WO2001060410A1 - Preparations a liberation lente contenant un compose physiologiquement actif peu soluble dans l'eau et methode de production et d'utilisation desdites preparations - Google Patents
Preparations a liberation lente contenant un compose physiologiquement actif peu soluble dans l'eau et methode de production et d'utilisation desdites preparations Download PDFInfo
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- WO2001060410A1 WO2001060410A1 PCT/JP2001/001191 JP0101191W WO0160410A1 WO 2001060410 A1 WO2001060410 A1 WO 2001060410A1 JP 0101191 W JP0101191 W JP 0101191W WO 0160410 A1 WO0160410 A1 WO 0160410A1
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- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 235000019669 taste disorders Nutrition 0.000 description 1
- VOCBWIIFXDYGNZ-IXKNJLPQSA-N testosterone enanthate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCC)[C@@]1(C)CC2 VOCBWIIFXDYGNZ-IXKNJLPQSA-N 0.000 description 1
- 229960003484 testosterone enanthate Drugs 0.000 description 1
- 150000004044 tetrasaccharides Chemical class 0.000 description 1
- XWMXMWHHTIEXRE-UHFFFAOYSA-N thiadiazole 1-oxide Chemical group O=S1C=CN=N1 XWMXMWHHTIEXRE-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
- 229960005342 tranilast Drugs 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 150000003627 tricarboxylic acid derivatives Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical group NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 description 1
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 208000027185 varicose disease Diseases 0.000 description 1
- 239000002550 vasoactive agent Substances 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 231100000889 vertigo Toxicity 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 208000037911 visceral disease Diseases 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- 229940118827 zinc phenolsulfonate Drugs 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- VRGNUPCISFMPEM-ZVGUSBNCSA-L zinc;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Zn+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O VRGNUPCISFMPEM-ZVGUSBNCSA-L 0.000 description 1
- MCOGTQGPHPAUJN-UHFFFAOYSA-L zinc;2-hydroxyacetate Chemical compound [Zn+2].OCC([O-])=O.OCC([O-])=O MCOGTQGPHPAUJN-UHFFFAOYSA-L 0.000 description 1
- BOVNWDGXGNVNQD-UHFFFAOYSA-L zinc;2-hydroxybenzenesulfonate Chemical compound [Zn+2].OC1=CC=CC=C1S([O-])(=O)=O.OC1=CC=CC=C1S([O-])(=O)=O BOVNWDGXGNVNQD-UHFFFAOYSA-L 0.000 description 1
- JDLYKQWJXAQNNS-UHFFFAOYSA-L zinc;dibenzoate Chemical compound [Zn+2].[O-]C(=O)C1=CC=CC=C1.[O-]C(=O)C1=CC=CC=C1 JDLYKQWJXAQNNS-UHFFFAOYSA-L 0.000 description 1
- MLVWCBYTEFCFSG-UHFFFAOYSA-L zinc;dithiocyanate Chemical compound [Zn+2].[S-]C#N.[S-]C#N MLVWCBYTEFCFSG-UHFFFAOYSA-L 0.000 description 1
- FYGDTMLNYKFZSV-BYLHFPJWSA-N β-1,4-galactotrioside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@H](CO)O[C@@H](O[C@@H]2[C@@H](O[C@@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-BYLHFPJWSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a sustained-release preparation of a physiologically active compound which is hardly soluble in water, a method for producing the same, and a use thereof.
- Sustained-release preparations of physiologically active compounds containing a poorly water-soluble polyvalent metal and a biodegradable polymer are disclosed in, for example, JP-A-09-221420, JP-A-11-315034, JP-A-11- It is disclosed in, for example, No. 322631, and it has been confirmed that release control and stabilization of a physiologically active compound are possible.
- an emulsion (S / O emulsion) containing a poorly water-soluble bioactive compound, a poorly water-soluble polyvalent metal and a biodegradable polymer is prepared. At this time, a stirring operation for several hours to half a day or more was required.
- the present invention provides a sustained-release preparation of a physiologically active compound, which has improved control and stabilization of the release of the biologically active compound and can be produced by a method suitable for mass production, a method for producing the same, and a use thereof. .
- an emulsion containing a bioactive compound that is hardly soluble in water, a polyvalent metal that is hardly soluble in water, and a biodegradable polymer is used for a short time (preferably 1 hour).
- a short time preferably 1 hour.
- a component obtained by treating a poorly water-soluble physiologically active compound or a poorly water-soluble polyvalent metal compound with water for example, by mixing a water-insoluble polyvalent metal compound and water, A polyvalent metal compound that is hardly soluble in water that has been treated with water; a polyvalent metal compound that is hardly soluble in water that has been treated with water is partially or wholly insoluble in the water.
- a sustained-release preparation comprising a biodegradable polymer
- sustained-release preparation according to the above (1), wherein the physiologically active compound is a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof;
- R 1 represents a group capable of forming an anion or a group capable of forming an anion
- X represents Indicates that the phenylene group and the phenylene group are bonded directly or via a spacer having an atomic chain of 2 or less, n is an integer of 1 or 2, and ring A may have a further substituent.
- R 2 represents a group capable of forming an anion or a group capable of forming an anion;
- R 3 represents a carbon atom which may be bonded via a hetero atom and may have a substituent;
- a sustained-release preparation according to the above (3) which is a compound represented by the formula:
- sustained-release preparation according to (3), wherein the compound having an angiotensin II antagonistic activity is oral sultan, eprosarin, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan or tasosartan;
- the compound having angiotensin II antagonistic activity is 2 ethoxy-11 [[2 '-(1H-tetrazol-5-yl) biphen-2-l-4-yl] methyl] benzi midazo 7-force
- a compound having an angiotensin II antagonistic activity is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1H-tetrazole-5- ⁇ ⁇ ) biphenyl 4 [Yl] methyl] benzimidazoyl 7-carboxylate or a salt thereof, the sustained-release preparation according to the above (3);
- a compound having an angiotensin II antagonistic activity is 2-ethoxy-1 _ [[2 '-(2,5-dihydro-5-oxo-1,2,4_oxadiazo-1-yl-3-yl) biphenyl-4-1' [rl] methyl] benzimidazole-7-carboxylic acid or a salt thereof, the sustained-release preparation according to the above (3);
- composition according to (25) which is a prophylactic or therapeutic agent for a circulatory disease
- composition according to (25) which is a prophylactic / therapeutic agent for hypertension
- a method for producing a sustained-release preparation of a poorly water-soluble physiologically active compound characterized by comprising:
- a water-insoluble bioactive compound is dispersed in an emulsion obtained by mixing a water-insoluble polyvalent metal compound and water with an organic solvent solution of a biodegradable polymer.
- a method for controlling the rate of release of a permanently soluble bioactive compound from a sustained-release preparation characterized in that:
- a water- and solvent-soluble emulsion is obtained by mixing a poorly water-soluble bioactive compound and a poorly water-soluble polyvalent metal compound with an organic solvent solution of a biodegradable polymer.
- a method of mixing a poorly water-soluble polyvalent metal compound with a biodegradable polymer in an organic solvent in the presence of water The method according to the above (37), wherein a water-insoluble physiologically active compound is dispersed in the obtained emulsion, and the water and the solvent are removed; (41) The water-insoluble physiologically active compound is contained in the internal phase.
- An emulsion comprising a water-soluble polyvalent metal compound and water, and an organic solvent solution of a biodegradable polymer in an external phase.
- the term “poorly soluble in water” refers to the water or saline required to dissolve 1 g of solute within 30 minutes when shaken vigorously at 20 ⁇ 5 every 5 minutes for 30 seconds. It means that the volume is 100 ml or more, preferably 1000 ml or more, more preferably 10,000 ml or more.
- the physiologically active compound in the present invention refers to a physiologically active compound effective for the prevention and treatment of disease states, diseases, etc. in mammals (eg, humans, cows, pigs, dogs, cats, mice, rats, rabbits, etc.). It is not particularly limited as long as it is capable of interacting with a component obtained by treating a water-insoluble polyvalent metal compound with water to provide sustained release or stabilization, and may be either peptide or non-peptide. It is preferable, but non-peptidic ones are preferable, and among them, a bioactive compound having a molecular weight of about 200 to 3,000 is preferable, and a bioactive compound having a molecular weight of about 300 to 2,000 is particularly preferable.
- the "poorly water-soluble physiologically active compound" used in the present invention include a compound having an angiotensin II antagonistic action (a compound having an angiotensin II receptor antagonistic action), a prodrug thereof or a salt thereof.
- angiotensin II antagonism refers to a potent or non-competitive inhibition of angiotensin II binding to an angiotensin II receptor on a cell membrane, and a strong vasoconstriction or vascular smoothness induced by angiotensin II. It is a function that reduces muscle growth and relieves symptoms of hypertension.
- the compound having an angiotensin II antagonistic activity used in the present invention may be either peptide or non-peptide, but a compound having a non-peptide antagonistic effect, which has an advantage of a long action time, is preferable.
- a compound having an angiotensin II antagonistic activity a compound having an oxygen atom in the molecule is preferable.
- an ether bond or a carbonyl group (the carbonyl group may form a hydroxyl group by resonance)
- the non-peptidic compound having angiotensin II antagonistic activity is not particularly limited, but imidazole derivatives are disclosed in JP-A-56-71073, JP-A-56-71074, JP-A-57-98270, and No. 58-157768, US Pat. Nos. 4,355,040 and 4,340,598, and the like, and EP-253310, EP-291969, EP-324377, EP-403158, WO-9100277, and JP-A-9100277. JP-A-63-23868 and JP-A-11-117876 disclose improved imidazole derivatives. Also, USP 5,183,899, EP-323841, EP-4093832 and JP-A-193393 are disclosed. No.
- EP-411766 and the like disclose pyrimidone derivatives
- EP-411766 and the like disclose quinazoline derivatives
- EP-430300 and the like disclose xanthine derivatives
- EP-434038 and the like disclose condensed imidazole derivatives
- EP- 442473 discloses pyrimidinedione derivatives
- EP-443568 discloses thienopyridone derivatives
- Journal of Medicinal Chemistry, Vol. 39, No. 3, pp. 625-656 (1996) describes representative compounds among these.
- any non-peptide compound having an angiotensin II antagonistic action may be used.
- Non-peptidic compounds having angiotensin II antagonistic activity include, for example, compounds of the formula (I)
- R 1 represents a group capable of forming an anion or a group capable of forming an anion
- X represents a phenylene group and a phenyl group bonded directly or via a spacer having an atomic chain of 2 or less.
- N represents an integer of 1 or 2
- ring A further has a substituent.
- R 2 represents a group capable of forming an anion or a group capable of forming an anion
- R 3 may be bonded via a hetero atom or may have a substituent.
- a benzimidazole derivative represented by a good hydrocarbon residue preferably a hydrocarbon residue which may have a substituent and is bonded through an oxygen atom
- a salt thereof is preferably used.
- examples of the group capable of forming an anion as R 1 include (1) lipoxidyl group, (2) tetrazolyl group, and (3 ) triflate Ruo b methanesulfonic acid amide group (- NHS0 2 CF 3), (4) a phosphate group, (5) a sulfonic acid group, (6) N, 5 containing S, one or more than two of O And a 7-membered (preferably 5-6-membered) monocyclic optionally substituted heterocyclic residue.
- Examples of the above-mentioned “5- to 7-membered (preferably 5- to 6-membered) monocyclic optionally substituted heterocyclic residue containing one or more of N, S, and O” include, for example, ,
- the bond between the heterocyclic residue represented by R 1 and the phenyl group to which the heterocyclic residue is bonded is as described above when g in the above formula represents —NH— or the like.
- the bond may be formed through one of a plurality of nitrogen atoms.
- R 1
- heterocyclic residue represented by R 1 examples include, for example, an NH 1 or 1 OH group as a proton donor such as an oxazine diazolone ring, an oxadiazolothion ring or a thiadiazolone ring, and a carbonyl group or a thiocarbonyl as a proton acceptor.
- a group having a group or a sulfinyl group at the same time is preferred.
- the heterocyclic residue represented by R 1 may form a condensed ring by bonding cyclic substituents.
- the preferred heterocyclic residue represented by R 1, 5 or 6-membered ring Further, a 5-membered ring residue is preferable.
- the heterocyclic residue represented by R 1 is represented by the formula N— j
- i —O— or 1 S—
- m has the same meaning as described above.
- the heterocyclic residue (R 1 ) has a tautomer as shown below. For example,
- the heterocyclic residue represented by represents all of the above a ′, b ′ and c ′.
- the group capable of forming an anion as R 1 is, at a substitutable position, an optionally substituted lower (C x _ 4 ) alkyl group or an acyl group (eg, lower (C 2 — 5 ) alkanoyl, Benzoyl).
- lower alkyl group which may be substituted include (1) a halogen atom, nitro, lower (CJ alkyl, lower (. 1 to 3 phenyl groups which may have an alkoxy, etc.) Low level
- Alkyl group e.g., methyl, triphenylmethyl, p- methoxybenzyl, p- two such Torobe Njiru
- a lower (C ⁇ - 4) alkoxy one lower (C - 4) alkyl group e.g., methoxymethyl , Ethoxymethyl, etc.
- Formula 1 CH (R 4 ) -0 COR 5 [wherein R 4 is (a) hydrogen, (b) a straight-chain or branched lower alkyl having 16 carbon atoms.
- a lower alkoxy group having 13 carbon atoms eg, phenyl or naphthyl group which may be substituted
- methoxy such as benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, ethoxy, n-propoxy, isopropoxy
- J a cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or a substituted or unsubstituted aryl group (eg, halogen) atom, nitro, lower (C ⁇ - 4) alkyl, lower (0, _ 4) alkoxycarbonyl
- groups capable of forming an anion as R 1 the above-mentioned optionally substituted have good lower (alkyl or Ashiru group (e.g., lower (C 2 - 5) Arukanoiru, etc. Benzoiru) protecting group such as
- an optionally substituted lower (( ⁇ ) alkyl group (which can form an anion as R 1 described above)
- Exemplified as a protective group of the group "optionally substituted lower (( ⁇ - 4) alkyl group” include those similar to), halogen atoms, nitro, Shiano, lower (C ⁇ alkoxy, 1 to 2 Lower (which may have a substituent such as an amino which may be substituted with alkyl.
- a group which can be converted into a group capable of forming an anion as R 1 is a compound which can be converted under biological or physiological conditions (for example, oxidation by an in vivo enzyme or the like).
- R 1 is optionally substituted lower (C ⁇ 4 ) alkyl (eg, methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) or an acyl group (e.g., lower (C 2 - 5) Arukanoiru, etc.
- lower (C ⁇ 4 ) alkyl eg, methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.
- an acyl group e.g., lower (C 2 - 5) Arukanoiru, etc.
- Benzoiru may be protected by Karupokishiru, tetrazolyl or 2, 5-dihydro - 5-Okiso - 1, 2, 4-Okisajiazo one rule 3- I le (preferably, tetrazolyl), cyano, and N-hydroxycarbamimidoyl (preferably cyano) are used, and tetrazolyl is particularly preferably used.
- X represents that an adjacent phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less (preferably a direct bond);
- the chain may be any divalent chain having 1 or 2 atoms constituting the straight chain portion, and may have a side chain.
- ri represents an integer of 1 or 2 (preferably 1).
- ring A represents a benzene ring which may further have a substituent other than substituent R 2 , and examples of the substituent include (1) halogen (eg, F, CI, Br, etc.) , (2) Shiano, (3) nitro, (4) lower optionally substituted ((: Bok 4) alkyl le, (5) lower ((4) alkoxy, (6) amino which may be substituted group (e.g., amino, N- lower (CI- 4) alkylamino (e.g., such as Mechiruamino), NN - di-lower (C 4) alkylamino (e.g., such as Jimechiruamino), N- Ariru amino (eg, such as Fueniruamino) , Alicyclic amino (eg, morpholino, piberidino, piperazino, N-phenylpiperazino, etc.), (7) Formula (1) CO—D ′ (where D ′ is a hydroxyl group
- Bibaroiruokishi lower (C Preparative 6) alkoxycarbonyl two Ruokishi (eg, main Bok alkoxycarbonyl O alkoxy, ethoxy Cal Poni Ruo carboxymethyl, etc.) or a lower.
- alkoxycarbonyl two Ruokishi eg, main Bok alkoxycarbonyl O alkoxy, ethoxy Cal Poni Ruo carboxymethyl, etc.
- Ji alkyl wherein the cycloalkyl exemplified as a protective group for groups that can form form an anion as a "(include those similar
- substituents may be 1 2 are simultaneously substituted at substitutable positions on the benzene ring, but with further rings A other than the substituent R 2, is substituted also optionally lower though ( ⁇ - 4) alkyl (e.g., hydroxyl, carboxyl, halogen such as optionally substituted lower (Ji DOO 4 optionally substituted with down) alkyl, etc.), are preferred, such as halogen, other than the substituent R 2 More preferably, ring A has no substituent.
- the group capable of forming an anion as R 2 includes, for example, (1) a carboxyl group which may be esterified or amidated, ) Tetrazolyl group, (3) trifluoromethane Nsuruhon acid amide group (one NHS0 2 CF 3), (4 ) a phosphate group, (5) and a sulfonic acid group.
- R 1 that these groups may be substituted lower alkyl group (the of it exemplified as a protective group for the group capable of forming an anion "optionally substituted lower (0, _ 4) alkyl group” include those similar to) or Ashiru group (e.g., lower (C 2 _ 5 ) may be protected by alkanols, benzoyls, etc.), under biological or physiological conditions (eg, in vivo reactions such as oxidation, reduction or hydrolysis by in vivo enzymes) or chemical Any group may be used as long as it is a group capable of forming an anion or a group capable of changing to an anion.
- Examples of the carboxyl that may be esterified or amidated as R 2 include, for example, a compound represented by the formula: CO—D wherein D is (1) a hydroxyl group, and (2) a substituted or unsubstituted amino (eg, amino , N- lower ( ⁇ - 4) Arukiruamino, N, N- di lower grade ( ⁇ - 4) such Arukiruamino) or (3) good an alkoxy ⁇ example be substituted, (i) the alkyl moiety a hydroxyl, a substituted is amino optionally (eg, amino, N - lower - 4) Arukiruamino, N, N-di-lower one 4) alkylamino Bruno, piperidino, morpholino etc.), halogen, lower (C ⁇ ) alkoxy, lower grade ( ( ⁇ _ 6) alkylthio, a lower (C 3 - 8) cycloalkoxy or an optionally substituted Jiokisoren
- an alkoxy group e.g, benzyl, p-cyclobenzyl, phenethyl, cyclopentylmethyl, such as cyclohexylmethyl cyclohexylene
- Ariru group e.g., halogen atom, nitro, lower ((:) alkyl, lower ( ⁇ - 4) alkoxy, etc.
- phenyl or naphthyl group which may have alkyl, lower alkoxy, etc.
- linear or branched lower alkoxy group having 1-6 carbon atoms eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.
- Lower alkenyloxy group eg, aryloxy, isobutenyloxy, etc.
- cycloalkyloxy group having 3-8 carbon atoms eg, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.
- C3-C8 cycloalkyl eg, cyclopentyl, cyclohexyl, cyclo
- Lower alkoxy groups eg, those having an alkoxy moiety such as methoxy such as benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, etc., ethoxy, n_propoxy, isopropoxy, etc.
- (j) 3 to 8 carbon atoms Eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.
- optionally substituted aryl group eg, halogen atom, nitro, lower ((: 4 ) alkyl, lower (C- 4 ) alkoxy, etc.
- aryl group eg, halogen atom, nitro, lower ((: 4 ) alkyl, lower (C- 4 ) alkoxy, etc.
- a lower alkenyloxy group having 2 to 3 carbon atoms which is substituted with a phenyl or naphthyl group optionally having (Eg,
- optionally esterified olepoxyl is preferable, and specific examples thereof include, for example, one C ⁇ H and a salt thereof, one COOMe, one CO ⁇ Et, one COOtBu, one COOPr, and pivalo.
- Yloxymethoxycarbonyl, 1 _ (cyclohexyloxycarbonyldioxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethoxy 2-propoxy 2-methoxymethoxycarbonyl, n-butylyloxymethoxycarbonyl, isobutylyloxymethoxycarbonyl, 1- (ethoxycarponyloxy) ethoxycarbonyl, 1- (acetoxy) ethoxycarbonyl, 1- (isobutylyloxy) ethoxycarbonyl , Cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxy Examples include carbonyl, cinnamixoxycarbonyl, and cyclopentylcarboxy2methoxymethoxycarbonyl, which are obtained under biological conditions, ie, under physiological conditions (eg, in vivo reactions
- R 2 wherein _C_ ⁇ - D [wherein, D is (1) a hydroxyl group a hydroxyl group or (2) Al kill moiety, Amino, halogen, lower (C 2 - 6) alkanoyloxy noisy Ruo alkoxy (e.g., Asetokishi , etc.
- Pibaroiruokishi a lower (C 3 - s) cycloalkanols noisy Ruo alkoxy, lower (one 6) alkoxy Cal Poni Ruo carboxymethyl (e.g., methoxycarbonyl O carboxy, ethoxycarbonyl O carboxymethyl, etc.), lower (C 3 _ 8) cycloalkyl Arukokishikaru Bonirokishi (e.g., cyclohexane, etc.
- the “hydrocarbon residue” in the “hydrocarbon residue which may be bonded via a hetero atom and has a substituent” represented by R 3 includes, for example, (1) a Alkyl group, (2) alkenyl group, (3) alkynyl group, (4) cycloalkyl group, (5) aryl group, (6) aralkyl group, etc., among which alkyl group, alkenyl group and cycloalkyl group Is preferred.
- the alkyl group of the above (1) is a lower alkyl group having about 1 to 8 carbon atoms, which may be linear or branched.
- the alkenyl group of the above (2) is a lower alkenyl group having about 2 to 8 carbon atoms, which may be linear or branched, such as vinyl, probenyl, 2-butenyl, 3-butenyl, isobutenyl, 2 Ooctenyl and the like.
- the alkynyl group of the above (3) is a lower alkynyl group having about 2 to 8 carbon atoms, which may be linear or branched.
- Examples of the cycloalkyl group (4) include lower cycloalkyls having about 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- alkyl group, alkenyl group, alkynyl group or cycloalkyl group is a hydroxyl group, an optionally substituted amino group (eg, amino, N-lower (C ⁇ 4 ) alkylamino, N, N-dilower (( : such as preparative 4) Arukiruamino), halogen, lower: the Ararukiru group (! C _ 4) alkoxy, lower ((. such alkylthio groups may be substituted wherein the (5), for example, benzyl, phenethyl, etc. Hue nil - lower (C ⁇ - 4) alkyl, and the like, as the Ariru group of (6), for example, phenyl and the like.
- an optionally substituted amino group eg, amino, N-lower (C ⁇ 4 ) alkylamino, N, N-dilower (( : such as preparative 4) Arukiruamino),
- aralkyl group or aryl group may be, for example, halogen (eg, F, C 1, Br, etc.), nitro, or an optionally substituted amino group (eg, amino, N- lower (C ⁇ - 4) alkylamino, N, N- di-lower (C, one 4) such Arukiruamino), lower (0, _ 4) alkoxy (e.g., methoxy, Etoki Shi, etc.), lower (C Preparative 4) alkylthio (e.g., methylthio, etc. Echiruchio), lower ((: 4).
- halogen eg, F, C 1, Br, etc.
- an optionally substituted amino group eg, amino, N- lower (C ⁇ - 4) alkylamino, N, N- di-lower (C, one 4) such Arukiruamino
- lower (0, _ 4) alkoxy e.g., methoxy, Etoki Shi,
- Alkyl (e.g., methyl, Echiru etc.) may have a like Among the above-mentioned, R As the “hydrocarbon residue” in the “hydrocarbon residue which may be bonded via a hetero atom and has a substituent” represented by 3 , an optionally substituted alkyl or alkenyl group ( example, a hydroxyl group, an amino group, halogen or lower (0 4) which may lower substituted with an alkoxy group (C ⁇ s) alkyl or lower - such as (C 2 5) alkenyl group) are preferable, especially, Lower (( ⁇ -5) alkyl (more preferably, ethyl) is preferred.
- R an optionally substituted alkyl or alkenyl group ( example, a hydroxyl group, an amino group, halogen or lower (0 4) which may lower substituted with an alkoxy group (C ⁇ s) alkyl or lower - such as (C 2 5) alkenyl group) are
- heteroatom in the “hydrocarbon residue which may be bonded through a heteroatom and has a substituent” represented by R 3 is _0—, — S (O) m— [ m represents an integer of 0 to 2], —NR ′ — [R ′ represents a hydrogen atom or a lower (dialkyl)], among which _ is preferably used.
- R 3 one 0_, one S (O) m— [m represents an integer of 0 to 2] or one NR ′ — [R ′ is a hydrogen atom or lower (C 4) alkyl And a lower (C ⁇ ) group which may be substituted with a substituent selected from a hydroxyl group, an amino group, a halogen and a lower (Ci ⁇ ) alkoxy group.
- alkyl or lower (c 2 _ 5) alkenyl group is preferable, especially, low-grade (C Preparative 5) alkyl or lower (C 1 ⁇ ) alkoxy (more preferably, Etoki sheet) are preferred.
- R 1 is (1) a carbonyl group, (2) a tetrazolyl group, or (3)
- ring a may be substituted in addition to the substituent R 2 a lower (C ⁇ - 4) alkyl (e.g., a hydroxyl group, a carboxyl group, which may lower substituted such with halogens (0 4) alkyl such as ) Or a benzene ring which may be frowned by a halogen (preferably a benzene ring having no substituent other than the substituent R 2 ), wherein R 2 is a group represented by the formula: CO—D (where D is (1) hydroxyl group or (2) alkyl moiety by hydroxyl, Amino, halogen, lower (C 2 _ 6) Al force Noiruokishi (eg, Asetokishi, etc.
- D is (1) hydroxyl group or (2) alkyl moiety by hydroxyl, Amino, halogen, lower (C 2 _ 6) Al force Noiruokishi (eg, Asetokishi, etc.
- Pibaroiruokishi a lower (C 3 one s) cyclo Arca noisy Ruo alkoxy, lower (C Medicine 6) alkoxy Cal Poni Ruo carboxymethyl (eg, main Toki deer Lupo sulfonyl O alkoxy, Etokishika Etc. Poniruokishi), lower (c 3 _ s) shea Kuroarukokishi force Lupo two proxy (eg, etc.
- Benzimidazo one-ru 7 Preferred is a sulfonate derivative or a pharmacologically acceptable salt thereof.
- benzimidazole derivatives are synthesized, for example, by a known method described in EP-425921, EP-459136, EP-553879, EP-578125, EP-520423, EP-668272 or a method analogous thereto. It is possible to When Candesartan cilexetil is used, it is preferable to use a stable C-type crystal described in EP-459136.
- the compound having an angiotensin II antagonistic activity or a prodrug thereof used in the present invention may be itself or a pharmacologically acceptable salt.
- salts include inorganic bases (eg, alkali metals such as sodium and potassium, and alkaline earths such as calcium and magnesium) when the compound having an angiotensin II antagonistic action has an acidic group such as a carboxyl group.
- Transition metals such as metals, zinc, iron, copper, etc.
- organic bases eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N '—Salts with organic amines such as dibenzylethylenediamine and basic amino acids such as arginine, lysine and orditin.
- Angiotensin ⁇ When the compound having an antagonistic action has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid) , Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), aspartic acid, glutamic acid, etc. Salts.
- an inorganic acid or an organic acid eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid
- Fumaric acid oxalic acid
- an AII antagonistic compound Compound having an angiotensin II antagonistic action used in the present invention [hereinafter may be referred to as an AII antagonistic compound.
- Prodrugs are compounds that convert to AII antagonist compounds by the reaction of enzymes or stomach acids under physiological conditions in vivo. That is, it refers to a compound that is enzymatically oxidized, reduced, hydrolyzed, etc., and changes to an AII antagonistic compound, and a compound, which is hydrolyzed, for example, by gastric acid or the like, to change to an AII antagonistic compound.
- Prodrugs of AII antagonist compounds include compounds in which the amino group of the AII antagonist compound is acylated, alkylated, and phosphorylated (e.g., the amino group of the AII antagonist compound is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo_1,3-dioxolen-4-yl) Methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, bivaloyloxymethylation, tert-butylated compounds, etc.
- the amino group of the AII antagonist compound is acylated, alkylated, and phosphorylated
- the amino group of the AII antagonist compound is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo_1,3-dioxolen-4-yl) Methoxycarbonylation, tetrahydrofur
- a compound in which the hydroxyl group of an AII antagonist compound is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of an AII antagonist compound is acetylated, palmitoylated, propanoylated, bivaloylated, succinylated, fumarylated, Alanylated, dimethylaminomethylcarbonylated compounds, etc.); Is esterified or amidated (e.g., AII antagonists), and the propyloxyl group is converted to ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, Ethoxycarbonyl oxethyl esterification, phthalidyl esterification, (5-methyl-2-oxo_1,3-dioxolen-1-yl) methyl esterification, cyclohexyloxyl. Methylamidated compounds,
- prodrugs of AII antagonist compounds can be used under physiological conditions, as described in Hirokawa Shoten, 1990, “Development of Drugs,” Volume 7, Molecular Design, pp. 163-198. It may change into an antagonist compound.
- the AII antagonist compound may be either a hydrate or a non-hydrate.
- a component obtained by treating a water-insoluble polyvalent metal compound with water refers to a water-insoluble water-soluble bioactive compound or / A component generated by water treatment in the coexistence of a degradable polymer. easily controls or stabilizes the release of poorly water-soluble bioactive compounds by changing treatment conditions and environment. Is possible.
- 7K processing is a short time, for example, processing within 1 hour, preferably within 30 minutes, and The treatment is more preferably within 10 minutes, more preferably within 5 minutes, and particularly preferably within 3 minutes.
- the amount of water added depends on the amount of the polyvalent metal compound, the type and amount of the bioactive compound, the type and amount of the biodegradable polymer, and the type and amount of the organic solvent solution of the biodegradable polymer. For example, it is generally selected from the range of 3 to 500%, more preferably 5 to 300%, and particularly preferably 10 to 150% based on the weight of the polyvalent metal compound. You.
- the water to be added may not be partially dissolved in the organic solvent of the biodegradable polymer, and is preferably finely dispersed and emulsified by a known method such as a homogenizer or ultrasonic waves.
- the water to be added may include a polyvalent metal compound (eg, zinc acetate, etc.), a basic amino acid (eg, arginine, histidine, lysine, etc.), albumin, gelatin, agar, dextrin, polyvinyl alcohol, Carbonic acid, oxalic acid, phosphoric acid, hydrochloric acid, etc., sodium hydroxide, citric acid, sodium ethylenediaminetetraacetate, sodium bisulfite, polyol compounds (eg, polyethylene glycol), paraoxybenzoic acid esters (methylparaben, Propylparaben), benzyl alcohol, chlorobutanol, thimerosal, etc. may be added.
- a polyvalent metal compound eg, zinc acetate, etc.
- a basic amino acid eg, arginine, histidine, lysine, etc.
- albumin e.g., albumin, gelatin, agar, dextrin,
- Examples of the component obtained by treating a water-insoluble polyvalent metal compound with water include, for example, a water-treated water-insoluble multivalent metal compound obtained by mixing a water-insoluble polyvalent metal compound with water.
- Examples of the metal compound include a polyvalent metal compound that is hardly soluble in water that has been treated with water, and a part or all of the polyvalent metal compound may be a hardly soluble polyvalent metal compound (unchanged compound).
- the water-treated water-insoluble multivalent metal compound forms an emulsion with a biodegradable polymer in an organic solvent in the presence of water.
- the inner phase contains a bioactive compound that is hardly soluble in water, a polyvalent metal compound that is hardly soluble in water and water, and the outer phase contains a solution of a biodegradable polymer in an organic solvent. It is preferable to produce the sustained-release preparation of the present invention via an emulsion, but by forming an emulsion in the coexistence of water, it is possible to adjust a stable and uniform emulsification system in a short time. .
- the biodegradable polymer used in the present invention includes, for example, ⁇ -hydroxy A polymer having a free carboxyl group synthesized from at least one of carboxylic acids (eg, glycolic acid, lactic acid, etc.), hydroxydicarboxylic acids (eg, malic acid, etc.), hydroxytricarboxylic acids (eg, citrate, etc.) , A copolymer or a mixture thereof; poly- ⁇ -cyanoacrylate; polyamino acid (eg, poly-g-benzyl L_glutamic acid, etc.); maleic anhydride-based copolymer (eg, styrene-maleic acid) And the like.
- carboxylic acids eg, glycolic acid, lactic acid, etc.
- hydroxydicarboxylic acids eg, malic acid, etc.
- hydroxytricarboxylic acids eg, citrate, etc.
- a copolymer or a mixture thereof poly- ⁇ -cyanoacrylate
- the type of polymerization may be random, block, or graft.
- any of D-, L- and DL-forms can be used.
- a polyhydroxycarboxylic acid polymer preferably a lactic acid-glycolic acid polymer
- an ester thereof, a poly- ⁇ -cyanoacrylate ester and the like are preferable. More preferably, it is a lactic acid-glycolic acid polymer.
- a lactic acid-glycolic acid polymer When a lactic acid-glycolic acid polymer is used as the biodegradable polymer, its composition ratio (mol%) is preferably 100 ⁇ 0 to 40/60, and particularly preferably 100 ⁇ 0 to 50 ⁇ 50.
- the weight average molecular weight of the lactic acid over glycolic acid polymer is normally about 3; 000 to about 50, 000, preferably about 4, 000 to about 40, 000, more preferably about 5, 000 to about 30, 000.
- the dispersity (weight average molecular weight / number average molecular weight) is usually preferably about 1.2 to about 4.0, and more preferably about 1.5 to 3.5.
- the weight average molecular weight, the number average molecular weight and the degree of dispersion in the present specification mean that the weight average molecular weight is 1,110,000, 707,000, 354,000, 189, 000, 156,000, 98, 900, 66, 437, 37, 200, 17, 100, 9, 830, 5, 870, 2, 500, 1, 303, and 500 types of polystyrene were used as standard substances and measured by gel permeation chromatography (GPC). It refers to the molecular weight in terms of polystyrene and the calculated degree of dispersion.
- GPC gel permeation chromatography
- the biodegradable polymer is dissolved in a mixed solvent of acetone and methanol, and phenolphthalein is used as an indicator.
- the lipoxyl group was titrated with a lium solution to calculate the number average molecular weight by terminal group quantification.
- this is referred to as a number average molecular weight determined by terminal group quantification.
- the number average molecular weight determined by end group quantification is an absolute value
- the number average molecular weight determined by GPC is determined by analysis or analysis conditions (for example, selection of mobile phase type, column type, reference material, selection of slice width, Since it is a relative value that fluctuates depending on the selection of the baseline, etc., it is difficult to make a clear numerical value.
- the number average molecular weight determined by GPC and the number average molecular weight determined by quantification of the terminal group are almost the same.
- the term "substantially the same as in the case of the lactic acid-dalicholic acid polymer” means that the number average molecular weight determined by terminal group determination is in the range of about 0.2 to about 1.5 times the number average molecular weight determined by GPC. Preferably, it is within the range of about 0.3 to about 1.2 times.
- lactic acid-glycolic acid polymer for example, non-catalytic dehydration / polycondensation of lactic acid and glycolic acid (Japanese Patent Application Laid-Open No. Sho 61-28521) or a catalyst derived from a cyclic material such as lactide and glycolide was used. It can be produced by ring-opening polymerization (Encyclopedic Handbook of Biomaterials and Bioengineering Part A: Materials, Volume 2, Marcel Dekker, Inc., 1995).
- the polymer synthesized by ring-opening polymerization is a polymer having no hepoxyl group, but a polymer obtained by chemically treating the polymer to form a free carboxyl group at the end (Journal Controlled). Releases (L Control led Release), Vol. 41, pp. 249-257, pp. 1996 can also be used.
- the lactic acid-glycolic acid polymer having a free hydroxyl group at the terminal described above can be produced without problems by a known production method (for example, a non-catalytic dehydration polycondensation method, see Japanese Patent Application Laid-Open No. Sho 61-28521).
- the polymer having a free carboxyl group that is not specified at the terminal can be produced by a known production method (for example, see WO94 / 15587).
- a lactate-glycolic acid polymer whose terminal has been converted into a free hydroxyl group by a chemical treatment after ring-opening polymerization is, for example, commercially available from Boehringer Ingelheim KG. Is also good.
- biodegradable polymers may be used alone or as a mixture of two or more.
- the polyvalent metal used in the present invention is not particularly limited as long as it is a compound that does not adversely affect the living body.
- metal species examples include divalent (eg, iron, zinc, copper, calcium, magnesium, aluminum, Polyvalent metals (preferably, zinc, etc.) such as tin, manganese, etc., trivalent (eg, iron, aluminum, manganese, etc.) and tetravalent (eg, tin, etc.) are used.
- the “polyvalent metal compound” used in the present invention may be used as a compound with an inorganic or organic substance or a metal oxide, or may be used as a metal ion. It is preferable to apply the component obtained by the above.
- Preferred specific examples of the polyvalent metal include, for example, iron, aluminum, zinc, calcium, and magnesium.
- a particularly preferred specific example of the polyvalent metal includes zinc.
- the inorganic substance examples include hydrogen halide (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, etc.), and inorganic acids such as sulfuric acid, nitric acid, thiocyanic acid, and the like.
- an organic acid such as an aliphatic carboxylic acid and an aromatic acid, and acetyl acetone are used.
- an aliphatic carboxylic acid having 1 to 9 carbon atoms eg, aliphatic monocarboxylic acid, aliphatic dicarboxylic acid, aliphatic tricarboxylic acid, etc.
- the aliphatic carboxylic acid may be either saturated or unsaturated.
- aliphatic monocarboxylic acids examples include saturated aliphatic monocarboxylic acids having 1 to 9 carbon atoms (eg, carbonic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid) And unsaturated carboxylic acids having 2 to 9 carbon atoms (eg, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, etc.).
- saturated aliphatic monocarboxylic acids having 1 to 9 carbon atoms eg, carbonic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid
- unsaturated carboxylic acids having 2 to 9 carbon atoms eg, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, etc
- aliphatic dicarboxylic acids examples include saturated aliphatic dicarboxylic acids having 2 to 9 carbon atoms (eg, malonic acid, succinic acid, daltaric acid, adipic acid, pimelic acid, etc.) and unsaturated aliphatic compounds having 2 to 9 carbon atoms.
- Aliphatic dicarboxylic acids eg, maleic acid, fumaric acid, citraconic acid, mesaconic acid, etc. are used.
- aliphatic tricarboxylic acid for example, a saturated aliphatic tricarboxylic acid having 2 to 9 carbon atoms (eg, tricarboxylic acid, 1,2,3-butanetricarboxylic acid, etc.) is used.
- a saturated aliphatic tricarboxylic acid having 2 to 9 carbon atoms eg, tricarboxylic acid, 1,2,3-butanetricarboxylic acid, etc.
- the aliphatic carboxylic acid may have one or two hydroxyl groups.
- Examples of such an aliphatic carboxylic acid include, for example, glycolic acid, lactic acid, glyceric acid, tartronic acid, lingoic acid, tartaric acid, and citric acid. And the like.
- the aliphatic carboxylic acid is preferably an aliphatic monocarboxylic acid. More preferably, it is an aliphatic monocarboxylic acid having 2 to 9 carbon atoms. A particularly preferred specific example of the aliphatic carboxylic acid is acetic acid.
- aromatic acid for example, benzoic acid, salicylic acid, phenolsulfonic acid and the like are used.
- Salts of iron and inorganic acids eg, iron halides (eg, iron chloride, iron bromide, iron iodide, iron fluoride, etc.), iron sulfate, iron nitrate, iron thiocyanate, etc.
- iron and organic acids Salts eg, iron aliphatic carboxylate (eg, iron carbonate, iron acetate, iron glycolate, iron lactate, iron tartrate, etc.), aromatic iron salts (eg, iron benzoate, iron salicylate, iron phenol sulfonate) )], Iron acetyl acetate, etc.
- Salts of zinc and inorganic acids eg, zinc halides (eg, zinc chloride, zinc bromide, zinc iodide, zinc fluoride, etc.), zinc sulfate, zinc nitrate, zinc thiocyanate, etc.
- zinc and organic acids Salts eg, zinc aliphatic carboxylate (eg, zinc carbonate, zinc acetate, zinc glycolate, zinc lactate, zinc tartrate, etc.), aromatic zinc salts (eg, zinc benzoate, zinc salicylate, Zinc phenol sulfonate)], zinc acetyl acetate, salt of calcium and inorganic acid [eg, calcium halide (eg, calcium chloride, calcium bromide, calcium iodide, calcium fluoride, etc.), calcium sulfate, Calcium nitrate, calcium thiocyanate, etc.), salts of calcium with organic acids [eg, calcium salts of aliphatic carboxylic acids (eg, calcium carbonate, potassium
- Salt of magnesium and inorganic acid eg, magnesium halide (eg, magnesium chloride Magnesium, magnesium bromide, magnesium iodide, magnesium fluoride, etc.), magnesium sulfate, magnesium nitrate, magnesium thiocyanate, etc.), salts of magnesium with organic acids [eg, magnesium salts of aliphatic carboxylic acids (eg, Magnesium carbonate, magnesium acetate, magnesium propionate, magnesium oxalate, magnesium tartrate, magnesium lactate, magnesium citrate, magnesium dalconate, etc., aromatic magnesium salts (eg, magnesium benzoate, magnesium salicylate, etc.)] , Magnesium acetate acetonate, etc., and
- Metal oxides eg, zinc oxide, iron oxide, calcium oxide, magnesium oxide, aluminum oxide, copper oxide, manganese oxide, etc.
- the polymetal compound is preferably zinc oxide, iron chloride, iron acetyl acetate, zinc acetate, zinc acetyl acetate, calcium acetate, calcium acetyl acetate, magnesium acetate, magnesium acetyl Acetinate is used, and more preferably, zinc oxide is used.
- a polyvalent metal which is the same as or different from the polyvalent metal used as the raw material (a polyvalent metal compound not treated with water) ) May be present in the sustained-release preparation of the present invention.
- a polyvalent metal may be present as a polyvalent metal compound (such as a compound with an inorganic or organic substance or a metal oxide). May be present as a metal ion, and may form a complex with one or both of a bioactive compound, a prodrug thereof, a salt thereof, and a biodegradable polymer.
- a part of the polyvalent metal that may be contained may be used as a biodegradable polymer in which zinc or a different metal salt is used.
- the metal salt of the biodegradable polymer can be produced, for example, by the method described in JP-A-09-221420 or a method analogous thereto.
- Preferred production methods of the sustained-release preparation of the present invention include a physiologically active compound that is hardly soluble in water, a component obtained by treating a water-soluble polyvalent metal compound with water, and a biodegradable polymer.
- a method of removing water and the solvent from the liquid is exemplified.
- a water-insoluble polyvalent metal compound can be added to the liquid. It may contain a polyvalent metal other than the polyvalent metal derived from the ⁇ component obtained by water treatment '', and may be used when preparing the ⁇ component obtained by water-treating a poorly water-soluble polyvalent metal compound ''.
- the water is added to the water to add a polyvalent metal other than the polyvalent metal derived from the “component obtained by treating the polyvalent metal compound having poor solubility in water with water”.
- a metal may be contained.
- Some or all of the polyvalent metal other than the polyvalent metal derived from the “component obtained by treating a poorly water-soluble polyvalent metal compound with water” in the liquid contains a physiologically active compound and biodegradation.
- a complex may be formed with one or both of the hydrophilic polymers.
- the amounts of the physiologically active compound and the “component obtained by treating a poorly water-soluble polyvalent metal compound with water” in the sustained-release preparation of the present invention may vary depending on the type of the physiologically active compound, the desired pharmacological effect and Depending on the duration of the effect, etc., a bioactive compound, a component obtained by treating a poorly water-soluble polyvalent metal compound with water '' and a biodegradable polymer as a starting material, the sum of the three
- the physiologically active compound is usually about 1 to about 50% by weight, more preferably about 15 to 45% by weight, particularly preferably about 20 to 40% by weight.
- the "poorly water-soluble polyvalent metal compound” is usually about 0.5 to about 20% by weight, more preferably about 1 to about 15% by weight, and particularly preferably about 2 to about 10% by weight.
- the form of the sustained-release preparation of the present invention is not particularly limited, but a parenteral preparation is preferable.Transdermal preparations, transmucosal preparations, implants, microcapsule injections, and the like can be considered. Injection preparations using microcapsules that do not burden the patient are preferred. BEST MODE FOR CARRYING OUT THE INVENTION
- one or more water-insoluble bioactive compounds and one or more water-insoluble water-soluble compounds are added in the weight ratio shown above.
- Organic solvent of biodegradable polymer containing water, a bioactive compound that is hardly soluble in water, and a component obtained by treating a water-soluble polyvalent metal compound with water by adding a valent metal compound and water make a solution.
- the bioactive compound that is hardly soluble in water, one or more polyvalent metal compounds that are hardly soluble in water, and water are not partially dissolved in the organic solvent solution of the biodegradable polymer, and are dispersed. It is preferable to disperse finely in a short time by a known method such as a homogenizer or an ultrasonic wave.
- Addition of water may be performed using any of the poorly water-soluble physiologically active compounds and the biodegradable polymers, provided that the poorly soluble polyvalent metal compound is present in the water and that the conditions can be sufficiently mixed by a known method. Alternatively, it may be carried out under conditions in which both do not coexist.
- a polyvalent metal compound that is hardly soluble in water is added to an organic solvent solution of a biodegradable polymer together with water and mixed well, and then the bioactive compound is added and redispersed. It may be one process in the method of preparing the organic solvent solution of the biodegradable polymer containing the compound.
- organic solvent examples include halogenated hydrocarbons (eg, dichloromethane, chloroform, dichloroethane, trichloroethane, carbon tetrachloride, etc.), ethers (eg, ethyl ether, isopropyl ether, etc.), fatty acid esters (eg, acetic acid) Examples include ethyl, butyl acetate, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), alcohols (eg, ethanol, methanol, etc.), and acetonitrile. These may be mixed and used at an appropriate ratio. Of these, dichloromethane is preferred as the halogenated hydrocarbon, and ethanol and methanol are preferred as the alcohol. These may be mixed and used at an appropriate ratio.
- dichloromethane is preferred as the halogenated hydrocarbon
- ethanol and methanol are preferred as the alcohol.
- An additive may be added to the above organic solvent solution.
- the additive include solubilizers for maintaining the stability and solubility of the drug, such as carbonic acid, oxalic acid, citric acid, phosphoric acid, and hydrochloric acid, sodium hydroxide, arginine, lysine, and salts thereof. May be added.
- albumin, gelatin, citric acid, sodium compounds such as sodium ethylenediaminetetraacetate, dextrin, sodium hydrogen sulfite, polyethylene glycol, etc., are generally used as drug stabilizing agents, or as preservatives.
- Paraoxybenzoic acid esters eg, methyl paraben, propyl paraben, etc.
- benzyl alcohol chlorobutanol, thimerosal Etc.
- the concentration of the biodegradable polymer in the organic solvent solution varies depending on the molecular weight of the biodegradable polymer and the type of organic solvent.For example, when dichloromethane is used as the organic solvent, it is generally used. Is selected from about 0.5 to about 70% by weight, more preferably about 1 to about 60% by weight, and particularly preferably about 2 to about 50% by weight.
- the ratio of dichloromethane in the mixed organic solvent is generally about 10 to about 99% by volume, more preferably It is selected from about 20 to about 98% by volume, particularly preferably about 30 to about 95% by volume.
- an organic solvent solution of a biodegradable polymer containing the obtained water, a physiologically active compound that is hardly soluble in water, and “a component obtained by treating a poorly water-soluble polyvalent metal compound with water” is used.
- O oil phase
- ZW aqueous phase
- the volume of the aqueous phase at this time is generally about 1 to about 100,000 times the oil phase volume, more preferably about 5 to about 5,000 times, and particularly preferably about 10 to 100 times. Double to about 20000 times.
- An emulsifier may be added to the above external water phase.
- the emulsifier may be any as long as it can form a stable o / w emulsion.
- anionic surfactants sodium oleate, sodium stearate, sodium lauryl sulfate, etc.
- nonionic surfactants polyoxyethylene sorbitan fatty acid ester [Tween 80, (Tween) 60, Atlas powder—company), polyoxyethylene castor oil derivatives CHCO-60, HCO-50, Nikko Chemicals, etc.
- polyvinylpyrrolidone polyvinyl alcohol, carboxymethyl cellulose, lecithin, gelatin, Hyaluronic acid or the like is used. These may be used alone or in combination of two or more.
- the concentration in use is preferably in the range of about 0.01 to: 0% by weight, more preferably in the range of about 0.05 to about 5% by weight.
- An osmotic pressure regulator may be added to the above external aqueous phase.
- the osmotic pressure adjusting agent may be any as long as it exhibits an osmotic pressure when used as an aqueous solution.
- Examples of the osmotic pressure regulator include polyhydric alcohols, monohydric alcohols, and monohydric alcohols. Examples include saccharides, disaccharides, oligosaccharides and amino acids or derivatives thereof.
- Examples of the polyhydric alcohols include dihydric alcohols such as glycerin, pentahydric alcohols such as arabitol, xylitol, and additol, and hexahydric alcohols such as mannitol, sorbitol, and dulcitol. Of these, hexahydric alcohols are preferred, and mannitol is particularly preferred.
- Examples of the above monohydric alcohols include methanol, ethanol, and isopropyl alcohol, and among them, methanol is preferable.
- Examples of the above monosaccharides include pentoses such as arabinose, xylose, lipose, and 2-deoxylipose, and hexoses such as glucose, fructose, galactose, manose, sorbose, rhamnose, and fucose. Hexasaccharides are preferred.
- oligosaccharides for example, trisaccharides such as maltotriose and raffinose monosaccharide, tetrasaccharides such as stachyose and the like are used, among which trisaccharides are preferable.
- disaccharides and oligosaccharides for example, dalcosamine, galactosamine, glucuronic acid, galacturonic acid and the like are used.
- Any of the above amino acids may be used as long as it is L-integrated, and examples thereof include glycine, leucine, and arginine. Of these, L-arginine is preferred. .
- osmotic pressure regulators may be used alone or as a mixture.
- osmotic pressure regulators are used at a concentration such that the osmotic pressure of the external aqueous phase is about 1/50 to about 5 times, preferably about 1/25 to about 3 times the osmotic pressure of physiological saline.
- a method for removing water and the organic solvent a method known per se or a method analogous thereto is used. For example, a method in which water and organic solvents are evaporated at normal pressure or gradually reduced pressure while stirring with a propeller-type stirrer or a magnetic stirrer, or water is adjusted while adjusting the degree of vacuum using a rotary evaporator or the like. And a method of evaporating an organic solvent. '
- the micro force cell obtained in this way is separated by centrifugation or filtration, and the bioactive compound, drug holding substance, emulsifier, etc. attached to the surface of the microcapsule are repeated several times with distilled water. Wash, disperse again in distilled water and freeze-dry.
- an anti-aggregation agent may be added to prevent aggregation of the particles.
- the coagulation inhibitor include water-soluble polysaccharides such as mannitol, lactose, glucose, starches (eg, corn starch), amino acids such as glycine, and proteins such as fibrin and collagen. Of these, mannitol is preferred.
- the water and the organic solvent in the micro force capsule may be removed by heating under reduced pressure so that the microcapsules do not fuse with each other.
- the polymer is heated at a temperature slightly higher than the midpoint glass transition temperature of the biodegradable polymer determined by a differential scanning calorimeter under a condition of a heating rate of 10 to 20 ° C per minute. . More preferably, heating is performed within a temperature range about 30 ° C. higher than the midpoint glass transition temperature of the biodegradable polymer.
- the temperature range is preferably higher than the midpoint glass transition temperature and 1 ° C higher than the midpoint glass transition temperature, and more preferably the midpoint glass transition temperature.
- the heating time varies depending on the amount of the microcapsule and the like, but generally, about 12 hours to about 168 hours, preferably about 2 hours after the microcapsule itself reaches a predetermined temperature. It is from 4 hours to about 120 hours, particularly preferably from about 48 hours to about 96 hours.
- the method of heating is not particularly limited as long as the method is capable of uniformly heating the aggregate of microcapsules.
- the heating and drying method for example, a method of heating and drying in a constant temperature bath, a fluidized bath, a moving tank or a kiln, a method of heating and drying with a microwave, and the like are used. Of these, the method of heating and drying in a thermostat is preferred.
- removal of water and organic solvent in the microcapsules may be (such as CO 2) supercritical fluid, pressurized gas (such as C_ ⁇ 2), or the like can also be performed by a method using a.
- the water, the water-insoluble physiologically active compound and the water-insoluble water-soluble polyvalent metal compound described in the above (I) in-water drying method are treated with water.
- a coacervation agent is gradually added to an organic solvent solution of the biodegradable polymer containing the obtained components under stirring to precipitate and solidify the microcapsules.
- the coacervation agent is preferably about 0.01-1.000 times the oil phase volume, preferably Is selected from about 0.05 to 500 times, particularly preferably about 0.1 to 200 times.
- the coacervation agent is not particularly limited as long as it does not dissolve both the bioactive compound and the biodegradable polymer, such as a polymer compound, a mineral oil compound, or a vegetable oil compound miscible with an organic solvent. .
- a polymer compound such as a polymer compound, a mineral oil compound, or a vegetable oil compound miscible with an organic solvent.
- silicone oil, sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane and the like are used. These may be used as a mixture of two or more.
- washing with heptane and the like is repeated to remove the bioactive compound and the coacervation agent other than the biodegradable polymer, and then drying under reduced pressure I do.
- freeze-drying, heating drying, supercritical fluid, desolvation with a pressurized gas, etc. may be used. Good.
- the water, the water-insoluble physiologically active compound and the water-insoluble water-soluble polyvalent metal compound described in the above (I) in-water drying method are treated with water.
- the nozzle include a two-fluid nozzle type, a pressure nozzle type, and a rotating disk type.
- washing is performed in the same manner as described in the above-mentioned in-water drying method (I), followed by freeze drying, and further, heating drying, desolvation with a supercritical fluid, pressurized gas, or the like. You may.
- water, a water-insoluble bioactive compound and a water-insoluble water-soluble polyvalent metal compound described in the in-water drying method of the microcapsule production method (I) are treated with water.
- the organic solvent solution of the biodegradable polymer containing the ⁇ obtained component '' was evaporated to dryness by evaporating the organic solvent and water while adjusting the degree of vacuum using, for example, a talliev aerator. It may be pulverized with a jet mill or the like to give a fine powder.
- crushed fine powder is washed in the same manner as described in the in-water drying method of the microcapsule production method (I), and then freeze-dried, furthermore, heated drying, supercritical fluid, Desolvation with a pressurized gas or the like may be performed.
- the microcapsules or fine powder obtained here can be used to determine the decomposition rate of the biodegradable polymer used, the “components obtained by treating a poorly water-soluble polyvalent metal compound with water”, the amount of water added, Drug release can be controlled according to the type and amount of the valent metal compound.
- the sustained-release preparation of the present invention is formulated as it is or as a raw material into various dosage forms, and is injected or implanted into intramuscular, subcutaneous, organs, etc., transmucosally into nasal cavity, rectum, uterus, etc.
- Dosage forms, inhalants, oral preparations eg, capsules (eg, hard capsules, soft capsules, etc.), solid preparations such as granules and powders, liquid preparations such as syrups, emulsions, suspensions, etc.
- oral preparations eg, capsules (eg, hard capsules, soft capsules, etc.)
- solid preparations such as granules and powders
- liquid preparations such as syrups, emulsions, suspensions, etc.
- a dispersant eg, a surfactant such as Tween 80, HC0-60, sodium hyaluronate, carboxymethylcellulose.
- a dispersant eg, a surfactant such as Tween 80, HC0-60, sodium hyaluronate, carboxymethylcellulose.
- Polysaccharides such as sodium alginate, etc.
- preservatives eg, methylparaben, propylparaben, etc.
- tonicity agents eg, sodium chloride, mannitol, sorbitol, glucose, proline, etc.
- an aqueous suspending agent e.g, it can be dispersed with vegetable oils such as sesame oil and corn oil to give sustained-release injections that can be actually used as an oily suspension.
- the particle size of the sustained-release preparation of the present invention may be in a range that satisfies the dispersibility and the needle penetration property when used as a suspension injection.
- the mean particle size is about 0.1. 3300 zzm, preferably in the range of about 0.5 to 150 m, more preferably in the range of about 1 to 100 zm.
- the sustained-release preparation of the present invention can be made into a sterile preparation by a method of sterilizing the production process, a method of sterilizing with a gamma ray, a method of combining these methods, or a method of adding a preservative.
- a method of sterilizing the production process a method of sterilizing with a gamma ray, a method of combining these methods, or a method of adding a preservative.
- the sustained-release preparation of the present invention has low toxicity, it can be used as a drug safe for mammals (eg, humans, cows, pigs, dogs, cats, mice, rats, rabbits, etc.).
- mammals eg, humans, cows, pigs, dogs, cats, mice, rats, rabbits, etc.
- the dosage of the sustained-release preparation of the present invention varies depending on the type and content of the bioactive compound as the active ingredient, the dosage form, the duration of release of the bioactive compound, the target disease, the target animal, and the like. However, any effective amount of the physiologically active compound may be used.
- the dose of the physiologically active compound as the main drug is preferably about 0.0 lmg to l OmgZkg body weight per adult. It can be appropriately selected from the range, more preferably from about 0.05 mg to 5 mgZkg body weight.
- the dose of the sustained-release preparation per dose is preferably in the range of about 0.05 mg to 5 Omg / kg body weight per adult, more preferably in the range of about 0.1 mg to 30 mgZ kg body weight. Can be.
- the frequency of administration may be once every few weeks, once a month, or once every few months (eg, every three months, four months, six months, etc.) It can be appropriately selected depending on the dosage form, duration of release of the physiologically active compound, target disease, target animal, and the like.
- the sustained-release preparation of the present invention is useful for bedridden patients, dementia, throat / esophageal diseases, digestive disorders, eating disorders * patients with dysphagia, patients who are difficult or impossible to treat with internal medicine such as during surgery. Can also be used advantageously.
- the bioactive compounds are compounds having angiotensin II antagonism, they are highly safe, and even if the blood concentration increases immediately after administration, the blood pressure does not drop too much.
- the sustained-release preparation of the present invention can be used as a therapeutic agent for the following diseases, and can maintain a constant blood concentration regardless of day and night. It is expected that the treatment effect will be clearer because the dose and frequency can be reduced, and there will be little change in the blood drug concentration and no change in the disease state due to interruption of taking.
- Intravenous administration of angiotensin II as well as drugs commonly used in emergency medical settings can immediately increase blood pressure, and continuous oral blood pressure can also be achieved by oral administration of antihypertensive drugs Therefore, not only acute emergency response but also long-term response is possible.
- Diseases targeted by compounds having angiotensin II antagonism as bioactive compounds include diseases caused by contraction and proliferation of blood vessels expressed through angiotensin II receptor and organ damage, presence of angiotensin II, or angiotensin II.
- Factors induced by the presence of tensin II include diseases whose onset or accelerated onset.
- Such disorders include, for example, hypertension, abnormal circadian blood pressure, cardiac disorders (cardiac hypertrophy, chronic heart failure including acute heart failure and congestive disorders, cardiomyopathy, angina, myocarditis arrhythmia, tachycardia, myocardium Cerebral vascular disorder (asymptomatic cerebral vascular disorder, transient cerebral ischemic attack, stroke, cerebral vascular dementia, hypertensive encephalopathy, etc.), cerebral edema, cerebral circulatory disorder, cerebrovascular disorder recurrence and Sequelae (neurological symptoms, psychiatric symptoms, subjective symptoms, impaired activities of daily living, etc.), ischemic peripheral circulatory disorders, myocardial ischemia, venous insufficiency, progression of heart failure after myocardial infarction, diabetes, diabetic complications (diabetic retina Disease, diabetic nephropathy, diabetic neuropathy, etc., kidney disease (nephritis, glomerulonephritis, glomerulosclerosis,
- Cancer and its associated cachexia, metastasis of the cancer endocrine diseases (Addison's disease, Cushing's syndrome, brown cell types, primary aldosteronism, etc.), Kreuzfeld-Jakob disease, urology and male genital diseases (cystitis, prostate Hypertrophy, prostate cancer, sexually transmitted diseases, etc., gynecological diseases (menopause, pregnancy poisoning, endometriosis, uterine fibroids, ovarian disease, mammary disease, sexually transmitted diseases, etc.), diseases caused by environmental and occupational factors ( Radiation damage, ultraviolet rays, infrared rays, laser single beam damage, altitude sickness, etc., respiratory diseases (cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary blood) ⁇ Pulmonary embolism, etc., infectious diseases (viral infections such as cytomegalovirus, influenza virus, herpes virus, rickettsial infections, bacterial infections, etc.), toxicemia (sepsis
- the bioactive compound has angiotensin II antagonistic activity, long-term inhibition of the action of angiotensin 11 will result in impaired biological functions and physiological effects that cause various diseases associated with adult diseases and aging. Alternatively, it can ameliorate or suppress abnormalities and suppress primary and secondary prevention or progression of diseases or conditions resulting therefrom.
- Such disorders or abnormalities in biological functions and physiological actions For example, impaired or abnormal cerebral circulation ⁇ renal circulation autoregulation ability, circulatory disorders (peripheral, brain, microcirculation, etc.), impaired brain blood barrier, decreased insulin sensitivity, salt sensitivity, coagulation ⁇ fibrinolytic abnormalities, Abnormal properties of blood and blood cell components (enhanced platelet aggregation, abnormal erythrocyte deformability, increased white blood cell adhesion, increased blood viscosity, etc.), growth factors and cytokins (PDGF, VEGF, FGF, , TNF-a, MCP-1 etc.), increase production and action of inflammatory cells, increase free radical production, promote fat deposition, impair endothelial function, endothelial cell and organ damage, edema, smoothness cells form status change, such as muscle (form change to such proliferating), production and hyperactivity vasoactive substance and thrombosis inducers (Endose phosphorus, etc.
- Toronpokisan Alpha 2 abnormal contractions such as a blood vessel Abnormal glucose tolerance, abnormal metabolism (abnormal serum lipids, abnormal blood glucose, etc.), abnormal proliferation of cells, angiogenesis (including abnormal angiogenesis in the formation of abnormal capillary networks in the outer membrane of atherosclerotic lesions), etc.
- angiogenesis including abnormal angiogenesis in the formation of abnormal capillary networks in the outer membrane of atherosclerotic lesions
- primary disorders of organs caused by various diseases eg, cerebrovascular disorders and related organ disorders, organ disorders due to cardiovascular diseases, organ disorders due to diabetes, organ disorders after invasion, etc. It can be used advantageously as a secondary preventive and therapeutic agent.
- the bioactive compound when the bioactive compound is a compound having an angiotensin II antagonistic activity (particularly, candesartan cilexetil, candesartan, etc.), it can be advantageously used as an agent for preventing or treating portal hypertension. It is. It is known that esophageal varices rupture occurs frequently at night (Hepatology 1994; 19: 595-601) .Since this drug can maintain a constant blood concentration regardless of day and night, Compared with the case of administration with a drug, it is possible to not only reduce the number of administrations, but also to expect a stable decrease in portal vein pressure due to a small change in blood drug concentration.
- the above features of the drug demonstrate its usefulness as a preventive for rupture of varices in the esophagus and stomach.
- the treatment effect is expected to be clearer because no change in the medical condition occurs due to discontinuation of taking the drug.
- compounds with angiotensin 11 antagonistic activity as physiologically active compounds are expected to be effective in promoting the production of hepatocyte growth factor (HGF). It can be expected to contribute to liver regeneration and liver brain recovery.
- HGF hepatocyte growth factor
- a method for treating a patient is to administer an orally administered angiotensin II antagonist for a certain period of time, confirm the reactivity of the patient, and then release the sustained release of the present invention. It is also conceivable to administer a sexual preparation.
- the orally administered angiotensin II antagonist and the angiotensin II antagonist contained in the sustained-release preparation may be the same or different.
- antihypertensive agents other than angiotensin II antagonists (calcium antagonists, diuretics, vein blockers, etc.) are administered orally in advance, and after confirming the reactivity of the patient, The formulation may be administered.
- the sustained-release preparation of the present invention may be used in combination with a diuretic antihypertensive (oral preparation) usually used in combination with an angiotensin II antagonist.
- lipid-lowering drugs or cholesterol-lowering drugs HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) inhibitors, insulin sensitizers, bone disease treatments, cardioprotectives , Coronary artery disease treatment, Other hypertension treatment, Chronic heart failure treatment, Diabetes treatment, Liver disease treatment, Gastric and duodenal ulcer treatment, Biliary disease treatment, Hypothyroidism treatment, Nephrotic syndrome treatment
- the drug may be used together with other pharmaceutical ingredients including drugs for treating chronic renal failure, drugs for gynecological diseases, drugs for urinary and male genital diseases or drugs for infections, in which case these compounds are administered as oral preparations And, if necessary, it may be administered in the form of suppositories as a rectal preparation.
- fibrates eg, clofibrate, benzafibrate, gemfiprodil, etc.
- nicotinic acid eg, acipimox and probucol
- bile acid binding Resins eg, cholestyramine, colestipol, etc.
- compounds that suppress cholesterol absorption eg, sitosterol and neomycin, etc.
- squalene epoxidase inhibitors eg, NB-598 and related compounds, etc.
- oxidosqualene-lanosterol cyclase such as a decalin derivative, an azadecalin derivative and an indane derivative. Also, combinations with the following various therapeutic agents are possible.
- Antihypertensives diuretics [eg, furosemide (Lasix), bumetaed (Lunetron), azosemide (Diart)], antihypertensive [eg, ACE inhibitors, (enalapril maleate (Renibase), etc.)) and Ca antagonists (manidipine) , Amlodipine, etc.), ⁇ or 3 receptor blockers, etc.)
- diuretics eg, furosemide (Lasix), bumetaed (Lunetron), azosemide (Diart)
- antihypertensive eg, ACE inhibitors, (enalapril maleate (Renibase), etc.)
- Ca antagonists manidipine
- Amlodipine etc.
- ⁇ or 3 receptor blockers etc.
- Drugs for chronic heart failure include inotropic drugs [eg, cardiac glycosides (digoxin, etc.), i3 receptor stimulants (catecholamine preparations such as denopamine and dobumin) and PDE inhibitors, etc.], diuretics [eg, furosemide ( Lasix), spironolactone (aldactone), etc., ACE inhibitors, [eg, enalapril maleate (renibeis, etc.)], Ca antagonists [eg, amlodipine, etc.] and jS receptor blockers, etc.
- inotropic drugs eg, cardiac glycosides (digoxin, etc.), i3 receptor stimulants (catecholamine preparations such as denopamine and dobumin) and PDE inhibitors, etc.
- diuretics eg, furosemide ( Lasix), spironolactone (aldactone), etc.
- ACE inhibitors eg, enalapril maleate (renibeis, etc.
- Antiarrhythmic drugs disopyramide, lidocaine, quinidine sulfate, flecainide acetate, mexiletine hydrochloride, amiodarone hydrochloride, and blockers, Ca antagonists, etc.
- calcium preparations e.g., calcium carbonate, etc.
- calcitonin preparations e.g., such as alfacalcidol (Alfaro Ichiru), Karushitorio Ichiru (mouth Cult roll), etc.
- sex hormones class e.g., estrogens, S.
- transient ol hormone preparations [e.g., conjugated estrogen (Premarin), etc.], (such Osten) Ivry flavone formulation, vitamin K 2, vitamin kappa 2 formulation [eg, menatetrenone (Gurage I) Etc.), bisphosphonic acid preparations (such as etidrone), prostaglandin ⁇ 2, fluorine compounds (eg, sodium fluoride, etc.), osteogenic proteins (BMP), fibroblast growth factor (FGF), platelet-derived proliferation Factor (PDGF), Transforming growth factor (TGF-), Insulin-like Factors 1 and 2 (IGF-1, -2), parathyroid hormone (PTH), European Patent Application Publication EP-A1-376197, EP-A1-460488 and EP-A1-719782 Compounds described in Japanese Patent Publication (e.g., (2R.4S)-(-) [4- (diethoxyphosporylmethyl) phenyl] -l,, 4, 5-tetrahydro-4-methy 7,8
- Antidiabetic drugs Actos, Rosiglitazone, Kinedak, Benfil, Humarin, Ouidalcon, Dalimicron, Daoneil, Novoline, Monoidone, Insulinins, Darcobium, Zimerin, Lastinone, Basilcon, Demerin S, Iszirins and the like;
- glycyrrhizin preparations [eg, strong minophagen, etc.], liver hydrolyzate, SH compounds [eg, daltathione, etc.], special amino acid preparations [eg, aminolevane, etc.], phospholipids [eg, polyenphosphatidylcholine, etc.], vitamins (Eg, vitamins B1, B2, B6, B12, C, etc.), corticosteroids (eg, dexamethasone, betamethasone, etc.), interferon (eg, interferon, ⁇ , etc.), hepatic encephalopathy drug [E.g., Lacquer mouth, etc.], hemostatic agents used at the time of rupture of esophagus and gastric varices [e.g., vasopressin, somatotocin, etc.] etc .;
- Drugs for gastric and duodenal ulcers Drugs: antacids [eg, histamine ⁇ 2 antagonists (cimetidine, etc.), proton pump inhibitors (lansoprazole, etc.)];
- bile drugs eg, dehydrocholic acid, etc.
- sedatives eg, magnesium sulfate, etc.
- Drugs for hypothyroidism dry thyroid (thyreoid), repothyroxine sodium (thyrazin S), liothyronidine sodium (thyronine, thyromin), etc .; drugs for nephrotic syndrome: usually adopted as the first choice Prednisolone (prednin), prednisolone sodium succinate (prednin), methylprednisolone sodium succinate (sol'medrol), betamethasone (lindelone), etc., are used as steroid therapy.
- antiplatelet drugs such as dipyridamole (versantin), dilazep hydrochloride (comerian), ticlopidine, clopidogrel, FXa inhibitor and anticoagulants are used;
- HM G Co A reductase inhibitor: seribas evening, atorvastatin, brabas evening, simbas evening, itapas evening, mouth bath evening, full bath evening, (+)-3 R, 5 S- 7- [4- (4-fluorophenyl) -1 6-isopropyl-12- (N-methyl-1N-methanesulfonylamino) pyrimidine-1-5-yl]-3,5-dihydroxy-1-6 (E) -heptene Acids and the like;
- Drugs for chronic renal failure diuretics [eg, furosemide (Lasix), bumetanide (Lunetron), azosemide (Diart)], antihypertensives (eg, ACE inhibitors, (enalapril maleate, Renibeis)) and When administered in combination with a Ca antagonist (manidipine), an ⁇ -receptor blocker, etc., it can be preferably used orally.
- diuretics eg, furosemide (Lasix), bumetanide (Lunetron), azosemide (Diart)
- antihypertensives eg, ACE inhibitors, (enalapril maleate, Renibeis)
- a Ca antagonist manidipine
- an ⁇ -receptor blocker etc.
- Antithrombotic drug Anticoagulant [eg, Heparin sodium, Heparin power Lucidum, Perufaline calcium (Phiphalin), Blood coagulation factor Xa inhibitor, Drug with a function to correct the coagulation / fibrinolysis system ], Thrombolytic drugs [eg, tPA, perokinase], antiplatelet drugs [eg, aspirin, -sulfinpyrazo mouth (anturane), dipyridamole (persantin), ticlopidine (panaludine), cyrosuzole (pletar), GPI Ib / II Ia antagonist (Leopro)]
- Anticoagulant eg, Heparin sodium, Heparin power Lucidum, Perufaline calcium (Phiphalin), Blood coagulation factor Xa inhibitor, Drug with a function to correct the coagulation / fibrinolysis system
- Thrombolytic drugs eg, tPA, perokinase
- antiplatelet drugs e
- Coronary vasodilators diphedipine, diltiazem, nicorazil, nitric acid, etc.
- Cardioprotective agents openers for cardiac ATP-K, Na-H exchange inhibitors, endothelin antagonists, perotinsin antagonists, etc.
- Anti-inflammatory drugs aspirin, acetaminophen, non-steroidal anti-inflammatory drugs (eg, indomethacin, etc.), steroid drugs (eg, dexamethasone, etc.), etc.
- Antiallergic drugs antihistamines (eg, chlorpheniramine maleate, etc.), stimulants (eg, bucillamine, etc.), other azelastine hydrochloride, seratrodast, tranilast, oxatomide, potent neominophagen, tranexamic acid, fumaric acid Ketotifen etc.
- Antineoplastics alkylating agents, antimetabolites, antitumor antibiotics, antitumor plant ingredients and other antitumor agents
- Central nervous system drugs anxiolytics, hypnotics, sedatives, narcotics, sedatives, autonomic nervous drugs, anti-parkinson drugs and other psychiatric drugs, etc.
- Gynecological treatments [eg, menopause treatments (conjugated estrogens, estradiol, testosterone enanthate, estradiol valerate, etc.), breast cancer treatments (tamoxifen quenate, etc.), endometriosis, uterine fibroids Drugs (lew prorelin acetate, danazol, etc.)
- Drugs for urinary and male genital disorders [eg, prostatic hypertrophy drugs (eg, muscarinic hydrochloride, prazosin hydrochloride, chlormadinone acetate, etc.), prostate cancer (leuprorelin acetate, goserelin acetate, chlormadinone acetate, etc.)]
- prostatic hypertrophy drugs eg, muscarinic hydrochloride, prazosin hydrochloride, chlormadinone acetate, etc.
- prostate cancer leuprorelin acetate, goserelin acetate, chlormadinone acetate, etc.
- Anti-infectives [eg, antibiotics (cefatiam hydrochloride, cefozopran hydrochloride, ampicillin, etc.), chemotherapeutics (sulfur, synthetic antibacterial, antiviral, etc.), biologicals (vaccines, immunoglobulins, etc. Blood products) etc. Other anti-obesity drugs (Mazindol, etc.), anti-rheumatic drugs, etc.
- each drug may be incorporated into one sustained-release preparation, but the above drug is mixed with a pharmacologically acceptable carrier, excipient, binder, diluent, etc. And can be administered separately or simultaneously with the sustained-release preparation of the present invention.
- the drugs are formulated separately, they can be administered separately by mixing them with a diluent at the time of use.However, the separately formulated individual drugs can be administered simultaneously or with a time lag. May be separately administered to the same subject.
- 2-Ethoxy 1 _ [[2 '-(1H-tetrazole-5-yl) biphenyl-4-yl] methyl] benzimidazo-l-u7-capillonic acid (hereinafter abbreviated as compound A) 1 g 0.36 g of zinc oxide (TYPE V, manufactured by Wako Pure Chemical Industries) and lactic acid-glycolic acid copolymer (lactic acid / daricholic acid 75/25 (mol%), weight average molecular weight 14,000, number average molecular weight 4 , 200, number average molecular weight 4,090 by terminal group determination, Wako Pure Chemical Industries) 3.6 g was added to a solution of 11 ml of dichloromethane and 0.4 ml of ethanol, and shaken at room temperature for 14 hours.
- compound A 1 g 0.36 g of zinc oxide (TYPE V, manufactured by Wako Pure Chemical Industries) and lactic acid-glycolic acid copolymer (lactic acid / daricholic acid 75
- This solution was poured into 800 ml of a 0.1% by weight aqueous solution of polyvinyl alcohol which had been adjusted to 15 ° C. in advance, and an OZW emulsion was prepared at 8,500 rpni using a evening mixer.
- the ⁇ / W emulsion was stirred at room temperature for 3 hours to evaporate dichloromethane and ethanol to solidify the oil phase, and then collected at 2,000 using a centrifuge. This was dispersed again in distilled water, and further centrifuged to wash free drug and the like.
- the collected microforce was added to distilled water in which a small amount of mannitol was dissolved, re-dispersed, and freeze-dried to obtain a powder.
- the encapsulation rate of compound 98 in the microcapsules is 98%.
- Compound A content in the capsules was 33.0%.
- Microcapsules were obtained in the same manner as in Reference Example 1, except that shaking and stirring for 14 hours was changed to dispersion and mixing for 1 minute using a homogenizer.
- the encapsulation rate of Compound A in the microcapsules was 100, and the content of Compound A in the microcapsules was 33.5%.
- a micro force cell was obtained in the same manner as in Comparative Example 1, except that 0.4 ml of distilled water was added, and the solid (compound A and zinc oxide) was dispersed (emulsified) with a homogenizer at the same speed for 1 minute together with the solid (compound A and zinc oxide).
- the encapsulation rate of Compound A in the micro force capsule was 97%, and the content of Compound A in the microcapsules was 32.6%.
- a microcapsule was obtained in the same manner as in Example 1 except that the amount of added distilled water was changed to 0.08 ml.
- the encapsulation rate of compound A in the microcapsules was 97%, and the content of compound A in the microcapsules was 32.5%.
- TYPE V manufactured by Wako Pure Chemical Industries
- This dried product was coarsely pulverized on a sieve having a pore size of 250 Hm, and 5 g of the dried product obtained was mixed with 0.4 g of mannitol, followed by jet milling (A-0JET , Manufactured by Seishin Enterprise Co., Ltd.) and pulverized at an air pressure of 2 kg / cm 2 to obtain fine particles having an average particle diameter of 21 m.
- the content of Compound A in the fine particles was 31.0%.
- the turbid solution obtained by dispersing (emulsifying) the mixture by the same formulation and operation as in Example 3 was spray-dried (Mobile Minor, manufactured by Futoku Japan) under the following conditions, and dried as a dried product under a cyclone. m fine particles were obtained.
- the sustained-release preparation of the present invention is a preparation containing a component obtained by treating a poorly water-soluble polyvalent metal compound with water.
- the preparation can be completed in a short time, and a bioactive compound can be obtained. Since it is contained at a high content and its release rate can be controlled, the desired pharmacological action of the bioactive compound can be expected over a long period of time.
- the bioactive compound that is poorly soluble in water is a compound that has angiotensin ⁇ antagonistic activity, it can maintain a constant blood concentration, and therefore has less fluctuation in blood drug concentration than when administered orally, and is stable Continued pharmacological action can be expected.
- the sustained-release preparation of the present invention is also used for bedridden, dementia, throat / esophageal diseases, digestive disorders, eating and dysphagia patients, patients who are difficult or impossible to treat with internal medicine such as during surgery. It is an excellent drug that can be used.
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- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
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- General Chemical & Material Sciences (AREA)
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- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
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Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002400845A CA2400845A1 (en) | 2000-02-21 | 2001-02-20 | Sustained-release preparation of physiologically active compound slightly soluble in water and production process and use of the same |
AU2001232348A AU2001232348A1 (en) | 2000-02-21 | 2001-02-20 | Sustained release preparations of physiologically active compound hardly solublein water and production process and use of the same |
EP01904560A EP1258254A4 (en) | 2000-02-21 | 2001-02-20 | COMPOSITIONS FOR DELAYED DELIVERY OF PHYSIOLOGICALLY ACTIVE COMPOUNDS THAT ARE LOW WATER-SOLUBLE, METHOD FOR THE PRODUCTION AND USE THEREOF |
US10/204,185 US20030068374A1 (en) | 2000-02-21 | 2001-02-20 | Sustained release preparations of physiologically active compound hardly soluble in water and production process and use of the same |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000-048980 | 2000-02-21 | ||
JP2000048980 | 2000-02-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001060410A1 true WO2001060410A1 (fr) | 2001-08-23 |
Family
ID=18570981
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2001/001191 WO2001060410A1 (fr) | 2000-02-21 | 2001-02-20 | Preparations a liberation lente contenant un compose physiologiquement actif peu soluble dans l'eau et methode de production et d'utilisation desdites preparations |
Country Status (5)
Country | Link |
---|---|
US (1) | US20030068374A1 (ja) |
EP (1) | EP1258254A4 (ja) |
AU (1) | AU2001232348A1 (ja) |
CA (1) | CA2400845A1 (ja) |
WO (1) | WO2001060410A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002074340A1 (fr) * | 2001-03-16 | 2002-09-26 | Takeda Chemical Industries, Ltd. | Procede de fabrication d'une preparation a liberation continue |
WO2003041739A1 (en) | 2001-11-13 | 2003-05-22 | Takeda Chemical Industries, Ltd. | Anticaner agents |
WO2004060399A1 (ja) * | 2002-12-27 | 2004-07-22 | Takeda Pharmaceutical Company Limited | 体重増加抑制剤 |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040102502A1 (en) * | 2000-10-25 | 2004-05-27 | Toshifumi Watanabe | Preventing/remedies for portal hypertension |
MY131170A (en) * | 2002-03-28 | 2007-07-31 | Nissan Chemical Ind Ltd | Therapeutic agent for glomerular disease |
US20050220881A1 (en) * | 2003-10-10 | 2005-10-06 | Bvm Holding Co. | Pharmaceutical composition |
EP1750862B1 (en) | 2004-06-04 | 2011-01-05 | Teva Pharmaceutical Industries Ltd. | Pharmaceutical composition containing irbesartan |
FR2882260A1 (fr) * | 2005-02-21 | 2006-08-25 | Flamel Technologies Sa | Forme pharmaceutique orale multimicroparticulaire a liberation modifiee d'antagonistes des recepteurs de l'angiotensine ii |
KR20080039510A (ko) * | 2005-08-22 | 2008-05-07 | 알렘빅 리미티드 | 발사르탄 제조 방법 |
PE20081364A1 (es) * | 2006-09-04 | 2008-12-04 | Novartis Ag | Composicion farmaceutica que comprende valsartan |
EP1897537A1 (en) * | 2006-09-04 | 2008-03-12 | Novartis AG | Composition comprising an angiotensin II receptor antagonist |
AU2008235790B2 (en) * | 2007-03-28 | 2013-06-06 | Takeda Pharmaceutical Company Limited | Solid pharmaceutical composition comprising a benzimidazole-7-carboxylate derivative and a pH control agent |
BRPI0814409A2 (pt) * | 2007-07-06 | 2014-10-14 | Nuon Therapeutics Inc | Tratamento de dor neuropática |
JP5635491B2 (ja) * | 2008-07-31 | 2014-12-03 | 武田薬品工業株式会社 | 固形医薬組成物 |
HUE054935T2 (hu) | 2014-12-05 | 2021-10-28 | Aragon Pharmaceuticals Inc | Rákellenes készítmények |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996007399A1 (en) * | 1994-09-09 | 1996-03-14 | Takeda Chemical Industries, Ltd. | Sustained release preparation containing metal salt of a peptide |
WO1999044590A1 (en) * | 1998-03-04 | 1999-09-10 | Takeda Chemical Industries, Ltd. | Sustained-release preparation for aii antagonist, production and use thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE268591T1 (de) * | 1995-06-27 | 2004-06-15 | Takeda Chemical Industries Ltd | Verfahren zur herstellung von zubereitungen mit verzögerter freisetzung |
-
2001
- 2001-02-20 AU AU2001232348A patent/AU2001232348A1/en not_active Abandoned
- 2001-02-20 CA CA002400845A patent/CA2400845A1/en not_active Abandoned
- 2001-02-20 EP EP01904560A patent/EP1258254A4/en not_active Withdrawn
- 2001-02-20 US US10/204,185 patent/US20030068374A1/en not_active Abandoned
- 2001-02-20 WO PCT/JP2001/001191 patent/WO2001060410A1/ja active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996007399A1 (en) * | 1994-09-09 | 1996-03-14 | Takeda Chemical Industries, Ltd. | Sustained release preparation containing metal salt of a peptide |
WO1999044590A1 (en) * | 1998-03-04 | 1999-09-10 | Takeda Chemical Industries, Ltd. | Sustained-release preparation for aii antagonist, production and use thereof |
Non-Patent Citations (1)
Title |
---|
See also references of EP1258254A4 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002074340A1 (fr) * | 2001-03-16 | 2002-09-26 | Takeda Chemical Industries, Ltd. | Procede de fabrication d'une preparation a liberation continue |
WO2003041739A1 (en) | 2001-11-13 | 2003-05-22 | Takeda Chemical Industries, Ltd. | Anticaner agents |
WO2004060399A1 (ja) * | 2002-12-27 | 2004-07-22 | Takeda Pharmaceutical Company Limited | 体重増加抑制剤 |
US7582662B2 (en) | 2002-12-27 | 2009-09-01 | Takeda Pharmaceutical Company Limited | Body weight gain inhibitor |
Also Published As
Publication number | Publication date |
---|---|
EP1258254A4 (en) | 2004-02-04 |
AU2001232348A1 (en) | 2001-08-27 |
US20030068374A1 (en) | 2003-04-10 |
EP1258254A1 (en) | 2002-11-20 |
CA2400845A1 (en) | 2001-08-23 |
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