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WO2000032230A1 - Preparations d'immunoglobuline - Google Patents

Preparations d'immunoglobuline Download PDF

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Publication number
WO2000032230A1
WO2000032230A1 PCT/JP1999/006656 JP9906656W WO0032230A1 WO 2000032230 A1 WO2000032230 A1 WO 2000032230A1 JP 9906656 W JP9906656 W JP 9906656W WO 0032230 A1 WO0032230 A1 WO 0032230A1
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WO
WIPO (PCT)
Prior art keywords
cyclodextrin
cyclodextrins
immunoglobulin
group
salt
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1999/006656
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English (en)
Japanese (ja)
Inventor
Rie Okubo
Masahiko Suzuki
Takashi Shiokari
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sankyo Co Ltd
Original Assignee
Sankyo Co Ltd
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 Co Ltd filed Critical Sankyo Co Ltd
Priority to AU14116/00A priority Critical patent/AU1411600A/en
Publication of WO2000032230A1 publication Critical patent/WO2000032230A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to a stable aqueous solution preparation and a freeze-dried preparation of immunoglobulin. [Background technology]
  • immunoglobulins particularly modified ⁇ -globulins
  • ⁇ -globulins have been widely used as pharmaceuticals in the prevention and treatment of infectious diseases.
  • it since it is a protein, it has the disadvantage that it is easily aggregated in aqueous solution by shaking, etc.
  • a stabilized ⁇ -globulin solution for example, by adding polypropylene glycol or poly (ethylene glycol)
  • cyclodextrins have been used as an example of the use of cyclodextrins to suppress aggregation during the dissolution of aqueous protein solutions or freeze-dried products. Inhibition of aggregation of Interieukin 2 and Bovine Insulin (Phram. Res 8 (6), 792-795, 1991) and inhibition of aggregation of Insul i ⁇ (rhem. Pharm. Bull. 45 (3), 525-531, 1997 ), review on coagulation prevention of protein (Phram. Technol.
  • Aqueous immunoglobulin-only preparations show aggregation of immunoglobulin, and freeze-dried immunoglobulin-only preparations have the disadvantage that they are denatured during storage or coagulate when made into aqueous solution at the time of use. Intensively studied to obtain a stable formulation overcoming these drawbacks.
  • cyclodextrins used in the present invention include natural cyclodextrin, modified cyclodextrin, and cyclodextrin polymer.Natural cyclodextrin includes glucose. Cyclic bonds, such as Q-, ⁇ -, y-, ⁇ -, £-, ⁇ - or ⁇ -cyclodextrin, etc.
  • modified cyclodextrin examples include cyclodextrin in which a hydrogen atom of a hydroxyl group of natural cyclodextrin is substituted with various substituents or a salt thereof, for example, an alkyl group.
  • the hydroxyl group of natural cyclodextrin and various acids are esterified.
  • Cyclodextrin or salts thereof for example, cyclodextrin sulfate ester or their salts (sodium salt is also referred to as cyclodextrin sulfate ,.), cyclocodetrin Phosphoric acid esters or their salts, some of them are: (3) Branched cyclodextrins in which the hydroxyl group at the 6-position of glucose constituting natural cyclodextrin and the hydroxyl group of sugars such as glucose and maltose are dehydrated and condensed.
  • the alkylated cyclodextrin is a cyclodextrin in which a hydrogen atom of a hydroxyl group of a natural type silicone dextrin is substituted with an alkyl group having 1 to 6 carbon atoms.
  • Trin a hydrogen atom of a hydroxyl group of a natural type silicone dextrin is substituted with an alkyl group having 1 to 6 carbon atoms.
  • alkylated cyclodextrins include, for example,
  • trimethyl_ ⁇ cyclodextrin triethyl- ⁇ cyclodextrin, dimethylethyl- ⁇ - cyclodextrin, trimethylen- ⁇ -cyclodextrin, triethyl cyclodextrin
  • cyclodextrin such as dimethylethyl-cyclodextrin, trimethyl y-cyclodextrin, triethyl ⁇ - cyclodextrin or dimethylethyl-y-cyclodextrin
  • Trialkylcyclodextrin which is a cyclodextrin substituted with three identical or different alkyl groups per molecule of glucose;
  • the alkyl is preferably an alkyl group having 1 to 4 carbon atoms, for example, a methyl, ethyl, propyl, or butyl group, and more preferably a methyl group or an ethyl group.
  • the modified cyclodextrin is preferably a cyclodextrin composed of 6 to 10 glucoses, for example, one, ⁇ -, ⁇ - , ⁇ or £. Cyclodextrin, more preferably cyclodextrin consisting of 6 to 8 glucoses, ⁇ -, ⁇ -, ⁇ -cyclodextrin.
  • the hydrogen atom of the hydroxyl group in which the alkyl group is not substituted is, for example, the above-mentioned acyl group, carboxyalkyl group, hydroxyalkyl group or sulfoalkyl group. of which may be substituted with a group other than the alkyl group 2
  • the acylated cyclodextrin is a cyclodextrin in which a hydrogen atom of a hydroxyl group of a natural cyclodextrin is substituted with an acyl group having an alkyl moiety having 1 to 6 carbon atoms:
  • acylated cyclodextrins include, for example,
  • the alkyl in the alkyl portion of the above-mentioned acyl group has the same meaning as described above.
  • the modified cyclodextrin also has the same meaning as described above.
  • Mono- or cyclo-cyclodextrin is also used.
  • the hydrogen atom of the hydroxyl group which is not substituted with an acyl group in the amino group is, for example, other than an acyl group such as the above-mentioned alkyl group, carboxyalkyl group, hydroxyalkyl group or sulfoalkyl group.
  • the carboxyalkylated cyclodextrin is a carboxyalkyl group in which the hydrogen atom of the hydroxyl group of natural cyclodextrin has an alkyl moiety having 1 to 6 carbon atoms. It is a substituted cyclodextrin:
  • Such carboxyalkylated cyclodextrins include, for example, carboxymethyl- ⁇ -cyclodextrin, phenolic reboxexil- ⁇ - cyclodextrin, and carboxypropyl- ⁇ -cyclodextrin.
  • preferred alkyl in the alkyl portion of the carboxyalkyl group has the same meaning as described above.
  • preferred modified cyclodextrin has the same meaning as described above.
  • the hydrogen atom of the hydroxyl group which is not substituted with a carboxyalkyl group is, for example, a carboxy group such as the above-mentioned alkyl group, acyl group, hydroxyalkyl group or sulfoalkyl group. It may be substituted with a group other than an alkyl group.
  • the above-mentioned hydroxyalkylated cyclodextrin is a cyclodextrin in which a hydrogen atom of a hydroxyl group of natural cyclodextrin is substituted with a hydroxyalkyl group having an alkyl moiety having 1 to 6 carbon atoms. It is.
  • Such hydroxyalkylated cyclodextrins include, for example, hydroxymethyl- ⁇ - cyclodextrin, 2—hydroxyxethyl- ⁇ -cyclodextrin, and 2—hydroxypropyl.
  • the alkyl in the alkyl portion of the above hydroxyalkyl group has the same meaning as described above.
  • the modified cyclodextrin also has the same meaning as described above.
  • the hydrogen atom of the hydroxy group which is not substituted with the hydroxyalkyl group is, for example, the above-mentioned alkyl group, acyl group, carboxyalkyl group or sulfoalkyl group. And the like.
  • the above-mentioned sulfoalkylated cyclodextrin means that the hydrogen atom of the hydroxyl group of natural cyclodextrin has 1 carbon atom.
  • Such cyclodextrins include, for example,
  • tris-norphomethyl- ⁇ -cyclodextrin trisulfoethyl- ⁇ -cyclodextrin, disnorrephomethyl-snorrechotinol- ⁇ -cyclodextrin, tris-norrehomethyl / 3-cyclodextrin Trin, trisulfoethyl-/ 3-cyclodextrin, disnolephomethylsulfoethyl _ -cyclodextrin, trisnorehomethyl- ⁇ - cyclodextrin, trisulfoethyl - ⁇ -Cyclodextrin or cyclosdextrin such as disulfomethylsulfoethyl- ⁇ -cyclodextrin, etc. Cyclodextrin substituted with three same or different three sulfoalkyl groups per glucose molecule A trisulfoalkylcyclodextrin;
  • the alkyl in the alkyl portion of the sulfoalkyl group has the same meaning as described above.
  • the modified cyclodextrin also has the same significance as described above.
  • the hydrogen atom of the hydroxyl group in which the sulfoalkyl group is not substituted may be, for example, the above-mentioned alkyl group, acyl group, hydroxyalkyl group or carboxyl group. It may be substituted with a substituent other than a sulfoalkyl group such as an alkyl group.
  • salts include, for example, sodium salts, Alkali metal salts such as calcium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.
  • Metal salt ammonium salt; t-octylamine salt, dibenzylamine salt, morpholine salt, dalcosamine salt, phenylidari Synalkyl ester salt, Ethylenediamine salt, x—Methyldalkamine salt, Guadidine salt, Getylamine salt, Triethylamine salt, Dicyclohexylamine salt,
  • cyclodextrin sulfate is a cyclodextrin in which a hydroxyl group of natural cyclodextrin and sulfuric acid are ester-bonded. .
  • Such cyclodextrins include, for example,
  • cyclodextrin One sulfate per glucose molecule that constitutes cyclodextrin, such as ⁇ -cyclodextrin sulfate, 3-cyclodextrin sulfate, and ⁇ -cyclodextrin sulfate A cyclodextrin monosulfate ester;
  • ⁇ -cyclodextrin trisulfate glucose constituting cyclodextrin such as 3-cyclodextrin trisulfate ester and ⁇ -cyclodextrin trisulfate Cyclodextrin trisulfate with three sulfates per molecule;
  • the modified cyclodextrin has the same meaning as described above:
  • the hydrogen atom of the hydroxyl group that does not form sulfate ester is for example, it may be substituted with a displaceable substituent such as the above-mentioned alkyl group, carboxyalkyl group, acyl group, hydroxyalkyl group or sulfoalkyl group.
  • a displaceable substituent such as the above-mentioned alkyl group, carboxyalkyl group, acyl group, hydroxyalkyl group or sulfoalkyl group.
  • These cyclode Kistrin sulfate can form a salt, and the present invention includes such a salt.
  • Such salts are synonymous with the above salts.
  • the above cyclodextrin phosphate is a cyclodextrin in which the hydroxyl group and the phosphoric acid of the natural cyclodextrin are ester-bonded:
  • Such cyclodextrin phosphates include, for example,
  • Cyclodextrin with one phosphate ester per molecule of glucose constituting cyclodextrin such as ⁇ -cyclodextrin phosphate, ⁇ -cyclodextrin phosphate, and ⁇ -cyclodextrin phosphate Linmonophosphate ester;
  • Cyclodextrin such as ⁇ -cyclodextrin diphosphate,
  • cyclodextrin per molecule of glucose constituting cyclodextrin such as ⁇ -cyclodextrin triphosphate, cyclodextrin triphosphate ester, and cyclodextrin triphosphate Cyclodextrin triphosphate in which three phosphates are present;
  • the present invention includes such salts.
  • branch cyclodextrins are, for example,
  • suitable modified cyclodextrin has the same significance as described above.
  • the hydrogen atom of the hydroxyl group at the 2- or 3-position of the glucose unit constituting the cyclodextrin is, for example, a substituent such as the above-mentioned alkyl group, carboxyalkyl group, acyl group, hydroxyalkyl group or sulfoalkyl group. It may be substituted.
  • These modified cyclodextrins were modified not only with cyclodextrin in which all the glucose molecules constituting cyclodextrin were modified, but also with some glucose molecules in which cyclodextrin was modified.
  • Cyclodextrins also include: In these modified cyclodextrins, all or some of the glucose molecules that make up cyclodextrins contain two or more of the above substituents. Cyclodextrins modified with the above substituents are also included.
  • the cyclodextrin polymer is a polymer of the above-mentioned natural type cyclodextrin, a polymer of modified cyclodextrin, or a natural or modified polymer of a known polymer chain. Copolymer having a dextrin incorporated therein, for example, poly- ⁇ -cyclodextrin, etc.
  • cyclodextrins used in the present invention, preferred is Are modified cyclodextrins, especially alkylcyclodextrins, salts of sulfoalkylcyclodextrins (also referred to as sulfoalkylestercyclodextrins) or salts of cyclodextrin sulfates Of these, dimethyl-cyclodextrin, sulfobutyl!
  • G-cyclodextrin sodium salt also referred to as sulfobutyl ether 1/3 cyclodextrin :
  • immunoglobulin fragments that have been treated with enzymes, modified immunoglobulins that have been chemically modified such as sulfonation and alkylation, and immunoglobulins that have been treated with acids, polyethylene glycol, or ion exchange resins.
  • concentration of cyclodextrins for stabilizing gloprin is from 0.01 to 100% by weight of immunoglobulin relative to 1 part by weight of immunoglobulin. Parts by weight, preferably from 0.1 to 10 parts by weight, and more preferably from 0.5 to 5 parts by weight.
  • the cyclodextrins are used as a freeze-dried product of immunoglobulin. By adding this, the stability of the immunoglobulin in the freeze-dried product over time and the effect of suppressing the aggregation of immunoglobulin when prepared into an aqueous solution for use can be obtained.
  • the cyclodextrins are alkylated cyclodextrins, sulfoalkylated cyclodextrins (also with sulfoalkyl ether cyclodextrins), or salts thereof, and acylated cyclodextrins.
  • the immunity described in (1) or (2) which is phosphorus, carboxyalkylated cyclodextrin, cyclodextrin sulfate, or a salt thereof, or cyclodextrin phosphate, or a salt thereof; Aqueous and lyophilized preparations
  • the cyclodextrin is an alkylated cyclodextrin, a sulfoalkylated cyclodextrin or a salt thereof (also referred to as a sulfoalkyl ether cyclodextrin :) or a cyclodextrin.
  • the aqueous immunoglobulin preparation and the lyophilized preparation according to any one of (1) to (3), wherein
  • Cyclodextrins are dimethyl; 3-cyclodextrin, sulfobutyl
  • the immunoglobulin according to any one of (1) to (4), which is a sodium salt of cyclodextrin sulfate (also known as cyclodextrin sulfate).
  • the cyclodextrins are sodium salts of sulfobutyl / 3-cyclodextrin (also with sulfobutyl ether cyclodextrin): (1) to (5) The aqueous immunoglobulin preparation and the freeze-dried preparation according to any one of 'is there:
  • the present invention The cyclodextrins to be used can be obtained according to the method described in the following literature.
  • natural cyclodextrin is obtained by converting starch into cyclodextrin glycosyltransferase.
  • modified cyclodextrins are naturally-occurring cyclodextrins. It can be produced by chemically modifying phosphorus (Croft AP and Bartsch RA; Tetrahedron 39, 1417, 1983: Synthesis of chemically modir led cyclodextrins);
  • the cyclodextrins can be obtained as commercial products.
  • the immunoglobulin used in the present invention can be obtained according to the method described in the following literature. For example, plasma may be separated and purified using Cohn's cold ethanol fractionation method 6 and 9 (Cohn, E, J. et al; J. Am. Chem. Soc. 68, 459). -475, 1946: Oncley J. es. ETal; J. Am. Chem. Soc. 71, 541-550, 1949), the purified immunoglobulin described above; can be produced by various treatments (Pepsin-treated human immunoglobulin; Schultze HE et al; Deutsche Med. Weinschr.
  • the immunoglobulin can be obtained as a commercial product.
  • the aqueous preparation or lyophilized preparation of the present invention can be prepared using isotonic agents (for example, sodium chloride, glucose, Sugars such as mannitol and saccharose), Stabilizing agents (for example, polyhydric alcohols such as glycerin and propylene glycol), soothing agents (for example, polyhydric alcohols such as albumin, glycerin and propylene glycol, lidocaine hydrochloride, and benzyl alcohol); Inert gases (eg, nitrogen, carbon dioxide, etc.) used to remove dissolved oxygen, antioxidants (eg, sodium bisulfite, sodium pyrosulfite, thiosulfate) It may also contain additives such as sodium, longgarite, L-ascorbic acid, erythorbic acid, etc., and stabilizers (chelates such as EDTA, thioglycolic acid, thioglycerin).
  • the aqueous solution or lyophilized product of the immunoglobulin to which cyclodextrins are added according to the present invention may be added to the aforementioned solution for the purpose of stabilization.
  • Water-soluble polymers such as propylene glycol and / or polyethylene glycol (Phram. Res. 14 (6), 736-741, 1997: J. Pham. Sci. 87 (2), 147-151, 1998 )
  • sugars such as glucose or lactose (Arakawa et al; Parm. Res. 8, 285-291, 1991: Protein-solvent interactons in pharmaceutical formulations: John F. Carpenter et al; Pharm. Res.
  • the aqueous solution preparation of the present invention can be prepared by adding immunoglobulin to an aqueous solution of cyclodextrins, dissolving immunoglobulin and cyclodextrins simultaneously in water, or immunoglobulin. Even if cyclodextrins are added to the aqueous solution (that is, cyclodextrins are added to the aggregated aqueous solution of immunoglobulin), a stabilized aqueous solution of immunoglobulin can be produced. Is prepared by dissolving immunoglobulin in an aqueous solution containing cyclodextrins or dissolving immunoglobulin and cyclodextrins in water simultaneously.
  • the lyophilized preparation of the present invention is prepared by first preparing an aqueous solution containing cyclodextrins and immunoglobulin in the same manner as the above aqueous preparation; producing the aqueous solution, dividing the aqueous solution into vials, and freeze-drying the vials. After leaking with nitrogen gas Examples of the use of this formulation include dissolving it in an aqueous solution as it is, or in the case of a lyophilized formulation, dissolving it in distilled water for injection, adding it to physiological saline, and injecting it intravenously.
  • human immunoglobulin G When used in combination with antibiotics in, for example, no or low ⁇ -globulinemia and severe infectious disease, human immunoglobulin G is usually used for adults. 5,000 to 50,000 mg for children, and 50 to 150 mg / kg for children, but the weight and weight of the stomach, but the age and symptoms;
  • y -Gloprin aqueous solution (Comparative Example 1) and sodium salt of 3-cyclodextrin sulfate (also called cyclodextrin sulfate; S- / 3-CD), dimethyl / 3—cyclodextrin (DM— (3—CD) or sulfobutyl / 3 / 3—Na salt of cyclodextrin (sulfobutyl ether——also known as cyclodextrin, SBE—
  • ⁇ -globulin aqueous solution is added.
  • FIG. 2 Lyophilized preparation of ⁇ -globulin (Comparative Example 2) and sulfoptyl; sodium salt of 3-cyclodextrin (sulfobutyl ether) and 3-cyclodextrin : Absorbance after re-dissolution of freeze-dried preparation of ⁇ -globulin (Example 2) to which was added;
  • Example 1 Production of aqueous solution preparation of ⁇ -globulin to which cyclodextrins were added As cyclodextrins, dimethyl; 3-cyclodextrin (manufactured by Nippon Shokuhin Kako Co., Ltd.), sulfoptyl / 3 —Saturated sodium salt of cyclodextrin (sulfobutyl ether- ⁇ -cyclodextrin):: Trade name: Captiso 1 TM, manufactured by Sidex Inc.
  • ⁇ One globulin (manufactured by Sigma Chemical Company) 5 Omg is dissolved in 5 mL of distilled water for injection (listed in the 13th revision of the Japanese Pharmacopoeia) ( ⁇ -globulin concentration 1%), and an aqueous solution of ⁇ -globulin is prepared. Prepared.
  • Example 2 Production of freeze-dried preparations of 1g- mouth brin to which sodium salt of 8-cyclodextrin is added.
  • a sodium salt of sulfobutyl / 3-cyclodextrin was selected from cyclodextrins, and distilled water for injection (listed in the 13th revised Japanese Pharmacopoeia) was added to prepare a 5% solution- ⁇ — Dissolve 1.0 g of globulin in 20 mL of the above solution / globulin concentration 5. /. ), Filtered through a 0.22 im membrane filter (Mirex GV, manufactured by Nippon Millipore Co., Ltd.), subdivided into 1 mL vials, and freeze-dried (Virtis Genesis 12 freeze-dryer, (Made by VIRTIS).
  • Example 2 The freeze-dried preparations obtained in Example 2 and Comparative Example 2 were observed for the presence or absence of aggregation after re-dissolution and the temporal stability at 40 C.
  • the freeze-dried preparation was dissolved in 1 mL of distilled water, and the absorbance (measurement device: UV-160 PC (manufactured by Shimadzu Corporation); measurement wavelength: 600 nm) was measured as an index of turbidity.
  • the freeze-dried preparation to which sodium salt of sulfobutyl- (3-cyclodextrin was added significantly suppressed the change in the absorbance value, and the effect of preventing the denaturation of ⁇ -globulin over time was observed.

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Abstract

Le problème ici abordé a trait à des préparations en solution aqueuse et lyophilisée d'immunoglobuline présentant une excellente stabilité. Le moyen proposé pour résoudre ce problème a trait à des préparations d'immunoglobuline améliorées du point de vue de la stabilité de l'immunoglobuline dans des solutions aqueuses ou des produits lyophilisés par l'addition de cyclodextrines.
PCT/JP1999/006656 1998-11-30 1999-11-29 Preparations d'immunoglobuline Ceased WO2000032230A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU14116/00A AU1411600A (en) 1998-11-30 1999-11-29 Immunoglobulin preparations

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JP33938198 1998-11-30
JP10/339381 1998-11-30

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WO2000032230A1 true WO2000032230A1 (fr) 2000-06-08

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PCT/JP1999/006656 Ceased WO2000032230A1 (fr) 1998-11-30 1999-11-29 Preparations d'immunoglobuline

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055076A1 (fr) * 2001-01-04 2002-07-18 Daiichi Pharmaceutical Co., Ltd. Preparation pharmaceutique contenant de la cyclodextrine

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BREWSTER MARCUS E. ET AL.: 'use of 2-Hydroxypropyl-beta-cyclodextrin as a Solubilizing and Stabilizing Excipient for Protein Drugs' PHARMACEUTICAL RESEARCH, vol. 8, no. 6, 1991, pages 792 - 795, XP002924542 *
RESSING MAAIKE E. ET AL.: 'The Influence of Sucrose, Dextran and Hydroxypropyl-beta-cyclodextrin as Lyoprotectants for a Freeze-Dried Mouse IgG2a Monoclonal Antibody(MN12)' PHARMACEUTICAL RESEARCH, vol. 9, no. 2, 1992, pages 266 - 270, XP002924539 *
TOKIHIRO KEIICHI ET AL.: 'Varying Effects of Cyclodextrin Derivatives on Aggregation and Thermal Behaviro of Insulin in Aqueous Solution' CHEM. PHARM. BULL., vol. 45, no. 3, March 1997, pages 525 - 531, XP002924540 *
TOTTERMAN ANN M. ET AL.: 'Intestinal Safety of Water-soluble beta-Cyclodextrins in Paediatric Oral Solution of Spironolactone: Effects on Human Intestinal Epithelial Caco-2Cells' J. PHARM. PHARMACOL., vol. 49, no. 1, 1997, pages 43 - 48, XP002924541 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055076A1 (fr) * 2001-01-04 2002-07-18 Daiichi Pharmaceutical Co., Ltd. Preparation pharmaceutique contenant de la cyclodextrine

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