JPH07126163A - Controllably releasable pilocarpine transmitting system - Google Patents
Controllably releasable pilocarpine transmitting systemInfo
- Publication number
- JPH07126163A JPH07126163A JP25309193A JP25309193A JPH07126163A JP H07126163 A JPH07126163 A JP H07126163A JP 25309193 A JP25309193 A JP 25309193A JP 25309193 A JP25309193 A JP 25309193A JP H07126163 A JPH07126163 A JP H07126163A
- Authority
- JP
- Japan
- Prior art keywords
- pilocarpine
- xerophthalmia
- xerostomia
- patient
- dry mouth
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 title claims abstract description 57
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 229960001416 pilocarpine Drugs 0.000 title claims abstract description 57
- 206010013781 dry mouth Diseases 0.000 claims abstract description 59
- 208000005946 Xerostomia Diseases 0.000 claims abstract description 39
- 210000002966 serum Anatomy 0.000 claims abstract description 21
- 208000005494 xerophthalmia Diseases 0.000 claims abstract description 19
- 229920000148 Polycarbophil calcium Polymers 0.000 claims abstract description 10
- 229940095498 calcium polycarbophil Drugs 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000008240 homogeneous mixture Substances 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 25
- 239000002552 dosage form Substances 0.000 claims description 16
- 238000009472 formulation Methods 0.000 claims description 14
- 230000004410 intraocular pressure Effects 0.000 claims description 9
- 238000001959 radiotherapy Methods 0.000 claims description 9
- 229920002125 Sokalan® Polymers 0.000 claims description 8
- 229920000642 polymer Polymers 0.000 claims description 7
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 6
- 229960001631 carbomer Drugs 0.000 claims description 6
- 238000002512 chemotherapy Methods 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims description 3
- 229940031574 hydroxymethyl cellulose Drugs 0.000 claims description 3
- 230000000977 initiatory effect Effects 0.000 claims description 3
- 230000004406 elevated intraocular pressure Effects 0.000 claims 1
- 210000003296 saliva Anatomy 0.000 abstract description 23
- 230000000694 effects Effects 0.000 abstract description 20
- 238000013270 controlled release Methods 0.000 abstract description 13
- 208000024891 symptom Diseases 0.000 abstract description 12
- 230000028327 secretion Effects 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 7
- 210000004087 cornea Anatomy 0.000 abstract description 6
- 210000000795 conjunctiva Anatomy 0.000 abstract description 5
- 230000003247 decreasing effect Effects 0.000 abstract description 4
- 230000002496 gastric effect Effects 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 2
- 210000000748 cardiovascular system Anatomy 0.000 abstract description 2
- 206010030043 Ocular hypertension Diseases 0.000 abstract 1
- 210000001124 body fluid Anatomy 0.000 abstract 1
- 239000010839 body fluid Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 23
- 229940079593 drug Drugs 0.000 description 21
- 239000003826 tablet Substances 0.000 description 18
- 229960002139 pilocarpine hydrochloride Drugs 0.000 description 13
- RNAICSBVACLLGM-GNAZCLTHSA-N pilocarpine hydrochloride Chemical compound Cl.C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C RNAICSBVACLLGM-GNAZCLTHSA-N 0.000 description 13
- 210000000214 mouth Anatomy 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 235000009508 confectionery Nutrition 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 210000003079 salivary gland Anatomy 0.000 description 6
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 6
- 239000000120 Artificial Saliva Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 206010039424 Salivary hypersecretion Diseases 0.000 description 5
- 208000021386 Sjogren Syndrome Diseases 0.000 description 5
- 230000002411 adverse Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000003792 electrolyte Substances 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 208000026451 salivation Diseases 0.000 description 5
- 235000019640 taste Nutrition 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 4
- 230000036765 blood level Effects 0.000 description 4
- 208000002925 dental caries Diseases 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000011010 flushing procedure Methods 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 4
- 230000035900 sweating Effects 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- 235000005979 Citrus limon Nutrition 0.000 description 3
- 244000131522 Citrus pyriformis Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 108010063954 Mucins Proteins 0.000 description 3
- -1 antispasmodics Substances 0.000 description 3
- 235000015218 chewing gum Nutrition 0.000 description 3
- 229940112822 chewing gum Drugs 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 210000003681 parotid gland Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000011775 sodium fluoride Substances 0.000 description 3
- 235000013024 sodium fluoride Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- KYLIZBIRMBGUOP-UHFFFAOYSA-N Anetholtrithion Chemical compound C1=CC(OC)=CC=C1C1=CC(=S)SS1 KYLIZBIRMBGUOP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 2
- 206010013774 Dry eye Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VNYBTNPBYXSMOO-UHFFFAOYSA-M Pyridostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=C[N+](C)=C1 VNYBTNPBYXSMOO-UHFFFAOYSA-M 0.000 description 2
- 239000001361 adipic acid Substances 0.000 description 2
- 235000011037 adipic acid Nutrition 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229960005238 anethole trithione Drugs 0.000 description 2
- 239000000607 artificial tear Substances 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004820 blood count Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960001446 distigmine Drugs 0.000 description 2
- GJHSNEVFXQVOHR-UHFFFAOYSA-L distigmine bromide Chemical compound [Br-].[Br-].C=1C=C[N+](C)=CC=1OC(=O)N(C)CCCCCCN(C)C(=O)OC1=CC=C[N+](C)=C1 GJHSNEVFXQVOHR-UHFFFAOYSA-L 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000005414 inactive ingredient Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 231100000957 no side effect Toxicity 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
- 231100000956 nontoxicity Toxicity 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000000734 parasympathomimetic agent Substances 0.000 description 2
- 229940127242 parasympathomimetic drug Drugs 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 239000004584 polyacrylic acid Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000002562 urinalysis Methods 0.000 description 2
- WIJKJARNQOXJNY-KVAGASMTSA-N 2-[3,4-bis(2-hydroxyethoxy)phenyl]-5-hydroxy-7-(2-hydroxyethoxy)-3-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-[[(2r,3r,4r,5r,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one;chromen-2-one;sodium;sulfuric acid Chemical compound [Na].OS(O)(=O)=O.C1=CC=C2OC(=O)C=CC2=C1.O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](OC=2C(C3=C(O)C=C(OCCO)C=C3OC=2C=2C=C(OCCO)C(OCCO)=CC=2)=O)O1 WIJKJARNQOXJNY-KVAGASMTSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose 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](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010006326 Breath odour Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- DZOVBAVEJYPSLL-UHFFFAOYSA-N Epiisopilosin Natural products CN1C=NC=C1CC1C(C(O)C=2C=CC=CC=2)C(=O)OC1 DZOVBAVEJYPSLL-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018276 Gingival bleeding Diseases 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 241000736262 Microbiota Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 108010093825 Mucoproteins Proteins 0.000 description 1
- 102000001621 Mucoproteins Human genes 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- DZOVBAVEJYPSLL-CFVMTHIKSA-N Pilosine Chemical compound CN1C=NC=C1C[C@@H]1[C@H]([C@@H](O)C=2C=CC=CC=2)C(=O)OC1 DZOVBAVEJYPSLL-CFVMTHIKSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229940086737 allyl sucrose Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003181 biological factor Substances 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960004484 carbachol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000000254 damaging effect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 230000009189 diving Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002070 germicidal effect Effects 0.000 description 1
- 208000024693 gingival disease Diseases 0.000 description 1
- 230000006589 gland dysfunction Effects 0.000 description 1
- 238000009499 grossing Methods 0.000 description 1
- 208000011759 gum bleeding Diseases 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- KUQWZSZYIQGTHT-UHFFFAOYSA-N hexa-1,5-diene-3,4-diol Chemical compound C=CC(O)C(O)C=C KUQWZSZYIQGTHT-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000004561 lacrimal apparatus Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 238000007449 liver function test Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 229940090002 mestinon Drugs 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000008368 mint flavor Substances 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229940051866 mouthwash Drugs 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229960002362 neostigmine Drugs 0.000 description 1
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 1
- 230000008035 nerve activity Effects 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 210000003254 palate Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 210000005037 parasympathetic nerve Anatomy 0.000 description 1
- 210000001002 parasympathetic nervous system Anatomy 0.000 description 1
- 230000001499 parasympathomimetic effect Effects 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 229960002151 pyridostigmine bromide Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 108010028349 saliva Orthana Proteins 0.000 description 1
- 229920006298 saran Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 210000003670 sublingual gland Anatomy 0.000 description 1
- 210000001913 submandibular gland Anatomy 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は一般に「ドライマウス症
候群」として知られる口内乾燥症、及び眼球乾燥症（結
膜及び角膜の乾燥）に全般的に関する。より詳細には、
本発明は患者の口内乾燥症又は眼球乾燥症の症状を軽減
する方法に関する。また本発明は高眼内圧を軽減する方
法に関する。FIELD OF THE INVENTION The present invention relates generally to xerostomia, commonly known as "dry mouth syndrome", and xerophthalmia (dryness of the conjunctiva and cornea). More specifically,
The present invention relates to a method of reducing the symptoms of xerostomia or xerophthalmia in a patient. The invention also relates to a method of reducing high intraocular pressure.
【０００２】[0002]
【従来技術】通常、ヒトは１日に０．５〜１リットルの
唾液を分泌する。個人差は大きいが平均して唾液の６５
％が顎下腺から、２３％が耳下腺から、８％が小粘膜か
ら、４％が舌下腺から分泌される。口内乾燥症は唾液腺
が充分な量の唾液を分泌しない状態である。これは不快
感をひきおこし、場合によっては非常に重くなることが
ある。唾液が分泌されないと口内はひりひりし、喉や舌
に急激な変化が起こることがある。急速に歯の齲蝕が起
こり、舌が平滑になったり、ひび割れたり、感染しやす
くなることがある。またしばしば味覚がなくなり、唾液
には重要な消化酵素が含まれているのでしばしば消化に
ついての問題を引き起こす。夜間に口内乾燥が続くと睡
眠が妨げられ、頻繁に（１時間ごとにすら）目をさます
ようになる。さらに口内乾燥症の結果、歯周病及び齲歯
が増加し、歯を失うこともある。2. Description of the Related Art Normally, humans secrete 0.5 to 1 liter of saliva per day. There are large individual differences, but saliva is 65 on average.
% Is secreted by the submandibular gland, 23% by the parotid gland, 8% by the small mucosa and 4% by the sublingual gland. Dry mouth is a condition in which the salivary glands do not secrete a sufficient amount of saliva. This causes discomfort and can be quite heavy in some cases. If saliva is not secreted, the mouth becomes sore that sudden changes in the throat and tongue may occur. Dental caries can occur rapidly, causing the tongue to become smooth, cracked, and susceptible to infection. It is also often tasteless and saliva often contains digestive problems because it contains important digestive enzymes. Continued dry mouth at night disturbs sleep and often (even hourly) wakes up. Further, as a result of xerostomia, periodontal disease and dental caries may increase, and teeth may be lost.
【０００３】口は体の中で最も外環境にさらされる領域
の一つである。通常、粘膜は鼻、口及び喉において連続
的な保護層を形成する。口内乾燥症の患者は、口内の体
液が減少するだけでなく、細胞と接触している体液を保
持し、刺激や感染に対する防御壁を形成するムコ蛋白及
びムコ多糖の量が充分でなくなる。口内乾燥症の影響の
始まりは気づかれず、その疾患を有するか否かの明確な
境界はない。また個々の患者により症状、程度、期間が
異なる。口内乾燥が最も共通してみられる症状である。
味覚の変化が食物の選択及び認知に変化をきたす。味覚
の変化の後、味覚が低下し、味覚が全くなくなることも
ある。The mouth is one of the most exposed areas of the body to the external environment. Mucous membranes usually form a continuous protective layer in the nose, mouth and throat. In patients with xerostomia, not only does fluid in the mouth decrease, but the amount of mucoprotein and mucopolysaccharide that holds fluid in contact with cells and forms a defense wall against irritation and infection becomes insufficient. The onset of the effects of xerostomia is unnoticed, and there is no clear demarcation of whether or not to have the disease. Moreover, the symptom, degree, and period vary depending on the individual patient. Dry mouth is the most common symptom.
Changes in taste change food selection and cognition. After a change in taste, the taste may be reduced and the taste may disappear altogether.
【０００４】口腔部（舌、歯肉、口、頬など）の粘膜組
織のただれ、潰瘍、裂溝、腫脹、出血、被膜、さらに舌
のびらんなどがおきる可能性がある。唾液の減少により
不完全消化、食物の蓄積、歯垢、歯肉出血、義歯ブリッ
ジ部の痛み、極度の口臭が生じる。また種々の口部組織
の腫脹や発語困難をきたす可能性がある。唇が乾燥した
りひび割れたりすることもある。齲歯発生率が劇的に増
加するかもしれない。Mucous tissue in the oral cavity (tongue, gums, mouth, cheeks, etc.) may have sores, ulcers, fissures, swelling, bleeding, capsules, and erosion of the tongue. Loss of saliva causes incomplete digestion, food accumulation, plaque, gum bleeding, denture bridge pain, and extreme bad breath. In addition, it may cause swelling of various oral tissues and difficulty in speech. Lips may be dry or cracked. The incidence of caries may increase dramatically.
【０００５】このような状態の患者は米国内で数百万人
いると推定される。しかし口内乾燥症患者の実数はつか
めていない。というのは、最近までこの問題の蔓延又は
深刻さはほとんど知られていなかったからである。５０
才以上の人口の約１０％及び６５才以上の人口の約２５
％が口内乾燥症患者と推定される。患者の大多数は女性
である。It is estimated that there are millions of patients in this state in the United States. However, the actual number of patients with xerostomia is unknown. Until recently, little was known about the prevalence or severity of this problem. Fifty
About 10% of the population over the age of 25 and about 25 of the population over the age of 65
% Is estimated to be dry mouth patients. The majority of patients are women.
【０００６】口内乾燥症のいくつかの直接的な第一の原
因は、シェーグレン症候群のような自己免疫疾患、放射
線治療、栄養失調、ホルモン平衡失調、関節炎及び老化
である。頭又は首の部分に１週間当たり１０００ラドほ
どの少ない放射線治療がなされても、６週間後には８５
％の患者が口内乾燥症になり、３カ月後には９５％が口
内乾燥症になる。放射線口内乾燥症はすぐに始まり、１
週間後に唾液分泌量が５０％を越えて減少し、６週間治
療後には７５％を越えて減少する。口内乾燥症は進行
性、持続性及び回復不能性で、照射３年後には唾液分泌
が９５％を越えて減少する。大唾液腺の一部のみが電離
放射線の通路にかかる患者では、照射されていない部分
が増殖し、損なわれた腺房を部分的に補う。口内乾燥症
の最も重篤なケースは、頭及び首部の外科手術後の放射
線療法、及び狼瘡、シェーグレン症候群、慢性関節リウ
マチのような自己免疫疾患により起こる。例えば、P.C.
Fox et al., J. Am.Dental Assoc. 110:519-525 (198
5)参照。Some of the immediate primary causes of xerostomia are autoimmune diseases such as Sjogren's syndrome, radiation therapy, malnutrition, hormonal imbalance, arthritis and aging. Even if the head or neck is treated with as little as 1000 rads of radiation per week, it will be 85 after 6 weeks.
% Patients have xerostomia, and after 3 months 95% have xerostomia. Radiation xerostomia begins immediately, 1
Saliva production decreases by more than 50% after a week, and decreases by more than 75% after 6 weeks of treatment. Dry mouth is progressive, persistent and irreversible, with saliva secretion decreasing by more than 95% after 3 years of irradiation. In patients where only part of the large salivary gland is exposed to the path of ionizing radiation, the unirradiated part proliferates and partially fills the damaged acini. The most severe cases of xerostomia are caused by radiation therapy after head and neck surgery and autoimmune diseases such as lupus, Sjogren's syndrome, and rheumatoid arthritis. For example, PC
Fox et al., J. Am. Dental Assoc. 110: 519-525 (198
See 5).
【０００７】放射線療法後における唾液分泌減少は、癌
であるという「悪いニュース」、あるいは吐気、頭痛、
嚥下困難などの数々の化学及び放射線療法の副作用で既
に損ねられている患者の生活の質に重大な影響を及ぼ
す。前記のように、唾液は口の硬、軟組織の保持のた
め、あるいは味覚、嚥下、発語などの口頭の機能を正常
に行うために重要である。Decreased salivation after radiation therapy is the "bad news" of cancer, or nausea, headache,
Numerous side effects of chemo- and radiotherapy, such as dysphagia, have a significant impact on a patient's quality of life, which has already been compromised. As mentioned above, saliva is important for maintaining the hard and soft tissues of the mouth or for normally performing oral functions such as taste, swallowing and speech.
【０００８】第二に、口内乾燥症は強力な抗高血圧薬、
抗うつ薬、鎮痙薬、利尿薬、筋弛緩薬、抗精神病薬、食
欲抑制薬、パーキンソン病治療薬を含む４００を越える
薬物の投与による副作用である。放射線療法及び化学療
法により引き起こされた唾液腺機能不全に加えて、涙腺
及び唾液腺分泌の低下を特徴とする他の多くの種類の慢
性炎症及び他の免疫疾患が知られている（例えばシェー
グレン症候群）。これは結果として乾性角結膜炎（ＫＣ
Ｓ）及び口内乾燥症となる慢性症状である。Second, xerostomia is a powerful antihypertensive drug,
It is a side effect of administration of more than 400 drugs including antidepressants, antispasmodics, diuretics, muscle relaxants, antipsychotics, appetite suppressants, and Parkinson's disease therapeutics. In addition to salivary gland dysfunction caused by radiotherapy and chemotherapy, many other types of chronic inflammation and other immune disorders characterized by decreased lacrimal glands and salivary gland secretions are known (eg Sjogren's syndrome). This results in keratoconjunctivitis sicca (KC
S) and dry mouth, which are chronic symptoms.
【０００９】シェーグレン症候群の治療は、症状の緩和
及び慢性の口内乾燥症及び眼球乾燥症（結膜及び角膜の
乾燥）の局所的な損傷影響を限定することを目的とす
る。眼球の乾燥は人工涙液の使用に反応する。人工涙液
は３０分毎に適用しなければならないこともある。徐放
性涙液製剤が文献に報告されているが限られた成功しか
収めていない。ソフトコンタクトレンズが角膜を保護す
るために推奨されているが、感染症の危険が増加する。
涙液の蒸発を防ぐために夜間サランラップでおおった
り、あるいは潜水用ゴーグルをつけることが提案されて
いる。シェーグレン症候群患者の口内乾燥症は治療が困
難であるが、水あるいは人工唾液の頻繁な摂取、チュー
インガム、キャンディなどで一時的に緩和される。The treatment of Sjogren's syndrome aims at relief of the symptoms and limiting the local damaging effects of chronic xerostomia and xerophthalmia (dry conjunctiva and cornea). Dry eyes respond to the use of artificial tears. Artificial tears may have to be applied every 30 minutes. Sustained-release tear formulations have been reported in the literature with limited success. Soft contact lenses are recommended to protect the cornea but increase the risk of infection.
To prevent evaporation of tears, it has been proposed to cover it with nighttime Saran wrap or put on diving goggles. Although it is difficult to treat xerostomia in patients with Sjogren's syndrome, it is temporarily relieved by frequent intake of water or artificial saliva, chewing gum, candy and the like.
【００１０】口内乾燥症の症例は、わずかに乾燥を感じ
るぐらいの軽いものから、患者が咀嚼、嚥下、消化、発
語などに重大な問題を有するようになる重いものまで様
々である。口を通しての呼吸もまた口内乾燥症を誘発す
ることがある。また季節的に誘発される口内乾燥症もあ
る。Balslev らの米国特許第 4,438,100号で述べられて
いるように、口内乾燥症の他の原因には、生理的なもの
（例えば、老化、閉経、術後、脱水症）や精神的なもの
（神経質）がある。Cases of xerostomia range from mild to slightly dry, to severe, which causes the patient to have significant problems with chewing, swallowing, digestion, speech, etc. Breathing through the mouth can also induce xerostomia. There is also seasonal dry mouth. Other causes of xerostomia, as described in Balslev et al., U.S. Pat. No. 4,438,100, are physiological (eg, aging, menopause, postoperative, dehydration) and psychological (nervous). ).
【００１１】最近まで口内乾燥症の治療には大きな欠点
があった。例えば、軽い症状の口内乾燥症は、液体、ハ
ードキャンディ、咽喉トローチ(throat lozenge)を摂る
ことによっていくらか軽減されていた。一般に食物は唾
液分泌を増加する。二次的な口内乾燥症の影響は、甘味
キャンディ、レモンドロップ、ペパーミントドロップ、
チューインガム等の甘味、酸味、あるいは苦味のある食
物により広く軽減できることが知られている。しかし口
内乾燥症患者は齲歯、歯肉疾患にかかりやすいので、従
来のキャンディやトローチの摂取により糖分の摂取が増
加することは現実の問題となる。さらに液体あるいはキ
ャンディは、より重篤な口内乾燥症の症例にはたいてい
効果がなく、軽い症例でも長時間持続する効果は得られ
ない。Until recently, the treatment of xerostomia had major drawbacks. For example, mild symptoms of xerostomia were somewhat alleviated by ingesting liquids, hard candy, and throat lozenge. Food generally increases salivation. Secondary dry mouth effects include sweet candy, lemon drop, peppermint drop,
It is known that it can be widely reduced by foods having sweetness, sourness, or bitterness such as chewing gum. However, since patients with xerostomia are susceptible to dental caries and gum disease, increasing the intake of sugar by the conventional intake of candy and troche is a real problem. Furthermore, liquids or candies are usually ineffective in more severe cases of dry mouth, and even light cases do not provide long-lasting effects.
【００１２】口内乾燥症に対する一般的な対策は合成唾
液の使用である。市販の人工唾液が多種あり、それらは
アルコール、鉱油、グリセリン、及びポリエチレングリ
コールの組合せを含有する。豚ムチン又はカルボキシメ
チルセルロース（ＣＭＣ）を基剤とし、全必須電解質、
緩衝液、及び任意に着香料及び／又は甘味料を含有する
多くの市販商品がある。通常、電解質はカリウム、ナト
リウム、マグネシウム、カルシウム、塩素、炭酸水素、
燐酸、及びフッ素である。ムチンを基剤とするデンマー
クブランドの商品（Saliva-Orthana) 及びオランダ製の
試験用を除いて、ほとんどの人工唾液はＣＭＣを基剤と
し、Orex（登録商標）(Young Dental)、Xero-Lube （登
録商標）(Scherer) 、Moi-Stir（登録商標）(Kingswood
Laboratories)、及びSalivart（登録商標）(Westport
Pharmaceuticals)の商標で市販されている。Va-Oralube
(First Texas Labs.,ダラス) は、適切な電解質及びＣ
ＭＣに加えてソルビトールとフッ素を含有する。Moi-St
ir（登録商標）(KingswoodCo., トロント) は高濃度の
ナトリウムを含有しミント味である。Salube (Oraphorm
Co., オーストラリア) は小さな滴下びんで市販されて
いる。Saliment (Richmond Pharm. Co.,オンタリオ) も
ＣＭＣを基剤としレモン味である。Xero-lube (Scherer
Labs., ダラス, テキサス州) 、Artisial (Jouvenal,
パリ, フランス) 、及びGlandosane (Fresenius, Bad H
omburg, 西ドイツ) は通常のスプレーびんで市販されて
いる。またグリセリン、ヒドロキシエチルセルロース、
及びポリエチレンオキサイド類も合成唾液の基剤として
使用できることが知られている。しかしながら、多くの
患者はこのような製剤が刺激性であったりあるいは味が
悪かったり、また口内を滑らかにする効果が比較的短時
間しか続かないことを知るのである。A common remedy for xerostomia is the use of synthetic saliva. There are many types of artificial saliva available on the market, which contain a combination of alcohol, mineral oil, glycerin, and polyethylene glycol. Based on pig mucin or carboxymethyl cellulose (CMC), all essential electrolytes,
There are many commercial products that contain a buffer and, optionally, flavoring and / or sweetening agents. Usually, electrolytes are potassium, sodium, magnesium, calcium, chlorine, hydrogen carbonate,
Phosphoric acid and fluorine. Most of the artificial saliva, except for mucin-based Danish branded products (Saliva-Orthana) and Dutch-made trials, are CMC-based and contain Orex® (Young Dental), Xero-Lube ( (Registered trademark) (Scherer), Moi-Stir (registered trademark) (Kingswood
Laboratories), and Salivart® (Westport
Marketed under the trademark of Pharmaceuticals). Va-Oralube
(First Texas Labs., Dallas) has a suitable electrolyte and C
It contains sorbitol and fluorine in addition to MC. Moi-St
ir® (Kingswood Co., Toronto) contains a high concentration of sodium and has a mint flavor. Salube (Oraphorm
Co., Australia) is marketed in small dropper bottles. Saliment (Richmond Pharm. Co., Ontario) is also CMC based and lemon flavored. Xero-lube (Scherer
Labs., Dallas, Texas), Artisial (Jouvenal,
Paris, France) and Glandosane (Fresenius, Bad H
(Omburg, West Germany) is sold in regular spray bottles. In addition, glycerin, hydroxyethyl cellulose,
It is known that and polyethylene oxides can also be used as a base for synthetic saliva. However, many patients find that such formulations are irritating or have a bad taste and that the mouth-smoothing effect lasts only for a relatively short time.
【００１３】口内乾燥症の症状を軽減するためのいま一
つの一般的な対策は、永続的又は着脱可能な歯科装置を
介して定常性又は制御性の合成唾液源を口に装着する方
法である。口蓋の唾液源は繰り返し再充填する必要があ
る。へりに唾液源を有する着脱可能な上顎義歯は煩雑さ
が少ない。この義歯には穴があり、そこから注射器で充
填し、使用時に流出させ、毎食後に洗浄する。このへり
の付いた着脱可能な義歯には約３ｍｌの合成唾液を入れ
るスペースがある。この義歯は注文品なので高価で、厚
さのために装着感が悪く、発語のじゃまになることがあ
り、一日に数回洗浄し再充填しなければならない。J.A.
Toljanic, Quintessence of Dental Technology, 1985
年 6月, 355-358 頁、及び The Journal of Prosthetic
Dentistry, 52巻, 4号, 540-544 頁には、図を示して
解説し、この問題に関する関連文献が挙げられている。
口内乾燥症に関する有益な背景技術文献としては P.C.
Fox et al. (1985), J. Am. Dental Assoc. 110:519-52
5(1985) がある。また、副交感神経様作用薬、すなわち
唾液分泌を制御する副交感神経系の作用を模倣した薬物
による実験もいくつか行われている。しかしながら、こ
れらの薬物については重大な副作用とともに投与量の制
御の問題が報告されている。これらの薬物は一般に錠剤
又はカプセルの形態で投与される。唾液分泌を促進する
薬物としては次のものが知られている。 (a) ピロカルピン化合物（塩酸塩、硝酸塩、又はヤボラ
ンジ葉もしくはその抽出物） (b) ネオスチグミン及びその臭化物、臭化ジスチグミン
（ウブレチド; Ubretid)、臭化ピリドスチグミン（メス
チノン; Mestinon) (c) ニコチン酸、ニコチン酸アミド (ニコビオン 500;
Nicobion 500) 、及びベンゾピロン（ベナロット; Vena
lot) (d) カルバコール（ドリル; Doryl)、ヨウ化カリウム、
及びアネトールトリチオン（スルファレムＳ２５; Sulf
arlem S 25)Another common remedy for reducing the symptoms of xerostomia is the application of a constant or controlled source of synthetic saliva to the mouth via a permanent or removable dental device. . The palate source of saliva needs to be refilled repeatedly. Detachable maxillary denture with saliva source on the lip is less complicated. The denture has a hole through which it is filled with a syringe, drained during use and washed after each meal. The removable denture with lip has a space for about 3 ml of synthetic saliva. This denture is custom made, so it is expensive, the thickness makes it uncomfortable to wear, and it can be a nuisance to speech, requiring cleaning and refilling several times a day. JA
Toljanic, Quintessence of Dental Technology, 1985
June, pp. 355-358, and The Journal of Prosthetic
Dentistry, Vol. 52, No. 4, pp. 540-544 is illustrated and illustrated and the relevant literature on this issue is cited.
PC as a useful background document for xerostomia
Fox et al. (1985), J. Am. Dental Assoc. 110: 519-52
There is 5 (1985). In addition, some experiments have been conducted with parasympathomimetic drugs, that is, drugs that mimic the actions of the parasympathetic nervous system that regulates salivary secretion. However, these drugs have been reported to have serious side effects as well as problems of dose control. These drugs are generally administered in the form of tablets or capsules. The following are known as drugs that promote salivary secretion. (a) pilocarpine compound (hydrochloride, nitrate, or javolandi leaf or its extract) (b) neostigmine and its bromide, distigmine bromide (Ubretid), pyridostigmine bromide (mestinone; Mestinon) (c) nicotinic acid, Nicotinamide (Nicobion 500;
Nicobion 500), and benzopyrone (Benalot; Vena
lot) (d) Carbachol (drill; Doryl), potassium iodide,
And anethole trithione (Sulfalem S25; Sulf
arlem S 25)
【００１４】間接的に唾液分泌を促進する薬物としては
次のものが知られている。アスコルビン酸（ビタミン
Ｃ）、クエン酸錠、リンゴ酸、レモングリセリン綿棒(s
wab)、及びパラフィンワックス 上記の情報は、Imfeld, Acta Parodontologics, 13巻,
4号, 1083/111-10996-124頁 (1984) 、及びVissink et
al., Ned Tijdschrift Geneesked, 129巻, 43号, 2054
-2057 (1985)にまとめられている。The following are known as drugs that indirectly promote salivary secretion. Ascorbic acid (vitamin C), citric acid tablets, malic acid, lemon glycerin swab (s
wab), and paraffin wax.The above information can be found in Imfeld, Acta Parodontologics, Vol. 13,
4, 1083 / 111-10996-124 (1984), and Vissink et.
al., Ned Tijdschrift Geneesked, Volume 129, Issue 43, 2054
-2057 (1985).
【００１５】以下の参考文献は口内乾燥症治療のための
組成物及び方法に関する。Balslev らの米国特許第 4,4
38,100号は、ムチン及び酸化殺菌剤を含有する粘性の人
工唾液を開示する。Mikhail の米国特許第 4,209,505号
は、ピロカルピン又はピロカルピン誘導体を含有する口
内乾燥を緩和するための口内洗剤を開示する。この文献
には、口内乾燥症を軽減しようと種々のタイプの治療食
も使用した（成功はしなかったが）ことも記されてい
る。The following references relate to compositions and methods for the treatment of xerostomia. Balslev et al. U.S. Pat. No. 4,4
38,100 discloses viscous artificial saliva containing mucin and oxidative germicide. Mikhail U.S. Pat. No. 4,209,505 discloses a mouthwash containing pilocarpine or a pilocarpine derivative for mitigating dry mouth. The document also notes that various types of therapeutic diets were also used (although with no success) in an attempt to reduce xerostomia.
【００１６】Reamらの米国特許第 4,151,270号は、唾液
分泌を刺激するよう処方されたチューインガム組成物を
教示する。このガムはフルクトース及び有機酸（アジピ
ン酸、アスコルビン酸、クエン酸、フマル酸、乳酸、リ
ンゴ酸、あるいは酒石酸など）を含有する。米国特許第
4,938,963号は、口内乾燥の症状を軽減するのに有効な
量のエリオジクチオン液状組成物を患者に経口投与する
ことからなる口内乾燥症の治療方法を開示する。エリオ
ジクチオン液状組成物はエリオジクチオン液状抽出物と
甘味料を含有する。Ream et al., US Pat. No. 4,151,270 teaches a chewing gum composition formulated to stimulate salivation. The gum contains fructose and organic acids such as adipic acid, ascorbic acid, citric acid, fumaric acid, lactic acid, malic acid or tartaric acid. US Patent No.
No. 4,938,963 discloses a method of treating xerostomia which comprises orally administering to a patient an amount of a liquid eriodictione composition effective to reduce the symptoms of dry mouth. The liquid eriodictione composition comprises a liquid eriodictione extract and a sweetener.
【００１７】米国特許第 4,917,674号は、口内を湿らす
二枚のパッドを有する、口内乾燥症患者を治療するため
の医療用具を開示する。それぞれのパッドは、水を飽和
状態にしみ込ませることができ、その水を口内に徐々に
補給するためのスポンジ部分を少なくとも一つ有する。
米国特許第 4,906,455号は、アジピン酸、フマル酸、コ
ハク酸、スベリン酸、セバシン酸、アゼライン酸及びピ
メリン酸からなる群より選択される食用品質の有機酸を
含有するガムを患者に少なくとも約２０分間噛ませる口
内乾燥症の治療方法を開示する。US Pat. No. 4,917,674 discloses a medical device for treating a patient with xerostomia which has two pads for moistening the mouth. Each pad is capable of being saturated with water and has at least one sponge portion for gradually replenishing the water in the mouth.
U.S. Pat. No. 4,906,455 discloses to a patient a gum containing an edible quality organic acid selected from the group consisting of adipic acid, fumaric acid, succinic acid, suberic acid, sebacic acid, azelaic acid and pimelic acid for at least about 20 minutes. A method of treating chewy dry mouth is disclosed.
【００１８】米国特許第 4,820,506号は、水に(a) 食用
品質の有機酸味料を約２〜約３重量％、(b) 糖、合成甘
味料、及び還元された糖関連化合物からなる群より選択
される口内微生物相に緩和な食用品質の甘味料、及び
(c) 飽和リン酸カルシウム溶液を溶解させた水性溶液か
ら実質的になる、ヒト唾液の分泌を促進する組成物を教
示する。US Pat. No. 4,820,506 discloses a group consisting of (a) about 2 to about 3% by weight of an edible quality organic acidulant in water, (b) a sugar, a synthetic sweetener, and a reduced sugar-related compound. An edible quality sweetener that is mild to the selected oral microbiota, and
(c) Teach a composition that promotes secretion of human saliva consisting essentially of an aqueous solution in which a saturated calcium phosphate solution is dissolved.
【００１９】経口的に摂取されるピロカルピンを用いる
口内乾燥症の治療法が従来より知られている。ピロカル
ピン５mgのカプセル又は錠剤を１日に３〜４回投与する
ことにより唾液腺機能は顕著に改善されるが、多数の副
作用も現れることが報告されている。しかしながら、こ
の治療法は、ピロカルピンが非常に強力な副交感神経様
作用薬であることから、体内の多くの副交感神経作用部
位に作用するという問題がある。このため、この薬物に
は多くの副作用がある可能性があり、また治療血中濃度
と中毒血中濃度があまり離れていない。A method for treating xerostomia using pilocarpine taken orally is conventionally known. It has been reported that administration of pilocarpine 5 mg capsules or tablets three to four times a day significantly improves salivary gland function, but also causes many side effects. However, this therapeutic method has a problem that it acts on many parasympathetic nerve action sites in the body because pilocarpine is a very potent parasympathomimetic drug. For this reason, this drug can have many side effects and the therapeutic and toxic blood levels are not too far apart.
【００２０】またピロカルピンは眼球乾燥症（結膜及び
角膜の乾燥）の治療に使用できることが知られている。
さらにピロカルピンは高眼内圧(excessive intraocular
pressure)を軽減するためにも使用されている。しかし
残念ながら、眼球乾燥症及び高眼内圧の治療を必要とす
る患者にピロカルピンを投与することによるこれらの疾
患の治療は、経口的に摂取されるピロカルピンを用いる
口内乾燥症の治療と同様の問題が伴う。したがって、有
効でしかも発汗、潮紅、胃痙攣のような通常ピロカルピ
ン治療に関係する副作用が実質的にない方法で、ピロカ
ルピンを患者に投与することによる眼球乾燥症及び高眼
内圧の治療方法が必要となってきた。It is also known that pilocarpine can be used to treat xerophthalmia (dry conjunctiva and cornea).
In addition, pilocarpine is associated with high intraocular pressure.
It is also used to reduce pressure). Unfortunately, however, treatment of these disorders by administering pilocarpine to patients in need of treatment for xerophthalmia and high intraocular pressure has similar problems to treatment of xerostomia with orally taken pilocarpine. Is accompanied by. Therefore, there is a need for a method for treating xerophthalmia and high intraocular pressure by administering pilocarpine to a patient in a manner that is effective and substantially free of side effects normally associated with pilocarpine treatment, such as sweating, flushing, and gastric cramping. Came.
【００２１】[0021]
【発明の要旨】本発明は、口内乾燥症、眼球乾燥症、又
は高眼内圧に罹患した患者の治療方法を提供する。この
治療方法は、治療有効量のピロカルピン又はその医薬上
許容される塩を、その患者のピロカルピン血清濃度を少
なくとも６時間、約５〜約４０ｎｇ／ｍｌに維持する量
で前記患者に投与することからなる。ピロカルピンをこ
の血清濃度に維持することにより、口内乾燥症、眼球乾
燥症、及び高眼内圧の症状を効果的に軽減するといった
ピロカルピンの治療的に有益な結果が達成される。SUMMARY OF THE INVENTION The present invention provides a method of treating a patient suffering from xerostomia, xerophthalmia, or high intraocular pressure. This method of treatment comprises administering to the patient a therapeutically effective amount of pilocarpine or a pharmaceutically acceptable salt thereof in an amount that maintains the patient's pilocarpine serum concentration at about 5 to about 40 ng / ml for at least 6 hours. Become. Maintaining pilocarpine at this serum concentration achieves therapeutically beneficial results for pilocarpine such as effectively alleviating the symptoms of xerostomia, xerophthalmia, and high intraocular pressure.
【００２２】本発明はまた、放射線療法を受ける患者の
口内乾燥症を予防する方法を提供する。この方法は、予
防有効量のピロカルピン又はその医薬上許容される塩
を、放射線療法を開始する前に、その患者のピロカルピ
ン血清濃度を少なくとも６時間、約５〜約４０ｎｇ／ｍ
ｌに維持する量で前記患者に投与することからなる。The present invention also provides a method of preventing xerostomia in a patient undergoing radiation therapy. This method comprises administering a prophylactically effective amount of pilocarpine or a pharmaceutically acceptable salt thereof to the patient's pilocarpine serum concentration of about 5 to about 40 ng / m 2 for at least 6 hours prior to initiating radiation therapy.
Administering to said patient in an amount maintained at l.
【００２３】さらに本発明は、化学療法を受ける患者の
口内乾燥症を予防する方法を提供する。この方法は、予
防有効量のピロカルピン又はその医薬上許容される塩
を、化学療法を開始する前に、その患者のピロカルピン
血清濃度を少なくとも６時間、約５〜約４０ｎｇ／ｍｌ
に維持する量で前記患者に投与することからなる。The invention further provides a method of preventing xerostomia in a patient undergoing chemotherapy. This method comprises administering a prophylactically effective amount of pilocarpine or a pharmaceutically acceptable salt thereof to the patient's serum concentration of pilocarpine for at least 6 hours at about 5 to about 40 ng / ml prior to initiating chemotherapy.
Comprising administering to said patient in an amount maintained at
【００２４】さらに本発明は、ピロカルピンの制御放出
性製剤を提供する。この製剤は、血清濃度が約５〜約４
０ｎｇ／ｍｌで長時間、例えば約６時間又はそれ以上持
続する速度でピロカルピンを放出することができる。こ
の製剤は、ピロカルピン及びカルシウムポリカルボフィ
ル(calcium polycarbophil) の均一混合物を含有し、単
位投与形態をとり、その中に約５〜約３０ｍｇのピロカ
ルピンを含有し、カルシウムポリカルボフィルのピロカ
ルピンに対する比が約１０：１〜約２０：１である。本
発明で使用されるカルシウムポリカルボフィルとして
は、米国薬局方に記載のもの、又は国際出願公開ＷＯ９
２／０３１２４（もしくは特表平５−５０２８９４号公
報）に記載のものが示される。例えば、ジビニルグリコ
ールで架橋されたポリアクリル酸のカルシウム塩が挙げ
られる。The present invention further provides a controlled release formulation of pilocarpine. This formulation has a serum concentration of about 5 to about 4
Pilocarpine can be released at a rate of 0 ng / ml for a long time, for example about 6 hours or more. This formulation contains a homogenous mixture of pilocarpine and calcium polycarbophil in unit dosage form, containing from about 5 to about 30 mg of pilocarpine, wherein the ratio of calcium polycarbophil to pilocarpine is It is about 10: 1 to about 20: 1. Examples of calcium polycarbophil used in the present invention include those described in the United States Pharmacopeia or International Application Publication WO9.
What is described in 2/03124 (or Japanese Patent Publication No. 5-502894) is shown. For example, a calcium salt of polyacrylic acid cross-linked with divinyl glycol may be mentioned.
【００２５】本発明は従来技術のピロカルピン錠剤と比
較して幾つかの有利な点を有する。ピロカルピンは体内
の多くの副交感神経作用部位に作用する非常に強力な副
交感神経様作用薬であるため、この薬物には多くの副作
用がある可能性があり、また治療血中濃度と中毒血中濃
度があまり離れていない。本明細書で説明する制御放出
性送達は、血清濃度を良好にかつ厳格に制御することが
でき、このため口内乾燥症及び眼球乾燥症を管理するた
めのはるかに良い治療対策を提供する。The present invention has several advantages over prior art pilocarpine tablets. Since pilocarpine is a very powerful parasympathomimetic that acts on many parasympathetic sites in the body, this drug can have many side effects, and therapeutic and toxic blood levels. Are not too far apart. The controlled release delivery described herein provides good and tight control of serum concentrations, thus providing a much better therapeutic approach to managing xerostomia and xerophthalmia.
【００２６】またピロカルピンを標準的な経口錠剤、カ
プセル、又は液体で投与する場合、その強力な性質と一
つにはその生物学的半減期が短いことにより、通常２４
時間中に５ｍｇを数回投与する。これは頻繁な投与を必
要とする。大多数の口内乾燥症患者は、他にも重いスト
レスの多い生理学的状態にある年配の患者である。この
ような従来の経口送達システムにより正確で規則に従っ
た投薬を自分で行うことは非常に困難である。When pilocarpine is administered in standard oral tablets, capsules, or liquids, it is usually 24 times due to its potent nature and partly due to its short biological half-life.
Dosage 5 mg several times over time. This requires frequent administration. The majority of patients with xerostomia are other elderly patients who are also under heavy stressful physiological conditions. Such conventional oral delivery systems make it very difficult to self-administer accurate and regular dosing.
【００２７】好ましくは、約０．１〜約３０重量％のカ
ルボマーポリマー（carbomer polymer) 及び、約０．１
〜約３０重量％のヒドロキシメチルセルロース及び／又
はヒドロキシプロピルメチルセルロースが単位投与量中
に含まれる。カルボマーポリマーとはアリルスクロース
で架橋されたポリアクリル酸である。本発明による持続
性送達方法は、２４時間又はそれ以下毎に１回又は２回
の投与を必要とするだけであり、自宅あるいは施設に収
容された環境にある患者集団に対してより正確で再現性
のある投薬を行うためのより良好な送達を可能にする。Preferably, about 0.1 to about 30% by weight carbomer polymer and about 0.1.
Approximately 30% by weight of hydroxymethylcellulose and / or hydroxypropylmethylcellulose is included in the unit dose. Carbomer polymer is polyacrylic acid cross-linked with allyl sucrose. The sustained delivery method according to the present invention requires only one or two administrations every 24 hours or less, and is more accurate and reproducible for patient populations in home or institutional housed environments. Allow better delivery for active dosing.
【００２８】最も重要な点は、従来技術の経口投与によ
る投与形態では初期血中濃度が非常に高くなることであ
る。血中濃度の低下は多くの生物学的因子に依存し、通
常、血中薬物濃度は次回の服用量が送達される前に治療
有効濃度未満に低下する。したがって、従来技術の経口
投与薬は、初めに高い血中濃度を示して好ましくない副
作用を引き起こし、その後は患者が所望の治療効果を得
られず無防備になる治療有効濃度より下の濃度になる。
本発明の持続性投与形態は、その均一な送達速度ゆえに
「山と谷」の影響を最小限にし、口内乾燥症及び眼球乾
燥症あるいは眼内圧力のより良好な治療的管理を可能に
する。Most importantly, the prior art oral dosage forms have very high initial blood levels. The reduction in blood concentration depends on many biological factors, and the blood drug concentration usually falls below the therapeutically effective concentration before the next dose is delivered. Thus, prior art orally-administered drugs initially exhibit high blood levels and cause undesired side effects, after which they are below therapeutically effective concentrations, which renders the patient vulnerable to the desired therapeutic effect.
The sustained dosage form of the present invention minimizes the effects of "peaks and valleys" due to its uniform delivery rate and allows for better therapeutic management of xerostomia and xerophthalmia or intraocular pressure.
【００２９】本発明の基本的側面は、ピロカルピン血清
濃度を約５〜約４０ｎｇ／ｍｌに維持することにより、
上記のような望ましくない副作用を伴うことなく所望の
治療効果が得られることを発見したことにある。好まし
くは、血清濃度を約５〜約２５ｎｇ／ｍｌに維持する。
このような血清濃度は唾液分泌を刺激し、結膜及び角膜
に体液を供給し、眼圧を緩和するのに充分である。同時
にこのような血清濃度は心血管に悪影響を及ぼすことが
なく、発汗、潮紅、又は胃痙攣を起こすこともない。A fundamental aspect of the invention is to maintain the pilocarpine serum concentration at about 5 to about 40 ng / ml,
It has been discovered that a desired therapeutic effect can be obtained without the above-mentioned undesirable side effects. Preferably, the serum concentration is maintained at about 5 to about 25 ng / ml.
Such serum concentrations are sufficient to stimulate salivation, provide fluid to the conjunctiva and cornea, and relieve intraocular pressure. At the same time, such serum concentrations do not adversely affect the cardiovascular system and cause sweating, flushing, or gastric cramping.
【００３０】所望の血清濃度を達成するための方法は限
定されない。好ましくは制御された経口送達システムを
採用するが、所望の血清濃度を長時間、例えば約６〜約
２４時間又はそれ以上、好ましくは少なくとも約８時
間、より好ましくは少なくとも約１０時間、最も好まし
くは少なくとも約１２時間持続するように修正してあれ
ば他の送達手段も採用できる。好適な投与形態として
は、錠剤、カプセル剤、散剤、顆粒剤、及び経口液剤又
は懸濁剤、バッカル剤などの経口投与製剤、及び舌下投
与製剤、皮下、筋肉又は静脈内投与製剤、及び直腸投与
製剤が挙げられる。局所投与には、本発明の化合物をク
リーム剤、軟膏剤又はローション剤の形態で使用する。The method for achieving the desired serum concentration is not limited. Preferably, a controlled oral delivery system is employed, but the desired serum concentration is prolonged, for example from about 6 to about 24 hours or more, preferably at least about 8 hours, more preferably at least about 10 hours, most preferably. Other delivery means can be employed, with modifications modified to last at least about 12 hours. Suitable dosage forms include tablets, capsules, powders, granules, and oral solutions or suspensions, oral preparations such as buccal preparations, sublingual preparations, subcutaneous, intramuscular or intravenous preparations, and rectal preparations. Dosage formulations are included. For topical administration, the compounds of the invention are used in the form of creams, ointments or lotions.
【００３１】本明細書及び特許請求の範囲において血清
ピロカルピン濃度という場合、特にことわりのない限
り、代表的な患者を基準にして決定した平均濃度を意味
する。明らかに、血液化学（酵素量及び濃度）、肝機能
などについて個体差があるため、ピロカルピンの半減期
は個体間で著しい差がある場合もある。したがって、あ
る人が本発明の投与形態を服用しても、所望の時間全て
にわたって目的とする血清濃度が得られないこともあ
る。しかしこのような人も、従来の即放出性ピロカルピ
ン製剤を服用した人によって達成される時間に比べては
るかに長時間、目的とする血清濃度が維持されるため本
発明の利益を享受することができる。In the present specification and claims, the serum pilocarpine concentration means the average concentration determined on the basis of a typical patient, unless otherwise specified. Obviously, the half-life of pilocarpine may vary significantly among individuals because there are individual differences in blood chemistry (enzyme amount and concentration), liver function, and the like. Therefore, even if a person takes the dosage form of the present invention, the desired serum concentration may not be obtained for all desired time. However, such individuals may also benefit from the present invention because the desired serum concentration is maintained for a much longer period of time than is achieved by those who have taken conventional immediate release pilocarpine formulations. it can.
【００３２】さらに、特異的な人の場合、従来の即放出
性ピロカルピン製剤が長時間の放出時間を反映した血清
プロファイルを示すことがある。このような人の場合
は、本発明の投与形態により目的とするピロカルピン血
清濃度を示す時間をさらに延長させ、その後の投与の必
要回数を減らすことができる。Furthermore, in the case of a specific person, conventional immediate release pilocarpine formulations may exhibit a serum profile reflecting a long release time. In the case of such a person, the administration form of the present invention can further prolong the time at which a desired serum concentration of pilocarpine is exhibited and reduce the number of subsequent administrations required.
【００３３】血漿中のピロカルピンの分析は、以下の一
般的なＨＰＬＣ分析法により行われる。血液サンプル
を、適当な濃度の酵素不活性化剤ＮａＦを含有するヘパ
リン化チューブに集める。サンプルを標準的な臨床遠心
分離機で約５〜１０分間遠心分離して血漿を分離する。
血漿を取り出し、さらに追加量のＮａＦを添加して酵素
を不活性化する。分析の準備が整うまで血漿サンプルを
冷凍しておく。Analysis of pilocarpine in plasma is carried out by the following general HPLC analysis method. Blood samples are collected in heparinized tubes containing the appropriate concentration of enzyme inactivator NaF. The sample is centrifuged in a standard clinical centrifuge for approximately 5-10 minutes to separate plasma.
Plasma is removed and additional amount of NaF is added to inactivate the enzyme. Freeze plasma samples until ready for analysis.
【００３４】血漿サンプルを室温にもどす。サンプルを
再び遠心分離して過剰のフッ化ナトリウムを除く。血漿
サンプルの一定量を取り、既知量の内部標準─ピロシン
(pilosine)を添加する。サンプルを一定量の塩化メチレ
ンで抽出する。有機層を分離し、溶媒を緩和な窒素気流
下、４０℃で蒸発乾固させる。既知量の１ｍＭ ＨＣｌ
を添加し、サンプルをエーテルで抽出して他の有機物質
を除去する。水層を真空下乾燥して残っているエーテル
を除去する。こうして調製したサンプルを下記の条件下
でＨＰＬＣにより分析した。 移動相：５５／３０／１５ ７ｍＭリン酸カリウム ｐ
Ｈ４．０／アセトニトリル／メタノールの混合物 カラム：１５０ｃｍ×４．６ｍｍ I.D. 5ミクロン Sph
erisorb ODS-1 含有 検出：ＵＶ検出器 ２１４ｎｍ 流速 １．２ｍｌ／分The plasma sample is returned to room temperature. The sample is centrifuged again to remove excess sodium fluoride. An aliquot of a plasma sample is taken and a known amount of internal standard-pyrosin
(pilosine) is added. Extract the sample with an aliquot of methylene chloride. Separate the organic layer and evaporate the solvent to dryness at 40 ° C. under a gentle stream of nitrogen. Known amount of 1 mM HCl
Is added and the sample is extracted with ether to remove other organics. The aqueous layer is dried under vacuum to remove residual ether. The sample thus prepared was analyzed by HPLC under the following conditions. Mobile phase: 55/30/15 7 mM potassium phosphate p
Mixture of H4.0 / acetonitrile / methanol Column: 150 cm x 4.6 mm ID 5 micron Sph
Containing erisorb ODS-1 Detection: UV detector 214nm Flow rate 1.2ml / min
【００３５】上記の条件は、必要ならば、適当な分離を
得るために最適化してもよい。ピロカルピンの血漿中濃
度はピーク高の比（ピロカルピン／内部標準）を試験サ
ンプルと標品で比較することにより求められる。製剤は
単位投与形態にするのが便利であり、当該分野で既知の
いかなる方法で調製してもよい。If desired, the above conditions may be optimized to obtain the proper separation. The plasma concentration of pilocarpine is determined by comparing the peak height ratio (pilocarpine / internal standard) with the test sample and the standard. The formulations are conveniently in unit dosage form and may be prepared by any method known in the art.
【００３６】好適な実施態様における送達システムは、
ピロカルピン及びカルシウムポリカルボフィルの均一混
合物を含有し、単位投与形態中に約５〜約３０ｍｇのピ
ロカルピンを含有し、カルシウムポリカルボフィルのピ
ロカルピンに対する比が約１０：１〜約２０：１である
単位投与形態である。本発明の制御放出性組成物は、カ
ルシウムポリカルボフィルとピロカルピン又はその塩を
他の賦形剤と共にもしくは賦形剤なしで、顆粒化、又は
直接圧縮、直接押出、直接混和および直接成形のような
直接法により直接成型することができる。The delivery system in the preferred embodiment is
A unit containing a homogeneous mixture of pilocarpine and calcium polycarbophil, containing from about 5 to about 30 mg pilocarpine in a unit dosage form, and having a ratio of calcium polycarbophil to pilocarpine of from about 10: 1 to about 20: 1. It is a dosage form. The controlled release composition of the present invention may be prepared by granulating or direct compression, direct extrusion, direct blending and direct molding of calcium polycarbophil and pilocarpine or a salt thereof with or without other excipients. It can be directly molded by the direct method.
【００３７】徐放性マトリックスには、医薬投与形態で
慣用の食用非毒性の成分を任意に添加してもよい。した
がって、本発明の組成物は、約０．１〜約９９重量％、
好ましくは約１〜約９５重量％の範囲内の量で１または
それ以上の賦形剤を任意に含んでもよい。例えば、ラク
トース、マンニトール、コーンスターチ、ポテトスター
チ、微結晶セルロース、カルボマーポリマー、ヒドロキ
シメチルセルロース、ヒドロキシプロピルメチルセルロ
ース、ポリビニルピロリドン、アカシア（アラビアゴ
ム）、ゼラチン、クロスカルメロースナトリウム、タル
ク、ステアリン酸マグネシウム、ステアリン酸などの賦
形剤、及び他の賦形剤、着色剤、希釈剤、緩衝剤、湿潤
剤、保存剤、着香剤、及び薬理学的に許容される担体な
どが挙げられる。任意に含んでもよい他の慣用成分とし
ては、保存剤、安定化剤、可塑剤、補助溶媒、接着防止
剤又はシリカ流動化剤又は滑沢剤〔例えば、Syloid（商
標）二酸化ケイ素〕、及びＦＤ＆Ｃ（米国食品医薬品化
粧品法）着色剤などである。The sustained release matrix may optionally contain non-edible ingredients which are commonly used in pharmaceutical dosage forms. Accordingly, the composition of the present invention comprises from about 0.1 to about 99% by weight,
One or more excipients may optionally be included, preferably in an amount in the range of about 1 to about 95% by weight. For example, lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, carbomer polymer, hydroxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, acacia (acacia gum), gelatin, croscarmellose sodium, talc, magnesium stearate, stearic acid, etc. And other excipients, colorants, diluents, buffers, wetting agents, preservatives, flavoring agents, and pharmaceutically acceptable carriers. Other conventional ingredients that may optionally be included are preservatives, stabilizers, plasticizers, co-solvents, anti-adhesion agents or silica fluidizers or lubricants (eg, Syloid ™ silicon dioxide), and FD & C. (US Food and Drug Cosmetics Act) Colorants.
【００３８】[0038]
実施例１−投与形態の調製 薬剤の定量組成 以下は、３段階の強さのピロカルピン塩酸塩制御放出性
錠剤（１５ｍｇ、２０ｍｇ及び２５ｍｇ）を調製するた
めに使用した基本顆粒の定量組成である（ＵＳＰは米国
薬局方の、ＮＦは米国国民医薬集の略称である）。Example 1-Preparation of Dosage Form Quantitative Composition of Drugs The following is the quantitative composition of the base granules used to prepare three-step strength pilocarpine hydrochloride controlled release tablets (15 mg, 20 mg and 25 mg) ( USP is the US Pharmacopeia and NF is the abbreviation for the American National Medicines Collection).
【００３９】[0039]
【表１】 [Table 1]
【００４０】(1) 必要に応じて、製造工程における損失
を補うためにラベル表示の５％まで越えて使用した。 (2) 不活性成分の量は表示値の９０〜１００％に調整し
た。 (3) 顆粒化液のアルコール含有量は、使用する顆粒化・
乾燥装置に合わせて０〜２０％Ｖ／Ｖに変更した。顆粒
化液は顆粒化塊を乾燥する間に除去された。 (4) アルコールの認可及び入手可能性により必要に応じ
て無水アルコール（ＵＳＰ）に置換した。 (5) ヒドロキシプロピルメチルセルロース（ＵＳＰ）の
代わりに任意にヒドロキシプロピルセルロース（ＮＦ）
を用いた。(1) If necessary, it was used beyond 5% of the label in order to compensate for the loss in the manufacturing process. (2) The amount of the inactive ingredient was adjusted to 90 to 100% of the indicated value. (3) The alcohol content of the granulation liquid is
It was changed to 0 to 20% V / V according to the drying device. The granulation liquid was removed while drying the granulation mass. (4) The alcohol was replaced with anhydrous alcohol (USP) as required depending on the approval and availability. (5) Optionally hydroxypropyl cellulose (NF) instead of hydroxypropyl methyl cellulose (USP)
Was used.
【００４１】薬剤の定量組成 ピロカルピン塩酸塩制御放出性１５ｍｇ、２０ｍｇ及び
２５ｍｇ錠剤は基本顆粒から下記に詳述するように製造
した。 ピロカルピン塩酸塩制御放出性１５ｍｇ錠剤 最終錠剤重量： ３２４．００ｍｇ(1) 錠剤機： ３／８インチ 円板面−はす縁又はそ
の均等物 ピロカルピン塩酸塩制御放出性２０ｍｇ錠剤 最終錠剤重量： ４３２．００ｍｇ(1) 錠剤機： ７／１６インチ 円板面−はす縁又は
その均等物 ピロカルピン塩酸塩制御放出性２５ｍｇ錠剤 最終錠剤重量： ５４０．００ｍｇ(1) 錠剤機： ７／１６インチ 円板面−はす縁又は
その均等物 (1) 最終錠剤重量は、目的薬物力価を得るために基本顆
粒のピロカルピン塩酸塩含量を基準にして±５％の範囲
で変更してもよい。Quantitative Composition of Drug Pilocarpine Hydrochloride Controlled Release 15 mg, 20 mg and 25 mg tablets were prepared from the basic granules as detailed below. Pilocarpine Hydrochloride Controlled Release 15mg Tablets Final Tablet Weight: 324.00mg (1) Tablet Machine: 3/8 inch Disc Face-Rasp Edge or Equivalent Pilocarpine Hydrochloride Controlled Release 20mg Tablets Final Tablet Weight: 432. 00mg (1) Tablet machine: 7/16 inch Disc surface-bevel edge or its equivalent Pilocarpine Hydrochloride Controlled Release 25mg Tablet Final tablet weight: 540.00mg (1) Tablet machine: 7/16 inch Disc surface -Bevel edge or its equivalent (1) The final tablet weight may be changed within a range of ± 5% based on the pilocarpine hydrochloride content of the basic granules in order to obtain the target drug potency.
【００４２】薬剤の定量組成 下記に説明するピロカルピン塩酸塩制御放出性１５ｍｇ
錠剤の組成物を製造し、実施例２の第１相臨床試験に使
用した。Quantitative composition of drug Pilocarpine hydrochloride controlled release 15 mg described below
A tablet composition was prepared and used in the Phase 1 clinical trial of Example 2.
【００４３】[0043]
【表２】 [Table 2]
【００４４】(1) 必要に応じて、製造工程における損失
を補うためにラベル表示の５％まで越えて使用した。 (2) 不活性成分の量は表示値の９０〜１１０％に調整し
た。 (3) 顆粒化液のアルコール含有量は、使用する顆粒化・
乾燥装置に合わせて０〜３０％Ｖ／Ｖに変更した。顆粒
化液は顆粒化塊を乾燥する間に除去された。 (4) アルコールの認可及び入手可能性により必要に応じ
て無水アルコール（ＵＳＰ）に置換した。 (5) ヒドロキシプロピルセルロース（ＮＦ．１）の代わ
りに任意にヒドロキシプロピルメチルセルロース（ＵＳ
Ｐ）を用いた。(1) If necessary, more than 5% of the label is used to make up for the loss in the manufacturing process. (2) The amount of the inactive ingredient was adjusted to 90 to 110% of the indicated value. (3) The alcohol content of the granulation liquid is
It was changed to 0 to 30% V / V according to the drying device. The granulation liquid was removed while drying the granulation mass. (4) The alcohol was replaced with anhydrous alcohol (USP) as required depending on the approval and availability. (5) Instead of hydroxypropyl cellulose (NF.1), optionally hydroxypropyl methyl cellulose (US
P) was used.
【００４５】実施例２ 米国食品医薬品局、第１相臨床試験を以下の手順にした
がって行なった。８人の健康なボランティアが試験に登
録した。各ボランティアはピロカルピン塩酸塩制御放出
性１５ｍｇ錠剤を１２時間毎に１錠合計３回服用した。
被験者は試験中、入院患者として綿密にモニターされ
た。Example 2 The US Food and Drug Administration Phase I clinical trial was conducted according to the following procedure. Eight healthy volunteers enrolled in the test. Each volunteer took a pilocarpine hydrochloride controlled release 15 mg tablet once every 12 hours for a total of 3 doses.
Subjects were closely monitored as inpatients during the study.
【００４６】この初期臨床試験の目的は、唾液分泌を促
進するピロカルピン塩酸塩の制御放出性製剤の安全性と
薬効を８人の正常人で実証することであった。特定の目
的は、多回投与耐性、初期薬効及び初期薬物動力学を評
価することであった。この試験に登録した８人の被験者
は全般的に非常に健康で、経口避妊薬以外は医薬品を服
用していなかった。口内乾燥の症状を訴える者はいなか
った。彼らは通常の唾液腺機能を示した。これらのボラ
ンティアは、Carolinas Medical Centerにおいて入院患
者として三夜過ごし、２日間は頻繁にモニターされ唾液
を採取された。繰り返し採血をするためにヘパリン化カ
テーテルを末梢血管に挿入した。被験者は、試験薬剤を
１２時間間隔で３回、水と共に経口で服用した。約２２
個（１０ｍｌ）の血液サンプル（合計２２０ｍｌ）を２
日間にわたって得た。非侵襲性のCarlson/Crittendenカ
ップを用い直接採取方法により耳下腺及び無刺激の全唾
液を繰り返し採取した。考えられる悪影響を観察するた
めに患者を綿密にモニターした。The purpose of this initial clinical trial was to demonstrate the safety and efficacy of a controlled release formulation of pilocarpine hydrochloride which stimulates salivation in 8 normal individuals. The specific purpose was to evaluate multidose resistance, initial efficacy and initial pharmacokinetics. The eight subjects enrolled in this study were generally very healthy and taking no medication other than oral contraceptives. No one complained of symptoms of dry mouth. They showed normal salivary gland function. These volunteers spent three nights in the Carolinas Medical Center as inpatients and were frequently monitored and saliva collected for two days. A heparinized catheter was inserted into the peripheral blood vessel for repeated blood sampling. Subjects took the study drug orally with water three times at 12 hour intervals. About 22
2 (10 ml) blood samples (total 220 ml)
Got over days. The parotid gland and unstimulated whole saliva were repeatedly collected by the direct collection method using a non-invasive Carlson / Crittenden cup. Patients were closely monitored to observe possible adverse effects.
【００４７】８人の被験者を注意深くモニターするため
に、幾つかの実験室的及び臨床的パラメーターを測定し
た。最初に全ての参加者に、ＥＫＧ、尿検査、全血球算
定、電解質測定、ＨＩＶ検査、及び肝機能検査を含めて
完全な身体的検査を行なった。３日間の入院中、その身
体的検査を毎日繰り返し、参加者が試験薬剤を服用した
日にＥＫＧ、全血球算定、尿検査、及び電解質測定を含
む実験室的検査を繰り返した。入院中は頻繁に血圧、脈
拍及び体温を測定した。毒性又は悪影響は、臨床医によ
り観察されず、いずれの被験者にもみられなかった。投
与量は許容量であり、ピロカルピン塩酸塩の即放出性投
与形態に通常みられる発汗、潮紅、胃痙攣などの副作用
はいずれの被験者にもみられなかった。Several laboratory and clinical parameters were measured in order to carefully monitor eight subjects. Initially, all participants underwent a complete physical examination including EKG, urinalysis, complete blood count, electrolyte measurement, HIV test, and liver function test. During the 3-day hospital stay, the physical examination was repeated daily and laboratory examinations including EKG, complete blood count, urinalysis, and electrolyte measurements were repeated on the day the participants took the study drug. Blood pressure, pulse and body temperature were frequently measured during hospitalization. No toxicity or adverse effects were observed by the clinician and were not seen in any subject. The dose was acceptable, and no side effects such as sweating, flushing, and gastric cramps that were usually observed in the immediate release dosage form of pilocarpine hydrochloride were observed in any of the subjects.
【００４８】１回投与後及び３回投与後に、被験者の無
刺激全唾液分泌量と耳下腺唾液分泌をモニターした。８
人の被験者から得た唾液量データを表３〜８に示す。図
１は、１回投与後及び３回投与後に時間間隔をかえて数
回測定した平均全唾液量データ（被験者８人）を示す。
図２及び図３は、それぞれ１回投与後及び３回投与後の
右及び左耳下腺唾液量の平均（被験者８人）を示す。こ
のデータは投与１時間以内に唾液分泌速度に刺激があ
り、少なくとも約８〜１２時間はその効果が持続するよ
うであることを示す。The unstimulated total salivary secretion and parotid salivary secretion of the subjects were monitored after the first administration and after the third administration. 8
Saliva volume data obtained from human subjects are shown in Tables 3-8. FIG. 1 shows the average total saliva amount data (8 subjects) measured several times after the first administration and after the third administration at different time intervals.
FIG. 2 and FIG. 3 show the averages of the amounts of saliva of the right and left parotid glands (8 subjects) after one administration and three administrations, respectively. This data indicates that there is stimulation of salivary rate within 1 hour of administration, and that effect appears to persist for at least about 8-12 hours.
【００４９】血液サンプルは１回投与後及び３回投与後
に採取した。８人の被験者から得たピロカルピン血漿濃
度データを表９及び表１０に詳細に示す。８人の被験者
から得た１回投与後及び３回投与後の平均血漿濃度デー
タを時間関数として図４及び図５にそれぞれ示す。この
データはＣmax （最大濃度）がピロカルピン塩酸塩約８
〜１２ｎｇ／ｍｌであることを示すようだ。Ｃmax に達
する時間は約１時間である。試験中、毒性又は悪影響は
観察されなかった。ピロカルピン塩酸塩制御放出性送達
システムは十分許容し得るものであり、ピロカルピン塩
酸塩の即放出性投与形態で通常みられる副作用は観察さ
れなかった。Blood samples were collected after one and three doses. Pilocarpine plasma concentration data obtained from 8 subjects are detailed in Tables 9 and 10. Mean plasma concentration data after a single dose and after three doses obtained from eight subjects are shown as a function of time in FIGS. 4 and 5, respectively. This data shows that C max (maximum concentration) is about 8 for pilocarpine hydrochloride.
It seems to indicate ~ 12 ng / ml. The time to reach C max is about 1 hour. No toxicity or adverse effects were observed during the study. The pilocarpine hydrochloride controlled release delivery system was well tolerated and no side effects commonly observed with immediate release dosage forms of pilocarpine hydrochloride were observed.
【００５０】８人の参加者全てにおいて、試験中の身体
的検査で特筆すべき変化はなかった。同様に、試験を通
じて実験室的パラメーターは平常値内で安定していた。
参加者の中で何らかのピロカルピンの望ましくない副作
用を経験したことを示唆するような症状あるいは訴えも
なかった。例えば、８人の被験者の中で発汗の増加、潮
紅あるいは消化器系の不快を訴えた者はいなかった。結
論として、上述のパラメーターによれば試験薬剤による
悪影響の形跡はなく、すべての参加者は試験中、健康で
あった。There were no notable changes in the physical examination during the study in all eight participants. Similarly, laboratory parameters remained stable within normal values throughout the study.
There were no symptoms or complaints suggesting that any of the participants experienced any unwanted side effects of pilocarpine. For example, none of the eight subjects complained of increased sweating, flushing or digestive discomfort. In conclusion, all the participants were healthy during the study with no evidence of adverse effects of the study drug according to the above parameters.
【００５１】[0051]
【表３】 [Table 3]
【００５２】[0052]
【表４】 [Table 4]
【００５３】[0053]
【表５】 [Table 5]
【００５４】[0054]
【表６】 [Table 6]
【００５５】[0055]
【表７】 [Table 7]
【００５６】[0056]
【表８】 [Table 8]
【００５７】[0057]
【表９】 [Table 9]
【００５８】[0058]
【表１０】 [Table 10]
【図１】本発明の組成物の１回投与後及び３回投与後に
時間間隔をかえて数回測定した平均全唾液量データ（被
験者８人）を示すグラフである。FIG. 1 is a graph showing average total saliva amount data (8 subjects) measured several times after changing the time interval after single administration and three administrations of the composition of the present invention.
【図２】本発明の組成物の１回投与後及び３回投与後の
右耳下腺唾液量データ（被験者８人）を示すグラフであ
る。FIG. 2 is a graph showing right parotid salivary volume data (8 subjects) after a single dose and three doses of the composition of the present invention.
【図３】本発明の組成物の１回投与後及び３回投与後の
左耳下腺唾液量データ（被験者８人）を示すグラフであ
る。FIG. 3 is a graph showing left parotid salivary volume data (8 subjects) after one-time administration and three-time administration of the composition of the present invention.
【図４】本発明の組成物の１回投与後の８人の被験者か
ら得た平均血漿濃度データを時間関数として示したグラ
フである。FIG. 4 is a graph showing mean plasma concentration data as a function of time obtained from 8 subjects after single administration of the composition of the present invention.
【図５】本発明の組成物の３回投与後の８人の被験者か
ら得た平均血漿濃度データを時間関数として示したグラ
フである。FIG. 5 is a graph showing mean plasma concentration data as a function of time obtained from 8 subjects after three doses of the composition of the present invention.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 47/32 Ｂ 47/38 Ｂ Ｃ ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical display area A61K 47/32 B 47/38 BC
Claims (10)
上許容される塩を、口内乾燥症、眼球乾燥症、又は高眼
内圧に罹患した患者に、当該患者のピロカルピン血清濃
度を少なくとも６時間、約５〜約４０ｎｇ／ｍｌに維持
する量で投与することからなる口内乾燥症、眼球乾燥
症、又は高眼内圧に罹患した患者の治療方法。1. A therapeutically effective amount of pilocarpine or a pharmaceutically acceptable salt thereof is administered to a patient suffering from xerostomia, xerophthalmia, or high intraocular pressure, the serum concentration of pilocarpine in the patient being at least about 6 hours. A method of treating a patient suffering from xerostomia, xerophthalmia, or elevated intraocular pressure, which comprises administering in an amount maintained at 5 to about 40 ng / ml.
射線療法を開始する前に予防有効量のピロカルピンを投
与する請求項１記載の方法。2. The method according to claim 1, wherein the patient is a person receiving radiation therapy and a prophylactically effective amount of pilocarpine is administered before the radiation therapy is started.
療法を開始する前に予防有効量のピロカルピンを投与す
る請求項１記載の方法。3. The method of claim 1, wherein the patient is a recipient of chemotherapy and the prophylactically effective amount of pilocarpine is administered prior to the initiation of chemotherapy.
発される口内乾燥症又は眼球乾燥症である請求項１記載
の方法。4. The method according to claim 1, wherein the dry mouth or xerophthalmia is chemically induced dry mouth or xerophthalmia.
する口内乾燥症又は眼球乾燥症である請求項１記載の方
法。5. The method according to claim 1, wherein the dry mouth or xerophthalmia is age-related dry mouth or xerophthalmia.
発される口内乾燥症又は眼球乾燥症である請求項１記載
の方法。6. The method according to claim 1, wherein the dry mouth or xerophthalmia is seasonally induced dry mouth or xerophthalmia.
フィル(calcium polycarbophil) の均一混合物を含有
し、単位投与形態中に約５〜約３０ｍｇのピロカルピン
を含有し、カルシウムポリカルボフィルのピロカルピン
に対する比が約１０：１〜約２０：１である単位投与形
態の製剤。7. A homogenous mixture of pilocarpine and calcium polycarbophil, containing from about 5 to about 30 mg pilocarpine in a unit dosage form, the ratio of calcium polycarbophil to pilocarpine being about 10: Formulation in unit dosage form from 1 to about 20: 1.
arbomer polymer)を約０．１〜約３０重量％含有する請
求項７記載の製剤。8. A carbomer polymer (c) in a unit dosage form.
8. The formulation according to claim 7, which contains about 0.1 to about 30% by weight of an arbomer polymer.
ロース、ヒドロキシプロピルメチルセルロース、又はそ
れらの混合物を約０．１〜約３０重量％含有する請求項
７記載の製剤。9. The formulation of claim 7 which contains from about 0.1% to about 30% by weight of hydroxymethylcellulose, hydroxypropylmethylcellulose, or a mixture thereof in a unit dosage form.
(carbomer polymer)を約０．１〜約３０重量％含有する
請求項９記載の製剤。10. A carbomer polymer in a unit dosage form.
The formulation according to claim 9, which contains about 0.1 to about 30% by weight of (carbomer polymer).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25309193A JPH07126163A (en) | 1993-10-08 | 1993-10-08 | Controllably releasable pilocarpine transmitting system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25309193A JPH07126163A (en) | 1993-10-08 | 1993-10-08 | Controllably releasable pilocarpine transmitting system |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH07126163A true JPH07126163A (en) | 1995-05-16 |
Family
ID=17246371
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP25309193A Withdrawn JPH07126163A (en) | 1993-10-08 | 1993-10-08 | Controllably releasable pilocarpine transmitting system |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07126163A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1171253A (en) * | 1997-08-29 | 1999-03-16 | Lion Corp | Salivation accelerator and composition for oral cavity |
| WO2001012225A1 (en) * | 1999-08-10 | 2001-02-22 | Santen Pharmaceutical Co., Ltd. | Water channel opener compositions and medicinal compositions for ophthalmic use |
| WO2006038596A1 (en) * | 2004-10-05 | 2006-04-13 | Astellas Pharma Inc. | Pharmaceutical composition for xerophthalmia and xerostomia treatment |
| JP2008508338A (en) * | 2004-08-02 | 2008-03-21 | グラクソ グループ リミテッド | New composition for xerostomia |
| JP2009114125A (en) * | 2007-11-06 | 2009-05-28 | Nippon Zettoc Co Ltd | Oral composition |
| WO2009139470A1 (en) * | 2008-05-16 | 2009-11-19 | 学校法人聖マリアンナ医科大学 | Pharmaceutical composition for treatment of fibromyalgia |
| JP2010120956A (en) * | 1996-08-15 | 2010-06-03 | Losan Pharma Gmbh | Easy to swallow oral medicament composition |
| JP2012501960A (en) * | 2008-09-05 | 2012-01-26 | 大塚製薬株式会社 | Pharmaceutical solid formulation |
-
1993
- 1993-10-08 JP JP25309193A patent/JPH07126163A/en not_active Withdrawn
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010120956A (en) * | 1996-08-15 | 2010-06-03 | Losan Pharma Gmbh | Easy to swallow oral medicament composition |
| JPH1171253A (en) * | 1997-08-29 | 1999-03-16 | Lion Corp | Salivation accelerator and composition for oral cavity |
| WO2001012225A1 (en) * | 1999-08-10 | 2001-02-22 | Santen Pharmaceutical Co., Ltd. | Water channel opener compositions and medicinal compositions for ophthalmic use |
| JP2008508338A (en) * | 2004-08-02 | 2008-03-21 | グラクソ グループ リミテッド | New composition for xerostomia |
| WO2006038596A1 (en) * | 2004-10-05 | 2006-04-13 | Astellas Pharma Inc. | Pharmaceutical composition for xerophthalmia and xerostomia treatment |
| JP2009114125A (en) * | 2007-11-06 | 2009-05-28 | Nippon Zettoc Co Ltd | Oral composition |
| WO2009139470A1 (en) * | 2008-05-16 | 2009-11-19 | 学校法人聖マリアンナ医科大学 | Pharmaceutical composition for treatment of fibromyalgia |
| JP2011121975A (en) * | 2008-05-16 | 2011-06-23 | Axis Inc | Pharmaceutical composition for improving pain accompanied by fibromyalgia syndrome, for improving pain accompanied by fibromyalgia syndrome |
| JP2011121976A (en) * | 2008-05-16 | 2011-06-23 | Axis Inc | Pharmaceutical composition for improving xerostomia accompanied by fibromyalgia syndrome |
| JP4746714B2 (en) * | 2008-05-16 | 2011-08-10 | Ａｘｉｓ株式会社 | Pharmaceutical composition for treating fibromyalgia |
| JP2012501960A (en) * | 2008-09-05 | 2012-01-26 | 大塚製薬株式会社 | Pharmaceutical solid formulation |
| JP2015061887A (en) * | 2008-09-05 | 2015-04-02 | 大塚製薬株式会社 | Pharmaceutical solid preparation |
| US9173844B2 (en) | 2008-09-05 | 2015-11-03 | Otsuka Pharmaceutical Co., Ltd. | Pharmaceutical solid preparation |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5741805A (en) | Controlled release pilocarpine delivery system | |
| EP0906089B1 (en) | Buccal delivery system | |
| US5614207A (en) | Dry mouth lozenge | |
| US8242131B2 (en) | Methods of treating middle-of-the-night insomnia | |
| US9161909B2 (en) | Adhesive compositions for the treatment of xerostomia | |
| US20180078534A1 (en) | Compositions and methods for treating middle-of-the-night insomnia | |
| AU703242B2 (en) | Film coated tablet of paracetamol and domperidone | |
| US20030022910A1 (en) | Compositions and methods for sublingual formulations of dihydroergotamine for the treatment of migraine | |
| AU2006206252B2 (en) | Methods and compositions for decreasing saliva production | |
| JP2000095675A (en) | Oral solid pharmaceutical composition for treating rhinitis of intraoral soluble type or mastication type | |
| US20120034300A1 (en) | Stabilized zolpidem pharmaceutical compositions | |
| US20090053309A1 (en) | Adhesive compositions for the treatment of xerostomia | |
| US20100249178A1 (en) | Compositions and methods for treating middle-of-the-night insomnia | |
| CA3195133A1 (en) | Treatment of bipolar disorders and psychosis using dexmedetomidine hydrochloride | |
| KR100801946B1 (en) | Pharmaceutical compositions and dosage forms for buccal and sublingual delivery of tizanidine and methods of administering tizanidine sublingually or buccally | |
| JPH07126163A (en) | Controllably releasable pilocarpine transmitting system | |
| KR20040084944A (en) | Ambroxol for treating painful conditions in the mouth and pharyngeal cavity | |
| WO1994001108A1 (en) | Controlled release pilocarpine delivery system | |
| MX2010009917A (en) | Modified release composition comprising doxofylline. | |
| Ivanivna et al. | MEDICAL CHEWING GUMS AS THE NEWEST MEDICINAL FORM | |
| AU2016203713A1 (en) | Solid compositions and methods for treating middle-of-the night insomnia | |
| AU2012238306A1 (en) | Solid compositions and methods for treating middle-of-the night insomnia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A300 | Withdrawal of application because of no request for examination |
Free format text: JAPANESE INTERMEDIATE CODE: A300 Effective date: 20001226 |