WO1999062958A1 - Derives de cyclodextrine alkyle acyle et leur utilisation en tant qu'excipients pour medicaments - Google Patents

Derives de cyclodextrine alkyle acyle et leur utilisation en tant qu'excipients pour medicaments Download PDF

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Publication number
WO1999062958A1
WO1999062958A1 PCT/JP1999/002806 JP9902806W WO9962958A1 WO 1999062958 A1 WO1999062958 A1 WO 1999062958A1 JP 9902806 W JP9902806 W JP 9902806W WO 9962958 A1 WO9962958 A1 WO 9962958A1
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Prior art keywords
cyd
groups
derivatives
mixture
cyclodextrin derivative
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PCT/JP1999/002806
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English (en)
Inventor
Kaneto Uekama
Fumitoshi Hirayama
Akira Kondo
Hiroshi Kawaji
Masaaki Ohta
Yasuhiro Okamoto
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Janssen Pharmaceutica N.V.
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Priority to AU39547/99A priority Critical patent/AU3954799A/en
Priority to JP2000552168A priority patent/JP2002517521A/ja
Priority to EP99922527A priority patent/EP1084149A1/fr
Publication of WO1999062958A1 publication Critical patent/WO1999062958A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof

Definitions

  • This invention relates to acylated alkylated cyclodextrin derivatives, and a process for preparing the same and use of the same as carriers for medica- ments.
  • Cyclodextrin (hereinafter also referred to as CyD) is an oligosaccharide wherein glucose residues are cyclicly bound by ⁇ -1, 4 bond and composed of 6, 7 or 8 glucose residues, and ones called ⁇ , ⁇ or ⁇ ⁇ CyD are known. Further, so-called branched cyclodextrins (here ⁇ inafter also referred to as branched CyD) are also known wherein glucosyl group(s) or maltosyl group(s) is/are ⁇ -1, 6 bound to one or two of the glucose units of these CyDs.
  • CyDs and branched CyDs have high inclu ⁇ sion ability on certain chemical substances, and are utilized for various uses such as stabilization of unstable substances, retention of volatile substances and solubilization of water-sparingly soluble or insolu ⁇ ble substances, in the pharmaceutical, food and cosmetic fields.
  • ⁇ ⁇ CyD has a solubility in water as comparatively high as 14.5 g/100 mL (25°C) and its hemolytic activity and muscular irritation are lower than those of ⁇ -CyD, but there is a limitation on ⁇ -CyD that the guest compounds of inclusion are limited to small molecules. Further, its price is 30 times as high as that of ⁇ -CyD and it has a disadvantage point also in an economical aspect.
  • ⁇ ⁇ CyD is the best among ⁇ ⁇ , ⁇ - and ⁇ -CyD on the aspect of safety such as hemolytic activity and actions to cause tissular disorder and has inclusion ability equal to that of ⁇ -CyD, but its price is about 100 times as high as that of ⁇ -CyD and there ⁇ fore it has not so been utilized from economical reason. Further, glucosylated or maltosylated branched CyDs rouse interest partially because their solubilities in water are increased compared with the corresponding unbranched CyDs, but they are not always satisfactory in behavior as carriers for the above medicaments.
  • this DM- ⁇ -CyD is extremely easy to dissolve in water and has strong inclusion ability, but has a problem that since its solubility and stability constant strikinly decrease at the side of high tempera ⁇ tures and the dissociation of the medicament from the medicament inclusion composite becomes easy, the desig ⁇ nation of sterilization conditions for the injection is hindered.
  • DM- ⁇ -CyD has a stronger hemolytic activity than ⁇ -CyD, and its action to cause tissular disorder at the time of intramusclular injection is also larger than ⁇ -CyD. This tendency is the same in TM- ⁇ - CyD, and TM- ⁇ -CyD shows intermediate values between DM- ⁇ -CyD and ⁇ -CyD.
  • HP- ⁇ -CyD large improvement is made on the lowering of solubility and the lowering of stability constant at high tempera ⁇ tures, and actions to cause tissular disorder such as hemolytic activity and muscular irritation are also considerably improved compared with ⁇ -CyD, but they are equal to those of ⁇ ⁇ CyD, and it is the state of things that HP- ⁇ -CyD is far inferior to ⁇ -CyD which has the lowest hemolytic activity and muscular irritation among natural CyDs. Uwagama et al.
  • HE- ⁇ -CyD 2-hydroxyethyl ⁇ CyD
  • DHP- ⁇ -CyD 3-dihydroxypropyl-CyD
  • the objects of the invention lie in providing CyD derivatives satisfying the above needs, and providing the actual use of such a CyD derivative as a carrier or delivery tool for sparingly soluble medica ⁇ ments.
  • the present inventors have synthesized various CyD derivatives, and examined their hemolysis-inhibiting action. As a re ⁇ sult, they found that CyDs having an acyl group and an alkyl group together in the molecule are CyD derivatives having a hemolytic activity that is significantly lower even compared with HE- ⁇ -CyD and ⁇ -CyD whose hemolytic activities have hitherto been recognized to be low. It was further recognized that these derivatives suffi ⁇ ciently retain the medicament inclusion ability of the corresponding CyDs. Therefore, according to the invention are provided acylated alkylated CyDs useful as solubilizers, adsorbents or agents having inclusion ability.
  • the acylated alkylated CyD according to the invention is, specifically, an acylated alkylated cyclo- dextrin derivative represented by the formula (I)
  • n is any of integers 6, 7 and 8, and the 1-position and the 4-position of the sugar residues at the both ends are mutually bound by a covalent bond,
  • R , R and R independently represent hy ⁇ drogen atoms, lower alkyl groups or C 2 _ 20 alkanoyl groups, or in some case, represent glucosyl groups or maltosyl groups whose hy ⁇ droxyl group(s) may be replaced with lower alkyloxy group(s) or C 2 combat 20 alkanyloxy group (s) ,
  • any of R , R and R of the number of total 3Xn composed of each n are simultaneously at least one lower alkyl group and at least one acyl group, and the residual groups, when exist, are hydrogen atoms or the glucosyl groups or maltosyl groups of the number of up to at most 2.
  • the degree of substitution of the acyl group and/or alkyl group is different or part thereof are epimerized, depending on starting materials, reaction conditions, etc. for preparing them, or there is also a case where it is convenient to pro ⁇ vide them as a form of a mixture.
  • the acy ⁇ lated alkylated CyD derivatives sufficiently meet the objects of the invention, even in the form of mixtures, and thus such mixtures are also provided by the inven- tion.
  • the acylated alkylated CyD derivatives or mixtures of two or more of the derivatives can effi ⁇ ciently be prepared by acylation reaction using corre ⁇ sponding partially alkylated CyD derivatives as starting materials.
  • a process for preparing an acy ⁇ lated alkylated CyD is also provided by the invention.
  • the acylated alkylated CyD derivatives or mixtures of two or more of the derivatives even if they are derived from ⁇ -CyD, not only show hemolytic activi- ties significantly lower compared with HE- ⁇ -CyD and ⁇ -CyD which have been recognized to have low hemolytic activity, but sufficiently retain the inclusion ability on medicaments which parent ⁇ -CyD inherently has. Moreover, rabbit muscular irritation of the acylated alkylated CyD derivatives is much weaker than that of DM- ⁇ -CyD.
  • acylated alkylated CyD derivatives or use of the derivatives as carriers or delivery tools for water soluble, sparingly water soluble or water insoluble medicaments As a specific embodiment of this use is provided a pharmaceutical preparation which comprises such an acylated alkylated cyclodextrin derivative or mixture of two or more of the derivatives and such a medicament in such a state that they are closely com ⁇ pounded. A process for preparing such a pharmaceutical preparation is also provided.
  • Fig. 1 is the mass spectrum (matrix: metha- nol, glycerol and m-nitrobenzyl alcohol, which is the same hereinafter) of DMA- ⁇ -CyD obtained in Example 1.
  • Fig. 2 is the H-NMR spectrum of DMA- ⁇ -CyD obtained in Example 1.
  • Fig. 3 is the H-NMR spectrum of DMA4- ⁇ -CyD obtained in Example 2.
  • Fig. 4 is the H-NMR spectrum of butyrated DM- ⁇ -CyD obtained in Example 3.
  • Fig. 5 is the H-NMR spectrum of octanoylated DM- ⁇ -CyD obtained in Example 4.
  • Fig. 6 is a drawing showing the results of the hemolytic activity test on various CyD derivatives.
  • the white square (D), black triangle (A), white triangle ( ⁇ ), white circle (O), black circle (•), white inverted triangle (V), and white diamond (O) represent DMA- ⁇ -CyD, DMA4- ⁇ -CyD, ⁇ ⁇ CyD, DM- ⁇ -CyD, TM- ⁇ -CyD, 2-HP- ⁇ -CyD with a degree of substitution (D. S. ) of 4.8 and sulfobutyl ether ⁇ -CyD with a D. S. of 3.5, respectively.
  • Fig. 7 is a graph showing the released amounts of cholesterol from the intact erythrocytes at the time when various CyD derivatives are contacted with erythro ⁇ cytes.
  • the vertical axis represents the released amount (%) of cholesterol supposing that the amount of choles ⁇ terol in all the erythrocytes is 100 %.
  • acylated alkylated in the invention means such a state that an acyl group and an alkyl group exist simultaneously on one molecule. Therefore, in the acylated alkylated CyD derivative in the invention, at least one of the hydroxyl groups in the CyD molecule is converted to an acyl ester, and at least one of the other hydroxyl groups is converted to an alkyl ether.
  • CyD derivative which simultaneously has an acyl group and an alkyl group on the CyD molecule has a significantly lower hemolytic activity than the corresponding CyD, as stated above.
  • a CyD derivative wherein 50 % (e. g, 7 as to ⁇ -CyD) or more of
  • R and R 1 when exist, are hydrogen atoms, or a mixture of two or more of the derivatives.
  • a CyD derivative wherein 50 % or more, particularly about 100% of R and R of the number of total 2Xn are lower alkyl groups,
  • R of the number of n are C 2 _ 20 alkanoyl groups, or a mixture of two or more of the derivatives.
  • acylated alkylated derivative there cas be mentioned a ⁇ -CyD derivative
  • R s and R s are lower alkyl groups and 4 or more of 7 R s are C 2 _ 20 alkanoyl groups, or a mixture of two or more of the derivatives.
  • the mixture there can, for example, be mentioned a mixture of two or more of compounds selected from the group consisting of compounds wherein 7 to 14 of all the R s
  • R 3 and R s are alkyl groups. In this occasion, the number
  • R which is a C 2 _ 20 alkanoyl group is the same or different between the two or more of compounds. However, most preferably, there can be men ⁇
  • the lower alkyl groups include straight-chain or branched alkyl groups having 1 to 6 carbon atoms, but as preferred ones, there can be mentioned methyl, ethyl, n-propyl, isopropyl, n ⁇ butyl, sec-butyl groups, etc. , and further preferred among them is a methyl group.
  • the alkyl part may be straight-chain or branched, and as preferred ones, there can be mentioned acetyl, n-propanoyl, n-butanoyl, n-pentanoyl (or valeryl), n-hexanoyl (or caproyl), n-heptanoyl (or enanthoyl), n-octanoyl (or capryloyl), n-dodecanoyl (or lauroyl), n-tetradecanoyl (or myristoyl) and n-octadecanoyl (or stearoyl) groups, etc. , and, above all, acetyl, n-propanoyl, n-butanoyl and n-hexanoyl are preferred, and further preferred among them is an acetyl group.
  • acylated alkylated CyD derivatives or mixtures of two or more of the derivatives according to the invention there can be mentioned heptakis (2, 6 ⁇ di-0-methyl-3- acetyl)- ⁇ -CyD with a degree of substitution (D. S. ) of 7 at the 3-position (hereinafter referred to as DMA- ⁇ -CyD, and the following abbreviations follow this) and mix ⁇ tures mainly containing this DMA- ⁇ -CyD, or a mixture of acetylated DA- ⁇ -CyDs with a lower substitution (D. S. 3.5-6) at the 3-position.
  • DMA- ⁇ -CyD degree of substitution
  • Such an acylated alkylated CyD of the inven ⁇ tion can be prepared by the following process, as an ⁇ other embodiment of the invention, which comprises reacting a partially alkylated CyD derivative repre- sented by the formula (II)
  • n is any of integers 6, 7 and 8, and the 1-position and the 4-position of the sugar residues at the both ends are mutually bound by a covalent bond,
  • R , R and R independently represent hy ⁇ drogen atoms, lower alkyl groups, glucosyl groups or maltosyl groups, provided that R ,
  • R and R of the number of total 3Xn composed of each n are, simultaneously, at least one lower alkyl group and at least one hydrogen atom, and the number of the glucosyl groups and maltosyl groups is at most 2, or a mixture of the derivatives with an activated C 2 _ 20 alkanoic acid in a polar solvent, if necessary in the presence of a condensing agent.
  • the partially alkylated CyD derivatives of the formula (II) themselves are known or available on the market, but ones prepared according to preparation processes known per se can also be used.
  • acid anhydrides or acid halides (chlorides, bromides) of alkanoic acids can be used, but preferably acid anhydrides can be men- tioned.
  • acid halide it is desirable to make a basic organic amine such as triethylamine coexist as a hydrogen halide-capturing agent, but it is advanta ⁇ geous to use pyridine as a solvent and a hydrogen ha ⁇ lide-capturing agent or condensing agent.
  • the acyl groups of the desired number can be introduced into a compound of the formula (II) by using pyridine in an amount enough to dissolve the CyD reactant and the acid anhydride reactant and carrying out reaction, usually, at a temperature around 80°C for several hours to 72 hours.
  • the desired acylated alkylated CyD derivatives can be isolated and purified from the thus obtained reaction mixture using solvent extraction, various chromatographies, and recrystallization per se known, but as stated above, they can also be separated, in a state of a mixture of two or more of the derivatives, from the reaction solvent and the unreacted reactant or the side reaction products.
  • the reaction mixture is added dropwise into ice water to decompose the excess acid anhydride, and the desired CyD derivative is extracted with chloroform.
  • Sodium carbonate is added to the extract, and the mixture is desalted and subjected to separation and purification using silica gel columns, and if necessary, subjected to recrystallization from an appropriate solvent.
  • the desired CyD derivative can be obtained by concentrating the obtained substance to dryness. The structure of the obtained substance can be confirmed by mass spectrum, elementary analysis, etc.
  • acylated alkylated CyD derivatives or mixtures of the derivatives of the invention have hemolytic activities and muscular irritation significantly lowered, compared with the previous CyDs, and have an action to solubilize water- sparingly soluble or insoluble medicaments at room temperature, and are useful as carriers or delivery tools for such medicaments.
  • a pharmaceutical preparation which comprises such an acylated alkylated CyD deriva ⁇ tive or a mixture of two or more of the derivatives and such a medicament in such a state that they are closely compounded.
  • the "state that they are closely compound ⁇ ed" means such a state that the CyD derivative and the medicament are homogeneously mixed or such a state that the medicament and the CyD derivative form an inclusion compound.
  • the preparation in such a state can be pre ⁇ pared by sufficiently kneading the CyD derivative and the medicament, in an aqueous solvent (including a mixed solvent between methanol, ethanol, acetonitrile, dimethylformamide or the like and water), in such a state that the CyD derivative and the medicament are suspended or dissolved, using a kneader or the like regularly used for the preparation of formulations.
  • the pharmaceutical preparation can be adminis ⁇ tered in an administration form such as parenteral administration, namely intravenous injection, intramus ⁇ cular injection, subcutaneous injection or topical administration to the skin or mucosa. , but administra- tion methods are not limited thereto, and it can also be administered by oral administration.
  • Medicaments or active ingredients applicable to the preparation according to the invention may be any medicaments including water-soluble or sparingly soluble ones, so long as they meet the objects of the invention, but there can, generally, be mentioned water-sparingly soluble or insoluble medicaments, or unstable medica ⁇ ments.
  • compositions according to the present invention are particularly suitable for active ingredients which exert their activ- ity during an extended period of time, i. e. drugs having a half-life of at least several hours.
  • analgesic and anti-inflammatory drugs NSAIDs, flurbiprofen, fentanyl, indomethacin, ketoprofen, nabumetone, paracetamol, piroxicam, tramadol
  • anti- arrhythmic drugs procainamide, quinidine, verapamil
  • antibacterial and antiprotozoal agents amoxicillin, ampicillin, benzathine penicillin, benzylpenicillin, cefaclor, cefadroxil, cefprozil, cefuroxime axetil, cephalexin, chloramphenicol, chloroquine, ciprofloxacin, clarithromycin, clavulanic acid, clindamycin, doxy- xycline, erythromycin, flucloxacillin, halofantrine, isoniazid, kanamycin, lincomycin, mefloquine, mino- cycline, n
  • the compounding ratio between the acylated alkylated CyD and the medicament can be an any ratio so long as it meets the objects, but in view of controlling the re ⁇ lease of the medicament from the preparation, the ratio of the acylated alkylated CyD : the medicament can be made to be 1 : 4 to 4 : 1, preferably 1 : 2 to 2 : 1, in terms of mole ratio.
  • auxiliaries or additives can, if necessary, be incorporated in a range not to have bad influence on the objects of the invention.
  • auxiliaries or additives there can be mentioned stabilizers, dissolution aids, suspending agents, emul ⁇ sifying agents, buffering agents, preservatives, isotonizing agents, or other proper additives, which are used regularly in the technical field.
  • Example 1 Synthesis of DMA- ⁇ -CyD DM- ⁇ -CyD (12 g) was dissolved in 60 mL of anhydrous pyridine, and 25 mg of 4-dimethylaminopyridine was added. Then, 12 mL of acetic anhydride was gradu ⁇ ally added dropwise, and the mixture was subjected to reaction at 80°C for 24 hours. After the completion of the reaction, the mixture was added dropwise into ice water to decompose the excess acid anhydride, and ex ⁇ tracted with chloroform.
  • Example 2 Synthesis of acetylated DM- ⁇ -CyD with a lower substitution at the 3-position
  • the acetylated DM- ⁇ -CyD was prepared by using a small amount of the acid anhydride (4.6 g, 45 mmol) to DM- ⁇ -CyD (10 g, 7.5 mmol).
  • the other condition of preparation was identical to that described in Example 1, except for the recrystallization due to the face that it was a mixture of components with different D. S. s.
  • the D. S. value was determined by a peak ratio of the CyD ano eric proton (H-l) and the methyl proton of acetyl groups in H-NMR spectra (see Fig. 3), and was 3.8.
  • the mixture is hereinafter referred to as DMA4- ⁇ CyD.
  • Example 3 Synthesis of butyrated DM- ⁇ -CyD
  • DM- ⁇ -CyD (5 g) was dissolved in 25 mL of anhy ⁇ drous pyridine, and 9 mL of n-butyric anhydride was added, and the mixture was subjected to reaction at 80°C for 24 hours. After the completion of the reaction, the mixture was added dropwise into ice water to decompose the excess acid anhydride, and extracted with chloro ⁇ form. Sodium carbonate was added to the extract to desalt it, and the mixture was subjected to separation and purification using a silica gel column. The ob- tained substance was concentrated to dryness to give the desired butyrated DM- ⁇ -CyD. This CyD derivative had a melting point of 108 to 111°C.
  • DMA- ⁇ -CyD was compared with those of the parent ⁇ -CyD and DM- and TM- ⁇ -CyDs.
  • the stability constant between DMA- ⁇ -CyD and flurbiprofen was determined by the solubility method i. e. , according to the method of Higuchi, T. et al. ,
  • the CyD derivative of various concentrations was diluted with 10 mM isotonized phosphate buffer (pH 7.4), and the resultant each dilution was incubated at 37°C. Then 4 mL of this dilution was taken, 0.2 mL of the 5 % erythrocyte suspension was added, and the mix ⁇ ture was incubated at 37°C for 30 minutes. The mixture was centrifuged at 1, 000 g for 5 minutes, 3 mL of the supernatant was measured for absorbance at 543 nm, and thereby its hemolytic activity was determined. Further, the specimen was observed visually using a microscope. The obtained results are shown in Fig. 6.
  • DMA- ⁇ -CyDs were weaker than those of ⁇ -CyD, DM- ⁇ -CyD and TM- ⁇ -CyD.
  • the hemolysis began at about 2 mM, 0.5 mM and 1 mM, and the concentrations to induce 50% hemolysis were about 4 mM, 1 mM and 2 mM for ⁇ -CyD, DM- ⁇ -CyD and TM- ⁇ -CyD, respectively.
  • the hemolysis of DMA4- ⁇ -CyD with D. S. 3.8 began at about 12 mM, and its 50% hemolysis concentration was about 22 mM. In the case of DMA- ⁇ -CyD with D. S.
  • Each DMA- ⁇ -CyD, DMA4- ⁇ -CyD, DM- ⁇ -CyD was di ⁇ luted with 10 mM isotonized phosphate buffer (pH 7.4), and the dilution was incubated at 37°C. Then, 4 mL of the dilution was taken, 0.2 mL of the 5 % erythrocyte suspension was added, and the mixture was incubated at 37°C for 30 minutes. The mixture was centrifuged at 1,000 g for 5 minutes, 5 mL of chloroform was added to 3 mL of the supernatant, and the mixture was shaken for 30 minutes to make extraction. The chloroform layer was taken, and concentrated to give a specimen. The speci ⁇ men was assayed for cholesterol amount using a Choleste ⁇ rol E-Test Wako (made by Wako Pure Chemical Industries, Ltd.). The obtained results are shown in Fig. 7.
  • DM- ⁇ -CyD induced about 80% release of cholesterol at a concentration of 0.5 mM at which the hemolyis only slightly occurred (see Figure 6).
  • DMA- ⁇ -CyDs induced only 10% release of cholesterol at the same concentration, and this release was the same as that of the control experiment conducted in the isotonic buffer.

Abstract

L'invention concerne des dérivés de cyclodextrine possédant au moins un groupe alkyle inférieur et au moins un groupe alcanoyle C2-20 dans la molécule. L'invention se rapporte également à des préparations pharmaceutiques dans lesquelles le dérivé et un médicament se trouvent dans un état dans lequel ils sont fortement composés. Enfin, l'invention concerne un dérivé de cyclodextrine possédant une activité hémolytique réduite et son utilisation en tant qu'excipient pour médicaments.
PCT/JP1999/002806 1998-05-29 1999-05-27 Derives de cyclodextrine alkyle acyle et leur utilisation en tant qu'excipients pour medicaments WO1999062958A1 (fr)

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Application Number Priority Date Filing Date Title
AU39547/99A AU3954799A (en) 1998-05-29 1999-05-27 Acylated alkylated cyclodextrin derivatives and their use as carriers for medicaments
JP2000552168A JP2002517521A (ja) 1998-05-29 1999-05-27 アシル化アルキル化シクロデキストリン誘導体及びその薬物担体としての使用
EP99922527A EP1084149A1 (fr) 1998-05-29 1999-05-27 Derives de cyclodextrine alkyle acyle et leur utilisation en tant qu'excipients pour medicaments

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WO2002102383A1 (fr) * 2001-06-13 2002-12-27 Otsuka Pharmaceutical Factory, Inc. Preparation de cilostazol aqueuse pour injections
WO2003059393A1 (fr) * 2002-01-15 2003-07-24 Altana Pharma Ag Complexes d'inclusion de pantoprazole cyclodextrine
US6835717B2 (en) 2000-03-08 2004-12-28 The Johns Hopkins University School Of Medicine β-cyclodextrin compositions, and use to prevent transmission of sexually transmitted diseases
WO2008009831A2 (fr) * 2006-07-21 2008-01-24 Centre National De La Recherche Scientifique - Cnrs Derives de cyclodextrines amphiphiles
US8785415B2 (en) 2003-03-28 2014-07-22 Ares Trading S.A. Oral formulations of cladribine
WO2017067980A1 (fr) 2015-10-20 2017-04-27 B. Braun Melsungen Ag Composition aqueuse comprenant du dantrolène

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EP0312352A2 (fr) * 1987-10-13 1989-04-19 CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. Dérivés de cyclodextrines et procédés pour les préparer
WO1989009235A1 (fr) * 1988-03-30 1989-10-05 Macherey-Nagel Gmbh & Co. Kg Cyclodextrines substituees et procede de separation chromatographique de composes organiques chiraux

Cited By (12)

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Publication number Priority date Publication date Assignee Title
US6835717B2 (en) 2000-03-08 2004-12-28 The Johns Hopkins University School Of Medicine β-cyclodextrin compositions, and use to prevent transmission of sexually transmitted diseases
US7202231B2 (en) 2000-03-08 2007-04-10 The Johns Hopkins University School Of Medicine β-Cyclodextrin compositions, and use to prevent transmission of sexually transmitted diseases
US7589080B2 (en) 2000-03-08 2009-09-15 The Johns Hopkins University School Of Medicine β-cyclodextrin compositions, and use to prevent transmission of sexually transmitted diseases
WO2002102383A1 (fr) * 2001-06-13 2002-12-27 Otsuka Pharmaceutical Factory, Inc. Preparation de cilostazol aqueuse pour injections
AU2002306329B2 (en) * 2001-06-13 2006-11-30 Otsuka Pharmaceutical Co., Ltd. Aqueous cilostazol preparation for injection
KR100720886B1 (ko) * 2001-06-13 2007-05-22 가부시키가이샤 오츠까 세이야꾸 고죠 주사용 실로스타졸 수성 제제
WO2003059393A1 (fr) * 2002-01-15 2003-07-24 Altana Pharma Ag Complexes d'inclusion de pantoprazole cyclodextrine
US8785415B2 (en) 2003-03-28 2014-07-22 Ares Trading S.A. Oral formulations of cladribine
WO2008009831A2 (fr) * 2006-07-21 2008-01-24 Centre National De La Recherche Scientifique - Cnrs Derives de cyclodextrines amphiphiles
WO2008009831A3 (fr) * 2006-07-21 2008-03-27 Centre Nat Rech Scient Derives de cyclodextrines amphiphiles
WO2017067980A1 (fr) 2015-10-20 2017-04-27 B. Braun Melsungen Ag Composition aqueuse comprenant du dantrolène
US11844782B2 (en) 2015-10-20 2023-12-19 Spepharm Ag Aqueous composition comprising dantrolene

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JP2002517521A (ja) 2002-06-18
AU3954799A (en) 1999-12-20

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