KR20120021483A - Pharmaceutical composition containing antidepressant - Google Patents

Pharmaceutical composition containing antidepressant Download PDF

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KR20120021483A
KR20120021483A KR1020100074900A KR20100074900A KR20120021483A KR 20120021483 A KR20120021483 A KR 20120021483A KR 1020100074900 A KR1020100074900 A KR 1020100074900A KR 20100074900 A KR20100074900 A KR 20100074900A KR 20120021483 A KR20120021483 A KR 20120021483A
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enteric
layer
drug
applying
coating
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KR1020100074900A
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Korean (ko)
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최재승
남경태
이경수
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근화제약주식회사
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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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes

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  • Bioinformatics & Cheminformatics (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

PURPOSE: A method for manufacturing a sustained release formulation of antidepressant is provided to obtain a formulation with same drug release pattern with conventional formulations. CONSTITUTION: A sustained release formulation of duloxetine hydrochloride comprises an inactive core, a drug layer containing duloxetin hydrochloride, separation layer, and enteric layer containing cellulose acetate phthalic acid. A method for preparing the sustained release formulation comprises: a step of preparing the inactive core; a step of applying drug liquid on the inactive core to form the drug layer; a step of applying the separation layer coating solution; and a step of applying the enteric coating solution.

Description

항우울제를 함유하는 약제학적 조성물{Pharmaceutical composition containing antidepressant}Pharmaceutical composition containing antidepressant

본 발명은 우울증 치료제인 둘록세틴 염산염의 지연 방출형 제제 및 이의 제조방법에 관한 것이다.The present invention relates to a delayed-release preparation of duloxetine hydrochloride, which is a therapeutic agent for depression, and a method for preparing the same.

둘록세틴 염산염은 우울증 치료제로서 현재 심발타(CYMBALTA)라는 상품명으로 펠렛을 함유한 캡슐제의 형태가 시판되고 있다. 둘록세틴 염산염은 분자식 C18H19HOS?HCl(분자량 333.88)인 세로토닌 및 노르에피네프린 재흡수 억제제이다.
Duloxetine hydrochloride is currently available in the form of capsule-containing capsules under the trade name CYMBALTA as a therapeutic agent for depression. Duloxetine hydrochloride is a serotonin and norepinephrine reuptake inhibitor of molecular formula C 18 H 19 HOS®HCl (molecular weight 333.88).

대한민국 등록특허 10-0356240에는 장용성둘록세틴 펠렛의 제조에 관한 내용이 기재되어 있다. 이 특허에는 장용 코팅제로서 히드록시프로필 메틸셀룰로스 아세테이트 숙시네이트(HPMCAS)를 사용하고 있다. HPMCAS를 현탁액 형태로 사용하는 경우 사용전에 현탁액을 20℃이하로 냉각시켜야 하며 직경이 작은 배관을 사용하고 분무 건조기의 배관 및 노즐을 냉각시킬 것을 권고하고 있다. HPMCAS를 수용액 형태로 적용하는 경우 암모니아, 특히 수성암모늄의 형태로 첨가하여 중화시켜 완전히 용해시킨 후 사용할 수 있다. 또한 둘록세틴은 많은 장용성 코팅과 반응하여 느리게 용해되거나 용해되지 않는 코팅을 형성하며 이러한 교차반응성 때문에 펠렛형 제제는 약물방출성이 나쁘고 생체내 이용율이 낮음을 언급하고 있다. 따라서 이러한 교차반응을 방지하기 위해 분리층을 이용하여 이를 방지하고자 하였다.
Republic of Korea Patent Registration 10-0356240 describes the preparation of enteric duloxetine pellets. This patent uses hydroxypropyl methylcellulose acetate succinate (HPMCAS) as an enteric coating. When using HPMCAS in suspension form, it is recommended that the suspension be cooled to below 20 ° C prior to use, use small diameter pipes, and cool the pipes and nozzles of the spray dryer. When HPMCAS is applied in the form of an aqueous solution, it can be added after neutralization by complete addition of ammonia, especially in the form of aqueous ammonium, to be used. It also mentions that duloxetine reacts with many enteric coatings to form a slowly dissolving or insoluble coating, and because of this cross-reactivity, pelletized formulations have poor drug release and low bioavailability. Therefore, to prevent this cross reaction by using a separation layer.

대한민국 공개특허 10-2009-0005237에는 장용성 코팅제로서 메타크릴산 공중합체와 히드록시프로필 메틸 셀룰로오스 프탈레이트(HPMCP)를 1이상 포함하여 둘록세틴 지연방출 펠렛을 제조하는 방법이 기재되어 있다. 이 특허에서는 상기 등록특허 10-0356240에서 언급한 HPMCAS에 비해 몇가지 이점을 기재하고 있는데 이는 메타크릴산 공중합체(상품명 Eudragit) 및 히드록시프로필 메틸셀룰로오스 프탈레이트는 공업적 규모로 사용하는데 더욱 적합하며 이는 이들이 실온에서 표준장치로 취급될 수 있으며 중화가 필요하지 않기 때문이다. 그러나 Eudragit을 사용시 높은 접합성(sticking)으로 인한 펠렛의 뭉침현상을 방지하기 위해서는 다량의 접합방지제(antisticking agent)를 첨가해줘야 하는 단점이 있다.
Korean Patent Laid-Open Publication No. 10-2009-0005237 describes a method for preparing duloxetine delayed-release pellets comprising at least one methacrylic acid copolymer and hydroxypropyl methyl cellulose phthalate (HPMCP) as an enteric coating. This patent describes several advantages over the HPMCAS mentioned in the above-mentioned patent 10-0356240, which is more suitable for use on an industrial scale, methacrylic acid copolymer (trade name Eudragit) and hydroxypropyl methylcellulose phthalate, which are This can be treated as a standard at room temperature and does not require neutralization. However, Eudragit has a disadvantage in that a large amount of antisticking agent must be added to prevent pellet agglomeration due to high sticking.

이 밖에도 산불안정한 약물을 안정화시키기 위해 사용하는 장용성 원료는 카르복시메틸에틸셀룰로오스(CMEC), 셀룰로오스아세테이트프탈산(CAP)등이 있으나 이들은 모두 중화과정을 거치거나 유기용매에 녹여 사용해야 하는 단점이 있다.
In addition, enteric materials used to stabilize acid-labile drugs include carboxymethylethyl cellulose (CMEC) and cellulose acetate phthalic acid (CAP), but these all have a disadvantage of being neutralized or dissolved in an organic solvent.

이와같이 둘록세틴 지연방출 펠렛을 제조하기 위한 방법이 몇몇 특허에 기재되어 있으나 각각의 장용성 원료의 중화, 작업성의 불량 등은 해결해야 할 과제이다. As described above, some methods for preparing duloxetine delayed-release pellets have been described in some patents, but neutralization of each enteric raw material and poor workability have to be solved.

둘록세틴 염산염은 산불안정성 약물로서 경구 투여시 위의 산성환경에서 쉽게 분해된다. 이러한 약물의 특성 때문에 현재 시판중인 심발타 캡슐(Cymbalta capsule, Eli Lilly)은 산성에서 녹지 않고 pH5 이상의 알칼리 환경에서 녹는 장용성 물질인 히드록시프로필메칠셀룰로오스 아세테이트 숙신산염(HPMCAS)으로 코팅된 펠렛을 함유하고 있다. Duloxetine hydrochloride is an acid labile drug that, upon oral administration, readily degrades in the acidic environment of the stomach. Due to the properties of these drugs, currently available Cymbalta capsules (Ely Lilly) contain pellets coated with hydroxypropylmethylcellulose acetate succinate (HPMCAS), an enteric substance that does not dissolve in acid but in an alkaline environment of pH 5 or higher. .

배경기술에서 언급된 장용성 코팅제인 HPMCAS, HPMCP, Eudragit등은 사용시 원료를 중화시키켜야 하고 유기용매를 사용하여 용해해야 하는 등 여러 문제점을 가지고 있다. 원료를 중화시키기 위해서 암모니아수가 권장되고 있으나 이는 추가적인 작업이 필요하여 원료 및 공정상의 비용을 증가시키고 암모니아의 강한 냄새로 인해 취급이 불편한 점, 호흡기로의 흡입으로 인한 인체 위해가 우려된다. 또한 유기용매의 사용은 공정시 배출되는 유기 용매로 인하여 인체에 해로우며 환경을 오염시키는 다량의 물질을 방출한다. Eudragit은 Eudragit L30D55라는 상품명으로 수분산액이 시판되고 있으나 작업시 다량의 탈크등 점착방지제를 투여해야 하고 이로 인해 무기질인 탈크가 작업중 침적되어 코팅액 이송라인 막힘 등의 문제점이 제기되어 이의 해결책이 시급히 요구된다.Enteric coating agents HPMCAS, HPMCP, Eudragit, etc. mentioned in the background art have various problems such as neutralizing raw materials and dissolving them using organic solvents. Ammonia water is recommended to neutralize the raw material, but this requires additional work, which increases the cost of raw materials and processes, is inconvenient to handle due to the strong smell of ammonia, and the human hazards caused by inhalation into the respiratory tract. In addition, the use of organic solvents release a large amount of substances that are harmful to the human body and pollute the environment due to the organic solvent discharged during the process. Eudragit is commercially available under the trade name Eudragit L30D55. However, a large amount of talc must be administered during the operation, which leads to problems such as clogging of the coating liquid transfer line due to deposition of inorganic talc during operation. .

본 발명에서는 위와 같은 문제를 해결하기 위해 강한 냄새 등이 없어 취급이 용이하여 작업성이 양호하고 유기용매를 사용하지 않아 공정 단가를 낮출 수 있는 제조방법을 고안하였다. In the present invention, there is no strong smell, etc. to solve the above problems, easy to handle, good workability and devised a manufacturing method that can lower the unit cost by not using an organic solvent.

산불안정성 약물을 안정하게 하기 위한 장용성 물질인 셀룰로오스 아세테이트 프탈산은 보통의 경우 유기용매에 녹여 사용하게 되어 있으나 FMC Biopolymer사에서 시판중인 Aquacoat CPD-30은 셀룰로오스 아세테이트 프탈산의 수분산액으로서 소량의 가소제와 물을 첨가하여 제제에 쉽게 적용할 수 있다는 장점이 있다.
Cellulose acetate phthalic acid, an enteric substance for stabilizing acid-labile drugs, is usually dissolved in organic solvents. However, Aquacoat CPD-30, commercially available from FMC Biopolymer, is an aqueous dispersion of cellulose acetate phthalic acid. There is an advantage that it can be easily applied to the formulation by addition.

본 발명에서는 기존 시판중인 심발타 캡슐과 동등한 용출률을 보이는 둘록세틴 지연방출제제를 개발하였고 아래 그 예를 기재하였다. In the present invention, a duloxetine delayed-release agent having a dissolution rate equivalent to that of commercially available Shimbalta capsules was developed and the example is described below.

기본적인 제조공정은 당핵에 둘록세틴 염산염의 약물층을 코팅하는 약물층 코팅 공정, 장용성 폴리머층과의 분리를 위한 분리층 코팅 공정, 장용막 코팅 공정, 마무리층 코팅 공정 순서와 같다. 당핵으로는 불활성 비드인 슈가스피어스를 사용하였으며 크기는 20~25메쉬(약 1.0mm~850mm)였다.
The basic manufacturing process is the same as the drug layer coating process for coating the drug layer of duloxetine hydrochloride on the nucleus, the separation layer coating process for separation from the enteric polymer layer, the enteric membrane coating process, and the finishing layer coating process. The sugar nucleus was inert beads, Sugas Pierce, and the size was 20-25 mesh (about 1.0mm ~ 850mm).

둘록세틴염산염의 약물코팅은 약물을 적량의 20% 에탄올에 녹인후 정전기방지제로 탈크와 콜로이드성 이산화 규소를 첨가하여 분산시킨후 유동층코팅기(MV-01, Vector사)에서 슈가스피어스에 분무 코팅하였다. 분무시 흡기온도는 60도로 하였으며 코팅후 10분간 추가 건조하였다. 이후 정제수에 히드록시프로필메칠셀롤로오스를 녹인후 탈크를 분산시켜 조제한 분리층 코팅액을 같은 조건에서 분무 코팅하였고 코팅후 10분간 추가건조하였다. 장용층 코팅은 Aquacoat CPD(30% 수분산액)에 가소제로 트리에틸시트레이트 또는 디에틸프탈레이트를 녹인후 흡기온도 45~50도에서 분무 코팅하였다. 최종적으로 히드록시프로필메칠셀룰로오스를 정제수에 녹인후 탈크를 분산키켜 만든 마무리층 코팅액을 분무 코팅하여 둘록세틴염산염 펠렛을 완성하였다.
In the drug coating of duloxetine hydrochloride, the drug was dissolved in an appropriate amount of 20% ethanol, dispersed by adding talc and colloidal silicon dioxide as an antistatic agent, and then spray-coated to Sugas Pierce in a fluidized bed coater (MV-01, Vector). The air intake temperature during spraying was 60 degrees and further dried for 10 minutes after coating. After dissolving hydroxypropyl methyl cellulose in purified water, the separation layer coating solution prepared by dispersing talc was spray-coated under the same conditions and further dried for 10 minutes after coating. The enteric layer coating was spray coated at an intake temperature of 45-50 degrees after dissolving triethyl citrate or diethyl phthalate as a plasticizer in Aquacoat CPD (30% aqueous dispersion). Finally, hydroxypropyl methyl cellulose was dissolved in purified water, followed by spray coating of a coating layer coating solution made by dispersing talc to complete duloxetine hydrochloride pellet.

완성된 펠렛은 미국약전(USP) 용출시험법의 지연방출제형 시험법 중 제1법에 따라 37도의 0.1N 염산액 750mL에서 120분간 용출시험을 실시한 뒤 곧바로 미리 37도로 가온한 0.2M 인산염 완충액 250mL을 가하여 pH6.8로 맞춘 후 360분간 용출시험을 계속하였다. 이때 교반속도는 50rpm, 장치는 패들법 조건에서 실시하였다.
The finished pellet was subjected to elution test for 120 minutes in 750 mL of 37 N 0.1N hydrochloric acid solution in accordance with the first method of the USP dissolution test in the USP dissolution test method, and 250 mL of 0.2M phosphate buffer warmed to 37 degrees in advance. After adding to pH6.8, dissolution test was continued for 360 minutes. At this time, the stirring speed was 50rpm, the device was carried out under the paddle method conditions.

실시예1~3은 전체 중량대비 약 50%의 당핵을 사용하고 동일한 양의 약물이 코팅된 펠렛에 대해 장용층 코팅량을 변화시킨 것이다. 이 때 장용층 코팅액 조성비율은 고정하고 코팅량만 변화시켰다. Examples 1 to 3 used about 50% of the total weight of the nucleus and changed the amount of enteric layer coating for pellets coated with the same amount of drug. At this time, the enteric layer coating liquid composition ratio was fixed and only the coating amount was changed.

표1. 실시예1의 조성(단위:mg)Table 1. Composition of Example 1 (Unit: mg)

Figure pat00001

Figure pat00001

표2. 실시예2의 조성(단위:mg)Table 2. Composition of Example 2 (Unit: mg)

Figure pat00002

Figure pat00002

표3. 실시예3의 조성(단위:mg)Table 3. Composition of Example 3 (Unit: mg)

Figure pat00003

Figure pat00003

실시예 4~6은 실시예 1~3에서 당핵의 양을 절반으로 줄였으며 나머지 조건은 동일하게 하였다. Examples 4 to 6 reduced the amount of the nucleus in half in Examples 1 to 3 and the remaining conditions were the same.

표4. 실시예4의 조성(단위:mg)Table 4. Composition of Example 4 (Unit: mg)

Figure pat00004

Figure pat00004

표5. 실시예5의 조성(단위:mg)Table 5. Composition of Example 5 (Unit: mg)

Figure pat00005
Figure pat00005

표6. 실시예6의 조성(단위:mg)Table 6. Composition of Example 6 (Unit: mg)

Figure pat00006
Figure pat00006

실시예 7은 장용층 코팅시 가소제로 수용성 가소제인 트리에틸시트레이트 대신 비수용성인 디에틸프탈레이트를 사용하였고 작업조건은 동일하게 하였다.
Example 7 used water-insoluble diethyl phthalate instead of water-soluble plasticizer triethyl citrate as a plasticizer for enteric layer coating, and the working conditions were the same.

표7. 실시예7의 조성(단위:mg)Table 7. Composition of Example 7 (Unit: mg)

Figure pat00007

Figure pat00007

심발타 캡슐 및 실시예 1~7까지의 펠렛에 대하여 pH1.2 완충액에서 용출시험을 실시한 결과 모두 120분까지 약물이 검출되지 않아 의도한 장용코팅이 잘 되었음을 확인할 수 있었다. pH6.8 완충액에서의 용출시험 결과는 아래와 같다.
Simulta capsules and pellets of Examples 1 to 7 as a result of the dissolution test in the pH 1.2 buffer all the drug was not detected until 120 minutes was confirmed that the intended enteric coating was well done. The results of the dissolution test in pH6.8 buffer are as follows.

표8. pH6.8에서의 용출률(단위:%)Table 8. Dissolution Rate at pH6.8 (Unit:%)

Figure pat00008

Figure pat00008

장용성 코팅층의 양이 증가할수록 용출률이 지연되는 경향을 보였다.(실시예1~3) 또한 당핵으로 사용한 슈가스피어스의 양이 감소했을 경우 같은 양의 분리층 및 장용층을 코팅하였을 때 용출률이 낮아지는 경향을 보였다.(실시예 4~6) As the amount of the enteric coating layer increased, the dissolution rate tended to be delayed. (Examples 1 to 3) Also, when the amount of sugas pierus used as the nucleus decreased, the dissolution rate decreased when the same amount of separation layer and enteric layer were coated. It showed a tendency. (Examples 4-6)

수용성 가소제를 사용한 실시예3과 비수용성 가소제를 사용한 실시예7은 용출시험시 유의성 있는 차이를 보이지 않아 가소제의 용해 특성에 대한 영향은 무시할 만 하였다.
Example 3 using the water-soluble plasticizer and Example 7 using the water-insoluble plasticizer showed no significant difference in the dissolution test, so the effect on the dissolution properties of the plasticizer was negligible.

실시예2는 용출 개시 약 15분까지는 심발타 캡슐보다 낮은 용출률을 보였으나 30분 이후부터는 대조약과 약 5%차이로 동등한 용출률을 보였다.Example 2 showed a lower dissolution rate than Simbalta capsule until about 15 minutes after the dissolution, but the dissolution rate was about 5% difference from the reference drug after 30 minutes.

장용 코팅제로서 셀룰로오스아세테이트 프탈산 수분산액인 Aquacoat CPD를 이용하여 제조공정을 단축되고 제조시 취급이 용이하여 작업성이 개선된 둘록세틴염산염의 지연방출형 제제를 제조하였으며 시판중인 심발타캡슐과 pH6.8완충액에서 용출률이 동등하였다.
Aquacoat CPD, an aqueous solution of cellulose acetate phthalic acid as an enteric coating, was used to prepare a delayed-release formulation of duloxetine hydrochloride, which shortened the manufacturing process and improved handling efficiency during manufacturing. The dissolution rates were equal at.

본 발명은 기존의 생산설비를 이용하면서 작업자에게 위해한 유기용매 또는 악취로부터 보호될 수 있는 재료를 이용하는 제제를 개발하였다. 본 발명을 통해 기존 시판품과 동일한 약물방출양상을 보이면서 제조방법 및 작업성이 개선되어 생산비용을 절감하고 작업자의 안전을 개선시킬수 있을 것으로 사료된다.The present invention has developed a formulation using materials that can be protected from organic solvents or odors that are harmful to workers while using existing production equipment. The present invention is expected to improve the manufacturing method and workability while reducing the production cost and improve the safety of the worker while showing the same drug release pattern as conventional commercial products.

도1은 심발타캡슐 및 실시예 1~3의 pH6.8 완충액에서의 용출시험 결과이다.
도2는 실시예4~6의 pH6.8 완충액에서의 용출시험 결과이다.Figure 1 is a dissolution test results in the pH 6.8 capsules of Simbalta capsules and Examples 1-3.
Figure 2 is a dissolution test results in the pH6.8 buffer of Examples 4-6.

Claims (3)

불활성 코어, 둘록세틴염산염을 포함하는 약물층, 분리층 및 셀룰로오스아세테이트프탈산을 포함하는 장용층으로 구성되며 (a) 장용층이 펠렛 전체 중량대비 5~20% 인 제제 (b) 장용층 코팅제가 셀룰로오스아세테이트프탈산 수분산액인 제제
An inert core, a drug layer comprising duloxetine hydrochloride, a separation layer and an enteric layer comprising cellulose acetate phthalic acid, wherein (a) the enteric layer is 5-20% of the total weight of the pellet (b) the enteric layer coating agent is cellulose Acetate phthalic acid aqueous solution
청구항1에서 셀룰로오스아세테이트프탈산 수분산액이 아쿠아코트 씨피디(Aquacoat CPD)인 지연방출형 제제
The delayed-release preparation of claim 1, wherein the aqueous cellulose acetate phthalic acid dispersion is Aquacoat CPD.
불활성 코어를 준비하는 단계, 불활성 코어 위에 약물액을 도포하여 약물층을 형성하는 단계, 분리층 코팅액을 도포하여 분리층을 형성하는 단계 및 장용성 코팅액을 도포하여 장용층을 형성하는 단계로 제조되는 지연방출형 제제 A delay prepared by preparing an inert core, applying a drug solution on the inert core to form a drug layer, applying a separation layer coating solution to form a separation layer, and applying an enteric coating solution to form an enteric layer. Release formulation
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104414993A (en) * 2013-08-20 2015-03-18 天津药物研究院 Duloxetine hydrochloride enteric micro-pellet capsule and preparation method thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104414993A (en) * 2013-08-20 2015-03-18 天津药物研究院 Duloxetine hydrochloride enteric micro-pellet capsule and preparation method thereof

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