WO2017146305A1 - Pharmaceutical composition for treatment of depression accompanied by acute coronary syndrome - Google Patents

Pharmaceutical composition for treatment of depression accompanied by acute coronary syndrome Download PDF

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WO2017146305A1
WO2017146305A1 PCT/KR2016/005618 KR2016005618W WO2017146305A1 WO 2017146305 A1 WO2017146305 A1 WO 2017146305A1 KR 2016005618 W KR2016005618 W KR 2016005618W WO 2017146305 A1 WO2017146305 A1 WO 2017146305A1
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citalopram
pharmaceutical composition
depression
coronary syndrome
acute coronary
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PCT/KR2016/005618
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French (fr)
Korean (ko)
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김재민
김성완
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전남대학교 산학협력단
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • the present invention relates to a pharmaceutical composition for treating depression associated with acute coronary syndrome.
  • Acute coronary syndrome is a serious disease with the highest mortality rate in the world.
  • Acute coronary syndrome is a term that encompasses all acute symptoms caused by a decrease in myocardial blood supply. These acute symptoms are ST elevation MI (STMI) and ST segment non-Elevation myocardial infarction (NSTEMI). ), Also known as unstable angina (UA).
  • STMI ST elevation MI
  • NSTEI ST segment non-Elevation myocardial infarction
  • U unstable angina
  • depression after acute coronary syndrome decreases the quality of life and increases the risk of dying from months to years after acute coronary syndrome, it is very important to effectively treat depression, the most powerful predictor of quality of life after acute coronary syndrome. It also plays a positive role in the rehabilitation of acute coronary syndrome patients.
  • the problem to be solved by the present invention is to provide a pharmaceutical composition for the treatment of depression that is common in acute coronary syndrome patients, and does not cause side effects even when administered with acute coronary syndrome treatment.
  • a pharmaceutical composition for treating depression comprising statins and S-citalopram.
  • statin is present in 10 to 20 mg pharmaceutical composition for treating depression.
  • statin is at least one selected from the group consisting of rosuvastatin, atorvastatin, pravastatin, mevastatin, and itavastatin.
  • statin is pravastatin or rosuvastatin.
  • statin and the S-citalopram include simultaneous administration, combined administration or continuous administration.
  • compositions for treating depression according to 1 above wherein the composition is administered in combination with an acute coronary agent.
  • a method of treating depression comprising administering a pharmaceutical composition for treating depression, comprising statins and S-citalopram.
  • statins and S-citalopram will increase the therapeutic effect against depression developed after Acute Coronary Syndrome at least about three times higher than the administration of S-citalopram alone, a commonly used antidepressant. It can be effective.
  • 1 is a view showing the treatment response rate for the group administered statin and S-citalopram according to the present invention.
  • FIG. 2 is a diagram showing the average Hamilton rating scale (HAM-D) (FIG. 2A) and the Beck Depression Scale score over time (FIG. 2B) for a group administered statins and S-citalopram according to the present invention. .
  • HAM-D average Hamilton rating scale
  • FIG. 2B Beck Depression Scale score over time
  • the present invention is intended to develop a drug that can be used in patients with acute coronary syndrome, that is, even when administered with acute coronary syndrome treatment does not cause side effects.
  • the present invention provides a composition for treating depression, in which depression is enhanced by a combination of statins and S-citalopram, preferably an aftereffect of depression after the onset of coronary syndrome.
  • composition according to the present invention may be administered in combination with an acute coronary agent.
  • the therapeutic response rate is 55.7%, 31.4% when using S-citalopram alone, and 25% when using placebo, and when statin and S-citalopram are used in combination It was confirmed that the treatment response compared to placebo was 4.7 times higher than that of S-citalopram alone.
  • the statin of the present invention may be included in 10 to 20 mg, the S-citalopram may be included in the amount of 5 to 10 mg in half the dose commonly used in patients with depression.
  • S-citalopram is a drug that suppresses the reuptake of serotonin at the synapse and shows the effect of serotonin for a longer time.
  • S-citalopram is administered in an amount of 10 to 20 mg. In this case, weight gain, worsening of depression, and suicidal thoughts It is known to have side effects such as hyperactivity and behavior (suicide propensity), abnormal behavioral manifestations.
  • statin and S-citalopram when statin and S-citalopram are used together, the amount of S-citalopram is reduced to 5 to 10 mg or more by 50% while statin is generally used after the onset of coronary syndrome. It has been confirmed that it can be usefully used for treatment.
  • the statin of the present invention may be at least one selected from the group consisting of rosuvastatin, atorvastatin, pravastatin, mevastatin, and itavastatin, preferably, the statin is pravastatin or rosuvastatin.
  • statins pravastatin and rosuvastatin are known to have side effects of depression and sleep disorders, and according to the present invention, by using S-citalopram together, it is useful for treating depression, which is a sequelae after the onset of coronary syndrome. It was confirmed that it can be used.
  • statins and S-citalopram are conveniently administered once daily.
  • the statin and the S-citalopram may comprise simultaneous administration, combined administration or continuous administration.
  • Statins and S-citalopram combinations of the invention may be administered simultaneously or sequentially in the same or different pharmaceutical compositions.
  • the delay in administration of the second active ingredient should not be such that it would lose the benefit of the synergistic effect of the present invention.
  • continuous administration does not include a delay of more than 12 hours and is preferably within 1 hour before and after meals.
  • statins and S-citalopram are conveniently provided in the same unit dose form as a capsule or tablet or a fluid containing two active agents in suitable concentrations.
  • statins and S-citalopram required to treat depression, a sequelae after the onset of coronary syndrome, will vary from patient to patient, and ultimately the general symptoms and disorders of body weight, route of administration, medication involved, age, sex and disease It is determined by the attending physician taking into account well known factors such as characteristics and severity.
  • S-citalopram and statins at the dosage ratios described herein can be easily formulated in conventional pharmaceutical carriers with conventional excipients.
  • the compounds of the invention are particularly suitable for oral administration but can also be administered rectally, vaginally, intranasally, topically, transdermally or parenterally, for example intramuscularly, intravenously or dural.
  • the compound may be administered alone, for example in a capsule, but is generally administered in conjunction with a pharmaceutically acceptable carrier or diluent.
  • the present invention includes a method of preparing a pharmaceutical composition comprising linking or associating statins with S-citalopram with a pharmaceutically acceptable carrier or vehicle.
  • Oral formulations may conveniently be prepared in unit dosage form such as capsules or tablets using conventional carriers or binders, for example magnesium stearate, chalk, starch, lactose, wax, gum or gelatin.
  • carriers or binders for example magnesium stearate, chalk, starch, lactose, wax, gum or gelatin.
  • Sustained release preparations can be obtained using liposomes or synthetic or natural polymers such as HPMC or PVP.
  • the formulations may be nasal drops or ocular drops, syrups, gels or creams, including solutions, suspensions, emulsions, oil-in-water or water-in-oil preparations in conventional vehicles such as water, saline, ethanol, vegetable oils or glycerin. And optionally with fragrances and / or preservatives and / or emulsifiers.
  • statin and S-citalopram in the treatment of depression in patients with coronary syndrome, a prospective cohort study and 24-week double-blind, placebo-controlled clinical trial data for patients with coronary syndrome. Used.
  • the initial dose of S-citalopram is 5 mg / day. After the second evaluation, the dosage is determined clinically by the investigator taking into account the severity of the depression and the tolerability of the drug. The drug was administered orally within 30 minutes after dinner once a day.
  • test drug provided S-citalopram as a placebo of the same form, and the placebo was given in the same form as the S-citalopram size.
  • the group treated with S-citalopram and statin had the highest therapeutic response rate in both HAM-D and BDI scores, and the lowest response rate in the group not taking both drugs. Seemed.
  • statin and S-citalopram together, the group taking each group, and the group not taking the group showed significant difference in depressive improvement with time, similar to the response rate of statin and S-citalopram.
  • both HAM-D and BDI scores showed the most remarkable improvement after one year and showed the least therapeutic response in the group not taking the two drugs (see FIG. 2).
  • statins can increase the effects of serotonin-based antidepressants on depression in patients with acute coronary syndrome, and thus, statins can be used to treat depression as well as to treat hyperlipidemia.

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  • Medicinal Chemistry (AREA)
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Abstract

The present invention relates to a pharmaceutical composition for the treatment of depression accompanied by acute coronary syndrome. If a lipophilic statin according to the present invention is administered in combination with S-citalopram, the treatment effect against the depression that occurs after the acute coronary syndrome can increase about three times or more as compared with a single administration of the S-citalopram, which is commonly used as an antidepressant.

Description

급성관동맥증후군에 동반되는 우울증 치료용 약제학적 조성물Pharmaceutical composition for the treatment of depression associated with acute coronary syndrome
본 발명은 급성관동맥증후군에 동반되는 우울증 치료용 약제학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for treating depression associated with acute coronary syndrome.
급성관동맥증후군(acute coronary syndrome, ACS)은 세계적으로 사망률 1위인 심각한 질환이다. 급성관동맥증후군은 심근의 혈액공급 저하에 기인하는 모든 급성 증상을 아우르는 용어이며, 이러한 급성 증상은 ST분절 상승 심근경색증(ST elevation MI, STEMI), ST분절 비상승 심근경색증(non ST elevation MI, NSTEMI), 불안정성 협심증(unstable angina, UA)을 통칭한다. 급성관동맥증후군 환자는 사망률이 높을 뿐 아니라, 그 치료비용도 커 개인 및 사회에 큰 부담을 안겨주는 질환이다.Acute coronary syndrome (ACS) is a serious disease with the highest mortality rate in the world. Acute coronary syndrome is a term that encompasses all acute symptoms caused by a decrease in myocardial blood supply. These acute symptoms are ST elevation MI (STMI) and ST segment non-Elevation myocardial infarction (NSTEMI). ), Also known as unstable angina (UA). Acute coronary syndrome patients not only have a high mortality rate, but also a large burden on the individual and society due to the high cost of treatment.
급성관동맥증후군의 후유증으로 우울증이 발병할 가능성이 일반인에 비해 3-4배 높다고 보고되었다. 특히 급성관동맥증후군 후 우울증이 발병한 경우 우울증이 발생하지 않은 환자에 비해 사망률이 3배 이상 높고, 재발과 장애를 보이는 경우도 훨씬 증가한다고 선행연구에서 보고된 바 있다.It is reported that the risk of developing depression due to sequelae of acute coronary syndrome is 3-4 times higher than that of the general public. In particular, in the case of depression after acute coronary syndrome, the mortality rate is more than three times higher than that in patients without depression, and recurrence and disability are much higher.
이렇게 급성관동맥증후군 후 우울증은 삶의 질을 저하시키고, 급성관동맥증후군 후 수개월에서 수년 사이에 사망할 위험도를 증가시키므로 급성관동맥증후군 후 삶의 질에 가장 강력한 예측 인자인 우울증을 효과적으로 치료하는 것이 매우 중요하며, 이는 또한 급성관동맥증후군 환자의 재활치료에 긍정적인 역할을 한다.Since depression after acute coronary syndrome decreases the quality of life and increases the risk of dying from months to years after acute coronary syndrome, it is very important to effectively treat depression, the most powerful predictor of quality of life after acute coronary syndrome. It also plays a positive role in the rehabilitation of acute coronary syndrome patients.
본 발명이 해결하고자 하는 과제는 급성관동맥증후군 환자에게서 흔하게 나타나는 우울증의 치료할 수 있고, 급성관동맥증후군 치료제와 함께 투여를 한다 해도 부작용을 일으키지 않는 우울증 치료용 약제학적 조성물을 제공하는 것이다.The problem to be solved by the present invention is to provide a pharmaceutical composition for the treatment of depression that is common in acute coronary syndrome patients, and does not cause side effects even when administered with acute coronary syndrome treatment.
1. 스타틴 및 S-시탈로프람을 포함하는, 우울증 치료용 약제학적 조성물.1. A pharmaceutical composition for treating depression, comprising statins and S-citalopram.
2. 위 1에 있어서, 상기 스타틴은 10 내지 20 mg 으로 존재하는 것인 우울증 치료용 약제학적 조성물.2. In the above 1, wherein the statin is present in 10 to 20 mg pharmaceutical composition for treating depression.
3. 위 1에 있어서, 상기 S-시탈로프람은 5 내지 10 mg으로 존재하는 것인 우울증 치료용 약제학적 조성물.3. The pharmaceutical composition for treating depression of 1, wherein the S-citalopram is present in 5 to 10 mg.
4. 위 1에 있어서, 상기 스타틴은 로수바스타틴, 아토르바스타틴, 프라바스타틴, 메바스타틴, 및 이타바스타틴으로 이루어진 군으로부터 선택되는 1종 이상인 우울증 치료용 약제학적 조성물.4. The pharmaceutical composition for treating depression according to 1 above, wherein the statin is at least one selected from the group consisting of rosuvastatin, atorvastatin, pravastatin, mevastatin, and itavastatin.
5. 위 1에 있어서, 상기 스타틴은 프라바스타틴 또는 로수바스타틴인 우울증 치료용 약제학적 조성물.5. The pharmaceutical composition of claim 1, wherein the statin is pravastatin or rosuvastatin.
6. 위 1에 있어서, 상기 스타틴과 상기 S-시탈로프람은 동시 투여, 배합 투여 또는 연속 투여를 포함하는, 우울증 치료용 약제학적 조성물.6. The pharmaceutical composition for treating depression according to 1 above, wherein the statin and the S-citalopram include simultaneous administration, combined administration or continuous administration.
7. 위 1에 있어서, 상기 조성물은 급성관동맥 치료제와 병용투여되는 것인 우울증 치료용 약제학적 조성물.7. The pharmaceutical composition for treating depression according to 1 above, wherein the composition is administered in combination with an acute coronary agent.
8. 스타틴 및 S-시탈로프람을 포함하는, 우울증 치료용 약제학적 조성물을 투여하는 단계를 포함하는, 우울증 치료 방법.8. A method of treating depression, comprising administering a pharmaceutical composition for treating depression, comprising statins and S-citalopram.
본 발명에 따른 스타틴과 S-시탈로프람을 병용투여하면, 일반적으로 사용되고 있는 우울증 치료제인 S-시탈로프람 단독 투여시보다 약 3배 이상 급성관동맥증후군 후 발병되는 우울증에 대하여 치료 효과를 상승시킬 수 있는 효과가 있다.Concomitant administration of statins and S-citalopram according to the present invention will increase the therapeutic effect against depression developed after Acute Coronary Syndrome at least about three times higher than the administration of S-citalopram alone, a commonly used antidepressant. It can be effective.
도 1은 본 발명에 따른 스타틴과 S-시탈로프람을 투여한 군에 대한 치료반응율을 나타내는 도면이다.1 is a view showing the treatment response rate for the group administered statin and S-citalopram according to the present invention.
도 2는 본 발명에 따른 스타틴과 S-시탈로프람을 투여한 군에 대한 평균 해밀턴 평가 척도(HAM-D)(도 2a)와 시간이 지남에 Beck 우울 척도 점수(도 2b)를 나타낸 도면이다.2 is a diagram showing the average Hamilton rating scale (HAM-D) (FIG. 2A) and the Beck Depression Scale score over time (FIG. 2B) for a group administered statins and S-citalopram according to the present invention. .
이하에서, 본 발명의 여러 측면 및 다양한 구현 예에 대해 더욱 구체적으로 살펴보도록 한다.Hereinafter, various aspects and various embodiments of the present invention will be described in more detail.
급성관동맥증후군(ACS)이 있는 환자에게서 흔하게 나타나는 우울증은 삶의 질을 저하시키고, 급성관동맥증후군 후 수개월에서 수년 사이에 사망할 위험도를 증가시킨다. 그렇지만, 급성 급성관동맥증후군 환자에 대한 우울증 치료에 있어서 항 우울제의 효과 및 안전성에 대한 자료는 제한적이다.Depression, commonly seen in patients with acute coronary syndrome (ACS), reduces the quality of life and increases the risk of dying from months to years after acute coronary syndrome. However, there are limited data on the effectiveness and safety of antidepressants in treating depression in patients with acute acute coronary syndrome.
이에, 본 발명에서는 급성관동맥증후군 환자에게도 사용할 수 있는, 즉 급성관동맥증후군 치료제와 함께 투여를 한다 해도 부작용을 일으키지 않는 약물의 개발을 하고자 하였다.Therefore, the present invention is intended to develop a drug that can be used in patients with acute coronary syndrome, that is, even when administered with acute coronary syndrome treatment does not cause side effects.
본 발명은 스타틴과 S-시탈로프람의 병용투여에 의해 우울증, 바람직하게는 관동맥증후군 발병 후에 나타나는 후유증인 우울증 치료효과를 상승시킨 우울증 치료제 복합 조성물을 제공한다.The present invention provides a composition for treating depression, in which depression is enhanced by a combination of statins and S-citalopram, preferably an aftereffect of depression after the onset of coronary syndrome.
본 발명에 따른 상기 조성물은 급성관동맥 치료제와 병용투여될 수 있다.The composition according to the present invention may be administered in combination with an acute coronary agent.
본 발명에 따르면 스타틴과 S-시탈로프람을 병용투여하면 치료반응율이 55.7%, S-시탈로프람 단독 투여시 31.4%, 위약사용시 25%로, 스타틴과 S-시탈로프람을 병용투여하면 일반적으로 사용되고 있는 우울증 치료제인 S-시탈로프람 단독 투여시보다 위약대비 치료반응이 4.7배 높아지는 것을 확인하였다.According to the present invention, when statin and S-citalopram are administered in combination, the therapeutic response rate is 55.7%, 31.4% when using S-citalopram alone, and 25% when using placebo, and when statin and S-citalopram are used in combination It was confirmed that the treatment response compared to placebo was 4.7 times higher than that of S-citalopram alone.
본 발명의 상기 스타틴은 10 내지 20 mg으로 포함될 수 있고, 상기 S-시탈로프람은 5 내지 10 mg으로 우울증 환자에서 통상 사용하는 용량의 절반 양으로 포함될 수 있다.The statin of the present invention may be included in 10 to 20 mg, the S-citalopram may be included in the amount of 5 to 10 mg in half the dose commonly used in patients with depression.
종래 S-시탈로프람은 시냅스에서 세로토닌의 재흡수를 억제하여 세로토닌을 보다 오랫동안 효과를 보이도록 하는 약물로서, 일반적으로 10 내지 20 mg을 투여하고 있는데, 이러한 경우 체중 증가, 우울증상의 악화, 자살 충동과 행동(자살성향), 비정상적인 행동 변화의 발현 등의 부작용이 있을 수 있는 것으로 알려져 있다. Conventional S-citalopram is a drug that suppresses the reuptake of serotonin at the synapse and shows the effect of serotonin for a longer time. Generally, S-citalopram is administered in an amount of 10 to 20 mg. In this case, weight gain, worsening of depression, and suicidal thoughts It is known to have side effects such as hyperactivity and behavior (suicide propensity), abnormal behavioral manifestations.
그러나 본 발명에서는 스타틴과 S-시탈로프람을 함께 사용하는 경우, S-시탈로프람 사용량을 5 내지 10 mg으로 50% 이상 줄이면서 스타틴 사용량은 일반적으로 사용하면 관동맥증후군 발병 후에 나타나는 후유증인 우울증의 치료에 유용하게 사용될 수 있음을 확인하였다.However, in the present invention, when statin and S-citalopram are used together, the amount of S-citalopram is reduced to 5 to 10 mg or more by 50% while statin is generally used after the onset of coronary syndrome. It has been confirmed that it can be usefully used for treatment.
본 발명의 상기 스타틴은 로수바스타틴, 아토르바스타틴, 프라바스타틴, 메바스타틴, 및 이타바스타틴으로 이루어진 군으로부터 선택되는 1종 이상일 수 있고, 바람직하게는 상기 스타틴은 프라바스타틴 또는 로수바스타틴이다.The statin of the present invention may be at least one selected from the group consisting of rosuvastatin, atorvastatin, pravastatin, mevastatin, and itavastatin, preferably, the statin is pravastatin or rosuvastatin.
한편, 스타틴 중에서도 프라바스타틴과 로수바스타틴은 우울증 및 수면장애 부작용이 있는 약물로 알려져 있는데, 본 발명에 따르면, S-시탈로프람을 함께 사용함으로써 오히려 관상동맥증후군 발병 후에 나타나는 후유증인 우울증의 치료에 유용하게 사용될 수 있음을 확인하였다.On the other hand, among the statins, pravastatin and rosuvastatin are known to have side effects of depression and sleep disorders, and according to the present invention, by using S-citalopram together, it is useful for treating depression, which is a sequelae after the onset of coronary syndrome. It was confirmed that it can be used.
본 발명에 따르면, 스타틴과 S-시탈로프람은 간편하게 하루 1회 투여된다.According to the invention, statins and S-citalopram are conveniently administered once daily.
상기 스타틴과 상기 S-시탈로프람은 동시 투여, 배합 투여 또는 연속 투여를 포함할 수 있다.The statin and the S-citalopram may comprise simultaneous administration, combined administration or continuous administration.
본 발명의 스타틴과 S-시탈로프람 배합물은 동일하거나 상이한 약제학적 조성물로 동시에 또는 연속적으로 투여될 수 있다. 연속 투여의 경우에, 2번째 활성 성분의 투여 지연이 본 발명의 공동상승 효과의 이득을 상실시킬 수 있을 정도여서는 안 된다. 전형적으로, 연속 투여는 12시간 초과의 지연을 포함하지 않고 바람직하게 식사 전후 1시간 이내이다.Statins and S-citalopram combinations of the invention may be administered simultaneously or sequentially in the same or different pharmaceutical compositions. In the case of continuous administration, the delay in administration of the second active ingredient should not be such that it would lose the benefit of the synergistic effect of the present invention. Typically, continuous administration does not include a delay of more than 12 hours and is preferably within 1 hour before and after meals.
투여를 용이하게 하기 위해, 스타틴 및 S-시탈로프람은 간편하게 캅셀제 또는 정제 또는 적당한 농도의 2개의 활성 제제를 함유하는 유체와 같은 동일한 단위 용량 형태로 제공된다.To facilitate administration, statins and S-citalopram are conveniently provided in the same unit dose form as a capsule or tablet or a fluid containing two active agents in suitable concentrations.
관동맥증후군 발병 후에 나타나는 후유증인 우울증을 치료하기 위해 필요한 스타틴과 S-시탈로프람의 양은 물론 환자마다 다양할 것이고 궁극적으로 체중, 투여 경로, 수반되는 약물 치료, 연령, 성별 및 질환의 일반적인 증상 및 질환 특성 및 중증도와 같은 널리 공지된 인자를 고려하여 담당 의사가 결정한다.The amount of statins and S-citalopram required to treat depression, a sequelae after the onset of coronary syndrome, will vary from patient to patient, and ultimately the general symptoms and disorders of body weight, route of administration, medication involved, age, sex and disease It is determined by the attending physician taking into account well known factors such as characteristics and severity.
본 발명에 기재된 용량 비율에서 S-시탈로프람과 스타틴은 통상적인 부형제와 함께 통상적인 약제 담체중에서 용이하게 제형화될 수 있다. 본 발명의 화합물은 특히 경구 투여에 적합하지만 또한 직장, 질내, 비강내, 국소적으로, 경피적으로 또는 비경구적으로, 예를 들어, 근육 내, 정맥 내 또는 경막으로 투여될 수 있다.S-citalopram and statins at the dosage ratios described herein can be easily formulated in conventional pharmaceutical carriers with conventional excipients. The compounds of the invention are particularly suitable for oral administration but can also be administered rectally, vaginally, intranasally, topically, transdermally or parenterally, for example intramuscularly, intravenously or dural.
당해 화합물은 예를 들어, 캅셀제 내에 단독으로 투여될 수 있지만 일반적으로 약제학적으로 허용되는 담체 또는 희석제와 연계하여 투여된다. 본 발명은 스타틴과 S-시탈로프람을 약제학적으로 허용되는 담체 또는 비히클과 연계하거나 연합시키는 단계를 포함하는 약제학적 조성물의 제조 방법을 포함한다.The compound may be administered alone, for example in a capsule, but is generally administered in conjunction with a pharmaceutically acceptable carrier or diluent. The present invention includes a method of preparing a pharmaceutical composition comprising linking or associating statins with S-citalopram with a pharmaceutically acceptable carrier or vehicle.
경구 제제는 간편하게, 통상적인 담체 또는 결합제, 예를 들어, 마그네슘 스테아레이트, 쵸크, 전분, 락토스, 왁스, 검 또는 젤라틴을 사용하여 캅셀제 또는 정제와 같은 단위 용량 형태로 제조될 수 있다.Oral formulations may conveniently be prepared in unit dosage form such as capsules or tablets using conventional carriers or binders, for example magnesium stearate, chalk, starch, lactose, wax, gum or gelatin.
리포좀 또는 HPMC 또는 PVP와 같은 합성 또는 천연 중합체를 사용하여 서방성 제제를 수득할 수 있다. 또한, 당해 제제는 물, 식염수, 에탄올, 식물성 오일또는 글리세린과 같은 통상적인 비히클중에 액제, 현탁제, 유제, 수중유 또는 유중수 제제를 포함하는 비강 점적제 또는 안구 점적제, 시럽, 겔 또는 크림으로서 임의로 향제 및/또는 방부제 및/또는 유화제와 함께 제공될 수 있다.Sustained release preparations can be obtained using liposomes or synthetic or natural polymers such as HPMC or PVP. In addition, the formulations may be nasal drops or ocular drops, syrups, gels or creams, including solutions, suspensions, emulsions, oil-in-water or water-in-oil preparations in conventional vehicles such as water, saline, ethanol, vegetable oils or glycerin. And optionally with fragrances and / or preservatives and / or emulsifiers.
이하에서 실시예 등을 통해 본 발명을 더욱 상세히 설명하고자 하며, 다만 이하에 실시예 등에 의해 본 발명의 범위와 내용이 축소되거나 제한되어 해석될 수 없다. 또한, 이하의 실시예를 포함한 본 발명의 개시 내용에 기초한다면, 구체적으로 실험 결과가 제시되지 않은 본 발명을 통상의 기술자가 용이하게 실시할 수 있음은 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속하는 것도 당연하다.Hereinafter, the present invention will be described in more detail with reference to examples and the like, but the scope and contents of the present invention are not limited or interpreted by the following examples. In addition, if it is based on the disclosure of the present invention including the following examples, it will be apparent that those skilled in the art can easily carry out the present invention, the results of which are not specifically presented experimental results, these modifications and modifications are attached to the patent It goes without saying that it belongs to the claims.
실시예Example
관동맥증후군이 있는 환자에서 우울증의 치료에 대한 스타틴과 S-시탈로프람 병용 투여 효과를 검증하고자 관동맥증후군 환자에 대한 전향적 코호트 연구 및 S-시탈로프람 24주 이중맹검, 위약대조 임상시험 자료를 사용하였다.To evaluate the effects of statin and S-citalopram in the treatment of depression in patients with coronary syndrome, a prospective cohort study and 24-week double-blind, placebo-controlled clinical trial data for patients with coronary syndrome. Used.
관동맥증후군에 동반된 우울장애를 가지고 있는 446명의 환자 중 300명이 무작위 배정되어 S-시탈로프람 임상시험에 참여하였고, 나머지 146명은 관찰연구에 참여하였다.Of the 446 patients with depressive disorder associated with coronary syndrome, 300 were randomized to participate in the S-citalopram trial, and the remaining 146 participated in the observational study.
(1) 약물 선정(1) drug selection
S-시탈로프람의 최초 용량은 5 mg/day이다. 2차 평가 후, 투여 용량은 우울증의 중증도 및 약물의 내약성을 고려하여 시험자가 임상적으로 판단하여 결정한다. 약물은 1일 1회 저녁 식사 후 30분 이내에 경구 투여하였다. The initial dose of S-citalopram is 5 mg / day. After the second evaluation, the dosage is determined clinically by the investigator taking into account the severity of the depression and the tolerability of the drug. The drug was administered orally within 30 minutes after dinner once a day.
시험약은 S-시탈로프람을 동일한 형태의 위약으로 제공하였고, 상기 위약은 S-시탈로프람 크기와 동일한 형태로 제공된다.The test drug provided S-citalopram as a placebo of the same form, and the placebo was given in the same form as the S-citalopram size.
(2) 대상자 선정 기준(2) Target selection criteria
Acute myocardial infarction(급성 심근경색증), Unstable angina(불안정성 협심증), Major depression, single episode without psychotic symptoms(주요 우울병, 정신병성 증상이 없는 단일에피소드), Major depression, recurrent without psychotic symptoms(정신병적 증상이 없이 재발하는 주요 우울병), Depressive disorder NOS(상세불명의 우울성 장애)를 갖되, 급성 ACS(불안정 협심증 또는 급성 심근 경색)로 진단을 받고 관상 동맥 조영술을 받았고, Beck Depression Inventory > 10이고, DSM-IV 기준에 따라 주요 또는 가벼운 우울 장애로 진단받았으며, 다양한 질문지를 작성할 수 있는 능력을 가지고, 시험의 목적을 이해하고, 피험자 동의서에 서명할 수 있는 경우로 선정하였다.Acute myocardial infarction, Unstable angina, Major depression, single episode without psychotic symptoms, Major depression, recurrent without psychotic symptoms Recurrent major depressive disorder), Depressive disorder NOS, diagnosed with acute ACS (unstable angina or acute myocardial infarction), underwent coronary angiography, Beck Depression Inventory> 10, DSM-IV The patient was diagnosed with major or mild depressive disorder according to the criteria, had the ability to complete various questionnaires, understood the purpose of the test, and signed the subject's consent.
다만, 환자가 ACS가 아닌 다른 원인으로 입원해 있는 동안 급성 ACS이 발현한 경우, 최근의 ACS가 관상 동맥 우회술을 받은 후 3개월 이내에 발생한 경우, 조절되지 않는 고혈압(수축기 혈압> 180mmHg 또는 이완기 혈압> 100mmHg)인 경우, 휴식 시 심박수 < 40회/분인 경우, 생명을 위협하거나 ACS로부터의 회복을 방해하는 중증의 신체 질병이 있는 경우, 지속적이고 임상적으로 유의한 실험실 검사 이상이 있는 경우, reserpine, guanethidine, clonidine, 또는 methyldopa, lithium, 항경련제 또는 neuroleptics의 병용 사용한 경우, 치매, 파킨슨병, 뇌종양, 정신증, 알코올 의존 및 기타 물질 의존과 같은 신경 정신과 질병의 병력이 있는 경우, 및 임신인 경우는 제외하였다.However, uncontrolled hypertension (deflator blood pressure> 180 mmHg or diastolic blood pressure) when acute ACS develops while the patient is hospitalized for a cause other than ACS, and recent ACS occurs within 3 months of receiving coronary artery bypass surgery. 100 mmHg), heart rate at rest <40 beats / minute, severe physical illness that threatens life or prevents recovery from ACS, persistent, clinically significant laboratory abnormalities, reserpine, Use of guanethidine, clonidine, or methyldopa, lithium, anticonvulsants or neuroleptics, with a history of neuropsychiatric disorders such as dementia, Parkinson's disease, brain tumors, psychosis, alcohol dependence and other substance dependence, and pregnancy It was.
(3) 주요결과변수 유형 유효성(Efficacy) (3) Efficacy of Key Result Variable Types
이들의 6개월 또는 1년 뒤의 우울증상에 대한 추적조사를 시행하였고, 치료반응은 해밀턴 우울척도(Hamilton Depression Scale; HAM-D)와 벡 우울척도(Beck Depression Inventory; BDI) 점수에서 50% 이상 감소한 경우로 정의하여 이를 결과변수로 사용하였다. 평가 시기는 4, 8, 12, 16, 20, 24주로 정하였다.Follow-up was conducted for depression after 6 months or 1 year and treatment response was over 50% in the Hamilton Depression Scale (HAM-D) and Beck Depression Inventory (BDI) scores. We defined it as a reduced case and used it as the outcome variable. Evaluation time was set to 4, 8, 12, 16, 20, 24 weeks.
결과result
S-시탈로프람 임상시험 참여자 중에서 S-시탈로프람과 스타틴을 함께 복용한 군에서 HAM-D와 BDI 점수 모두에서 가장 높은 치료 반응율을 보였고, 두 약물 모두 복용하지 않은 군에서 가장 낮은 치료 반응율을 보였다.Among the S-citalopram trial participants, the group treated with S-citalopram and statin had the highest therapeutic response rate in both HAM-D and BDI scores, and the lowest response rate in the group not taking both drugs. Seemed.
또한 스타틴과 S-시탈로프람을 함께 복용한 군, 각각 복용한 군, 복용하지 않은 군은 시간에 따라 우울증상의 호전도에서 유의한 차이를 보였는데, 치료반응율과 비슷하게 스타틴과 S-시탈로프람은 함께 투여 시, 1년 후 HAM-D와 BDI 점수 모두 가장 현저한 호전을 보였고 두약물을 복용하지 않은 군에서 가장 적은 치료반응을 보이는 것이 확인되었다(도 2 참조).In addition, the group taking statin and S-citalopram together, the group taking each group, and the group not taking the group showed significant difference in depressive improvement with time, similar to the response rate of statin and S-citalopram. When administered together, both HAM-D and BDI scores showed the most remarkable improvement after one year and showed the least therapeutic response in the group not taking the two drugs (see FIG. 2).
결론적으로 본 발명에 따르면 급성관동맥증후군 환자의 우울증에 대하여 스타틴이 세로토닌 계열 항우울제의 효과를 증대시킬 수 있음을 알 수 있고, 이를 통해 스타틴이 고지혈증 치료뿐만 아니라 우울증 치료에도 사용될 수 있다.In conclusion, according to the present invention, it can be seen that statins can increase the effects of serotonin-based antidepressants on depression in patients with acute coronary syndrome, and thus, statins can be used to treat depression as well as to treat hyperlipidemia.

Claims (8)

  1. 스타틴 및 S-시탈로프람을 포함하는, 우울증 치료용 약제학적 조성물.A pharmaceutical composition for treating depression, comprising statins and S-citalopram.
  2. 청구항 1에 있어서, 상기 스타틴은 10 내지 20 mg의 양으로 존재하는 것인 우울증 치료용 약제학적 조성물.The pharmaceutical composition of claim 1, wherein the statin is present in an amount of 10 to 20 mg.
  3. 청구항 1에 있어서, 상기 S-시탈로프람은 5 내지 10 mg의 양으로 존재하는 것인 우울증 치료용 약제학적 조성물.The pharmaceutical composition of claim 1, wherein the S-citalopram is present in an amount of 5 to 10 mg.
  4. 청구항 1에 있어서, 상기 스타틴은 로수바스타틴, 아토르바스타틴, 프라바스타틴, 메바스타틴, 및 이타바스타틴으로 이루어진 군으로부터 선택되는 1종 이상인 우울증 치료용 약제학적 조성물.The pharmaceutical composition of claim 1, wherein the statin is at least one selected from the group consisting of rosuvastatin, atorvastatin, pravastatin, mevastatin, and itavastatin.
  5. 청구항 1에 있어서, 상기 스타틴은 프라바스타틴 또는 로수바스타틴인 우울증 치료용 약제학적 조성물.The pharmaceutical composition of claim 1, wherein the statin is pravastatin or rosuvastatin.
  6. 청구항 1에 있어서, 상기 스타틴과 상기 S-시탈로프람은 동시 투여, 배합 투여 또는 연속 투여를 포함하는, 우울증 치료용 약제학적 조성물.The pharmaceutical composition of claim 1, wherein the statin and the S-citalopram comprise simultaneous administration, combined administration or continuous administration.
  7. 청구항 1에 있어서, 상기 조성물은 급성관동맥 치료제와 병용투여되는 것인 우울증 치료용 약제학적 조성물.The pharmaceutical composition of claim 1, wherein the composition is administered in combination with an acute coronary agent.
  8. 스타틴 및 S-시탈로프람을 포함하는, 우울증 치료용 약제학적 조성물을 투여하는 단계를 포함하는, 우울증 치료 방법.A method of treating depression, comprising administering a pharmaceutical composition for treating depression, comprising statins and S-citalopram.
PCT/KR2016/005618 2016-02-24 2016-05-27 Pharmaceutical composition for treatment of depression accompanied by acute coronary syndrome WO2017146305A1 (en)

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