumi Hisaoka
Atsushi Kurihara
Atsuko Mizota
Seigo Ueda
Wataru Kato
Tomowo Kobayashi
Kazuhiko Sasagawa
Original Assignee
Sankyo Company, Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Publication of WO1993021918A1 publication Critical patent/WO1993021918A1/fr

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to a fat emulsion containing an anticancer substance, and more particularly, to a preparation which remarkably improves the anticancer activity of rhizoxin / fatty acid ester.
  • these preparations can control the release of the drug from the preparation, prevent inactivation of the drug in the body, and provide selective distribution of the drug to the site of action. It is desirable to have characteristics such as the ability to retain the drug locally at the site.
  • One of such preparations is to use a carrier. In other words, this is a method of changing the pharmacokinetics of the drug contained in accordance with the pharmacokinetic characteristics of the carrier.
  • Carriers currently being studied include ribosomes, microcapsules, microspheres, fat emulsions, polymer complexes, and many others.
  • the fat emulsion is easy to include the fat-soluble compound and is relatively easy to prepare, and it is possible to prepare fat particles having different average particle diameters according to the purpose. Formulation with a particle size is easy. Therefore, steroids (Japanese Patent Application Laid-Open No. 57-16818), Prossu Grandin's (Japanese Patent Application Laid-Open No. Hei 1-157094, Japanese Patent Application Laid-Open No. Hei 1-157095) and Fat emulsions such as anticancer agents (Japanese Patent Application Laid-Open No. 59-122422) have been reported, and a certain improvement in therapeutic effect has been recognized.
  • Fat emulsions of anticancer drugs impart selectivity to anticancer drugs because existing anticancer drugs have low selectivity for cancer and have a strong cell killing effect, but also cause damage to normal cells and develop side effects. It is a preparation prepared for the purpose of However, its selective specificity has not yet been fully effective, and complete treatment or prevention of cancer with chemotherapy has not been realized.
  • the present inventors have found that the anti-cancer drug obtained by selecting lysoxine fatty acid ester as the anti-cancer agent and the fat emulsion described below as a fat emulsion has a significantly higher anti-cancer effect than the fat emulsion of the conventional anti-cancer drug 5 '.
  • the present invention was found to have an effect and low toxicity, and completed the present invention.
  • the present invention relates to a fat emulsion comprising
  • Rhizoxin is represented by the following formula and is known in the literature (Journal of Antibiotics (J. Antibiotics), Vol. 37, pp. 354-362, 1989). The compound is known to have anti-tumor activity.
  • One fatty acid ester represented by the following formula is a known compound described in JP-A-62-87.
  • the fat emulsion of the present invention may have any average particle diameter in the range of 200 to 950 nm, but is preferably 200 to 600 nm, more preferably 200 to 400 nm.
  • Examples of the fat emulsion base that forms the fat emulsion of the present invention include vegetable oils such as soybean oil, cottonseed oil, sesame oil, safflower oil, and corn oil; mono-, di-, or triesters of medium- or long-chain fatty acids of glycerin (for example, monoglycera cabronate Single glycerides such as amide, caprylic acid monoglyceride, caproic acid diglyceride, caprylic acid diglyceride, dioctyldecyl triglyceride, caprylic acid triglyceride, medium chain fatty acid triglyceride (trade name Coat Ace MT), hard fats (Mixed glycerides such as pharmazol) can be used singly or as a mixture, and preferably, medium-chain fatty acid triglyceride (trade name: COLOACE) MT), and the concentration of the fat emulsion base is preferably 1 to 30% (V / V
  • the emulsifier for forming the fat emulsion of the present invention As the emulsifier for forming the fat emulsion of the present invention,
  • Phospholipids such as phosphatidylcholine (also known as lecithin), phosphatidylethanolamine, phosphatidylserine, etc. ⁇
  • Polyoxyethylene castor oil esters such as polyoxyethylene castor oil 50, boroxyethylene castor oil 60; polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 (HC 0 Polyoxyethylene hard castor oil esters such as 60); polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan trioleate; polyoxyethylene [42] ⁇ ⁇ Polyoxypropylene [67] glycol, polyoxystyrene [160] polyoxypropylene [301 polyoxypropylene-boroxypropylene copolymer such as glycol; polyoxystyrene stear Polyoxyethylene fatty acid esters, such as polyoxyethylene glycol, polyoxyethylene laurate; Nonionic surfactants such as polyoxyxylene sterol ethers such as ethylene cholesterol ether and polyoxycholestanol ether can be used, and preferred are polyoxyxylene hardened castor oil esters. , Also, ? The
  • emulsifying auxiliaries can be used according to the conditions.
  • suitable stabilizers include glycerin S.
  • suitable tonicity agents include budou sugar and salt.
  • suitable pH regulators include various acid bases (eg, hydrochloric acid, sodium phosphate, sodium acetate). , Sodium hydroxide).
  • the fat emulsion of the present invention can be diluted with an appropriate amount of water after preparation, and the dilution factor is not particularly limited as long as the emulsion is stable, but is preferably 2 to 100 times.
  • composition of the fat emulsion is 0.01-13 ⁇ 4W / V for the rhizoxin fatty acid ester, 0.01-13 ⁇ 4W / V for the emulsion, and 303 ⁇ 4V / V for the emulsifying base.
  • the average particle size is 910nm
  • the average particle size is 600nm
  • the average particle size is 380mn
  • the average particle size is 221nm
  • Medium-chain fatty acid triglyceride is used as a fat emulsion base and poly is used as an emulsifier.
  • the fat emulsion of the present invention can be produced, for example, by the method described in tff.
  • a microfluidizer As a high-pressure emulsifier used for emulsification, a microfluidizer (maximum processing pressure 1
  • Coto Ace MT medium-chain fatty acid triglyceride, manufactured by Nisshin Oil Co., Ltd.
  • the total volume was adjusted to 10 O ml, and the mixture was subjected to oiling three times at a pressure of 140 kg / cm 2 using a high-pressure emulsifier Microfluidizer M-120E to obtain a fat emulsion having an average particle diameter of 910 runs. .
  • a fat emulsion having an average of 600 was obtained in the same manner as in Example 1 except that the number of emulsifications described in Example 1 was changed to 5.
  • a fat emulsion having an average particle size of 22 lrnrn was obtained in the same manner as in Example 3, except that the amount of 2'sochol HC060 described in Example 3 was changed to 500 mg.
  • a fat emulsion having an average particle diameter of 99 nm was obtained in the same manner as in Example 3, except that the amount of Nikkor HC060 described in Example 3 was changed to 400 mg.
  • a fat emulsion having an average particle diameter of 69 nm was obtained in the same manner as in Example 3, except that the amount of Nikkor HC060 described in Example 3 was changed to 1200 mg.
  • the anticancer effect of rhizoxin / fatty acid ester can be remarkably enhanced.
  • the present inventors studied the anticancer effect using the following tumor tissues.
  • new blood vessels having characteristics different from those of normal tissue capillaries develop. Since this new blood vessel is a blood vessel having an incomplete endothelium, it can pass through even a large molecule substance to reach a cancer tissue.
  • many of the capillaries in normal tissues have blood vessels with continuous endothelium and cannot pass large molecular substances.] (Critical Reviews in Therapeutic Drug Carrier Systems, 6, Issue 3, 193, (1989)).
  • there is a structural difference between the two blood vessels and it is thought that the preparation of a fat emulsion having a certain size will make a significant difference, and the tumor selectivity will be obtained. available.
  • Sample preparation-Fat emulsions prepared in Examples 2, 3 and 4, and Comparative Examples 1 and 2 were used as samples 1, 2, 3, 4, and 1, respectively.
  • compound 110 O mg As a positive control of the anticancer effect, compound 110 O mg.
  • Butyl hydroxytoluene 10 mg and nicole HC06060 Omg were dissolved in N, N-dimethylacetamide to make the total amount 1 O O mg.
  • the solution was diluted to an appropriate dilution with a physiological saline solution to prepare a sample X.
  • a physiological saline solution containing no rhizoxin 'fatty acid ester was used as control sample 0.
  • mice Male, 9 weeks old, weighing 19 to 22 g were used as one group, and one group was used per sample.
  • the anticancer activity was evaluated based on (a) the size of the tumor mystery on day, (b) the survival rate of tumor-bearing mice (ILS%: Increase in Life Span), and (c) complete cure on day 120. did.
  • the tumor and the survival rate were calculated from the following equations.
  • Survival rate (111) Median days of survival in the control sample-administered group The anti-cancer activity of each sample was examined at various doses and compared at the obtained optimal dose. That is, the highest dose that did not cause mouse s' death within 10 days after sample administration and reduced body weight to less than 15% was defined as the optimal dose.
  • Table 1 shows the results of the anticancer activity at that time.
  • mice / animal fibrosarcoma of mouse experimental cancer were implanted subcutaneously in the right fovea of each group consisting of 3 animals. Let the cancer cell transplant day be day 0, and 13 B later,
  • Samples 2, 4, ⁇ and X prepared in (1) of Test Example 1 were intravenously administered once.
  • the doses were 60 rag / kg, 15 mg / kg, 4.5 mg / kg, and & mg / kg, respectively, which were the optimal doses at which the anticancer effect of each sample was most strongly exhibited.
  • Rhizoxin cancer tissue - palmitic acid ester concentration the sample 2 as compared with the sample X, 4 and I especially 9 higher was observed trend that forces s in the case of administration, high when given samples 2 and 4 projecting, moreover Showed persistence.
  • the fat emulsion of lysoxine / fatty acid ester with an average particle size of 200 to 950 nm accumulates in cancer cells at a higher concentration than other fibers when administered to a living body, and is extremely selective. It turned out that it could be an excellent control »j.
  • FIG. 1 is a graph showing the accumulation property of a drug on a cancer tissue.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à une émulsion de matières grasses, qui comprend: (a) un ester d'acide gras de rhizoxine, représenté par la formule générale (I) et possédant un diamètre particulaire moyen de 200 à 950 nm, formule dans laquelle n répresente un nombre compris entre 7 et 17; (b) au moins une base d'émulsion de matières grasses, choisie parmi les huiles végétales et des monoglycérides, des diglycérides et des triglycérides d'acides gras synthétiques et semisynthétiques à chaînes moyennes et à chaînes longues; et (c) au moins un agent émulsifiant choisi parmi des phospholipides et des tensioactifs non ioniques. Lorsqu'elle est administrée à un organisme vivant, cette émulsion de matières grasses a une forte tendance à s'accumuler dans les tissus cancéreux, déployant ainsi un excellent effet antitumoral.
PCT/JP1993/000505 1992-04-28 1993-04-20 Emulsion de matieres grasses contenant un ester d'acide gras de rhizoxine WO1993021918A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4/109502 1992-04-28
JP10950292 1992-04-28

Publications (1)

Publication Number Publication Date
WO1993021918A1 true WO1993021918A1 (fr) 1993-11-11

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AU (1) AU3905993A (fr)
WO (1) WO1993021918A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59122423A (ja) * 1982-12-28 1984-07-14 Green Cross Corp:The 制癌剤含有脂肪乳剤
JPS6287A (ja) * 1985-02-28 1987-01-06 Sankyo Co Ltd リゾキシン誘導体
JPH01143834A (ja) * 1987-12-01 1989-06-06 Taisho Pharmaceut Co Ltd 制癌物質を含有する脂肪乳剤
JPH02167217A (ja) * 1988-09-29 1990-06-27 Shiseido Co Ltd 乳化組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59122423A (ja) * 1982-12-28 1984-07-14 Green Cross Corp:The 制癌剤含有脂肪乳剤
JPS6287A (ja) * 1985-02-28 1987-01-06 Sankyo Co Ltd リゾキシン誘導体
JPH01143834A (ja) * 1987-12-01 1989-06-06 Taisho Pharmaceut Co Ltd 制癌物質を含有する脂肪乳剤
JPH02167217A (ja) * 1988-09-29 1990-06-27 Shiseido Co Ltd 乳化組成物

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