KR101701203B1 - Ultrafine particles of inclusion complex of peracetylated cyclodextrin and drug using supercritical carbon dioxide, preparation method thereof and use thereof - Google Patents
Ultrafine particles of inclusion complex of peracetylated cyclodextrin and drug using supercritical carbon dioxide, preparation method thereof and use thereof Download PDFInfo
- Publication number
- KR101701203B1 KR101701203B1 KR1020140140036A KR20140140036A KR101701203B1 KR 101701203 B1 KR101701203 B1 KR 101701203B1 KR 1020140140036 A KR1020140140036 A KR 1020140140036A KR 20140140036 A KR20140140036 A KR 20140140036A KR 101701203 B1 KR101701203 B1 KR 101701203B1
- Authority
- KR
- South Korea
- Prior art keywords
- superfine
- carbon dioxide
- drug
- supercritical carbon
- cyclodextrin
- Prior art date
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- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 239000001569 carbon dioxide Substances 0.000 title claims abstract description 40
- 229910002092 carbon dioxide Inorganic materials 0.000 title claims abstract description 40
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 31
- 239000003814 drug Substances 0.000 title abstract description 44
- 229940079593 drug Drugs 0.000 title abstract description 43
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title abstract description 14
- 238000002360 preparation method Methods 0.000 title description 9
- 239000011882 ultra-fine particle Substances 0.000 title description 8
- 239000002245 particle Substances 0.000 claims abstract description 47
- 239000000203 mixture Substances 0.000 claims abstract description 22
- 239000008203 oral pharmaceutical composition Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 25
- 229960000381 omeprazole Drugs 0.000 claims description 25
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 21
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000001116 FEMA 4028 Substances 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 7
- 229960004853 betadex Drugs 0.000 claims description 7
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 5
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000007884 disintegrant Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 3
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims 5
- 238000004519 manufacturing process Methods 0.000 abstract description 13
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- 239000012808 vapor phase Substances 0.000 abstract description 2
- SBQLYHNEIUGQKH-UHFFFAOYSA-N omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 description 20
- 238000001046 rapid expansion of supercritical solution Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
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- 206010002383 Angina Pectoris Diseases 0.000 description 5
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 5
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 238000011282 treatment Methods 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
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- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 2
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- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QWYCCHGHTLOPJM-UHFFFAOYSA-N [Mo].C(=O)=O Chemical compound [Mo].C(=O)=O QWYCCHGHTLOPJM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000004480 active ingredient Substances 0.000 description 2
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 2
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- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 2
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
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- A—HUMAN NECESSITIES
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
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Abstract
본 발명은 초임계이산화탄소를 이용한 퍼아세틸레이티드 사이클로덱스트린 및 약물의 포접체 초미립자 및 이의 제조방법에 관한 것이다. 또한, 본 발명은 상기 포접체 초미립자를 포함하는 경구용 약제 조성물에 관한 것이다. 본 발명에 따른 포접체 초미립자는, 초임계이산화탄소 내의 퍼아세틸레이티드 사이클로덱스트린(PAc-CD) 및 약물의 혼합물을 모세관 노즐을 통하여 대기상 또는 용액상으로 방출하여 제조됨으로써, 간단하고, 경제적 방법으로 포접체 초미립자을 제조할 수 있고, 상기 포접체 초미립자는 포접율 및 분산성이 우수하여 경구용 조성물로 이용될 수 있다.TECHNICAL FIELD The present invention relates to peracetylated cyclodextrins using supercritical carbon dioxide and superabsorbent superfine particles of a drug and a method for producing the same. The present invention also relates to an oral pharmaceutical composition comprising the superfine superfine particle. The superfine superfine particle according to the present invention is produced by discharging a mixture of peracetylated cyclodextrin (PAc-CD) and drug in supercritical carbon dioxide through a capillary nozzle in a vapor phase or a solution phase, Microporous superfine particles can be produced, and the superfine superfine particles are excellent in porosity and dispersibility and can be used as an oral composition.
Description
본 발명은 초임계이산화탄소를 이용한 퍼아세틸레이티드 사이클로덱스트린 및 약물의 포접체 초미립자 및 이의 제조방법에 관한 것이다.TECHNICAL FIELD The present invention relates to peracetylated cyclodextrins using supercritical carbon dioxide and superabsorbent superfine particles of a drug and a method for producing the same.
또한, 본 발명은 상기 포접체 초미립자를 포함하는 경구용 약제 조성물에 관한 것이다.The present invention also relates to an oral pharmaceutical composition comprising the superfine superfine particle.
약물 중 하나인 몰시도민(또는 N-(에톡시카르보닐)-3-(4-모르폴리닐)시드논 이민)은 대표적인 신규한 항 협심증 물질, 시드논이민으로 알려져 있으며, 특허 제 6734호에 의한 특정 약물로 알려져 있다. 이 화합물은 혈관의 평활근 완화와 혈소판 활성화의 초기상태 저해를 유발하는 모든 형태의 협심증 발작 예방 치료에 특히 유용하게 이용된다. 이 화합물의 활성은 그의 생체변형 기간 중 일산화질소(NO) 라디칼을 직접 방출할 수 있게 하는 능력에 기인한다. 보다 상세하게는 몰시도민은 프로드러그(기존 약물의 치료 효과를 향상시키기 위한 약물)이다. 경구 투여 후 몰시도민은 완전히 흡수되고, 간에서 효소적 변형(가수분해 및 탈카르복실화 반응)을 일으키게 된다. 생성된 SIN-1(Linsidiomine, 3-morpholino-sydnonimine)은 그 스스로 빠르게 혈액에서 효소적 간섭없이 SIN-1A(N-nitroso-N-morpholino-aminoacetonitrile)로 변형된다. SIN-1 및 SIN-1A는 몰시도민의 활성 대사산물인 것이다. 또한, SIN-1A는 산화에 의해 일산화질소(NO)의 방출로 불활성의 SIN-1C(N-cyano-methylamino-morpholine)로 분해된다. SIN-1C는 번드 로센크란쯔(Bernd Rosenkranz)의 몰시도민의 임상적 약력학(Clinical Pharmacokinetics of Molsidomine), Clinical Pharmacokinet. 1996, May; 30(5)372-384 등의 문헌에 기술된 바와 같이 간에서 그 스스로가 대사하게 된다.One of the drugs, molocimin (or N- (ethoxycarbonyl) -3- (4-morpholinyl) cydononimine) is known as a representative novel anti-angina drug, seednimine, Is known as a specific drug. This compound is particularly useful in the prevention of angina pectoris in all forms of angiotomy and platelet activation inhibition. The activity of this compound is due to its ability to directly release nitrogen monoxide (NO) radicals during its bio-modification period. More specifically, morpholine is a prodrug (a drug for improving the therapeutic effect of existing drugs). After oral administration, the mordantine is completely absorbed and causes enzymatic modification (hydrolysis and decarboxylation) in the liver. The resulting SIN-1 (Linsidiomine, 3-morpholino-sydnonimine) itself transforms rapidly into SIN-1A (N-nitroso-N-morpholino-aminoacetonitrile) without enzymatic interference in the blood. SIN-1 and SIN-1A are the active metabolites of mollcimin. In addition, SIN-1A is degraded to an inactive SIN-1C (N-cyano-methylamino-morpholine) by the release of nitrogen monoxide (NO) by oxidation. SIN-1C is the clinical pharmacokinetics of Molsidomine of Bernd Rosenkranz, Clinical Pharmacokinet. 1996, May; 30 (5) 372-384, as described in the literature.
몰시도민은 2mg 또는 4mg 복용량을 함유하는 가분의 타블렛 형태로 현재 시판되고 있으며, 일반적으로 진력에 따른 협심증의 치료에는 1일에 3회 투여되고, 휴식 협심증 또는 심각한 진력의 협심증 치료에는 1일에 4회 투여된다. 더욱이 최근에는 하루에 2회 투여되는 8mg의 몰시도민의 신규 서방형(Controlled Released Type) 생약 제형이 협심증의 장기간 예방적 치료용으로 제안되고 있다. 이 제형에 있어, 몰시도민의 최대 혈장 농도는 투여 후 1∼3시간 사이에 관찰된다. 몰시도민은 일반적으로 4mg 복용량으로 4∼5시간 동안, 그리고 8mg 복용량으로는 10∼12시간 동안 작용한다. 일반적으로, 환자의 관점에서 장시간의 치료적 효과를 갖는 생약의 제형이 유리한데, 이는 하루에 약물을 섭취해야 하는 횟수를 감소시키고, 이로 인하여 환자를 보다 편리하게 할 수 있기 때문이다. Molotriamine is currently marketed in the form of a mild tablet containing a 2 mg or 4 mg dose and is generally administered three times per day for the treatment of angina pectoris according to power, and for angina pectoris of the rest or severe labor, Lt; / RTI > Furthermore, recently, a new controlled-release type herbal formulation of 8 mg of mothiamine administered twice a day has been proposed for long-term prophylactic treatment of angina. In this formulation, the maximum plasma concentration of molocidin is observed between 1 and 3 hours after administration. Molimidimines generally work for 4 to 5 hours at 4 mg dose and for 10 to 12 hours at 8 mg dose. In general, formulations of herbal medicines with long-term therapeutic effects from the patient's point of view are advantageous because they reduce the number of times a drug is consumed per day, which makes the patient more convenient.
캅토 프릴, (captopril, 1-[(2S)-3-메르캅토-2-메틸 프로피오닐]-L-프롤린)은 경구용 안지오텐신 전환 효소의 활성 억제제로서 고혈압과 울혈성 심부전의 치료 등에 널리 사용되어왔다. 경구 투여 후, 항 고혈압 작용의 지속 시간이 6-8 시간으로 임상적으로 38-75 mg씩 1일 3회의 투여가 필요하다. 또한, 그 효과와 용도로 인해 그 동안 캅토 프릴의 다양한 약물 방출 조절 방법이 연구되어 왔다.(Captopril, 1 - [(2S) -3-mercapto-2-methylpropionyl] -L-proline) is widely used for the treatment of hypertension and congestive heart failure as an inhibitor of the activity of oral angiotensin converting enzyme come. After oral administration, the duration of antihypertensive action is 6-8 hours, and clinically 38-75 mg three times a day is necessary. In addition, due to its effectiveness and use, various methods of modulating drug release of captopril have been studied.
살부타몰황산염(salbutamol sulfate)은 빠르게 반응하는 교감신경 β2수용체 작용제이며 천식과 만성 폐쇄성 폐질환과 같은 기관지 경련을 가라앉히는 데에 사용된다.Salbutamol sulfate is a fast-acting sympathetic β2 receptor agonist and is used to relieve bronchospasm, such as asthma and chronic obstructive pulmonary disease.
오메프라졸(OMP)은 프로톤 펌프의 억제제로서 소화성 궤양, 식도염, 미란성 식도염, Zollinger-엘리슨 증후군, 십이지장궤양, 여러 내분비 선종, 소화 불량, 및 헬리코박터 파이로리 감염과 체계적인 비만 세포증 등의 치료에 광범위하게 사용 된다. OMP는 물에 난용성으로, 이것이 낮은 용해 속도와 함께 이 약물의 생체 이용률이 낮은 이유가 된다. 오메프라졸의 더 큰 단점은 열, 광, 수분, 용매, UV 광, 각종 염, 금속 이온 및 산성 매체, 심지어 코팅 배합물에 노출 시 불안정한 물리 화학적 특성에 있다. 이러한 불안정성과 용해도 한계를 극복하기 위하여 과거에 사이클로덱스트린(cyclodextrin)을 사용하거나, 분무건조, 냉동건조, 물리 혼합 등 여러 가지 방법들이 시도되어 왔다. OMP는 난용성 약물이지만 그것의 용해도 및 반감기는 산도에 따라 크게 달라진다.Omeprazole (OMP) is widely used for the treatment of peptic ulcer, esophagitis, erosive esophagitis, Zollinger-Ellison syndrome, duodenal ulcer, various endocrine adenomas, dyspepsia, and Helicobacter pylori infection and systemic mastocytosis as inhibitors of proton pumps . OMP is poorly soluble in water, which is why the drug has low bioavailability with low dissolution rate. A further disadvantage of omeprazole is its unstable physico-chemical properties upon exposure to heat, light, moisture, solvents, UV light, various salts, metal ions and acid media, and even coating formulations. In order to overcome this instability and solubility limit, various methods such as spray drying, freeze drying, and physical mixing have been attempted in the past using cyclodextrin. OMP is an insoluble drug, but its solubility and half-life depend greatly on acidity.
한편, 사이클로덱스트린(cyclodextrin)은 1891년 빌리어(Villier)에 의해 처음 발견된 포도당의 중합체로서, 6개 이상의 포도당이 알파-1,4-글루코사이드 결합(α-1,4-glucoside linkage)을 이룬 환상의 비환원성 말토올리고당이다. 특히, 6, 7, 8개의 포도당으로 이루어진 것을, 각각 알파-사이클로덱스트린(α-cyclodextrin), 베타-사이클로덱스트린(β-cyclodextrin), 감마-사이클로덱스트린(γ-cyclodextrin)이라고 한다. 사이클로덱스트린은 환상형의 도우넛 구조로 이루어져 있고, 내측에 소수성 공동을 분자 외부에는 친수성을 갖는 독특한 특성을 가지고 있다. 이러한 특성으로 인해 내측 공동에 각종 소수성 유기화합물을 인식하여 우수한 물성의 포접화합물을 형성할 수 있다. 이러한 성질을 갖는 사이클로덱스트린은 환경분야(문헌[Murai, S, et al., Environ. Sci. Technol., Vol. 32, pp. 782-787, 1998] 참조)에 이용되기도 하고, 소수성 항암제나 약물을 포접시켜서 약물 전달매체로서 약학분야([Hirayama, F., et al., Adv. Drug Del. Rev., Vol.36, pp.125-141, 1999] 참조)에 이용되기도 하며, 그 외에도 식품, 화장품, 농약 분야 등의 다양한 응용 분야에 사용되고 있는 우수한 생체적합성을 가진 물질로 알려져 있다(문헌[Szejtli, J. et al., Comprehensive supramolecular chemistry, vol. 3, Cyclodextrins, Pergamon, 1996] 참조). 이러한 연구들은 사이클로덱스트린의 포접능을 이용하여 불안정한 물질을 안정화하거나 용해도의 변화에 의한 용도 확대뿐 아니라, 특정 물질만을 인식하여 용이하게 분리할 수 있는 가능성을 제시하고 있다.Cyclodextrin, on the other hand, was first discovered by Villier in 1891 as a polymer of glucose, in which six or more sugars are linked by an alpha-1,4-glucoside linkage It is a cyclic non-reducing maltooligosaccharide. Particularly, it is called alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin each consisting of 6, 7 and 8 glucose. Cyclodextrins are composed of a donut structure in the form of a ring, and have a hydrophobic cavity inside and a hydrophilic property outside the molecule. Due to these characteristics, it is possible to recognize various hydrophobic organic compounds in the inner cavity and to form inclusion compounds of excellent physical properties. Cyclodextrins having such properties may be used in the environmental field (see Murai, S, et al., Environ. Sci. Technol., Vol. 32, pp. 782-787, 1998), and hydrophobic anticancer drugs (See Hirayama, F., et al., Adv. Drug Del. Rev., Vol. 36, pp. 125-141, 1999) as a drug delivery medium, (See, for example, Szejtli, J. et al., Comprehensive supramolecular chemistry, vol. 3, Cyclodextrins, Pergamon, 1996), which is used in various fields of applications such as cosmetics and agricultural chemicals. These studies suggest the possibility of not only stabilizing unstable substances by using the potency of cyclodextrin or expanding the use by changing the solubility, but also to recognize only specific substances and easily isolate them.
초임계이산화탄소는 단백질 추출, 생물량 변환반응(bioconversion)으로 유망하고, 고분자 합성, 및 의약품의 입자 공학에도 이용되고 있다. 최근에는 초임계이산화탄소내에서 퍼플루오로알킬 에스터 작용기를 작는 사이클로덱스트린(perfluoroalkyl ester functionalized cyclodextrin)과 약물의 포접체에 대한 연구(문헌 H.S. Ganapathy, M.Y. Lee, C. Park, K.T. Lim, J. Fluorine Chem. vol. 129 (2008) 1162-1166., H.S. Ganapathy, M.Y. Lee, M.H. Woo, Y.T. Jeong, K.T. Lim, Key Eng. Mater. Vol. 342 (2007) 493-496 참조)이 보고 된 바 있지만, 이 방법은 퍼플루오로알킬 에스터와 사이클로덱스트린과의 복잡한 제조과정을 포함하고, 불소계를 포함하므로 경구투여용으로는 부적합한 단점이 있다. 또한, 초임계이산화탄소에서 퍼아세틸레이티드 사이클로덱스트린과 친수성 약물인 몰시도민의 약물포접체 제조에 대하여 알려진바 있다. 그러나, 이 방법은 단순한 제조과정으로, 약물포접체 크기를 미세하게 조절하지 못하고 괴상으로 밖에 만들지 못하는 단점이 있다. Supercritical carbon dioxide is promising for protein extraction, bioconversion, polymer synthesis, and particle engineering of pharmaceuticals. Recently, a study on the perfluoroalkyl ester functionalized cyclodextrin and the porosity of drugs in supercritical carbon dioxide (HS Ganapathy, MY Lee, C. Park, KT Lim, J. Fluorine Chem 342 (2007) 493-496) have been reported, however, it has been reported that, in addition to the above, The method includes a complicated preparation process of a perfluoroalkyl ester and a cyclodextrin, and includes a fluorine-based method, which is disadvantageous for oral administration. It is also known to manufacture peracetylated cyclodextrins and suppositories for the hydrophilic drug morpholinium in supercritical carbon dioxide. However, this method is a simple manufacturing process, and has a disadvantage in that it can not control the size of the drug cartilage finely and can only make it into a blocky form.
한편, 초임계 유체에 용해된 물질을 급속팽창함으로서 미립자를 만드는 통상적인 방법은 RESS(rapid expansion of supercritical solutions)과 RESOLV(rapid expansion of supercritical solution into a liquid solvent) 방식이 있다. RESS 방법은 가압된 초임계 용액을 대기상으로 급속 팽창하는 방식에 근거한다. RESOLV 방법은 가압된 초임계 용액을 계면활성제가 포함된 외부용액, 주로 물 속으로 급속 팽창하는 방식에 근거한다. 그러나, 초임계 이산화탄소를 이용한 약물 포접체의 미립화 방법에 대해서는 보고된 바가 없다.On the other hand, a conventional method of making fine particles by rapidly expanding a substance dissolved in a supercritical fluid is a rapid expansion of supercritical solutions (RESS) and a rapid expansion of a supercritical solution into a liquid solvent (RESOLV). The RESS method is based on the rapid expansion of the pressurized supercritical solution to the atmosphere. The RESOLV method is based on the method of rapidly expanding the pressurized supercritical solution into an external solution containing a surfactant, mainly water. However, there has been no report on the atomization method of drug cartilage using supercritical carbon dioxide.
따라서, 무독성 초임계 이산화탄소 매질을 사용하여 초미립자 형태의 약물 포접체를 제조하는 방법에 대한 연구의 필요성이 절실히 요구되고 있다.Accordingly, there is a great demand for research on a method for producing ultrafine particle-type drug cartilage using a non-toxic supercritical carbon dioxide medium.
본 발명자들은 포접체 초미립자에 대해 탐색하던 중, 초임계이산화탄소 내의 퍼아세틸레이티드 사이클로덱스트린(PAc-CD) 및 약물의 혼합물을 모세관 노즐을 통하여 대기상 또는 용액상으로 방출할 경우, 간단하고 경제적 방법으로 포접체 초미립자을 제조할 수 있는 것을 확인하고, 본 발명을 완성하였다.The present inventors have found that when a superacetated cyclodextrin (PAc-CD) in a supercritical carbon dioxide and a mixture of a drug are released into a gas phase or a solution phase through a capillary nozzle while searching for superfine superfine particles, It was confirmed that the microporous superfine particles can be produced, and the present invention has been completed.
따라서, 본 발명은 초임계이산화탄소를 이용한 퍼아세틸레이티드 사이클로덱스트린 및 약물의 포접체 초미립자 및 이의 제조방법을 제공하고자 한다.Accordingly, the present invention provides peracetylated cyclodextrins and superabsorbent ultrafine particles of a drug using supercritical carbon dioxide, and a process for producing the same.
또한, 본 발명은 상기 포접체 초미립자를 포함하는 경구용 약제 조성물을 제공하고자 한다.The present invention also provides an oral pharmaceutical composition comprising the superfine superfine particle.
상기와 같은 목적을 달성하기 위해서,In order to achieve the above object,
본 발명은 The present invention
(1) 초임계이산화탄소 내에서 퍼아세틸레이티드 사이클로덱스트린(PAc-CD) 및 약물을 혼합하는 단계; 및 (2) 상기 혼합물을 모세관 노즐을 통하여 외부로 방출하는 단계를 포함하는, 포접체 초미립자의 제조방법을 제공한다. (1) mixing peracetylated cyclodextrin (PAc-CD) and drug in supercritical carbon dioxide; And (2) releasing the mixture through the capillary nozzle to the outside.
또한, 본 발명은 상기 제조방법에 의해 제조된 포접체 초미립자를 제공한다.The present invention also provides the superfine particle of the present invention produced by the above production method.
또한, 본 발명은 상기 포접체 초미립자를 포함하는 경구용 약제 조성물을 제공한다.The present invention also provides an oral pharmaceutical composition comprising the superfine superfine particle.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은, (1) 초임계이산화탄소 내에서 퍼아세틸레이티드 사이클로덱스트린(PAc-CD) 및 약물을 혼합하는 단계; 및 (2) 상기 혼합물을 모세관 노즐을 통하여 외부로 방출하는 단계를 포함하는, 포접체 초미립자의 제조방법을 제공한다. (1) mixing peracetylated cyclodextrin (PAc-CD) and drug in supercritical carbon dioxide; And (2) releasing the mixture through the capillary nozzle to the outside.
상기 (1)단계는 반응기 내의 초임계이산화탄소 내에서 퍼아세틸레이티드 사이클로덱스트린(PAc-CD) 및 약물을 교반하여 혼합하는 단계이다. In the step (1), peracetylated cyclodextrin (PAc-CD) and the drug are stirred and mixed in supercritical carbon dioxide in the reactor.
상기 반응기 내의 초임계이산화탄소는 6~45MPa의 압력 및 30~60℃의 온도인 것이 바람직하고, 20.7MPa의 압력 및 45℃의 온도인 것이 더욱 바람직하나, 이에 한정되는 것은 아니다. 온도와 압력이 45℃에서 20.7MPa 이하일 경우 PAc-CD의 초임계이산화탄소에 대한 용해력이 포접체 제조에 어려움이 있을 수 있다.The supercritical carbon dioxide in the reactor is preferably a pressure of 6 to 45 MPa and a temperature of 30 to 60 ° C, more preferably a pressure of 20.7 MPa and a temperature of 45 ° C, but is not limited thereto. If the temperature and pressure are below 20.7 MPa at 45 ° C, the solubility of PAc-CD in supercritical carbon dioxide may be difficult to manufacture.
상기 퍼아세틸레이티드 사이클로덱스트린(PAc-CD)은 퍼아세틸레이티드 알파-사이클로덱스트린, 퍼아세틸레이티드 베타-사이클로덱스트린 또는 퍼아세틸레이티드 감마-사이클로덱스트일 수 있으나, 이에 한정되는 것은 아니며, 초임계이산화탄소 대비 0.1 내지 2Owt%로 포함되는 것이 바람직하며, 초임계이산화탄소에 잘 용해된다.The peracetylated cyclodextrin (PAc-CD) may be peracetylated alpha-cyclodextrin, peracetylated beta-cyclodextrin or peracetylated gamma-cyclodextrin, but is not limited to, It is preferable that it is contained in an amount of 0.1 to 20 wt% based on the critical carbon dioxide, and it is dissolved well in supercritical carbon dioxide.
상기 약물은 PAc-CD에 포접되는 물질이라면 제한없이 사용할 수 있다. 일 예로, 약물은 몰시도민, 살부타몰, 살부타몰황산염, 캅토프릴, 오메프라졸, 케토로락(Ketorolac), 염산 아젤라스틴(azelastine hydrochloride), 염산 오로파타딘(Olopatadine hydrochloride), 염산 옥시메타졸린(Oxymetazoline hydrochloride), 염산 키실로메타졸린(Xylometazoline hydrochloride), 염산페닐레프린(Phenylephrine hydrochloride), 모메타손(Mometasone), 부데소니드(Budesonide), 플루티카손 프로피오네이트(Fluticasone propionate), 플루티카손 푸로에이트(Fluticasone furoate), 시클레소니드(Ciclesonide), 플루니솔라이드(Flunisolide), 베클로메타손 디프로피오네이트(Beclomethasone dipropionate), 및 트리암시놀론 아세토니드(Triamcinolone acetonide)로 이루어진 군으로부터 선택된 1종 이상인 것이 바람직하고, 오메프라졸 또는 몰시도민인 것이 더욱 바람직하나 이에 한정되는 것은 아니다.The drug can be used without limitation as long as it is encapsulated in PAc-CD. For example, the drug may be selected from the group consisting of morpholinium, salbutamol, salbutamol sulfate, captopril, omeprazole, Ketorolac, azelastine hydrochloride, olopatadine hydrochloride, But are not limited to, oxymetazoline hydrochloride, Xylometazoline hydrochloride, Phenylephrine hydrochloride, Mometasone, Budesonide, Fluticasone propionate, One selected from the group consisting of Fluticasone furoate, Ciclesonide, Flunisolide, Beclomethasone dipropionate, and Triamcinolone acetonide. Or more, and more preferably omeprazole or morpholine, but is not limited thereto.
상기 초임계이산화탄소 내에서 PAc-CD와 약물을 혼합할 때, PAc-CD 대비 약물의 비는 0.1 내지 50 인 것이 바람직하고, 1:1인 것이 더욱 바람직하다. 약물은 초임계이산화탄소에 용해되지 않지만 PAc-CD가 용해된 상태에서는 포접체가 형성되면서 초임계이산화탄소에 용해되는 것 같은 현상이 나타난다. 반응 시간은 1 분 내지 36 시간 동안 진행되며, 20 시간 동안 진행되는 것이 바람직하다.When the drug is mixed with PAc-CD in supercritical carbon dioxide, the ratio of PAc-CD to drug is preferably 0.1 to 50, more preferably 1: 1. Although the drug does not dissolve in supercritical carbon dioxide, when the PAc-CD is dissolved, the inclusion body is formed and dissolves in supercritical carbon dioxide. The reaction time is from 1 minute to 36 hours, preferably 20 hours.
상기 (2)단계는 초임계이산화탄소 내의 PAc-CD 및 약물의 혼합물을 모세관 노즐을 통하여 외부로 방출하는 단계이다. The step (2) is a step of discharging the mixture of PAc-CD and the drug in the supercritical carbon dioxide to the outside through the capillary nozzle.
상기 혼합물은 빠르게 감압하여 모세관 노즐을 통하여 대기상(RESS 방식) 또는 용액상(RESOLV 방식)으로 방출될 수 있다. The mixture may be rapidly depressurized and released via a capillary nozzle in a RESS mode or in a solution phase (RESOLV mode).
상기 용액은 물 및 에틸렌글리콜의 혼합용액인 것이 바람직하며, 물 대비 에틸렌글리콜의 중량 비는 1:0.01 내지 1: 100인 것이 바람직하다. The solution is preferably a mixed solution of water and ethylene glycol, and the weight ratio of ethylene glycol to water is preferably 1: 0.01 to 1: 100.
또한, 상기 용액은 0~20 wt%의 계면활성제 또는 염을 포함할 수 있다. The solution may also contain from 0 to 20 wt% of a surfactant or salt.
상기 계면활성제는 소듐도데실설포네이트(sodium dodecyl sulfonate, SDS), 소듐라우릴설페이트(sodium lauryl sulfate, SLS), 플루로닉(Pluronic) F127, 플루로닉(Pluronic) F68, 폴리(에틸렌글리콜)(poly(ethylene glycol), PEG), 폴리옥시에틸렌소르비탄모노올레이트(polyoxyethylene sorbitan monooleate, Tween 80), 폴록사머(Poloxamer, Lutrol F68), 폴리에틸렌글리콜-15-히드록시스테아레이트(polyethylene glycol-15-hydroxystearate, Solutol HS15), 히드록시프로필메틸셀룰로오스(Hydroxypropyl methyl cellulose, HPMC), 폴리(N-비닐-2-피롤리돈)(poly(N-vinyl-2-pyrrolidone, PVP), 실웨트(Silwet) L77, 폴리(비닐알콜)(poly(vinylalcohol), PVA), 소혈청알부민(bovine serum albumin, BSA), 및 자당지방산에스테르(sucrose fatty acid esters) 등일 수 있다.The surfactant may be selected from the group consisting of sodium dodecyl sulfonate (SDS), sodium lauryl sulfate (SLS), Pluronic F127, Pluronic F68, poly (ethylene glycol) (PEG), polyoxyethylene sorbitan monooleate (Tween 80), poloxamer (Lutrol F68), polyethylene glycol-15-hydroxystearate (polyethylene glycol-15 Hydroxystearate, Solutol HS15), hydroxypropyl methyl cellulose (HPMC), poly (N-vinyl-2-pyrrolidone, PVP), Silwet ) L77, poly (vinylalcohol), PVA, bovine serum albumin (BSA), and sucrose fatty acid esters.
상기 염은 NaCl, KCl, NaOH, Na2SO3, Na2CO3, NaHCO2, 및 알긴산나트륨(sodium alginate) 등일 수 있다. The salt and the like NaCl, KCl, NaOH, Na 2 SO 3,
상기 초임계이산화탄소 내의 PAc-CD 및 약물의 혼합물은 모세관 노즐을 통해 분사되어 초미립자를 형성할 있다. 모세관 현상이라 함은 폭이 좁은 관에서 액체 분자 간의 인력과 상기 액체의 표면과 관의 표면 사이에 작용하는 상호 간의 인력에 의해 발생한다. 상기 모세관 노즐은 폭이 좁은 관 형태로서, 금속, 유리, 석영(Quartz), 테플론(Teflon) 및 내화학성 재질의 중합체(polymer) 등의 재질로 구현될 수 있다.The mixture of PAc-CD and drug in the supercritical carbon dioxide is injected through a capillary nozzle to form ultra-fine particles. Capillary phenomenon is caused by attraction between liquid molecules in a narrow tube and mutual attraction between the surface of the liquid and the surface of the tube. The capillary nozzle may have a narrow tube shape and may be formed of a material such as a metal, glass, quartz, Teflon, and a polymer of a chemical resistant material.
상기 모세관의 구경은 25 내지 1000 μm일 수 있고, 모세관의 길이 대비 구경의 비는 1 내지 5000일 수 있다.The diameter of the capillary may be 25 to 1000 μm, and the ratio of capillary length to diameter may be 1 to 5000.
또한, 본 발명은 상기 제조방법에 의해 제조된 포접체 초미립자를 제공한다. The present invention also provides the superfine particle of the present invention produced by the above production method.
상기 포접체 초미립자의 직경은 10~1000 nm일 수 있고, 일 실시예에 따라, 대기상(RESS 방식)에 방출시는 50~300 nm일 수 있고, 용액상(RESOLV 방식)에 방출시는 50~600 nm일 수 있다. The diameter of the superfine superfine particle may be 10 to 1000 nm, and may be 50 to 300 nm at the time of release in the air phase (RESS mode), 50 to 300 nm at the time of release in the solution phase (RESOLV mode) To 600 nm.
또한, 본 발명은 상기 포접체 초미립자를 포함하는, 경구용 약제 조성물을 제공한다.The present invention also provides an oral pharmaceutical composition comprising the superfine porous body.
상기 약제 조성물이라 함은, 상기 Pac-CD 및 약물의 포접체 초미립자를 유효성분으로 포함하는 조성물을 의미한다. 또한, 본 발명의 경구용 약제 조성물은 통상의 약제학적으로 허용 가능한 액체 또 는 고체 담체 및 부형제 등의 첨가제를 더욱 포함할 수 있다. 바람직하게, 본 발명의 약제 조성물은 부형제, 붕해제, 유동화제 및 활택제로 이루어진 군에서 선택 된 1종 이상의 첨가제를 포함할 수 있다. The above pharmaceutical composition means a composition comprising Pac-CD and microcapsules of drug as an active ingredient. In addition, the oral pharmaceutical composition of the present invention may further contain additives such as conventional pharmaceutically acceptable liquid or solid carriers and excipients. Preferably, the pharmaceutical composition of the present invention may contain one or more additives selected from the group consisting of excipients, disintegrants, fluidizers, and glidants.
상기 부형제로는 유당, 백당, 포도당, 과당, 만니톨, 옥수수전분, 감자전분, <30> 밀전분, 프리젤라티나이즈드전분, 미결정셀룰로오스 또는 셀룰로오스 유도체, 덱스트린, 인산일수소칼슘, 인산이수소칼슘, 탄산칼슘, 폴라크릴린칼륨, 아세트산, 탄산암모늄, 인산암모늄, 붕산, 젖산, 구연산, 인산칼륨, 인산나트륨, 아세트산나트륨, 구연산나트륨, 젖산나트륨, 아스코르빈산, 및 아스코르빌파르미테이트로 이루어진 군에서 선택된 1종 이상의 것을 사용할 수 있다. 상기 부형제의 함량은 바람직하게, 전체 약제 조성물에 포함되는 첨가제의 전체 중량을 기준으로 20.0 내지 60.0 중량%로 포함할 수 있다.Examples of the excipient include lactose, saccharin, glucose, fructose, mannitol, corn starch, potato starch, wheat starch, pregelatinized starch, microcrystalline cellulose or cellulose derivatives, dextrin, calcium monohydrogen phosphate, calcium dihydrogen phosphate Calcium carbonate, polacrilin potassium, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, citric acid, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, sodium lactate, ascorbic acid and ascorbyl palmitate At least one selected from the group consisting of The content of the excipient may preferably be from 20.0 to 60.0% by weight, based on the total weight of the additive contained in the overall pharmaceutical composition.
상기 붕해제로는 미결정셀룰로오스, 저치환도 히드록시프로필셀룰로오스, 크로스카멜로오스나트륨, 전분글리콘산나트륨, 카르복시메틸셀룰로오스나트륨, 카르복시메틸셀룰로오스칼슘, 및 크로스포비돈로 이루어진 군에서 선택된 1종 이상을 사용할 수 있다. 상기 붕해제의 함량은 바람직하게, 전체 약제 조성물에 포함되는 첨가제의 전체 중량을 기준으로 0.1-20.0 중량%로 포함할 수 있다.As the disintegrant, at least one selected from the group consisting of microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glyconate, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, and crospovidone is used . The content of the disintegrant may preferably be 0.1 to 20.0% by weight, based on the total weight of the additive contained in the total pharmaceutical composition.
상기 유동화제로는 콜로이드성실리카무수물, 실리카디옥사이드침전물, 마그네슘스테아레이트, 스테아르산, 폴리에틸렌글리콜(PEG), 및 이들의 혼합물로 이루어진 군에서 선택된 1종 이상을 사용할 수 있다. 상기 유동화제의 함량은 바람직하게, 전체 약제 조성물에 포함되는 첨가제의 전체 중량을 기준으로 0.1-3.0 중량%로 포함할 수 있다.As the fluidizing agent, at least one selected from the group consisting of colloidal silica anhydride, silica dioxide precipitate, magnesium stearate, stearic acid, polyethylene glycol (PEG), and mixtures thereof may be used. The content of the fluidizing agent is preferably 0.1 to 3.0% by weight based on the total weight of the additives contained in the total pharmaceutical composition.
상기 활택제로는 스테아린산마그네슘, 스테아린산, 스테아린산 아연, 스테아린산 칼슘, 활석, 스테아릴푸마르산나트륨, 탈크, 실리콘디옥사이드, 및 콜로이달실리콘디옥사이드으로 이루어진 군에서 선택된 1종 이상을 사용할 수 있다. 상기 활택제의 함량은, 바람직하게는 전체 약제 조성물에 포함되는 첨가제의 전체 중량을 기준으로 0.1 - 3.0 중량%로 포함할 수 있다.As the lubricant, at least one selected from the group consisting of magnesium stearate, stearic acid, zinc stearate, calcium stearate, talc, sodium stearyl fumarate, talc, silicon dioxide, and colloidal silicon dioxide may be used. The content of the lubricant may preferably be 0.1 to 3.0% by weight based on the total weight of the additives contained in the total pharmaceutical composition.
본 발명에 따른 경구용 약제 조성물의 제형은 고체형태의 제제, 액상 제제 등을 포함하며, 정제, 캡슐제, 과립제, 산제, 환제, 건조 시럽제 등의 경구 투여용 고형제제로 제형화 할 수 있고, 바람직하게는 경구투여에 적합한 정제 또는 캡슐제 형태이다.The pharmaceutical composition for oral administration according to the present invention may be formulated as a solid preparation for oral administration such as tablets, capsules, granules, powders, pills, and dry syrups, Preferably in the form of tablets or capsules suitable for oral administration.
바람직한 약학적 제제는 단위 투약형태이다. 그러한 형태에서, 제제는 적당량의 유효성분을 포함하는 단위 투여형태로 세분된다. 단위 투약형태는 제제의 분리된 양을 함유하는 포장된 제제일 수 있으며, 예를 들면, 바이알 또는 앰플 내의 포장된 정제, 캡슐 또는 분말이다. 더욱 바람직하게는 정제 및 캡슐제의 형태이며 유효 투여량은 1일 160mg이다.A preferred pharmaceutical formulation is in unit dosage form. In such form, the agent is subdivided into unit dosage forms containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged preparation containing a discrete amount of the preparation, for example, a packaged tablet, capsule or powder in a vial or ampoule. More preferably in the form of tablets and capsules, with an effective dosage of 160 mg per day.
본 발명에 따른 포접체 초미립자는, 초임계이산화탄소 내의 퍼아세틸레이티드 사이클로덱스트린(PAc-CD) 및 약물의 혼합물을 모세관 노즐을 통하여 대기상 또는 용액상으로 방출하여 제조됨으로써, 간단하고, 경제적 방법으로 포접체 초미립자을 제조할 수 있고, 상기 포접체 초미립자는 포접율 및 분산성이 우수하여 경구용 조성물로 이용될 수 있다. The superfine superfine particle according to the present invention is produced by discharging a mixture of peracetylated cyclodextrin (PAc-CD) and drug in supercritical carbon dioxide through a capillary nozzle in a vapor phase or a solution phase, Microporous superfine particles can be produced, and the superfine superfine particles are excellent in porosity and dispersibility and can be used as an oral composition.
도 1은 퍼아세틸레이티드-베타-사이클로덱스트린(PAc-β-CD)의 분자구조 모형을 나타내는 도이다.
도 2는 초임계이산화탄소를 이용한 약물 포접체 의 제조장비를 나타내는 도이다. 여기서 1: 고압주입펌프, 2: 체크밸브, 3: 저장셀, 4: 압력계, 5: 반응셀, 6: 교반기, 7: 마그네틱바, 8: on/off 밸브, 9: 필터, 10: 유량 조절 밸브, 11: 항온시스템, 12: 유량측정계, 13: 노즐, 14: 포집용기, 15: 배기를 나타낸다.
도 3은 RESS 방식으로 포집한 약물 포접체 초미립자의 광학현미경 이미지를 나타내는 도이다.
도 4는 RESS 방식으로 제조된 약물 포접체 초미립자의 주사전자현미경(SEM) 이미지를 나타내는 도이다.
도 5는 RESOLV 방식으로 제조된 약물 포접체 초미립자의 평균입자지름(DLS)을 나타내는 도이다.
도 6은 오일 현탁된 포접체 초미립자로부터 약물의 방출 속도를 나타내는 도이다. 여기서 (▲)몰시도민, (▼)오메프라졸, (■)PAc-β-CD/몰시도민 포접체 초미립자 (RESS 방식), 및 (●)PAc-β-CD/오메프라졸 포접체 초미립자 (RESOLV 방식)을 나타낸다.1 is a diagram showing a molecular structure model of peracetylated-beta-cyclodextrin (PAc -? - CD).
FIG. 2 is a view showing an apparatus for manufacturing a drug cartilage using supercritical carbon dioxide. FIG. 1: high pressure injection pump 2: check valve 3: storage cell 4: pressure gauge 5: reaction cell 6: stirrer 7: magnetic bar 8: on / off valve 9: Valve, 11: constant temperature system, 12: flow meter, 13: nozzle, 14: collection container, 15: exhaust.
Fig. 3 is an optical microscope image of ultrafine particles of drug-coated microcapsules captured by the RESS system.
Fig. 4 is a scanning electron microscope (SEM) image of ultrafine particles of drug coated body manufactured by the RESS system.
5 is a graph showing the mean particle diameter (DLS) of the drug-coated superfine particles produced by the RESOLV method.
6 is a graph showing the release rate of the drug from the oil-suspended superfine particle. Here, supercapacitors (▲), (▼) omeprazole, (■) PAc-β-CD / molybdenum microsphere superfine particles (RESS method) and (●) PAc-β-CD / omeprazole superfine particles .
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.
Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.
실시예 1.Example 1. RESS 방식을 이용한 포접체 초미립자Ultra-fine particles using RESS method 의 제조Manufacturing
1-1. PAc-β-CD/오메프라졸 포접체 초미립자의 제조1-1. Preparation of PAc-β-CD / omeprazole graft superfine particle
50mL 고압 반응기 셀(5) 내부에 PAc-β-CD(도1 참조) 100mg과 오메프라졸 18mg을 첨가하고, 이산화탄소 실린더(1)에서 나온 이산화탄소를 고압 실린지 펌프(2)를 거쳐 20.7MPa 압력으로 주입한다. 이후 항온기(6)를 이용하여 온도를 45℃로 유지하며 교반기(11)와 마그네틱 바(4)를 이용하여 교반시킨다. PAc-β-CD는 초임계이산화탄소에 잘 용해되지만 오메프라졸은 용해되지 않기 때문에 처음에는 녹지 않는 고형물이 존재하지만 일정한 시간이 지나면서 사라지는 현상이 관찰된다. 이것은 분명하게 사이클로덱스트린과 오메프라졸이 포접체가 되었음을 간접적으로 증명할 수 있다. 상기 PAc-CD와 오메프라졸-이산화탄소 혼합용액을 20시간동안 방치한 뒤 100 μm 구경 (L/D = 2)의 모세관 노즐을 통하여 대기상으로 빠르게 방출(12)하여 포접체 초미립자를 수득하였다.100 mg of PAc-β-CD (see FIG. 1) and 18 mg of omeprazole were added to a 50 mL high-
상기 포접체 초미립자의 크기를 광학 현미경과 FESEM을 사용하여 관찰하였고, 그 결과 약 100 nm로 측정되었다.
The size of the superfine superfine particle was observed using an optical microscope and FESEM, and the result was measured to be about 100 nm.
1-2. PAc-β-CD/몰시도민 포접체 초미립자의 제조1-2. Production of ultra-fine particles of PAc-β-CD / molybdenum complexes
50mL 고압 반응기 셀(5) 내부에 PAc-β-CD(도1 참조) 100mg과 몰시도민 12mg을 첨가하고, 이산화탄소 실린더(1)에서 나온 이산화탄소를 고압 실린지 펌프(2)를 거쳐 20.7MPa 압력으로 주입한다. 이후 항온기(6)를 이용하여 온도를 45℃로 유지하며 교반기(11)와 마그네틱 바(4)를 이용하여 교반시킨다. PAc-β-CD는 초임계이산화탄소에 잘 용해되지만 몰시도민은 용해되지 않기 때문에 처음에는 녹지 않는 고형물이 존재하지만 일정한 시간이 지나면서 사라지는 현상이 관찰된다. 이것은 분명하게 사이클로덱스트린과 몰시도민이 포접체가 되었음을 간접적으로 증명할 수 있다. 상기 PAc-CD와 몰시도민-이산화탄소 혼합용액을 20시간동안 방치한 뒤 100 μm 구경 (L/D = 2)의 모세관 노즐을 통하여 대기상으로 빠르게 방출(12)하여 포접체 초미립자를 수득하였다.100 mg of PAc-β-CD (see FIG. 1) and 12 mg of morpholine were added to a 50 mL high-
상기 포접체 초미립자의 크기를 광학 현미경과 FESEM을 사용하여 관찰하였고, 그 결과 약 90 nm로 측정되었다.The size of the superfine particles was observed using an optical microscope and FESEM, and the result was measured to be about 90 nm.
다양한 실험조건에 따른 포접체 초미립자의 제조 결과를 표 1에 나타내었다.Table 1 shows the results of preparation of superfine superfine particles according to various experimental conditions.
(wt %)PAc - CD
(wt%)
(m)Capillary Internal diameter
(m)
(mm)Capillary length
(mm)
(cm)Spray length
(cm)
Particle size
(optical microscope)
(m)Average
Particle size
(optical microscope)
(m)
Particle size (SEM)
(nm)Average
Particle size (SEM)
(nm)
4.4
실시예 2.Example 2. RESOLV 방식을 이용한 포접체 초미립자Ultra-fine spherical particles using RESOLV method 의 제조Manufacturing
2-1. PAc-β-CD/오메프라졸 포접체 초미립자의 제조2-1. Preparation of PAc-β-CD / omeprazole graft superfine particle
50mL 고압 반응기 셀(5) 내부에 PAc-β-CD(도1 참조) 40mg과 오메프라졸 7mg을 첨가하고 이산화탄소 실린더(1)에서 나온 이산화탄소를 고압 실린지 펌프(2)를 거쳐 20.7MPa 압력으로 주입한다. 이후 항온기(6)를 이용하여 온도를 45℃로 유지하며 교반기(11)와 마그네틱 바(4)를 이용하여 교반시킨다. 상기 PAc-CD와 오메프라졸-이산화탄소 혼합용액을 20시간동안 방치한 뒤 100 μm 구경 (L/D = 200)의 모세관 노즐을 통하여 소듐도데실설포네이트(sodium dodecyl sulfonate, SDS) 1 wt%가 포함된 수용액상으로 빠르게 방출(12)하여 포접체 초미립자를 수득하였다.40 mg of PAc-β-CD (see FIG. 1) and 7 mg of omeprazole were added to a 50 mL high-
상기 포접체 초미립자의 크기를 광학 현미경과 FESEM을 사용하여 관찰하였고, 그 결과 약 170 nm 로 측정되었다.
The size of the superfine particles was observed using an optical microscope and FESEM, and the result was measured to be about 170 nm.
2-2. PAc-β-CD/몰시도민 포접체 초미립자의 제조2-2. Production of ultra-fine particles of PAc-β-CD / molybdenum complexes
50mL 고압 반응기 셀(5) 내부에 PAc-β-CD(도1 참조) 40mg과 몰시도민 5mg을 첨가하고 이산화탄소 실린더(1)에서 나온 이산화탄소를 고압 실린지 펌프(2)를 거쳐 20.7MPa 압력으로 주입한다. 이후 항온기(6)를 이용하여 온도를 45℃로 유지하며 교반기(11)와 마그네틱 바(4)를 이용하여 교반시킨다. 상기 PAc-CD와 몰시도민-이산화탄소 혼합용액을 20시간동안 방치한 뒤 100 μm 구경 (L/D = 200)의 모세관 노즐을 통하여 소듐도데실설포네이트(sodium dodecyl sulfonate, SDS) 1 wt%가 포함된 수용액상으로 빠르게 방출(12)하여 포접체 초미립자를 수득하였다.40 mg of PAc-β-CD (see FIG. 1) and 5 mg of molybdenum were added to a 50 mL high-pressure reactor cell (5) and carbon dioxide from the carbon dioxide cylinder (1) was injected at 20.7 MPa pressure through a high- do. Thereafter, the temperature was maintained at 45 캜 using a
상기 포접체 초미립자의 크기를 광학 현미경과 FESEM을 사용하여 관찰하였고, 그 결과 약 150 nm 로 측정되었다.The size of the superfine particles was observed using an optical microscope and FESEM, and the result was measured to be about 150 nm.
다양한 실험조건에 따른 포접체 초미립자의 제조 결과를 표 2에 나타내었다.Table 2 shows the results of preparation of the supercoated particles according to various experimental conditions.
(wt %)PAc - CD
(wt%)
(m)Capillary Internal diameter
(m)
(mm)Capillary length
(mm)
(bar)pressure
(bar)
Particle size
(m)Average
Particle size
(m)
실험예 1.Experimental Example 1 포접체 초미립자Superfine superfine particle 로부터 약물의 방출 속도 측정The release rate of the drug from
상기 실시예 1-2 및 2-1에서 제조한 포접체 초미립자의 오일 현탁액(oily suspension)으로부터 약물의 생체외(in-vitro) 방출 속도(release rate)는 일본 파마코포이아(Japanese Pharmacopoeia) XIV에 설명된 용해 시험의 패들법(paddle method)에 따라서 측정한다.The in-vitro release rate of the drug from oily suspensions of the superfine superalloy particles prepared in Examples 1-2 and 2-1 was measured according to Japanese Pharmacopoeia XIV It is measured according to the paddle method of the dissolution test described.
약물 전달체로 사용되는 것을 실험하기 위하여 1:1 몰 농도의 포접체 초미립자(몰시도민: 1mg, PAc-β-CD: 8mg; 및 오메프라졸: 1mg, PAc-β-CD: 6mg)는 10mL 피넛오일에 현탁된다. 이후 상기 오일 현탁액에 중성(몰시도민) 또는 pH 4(오메프라졸)의 30mL 수용액이 첨가되고, 37℃에서 혼합물은 60rpm으로 교반하면서 유지된다. 시료 용액(0.3mL)은 솜마개(cotton plug)로 drawn되고 물에 희석된다. 오일 상에서 약물의 방출 속도를 스펙트로메타(Lambda 40 UV-Vis spectrometer, Perkin Elmer)로 측정한다.In order to test the drug delivery system, 10 mL of peanut super-fine particles (1 mg of morcotidine, 8 mg of PAc-β-CD and 1 mg of omeprazole and 6 mg of PAc-β-CD) Suspended. A 30 mL aqueous solution of neutral (molybdenum) or pH 4 (omeprazole) is then added to the oil suspension, and the mixture is maintained at 37 DEG C with stirring at 60 rpm. The sample solution (0.3 mL) is drawn with a cotton plug and diluted in water. The rate of release of the drug in oil phase is measured with a
오일 현탁된 포접체 초미립자로부터 약물의 방출 속도를 도 6에 나타내었다. 여기서 (▲)몰시도민, (▼)오메프라졸, (■)PAc-β-CD/몰시도민 포접체 초미립자 (RESS 방식), 및 (●)PAc-β-CD/오메프라졸 포접체 초미립자 (RESOLV 방식)을 나타낸다.The release rate of the drug from the oil-suspended microcapsule superfine particle is shown in Fig. Here, supercapacitors (▲), (▼) omeprazole, (■) PAc-β-CD / molybdenum microsphere superfine particles (RESS method) and (●) PAc-β-CD / omeprazole superfine particles .
도 6에 나타난 바와 같이, 순수한 약물은 측정과 동시에 30%가 방출되고, 1시간 이내에 100% 방출되지만, RESS 방식으로 제조된 몰시도민 포접체는 15 내지 20%가 1시간 후 방출되고, 35 내지 40%가 3시간 후 방출되고, 65 내지 70%가 5시간 후 방출되며, >95%이 8시간 후 방출되는 결과가 나타난다. 또한, RESOLV 방식으로 제조된 오메프라졸 포접체는 25 내지 30%가 1시간 후 방출되고, 30 내지 35%가 3시간 후 방출되고, 40 내지 45%가 5시간 후 방출되며, >95%이 12시간 후 방출되는 결과가 나타난다. 이 결과들은 본 발명에 의한 포접체 초미립자의 우수한 방출 제어 능력을 보여주고 있다.As shown in FIG. 6, the pure drug is released 30% at the same time as the measurement, and 100% is released within 1 hour, but 15-20% is released after one hour from the molocinum phosgene manufactured by the RESS method, 40% is released after 3 hours, 65-70% is released after 5 hours, and> 95% is released after 8 hours. In addition, 25-30% of the omeprazole grafts prepared by the RESOLV method are released after 1 hour, 30-35% after 3 hours, 40-45% after 5 hours,> 95% The results are shown after the release. These results show excellent release control ability of the superfine particle of the present invention.
Claims (17)
(2) 상기 혼합물을 모세관 노즐을 통하여 소듐도데실설포네이트를 포함하는, 1:1 중량비의 물과 에틸렌글리콜의 혼합용액상으로 방출하는 단계를 포함하는, 오메프라졸 포접체 초미립자의 제조방법.(1) mixing peracetylated beta-cyclodextrin (PAc- beta -CD) and omeprazole in supercritical carbon dioxide; And
(2) releasing the mixture through a capillary nozzle into a mixed solution of water and ethylene glycol at a weight ratio of 1: 1, including sodium dodecylsulfonate.
상기 초임계이산화탄소는 6~45MPa의 압력 및 30~60℃의 온도인 것을 특징으로 하는, 오메프라졸 포접체 초미립자의 제조방법.The method according to claim 1,
Wherein the supercritical carbon dioxide has a pressure of 6 to 45 MPa and a temperature of 30 to 60 ° C.
상기 퍼아세틸레이티드 베타-사이클로덱스트린은 초임계이산화탄소 대비 0.1 내지 20wt%로 포함된 것을 특징으로 하는, 오메프라졸 포접체 초미립자의 제조방법.The method according to claim 1,
Wherein the peracetylated beta-cyclodextrin is contained in an amount of 0.1 to 20 wt% based on supercritical carbon dioxide.
상기 퍼아세틸레이티드 베타-사이클로덱스트린 대비 오메프라졸의 비는 0.1 내지 50인 것을 특징으로 하는, 오메프라졸 포접체 초미립자의 제조방법.The method according to claim 1,
Wherein the ratio of the peracetylated beta-cyclodextrin to the omeprazole is from 0.1 to 50.
상기 모세관 노즐의 구경은 25 내지 1000 μm인 것을 특징으로 하는, 오메프라졸 포접체 초미립자의 제조방법.The method according to claim 1,
Wherein the diameter of the capillary nozzle is 25 to 1000 m.
상기 모세관 노즐의 길이 대비 구경의 비는 1 내지 5000인 것을 특징으로 하는, 오메프라졸 포접체 초미립자의 제조방법.The method according to claim 1,
Wherein the ratio of the length to the diameter of the capillary nozzle is from 1 to 5,000.
상기 포접체 초미립자의 직경은 10~1000 nm인 것을 특징으로 하는, 오메프라졸 포접체 초미립자.15. The method of claim 14,
Characterized in that the diameter of the superfine superfine particles is 10 to 1000 nm.
상기 조성물은 부형제, 붕해제, 유동화제 및 활택제로 이루어진 군에서 선택된 1종 이상의 첨가제를 더 포함하는 것을 특징으로 하는, 경구용 약제 조성물.17. The method of claim 16,
Wherein the composition further comprises at least one additive selected from the group consisting of excipients, disintegrants, fluidizers, and glidants.
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