KR101985838B1 - Delayed-release pharmaceutical composition containing n-desalkylquetiapine as active ingredient and a method for manufacturing the same - Google Patents

Delayed-release pharmaceutical composition containing n-desalkylquetiapine as active ingredient and a method for manufacturing the same Download PDF

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KR101985838B1
KR101985838B1 KR1020170116389A KR20170116389A KR101985838B1 KR 101985838 B1 KR101985838 B1 KR 101985838B1 KR 1020170116389 A KR1020170116389 A KR 1020170116389A KR 20170116389 A KR20170116389 A KR 20170116389A KR 101985838 B1 KR101985838 B1 KR 101985838B1
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pharmaceutical composition
release pharmaceutical
active ingredient
biodegradable polymer
sustained
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김동욱
박천웅
한창수
차선희
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청주대학교 산학협력단
충북대학교 산학협력단
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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Abstract

본 발명은 quetiapine의 활성 대사체인 N-desalkylquetiapine 유리염기를 활성성분으로 포함하는 서방성 약학 조성물로서, 활성성분의 봉입율과 수득율이 우수하며, 주사제형으로 근육 투여 시 장기간의 약효가 유지되는 것을 특징으로 한다.The present invention relates to a sustained-release pharmaceutical composition comprising N-desalkylquetiapine free base, which is an active metabolite of quetiapine, as an active ingredient. It is excellent in the encapsulation rate and yield of the active ingredient and maintains the long- .

Description

N-desalkylquetiapine을 생리활성물질로 포함하는 서방성 약학 조성물 및 이의 제조방법 {DELAYED-RELEASE PHARMACEUTICAL COMPOSITION CONTAINING N-DESALKYLQUETIAPINE AS ACTIVE INGREDIENT AND A METHOD FOR MANUFACTURING THE SAME}TECHNICAL FIELD The present invention relates to a sustained-release pharmaceutical composition comprising N-desalkylketiapine as a physiologically active substance and a method for producing the same. [0002] The present invention relates to a sustained-release pharmaceutical composition comprising N-desalkylketiapine as a physiologically active substance,

본 발명은 quetiapine의 활성 대사체인 N-desalkylquetiapine을 활성성분으로 포함하는 서방성 약학 조성물 주사제제로서, 근육 투여 시 장기간의 약효가 유지되는 것을 특징으로 한다.The present invention relates to a sustained-release pharmaceutical composition injecting agent comprising N-desalkylquetiapine, which is an active metabolite of quetiapine, as an active ingredient.

N-desalkylquetiapine은 쎄로켈(Seroquel)이라는 이름으로 판매되고 있는 항정신성 의약품의 주성분인 quetiapine이 인체 내의 CYP3A4를 통한 간대사로 발생되는 활성대사물질로서 quetiapine이 나타내는 정신분열증, 조울증, 우울증 등의 치료효과에 있어 많은 기여를 하는 것으로 알려져 있다.N-desalkylketiapine is an active metabolite of hepatic metabolism caused by CYP3A4 in the human body, quetiapine, which is a major component of antipsychotic drugs sold under the name Seroquel. It is a therapeutic effect of quetiapine, schizophrenia, manic depression and depression It is known to make a lot of contributions.

한편, N-desalkylquetiapine에 대해서는, 모체인 quetiapine을 개발한 아스트라제네카(AstraZeneca)사에서, 이에 관한 다양한 활성을 연구한 바 있으며, 그 예로 미국 특허 US20110136784 (anxiety disorder), US20110136786 (mooddisorder), US20110144088 (sleep disorder), US20110144089 (schizophrenia and other disorder) 등이 있다.On the other hand, regarding N-desalkylketiapine, AstraZeneca, which developed quetiapine, has studied various activities related thereto. Examples thereof include anxiety disorder, US 20110136786 (mooddisorder), US 20110144088 (sleep disorder, < / RTI > US 20110144089 (schizophrenia and other disorder).

N-desalkylquetiapine은 다양한 염(salt) 형태가 가능하지만, 일반적으로는 2HCl 염 형태로 사용되며, quetiapine을 합성 또는 생산 하는 전구물질로 사용되기도 한다.N-desalkylketiapine can be in a variety of salt forms, but is generally used in the form of a 2HCl salt, and is sometimes used as a precursor to synthesize or produce quetiapine.

한편 Quetiapine 및 그 대사체 염형태에 대한 구조 및 물리화학적인 특성을 비교해 보면 아래 표 1과 같다.The structural and physicochemical characteristics of quetiapine and its metabolites are shown in Table 1 below.

QuetiapineQuetiapine NorquetiapineNorquetiapine 2HCl2HCl NorquetiapineNorquetiapine
(( freebasefreebase )) 2D Structure2D Structure

Figure 112017088345943-pat00001
Figure 112017088345943-pat00001
Figure 112017088345943-pat00002
Figure 112017088345943-pat00002
Figure 112017088345943-pat00003
Figure 112017088345943-pat00003
 Molecular FormulaMolecular Formula C21H25N3O2SC 21 H 25 N 3 O 2 S C17H19Cl2N3SC 17 H 19 Cl 2 N 3 S C17H17N3SC 17 H 17 N 3 S Molecular WeightMolecular Weight 383.51 g/mol383.51 g / mol 368.32 g/mol368.32 g / mol 295.40 g/mol295.40 g / mol SolubilitySolubility 38.32 (ug/mL)38.32 (ug / mL) 325.78 (ug/mL)325.78 (ug / mL) 6.82 (ug/mL)6.82 (ug / mL) LogPLogP 2.942.94 3.123.12 3.183.18 pKapKa pKa1 = 2.78,
pKa2 = 7.46 pKa1 = 2.78,
pKa2 = 7.46 pKa1 = 3.93,
pKa2 = 8.49 pKa1 = 3.93,
pKa2 = 8.49 pKa1 = 3.90,
pKa2 = 8.55 pKa1 = 3.90,
pKa2 = 8.55

이와 관련하여 한국특허 제2016-0025946호에서는 Quetiapine을 활성성분으로 포함하는 서방화 기술에는 서방성 경구투여 제제를 개시하고 있으며, 오심, 구토, 어지러움, 몽롱함, 두통, 정좌불능 등 정신과 관련된 부작용을 감소시키는 효과에 대하여 기재되어 있다. In this regard, Korean Patent No. 2016-0025946 discloses a sustained-release oral administration formulation containing quetiapine as an active ingredient and reduces the psychiatric side effects such as nausea, vomiting, dizziness, blurred vision, headache, Is described.

그러나 상기 서방화 제제는 경구투여용 서방화 제제로서, 1일 1회 투여만으로 장기적인 약리활성을 보이기 위한 제제로는 적합하지 않다. However, the sustained-release preparation is not suitable as a preparation for long-term pharmacological activity only once a day as a sustained-release preparation for oral administration.

본 발명은 종래의 경구 투여 서방성 제제의 지속 시간을 더욱 개선하기 위해 안출된 것으로, 본 발명에 따른 조성물은 활성성분으로서 Quetiapine의 대사체인 N-desalkylquetiapine을, 서방화 기제로서 생분해성 고분자를 사용한 주사제형 약학 조성물이다. The present invention has been conceived to further improve the duration of conventional sustained-release sustained-release preparations. The composition according to the present invention comprises N-desalkylquetiapine, which is a metabolite of quetiapine, as an active ingredient, Lt; / RTI >

본 발명은 활성성분으로 N-desalkylquetiapine의 유리 염기(free base)를 사용하여, 용매증발법을 통한 서방성 주사제형 조성물 제조 시 용매 내에서의 용해도 문제 인해 현저히 낮게 나타나는 활성성분 봉입율을 개선하였으며, 본 발명에 의한 서방성 약학 조성물은 1회 근육 주사만으로도 2주~4주 이상의 장기간 약리활성 효과를 나타낸다. The present invention improves the inclusion rate of the active ingredient which is significantly lowered due to the solubility problem in the solvent during the preparation of the sustained release injectable composition through the solvent evaporation method using the free base of N-desalkylketiapine as the active ingredient, The sustained-release pharmaceutical composition of the present invention shows a long-term pharmacological activity effect for two weeks to four weeks or more with only one intramuscular injection.

본 발명에 의한 서방성 약학 조성물은 생리활성약제로 Quetiapine의 활성대사체인 N-desalkylquetiapine 또는 이의 염을 포함하며,The sustained-release pharmaceutical composition according to the present invention contains N-desalkylketiapine or its salt as an active metabolite of quetiapine as a physiologically active agent,

생리활성약제 및 생분해성 고분자를 유기용매에 각각 용해시키는 단계;Dissolving the physiologically active agent and the biodegradable polymer in an organic solvent;

생리활성약제 용액 및 생분해성 고분자 용액을 혼합하는 단계;Mixing a biologically active agent solution and a biodegradable polymer solution;

상기 생리활성약제 용액 및 생분해성 고분자 용액의 혼합물을 수성 매질에 투입한 뒤 교반하여 에멀젼을 생성하는 단계; 및Adding a mixture of the physiologically active drug solution and the biodegradable polymer solution to an aqueous medium and stirring to produce an emulsion; And

상기 에멀젼을 동결 건조시키는 단계를 통하여 제조될 수 있다.And lyophilizing the emulsion.

본 발명은 상기 생리활성약제로 N-desalkylquetiapine의 유리염기(free base)를 사용한다. The present invention uses a free base of N-desalkylketiapine as the physiologically active agent.

일반적으로 사용되는 N-desalkylquetiapine의 경우, 유기용매에 녹인 생분해성 고분자와 교반하여도 고분자와의 용해도 특성 차이로 인해 거의 봉입이 이루어지지 않아 서방성 주사제형을 위한 약학 조성물로 제조하는 것이 불가능하다. 그러나, 본 출원인은 연구를 거듭한 끝에, N-desalkylquetiapine 유리 염기를 활성성분으로 사용하는 경우, 활성성분의 생분해성 고분자 내 봉입율이 놀라울 정도로 향상되는 것을 발견하였다.In the case of N-desalkylketiapine which is generally used, it is impossible to prepare a pharmaceutical composition for sustained-release injectable formulation because it is hardly sealed due to a difference in solubility characteristics with polymers even when it is stirred with a biodegradable polymer dissolved in an organic solvent. However, the Applicant has repeatedly found that when the N-desalkylquetiapine free base is used as the active ingredient, the inclusion rate of the active ingredient in the biodegradable polymer is remarkably improved.

이로 인하여, 본 발명의 생분해성 고분자는 PLGA를 사용하며, 본 발명에 의한 서방성 약학 조성물은 생분해성 고분자 내 생리활성약제의 봉입율이 30 내지 50%인 것을 특징으로 한다.Accordingly, PLGA is used as the biodegradable polymer of the present invention, and the sustained release pharmaceutical composition of the present invention is characterized in that the encapsulation rate of the physiologically active agent in the biodegradable polymer is 30 to 50%.

또한, 서방성 약학 조성물은 동결건조에 의한 미립구 수득 시 수득율이 60 내지 80%로 매우 우수하게 나타나며, 제조된 미립구의 크기도 10um정도로 일반적인 근육 투여를 위한 주사제형으로 적합하다.In addition, the sustained-release pharmaceutical composition shows a very good yield of 60-80% when microspheres are obtained by freeze-drying, and the size of the prepared microspheres is about 10 μm, which is suitable as an injectable form for general muscle administration.

아울러 본 발명은 상기한 방법에 의하여 제조된 서방성 약학 조성물을 제공한다.The present invention also provides a sustained-release pharmaceutical composition prepared by the above-mentioned method.

본 발명에 N-desalkylquetiapine 유리염기를 활성성분으로 포함하는 서방성 약학 조성물은 주사제형 약학 조성물로 제조시 봉입율 및 수득율이 매우 우수하게 나타나며, 1회 근육투여만으로 2~4주 이상 지속적인 약리활성 효과를 보인다.The sustained release pharmaceutical composition comprising N-desalkylquetiapine free base as an active ingredient of the present invention shows excellent encapsulation efficiency and yield in the preparation of an injectable pharmaceutical composition, Respectively.

도 1은 본 발명의 실시예 1 및 2에 의한 조성물에 대하여 pH 7.4 용출액 조건에서 20일 간 활성성분의 용출율을 측정하여 그래프로 나타낸 것이다.
도 2는 본 발명의 실시예 3 및 4에 의한 조성물에 대하여 pH 7.4 용출액 조건에서 20일 간 활성성분의 용출율을 측정하여 그래프로 나타낸 것이다.
도 3은 본 발명의 실시예2의 조성물에 대한 in vivo 테스트 결과를 나타낸 것이다.FIG. 1 is a graph showing the dissolution rate of the active ingredient for 20 days under the pH 7.4 eluant condition for the composition according to Examples 1 and 2 of the present invention.
FIG. 2 is a graph showing the dissolution rate of the active ingredient for 20 days under the pH 7.4 eluant condition for the composition according to Examples 3 and 4 of the present invention.
Figure 3 shows in vivo test results for the composition of Example 2 of the present invention.

이하, 본 발명에 의한 N-desalkylquetiapine을 생리활성물질로 포함하는 서방성 약학 조성물의 제조방법을 구체적으로 설명한다.Hereinafter, a method of preparing a sustained-release pharmaceutical composition comprising N-desalkylquetiapine according to the present invention as a physiologically active substance will be described in detail.

실시예 1 내지 4 : N-desalkylquetiapine 유리염기, 용매증발법Examples 1 to 4: N-desalkylketiapine free base, solvent evaporation method

O/W 에멀젼을 용매증발법을 이용하여 조성물 입자를 제조하였다. The O / W emulsion was prepared by using a solvent evaporation method.

N-desalkylquetiapine와 PLGA를 디클로로메탄·메탄올 용액에 녹여 준비하였으며 이때 약물과 PLGA 비율은 1:5이다. N-desalkylketiapine and PLGA were dissolved in a dichloromethane-methanol solution, and the ratio of drug to PLGA was 1: 5.

PLGA는 PLGA 502, 502H, 503, 503H에 대하여 각각 실험을 실시하였으며 PLGA 기준으로 20 mg당 디클로로메탄 : 메탄올 9 : 1 용액을 1 mL를 첨가하여 유상을 준비하였다. PLGA was tested for PLGA 502, 502H, 503, and 503H, and 1 mL of dichloromethane: methanol 9: 1 solution of 20 mg per PLGA was added to prepare an oil phase.

수상은 폴리비닐 알콜 500(PVA)을 0.2%(w/v) 농도로 준비하였으며 유상과 수상의 비율이 1:20(v/v)으로 진행하였다. The water phase was prepared with polyvinyl alcohol 500 (PVA) at a concentration of 0.2% (w / v) and the ratio of oil phase to water phase was 1:20 (v / v).

본 실험에서는 약물 60 mg에 대하여 PLGA 300 mg에 디클로로메탄·메탄올 용액 15 mL를 첨가하여 유상을 만들었고 수상 300 mL로 실시하였다. 주사기 펌프를 사용하여 유상을 2800 rpm 호모게나이저가 작동되고 있는 수상에 1ml/sec 속도로 주입하였으며 유상이 다 주입되고 난후부터 1분까지 작동시켰다. In this experiment, 15 mL of dichloromethane · methanol solution was added to 300 mg of PLGA to make 60 mL of the drug, and an oil phase was prepared. Using a syringe pump, the oil phase was injected at a rate of 1 ml / sec into the water phase in which the 2800 rpm homogenizer was operated, and the oil phase was operated for 1 minute after the injection.

얻어진 에멀젼은 3시간이상 상온에서 400rpm 회전속도로 두어 용매를 날려버렸다. 표면의 불순물을 제거하기 위해 얻어지는 입자는 원심분리기(1500rpm, 3min)를 사용하여 입자를 가라앉힌 후 상층액을 버리고 증류수를 넣어 세척하였으며 이는 3회 실시 되었다. 그 후 0.45 ㎛ filter를 사용하여 입자를 수득하였으며 동결건조를 위하여 5mL 증류수에 재분산시켜 이틀 전처리 후 동결건조를 실시하였다.The obtained emulsion was left at a rotating speed of 400 rpm at room temperature for 3 hours or more to blow off the solvent. Particles obtained to remove impurities on the surface were centrifuged (1500 rpm, 3 min) to allow the particles to settle, and the supernatant was discarded and washed with distilled water. This was performed three times. After that, the particles were obtained by using 0.45 ㎛ filter and re - dispersed in 5 mL of distilled water for freeze - drying, followed by freeze - drying after pretreatment for two days.

비교예 1 : N-desalkylquetiapine, 용매증발법Comparative Example 1: N-desalkylketiapine, solvent evaporation method

활성성분으로 N-desalkylquetiapine사용하였으며, 생분해성 고분자로 PLGA 503을 사용한 것을 제외하고 실시예 1 내지 4와 동일하게 실시하였다.N-desalkylketiapine was used as an active ingredient, and PLGA 503 was used as a biodegradable polymer.

비교예 2 내지 3: N-desalkylquetiapine스프레이 건조법Comparative Examples 2 to 3: N-desalkylketiapine spray drying method

스프레이 건조 방법을 사용하여 조성물 입자를 제조하였다. The spray drying method was used to prepare the composition particles.

PLGA 502H 및 PLGA 503H에 대하여 각 실시하였으며, 활성성분으로는 N-desalkylquetiapine을 사용하였다.PLGA 502H and PLGA 503H, respectively, and N-desalkylketiapine was used as an active ingredient.

N-desalkylquetiapine와 PLGA를 각각 500mg, 2.5g을 재서 디클로로메탄·메탄올 용액(9:1) 100 mL에 녹여 다음과 같은 조건으로 입자를 제조하였다. 건조 조건은 하기 표 2와 같다.500 mg and 2.5 g of N-desalkylketiapine and PLGA were respectively dissolved in 100 mL of a dichloromethane-methanol solution (9: 1) and granules were prepared under the following conditions. The drying conditions are shown in Table 2 below.

Spray dry conditionSpray dry condition InletInlet 50 ℃50 ℃ OutletOutlet 38 ℃38 ° C Flow rateFlow rate 0.1 m3/min0.1 m 3 / min AtomizingAtomizing 50 kPa50 kPa BlowerBlower 0.16 m3/ml0.16 m < 3 > / ml

실험 결과Experiment result

상기 각 실시예 및 비교예에 따른 봉입율, 수득율, 입자모양, 초기약물방출양(24시간)을 하기 표 3에 나타내었다.The encapsulation rate, yield, particle shape and initial drug release (24 hours) according to each of the examples and comparative examples are shown in Table 3 below.

구분division 실시예 1Example 1 실시예 2Example 2 실시예 3Example 3 실시예 4Example 4 비교예 1Comparative Example 1 비교예2Comparative Example 2 비교에 3Compare to 3 PLGA 종류PLGA type PLGA 502PLGA 502 PLGA 502HPLGA 502H PLGA
503 PLGA
503 PLGA 503H PLGA 503H PLGA
503PLGA
503 PLGA
502HPLGA
502H PLGA
503HPLGA
503H 봉입율
(%)Inclusion rate
(%) 30.330.3 41.241.2 32.732.7 48.348.3 0.10.1 99.899.8 100.7100.7 수득율
(%)Yield
(%) 70%~80%70% to 80% 68.268.2 46.646.6 36.636.6

한편 용매증발법 및 스프레이 건조방식의 제조방법에 따른 입자 형태 상 차이에 대하여는 하기 표 4에 나타내었다The particle shape differences according to the solvent evaporation method and the spray drying method are shown in Table 4 below

용매증발법Solvent evaporation method 스프레이 건조 방식Spray drying method

Figure 112017088345943-pat00004
Figure 112017088345943-pat00004
Figure 112017088345943-pat00005
Figure 112017088345943-pat00005
Figure 112017088345943-pat00006
Figure 112017088345943-pat00006
 왼쪽에 얻어진 입자의 사진은 실시예와 비교예 1에서 사용된 제조법인 용매증발법을 통해 얻어진 약물 PLGA 502H 입자이며 단일 입자에 구형의 형태를 띄고 있는 입자를 얻어짐을 확인 할 수 있었다. 그에 비해 스프레이 건조방식을 통해 얻어진 약물 PLGA 502H 입자의 경우 구형 단독의 입자를 얻기보다는 입자들 간의 연결다리가 형성되어 단일 입자로 얻기 힘든 것을 확인 할 수 있으며 또한 입자의 형태가 균일성이 용매증발법보다 떨어짐을 확인할 수 있다. 단 이때 사용되어지는 스프레이 건조방식의 경우 염산염 형태의 약물의 사용하여 제조하였다. 스프레이 건조방식으로 제조한 입자의 경우 높은 약물 효율을 보이기는 하나 용출양상에 있어서 지나친 초기 방출이 관찰되었다. 이는 염산염의 용해도와 제조된 입자 표면에 존재하는 약물양이 많기에 다음과 같은 결과를 가진 것으로 보였다. 그에 비해 유리염기 약물로 용매증발법으로 제조한 입자의 경우 보다 초기 방출이 줄어든 것을 확인할 수 있어으며 좀더 방출속도가 제어된 용출양상을 보였다. 용매증발법을 사용하여 내에서는 비교예 1과 같이 염산염을 사용하여 입자를 제조해보았으나 봉입율이 낮게 관찰되었다.The photographs of the particles obtained on the left side show that the drug PLGA 502H particles obtained through the solvent evaporation method, which is the manufacturing method used in Examples and Comparative Example 1, are spherical particles in a single particle. On the other hand, in the case of the drug PLGA 502H particles obtained through the spray drying method, it is possible to confirm that it is difficult to obtain a single particle because the bridge between the particles is formed rather than the spherical single particle, and the uniformity of the particle shape is obtained by the solvent evaporation method It can be confirmed that it is lower than the above. However, in the case of the spray drying method used at that time, a hydrochloride salt type drug was used. Particles prepared by spray drying showed high drug efficiency, but excessive initial release was observed in the dissolution profile. It was shown that the solubility of hydrochloride and the amount of drug present on the surface of the prepared particles were as follows. On the other hand, it was confirmed that the initial release was reduced as compared with the particles prepared by the solvent evaporation method as the free base drug, and the release rate was controlled more by the release rate. In the solvent evaporation method, particles were prepared using hydrochloride as in Comparative Example 1, but the inclusion rate was observed to be low.

고찰Review

상기 표 3에 나타난 바와 같이, N-desalkylquetiapine 유리염기를 용매증발법을 이용하여 수득한 실시예 1 내지 4 조성물의 경우 유효성분 봉입율이 30내지 50%로 우수하게 나타났으며, 수득율도 60 내지 80%로 주사제형으로 제조하기에 적합하게 나타났다.As shown in Table 3, the compositions of Examples 1 to 4 obtained by using the solvent evaporation method of N-desalkylquetiapine free base exhibited excellent coverage of the active ingredient of 30 to 50% 80%, respectively.

반면, N-desalkylquetiapine을 활성성분으로 사용하여 용매증발법으로 수득한 비교예 1 조성물의 경우, 봉입이 사실상 이루어지지 않는 것으로 나타나는바, 활성성분이 모두 씻겨 나간 것으로 보인다.On the other hand, in the case of the composition of Comparative Example 1 obtained by the solvent evaporation method using N-desalkylquetiapine as an active ingredient, it was shown that the sealing was not practically performed, and all of the active ingredients seem to be washed away.

한편, 스프레이 건조법으로 수득한 비교예 2 내지 3 조성물의 경우 봉입율은 매우 높게 나타났으나, 수득율이 낮으며 입자들 끼리 달라붙는 현상으로 나타나 주사제형으로 사용하기에 적합하지 않은 것으로 나타났다.On the other hand, the compositions of Comparative Examples 2 to 3 obtained by the spray drying method showed a very high encapsulation rate, but the yield was low and the particles were sticking to each other.

in-vivo 테스트in-vivo testing

실시예 중 가장 적합하다고 판단되는 용출양상을 가지고 있는 실시예 2를 통하여 동물 실험을 진행하였다. 동물 실험은 총 12마리의 생쥐를 무작위적으로 유리염기약물 용액을 투여하는 대조군과 제조한 약물 PLGA 502H 입자를 투여하는 실험군 두군으로 나누어 진행하였다. 실험은 쥐의 허벅지 부분에 근육 주사하여 정해진 시간 별로 혈액을 샘플링하여 LC-MS를 통하여 분석 하는 방법으로 진행되었다.Animal experiments were carried out in Example 2, which has the dissolution profile which is considered to be the most suitable among the examples. A total of 12 mice were randomly divided into two groups: a control group in which the free base drug solution was administered and a test group in which the prepared drug PLGA 502H particles were administered. The experiment was performed by injecting the muscle in the thigh of the mouse and sampling the blood by the predetermined time and analyzing it through LC-MS.

대조군과 실험군에서 약물투여 후 혈중내에 존재하는 약물의 농도를 보여주는 도 3에 나타내었다. 대조군의 경우 12시간 정도까지 약물이 농도가 관찰된 것으로 보이며 제조한 입자를 투여한 실험군의 경우 11일까지 약물농도가 관찰되는 것으로 관찰되었다. 용출결과를 통해 예상되었던 20일이상의 장기지속성보다는 짧게 관찰되었으나 생체 내에서 장기지속성이 유지되는 것을 확인할 수 있었다.Figure 3 shows the concentration of drug in the blood after administration of the drug in the control and experimental groups. In the control group, the drug concentration was observed up to 12 hours and the drug concentration was observed up to 11 days in the experimental group administered the manufactured particles. The results of the dissolution showed that the long - term persistence was observed rather than the long - term persistence of 20 days or more, but the long - term persistence was maintained in vivo.

in vivo 용출양상과 in vitro에서의 용출양상간의 상관관계를 미국 FDA에서 권장하는 LEVEL A법을 통하여 in vivo 결과를 흡수율로 전환하여 그 상관관계를 확인하였으며 R2 값이 0.9893으로 높은 상관관계가 있음을 보였다. 이를 통하여 in vitro의 결과를 통하여 in vivo 용출양상을 충분히 예상할 수 있을 것이라고 기대된다. The correlation between the in vivo dissolution profile and the in vitro dissolution profile was converted to the absorption rate in vitro by the LEVEL A method recommended by the US FDA and the correlation was confirmed. The R2 value was highly correlated with 0.9893 It looked. It is expected that the in vivo dissolution profile will be fully predicted through in vitro results.

Claims (7)

생리활성약제로 Quetiapine을 포함하는 서방성 약학 조성물로서,
생리활성약제로서 N-desalkylquetiapine 유리염기(free base) 및 생분해성 고분자를 유기용매에 각각 용해시키는 단계;
생리활성약제 용액 및 생분해성 고분자 용액을 혼합하는 단계;
상기 생리활성약제 용액 및 생분해성 고분자 용액의 혼합물을 수성 매질에 투입한 뒤 교반하여 에멀젼을 생성하는 단계; 및
상기 에멀젼을 용매증발법에 의해 동결 건조시키는 단계를 포함하며,
상기 서방성 약학 조성물은 상기 생분해성 고분자 내에 봉입된 생리활성약제의 봉입율이 30 내지 50%인 것을 특징으로 하는 서방성 약학 조성물의 제조방법.A sustained-release pharmaceutical composition comprising quetiapine as a physiologically active agent,
Dissolving each of N-desalkylketiapine free base and biodegradable polymer as a physiologically active agent in an organic solvent;
Mixing a biologically active agent solution and a biodegradable polymer solution;
Adding a mixture of the physiologically active drug solution and the biodegradable polymer solution to an aqueous medium and stirring to produce an emulsion; And
And lyophilizing the emulsion by a solvent evaporation method,
Wherein the sustained release pharmaceutical composition has an encapsulation rate of the bioactive drug encapsulated in the biodegradable polymer of 30 to 50%. 삭제delete 제1항에 있어서,
상기 생분해성 고분자는 PLGA인 것을 특징으로 하는 서방성 약학 조성물의 제조방법.The method according to claim 1,
Wherein the biodegradable polymer is PLGA. 삭제delete 제1항에 있어서,
상기 서방성 약학 조성물은 수득율이 60 내지 80%인 것을 특징으로 하는 서방성 약학 조성물의 제조방법.The method according to claim 1,
Wherein the sustained release pharmaceutical composition has a yield of 60 to 80%. 제1항에 있어서,
상기 서방성 약학 조성물은 주사제제인 것을 특징으로 하는 서방성 약학 조성물의 제조방법.The method according to claim 1,
Wherein the sustained release pharmaceutical composition is an injection preparation. 제 1항의 방법에 의하여 제조된 서방성 약학 조성물.A sustained release pharmaceutical composition prepared by the method of claim 1.
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