KR20240060315A - Stable liquid formulation comprising Botulinum Toxin - Google Patents
Stable liquid formulation comprising Botulinum Toxin Download PDFInfo
- Publication number
- KR20240060315A KR20240060315A KR1020220141778A KR20220141778A KR20240060315A KR 20240060315 A KR20240060315 A KR 20240060315A KR 1020220141778 A KR1020220141778 A KR 1020220141778A KR 20220141778 A KR20220141778 A KR 20220141778A KR 20240060315 A KR20240060315 A KR 20240060315A
- Authority
- KR
- South Korea
- Prior art keywords
- botulinum toxin
- liquid formulation
- present
- albumin
- acetylmethionine
- Prior art date
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- 229940053031 botulinum toxin Drugs 0.000 title claims abstract description 76
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- 239000007788 liquid Substances 0.000 claims abstract description 36
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
- A61K38/4893—Botulinum neurotoxin (3.4.24.69)
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
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- 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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/24—Metalloendopeptidases (3.4.24)
- C12Y304/24069—Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin
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Abstract
본 발명은 보툴리눔 독소 및 N-아세틸메티오닌을 포함하는 액상 제제 및 이의 제조방법, 이의 용도에 관한 것이다.The present invention relates to a liquid preparation containing botulinum toxin and N-acetylmethionine, a method for producing the same, and a use thereof.
Description
본 발명은 보툴리눔 독소 및 N-아세틸메티오닌을 포함하는 액상 제제 및 이의 제조방법, 이의 용도에 관한 것이다.The present invention relates to a liquid preparation containing botulinum toxin and N-acetylmethionine, a method for producing the same, and a use thereof.
보툴리눔 독소는 클로스트리디움 보툴리눔(Clostridium botulinum)과 같은 박테리아에 의해서 생산되는 신경독소 단백질의 일종으로, 시냅스전 신경말단에 비가역적으로 부착하여 신경접합부에 아세틸콜린의 분비를 억제함으로써 근육의 수축을 차단하여 이차적으로 근육의 이완효과를 나타내는 작용을 한다. 이러한 기능으로, 보툴리눔 독소는 1989년 미국 FDA 승인 이후, 치료 또는 미용 목적으로 사용되고 있다(KR 10-2010-0107475 A, KR 10-2008-0049152 A 등). Botulinum toxin is a type of neurotoxin protein produced by bacteria such as Clostridium botulinum. It attaches irreversibly to presynaptic nerve terminals and blocks muscle contraction by inhibiting the secretion of acetylcholine at the nerve junction. It has a secondary effect of relaxing muscles. With these functions, botulinum toxin has been used for therapeutic or cosmetic purposes since its approval by the US FDA in 1989 (KR 10-2010-0107475 A, KR 10-2008-0049152 A, etc.).
치료 목적으로는 사시 (strabismus), 사경(torticollis) 또는 안면 경련(blepharospasm)과 같은 신경근육질환에, 미용 목적으로는 주름, 찌푸린 주름 제거 및 사각턱 치료, 다한증(hyperhidrosis) 또는 편두통(migraine) 치료에 주사제로 사용되고 있다. 부작용으로는 연하곤란(dysphagia), 목소리 변화(voice change), 구강건조 (dry mouth) 및 몽롱 (blurred vision) 등과 같은 사례들이 보고되었으나, 아직 보툴리눔 독소로 인한 직접적인 사망사고가 없어 적절하게 사용하면 매우 안전한 약품으로 평가받고 있다. For therapeutic purposes, it is used to treat neuromuscular diseases such as strabismus, torticollis or blepharospasm, and for cosmetic purposes, it is used to remove wrinkles, frown lines and square jaw, and to treat hyperhidrosis or migraine. It is used as an injection. Side effects such as dysphagia, voice change, dry mouth, and blurred vision have been reported, but there have been no direct deaths due to botulinum toxin, so it is very effective when used appropriately. It is evaluated as a safe drug.
다만, 보툴리눔 독소와 같은 단백질 제제의 경우 약제화 과정에 많은 문제점이 발생한다. 이는 단백질의 불안정성에 기인하며 보툴리눔 독소와 같이 극히 낮은 농도로 약제화가 이루어지는 단백질 제제의 경우 그 문제가 심각하다.However, in the case of protein preparations such as botulinum toxin, many problems arise in the pharmaceutical preparation process. This is due to the instability of proteins, and the problem is serious in the case of protein preparations that are medicated at extremely low concentrations, such as botulinum toxin.
종래의 상업용 보툴리눔 독소 제제는 단백질의 안정성을 높이기 위하여 동결건조되거나 진공-건조된 건조 분말 형태로 제조되고 있다. 하지만, 동결건조 등의 방법으로 제조된 건조 분말 제형의 경우, 사용시 재수화 과정을 거쳐야 하므로 사용상의 불편함이 있을 뿐 아니라, 재수화 과정에서 희석 과정의 오류 등으로 인해 투여되는 보툴리눔 독소 량의 편차, 특히 활성 측면에서의 편차 등이 발생하는 문제가 있어, 사용자의 편의성 및 재수화 과정에서의 오류를 최소화할 수 있는 액상 제제에 대한 수요가 커지고 있다.Conventional commercial botulinum toxin preparations are manufactured in the form of lyophilized or vacuum-dried dry powder to increase protein stability. However, in the case of dry powder formulations manufactured by methods such as freeze-drying, not only are there inconveniences in use because they must go through a rehydration process when used, but also there is variation in the amount of botulinum toxin administered due to errors in the dilution process during the rehydration process. , In particular, there are problems such as deviations in activity, so there is a growing demand for liquid preparations that can minimize errors in the rehydration process and provide user convenience.
아직 보툴리눔 독소의 활성을 오래 유지하면서 장기간 동안 보관할 수 있는 안정한 액상 제제의 개발이 미비하므로, 새로운 조성의 보툴리눔 독소를 포함하는 액상 제제의 개발이 여전히 요구된다.Since the development of a stable liquid formulation that can be stored for a long period of time while maintaining the activity of botulinum toxin is still insufficient, the development of a liquid formulation containing botulinum toxin with a new composition is still required.
본 발명의 하나의 목적은 보툴리눔 독소 및 N-아세틸메티오닌을 포함하는 액상 제제를 제공하는 것이다.One object of the present invention is to provide a liquid formulation containing botulinum toxin and N-acetylmethionine.
본 발명의 다른 목적은 상기 액상 제제를 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for producing the liquid formulation.
본 발명의 다른 목적은 상기 액상 제제를 이용하여 보툴리눔 독소를 안정화시키는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for stabilizing botulinum toxin using the liquid formulation.
이를 구체적으로 설명하면 다음과 같다. 한편, 본 발명에서 개시된 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 발명에서 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 볼 수 없다.This is explained in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Additionally, the scope of the present invention cannot be considered to be limited by the specific description described below.
또한, 당해 기술분야의 통상의 지식을 가진 자는 통상의 실험만을 사용하여 본 발명에 기재된 본 발명의 특정 양태에 대한 다수의 등가물을 인지하거나 확인할 수 있다. 또한, 이러한 등가물은 본 발명에 포함되는 것으로 의도된다.Additionally, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Additionally, such equivalents are intended to be encompassed by this invention.
본 발명을 구현하는 하나의 양태는 보툴리눔 독소 및 N-아세틸메티오닌을 포함하는 액상 제제를 제공한다.One aspect embodying the present invention provides a liquid formulation containing botulinum toxin and N-acetylmethionine.
구체적으로, 상기 액상 제제는 보툴리눔 독소; 및 N-아세틸메티오닌을 포함하는 것을 특징으로 하거나, 보툴리눔 독소; 알부민; 및 N-아세틸메티오닌을 포함하는 것을 특징으로 할 수 있으나, 이에 제한되지 않는다. 또한, 본 발명의 액상 제제는 등장화제, 비이온성 계면활성제, 완충제, 또는 이들의 조합을 추가로 포함하는 것일 수 있으나, 이에 제한되지 않는다. Specifically, the liquid formulation includes botulinum toxin; and N-acetylmethionine, or botulinum toxin; albumin; and N-acetylmethionine, but is not limited thereto. Additionally, the liquid formulation of the present invention may further include an isotonic agent, a nonionic surfactant, a buffer, or a combination thereof, but is not limited thereto.
본 발명에서 용어 "액상 제제"는 의약품의 형태를 액상으로 제제화한 약물을 의미하며, 이는 액상의 내용 제제 및 외용 제제를 모두 포함한다.In the present invention, the term “liquid preparation” refers to a drug formulated into a liquid form, and includes both liquid oral preparations and external preparations.
본 발명의 액상 제제는 약리 효과를 나타내는 보툴리눔 독소가 액상으로 제제화될 때 이를 일정 기간 동안 안정하게 유지 및/또는 저장시킬 수 있는 물질을 포함한다. 상기 액상 제제의 약리효과를 나타내는 보툴리눔 독소 이외에 포함되는 성분은 안정화제와 혼용될 수 있다. 본 발명에서 용어, "안정화제"란 제제에서 유효성분 등의 구성 성분을 일정 기간 동안 안정하게 유지시키는 물질을 말한다.The liquid preparation of the present invention contains a substance that can stably maintain and/or store the botulinum toxin exhibiting pharmacological effects for a certain period of time when it is formulated in liquid form. Components other than botulinum toxin, which exhibits pharmacological effects in the liquid formulation, may be mixed with a stabilizer. In the present invention, the term "stabilizer" refers to a substance that keeps components such as active ingredients stable in a preparation for a certain period of time.
본 발명의 액상 제제는 장기간 보관에도 보툴리눔 독소의 약리 효과가 오래 유지될 수 있도록 안정화할 수 있는 안정화제의 조성을 포함하는 것을 특징으로 한다. The liquid formulation of the present invention is characterized by containing a stabilizer that can stabilize the pharmacological effect of botulinum toxin so that it can be maintained for a long time even when stored for a long period of time.
본 발명에서, 용어 "보툴리눔 독소(Botulinum toxin)"는 "클로스트리디움 보툴리눔 독소"로도 지칭되며, 클로스트리디움 보툴리눔(Clostridium botulinum) 유래 단백질의 일종으로, 시냅스전 신경말단에 비가역적으로 부착하여 신경접합부에 아세틸콜린의 분비를 억제함으로써 근육의 수축을 차단하여 이차적으로 근육의 이완효과를 나타내는 작용을 하는 단백질을 지칭한다. In the present invention, the term "Botulinum toxin" is also referred to as "Clostridium botulinum toxin" and is a type of protein derived from Clostridium botulinum , which irreversibly attaches to presynaptic nerve terminals and causes nerve damage. It refers to a protein that blocks muscle contraction by inhibiting the secretion of acetylcholine at the junction, thereby producing a secondary muscle relaxation effect.
보툴리눔 독소 단백질은 약 150kD의 분자량을 가지며, 혈청학적 특징에 따라 A에서 G까지의 7가지 형으로 나뉜다. 보툴리눔 독소 A형은 인간에 대해서 알려진 가장 치명적인 천연물질이며 혈청형 A 이외에도, 6 가지의 다른 일반적으로 면역학적으로 상이한 보툴리눔 독소, 즉 보툴리눔 독소 혈청형 B, C, D, E, F, 및 G가 규명되었다. 상이한 혈청형은 형-특이적 항체에 의한 중화에 의해서 식별될 수 있으며, 이들이 유발하는 마비의 중증도 및 이들이 가장 영향을 미치는 동물 종은 상이하다.Botulinum toxin protein has a molecular weight of approximately 150 kD and is divided into seven types from A to G depending on serological characteristics. Botulinum toxin type A is the most lethal natural agent known to humans. In addition to serotype A, there are six other commonly immunologically different botulinum toxins, namely botulinum toxin serotypes B, C, D, E, F, and G. has been identified. Different serotypes can be identified by neutralization with type-specific antibodies, and the severity of paralysis they cause and the animal species they most affect differ.
보툴리눔 독소 분자의 분자량은, 알려진 보툴리눔 독소 혈청형 7가지 모두에서, 약 150kD이다. 한편, 클로스트리디움계 박테리아에 의해서 보툴리눔 독소는 관련된 비-독소 단백질과 함께 150kD 보툴리눔 독소 단백질 분자를 포함하는 복합체로서 방출된다. 그러므로, 보툴리눔 독소 타입 A 복합체는 클로스트리디움계 박테리아에 의해서, 900kD, 500kD 및 300kD 형으로 생성될 수 있다. 보툴리눔 독소 타입 B 및 C는 500kD 복합체로, 보툴리눔 독소 타입 D는 300kD 및 500kD 복합체로 생성될 수 있다. 보툴리눔 독소 타입 E 및 F는 약 300kD 복합체로 생성될 수 있다. 이 복합체들(즉, 분자량이 약 150kD 보다 큰 것)은 비독성 적혈구응집소 단백질 및 비-독소 및 비독성 비적혈구응집소 단백질을 포함하는 것으로 여겨진다. The molecular weight of the botulinum toxin molecule is approximately 150 kD for all seven known botulinum toxin serotypes. On the other hand, botulinum toxin is released by Clostridial bacteria as a complex containing a 150 kD botulinum toxin protein molecule along with associated non-toxin proteins. Therefore, botulinum toxin type A complex can be produced by clostridial bacteria in 900kD, 500kD and 300kD types. Botulinum toxin types B and C can be produced as 500 kD complexes, and botulinum toxin type D as 300 kD and 500 kD complexes. Botulinum toxin types E and F can be produced as approximately 300 kD complexes. These complexes (i.e., those with a molecular weight greater than about 150 kD) are believed to include a non-toxic hemagglutinin protein and a non-toxic and non-toxic non-hemagglutinin protein.
보툴리눔 독소는 약 150 kD의 순수 신경독소 성분과 아울러 비-독소 단백질을 포함하는 고분자량의 복합체 형태를 포함한다. 따라서, 복합체화된 형태는 보툴리눔 신경독소 단백질 및 하나 또는 그 이상의 비-독소 헤마글루티닌 단백질 및/또는 하나 또는 그 이상의 비-독소 비-헤마글루티닌 단백질을 포함할 수 있다. 구체적으로, 보툴리눔 독소 복합체 단백질은 보툴리눔 신경독소(BoNT; Botulinum neurotoxin), 비독성 비헤마글루티닌(NTNH; nontoxic nonhemagglutinin), 및 헤마글루티닌(HA) 단백질의 복합체일 수 있다. 상기 복합체의 분자량은 약 150 kD보다 클 수 있다. 예를 들어, 보툴리눔 독소 A형의 복합체화된 형태는 약 900 kD, 약 500 kD 또는 약 300 kD의 분자량을 가질 수 있다. 본 발명의 클로스트리디움 보툴리눔 독소 복합체의 정제 방법은 상기 다양한 복합체를 정제할 수 있다. Botulinum toxin contains a pure neurotoxin component of approximately 150 kD as well as a high molecular weight complex form containing non-toxin proteins. Accordingly, the complexed form may comprise a botulinum neurotoxin protein and one or more non-toxin hemagglutinin proteins and/or one or more non-toxin non-hemagglutinin proteins. Specifically, the botulinum toxin complex protein may be a complex of botulinum neurotoxin (BoNT), nontoxic nonhemagglutinin (NTNH), and hemagglutinin (HA) proteins. The molecular weight of the complex may be greater than about 150 kD. For example, the complexed form of botulinum toxin type A may have a molecular weight of about 900 kD, about 500 kD, or about 300 kD. The method for purifying the Clostridium botulinum toxin complex of the present invention can purify the various complexes.
일 구현예로, 본 발명의 보툴리눔 독소는 A형 독소일 수 있다. In one embodiment, the botulinum toxin of the present invention may be a type A toxin.
전술한 구현예 중의 어느 하나의 구현예로, 본 발명의 보툴리눔 독소는 비독성 단백질과 결합한 복합체 형태일 수 있다. 구체적으로, 본 발명의 보툴리눔 독소 복합체 단백질은 보툴리눔 독소(BoNT; Botulinum neurotoxin), 비독성 비헤마글루티닌(NTNH; nontoxic nonhemagglutinin), 및 헤마글루티닌(HA: hemagglutinin) 단백질의 복합체일 수 있다. 보다 구체적으로, 본 발명의 보툴리눔 독소 복합체 단백질은 BoNT, NTNH, HA70(hemagglutinin 70), HA33(hemagglutinin 33) 및 HA17(hemagglutinin 17)의 복합체일 수 있다. 보다 구체적으로 상기 HA70은 HA20(hemagglutinin 20)와 HA50(hemagglutinin 50)으로 나누어지거나, 상기 BoNT는 약 50 kD 경쇄(LC: Light chain)와 약 100 kD 중쇄(HC: Heavy chain)로 나누어질 수 있다. 그러나 이에 제한되지 않는다.In any one of the above-described embodiments, the botulinum toxin of the present invention may be in the form of a complex bound to a non-toxic protein. Specifically, the botulinum toxin complex protein of the present invention may be a complex of botulinum toxin (BoNT), nontoxic nonhemagglutinin (NTNH), and hemagglutinin (HA) proteins. More specifically, the botulinum toxin complex protein of the present invention may be a complex of BoNT, NTNH, hemagglutinin 70 (HA70), hemagglutinin 33 (HA33), and hemagglutinin 17 (HA17). More specifically, the HA70 can be divided into HA20 (hemagglutinin 20) and HA50 (hemagglutinin 50), or the BoNT can be divided into about 50 kD light chain (LC) and about 100 kD heavy chain (HC). . However, it is not limited to this.
전술한 구현예 중의 어느 하나의 구현예로, 본 발명의 보툴리눔 독소 복합체 단백질은 150kD 초과의 분자량을 갖는 것일 수 있다. 구체적으로 약 250 kD 내지 1400 kD의 분자량을 가질 수 있으며, 보다 구체적으로 280kD 내지 1300kD, 300kD 내지 1200kD, 700kD 내지 1100kD, 800kD 내지 1000kD, 또는 약 900kD의 분자량을 가질 수 있으나, 이에 제한되지는 않는다.In any one of the above-described embodiments, the botulinum toxin complex protein of the present invention may have a molecular weight of more than 150 kD. Specifically, it may have a molecular weight of about 250 kD to 1400 kD, and more specifically, it may have a molecular weight of 280 kD to 1300 kD, 300 kD to 1200 kD, 700 kD to 1100 kD, 800 kD to 1000 kD, or about 900 kD, but is not limited thereto.
본 발명의 보툴리눔 독소는 클로스트리디움 보툴리눔 (Clostridium botulinum) 배양액으로부터 수득한 것이거나, 상업적으로 수득한 것을 모두 포함할 수 있으며, 상기 보툴리눔 독소는 최종적으로 100 unit/ml이 되도록 포함될 수 있으나, 이에 제한되지 않는다. The botulinum toxin of the present invention may be obtained from Clostridium botulinum culture medium or may include commercially obtained botulinum toxin, and the botulinum toxin may be included to a final concentration of 100 units/ml, but is limited thereto. It doesn't work.
본 발명에서, 용어 "N-아세틸메티오닌(N-acetylmethionine)"은 아미노산 중 하나로 본 발명의 목적상 목적상 보툴리눔 독소의 약리 효과가 오래 유지될 수 있도록 하는데 도움을 주는 역할을 한다. In the present invention, the term "N-acetylmethionine" is one of the amino acids and, for the purpose of the present invention, plays a role in helping to maintain the pharmacological effect of botulinum toxin for a long time.
본 발명의 액상제제는 상기 N-아세틸메티오닌을 약 0.01 내지 0.5%(w/v), 약 0.05 내지 0.5%(w/v), 약 0.1 내지 0.5%(w/v), 약 0.1%(w/v), 약 0.2%(w/v), 약 0.3%(w/v), 약 0.4%(w/v), 또는 약 0.5%(w/v)의 농도로 포함하는 것일 수 있으나, 이에 제한되지 않는다.The liquid formulation of the present invention contains N-acetylmethionine in an amount of about 0.01 to 0.5% (w/v), about 0.05 to 0.5% (w/v), about 0.1 to 0.5% (w/v), about 0.1% (w). /v), it may be included at a concentration of about 0.2% (w/v), about 0.3% (w/v), about 0.4% (w/v), or about 0.5% (w/v). Not limited.
일 예로, 본 발명의 액상 제제는 다양한 부형제 중 N-아세틸메티오닌을 첨가하였을 때, 보툴리눔 독소의 활성 유지 효과가 가장 우수함을 확인하였다. As an example, it was confirmed that the liquid formulation of the present invention had the best effect in maintaining the activity of botulinum toxin when N-acetylmethionine was added among various excipients.
본 발명에 따른 액상 제제는 알부민(albumin)을 추가로 포함할 수 있다. 상기 알부민은 단백질의 일종으로, 특히 금속 이온, 약물 및 이종 생물학을 비롯한 다양한 물질을 운반하는 혈장 단백질로 알려져 있으며, 배양 환경의 pH 조절 및 삼투압 유지에 관련되어 있다고 알려져 있다. 본 발명에서 상기 알부민은 이에 제한되는 것은 아니나, 사람의 혈장이나 혈청 등으로부터 추출하여 수득(Human Serum Albumin; HSA) 하거나, 재조합하여 제조(Recombinant Human Serum Albumin; rHSA)한 것을 사용할 수 있으며, 구체적으로, 상기 알부민은 동물 유래 HSA 또는 식물 유래 재조합 HSA가 사용될 수 있으나, 이에 제한되지 않는다. 재조합 알부민의 경우 혈액 매개 오염물질이 포함되지 않고, 정의된 물질만을 이용할 수 있는 바, 면역원성이 낮은 이점을 갖는다.The liquid formulation according to the present invention may additionally include albumin. The albumin is a type of protein, and is known as a plasma protein that transports various substances including metal ions, drugs, and xenobiotics, and is known to be involved in controlling pH and maintaining osmotic pressure in the culture environment. In the present invention, the albumin is not limited to this, but can be obtained by extracting from human plasma or serum (Human Serum Albumin; HSA), or manufactured by recombinant (Recombinant Human Serum Albumin; rHSA). Specifically, , the albumin may be animal-derived HSA or plant-derived recombinant HSA, but is not limited thereto. Recombinant albumin has the advantage of low immunogenicity because it does not contain blood-borne contaminants and only defined substances can be used.
본 발명의 액상제제는 상기 알부민을 약 0.01 내지 1%(w/v), 약 0.05 내지 1%(w/v), 약 0.1 내지 1%(w/v), 약 0.1 내지 0.8%(w/v), 약 0.2 내지 0.7%(w/v), 약 0.3 내지 0.6%(w/v), 약 0.3%(w/v), 약 0.4%(w/v), 약 0.5%(w/v), 또는 약 0.6%(w/v)의 농도로 포함하는 것일 수 있으나, 이에 제한되지 않는다.The liquid formulation of the present invention contains the albumin in an amount of about 0.01 to 1% (w/v), about 0.05 to 1% (w/v), about 0.1 to 1% (w/v), and about 0.1 to 0.8% (w/). v), about 0.2 to 0.7% (w/v), about 0.3 to 0.6% (w/v), about 0.3% (w/v), about 0.4% (w/v), about 0.5% (w/v) ), or at a concentration of about 0.6% (w/v), but is not limited thereto.
본 발명에 따른 액상제제의 구체적인 예시로서, 보툴리눔 독소; 및 N-아세틸메티오닌을 포함하는 것일 수 있고, 보다 구체적인 예시로는 100 Unit/ml의 보툴리눔 독소; 및 0.01 내지 0.5%(w/v)의 N-아세틸메티오닌을 포함하는 액상제제를 들 수 있다. Specific examples of the liquid preparation according to the present invention include botulinum toxin; and N-acetylmethionine, and more specific examples include botulinum toxin at 100 Unit/ml; and a liquid formulation containing 0.01 to 0.5% (w/v) of N-acetylmethionine.
본 발명에 따른 액상 제제는 알부민을 추가로 포함하는 것일 수 있다. 구체적인 예시로서, 보툴리눔 독소; 알부민; 및 N-아세틸메티오닌을 포함하는 것일 수 있고, 보다 구체적인 예시로는 100 Unit/ml의 보툴리눔 독소; 0.01 내지 1%(w/v)의 알부민; 및 0.01 내지 0.5%(w/v)의 N-아세틸메티오닌을 포함하는 액상제제를 들 수 있다. The liquid preparation according to the present invention may additionally contain albumin. As specific examples, botulinum toxin; albumin; and N-acetylmethionine, and more specific examples include botulinum toxin at 100 Unit/ml; 0.01 to 1% (w/v) albumin; and a liquid formulation containing 0.01 to 0.5% (w/v) of N-acetylmethionine.
본 발명의 액상 제제는 비이온성 계면활성제 및/또는 등장화제를 추가로 포함할 수 있다. The liquid formulation of the present invention may further include a nonionic surfactant and/or an isotonic agent.
상기 비이온성 계면활성제는 단백질 용액의 표면장력을 낮추어 소수성 표면에 단백질이 흡착되거나 응집되는 것을 방지하여 줄 수 있다. The nonionic surfactant can prevent proteins from adsorbing or aggregating on hydrophobic surfaces by lowering the surface tension of the protein solution.
본 발명에 사용될 수 있는 비이온성 계면활성제의 구체적인 예로는 폴리소르베이트류(예컨대, 폴리소르베이트 20(폴리옥시에틸렌(20) 소르비탄 모노라우레이트), 폴리소르베이트 40(폴리옥시에틸렌(20) 소르비탄 모노팔미테이트), 폴리소르베이트 60(폴리옥시에틸렌(20) 소르비탄 모노스테아레이트), 폴리소르베이트 80(폴리옥시에틸렌(20) 소르비탄 모노올레이트); 상기 폴리옥시에틸렌 뒤의 수치(20)은 옥시에틸렌기(-(CH2CH2O)-)의 총 개수를 의미함), 폴록사머(PEO-PPO-PEO 공중합체; PEO: poly(ethylene oxide), PPO: poly(propylene oxide)), 폴리에틸렌-폴리프로필렌 글리콜, 폴리옥시에틸렌 화합물(예컨대, 폴리옥시에틸렌-스테아레이트, 폴리옥시에틸렌 알킬 에테르(알킬: C1-C30), 폴리옥시에틸렌 모노알릴 에테르, 알킬페닐 폴리옥시에틸렌 코폴리머(알킬: C1-C30) 등), 소듐 도데실 설페이트(sodium dodecyl sulphate, SDS) 등일 수 있으며, 또는 폴리소르베이트 또는 폴록사머를 들 수 있으며, 이들이 하나 또는 둘 이상의 조합 형태로도 사용될 수 있다. Specific examples of nonionic surfactants that can be used in the present invention include polysorbates (e.g., polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) Sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate); (20) refers to the total number of oxyethylene groups (-(CH2CH2O)-), poloxamer (PEO-PPO-PEO copolymer; PEO: poly(ethylene oxide), PPO: poly(propylene oxide)), Polyethylene-polypropylene glycol, polyoxyethylene compounds (e.g., polyoxyethylene-stearate, polyoxyethylene alkyl ether (alkyl: C1-C30), polyoxyethylene monoallyl ether, alkylphenyl polyoxyethylene copolymer (alkyl: C1-C30), etc.), sodium dodecyl sulphate (SDS), etc., or polysorbate or poloxamer, and these may be used in the form of one or a combination of two or more.
구체적으로, 상기 비이온성 계면활성제는 폴록사머 188, 폴리소르베이트 20, 폴리소르베이트 40, 폴리소르베이트 60, 또는 폴리소르베이트 80일 수 있으며, 이들이 조합되어 사용될 수 있으나, 특별히 이에 제한되는 것은 아니다. Specifically, the nonionic surfactant may be poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80, and may be used in combination, but is not particularly limited thereto. .
본 발명에서 상기 비이온성 계면활성제는 본 발명의 액상 제제에 약 0.2%(w/v) 이하의 농도, 예컨대 약 0.001 내지 약 0.2%(w/v), 약 0.001 내지 약 0.1%(w/v), 약 0.005 내지 약 0.1%(w/v), 약 0.001 내지 약 0.08%(w/v), 약 0.002 내지 약 0.08%(w/v), 약 0.005 내지 약 0.05%(w/v), 약 0.01 내지 약 0.05%(w/v), 또는 약 0.05%(w/v)로 포함될 수 있으나, 특별히 이에 제한되지 않는다.In the present invention, the nonionic surfactant is added to the liquid formulation of the present invention at a concentration of about 0.2% (w/v) or less, such as about 0.001 to about 0.2% (w/v), about 0.001 to about 0.1% (w/v). ), about 0.005 to about 0.1% (w/v), about 0.001 to about 0.08% (w/v), about 0.002 to about 0.08% (w/v), about 0.005 to about 0.05% (w/v), It may be included in an amount of about 0.01 to about 0.05% (w/v), or about 0.05% (w/v), but is not particularly limited thereto.
상기 등장화제는 액상 제제의 삼투압 조정을 위해 첨가되는 물질로, 적정 삼투압을 유지하면서 보툴리눔 독소를 안정화하는데 기여할 수 있는 한, 등장화제로 제한 없이 본 발명의 액상 제제에 포함될 수 있다. The isotonic agent is a substance added to adjust the osmotic pressure of the liquid formulation, and may be included in the liquid formulation of the present invention without limitation as long as it can contribute to stabilizing the botulinum toxin while maintaining an appropriate osmotic pressure.
상기 등장화제는 수용성 무기염을 포함할 수 있으며, 구체적으로, 본 발명의 액상 제제는 염화나트륨, 글리세린, 염화칼륨, 및 덱스트로오스로 이루어진 군에서 선택된 어느 하나 이상인 것을 등장화제로 포함할 수 있으나, 이에 제한되지 않는다. The isotonic agent may include a water-soluble inorganic salt, and specifically, the liquid formulation of the present invention may include at least one selected from the group consisting of sodium chloride, glycerin, potassium chloride, and dextrose as an isotonic agent. Not limited.
본 발명에서 상기 등장화제는 본 발명의 액상 제제에 약 5%(w/v) 이하의 농도, 예컨대 약 0.01 내지 약 5%(w/v), 약 0.1 내지 약 5%(w/v), 약 0.1 내지 약 3%(w/v), 약 0.1 내지 약 2%(w/v), 약 0.5 내지 약 1.5%(w/v), 약 0.75 내지 약 1.25%(w/v) 또는 약 0.9%(w/v)로 포함될 수 있으나, 특별히 이에 제한되지 않는다.In the present invention, the isotonic agent is used in the liquid formulation of the present invention at a concentration of about 5% (w/v) or less, such as about 0.01 to about 5% (w/v), about 0.1 to about 5% (w/v), About 0.1 to about 3% (w/v), about 0.1 to about 2% (w/v), about 0.5 to about 1.5% (w/v), about 0.75 to about 1.25% (w/v) or about 0.9 It may be included as % (w/v), but is not particularly limited thereto.
본 발명의 액상 제제는 완충제를 추가로 포함할 수 있다. 일 예로, 상기 완충제는 아세트산과 그 염, 구연산과 그 염, 및 인산과 그 염으로 이루어진 군에서 선택된 어느 하나 이상인 것일 수 있으며, 그 예로, 인산과 그 염(예를 들어, 인산염, 인산나트룸, 인산칼륨, 또는 이들의 수소 또는 이수소 염), 구연산과 그 염 (예를 들어, 구연산 나트륨), 아세트산과 그 염(예를 들어, 아세트산 나트륨), 또는 인산 나트륨일 수 있으나, 이에 제한되지 않는다. The liquid formulation of the present invention may additionally contain a buffering agent. For example, the buffering agent may be at least one selected from the group consisting of acetic acid and its salts, citric acid and its salts, and phosphoric acid and its salts, for example, phosphoric acid and its salts (e.g., phosphate, sodium phosphate). , potassium phosphate, or hydrogen or dihydrogen salts thereof), citric acid and its salts (e.g., sodium citrate), acetic acid and its salts (e.g., sodium acetate), or sodium phosphate. No.
본 발명에서 상기 완충제는 본 발명의 액상 제제에 약 5.0% (w/v)이하의 농도, 약 4.0% (w/v)이하의 농도, 약 3.0% (w/v)이하의 농도, 약 2.0% (w/v)이하의 농도, 약 1.0% (w/v)이하의 농도, 약 0.9% (w/v)이하의 농도, 약 0.8% (w/v)이하의 농도, 예컨대 약 0.01 내지 약 5.0%(w/v), 약 0.01 내지 약 4.0%(w/v), 약 0.01 내지 약 3.0%(w/v), 약 0.01 내지 약 2.0%(w/v), 약 0.01 내지 약 1.0%(w/v), 약 0.01 내지 약 5.0%(w/v), 약 0. 1 내지 약 1.0%(w/v), 약 0. 01 내지 약 0.9%(w/v), 약 0. 05 내지 약 0.9%(w/v), 약 0. 1 내지 약 1.00%(w/v), 약 0.4 내지 약 0.9%(w/v), 약 0.4 내지 약 2.0%(w/v), 약 0.3 내지 약 1.0%(w/v), 약 0.3 내지 약 0.8%(w/v), 또는 약 0.05%(w/v), 또는 약 0.7%(w/v)로 포함될 수 있으나, 특별히 이에 제한되지 않는다.In the present invention, the buffering agent is used in the liquid formulation of the present invention at a concentration of about 5.0% (w/v) or less, a concentration of about 4.0% (w/v) or less, a concentration of about 3.0% (w/v) or less, and a concentration of about 2.0% or less. % (w/v) or less, a concentration of about 1.0% (w/v) or less, a concentration of about 0.9% (w/v) or less, a concentration of about 0.8% (w/v) or less, such as about 0.01 to About 5.0% (w/v), about 0.01 to about 4.0% (w/v), about 0.01 to about 3.0% (w/v), about 0.01 to about 2.0% (w/v), about 0.01 to about 1.0 % (w/v), about 0.01 to about 5.0% (w/v), about 0.1 to about 1.0% (w/v), about 0.01 to about 0.9% (w/v), about 0. 05 to about 0.9% (w/v), about 0.1 to about 1.00% (w/v), about 0.4 to about 0.9% (w/v), about 0.4 to about 2.0% (w/v), about It may be included in an amount of 0.3 to about 1.0% (w/v), about 0.3 to about 0.8% (w/v), or about 0.05% (w/v), or about 0.7% (w/v), but is specifically limited thereto. It doesn't work.
본 발명의 액상 제제는 약학적으로 허용가능한 염 형태를 포함할 수 있다.The liquid formulation of the present invention may contain a pharmaceutically acceptable salt form.
상기 용어, "약학적으로 허용가능"은 의약학적 판단의 범위 내에서，과도한 독성，자극, 또는 알레르기 반응 등을 유발하지 않고 원하는 용도에 효과적으로 사용 가능한 물질을 의미한다. The term "pharmaceutically acceptable" refers to a substance that can be effectively used for the desired purpose without causing excessive toxicity, irritation, or allergic reactions, within the scope of medical judgment.
본 발명의 용어, "약학적으로 허용가능한 염" 이란 약학적으로 허용되는 무기산, 유기산, 또는 염기로부터 유도된 염을 포함한다. 적합한 산의 예로는 염산, 브롬산, 황산, 질산, 과염소산, 푸마르산，말레산, 인산, 글리콜산, 락트산, 살리실산，숙신산, 톨루엔-p-설폰산, 타르타르산, 아세트산，시트르산, 메탄설폰산，포름산, 벤조산, 말론산, 나프탈렌-2-설폰산， 벤젠설폰산 등을 들 수 있다. 적합한 염기로부터 유도된 염은 나트륨, 칼륨 등의 알칼리 금속，마그네슘 등의 알칼리 토금속，및 암모늄 등을 포함할 수 있다.As used herein, the term “pharmaceutically acceptable salt” includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, and formic acid. , benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, etc. Salts derived from suitable bases may include alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium.
또한, 본 발명에 따른 액상 제제는 추가로 약학적으로 허용가능한 담체, 부형제 등을 포함할 수 있고, 이러한 담체, 부형제는 비자연적으로 존재하는 것일 수 있다.In addition, the liquid preparation according to the present invention may additionally contain pharmaceutically acceptable carriers, excipients, etc., and such carriers and excipients may exist unnaturally.
구체적으로, "약학적으로 허용가능한 담체"는 생물체를 자극하지 않고 본 발명의 액상 제제의 특성을 저해하지 않는 담체 또는 희석제를 말한다. 액상 용액으로 제제화되는 조성물에 있어서 허용되는 약학적 담체로는, 멸균, 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 하나 이상의 성분을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다.Specifically, “pharmaceutically acceptable carrier” refers to a carrier or diluent that does not irritate living organisms and does not inhibit the properties of the liquid preparation of the present invention. Acceptable pharmaceutical carriers in compositions formulated as liquid solutions include those that are sterile and biocompatible, such as saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, and ethanol. And one or more of these ingredients can be mixed and used, and other common additives such as antioxidants, buffers, and bacteriostatic agents can be added as needed.
보다 구체적으로, 상기 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 폴리카프로락톤(polycaprolactone), 폴리락틱액시드(Poly Lactic Acid), 폴리-L-락틱액시드(poly-L-lactic acid), 광물유 등을 들 수 있다.More specifically, carriers, excipients, and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, and calcium phosphate. , calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, polycaprolactone, polylactic acid. (Poly Lactic Acid), poly-L-lactic acid, mineral oil, etc.
본 발명의 액상 제제는 보툴리눔 독소의 투여로 예방, 치료 또는 개선의 효과를 얻을 수 있는 질환, 예를 들어 항진성 골격근을 특징으로 하는 신경근육 장애의 치료 또는 예방을 위하여 사용될 수 있다. 또한, 두통, 편두통, 긴장성 두통, 부비동 두통, 경추성 두통, 발한 장애, 겨드랑이 다한증, 손 다한증, 발 다한증, 프레이 증후군, 과운동성 피부 주름(hyperkinetic skin line), 안면 주름, 미간 주름, 눈가 주름, 입가 주름, 코입술 주름, 피부 장애, 이완불능증, 사시, 만성 치열, 안검경련, 근골격 통증, 섬유근통, 췌장염, 빈맥, 전립선 비대, 전립선염, 요폐, 요실금, 과민성 방광, 반측안면 경련, 떨림, 근경련, 위장관 장애, 당뇨병, 타액과다증, 배뇨근-조임근 협동장애, 뇌졸중 후 강직, 상처 회복, 소아 뇌성마비, 평활근 경련, 재협착, 국소 근긴장이상, 간질, 경부 근긴장이상증, 갑상선 장애, 고칼슘혈증, 강박 장애, 관절염 통증, 레이노 증후군, 튼살, 복막 유착, 혈관경련, 콧물, 근육 경축, 후두 근긴장이상, 필기 경련 및 수근관 증후군 등의 질환 치료 및 미용 목적 등으로 다양하게 사용될 수 있으나, 이에 제한되지 않는다.The liquid preparation of the present invention can be used for the treatment or prevention of diseases that can be prevented, treated or improved by the administration of botulinum toxin, for example, neuromuscular disorders characterized by hyperactive skeletal muscles. In addition, headaches, migraines, tension headaches, sinus headaches, cervicogenic headaches, sweating disorders, axillary hyperhidrosis, hand hyperhidrosis, foot hyperhidrosis, Frey syndrome, hyperkinetic skin lines, facial wrinkles, glabellar wrinkles, wrinkles around the eyes, Wrinkles around the mouth, nasolabial folds, skin disorders, achalasia, strabismus, chronic dentition, blepharospasm, musculoskeletal pain, fibromyalgia, pancreatitis, tachycardia, enlarged prostate, prostatitis, urinary retention, urinary incontinence, overactive bladder, hemifacial spasm, tremor, muscle Convulsions, gastrointestinal disorders, diabetes, hypersalivation, detrusor-sphincter coordination disorder, post-stroke stiffness, wound recovery, pediatric cerebral palsy, smooth muscle spasms, restenosis, focal dystonia, epilepsy, cervical dystonia, thyroid disorders, hypercalcemia, obsessive-compulsive disorder. It can be used in a variety of ways, including for the treatment of diseases such as disability, arthritis pain, Raynaud's syndrome, stretch marks, peritoneal adhesions, vasospasm, runny nose, muscle spasms, laryngeal dystonia, writing spasm, and carpal tunnel syndrome, and for cosmetic purposes, but is not limited to this.
본 발명에서 용어 "예방"은 상기 보툴리눔 독소 또는 이를 포함하는 액상 제제의 투여로 질환을 억제 또는 액상 제제의 투여로 질환의 발병을 억제 또는 지연시키는 모든 행위를 의미하며, 본 발명에서 용어 "치료"는 보툴리눔 독소 또는 이를 포함하는 액상 제제의 투여로 목적하는 질환의 증세가 개선, 호전되거나 이롭게 되는 모든 행위를 의미한다.In the present invention, the term "prevention" refers to any act of suppressing a disease by administering the botulinum toxin or a liquid preparation containing it, or suppressing or delaying the onset of a disease by administering a liquid preparation, and in the present invention, the term "treatment" refers to any action that improves, improves, or benefits the symptoms of the target disease by administering botulinum toxin or a liquid preparation containing it.
본 발명의 구체적인 실시 형태에서, 본 발명의 액상 제제는 신경근육 장애의 치료 또는 예방을 위해 이용되는 것일 수 있으나, 이에 제한되지 않는다. In a specific embodiment of the present invention, the liquid preparation of the present invention may be used for the treatment or prevention of neuromuscular disorders, but is not limited thereto.
또한, 본 발명의 액상 제제는 피하 투여에 적합한 제형 및 조성을 가져, 피하 투여의 경로로 투여되는 것일 수 있으나, 이에 제한되지 않는다.In addition, the liquid preparation of the present invention may have a formulation and composition suitable for subcutaneous administration and may be administered by a subcutaneous route, but is not limited thereto.
본 발명에서 용어 "투여"는 어떠한 적절한 방법으로 환자에게 액상 제제를 도입하는 것을 의미하며, 예를 들어 근육 내 투여, 피하 투여 등이 될 수 있으나, 이에 제한되지 않는다. In the present invention, the term “administration” refers to introducing a liquid preparation into a patient by any appropriate method, for example, intramuscular administration, subcutaneous administration, etc., but is not limited thereto.
본 발명의 액상 제제의 전체 투여 용량은 하루에 환자 체중 1 kg당 약 0.0001 mg 내지 500 mg일 수 있고, 액상 제제는 상기 용량을 적절히 투여할 수 있도록 제형화될 수 있다. 그러나 상기 보툴리눔 독소의 용량은 투여 경로 및 치료 횟수뿐만 아니라 환자의 연령, 체중, 건강 상태, 성별, 질환의 중증도, 식이 및 배설율 등 다양한 요인들을 고려하여 환자에 대한 유효 투여량이 결정되는 것이므로, 이러한 점을 고려할 때 당해 분야의 통상적인 지식을 가진 자라면 상기 본 발명의 액상 제제의 특정한 용도에 따른 적절한 유효 투여량을 결정할 수 있을 것이다. The total administration dose of the liquid formulation of the present invention may be about 0.0001 mg to 500 mg per kg of patient body weight per day, and the liquid formulation may be formulated to appropriately administer the above dose. However, the effective dose for the patient is determined by considering various factors such as the route of administration and number of treatments, as well as the patient's age, weight, health status, gender, severity of the disease, diet, and excretion rate. Considering this, a person skilled in the art will be able to determine the appropriate effective dosage according to the specific use of the liquid preparation of the present invention.
본 발명에서, 용어"약(about)"은 용어 뒤에 기재되는 정확한 숫자뿐만 아니라, 거의 그 숫자이거나 그 숫자에 가까운 범위까지 포함한다. 그 숫자가 제시된 문맥을 고려하여, 언급된 구체적인 숫자와 가깝거나 거의 그 숫자인지 여부를 결정할 수 있다. 일 예로, 용어 "약"은 숫자 값의 -10% 내지 +10% 범위를 지칭할 수 있다. 다른 예로, 용어 "약"은 주어진 숫자 값의 -5% 내지 +5% 범위를 지칭할 수 있다. 그러나 이에 제한되지 않는다.In the present invention, the term “about” includes not only the exact number written after the term, but also a range that is approximately that number or close to that number. By considering the context in which the number is presented, one can determine whether it is close to or close to the specific number mentioned. As an example, the term “about” may refer to a range of -10% to +10% of a numeric value. As another example, the term “about” may refer to a range of -5% to +5% of a given numeric value. However, it is not limited to this.
본 발명을 구현하는 또 다른 하나의 양태는 상기 액상 제제의 제조방법을 제공한다.Another aspect embodying the present invention provides a method for producing the liquid formulation.
구체적으로, 상기 제조방법은 보툴리눔 독소; N-아세틸메티오닌을 서로 혼합하는 단계를 포함할 수 있으며, 추가로 알부민을 추가로 혼합하는 단계를 포함할 수 있으나, 이에 제한되지 않는다. Specifically, the manufacturing method includes botulinum toxin; It may include mixing N-acetylmethionine with each other, and may further include mixing albumin, but is not limited thereto.
본 발명을 구현하는 또 다른 하나의 양태는 상기 액상 제제를 이용하여 보툴리눔 독소를 안정화시키는 방법을 제공한다. Another aspect embodying the present invention provides a method of stabilizing botulinum toxin using the liquid formulation.
상기 액상 제제는 알부민, 등장화제, 비이온성 계면활성제, 및 완충제로 이루어진 군에서 선택되는 하나 이상의 성분을 더 포함할 수 있으나, 이에 제한되는 것은 아니다. The liquid formulation may further include one or more ingredients selected from the group consisting of albumin, isotonicity agent, nonionic surfactant, and buffer, but is not limited thereto.
액상 제제 및 이를 구성하는 요소들에 대해서는 앞서 설명한 바와 같다. The liquid formulation and its constituent elements are as described above.
본 발명의 보툴리눔 독소와 같은 단백질 제제의 경우에 약제화 과정에서 많은 문제점이 발생한다. 이는 단백질의 불안정성에 기인하며 보툴리눔 독소와 같이 극히 낮은 농도로 약제화가 이루어지는 단백질의 경우에 문제가 심각하다. 보툴리눔 독소는 독성이 매우 강하기 때문에, 치료 또는 미용 목적으로의 사용을 위해서는 미량이 투여되어야 하므로, 고농도의 보툴리눔 독소의 액상 제제 보다는 낮은 농도의 보툴리눔 독소의 액상 제제가 선호된다.In the case of protein preparations such as the botulinum toxin of the present invention, many problems arise during the pharmaceutical preparation process. This is due to the instability of the protein, and the problem is serious in the case of proteins that are medicated at extremely low concentrations, such as botulinum toxin. Since botulinum toxin is very toxic, a small amount must be administered for use for therapeutic or cosmetic purposes, so a liquid preparation of botulinum toxin with a low concentration is preferred over a liquid preparation of botulinum toxin with a high concentration.
이러한 측면에서, 보툴리눔 독소의 활성을 일정하게 유지할 수 있는 새로운 형태의 액상 제제에 대한 수요가 절실한 상황이다. 본 발명의 액상 제제는 장기간 보관하더라도 보툴리눔 독소의 활성을 유지할 수 있으며, 투약 안정성도 우수하다.In this respect, there is an urgent need for a new type of liquid preparation that can maintain the activity of botulinum toxin at a constant level. The liquid preparation of the present invention can maintain the activity of botulinum toxin even when stored for a long period of time and has excellent dosing stability.
본 발명에 따른 보툴리눔 독소의 액상 제제는 재수화 과정을 거칠 필요 없이 즉시 사용가능한 형태이므로 사용자 편의성이 제고될 뿐 아니라, 재수화 과정에서의 희석 오류 등으로 인한 보툴리눔 독소 활성 편차 등을 감소시킬 수 있으며, 정량 투여가 가능하다. 뿐만 아니라 액상 상태에서의 보관 안정성이 월등하고, 상온 또는 냉장 조건에서도 장기간 보툴리눔 독소의 활성이 유지되는 효과가 있다.The liquid preparation of botulinum toxin according to the present invention is in a form that can be used immediately without the need for a rehydration process, which not only improves user convenience, but also reduces deviations in botulinum toxin activity due to dilution errors during the rehydration process. , quantitative administration is possible. In addition, the storage stability in the liquid state is superior, and the activity of botulinum toxin is maintained for a long period of time even under room temperature or refrigerated conditions.
도 1은 부형제 종류별 잔존 역가를 평가한 결과를 나타낸 것이다.
도 2는 부형제 및 알부민 조합에 따른 잔존 역가를 평가한 결과를 나타낸 것이다.Figure 1 shows the results of evaluating the remaining titer for each type of excipient.
Figure 2 shows the results of evaluating the residual titer according to the combination of excipients and albumin.
이하 본 발명을 실시예 및 실험예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예 및 실험예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예 및 실험예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples and experimental examples. However, these examples and experimental examples are for illustrative purposes only and the scope of the present invention is not limited to these examples and experimental examples.
실시예 1. 보툴리눔 A형 독소 액상 제제의 제조Example 1. Preparation of botulinum type A toxin liquid preparation
보툴리눔 A형 독소(분자량 약 900kD)의 액상 제제는 하기와 같은 방법으로 제조하였다. 완충제로 인산 나트륨(Sodium Phosphate) 50 mmol에 등장화제로 염화나트륨(Sodium chloride) 0.9%, 계면활성제로 폴리소르베이트 20을 0.05%(w/v)의 농도로 첨가하였다. 보툴리눔 A형 독소와 등장화제, 계면활성제가 포함된 완충제에 각각의 부형제들을 해당 농도별로 첨가하면서 균질하게 혼합 및 용해시킨 후 적정 pH 6.0으로 보정 후 0.22㎛ 로 필터하였다. 필터된 용액을 이용, 최종적으로 100 unit/ml이 되도록 보툴리눔 독소 액상 제제를 제조하였다(표 1).A liquid preparation of botulinum type A toxin (molecular weight approximately 900 kD) was prepared as follows. To 50 mmol of sodium phosphate as a buffer, 0.9% of sodium chloride as an isotonic agent and polysorbate 20 as a surfactant were added at a concentration of 0.05% (w/v). Each excipient was added at the corresponding concentration to a buffer containing botulinum type A toxin, isotonic agent, and surfactant, mixed and dissolved homogeneously, adjusted to an appropriate pH of 6.0, and filtered at 0.22㎛. Using the filtered solution, a botulinum toxin liquid preparation was prepared to a final concentration of 100 units/ml (Table 1).
부형제 후보군들은 하기 표 2의 농도로 첨가하였다. 하기의 부형제 후보군 들은 식약처에 고시한 첨가제의 최대 함량을 토대로 각각 농도를 조절하여 첨가하였다.Excipient candidates were added at the concentrations shown in Table 2 below. The following excipient candidates were added with their respective concentrations adjusted based on the maximum content of additives notified by the Ministry of Food and Drug Safety.
실시예 2. 보툴리눔 A형 독소의 안정성 평가Example 2. Safety evaluation of botulinum type A toxin
실시예 1에서 제조된 보툴리눔 독소 액상 제제의 안정성 평가를 위해 Anti-SNAP25 항체를 이용한 ELISA 방법을 사용하여 37℃ 가속조건에서 SNAP25 절단에 미치는 영향을 확인하였으며, 이를 통해 독소의 역가를 계산하였다. 제조된 보툴리눔 독소 액상제제는 37℃ 가속조건에서 보관하면서 일정기간(1주일)마다 샘플링을 하여 보관시간에 따라 변화하는 독소 역가를 확인하였다.To evaluate the stability of the botulinum toxin liquid preparation prepared in Example 1, an ELISA method using an anti-SNAP25 antibody was used to confirm the effect on SNAP25 cleavage under accelerated conditions at 37°C, and through this, the titer of the toxin was calculated. The manufactured botulinum toxin liquid preparation was stored under accelerated conditions at 37°C and sampled at regular intervals (one week) to confirm the toxin titer changing with storage time.
ELISA는 다음과 같은 방법으로 진행하였다. 검정하고자 하는 액상 제제와 Recombinant SNAP25(abcam, USA)를 각각 100:1의 비율로 섞어준 뒤 37℃ 챔버에서 효소 반응을 하였다. 21시간 후, 액상 제제-SNAP25 혼합물을 꺼내어 10mM EDTA(ethylene-diamine-tetraacetic acid)가 첨가된 Coating buffer(100mM Bicarbonate/carbonate, pH 9.6)와 1:1 비율로 섞어준 뒤, 96 well plate(Thermo, USA)에 well 당 100ul씩 분주하여 실온에서 2시간동안 coating하였다. 코팅이 끝난 후 Washing buffer(Thermo, USA)로 3 회 세척 후 5% skim milk를 이용하여 실온에서 2시간 blocking 하였다. 이후 Washing buffer로 3회 세척하였고, 5% skim milk에 희석시킨 절단된 SNAP25에 대한 특이적 항체(mybiosource, USA)를 각 well에 100ul씩 분주하여 실온에서 2시간 반응하였다. 이후 Washing buffer로 3회 세척하였고 5% skim milk에 희석한 HRP가 결합된 2차 항체(abcam, USA)를 상온에서 2시간 동안 반응하였다. 반응 후, Washing buffer로 3회 세척하였고, TMB Substrate solution(Thermo, USA)을 각 well에 100ul씩 분주하여 발색 반응을 유도하였다. 동량의 2N 황산(Sigma, USA)을 첨가해 반응을 중지 시킨 뒤, 흡광도 분석기(BioTek, USA)를 이용하여 450nm 에서 흡광도를 측정하였고, 측정된 수치는 positive와 negative control의 수치를 이용하여 독소 역가를 %로 나타내었다. 독소 역가는 하기의 식으로 계산하였다.ELISA was performed in the following manner. The liquid preparation to be tested and Recombinant SNAP25 (abcam, USA) were mixed at a ratio of 100:1, and then an enzyme reaction was performed in a chamber at 37°C. After 21 hours, the liquid agent-SNAP25 mixture was taken out and mixed with Coating buffer (100mM Bicarbonate/carbonate, pH 9.6) containing 10mM EDTA (ethylene-diamine-tetraacetic acid) in a 1:1 ratio, then placed in a 96 well plate (Thermo , USA) and coated at room temperature for 2 hours. After coating was completed, it was washed three times with washing buffer (Thermo, USA) and blocked for 2 hours at room temperature using 5% skim milk. Afterwards, the cells were washed three times with washing buffer, and 100ul of a specific antibody against cleaved SNAP25 (mybiosource, USA) diluted in 5% skim milk was dispensed into each well and reacted at room temperature for 2 hours. Afterwards, it was washed three times with washing buffer and reacted with HRP-conjugated secondary antibody (abcam, USA) diluted in 5% skim milk for 2 hours at room temperature. After the reaction, it was washed three times with washing buffer, and 100 ul of TMB Substrate solution (Thermo, USA) was dispensed into each well to induce a color reaction. After stopping the reaction by adding an equal amount of 2N sulfuric acid (Sigma, USA), the absorbance was measured at 450 nm using an absorbance analyzer (BioTek, USA), and the measured value was used to determine the toxin titer using the positive and negative control values. is expressed as %. Toxin titer was calculated using the following formula.
독소 역가 (%) = (검정하고자 하는 액상 제제 실험군의 발색수치 - 독소를 처리하지 않은 실험군의 발색수치) / (100 Unit/ml 농도의 BoNT/A 원액만 처리한 실험군의 발색수치- 독소를 처리하지 않은 실험군의 발색수치) x 100Toxin titer (%) = (Color development value of the experimental group of the liquid preparation to be tested - Color development value of the experimental group not treated with toxin) / (Color development value of the experimental group treated with only BoNT/A stock solution at a concentration of 100 Unit/ml - Treatment with toxin Color development value of the experimental group without) x 100
실시예 3. 보툴리눔 A형 독소 액상 제제의 안정화제 평가Example 3. Evaluation of stabilizers of botulinum type A toxin liquid formulation
상기 실시예 1의 보툴리눔 A형 독소의 액상 제제에 대하여 실시예 2의 방법에 따라 37℃ 가속조건에서 1주 간격으로 역가를 평가하는 실험을 수행하였다. For the liquid preparation of botulinum type A toxin of Example 1, an experiment was performed to evaluate the potency at 1 week intervals under accelerated conditions at 37°C according to the method of Example 2.
3-1. 부형제 종류별 잔존 역가 평가3-1. Residual potency evaluation by excipient type
부형제 종류별 잔존 역가를 평가를 수행하였다. 구체적으로, 부형제는 메글루민+글루탐산 (Meglumine+Glutamic acid), N-아세틸시스테인(N-Acetylcysteine), N-아세틸메티오닌(N-acetylmethionine), 글루타치온(Glutathion), 또는 PEG3350을 사용하였으며, 보툴리눔 독소 액상 제제 조성에 포함된 상기 부형제의 농도는 상기 표 2와 같다. The residual potency of each type of excipient was evaluated. Specifically, the excipients used were Meglumine+Glutamic acid, N-Acetylcysteine, N-acetylmethionine, Glutathione, or PEG3350, and botulinum toxin The concentrations of the excipients included in the liquid formulation composition are shown in Table 2 above.
그 결과, 도 1에 나타낸 바와 같이 부형제 중 N-아세틸메티오닌이 6주 이상 잔존 역가가 90% 이상을 유지함을 확인하였으며, 상기 부형제의 보툴리눔 독소의 활성 유지 효과가 우수함을 알 수 있었다. As a result, as shown in Figure 1, it was confirmed that the residual titer of N-acetylmethionine among the excipients was maintained at more than 90% for more than 6 weeks, and it was confirmed that the excipient had an excellent effect of maintaining the activity of botulinum toxin.
3-2. rHSA와 부형제의 조합에 따른 잔존 역가 평가3-2. Evaluation of residual potency according to combination of rHSA and excipients
rHSA를 포함할 경우에도 잔존 역가가 우수한지를 확인하고자, 실시예 3-1의 부형제에 rHSA를 추가로 포함하여 잔존 역가를 평가하였다. To confirm whether the residual titer was excellent even when rHSA was included, rHSA was additionally included in the excipient of Example 3-1 and the residual titer was evaluated.
그 결과, 도 2에 나타난 바와 같이, rHSA 및 N-아세틸메티오닌 조합의 경우에 37℃ 가속조건에서 10주 90% 이상으로 잔존 역가가 가장 우수함을 확인하였다. As a result, as shown in Figure 2, it was confirmed that the combination of rHSA and N-acetylmethionine had the best residual titer of over 90% for 10 weeks under accelerated conditions at 37°C.
상기 결과는, 보툴리눔 독소를 포함하는 조성물에 rHSA 및 N-아세틸메티오닌의 조합이 안정화제로서 보툴리눔 독소를 액상 제제에서 역가 감소없이 장기간 보존할 수 있음을 시사하는 것이다.The above results suggest that the combination of rHSA and N-acetylmethionine in a composition containing botulinum toxin, as a stabilizer, can preserve botulinum toxin for a long period of time without reducing its potency in a liquid formulation.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing its technical idea or essential features. In this regard, the embodiments described above should be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed as including the meaning and scope of the patent claims described below rather than the detailed description above, and all changes or modified forms derived from the equivalent concept thereof are included in the scope of the present invention.
Claims (14)
Liquid preparation containing botulinum toxin and N-acetylmethionine.
상기 보툴리눔 독소는 보툴리눔 독소 A형인 것인, 액상 제제.
According to paragraph 1,
A liquid formulation wherein the botulinum toxin is botulinum toxin type A.
상기 N-아세틸메티오닌은 전체 액상 제제를 기준으로 0.01 내지 0.5%(w/v)로 포함하는 것인, 액상 제제.
According to paragraph 1,
A liquid formulation containing 0.01 to 0.5% (w/v) of N-acetylmethionine based on the total liquid formulation.
상기 액상제제는 알부민(Albumin)을 추가로 포함하는 것인, 액상 제제.
According to paragraph 1,
The liquid formulation further contains albumin.
상기 알부민은 재조합 알부민인 것인, 액상 제제.
According to paragraph 4,
A liquid formulation wherein the albumin is recombinant albumin.
상기 알부민은 전체 액상 제제를 기준으로 0.01 내지 1%(w/v)로 포함하는 것인, 액상 제제.
According to clause 4,
A liquid formulation containing the albumin in an amount of 0.01 to 1% (w/v) based on the total liquid formulation.
상기 액상 제제는 비이온성 계면활성제 및 등장화제를 추가로 포함하는 것인, 액상 제제.
According to paragraph 1,
The liquid formulation further comprises a nonionic surfactant and an isotonic agent.
상기 비이온성 계면활성제는 폴리소르베이트 20, 폴리소르베이트 40, 폴리소르베이트 60, 폴리소르베이트 80 및 폴리소르베이트 100으로 이루어진 군에서 선택된 어느 하나 이상인 것인, 액상 제제.
In clause 7,
A liquid formulation wherein the nonionic surfactant is at least one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 100.
상기 액상 제제는 0.005 내지 0.1%(w/v)의 농도로 비이온성 계면활성제를 추가로 포함하는 것인, 액상 제제.
According to paragraph 1,
The liquid formulation further includes a nonionic surfactant at a concentration of 0.005 to 0.1% (w/v).
상기 등장화제는 염화나트륨, 글리세린, 염화칼륨, 및 덱스트로오스로 이루어진 군에서 선택된 어느 하나 이상인 것인, 액상 제제.
In clause 7,
A liquid formulation wherein the isotonic agent is at least one selected from the group consisting of sodium chloride, glycerin, potassium chloride, and dextrose.
100 Unit/ml의 보툴리눔 독소; 및
0.01 내지 0.5%(w/v)의 N-아세틸메티오닌을 포함하는 것인, 액상 제제.
The method of claim 1, wherein the liquid formulation is
100 Unit/ml of botulinum toxin; and
A liquid formulation comprising 0.01 to 0.5% (w/v) of N-acetylmethionine.
100 Unit/ml의 보툴리눔 독소;
0.01 내지 0.5%(w/v)의 N-아세틸메티오닌; 및
0.01 내지 1%(w/v)의 알부민을 포함하는 것인, 액상 제제.
The method of claim 1, wherein the liquid formulation is
100 Unit/ml of botulinum toxin;
0.01 to 0.5% (w/v) of N-acetylmethionine; and
A liquid formulation comprising 0.01 to 1% (w/v) of albumin.
A method of stabilizing botulinum toxin using a liquid formulation containing botulinum toxin and N-acetylmethionine.
상기 액상 제제에 알부민을 추가로 포함하는, 방법.According to clause 13,
A method further comprising albumin in the liquid formulation.
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