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WO2016121829A1 - Agent permettant le traitement ou la prévention de la dermatite utilisant des nanoparticules comme principe actif - Google Patents

Agent permettant le traitement ou la prévention de la dermatite utilisant des nanoparticules comme principe actif Download PDF

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Publication number
WO2016121829A1
WO2016121829A1 PCT/JP2016/052379 JP2016052379W WO2016121829A1 WO 2016121829 A1 WO2016121829 A1 WO 2016121829A1 JP 2016052379 W JP2016052379 W JP 2016052379W WO 2016121829 A1 WO2016121829 A1 WO 2016121829A1
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dermatitis
amino acid
therapeutic
skin
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Japanese (ja)
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昇一 城武
恵子 宇高
道之 笠井
栄紀 佐野
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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

Definitions

  • the present invention relates to a dermatitis treatment or prevention agent comprising nano-sized cyanoacrylate polymer particles as an active ingredient.
  • DDS drug delivery system
  • sustained release mainly for application to human medicine
  • drugs are conjugated to cyanoacrylate polymer particles.
  • DDS is known (Patent Documents 1 and 2 and Non-Patent Document 1).
  • Patent Documents 3 to 5 the present inventor has also disclosed a method for producing cyanoacrylate polymer particles, antibacterial agent-conjugated particles, and plasmid-conjugated particles with little variation in particle size.
  • Patent Documents 3 to 5 In the conventional polymer particle synthesis method, saccharides and polysorbate are allowed to coexist in the polymerization reaction system for the purpose of starting and stabilizing the anionic polymerization reaction of cyanoacrylate.
  • Patent Document 6 the cyanoacrylate polymer particles themselves have antibacterial activity against Gram-positive bacteria. Furthermore, in addition to the anticancer activity of amino acid-conjugated cyanoacrylate polymer particles (Patent Document 7), it was found that antibacterial activity can be exerted against various bacteria regardless of Gram stainability (Patent Documents 8 and 9). . Nano-sized polymer particles specifically adhere to the bacterial surface (cell wall), leading the bacteria to lysis.
  • Cyanoacrylate nanoparticles exhibit antibacterial activity with a mechanism of action completely different from antibiotics, and are also effective against multi-drug resistant bacteria such as MRSA (Methicillin-resistant Staphylococcus aureus) and VRE (Vancomycin resistant enterococcus) .
  • MRSA Metal-resistant Staphylococcus aureus
  • VRE Vancomycin resistant enterococcus
  • Atopic dermatitis is a skin disease with a high prevalence in Japan. Increasing in recent years, patients are forced to suffer a lot of mental and physical pain.
  • Non-patent Document 2 The basics of pharmacotherapy for atopic dermatitis include the use of steroid topical drugs, calcineurin-inhibiting drugs, and anti-histamine / anti-allergic drugs as needed according to severity. Accordingly, oral steroids and oral calcineurin inhibitor are used (Non-patent Document 2). However, there are many patients who are afraid of side effects due to continuous use of steroids and avoid steroids, and there is a problem of infectivity due to immunosuppression, so new treatment means are required.
  • An object of the present invention is to provide a novel means capable of treating or preventing dermatitis such as atopic dermatitis.
  • the present invention contains at least one selected from the group consisting of amino acids, amino acid derivatives, oligomers and polymers thereof, and contains cyanoacrylate polymer particles having an average particle size of less than 1000 nm as an active ingredient.
  • An agent for treating or preventing inflammation is provided.
  • the present invention contains at least one selected from the group consisting of amino acids, amino acid derivatives, oligomers and polymers thereof, and contains cyanoacrylate polymer particles having an average particle size of less than 1000 nm as an active ingredient.
  • the present invention provides an inhibitor of type IV allergic reaction or type IV allergic reaction.
  • the present invention contains at least one selected from the group consisting of amino acids, amino acid derivatives, oligomers and polymers thereof, and contains cyanoacrylate polymer particles having an average particle size of less than 1000 nm as an active ingredient.
  • a therapeutic or prophylactic agent for allergic symptoms involving type I allergic reaction or type IV allergic reaction is provided.
  • the present invention includes at least one selected from the group consisting of amino acids, amino acid derivatives, and oligomers and polymers thereof in skin lesions to be treated or skin regions where prevention of the occurrence of dermatitis is desired.
  • Providing a method of treating or preventing dermatitis comprising administering an effective amount of cyanoacrylate polymer particles having an average particle size of less than 1000 nm.
  • the present invention provides a cyanoacrylate polymer having an average particle size of less than 1000 nm, comprising at least one selected from the group consisting of amino acids, amino acid derivatives, and oligomers and polymers thereof for a subject in need thereof.
  • a method for suppressing a type I allergic reaction or a type IV allergic reaction comprising administering an effective amount of particles.
  • the present invention provides a cyanoacrylate polymer having an average particle size of less than 1000 nm, comprising at least one selected from the group consisting of amino acids, amino acid derivatives, and oligomers and polymers thereof for a subject in need thereof.
  • a method of treating or preventing allergic symptoms involving type I allergic reactions or type IV allergic reactions comprising administering an effective amount of particles.
  • the present invention provides a novel means for treating or preventing dermatitis different from steroidal drugs.
  • the cyanoacrylate nanoparticles which are the active ingredients of the therapeutic or prophylactic agent of the present invention, are not used as a DDS for drugs, but the particles themselves exhibit a therapeutic and prophylactic effect for dermatitis.
  • the therapeutic or prophylactic agent of the present invention is preferably used even for patients who are anxious about steroidal drugs, patients who cannot use steroidal drugs due to side effects, and patients who are found to be susceptible to immunological decline. be able to.
  • the treatment schedule for NC / NgaSlc mice is shown (Study 1). It is the photograph of the skin lesion part of the NC / NgaSlc mouse
  • FIG. 1 It is the graph which scored the skin inflammation state of the lesioned part shown in FIG.
  • FIG. 1 is an HE-stained image of the dorsal skin tissue of NC / NgaSlc mice on the 8th day after applying DNFB after observing tape stripping-induced dermatitis according to the schedule shown in FIG. It is the result of having measured the blood IgE density
  • a comparison between the start of the experiment (blood collection 1) and the end of the experiment (blood collection 2) is shown.
  • the treatment schedule with respect to the BALB / c mouse which examined the effect of the nanoparticle water in the dermatitis prevention model is shown (examination 2).
  • FIG. 8 is an HE-stained image of dorsal skin tissue of BALB / c mice in which dermatitis was induced according to the schedule shown in FIG. 7. The dorsal skin 3 days after DNFB application was compared between the applied head side and the unapplied caudal side.
  • FIG. 14 is an HE-stained image of the dorsal skin tissue of BALB / c mice in which dermatitis was induced after spraying with nanoparticle water or water as a prevention model in the schedule shown in FIG. 13.
  • DNFB is applied to the back and tail side of the tissue on the third day.
  • the dorsal temporal skin applied to DNFB at the start of the experiment was also stained.
  • the dorsal temporal side of BALB / c mice in which dermatitis was induced by the schedule shown in FIG. 13 (DNFB was applied only at the start of the experiment as a treatment model, and then sprayed with nanoparticle water or water) and the caudal side (prevention model) As a result of spraying nanoparticle water or water, applying DNFB before the end of the experiment, and examining the expression levels of various cytokines on the third day).
  • the treatment schedule with respect to the BALB / c mouse made into the tape stripping induction dermatitis model is shown (examination 4).
  • FIG. 20 is an HE-stained image of the back skin tissue of BALB / c mice in which dermatitis was induced by repeated tape stripping according to the schedule shown in FIG. 19 (day 14). Two tissues randomly selected from each group of nanoparticle water or water spray are shown.
  • FIG. 20 shows the results of examining the expression levels of various cytokines in the back skin of BALB / c mice in which dermatitis was induced by repeated tape stripping according to the schedule shown in FIG. Measurements were made on cranial and caudal skin treated the same way, respectively.
  • the treatment schedule for hairless mice examined as a hapten-induced chronic dermatitis model by repeated DNFB application is shown (Study 5).
  • FIG. 25 shows the result of scoring skin inflammation for each group of hairless mice in which dermatitis was induced according to the schedule shown in FIG. 24 and examining changes in the score.
  • FIG. 25 is a photograph of a skin lesion of a hairless mouse in which dermatitis is induced according to the schedule shown in FIG. 24 (day 33).
  • a to D represent groups A to D, respectively.
  • the central A-1 to D-1 are the right auricular skin tissue, and the right A-2 to D-2 are the cranial dorsal skin tissue.
  • the bar in the tissue image indicates 100 ⁇ m.
  • 24 is the relative expression level of various cytokines at the site of inflammation induction in hairless mice in which dermatitis was induced by the schedule shown in FIG. 24 (day 34).
  • the particles used in the present invention are nano-sized polymer particles (average particle size of less than 1000 nm) obtained by anionic polymerization of a cyanoacrylate monomer, and amino acids, amino acid derivatives, oligomers and polymers thereof (hereinafter collectively referred to as “general names”). And at least one selected from “amino acid molecules”. Furthermore, at least 1 sort (s) selected from the group which consists of saccharide
  • amino acid molecules, sugars and polysorbates can be used as polymerization initiators / stabilizers for anionic polymerization of cyanoacrylate monomers.
  • a nanoparticle production method using sugar and / or polysorbate as a polymerization initiator / stabilizer is described in Patent Document 3, Patent Document 4 (antibacterial agent-conjugated particle), Patent Document 5 (plasmid-conjugated particle) and the like.
  • Nanoparticle production methods using amino acid molecules as polymerization initiators / stabilizers are described in Patent Documents 8 and 9 (use of amino acid molecules alone) and the like.
  • Patent Document 7 describes a production method in which an amino acid and a saccharide / polysorbate are used in combination. Any one of these polymerization initiators / stabilizers may be used, or two or more thereof may be used in combination.
  • an “amino acid” refers to a compound having an amino group and a carboxy group in the molecule. As defined in general amino acids, the amino group hydrogen is substituted for other parts in the molecule. Also included are imino acids, which are cyclic compounds that have been converted to secondary amines. Representative examples of amino acids that can be used in the present invention include 20 kinds of ⁇ -amino acids (arginine, histidine, lysine, aspartic acid, glutamic acid, alanine, glycine, leucine, valine, isoleucine, serine, which constitute natural proteins.
  • Threonine phenylalanine, tryptophan, tyrosine, cystine or cysteine, glutamine, asparagine, proline, methionine
  • ⁇ -, ⁇ - and ⁇ -amino acid based molecules are also included.
  • arginine histidine, lysine, aspartic acid, glutamic acid, alanine, glycine, leucine, valine, isoleucine, serine, threonine, phenylalanine, tryptophan, tyrosine, cystine or cysteine, glutamine, asparagine, proline, methionine, ⁇ -Alanine, ⁇ -aminobutyric acid (GABA; neurotransmitter), carnitine, ⁇ -aminolevulinic acid, ⁇ -aminovaleric acid and the like.
  • GABA neurotransmitter
  • amino acids examples include arginine, histidine, lysine, aspartic acid, glutamic acid, alanine, glycine, leucine, valine, isoleucine, serine, threonine, phenylalanine, tryptophan, tyrosine, cystine or cysteine, glutamine, asparagine, proline, and methionine.
  • At least one selected from among the group consisting of glycine and aspartic acid can be mentioned, but not limited thereto.
  • amino acid derivative refers to a compound having a structure in which any group is modified or substituted in an amino acid as defined above.
  • amino acid derivatives that naturally exist as biological components can be preferably used in the present invention.
  • Specific examples of amino acid derivatives that can be used include creatine (arginine derivative with 1-methylguanidinoacetic acid), ornithine (arginine derivative with urea cycle product), thyroxine (aromatic amino acids triiodothyronine; T4), Desmosine (constituent component of keratin elastin and collagen; a structure in which three side chains of allicin and one side chain of lysine are combined), hydroxyproline and hydroxylysine (constituent components of gelatin and collagen), phosphoserine (serine and phosphate) Ester; casein component), theanine (tea component, glutamic acid derivative), kainic acid (component of seaweed insects), tricolominic acid (shime
  • amino acid “oligomer” refers to an oligopeptide in which 10 or less amino acid residues are bonded by peptide bonds
  • an amino acid “polymer” refers to a polypeptide in which 11 or more amino acid residues are bonded by peptide bonds. Say. Any of them may contain not only amino acids but also amino acid derivatives as residues.
  • the upper limit of the number of residues of the polypeptide is not particularly limited, but may be, for example, 500 residues or less.
  • those having 11 to 100 residues, 11 to 50 residues, 11 to 30 residues, 11 to 20 residues, or 11 to 15 residues can be preferably used.
  • Oligopeptides can be used more preferably than polypeptides. Among these, oligopeptides having 2 to 7 residues, 2 to 5 residues, or 2 or 3 residues can be more preferably used.
  • nano-sized (less than 1000 nm) cyanoacrylate polymer particles are used under the condition that any of the 20 ⁇ -amino acids constituting the natural protein does not use saccharides or polysorbate.
  • “Sugar” includes monosaccharides having a hydroxyl group (such as glucose, mannose, ribose and fructose), disaccharides having a hydroxyl group (such as maltose, trehalose, lactose and sucrose) and polysaccharides having a hydroxyl group (such as dextran and mannan). Etc.). These sugars may be either cyclic or chain-like, and when they are cyclic, they may be any one of pyranose type, furanose type and the like. In addition, there are various isomers of sugar, and any of them may be used.
  • Polysorbate includes various Tween-based surfactants such as polyoxyethylene sorbitan monolaurate (trade name “Tween 20”) and polyoxyethylene sorbitan monooleate (trade name “Tween 80”).
  • Monosaccharides, disaccharides and polysaccharides, and polysorbates can be used alone or in combination of two or more.
  • sugars and polysorbates described above glucose, dextran, and Tween 20 (trade name) are available at low cost, which is advantageous in terms of cost.
  • dextran dextran having a polymerization degree of about 50,000 or more in average molecular weight is preferable. There is no particular upper limit on the molecular weight of dextran, but it is usually about 500,000 or less.
  • Nanoparticles used in the present invention are particles synthesized using amino acid-based molecules as polymerization initiators / stabilizers and without using either sugar or polysorbate (that is, containing amino acid-based molecules, both sugar and polysorbate Particles that do not contain), as well as particles synthesized using amino acid molecules and sugars as polymerization initiators / stabilizers and without using polysorbates (that is, containing amino acid molecules and sugars, without polysorbates, such as SDS) Particles that do not contain other surfactants are preferred.
  • an alkyl cyanoacrylate monomer is preferable.
  • the alkyl group preferably has 1 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, still more preferably 3 to 5 carbon atoms, and may be linear or branched. Further, at least one of carbon atoms constituting the alkyl group may be replaced with a halogen atom (chlorine, bromine, iodine).
  • halogen atom chlorine, bromine, iodine.
  • preferable cyanoacrylate monomers include methyl-2-cyanoacrylate, ethyl-2-cyanoacrylate, n-propyl-2-cyanoacrylate, i-propyl-2-cyanoacrylate, and n-butyl-2-cyanoacrylate.
  • n-butyl-2-cyanoacrylate represented by the following formula, which is conventionally used as an adhesive for stitching wounds in the surgical field, can be preferably used.
  • At least one polymerization initiator / stabilizer is dissolved in a suitable solvent, and then at least one cyanoacrylate monomer is added under stirring, and the polymerization reaction proceeds by continuing appropriate stirring. You can do it.
  • at least one amino acid molecule is used as a polymerization initiator / stabilizer.
  • at least one polymerization initiator / stabilizer selected from the group consisting of sugar and polysorbate may be used in combination. Only one type of cyanoacrylate monomer may be used, or two or more types may be used.
  • the concentration of sugar and / or polysorbate in the polymerization reaction solution at the start of the reaction is not particularly limited. About 0.5% to 10%, preferably about 0.75% to 7.5%.
  • the concentration of sugar means w / v%, and the concentration of polysorbate means v / v%.
  • concentration ranges are “0.5 w / v% to 10 w / v%”. ”,“ 0.75 w / v% to 7.5 w / v% ”.
  • sugar when used in combination at 5 w / v% and polysorbate at 1 v / v%, the total concentration is 6%.
  • a monosaccharide eg glucose
  • it is preferably used at about 2.5 w / v% to 10 w / v%.
  • the concentration of amino acid molecules in the polymerization reaction solution at the start of the reaction is not particularly limited, but is usually 0.1 w / v % To 3w / v%.
  • the concentration of amino acid molecules used may be lower.
  • an aqueous solvent mainly composed of water for example, water, a lower alcohol aqueous solution, etc.
  • water is preferably used. Since anionic polymerization is initiated by hydroxide ions, the pH of the reaction solution affects the polymerization rate. When the pH of the reaction solution is high, the hydroxyl ion concentration is high, so that the polymerization is fast, and when the pH is low, the polymerization is slow.
  • an appropriate polymerization rate is usually obtained under acidic conditions with a pH of about 1.5 to 3.0.
  • the acid added to make the reaction solution acidic is not particularly limited, and either an inorganic acid or an organic acid can be used.
  • hydrochloric acid does not adversely affect the reaction and is volatilized after the reaction. Therefore, hydrochloric acid can be preferably used in the production of amino acid-based molecule-containing particles, but usable acid is not limited thereto.
  • the concentration of acid such as hydrochloric acid is not particularly limited, but can be appropriately selected within a range of about 0.0005N to 0.5N.
  • a method for synthesizing nano-sized polymer particles by polymerizing a cyanoacrylate monomer using an amino acid as a polymerization initiator a method called a mini-emulsion method is known (Weiss, CK et al., Preparatio, Macromolecules, 2007). , Vol. 40, p. 928-938; WO 2008/003706 A1), in this method, in a mini-emulsion composed of two phases of O phase containing lipophilic solvent such as hexadecane and W phase containing hydrochloric acid etc. Anionic polymerization is performed, and the use of a surfactant such as SDS is also essential.
  • a surfactant such as SDS
  • nanopolymer particles can be synthesized by a polymerization reaction in a single-phase aqueous solvent that does not contain an O phase. Therefore, it is necessary to use an organic solvent or a surfactant as a solvent. No.
  • nanopolymer particles can be produced using a polymerization initiator / stabilizer other than polysorbate. Therefore, including a Tween surfactant, an anionic surfactant, a cationic surfactant, Nanoparticles that do not contain any of an ionic surfactant, an amphoteric surfactant, and a nonionic surfactant can be prepared.
  • a Tween surfactant including a Tween surfactant, an anionic surfactant, a cationic surfactant, Nanoparticles that do not contain any of an ionic surfactant, an amphoteric surfactant, and a nonionic surfactant can be prepared.
  • the concentration of the cyanoacrylate monomer in the polymerization reaction solution at the start of the reaction is not particularly limited, but is usually about 0.5 v / v% to 2.0 v / v%, preferably about 0.8 v / v% to 1.2 v / v%. It is.
  • the reaction temperature is not particularly limited, but it is preferable because it is carried out at room temperature.
  • the reaction time varies depending on the pH of the reaction solution, the type of solvent, and the like, and therefore is appropriately selected depending on these factors. Although not particularly limited, the reaction time is usually about 10 minutes to 5 hours, preferably about 30 minutes to 4 hours. Since the obtained amino acid molecule-containing particles are usually used as neutral particles, it is preferable to neutralize the reaction solution by adding a base such as an aqueous sodium hydroxide solution after the reaction.
  • the reaction liquid after completion of the reaction may be filtered and washed with sterilized water as appropriate to collect the particles.
  • nano-sized cyanoacrylate polymer particles having an average particle diameter of less than 1000 nm can be easily produced.
  • the lower limit of the particle size is not particularly limited, but the particle size of the particles produced by the above polymerization reaction is usually about 7 nm or more.
  • the average particle size of the particles is 20 nm to 600 nm, more preferably 50 nm to 550 nm.
  • the size of the particles can be adjusted by adjusting the concentration and pH of the cyanoacrylate monomer in the reaction solution and the reaction time.
  • the particle size can also be adjusted by changing the concentration and type of the polymerization initiator / stabilizer (patent) References 3, 4 etc.).
  • concentration and type of the polymerization initiator / stabilizer (patent) References 3, 4 etc.).
  • the pH of the reaction solution is increased, when the reaction time is increased, and when the sugar concentration of the reaction solution is decreased, the particle size increases, and when polysorbate is used as a polymerization initiator / stabilizer, particles are increased. The size becomes smaller. By appropriately combining these reaction conditions, particles having a desired size can be produced.
  • the charge (zeta potential) of the nanoparticles is not particularly limited, but is usually about -50 mV to 0 mV.
  • the zeta potential indicates the charge on the particle surface and is an index of particle dispersibility.
  • the particle size and the zeta potential can be easily measured using, for example, a commercially available apparatus using a He / Ne laser (for example, a Zetasizer manufactured by Malvern Inst. UK).
  • Nanoparticles produced using amino acid-based molecules as polymerization initiators / stabilizers not only contain amino acid-based molecules attached to the particles, but also the -COO group in the amino acid structure of the ethylene end of cyanoacrylate. It is considered that it is bound to carbon and contained in the particle by a covalent bond.
  • the content of amino acid molecules in the particles obtained by the above method is usually about 20% to about 65%.
  • the content of amino acid-based molecules is determined by measuring the absorbance of the filter-passed solution when the filter is washed after polymerization at an appropriate wavelength, and the amount of amino-acid-based molecules in the filter-passed solution (ie, (Quantity) can be calculated by the following formula after obtaining by the absorbance method.
  • Amino acid molecule content (Amino acid molecule addition amount)-(Amount of amino acid molecule in the filter passage liquid)
  • Amino acid molecule content (%) Amino acid molecule content ⁇ Amino acid molecule addition x
  • the amino acid molecule-containing nanoparticles used in the present invention do not contain an antibacterial active ingredient against bacteria. It is known that cyanoacrylate polymer nanoparticles containing amino acids can exhibit antibacterial activity against both gram-positive and gram-negative bacteria, as described in Patent Documents 8 and 9, and are applied to the bacterial surface (cell wall). It exhibits antibacterial action by directing bacteria to lysis by specific adhesion. It has been confirmed that the cytotoxic activity of the nanoparticles is not exerted on normal mammalian cells, and the nanoparticles do not have in vivo toxicity. In addition, the amino acid molecule-containing nanoparticles used in the present invention do not contain an antibacterial active ingredient against fungi.
  • antibacterial active ingredient refers to a chemical substance component that can biochemically act on the metabolic pathway or physiological function of bacteria or fungi to inhibit the growth of the bacteria. Or it refers to antibiotics and other chemical components that can be used for fungal antibacterial activity. “No antibacterial active ingredient” means that it does not contain any antibacterial active ingredient, or even if it is contained in a very small amount, it cannot be used for antibacterial bacteria or fungi sensitive to the antibacterial active ingredient. This means that the antibacterial active ingredient is contained only in a trace amount.
  • the nanoparticles used in the present invention can also be said to be “substantially free” of antibacterial active ingredients against bacteria and fungi.
  • a trace amount that does not allow antibacterial activity means that the amount of antibacterial active ingredient contained in a particle per unit volume of the particle is defined as the concentration contained in the particle, and an antibacterial active ingredient having the same concentration as this content concentration It means an amount that does not prevent the growth of sensitive bacteria or fungi when it is allowed to act on sensitive bacteria or fungi alone without containing them.
  • the nanoparticles used in the present invention may be particles that do not contain any antibacterial active ingredient such as antibiotics.
  • the amino acid molecule-containing nanoparticles do not contain a chemical substance component having a therapeutic or preventive activity against dermatitis, such as a conventionally used dermatitis therapeutic agent.
  • a chemical substance component having a therapeutic or preventive activity against dermatitis such as a conventionally used dermatitis therapeutic agent.
  • the term “excluded” as used herein is the same as described above, and does not contain such a chemical substance component at all, or even if it contains such a chemical substance, it is extremely small, and can exert a therapeutic and preventive effect on skin lesions. It means that the chemical substance component is contained only in such a small amount as to be impossible.
  • Nanoparticles used in the present invention are not DDS as a dermatitis treatment drug, but the nanoparticles themselves control the skin inflammatory reaction through the improvement of skin barrier function and the immune response involved in controlling the number of superficial bacteria, Has the effect of treating and preventing inflammation.
  • the target dermatitis in the present invention is not particularly limited, but first, it may be dermatitis accompanied by pruritus (pruritic dermatitis). Specific examples of pruritic dermatitis include, but are not limited to, atopic dermatitis, contact dermatitis, infectious dermatitis, dermatitis due to psoriasis and autoimmune mechanism, drug eruption, and the like.
  • the target dermatitis may secondly be dermatitis related to skin injury.
  • dermatitis include, but are not limited to, radiation dermatitis, burns, acne and the like.
  • the amino acid molecule-containing nanoparticles have the action of suppressing type I and type IV allergic reactions. Therefore, the agent of the present invention comprising amino acid molecule-containing nanoparticles as an active ingredient is used as an inhibitor of type I allergic reaction or type IV allergic reaction, such as dermatitis involving type I allergic reaction or type IV allergic reaction. It is useful as an agent for treating or preventing allergic symptoms. It is known that the above pruritic dermatitis can involve type I allergic reaction or type IV allergic reaction.
  • the nano-sized cyanoacrylate polymer particles used in the present invention have antibacterial activity against bacteria (Patent Documents 8 and 9).
  • the antibacterial activity of the particles is expected to be effective against infected bacteria.
  • the agent of the present invention can be used, the dermatitis targeted in the present invention can be dermatitis other than dermatitis mainly caused by bacterial infection.
  • the agent of the present invention is used by locally administering to a skin lesion to be treated or a skin region where prevention of the occurrence of dermatitis is desired.
  • the local administration method include intracutaneous administration with injections, drops, etc., topical application with ointments, creams, patches, and the like.
  • the dosage is appropriately selected according to symptoms, age, body weight, administration method, etc., and is not particularly limited.
  • the amount of amino acid molecule-containing particles that are active ingredients for the target animal is about 0.01 ⁇ g to 10,000 mg per day. For example, it is about 1 ⁇ g to 100 mg, and is administered once or several times. Depending on the degree of symptom improvement, it may be administered once or several times daily for several days to several months, or once or several times every other day, or symptoms may occur Sometimes it may be administered.
  • the administration target of the agent of the present invention is a mammal, and examples thereof include humans, dogs, cats, rabbits, and hamsters.
  • the agent of the present invention may be used alone or in combination with other pruritic skin disease treatment or prevention agents and the like.
  • Standard treatments conventionally used for pruritic skin diseases are steroids, calcineurin inhibitors and antihistamines, but the agents of the present invention are considered to have a different mechanism of action from these standard treatments. Therefore, it is also possible to use the agent of the present invention in combination with a steroid agent or the like.
  • Nanosized polymer particles containing amino acids and dextran were produced according to the methods described in International Publication Nos. 2012/133648 and 2013/108871. The specific procedure is as follows.
  • the average particle diameter and zeta potential of the nanoparticles were measured using a commercially available zeta sizer (MalvernMInst. UK). Further, the amount of amino acid molecules in the filter passage liquid at the time of filter washing was determined by an absorbance method, and the amino acid content of the particles was calculated. The results are shown in Table 1.
  • Nanoparticles were suspended in sterilized water to prepare nanoparticle water (diluted to 0.3% (w / v), particle concentration 6 ⁇ g / ml) and used in the experiment. All of the mice used below were carried out in accordance with the experimental plan approved by the Kochi University Animal Experiment Committee, and were reared and experimented in an SPF environment.
  • NC / NgaSlc mice (Japan SLC, Shizuoka) are known to spontaneously develop dermatitis by tape stripping after shaving and depilation of the back, and are used as a model for atopic dermatitis (Matsuda , M., et.al. Int. Immunol. 9: 461, 1997).
  • 5 male 5-week-old NC / NgaSlc mice were used, and treatment was performed according to the schedule shown in FIG.
  • the back of the NC / NgaSlc mouse was shaved with a shaver and then removed with a hair removal cream (Epilat, Kracie Home Products, Tokyo).
  • the depilatory cream was wiped off, and tape stripping (Scotch Mending Tape, cat.no.810-3-24, 3M Japan, Tokyo) was performed 8 times with an adhesive tape the next day to induce dermatitis. The same operation was repeated when hair grew on the way. Three weeks later, in any mouse, the onset of dermatitis was confirmed over a wide area of the back (FIG. 2A).
  • mice that developed dermatitis 3 were the nanoparticle water spray group and 2 were the water spray group.
  • Nanoparticle water or sterilized water was sprayed every 2 days on the dorsal skin including the lesion.
  • a total liquid volume of 0.3 to 0.4 mL (1.8 to 2.4 ⁇ g as the amount of nanoparticles) was sprayed on 8 to 10 cm 2 of the back of one mouse.
  • the number of bacteria in the center of the back was measured on the 2nd, 6th and 8th days.
  • a mouse standard agar medium for viable cell count measured back central part of the (Petain check, Eiken) was pressed for 5 seconds, incubated for 24 hours at 37 ° C.
  • mice After leaving for 2 weeks from the 30th day in FIG. 1, all mice were again shaved and depilated for the purpose of inducing a hapten-induced type IV allergic reaction.
  • Photographs were taken on the second day after application of DNFB (Fig. 2D). On day 6 after application of DNFB, a serum sample was collected, then euthanized, and the skin on the back of the head with DNFB applied and the skin near the base of the tail without DNFB were collected and stained with hematoxylin-eosin (HE). Performed (FIGS. 5A-5D).
  • the degree of dermatitis of the mice A to D shown in FIG. 2 was scored according to the criteria shown in Table 2 below. Scoring was based on the literature reported by Fan et al. (Fan et al., Exp Biol Med, 226, 1045-1050, 2001). The degree of score was evaluated with a score of 0 to 3 for three skin lesions.
  • the number of colonies in the agar medium was 5, 7, and 8 for the nanoparticle water spray group, whereas that for the distilled water spray group was 48 and 85. It was confirmed that the antibacterial ability of nanoparticulate water was exhibited early after spraying.
  • Photographs were taken on days 0, 3, 7, 11, 13, 15, 22, 23, and 24, and dermatitis was scored according to the criteria shown in Table 2 above. The dorsal head side and caudal side were scored separately, and the total value was evaluated.
  • Blood sampling is performed before tape stripping (FIG. 7, blood sampling 1), 22 days after induction of tape stripping (FIG. 7, blood sampling 2), and 2 days after starting re-induction with DNFB application (FIG. 7, blood sampling 3).
  • the amount of IgE in the serum fraction was measured by sandwich ELISA.
  • the skin tissue on the dorsal head side and the caudal side of the mouse was collected. A part of the skin tissue was used for HE tissue staining evaluation. In addition, mRNA was extracted from the remaining part, and various cytokine expression levels (IL-1 ⁇ , TNF- ⁇ , IL-6, IL-17A, IL-4, IFN- ⁇ ) were examined by quantitative RT-PCR. . The expression level was normalized with respect to the HPRT gene and evaluated by relative expression level. Table 5 shows primer sequences for each mouse cytokine.
  • the degree of dermatitis induced when restimulated with DNFB application was milder in the nanoparticle water spray group than in the water spray group, suggesting a preventive effect.
  • the skin damage caused by shaving with a shaver and hair removal cream before DNFB application was lower in the nanoparticle water spray group.
  • HE skin histopathological image Fig. 11 shows an HE-stained image of skin tissue after reinduction of inflammation.
  • DNFB-applied dorsal epidermis thickening and dermal inflammation were milder in the nanoparticle water spray group than in the water spray group.
  • epidermal thickening was markedly suppressed in the nanoparticle water spray group, and no inflammatory cell infiltration was observed.
  • Cytokine expression level Fig. 12 shows the results of examining various cytokine expression levels by dividing the dermatitis induction part of the back into the dorsal head side (with DNFB application) and caudal side (without DNFB application).
  • cytokines associated with the disruption of barrier function such as IL-1 ⁇ , TNF- ⁇ , IL-6, etc., with or without nanoparticulate water spray, do not have DNFB applied to the dorsal temporal side and DNFB Expression was observed on the tail side of the painted area.
  • DNFB IL-17A, IL-4, and IFN- ⁇
  • cytokines produced by T cells were low in both cranial and caudal skin with and without nanoparticle water spray .
  • the nanoparticle water spray group is more effective than the distilled water spray group. It is concluded that Furthermore, compared with the distilled water spray group, the nanoparticle water spray group showed mild epidermal thickening and dermal inflammation, and the lesion was mild even after induction of dermatitis by DNFB application again. It is thought that spraying plays a role in controlling this and protecting the skin against repeated inflammation induction.
  • the blood IgE level at the end of the experiment was significantly higher than the blood IgE level at the start of the experiment and before reinducing the inflammation, but unlike the NC / NgaSlc mice, the BALB / c mice had nanoparticles. There was no significant difference between the water spray group and the water spray group.
  • Photographing was performed on days 0, 3, 7, 11, 13, 15, 22, 23, 24, and the therapeutic effect on skin inflammation was observed, and the degree of dermatitis was scored according to the criteria shown in Table 2 above. . It was scored separately for the dorsal head side (treatment model) and caudal side (prevention model) and evaluated.
  • Blood samples were collected on day 0 (blood collection 1), day 22 (blood collection 2) and day 24 (blood collection 3), and the IgE amount of the serum fraction was measured by sandwich ELISA.
  • mice skin tissues on the dorsal head side (treatment model) and caudal side (prevention model) of mice were collected, and HE tissue staining observation and cytokine expression level measurement were performed.
  • FIG. 14 shows a photograph of the back of the mouse
  • FIG. 15 shows score evaluation results of the inflammatory state.
  • the therapeutic effect on dermatitis induced by tape stripping and DNFB application was superior to nanoparticle water spray than water spray.
  • the degree of dermatitis induced when restimulated by DNFB application was lower in the nanoparticle water spray group than in the water spray group, and was superior in the preventive effect.
  • damage to the skin when shaving with a shaver and a hair removal cream before applying DNFB was lower in the nanoparticle water spray group.
  • FIG. 17 shows an HE stained image of the skin pathological tissue after induction of inflammation.
  • a preventive model of dermatitis the skin thickening on the dorsal and caudal side where nanoparticle water or water was sprayed first and dermatitis was induced before the end of the experiment was observed in the nanoparticle spray group than in the water spray group. It was mild.
  • the skin on the back of the head which was previously applied with DNFB and subsequently sprayed with nanoparticulate water or water, also showed that epidermal thickening was milder in the nanoparticle spray group than in the water spray group. there were.
  • FIG. 18 shows the results of examining the expression levels of various cytokines divided into models.
  • Cytokines associated with disruption of barrier function such as IL-1 ⁇ , TNF- ⁇ , and IL-6 are induced by applying DNFB before the end of the experiment as a model for preventing dermatitis with or without nanoparticle spraying.
  • DNFB was first applied as a treatment model for the caudal part and the existing dermatitis, and expression was observed in both the dorsal head side without DNFB application immediately before the end of the experiment. Furthermore, a high tendency was observed in the dorsal caudal side where DNFB was applied before skin collection.
  • cytokines produced by T cells IL-17A, IL-4, IFN Regardless of the presence or absence of nanoparticle spraying, - ⁇ increased in expression on the dorsal caudal side where DNFB was applied before the end of the experiment compared to the cranial side where DNFB was not applied before the end of the experiment.
  • the expression level of IFN- ⁇ tended to increase in the nanoparticle water spray group compared to the water spray group.
  • Tape stripping was repeatedly performed according to the schedule shown in FIG. After shaving and removing the back of 12-week-old BALB / c mice, measuring the amount of water transpiration (indicator of skin barrier function) and stripping the tape so that the value is in the range of 30-50 g / hm 2 ( 3-5 times).
  • the Multi Probe Adapter System (abbreviation MPA5) (software: CK-MPA-multi-probe version 1.5.1.4) of Courage + Khazaka electronic GmbH (Cologne, Germany)
  • a probe to which a Tewameter (registered trademark) probe (TM300MP) was connected was used. In the measurement, the probe was pressed against the left foot base so as not to be displaced.
  • the thickness of the epidermis is thicker in the water spray group than in the nanoparticle water spray group in the HE-stained skin sample collected on the 14th day, as shown in FIG.
  • cytokines associated with disruption of epidermal barrier function such as IL-1 ⁇ , TNF- ⁇ , IL-6 after repeated tape stripping was examined by RT-PCR method (results are shown in FIG. 23). Regardless of the presence or absence of nanoparticle water spray, the same level of expression was observed on both the dorsal caudal side and the cranial side.
  • the expression levels of cytokines produced by T cells were low for IL-4 and IFN- ⁇ , and there was no significant difference between the two groups, but IL- The expression level of 17A was higher in the water spray group than in the nanoparticle water spray group, suggesting that the skin barrier function was more impaired in the water spray group than in the nanoparticle water spray group.
  • the dermatitis score was defined as shown in Table 7 below, and the degree of dermatitis was scored. For each mouse, a score of 0 to 3 was assigned to 7 items of erythema, scales, wrinkles, protuberances, crusts, left auricle thickening / deformation, and right auricle thickening / deformation. did. The maximum score per animal is 21 points. The dermatitis score was measured on mice of each experimental group on day 5, day 12, day 19, day 26, day 33.
  • FIG. 25 shows the results of tracking the changes in the dermatitis scores on the back of the head and DNA after application of DNFB. Moreover, the image of the head side dorsal skin and both ears of each experimental group on day33 is shown in FIG.
  • the dermatitis score was clearly lower in group A sprayed with nanoparticle water together with DNFB application than group C (positive control group) and water spray B group that were not sprayed with nanoparticle water (FIG. 25).
  • Group D represents a negative control in which neither DNFB application nor spraying was performed.
  • dermatitis and auricular deformation were clearly observed in Group B and Group C, while the nanoparticle water spray group (Group A) was the same as the negative control (Group D), with marked symptoms. Suppressed.
  • Fig. 28 shows the results of measurement of skin moisture transpiration.
  • Group B and Group C the amount of transpiration increased significantly on day 12 after application of DNFB, and high transpiration was observed thereafter.
  • the nano-particle water spray group Group A
  • group A showed significantly lower values than groups B and C.
  • FIGS. 30A to 30D are typical pinna and cranial dorsal skin symptoms and HE-stained images of Groups A to D.
  • FIG. A-1, B-1, C-1, and D-1 are HE tissue staining photographs of the right auricular skin
  • A-2, B-2, C-2, and D-2 are HE on the dorsal skin. It is a tissue staining photograph.
  • the black bar indicates 100 ⁇ m.
  • Group C skin inflammation was strongly observed as in Group B, and changes in the auricle and back skin were observed more strongly than Group A.
  • results are shown in FIG.
  • the amount of anti-DNP antibody does not change much between the three groups: nanoparticle water spray group (A), water spray group (B), and non-spray group (C), and immune response to DNP (reaction between B cells and Th cells) was confirmed to be innocent. This suggests that it is unlikely that the hapten-induced immune response itself has decreased due to a decrease in the reactivity of DNFB to the skin due to the presence of nanoparticles associated with the skin.
  • Results are shown in FIG. In the nano-particle water spray group (Group A), the number of bacteria varies compared to the water spray group (Group B), the non-spray group (Group C), and the untreated group (Group D) that does not perform pretreatment or DNFB application. Less and lower value.
  • Results are shown in FIG.
  • the aggregation value of the nanoparticle water spray group (Group A) is significantly lower than that of the water spray group (Group B) and the group without spray spray (Group C).
  • the skin inflammation score value was lower than that in the water spray group and the non-spray group.
  • the skin inflammation score value was related not only to the thickening of the auricle, which is an index of immune responsiveness, but also to the back skin moisture transpiration amount and the water retention level, which is an index of skin barrier function.
  • the epithelial proliferation-related cytokines were expressed along with the Th17 cell line, whereas in the water spray group and the non-spray group, it was expressed through a skin damage-related signal.
  • the number of superficial bacteria in the nanoparticle water spray group was controlled to a certain low value compared with the other three groups.
  • nanoparticle water spray controls the skin inflammatory reaction through the improvement of the skin barrier function and the immune response involved in controlling the number of superficial bacteria.

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Abstract

La présente invention concerne un nouveau moyen permettant de traiter ou de prévenir la dermatite atopique et d'autres types de dermatites. L'agent pour le traitement ou la prévention de la dermatite selon l'invention contient comme principe actif des particules de polymère de cyanoacrylate de taille particulaire moyenne inférieure à 1 000 nm (nanoparticules contenant des molécules d'acides aminés), lesdites particules comprenant au moins un élément choisi dans le groupe comprenant des acides aminés, des dérivés d'acides aminés, et des oligomères et polymères de ces derniers. Les nanoparticules contenant des molécules d'acides aminés présentent un effet suppresseur des réactions allergiques de type I et de type IV et sont par conséquent utilisables, par exemple, comme agent pour le traitement ou la prévention de symptômes de l'allergie, tels que la dermatite, impliquant une réaction allergique de type I ou une réaction allergique de type IV.
PCT/JP2016/052379 2015-01-27 2016-01-27 Agent permettant le traitement ou la prévention de la dermatite utilisant des nanoparticules comme principe actif Ceased WO2016121829A1 (fr)

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US10238617B2 (en) 2016-12-19 2019-03-26 Axcella Health Inc. Amino acid compositions and methods for the treatment of liver diseases
US10471034B2 (en) 2016-12-19 2019-11-12 Axcella Health Inc. Amino acid compositions and methods for the treatment of liver diseases
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US11602511B2 (en) 2016-12-19 2023-03-14 Axcella Health Inc. Amino acid compositions and methods for the treatment of liver diseases
US10660870B2 (en) 2017-08-14 2020-05-26 Axcella Health Inc. Compositions and methods for the treatment of liver diseases and disorders associated with one or both of hyperammonemia or muscle wasting
US10682325B2 (en) 2017-08-14 2020-06-16 Axcella Health Inc. Compositions and methods for the treatment of liver diseases and disorders associated with one or both of hyperammonemia or muscle wasting
US11571404B2 (en) 2017-08-14 2023-02-07 Axcella Health Inc. Compositions and methods for the treatment of liver diseases and disorders associated with one or both of hyperammonemia or muscle wasting
US10596136B2 (en) 2018-06-20 2020-03-24 Axcella Health Inc. Compositions and methods for the treatment of fat infiltration in muscle
US10973793B2 (en) 2018-06-20 2021-04-13 Axcella Health Inc. Compositions and methods for the treatment of fat infiltration in muscle
US11833127B2 (en) 2018-06-20 2023-12-05 Axcella Health Inc. Compositions and methods for the treatment of fat infiltration in muscle
US12357581B2 (en) 2019-04-10 2025-07-15 Sinteff Tto As Nanoparticles comprising copolymeric or homopolymeric compounds which comprise cyanoacrylate subunits

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