KR102586379B1 - Adhesive composition for patch capable of controlling drug delivery and patch using the composition - Google Patents
Adhesive composition for patch capable of controlling drug delivery and patch using the composition Download PDFInfo
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- KR102586379B1 KR102586379B1 KR1020210092811A KR20210092811A KR102586379B1 KR 102586379 B1 KR102586379 B1 KR 102586379B1 KR 1020210092811 A KR1020210092811 A KR 1020210092811A KR 20210092811 A KR20210092811 A KR 20210092811A KR 102586379 B1 KR102586379 B1 KR 102586379B1
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J133/00—Adhesives based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Adhesives based on derivatives of such polymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J11/00—Features of adhesives not provided for in group C09J9/00, e.g. additives
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J7/00—Adhesives in the form of films or foils
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Abstract
본 발명은 약물전달 조절이 가능한 패치용 점착제 조성물 및 그 조성물을 이용한 패치에 관한 것으로, 더욱 상세하게는 상기 패치용 점착제 조성물은 메톡시폴리에틸렌글리콜 모노아크릴레이트와 탄소수가 16 이상인 알킬기를 갖는 아크릴이 함유된 아크릴 혼합물, 중합개시제 및 용제로 이루어지며, 상기 패치는 상기의 성분으로 이루어지는 패치용 점착제 조성물에 약물 및 경화제를 혼합하여 제조된다.
상기의 성분으로 이루어지는 약물전달 조절이 가능한 패치용 점착제 조성물 로 제조된 패치는 융점(Tm)과 결정화온도(Tc)를 나타내며, 소수성과 친수성을 동시에 나타내는 양친매성 점착제가 사용되어 원활한 약물 혼용성 및 약물전달 조절이 가능하다.The present invention relates to an adhesive composition for a patch capable of controlling drug delivery and a patch using the composition. More specifically, the adhesive composition for a patch contains methoxypolyethylene glycol monoacrylate and acrylic having an alkyl group having 16 or more carbon atoms. It is composed of an acrylic mixture, a polymerization initiator, and a solvent, and the patch is manufactured by mixing a drug and a curing agent with an adhesive composition for a patch composed of the above components.
The patch manufactured with the adhesive composition for patches capable of controlling drug delivery consisting of the above ingredients exhibits melting point (Tm) and crystallization temperature (Tc), and an amphipathic adhesive that exhibits both hydrophobic and hydrophilic properties is used to ensure smooth drug miscibility and drug mixing. Delivery can be controlled.
Description
본 발명은 약물전달 조절이 가능한 패치용 점착제 조성물 및 그 조성물을 이용한 패치에 관한 것으로, 더욱 상세하게는 융점(Tm)과 결정화온도(Tc)를 나타내며, 소수성과 친수성을 동시에 나타내는 양친매성 점착제가 사용되어 원활한 약물 혼용성 및 약물전달 조절이 가능한 패치를 제공하는 약물전달 조절이 가능한 패치용 점착제 조성물 및 그 조성물을 이용한 패치에 관한 것이다.The present invention relates to an adhesive composition for a patch capable of controlling drug delivery and a patch using the composition, and more specifically, to the use of an amphipathic adhesive that exhibits a melting point (Tm) and a crystallization temperature (Tc) and is both hydrophobic and hydrophilic. It relates to an adhesive composition for a patch capable of controlling drug delivery, which provides a patch capable of smooth drug miscibility and drug delivery control, and a patch using the composition.
일반적으로, 습포제 등의 함수형 피부패치는 소듐 폴리아크릴레이트, 폴리아크릴산, 아크릴산-소듐 아크릴레이트 공중합체, 가교 폴리아크릴산 등과 알루미늄 화합물의 이온성 가교에 의해 형성된다. 이온성 가교가 불충분한 경우에는, 점착층이 지지체인 부직포 등에 스며나올 뿐만 아니라, 피부에 "접착제 잔류"가 일어나 환자에게 불쾌감을 준다. 또한, 과도한 가교는 점착층을 경화시켜서 점착성이 열화되어, 피부로부터의 이탈 또는 약품의 경피흡수의 악화 등의 문제를 초래한다. 따라서, 알루미늄 화합물과 아크릴레이트계 폴리머 사이의 가교는 품질의 관점에서 매우 중요하다.Generally, hydrous skin patches such as poultices are formed by ionic cross-linking of aluminum compounds with sodium polyacrylate, polyacrylic acid, acrylic acid-sodium acrylate copolymer, cross-linked polyacrylic acid, etc. If ionic crosslinking is insufficient, not only does the adhesive layer ooze out into the support, such as a non-woven fabric, but also “adhesive residue” occurs on the skin, causing discomfort to the patient. In addition, excessive crosslinking hardens the adhesive layer and the adhesiveness deteriorates, resulting in problems such as detachment from the skin or worsening of transdermal absorption of the drug. Therefore, crosslinking between the aluminum compound and the acrylate-based polymer is very important from a quality standpoint.
현재 시중에 유통 판매되고 있는 대부분의 파스와 같은 패치나 스포츠 테이프는 저 자극성 점착제에 약물을 혼합하여 제조되는데, 상기의 방법으로 제조되는 패치나 스포츠 테이프는 약물의 방출 속도를 제어 할 수 없고, 박리시 통증 유발이나 격렬한 운동 등으로 체온이 상승하게 되면 들뜸 및 박리 등이 빈번하게 발생되는 문제점이 있으며, 국내 제품 뿐만 아니라 해외 판매되는 패치나 스포츠 테이프의 대부분도 동일한 거동을 나타내는 문제점이 있었다.Most patches and sports tapes, such as patches, currently sold on the market are manufactured by mixing drugs with low-irritant adhesives. However, patches or sports tapes manufactured using the above method cannot control the release speed of the drug and are prone to peeling. There is a problem that lifting and peeling frequently occur when the body temperature rises due to pain or intense exercise, and most of the patches and sports tapes sold overseas as well as domestic products have the same behavior.
또한, 종래에 판매되고 있는 파스와 같은 패치제는 수십년간 변하지 않은 단순 약물 전달 방식이 사용되어 약물의 첨가량으로 피부전달 양을 결정하기 때문에 피부 조건에 따라 과량 또는 미량의 약물이 전달되는 경우기 빈번하게 발생하여 이로 인한 피부트러블 등과 같은 부작용이 항상 존재하는 문제점이 있었다.In addition, patches such as patches sold conventionally use a simple drug delivery method that has not changed for decades and determine the amount of drug delivered to the skin by the amount of drug added, so excessive or trace amounts of drug are often delivered depending on skin conditions. There was a problem that side effects such as skin troubles were always present.
본 발명의 목적은 융점(Tm)과 결정화온도(Tc)를 나타내며, 소수성과 친수성을 동시에 나타내는 양친매성 점착제가 사용되어 원활한 약물 혼용성 및 약물전달 조절이 가능한 패치를 제공하는 약물전달 조절이 가능한 패치용 점착제 조성물 및 그 조성물을 이용한 패치를 제공하는 것이다.The purpose of the present invention is to provide a patch capable of controlling drug delivery, which provides a patch capable of smooth drug miscibility and drug delivery control by using an amphipathic adhesive that exhibits melting point (Tm) and crystallization temperature (Tc) and is both hydrophobic and hydrophilic. To provide an adhesive composition and a patch using the composition.
본 발명의 목적은 메톡시폴리에틸렌글리콜 모노아크릴레이트와 탄소수가 16 이상인 알킬기를 갖는 아크릴이 함유된 아크릴 혼합물, 중합개시제 및 용제로 이루어지는 것을 특징으로 하는 약물전달 조절이 가능한 패치용 점착제 조성물을 제공함에 의해 달성된다.The object of the present invention is to provide an adhesive composition for a patch capable of controlling drug delivery, which consists of an acrylic mixture containing methoxypolyethylene glycol monoacrylate and acrylic with an alkyl group having 16 or more carbon atoms, a polymerization initiator, and a solvent. achieved.
본 발명의 바람직한 특징에 따르면, 상기 약물전달 조절이 가능한 패치용 점착제 조성물은 메톡시폴리에틸렌글리콜 모노아크릴레이트와 탄소수가 16 이상인 알킬기를 갖는 아크릴이 함유된 아크릴 혼합물 100 중량부, 중합개시제 0.01 내지 0.1 중량부 및 용제 적량으로 이루어지는 것으로 한다.According to a preferred feature of the present invention, the adhesive composition for a patch capable of controlling drug delivery is 100 parts by weight of an acrylic mixture containing methoxypolyethylene glycol monoacrylate and acrylic having an alkyl group having 16 or more carbon atoms, and 0.01 to 0.1 weight of a polymerization initiator. It shall be composed of parts and solvents in appropriate amounts.
본 발명의 더 바람직한 특징에 따르면, 상기 아크릴 혼합물은 메톡시폴리에틸렌글리콜 모노아크릴레이트의 함량이 5 내지 50 중량%인 것으로 한다.According to a more preferred feature of the present invention, the acrylic mixture contains 5 to 50% by weight of methoxypolyethylene glycol monoacrylate.
본 발명의 더욱 바람직한 특징에 따르면, 상기 탄소수가 16 이상인 알킬기를 갖는 아크릴은 세틸아크릴레이트(Cetyl acrylate), 스테아릴아크릴레이트(Stearyl acrylate) 및 베헤닐아크릴레이트(Behenyl acrylate)로 이루어진 그룹에서 선택된 하나 이상으로 이루어지는 것으로 한다.According to a more preferred feature of the present invention, the acrylic having an alkyl group having 16 or more carbon atoms is one selected from the group consisting of cetyl acrylate, stearyl acrylate, and behenyl acrylate. The above shall be accomplished.
또한, 본 발명의 목적은 상기 약물전달 조절이 가능한 패치용 점착제 조성물 100 중량부, 약물 10 내지 30 중량부 및 경화제 0.3 내지 3 중량부로 이루어지는 것을 특징으로 하는 약물전달 조절이 가능한 패치를 제공함에 의해서도 달성될 수 있다.In addition, the object of the present invention is achieved by providing a patch capable of controlling drug delivery, characterized in that it consists of 100 parts by weight of the adhesive composition for the patch capable of controlling drug delivery, 10 to 30 parts by weight of the drug, and 0.3 to 3 parts by weight of the curing agent. It can be.
본 발명에 따른 약물전달 조절이 가능한 패치용 점착제 조성물 및 그 조성물을 이용한 패치는 융점(Tm)과 결정화온도(Tc)를 나타내며, 소수성과 친수성을 동시에 나타내는 양친매성 점착제가 사용되어 원활한 약물 혼용성 및 약물전달 조절이 가능한 패치를 제공하는 탁월한 효과를 나타낸다.The adhesive composition for a patch capable of controlling drug delivery according to the present invention and the patch using the composition exhibit a melting point (Tm) and a crystallization temperature (Tc), and an amphipathic adhesive that exhibits both hydrophobicity and hydrophilicity is used to ensure smooth drug miscibility and stability. It has an excellent effect in providing a patch that can control drug delivery.
도 1은 합성예 1을 통해 제조된 약물전달 조절이 가능한 패치용 점착제 조성물의 시차주사열량(DSC) 측정결과를 나타낸 그래프이다.
도 2는 합성예 2를 통해 제조된 약물전달 조절이 가능한 패치용 점착제 조성물의 시차주사열량(DSC) 측정결과를 나타낸 그래프이다.
도 3은 합성예 3을 통해 제조된 패치용 점착제 조성물의 시차주사열량(DSC) 측정결과를 나타낸 그래프이다.
도 4는 본 발명의 실시예 1 내지 2 및 비교예 1 내지 2를 통해 제조된 패치의 시간에 흐름에 따른 약물 방출량을 측정하여 나타낸 그래프이다.Figure 1 is a graph showing the differential scanning calorimetry (DSC) measurement results of the adhesive composition for a patch capable of controlling drug delivery prepared through Synthesis Example 1.
Figure 2 is a graph showing the differential scanning calorimetry (DSC) measurement results of the adhesive composition for a patch capable of controlling drug delivery prepared through Synthesis Example 2.
Figure 3 is a graph showing the differential scanning calorimetry (DSC) measurement results of the adhesive composition for patches prepared through Synthesis Example 3.
Figure 4 is a graph showing the drug release amount measured over time in patches manufactured through Examples 1 to 2 and Comparative Examples 1 to 2 of the present invention.
이하에는, 본 발명의 바람직한 실시예와 각 성분의 물성을 상세하게 설명하되, 이는 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 발명을 용이하게 실시할 수 있을 정도로 상세하게 설명하기 위한 것이지, 이로 인해 본 발명의 기술적인 사상 및 범주가 한정되는 것을 의미하지는 않는다.Below, preferred embodiments of the present invention and the physical properties of each component are described in detail, but are intended to be described in detail so that those skilled in the art can easily practice the invention. This does not mean that the technical idea and scope of the present invention are limited.
본 발명에 따른 약물전달 조절이 가능한 패치용 점착제 조성물은 메톡시폴리에틸렌글리콜 모노아크릴레이트와 탄소수가 16 이상인 알칼(Alkyl)기를 갖는 아크릴이 함유된 아크릴 혼합물, 중합개시제 및 용제로 이루어지며, 메톡시폴리에틸렌글리콜 모노아크릴레이트와 탄소수가 16 이상인 알킬기를 갖는 아크릴이 함유된 아크릴 혼합물 100 중량부, 중합개시제 0.01 내지 0.1 중량부 및 용제 50 내지 150 중량부로 이루어지는 것이 바람직하다.The adhesive composition for a patch capable of controlling drug delivery according to the present invention is composed of methoxypolyethylene glycol monoacrylate, an acrylic mixture containing acrylic with an alkyl group having 16 or more carbon atoms, a polymerization initiator, and a solvent, and methoxypolyethylene It is preferably composed of 100 parts by weight of an acrylic mixture containing glycol monoacrylate and an acrylic having an alkyl group having 16 or more carbon atoms, 0.01 to 0.1 parts by weight of a polymerization initiator, and 50 to 150 parts by weight of a solvent.
온도 감응성 고분자는 외부 온도에 따라서 그 성질이 바뀌는 고분자로서 특정 온도에서 가역적인 상전이가 일어난다. 이러한 상전이를 약물 전달 시스템에 이용하기 위해서 본 발명에서는 융점(Tm)과 결정화온도(Tc)를 조절함으로서 약물전달 조절을 용이하게 할 수 있다. 좀더 원활한 약물 혼용성 및 약물전달 조절을 용이하게 하기위해 소수성과 친수성 고분자의 특성을 동시에 갖는 양친매성 점착제를 제조하여 양친매성 점착제의 소수성기와 친수성기의 상호작용을 이용하여 다양한 약물을 사용할 수 있으며 약물을 효율적으로 방출할 수 있다.Temperature-sensitive polymers are polymers whose properties change depending on the external temperature, and a reversible phase transition occurs at a specific temperature. In order to use this phase transition in a drug delivery system, the present invention can facilitate drug delivery control by adjusting the melting point (Tm) and crystallization temperature (Tc). In order to facilitate smoother drug miscibility and control of drug delivery, an amphiphilic adhesive that has both hydrophobic and hydrophilic polymer properties is manufactured, and various drugs can be used by utilizing the interaction between the hydrophobic and hydrophilic groups of the amphipathic adhesive. It can be released efficiently.
점착제에 융점과 결정화온도를 갖게 하기 위해서 상온에서 결정성을 갖는 모노머를 도입하였는데, 상온에서 결정성이 있는 모노머는 아래 화학식 1에 나타낸 것과 같은 탄소수 16이상의 직쇄상 알킬기를 갖는 것이 바람직한데, 아크릴레이트 단량체로는 세틸아크릴레이트(Cetyl acrylate), 스테아릴아크릴레이트(Stearyl acrylate) 및 베헤닐아크릴레이트(Behenyl acrylate) 등으로 이루어지는 것이 바람직하다.In order to provide the adhesive with a melting point and crystallization temperature, a monomer with crystallinity at room temperature was introduced. The monomer with crystallinity at room temperature preferably has a straight-chain alkyl group of 16 or more carbon atoms as shown in Formula 1 below, acrylate The monomer preferably consists of cetyl acrylate, stearyl acrylate, and behenyl acrylate.
<화학식 1><Formula 1>
또한, 상기에 나열된 탄소수 16이상의 직쇄상 알킬기를 갖는 아크릴 모노머는 단일 또는 두개 이상을 혼합하여 사용할 수 있으며 이들의 조합으로 점착제의 융점과 결정화온도를 조절 할 수 있다.In addition, the acrylic monomers listed above having a linear alkyl group of 16 or more carbon atoms can be used singly or in combination of two or more, and the melting point and crystallization temperature of the adhesive can be adjusted by their combination.
점착제의 융점은 20 내지 45℃ 범위가 적당한데, 점착제의 융점이 45℃를 초과하게 되면 체온에서의 방출 속도는 더 느리게 조절할 수 있지만 점착제 자체의 결정성으로 인해 점착력 저하의 원인이 된다. 또한, 점착제의 결정화 온도가 25℃미만이면 점착력은 상승할 수 있으나 일반 시중에서 판매되는 점착제와 방출 속도에서 큰차이를 나타내지 못한다.The appropriate melting point of the adhesive is in the range of 20 to 45 ℃. If the melting point of the adhesive exceeds 45 ℃, the release rate at body temperature can be adjusted more slowly, but the crystallinity of the adhesive itself causes a decrease in adhesive strength. Additionally, if the crystallization temperature of the adhesive is less than 25°C, the adhesive strength may increase, but there is no significant difference in release rate from commercially available adhesives.
또한, 본 발명에서는 의료 패치제와 스포츠 테이프 등 다양한 종류의 약물에서 친화성이 좋도록 점착제 폴리머 사이드 체인(chain)에 친수성기를 도입하여 소수성과 친수성을 모두 갖는 양친화적(amphiphilic)인 특징을 갖게 하여 온도에 따라 그 형태를 바꾸는데 좀더 원활한 성질을 나타내도록 하였다.In addition, in the present invention, a hydrophilic group is introduced into the side chain of the adhesive polymer to improve affinity with various types of drugs such as medical patches and sports tapes, so that it has amphiphilic characteristics with both hydrophobicity and hydrophilicity. It changes its shape depending on the temperature and exhibits smoother properties.
친수성기를 갖는 모노머로서는 아래 화학식 2 또는 3의 구조를 나타내는 메톡시폴리에틸렌글리콜 모노아크릴레이트{Methoxy polyethylene glycol mono (Meth)Acrylate, MPEGA}모노머를 사용하였다.As a monomer having a hydrophilic group, a methoxy polyethylene glycol mono (Meth) Acrylate, MPEGA monomer having the structure of formula 2 or 3 below was used.
<화학식 2><Formula 2>
<화학식 3><Formula 3>
이때, 상기 메톡시폴리에틸렌글리콜 모노아크릴레이트의 함량은 아크릴 혼합물에서 5 내지 50 중량%를 차지하는데, 메톡시폴리에틸렌글리콜 모노아크릴레이트 함량이 5 중량% 미만이면 충분한 친수성기를 확보할 수 없고 메톡시폴리에틸렌글리콜 모노아크릴레이트의 함량이 50 중량%를 초과하게 되면 친수성은 충분하나 점착제의 점착력이 저하된다.At this time, the content of the methoxypolyethylene glycol monoacrylate accounts for 5 to 50% by weight in the acrylic mixture. If the methoxypolyethylene glycol monoacrylate content is less than 5% by weight, sufficient hydrophilic groups cannot be secured and methoxypolyethylene glycol If the content of monoacrylate exceeds 50% by weight, the hydrophilicity is sufficient, but the adhesive strength of the adhesive decreases.
또한, 본 발명에 따른 약물전달 조절이 가능한 패치은 상기 약물전달 조절이 가능한 패치용 점착제 조성물 100 중량부, 약물 10 내지 30 중량부 및 경화제 0.3 내지 3 중량부로 이루어지는데, 상기의 성분으로 이루어진 혼합물을 이형지에 도포하고 건조한 후에 숙성하는 과정을 통해 제조된다.In addition, the patch capable of controlling drug delivery according to the present invention consists of 100 parts by weight of the adhesive composition for the patch capable of controlling drug delivery, 10 to 30 parts by weight of the drug, and 0.3 to 3 parts by weight of the curing agent, and the mixture of the above components is mixed with a release paper. It is manufactured through a process of applying it to a surface, drying it, and then maturing it.
이때, 상기 약물의 양과 종류는 특별히 한정되지 않고 다양한 성분이 사용될 수 있으나, 일예로 패치나 스포츠 테이프의 적용용도에 맞게 진통과 염증을 완화하는 특성을 나타내는 케토프로펜을 사용할 수 있으며, 상기 케토프로펜은 질량농도가 20%인 것을 사용하는 것이 바람직하나 이에 한정하지는 않는다. 이때, 케토프로펜을 희석하는데 사용되는 희석제는 특별하 한정되지 않지만 에틸아세테이트를 사용할 수 있다.At this time, the amount and type of the drug are not particularly limited and various ingredients may be used, but for example, ketoprofen, which exhibits pain-relieving and inflammation-relieving properties suitable for application as a patch or sports tape, can be used, and the ketopro It is desirable to use a pen with a mass concentration of 20%, but it is not limited to this. At this time, the diluent used to dilute ketoprofen is not particularly limited, but ethyl acetate can be used.
또한, 상기 경화제는 0.3 내지 3 중량부가 함유되며, 경화제의 성분은 특별히 한정되지 않고 다양한 성분을 사용할 수 있으나, 일 예로 4관능 에폭시 경화제를 사용할 수 있다.In addition, the curing agent contains 0.3 to 3 parts by weight, and the components of the curing agent are not particularly limited and various components can be used. For example, a tetra-functional epoxy curing agent can be used.
이하에서는, 본 발명에 따른 약물전달 조절이 가능한 패치용 점착제 조성물 및 그 조성물을 이용한 패치의 제조방법과 그 제조방법으로 제조된 패치용 점착제 및 패치의 물성을 실시예를 들어 설명하기로 한다.Hereinafter, the adhesive composition for a patch capable of controlling drug delivery according to the present invention, the manufacturing method of a patch using the composition, and the physical properties of the adhesive for the patch and the patch manufactured by the manufacturing method will be described by way of examples.
<합성예 1><Synthesis Example 1>
교반기, 환류 냉각기, 질소 도입관, 온도계 및 적하조를 구비한 반응장치를 준비하고, 2-에틸헥실아크릴레이트(2-Ethyl hexyl acrylate) 단량체 50g, 스테아릴아크릴레이트(Stearyl acrylate) 단량체 30g, 메톡시폴리에틸렌글리콜(400) 모노 아크릴레이트(Methoxy polyethylene glycol(400) mono acrylate) 단량체 15g, 아크릴산 5g으로 이루어진 아크릴 혼합물(I) 100g을 제조하고, 제조된 상기 아크릴 혼합물 중 30g과 중합 개시제(AIBN,Azobis isobutyronitrile) 0.05g 및 용제(아세트산 에틸) 적량을 혼합하여 제1혼합물을 제조한 후에 80℃로 가열하여 반응 개시를 확인하고, 중합 개시제(AIBN) 0.05g 및 용제(아세트산 에틸) 적량을 혼합하여 제2혼합물을 제조하고, 상기 제1혼합물에 상기 아크릴 혼합물(I)의 나머지 70g과 상기 제2혼합물을 각각 1시간 동안 적하하고 환류상태를 유지한채 5시간 동안 반응시키고, 반응 종료 후 냉각하여 아세트산 에틸 30g을 혼합하여 희석하는 과정을 통해 약물전달 조절이 가능한 패치용 점착제 조성물을 제조하였다.Prepare a reaction device equipped with a stirrer, reflux cooler, nitrogen introduction tube, thermometer, and dropping tank, and add 50 g of 2-Ethyl hexyl acrylate monomer, 30 g of stearyl acrylate monomer, and 100 g of an acrylic mixture (I) consisting of 15 g of Methoxy polyethylene glycol (400) mono acrylate monomer and 5 g of acrylic acid was prepared, and 30 g of the acrylic mixture prepared was mixed with a polymerization initiator (AIBN, Azobis). After preparing the first mixture by mixing 0.05 g of isobutyronitrile) and an appropriate amount of solvent (ethyl acetate), it was heated to 80°C to confirm the initiation of reaction, and then mixed with 0.05 g of polymerization initiator (AIBN) and an appropriate amount of solvent (ethyl acetate) to prepare the first mixture. 2 mixtures were prepared, the remaining 70 g of the acrylic mixture (I) and the second mixture were added dropwise to the first mixture over 1 hour each, reacted for 5 hours while maintaining reflux, and cooled after completion of the reaction to form ethyl acetate. An adhesive composition for a patch capable of controlling drug delivery was prepared by mixing and diluting 30g.
이때, 합성예 1을 통해 제조된 약물전달 조절이 가능한 패치용 점착제 조성물의 불휘발분은 40% 였다.At this time, the non-volatile content of the adhesive composition for a patch capable of controlling drug delivery prepared through Synthesis Example 1 was 40%.
<합성예 2><Synthesis Example 2>
상기 합성예 1과 동일하게 진행하되, 2-에틸헥실아크릴레이트(2-Ethyl hexyl acrylate) 단량체 50g, 베헤닐 아크릴레이트(Behenyl acrylate) 단량체 30g, 메톡시폴리에틸렌글리콜(400) 모노 아크릴레이트(Methoxy polyethylene glycol(400) mono acrylate) 단량체 15g 및 아크릴산 5g으로 이루어진 아크릴 혼합물(I)을 사용하여 약물전달 조절이 가능한 패치용 점착제 조성물을 제조하였다.Proceed in the same manner as Synthesis Example 1, except that 50 g of 2-Ethyl hexyl acrylate monomer, 30 g of Behenyl acrylate monomer, and methoxy polyethylene glycol (400) monomer were added. An adhesive composition for a patch capable of controlling drug delivery was prepared using an acrylic mixture (I) consisting of 15 g of glycol (400) mono acrylate) monomer and 5 g of acrylic acid.
이때, 합성예 2를 통해 제조된 약물전달 조절이 가능한 패치용 점착제 조성물의 불휘발분은 40% 였다.At this time, the non-volatile content of the adhesive composition for a patch capable of controlling drug delivery prepared through Synthesis Example 2 was 40%.
<합성예 3><Synthesis Example 3>
상기 합성예 1과 동일하게 진행하되, 2-에틸헥실아크릴레이트(2-Ethyl hexyl acrylate) 단량체 65g, n-부틸아크릴레이트(n-Butyl acrylate) 단량체 30g 및 아크릴산 5g으로 이루어진 아크릴 혼합물(I)을 사용하여 패치용 점착제 조성물을 제조하였다.Proceed in the same manner as Synthesis Example 1, except that an acrylic mixture (I) consisting of 65 g of 2-Ethyl hexyl acrylate monomer, 30 g of n-Butyl acrylate monomer, and 5 g of acrylic acid was prepared. An adhesive composition for a patch was prepared using this method.
상기 합성예 3을 통해 제조된 패치용 점착제 조성물의 불휘발분은 40% 였다.The non-volatile content of the adhesive composition for patches prepared through Synthesis Example 3 was 40%.
<실시예 1><Example 1>
상기 합성예 1을 통해 제조된 약물전달 조절이 가능한 패치용 점착제 조성물 100g, 약물(질량농도가 20%인 케토프로펜) 20.27g 및 경화제(4관능 에폭시 경화제) 1g을 혼합하여 제조된 혼합물을 50㎛ 두께의 PET 이형지(캐리어로 25㎛ 두께의 PET를 사용)에 20㎛의 두께로 도포하고 110℃의 온도에서 2분 동안 건조하고, 60℃의 온도에서 48시간 동안 숙성하여 약물전달 조절이 가능한 패치를 제조하였다.A mixture prepared by mixing 100 g of the adhesive composition for a patch capable of controlling drug delivery prepared through Synthesis Example 1, 20.27 g of the drug (ketoprofen with a mass concentration of 20%), and 1 g of the curing agent (tetrafunctional epoxy curing agent) was mixed for 50 minutes. It is applied at a thickness of 20㎛ on ㎛ thick PET release paper (25㎛ thick PET is used as a carrier), dried at 110℃ for 2 minutes, and aged at 60℃ for 48 hours to control drug delivery. A patch was prepared.
<실시예 2><Example 2>
상기 실시예 1과 동일하게 진행하되, 상기 합성예 2를 통해 제조된 약물전달 조절이 가능한 패치용 점착제 조성물을 사용하여 약물전달 조절이 가능한 패치를 제조하였다.Proceeding in the same manner as in Example 1, a patch capable of controlling drug delivery was manufactured using the adhesive composition for a patch capable of controlling drug delivery prepared through Synthesis Example 2.
<비교예 1><Comparative Example 1>
상기 실시예 1과 동일하게 진행하되, 상기 합성예 3을 통해 제조된 약물전달 조절이 가능한 패치용 점착제 조성물을 사용하여 약물전달 조절이 가능한 패치를 제조하였다.A patch capable of controlling drug delivery was prepared in the same manner as in Example 1, but using the adhesive composition for a patch capable of controlling drug delivery prepared in Synthesis Example 3.
<비교예 2><Comparative Example 2>
시판품(케토톱).Commercial product (Ketotop).
상기 합성예 1 내지 3을 통해 제조된 패치용 점착제 조성물의 DSC측정결과를 아래 표 1 및 아래 도 1 내지 3에 나타내었다.The DSC measurement results of the adhesive compositions for patches prepared through Synthesis Examples 1 to 3 are shown in Table 1 below and Figures 1 to 3 below.
{단, 아래 도 1은 합성예 1을 통해 제조된 약물전달 조절이 가능한 패치용 점착제 조성물의 DSC 측정결과이며, 도 2는 합성예 2를 통해 제조된 약물전달 조절이 가능한 패치용 점착제 조성물의 DSC 측정결과이고, 도 3은 합성예 3을 통해 제조된 패치용 점착제 조성물의 DSC 측정결과이다.}{However, Figure 1 below shows the DSC measurement results of the adhesive composition for a patch capable of controlling drug delivery prepared through Synthesis Example 1, and Figure 2 is the DSC measurement result of the adhesive composition for a patch capable of controlling drug delivery prepared through Synthesis Example 2. These are the measurement results, and Figure 3 is the DSC measurement results of the adhesive composition for patches prepared through Synthesis Example 3.}
<표 1><Table 1>
상기 표 1에 나타낸 것처럼, 본 발명의 합성예 1 내지 2를 통해 제조된 패치용 점착제 조성물은 융점(Tm) 결정화온도(Tc)가 확인된 반면, 합성예 3을 통해 제조된 패치용 점착제 조성물은 융점과 결정화온도가 측정되지 않았다.As shown in Table 1, the melting point (Tm) and crystallization temperature (Tc) of the adhesive composition for a patch prepared through Synthesis Examples 1 to 2 of the present invention were confirmed, while the adhesive composition for a patch prepared through Synthesis Example 3 was Melting point and crystallization temperature were not measured.
또한, 상기 실시예 1 내지 2 및 비교예 1 내지 2를 통해 제조된 패치의 접착력, 약물함량 및 약물방출량을 측정하여 아래 표 2 및 도 4에 나타내었다.In addition, the adhesion, drug content, and drug release amount of the patches prepared through Examples 1 to 2 and Comparative Examples 1 to 2 were measured and shown in Table 2 and Figure 4 below.
단, 점착력은 KS T 1028에 따라 UTM 장비를 사용하여 측정하였다. 폭 25㎜ 테이프를 SUS304 피착제에 고무롤러(2.0㎏ 하중)를 이용하여 압착한 후 상온에서 30분간 방치하였고, 300㎜/min의 속도로 180° Peel 값을 측정하였다.However, adhesive strength was measured using UTM equipment according to KS T 1028. A 25 mm wide tape was pressed to a SUS304 adherend using a rubber roller (2.0 kg load) and left at room temperature for 30 minutes, and the 180° Peel value was measured at a speed of 300 mm/min.
또한, 약물함량은 액체크로마토그래피법(HPLC; High performance liquid chromatography)으로 평가 진행 하였으며, 함량평가를 위한 활성물질의 농도는 약전표준에 의거하여 90 내지 110%로 설정하여 측정 진행 하였으며, 샘플 Size는 70㎠로 10매 이상을 가지고 실험을 진행 하였다. 리지를 떼어내고 부직포의 접착면이 겹치도록 포개어 붙인 다음 질량을 정밀하게 달아 1 매의 평 질량을 구해 잘게 자르고. 케토프로펜(C16H14O3) 약 30 mg에 해당하는 양을 정밀하게 달아 메탄올·클로르포름 혼용액(1:1)을 250mL를 넣고 2시간 동안 40℃ 부근 수욕에서 초음파 처리하후, 그대로 교반기로 옮겨서 2시간 동안 교반하여 추출액을 500mL 용량플라스크에 옮긴다. 추출 잔류물에 메탄올·클로르포름 혼용액(1:1)을 100mL 넣고 40℃ 부근 수욕에서 30분 동안 초음파 처리하고, 그대로 교반기로 옮겨서 30분 동안 교반한 다음 추출액을 500mL 용량플라스크에 합하는 과정을 2 회 실시하였다. 메탄올·클로르포름혼용액(1:1)을 가하여 정확히 표선을 맞춘다. 이 액을 여과하여 검액으로 하였고. 따로 케토프로펜 표준품 약 30mg을 정밀하게 달아 메탄올·클로르포름혼용액을 넣어 정확하게 100mL로 했다. 이 액 10mL를 정확하게 취하여 메탄올·클로르포름혼용액을 넣어 50 mL로 하여 표준액으로 하며, 검액 및 표준액 20㎕씩을 가지고 다음 조건으로 액체크로마토그래프법에 따라 시험하여 각 액의 케토프로펜의 피크면적 AT(Area Test) 및 AS(Area Standard)를 측정하였다.In addition, the drug content was evaluated using high performance liquid chromatography (HPLC), the concentration of the active substance for content evaluation was set to 90 to 110% based on pharmacopoeial standards, and the sample size was measured. The experiment was conducted with more than 10 sheets measuring 70㎠. Remove the ridges, stack them so that the adhesive sides of the non-woven fabric overlap, then accurately weigh the mass to obtain the average mass of one sheet and cut it into small pieces. Accurately weigh approximately 30 mg of ketoprofen (C 16 H 14 O 3 ), add 250 mL of methanol/chloroform mixture (1:1), sonicate in a water bath at around 40°C for 2 hours, and then cool as is. Transfer to a stirrer, stir for 2 hours, and transfer the extract to a 500 mL volumetric flask. Add 100 mL of methanol/chloroform mixture (1:1) to the extraction residue, sonicate in a water bath around 40°C for 30 minutes, transfer to a stirrer, stir for 30 minutes, and then add the extract to a 500 mL volumetric flask. It was conducted twice. Add methanol·chloroform mixed solution (1:1) and accurately match the marked line. This solution was filtered and used as the sample solution. Separately, approximately 30 mg of the ketoprofen standard was accurately weighed and methanol/chloroform mixed solution was added to make exactly 100 mL. Accurately take 10 mL of this solution, add methanol·chloroform mixed solution to make 50 mL, and use it as a standard solution. Using 20 ㎕ each of the sample solution and standard solution, test according to the liquid chromatography method under the following conditions to determine the peak area of ketoprofen in each solution AT. (Area Test) and AS (Area Standard) were measured.
케토프로펜 함량 산출 식Ketoprofen content calculation formula
케토프로펜(CKetoprofen (C 3535 HH 1414 OO 33 )양(mg)(%) = 케토프로펜 표준품의 양(mg) × (A)Amount (mg)(%) = Amount of ketoprofen standard (mg) × (A TT /A/A SS ) × 100) × 100
위 실험에서 케토프로펜 표준품의 양은 약전 기준 70㎠ 당 30mg의 정량값 30mg으로 진행하였으며, AT는 상기 실시예 1 내지 2 및 비교예 1 내지 2로 제조된 패치이며, AS는 케토프로펜30mg을 녹여 70㎠로 잘라 진행하였으고 HPLC 면적계산을 진행하였다.In the above experiment, the amount of ketoprofen standard was carried out at 30mg, which is the quantitative value of 30mg per 70㎠ based on the Pharmacopoeia, and A T was The patches were manufactured in Examples 1 to 2 and Comparative Examples 1 to 2 , and A S is 30mg of ketoprofen was dissolved and cut into 70㎠, and HPLC area calculation was performed.
또한, 약물 방출량 평가는 미국약전의 방출평가 방법 중 제 5법인 Paddle over disk법으로 활성물질 함유 경피 약물전달시스템 제품의 활성물질의 방출특성 평가 진행하였으며, 인산완충식염수(pH 7.4 buffer)를 이용하여 32±0.5℃에서 시간에 따른 활성물질의 방출을 평가하였다.In addition, the drug release rate was evaluated using the Paddle over disk method, the 5th release evaluation method of the United States Pharmacopoeia, to evaluate the release characteristics of the active material of the transdermal drug delivery system product containing the active material, using phosphate buffered saline (pH 7.4 buffer). The release of active substances over time was evaluated at 32 ± 0.5°C.
<표 2><Table 2>
상기 표 2에 나타낸 것처럼, 본 발명의 실시예 1 내지 2를 통해 제조된 패치는 비교예 1 내지 2를 통해 제조된 패치에 비해 점착력과 약물함량은 대등하면서도 점착력의 저하 없이 융점 온도를 조절함으로 인해 약물 방출 속도를 점착성 고분자를 통해서 조절 할 수 있으며, 다양한 종류의 약물에서 친화성이 좋도록 점착제 폴리머 사이드 chain에 친수성기를 도입하여 소수성과 친수성을 모두 갖는 양친화적(amphiphilic)인 특징을 갖게 하여 다양한 약물을 사용할 수 있게 하였고, 또한, 온도에 따라 그 형태를 바꾸는데 좀더 원활한 성질을 보이도록 하였다.As shown in Table 2, the patches manufactured through Examples 1 to 2 of the present invention have comparable adhesive strength and drug content to the patches manufactured through Comparative Examples 1 to 2, but the melting point temperature is controlled without deterioration of the adhesive strength. The drug release rate can be controlled through adhesive polymers, and by introducing a hydrophilic group into the side chain of the adhesive polymer to ensure good affinity for various types of drugs, it has amphiphilic characteristics that have both hydrophobic and hydrophilic properties, making it suitable for use with a variety of drugs. It was made possible to use, and it also showed more smooth properties in changing its shape depending on the temperature.
따라서, 본 발명에 따른 약물전달 조절이 가능한 패치용 점착제 조성물 및 그 조성물을 이용한 패치는 융점(Tm)과 결정화온도(Tc)를 나타내며, 소수성과 친수성을 동시에 나타내는 양친매성 점착제가 사용되어 원활한 약물 혼용성 및 약물전달 조절이 가능한 패치를 제공한다.Therefore, the adhesive composition for a patch capable of controlling drug delivery according to the present invention and the patch using the composition exhibit a melting point (Tm) and a crystallization temperature (Tc), and an amphipathic adhesive that exhibits both hydrophobicity and hydrophilicity is used to enable smooth drug mixing. Provides a patch that can control sex and drug delivery.
Claims (5)
상기 아크릴 혼합물은 메톡시폴리에틸렌글리콜 모노아크릴레이트의 함량이 5 내지 50 중량%이고,
상기 탄소수가 16 이상인 알킬기를 갖는 아크릴은 세틸아크릴레이트 및 베헤닐아크릴레이트로 이루어진 그룹에서 선택된 하나 이상으로 이루어지는 것을 특징으로 하는 약물전달 조절이 가능한 패치용 점착제 조성물.
It consists of an acrylic mixture containing methoxypolyethylene glycol monoacrylate and acrylic with an alkyl group having 16 or more carbon atoms, a polymerization initiator, and a solvent.
The acrylic mixture has a methoxypolyethylene glycol monoacrylate content of 5 to 50% by weight,
An adhesive composition for a patch capable of controlling drug delivery, wherein the acrylic having an alkyl group having 16 or more carbon atoms is made of at least one selected from the group consisting of cetyl acrylate and behenyl acrylate.
상기 약물전달 조절이 가능한 패치용 점착제 조성물은 메톡시폴리에틸렌글리콜 모노아크릴레이트 및 탄소수가 16 이상인 알킬기를 갖는 아크릴이 함유된 아크릴 혼합물 100 중량부, 중합개시제 0.01 내지 0.1 중량부 및 용제 적량으로 이루어지는 것을 특징으로 하는 약물전달 조절이 가능한 패치용 점착제 조성물.
In claim 1,
The adhesive composition for a patch capable of controlling drug delivery is characterized by consisting of 100 parts by weight of an acrylic mixture containing methoxypolyethylene glycol monoacrylate and acrylic with an alkyl group having 16 or more carbon atoms, 0.01 to 0.1 parts by weight of a polymerization initiator, and an appropriate amount of solvent. An adhesive composition for a patch capable of controlling drug delivery.
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