CA-3252151-A1 - HYALURONIC ACID DERIVATIVE, PHARMACEUTICAL COMPOSITION, AND METHOD FOR PRODUCING PHARMACEUTICAL COMPOSITION

CA3252151A1CA 3252151 A1CA3252151 A1CA 3252151A1CA-3252151-A1

Abstract

A hyaluronic acid derivative into which a steryl group is introduced according to the present invention is such that a ratio A1/A2 of areas A1 and A2, calculated by the following method from a chromatogram derived through gel permeation chromatography measurement, is 0.90 or greater. A2 is an area value surrounded by: a curve from an intersection point (Ub), at which a perpendicular line drawn from a refractive index intensity maximum point (Kb) on a chromatogram of 50 kDa polyacrylic acid serving as a standard substance to a baseline (B) intersects a chromatogram of the hyaluronic acid derivative, to the end point of the chromatogram of the hyaluronic acid derivative; a perpendicular line drawn from the refractive index intensity maximum point (Kb) to the baseline (B); and the baseline (B). A1 is an area value surrounded by a curve from the starting point of the chromatogram of the hyaluronic acid derivative to the intersection point (Ub), a perpendicular line drawn from the refractive index intensity maximum point (Kb) to the baseline (B), and the baseline (B).

Inventors

Kohei YABUUCHI
Takashi Nakai
Fumiyasu MOMOSE
Hiroshi (deceased) SHIKU

Assignees

ASAHI KASEI KABUSHIKI KAISHA

Dates

Publication Date: 20260301
Application Date: 20230531
Priority Date: 20220531

Claims (1)

<pat:ClaimStatement>CLAIMS</pat:ClaimStatement> <pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1</pat:ClaimNumber> <pat:ClaimText>1. A hyaluronic acid derivative having an introduced steryl group, wherein a ratio A1/A2 of areas A1 and A2 calculated by a method mentioned below from chromatograms obtained by gel permeation chromatography measurements is 0.90 or more, (i) an intersection point Ub is determined by: a perpendicular line drawn from a maximum point Kb of a refractive index intensity on the chromatogram of a 50 kDa polyacrylic acid serving as a standard substance to a baseline B; and the chromatogram of the hyaluronic acid derivative; and (ii) the area A2 surrounded by: a curve from the intersection point Ub to an end point on the chromatogram of the hyaluronic acid derivative; a perpendicular line drawn from the maximum point Kb of the refractive index intensity to the baseline B; and the baseline is determined, and the area A1 surrounded by: a curve from a starting point to the intersection point Ub on the chromatogram of the hyaluronic acid derivative; the perpendicular line drawn from the maximum point Kb of the refractive index intensity to the baseline B; and the baseline is determined. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00002"> <pat:ClaimNumber>2</pat:ClaimNumber> <pat:ClaimText>2. The hyaluronic acid derivative according to claim 1, wherein a ratio Da/Db of distances Da and Db calculated by a method described below from chromatograms obtained by a gel permeation chromatography measurement is more than 0.00 and 1.20 or less, (i) an intersection point Ba is determined by: a perpendicular line drawn from a maximum point Ka of a refractive index intensity on the chromatogram of a 150 kDa polyacrylic acid serving as a standard substance to the baseline B; and the baseline, and a length La between the maximum point Ka of the refractive index intensity and the intersection point Ba is determined; (ii) among two points at which the refractive index intensity on the chromatogram reaches La/20, one point at which an elution time is earlier is determined as a point R1, and another point at which the elution time is later is determined as a point S1; (iv) an intersection point Ta is determined by: a straight line D1 that connects the point R1 and the point S1; and the perpendicular line drawn from the maximum point Ka of the refractive index intensity to the baseline B, and an intersection point Tb is determined by: the perpendicular line drawn from the maximum point Kb of the refractive index intensity to the baseline B; and the straight line D1; and (v) the distance Da is determined as a distance between the point R1 and the intersection point Ta, and the distance Db is determined as a distance between the intersection point Ta and the intersection point Tb. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00003"> <pat:ClaimNumber>3</pat:ClaimNumber> <pat:ClaimText>3. The hyaluronic acid derivative according to claim 1 or 2, wherein the ratio A1/A2 of the areas A1 and A2 is 1.70 or more. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00004"> <pat:ClaimNumber>4</pat:ClaimNumber> <pat:ClaimText>4. A hyaluronic acid derivative having an introduced steryl group, wherein a ratio Pt/Pr of a retention time Pt at a maximum point of a refractive index intensity of the hyaluronic acid derivative relative to a retention time Pr at a maximum point of a refractive index intensity of a 50 kDa polyacrylic acid as a standard substance, calculated from chromatograms obtained by gel permeation chromatography measurements, is 0.5 or more and less than 1.0. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00005"> <pat:ClaimNumber>5</pat:ClaimNumber> <pat:ClaimText>5. A hyaluronic acid derivative having an introduced steryl group, wherein a weight-average molecular weight of the hyaluronic acid derivative is 110,000 or more and less than 500,000, the weight-average molecular weight being calculated from a chromatogram obtained by a gel permeation chromatography measurement based on a calibration curve obtained using polyacrylic acids having a molecular weight of 2 kDa, 4 kDa, 8 kDa, 18 kDa, 40 kDa, or 150 kDa as standard substances. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00006"> <pat:ClaimNumber>6</pat:ClaimNumber> <pat:ClaimText>6. The hyaluronic acid derivative according to claim 1, 4 or 5, wherein the hyaluronic acid derivative comprises at least one repeating unit of general formula (I): [Chemical Formula 1] [Image disponible dans le document PDF, Image available in the PDF document] (I) (in the general formula, each of R1, R2, R3, and R4 is independently selected from the group consisting of a hydrogen atom, <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>1</mn><mo>−</mo><mn>6</mn></mrow></msub><annotation encoding="application/x-tex">C_{1-6}</annotation></semantics></math> alkyls, a formyl and <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>1</mn><mo>−</mo><mn>6</mn></mrow></msub><annotation encoding="application/x-tex">C_{1-6}</annotation></semantics></math> alkylcarbonyls; Z is a direct bond or a peptide linker consisting of 2 to 30 arbitrary amino acid residues; <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msup><mi>X</mi><mn>1</mn></msup><annotation encoding="application/x-tex">X^1</annotation></semantics></math> is a group selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] . [Image disponible dans le document PDF, Image available in the PDF document] -COO-R, -O-COO-R, -S-R, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] -NRb-CO-Yb-S-R, and <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><mrow><mi>−</mi><mi>S</mi><mo>−</mo><mi>S</mi><mo>−</mo><mi>R</mi></mrow><annotation encoding="application/x-tex">-S-S-R</annotation></semantics></math>; each of Ra, Rb and Rc is independently selected from the group consisting of a hydrogen atom, <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>1</mn><mo>−</mo><mn>20</mn></mrow></msub><annotation encoding="application/x-tex">C_{1-20}</annotation></semantics></math> alkyls, amino <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>2</mn><mo>−</mo><mn>20</mn></mrow></msub><annotation encoding="application/x-tex">C_{2-20}</annotation></semantics></math> alkyls and hydroxy <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>2</mn><mo>−</mo><mn>20</mn></mrow></msub><annotation encoding="application/x-tex">C_{2-20}</annotation></semantics></math> alkyls, in an alkyl moiety of which a group selected from the group consisting of -O- and -NRf- may be inserted; <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msup><mi>R</mi><mi>f</mi></msup><annotation encoding="application/x-tex">R^f</annotation></semantics></math> is selected from the group consisting of a hydrogen atom, <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>1</mn><mo>−</mo><mn>12</mn></mrow></msub><annotation encoding="application/x-tex">C_{1-12}</annotation></semantics></math> alkyls, amino <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>2</mn><mo>−</mo><mn>12</mn></mrow></msub><annotation encoding="application/x-tex">C_{2-12}</annotation></semantics></math> alkyls and hydroxy <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>2</mn><mo>−</mo><mn>12</mn></mrow></msub><annotation encoding="application/x-tex">C_{2-12}</annotation></semantics></math> alkyls, in an alkyl moiety of which a group selected from the group consisting of -O- and -NH- may be inserted; R is a steryl group; Y is C2-30 alkylene or (CH2CH2O)m-CH2CH2-, and a group selected from the group consisting of <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><mrow><mi>−</mi><mi>O</mi></mrow><annotation encoding="application/x-tex">-O</annotation></semantics></math>-, <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><mrow><mi>−</mi><mi>N</mi><msup><mi>R</mi><mi>g</mi></msup></mrow><annotation encoding="application/x-tex">-NR^g</annotation></semantics></math>- and <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><mrow><mi>−</mi><mi>S</mi></mrow><annotation encoding="application/x-tex">-S</annotation></semantics></math>-S- may be inserted in the alkylene; <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msup><mi>R</mi><mi>g</mi></msup><annotation encoding="application/x-tex">R^g</annotation></semantics></math> is selected from the group consisting of a hydrogen atom, <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>1</mn><mo>−</mo><mn>20</mn></mrow></msub><annotation encoding="application/x-tex">C_{1-20}</annotation></semantics></math> alkyls, amino <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>2</mn><mo>−</mo><mn>20</mn></mrow></msub><annotation encoding="application/x-tex">C_{2-20}</annotation></semantics></math> alkyls and hydroxy <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>2</mn><mo>−</mo><mn>20</mn></mrow></msub><annotation encoding="application/x-tex">C_{2-20}</annotation></semantics></math> alkyls, in an alkyl moiety of which a group selected from the group consisting of -O- and -NH- may be inserted; <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msup><mi>Y</mi><mi>a</mi></msup><annotation encoding="application/x-tex">Y^a</annotation></semantics></math> is a <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>1</mn><mo>−</mo><mn>5</mn></mrow></msub><annotation encoding="application/x-tex">C_{1-5}</annotation></semantics></math> alkylene; <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msup><mi>Y</mi><mi>b</mi></msup><annotation encoding="application/x-tex">Y^b</annotation></semantics></math> is a <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>2</mn><mo>−</mo><mn>8</mn></mrow></msub><annotation encoding="application/x-tex">C_{2-8}</annotation></semantics></math> alkylene or a <math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><msub><mi>C</mi><mrow><mn>2</mn><mo>−</mo><mn>8</mn></mrow></msub><annotation encoding="application/x-tex">C_{2-8}</annotation></semantics></math> alkenylene; and m is an integer of 1 or more and 100 or less.) </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7</pat:ClaimNumber> <pat:ClaimText>7. The hyaluronic acid derivative according to claim 1, 4 or 5, wherein the steryl group is a cholesteryl group. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00008"> <pat:ClaimNumber>8</pat:ClaimNumber> <pat:ClaimText>8. The hyaluronic acid derivative according to claim 1, 4 or 5, wherein an introduction ratio of the steryl group relative to a disaccharide repeating unit that constitutes the hyaluronic acid derivative is 30% or more and 60% or less. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00009"> <pat:ClaimNumber>9</pat:ClaimNumber> <pat:ClaimText>9. The hyaluronic acid derivative according to claim 1, 4 or 5, wherein the weight-average molecular weight (absolute molecular weight) of the hyaluronic acid derivative is 4,000 or more and 1,000,000 or less. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00010"> <pat:ClaimNumber>10</pat:ClaimNumber> <pat:ClaimText>10. The hyaluronic acid derivative according to claim 9, wherein the weight- average molecular weight (absolute molecular weight) of the hyaluronic acid derivative is 5,000 or more and 25,000 or less. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00011"> <pat:ClaimNumber>11</pat:ClaimNumber> <pat:ClaimText>11. A pharmaceutical composition comprising: a hyaluronic acid derivative of clam 1, 4 or 5; and a medicinal ingredient. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00012"> <pat:ClaimNumber>12</pat:ClaimNumber> <pat:ClaimText>12. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is used to prevent or treat at least one disease selected from the group consisting of cancers, infectious diseases and immune diseases. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00013"> <pat:ClaimNumber>13</pat:ClaimNumber> <pat:ClaimText>13. The pharmaceutical composition according to claim 11, wherein the medicinal ingredient comprises at least one selected from the group consisting of cancer antigens, antigens derived from infectious diseases, and autoantigens in immune diseases, and the pharmaceutical composition further comprises an adjuvant. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00014"> <pat:ClaimNumber>14</pat:ClaimNumber> <pat:ClaimText>14. The pharmaceutical composition according to claim 13, wherein the medicinal ingredient comprises a cancer antigen or an antigen derived from infectious diseases. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00015"> <pat:ClaimNumber>15</pat:ClaimNumber> <pat:ClaimText>15. A method for producing a pharmaceutical composition comprising a hyaluronic acid derivative of claim 1, 4 or 5 and a medicinal ingredient, the method comprising: a preparation step in which the medicinal ingredient is dissolved in an organic solvent or an organic solvent containing water to prepare an oil phase comprising the medicinal ingredient; and a mixing step in which the oil phase and an aqueous phase comprising the hyaluronic acid derivative are mixed such that a mixing ratio of the oil phase and the aqueous phase, based on volume, becomes 20:100 to 0.01:100. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00016"> <pat:ClaimNumber>16</pat:ClaimNumber> <pat:ClaimText>16. The method for producing a pharmaceutical composition according to claim 15, wherein a pH of the aqueous phase comprising the hyaluronic acid derivative is 6.00 or more and 11.00 or less. </pat:ClaimText> </pat:Claim> </pat:Claims>

Description

DESCRIPTION TITLE OF INVENTION: HYALURONIC ACID DERIVATIVE, PHARMACEUTICAL COMPOSITION, AND METHOD FOR PRODUCING PHARMACEUTICAL COMPOSITION TECHNICAL FIELD [0001] The present invention relates to a hyaluronic acid derivative, a pharmaceutical composition, and a method for producing a pharmaceutical composition. The present invention claims priority on the basis of Japanese Patent Application No. 2022-088995 filed in Japan on May 31, 2022, the contents of which are incorporated herein by reference. BACKGROUND ART [0002] In recent years, biopharmaceuticals that contain proteins, peptides, or nucleic acids as active ingredients have been put into practical use, and their number continues to increase year by year. Biopharmaceuticals can fill unmet medical needs that could not be satisfied by conventional small molecular drugs. However, there are problems in that biopharmaceuticals are difficult to be absorbed from the gastrointestinal tract or mucous membranes, are unstable in vivo, and have a short half-life in the blood. Therefore, biopharmaceuticals require frequent administration by injection, which places a heavy burden on both patients and medical personnel. Therefore, drug base materials (base materials of a sustained release drug delivery system) that can encapsulate biopharmaceuticals without impairing pharmacological activity and gradually release active ingredients thereof in vivo are required. [0003] Against such a background, Patent Document 1 proposes a base material for a sustained release drug delivery system, the material being made of a highly safe hyaluronic acid derivative. This hyaluronic acid derivative spontaneously associates in an aqueous solution, can efficiently encapsulate drugs, especially biopharmaceuticals, while maintaining biological activities thereof, and aggregates under physiological saline concentrations (or disperses even under physiological saline concentrations) and exhibits good retention in the blood. When biopharmaceuticals are used as active ingredients, especially, the hyaluronic acid derivative can be used as a carrier that can efficiently encapsulate many drugs while maintaining pharmacological activities thereof, a sustained release carrier into the blood that exhibits a good retention in the blood, or a targeting carrier, and is considered usable as a local (such as subcutaneous) sustained release carrier that allows continuous sustained-release of drugs. [0004] Furthermore, cancer vaccines using the above-mentioned hyaluronic acid derivatives as carriers have also been reported (see, for example, Patent Document 2). Citation List Patent Document [0005] Patent Document 1: International Patent Application Publication No. 2010/053140 Patent Document 2: International Patent Application Publication No. 2020/158771 SUMMARY OF INVENTION Technical Problem [0006] However, the hyaluronic acid derivative used in Patent Document 2 or the like has a broad and non-uniform particle size distribution, and the relationship between the particle size distribution of the hyaluronic acid derivative and its delivery to the immune cells in lymph nodes or activation ability of the immune cells has not been specifically investigated, and there is a room for improvement. [0007] The present invention has been made in view of the above-mentioned circumstances, and provides a hyaluronic acid derivative which exhibits excellent delivery properties to immune cells in lymph nodes and activation ability against the immune cells, when formulated with a medicinal ingredient, as well as a pharmaceutical composition using the hyaluronic acid derivative and a method for producing the same. Solution to Problem [8000] The present invention encompasses the following aspects. (1) A hyaluronic acid derivative having an introduced steryl group, wherein the ratio A1/A2 of areas A1 and A2 calculated by the following method from chromatograms obtained by gel permeation chromatography measurements is 0.90 or more, (i) an intersection point Ub is determined by: a perpendicular line drawn from the maximum point Kb of the refractive index intensity on the chromatogram of a 50 kDa polyacrylic acid serving as a standard substance to the baseline B; and the chromatogram of the hyaluronic acid derivative; and (ii) the area A2 surrounded by: a curve from the intersection point Ub to the end point on the chromatogram of the hyaluronic acid derivative; a perpendicular line drawn from the maximum point Kb of the refractive index intensity to the baseline B; and the baseline is determined, and the area A1 surrounded by: a curve from the starting point to the intersection point Ub on the chromatogram of the hyaluronic acid derivative; the perpendicular line drawn from the maximum point Kb of the refractive index intensity to the baseline B; and the baseline is determined. (2) The hyaluronic acid derivative according to (1), wherein the ratio Da/Db of distances Da and Db calculated by the following method from chromatogra