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WO2017048018A1 - Composition pharmaceutique contenant un médicament anionique, et son procédé de préparation - Google Patents

Composition pharmaceutique contenant un médicament anionique, et son procédé de préparation Download PDF

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Publication number
WO2017048018A1
WO2017048018A1 PCT/KR2016/010269 KR2016010269W WO2017048018A1 WO 2017048018 A1 WO2017048018 A1 WO 2017048018A1 KR 2016010269 W KR2016010269 W KR 2016010269W WO 2017048018 A1 WO2017048018 A1 WO 2017048018A1
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WIPO (PCT)
Prior art keywords
acid
formula
group
integer
copolymer
Prior art date
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PCT/KR2016/010269
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English (en)
Korean (ko)
Inventor
남혜영
김봉오
서민효
손지연
최지혜
김상훈
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Samyang Biopharmaceuticals Corp
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Samyang Biopharmaceuticals Corp
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Priority to DK16846839.5T priority Critical patent/DK3357491T3/da
Priority to AU2016324450A priority patent/AU2016324450B2/en
Priority to EP16846839.5A priority patent/EP3357491B1/fr
Priority to SG11201802073YA priority patent/SG11201802073YA/en
Priority to CA2998092A priority patent/CA2998092C/fr
Priority to RU2018113459A priority patent/RU2721558C2/ru
Priority to US15/759,943 priority patent/US11253598B2/en
Priority to MX2018003096A priority patent/MX386005B/es
Priority to JP2018533597A priority patent/JP6638072B2/ja
Application filed by Samyang Biopharmaceuticals Corp filed Critical Samyang Biopharmaceuticals Corp
Priority to ES16846839T priority patent/ES2883290T3/es
Priority to CN201680053810.0A priority patent/CN108024960B/zh
Priority claimed from KR1020160117053A external-priority patent/KR101828877B1/ko
Publication of WO2017048018A1 publication Critical patent/WO2017048018A1/fr
Priority to IL257937A priority patent/IL257937B/en
Anticipated expiration legal-status Critical
Priority to ZA2018/02303A priority patent/ZA201802303B/en
Priority to US17/572,195 priority patent/US20220125929A1/en
Ceased legal-status Critical Current

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention relates to a pharmaceutical composition containing an anionic drug and to delivering the same, and to a method of preparing the same.
  • nucleic acid materials Numerous studies have been conducted on non-viral carriers used for the delivery of nucleic acid materials. The most representative ones are cationic lipids using cationic lipids and lipoplexes and polycation polymers and nucleic acids.
  • the cationic lipids or polycationic polymers studied so far have less results than viral carriers, but have severe toxicity when used in amounts necessary to achieve a striking effect, resulting in inadequate use in medicine.
  • the lipid-nucleic acid complexes which combine the cationic lipids with the nucleic acids and deliver the nucleic acids into the cells, are very widely used in cell line experiments, but do not exhibit a structure that can have stability in blood. It is possible to use it in vivo (see US Pat. No. 6,458,382).
  • anionic drug delivery compositions that form a complex by electrostatic interaction of a nucleic acid with a cationic lipid such that the complex is encapsulated within the micellar structure of the amphiphilic block copolymer.
  • this also provides room for improvement in blood stability of the nucleic acid and specific targeting to cancer tissues.
  • Korean Patent No. 1296326 discloses an anionic drug as an active ingredient; Cationic Lipids; An amphiphilic block copolymer and a polylactic acid, wherein the anionic drug forms a complex with the cationic lipid, and the complex has a structure encapsulated inside a micellar structure formed by the amphiphilic block copolymer and the polylactic acid.
  • An anionic drug delivery composition is disclosed.
  • polylactic acid used in this patent is a general polylactic acid polymer having a carboxyl group at its terminal, and has a problem of insufficient drug delivery effect.
  • siRNA short interfering RNA
  • siRNAs are short, double-stranded RNA strands that inhibit the expression of glycolysis by cleaving mRNAs of genes complementary to these (McManus and Sharp, Nature Rev. Genet. 3: 737 (2002); Elbashir, et. al., Genes Dev. 15: 188 (2001).
  • siRNAs are known to be rapidly degraded by nucleases in blood and rapidly excreted in vitro through the kidneys.
  • siRNA is known to have a strong negative charge does not easily cross the cell membrane. Therefore, in order to use siRNA as a therapeutic agent, siRNA needs to be stabilized in the blood, efficiently delivered into a target tissue or cell, and development of a non-toxic carrier.
  • an object of the present invention is to provide a composition for anionic drug delivery comprising a micellar structure containing polylactic acid salt to effectively deliver the anionic drug in the body.
  • the present invention is an anionic comprising administering the composition It is an object to provide a method of delivery of a drug.
  • an object of the present invention is to provide a method for preparing a pharmaceutical composition that can effectively deliver such a negative drug.
  • the present invention comprises an anionic drug delivery composition comprising a micellar structure containing polylactic acid salt to effectively deliver an anionic drug to the body, uses for the anionic drug delivery of the composition and administering the composition. It relates to a method of delivery of anionic drugs.
  • the anionic drug delivery composition comprising the micelle structure according to the present invention is a structure containing a complex of a drug and a divalent compound in the micelle structure of the amphiphilic block co-polymer and the polylactic acid salt.
  • the anionic drug forms a complex by electrostatic interaction with the cationic compound, and the complex thus formed is enclosed in a micelle structure formed by an amphiphilic block copolymer and a polylactic acid salt. It is done.
  • the composition is soluble in water and comprises polylactic acid as a component to form micelle structures, thereby increasing the stability of blood and avoiding reticulum endothelial system (RES) during infusion into the target site, specifically cancer tissue. It is also useful for evasion and / or targeting of reticulum endothelial system (RES) because of its high efficiency in delivery.
  • RES reticulum endothelial system
  • step (a) Dissolving a polylactate in a water-soluble organic solvent or a mixed solvent of an aqueous solution and an organic solvent; (b) removing the organic solvent layer of step (a);
  • step (c) process of micellizing by adding an aqueous solution to the mixture from which the organic solvent of step (b) is removed
  • the anionic drug is isolated from the outside by using a micellar structure formed of a cationic compound and an amphiphilic block polymer and a polylactic acid salt. You can increase the stability. Therefore, the pharmaceutical composition can increase the stability of the anionic drug in the blood or body fluid when administered in the body, and particularly has the advantage that the anionic drug can be efficiently delivered into the cell avoiding the reticuloendothelial system.
  • FIG. 1 is a diagram showing a schematic structure of a polymer micelle delivery vehicle in which a complex of an anionic drug and a bipolar compound according to the present invention is encapsulated.
  • Figure 2 is a view showing the NMR results of the polylactic acid sodium salt according to Preparation Example 8.
  • composition of the composition according to the present invention the anionic drug and the cationic compound is enclosed in the micellar structure formed by the amphiphilic block polymer and polylactic acid salt, the complex of such anionic drug and cationic compound is enclosed
  • the approximate structure of the polymerized micelle transporter is shown in FIG. 1.
  • anionic drugs bind to each other through an electrostatic interaction with a cationic compound to form a complex of a negative drug and a cationic compound.
  • the anionic drug and cationic compound complex formed are encapsulated in a micellar structure formed by an amphiphilic block copolymer and a polylactic acid salt.
  • the micellar structure formed by the amphiphilic block copolymer and the polylactic acid salt is a hydrophilic portion of the amphiphilic block copolymer in an aqueous environment.
  • the polylactic acid salt that forms the outer wall of the micelle and contains the hydrophobic portion of the amphiphilic block copolymer and the amphiphilic block co-polymer as a separate component forms the inner wall of the micelle, and the anionic drug and the cation inside the formed micelle. It is a structure encapsulated with a compound of a sex compound.
  • the anionic drug and the cationic compound complex is maintained in the micelle structure formed by the amphiphilic block copolymer and the polylactic acid salt to improve stability in blood or body fluids.
  • the particle size of the micelles 10 to 200 m, more preferably 10 to 150nm.
  • the standard charge of the micelle particles is -20 to 20 mV, more preferably -10 to 10 mV. The particle size and standard charge are most preferred in terms of stability of the micellar structure and the content of constituents, the absorption of anionic drugs in the body, and the convenience of sterilization as a pharmaceutical composition.
  • the anionic drug included as an active ingredient in the composition according to the present invention is a concept including all substances having a negatively charged pharmacological activity in the molecule in aqueous solution.
  • the anionicity may be imparted from one or more functional groups selected from the group consisting of carboxyl groups, phosphate groups and sulfate groups.
  • the anionic drug may be a polyanionic drug or nucleic acid such as peptide, protein or heparin.
  • the nucleic acid material may be a deoxyribonucleic acid, a ribo nucleic acid or a backbone, a nucleic acid drug such as a polynucleotide derivative whose sugar or base is chemically modified or modified at the end, and more specifically, RNA, DNA, siRNA (short interfering RNA), aptamer, antisense oligodeoxynucleotide (ODN), antisense RNA (antisense RNA), ribozyme (ribozyme) and DNAzyme (DNAzyme) may be one or more selected from the group consisting of. .
  • the nucleic acid may be chemically modified or terminally modified with a backbone, sugar or base for the purpose of increasing blood stability or weakening the immune response. Specifically, some of the phosphodiester bonds of the nucleic acid
  • a phosphorothioate or boranophosphate bond or a methyl, methoxyethyl group, at the 2'-OH position of some ribose base, It may include one or more modified nucleotides in which various functional groups such as fluorine are introduced.
  • At least one terminus of the nucleic acid is cholesterol, tocopherol and carbon number
  • siRNA can be modified at the 5 'end, or 3' end, or both ends of the sense and / or antisense strand, and preferably at the end of the sense strand.
  • the cholester, tocopherol and fatty acids having 10 to 24 carbon atoms having 10 to 24 carbon atoms
  • the siRNA mediates the degradation of mRNA complementary to the siRNA sequence when present in the same cell as the target gene, thereby exerting the expression of the target gene.
  • duplex RNA or single-stranded RNA that forms a double strand inside single-stranded RNA that can be reduced or inhibited. Bonding between the double strands is via hydrogen bonds between the nucleotides, and not all nucleotides within the double strands must complementarily bind to each other, and both strands may or may not be separated.
  • the length of the siRNA is about 15 to 60 (the number of single nucleotides of the double-stranded RNA, that is, the number of base pairs, and in the case of a single-stranded RNA, the length of the double stranded RNA within the single-stranded RNA). Nucleotides, specifically about 15 to 30 nucleotides, and more specifically about 19 to 25 nucleotides
  • SiRNA which is a nucleotide.
  • the double-stranded siRNA may have an overhang of 1-5 nucleotides at either the 3 'or 5' end, at one end, or at both ends.
  • both ends may be in the form of blunts without protrusions.
  • siRNA disclosed in US Patent Publication No. 2002-0086356, US Patent No. 7,056,704, which is incorporated herein by reference.
  • the siRNA may have a symmetrical structure in which the two strands are the same length, or an asymmetric double stranded structure in which one strand is shorter than the other strand.
  • antisense of 19 to 21 nucleotides nucleotides, nt
  • siRNA can be an asymmetric siRNA with nucleotide overhangs. Specifically, it may be siRNA disclosed in International Patent Publication No. 09/078685.
  • the anionic drugs by weight of the total composition, from 0.001 to 10 parts by weight 0/0, specifically, is preferably contained in an amount of 0.01 to 5% by weight.
  • the anionic When the content of the drug 0.001 0/0 is less than an amount of the delivery system to be used as compared to the drug may cause side effects due to too many delivery system, when it exceeds 10% by weight, the size of the micelle becomes too large stability misael There is a risk of lowering and increasing the loss rate during filter sterilization.
  • the cationic compound is bonded by an electrostatic interaction with the anionic drug to form a complex, the complex is encapsulated inside the micelle structure of the amphiphilic block copolymer.
  • the cationic compound includes all types of compounds capable of forming a complex by electrostatic interaction with the anionic drug, and may be, for example, a lipid and a polymer type.
  • Cationic lipids include ⁇ , ⁇ -dioleyl- ⁇ , ⁇ -dimethylammonium chloride (DODAC), ⁇ , ⁇ -distearyl- ⁇ , ⁇ -dimethylammonium bromide (DDAB), N- (l- (2, 3-dioleoyloxy) propyl- ⁇ , ⁇ , ⁇ -trimethylammonium chloride (DOTAP), N, N-dimethyl- (2,3-dioleoyloxy) propylamine (DODMA), ⁇ , ⁇ , ⁇ - Trimethyl- (2,3-dioleoyloxy) propylamine (DOTMA), 1,2-diacyl-3-trimethylammonium-propane (TAP), 1,2-diacyl-3-dimethylammonium-propane (DAP ), 3beta- [ ⁇ - ( ⁇ ', ⁇ ', ⁇ '-trimethylaminoethane) carbamoyl] cholester (
  • (Aminoethane) carbamoyl] cholesterol AC-cholesterol
  • cholesteryloxypropane-1-amine COPA
  • N- (N'-aminoethane) carbamoylpropanoic tocopherol AC-tocopherol
  • N- It may be one or a combination of two or more selected from the group consisting of (N′_methylaminoethane) carbamoylpropanoic tocopherol (MC-tocopherol).
  • Such cationic When using lipids, it is desirable to use less polycationic lipids with high cation density in the molecule in order to reduce the toxicity caused by cationic lipids, and more specifically, the functional groups capable of exhibiting cations in aqueous solution per molecule. It can be one.
  • the cationic lipid is 3beta- [ ⁇ - ( ⁇ ', ⁇ ', ⁇ '-trimethylaminoethane) carbamoyl] cholester (TC-cholester) : 3beta [ ⁇ - ( ⁇ ', ⁇ '-dimethylaminoethane) carbamoyl] cholesterol (DC-cholesterol), 3beta [N- ( ⁇ '-monomethylaminoethane) carbamoyl] cholester (MC -Cholester), 3-beta [ ⁇ - (aminoethane) carbamoyl] cholesterol (AC-cholesterol), N- (l- (2,3-dileoyloxy) propyl- ⁇ , ⁇ , ⁇ -trimethylammonium chloride (DOTAP), ⁇ , ⁇ -dimethyl- (2,3-dileoyloxy) propylamine (DODMA), and ⁇ , ⁇ , ⁇ -trimethyl-
  • DC-cholesterol 3
  • polyarginine polyamidoa
  • PAMAM polyethylenimine
  • dextran dextran
  • hyaluronic acid albumin
  • albumin albumin
  • PEI polymer 3 ⁇ 4riethyleneimine
  • PVAm polyamine and polyvinylamine
  • the cationic lipid may be a cationic lipid of Formula 7:
  • n and m are each 0 to 12
  • a and b are each 1 to 6
  • R1 and R2 are each independently selected from the group consisting of saturated and unsaturated hydrocarbons of 1 to 25 carbon atoms will be.
  • n and m are independently 1 to 9, and may be 2 ⁇ n + m ⁇ 10.
  • a and b may be 2 to 4.
  • R 1 and R 2 are each independently lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, capita Lignoceryl, cerotyl, myristoleyl, palmitoleyl, sapienyl, oleyl, linoleyl, arachidyl It may be selected from the group consisting of (arachidonyl), eicosapentaenyl, ethucyl, erucyl, docososahexaenyl, and serrotyl.
  • cationic lipids include 1,6-dileoyltriethylenetetramide, 1,8-dilinoleylyltetraethylenementamide, 1,4-dimyristoleoyldiethylenetriamide, 1,10- At least one selected from the group consisting of distearoylpentaethylenenucleamide and 1,10-dioleoylpentaethylenenucleamide.
  • Cationic compounds used in the present invention based on the weight of the total composition may be included 0.01 to 50% by weight, specifically 1 to 10% by weight.
  • the cationic content of the lipids not being a sufficient amount to form an anionic drug and the complex is less than 0.01%, 50 weight exceeds 0/0, the size of the micelle so increases the stability of the misael decreases filter sterilization The loss rate may increase.
  • the ratio of the amount of charge of the anionic drug ( ⁇ ) and the cationic compound ( ⁇ ) ( ⁇ / ⁇ ; cationic charge ratio of the cationic compound to the anionic charge of the anionic drug) is 0.1 to 128. Specifically, it is 5 to 64, more specifically 1 to 32, and even more specifically 1 to 24, most preferably 6 to 24. If the ratio ( ⁇ / ⁇ ) is less than 0.1, since it is difficult to form a complex containing a sufficient amount of anionic drugs, it is advantageous to form a complex containing a sufficient amount of anionic drugs at a ⁇ or more. On the other hand, when the ratio ( ⁇ / ⁇ ) exceeds 128, it may cause toxicity, so it is preferable to set it to 128 or less.
  • amphiphilic block copolymer is a hydrophilic A block and
  • the AB type block copolymer may be a hydrophobic B block copolymer comprising a hydrophobic B block forming a core (inner wall) and a hydrophilic A block forming a shell (outer wall). Forms shell-type polymer micelles.
  • the hydrophilic A block may be at least one selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, polyvinylpyridone, polyacrylamide and derivatives thereof. More specifically, the hydrophilic A block
  • hydrophilic A block It may be at least one selected from the group consisting of monomethoxy polyethylene glycol, monoacetoxy polyethylene glycol, polyethylene glycol, copolymers of polyethylene and propylene glycol and polyvinylpyridone.
  • the hydrophilic A block It may be at least one selected from the group consisting of monomethoxy polyethylene glycol, monoacetoxy polyethylene glycol, polyethylene glycol, copolymers of polyethylene and propylene glycol and polyvinylpyridone.
  • the number average molecular weight may be 200 to 50,000 Daltons, more specifically 1,000 to 20,000 Daltons, and more specifically 1,000 to 5,000 Daltons.
  • a functional group capable of reaching a specific tissue or cell, a ligand, or a functional group capable of promoting intracellular delivery at the end of the hydrophilic A block is necessary.
  • the functional group or ligand may be one or more selected from the group consisting of monosaccharides, polysaccharides, vitamins, peptides, proteins and antibodies to cell surface receptors.
  • the functional group or ligand is an anamide (anisamide), vitamin B9 (folic acid), vitamin B12, vitamin A, galactose, lactose, mannose, hyaluronic acid, RGD peptide, NGR peptide, transferrin, transferrin receptor It may be one or more selected from the group consisting of.
  • the hydrophobic B block is a biocompatible biodegradable polymer, and in one embodiment, may be at least one selected from the group consisting of polyester, polyanhydride, polyamino acid, polyorthoester and polyphosphazine. More specifically, the hydrophobic B specific polylactide, polyglycolide,
  • Polycaprolactone polydioxan-2-one, copolymer of polylactide and glycolide, copolymer of polylactide and polydioxan-2-one, copolymer of polylactide and polycaprolacron and polyglycol Consisting of a copolymer of a lide and a polycaprolactone
  • the hydrophobic B Blocks have a number average molecular weight of 50 to 50,000 Daltons, more specifically 200 to
  • tocopherols tocopherols, cholesterol, or fatty acids having 10 to 24 carbon atoms
  • Amphiphilic block comprising said hydrophilic block (A) and hydrophobic block (B)
  • the content of the copolymer composition is, based on the total dry weight, 40 to 99.98% by weight, in particular from 85 to 99.8 parts by weight 0/0, more specifically, is preferably 90 to 99.8 wt. 0/0. If the amphiphilic block the amount of the copolymer 40 parts by weight 0 / under 0 reduced is too large the stability of the micelle size of the micelles and may cause greater the city filter sterilized loss rate, which when to embedded content exceeds 99.98 increase% The content of anionic drugs becomes too small.
  • the composition ratio of the hydrophilic block (A) and the hydrophobic block (B) is 40 to 70 weight 0 based on the weight of the copolymer .
  • ⁇ specifically, may range from 50 to 60% by weight.
  • hydrophilic beulteuk (A) ratio is 40 parts by weight 0/0 if less difficult to form the misael solubility in water of the polymer is low
  • the copolymer is a hydrophilic block in order to have the solubility in a cheungbun water to form micelles ol because of the difficulty of use as a solubilizing composition of the drug / cationic lipid complex
  • - is (a) not less than the ratio of 40% by weight of the good on the other hand, 70 parts by weight when it is more than 0 / lowers the hydrophilicity is so high that the stability of the polymeric micelles anionic.
  • the ratio of the hydrophilic block (A) is preferably 70% by weight or less.
  • the amphiphilic block copolymer encapsulates the anionic drug and the cationic lipid complex inside the micellar structure in an aqueous solution, wherein the anionic drug and the cationic lipid are compared to the weight (b) of the amphiphilic block copolymer.
  • Weight (a) ratio of the composite [a / b X 100; (Anionic drug weight + amount Lee Eun-sung lipid weight) / amphiphilic block copolymer weight X 100] is from 0.001 to 100 parts by weight 0/0, and specifically from 0.01 to 50 parts by weight 0 /., More specifically from 0.1 to 10 parts by weight 0/0 can be.
  • the weight ratio is less than 0.001 weight 0 /., The content of the anionic drug and the cationic lipid complex is too low to stratify the effective content that the negatively effective drug can act effectively. This is difficult, on the contrary, when it exceeds 100% by weight, it does not form a micelle structure of the appropriate size in consideration of the molecular weight of the amphiphilic block-heap sieve and the amount of the anionic drug and lipid complex.
  • the micellar structure of the composition according to the invention is characterized in that it comprises polylactic acid salt (PLANa).
  • the polylactic acid salt is distributed in the core (inner wall) of micelles to enhance the hydrophobicity of the core to stabilize the micelles and to effectively avoid the reticulum endothelial system (RES) in the body. That is, the carboxylic acid anion of polylactic acid is more effectively combined with the cationic complex than polylactic acid to reduce the surface potential of the polymer micelles, thereby reducing the positive charge of the surface potentials compared to the polymer micelles that do not contain polylactic acid. Is less trapped by and has the advantage of excellent delivery efficiency to the desired site (eg cancer cells, inflammatory cells, etc.).
  • the desired site eg cancer cells, inflammatory cells, etc.
  • the polylactic acid salt included may have a number average molecular weight of 500 to 50,000 Daltons, specifically 1,000 to 10,000 Daltons. If the molecular weight is less than 500 Daltons, the hydrophobicity is too low to be present in the core (inner wall) of the micelle, and if the molecular weight exceeds 50,000 Daltons, there is a problem that the particles of the polymer micelle become large.
  • the polylactic acid salt may be used in an amount of 1 to 200 parts by weight, specifically 10 to 100 parts by weight, more specifically 30 to 60 parts by weight, based on 100 parts by weight of the amphipathic block polymer.
  • the content of the polylactic acid salt exceeds 200 parts by weight relative to 100 parts by weight of the amphiphilic block polymer, the size of the micelle increases, making it difficult to filter using a sterile membrane, and when the content is less than 1 part by weight, the desired effect cannot be sufficiently obtained.
  • it can contain 10 to 1,000 parts by weight of the amphipathic block copolymer relative to 1 part by weight of anionic drug, and 5 to 500 parts by weight of polylactic acid salt.
  • the amphiphilic block copolymer may be contained in an amount of 50 to 800 parts by weight, more preferably 100 to 500 parts by weight. Preferably, it may contain 10 to 300 parts by weight of polylactic acid salt, more preferably 50 to 100 parts by weight.
  • the terminal opposite of sodium carboxylate in the terminal of the polylactic acid salt is hydroxy, aceoxy, benzoyloxy, decanoyloxy, palmitoyloxy and It may be substituted with one selected from the group consisting of alkoxy having 1 to 2 carbon atoms.
  • the polylactic acid salt of the present invention is characterized in that at least one selected from the group consisting of compounds of the formula (1) to (6).
  • A is -COO-CHZ-; ⁇ is -COO-CHY-, -COO-CH 2 CH 2 CH 2 CH 2 CH 2 -or -COO-CH 2 CH 2 OCH 2 ; R is a hydrogen atom or an acetyl, benzoyl, decanoyl, palmitoyl, methyl, or ethyl group; Z and Y are each a hydrogen atom or a methyl or phenyl group; M is Na, K, or Li; n is an integer from 1 to 30; m is an integer of 0-20.
  • X is a methyl group
  • Y ' is a hydrogen atom or a phenyl group
  • p is an integer from 0 to 25
  • q is an integer from 0 to 25, provided that p + q is an integer from 5 to 25
  • R is a hydrogen atom or an acetyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl group
  • M is Na, K, or Li
  • Z is a hydrogen atom, a methyl or a phenyl group.
  • D, L-lactic acid, D-polylactic acid, polymandelic acid, copolymer of D, L-lactic acid and glycolic acid, copolymer of D, L-lactic acid and mandelic acid, D, L-lactic acid and caprolactone It is selected from the group consisting of a co-polymer of and a copolymer of D, L- lactic acid and 1,4-dioxane-2-one;
  • R is a hydrogen atom or an acetyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl group;
  • M is independently Na, K, or Li.
  • S-0-PAD-C00-Q In Equation 4, S is High; L is -NR,-or -0-, where
  • Ri is a hydrogen atom or C 1-10 alkyl
  • Q is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 C3 ⁇ 4, or CH 2 C 6 H 5
  • a is an integer from 0 to 4
  • b is an integer from 1 to 10
  • M is Na,, or Li
  • PAD is composed of D, L-polylactic acid, D-polylactic acid, polymandelic acid, co-polymer of D, L-lactic acid and glycolic acid, co-polymer of D, L-lactic acid and mandelic acid, D, L-lactic acid and
  • R ' is -PAD-0-C (0) -CH 2 CH 2 -C (0) -OM, wherein PAD is
  • X and X ' are independently hydrogen, alkyl having 1 to 10 carbon atoms or aryl having 6 to 20 carbon atoms; Y and Z are independently Na, K, or Li; m and n are independently integers from 0 to 95, with 5 ⁇ m + n ⁇ 100; a and b are independently an integer from 1 to 6; R is-(CH 2 ) k- , divalent alkenyl having 2 to 10 carbon atoms, divalent aryl having 6 to 20 carbon atoms, or a combination thereof, wherein k is 0 to 10 Is an integer.
  • the polylactic acid salt is a compound of Formula 1 or Formula 2
  • compositions of the present invention improve the intracellular delivery efficiency of anionic drugs.
  • it can further include a fusible lipid of from 0.1 to 10% increase.
  • the fusion lipid When the fusion lipid is combined with the complex of the anionic drug and the cationic lipid, the hydrophobic interaction is combined to form a complex of the anionic drug, the cationic lipid and the fusion lipid, and the complex including the fusion lipid is Encapsulated Inside the Micellar Structure of the Amphiphilic Block Copolymer
  • the fusion lipid may be one or a combination of two or more selected from the group consisting of phospholipids, cholesterol, and tocopheres.
  • the phospholipid may be at least one selected from the group consisting of phosphatidyl ethanolamine (PE), phosphatidylcholine (PC), and phosphatidic acid. remind
  • PE Phosphatidylethanolamine
  • Phosphatidylcholine (PC) and phosphatidic acid can be in the form combined with one or two C10-24 fatty acids.
  • the cholesterol and tocope include ' analogues, derivatives, and metabolites of cholesterol and tocope.
  • the fusion lipids include dilauuroyl phosphatidylethanolamine, dimyristoyl phosphatidylethanolamine, and dipalmitoyl phosphatidylethanolamine.
  • phosphatidylethanolamine dilinoleoyl phosphatidylethanolamine, 1-palmitoyl-2-leleoyl phosphatidylethanolamine (1-palmitoyl-2-oleoyl phosphatidylethanolamine), 1,2-dipitanoyl-3-sn -Phosphatidylethanolamine (I, 2 -diphytanoyl-3-sn-phosphatidylethanolamine), dilauuroyl phosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, dipalmitoylline Work
  • Dioleoyl phosphatidic acid Dioleoyl phosphatidic acid, dilinoleoyl phosphatidic acid, 1-palmitoyl-2-oleoyl phosphatidic acid (l-pahnitoyl-2-oleoyl
  • phosphatidic acid 1,2-dipitanoyl-3-sn-phosphatidic acid (l, 2-diphytanoyl-3-sn-phosphatidic acid), one or more selected from the group consisting of cholesterol and tocophere May be a combination.
  • the fusion lipid is dioleoyl
  • Dioleoyl phosphatidylethanolamine DOPE
  • dipalmitoleoylphosphocholine (1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine, DPPC
  • dioleoylphosphocholine l, 2 -dioleoyl- sn-glycero-3-phosphocholine, DOPC
  • Dipalmitooleoylphosphoethanolamine (l, 2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine, DPPE) may be one or more selected from the group consisting of ⁇ amphipathic block according to one embodiment Copolymer and
  • compositions containing anionic drug-cationic compound complexes encapsulated in a polylactic acid micellar construct can be administered via routes of administration such as blood vessels, muscles, subcutaneous, oral, bone, transdermal or topical tissue, and are suitable for such routes of administration. And may be formulated into a variety of oral or parenteral formulations.
  • the oral dosage formulation may include various preparations, such as eye drops and injections, such as tablets, capsules, powder formulations, liquids, and the like, and parenteral dosage formulations.
  • the composition may be an injection formulation. For example, when lyophilizing the composition according to the invention, it is distilled water for injection, 0.9%
  • the present invention also provides a method of preparing a pharmaceutical composition comprising an amphiphilic block copolymer micelle containing the anionic drug.
  • the anionic drug, bi-lipid lipid, amphiphilic blotting Method for producing a composition for anionic drug delivery comprising a copolymer and a polylactic acid salt
  • step (b) removing the organic solvent layer from the mixture prepared in step (a);
  • step (c) adding the aqueous solution to the mixture from which the organic solvent of step (b) has been removed, and then micellizing.
  • an anionic drug, a cationic compound, an amphiphilic block copolymer and a polylactic acid salt are mixed to form a complex in a water-soluble organic solvent or a mixed solvent of an aqueous solution and an organic solvent.
  • the water-miscible organic solvent may be at least one selected from the group consisting of acetone, ethanol, methanol and acetic acid
  • the organic solvent of the mixed solvent is a group consisting of ethyl acetate, acetonitrile, methylene chloride, chloroform and dioxane It may be one or more selected from.
  • the aqueous solution may be distilled water, water for injection, or a complete solution.
  • the mixing ratio of the organic solvent and the aqueous solution in the mixed solvent is not particularly limited, and may be, for example, 1: 0.1 to 50, more specifically 1: 0.5 to 10 (organic solvent volume: aqueous solution volume), but is not limited thereto. It is not.
  • step (b) the organic solvent is removed by evaporation from the mixture prepared in step (a).
  • step (c) the remaining mixture after the organic solvent is evaporated is dissolved in an aqueous solution, thereby encapsulating the complex of the anionic drug and the cationic compound in the micelle structure formed by the amphiphilic block copolymer and the polylactic acid salt.
  • the aqueous solution and the amount of use thereof are as described above.
  • step (c) it may further comprise a step of lyophilizing by adding a (d) lyophilization aid.
  • the preparation method sterilizing the aqueous solution of the polymer micelle obtained in step (c) before lyophilization of the step (d) with a sterile filter
  • the process may further include.
  • the lyophilization aid used in the present invention may be used to help the lyophilized composition to maintain a cake form or to uniformly dissolve quickly in the process of reconstitution after lyophilizing the amphiphilic block copolymer composition.
  • By adding, specifically, may be at least one selected from the group consisting of lactose, manny, sorbbi and sucrose ⁇
  • the content of the lyophilization aid based on the total dry weight of the lyophilized composition, 1 to 90 weight 0/0, and more specifically 10 to 60 wt. 0/0.
  • a composition in which an anionic drug and a cationic compound complex is encapsulated in an amphiphilic block copolymer and a polylactic acid salt structure is prepared.
  • the micelle particles in the prepared composition are stable in bloodemia, and have a size of 10 to 200 nm, more specifically 10 to
  • MPEG-PLA of 4,000 Daltons was synthesized [Preparation Example 2].
  • MPEG-PLA block having a number average molecular weight of 2,000-1,750 Daltons using monomethoxypolyethylene glycol (molecular weight 2,000 Daltons or less, NOF corporation) in the same manner Co-polymer was synthesized [Preparation Example 3].
  • MPEG-PLA-tocopherol (number average molecular weight 5,000-4,000-530 Daltons) was obtained according to the process described in Preparation Example 2 of WO2012-091523 [Preparation Example 4].
  • aqueous sodium hydrogen carbonate solution (0.1 ⁇ 1) 150 1 was slowly added and stirred at 60 rpm for 60 to 2 hours. After adding 15 g of sodium chloride at room temperature and dissolving with stirring, the aqueous layer was removed using a separatory funnel.
  • 1,6 dioTETA (/ P ratio 18) was dissolved in 94.63 ⁇ of chloroform and siRNA 100 was dissolved in 80 ⁇ l of distilled water.
  • 505.37 ⁇ of chloroform was added so that the volume ratio of the organic layer to the aqueous layer was 10 times as a whole.
  • An emulsion was prepared using an ultrasonic grinder while siRNA was added to the solution mixture of 1,6 dioTETA and mPEG-PLA-tocopherol in chloroform.
  • the emulsion was added to 2320 ⁇ of distilled water to prepare a composite emulsion using an ultrasonic mill.
  • the prepared complex emulsion was placed in a 1-neck equilateral polar flask and distilled under reduced pressure in a rotary evaporator to selectively remove chloroform, thereby siRNA / 1,6-dioleoyl.
  • Polymeric micelles containing triethylenetetraamide (dioTETA) / mPEG-PLA-tocopherol (2k-1.7k) were prepared (see Table 1).
  • siRNA lipid N / P ratio mg of polymer. The same applies in the following table.
  • the dioTETA solution, PLA solution, and 24 mg solution of mPEG-PLA-tocopherol were mixed together, and an emulsion was prepared using an ultrasonic mill while adding dropwise siRNA solution.
  • the solvent was removed by distillation under reduced pressure in a 1-neck equiaxed polar flask coated with 6 mg of oil emulsion mPEG-PLA-tocopherol and a rotary evaporator. 3 ml of distilled water was added to the flask, and the mixture was shaken gently to prepare siRNA / dioTETA / mPEG-PLA-tocopherol (2k-1.7k) / PLA-containing polymer micelle (see Table 2).
  • Example 3-6 Preparation of a Composition Containing siRNA / dioTETA / mPEG-PLA-Tocope (2k-1.7k) / PLANa (1.7k)
  • composition Composition siRNA lipid Polymer 1 Polymer 2 Example 3 siR A / dioTETA / mPEG-5-8-1-0.3 150 ⁇ ⁇ 1.26 mg 30 mg 9 mg
  • Example 4 siRNA / dioTETA / mPEG- 5-24-1-0.3 150 ⁇ 8 3.79 mg 30 mg 9 mg PLA-Tocope (2k- 1.7k) / PLANa (1.7k)
  • Example 1 2 1 Preparation of a composition containing 1 siRNA-cholester / dioTETA / mPEG-PLA-tocope ( 2 k-1.7k) PLANa (1.7k)
  • siRNA-cholester was used to prepare a composition containing siRNA-cholesterol / dioTETA / mPEG-PLA-tocopherol (2k-1.7k) / PLANa (1.7k) using the same procedure as in Example 1.
  • the mixture was distilled under reduced pressure in a rotary distillation concentrator to remove the solvent. Add 3 ml of distilled water to the flask, shake gently to dissolve the composition
  • siRNA-PEG / dioTETA / mPEG-PLA-tocopherol (2k-1.7k) / PLANa (1.7k) containing composition was subjected to the same procedure as in Example 1 using siRNA-PEG.
  • bPEI Dissolve 0.3 mg in distilled water was dissolved 15 ⁇ siRNA 150 ⁇ ⁇ in distilled water to 120 ⁇ .
  • the bPEI aqueous solution and the siRNA aqueous solution are mixed with 105 ⁇ l of HBS complete aqueous solution (10 mM HEPES, 1 mM NaCl).
  • 9 mg PLANa (1.7k) was dissolved in 180 ⁇ l of chloroform and 30 mg of mPEG-PLA-tocopherol (2k-1.7k) was dissolved in 100 ⁇ l of chloroform. 2140 ⁇ of chloroform was added so that the volume ratio of the organic layer to the aqueous layer was 10 times as a whole.
  • the PLANa solution was mixed with a 24 mg solution of mPEG-PLA-tocopherol, and an emulsion was prepared by using an ultrasonic mill while adding dropwise HBS complete aqueous solution mixed with bPEI and siRNA.
  • the emulsion was placed in a 1-neck equilateral flask coated with 6 mg of mPEG-PLA-tocopherol and distilled under reduced pressure in a rotary evaporator to remove the solvent. 6 ml of distilled water was added to the flask, and the mixture was shaken gently to prepare a siRNA / bPEI / mPEG-PLA-tocopherol (2k-1.7k) / PLANa (1.7k) -containing composition (Table 12).
  • Table 12 Table 12
  • lipids were prepared in the same manner as in Example 1 to contain siRNA / 1,10-dioleoyl pentaethylenenucleamide (dioPEHA) / mPEG-PLA-tocofe (2k-1.7k) / PLANa (1.7k) SiRNA / 1,8-dilinoleoyl tetraethylenepentamide with composition 9
  • composition 10 (dilTEPA) / mPEG-PLA-tocophere (2k-1.7k) / PLANa (L7k) containing composition 10
  • siRNA-PEG was used to prepare siRNA-PEG / dioTETA / mPEG-PLA-tocopherol (2k-1.7k) / PLANa (1.7k) / DOPE containing composition.
  • the amount of DOPE was added 1 and 4 times the amount of dioTETA, respectively. This mixture
  • the solvent was removed by distillation under reduced pressure in a rotary distillation thickener. 3 ml of distilled water was added to the polar flask, and the composition was prepared by gently shaking to dissolve it (Table 14).
  • Example 1 siR A / dioTETA / mPEG-PLA-5-16-1-0.3 28.07 nm -1.29 mV tocopherol (2k-1.7k) / PLANa (1.7k)
  • Example 12 siRNA-cholester /dioTETA/mPEG-5-16-1-0.3 27.73 nm -4.38 mV
  • the formulations were injected intravenously into Balb / c mice at lmg / kg and blood was drawn 5 hours and 6 hours later.
  • the blood is collected in a new tube by centrifugation at I3000 rpm for 4 minutes at 4 minutes, and the standard formulation is prepared by diluting in PBS at a total of 11 concentrations ranging from 4 ⁇ to 0.00256 ⁇ .
  • ⁇ ⁇ of the diluted standard formulation was added to the 96 well plate for PCR, and 9 ⁇ l of Balb / c mouse serum and 90 ⁇ of 0.25% triton X-100 were added.
  • Triton X-100 90 ⁇ l of 0.25% Triton X-100 was added to the blood sample ⁇ ⁇ of the experimental group, followed by a pretreatment step to release the carrier.
  • the siRNA exposed as the formulation was released was synthesized into cDNA via reverse transcription (RT) step and qRT-PCR (Bio-Rad CFX96 Real-Time System) was performed using the synthesized cDNA. Analysis was performed using the Bio-Rad CFX Manager program.
  • Example 2 1 1650.82 5362.87 As can be seen in Table 16, the formulations prepared in Examples 1 and 2 of the present invention have a concentration of 5 to 8 times the concentration of the formulations present in blood compared to Comparative Examples 1 and 2 at 0.5 hours. The higher the degree, the more stable the blood.
  • siRNA / dioTETA / mPEG-PLA-tocope / PLANa polymer micelles distributed in liver, liver and cancer tissues was confirmed.
  • mice were prepared by injecting Balb / c nude mice subcutaneously with an A2780cis human ovarian cancer cell line.
  • the formulation was administered intravenously with a total of four doses, one at a dose of l mg / kg. Liver and cancer tissues were removed and weighed 200 mg 24 hours after the last dose, and then placed in 1.8 mL of 0.25% Triton X-100 and ground with a tissue grinder. Threadard tissue sample is to use the tissue administered with saline and change the tissue in the same way. Concentrations of standard formulations are prepared by dilution in PBS at 11 concentrations ranging from 4 ⁇ to 0.00256 ⁇ .
  • tissue ground for the standard is added to a 96-well plate for PCR, and the formulation ⁇ ⁇ was added to the standard.
  • Tissue samples to be analyzed in the experimental group are subjected to a pretreatment step in which 100 ⁇ is added and the formulation is released.
  • the exposed siRNA was synthesized into cDNA by reverse transcription (RT) step and qRT-PCR (Bio-Rad CFX96 Real-Time System) was performed using the synthesized cDNA. The analysis was performed using the Bio- Rad CFX Manager program.
  • Example 2 according to the present invention was shown to reduce the liver tissue distribution, cancer tissue distribution increased compared to Comparative Example 1.
  • PLANa-containing polymer micelle carrier according to the present invention can be specifically targeted to cancer tissues.
  • siRNA / dioTETA / mPEG-PLA-tocope / PLANa polymer micelles was confirmed by analysis of gene suppression ability.
  • Cancer-induced mice were prepared by feeding A549 human lung cancer tumor isolates to Balb / c nude mice.
  • the formulation was administered intravenously three times, once per dose, at a dose of 0.5 mg / kg.
  • Physiological saline was administered as a control group, 5 dogs for each formulation.
  • the cancer tissue was extracted, and the first milling was performed using a mortar and pestle under liquid nitrogen, and the tissue was once again changed using a QIAGEN tissue crusher (TissueLyser).
  • HPRT mRNA is removed from the cells using 600 ⁇ 1 of working homogenizing solution, Homogenizing solution 600 ⁇ 1 + Proteinase K (23 mg / mL) 6 ⁇ 1, which is prepared in 10 mg of twice-broken cancer tissue.
  • Samples obtained by the above method were analyzed using a bDNA assay kit. The assay was followed by the manufacturer of the kit (Panomics bDNA assay).
  • GAPDH mRNA a gene that is not affected by HPRT siRNA, was also analyzed in the same manner, and the average amount of HPRT mRNA expression in cancer tissues was calculated by correcting the measured HPRT mRNA amount.
  • Table 18 The analysis results are shown in Table 18 below.
  • Example 2 according to the present invention can be seen that inhibits the mRNA 54% of the target gene HPRT in cancer tissues in vivo.

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Abstract

La présente invention concerne une composition pharmaceutique pour administration de médicament anionique, et un procédé de préparation associé, la composition pharmaceutique pour administration de médicament anionique contenant : un médicament anionique en tant que substance active ; un composé cationique ; un copolymère séquencé amphiphile ; et un polylactate, où le médicament anionique forme un complexe avec le lipide cationique, et le complexe est encapsulé dans une structure de micelle formée par le copolymère séquencé amphiphile et le polylactate.
PCT/KR2016/010269 2015-09-15 2016-09-12 Composition pharmaceutique contenant un médicament anionique, et son procédé de préparation Ceased WO2017048018A1 (fr)

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JP2018533597A JP6638072B2 (ja) 2015-09-15 2016-09-12 アニオン性薬物含有医薬組成物及びその製造方法
EP16846839.5A EP3357491B1 (fr) 2015-09-15 2016-09-12 Composition pharmaceutique pour l'administration d'un médicament anionique
ES16846839T ES2883290T3 (es) 2015-09-15 2016-09-12 Composición farmacéutica para el suministro de un fármaco aniónico
CA2998092A CA2998092C (fr) 2015-09-15 2016-09-12 Composition pharmaceutique contenant un medicament anionique, et son procede de preparation
RU2018113459A RU2721558C2 (ru) 2015-09-15 2016-09-12 Фармацевтическая композиция, содержащая анионное лекарственное средство, и способ ее получения
US15/759,943 US11253598B2 (en) 2015-09-15 2016-09-12 Pharmaceutical composition containing anionic drug, and preparation method therefor
MX2018003096A MX386005B (es) 2015-09-15 2016-09-12 Composicion farmaceutica que contiene farmaco anionico, y metodo de preparacion para la misma.
DK16846839.5T DK3357491T3 (da) 2015-09-15 2016-09-12 Farmaceutisk sammensætning til afgivelse af et anionisk medikament
SG11201802073YA SG11201802073YA (en) 2015-09-15 2016-09-12 Pharmaceutical composition containing anionic drug, and preparation method therefor
AU2016324450A AU2016324450B2 (en) 2015-09-15 2016-09-12 Pharmaceutical composition containing anionic drug, and preparation method therefor
CN201680053810.0A CN108024960B (zh) 2015-09-15 2016-09-12 含有阴离子药物的药物组合物及其制备方法
IL257937A IL257937B (en) 2015-09-15 2018-03-07 A pharmaceutical preparation containing an anionic drug and a preparation method for it
ZA2018/02303A ZA201802303B (en) 2015-09-15 2018-04-09 Pharmaceutical composition containing anionic drug, and preparation method therefor
US17/572,195 US20220125929A1 (en) 2015-09-15 2022-01-10 Pharmaceutical composition containing anionic drug, and preparation method therefor

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EP3391875A4 (fr) * 2015-12-18 2019-08-14 Samyang Biopharmaceuticals Corporation Procédé de préparation de micelle polymère contenant un médicament anionique
JP2021503461A (ja) * 2017-11-16 2021-02-12 サムヤン バイオファーマシューティカルズ コーポレイションＳａｍｙａｎｇ Ｂｉｏｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏｒｐｏｒａｔｉｏｎ アニオン性薬物含有医薬組成物の凍結乾燥のための組成物及び方法
CN113350513A (zh) * 2021-05-18 2021-09-07 上海工程技术大学 一种抗癌药物喜树碱用载体及其制备方法和应用
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US20230039124A1 (en) * 2019-12-20 2023-02-09 Samyang Holdings Corporation Kit for preparing nanoparticle composition for drug delivery, comprising polylactic acid salt
WO2023121388A1 (fr) * 2021-12-23 2023-06-29 주식회사 삼양홀딩스 Composition de nanoparticules pour administration de médicament pulmonaire

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EP3391875A4 (fr) * 2015-12-18 2019-08-14 Samyang Biopharmaceuticals Corporation Procédé de préparation de micelle polymère contenant un médicament anionique
JP2021503461A (ja) * 2017-11-16 2021-02-12 サムヤン バイオファーマシューティカルズ コーポレイションＳａｍｙａｎｇ Ｂｉｏｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏｒｐｏｒａｔｉｏｎ アニオン性薬物含有医薬組成物の凍結乾燥のための組成物及び方法
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US20230039124A1 (en) * 2019-12-20 2023-02-09 Samyang Holdings Corporation Kit for preparing nanoparticle composition for drug delivery, comprising polylactic acid salt
CN113350513A (zh) * 2021-05-18 2021-09-07 上海工程技术大学 一种抗癌药物喜树碱用载体及其制备方法和应用
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