+

WO1997038969A1 - POLYMERES SENSIBLES AU pH - Google Patents

POLYMERES SENSIBLES AU pH Download PDF

Info

Publication number
WO1997038969A1
WO1997038969A1 PCT/JP1997/001256 JP9701256W WO9738969A1 WO 1997038969 A1 WO1997038969 A1 WO 1997038969A1 JP 9701256 W JP9701256 W JP 9701256W WO 9738969 A1 WO9738969 A1 WO 9738969A1
Authority
WO
WIPO (PCT)
Prior art keywords
lower alkyl
polymer
hydrogen atom
polymerization
glycol dimethacrylate
Prior art date
Application number
PCT/JP1997/001256
Other languages
English (en)
Japanese (ja)
Inventor
Masaru Yoshida
Masaharu Asano
Hideki Omichi
Ryoichi Katakai
Munehiro NEGISHI
Masaharu Miyajima
Original Assignee
Japan Atomic Energy Research Institute
Zeria Pharmaceutical 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 Japan Atomic Energy Research Institute, Zeria Pharmaceutical Co., Ltd. filed Critical Japan Atomic Energy Research Institute
Priority to AU25217/97A priority Critical patent/AU2521797A/en
Publication of WO1997038969A1 publication Critical patent/WO1997038969A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F20/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
    • C08F20/52—Amides or imides
    • C08F20/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F20/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis

Definitions

  • the present invention relates to a novel polymer, and more particularly to a polymer having pH sensitivity, a pharmaceutical base for directing colon delivery by the polymer, and a segment of the polymer.
  • Techniques for selectively releasing drugs in the large intestine include: (1) a formulation coated with amylose, which is degraded by amylase possessed by bacteria in the large intestine (STP Pharma Sci. Y., Vol. 5. 1995); Coating preparation designed to dissolve in the large intestine by having a two-piece covering structure in order to cope with a pH change in the digestive tract in which the increased pH in the lower part is decreased in the large intestine (International Patent Publication WO 94 Z10983) 3 Formulation designed to release the drug in the large intestine by controlling the release time by the amount of coating using a pH-dependent soluble polymer (A1iment. Pharmco 1.Ther., vol.
  • the present invention provides a compound represented by the formula (1) as a segment, Provide a polymer with a polymerization degree of 30 to 5000 (
  • R is a hydrogen atom, lower alkyl, amino lower alkyl, carboxy lower alkyl, mercapto, benzyl or indolemethyl
  • R is a hydrogen atom or lower alkyl
  • m And n represent 0 or an integer of 1 to 15, provided that m and n are not simultaneously 0.
  • the present invention also provides a polymer obtained by crosslinking the above polymer with a crosslinking agent. Furthermore, the present invention provides a pharmaceutical base for directing large intestine delivery by the bolimer of the present invention.
  • the present invention provides a compound represented by the formula (1), which is a segment of the polymer of the present invention.
  • the mode of polymerization of the polymer of the present invention may be either the same type of polymerization of the compound of the formula (1) or the different type of polymerization. In each case, the degree of polymerization is 30 to 5000, preferably 30 to 3000.
  • the polymerization sequence may be any of an alternating type, a random type and a block type.
  • the alternating type of the polymerization sequence is a state in which different molecules are bonded alternately, for example, a bonding form such as one AB AB AB AB—, and the random type is a state having no regularity,
  • a binding form such as one AAB AAABB ABB—
  • the block type refers to a binding form in which A and B monomer units are continuous to some extent and form a block-like arrangement.
  • one A AAA—BBBB—AAA It refers to a binding form such as A-.
  • the lower alkyl in the present invention is an alkyl having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-tert-butyl and the like.
  • a compound in which R1 is a hydrogen atom and m is 0 is preferably used.
  • the cross-linking agent used to form the bridge polymer is a carbon-carbon double bond
  • t and t may be shifted, for example, diethylene glycol dimethacrylate, diethylene glycol diacrylate, triethylene glycol dimethacrylate, Rate, tetradecaethylene glycol dimethacrylate, tetradecaethylene glycol diacrylate, and the like can be preferably used.
  • a catalyst polymerization method As a method for producing the polymer of the present invention, a catalyst polymerization method, a photopolymerization method, an ionizing radiation polymerization method such as an electron beam or an a-beam is appropriately selected and adopted, but any method can be used as long as a desired polymer can be obtained. It is not particularly limited.
  • the polymerization reaction can be carried out in the presence or absence of an organic solvent, water and the like.
  • the polymers of the present invention are characterized by a high sensitivity to pH, i.e. they tend to shrink in the acidic region and swell with increasing pH in the neutral to alkaline region. Therefore, the drug containing the polymer of the present invention as a base is not released due to the contraction of the polymer in the stomach (pH 44), and is gradually released in the small intestine (pH 7.7.5). After swelling, when reaching the large intestine (pH of about 6.5), which has a lower pH than that of the small intestine, the polymer of the present invention is directed to large intestine delivery because the polymer starts to contract again and releases a drug with water. Useful as a drug base.
  • the drug using the polymer of the present invention as a base may be any drug that is required to be selectively released in the large intestine by oral administration, preferably a drug for treating ulcerative colitis, a drug for treating Crohn's disease And steroids and peptides that are inactivated in the stomach and small intestine.
  • the segment for producing the polymer of the present invention is a compound represented by the formula (1).
  • X is an acryloyl group which is a hydrogen atom or a methacryloyl group which is methyl, and the amino acids bonded thereto are glycine and alanine.
  • compounds such as phosphorus, leucine, isoleucine, asparagine, lysine, cystine, phenylalanine, and triptophan, which are singly or plurally combined.
  • the binding amino acid may be any of D-form, L-form and D-L-form.
  • segment compound of the polymer of the present invention examples include acryloylglycine, acryloylu L-alanine, acryloylu D-alanine, and acryloylu D W /
  • the segment compound of the formula (1) which is a raw material for producing the polymer of the present invention, can be produced as follows.
  • L-proline propyl ester hydrochloride (0.5 Omo 1) is converted to tetrahydrofuran ( THF (500 ml) (mixture A), and a mixture of THF 77 ml and triethylamine (0.55 ml) was added dropwise to the solution while stirring under ice cooling (mixture A).
  • the polymer of the present invention can be produced by the following method.
  • the crosslinked polymer can be prepared as follows.
  • AProOiPr (1 Ommo 1), tetradecaethylene glycol dimethacrylate (0.01 mmo 1), and acetone (1 ml) are mixed. 1 hour, 40 at 10 kGy / h. Irradiation in a C, nitrogen atmosphere gave a crosslinked polymer. In this case, the insoluble component in ethanol was converted into a crosslinked polymer by extraction under the boiling point of ethanol. The yield of crosslinked polymer was 99%.
  • the polymer obtained in this way had a degree of polymerization of 30 to 5,000, and showed high sensitivity to pH, which contracts and swells depending on the change in pH.
  • Glycine methyl ester hydrochloride (0. lmol) is dissolved in acetonitrile, and N-methylmorpholine (0. lmo1) and methacrylic acid (0.1 lmol) are sequentially added. While maintaining the temperature of the solution system at 110 ° C, add a mixture of dicyclohexylcarpoimide (0.1 ml) and THF (200 ml). The by-product zinclohexylurea crystals were removed by precipitation with ethyl acetate. Methacryloyl glycine methyl ester (MA-G 1 yOMe) was purified by column chromatography (ethyl acetate / benzene, 1 ⁇ 4).
  • Rf 0.78 (ethyl benzene, 1 ⁇ 2).
  • Methacryloylglycine (MA—G 1 y OH) is obtained by dissolving MA—G 1 y OMe (0.0511 0 1) in 1 ⁇ (501111), and gently converting it into a 1M sodium hydroxide (50 ml) solution. And saturated citric acid was added.
  • Rf 0.34 (ethanol).
  • Example 24 0.02 mmol of a tetradecaethylene glycol dimethacrylate crosslinking agent was added. This solution was degassed with nitrogen gas, and irradiated with 20 kGy at 25 ° C using a beam emitted from a cobalt 60 radiation source to obtain a copolymer.
  • the ⁇ sensitivity of the polymers obtained in Examples 1 to 32 was confirmed by measuring the swelling ratio of the polymer at each pH.
  • Example 25 20 mg of the polymer obtained in Example 25 was incorporated with 4 mg of 5-aminosalicylic acid, incubated at 37 ° C. in a buffer at pH 3.0 for 2 hours, and then incubated in a buffer at pH 7.5. After incubation for an additional hour, the cells were incubated in a buffer at pH 6.5 for 2 hours.
  • the release amount of 5-aminosalicylic acid under each pH condition was 0.1% at pH 3.0, 5% at pH 7.5, and 80% at pH 6.5.
  • Example 35 After incorporation of 40 mg of indomethacin into 20 mg of the polymer obtained in Example 25 and incubation at 37 ° C for 2 hours in a buffer of ⁇ 3.0, then 4 hours in a buffer of ⁇ 7.5 After incubation, the cells were incubated for 2 hours in a buffer of ⁇ 6.5. Under each pH condition, the release of indomethacin was 2% at ⁇ 3.0, 8% at ⁇ 7.5, and 85% at ⁇ 6.5.
  • Example 35 Example 35
  • Example 31 20 Omg of the polymer obtained in Example 31 was incorporated with 2 Omg of 5-aminosalicylic acid and incubated at 37 for 2 hours in a pH 3.0 buffer, then in a pH 7.5 buffer solution. After incubating for 4 hours, the cells were further incubated in a pH 6.5 buffer for 2 hours. The release of 5-aminosalicylic acid under each pH condition was 0.5% at pH 3.0, 2% at pH 7.5, and 50% at pH 6.5.
  • the drug entrapped by the polymer of the present invention was not released at the gastric pH of 3.0, the gel swelled at the lower middle intestine pH of 7.5, and the colon pH was 6 In 5 it was demonstrated that the drug was released in large quantities with shrinkage of the gel.
  • the polymer of the present invention may be useful as a pharmaceutical base for colon delivery.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

L'invention concerne de nouveaux polymères, notamment des polymères sensibles au pH, une base pour médicaments destinés à être administré dans le gros intestin au moyen de ces polymères, et des segments de ceux-ci. Les polymères comprennent des segments d'un composé représenté par la formule générale (1), et sont préparés par polymérisation de segments de types identiques ou différents, et présentent un degré de polymérisation compris entre 30 et 5000; dans la formule, X représente hydrogène ou méthyle; R représente hydrogène, alkyle inférieur, amino-alkyle inférieur, carboxy-alkyle inférieur, mercapto, benzyle ou indoleméthyle; R1 représente hydrogène ou alkyle inférieur; et m et n représentent chacun un nombre entier compris entre 0 et 15, à condition que m et n ne soient pas tous deux égaux à 0.
PCT/JP1997/001256 1996-04-12 1997-04-11 POLYMERES SENSIBLES AU pH WO1997038969A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU25217/97A AU2521797A (en) 1996-04-12 1997-04-11 Ph-sensitive polymers

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9140896 1996-04-12
JP8/91408 1996-04-12

Publications (1)

Publication Number Publication Date
WO1997038969A1 true WO1997038969A1 (fr) 1997-10-23

Family

ID=14025564

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/001256 WO1997038969A1 (fr) 1996-04-12 1997-04-11 POLYMERES SENSIBLES AU pH

Country Status (2)

Country Link
AU (1) AU2521797A (fr)
WO (1) WO1997038969A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000032560A1 (fr) * 1998-12-03 2000-06-08 Pola Chemical Industries Inc. Nouveau compose, polymere prepare a partir de ce compose, et composition renfermant ce polymere
JP2017519098A (ja) * 2014-06-11 2017-07-13 マサチューセッツ インスティテュート オブ テクノロジー 腸溶性エラストマー
JP2021084943A (ja) * 2019-11-26 2021-06-03 株式会社リコー 活性エネルギー線硬化型水性組成物、活性エネルギー線硬化型水性インク、収容容器、像形成装置、像形成方法、硬化物、及び加飾体
US11576859B2 (en) 2015-10-23 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained release of therapeutic agents and methods of use thereof
US11576866B2 (en) 2016-09-30 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained delivery of adamantane-class drugs
US11992552B2 (en) 2015-12-08 2024-05-28 Lyndra Therapeutics, Inc. Geometric configurations for gastric residence systems
US12023406B2 (en) 2017-06-09 2024-07-02 Lyndra Therapeutics, Inc. Gastric residence systems with release rate-modulating films
US12109305B2 (en) 2016-05-27 2024-10-08 Lyndra Therapeutics, Inc. Materials architecture for gastric residence systems

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58501174A (ja) * 1981-07-31 1983-07-21 ティロッツ・ファルマ・アクチエンゲゼルシャフト 経口投与可能な薬剤組成物
JPH0551479A (ja) * 1991-08-23 1993-03-02 Japan Atom Energy Res Inst 環境応答機能を有する多孔性ポリマー膜の製造方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58501174A (ja) * 1981-07-31 1983-07-21 ティロッツ・ファルマ・アクチエンゲゼルシャフト 経口投与可能な薬剤組成物
JPH0551479A (ja) * 1991-08-23 1993-03-02 Japan Atom Energy Res Inst 環境応答機能を有する多孔性ポリマー膜の製造方法

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000032560A1 (fr) * 1998-12-03 2000-06-08 Pola Chemical Industries Inc. Nouveau compose, polymere prepare a partir de ce compose, et composition renfermant ce polymere
US6703468B1 (en) 1998-12-03 2004-03-09 Pola Chemical Industries Inc. Compound, polymer prepared from the compound, and composition comprising the polymer
JP2017519098A (ja) * 2014-06-11 2017-07-13 マサチューセッツ インスティテュート オブ テクノロジー 腸溶性エラストマー
US10413507B2 (en) 2014-06-11 2019-09-17 Massachusetts Institute Of Technology Enteric elastomers
US11576859B2 (en) 2015-10-23 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained release of therapeutic agents and methods of use thereof
US11992552B2 (en) 2015-12-08 2024-05-28 Lyndra Therapeutics, Inc. Geometric configurations for gastric residence systems
US12109305B2 (en) 2016-05-27 2024-10-08 Lyndra Therapeutics, Inc. Materials architecture for gastric residence systems
US11576866B2 (en) 2016-09-30 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained delivery of adamantane-class drugs
US12023406B2 (en) 2017-06-09 2024-07-02 Lyndra Therapeutics, Inc. Gastric residence systems with release rate-modulating films
JP2021084943A (ja) * 2019-11-26 2021-06-03 株式会社リコー 活性エネルギー線硬化型水性組成物、活性エネルギー線硬化型水性インク、収容容器、像形成装置、像形成方法、硬化物、及び加飾体

Also Published As

Publication number Publication date
AU2521797A (en) 1997-11-07

Similar Documents

Publication Publication Date Title
Fetsch et al. Polypeptoids from n-substituted glycine n-carboxyanhydrides: Hydrophilic, hydrophobic, and amphiphilic polymers with poisson distribution
Davaran et al. Release of 5-amino salicylic acid from acrylic type polymeric prodrugs designed for colon-specific drug delivery
CN102079713B (zh) 可交联聚合季铵盐型抗菌单体及其制备方法以及在牙科修复材料中的应用
US5840900A (en) High molecular weight polymer-based prodrugs
AU772653B2 (en) Use of poly(diallylamine) polymers
US5910569A (en) Iodothyronine polymers
US9289510B2 (en) Polymeric drug delivery conjugates and methods of making and using thereof
TW200838553A (en) Polymer encapsulation and/or binding
WO1997038969A1 (fr) POLYMERES SENSIBLES AU pH
CN112029091B (zh) 一种pH/还原双重响应性嵌段共聚物PEG-b-PAsp-g-CPA
EP0087957B1 (fr) Complexes de néocarzinostatine, méthode pour leur production, et agent antitumeur contenant ces complexes comme composant actif
CN111454457B (zh) 一种以树状分子为侧链的手性肽类抗菌聚合物及其制备方法
CN102643420A (zh) 一种异端基双官能团聚烷基醚类化合物及其用途
WO1991006569A1 (fr) Polymeres d'iodothyronine
CN109970831B (zh) 吉西他滨前药化合物、仿生纳米药物载体及其制备方法
CN117586494A (zh) 一种侧链含未保护羟基聚氨基酸及其制备方法
WO2011139752A2 (fr) Préparation de polypeptides et de leurs sels
CN101759855B (zh) pH响应型两亲接枝聚膦腈及其合成方法
WO2010065362A1 (fr) Améliorations apportées à la synthèse de polypeptides pour l'administration de médicaments
EP0536343B1 (fr) Conjugues polymeres cibles de cyclosporine et procede de preparation
Yamada et al. Convenient phosgene-free synthesis of polypeptides bearing reactive alkene moiety through polycondensation of activated urethane derivative of α-amino acid
CA1296459C (fr) Hydrogels a plus grande capacite de charge d'agent actif solubles dans un solvant organique, leur preparation et leur utilisation
JP7560274B2 (ja) 共重合体、該共重合体の製造方法、およびカルボキシ基またはその塩を有する共重合体の製造方法
JPH02124861A (ja) イソポリペプチド及びその製造方法
CN105169405A (zh) 阿霉素类高分子药物的制备方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载