KR20060069016A - Controlled release pharmaceutical compositions of pseudoephedrine or its salt - Google Patents
Controlled release pharmaceutical compositions of pseudoephedrine or its salt Download PDFInfo
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- KR20060069016A KR20060069016A KR1020040108002A KR20040108002A KR20060069016A KR 20060069016 A KR20060069016 A KR 20060069016A KR 1020040108002 A KR1020040108002 A KR 1020040108002A KR 20040108002 A KR20040108002 A KR 20040108002A KR 20060069016 A KR20060069016 A KR 20060069016A
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- pseudoephedrine
- release
- pharmaceutical composition
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- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 title claims abstract description 42
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical group CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 title claims abstract description 38
- 229960003908 pseudoephedrine Drugs 0.000 title claims abstract description 37
- 150000003839 salts Chemical class 0.000 title claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 17
- 238000013270 controlled release Methods 0.000 title description 6
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 30
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims abstract description 30
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 30
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 28
- 239000010410 layer Substances 0.000 claims abstract description 16
- 239000011247 coating layer Substances 0.000 claims abstract description 8
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 claims description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- 229960001803 cetirizine Drugs 0.000 claims description 11
- 239000000314 lubricant Substances 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000454 talc Substances 0.000 claims description 4
- 229910052623 talc Inorganic materials 0.000 claims description 4
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 4
- 239000008203 oral pharmaceutical composition Substances 0.000 claims description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 229960004667 ethyl cellulose Drugs 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000011162 core material Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000000576 coating method Methods 0.000 description 10
- 238000005507 spraying Methods 0.000 description 10
- 238000013268 sustained release Methods 0.000 description 10
- 239000012730 sustained-release form Substances 0.000 description 10
- 239000002775 capsule Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 229960004342 cetirizine hydrochloride Drugs 0.000 description 8
- 239000011248 coating agent Substances 0.000 description 8
- 229960004756 ethanol Drugs 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 description 5
- 238000007922 dissolution test Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229960004592 isopropanol Drugs 0.000 description 2
- -1 sulfate salts Chemical class 0.000 description 2
- 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
- 229920002261 Corn starch Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940022682 acetone Drugs 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229940078495 calcium phosphate dibasic Drugs 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229960002337 magnesium chloride Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000000133 nasal decongestant Substances 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
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
본 발명은 코어; 치료학적으로 유효한 양의 슈도에페드린 또는 그의 염이 상기 코어 상에 코팅된 약물-코팅 층; 및 조성물 총 중량에 대하여 1.5 ∼ 5 중량%의 에칠셀룰로오스가 상기 약물-코팅 층 상에 코팅된 방출-제어 층을 포함하는 경구용 약제학적 조성물을 제공한다.The present invention is a core; A drug-coating layer coated on said core with a therapeutically effective amount of pseudoephedrine or a salt thereof; And a release-controlling layer coated on the drug-coating layer with 1.5 to 5% by weight of ethylcellulose based on the total weight of the composition.
슈도에페드린, 에칠셀룰로오스Pseudoephedrine, Ethyl Cellulose
Description
도 1은 실시예 1에서 제조한 조성물에 있어서 에칠셀룰로오스의 양에 따른 슈도에페드린의 용출율 변화를 나타내는 도면이고,1 is a view showing the change in dissolution rate of pseudoephedrine according to the amount of ethyl cellulose in the composition prepared in Example 1,
도 2는 실시예 2에서 제조한 조성물에 있어서, 에칠셀룰로오스와 활택제 종류에 따른 슈도에페드린의 용출율 변화를 나타내는 도면이고,FIG. 2 is a diagram showing the dissolution rate of pseudoephedrine according to ethyl cellulose and lubricant type in the composition prepared in Example 2,
도 3은 실시예 3에서 제조한 조성물에 있어서, 에칠셀룰로오스의 점도에 따른 슈도에페드린의 용출율 변화를 나타내는 도면이다.3 is a diagram showing a change in dissolution rate of pseudoephedrine according to the viscosity of ethylcellulose in the composition prepared in Example 3.
본 발명은 슈도에페드린 또는 그의 염을 함유하는 방출제어형 약제학적 조성물에 관한 것이며, 더욱 상세하게는 소량의 에칠셀룰로오스로 이루어진 방출-제어 층을 포함하는 방출제어형 약제학적 조성물에 관한 것이다.The present invention relates to controlled release pharmaceutical compositions containing pseudoephedrine or salts thereof, and more particularly to controlled release pharmaceutical compositions comprising a release-controlled layer consisting of a small amount of ethylcellulose.
슈도에페드린 또는 그의 염 (예를 들어, 염산염 또는 설페이트염)은 비충혈제거제로 알려져 있는 교감신경 흥분제이다. 슈도에페드린 또는 그의 염은 생체내 반감기가 약 4.2 ∼ 7 시간으로 매우 짧기 때문에, 지속적인 방출을 나타낼 수 있 는 방출제어형 제제를 개발하기 위한 다양한 연구가 수행되어 왔다.Pseudoephedrine or salts thereof (eg, hydrochloride or sulfate salts) are sympathetic stimulants known as nasal decongestants. Since pseudoephedrine or a salt thereof has a very short half-life in vivo of about 4.2 to 7 hours, various studies have been conducted to develop a controlled release formulation capable of exhibiting sustained release.
한편, 국제특허공개 제WO98/41194호는 슈도에페드린 등을 (i) 불활성 매트릭스, 친수성 매트릭스, 지질 매트릭스, 불활성 및 지질 매트릭스의 혼합물, 친수성 및 불활성 매트릭스의 혼합물로부터 선택된 하나 이상의 부형제(vehicle) 및 (ii) 생리적 pH 조건에서 수성상에서 용해가능한 하나 이상의 알칼리화제와 함께 제제화한 방출제어형 약제학적 조성물을 개시한 바 있다.On the other hand, WO 98/41194 discloses pseudoephedrine and the like by using one or more excipients selected from (i) an inert matrix, a hydrophilic matrix, a lipid matrix, a mixture of inert and lipid matrices, a mixture of hydrophilic and inert matrices, and (ii A controlled release pharmaceutical composition formulated with one or more alkalizers soluble in aqueous phase at physiological pH conditions.
그러나, 상기 선행기술은 불활성, 친수성, 또는 지질 매트릭스 또는 이들의 혼합 매트릭스를 사용함으로써, 매트릭스의 특성상 원하는 활성물질의 방출을 이룩하기 위해서 방출조절물질의 첨가를 필요로 하고 있다. 또한, 상기 선행기술에 따른 약제학적 조성물의 제조시, 매트릭스를 제조하는 공정에서의 연합시간, 사용되는 연합장치, 건조조건, 입자크기 등 많은 변수들이 활성물질의 방출에 영향을 미쳐 제조공정에 따른 제형의 균일성을 확보하는데 어려운 점이 있다.However, the prior art requires the addition of release modifiers to achieve the release of the desired active substance by the nature of the matrix, by using inert, hydrophilic, or lipid matrices or mixed matrices thereof. In addition, in the preparation of the pharmaceutical composition according to the prior art, many variables such as the association time in the process for preparing the matrix, the association apparatus used, drying conditions, particle size, etc. affect the release of the active material, It is difficult to ensure uniformity of the formulation.
또한, 한국특허공개 제2004-5257호에는 불활성 코어, 서방출성 약물층, 서방출 코팅제어막 및 속방출성 약물층으로 이루어진 염산슈도에페드린 및 염산세티리진을 함유하는 경구투여 약제학적 조성물이 개시되어 있다. 미국특허 제6,171,618호 및 제6,537,573호에는 슈도에페드린 HCl, 무수 유당, 칼슘 포스페이트 이염기, 에칠셀룰로오스, 포비돈, 이소프로필 알콜, 에탄올, 소듐 클로라이드 및 마그네슘 클로라이드를 포함하는 용액을 과립으로 만들고 타정하여 정제 코어를 제조하고, 상기 제조된 정제 코어에 슈도에페드린 HCl, 에칠셀룰로오스, 셀룰로오스 아세테이트, 글리세린 95%, 정제수, 이소프로필 알콜, 에탄올 및 아세톤을 포함하는 막 코 팅액을 분사하여 코팅하고, 여기에 세티리진 HCl과 슈도에페드린 HCl을 포함하는 용액으로 코팅하는 단계를 포함하는 방법에 의하여 제조되는 세티리진과 슈도에페드린을 함유하는 고형 제제가 개시되어 있다. 그러나, 슈도에페드린만을 포함하는 서방출성 약제학적 조성물은 개시되어 있지 않고 슈도에페드린과 세티리진의 복합 약물을 포함하는 서방출성 조성물만이 개시되어 있다. 그러나, 이 복합 서방출성 조성물은 복잡한 제조공정을 거쳐서 제조될 뿐만 아니라 상기 조성물을 제조하는데 사용되는 원료 물질이 상대적으로 많아 제조비용이 증가하고 생체내에 유해 물질이 포함되어질 가능성이 높다. In addition, Korean Patent Publication No. 2004-5257 discloses an oral administration pharmaceutical composition containing pseudoephedrine hydrochloride and cetirizine hydrochloride comprising an inert core, a sustained release drug layer, a sustained release coating control film, and a rapid release drug layer. . U.S. Pat.Nos. 6,171,618 and 6,537,573 describe tablet cores by granulating and tableting a solution comprising pseudoephedrine HCl, anhydrous lactose, calcium phosphate dibasic, ethylcellulose, povidone, isopropyl alcohol, ethanol, sodium chloride and magnesium chloride To the prepared tablet core, sprayed and coated with a membrane coating solution comprising pseudoephedrine HCl, ethylcellulose, cellulose acetate, glycerin 95%, purified water, isopropyl alcohol, ethanol and acetone, and to which there are cetirizine HCl and pseudoephedrine A solid formulation containing cetirizine and pseudoephedrine prepared by a method comprising coating with a solution comprising HCl is disclosed. However, no sustained release pharmaceutical composition comprising only pseudoephedrine is disclosed and only a sustained release composition comprising a combined drug of pseudoephedrine and cetirizine is disclosed. However, the composite sustained-release composition is not only manufactured through a complicated manufacturing process but also has a relatively large amount of raw materials used to prepare the composition, which increases the manufacturing cost and is likely to contain harmful substances in vivo.
따라서, 별도의 방출조절 물질의 첨가 없이, 간단한 방법으로 제조할 수 있는 슈도에페드린 또는 그의 염의 방출제어형 약제학적 조성물의 개발이 당업계에 요구된다.Accordingly, there is a need in the art for the development of controlled release pharmaceutical compositions of pseudoephedrine or salts thereof which can be prepared in a simple manner without the addition of a separate release controlling substance.
본 발명은 소량의 에칠셀룰로오스를 사용함으로써, 별도의 방출조절 물질을 사용함이 없이 슈도에페드린 또는 그의 염의 생체내에서의 방출을 효과적으로 조절할 수 있으며, 제조공정이 단순하여 제품의 균일성을 효과적으로 유지할 수 있는 방출제어형 약제학적 조성물을 제공한다.The present invention can effectively control the release of pseudoephedrine or its salts in vivo without using a separate release control material by using a small amount of ethyl cellulose, and the manufacturing process is simple, the release can effectively maintain the uniformity of the product Provided are controlled pharmaceutical compositions.
따라서, 본 발명은 슈도에페드린 또는 그의 염을 포함하는 경구용 약제학적 조성물을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide an oral pharmaceutical composition comprising pseudoephedrine or a salt thereof.
본 발명의 일 태양에 따라, 코어; 치료학적으로 유효한 양의 슈도에페드린 또는 그의 염이 상기 코어 상에 코팅된 약물-코팅 층; 및 조성물 총 중량에 대하여 1.5 ∼ 5 중량%의 에칠셀룰로오스가 상기 약물-코팅 층 상에 코팅된 방출-제어 층을 포함하는 경구용 약제학적 조성물이 제공된다.According to one aspect of the invention, a core; A drug-coating layer coated on said core with a therapeutically effective amount of pseudoephedrine or a salt thereof; And a release-controlling layer wherein 1.5-5% by weight of ethylcellulose relative to the total weight of the composition is coated on the drug-coating layer.
본 발명의 약제학적 조성물은 소량 즉, 5 중량% 이하의 에칠셀룰로오스를 사용함으로써, 별도의 방출조절 물질을 사용함이 없이 슈도에페드린 또는 그의 염의 생체내에서의 방출을 효과적으로 조절할 수 있으며, 1일 투여 횟수를 줄일 수 있다. 또한, 본 발명의 약제학적 조성물은 다양한 중합체를 사용하는 매트릭스형 방출제어 조성물에 비해 용출율의 변화가 적으므로, 위장관 운동 등의 생체내 인자에 의한 영향을 줄일 수 있을 뿐 아니라, 제조공정이 단순하여 제품의 균일성을 효과적으로 확보할 수 있다. The pharmaceutical composition of the present invention can effectively control the release of pseudoephedrine or its salts in vivo without using a separate release controlling substance by using a small amount, that is, 5 wt% or less of ethylcellulose, and the frequency of daily administration Can be reduced. In addition, the pharmaceutical composition of the present invention has less change in dissolution rate compared to the matrix type release control composition using various polymers, and therefore, the effect of in vivo factors such as gastrointestinal motility can be reduced, and the manufacturing process is simple. Product uniformity can be effectively ensured.
본 발명의 조성물에 사용되는 상기 코어 물질로는 약제학 분야에서 통상적으로 사용되는 코어물질을 사용할 수 있으며, 예를 들면, Non-pareilTM, Nu-CoreTM, Nu-PareilTM 등의 슈가 스피어(sugar sphere)를 사용할 수 있으며, 옥수수 전분 등이 혼합된 슈가 스피어를 사용할 수도 있다. 상기 코어의 입자크기는 0.5 mm 이상인 것이 바람직하며, 1,000 ∼ 1,500㎛ 인 것이 더욱 바람직하며, 그 형태는 구형이 바람직하다. As the core material used in the composition of the present invention, a core material commonly used in the pharmaceutical field may be used, and for example, sugar spheres such as Non-pareil ™ , Nu-Core ™ , Nu-Pareil ™, and the like (sugar) sphere) and sugar spheres mixed with corn starch or the like may be used. It is preferable that the particle size of the said core is 0.5 mm or more, It is more preferable that it is 1,000-1,500 micrometers, The form is preferable spherical shape.
상기 약물-코팅 층은 치료학적으로 유효한 양의 슈도에페드린 또는 그의 염을 적절한 용매, 예를 들어 물에 용해시켜 제조한 용액을 통상의 방법, 예를 들어 유동층 코팅법 등에 따라 코어 상에 코팅함으로써 형성시킬 수 있다. 상기 치료학 적으로 유효한 양은 120 ∼ 240 mg/day 일 수 있으며, 단위 투여 형태(제형)는 60∼ 120 mg의 슈도에페드린을 포함할 수 있다. 슈도에페드린의 염으로는 통상의 산부가염, 예를 들어 염산염 및 설페이트염 등을 포함한다.The drug-coating layer may be formed by coating a solution prepared by dissolving a therapeutically effective amount of pseudoephedrine or a salt thereof in a suitable solvent such as water on a core according to a conventional method such as fluidized bed coating or the like. Can be. The therapeutically effective amount may be 120-240 mg / day, and the unit dosage form (formulation) may include 60-120 mg of pseudoephedrine. Salts of pseudoephedrine include common acid addition salts such as hydrochloride and sulfate salts and the like.
본 발명의 조성물은 조성물 총 중량에 대하여 1.5 ∼ 5 중량%의 에칠셀룰로오스가 상기 약물-코팅 층상에 코팅된 방출-제어 층을 포함한다. 에칠셀룰로오스는 점도에 따른 형태를 모두 사용할 수 있으며 (점도에 따른 분류 상품명: Ethocl 4 cps, 7 cps,10 cps,14cps, 20 cps, 45 cps, 100 cps) 실시예와 같이 에칠셀룰로오스의 양의 변화와 점도의 변화에 따라 슈도에페드린 또는 그 염의 방출을 효과적으로 조절할 수 있다.The composition of the present invention comprises a release-controlling layer coated on said drug-coating layer with 1.5-5% by weight of ethylcellulose relative to the total weight of the composition. Ethyl cellulose can be used in all forms according to the viscosity (classification according to viscosity: Ethocl 4 cps, 7 cps, 10 cps, 14 cps, 20 cps, 45 cps, 100 cps) change in the amount of ethyl cellulose as in the embodiment The release of pseudoephedrine or its salts can be effectively controlled by the change of the viscosity.
또한, 본 발명의 상기 방출-제어 층은 탈크, 경질무수규산, 스테아린산마그네슘 및 산화티탄과 같은 활택제를 더 포함할 수 있다. 상기 활택제는 바람직하게는, 스테아린산 또는 스테아린산마그네슘이 될 수 있다. 활택제는 슈도에페린드린의 약물의 방출을 지연시킬 수 있는 동시에 사용되는 에칠셀룰로오스의 양을 줄이는 효과가 있다. 본 발명의 조성물에 사용되는 상기 활택제는 조성물 총 중량에 대하여 1 내지 5 중량 %, 바람직하게는 1 내지 3 중량 % 포함되는 것이 바람직하다. In addition, the release-controlling layer of the present invention may further comprise lubricants such as talc, light silicic anhydride, magnesium stearate and titanium oxide. The lubricant may preferably be stearic acid or magnesium stearate. Glidants can delay the release of drugs of pseudoephedrine and at the same time reduce the amount of ethylcellulose used. The lubricant used in the composition of the present invention is preferably included 1 to 5% by weight, preferably 1 to 3% by weight based on the total weight of the composition.
본 발명의 조성물은 통상적인 코팅 방법, 예를 들어 유동층 코팅방법에 의해 제조할 수 있다. 예를 들어, 유동층 과립기에 먼저 코어물질을 유동화시키면서, 슈도에페드린 또는 그의 염을 물 또는 적절한 용매에 용해 또는 현탁시켜 상기 코어상에 분무하면서 피복시킨 후, 에칠셀룰로오스 또는 에칠셀룰로오스 및 활택제를 적절한 유기용매에 용해시켜 분사함으로써 본 발명의 조성물을 제조할 수 있다.The compositions of the present invention can be prepared by conventional coating methods, for example fluidized bed coating methods. For example, the fluidized bed granulator is first fluidized with a core material, while pseudoephedrine or a salt thereof is dissolved or suspended in water or a suitable solvent to be coated on the core while spraying, and then ethyl cellulose or ethyl cellulose and a lubricant are coated with a suitable organic solvent. The composition of this invention can be manufactured by melt | dissolving in and spraying.
본 발명의 조성물은 상기 방출 제어-층 상에 슈도에페드린과 복합 투여 가능한 약물이 더 코팅되어질 수 있다. 상기 약물의 예에는 세티리진 또는 그의 염이 포함된다. 세티리진의 염으로는 통상의 산 부가염, 예를 들면 염산염 등을 포함한다. 바람직하게는, 상기 세티리진은 속방출성 성분으로서 상기 방출 제어-층 상에 코팅되는 것이다. 상기 방출 제어-층에 더 코팅되는 약물, 예를 들면 세티리진은 약제학적으로 유효한 양을 적절한 용매, 예를 들어 물에 용해시켜 제조한 용액을 통상의 방법, 예를 들어 유동층 코팅법 등에 따라 코어 상에 코팅함으로써 코팅되어질 수 있다. 상기 치료학적으로 유효한 양은 세티리진의 경우 5 ∼ 10 mg/day 일 수 있으며, 단위 투여 형태(제형)는 2.5 ∼ 10 mg의 세티리진을 포함할 수 있다. The composition of the present invention may be further coated with a drug that can be administered in combination with pseudoephedrine on the release control layer. Examples of such drugs include cetirizine or a salt thereof. Salts of cetirizine include conventional acid addition salts such as hydrochloride. Preferably, the cetirizine is to be coated on the release control layer as a rapid release component. Drugs, such as cetirizine, which are further coated on the release control layer, can be prepared by dissolving a solution prepared by dissolving a pharmaceutically effective amount in an appropriate solvent, for example, water, according to a conventional method, for example, fluidized bed coating. It can be coated by coating on. The therapeutically effective amount may be 5-10 mg / day for cetirizine, and the unit dosage form (formulation) may include 2.5-10 mg of cetirizine.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.
실시예 Example
실시예 1Example 1
유동층 과립기에 슈가 스피어 700g을 유동시키면서 슈도에페드린 1,246g을 물 935g에 녹인 액을 흡기온도 및 배기온도를 각각 30 ℃ 및 26 ℃에서 분당 5.5g 씩 분사시켜 약물을 피복하였다. 피복된 입자 1kg을 유동층 코팅기에 넣고, 에칠셀룰로오스 45 cps 50g을 에탄올 1,000g에 용해시킨 용액을 흡기온도 및 배기온도를 각각 32 ℃ 및 28 ℃에서 분당 5.5g 씩 분사시켜 피복시킨 다음, 공정 중 피복된 에칠셀룰로오스의 양이 2%, 3%, 4%, 5% 되는 시기에 시료를 취하여 2호 캅셀에 충 진하였다.The drug was coated by spraying 700 g of sugar spear in the fluidized bed granulator with 1,246 g of pseudoephedrine in 935 g of water and spraying 5.5 g per minute at 30 ° C and 26 ° C, respectively. 1 kg of coated particles were placed in a fluidized bed coater, and a solution in which 50 g of ethyl cellulose was dissolved in 1,000 g of ethanol was coated by spraying 5.5 g per minute at intake temperature and exhaust temperature at 32 ° C. and 28 ° C., respectively, followed by in-process coating. Samples were taken and filled into No. 2 capsules at the 2%, 3%, 4%, and 5% amounts of ethylcellulose.
실시예 2Example 2
유동층 과립기에 슈가 스피어 700g을 유동시키면서 슈도에페드린 1,246g을 물 935g에 녹인 액을 흡기온도 및 배기온도를 각각 30 ℃ 및 26 ℃에서 분당 5.5g 씩 분사시켜 약물을 피복하였다. 피복된 입자 600g을 유동층 코팅기에 나누어 넣고, 에탄올 360g에 에칠셀룰로오스 100 cps 18g을 녹인 용액에 각각 12 g의 탈크, 스테아린산마그네슘, 경질무수규산, 및 산화티탄을 각각 현탁하여 흡기온도 및 배기온도를 각각 32 ℃ 및 28 ℃에서 분당 5.5g 씩 분사시켜 피복하여 2호 캅셀에 충진하였다.The drug was coated by spraying 700 g of sugar spear in the fluidized bed granulator with 1,246 g of pseudoephedrine in 935 g of water and spraying 5.5 g per minute at 30 ° C and 26 ° C, respectively. 600 g of coated particles were divided into a fluidized bed coater, and 12 g of talc, magnesium stearate, light silicic anhydride, and titanium oxide were respectively suspended in a solution of 18 g of
실시예 3Example 3
유동층 과립기에 슈가 스피어 700g을 유동시키면서 슈도에페드린 1,246g을 물 935g에 녹인 액을 흡기온도 및 배기온도를 각각 30 ℃ 및 26 ℃에서 분당 5.5g 씩 분사시켜 약물을 피복하였다. 피복된 입자 600g을 유동층 코팅기에 나누어 넣고, 각각 18g의 에칠셀룰로오스 10cps, 45cps 및 100cps을 에탄올 360g에 각각 녹인 용액을 흡기온도 및 배기온도를 각각 32 ℃ 및 28 ℃에서 분당 5.5g 씩 분사시켜 피복하여 2호 캅셀에 충진하였다.The drug was coated by spraying 700 g of sugar spear in the fluidized bed granulator with 1,246 g of pseudoephedrine in 935 g of water and spraying 5.5 g per minute at 30 ° C and 26 ° C, respectively. 600 g of coated particles were divided into a fluidized bed coater, and 18 g of ethylcellulose 10cps, 45cps, and 100cps were dissolved in 360g of ethanol, respectively, and sprayed at an intake temperature and an exhaust temperature of 5.5g / min at 32 ° C and 28 ° C, respectively. 2 capsules were filled.
실시예 4Example 4
유동층 과립기에 슈가 스피어 700g을 유동시키면서 슈도에페드린 1,246g을 물 935g에 녹인 액을 흡기온도 및 배기온도 각각 30 ℃ 및 26 ℃에서 분당 5.5g 씩 분사시켜 약물을 피복하였다. 피복된 입자에 에칠셀룰로오스 100 cps 57g 및 스테아린산 마그네슘 38g을 에탄올 570g에 용해 또는 현탁시켜 분무 피복하여 서방성 코어를 형성하였다. 얻어진 슈도에페드린 서방성 코어에 염산 세티리진 57g 및 히드록시프로필메칠셀룰로오스 57g을 에탄올 1,140g에 용해시킨 용액을 에탄올 360g에 각각 녹인 용액을 흡기온도 및 배기온도를 각각 32 ℃ 및 28 ℃에서 분당 5.5g 씩 분사시켜 피복하여 2호 캅셀에 충진하였다.The drug was coated by spraying a liquid of 1,246 g of pseudoephedrine in 935 g of water while flowing 700 g of sugar spear in a fluidized bed granulator at 5.5 ° C and 26 ° C, respectively, at a temperature of 30 ° C and 26 ° C. 57 g of
시험예. 용출시험Test example. Dissolution Test
실시예 1, 2,3 및 4에서 제조한 캅셀의 용출시험을 대한약전 일반시험법 용출시험법 중 제 2법에 따라 37 ℃에서 아래의 조건으로 실시하였으며, 실시예 1,2 및 3에 대한 결과는 표 1 및 도1 ∼ 도3과 같고, 실시예 4에 대한 결과는 표 2와 같다. The dissolution test of the capsules prepared in Examples 1, 2, 3 and 4 was carried out under the following conditions at 37 ° C. in accordance with the second method of the Korean Pharmacopoeia General Test Method Dissolution Test Method, The results are shown in Table 1 and FIGS. 1 to 3, and the results for Example 4 are shown in Table 2.
1. 용출시험 조건 1. Dissolution test conditions
(1) 회전속도 : 125 rpm (1) Speed: 125 rpm
(2) 용출액 채취시간 : 염산 슈도에페드린 1 시간, 4 시간, 8 시간, 12 시간(2) Eluate collection time: 1 hour, 4 hours, 8 hours, 12 hours of pseudoephedrine hydrochloride
염산 세티리진 1 시간 (실시예 4의 경우)Cetirizine hydrochloride 1 hour (for Example 4)
(3) 용출액 : 제1액, 500 mL (3) Eluent: first solution, 500 mL
(4) 검액 채취량 : 각 시점에서 5 mL를 취한 후, 용출액 동량으로 보충하였다. (4) Sampling Amount: 5 mL was taken at each time point, and then replenished with the same amount of eluate.
2. 표준액의 조제 2. Preparation of Standard Solution
50 mL 용량 플라스크에 염산슈도에페드린 표준품 120 mg을 정밀히 취하여 메탄올로 녹인 후 표선한 액 5 mL를 취하여 50 mL 용량 플라스크로 옮기고 용출액으로 표선하여 표준액으로 하였다. 120 mg of pseudoephedrine hydrochloride was precisely taken into a 50 mL flask, dissolved in methanol, and 5 mL of the labeled solution was transferred to a 50 mL flask, and labeled with an eluent to obtain a standard solution.
실시예 4의 경우, 50 mL 용량 플라스크에 염산세티리진 표준품 5 mg을 정밀히 취하여 메탄올로 녹인 후 표선한 액 5 mL를 취하여 50 mL 용량 플라스크로 옮기고 용출액으로 표선하여 표준액으로 하였다.In the case of Example 4, 5 mg of cetirizine hydrochloride standard was precisely taken into a 50 mL volumetric flask, dissolved in methanol, and 5 mL of the marked solution was taken into a 50 mL volumetric flask, and labeled with an eluent to obtain a standard solution.
3. 검액의 조제 3. Preparation of Test Solution
본 발명의 제제 6 캡슐을 가지고 용출시험기에 1 캡슐씩을 넣고 용출 개시 후, 1시간, 4시간 , 8시간 및 12 시간이 경과한 시점에서 용출액을 각각 취하여 여과한 여액을 검액으로 하였다. With 6 capsules of the formulation of the present invention, 1 capsule was added to the dissolution tester, and the eluate was taken at 1 hour, 4 hours, 8 hours, and 12 hours after the start of dissolution, and the filtrate was filtered.
4. 분석 조건4. Analysis condition
(1) 칼럼 : 안지름 약 4.6 mm, 길이 250 mm인 스테인레스강관에 5 ㎛의 액체크로마토그래피용 옥타데실실릴화한 실리카겔을 충전한 칼럼 또는 이와 유사한 칼럼. (1) Column: A column or a similar column packed with a stainless steel pipe having an inner diameter of about 4.6 mm and a length of 250 mm, filled with octadecylsilylated silica gel for 5 µm liquid chromatography.
(2) 이동상 : 헵탄설폰산나트륨 0.2 g을 물 470 mL에 녹인 후 아세토니트릴 630 mL를 추가하고 1N-황산으로 pH 2.5로 맞추어 5분 동안의 초음파로 기체를 제거하였다. (2) Mobile phase: 0.2 g of sodium heptane sulfonate was dissolved in 470 mL of water, and then 630 mL of acetonitrile was added, and pH was adjusted to 2.5 with 1N-sulfuric acid to remove gas by ultrasonication for 5 minutes.
(3) 검출기 : 자외가시부흡광광도계 210nm (3) Detector: ultraviolet visible absorption spectrophotometer 210nm
(4) 유출속도 : 1.0 mL/min (4) Outflow rate: 1.0 mL / min
(5) 주입량 : 20 ㎕ (5) Injection amount: 20 μl
상기 표1 및 도1 내지 도3의 결과에서 확인할 수 있는 바와 같이, 방출 제어-층에 포함되는 에칠셀룰로오스의 함량 및 그의 점도를 적절히 변화시킴으로써 슈도에페드린의 방출을 효과적으로 조절할 수 있었다. 또한, 방출 제어-층에 에칠셀룰로오스와 함께 적절한 활택제를 더 포함시킴으로써 슈도에페드린의 방출을 효과적으로 조절할 수 있었으며, 아울러 사용되는 에칠셀룰로오스의 양을 감소시킬 수 있었다. 따라서, 에칠셀룰로오스의 사용량을 줄임으로써, 에칠셀룰로오스를 용해하는데 사용되는 용매의 사용량을 줄일 수 있고 그에 따라 생체내 유해한 인자를 감소시킬 수 있는 동시에 제조 공정을 간단하게 할 수 있다.As can be seen from Table 1 and the results of FIGS. 1 to 3, the release of pseudoephedrine could be effectively controlled by appropriately changing the content and viscosity of the ethyl cellulose contained in the emission control layer. In addition, the inclusion of an appropriate lubricant in addition to the ethylcellulose in the release control layer was able to effectively control the release of pseudoephedrine, and also to reduce the amount of ethylcellulose used. Thus, by reducing the amount of ethyl cellulose used, the amount of solvent used to dissolve the ethyl cellulose can be reduced, thereby reducing harmful factors in vivo and simplifying the manufacturing process.
표 2에 나타낸 바와 같이, 방출제어-층 상에 염산세티리진 속방출성 제제를 코팅하더라도 염산슈도에페드린의 서방출성은 변화되지 않으면서도, 염산세티리진 은 속방출성으로 용출시킬 수 있었다. 이는 본 발명의 서방출성 염산슈도에페드린 제제가 세티리진과의 복합 제제로서도 유용하게 이용될 수 있다는 것을 나타낸다. As shown in Table 2, even when the cetirizine hydrochloride release agent was coated on the release control layer, cetirizine hydrochloride could be eluted with rapid release, while the sustained release property of pseudoephedrine hydrochloride was not changed. This shows that the sustained-release pseudohydrophedrine hydrochloride of the present invention can be usefully used as a co-formulation with cetirizine.
본 발명에 따른 약제학적 조성물은 소량의 에칠셀룰로오스를 사용함으로써, 별도의 방출조절 물질을 사용함이 없이 슈도에페드린 또는 그의 염의 생체내에서의 방출을 효과적으로 조절할 수 있으며, 제조공정이 단순하여 제품의 균일성을 효과적으로 유지할 수 있다.The pharmaceutical composition according to the present invention can effectively control the release of pseudoephedrine or its salts in vivo without using a separate release controlling substance by using a small amount of ethyl cellulose, and the uniformity of the product due to the simple manufacturing process Can be effectively maintained.
Claims (6)
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