Author: claimsbot

1. A degradable polymeric drug delivery composition comprising a water-insoluble drug blended with a copolymer comprising biocompatible tyrosine-derived diphenol compound monomer units with pendant carboxylic acid groups polymerized with biocompatible tyrosine-derived diphenol compound monomer units with pendant carboxylic acid ester groups, and poly(alkylene oxide) blocks, wherein a molar fraction in the copolymer of biocompatible diphenol compound monomer units with pendant carboxylic acid groups and polyalkylene oxide blocks relative to a weight percentage of the water-insoluble drug in the composition is effective to provide pseudo-zero order release of the drug from the composition during a sustained-release phase of drug delivery under physiological conditions.
2. The composition of claim 1, wherein said copolymer comprises from about 1 mol % to about 75 mol % tyrosine-derived diphenol compound monomer units with pendant carboxylic acid groups, from about 25 mol % to about 99 mol % tyrosine-derived diphenol compound monomer units with pendant carboxylic acid ester groups, and from about 1 mol % to about 40 mol % poly(alkylene oxide) copolymer blocks.
3. The composition of claim 1, wherein said water-insoluble drug is selected from the group consisting of peptides, cyclic peptides, eicosanoids, anti-inflammatory drugs, autonomic drugs, biologics, gene therapy agents, anti-infectives, retinoids, RNAi, photo sensitizers, steroids, mixture drugs, immunomodulators, chemotherapeutic agents, G-coupled protein receptor antagonists, receptor tyrosine kinase (RTK) inhibitors, growth hormone inhibitors, integrin inhibitors, Sdf1CXCR4 pathway inhibitors, and nACh receptor antagonists.
4. The composition of claim 3, wherein said peptide is a macrolide or cyclic peptide.
5. The composition of claim 4, wherein said cyclic peptide is voclosporin.
6. The composition of claim 1, wherein said water-insoluble drug is present in an amount from about 0.5 wt % to about 80 wt % of the composition.
7. The composition of claim 1, further comprising one or more additional components selected from the group consisting of poly(alkylene oxides), polyvinyl alcohols, polypyrrolidones, polyvinyl pyrrolidones, water soluble polyacrylates, polyacrylic acid, poly(hydroxymethyl methacrylate), poly(L-lactic acid), poly(lactic acid-co-glycolic acid), polyanhydrides, polycaprolactones, poly(ortho esters), polyphosphazines, polyphosphoesters, sorbitol, sorbitol derivatives, polysorbates, polysaccharides, porogens, antioxidants, plasticizers, penetration enhancers and surfactants.
8. The composition of claim 7, wherein said additional component is a poly(lactic acid-co-glycolic acid).
9. The composition of claim 1, characterized by being fabricated as an ocular implant, punctal plug, contact lens, film, injectable particle or microsphere suspension, mucoadhesive formulation, an in-situ forming gel or film, gel, iontophoresis formulation, tablet, rod, hollow rod, microsphere, nanosphere, fiber mat, fiber, dermal patches, subcutaneous implant or ointment.
10. The composition of claim 1 wherein said tyrosine-derived diphenol compound monomer units with pendant carboxylic acid ester groups are desaminotyrosyl-tyrosine esters selected from the group consisting of methyl, ethyl, butyl, hexyl, octyl and benzyl esters.
11. A method for treating an ocular condition in a patient in need thereof comprising contacting an eye of the patient with a degradable polymeric drug delivery composition comprising a water-insoluble drug blended with a copolymer comprising biocompatible tyrosine-derived diphenol compound monomer units with pendant carboxylic acid groups polymerized with biocompatible tyrosine-derived diphenol compound monomer units with pendant carboxylic acid ester groups, and poly(alkylene oxide) blocks, wherein a molar fraction in the copolymer of biocompatible tyrosine-derived diphenol compound monomer units with pendant carboxylic acid groups and polyalkylene oxide blocks relative to a weight percentage of the water-insoluble drug in the composition is effective to provide pseudo-zero order release of the drug from the composition during a sustained-release phase of drug delivery under physiological conditions.
12. The method of claim 11, wherein said copolymer comprises from about 1 mol % to about 75 mol % tyrosine-derived diphenol compound monomer units with pendant carboxylic acid groups, from about 25 mol % to about 99 mol % tyrosine-derived diphenol compound monomer units with pendant carboxylic acid ester groups, and from about 1 mol % to about 40 mol % poly(alkylene oxide) copolymer blocks.
13. The method of claim 11, wherein said water-insoluble drug is selected from the group consisting of peptides, cyclic peptides, eicosanoids, anti-inflammatory drugs, auto-nomic drugs, biologics, gene therapy agents, anti-infectives, retinoids, RNAi, photo sensitizers, steroids, mixture drugs, immunomodulators, chemotherapeutic agents, G-coupled protein receptor antagonists, receptor tyrosine kinase (RTK) inhibitors, growth hormone inhibitors, integrin inhibitors, Sdf1CXCR4 pathway inhibitors, and nACh receptor antagonists.
14. The method of claim 11, wherein said water-insoluble drug is present in an amount from 0.5 wt % to about 80 wt % of the composition.
15. The method of claim 13, wherein said peptide is a macrolide or cyclic peptide.
16. The method of claim 15, wherein said cyclic peptide is voclosporin.
17. The method of claim 11, wherein said ocular condition is selected from the group consisting of idiopathic uveitis, corneal transplantation, dry eye syndrome, age-related macular degeneration (AMD, wet and dry), diabetic eye conditions, blepharitis, glaucoma, ocular hypertension, post-operative eye pain and inflammation, posterior segment neovascularization (PSNV), proliferative vitreoretinopathy (PVR), cytomegalovirus retinitis (CMV), endophthalmitis, choroidal neovascular membranes (CNVM), vascular occlusive diseases, allergic eye disease, tumors, retinitis pigmen-tosa, eye infections, scleritis, ptosis, miosis, eye pain, mydriasis, neuralgia, aging (e.g. muscle relaxants and other aesthetic products), cicatrizing ocular surface diseases, ocular infections, inflammatory ocular diseases, ocular surface diseases, corneal diseases, retinal diseases, ocular manifestations of systemic diseases, hereditary eye conditions, ocular tumors and increased intraocular pressure.
18. The method of claim 11, wherein said composition is fabricated as an ocular implant, punctal plug, contact lens, film, injectable particle or microsphere suspension, mucoadhesive formulation, an in-situ forming gel or film, gel, iontophoresis formulation, tablet, rod, hollow rod, microsphere, nanosphere, fiber mat, fiber, dermal patches, subcutaneous implant or ointment.
19. The method of claim 11 wherein said tyrosine-derived diphenol compound monomer units with pendant carboxylic acid ester groups are desaminotyrosyl-tyrosine esters selected from the group consisting of methyl, ethyl, butyl, hexyl, octyl and benzyl esters.
20. A method of manufacturing a degradable polymeric drug delivery composition comprising (a) blending a water-insoluble drug with a copolymer comprising tyrosine-derived diphenol compound monomer units with pendant carboxylic acid groups, tyrosine-derived diphenol compound monomer units with pendant carboxylic acid ester groups, and poly(alkylene oxide) copolymer blocks, and (b) forming a drug delivery article with the blend, wherein (i) the composition comprises a drug loading from about 0.5 wt % to about 80 wt % of the composition, and (ii) a mole percent of diphenol compound monomer units with pendant carboxylic acid groups, and poly(alkylene oxide) copolymer blocks in said copolymer relative to a weight percentage of the drug in the composition is effective to provide an essentially zero-order release of the drug from the composition during a sustained-release phase of drug delivery under physiological conditions.
21. The method of claim 20, wherein said water-insoluble drug is a macrolide or cyclic peptide.
22. The method of claim 20, wherein said drug delivery article is formed into an ocular implant, punctal plug, contact lens, film, injectable particle or microsphere suspension, mucoadhesive formulation, an in-situ forming gel or film, ointment, gel or iontophoresis formulation, tablet, rod, hollow rod, microsphere, nanosphere, fiber mat, fiber, dermal patches, subcutaneous implant or ointment.

The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.

What is claimed is:

1. A compound represented by the structural formula
882
or a pharmaceutically acceptable salt or solvate thereof, wherein:
the dotted line represents an optional double bond;
a is 0 to 2;
b is 0 to 2;
n is 1, 2 or 3;
p is 1, 2 or 3;
r is 0, 1, 2, or 3;
with the provisos that when M2 is N, p is not 1; and that when r is 0, M2 is C(R3); and that the sum of p and r is 1 to 4;
M1 is C(R3) or N;
M2 is C(R3) or N;
X is a bond or C1-C6 alkylene;
Y is C(O), C(S), (CH2)q, NR4C(O), C(O)NR4, C(O)CH2, SO2, N(R4), NHC(NCN) or C(NCN)NH; with the provisos that when M1 is N, Y is not NR4C(O) or NHC(NCN); when M2 is N, Y is not C(O)NR4 or C(NCN)NH; and when Y is N(R4), M1 is CH and M2 is C(R3);
q is 1 to 5, provided that when both M1 and M2 are N, q is 2 to 5;
Z is a bond, C1-C6 alkylene, C1-C6 alkenylene, C(O), CH(CN), SO2 or CH2C(O)NR4;
883
Q is N(R8), S or O;
k is 0, 1, 2, 3 or 4;
k1 is 0, 1, 2 or 3;
k2 is 0, 1 or 2;
R is H, C1-C6 alkyl, halo(C1-C6)alkyl-, C1-C6 alkoxy, (CG-C6)alkoxy-(C1-C6)alkyl-, (C1-C6)-alkoxy-(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl-SO0-2, R32-aryl(C1-C6)alkoxy-, R32-aryl(C1-C6)alkyl-, R32-aryl, R32-aryloxy, R32-heteroaryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, (C3-C6)cycloalkyl-(C1-C6)alkoxy, (C3-C6)cycloalkyl-oxy-, R37-heterocycloalkyl, R37-heterocycloalkyl-oxy-, R37-heterocycloalkyl-(C1-C6)alkoxy, N(R30)(R31)(C1-C6)alkyl-, N(R30)(R31), NH(C1-C6)alkyl-O(C1-C6)alkyl, NHC(O)NH(R29); R29S(O)0-2, halo(C1-C6)alkyl-S(O)0-2, N(R30)(R31)(C1-C6)alkyl-S(O)02 or benzoyl;
R8 is H, C1-C6 alkyl, halo(C1-C6)alkyl-, (C1-C6)alkoxy-(C1-C6)alkyl-, R32-aryl(C1-C6)alkyl-, R32-aryl, R32-heteroaryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, R37-heterocycloalkyl, N(R30)(R31)(C1-C6)alkyl-, R29S(O)2, halo(C1-C6)alkyl-S(O)2, R29S(O)0-1(C2-C6)alkyl-, halo(C1-C6)alkyl-S(O)0-1(C2-C6)alkyl-;
R2 is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or NO, with the remaining ring atoms being carbon; a five-membered heteroaryl ring having 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, with the remaining ring atoms being carbon; R32-quinolyl; R32-aryl; heterocycloalkyl; (C3-C6)cycloalkyl; C1-C6 alkyl; hydrogen; thianaphthenyl;
884
wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R6;
R3 is H, halogen, C1-C6 alkyl, OH, (C1-C6)alkoxy or NHSO2(C1-C6)alkyl;
R4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R33-aryl, R33-aryl(C1-C6)alkyl, and R32-heteroaryl;
R5 is hydrogen, C1-C6 alkyl, C(O)R20, C(O)2R20, C(O)N(R20)2, (C1-C6)alkyl-SO2, or (C1-C6)alkyl-SO2NH;
or R4 and R5, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring;
R6 is 1 to 3 substituents independently selected from the group consisting of OH, halogen, C1-C6 alkyl-, C1-C6 alkoxy, C1-C6 alkylthio, CF3, NR4R5, CH2NR4R5, NHSO2R22, N(SO2R22)2, phenyl, R33-phenyl, NO2, CO2R4, CON(R4)2,
885
R7 is N(R29), O or S(O)0-2;
R12 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, or fluoro, provided that when R12 is hydroxy or fluoro, then R12 is not bound to a carbon adjacent to a nitrogen; or two R12 substituents form a C1 to C2 alkyl bridge from one ring carbon to another non-adjacent ring carbon; or R12 is O;
R13 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, or fluoro, provided that when R13 is hydroxy or fluoro then R13 is not bound to a carbon adjacent to a nitrogen; or two R13 substituents form a C, to C2 alkyl bridge from one ring carbon to another non-adjacent ring carbon; or R13 is O;
R20 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, CF3, OCF3, hydroxyl, or methoxy; or when two R20 groups are present, said two R20 groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring;
R22 is C1-C6 alkyl, R34-aryl or heterocycloalkyl;
R24 is H, C1-C6 alkyl, SO2R22 or R34-aryl;
R25 is independently selected from the group consisting of CG-C6 alkyl, halogen, CN, NO2, CF3, OH, C1-C6 alkoxy, (C1-C6)alkyl-C(O), aryl-C(O), C(O)OR29, N(R4)(R5), N(R4)(R5)C(O), N(R4)(R5)S(O)1-2, R22S(O)0-2, halo-(C1-C6)alkyl- or halo-(C1-C6)alkoxy-(C1-C6)alkyl-;
R29 is H, C1-C6 alkyl, C3-C6 cycloalkyl, R35-aryl or R35-aryl(C1-C6)alkyl-;
R30 is H, C1-C6 alkyl-, R35-aryl or R35-aryl(C1-C6)alkyl-;
R31 is H, C1-C6 alkyl-, R35-aryl, R35-aryl(C1-C6)alkyl-, R35-heteroaryl, (C1-C6)alkyl-C(O), R35-aryl-C(O), N(R4)(R5)C(O), (C1-C6)alkyl-S(O)2 or R35-aryl-S(O)2;
or R30 and R31 together are (CH2)4-5, (CH2)2O(CH2)2 or (CH2)2N(R38)(CH2)2 and form a ring with the nitrogen to which they are attached;
R32 is 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, R35-aryl-O, SR22, CF3, OCF3, OCHF2, NR39R40, phenyl, R33-phenyl, NO2, CO2R39, CON(R39)2, S(O)2R22, S(O)2N(R20)2, N(R24)S(O)2R22, CN, hydroxy-(C1-C6)alkyl-, OCH2CH2OR22, and R35-aryl(C1-C6)alkyl-O, or two R32 groups on adjacent carbon atoms together form a OCH2O or O(CH2)2O group;
R33 is 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, CF3, OCF3, OCHF2 and O(C1-C6)alkyl;
R34 is 1 to 3 substituents independently selected from the group consisting of H, halogen, CF3, OCF3, OH and OCH3;
R35 is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, CF3, N(R36)2, COOR20 and NO2;
R36 is independently selected form the group consisting of H and C1-C6 alkyl;
R37 is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, CF3, N(R36)2, COOR20, C(O)N(R29)2 and NO2, or R37 is one or two O groups;
R38 is H, C1-C6 alkyl, R35-aryl, R35-aryl(C1-C6)alkyl-, (C1-C6)alkyl-SO2 or halo(C1-C6)alkyl-SO2;
R39 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R33-aryl, R33-aryl(C1-C6)alkyl, and R32-heteroaryl; and
R40 is hydrogen, C1-C6 alkyl, C(O)R20, C(O)2R20, C(O)N(R20)2 (C1-C6)alkyl-SO2, or (C1-C6)alkyl-SO2NH;
or R39 and R40, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring.
2. A compound of claim 1 wherein M1 is N, a is 0, and n is 2, and the optional double bond is not present.
3. A compound of claim 2 wherein M2 is C(R3) wherein R3 is hydrogen or fluorine, b is 0, r is 1, and p is 2.
4. A compound of claim 3 wherein X is a bond.
5. A compound of claim 4 wherein Y is C(O).
6. A compound of claim 5 wherein Z is straight or branched C1-C3 alkyl.
7. A compound of claim 6 wherein R is a six-membered heteroaryl ring, optionally substituted with one R6 substituent.
8. A compound of claim 7 wherein R2 is pyrimidy, R6-pyrimidyl, pyridyl, R6-pyridyl or pyridazinyl and R6 is NH2.
9. A compound of claim 8 wherein R2 is
886
10. A compound of claim 2 wherein R1 is
887
11. A compound of claim 10 wherein R is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (C1-C6)alkylthio, heteroaryl or R32-aryl; R25 is halogen or CF3; and k and k1 are 0 or 1.
12. A compound of claim 11 wherein R is CH3, CH2CH3, OCH3, OCH2CH3, OCH2CH2CH3, OCH((CH3)2, CH2CH3, SCH3, SCH2CH3, pyridyl, pyrimidyl, pyrazinyl, furanyl, oxazolyl or R32-phenyl.
13. A compound of claim 12 wherein R2 is
888
14. A compound of claim 1 selected from the group consisting of
889
890
891
892
893
894
895
15. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically effective carrier.
16. A method of treating allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, obesity, sleeping disorders, disturbances of the central nervous system, attention deficit hyperactivity disorder, hypo and hyperactivity of the central nervous system, Alzheimer’s disease, schizophrenia, and migraine comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1.
17. The method of claim 14 wherein allergy-induced airway responses are treated.
18. The method of claim 14 wherein allergy or nasal congestion is treated.
19. A pharmaceutical composition comprising an effective amount of a compound of claim 1, and an effective amount of H1 receptor antagonist, and a pharmaceutically effective carrier.
20. A method of treating allergy, allergy-induced airway responses, and congestion comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1 in combination with an effective amount of an H1 receptor antagonist.
21. The method of claim 20 wherein said H1 receptor antagonist is selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.
22. The method of claim 21 wherein said H1 receptor antagonist is selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine.
23. The method of claim 22 wherein said H1 receptor antagonist is selected from: loratadine or descarboethoxyloratadine.

1. An impact modifier which comprises a graft copolymer comprising:
a rubber polymer (A) obtained from a mixture comprising one or more kinds of (meth)acrylic monomers and having a glass transition temperature of 0\xb0 C. or lower and being in the form of particles where 80 wt % or more of them has a particle diameter within the range of 400 to 1,000 nm and wherein the particles exhibit a peak position in which a group from 510-610 nm is heaviest as determined from a particle diameter distribution on a weight basis; and
branches (B) grafted thereto obtained from one or more kinds of vinyl monomers.
2. The impact modifier according to claim 1, wherein one or more kinds of monomer units which are derived from vinyl monomers having one or more functional groups selected from the group consisting of epoxy group, hydroxyl group, and isobomyl group are components of the rubber polymer (A) andor the branches (B).
3. The impact modifier according to claim 1, further comprising inorganic filler (C).
4. The impact modifier according to claim 1, wherein the rubber polymer (A) includes a composite rubber comprising an acrylic rubber (A1) component containing at least one of a (meth)acrylate of an alcohol having a branched side chain or an alcohol having an alkyl group with 13 or more carbon atoms as a constituent component, and an acrylic rubber (A2) component containing n-butyl acrylate as a constituent component, and wherein the glass transition temperature (Tg1) comes from the acrylic rubber (A1) component is lower than the glass transition temperature (Tg2) comes from the acrylic rubber (A2) component.
5. The impact modifier according to claim 4, wherein the acrylic rubber (A1) component comprises one or more kinds of compounds selected from the group consisting of 2-ethylhexyl acrylate, ethoxyethyl acrylate, methoxytripropylene glycol acrylate, 4-hydroxybutyl acrylate, tridecyl methacrylate, stearyl methacrylate, and stearyl acrylate.
6. The impact modifier according to claim 1, wherein d=d85-d15 of the rubber polymer (A) is 180 nm or less when the rubber polymer (A) comprises particles and each of 80 wt % or more of them has a particle diameter within the range of 400 to 1,000 nm based on a particle diameter distribution on a weight basis measured by Capillary Hydro Dynamic Flow Fractionation, and when difference between the diameter correspond to 85% of cumulative distribution from the smallest particle diameter on a weight basis (d85) and the diameter correspond to 15% of it (d15) is defined as d.
7. The impact modifier according to claim 1, wherein the heaviest group of the rubber polymer (A) in the groups having peak values of diameter within the range of 400 to 1,000 nm forms 70% by weight or more of the gross weight of the particles having diameter within the range of 400 to 1,000 nm when the particle diameter distribution of the rubber polymer (A) is measured by Capillary Hydro Dynamic Flow Fractionation.
8. The impact modifier according to claim 4, wherein the composite rubber comprising the acrylic rubber (A1) component which is within a range from 5 to 95% by weight and the acrylic rubber (A2) component which is within a range from 95 to 5% by weight.
9. The impact modifier according to claim 1, wherein the heaviest group of the rubber polymer (A) in the groups having peak values of diameter within the range of 400 to 1,000 nm forms 90% by weight or more of the gross weight of the particles which is measured by Capillary Hydro Dynamic Flow Fractionation.
10. The impact modifier according to claim 1, wherein the rubber polymer (A) comprising units come from monomers having two or more unsaturated bonds which is within a range of 2% by weight or less.
11. The impact modifier according to claim 1, wherein the branches (B) is obtained by multi-stage polymerization.
12. The impact modifier according to claim 1, wherein the branches (B) comprises units come from monomers which work as crosslinking agents andor graft cross agents.
13. The impact modifier according to claim 1, further comprising compound (R) having a sulfonic acid group, sulfosuccinic acid group, or a sulfuric acid group, or a salt of compound (R).
14. The impact modifier according to claim 13, wherein the compound (R) or the salt has one or more phenyl skeletons.
15. The impact modifier according to claim 13, wherein the compound (R) or the salt is used as emulsifiers for the emulsion polymerization to produce the graft copolymer.
16. The impact modifier according to claim 15, further comprising carbonic acid-type emulsifier used as emulsifiers for the polymerization to produce the graft copolymer.
17. The impact modifier according to claim 1, further comprising a compound having one or more structures which are selected from the group consisting of mercapto group, sulfuric acid group, ammonium group, and calcium atom.
18. The impact modifier according to claim 1, wherein the rubber polymer (A) is obtained by seed polymerization.
19. A process for producing the impact modifier of claim 1, wherein there are two or more processes of polymerization for the rubber polymer (A).
20. A process for producing the impact modifier of claim 4, wherein the (A1) component is produced by a process of polymerization after a forced emulsification treatment process.
21. The process for producing the impact modifier according to claim 20, wherein there are two or more processes of polymerization to produce the (A1) component.
22. The process for producing the impact modifier according to claim 20, wherein all of raw materials which constitute the (A2) component are added to the (A1) component at the same time and these are polymerized after catalysts are added.
23. The process for producing the impact modifier according to claim 19, wherein calcium salt is used as a coagulating agent when the obtained graft copolymer is collected as powder by wet coagulation.
24. The process for producing the impact modifier according to claim 19, wherein the impact modifier is collected as powder by spray-drying.
25. A thermoplastic resin composition comprising a thermoplastic resin and the impact modifier of claim 1.
26. The thermoplastic resin composition according to claim 25, wherein the thermoplastic resin comprising one or more kinds of resins selected from the group consisting of polycarbonate resin, polyester resin, styrene resin, acrylic resin, polyamide resin, and vinyl chloride resin.
27. The thermoplastic resin composition according to claim 25, wherein the thermoplastic resin comprising one or more kinds of resins selected from the group consisting of polycarbonate resin, polyester resin, and ABS resin.
28. The thermoplastic resin composition according to claim 25, further comprising fibered reinforcements.
29. The thermoplastic resin composition according to claim 25, further comprising flame retardants.
30. The thermoplastic resin composition according to claim 29, wherein the flame retardants are halogen flame retardants, phosphoric acid flame retardants, or silicone flame retardants.
31. The thermoplastic resin composition according to claim 29, wherein the flame retardants are organic metal salt compounds containing halogen atoms.

The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.

1. A fibre optic distributed acoustic sensor comprising an interrogator unit and an optical fibre, the interrogator unit being configured to transmit optical pulse into said optical fibre and detect radiation backscattered from within the fibre wherein said optical fibre comprises a micro structured optical fibre wherein the microstructure is configured so as to provide different sensitivity to incident acoustic stimuli from different directions transverse to the path of the fiber.
2. A sensor as claimed in claim 1 wherein said microstructured optical fibre comprises a photonic band-gap fibre.
3. A sensor as claimed in claim 2 wherein said photonic band-gap fibre comprises a core region surrounded by a plurality of holes, the holes arranged to provide light guiding within the core region.
4. A sensor as claimed in claim 3 wherein said core region is hollow.
5. A sensor as claimed in claim 1 wherein said microstructured optical fibre comprises a holey fibre comprising a core region surrounded by a cladding region comprising a plurality of holes, the holes being arranged to effectively control the refractive index of the cladding region so as to provide light guiding within the core.
6. A sensor as claimed in claim 5 wherein said microstructured optical fibre comprises a hole-assisted fibre wherein the cladding comprises of a solid material having a different refractive index to the core.
7. A sensor as claimed in claim 1 wherein said microstructured optical fibre comprises a Bragg fibre.
8. A sensor as claimed in claim 1 wherein the microstructured fibre is configured to be more compliant than an equivalent fully solid optical fibre.
9. A sensor as claimed in claim 1 wherein the microstructured fibre is configured so as to exhibit a strong dependence on refractive index to strain.
10. A sensor as claimed in claim 1 wherein the microstructured fibre is configured so as to be more compliant in one transverse direction than the orthogonal transverse direction.
11. A sensor as claimed in claim 1 wherein the microstructured fibre is configured so as to exhibits a stronger change in refractive index if deformed in one transverse direction as compared to the orthogonal transverse direction.
12. A method of distributed acoustic sensing comprising, launching at least one pulse of optical radiation into an optical fibre and detecting radiation backscattered from within the fibre wherein the optical fibre is a microstructured optical fibre configured to provide different sensitivity to incident acoustic stimuli from different directions transverse to the path of the fiber.
13. A method as claimed in claim 12 wherein detecting backscattered radiation comprises detecting radiation which is Rayleigh backscattered.
14. A method as claimed in claim 12 comprising processing the detected backscatter to determine the acoustic signals incident on a plurality of sensing portions of the fibre.
15. A method as claimed in claim 12 wherein the microstructured fibre is one of a photonic band gap fibre, a holey fibre and a Bragg fibre.
16. A method as claimed in claim 12 wherein the microstructured fibre is arranged to exhibit a strong dependence of refractive index with strain.
17. A method as claimed in claim 12 wherein the microstructured fibre has a hollow core.
18. A method as claimed in claim 12 wherein the microstructured fibre is configured so as to be more compliant in one transverse direction than the orthogonal transverse direction.
19. A method as claimed in claim 12 wherein the microstructured fibre is configured so as to exhibits a stronger change in refractive index if deformed in one transverse direction as compared to the orthogonal transverse direction.