WO2007080898A1 - Preparation d’hydrogel a liberation prolongee - Google Patents

Preparation d’hydrogel a liberation prolongee Download PDF

Info

Publication number
WO2007080898A1
WO2007080898A1 PCT/JP2007/050180 JP2007050180W WO2007080898A1 WO 2007080898 A1 WO2007080898 A1 WO 2007080898A1 JP 2007050180 W JP2007050180 W JP 2007050180W WO 2007080898 A1 WO2007080898 A1 WO 2007080898A1
Authority
WO
WIPO (PCT)
Prior art keywords
galectin
gelatin
sustained
release
mouth gel
Prior art date
Application number
PCT/JP2007/050180
Other languages
English (en)
Japanese (ja)
Inventor
Yasuhiko Tabata
Mahito Hirai
Original Assignee
Medgel Corporation
Institute Of Gene And Brain Science
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 Medgel Corporation, Institute Of Gene And Brain Science filed Critical Medgel Corporation
Publication of WO2007080898A1 publication Critical patent/WO2007080898A1/fr

Links

Classifications

    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

  • the present invention relates to a sustained-release nose-mouth gel preparation containing galectin 1 or a galectin 1 derivative.
  • Patent Document 1 discloses two types of matrices, a matrix formed by blending a biodegradable polymer with a physiologically active substance, and a matrix composed of a biodegradable polymer alone. Sustained release implants are disclosed that are layered or adjacent.
  • JP 2005-511523 includes at least one polycationic polymer complexed with at least one first negative electropharmacologically active agent and is administered to a patient.
  • a sustained release drug delivery composition configured to release the at least one first negatively charged pharmacologically active agent slowly.
  • This document states that the release of a negatively charged (negatively charged) therapeutic agent in its entirety is controlled by the charge interaction between the polycationic polymer and the therapeutic agent. Also described is that this system can be used for the sustained release of negatively charged hydrophilic drugs such as negatively charged oligonucleotides and other active agents having negatively charged peptides and proteins.
  • Patent Document 3 discloses a therapeutic agent for neurological disorders including nerve injury, neurodegeneration, and nerve transplant function decline, comprising galectin 1 or a derivative thereof as an active ingredient. ing.
  • this therapeutic agent contains galectin 1 or a derivative thereof in a collagen gel and, if necessary, other neurotrophic factors. It may be added and embedded directly in the neuropathy local area.
  • necessary components such as a drug and a carrier are enclosed in a tube having a biocompatible material (eg, silicone rubber, collagen, polypropylene, polyester, polyamide, etc.).
  • the release of the negatively charged therapeutic agent is controlled by the charge interaction between the polycationic polymer and the therapeutic agent.
  • the interaction between the negatively charged therapeutic agent and the polycation polymer is not uniquely determined solely by the electrical interaction, various factors such as the size of the molecule and the three-dimensional structure are complicated. It is determined by intertwining. Therefore, even in the sustained release drug delivery composition of Patent Document 2, when galectin 1 is encapsulated, it is difficult to control the elution of galectin 1 in vivo, and it is still difficult to realize sustained release. It was.
  • galectin 1 or a derivative thereof is contained in a collagen gel, and if necessary, other neurotrophic factor is added and directly embedded in the neuropathy locally. Since it was in a form and no special treatment was applied to control the elution of galectin 1, it was still difficult to achieve sustained release.
  • Patent Document 1 Japanese Patent No. 2702729
  • Patent Document 2 Special Table 2005—511523
  • Patent Document 3 International Publication No. 00Z06724
  • the present invention has been made in view of the above circumstances, and a galectin in a living body of a mammal.
  • Controlled release nose mouth gel that can control elution of 1 or galectin 1 derivatives
  • the purpose is to provide a formulation.
  • a sustained-release hide-mouth gel formulation comprising a cationic gelatinoid mouth gel and galectin 1 or a galectin 1 derivative.
  • galectin 1 or galectin 1 derivative interacts with a cationic gelatinoid mouth gel, elution of galectin 1 or galectin 1 derivative can be controlled in the living body of mammals.
  • a sustained-release hide-mouth gel preparation is obtained.
  • the galectin 1 derivative refers to a compound produced by a change in a small part of the galectin 1 molecule.
  • Galectin 1 derivatives include mutant galectin-1 formed by substituting, deleting, or adding one or more amino acid residues in the amino acid sequence of galectin 1.
  • the sustained-release hyde mouth can control the elution of galectin 1 or galectin 1 derivatives in the living body of mammals.
  • a gel formulation is obtained.
  • FIG. 1 is a graph showing the results of an in vitro sustained release test.
  • FIG. 2 is a graph showing the results of an in vivo short-term sustained release test (first time).
  • FIG. 3 is a graph showing the results of an in vivo short-term sustained release test (second time).
  • FIG. 4 is a graph showing the results of an in vivo sustained release test.
  • the cationic gelatin-hyde mouth gel described above has 10% or more and 60% or less of carboxyl groups in the gelatin-hide mouth gel to amino groups. May be substituted.
  • the strength of interaction as a total including electrostatic action between galectin 1 or galectin 1 derivative and cationic gelatino or id mouth gel is within a preferable range.
  • Elution rate of galectin 1 or galectin 1 derivative in the mammalian body It will be within the range suitable for the therapeutic purpose.
  • the cationic gelatin-hide mouth gel may have a water content of 80% or more and 99.8% or less. According to this configuration, the elution rate of galectin 1 or galectin 1 derivative in the mammal's living body falls within a range suitable for therapeutic purposes such as mammalian nerve regeneration.
  • the aforementioned galectin-11 or galectin-11 derivative may comprise recombinant galectin-11.
  • the recombinant galectin 1 refers to a galectin 1 produced by a genetic recombination technique that does not use natural galectin 1.
  • the above-described galectin 1 derivative is substituted, deleted, or added to one or more amino acid residues in the amino acid sequence of galectin 1.
  • the mutant galectin 1 may be included.
  • the above-described galectin 1 derivative contains a part of galectin 1 or a part of galectin 1 derivative. But you can. For example, as a part of galectin 1 or a part of galectin 1 derivative, a part of galectin 1 or galectin 1 derivative that is conventionally known to be important for physiological activity can be configured.
  • the sustained-release hide-mouth gel formulation of the present invention may be configured to be administered in the vicinity of the spinal cord of a mammal.
  • the sustained-release hide-mouth gel preparation can be configured to have a fluidity that can be filled using an osmotic pump with respect to an injury site of a mammalian spinal cord.
  • a sustained-release hyde mouth gel preparation using a gelatinoid mouth gel processed into a granular form, it can be configured to be injected onto the damaged site of the spinal cord of a mammal.
  • the hyde mouth gel refers to a gel in which an aqueous liquid is held inside a polymer cross-linked structure.
  • Gelatin nose mouth gel is a gel-like substance obtained by hydrating gelatin, and is a kind of bioabsorbable polymer hide mouth gel. More details The raw material for gelatinoid mouth gel is gelatin, which is a protein obtained by heat-denaturing a substance called collagen contained in animal bones and skin and highly purified.
  • the gelatin derivative has a hydrophobic property such as guazyl group, thiol group, amino group, carboxyl group, sulfate group, phosphate group, alkyl group, acyl group, and benzyl group with respect to gelatin. It includes modified gelatin into which residues and hydrophobic substances with low molecular weight have been introduced.
  • Naturally derived gelatin is preferably used as gelatin.
  • Naturally-derived gelatin is a collagen that can be collected from all parts of the body, such as skin, bones, and tendons of various animal species, including cattle, pigs, and fish. It can be obtained by modification by various treatments such as alkaline hydrolysis, acid hydrolysis, and enzymatic decomposition.
  • modified gelatin of recombinant collagen may be used.
  • a positively charged gelatin or id mouth gel is used.
  • the inventor has found that the positively charged gelatin nodule gel force interacts better with galectin-1 or galectin-1 derivatives.
  • the positive charge of the gelatin hydrate gel plays an important role in forming a stable complex with galectin 1 or galectin 1 derivatives.
  • it can be cationized by previously introducing an amino group or the like into gelatin. As a result, the binding force between the gelatin hydrate gel and the drug is increased, and a more stable gelatin hydrate gel complex can be formed.
  • the step of cationization is not particularly limited as long as it is a method capable of introducing a functional group that becomes cationized under physiological conditions, but a 1, 2 or tertiary amino group is added to the hydroxyl group or carboxyl group of gelatin.
  • a method in which the ammonia group is introduced under mild conditions is preferable.
  • ethylenediamine, N, N-dimethyl-1,3-diaminopropane and other alkyldiamins, trimethylammo-muacetohydrazide, spermine, spermidine or cetylamide hydrochloride, etc. are used as various condensing agents such as 1-ethyl-3.
  • the cation ratio can be used as an index indicating the degree of cation of the cation gelatin.
  • Cationization rate (number of amino groups per molecule of cation gelatin) Z (number of amino groups per gelatin molecule before cation) Z (number of carboxyl groups per gelatin molecule before cation) * 100 It is expressed in (%).
  • the cation ratio is preferably 10% or more and 60%, particularly preferably 30% or more and 50% or less. If the cationic rate is lower than these lower limits, the interaction between the gelatinoid mouth gel and galectin 1 or galectin 1 derivative is weakened. On the other hand, if the cationic rate power S exceeds these upper limits, the cationization of the gelatin nozzle gel may become difficult in the production process.
  • the gelatin nozzle gel insoluble or sparingly soluble in water. This makes it possible to freely control the release of the drug according to the biodegradability of the gelatin hydrogel in the living body.
  • the sustained release rate of the drug can be controlled by decomposing gelatino or id mouth gel in the living body.
  • Gelatin nodule mouth gels can be insolubilized or hardly soluble by forming chemical crosslinks between molecules of gelatin or gelatin derivatives using various chemical crosslinkers.
  • the chemical cross-linking agent include water-soluble carbodiimides such as dartal aldehyde such as EDC, such as propylene oxide, diepoxy compounds, hydroxyl groups, carboxyl groups, amino groups, thiol groups, and imidazole groups.
  • An agent can be used. Preference is given to dartalaldehyde.
  • the bioabsorbable polymer may be chemically cross-linked by thermal dehydration treatment, ultraviolet rays, gamma rays, or electron beam irradiation. More In addition, these crosslinking treatments may be used in combination.
  • the hyde-mouth gel may be prepared by physical crosslinking using salt crosslinking, electrostatic interaction, hydrogen bonding, hydrophobic interaction, and the like.
  • the drug incorporated in the complex is in accordance with the degradation of the gelatino and id lip gel in vivo. It is gradually released out of the complex. This release rate is determined by the degree of degradation and absorption in the body of the gelatin hydrate gel used, and the strength and stability of the bond between the drug and the gelatinogel in the complex.
  • the degree of degradation and absorption of gelatino and id mouth gels in the living body can be adjusted by adjusting the degree of cross-linking during the preparation of the hide mouth gel.
  • the degree of cross-linking of the hard mouth gel can be evaluated using the water content as an index.
  • the water content is the weight percent of water in the hyde mouth gel with respect to the weight of the swollen hide mouth gel. If the moisture content is high, the degree of cross-linking of the hyde mouth gel is low. Therefore, specifically, the water content showing a preferable sustained release effect is 80 wt% or more and 99.8 wt% or less, particularly preferably 90 wt% or more and 97 wt% or less, and most preferably 92 wt% or more and 97 wt%. It is as follows. If the water content of gelatin or id mouth gel is higher than these upper limits, it becomes difficult to control the release rate of galectin 1, and the desired sustained release effect cannot be obtained.
  • the preferred range of the concentration of gelatin or the gelatin derivative and the crosslinking agent in preparing the hydrogen is a concentration of gelatin or gelatin derivative of 1 to 20 wZw%, Agent concentration: 0.01-: LwZ w%.
  • the crosslinking reaction conditions There are no particular limitations on the crosslinking reaction conditions.
  • the reaction can be performed at 0 to 40 ° C, preferably 25 to 30 ° C, for 1 to 48 hours, preferably 12 to 24 hours.
  • the concentration of gelatin or gelatin derivative, the concentration of crosslinking agent, and the crosslinking time increase, the degree of crosslinking of the hard mouth gel increases and the bioabsorbability decreases.
  • the cross-linking reaction of gelatin or gelatin derivatives can also be performed by heat treatment.
  • Examples of crosslinking by heat treatment are as follows.
  • a gelatin film is obtained by casting an aqueous gelatin solution (preferably about 10% by weight) onto a plastic petri dish and air drying. The The film is allowed to stand under reduced pressure, preferably about 110 mmHg, usually 110 to 160 ° C, preferably 120 to 150 ° C, usually 1 to 48 hours, preferably 6 to 24 hours.
  • the gelatin film is cross-linked by ultraviolet rays, the obtained gelatin film is usually left at room temperature, preferably 0 to 40 ° C. under a sterilizing lamp.
  • a sponge-like molded body is obtained by freeze-drying a gelatin aqueous solution.
  • This can likewise be crosslinked by heat treatment and UV, gamma and electron beams.
  • the above-mentioned crosslinking methods can be used in combination.
  • the shape (three-dimensional structure) of the gelatin hydrated gel for encapsulating galectin 1 or galectin 1 derivatives is not particularly limited, but for example, cylindrical, prismatic, sheet, disc, spherical, paste There is a shape. Columns, prisms, sheets and discs are particularly suitable for use as embedded pieces.
  • a cylindrical, prismatic, sheet, or disk-shaped gelatinoid mouth gel is obtained by adding an aqueous solution of a crosslinking agent to an aqueous solution of gelatin or a gelatin derivative, or by adding gelatin or a gelatin derivative to an aqueous solution of a crosslinking agent. It can be prepared by adding it, pouring it into a bowl having a desired shape, and causing a crosslinking reaction. Further, an aqueous crosslinking agent solution may be added to the formed gelatin gel as it is or after drying. To stop the cross-linking reaction, add the ability to contact low molecular weight substances with amino groups such as ethanolamine and glycine, or an aqueous solution with a pH of 2.5 or lower.
  • the obtained gelatinoid mouth gel was washed with distilled water, ethanol, 2-propanol, acetone, etc. and used for preparation of the preparation.
  • the gelatin-hide mouth gel of the present invention can be appropriately used after being cut into an appropriate size and shape, lyophilized and sterilized.
  • lyophilization for example, place gelatin-hide mouth gel in distilled water and freeze in liquid nitrogen for 30 minutes or more, or at 80 ° C for 1 hour or more, and then dry in a freeze dryer for 1 to 3 days. This can be done.
  • the gelatin-hide mouth gel of the present invention comprises galectin 1 or galectin to be released slowly.
  • the gelatin hydrated gel of the present invention is degraded by hydrolysis and oxygen degradation in the living body, or by the action of biologically active substances such as enzymes. It is hydrolyzed.
  • the drug used for producing a sustained-release preparation in the present invention is galectin-1 or galectin-1 derivative.
  • Galectin-1 is a cytoplasmic protein belonging to the galectin family. Of these, natural galectin 1 is particularly preferred.
  • the galectin-1 derivative includes mutant galectin-1 obtained by substituting, deleting, or adding one or more amino acid residues in the amino acid sequence of natural galectin-1.
  • Galectin-1 derivatives also include recombinant galectin-1 obtained using a gene recombination technique. When administered to humans, natural human galectin-11 or recombinant human galectin-11 is preferred.
  • the galectin 1 derivative includes a part of galectin 1 or a part of galectin 1 derivative and having a physiological activity similar to that of galectin 1.
  • Galectins are a family of animal lectins. Galectins are known to have binding specificity for galactose and to characterize the galectin family, and have a predetermined primary amino acid sequence. Galectins are generally soluble and have no metal requirements. Galectins exhibit properties as cytoplasmic proteins, do not have disulfide bonds, additional sugar chains, or signal sequences, and generally have an N-terminal amino acid acetylated. However, the location of galectin expression is not limited to the cytoplasm, but varies with the nucleus, cell surface, and extracellular matrix, and often varies depending on the type of galectin molecule and the tissue and timing of expression.
  • galectins are known to be widely distributed in vertebrates as well as invertebrates such as nematodes, insects, and sponges, but recently they have galactose binding activity in fungi (mushrooms).
  • the existence of galectins Yes.
  • the life phenomena involved in galectins include development, differentiation, morphogenesis, tumor metastasis, cell death, pricing, etc., but unresolved parts are related to the mechanism of functional expression, particularly in relation to sugar chain recognition. There are many.
  • galectins can be classified into three types: proto, chimera, and tandem repeat type, based on the molecular construction mode.
  • mammalian galectins be called with numbers assigned in order of discovery (order of registration with GenBank).
  • GenBank order of registration with GenBank
  • Galectin 1 is an animal lectin that binds to ⁇ -galactosid. Galectin 1 has 6 cysteines in the molecule and exhibits lectin activity only in the reduced state. It has been reported that it is involved in cell adhesion and cell proliferation by binding to glycolipids and glycoprotein sugar chains on the cell surface by lectin activity. Galectin 1 belongs to the above proto type. As functions of galectin 1, for example, apoptotic cell proliferation induced by activated sputum cells, regeneration of mRNA splicing nerve axons (oxidized galectin 1), abnormal neurite outgrowth of olfactory nerve, and the like are known.
  • togalectin 1 has a function related to nerve regeneration, which is considered to be applicable to at least regenerative medicine.
  • the nerve regeneration cascade can be moved starting from (acidic ⁇ type) galectin 1, and it also acts as a nerve regeneration promoting factor and nerve axon elongation. Therefore, if sustained release in mammals can be achieved, the physiological activity of galectin-1 may be applicable to the treatment of spinal cord injury patients.
  • human galectin 1 is a literature on recombinant human galectin 1, but it is described in the journal "Biochemistry” 72 ⁇ No. 10 "It is in a reduced state in cells after nerve injury. Galectin 1 is secreted by the regenerative axon Schwann cell, most of which binds to the sugar chains present on the cell surface, and some of the secreted galectin 1 diffuses into the interstitial fluid, but is damaged. The cell has increased permeability through the cell membrane, and galectin 1 diffuses out of the cell.A single molecule of galectin released to the outside of the cell that does not bind to sugar is capable of disulfide binding in an acidic environment.
  • galectin 1 It forms acid ⁇ type galectin 1 and exists as a monomer.Oxidized galectin 1 without lectin activity is an isolated nerve cell. Since it does not act directly on cells, it acts as a cytoforce-in-like factor on cell systems that constitute damaged parts other than nerves, such as Schwann cells, fibroblasts, pericytes, and recruitment macrophages, and axon regeneration It is thought that it promotes. There is a detailed description.
  • the sustained-release hide-mouth gel preparation of the present invention is a sustained-release gelatin-hide mouth gel preparation containing galectin-1 or a galectin-1 derivative.
  • This sustained-release hyde mouth gel preparation can be prepared, for example, by dripping a solution containing galectin 1 or galectin-1 derivative into the freeze-dried gelatino or the id mouth gel described above, or displacing the gelatin hyde mouth gel with galectin 1 or It can be obtained by dipping in a solution containing the galectin 1 derivative and impregnating the galectin 1 or galectin 1 derivative in the hide mouth gel.
  • the galectin for the gelatin nose mouth gel is the galectin for the gelatin nose mouth gel
  • the molar ratio of 1 or galectin 1 derivative is preferably about 5 times or less.
  • Nono id port gels are molar ratios of from about 5 to about 1/10 4 times.
  • This impregnation operation is usually completed at 4-37 ° C for 15 minutes-1 hour, preferably at 4-25 ° C for 15-30 minutes, during which time the hydrogen contains galectin 1 or galectin 1 derivatives.
  • the galectin 1 or galectin 1 derivative forms a complex by a physicochemical interaction with the bioabsorbable polymer, and the galectin 1 or galectin 1 derivative is in the hydose mouth gel. Fixed to.
  • the gelatin hydrated gel thus obtained and galectin 1 or galectin 1 derivative may be coupled with galectin 1 or galectin. It is considered that the functional group of 1 derivative or the coordinate bond between the metal and the functional group on the hyde-mouth gel is involved alone or in combination.
  • Other components may be added to the sustained-release nose-mouth gel preparation of the present invention, if desired, depending on the purpose such as the stability of the resulting hide-mouth gel and the sustained release of the drug.
  • examples of other components include amino sugars or their high molecular weight compounds, chitosan oligomers, and basic amino acids.
  • examples thereof include basic polymers such as acids or oligomers thereof, high molecular weight polymers, polyallylamine, polyjetylaminoethyl acrylamide, and polyethyleneimine.
  • the sustained-release hide-mouth gel formulation of the present invention can be administered to a living body by an arbitrary method.
  • galectin 1 or galectin 1 derivative is directionally and continuously released at a specific target site.
  • local administration is particularly preferred.
  • the sustained-release Hyde Mouth Gel preparation can be further released by mixing with a pharmaceutically acceptable carrier (stabilizer, preservative, solubilizer, pH adjuster, thickener, etc.) as necessary.
  • a formulation can be prepared.
  • a known carrier can be used as such a carrier.
  • various additives for adjusting the sustained release effect can be included.
  • it is further desirable to go through a sterilization process such as sterilization filtration.
  • the sustained-release hide-mouth gel formulation of the present invention can be formulated into various shapes depending on the purpose.
  • solid, semi-solid preparations such as granular, circular and prismatic, sheet, disk, stick, and rod shapes can be mentioned.
  • it is a solid preparation excellent in sustained release effect at a specific target site and suitable for local administration.
  • it can also be used as a paste-form preparation having fluidity.
  • a sustained-release hide-mouth gel preparation formulated in a sheet form is suitable for local implantation.
  • any sustained release nose mouth gel preparation can be used in combination with another material depending on the use site.
  • a sustained-release hide-mouth gel preparation may be used by mixing with a paste-like substance for the purpose of fixing to a specific site.
  • the dosage of the sustained-release hide-mouth gel formulation of the present invention can be appropriately selected so as to be sufficient to bring about a therapeutic response.
  • a dose is also selected in the range of about 0.01 to about 10,000 g, preferably about 0.1 to about 1,000 g per adult patient, which is placed or infused at the lesion or surrounding area can do.
  • multiple doses can be administered.
  • the sustained-release nodule gel preparation of the present invention has the sustained-release effect and the stable effect of galectin 1 or galectin 1 derivative, so that galectin 1 or galectin 1 derivative can be controlled at a desired site. It can be released for a long time with a high release rate. Therefore, the action of galectin 1 or galectin 1 derivative is within the lesion site. It is effectively demonstrated.
  • the sustained-release Hyde Mouth gel formulation is preferred to be applied around nerves when nerve regeneration of spinal injury is the goal.
  • the names of E50, E10, E3, EO.5, etc. were given to the resulting cationized gelatin depending on the amount of ethylenediamine that was calorie to the gelatin during the preparation of the cationic gelatin.
  • the numbers represent the amount (molar ratio) of ethylenediamine added to the carboxyl group in gelatin when preparing cationic gelatin.
  • the preparation method of the following cationized gelatin shows the preparation method of E50 as an example, and the amount of cationized gelatin represented by other abbreviations is appropriately changed in the amount (molar ratio) to which ethylenediamine is added. Can be produced.
  • Cationic gelatins such as E50, E10, E3, and EO.5 were cross-linked with glutaraldehyde to prepare cationic gelatino and id mouth gels of E50, E10, E3, and EO.5.
  • the cation ratio was confirmed by quantifying amino groups by the TNBS method after preparation of cationized gelatin. This quantitative method is a general method often used for quantitative determination of amino groups.
  • Ma TNBS means sodium 2,4,6-tri-trobenzenesulfonate dihydrate.
  • Gelatin molecular weight 100000, derived from pig skin, isoelectric point 9.0, provided by Nitta Gelatin
  • Ethylenediamine (Wako Pure Chemicals, code 053- 0093 6, lot No. CEN-3313) After adding 55.8 g, the pH was adjusted to 5 with concentrated hydrochloric acid (Nacalai Tester, code 18 321- 05, lot No. V5H6401).
  • the cationized gelatin of E10, E3, and E0.5 can be appropriately selected by changing the molar ratio of ethylenediamine added in the same manner as the production method of the cationized gelatin of E50. It was produced by adjusting the degree of ON.
  • the water content of E10, E3, and EO.5 cationic gelatin nozzles was crosslinked so that the water content was 80% or more and 99.8% or less.
  • key-on gelatin In contrast to cationized gelatin, key-on gelatin (key-on ratio 61%) is a gelatin with reduced amino groups.
  • the amino group of the anion gelatin obtained by the above TNBS method is quantified. It can be obtained by In other words, the ionization rate of 61% means that 61% of the original amino group has been replaced by succinic anhydride.
  • This gel gelatin was cross-linked with dartalaldehyde to produce a gel gelatin gelatin.
  • SM50 is a cationized gelatin in which ethylenediamine is replaced with spermine for the preparation method of E50 cationized gelatin.
  • the SM50 cationized gelatin was cross-linked with glutaraldehyde to produce a SM50 cationic gelatin hydrated gel.
  • CIO Hydrophobic group-introduced gelatin
  • PLA Molecular weight 1000
  • This solution was slowly added to gelatin-DMSO solution with stirring and reacted at 37 ° C overnight.
  • the reaction solution was dialyzed, filtered and freeze-dried to obtain cholesterol-g-gelatin.
  • Cholesterol g -gelatin was cross-linked with glutaraldehyde to prepare cholesterol g gelatin-hide mouth gel.
  • E50 + hydrophobic group-introduced gelatin E50 + hydrophobic group-introduced gelatin was prepared so that the mixing ratio of E50 and hydrophobic group-introduced gelatin was 1: 1. This E50 + hydrophobic group-introduced gelatin was cross-linked with dartalaldehyde to prepare an E50 + hydrophobic group-introduced gelatin nose mouth gel.
  • reaction solution was passed through a PD-10 column (amersham biosciences ⁇ code 17—0851-01), and a fraction of every 500 liters was obtained using an auto well Gamma system (Aloka, ARC-300). Measured and separated into labeled recombinant human galectin-11 and unreacted Na 125 I.
  • galactose-introduced gelatin and mannose-introduced gelatin have some effects of improving the sustained release of recombinant human galectin 1.
  • E50, SM50, and hydrophobic group-introduced gelatin + E50 The effect of improving the sustained release of galectin 1 was not sufficient.
  • the sustained release of recombinant human galectin 1 was improved in an in vivo degradation test by using a cationic E50 gelatin-hide mouth gel with a water content of 97 wt% or less.
  • the sustained release of recombinant human galectin 1 was further improved in an in vivo degradation test by using a cationic E50 gelatin hyde mouth gel having a water content of 92 wt% or more and 97 wt% or less.
  • recombinant human galectin 1 was used as galectin 1, but natural human galectin 1 may be used, or a polypeptide composed of a part thereof may be used. This is also because the physiological activity of human galectin 1 is exhibited in this case, and the effect of nerve regeneration is obtained in the same manner as in the above examples.
  • the sustained-release hide-mouth gel preparation according to the present invention is useful for the treatment of neuropathy.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Psychiatry (AREA)
  • Inorganic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne la préparation d'hydrogel à libération prolongée contenant un hydrogel de gélatine cationique et la galectine-1 ou un dérivé de galectine-1. La préparation d'hydrogel à libération prolongée de l'invention peut réguler l'élution de la galectine-1 ou d’un dérivé de galectine-1 in vivo chez un mammifère. Dans l'hydrogel de gélatine cationique, le rapport de substitution des groupes carboxyle par des groupes amine dans l'hydrogel de gélatine peut être supérieur ou égal à 10 % et inférieur ou égal à 60 %. En outre, la teneur en eau de l'hydrogel de gélatine cationique peut être supérieure ou égale à 80 % et inférieure ou égale à 99,8 %
PCT/JP2007/050180 2006-01-10 2007-01-10 Preparation d’hydrogel a liberation prolongee WO2007080898A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006-002648 2006-01-10
JP2006002648A JP2007182407A (ja) 2006-01-10 2006-01-10 徐放性ハイドロゲル製剤

Publications (1)

Publication Number Publication Date
WO2007080898A1 true WO2007080898A1 (fr) 2007-07-19

Family

ID=38256303

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/050180 WO2007080898A1 (fr) 2006-01-10 2007-01-10 Preparation d’hydrogel a liberation prolongee

Country Status (2)

Country Link
JP (1) JP2007182407A (fr)
WO (1) WO2007080898A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009060608A1 (fr) * 2007-11-07 2009-05-14 Ono Pharmaceutical Co., Ltd. Composition à libération prolongée contenant du sdf-1
WO2009116509A1 (fr) * 2008-03-18 2009-09-24 日本化薬株式会社 Conjugué de polymère et de substance physiologiquement active
US8188222B2 (en) 2006-11-08 2012-05-29 Nippon Kayaku Kabushiki Kaisha High molecular weight derivative of nucleic acid antimetabolite
US8323669B2 (en) 2006-03-28 2012-12-04 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of taxane
US8334364B2 (en) 2006-11-06 2012-12-18 Nipon Kayaku Kabushiki Kaisha High-molecular weight derivative of nucleic acid antimetabolite
US8703878B2 (en) 2007-09-28 2014-04-22 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of steroids
US8808749B2 (en) 2009-05-15 2014-08-19 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of bioactive substance having hydroxy group
US8940332B2 (en) 2006-05-18 2015-01-27 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of podophyllotoxins
US9018323B2 (en) 2010-11-17 2015-04-28 Nippon Kayaku Kabushiki Kaisha Polymer derivative of cytidine metabolic antagonist
US9149540B2 (en) 2008-05-08 2015-10-06 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of folic acid or folic acid derivative
JP2016052314A (ja) * 2011-01-19 2016-04-14 セウォン セロンテック カンパニー リミテッドＳｅｗｏｎ Ｃｅｌｌｏｎｔｅｃｈ Ｃｏ．，Ｌｔｄ． 放射線架橋化されたコラーゲンゲルの製造方法と使用方法
US9346923B2 (en) 2011-09-11 2016-05-24 Nippon Kayaku Kabushiki Kaisha Method for manufacturing block copolymer
US9434822B2 (en) 2004-09-22 2016-09-06 Nippon Kayaku Kabushiki Kaisha Block copolymer, micelle preparation, and anticancer agent containing the same as active ingredient

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5594633B2 (ja) * 2010-10-05 2014-09-24 独立行政法人物質・材料研究機構 ２成分系組織接着剤及びその製造方法
JP5747264B2 (ja) * 2010-10-05 2015-07-08 国立研究開発法人物質・材料研究機構 組織接着膜及びその製造方法
JP2013075835A (ja) * 2011-09-29 2013-04-25 Fuso Pharmaceutical Industries Ltd ゼラチンハイドロゲルを用いたヘパリンの徐放

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006724A1 (fr) * 1998-07-31 2000-02-10 Kirin Beer Kabushiki Kaisha Medicaments permettant de soigner la neuropathie contenant de la galectine-1 ou ses derives comme substance active
JP2001199903A (ja) * 1999-11-09 2001-07-24 Eizo Mori 核酸含有複合体
JP2004155668A (ja) * 2002-11-01 2004-06-03 Medgel Corp Ｎｋ４をコードするｄｎａを含有する徐放性製剤
JP2005220070A (ja) * 2004-02-05 2005-08-18 Medgel Corp 神経再生および保護のための生体吸収性高分子ハイドロゲル製剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006724A1 (fr) * 1998-07-31 2000-02-10 Kirin Beer Kabushiki Kaisha Medicaments permettant de soigner la neuropathie contenant de la galectine-1 ou ses derives comme substance active
JP2001199903A (ja) * 1999-11-09 2001-07-24 Eizo Mori 核酸含有複合体
JP2004155668A (ja) * 2002-11-01 2004-06-03 Medgel Corp Ｎｋ４をコードするｄｎａを含有する徐放性製剤
JP2005220070A (ja) * 2004-02-05 2005-08-18 Medgel Corp 神経再生および保護のための生体吸収性高分子ハイドロゲル製剤

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FUKUNAKA Y. ET AL.: "Controlled release of plasmid DNA from cationized gelatin hydrogels based on hydrogel degradation", JOURNAL OF CONTROLLED RELEASE, vol. 80, no. 1-3, 2002, pages 333 - 343, XP004348646 *
KUSHIBIKI T. ET AL.: "In vivo release and gene expression of plasmid DNA by hydrogels of gelatin with different cat-ionization extents", JOURNAL OF CONTROLLED RELEASE, vol. 90, no. 2, 2003, pages 207 - 216, XP004431313 *
KUSHIBIKI T. ET AL.: "Seitai Kyushusei Cationized Gelatin Hydrogels o Mochiita Plasmid DNA no Johoka to Sono Seibutsu Kassei no Zokyo NK4 Plasmid DNA no Shuyo Ten-i Yokusei Koka o Rei to shite", INFLAMMATION AND REGENERATION, vol. 24, no. 6, 2004, pages 634 - 641, XP008084273 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9434822B2 (en) 2004-09-22 2016-09-06 Nippon Kayaku Kabushiki Kaisha Block copolymer, micelle preparation, and anticancer agent containing the same as active ingredient
US8323669B2 (en) 2006-03-28 2012-12-04 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of taxane
US8940332B2 (en) 2006-05-18 2015-01-27 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of podophyllotoxins
US8334364B2 (en) 2006-11-06 2012-12-18 Nipon Kayaku Kabushiki Kaisha High-molecular weight derivative of nucleic acid antimetabolite
US8188222B2 (en) 2006-11-08 2012-05-29 Nippon Kayaku Kabushiki Kaisha High molecular weight derivative of nucleic acid antimetabolite
USRE46190E1 (en) 2007-09-28 2016-11-01 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of steroids
US8703878B2 (en) 2007-09-28 2014-04-22 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of steroids
US8435953B2 (en) 2007-11-07 2013-05-07 Yasuhiko Tabata Sustained release composition containing SDF-1
JP5248519B2 (ja) * 2007-11-07 2013-07-31 小野薬品工業株式会社 Ｓｄｆ−１を含有してなる徐放性組成物
US9107953B2 (en) 2007-11-07 2015-08-18 Ono Pharmaceutical Co., Ltd. Sustained release composition containing SDF-1
WO2009060608A1 (fr) * 2007-11-07 2009-05-14 Ono Pharmaceutical Co., Ltd. Composition à libération prolongée contenant du sdf-1
US8920788B2 (en) 2008-03-18 2014-12-30 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of physiologically active substances
JP5687899B2 (ja) * 2008-03-18 2015-03-25 日本化薬株式会社 生理活性物質の高分子結合体
JPWO2009116509A1 (ja) * 2008-03-18 2011-07-21 日本化薬株式会社 生理活性物質の高分子結合体
WO2009116509A1 (fr) * 2008-03-18 2009-09-24 日本化薬株式会社 Conjugué de polymère et de substance physiologiquement active
US9149540B2 (en) 2008-05-08 2015-10-06 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of folic acid or folic acid derivative
US8808749B2 (en) 2009-05-15 2014-08-19 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of bioactive substance having hydroxy group
US9018323B2 (en) 2010-11-17 2015-04-28 Nippon Kayaku Kabushiki Kaisha Polymer derivative of cytidine metabolic antagonist
JP2016052314A (ja) * 2011-01-19 2016-04-14 セウォン セロンテック カンパニー リミテッドＳｅｗｏｎ Ｃｅｌｌｏｎｔｅｃｈ Ｃｏ．，Ｌｔｄ． 放射線架橋化されたコラーゲンゲルの製造方法と使用方法
US9346923B2 (en) 2011-09-11 2016-05-24 Nippon Kayaku Kabushiki Kaisha Method for manufacturing block copolymer

Also Published As

Publication number Publication date
JP2007182407A (ja) 2007-07-19

Similar Documents

Publication Publication Date Title
WO2007080898A1 (fr) Preparation d’hydrogel a liberation prolongee
Cai et al. Injectable glycosaminoglycan hydrogels for controlled release of human basic fibroblast growth factor
CA2140053C (fr) Systeme a base de collagene pour l'administration de drogue injectable, et utilisation
JP6144249B2 (ja) ポリペプチド−ポリマー抱合体およびその使用方法
Jeon et al. Affinity-based growth factor delivery using biodegradable, photocrosslinked heparin-alginate hydrogels
US8101205B2 (en) Controlled release composition
JP5539727B2 (ja) ヒドロゲルを形成する新規な注入可能なキトサン混合物
EP3031466B1 (fr) Compositions de peptide amphiphile purifiées et leurs utilisations
JP2018511622A (ja) 擬塑性ミクロゲルマトリクスの組成物およびキット
Daamen et al. A biomaterial composed of collagen and solubilized elastin enhances angiogenesis and elastic fiber formation without calcification
Chen et al. Loading of VEGF to the heparin cross-linked demineralized bone matrix improves vascularization of the scaffold
JP2011519292A (ja) 成長因子／両親媒性ポリマー複合体、可溶性のカチオン塩及び有機支持体を含有する骨形成組成物
JP7384767B2 (ja) コラーゲンに基づく治療送達系
JP2000511512A (ja) 酸化ポリサッカライドで架橋したゼラチンを含有する新規医薬
JP2018511622A5 (fr)
Doǧan et al. Controlled release of EGF and bFGF from dextran hydrogels in vitro and in vivo
JP4878730B2 (ja) Ｈｇｆヒドロゲル徐放性製剤
Kasper et al. Evaluation of bone regeneration by DNA release from composites of oligo (poly (ethylene glycol) fumarate) and cationized gelatin microspheres in a critical‐sized calvarial defect
JP2008527033A (ja) 増殖因子組成物
Amirian et al. Gelatin Based Hydrogels for Tissue Engineering and Drug Delivery Applications
JP2005220070A (ja) 神経再生および保護のための生体吸収性高分子ハイドロゲル製剤
Verma Collagen-Based Biomaterial as Drug Delivery Module
Adhirajan et al. Functionally modified gelatin microspheres as a growth factor’s delivery system: development and characterization
WO2007046540A1 (fr) Agent therapeutique pour la regeneration du complexe dentine-pulpe dentaire
KR100823627B1 (ko) 히알루론산 유도체를 포함하는 다층막

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07706527

Country of ref document: EP

Kind code of ref document: A1