KR102176811B1 - Composition for promoting hair growth - Google Patents
Composition for promoting hair growth Download PDFInfo
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- KR102176811B1 KR102176811B1 KR1020190022696A KR20190022696A KR102176811B1 KR 102176811 B1 KR102176811 B1 KR 102176811B1 KR 1020190022696 A KR1020190022696 A KR 1020190022696A KR 20190022696 A KR20190022696 A KR 20190022696A KR 102176811 B1 KR102176811 B1 KR 102176811B1
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- peptide
- hair
- composition
- hair growth
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Abstract
본 발명의 펩타이드는 발모를 촉진하는 데에 우수한 효능을 가지고 있어, 이를 포함하는 조성물을 발모 촉진 용도 또는 탈모 예방, 개선, 치료 용도로 사용할 수 있다. Since the peptide of the present invention has excellent efficacy in promoting hair growth, a composition comprising the same can be used for promoting hair growth or preventing, improving, and treating hair loss.
Description
본 발명은 우수한 발모 촉진 효과를 갖는 펩타이드를 포함하는 발모 촉진용 조성물에 관한 것이다.The present invention relates to a composition for promoting hair growth comprising a peptide having an excellent hair growth promoting effect.
최근 미용에 관심이 높아지면서 탈모 치료에 관한 관심 또한 높아지고 있다. 모발은 생명에 직접적인 중요한 생리적 기능은 가지고 있지 않지만 외부의 충격으로부터 완충과 자외선 차단, 외부자극으로부터 인체를 보호하며, 신체에 불필요한 비소, 수은, 아연 등의 중금속을 흡수하여 체외로 배출하는 기능을 가지고 있다. 모발은 모발이 성장하는 성장기(anagen), 성장이 멈추고 모구부가 축소되면서 대사과정이 늦어지는 퇴행기(catagen), 모낭이 수축되면서 모근이 위쪽으로 밀려 올라가 모발이 빠지게 되는 휴지기(telogen)로 구분되며, 같은 장소에서 새로운 모발이 생성됨으로 인해 오래된 모발이 탈락하고 성장기로 전환되는 모주기(hair cycle)을 가지고 일생 동안 성장과 탈락을 반복한다.Recently, as interest in beauty has increased, interest in hair loss treatment is also increasing. Hair does not have a direct important physiological function to life, but it buffers against external shocks, blocks UV rays, protects the human body from external irritation, and absorbs heavy metals such as arsenic, mercury, and zinc that are unnecessary to the body and discharges them out of the body. have. Hair is divided into a growth phase (anagen) in which the hair grows, a catagen phase in which the metabolic process is delayed as the growth stops and the hair bulb is reduced, and a telogen, in which the hair roots are pushed upward as the hair follicle is contracted and the hair falls out. As new hairs are created in the same place, old hairs fall off and have a hair cycle that converts to a growing phase, and growth and dropping are repeated throughout life.
이러한 모발이 정상적으로 있어야 할 곳에 없는 상태를 탈모라 하며, 그 원인으로 남성호르몬 관여에 의한 모포 기능의 저하, 두피생리기능의 저하, 두피 긴장에 의한 국소혈류장애, 영양불량, 스트레스, 약물에 의한 부작용, 유전적 요인, 화학물질, 백혈병, 결핵, 악성 임파종 등의 질병을 들고 있다. 위와 같은 기능 외에 탈모가 심한 경우 사회생활을 하는데 문제가 있을 수 있으며 심리적으로도 위축되어 심각한 영향을 미칠 수 있어 삶의 질 측면에서 탈모 치료는 매우 중요하다.Hair loss is the condition where such hair is not normally located, and its causes include decrease in follicle function due to male hormone involvement, decrease in scalp physiological function, local blood flow disorder due to scalp tension, malnutrition, stress, side effects from drugs. , Genetic factors, chemicals, leukemia, tuberculosis, malignant lymphoma and other diseases. In addition to the above functions, if hair loss is severe, there may be a problem in social life, and it may have a serious effect due to psychological atrophy, so hair loss treatment is very important in terms of quality of life.
현재 탈모 치료법으로 가장 많이 쓰이고 있는 방법은 자기 자신의 머리털을 이용하여 이식하는 자가 모발이식 수술법과 미녹시딜과 프로페시아를 사용하는 약물 치료가 널리 사용되고 있다. 미녹시딜의 경우 혈관확장을 통한 모세포에 영양공급증가 및 칼륨 채널 개방 효과(potassium channel opening effect) 등이 모발 성장을 유도하며, 프로페시아의 경우 DHT(dihydrotestosterone)의 생성을 저해하는 효과로 모발 성장을 유도하지만, 이 두 약물 모두 치료할 당시에는 발모 효능이 나타나나, 치료가 중단되면 탈모가 다시 진행되고 모발성장의 효과보다는 탈모방지의 효과가 더욱 크며, 프로페시아의 경우 성기능 장애, 임신한 여성의 경우 기형아 출산과 같은 부작용이 나타날 수 있다. 최근, 탈모와 관련된 유전자를 모낭에 전달하거나 유전자 발현을 차단하는 방법으로 시술되는 유전자 치료법이 개발되었으나, 치료의 효능 및 안전성이 불확실하고, 치료비용이 고가이어서 임상적용이 용이하지 않다는 문제점이 있다.Currently, the most widely used methods for hair loss treatment include self-transplantation using one's own hair, and drug treatment using minoxidil and Propecia. In the case of minoxidil, increased nutrient supply to the hair cells through vasodilation and the effect of opening a potassium channel induces hair growth, and in the case of Propecia, it induces hair growth by inhibiting the production of dihydrotestosterone (DHT). , When both of these drugs are treated, hair growth is effective, but when treatment is stopped, hair loss progresses again and the effect of preventing hair loss is greater than that of hair growth.Propecia has sexual dysfunction, and pregnant women have birth defects. The same side effects can occur. Recently, gene therapy, which is performed by transferring genes related to hair loss to hair follicles or blocking gene expression, has been developed, but there is a problem in that the efficacy and safety of the treatment are uncertain, and the treatment cost is high, so clinical application is not easy.
한편, 최근에는 줄기세포를 이용한 탈모치료 방법 등도 시도되고 있으나, 현재 줄기세포를 이용한 탈모치료 방법은 전무하며, 연구중인 방법은 모유두세포를 상피세포와 섞어 주입하여 모낭을 재생하는 방법이 있지만, 이는 동물실험 수준에서 재현되는 수준이라 치료법으로는 아직 많은 연구가 필요하다. 이러한 문제점을 개선하기 위하여 줄기세포가 아닌 줄기세포 배양시 생산되는 배양액을 사용하여 탈모를 치료하고자 하는 시도가 이루어지고 있으나, 아직 상업화 수준의 실효성을 거두고 있지 못한 실정이며, 임상적 실험을 통해서 유효성을 검증하고 있다.Meanwhile, recently, a method of treating hair loss using stem cells has also been attempted, but there is currently no method of treating hair loss using stem cells, and the method under study includes a method of regenerating hair follicles by injecting dermal papilla cells with epithelial cells. Since it is reproduced at the level of animal testing, a lot of research is still needed as a treatment. In order to improve this problem, attempts have been made to treat hair loss using a culture medium produced when culturing stem cells rather than stem cells, but it has not yet achieved the effectiveness at the level of commercialization. I am verifying.
본 발명은 우수한 발모 촉진 효능을 가진 펩타이드 및 이를 포함하는 조성물을 제공함에 그 목적이 있다.An object of the present invention is to provide a peptide having an excellent hair growth promoting effect and a composition comprising the same.
1. 서열번호 1 또는 2의 서열을 포함하고, 50개 이하의 아미노산 잔기로 이루어진 펩타이드.1. A peptide comprising the sequence of SEQ ID NO: 1 or 2 and consisting of 50 or less amino acid residues.
2. 위 1의 펩타이드를 포함하는 발모 촉진용 조성물.2. A composition for promoting hair growth comprising the peptide of 1 above.
3. 위 1의 펩타이드를 포함하는 발모 촉진용 약학적 조성물.3. A pharmaceutical composition for promoting hair growth comprising the peptide of 1 above.
4. 위 1의 펩타이드를 포함하는 발모 촉진용 화장료 조성물.4. Cosmetic composition for promoting hair growth comprising the peptide of 1 above.
5. 위 1의 펩타이드를 포함하는 발모 촉진용 건강기능식품.5. Health functional food for promoting hair growth containing the peptide of 1 above.
본 발명의 펩타이드는 발모를 촉진하는 데에 우수한 효능을 가지고 있어, 이를 포함하는 조성물을 발모 촉진 용도 또는 탈모 예방 또는 치료 용도로 사용할 수 있다.The peptide of the present invention has excellent efficacy in promoting hair growth, and a composition comprising the same can be used for promoting hair growth or for preventing or treating hair loss.
도 1은 음성대조군, 양성대조군, 서열번호 1의 아미노산 서열로 이루어진 펩타이드(DPS-4)를 처리한 실험군, 서열번호 2의 아미노산 서열로 이루어진 펩타이드(DPS-5)를 처리한 실험군 및 서열번호 3의 아미노산 서열로 이루어진 펩타이드(DPS-8)를 처리한 실험군의 모발 성장 정도의 외관 사진이다.
도 2는 음성대조군, 양성대조군, 서열번호 1의 아미노산 서열로 이루어진 펩타이드(DPS-4)를 처리한 실험군, 서열번호 2의 아미노산 서열로 이루어진 펩타이드(DPS-5)를 처리한 실험군 및 서열번호 3의 아미노산 서열로 이루어진 펩타이드(DPS-8)를 처리한 실험군의 모발 성장 정도를 조직학적으로 관찰한 결과이다.1 is a negative control group, a positive control group, an experimental group treated with a peptide consisting of the amino acid sequence of SEQ ID NO: 1 (DPS-4), an experimental group treated with a peptide consisting of the amino acid sequence of SEQ ID NO: 2 (DPS-5), and SEQ ID NO: 3 This is a photograph of the appearance of the hair growth degree of the experimental group treated with the peptide (DPS-8) consisting of the amino acid sequence of.
2 is a negative control group, a positive control group, an experimental group treated with a peptide consisting of the amino acid sequence of SEQ ID NO: 1 (DPS-4), an experimental group treated with a peptide consisting of the amino acid sequence of SEQ ID NO: 2 (DPS-5), and SEQ ID NO: 3 This is the result of histological observation of the hair growth degree of the experimental group treated with the peptide (DPS-8) consisting of the amino acid sequence of.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 서열번호 1 또는 2의 서열을 포함하고, 50개 이하의 아미노산 잔기로 이루어진 펩타이드를 제공한다. The present invention provides a peptide comprising the sequence of SEQ ID NO: 1 or 2 and consisting of 50 or less amino acid residues.
서열번호 1의 아미노산 서열(CLEYFKGAIPLRK) 또는 서열번호 2의 아미노산 서열(KRVKNAVKYLQ)을 포함하고, 50개 이하의 아미노산 잔기로 이루어진 펩타이드는 화학적으로 합성할 수 있다. 화학적으로 합성하여 제조하는 경우, 당 분야에 널리 공지된 화학적 합성(Creighton, Proteins; Structures and Molecular Principles, W. H. Freeman and Co., NY, 1983)에 의해 제조될 수 있다. 대표적인 방법으로서 액체 또는 고체상 합성, 단편 응축, F-MOC 또는 T-BOC 화학법이 있으나, 이에 제한되지 않는다. (Chemical Approaches to the Synthesis of Peptides and Proteins, Williams et al., Eds., CRC Press, Boca Raton Florida, 1997; A Practical Approach, Atherton & Sheppard, Eds., IRL Press, Oxford, England, 1989).A peptide comprising the amino acid sequence of SEQ ID NO: 1 (CLEYFKGAIPLRK) or the amino acid sequence of SEQ ID NO: 2 (KRVKNAVKYLQ) and consisting of 50 or less amino acid residues can be chemically synthesized. When prepared by chemical synthesis, it can be prepared by chemical synthesis (Creighton, Proteins; Structures and Molecular Principles, WH Freeman and Co., NY, 1983) well known in the art. Representative methods include, but are not limited to, liquid or solid phase synthesis, fragment condensation, F-MOC or T-BOC chemistry. (Chemical Approaches to the Synthesis of Peptides and Proteins, Williams et al ., Eds., CRC Press, Boca Raton Florida, 1997; A Practical Approach, Atherton & Sheppard, Eds., IRL Press, Oxford, England, 1989).
또한 본 발명의 펩타이드는 유전공학적 방법에 의해 제조될 수 있으나, 하기의 방법에 제한되지 않는다. 우선, 통상적인 방법에 따라 상기 펩타이드를 코딩하는 DNA 서열을 제작한다. DNA 서열은 적절한 프라이머를 사용하여 PCR 증폭함으로써 제작할 수 있다. 다른 방법으로 당업계에 공지된 표준 방법에 의해, 예컨대, 자동 DNA 합성기(예를 들면, Biosearch 또는 Applied iosystems사에서 판매하는 것)를 사용하여 DNA 서열을 합성할 수도 있다. 제작된 DNA 서열은 이 DNA 서열에 작동 가능하게 연결되어 그 DNA 서열의 발현을 조절하는 하나 또는 그 이상의 발현 조절 서열(예: 프로모터, 인핸서 등)을 포함하는 벡터에 삽입시키고, 이로부터 형성된 재조합 발현 벡터로 숙주세포를 형질전환시킨다. 생성된 형질전환체를 상기 DNA 서열이 발현되도록 하기에 적절한 배지 및 조건 하에서 배양하여, 배양물로부터 상기 DNA 서열에 의해 코딩된 실질적으로 순수한 펩타이드를 회수한다. 상기 회수는 당업계에 공지된 방법(예컨대, 크로마토그래피)을 이용하여 수행할 수 있다. 상기에서 '실질적으로 순수한 펩타이드'라 함은 본 발명에 따른 펩타이드가 숙주로부터 유래된 어떠한 다른 단백질도 실질적으로 포함하지 않는 것을 의미한다. 본 발명의 펩타이드 합성을 위한 유전공학적 방법은 다음의 문헌을 참고할 수 있다: Maniatis et al., Molecular Cloning; A laboratory Manual, Cold Spring Harbor laboratory, 1982; Sambrook et al., Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Press, N.Y., Second(1998) and Third(2000) Edition; Gene Expression Technology, Method in Enzymology, Genetics and Molecular Biology, Method in Enzymology, Guthrie & Fink (eds.), Academic Press, San Diego, Calif, 1991; Hitzeman et al., J.Biol. Chem., 255:12073-12080, 1990.In addition, the peptide of the present invention may be prepared by a genetic engineering method, but is not limited to the following method. First, a DNA sequence encoding the peptide is prepared according to a conventional method. DNA sequences can be prepared by PCR amplification using appropriate primers. Alternatively, DNA sequences may be synthesized by standard methods known in the art, for example, using an automatic DNA synthesizer (eg, those sold by Biosearch or Applied iosystems). The produced DNA sequence is operably linked to this DNA sequence and inserted into a vector containing one or more expression control sequences (eg, promoters, enhancers, etc.) that control the expression of the DNA sequence, and recombinant expression formed therefrom The host cell is transformed with the vector. The resulting transformant is cultured under a medium and conditions appropriate to allow the DNA sequence to be expressed, to recover a substantially pure peptide encoded by the DNA sequence from the culture. The recovery can be performed using a method known in the art (eg, chromatography). In the above, "substantially pure peptide" means that the peptide according to the present invention does not substantially contain any other protein derived from a host. The genetic engineering method for synthesizing the peptides of the present invention may be referred to the following literature: Maniatis et al ., Molecular Cloning; A laboratory Manual, Cold Spring Harbor laboratory, 1982; Sambrook et al ., Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Press, NY, Second (1998) and Third (2000) Edition; Gene Expression Technology, Method in Enzymology, Genetics and Molecular Biology, Method in Enzymology, Guthrie & Fink (eds.), Academic Press, San Diego, Calif, 1991; Hitzeman et al ., J. Biol. Chem, 255:. 12073 - 12080 , 1990.
본 발명의 펩타이드는 50개 이하의 아미노산 서열로 이루어진 것으로서, 구체적으로는 50개 이하, 45개 이하, 40개 이하, 35개 이하, 30개 이하, 25개 이하, 20개 이하 또는 15개 이하일 수 있는데, 이는 서열번호 1 또는 2의 아미노산 서열의 N-말단 또는 C-말단에 수개의 아미노산 잔기가 부가적으로 결합된 것일 수 있다. The peptide of the present invention is composed of a sequence of 50 or less amino acids, specifically 50 or less, 45 or less, 40 or less, 35 or less, 30 or less, 25 or less, 20 or less, or 15 or less. There may be several amino acid residues additionally linked to the N-terminus or C-terminus of the amino acid sequence of SEQ ID NO: 1 or 2.
본 발명의 펩타이드는 동일 용도의 긴 길이의 아미노산 서열로 이루어진 펩타이드에 비해 그 길이가 상대적으로 짧아, 체내 흡수가 용이하고, 특히 경피 흡수율이 좋아 펩타이드가 갖는 효능을 극대화시킬 수 있다는 장점이 있다.Peptides of the present invention have the advantage of being relatively short in length compared to peptides consisting of a long amino acid sequence for the same purpose, so that they are easily absorbed in the body, and in particular, have a good transdermal absorption rate, so that the efficacy of the peptide can be maximized.
본 발명의 펩타이드는 서열번호 1 또는 2의 서열을 포함하고, 50개 이하의 아미노산 잔기로 이루어진 펩타이드의 기능적 동등물 및 변이체를 포함하는 것일 수 있다.The peptide of the present invention may include the sequence of SEQ ID NO: 1 or 2, and may include functional equivalents and variants of the peptide consisting of 50 or less amino acid residues.
상기 펩타이드의 기능적 동등물이란, 펩타이드의 활성을 전체적으로 변경시키지 않는 펩타이드를 포함하는 것으로, 기능적으로 동일한 작용을 할 수 있는 펩타이드가 본 발명의 범위에 포함된다. 상기 변이체란, 예를 들면 상기 아미노산 서열에서 하나 또는 수개의 아미노산이 결실, 치환 또는 부가된 것, 상기 아미노산 서열과 95 % 이상, 바람직하게는 98 % 이상, 보다 바람직하게는 99 % 이상의 동일성을 갖는 것 등을 말한다. 여기서 "동일성"이란, 2개의 아미노산 서열에 갭을 도입하거나, 도입하지 않고 가장 높은 일치도가 되도록 정렬(얼라인먼트)시켰을 때에, 상기 갭의 수를 포함한, 한쪽 아미노산 서열의 전체 아미노산 잔기수에 대한 다른 쪽의 아미노산 서열의 동일한 아미노산 잔기수의 비율(%)을 말한다. 또한, "수개"란, 2 내지 10의 정수, 예를 들면 2 내지 7, 2 내지 5, 2 내지 4, 2 내지 3의 정수를 말한다. 천연 변이체의 구체예로는 SNP(일염기 다형) 등의 다형에 기초하는 변이체나 스플라이스 변이체 등을 들 수 있다. 상기 치환은 보존적 아미노산 치환인 것이 바람직하다. 보존적 아미노산 치환이면, 상기 아미노산 서열을 갖는 펩타이드와 실질적으로 동등한 구조 또는 성질을 가질 수 있기 때문이다. 보존적 아미노산이란, 서로 비극성 아미노산(글리신, 알라닌, 페닐알라닌, 발린, 류신, 이소류신, 메티오닌, 프롤린, 트립토판) 및 극성 아미노산(비극성 아미노산 이외의 아미노산), 하전 아미노산(산성 아미노산(아스파라긴산, 글루탐산) 및 염기성 아미노산(아르기닌, 히스티딘, 리신)) 및 비하전 아미노산(하전 아미노산 이외의 아미노산), 방향족 아미노산(페닐알라닌, 트립토판, 티로신), 분지상 아미노산(류신, 이소류신, 발린) 및 지방족 아미노산(글리신, 알라닌, 류신, 이소류신, 발린) 등이 알려져 있다. 또한, 아미노산 서열상의 변이 또는 수식에 의해서 펩타이드의 열, pH 등에 대한 구조적 안정성이 증가하거나 펩타이드 활성이 증가한 펩타이드를 포함할 수 있다.The functional equivalent of the peptide includes a peptide that does not change the activity of the peptide as a whole, and peptides capable of functionally performing the same function are included in the scope of the present invention. The variant is, for example, one or several amino acids deleted, substituted, or added in the amino acid sequence, having 95% or more, preferably 98% or more, more preferably 99% or more identity with the amino acid sequence. Things, etc. Here, "identity" means that when a gap is introduced into the two amino acid sequences or aligned (aligned) so as to have the highest degree of identity without introduction, the other to the total number of amino acid residues in one amino acid sequence, including the number of gaps. It refers to the ratio (%) of the number of identical amino acid residues in the amino acid sequence of In addition, "several" means an integer of 2 to 10, for example, an integer of 2 to 7, 2 to 5, 2 to 4, and 2 to 3. Specific examples of natural variants include variants based on polymorphisms such as SNP (monobase polymorphism), splice variants, and the like. It is preferable that the substitution is a conservative amino acid substitution. This is because conservative amino acid substitutions may have substantially the same structure or properties as the peptide having the amino acid sequence. Conservative amino acids are non-polar amino acids (glycine, alanine, phenylalanine, valine, leucine, isoleucine, methionine, proline, tryptophan) and polar amino acids (amino acids other than non-polar amino acids), charged amino acids (acidic amino acids (aspartic acid, glutamic acid)) and basic amino acids. Amino acids (arginine, histidine, lysine)) and uncharged amino acids (amino acids other than charged amino acids), aromatic amino acids (phenylalanine, tryptophan, tyrosine), branched amino acids (leucine, isoleucine, valine) and aliphatic amino acids (glycine, alanine, leucine) , Isoleucine, valine) and the like are known. In addition, it may include a peptide having increased structural stability to heat, pH, or the like of the peptide due to a mutation or modification in the amino acid sequence or increased peptide activity.
본 발명은 상기 펩타이드를 포함하는 발모 촉진용 조성물을 제공한다.The present invention provides a composition for promoting hair growth comprising the peptide.
본 발명의 조성물은 상기 펩타이드를 포함하고 있어, 발모 촉진 능력이 우수하여 발모 촉진 또는 탈모 예방, 개선 또는 치료 용도로 사용될 수 있는데, 상기 발모 촉진 또는 탈모 예방, 개선, 치료는 γδ T 세포 리크루팅(recruiting)을 통해 모유두세포(Dermal papilla cell)를 자극함으로써 모공(hair follicle)의 성장기를 유도하는 기전에 의할 수 있으나, 반드시 이에 제한되는 것은 아니며, 상기 기전은 종래에 알려진 바가 없다.The composition of the present invention contains the peptide, and has excellent hair growth promoting ability, and thus can be used for promoting hair growth or preventing, improving, or treating hair loss, and the promotion of hair growth or hair loss prevention, improvement, and treatment are γδ T cell recruiting (recruiting ) Through the stimulation of the hair follicle cells, but not necessarily limited thereto, and the mechanism is not known in the art.
본 발명의 조성물은 경구 투여, 비경구 투여, 국소 투여 또는 변형 방출 등의 방식에 의해 전달될 수 있으나, 특별히 이에 제한되지는 아니하고, 본 발명의 펩타이드를 발모 촉진 또는 탈모 예방, 치료, 개선 대상 부위에 효과적으로 전달할 수 있는 방법이라면 어떠한 방식이든 선택될 수 있다.The composition of the present invention may be delivered by means of oral administration, parenteral administration, topical administration or modified release, but is not particularly limited thereto, and the peptide of the present invention promotes hair growth or prevents, treats, or improves hair growth. Any method can be chosen as long as it can be effectively communicated to.
본 발명의 조성물은 구체적으로, 경피 흡수 방식에 의해 전달될 수 있고, 예를 들면, 카타플라스마제 또는 첩부제의 부착, 플라스터의 부착, 마이크로 니들 패치 부착, 경피 주사제 주입, 연고 또는 크림을 포함하는 에멀젼 형태나 산제 형태의 피부 도포, 스프레이(에어로졸 형태를 포함) 분사 등의 방식에 의해 경피 흡수 경로로 발모 촉진 또는 탈모 예방, 개선, 치료 대상 부위에 전달될 수 있으나 특별히 이에 제한되지 아니하며, 이러한 경우 대상 부위에 보다 직접적으로 본 발명의 펩타이드를 전달할 수 있어 전달 과정에서의 펩타이드 활성 변성을 막아 효율적인 전달이 가능하고, 타 방법에 비해 전달 속도가 상대적으로 우수할 수 있다.The composition of the present invention may specifically be delivered by a transdermal absorption method, including, for example, cataplasmase or patch attachment, plaster attachment, microneedle patch attachment, transdermal injection injection, ointment or cream. Hair growth promotion or hair loss prevention, improvement, or delivery to the target area for treatment through a percutaneous absorption route by means of skin application in the form of emulsion or powder, spray (including aerosol form) spraying, etc., but is not particularly limited thereto, in this case Since the peptide of the present invention can be delivered more directly to the target site, efficient delivery is possible by preventing peptide activity denaturation in the delivery process, and the delivery speed can be relatively superior compared to other methods.
상기 경구 투여에 있어서, 본 발명의 조성물은 경구 투여를 위한 고체, 반고체 또는 액체 투여형으로 제공될 수 있다. 상기 경구 투여는 또한 협측, 설하 및 설하 투여를 포함한다. 적합한 경구 투여형은 정제, 패스트멜트(급속용해 정제), 추어블 정제, 캡슐, 환제, 스트립, 트로키제, 함당정제, 파스틸, 카시에제, 펠릿, 약용 츄잉 껌, 벌크 분말, 발포성 또는 비발포성 분말 또는 과립, 구강 미스트, 용액, 에멀젼, 현탁액, 웨이퍼, 스프린클, 엘릭서(elixir) 및 시럽을 포함하나 이에 한정되지는 않는다. 활성 성분(들) 이외에, 본 발명의 조성물은 결합제, 충전제, 희석제, 붕해제, 습윤제, 윤활제, 활택제, 착색제, 염료-이동 저해제, 감미료, 향료, 유화제, 현탁 및 분산제, 방부제, 용제, 비수성 액체, 유기산 및 이산화탄소 공급원을 포함하나 이에 제한되지 않는 하나 이상의 부형제를 포함할 수 있다.In the above oral administration, the composition of the present invention may be provided in a solid, semi-solid or liquid dosage form for oral administration. The oral administration also includes buccal, sublingual and sublingual administration. Suitable oral dosage forms include tablets, fast melts (quick-dissolving tablets), chewable tablets, capsules, pills, strips, troches, sugar tablets, pastilles, cachets, pellets, medicinal chewing gum, bulk powder, effervescent or Non-foaming powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs and syrups. In addition to the active ingredient(s), the compositions of the present invention can be used as binders, fillers, diluents, disintegrants, wetting agents, lubricants, lubricants, colorants, dye-migration inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non It may include one or more excipients including, but not limited to, aqueous liquids, organic acids, and carbon dioxide sources.
결합제 또는 과립화제는 압축 후 정제가 손상되지 않도록 정제에 응집력을 부여한다. 적합한 결합제 또는 과립화제는 전분, 예를 들어 옥수수 전분, 감자 전분 및 예비-젤라틴 화 전분(예, STARCH 1500®); 젤라틴; 설탕, 포도당, 덱스트로스, 당밀 및 유당과 같은 당; 아카시아, 알지닉 산, 알지네이트, 아이리시 모스 추출물, 판와르(panwar) 검, 가티(ghatti) 검, 이삽골 허스크(isabgol husks)의 점액, 카복시메틸셀룰로스, 메틸셀룰로스, 폴리비닐피롤리돈(PVP), 비검(Veegum), 낙엽송(larch) 아라보갈락탄, 분말형 트리가칸트, 및 구아검와 같은 천연 또는 합성 검; 에틸 셀룰로스, 셀룰로스 아세테이트, 카복시메틸 셀룰로스, 메틸 셀룰로스, 히드록시에틸셀룰로스(HEC), 히드록시프로필셀룰로스(HPC) 및 히드록시프로필메틸 셀룰로스(HPMC)와 같은 셀룰로스; AVICEL® CL-611, AVICEL® PH-101, AVICEL® PH-102, AVICEL® PH-103, AVICEL® PH-105, AVICEL® PH-112, AVICEL® PH-113, AVICEL® PH-200, AVICEL® PH-301, AVICEL® PH-302, AVICEL® RC-501, AVICEL® RC-581, 및 AVICEL® RC-591과 같은 미결정 셀룰로스; 및 이들의 혼합물을 포함하나 이에 한정되지는 않는다. 적합한 충진제는 탈크, 칼슘 카보네이트, 미결정 셀룰로스, 분말 셀룰로스, 덱스트레이트, 카올린, 만니톨, 실리식산, 소르비톨, 전분, 예비-젤라틴화 전분 및 이들의 혼합물을 포함하나 이에 한정되지는 않는다. 본 발명의 조성물 중의 결합제 또는 충진제의 양은 제제의 유형에 따라 달라지며, 당업자는 용이하게 인식할 수 있다. 본 발명의 조성물은 약 50 내지 약 99 중량 %의 결합제 또는 충전제를 함유할 수 있다.The binder or granulating agent imparts cohesiveness to the tablet so that the tablet is not damaged after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch and pre-gelatinized starch (eg STARCH 1500 ® ); gelatin; Sugars such as sugar, glucose, dextrose, molasses and lactose; Acacia, alginic acid, alginate, Irish moss extract, panwar gum, ghatti gum, mucus of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP) ), natural or synthetic gums such as Veegum, larch arabgalactan, powdered trigacanth, and guar gum; Cellulose such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) and hydroxypropylmethyl cellulose (HPMC); AVICEL ® CL-611, AVICEL ® PH-101, AVICEL ® PH-102, AVICEL ® PH-103, AVICEL ® PH-105, AVICEL ® PH-112, AVICEL ® PH-113, AVICEL ® PH-200, AVICEL ® microcrystalline cellulose, such as PH-301, AVICEL ® PH- 302, AVICEL ® RC-501, AVICEL ® RC-581, and AVICEL ® RC-591; And mixtures thereof, but are not limited thereto. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch and mixtures thereof. The amount of the binder or filler in the composition of the present invention depends on the type of preparation, and can be readily recognized by those skilled in the art. The composition of the present invention may contain from about 50 to about 99% by weight of a binder or filler.
적합한 희석제는 디칼슘 포스페이트, 칼슘 설페이트, 락토오스, 소르비톨, 수크로즈, 이노시톨, 셀룰로스, 카올린, 만니톨, 나트륨 클로라이드, 건조 전분 및 분말형 설탕을 포함하나 이에 한정되지는 않는다. 만니톨, 락토오스, 소르비톨, 수크로스 및 이노시톨과 같은 특정 희석제는 충분한 양으로 존재할 때 씹는 것에 의해 구강 내에 붕괴를 허용하는 일부 압축된 정제에 특성을 부여할 수 있다. 이러한 압축된 정제는 츄어블 정제로 사용될 수 있다. 본 발명의 조성물 중의 희석제의 양은 제제의 유형에 따라 달라지며, 당업자는 용이하게 인식할 수 있다. 본 발명의 조성물은 약 10 내지 약 99 중량%의 희석제를 함유할 수 있다.Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient amounts, can characterize some compressed tablets that allow disintegration in the oral cavity by chewing. These compressed tablets can be used as chewable tablets. The amount of the diluent in the composition of the present invention depends on the type of preparation, and can be readily recognized by those skilled in the art. The compositions of the present invention may contain from about 10 to about 99% by weight of a diluent.
적합한 붕해제는 한천; 벤토나이트; 메틸셀룰로스 및 카복시메틸 셀룰로스와 같은 셀룰로스; 목재 제품; 천연 스펀지; 양이온 교환 수지; 알지닉산; 구아 검 및 비검(Veegum) HV와 같은 검; 시트러스 펄프; 크로스 카르멜로스와 같은 가교결합된 셀룰로스; 크로스포비돈(crospovidone)과 같은 가교결합된 중합체; 가교결합된 전분; 칼슘 카보네이트; 나트륨 전분 글리콜레이트와 같은 미결정 셀룰로스; 폴라크릴린 포타슘; 옥수수 전분, 감자 전분, 타피오카 전분 및 예비-젤라틴화 전분과 같은 전분; 점토; 얼라인(align); 및 이들의 혼합물을 포함하나 이에 한정되지는 않는다. 본 발명의 조성물 중 붕해제의 양은 제제의 유형에 따라 달라지며, 당업자는 쉽게 인식할 수 있다. 본 발명의 조성물은 약 0.5 내지 약 15 중량 % 또는 약 1 내지 약 5 중량 %의 붕해제를 함유할 수 있다.Suitable disintegrants include agar; Bentonite; Cellulose such as methylcellulose and carboxymethyl cellulose; Wood products; Natural sponge; Cation exchange resin; Alginic acid; Gums such as guar gum and Veegum HV; Citrus pulp; Crosslinked cellulose such as croscarmellose; Crosslinked polymers such as crospovidone; Crosslinked starch; Calcium carbonate; Microcrystalline cellulose such as sodium starch glycolate; Polyacrylline potassium; Starches such as corn starch, potato starch, tapioca starch and pre-gelatinized starch; clay; Align; And mixtures thereof, but are not limited thereto. The amount of the disintegrant in the composition of the present invention varies depending on the type of preparation, and can be easily recognized by those skilled in the art. The composition of the present invention may contain from about 0.5 to about 15% by weight or from about 1 to about 5% by weight of a disintegrant.
적합한 윤활제는 칼슘 스테아레이트; 마그네슘 스테아레이트; 미네랄 오일; 경질 미네랄 오일; 글리세린; 소르비톨; 만니톨; 글리세롤 베헤네이트 및 폴리에틸렌 글리콜(PEG)과 같은 글리세롤; 스테아릭산; 나트륨 라우릴 설페이트; 탈크; 땅콩유, 면실유, 해바라기유, 참기름, 올리브유, 옥수수유 및 콩기름을 포함하는 경화된 식물성 기름; 징크 스테아레이트; 에틸 올레에이트; 에틸 라우레이트; 한천; 전분; 석송(lycopodium); AEROSIL® 200 및 CAB-O-SIL®과 같은 실리카 또는 실리카 겔; 및 이들의 혼합물을 포함하나 이에 한정되지는 않는다. 본 발명의 조성물 중의 윤활제의 양은 제제의 유형에 따라 달라지며, 당업자는 용이하게 인식할 수 있다. 본 발명의 조성물은 약 0.1 내지 약 5 중량 %의 윤활제를 함유할 수 있다.Suitable lubricants include calcium stearate; Magnesium stearate; Mineral oil; Light mineral oil; glycerin; Sorbitol; Mannitol; Glycerol such as glycerol behenate and polyethylene glycol (PEG); Stearic acid; Sodium lauryl sulfate; Talc; Hardened vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; Zinc stearate; Ethyl oleate; Ethyl laurate; Agar; Starch; Lycopodium; Silica or silica gels, such as AEROSIL ® 200 and CAB-O-SIL ®; And mixtures thereof, but are not limited thereto. The amount of the lubricant in the composition of the present invention depends on the type of formulation and can be readily recognized by those skilled in the art. The compositions of the present invention may contain from about 0.1 to about 5% by weight of a lubricant.
적합한 활택제는 콜로이드성 실리콘 다이옥사이드, CAB-O-SIL® 및 석면을 함유하지 않은 탈크를 포함하지만 이에 한정되지는 않는다. 적절한 착색제는 승인된, 인증된, 수용성 FD&C 염료, 알루미나 수화물 상에 현탁된 수불용성 FD&C 염료, 칼라 레이크 및 이들의 혼합물을 포함하나 이에 한정되지는 않는다. 컬러 레이크는 수용성 염료를 중금속의 함수 산화물에 흡착시켜서 형성된 수용성 염료의 불용성 형태이다. 적합한 향료는 박하 및 살리실산 메틸과 같은 식물에서 추출한 천연 향료 및 과일과 같은 쾌적한 미각 감각을 생성하는 화합물의 합성 배합물을 포함하나 이에 한정되지는 않는다. 적합한 감미료는 수크로스, 락토오스, 만니톨, 시럽, 글리세린 및 인공 감미료, 예컨대 사카린 및 아스파탐을 포함하지만 이에 한정되지는 않는다. 적합한 유화제는 젤라틴, 아카시아, 트라가칸트, 벤토나이트, 및 폴리옥시에틸렌 소르비탄 모노올레에이트 (TWEEN® 20), 폴리옥시에틸렌 소르비탄 모노올레에이트 80 (TWEEN® 80) 및 트리에탄올아민 올레에이트와 같은 계면 활성제를 포함하지만 이에 한정되지는 않는다. 적합한 현탁 및 분산제는 나트륨 카복시메틸 셀룰로스, 펙틴, 트라가칸트, 비검, 아카시아, 나트륨 카보메틸셀룰로스, 히드록시프로필 메틸셀룰로스 및 폴리비닐피롤리돈을 포함하나 이에 한정되지는 않는다. 적합한 방부제는 글리세린, 메틸 및 프로필파라벤, 벤조산, 나트륨 벤조에이트 및 알콜을 포함하지만 이에 한정되지는 않는다. 적합한 습윤제는 프로필렌 글리콜 모노스테아레이트, 소르비탄 모노올레에이트, 디에틸렌 글리콜 모노라우 레이트 및 폴리옥시에틸렌 라우릴에테르를 포함하지만 이에 한정되지는 않는다. 적합한 용매는 글리세린, 소르비톨, 에틸 알콜 및 시럽을 포함 하나 이에 한정되지는 않는다. 에멀젼에 사용되는 적합한 비수성 액체는 광유 및 면실유를 포함하나 이에 한정되지는 않는다. 적합한 유기산은 시트릭산 및 타르타릭산을 포함하나 이에 한정되지는 않는다. 적합한 이산화탄소 공급원은 나트륨 바이카보네이트 및 나트륨 카보네이트를 포함하지만 이에 한정되지는 않는다.Suitable lubricants include talc containing no colloidal silicon dioxide, CAB-O-SIL ® and asbestos, but are not limited to. Suitable colorants include, but are not limited to, approved, certified, water soluble FD&C dyes, water insoluble FD&C dyes suspended on alumina hydrates, color lakes and mixtures thereof. Color lakes are the insoluble form of water-soluble dyes formed by adsorbing water-soluble dyes onto hydrous oxides of heavy metals. Suitable flavors include, but are not limited to, natural flavors derived from plants such as peppermint and methyl salicylate, and synthetic combinations of compounds that produce a pleasant taste sensation such as fruits. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrup, glycerin and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers are gelatin, acacia, tragacanth, bentonite, and interfaces such as polyoxyethylene sorbitan monooleate (TWEEN ® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN ® 80) and triethanolamine oleate. Including, but not limited to, active agents. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethyl cellulose, pectin, tragacanth, vegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparabens, benzoic acid, sodium benzoate and alcohols. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laurylether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol and syrup. Suitable non-aqueous liquids for use in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable carbon dioxide sources include, but are not limited to, sodium bicarbonate and sodium carbonate.
많은 부형제가 동일한 제제 내에서도 복수의 기능을 제공할 수 있음이 이해되어야 한다.It should be understood that many excipients can serve multiple functions even within the same formulation.
경구 투여를 위해 본 발명의 조성물은 압축된 정제, 정제 분쇄물, 저작 가능한 함당 정제, 급속 용해 정제, 다중 압축 정제, 장용 코팅 정제 또는 당 코팅 또는 필름 코팅 정제로서 제공될 수 있다. 장 코팅 정제는 위산의 작용에 저항하지만 장에서 용해되거나 분해되어 위의 산성 환경에서 활성 성분을 보호하는 물질로 코팅된 압축 정제이다. 장용 코팅은 지방산, 지방, 페닐 살리실레이트, 왁스, 셸락, 암모네이트된 셸락 및 셀룰로스 아세테이트 프탈레이트를 포함하나 이에 한정되지 않는다. 당 코팅된 정제는 당 코팅에 의해 둘러싸인 압축 정제이며, 이는 불쾌한 맛 또는 냄새를 은폐하고 정제에서 활성 성분 또는 부형제를 산화로부터 보호하는데 유용할 수 있다. 필름 코팅된 정제는 수용성 물질의 얇은 층 또는 필름으로 덮인 압축 정제이다. 필름 코팅에는 히드록시에틸셀룰로스, 나트륨 카복시메틸셀룰로스, 폴리에틸렌 글리콜 4000 및 셀룰로스 아세테이트 프탈레이트가 포함되나 이에 한정되지는 않는다. 필름 코팅은 당 코팅과 동일한 일반적인 특성을 부여한다. 다중 압축 정제는 층을 이루는 정제 및 프레스 코팅 또는 드라이 코팅 된 정제를 포함하여 하나 이상의 압축 주기에 의해 만들어진 압축 정제이다.For oral administration, the compositions of the present invention may be provided as compressed tablets, pulverized tablets, chewable sugar tablets, fast dissolving tablets, multiple compressed tablets, enteric coated tablets or sugar coated or film coated tablets. Enteric coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or decomposes in the intestine to protect the active ingredient in the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammonated shellac and cellulose acetate phthalate. Sugar coated tablets are compressed tablets surrounded by a sugar coating, which may be useful to mask an unpleasant taste or odor and to protect the active ingredient or excipient in the tablet from oxidation. Film coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made by one or more compression cycles, including layered tablets and press coated or dry coated tablets.
정제 투여형은 분말, 결정질 또는 과립 형태의 활성 성분(들)을, 단독으로 또는 결합제, 붕해제, 제어 방출 중합체(controlled-release polymer) 윤활제, 희석제 및/또는 착색제를 함유할 수 있다. 향료 또는 감미료는 저작 가능한 정제 또는 로젠지의 형성에 특히 유용하다.Tablet dosage forms may contain the active ingredient(s) in powder, crystalline or granular form, alone or with binders, disintegrants, controlled-release polymer lubricants, diluents and/or coloring agents. Flavors or sweeteners are particularly useful in the formation of chewable tablets or lozenges.
경구 투여를 위해 본 발명의 조성물은 젤라틴, 메틸 셀룰로스, 전분 또는 칼슘 알지네이트로 제조될 수 있는 연질 또는 경질 캡슐로서 제공될 수 있다. 건식 충진 캡슐 (DFC)으로도 알려진 경질 젤라틴 캡슐은 2 개의 섹션으로 구성되어 하나는 다른 섹션 위로 미끄러져 하나의 활성 성분을 완전히 둘러싼다. 연질 탄성 캡슐 (SEC)은 글리세린, 소르비톨 또는 유사한 폴리올의 첨가에 의해 가소화된 젤라틴 껍질과 같은 부드럽고 구형의 껍질이다. 연질 젤라틴 껍질에는 미생물의 성장을 막기 위한 방부제가 함유되어 있을 수 있다. 적합한 방부제는 메틸- 및 프로필- 파라벤 및 소르브산을 비롯한 본원에 기재된 것들이다. 본원에서 제공되는 액체, 반고체 및 고형 투여형은 캡슐 내에 캡슐화 될 수 있다. 적합한 액체 및 반고체 투여형은 프로필렌 카보네이트, 식물성 오일 또는 트리글리세라이드 중의 용액 및 현탁액을 포함한다. 이러한 용액을 함유하는 캡슐은 미국특허 제 4,328,245 호; 4,409,239; 및 4,410,545에 기재된 바에 따라 제조될 수 있다. 캡슐은 또한 활성 성분(들)의 용해를 변형시키거나 유지하기 위해 당업자에게 공지된 바와 같이 코팅 될 수 있다.For oral administration, the compositions of the present invention may be presented as soft or hard capsules which may be made of gelatin, methyl cellulose, starch or calcium alginate. Hard gelatin capsules, also known as dry fill capsules (DFC), are made up of two sections, one sliding over the other, completely enclosing one active ingredient. Soft elastic capsules (SEC) are soft, spherical shells such as gelatin shells plasticized by the addition of glycerin, sorbitol or similar polyols. Soft gelatin shells may contain preservatives to prevent the growth of microorganisms. Suitable preservatives are those described herein including methyl- and propyl-parabens and sorbic acid. Liquid, semi-solid and solid dosage forms provided herein can be encapsulated within capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions are described in US Pat. Nos. 4,328,245; 4,409,239; And 4,410,545. Capsules can also be coated as known to those of skill in the art to modify or maintain dissolution of the active ingredient(s).
경구 투여를 위해 본 발명의 조성물은 에멀젼, 용액, 현탁액, 엘릭서 및 시럽을 포함하는 액체 또는 반고체 투여형으로 제공될 수 있다. 에멀션은 2 단계 시스템으로 하나의 액체가 다른 액체를 통해 작은 구체 형태로 분산되며, 이는 수 중유 또는 유 중수 일 수 있다. 에멀젼은 비수성 액체 또는 용매, 유화제 및 방부제를 포함할 수 있다. 현탁액은 현탁화제 및 방부제를 포함할 수 있다. 알콜성 수용액은 아세탈, 예컨대 저급 알킬 알데히드의 디(저급 알킬)아세탈, 예를 들어 아세트 알데히드 디 에틸 아세탈; 및 하나 이상의 히드록실기를 갖는 수혼화성 용매, 예를 들어 프로필렌 글리콜 및 에탄올을 포함한다. 엘릭서는 투명하고 단맛을 지닌 수 알콜성 용액이다. 시럽은 설탕과 같은 당의 농축 수용액이며, 또한 방부제를 함유할 수 있다. 액체 투여형의 경우, 예를 들어, 폴리에틸렌 글리콜 중의 용액을 충분한 양의 액체 담체, 예를 들어 물로 희석하여 투여하기에 편리하게 측정할 수 있다.For oral administration, the compositions of the present invention may be provided in liquid or semi-solid dosage forms including emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-stage system in which one liquid is dispersed in the form of small spheres through another liquid, which can be oil-in-water or water-in-oil. Emulsions may contain non-aqueous liquids or solvents, emulsifiers and preservatives. Suspensions may contain suspending agents and preservatives. Alcoholic aqueous solutions include acetals, such as di(lower alkyl)acetals of lower alkyl aldehydes, such as acetaldehyde di ethyl acetal; And water-miscible solvents having one or more hydroxyl groups such as propylene glycol and ethanol. Elixir is a clear, sweet, aqueous alcoholic solution. Syrup is a concentrated aqueous solution of sugars such as sugar, and may also contain preservatives. In the case of liquid dosage forms, for example, a solution in polyethylene glycol can be conveniently measured for administration by diluting it with a sufficient amount of a liquid carrier, for example water.
다른 유용한 액체 및 반고체 투여형은 본 발명의 조성물 및 1,2-디메톡시메탄, 디글라임, 트리글라이드, 테트라글림(tetraglyme)을 포함하는 디알킬화된 모노- 또는 폴리- 알킬렌 글리콜을 함유하는 것들을 포함하나 이에 한정되지는 않는다. 폴리에틸렌 글리콜 -550- 디메틸 에테르, 폴리에틸렌 글리콜 -750- 디메틸 에테르 (여기서, "350", "550"및 "750"은 대략 수평균 분자량(Mn)의 폴리에틸렌 글리콜을 각각 얻었다. 이러한 투여형은 부틸화 히드록시 톨루엔(BHT), 부틸화 히드록시 아니솔(BHA), 프로필 갈레이트, 비타민 E, 히드로퀴논, 히드록시쿠마린, 에탄올아민, 레시틴, 세팔린, 아스코르빅산, 말레익산, 소르비톨, 포스포릭산, 비스설피이트, 나트륨 메타설피트, 티오디프로피오닉산 및 그의 에스테르, 및 디티오카르바메이트를 포함한다.Other useful liquid and semi-solid dosage forms include compositions of the present invention and those containing dialkylated mono- or poly-alkylene glycols including 1,2-dimethoxymethane, diglyme, triglide, tetraglyme. Including, but not limited to. Polyethylene glycol -550-dimethyl ether, polyethylene glycol -750-dimethyl ether (where "350", "550" and "750" each obtained polyethylene glycol of approximately number average molecular weight (Mn). These dosage forms are butylated. Hydroxy toluene (BHT), butylated hydroxy anisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, maleic acid, sorbitol, phosphoric acid , Bissulfite, sodium metasulfite, thiodipropionic acid and esters thereof, and dithiocarbamate.
경구 투여를 위해 본 발명의 조성물은 또한 리포좀, 미셀, 마이크로 스피어 또는 나노 시스템의 형태로 제공될 수 있다. 미셀(micelle) 투여형은 미국특허 제6,350,458호에 기재된 바에 제조될 수 있다.For oral administration, the compositions of the present invention may also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micelle dosage forms can be prepared as described in US Pat. No. 6,350,458.
경구 투여를 위해 본 발명의 조성물은 액체 투여형으로 재구성될 비발포성 또는 발포성, 과립 또는 분말로서 제공될 수 있다. 비발포성 과립 또는 분말에 사용되는 부형제는 희석제, 감미제 및/또는 습윤제를 포함할 수 있다. 비등성 과립 또는 분말에 사용되는 부형제는 유기산 및 이산화탄소의 공급원을 포함한다.For oral administration the compositions of the present invention may be provided as non-foaming or effervescent, granules or powders to be reconstituted into liquid dosage forms. Excipients used in non-foaming granules or powders may include diluents, sweetening and/or wetting agents. Excipients used in the effervescent granules or powders include a source of organic acids and carbon dioxide.
착색제 및 향료는 본원에 기재된 모든 투여형에 사용될 수 있다.Colorants and fragrances can be used in all dosage forms described herein.
경구 투여를 위해 본 발명의 조성물은 지연 -, 지속 -, 펄스 -, 조절 -, 표적 - 및 프로그램된 방출 형태를 포함하는 즉시 또는 변형 방출 복용 형태로 제형화될 수 있다.For oral administration the compositions of the present invention may be formulated in immediate or modified release dosage forms including delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release forms.
본 발명의 조성물은 국소 또는 전신 투여를 위해 주사, 주입 또는 이식에 의해 비경구적으로 투여될 수 있다. 본원에서 비경구 투여는 정맥 내, 동맥 내, 복강 내, 척수강 내, 심실 내, 요도 내, 흉골 내, 두개 내, 근육 내, 활액 내, 관내 및 피하 투여를 포함한다.The compositions of the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intraluminal and subcutaneous administration.
비경구 투여를 위해 본 발명의 조성물은 주입 전에 용액, 현탁액, 에멀젼, 미셀, 리포솜, 마이크로 스피어, 나노 시스템 및 액체의 용액 또는 현탁액에 적합한 고체 형태를 포함하는 비경구 투여에 적합한 임의의 투여형으로 제형화될 수 있다. 이러한 투여형은 당업자에게 공지된 통상적인 방법에 따라 제조될 수 있다(Remington: The Science and Practice of Pharmacy, supra).For parenteral administration, the compositions of the present invention may be prepared in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solutions or suspensions of liquids prior to injection. It can be formulated. Such dosage forms can be prepared according to conventional methods known to those skilled in the art (Remington: The Science and Practice of Pharmacy, supra).
비경구 투여용 조성물은 수성 비히클, 수-혼화성 비히클, 비-수성 비히클, 항미생물제 또는 미생물의 성장에 대한 방부제, 안정화제, 용해도 향상제, 등장화제, 완충제, 산화방지제, 국소마취제, 현탁 및 분산제, 습윤 또는 유화제, 착화제, 격리 또는 킬레이트제, 동결방지제, 평활보호제, 농후제, pH 조절제, 불활성 가스를 포함하나 이에 한정되지 않는 하나 이상의 부형제를 포함할 수 있다.Compositions for parenteral administration include aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents. , A wetting or emulsifying agent, a complexing agent, a sequestering or chelating agent, a cryoprotectant, a leveling agent, a thickening agent, a pH adjusting agent, an inert gas, and one or more excipients, including but not limited thereto.
적합한 수성 비히클은 물, 식염수, 생리 식염수 또는 인산완충 식염수(PBS), 염화나트륨 주사제, 링거 주사제, 등장성 덱스트로스 주사제, 멸균수 주사제 및 덱스트로스 및 락테이트 링거 주사제를 포함하나 이에 한정되지는 않는다. 적합한 비수성 비히클은 식물성 유래의 고정유, 피마 자유, 옥수수유, 면실유, 올리브유, 땅콩유, 박하유, 잇꽃유, 참기름, 대두유, 수소화 식물성유, 수소화 대두유, 코코넛유의 중쇄 트리글리 세라이드, 종자유를 포함하나 이에 한정되지는 않는다. 적합한 수혼화성 비히클은 에탄올, 1,3-부탄디올, 액체 폴리에틸렌 글리콜(예, 폴리에틸렌 글리콜 300 및 폴리에틸렌 글리콜 400), 프로필렌 글리콜, 글리세린, N- 메틸-2-피롤리돈, N,N-디메틸아세트아미드, 디메틸술폭시드를 포함하나 이에 한정되지는 않는다.Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, and dextrose and lactate Ringer's injection. Suitable non-aqueous vehicles include fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, mentha oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, medium chain triglycerides of coconut oil, seed oil. It is not limited thereto. Suitable water-miscible vehicles are ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g. polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide. And dimethylsulfoxide, but is not limited thereto.
적합한 항균제 또는 보존제는 페놀, 크레졸, 수은, 벤질 알콜, 클로로부탄올, 메틸 및 프로필 p-히드록시벤조에이트, 티메로살, 벤잘코늄 클로라이드(예, 벤즈에토늄 클로라이드), 메틸- 및 프로필- 파라벤, 그리고 소르빅 산을 포함하나 이에 한정되지 않는다. 적합한 등장화제는 염화나트륨, 글리세린 및 덱스트로스를 포함하나 이에 한정되지 않는다. 적합한 완충제는 포스페이트 및 시트레이트를 포함하나 이에 한정되지 않는다. 적합한 항산화제는 바이설파이트 및 메타바 설파이트 나트륨을 포함하는 본원에 기재된 것들이다. 적합한 국소 마취제는 프로카인 하이드로클로라이드를 포함하나 이에 한정되지 않는다. 적합한 현탁 및 분산제는 나트륨 카복시메틸셀룰로스, 히드록시프로필 메틸셀룰로스 및 폴리비닐피롤리돈을 비롯한 본원에 기재된 것들이다. 적합한 유화제는 폴리 옥시에틸렌 소르비탄 모노라우레이트, 폴리옥시에틸렌 소르비탄 모노올레 에이트 80 및 트리에탄올아민 올레에이트를 포함하는 본원에 기재된 것들이다. 적합한 격리 또는 킬레이트제로는 EDTA가 포함되나 이에 한정되지 않는다. 적합한 pH 조절제는 수산화나트륨, 염산, 시트르산 및 젖산을 포함하나 이에 한정되지 않는다. 적합한 착화제는 α-시클로 덱스트린, β-시클로덱스트린, 히드록시프로필-β-시클로덱스트린, 설폭시 부틸에테르-β-시클로덱스트린 및 설포부틸에테르 7-β-시클로 덱스트린 (CAPTISOL®)을 포함하는 시클로덱스트린을 포함하나 이에 한정되지 않는다.Suitable antimicrobial agents or preservatives are phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (e.g. benzethonium chloride), methyl- and propyl-parabens, And, including, but not limited to, sorbic acid. Suitable tonicity agents include, but are not limited to, sodium chloride, glycerin and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those described herein including bisulfite and metaba sulfite sodium. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein including sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Suitable emulsifiers are those described herein including poly oxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents are cyclodextrins including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfoxy butylether-β-cyclodextrin and sulfobutylether 7-β-cyclodextrin (CAPTISOL ® ). Including, but not limited to, dextrin.
본 발명의 조성물이 다중 투여량으로 투여될 때, 다중 투여량의 비경구 투여 제제는 정균 또는 곰팡이 제거 농도의 항미생물제를 함유해야 한다. 모든 비경구용 제제는 당해 분야에 공지되고 실시되는 바와 같이 무균이어야 한다.When the composition of the present invention is administered in multiple doses, the multiple dose parenteral formulation should contain a bacteriostatic or fungal-removing concentration of an antimicrobial agent. All parenteral formulations should be sterile as known and practiced in the art.
비경구 투여용 조성물은 즉시 사용할 수 있는 멸균 용액으로서 제공될 수 있다. 다른 구현예에서, 본 발명의 조성물은 사용 전에 비히클로 재구성될 동결 건조된 분말 또는 피하 내 정제를 포함하는 무균의 건조 가용성 제품으로서 제공된다. 또 다른 구현예에서, 본 발명의 조성물은 즉시 사용할 수있는 무균 현탁액으로서 제공된다. 또 다른 구현예에서, 본 발명의 조성물은 사용 전에 비히클로 재구성되는 무균의 건조한 불용성 제품으로서 제공된다. 또 다른 구현예에서, 본 발명의 조성물은 즉시 사용 가능한 무균 유화액으로서 제공된다.Compositions for parenteral administration may be provided as ready-to-use sterile solutions. In another embodiment, the composition of the present invention is provided as a sterile, dry soluble product comprising a lyophilized powder or subcutaneous tablet to be reconstituted with a vehicle prior to use. In another embodiment, the composition of the present invention is provided as a ready-to-use sterile suspension. In another embodiment, the compositions of the present invention are provided as sterile, dry insoluble products that are reconstituted with a vehicle prior to use. In another embodiment, the composition of the present invention is provided as a ready-to-use sterile emulsion.
비경구 투여를 위해 본원에서 제공되는 본 발명의 조성물은 지연-, 지속-, 펄스-, 조절-, 표적- 및 프로그램된 방출 형태를 포함하는 즉시 또는 변형된 방출 투여형으로서 제형화될 수 있다.The compositions of the invention provided herein for parenteral administration can be formulated as immediate or modified release dosage forms including delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release forms.
비경구 투여를 위해 본 발명의 조성물은 이식된 저장소로서 투여하기 위한 현탁액, 고체, 반고체 또는 요변성 액체로서 제제화될 수 있다. 일 실시예에서, 본 발명의 조성물은 체액에 불용성이지만 조성물 중의 활성 성분(들)이 통과할 수 있게 하는 외부 중합체 막으로 둘러싸인 고체 내부 매트릭스에 분산되어 있다.For parenteral administration, the compositions of the present invention may be formulated as a suspension, solid, semi-solid or thixotropic liquid for administration as an implanted reservoir. In one embodiment, the composition of the present invention is dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient(s) in the composition to pass.
적합한 내부 매트릭스는 폴리메틸메타크릴레이트, 폴리부틸-메타 크릴레이트, 가소화 또는 비소성 폴리비닐클로라이드, 가소화 나일론, 가소 화 폴리에틸렌 테레프탈레이트, 천연 고무, 폴리이소프렌, 폴리이소부틸렌, 폴리부타디엔, 폴리에틸렌, 에틸렌-비닐 아세테이트 공중합체, 실리콘 고무, 폴리디메틸실록산, 실리콘 카보네이트 공중합체, 친수성 중합체, 예를 들면 아크릴 및 메타크릴산의 에스터의 하이드로겔, 콜라겐, 가교결합된 폴리비닐 알코올 및 가교 결합된 부분적으로 가수분해된 폴리비닐 아세테이트를 포함하나 이에 한정되지는 않는다.Suitable inner matrices are polymethylmethacrylate, polybutyl-methacrylate, plasticized or non-fired polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, Polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers, for example hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol and crosslinked Includes, but is not limited to, partially hydrolyzed polyvinyl acetate.
적합한 외부 폴리머 막은 폴리에틸렌, 폴리프로필렌, 에틸렌/프로필렌 공중합체, 에틸렌/에틸 아크릴레이트 공중합체, 에틸렌/비닐 아세테이트 공중합체, 실리콘 고무, 폴리디메틸 실록산, 네오프렌 고무, 염소화 폴리에틸렌, 폴리비닐클로라이드, 비닐아세테이트, 비닐리덴 클로라이드, 에틸렌 및 프로필렌과의 비닐 클로라이드 공중합체, 이오노머 폴리에틸렌 테레프탈레이트, 부틸 고무 에피클로로하이드린 고무, 에틸렌/비닐 알코올 공중합체, 에틸렌/비닐아세테이트/비닐 알코올 3원 공중합체, 및 에틸렌/비닐옥시에탄올 공중합체를 포함하나 이에 한정되지는 않는다.Suitable outer polymer membranes are polyethylene, polypropylene, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, ethylene/vinyl acetate copolymer, silicone rubber, polydimethyl siloxane, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl acetate, Vinylidene chloride, vinyl chloride copolymer with ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinylacetate/vinyl alcohol terpolymer, and ethylene/vinyl Including, but not limited to, oxyethanol copolymer.
본 발명의 조성물은 피부, 구멍 또는 점막에 국소 투여 될 수 있다. 본원에서 국소 투여는 피부(내), 결막 내, 각막 내, 안 내, 귀관 내, 경피, 비강, 질, 요도, 호흡기 및 직장 투여를 포함한다.The composition of the present invention can be topically administered to the skin, pores or mucous membranes. Local administration herein includes intradermal (intra), intraconjunctival, intracorneal, intraocular, intraocular, transdermal, nasal, vaginal, urethral, respiratory and rectal administration.
본 발명의 조성물은 에멀젼, 용액, 현탁액, 크림, 겔, 하이드로겔, 연고, 분말, 드레싱, 엘릭서, 로션, 현탁액, 팅크, 페이스트, 폼, 필름, 에어로졸, 관개, 스프레이, 좌약, 붕대 및 피부 패치를 포함하는 국소 또는 전신 효과를 위한 국소 투여에 적합한 임의의 투여형으로 제제화될 수 있다. 본 발명의 조성물의 국소 제제는 또한 리포솜, 미셀, 마이크로 스피어, 나노 시스템 및 이들의 혼합물을 포함할 수 있다.Compositions of the present invention include emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigation, sprays, suppositories, bandages and skin patches. It can be formulated in any dosage form suitable for topical administration for local or systemic effects, including. Topical formulations of the compositions of the present invention may also include liposomes, micelles, microspheres, nanosystems and mixtures thereof.
본원에 제공되는 국소 제제에 사용하기에 적합한 담체 및 부형제는 수성 비히클, 수-혼화성 비히클, 비수성 비히클, 항미생물제 또는 미생물의 성장에 대한 방부제, 안정화제, 용해도 향상제, 등장화제, 완충제, 산화방지제, 국소마취제, 현탁 및 분산제, 습윤 또는 유화제, 착화제, 격리 또는 킬레이트제, 침투 강화제, 동결 방지제, 평활보호제, 농후제, pH 조절제, 불활성 가스를 포함하나 이에 한정되지 않는다.Carriers and excipients suitable for use in the topical formulations provided herein are aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffers, oxidizing agents. Including, but not limited to, inhibitors, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancing agents, anti-freezing agents, smoothing agents, thickening agents, pH adjusting agents, and inert gases.
본 발명의 조성물은 또한 전기 천공법, 이온 삼투압법, 음파 영동법, 초음파 도입법, 또는 미세 바늘 또는 POWDERJECT™ 및 BIOJECT™과 같은 니들-프리 주입법에 의해 국소 투여 될 수 있다.The compositions of the present invention can also be administered topically by electroporation, iontophoresis, sonophoresis, ultrasound transduction, or microneedle or needle-free injection methods such as POWDERJECT ™ and BIOJECT ™ .
본 발명의 조성물은 연고, 크림 및 겔의 형태로 제공 될 수 있다. 적합한 연고제는 라드, 벤조인 라드, 올리브유, 면실유 및 백색 바셀린을 포함하는 유성 또는 탄화수소 비히클; 친수성 페트롤라툼, 히드록시스테아린 설페이트 및 무수 라놀린과 같은 유화성 또는 흡수성 비히클; 친수성 연고와 같은 수분 제거 가능한 비히클; 다양한 분자량의 폴리에틸렌 글리콜을 포함하는 수용성 연고제; 세틸 알코올, 글리세릴 모노 스테아레이트, 라놀린 및 스테아린 산을 포함한 유중수 에멀젼(W / O) 또는 수중유 (O / W) 에멀젼 중 하나인 에멀젼 비히클을 포함한다(Remington : The Science and Practice of Pharmacy, supra). 이러한 비히클들은 피부 연화제이지만 일반적으로 항산화제와 방부제가 추가되어야 한다.The composition of the present invention may be provided in the form of ointments, creams and gels. Suitable ointments include oily or hydrocarbon vehicles including lard, benzoin lard, olive oil, cottonseed oil and white petrolatum; Emulsifying or absorbing vehicles such as hydrophilic petrolatum, hydroxystearin sulfate and anhydrous lanolin; Moisture-removable vehicles such as hydrophilic ointments; Water-soluble ointments comprising polyethylene glycols of various molecular weights; Emulsion vehicles, either water-in-oil (W/O) or oil-in-water (O/W) emulsions containing cetyl alcohol, glyceryl mono stearate, lanolin and stearic acid (Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollients, but usually antioxidants and preservatives must be added.
적합한 크림 베이스는 수중유 또는 유중수일 수 있다. 적합한 크림 비히클은 물로 세척 가능하고, 오일 상(oil phase), 유화제 및 수성 상을 함유할 수 있다. 유상은 "내부"상으로도 불리고, 이는 일반적으로 페트로라툼 및 세틸 또는 스테아릴 알콜과 같은 지방산을 포함한다. 반드시 그런 것은 아니지만, 통상적으로 수성 상의 부피는 오일 상을 초과하고, 일반적으로 보습제를 함유한다. 크림 제형의 유화제는 비이온성, 음이온성, 양이온성 또는 양성 계면 활성제일 수 있다.Suitable cream bases may be oil-in-water or water-in-oil. Suitable cream vehicles are washable with water and may contain an oil phase, an emulsifier and an aqueous phase. The oil phase is also referred to as the "internal" phase, which generally includes fatty acids such as petrolatum and cetyl or stearyl alcohol. Not necessarily, but typically the volume of the aqueous phase exceeds the oil phase and generally contains a moisturizer. Emulsifiers in cream formulations can be nonionic, anionic, cationic or amphoteric surfactants.
겔은 반고체, 서스펜션형 시스템이다. 단상(single-phase) 겔은 액체 캐리어 전체에 실질적으로 균일하게 분포된 유기 거대 분자를 함유한다. 적합한 겔화제는 카보머, 카복시폴리알킬렌 및 CARBOPOL®와 같은 가교결합된 아크릴산 중합체; 폴리에틸렌 옥사이드, 폴리옥시에틸렌-폴리옥시프로필렌 공중합체 및 폴리비닐알코올과 같은 친수성 중합체; 히드록시프로필 셀룰로스, 히드록시에틸 셀룰로스, 히드록시프로필 메틸셀룰로스, 히드록시프로필 메틸셀룰로스 프탈레이트 및 메틸 셀룰로스와 같은 셀룰로스계 중합체; 트라가 칸트 및 크산탄 검과 같은 검; 알긴산 나트륨; 및 젤라틴을 포함하나 이에 한정되지는 않는다. 균일한 겔을 제조하기 위해, 알코올 또는 글리세린과 같은 분산제를 첨가하거나, 겔화제를 분쇄, 기계적 혼합 및/또는 교반에 의해 분산시킬 수 있다.Gels are semi-solid, suspension systems. Single-phase gels contain organic macromolecules distributed substantially evenly throughout the liquid carrier. Suitable gelling agent is an acrylic acid polymer cross-linked, such as carbomer, carboxy polyalkylene and CARBOPOL ®; Hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymer and polyvinyl alcohol; Cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; Gums such as tragacanth and xanthan gum; Sodium alginate; And gelatin, but is not limited thereto. To prepare a homogeneous gel, a dispersing agent such as alcohol or glycerin may be added, or the gelling agent may be dispersed by grinding, mechanical mixing and/or stirring.
본 발명의 조성물은 좌약, 페서리(pessary), 바우지(bougy), 습포 또는 찜질제, 페이스트, 분말, 드레싱, 크림, 깁스, 피임약, 연구, 용액, 에멀젼, 현탁액, 탐폰, 겔, 거품, 스프레이 또는 관장의 형태로 직장, 요도, 질, 질주위로 투여될 수 있다. 이러한 투여형은 Remington: The Science and Practice of Pharmacy, supra에 기재된 통상의 방법을 이용하여 제조될 수 있다.The composition of the present invention is a suppository, pessary, bougy, poultice or poultice, paste, powder, dressing, cream, cast, contraceptive, study, solution, emulsion, suspension, tampon, gel, foam, spray Alternatively, it may be administered to the rectum, urethra, vagina, or peri-vaginal in the form of an enema. Such dosage forms can be prepared using conventional methods described in Remington: The Science and Practice of Pharmacy, supra.
직장, 요도 및 질 좌약은 상온에서 고체이지만 체온에서 용융되거나 연화되어 오리피스 내부의 활성 성분(들)을 방출하는 신체 오리피스에 삽입하기 위한 고체이다. 직장 및 질 좌약에서 이용되는 담체는 체온 부근에서 융점을 생성시키는 보강제와 같은 염기 또는 비히클; 및 바이설파이트 및 메타바이설파이트 나트륨을 포함하는 본원에 기재된 항산화제를 포함한다. 적합한 비히클은 코코아 버터(테오 브로마 오일), 글리세린-젤라틴, 카보왁스(폴리옥시에틸렌글리콜), 경랍(spermaceti), 파라핀, 백색 및 황색 왁스 및 지방산의 모노-, 디- 및 트리글리세라이드의 적절한 혼합물 및 폴리비닐 알코올과 같은 하이드록시 겔, 히드록시에틸 메타크릴레이트 및 폴리아크릴산을 포함하나 이에 한정되지는 않으며; 다양한 담체의 조합도 사용할 수 있다. 직장 및 질 좌약은 압축 또는 성형하여 줄비될 수 있다. 직장 및 질 좌약의 전형적인 중량은 약 2 내지 약 3 g이다.Rectal, urethral and vaginal suppositories are solids for insertion into body orifices that are solid at room temperature but melt or soften at body temperature to release the active ingredient(s) inside the orifice. Carriers used in rectal and vaginal suppositories include bases or vehicles such as adjuvants that create a melting point near body temperature; And antioxidants described herein including bisulfite and metabisulfite sodium. Suitable vehicles are cocoa butter (theo broma oil), glycerin-gelatin, carbo wax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes and suitable mixtures of mono-, di- and triglycerides of fatty acids. And hydroxy gels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid, but are not limited thereto; Combinations of various carriers may also be used. Rectal and vaginal suppositories can be compressed or molded and compressed. Typical weights for rectal and vaginal suppositories are about 2 to about 3 grams.
본 발명의 조성물은 용액, 현탁액, 연고, 에멀젼, 겔 형성 용액, 용액 분말, 겔, 안구 삽입물 및 임플란트 형태로 안과적으로 투여될 수 있다.The compositions of the present invention can be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, solution powders, gels, ocular inserts and implants.
본 발명의 조성물은 호흡관으로 비강 내로 또는 흡입에 의해 투여될 수 있다. 본 발명의 조성물은 가압된 용기, 펌프, 분무기, 전자 유체 역학을 사용하여 미세 안개를 생성하는 분무기와 같은 분무기 또는 네뷸라이저를 단독으로 또는 1,1,1,2- 테트라 플루오로에탄 또는 1,1,1,2,3,3,3- 헵타플루오로 프로판과 같은 적절한 추진체와 함께 사용하여 전달을 위한 에어로졸 또는 용액의 형태로 제공될 수 있다. 본 발명의 조성물은 또한 단독으로 또는 락토오스 또는 인지질과 같은 불활성 담체와 조합하여 통기용 건조 분말로서; 그리고 점비액으로서 제공될 수 있다. 비강 내 사용을 위해, 분말은 키토산 또는 사이클로 덱스트린을 포함하는 생물 부착제를 포함할 수 있다.The composition of the present invention can be administered intranasally or by inhalation into the respiratory tract. The composition of the present invention is a pressurized vessel, a pump, a nebulizer, such as a nebulizer, such as a nebulizer that uses electrohydrodynamics to create a fine mist, alone or 1,1,1,2-tetrafluoroethane or 1, It can be provided in the form of an aerosol or solution for delivery using with a suitable propellant such as 1,1,2,3,3,3- heptafluoro propane. The composition of the present invention can also be used alone or in combination with an inert carrier such as lactose or phospholipid as a dry powder for ventilation; And it can be provided as a nasal drops. For intranasal use, the powder may contain biological adhesives including chitosan or cyclodextrin.
가압 용기, 펌프, 분무기, 분무기 또는 분무기에서 사용하기 위한 용액 또는 현탁액은 에탄올, 수성 에탄올 또는 활성 성분의 분산, 가용화 또는 방출 연장을 위한 적합한 대체 제제(들); 용매로서 추진체; 및/또는 소르비탄 트리올레에이트, 올레산 또는 올리고 락틱산과 같은 계면 활성제를 포함할 수 있다.Solutions or suspensions for use in pressurized vessels, pumps, nebulizers, nebulizers or nebulizers may include ethanol, aqueous ethanol or suitable alternative agent(s) for dispersing, solubilizing or extending release of the active ingredient; Propellant as a solvent; And/or a surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.
본 발명의 조성물은 약 50 마이크로 미터 또는 그 이하, 또는 약 10 마이크로미터 이하와 같은 흡입에 의한 전달에 적합한 크기로 미세화될 수 있다. 이러한 크기의 입자는 나선형 제트 밀링, 유동층 제트 밀링, 나노 입자 형성을 위한 초임계 유체 처리, 고압 균질화 또는 분무 건조와 같은 당업자에게 공지된 분쇄 방법을 사용하여 제조될 수 있다.The compositions of the present invention may be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of this size can be prepared using grinding methods known to those skilled in the art such as spiral jet milling, fluid bed jet milling, supercritical fluid treatment to form nanoparticles, high pressure homogenization or spray drying.
흡입기 또는 주입기에서 사용하기 위한 캡슐, 블리스터 및 카트리지는 본 발명의 조성물의 분말 혼합물; 락토오스 또는 전분과 같은 적합한 분말 베이스; 및 l- 류신, 만니톨 또는 마그네슘 스테아레이트와 같은 성능 개질제를 함유하도록 제형화될 수 있다. 락토오스는 무수물이거나 일 수화물의 형태일 수 있다. 다른 적합한 부형제 또는 담체는 덱스트란, 글루코오스, 말토오스, 소르비톨, 자일리톨, 프룩 토스, 수크로오스 및 트레할로오스를 포함하나 이에 한정되지 않는다. 흡입/비강 내 투여를 위해 본 발명의 조성물은 멘톨 및 레보 멘톨과 같은 적합한 향료; 및/또는 사카린 및 사카린 나트륨과 같은 감미료를 더 포함할 수 있다.Capsules, blisters and cartridges for use in an inhaler or injector comprise a powder mixture of the composition of the present invention; Suitable powder bases such as lactose or starch; And performance modifiers such as l-leucine, mannitol or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. For inhalation/intranasal administration the compositions of the present invention may contain suitable fragrances such as menthol and levomenthol; And/or a sweetener such as saccharin and saccharin sodium.
국소 투여를 위해 본 발명의 조성물은 즉시 방출되거나 또는 지연 방출, 지속 방출, 펄스 방출, 제어 방출, 표적 방출 및 프로그램 방출을 포함하는 변형 방출되도록 제형화될 수 있다.For topical administration the compositions of the present invention may be formulated for immediate release or modified release including delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.
본 발명의 조성물은 변형된 방출 투여형으로 제제화될 수 있다. 본원에서 사용된 용어 "변형된 방출(modified release)"은 동일한 경로로 투여될 때 활성 성분(들)의 방출 속도 또는 방출 장소가 즉각적인 투여형의 방출 속도 또는 방출 장소와 상이한 투여형을 지칭한다. 변형 방출형은 지연형, 연장형, 지속형, 박동성, 조절형, 촉진형 및 신속형, 표적화형, 프로그램된 방출형 및 위장 유지형을 포함하지만 이에 한정되지는 않는다. 변형된 방출 투여형의 본 발명 조성물은 매트릭스 조절 방출 장치, 삼투압 조절 방출 장치, 다입자 조절 방출 장치, 이온 교환 수지, 장용 코팅, 다층 코팅, 미세구, 리포솜 및 이들의 조합물을 포함하나 이에 한정되지는 않는다. 활성 성분(들)의 방출속도는 활성 성분(들)의 입자 크기 및 다형체를 변화시킴으로써 또한 변경될 수 있다.The composition of the present invention can be formulated in a modified release dosage form. The term “modified release” as used herein refers to a dosage form in which the rate or location of release of the active ingredient(s) when administered by the same route differs from the rate or location of release of the immediate dosage form. Modified release forms include, but are not limited to, delayed, extended, sustained, pulsatile, controlled, accelerated and rapid, targeted, programmed release and gastrointestinal maintenance. Compositions of the present invention in modified release dosage forms include, but are limited to, matrix controlled release devices, osmotic pressure controlled release devices, multi-particle controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. It doesn't work. The release rate of the active ingredient(s) can also be altered by changing the particle size and polymorph of the active ingredient(s).
변형된 방출의 예시는 미국특허 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,958,458; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,270,798; 6,375,987; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,623,756; 6,699,500; 6,793,936; 6,827,947; 6,902,742; 6,958,161; 7,255,876; 7,416,738; 7,427,414; 7,485,322; Bussemer et al., Crit. Rev. Ther. Drug Carrier Syst. 2001, 18, 433-458; Modified-Release Drug Delivery Technology, supra; Maroni et al., Expert. Opin. Drug Deliv. 2005, 2, 855-871; Shi et al., Expert Opin. Drug Deliv. 2005, 2, 1039-1058; Polymers in Drug Delivery; Ijeoma et al., Eds.; CRC Press: 2006; Badawy et al., J. Pharm. Sci. 2007, 9, 948-959; Conway, Recent Pat. Drug Deliv. Formul. 2008, 2, 1-8; Gazzaniga et al., Eur. J. Pharm. Biopharm. 2008, 68, 11-18; Nagarwal et al., Curr. Drug Deliv. 2008, 5, 282-289; Gallardo et al., Pharm. Dev. Technol. 2008, 13, 413-423; Chrzanowski, AAPS PharmSciTech. 2008, 9, 635-638; Chrzanowski, AAPS PharmSciTech. 2008, 9, 639-645; Kalantzi et al., Recent Pat. Drug Deliv. Formul. 2009, 3, 49-63; Saigal et al., Recent Pat. Drug Deliv. Formul. 2009, 3, 64-70; and Roy et al., J. Control Release 2009, 134, 74-80에 기재된 것을 포함하나 이에 한정되지는 않는다.Examples of modified release are described in U.S. Patent 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,958,458; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,270,798; 6,375,987; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,623,756; 6,699,500; 6,793,936; 6,827,947; 6,902,742; 6,958,161; 7,255,876; 7,416,738; 7,427,414; 7,485,322; Bussemer et al ., Crit. Rev. Ther. Drug Carrier Syst. 2001, 18, 433-458; Modified-Release Drug Delivery Technology, supra; Maroni et al ., Expert. Opin. Drug Deliv. 2005, 2855-871; Shi et al ., Expert Opin. Drug Deliv. 2005, 2, 1039-1058; Polymers in Drug Delivery; Ijeoma et al ., Eds.; CRC Press: 2006; Badawy et al ., J. Pharm. Sci. 2007, 9948-959; Conway, Recent Pat. Drug Deliv. Formul. 2008, 2, 1-8; Gazzaniga et al ., Eur. J. Pharm. Biopharm. 2008, 68, 11-18; Nagarwal et al ., Curr. Drug Deliv. 2008, 5282-289; Gallardo et al ., Pharm. Dev. Technol. 2008, 13413-423; Chrzanowski, AAPS PharmSciTech. 2008, 9635-638; Chrzanowski, AAPS PharmSciTech. 2008, 9639-645; Kalantzi et al ., Recent Pat. Drug Deliv. Formul. 2009, 3, 49-63; Saigal et al ., Recent Pat. Drug Deliv. Formul. 2009, 3, 64-70; and Roy et al, J. Control Release 2009, 134, 74 -. 80 include those described in but is not limited thereto.
본 발명은 상기 펩타이드를 포함하는 발모 촉진 또는 탈모 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for promoting hair growth or preventing or treating hair loss comprising the peptide.
본 발명의 펩타이드를 포함하는 발모 촉진 또는 탈모 예방 또는 치료용 약학적 조성물은 약학적으로 허용가능한 담체를 추가로 포함할 수 있으며, 담체와 함께 제제화될 수 있다. 본 발명에서 용어, '약학적으로 허용가능한 담체'란 생물체를 자극하지 않고 투여 화합물의 생물학적 활성 및 특성을 저해하지 않는 담체 또는 희석제를 말한다. 액상 용액으로 제제화되는 조성물에 있어서 허용되는 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로오스 용액, 말토덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다.The pharmaceutical composition for promoting hair growth or preventing or treating hair loss comprising the peptide of the present invention may further include a pharmaceutically acceptable carrier, and may be formulated together with the carrier. In the present invention, the term'pharmaceutically acceptable carrier' refers to a carrier or diluent that does not stimulate an organism and does not inhibit the biological activity and properties of the administered compound. Acceptable pharmaceutical carriers for compositions formulated as liquid solutions are sterilized and biocompatible, and include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers, and bacteriostatic agents may be added as necessary. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to prepare injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
본 발명의 약학적 조성물은 본 발명 펩타이드를 유효성분으로 포함하는 어떠한 제형으로도 적용가능하며, 경구용 또는 비경구용 제형으로 제조할 수 있다. 구체적인 제형으로서, 구강(oral), 직장(rectal), 비강(nasal), 국소(topical; 볼 및 혀 밑을 포함), 피하, 질(vaginal) 또는 비경구(parenteral; 근육 내, 피하 및 정맥 내를 포함) 투여에 적당한 것 또는 흡입(inhalation) 또는 주입(insufflation)에 의한 투여에 적당한 형태를 포함할 수 있으나, 반드시 이에 제한되지 않는다.The pharmaceutical composition of the present invention can be applied to any formulation containing the peptide of the present invention as an active ingredient, and can be prepared in an oral or parenteral formulation. Specific formulations include oral, rectal, nasal, topical (including cheek and sublingual), subcutaneous, vaginal or parenteral; intramuscular, subcutaneous and intravenous Including) may include a form suitable for administration or a form suitable for administration by inhalation or infusion, but is not limited thereto.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The effective dose level depends on the patient's disease type, severity, drug activity, drug sensitivity, time of administration, route of administration and rate of excretion, duration of treatment, factors including concurrent drugs and other factors well known in the medical field. Can be determined. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.
본 발명의 약학적 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 매우 다양하며, 적정한 투여량은 예를 들면 환자의 체내에 축적된 약물의 양 및/또는 사용되는 본 발명의 펩타이드의 구체적 효능정도에 따라 달라질 수 있다. 일반적으로 인비보(in vivo) 동물모델 및 인비트로(in vitro)에서 효과적인 것으로 측정된 EC50을 기초로 계산될 수 있으며, 예를 들면 체중 1kg당 0.01 μg 내지 1 g 일 수 있으며, 일별, 주별, 월별 또는 연별의 단위 기간으로, 단위 기간 당 일회 내지 수회 나누어 투여될 수 있으며, 또는 인퓨전 펌프를 이용하여 장기간 연속적으로 투여될 수 있다. 반복투여 횟수는 약물이 체내 머무는 시간, 체내 약물 농도 등을 고려하여 결정된다. 질환 치료 경과에 따라 치료가 된 후라도, 재발을 위해 조성물이 투여될 수 있다.The dosage of the pharmaceutical composition of the present invention varies greatly depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease, and the appropriate dosage is, for example. It may vary depending on the amount of drug accumulated in the patient's body and/or the specific efficacy of the peptide of the present invention used. In general, it can be calculated based on the EC50 measured to be effective in an in vivo animal model and in vitro , for example, 0.01 μg to 1 g per 1 kg of body weight, daily, weekly, In a monthly or annual unit period, the administration may be divided once or several times per unit period, or may be continuously administered for a long period of time using an infusion pump. The number of repeated administrations is determined in consideration of the duration of the drug and the concentration of the drug in the body. The composition may be administered for recurrence even after treatment is performed according to the course of the disease treatment.
본 발명의 약학적 조성물은 발모 촉진 또는 탈모 예방 또는 치료와 관련하여 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 또는 유효성분의 용해성 및/또는 흡수성을 유지/증가시키는 화합물을 추가로 함유할 수 있다. 또한 선택적으로, 화학치료제, 항염증제, 항바이러스제 및/또는 면역조절제 등을 추가로 포함할 수 있다.The pharmaceutical composition of the present invention may further contain at least one active ingredient exhibiting the same or similar function in relation to promoting hair growth or preventing or treating hair loss, or a compound that maintains/increases the solubility and/or absorption of the active ingredient. have. In addition, optionally, a chemotherapeutic agent, an anti-inflammatory agent, an antiviral agent and/or an immunomodulatory agent may be further included.
또한, 본 발명의 약학적 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캅셀, 멸균 주사용액, 멸균 분말의 형태일 수 있다.In addition, the pharmaceutical compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. The formulation may be in the form of a powder, granule, tablet, emulsion, syrup, aerosol, soft or hard gelatin capsule, sterile injectable solution, or sterile powder.
본 발명은 상기 펩타이드를 포함하는 발모 촉진 또는 탈모 예방 또는 개선용 화장료 조성물을 제공한다.The present invention provides a cosmetic composition for promoting hair growth or preventing or improving hair loss comprising the peptide.
본 발명의 조성물이 화장료 조성물로 제조되는 경우, 본 발명의 조성물은 상기 펩타이드 뿐만 아니라, 화장료 조성물에 통상적으로 이용되는 성분들을 포함할 수 있으며, 예컨대 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함할 수 있다.When the composition of the present invention is prepared as a cosmetic composition, the composition of the present invention may include not only the peptide, but also components commonly used in cosmetic compositions, such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and It may include conventional adjuvants such as perfume, and a carrier.
상기 조성물을 첨가할 수 있는 제품으로는, 예를 들어, 수렴화장수, 유연화장수, 영양화장수, 각종크림, 에센스, 팩, 파운데이션 등과 같은 화장품류와 클렌징, 세안제, 비누, 트리트먼트, 미용액 등이 있으나, 이에 제한되지 않는다.Products to which the composition can be added include cosmetics such as astringent lotion, softening lotion, nutrient lotion, various creams, essences, packs, and foundations, and cleansing, face wash, soap, treatments, and essences. , Is not limited thereto.
본 발명의 화장료 조성물의 구체적인 제형으로서는 스킨로션, 스킨 소프너, 스킨토너, 아스트린젠트, 로션, 밀크로션, 모이스처 로션, 영양로션, 맛사지크림, 영양크림, 모이스처 크림, 핸드크림, 에센스, 영양에센스, 팩, 비누, 샴푸, 클렌징폼, 클렌징로션, 클렌징크림, 바디로션, 바디클렌저, 유액, 립스틱, 메이컵 베이스, 파운데이션, 프레스파우더, 루스파우더, 아이섀도, 린스, 젤, 왁스, 미스트 등의 제형을 포함하나, 반드시 이에 제한되지 않는다.Specific formulations of the cosmetic composition of the present invention include skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, essence, nutrition essence, pack, Soap, shampoo, cleansing foam, cleansing lotion, cleansing cream, body lotion, body cleanser, emulsion, lipstick, makeup base, foundation, press powder, loose powder, eye shadow, conditioner, gel, wax, mist, etc. However, it is not necessarily limited thereto.
상기 조성물은 상기 펩타이드를 나노리포좀 내부에 함유시켜 안정화하여 제형화할 수도 있다. 상기 펩타이드를 나노리포좀 내부에 함유시키면, 펩타이드의 성분이 안정화되어 제형화시 침전형성, 변형 등의 문제점을 해결할 수 있으며, 성분의 용해도 및 경피흡수율을 높일 수 있어 상기 펩타이드로부터 기대되는 효능을 최대로 발현시킬 수 있다.The composition may be formulated by stabilizing the peptide by containing it inside the nanoliposome. When the peptide is contained inside the nanoliposome, the components of the peptide are stabilized and problems such as precipitation formation and transformation can be solved during formulation, and the solubility and transdermal absorption of the component can be increased to maximize the efficacy expected from the peptide. Can be expressed.
본 발명은 상기 펩타이드를 포함하는 발모 촉진 또는 탈모 예방 또는 개선용 건강기능식품을 제공한다.The present invention provides a health functional food for promoting hair growth or preventing or improving hair loss comprising the peptide.
본 발명의 건강기능식품은 말초신경질환 예방 또는 개선을 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태의 식품으로 제조 및 가공할 수 있다.The health functional food of the present invention can be manufactured and processed into foods in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing or improving peripheral nerve diseases.
본 발명의 건강기능식품이라 함은, 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 것일 수 있고, 이는 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The health functional food of the present invention may be manufactured and processed using raw materials or ingredients having useful functions for the human body according to the Health Functional Food Act No.6727, which is a nutrient for the structure and function of the human body. It refers to ingestion for the purpose of controlling or obtaining beneficial effects for health purposes such as physiological effects.
본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The health functional food of the present invention may contain ordinary food additives, and whether it is suitable as a food additive is determined according to the general rules and general test methods for food additives approved by the Food and Drug Administration, unless otherwise specified. It is judged according to standards and standards.
상기 식품 첨가물 공전에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 포함하나, 이에 제한되지 않는다.Examples of the items listed in the food additive process include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as reduced pigment, licorice extract, crystalline cellulose, high color pigment, and guar gum; It includes, but is not limited to, mixed preparations such as a sodium L-glutamate preparation, an alkali additive for noodles, a preservative preparation, and a tar color preparation.
예를 들어, 정제 형태의 건강기능식품은 본 발명의 펩타이드를 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수도 있다.For example, in the health functional food in the form of a tablet, a mixture obtained by mixing the peptide of the present invention with an excipient, a binder, a disintegrant, and other additives is granulated by a conventional method, and then a lubricant is added thereto and compression molding, or the mixture Can be directly compression molded. In addition, the health functional food in the form of a tablet may contain a mating agent or the like, if necessary.
캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의 펩타이드를 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 본 발명의 펩타이드를 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.Among the capsule-type health functional foods, hard capsules can be prepared by filling a mixture of the peptides of the present invention into an ordinary hard capsule with additives such as excipients, and soft capsules mixing the peptides of the present invention with additives such as excipients. One mixture can be prepared by filling a capsule base such as gelatin. The soft capsules may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary.
환 형태의 건강기능식품은 본 발명의 펩타이드와 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다.The cyclic health functional food can be prepared by molding a mixture of the peptide of the present invention, an excipient, a binding agent, a disintegrant, etc., by a conventionally known method, and can be coated with a white sugar or other coating agent if necessary. Alternatively, the surface may be coated with a material such as starch or talc.
과립 형태의 건강기능식품은 본 발명의 펩타이드와 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.The health functional food in the form of a granule can be prepared in granular form by a mixture of the peptide of the present invention, an excipient, a binder, a disintegrant, etc. by a conventionally known method, and may contain a flavoring agent, a flavoring agent, etc., if necessary. have.
상기 건강기능식품은 음료류, 육류, 초코렛, 식품류, 과자류. 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복함제 및 건강보조식품류 등일 수 있다.The health functional foods are beverages, meat, chocolate, foods, sweets. It may be pizza, ramen, other noodles, gums, candy, ice cream, alcoholic beverages, vitamin complexes, and health supplements.
상기 탈모란 정상적인 발모 수준을 벗어나 머리카락의 숫자가 일반적인 숫자보다 적은 경우라면 특별한 제한없이, 그 원인을 불문하고 이에 속할 수 있으며, 구체적으로는 장년성 탈모, 결발성 탈모, 신경성 탈모, 트리코틸로 마니아, 악성 탈모, 비강성 탈모, 지루성 탈모, 소아탈모, 남성형 탈모, 여성형 탈모, 원형 탈모 및 휴지기 탈모로 이루어진 군에서 선택된 적어도 하나일 수 있다.The hair loss may belong to any of the causes without particular limitation, as long as the number of hairs exceeds the normal hair growth level and the number of hairs is less than the general number, specifically, adult hair loss, intermittent hair loss, neurogenic hair loss, tricotillomania , Malignant hair loss, non-rigid hair loss, seborrheic hair loss, pediatric hair loss, male type alopecia, female type hair loss, circular alopecia and at least one selected from the group consisting of telogen hair loss.
보다 구체적으로, 상기 탈모는 원형 탈모, 유전성 안드로겐 탈모, 휴지기 탈모, 외상성 탈모, 발모벽, 압박성 탈모, 생장기 탈모, 비강성 탈모, 매독성 탈모, 지루 탈모, 증후성 탈모, 반흔성 탈모 및 선천성 탈모로 이루어진 군에서 선택된 적어도 하나일 수 있다.More specifically, the hair loss is circular hair loss, hereditary androgen hair loss, telogen hair loss, traumatic hair loss, hair growth wall, pressure hair loss, growth stage hair loss, non-rigid hair loss, syphilis hair loss, seborrheic hair loss, symptomatic hair loss, scarring hair loss and congenital hair loss. It may be at least one selected from the group consisting of hair loss.
상기 발모 촉진 또는 탈모 예방, 개선, 치료의 대상이 되는 모발로서 특별한 제한은 없으나, 구체적으로는 체모, 두발, 눈썹, 속눈썹, 음모, 코털, 수염으로 이루어진 군에서 적어도 하나일 수 있다.There is no particular limitation as hair that is the target of promoting hair growth or preventing, improving, or treating hair loss, but specifically, it may be at least one from the group consisting of body hair, hair, eyebrows, eyelashes, pubic hair, nose hair, and beard.
이하, 본 발명을 구체적으로 설명하기 위해 실시예를 들어 상세하게 설명하기로 한다. Hereinafter, examples will be described in detail to illustrate the present invention in detail.
이하, 서열번호 1의 아미노산 서열로 이루어진 펩타이드는 'DPS-4', 서열번호 2의 아미노산 서열로 이루어진 펩타이드는 'DPS-5', 서열번호 3의 아미노산 서열로 이루어진 펩타이드는 'DPS-8'로 각각 약칭될 수 있다.Hereinafter, the peptide consisting of the amino acid sequence of SEQ ID NO: 1 is'DPS-4', the peptide consisting of the amino acid sequence of SEQ ID NO: 2 is'DPS-5', and the peptide consisting of the amino acid sequence of SEQ ID NO: 3 is'DPS-8'. Each can be abbreviated.
실시예 1. 실험방법Example 1. Experimental method
본 발명의 실험동물로는 생후 40일 C57BL/6 생쥐를 ㈜나라바이오텍에서 구입하였으며 약 10일간 순화시킨 후 건강한 동물을 대상으로 실험하였다. 실험 기간 중 사육 환경 조건은 온도 21-25℃, 상대 습도 45-65%, 조명 시간은 12시간을 유지하였으며 사료와 음수를 자유 급여 하였다. As an experimental animal of the present invention, 40 days old C57BL/6 mice were purchased from Nara Biotech Co., Ltd., and after being purified for about 10 days, healthy animals were tested. During the experiment, the breeding environment conditions were kept at a temperature of 21-25℃, relative humidity of 45-65%, and lighting time for 12 hours. Feed and drinking water were fed freely.
모발이 휴지기에 들어선 생후 50일된 마우스의 등 피부 모발을 1차적으로 clipper을 이용하여 제모한 뒤, 바디네이처 로즈힙 오일 제모크림을 이용하여 2차 제모를 실시하였다. 제모 24시간 후 몸무게, 크기 등 특성이 유사한 마우스를 7마리씩 4군으로 나눈 후 개별적으로 사육하여 모발의 성장 정도를 측정하였다. The back skin hair of a 50-day-old mouse whose hair entered the resting period was first epilated using a clipper, and then a second epilation was performed using Body Nature Rosehip Oil Depilatory Cream. After 24 hours of hair removal, mice with similar characteristics such as weight and size were divided into 4 groups of 7 animals each, and then individually reared to measure the degree of hair growth.
서열번호 1의 아미노산 서열로 이루어진 펩타이드(DPS-4) 50 ㎍, 서열번호 2의 아미노산 서열로 이루어진 펩타이드(DPS-5) 50 ㎍, 서열번호 3의 아미노산 서열로 이루어진 펩타이드(DPS-8, EDCS) 각각을 dimethyl sulfoxide (Sigma)와 acetone (Merck), glycerol (Biopure)에 용해시킨 용액을 2주동안 같은 시간대에 한번씩 마우스 등 피부에 도포하였다. Dimethyl sulfoxide (Sigma)와 acetone (Merck), glycerol (Biopure)를 포함하는 용액을 음성대조군으로 설정하였으며, Dimethyl sulfoxide (Sigma)에 녹인 100 ㎍ tofacitinib citrate (Sigma)와 acetone (Merck), glycerol (Biopure)를 포함하는 용액을 양성대조군으로 두어 평가하였으며 도포 용액의 구성은 하기 표 1과 같다. 50 μg of a peptide consisting of the amino acid sequence of SEQ ID NO: 1 (DPS-4), 50 μg of a peptide consisting of the amino acid sequence of SEQ ID NO: 2 (DPS-5), and a peptide consisting of the amino acid sequence of SEQ ID NO: 3 (DPS-8, EDCS) A solution each of which was dissolved in dimethyl sulfoxide (Sigma), acetone (Merck), and glycerol (Biopure) was applied to the skin of a mouse once at the same time for 2 weeks. A solution containing dimethyl sulfoxide (Sigma), acetone (Merck), and glycerol (Biopure) was set as a negative control, and 100 ㎍ tofacitinib citrate (Sigma), acetone (Merck), and glycerol (Biopure) dissolved in dimethyl sulfoxide (Sigma). The solution containing the was evaluated by placing it as a positive control group, and the composition of the coating solution is shown in Table 1 below.
이후 제모 부위에서 7일, 14일 후 성장한 모발에 해당하는 마우스의 등 피부조직을 hematoxylin & eosin 염색하여 모발 성장주기와 모낭의 존재를 확인하였다. After that, the back skin tissue of the mouse corresponding to the hair grown after 7 and 14 days at the epilation site was stained with hematoxylin & eosin to confirm the hair growth cycle and the presence of hair follicles.
실시예 2. 발모 촉진 효능의 외관 평가Example 2. Evaluation of appearance of hair growth promoting efficacy
도 1은 음성대조군, 양성대조군, 서열번호 1의 아미노산 서열로 이루어진 펩타이드(DPS-4)를 처리한 실험군, 서열번호 2의 아미노산 서열로 이루어진 펩타이드(DPS-5) 및 서열번호 3의 아미노산 서열로 이루어진 펩타이드(DPS-8)를 처리한 실험군의 모발 성장 정도의 외관 사진을 확인할 수 있는데, 이를 참조하면, 음성대조군에 비하여 본 발명 펩타이드(DPS-4, DPS-5)를 처리한 경우 모발 성장 정도가 현저히 높음을 확인할 수 있고, Tofacitinib을 처리한 양성대조군에 비하여도 그 성장의 정도가 유의미하게 높음을 확인할 수 있다. 반면, 서열번호 3의 아미노산 서열로 이루어진 펩타이드(DPS-8)를 처리한 실험군의 경우, 음성대조군의 모발 성장 정도와 유의미한 차이를 보이지 못할 정도로 모발의 성장 정도가 극히 미미함을 확인할 수 있다.1 is a negative control group, a positive control group, an experimental group treated with a peptide consisting of the amino acid sequence of SEQ ID NO: 1 (DPS-4), a peptide consisting of the amino acid sequence of SEQ ID NO: 2 (DPS-5) and the amino acid sequence of SEQ ID NO: 3 You can see the appearance picture of the hair growth degree of the experimental group treated with the formed peptide (DPS-8). Referring to this, the degree of hair growth when the peptides of the present invention (DPS-4, DPS-5) were treated compared to the negative control group. It can be seen that is remarkably high, and it can be seen that the degree of growth is significantly higher than that of the positive control group treated with Tofacitinib. On the other hand, in the case of the experimental group treated with the peptide (DPS-8) consisting of the amino acid sequence of SEQ ID NO: 3, it can be confirmed that the degree of growth of the hair is very insignificant so that no significant difference from the degree of hair growth of the negative control group is shown.
실시예 3. 발모 촉진 효능의 조직학적 평가Example 3. Histological evaluation of hair growth promoting efficacy
도 2는 음성대조군, 양성대조군, 서열번호 1의 아미노산 서열로 이루어진 펩타이드(DPS-4)를 처리한 실험군, 서열번호 2의 아미노산 서열로 이루어진 펩타이드(DPS-5) 및 서열번호 3의 아미노산 서열로 이루어진 펩타이드(DPS-8)를 처리한 실험군의 모발 성장 정도를 조직학적으로 관찰한 결과를 확인할 수 있는데, 이를 참조하면, 음성대조군에 비하여 본 발명 펩타이드(DPS-4, DPS-5)를 처리한 경우, 염색된 부위에서 성장된 모발의 길이와 두께의 종합적인 측면에서 그 성장 정도가 대조군들에 비해 유의미하게 높음을 확인할 수 있다. 그러나, 서열번호 3의 아미노산 서열로 이루어진 펩타이드(DPS-8)를 처리한 실험 군의 경우, 음성대조군의 성장 정도와 유의미한 차이를 보이지 못할 정도로 모발의 성장 정도가 극히 미미함을 확인할 수 있다.2 is a negative control group, a positive control group, an experimental group treated with a peptide consisting of the amino acid sequence of SEQ ID NO: 1 (DPS-4), a peptide consisting of the amino acid sequence of SEQ ID NO: 2 (DPS-5) and the amino acid sequence of SEQ ID NO: 3 The result of histological observation of the hair growth degree of the experimental group treated with the composed peptide (DPS-8) can be confirmed. Referring to this, compared to the negative control group, the peptides of the present invention (DPS-4, DPS-5) were treated. In this case, it can be seen that the degree of growth is significantly higher than that of the control group in terms of the overall length and thickness of the hair grown in the dyed area. However, in the case of the experimental group treated with the peptide (DPS-8) consisting of the amino acid sequence of SEQ ID NO: 3, it can be confirmed that the degree of growth of the hair is very insignificant such that no significant difference from the growth degree of the negative control group is shown.
상기의 실험은 본 발명 펩타이드의 우수한 발모 촉진 효능을 in vivo 상에서 확인한 것으로서, 이를 우수한 발모 촉진제로 사용할 수 있음을 암시케 한다.The above experiment confirmed the excellent hair growth promoting effect of the peptide of the present invention in vivo , suggesting that it can be used as an excellent hair growth promoter.
<110> GENECELLPHARM
<120> COMPOSITION FOR PROMOTING HAIR GROWTH
<130> 18P10020
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<220>
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Cys Leu Glu Tyr Phe Lys Gly Ala Ile Pro Leu Arg Lys
1 5 10
<210> 2
<211> 11
<212> PRT
<213> Artificial Sequence
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Lys Arg Val Lys Asn Ala Val Lys Tyr Leu Gln
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<212> PRT
<213> Artificial Sequence
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<223> DPS-8
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Glu Asp Cys Ser
1
<110> GENECELLPHARM
<120> COMPOSITION FOR PROMOTING HAIR GROWTH
<130> 18P10020
<160> 3
<170> KoPatentIn 3.0
<210> 1
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
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Cys Leu Glu Tyr Phe Lys Gly Ala Ile Pro
Claims (5)
Peptide consisting of the sequence of SEQ ID NO: 2.
A composition for promoting hair growth comprising a peptide consisting of the sequence of SEQ ID NO: 1 or 2.
A pharmaceutical composition for promoting hair growth comprising a peptide consisting of the sequence of SEQ ID NO: 1 or 2.
Cosmetic composition for promoting hair growth comprising a peptide consisting of the sequence of SEQ ID NO: 1 or 2.
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Int. J. Mol. Sci., Vol. 12, pp. 3740-3756(2011.06.08.)* |
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