KR20010021644A - Novel Comosition - Google Patents

Novel Comosition Download PDF

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KR20010021644A
KR20010021644A KR1020007000202A KR20007000202A KR20010021644A KR 20010021644 A KR20010021644 A KR 20010021644A KR 1020007000202 A KR1020007000202 A KR 1020007000202A KR 20007000202 A KR20007000202 A KR 20007000202A KR 20010021644 A KR20010021644 A KR 20010021644A
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pharmaceutical composition
pindolol
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depression
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폴 존 커밍스
이안 프레데릭 털로우치
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피터 기딩스
스미스클라인비이참피이엘시이
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Abstract

급속 방출 형태의 SSRI 및 서방성 방출 형태의 β-차단제를 포함하는 제약 조성물.A pharmaceutical composition comprising SSRIs in the form of rapid release and β-blockers in the form of sustained release.

Description

신규한 조성물 {Novel Comosition}Novel Comosition

본 발명은 선택적 세로토닌 재흡수 억제제 (selective serotonin re-uptake inhibitor, SSRI)의 신규한 제제에 관한 것이다. 구체적으로는 본 발명은 SSRI의 치료 활성을 증가시키고, 특히 치료 효과의 징후를 향상시키는 제제를 제공한다.The present invention relates to novel formulations of selective serotonin re-uptake inhibitors (SSRIs). In particular, the present invention provides agents which increase the therapeutic activity of SSRIs, and in particular, enhance the manifestation of the therapeutic effect.

아티가스 (Artigas) 등 (Arch. Gen Psychiatry, Vol. 51, pp248-251, Mar. 1994)은 SSRI 파록세틴 (20 mg, 하루 1회)을 사용한 치료 중에 핀돌올 (2.5 mg, 하루 3회)을 함께 투여하는 것이 이전에 파록세틴의 치료로부터 효과를 나타내지 않았던 환자의 우울증을 경감시키는 것을 보고하였다.Artigas et al. (Arch. Gen Psychiatry, Vol. 51, pp248-251, Mar. 1994) used pindolol (2.5 mg, 3 times a day) during treatment with SSRI paroxetine (20 mg, once a day). Co-administration has been reported to alleviate depression in patients who have not previously had an effect from treatment with paroxetine.

그 후에, SSRI 시탈로프롤람, 플루복스아민 및 파록세틴의 효과가 특히 파록세틴-핀돌올의 조합을 제외하고는 핀돌올, 펜부톨올, 프로프란올 및 테르타톨올 및 세로토닌 IA 수용체 길항제로 알려진 다른 화합물과의 특정 조합으로 공동 투여하여 증가될 수 있는 것으로 유럽 특허 제EP-A-0714663호에 제안되었다.Subsequently, the effects of SSRI citaloprolam, fluvoxamine and paroxetine are combined with other compounds known as pindolol, phenbutolol, propranol and tertatolol and serotonin IA receptor antagonists, with the exception of the combination of paroxetine-pindolol, in particular It has been proposed in EP-A-0714663 which can be increased by co-administration in certain combinations of.

공동 투여 방법, 특히 하루 동안에 3회에 약물을 복용하는 것을 포함하는 (파록세틴 복용 및 첫번째 핀돌올 복용이 동시에 행해지는 것으로 가정됨) 아티가스에 의하여 제안된 방법에서의 문제점은 환자를 복약 준수하게 하는 것이다.The problem with the co-administration method, especially the method proposed by Articas, which involves taking the drug three times in a day (assuming paroxetine and the first pindolol dose are taken simultaneously), makes the patient adhere to medication. will be.

본 발명은 SSRI 및 약효 증가 화합물의 동시 투여와 관련된 문제점을 극복하는 것이 목적이다.It is an object of the present invention to overcome the problems associated with simultaneous administration of SSRIs and potentiating compounds.

넓은 관점에서, 본 발명은 급속 방출 형태의 SSRI 및 서방성 방출 형태의 β-차단제를 포함하는 SSRI 조성물을 제공한다. 조성물은 편리하게는 정제 또는 캡슐 형태이다.In a broad aspect, the present invention provides an SSRI composition comprising SSRIs in the form of rapid release and β-blockers in the form of sustained release. The composition is conveniently in the form of a tablet or capsule.

본 발명에 사용되는 전형적인 SSRI는 파록세틴, 플루복스아민, 시탈로프람 및 세르트랄린이다. 바람직하게는 SSRI는 파록세틴이다. 동시 투여되는 β-차단제는 바람직하게는 핀돌올이다.Typical SSRIs used in the present invention are paroxetine, fluvoxamine, citalopram and sertraline. Preferably the SSRI is paroxetine. The co-administered β-blocker is preferably pindolol.

SRRI와 β-차단제의 바람직한 조합은 파록세틴과 핀돌올이다. 바람직하게는 정제 또는 캡슐은 속방형 파록세틴 20 mg과 서방형 핀돌올 7.5 mg을 함유한다.Preferred combinations of SRRI and β-blockers are paroxetine and pindolol. Preferably the tablet or capsule contains 20 mg of immediate release paroxetine and 7.5 mg of sustained release pindolol.

전형적으로는 β-차단제의 서방형은 12-16 시간에 걸쳐서 연속적으로 일일 복용량을 3회 동등한 양으로 방출하여 제공된다. 다른 방법으로는, 복용량은 간격을 둔 3회 트랜치로 방출될 수 있다.Typically, sustained release of β-blockers are provided by releasing three equivalent daily doses in succession over 12-16 hours. Alternatively, the dose may be released in three spaced intervals.

SSRI가 연속 방출 제제로 β-차단제와 조합될 때, 본 발명의 조성물은 바람직하게는 한 층은 통상적인 급속 방출 제제의 SSRI를 함유하고 다른 층은 서방성 방출 제제인 β-차단제를 함유하는 이중층 정제로 제공된다.When SSRIs are combined with β-blockers in a continuous release formulation, the compositions of the present invention preferably comprise one layer containing the SSRI of a conventional rapid release formulation and the other layer containing a β-blocker, a sustained release formulation. It is provided as a tablet.

서방성 방출은 β-차단제 또는 SRRI와 상호작용하지 않는 통상적인 서방성 방출 부형제 또는 부형제의 블렌드와 함께 β-차단제를 제제하여 제공될 수 있다.Sustained release can be provided by formulating a β-blocker with a conventional sustained release release excipient or blend of excipients that does not interact with the β-blocker or SRRI.

적합하게는, 서방성 방출성은 위액 중에서 팽윤하여 전형적으로는 환자의 소화관을 통하여 정제가 통과할 때 용해하고(거나) 침식되는 겔을 형성하고, 활성 성분을 방출하는 부형제 중에 β-차단제를 혼입하여 제공된다. 방출 속도는 부형제의 분자량을 변화시키고(거나) 주요 부형제와는 다른 속도로 용해하거나 분해하여 팽윤되거나 겔화된 주요 부형제 중에서 미세 기공을 형성하는 물질과 함께 주요 부형제를 공동 제제화하여 통상적인 방법으로 조절될 수 있다.Suitably, the sustained release release swells in gastric fluid, typically forming a gel that dissolves and / or erodes as the tablet passes through the patient's digestive tract, and incorporates a β-blocker in an excipient that releases the active ingredient. Is provided. The release rate can be controlled in a conventional manner by varying the molecular weight of the excipient and / or co-formulating the major excipients with materials that form micropores in the swollen or gelled major excipients by dissolving or degrading at a different rate than the major excipients. Can be.

적합한 주요 부형제는 예를 들어 상품명 Methocel K4M 및 E5로 판매되는 메틸 셀룰로오스, 에틸 셀룰로오스, 예를 들어 상품명 Carbopol 974P로 판매되는 폴리아크릴산, 예를 들어 상품명 Eudragit L30D 및 RS30D로 판매되는 폴리아크릴산 에스테르, 크산 검 및 전분과 같은 팽윤가능한 결합제로부터 선택될 수 있다.Suitable main excipients are, for example, methyl cellulose sold under the trade names Methocel K4M and E5, for example polyacrylic acid sold under the trade name Carbopol 974P, for example polyacrylic acid esters sold under the trade names Eudragit L30D and RS30D, xan gum And swellable binders such as starch.

주요 부형제의 방출 분포는 락토오스, 특히 락토오스 일수화물, 예를 들어 상품명 Avicel pH102로 판매되는 미정질 셀룰로오스, 황산칼슘, 예를 들어 상품명 Encompress로 판매되는 인산이칼슘, 예를 들어 상품명 Povidone 30으로 판매되는 폴리비닐 피롤리돈, 예를 들어 상품명 Lubritab으로 판매되는 수소화 식물성유 등의 충전제 및 붕해제를 혼입하여 변경할 수 있다.The release distribution of the main excipients is lactose, in particular lactose monohydrate, for example microcrystalline cellulose sold under the trademark Avicel pH102, for example dicalcium phosphate sold under the trade name Encompress, for example under the name Povidone 30 It can be modified by incorporating polyvinyl pyrrolidone, for example fillers and disintegrants such as hydrogenated vegetable oil sold under the trade name Lubritab.

통상적인 정제화 부형제는 마그네슘 스테아레이트, 예를 들어 상품명 Compritol 888로 판매되는 글리세릴 베헤네이트와 같은 다이 윤활제 등으로 정제 제조를 돕는 데 포함될 수도 있다.Conventional tableting excipients may be included to aid in tablet manufacture with magnesium stearate, for example a die lubricant such as glyceryl behenate sold under the name Compritol 888.

다른 방법으로는, 조성물은 β-차단제의 코팅된 펠렛을 포함하는 캡슐 모양일 수 있고, 이는 SSRI의 분말 제제 중에 분산되어 있고, 모두 녹기 쉬운 캡슐 안에 함유된, 용해 시간이 서로 다른 코팅된 펠렛의 혼합물이다.Alternatively, the composition may be in the form of a capsule comprising coated pellets of β-blockers, which are dispersed in a powder formulation of SSRI and contained in capsules of different dissolution times, all contained in a soluble capsule. Mixture.

적합하게는, β-차단제의 펠렛의 코팅은 위액에는 저항성이지만 예를 들면 소화관에서는 용해하는 물질이다. 용해 시간은 코팅 두께를 달리하여 변화시킬 수 있다. 바람직하게는 코팅된 펠렛은 혼합되어 실질적으로는 핀돌올의 연속적인 방출을 제공하지만, 필요한 경우 핀돌올이 12-14 시간 등의 소정의 투약 기간에 걸쳐 3회 트랜치로 방출되도록 펠렛은 3개의 코팅 두께를 가진 혼합물일 수 있다. SSRI의 분말형 제제는 SSRI를 통상적인 부형제와 혼합하여 제조할 수 있다. 활성 성분의 조합을 함유하는 녹기 쉬운 캡슐은 통상적으로는 젤라틴으로 제조될 수 있다.Suitably, the coating of pellets of β-blockers is a substance resistant to gastric juice but soluble in, for example, the digestive tract. Dissolution time can be varied by varying the coating thickness. Preferably the coated pellets are mixed to provide substantially continuous release of pindolol, but the pellet is coated in three coatings so that the pindolol is released in three trenches over a predetermined dosing period, such as 12-14 hours, if necessary. It may be a mixture having a thickness. Powdered formulations of SSRIs can be prepared by mixing SSRIs with conventional excipients. Dissolvable capsules containing a combination of active ingredients can typically be made from gelatin.

본 발명에서 사용될 수 있는 상기 기재된 친수성 매트릭스 유형 및 장용성 코팅 유형의 전형적인 서방성 방출 제제는 그 문제에 대한 표준 교과서들에 개시되어 있다.Typical sustained release release formulations of the hydrophilic matrix type and enteric coating type described above that can be used in the present invention are disclosed in standard textbooks for that matter.

본 발명자들은 서방성 방출 β-차단제 제제가 산/완충액 중에서 용해 시간이 T50%1.73 시간, T90%8.45 시간 및 T100%14 시간으로 시험관 내 측정된 방출 분포를 가질 때, 임상 용도에 적합한 방출 분포를 얻는 것을 드디어 발견하였다.We believe that sustained release β-blocker formulations are suitable for clinical use when the dissolution time in acid / buffer has a release distribution measured in vitro with T 50% 1.73 h, T 90% 8.45 h and T 100% 14 h. It was finally found to obtain the release distribution.

따라서, 본 발명의 바람직한 일 실시양태는 SSRI와, T50%1.73 시간±20%, T90%8.45 시간±20% 및 T100%14 시간±20%의 시험관 내 방출 분포를 가진 서방성 방출 형태인 β-차단제의 제제를 제공한다.Thus, one preferred embodiment of the present invention is a sustained release form with SSRI and in vitro release distribution of T 50% 1.73 hours ± 20%, T 90% 8.45 hours ± 20% and T 100% 14 hours ± 20% Provided are formulations of phosphorus β-blockers.

바람직하게는, SSRI는 가장 바람직하게는 20 mg의 복용량으로 파록세틴 염산염이고, β-차단제는 가장 바람직하게는 7.5 mg의 복용량으로 핀돌올이다.Preferably, the SSRI is paroxetine hydrochloride in a dose of 20 mg most preferably and the β-blocker is pindolol in a dose of 7.5 mg most preferably.

핀돌올은 전형적으로는 구매 가능한 라세미체로 사용된다. 그러나, 그의 활성 이성질체는 라세미체의 공인된 분량에 대한 생물학적으로 동등하게 조절된 복용량으로 사용될 수 있다.Pindolol is typically used as a commercially available racemate. However, its active isomers may be used in biologically equally controlled dosages for recognized amounts of racemates.

본 발명의 조성물, 특히 파록세틴 염산염 및 핀돌올의 조성물의 치료 용도는 본 명세서에서 "질환"으로 언급되는 알코올 중독증, 불안, 우울증, 강박성 질환 (OCD), 공황 질환, 만성 통증, 비만, 노인성 치매, 편두통, 대식증, 식욕 부진증, 사회 공포증, 월경전 증후군 (PMS), 청년기 우울증, 발모벽, 기분변조 및 물질 남용의 치료를 포함한다.Therapeutic uses of the compositions of the invention, in particular paroxetine hydrochloride and pindolol, include alcoholism, anxiety, depression, obsessive compulsive disease (OCD), panic disease, chronic pain, obesity, senile dementia, referred to herein as "diseases", Migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression, hair growth, mood alteration and substance abuse.

따라서, 본 발명은 또한Thus, the present invention also

인간 및 동물의 질환의 치료 또는 예방을 위한 정제 또는 캡슐의 제조를 위한 SSRI 및 서방성 방출 형태의 β-차단제의 용도, 및The use of SSRIs and sustained release forms of β-blockers for the manufacture of tablets or capsules for the treatment or prevention of diseases of humans and animals, and

SSRI 및 서방성 방출 형태의 β-차단제를 포함하는 정제 또는 캡슐을 질환의 치료 또는 예방을 필요로 하는 개인 또는 동물에게 투여하는 것을 포함하는, 질환의 치료 또는 예방 방법A method of treating or preventing a disease comprising administering a tablet or capsule comprising an SSRI and a sustained release form of β-blocker to an individual or animal in need thereof.

을 제공한다.To provide.

본 발명의 용도 및 방법에서, 정제 또는 캡슐은 바람직하게는 상기에 지시된 바람직한 값을 가진 본 발명의 조성물이다.In the uses and methods of the present invention, the tablet or capsule is preferably a composition of the present invention having the preferred values indicated above.

본 발명은 다음 실시예에서 예시된다.The invention is illustrated in the following examples.

<실시예 1><Example 1>

파록세틴 및 서방성 방출 핀돌올의 이중층 정제를 다음과 같이 제조하였다.Bilayer tablets of paroxetine and sustained release pindolol were prepared as follows.

<핀돌올 성분><Pindolol component>

일단 수화된 매트릭스의 다공성을 증가시키는 가용성 충전제/붕해제와 함께 친수성 매트릭스를 기재로 하는 핀돌올의 서방성 방출형은The sustained release form of pindolol based on a hydrophilic matrix with a soluble filler / disintegrant that increases the porosity of the hydrated matrix once

핀돌올 기재 7.5 중량부7.5 parts by weight of pindolol base

메틸셀룰로오스 (Methocel K4M) 35 중량부Methyl cellulose (Methocel K4M) 35 parts by weight

락토오스 일수화물 25 중량부Lactose Monohydrate 25 parts by weight

미정질 셀룰로오스 (Avicel pH102) 32 중량부32 parts by weight of microcrystalline cellulose (Avicel pH102)

의 혼합물의 고전단 습윤 입상화에 의하여 제조되었다.It was prepared by high shear wet granulation of a mixture of.

건조시키고 체에 걸른 후, 윤활제로서 글리세릴 베헤네이트 (Compritol 888) 0.5 중량부를 텀블 혼합으로 혼입하였다.After drying and sieving, 0.5 parts by weight of glyceryl behenate (Compritol 888) was incorporated as a lubricant in tumble mixing.

<파록세틴 성분><Paroxetine ingredient>

파록세틴의 속방형 방출 제제는 파록세틴 염산염 20 중량부와 통상의 부형제 80 중량부를 혼합하여 제조하였다.Immediate release formulations of paroxetine were prepared by mixing 20 parts by weight of paroxetine hydrochloride with 80 parts by weight of conventional excipients.

<정제화><Purification>

서방성 방출 핀돌올 제제 100 mg의 양을 첫번째 충전 위치에서 회전 정제화 압반에서 정제 주형 내로 충전하였다. 분말 제제를 정제 주형에 넣기 위해 예비적으로 가볍게 압착한 후에, 압반을 두번째 충전 위치로 이동시켜, 파록세틴 제제 152 mg이 서방성 방출 제제의 상부에 도입되도록 하였다. 이어서 정제 주형 안의 두 층 혼합물에 완전한 압착을 가하여 각 활성 성분이 이중층 정제의 개별 층으로 존재하는, 파록세틴 염산염 20 mg 및 서방성 방출 기재의 핀돌올 7.5 mg을 함유하는 정제 252 mg을 제조하였다.An amount of 100 mg of the sustained release pindolol formulation was filled into a tablet mold in a rotary tableting platen at the first filling position. After preliminarily pressing the powder formulation into the tablet mold, the platen was moved to the second filling position to allow 152 mg of paroxetine formulation to be introduced on top of the sustained release formulation. Complete compression of the two layer mixture in the tablet template was then made to prepare a tablet 252 mg containing 20 mg of paroxetine hydrochloride and 7.5 mg of sustained release release pindolol, with each active ingredient present as a separate layer of the bilayer tablet.

Claims (13)

급속 방출 형태의 SSRI 및 서방성 방출 형태의 β-차단제를 포함하는 (comprising) 제약 조성물.A pharmaceutical composition comprising SSRIs in the form of rapid release and β-blockers in the form of sustained release. 제1항에 있어서, 한 층이 급속 방출 제제인 SSRI를 함유하고, 다른 한 층이 서방성 방출 제제인 β-차단제를 함유하는 이중층 정제 형태의 제약 조성물.The pharmaceutical composition according to claim 1, wherein one layer contains SSRI, a rapid release formulation, and the other layer contains a β-blocker, a sustained release formulation. 제1항에 있어서, 급속 방출 제제인 SSRI 및 서방성 방출 제제인 β-차단제의 혼합물을 함유하는 캡슐 형태의 제약 조성물.The pharmaceutical composition of claim 1 containing a mixture of SSRI, a rapid release formulation, and β-blocker, a sustained release formulation. 제1항 내지 제3항 중 어느 한 항에 있어서, β-차단제가 T50%1.73 시간±20%, T90%8.45 시간±20% 및 T100%14 시간±20%의 시험관 내 방출 분포를 가지는 서방성 방출 형태인 제약 조성물.The method of claim 1, wherein the β-blocker has an in vitro release distribution of T 50% 1.73 h ± 20%, T 90% 8.45 h ± 20% and T 100% 14 h ± 20%. The pharmaceutical composition is in a sustained release form. 제1항 내지 제4항 중 어느 한 항에 있어서, SSRI가 파록세틴 또는 제약상 허용되는 그의 유도체인 제약 조성물.The pharmaceutical composition according to any one of claims 1 to 4, wherein the SSRI is paroxetine or a pharmaceutically acceptable derivative thereof. 제5항에 있어서, 파록세틴이 염산염 형태인 제약 조성물.6. The pharmaceutical composition of claim 5, wherein the paroxetine is in hydrochloride form. 제1항 내지 제6항 중 어느 한 항에 있어서, β-차단제가 핀돌올인 제약 조성물.The pharmaceutical composition according to any one of claims 1 to 6, wherein the β-blocker is pindolol. 제7항에 있어서, 핀돌올이 라세미체로 존재하는 제약 조성물.8. A pharmaceutical composition according to claim 7, wherein the pindolol is present in the racemate. 제8항에 있어서, 파록세틴 염산염 20 mg 및 핀돌올 라세미체 7.5 mg을 함유하는 제약 조성물.The pharmaceutical composition of claim 8 which contains 20 mg of paroxetine hydrochloride and 7.5 mg of pindolol racemate. 제7항에 있어서, 핀돌올이 활성 이성질체로 존재하는 제약 조성물.8. A pharmaceutical composition according to claim 7, wherein pindolol is present as the active isomer. 제1항 내지 제10항 중 어느 한 항에 따른 제약 조성물의 유효량 또는 예방양을 알코올 중독증, 불안, 우울증, 강박성 질환 (OCD), 공황 질환, 만성 통증, 비만, 노인성 치매, 편두통, 대식증, 식욕 부진증, 사회 공포증, 월경전 증후군 (PMS), 청년기 우울증, 발모벽, 기분변조 및 물질 남용의 치료를 필요로 하는 환자에게 투여하는 것을 포함하는 상기 질환의 치료 방법.An effective amount or prophylactic amount of a pharmaceutical composition according to any one of claims 1 to 10 is determined by alcoholism, anxiety, depression, obsessive compulsive disease (OCD), panic disease, chronic pain, obesity, senile dementia, migraine, bulimia, appetite A method of treating said disease, comprising administering to a patient in need of treatment of underuse, social phobia, premenstrual syndrome (PMS), adolescent depression, hair growth, mood alteration, and substance abuse. 알코올 중독증, 불안, 우울증, 강박성 질환 (OCD), 공황 질환, 만성 통증, 비만, 노인성 치매, 편두통, 대식증, 식욕 부진증, 사회 공포증, 월경전 증후군 (PMS), 청년기 우울증, 발모벽, 기분변조 및 물질 남용의 치료 또는 예방용 약물의 제조에서 제1항 내지 제10항 중 어느 한 항에서 정의된 제약 조성물의 용도.Alcoholism, anxiety, depression, obsessive compulsive disease (OCD), panic disease, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression, hair growth walls, mood alteration and Use of a pharmaceutical composition as defined in any of claims 1 to 10 in the manufacture of a medicament for the treatment or prophylaxis of substance abuse. 알코올 중독증, 불안, 우울증, 강박성 질환 (OCD), 공황 질환, 만성 통증, 비만, 노인성 치매, 편두통, 대식증, 식욕 부진증, 사회 공포증, 월경전 증후군 (PMS), 청년기 우울증, 발모벽, 기분변조 및 물질 남용의 치료 또는 예방에 사용하기 위한 제1항 내지 10항 중 어느 한 항에서 정의된 제약 조성물.Alcoholism, anxiety, depression, obsessive compulsive disease (OCD), panic disease, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression, hair growth walls, mood alteration and A pharmaceutical composition as defined in any one of claims 1 to 10 for use in the treatment or prevention of substance abuse.
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