KR102598159B1 - Microneedle comprising surface-modified microspheres and its preparation method - Google Patents
Microneedle comprising surface-modified microspheres and its preparation method Download PDFInfo
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- KR102598159B1 KR102598159B1 KR1020220143143A KR20220143143A KR102598159B1 KR 102598159 B1 KR102598159 B1 KR 102598159B1 KR 1020220143143 A KR1020220143143 A KR 1020220143143A KR 20220143143 A KR20220143143 A KR 20220143143A KR 102598159 B1 KR102598159 B1 KR 102598159B1
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- microneedle
- microspheres
- drug
- modified
- water
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
본 발명에서는 체내 체류 지속성이 증진되어 서방성 효과가 우수하여 지속적인 약물 투여가 필요한 질환 치료에 사용하기에 적합한 표면개질 미립구를 포함하는 마이크로니들 및 그 제조방법이 제공된다.
본 발명에 따른 약물을 함유하는 표면개질 미립구를 포함하는 마이크로니들은 체내 체류 지속성이 증진되어 서방성 효과가 우수하여 지속적인 약물 투여가 필요한 질환 치료에 사용하기에 유용하다.The present invention provides a microneedle containing surface-modified microspheres suitable for use in the treatment of diseases that require continuous drug administration due to improved persistence in the body and excellent sustained-release effect, and a method for manufacturing the same.
Microneedles containing surface-modified microspheres containing a drug according to the present invention have improved retention in the body and excellent sustained-release effect, making them useful for the treatment of diseases that require continuous drug administration.
Description
본 발명은 표면개질 미립구를 포함하는 마이크로니들 및 그 제조방법에 관한 것으로, 더 상세하게는 체내 체류 지속성이 증진되어 서방성 효과가 우수하여 지속적인 약물 투여가 필요한 질환 치료에 사용하기에 적합한, 표면개질 미립구를 포함하는 마이크로니들 및 그 제조방법에 관한 것이다.The present invention relates to a microneedle containing surface-modified microspheres and a method of manufacturing the same. More specifically, the present invention relates to a microneedle containing surface-modified microspheres and a method of manufacturing the same. More specifically, the surface-modified microneedle has improved retention in the body and has an excellent sustained-release effect, making it suitable for use in the treatment of diseases that require continuous drug administration. It relates to a microneedle containing microspheres and a method of manufacturing the same.
피부를 통하여 약물을 전달하는 것은 이의 사용 편리성으로 인하여, 다양한 분야 및 형태로 사용되고 있다. 이러한 피부를 통과하는 약물은, 주로 피부를 통하여 체순환계(systemic circulation)로 전달시키기 위한 것이나, 이외에도 아토피 치료제, 여드름 치료제, 피부병 치료제 등의 약물은 피부 자체의 기관에 전달시키려는 목적으로 사용되기도 한다. 이런 편리성 및 기능성에도 불구하고, 피부의 구조상 약물을 피부를 통과하여 전달하는 것에는 많은 어려움이 존재하여, 피부를 통과하는 약물을 개발하는 것이 쉽지 않다. 피부의 각질층은, 케라틴이 풍부한 각질세포로 이루어져 있는 브릭(brick) 구조와, 이러한 각질세포 사이를 세라마이드, 지방산, 또는 왁스 등과 같은 지질이 채운 모르타르(mortar) 구조로 이루어져 있다. 이러한 구조는 장벽으로 역할하여 물질 투과성이 아주 낮은 특성을 가지게 된다. 500Da 이하의 저분자 구조 성분들만이 확산방식에 의해서 피부 내로 전달될 수 있으며, 지질 친화성이 우수한 물질만이 피부를 통과할 수 있다.Delivery of drugs through the skin is used in various fields and forms due to its convenience. Drugs that pass through the skin are mainly intended to be delivered to the systemic circulation through the skin, but in addition, drugs such as atopy treatment, acne treatment, and skin disease treatment are also used for the purpose of being delivered to the organs of the skin itself. Despite this convenience and functionality, there are many difficulties in delivering drugs through the skin due to the structure of the skin, so it is not easy to develop drugs that pass through the skin. The stratum corneum of the skin is composed of a brick structure composed of keratin cells rich in keratin, and a mortar structure filled with lipids such as ceramides, fatty acids, or waxes between these keratin cells. This structure acts as a barrier and has very low material permeability. Only low-molecular structural components of 500 Da or less can be delivered into the skin by diffusion, and only substances with excellent lipid affinity can pass through the skin.
이를 극복하기 위해 마이크로니들(microneedle) 등의 새로운 시스템이 개발되고 있으며, 마이크로니들은 부속 장비 없이 패치 형태로 적용할 수 있어 일상 생활에서 간편하게 적용할 수 있다는 장점이 있다. 그 중, 마이크로니들 패치는 여러개의 마이크로니들이 패치 안에 부착되어 있고 마이크로니들이 피부 표면에 작은 구멍들을 뚫어 약물을 전달하는 방식이다. To overcome this, new systems such as microneedle are being developed, and microneedles have the advantage of being easy to apply in daily life as they can be applied in the form of a patch without any attached equipment. Among them, the microneedle patch is a method in which several microneedles are attached to the patch and the microneedles create small holes on the skin surface to deliver drugs.
최근에 생분해성 고분자를 기초로 하는 용해성 마이크로니들이 개발되어 마이크로니들이 피부 내로 침투된 후, 체내에서 생분해되면서 효능물질이 피부 내로 용출되는 방식이 개발되고 있다 (특허등록 10-2234446호). 이와 같이 용해성 마이크로니들에 의해 피부내로 삽입된 효능물질은 피부 탄성으로 인하여 피하에서 이탈되어 체내 체류 지속성이 떨어지는 문제점이 있다. 효능물질이 오랜 기간에 걸쳐 약효가 발효될 필요가 있는 서방성 약물의 경우는 특히 체내 체류 지속성이 높을 필요성이 있다. Recently, soluble microneedles based on biodegradable polymers have been developed, and a method has been developed in which the microneedles penetrate into the skin and then biodegrade in the body and the effective substances are eluted into the skin (Patent Registration No. 10-2234446). In this way, the effective substance inserted into the skin by dissolving microneedles has a problem in that it is released from the subcutaneous layer due to the elasticity of the skin and its persistence in the body is reduced. In the case of sustained-release drugs, where the efficacy of the active substance needs to be fermented over a long period of time, there is a need to have a high persistence in the body.
따라서 체내 체류 지속성이 증진되어 서방성 효과가 우수하여 지속적인 약물 투여가 필요한 질환 치료에 사용하기에 적합한 마이크로니들의 개발이 요구되고 있다.Therefore, there is a need for the development of microneedles that are suitable for use in the treatment of diseases that require continuous drug administration due to their improved persistence in the body and excellent sustained-release effect.
이에 본 발명자들은 종래 기술에서의 요구에 부응하기 위해 지속적으로 연구한 결과, 약물을 포함하는 표면이 개질된 미립구를 이용하여 제조된 마이크로니들의 경우 놀랍게도 체내 체류 지속성이 증진되고 서방성 효과가 우수하여 지속적인 약물 투여가 필요한 질환 치료에 사용하기에 적합하다는 것을 확인하여 본 발명을 완성하게 되었다. Accordingly, the present inventors have continuously researched to meet the needs of the prior art, and as a result, the microneedles manufactured using surface-modified microspheres containing drugs have surprisingly improved retention in the body and excellent sustained release effect. The present invention was completed by confirming that it was suitable for use in the treatment of diseases requiring continuous drug administration.
따라서 본 발명의 목적은 표면개질 미립구를 포함하는 마이크로니들을 제공하는 것이다.Therefore, the purpose of the present invention is to provide microneedles containing surface-modified microspheres.
본 발명의 또 다른 목적은 표면개질 미립구를 포함하는 마이크로니들의 제조방법을 제공하는 것이다. Another object of the present invention is to provide a method for manufacturing microneedles containing surface-modified microspheres.
본 발명의 또 다른 목적은 상기 마이크로니들을 포함하는 마이크로니들 경피 패치를 제공하는 것이다. Another object of the present invention is to provide a microneedle transdermal patch containing the microneedles.
상기 본 발명의 목적을 달성하기 위하여, 약물을 함유하는 표면개질 미립구를 포함하는 마이크로니들을 제공한다. In order to achieve the object of the present invention, a microneedle containing surface-modified microspheres containing a drug is provided.
본 발명에서 '표면개질'은 미립구의 표면에 골프공에서 볼 수 있는 딤플(dimple) 구조, 주름 등의 홈이 생성되어 있는 표면을 갖는 미립구를 의미한다. In the present invention, 'surface modification' refers to microspheres having grooves such as dimple structures and wrinkles that can be seen in golf balls on the surface of the microspheres.
본 발명에서 '미립구(microsphere)'는 생분해성 미립구(Biodegradable microsphere)로 체내로 약물 등을 전달하는 전달체(carrier)이다. 생분해성 미립구는 주 구성성분인 생분해성 고분자의 분해기전 및 분해속도에 따라 생체내 소실 기간이 정해지는데, 이들 고분자의 생체내 소실 속도에 따라 내부 봉입된 약물의 방출은 일정 기간에 걸쳐 이루어진다. 상기 미립구의 평균 크기는 특별히 제한되지는 않으나 마이크로니들에 내입되어 사용하기에 적절한 크기이며, 대략적으로 50μm 이하, 바람직하게는 10 ㎛ 이하일 수 있다.In the present invention, 'microspheres' are biodegradable microspheres and are carriers that deliver drugs, etc. into the body. The in-vivo disappearance period of biodegradable microspheres is determined by the decomposition mechanism and decomposition rate of the biodegradable polymer, which is the main component. Depending on the in-vivo disappearance rate of these polymers, the drug encapsulated inside is released over a certain period of time. The average size of the microspheres is not particularly limited, but is an appropriate size for use in a microneedle, and may be approximately 50 μm or less, preferably 10 μm or less.
본 발명에서 표면개질 미립구는 단일 에멀젼의 형태로써 수중유 (O/W; oil in water), 유중수 (W/O; water in oil), 유중유 (O/O; oil in oil), S/O(solid in oil), S/W (soild in water) 형일 수 있으며, 바람직하게는 수중유 (O/W; oil in water)형 에멀젼이다. In the present invention, the surface-modified microspheres are in the form of a single emulsion and contain oil in water (O/W; oil in water), water in oil (W/O; water in oil), oil in oil (O/O; oil in oil), S/ It may be of O (solid in oil) or S/W (soil in water) type, and is preferably an oil in water (O/W; oil in water) type emulsion.
본 발명에서 미립구의 제조방법은 용매 증발법(solvent evaporation method)이 사용될 수 있으며, 이는 미립구 제조 시에 사용된 유기용매를 증발시키고 경화하는 단계를 포함하여 구성된다. 그 외에 분무 건조법(spary drying method)과 초음파 파쇄법(sonication) 등이 사용될 수 있다. In the present invention, the method for producing microspheres may be a solvent evaporation method, which includes the steps of evaporating and curing the organic solvent used in producing microspheres. In addition, spray drying method and ultrasonic disruption method can be used.
용매 증발법으로 생분해성 미립구 제조시, 단일 에멀젼인 수중유(O/W)형 미립구의 경우는 내부 유상(oil phase)으로 물과 섞이지 않는 비극성 유기용매를 사용하며, 생분해성 고분자와 약물을 상기 비극성 유기용매에 동시에 용해하고 이를 계면활성제가 용해된 수상에 빠르게 분산하여 제조할 수 있다. 구체적으로 본 발명에서의 미립구는 i) 약물 및 계면활성 생분해성 고분자를 유기 용매에 용해하여 유상을 준비하는 단계; ii) 수용성 고분자가 용해된 수상에 상기 유상을 혼합하여 수중유 에멀젼을 형성하는 단계; iii) 상기 수중유 에멀젼에서 용매를 증발시켜 표면이 개질된 미립구를 얻는 단계;를 포함하는 방법에 의해 제조될 수 있다.When producing biodegradable microspheres using the solvent evaporation method, in the case of single emulsion oil-in-water (O/W) type microspheres, a non-polar organic solvent that is immiscible with water is used as the internal oil phase, and biodegradable polymers and drugs are used as described above. It can be prepared by simultaneously dissolving in a non-polar organic solvent and quickly dispersing it into the aqueous phase in which the surfactant is dissolved. Specifically, the microspheres in the present invention include the following steps: i) dissolving a drug and a surface-active biodegradable polymer in an organic solvent to prepare an oil phase; ii) mixing the oil phase with an aqueous phase in which water-soluble polymers are dissolved to form an oil-in-water emulsion; iii) evaporating the solvent in the oil-in-water emulsion to obtain surface-modified microspheres.
본 발명에서 '약물'은 지속적인 약물 투여가 필요한 질환에 사용되는(서방성 효과를 요구되는) 약물이면 상기 약물 범위에 국한되지 않으나, 바람직하게는 유기화합물 또는 무기화합물과 같은 약제; 펩타이드, 단백질, 항체, 핵산, 세포 및 유전자와 같은 생물학적 제제; 백신, 호르몬 또는 이들의 혼합물일 수 있고, 바람직하게는 물에 난용성 약물이다. 본 발명의 실시예에서는 약물의 일례로 타크로리무스를 사용하였다.In the present invention, 'drug' is not limited to the scope of the above drug as long as it is a drug used for diseases that require continuous drug administration (requiring a sustained-release effect), but is preferably a drug such as an organic compound or an inorganic compound; Biological products such as peptides, proteins, antibodies, nucleic acids, cells, and genes; It may be a vaccine, a hormone, or a mixture thereof, and is preferably a drug that is poorly soluble in water. In the examples of the present invention, tacrolimus was used as an example of a drug.
타크로리무스는 화학식 1의 구조를 가지며, 칼시뉴린(Calcineurin)을 억제하여 IL-2나 IL-2와 같은 염증매개물질 생성 억제하여 중등도-중증의 아토피성 피부염 치료에 사용된다: Tacrolimus has the structure of Formula 1 and is used to treat moderate to severe atopic dermatitis by inhibiting the production of inflammatory mediators such as IL-2 and IL-2 by inhibiting calcineurin:
(화학식 1) (Formula 1)
본 발명에서 계면활성 생분해성 고분자는 체내에서 자연스럽게 생분해됨으로써 체외로 배출될 수 있는 것일 수 있다. 또한, 물에 난용성인 약물을 유화시킬 수 있는 계면활성제의 기능을 가질 수 있다. 상기 계면활성 생분해성 고분자로는 천연에서 유래하는 것이거나, 합성적으로 제조되는 모든 것을 사용할 수 있다. 트윈계열, 폴록사머류, 폴리락테이트-코-글라이클레이트(PLGA) 또는 폴리(D,L-락트산)(PDLA), 및 폴리D,L-락트산-폴리카프로락톤의 공중합체로 사용할 수 있다. 본 발명에서는 일례로 PLGA를 사용하였다. 계면활성 생분해성 고분자는 중량평균분자량 5,000 내지 1,000,000 일 수 있다.In the present invention, the surface-active biodegradable polymer may be naturally biodegraded in the body and thus discharged outside the body. In addition, it can have the function of a surfactant that can emulsify drugs that are poorly soluble in water. The surface-active biodegradable polymer can be anything that is naturally derived or synthetically produced. It can be used as a copolymer of Tween series, poloxamers, polylactate-co-glyclate (PLGA) or poly(D,L-lactic acid) (PDLA), and polyD,L-lactic acid-polycaprolactone. . In the present invention, PLGA was used as an example. The surface-active biodegradable polymer may have a weight average molecular weight of 5,000 to 1,000,000.
사용되는 약물과 계면활성 생분해성 고분자의 함량은 특별히 제한되지는 않으나, 중량비로 0.1~10 : 10, 0.5~7 : 10, 3~7 : 10, 또는 바람직하게 4~6 : 10을 사용할 수 있다. 상기 범위에서 미립구에 원하는 홈 (딤플 구조)이 생성되어 있는 표면이 효과적으로 형성될 수 있다The content of the drug and surface-active biodegradable polymer used is not particularly limited, but can be used in a weight ratio of 0.1 to 10:10, 0.5 to 7:10, 3 to 7:10, or preferably 4 to 6:10. . Within the above range, a surface in which desired grooves (dimple structures) are created in the microspheres can be effectively formed.
유기 용매는 특별히 제한되지는 않으며, 디클로로메탄, 메탄올, 에탄올, 클로로포름, 헥산, 에틸아세테이트, 및 이들의 혼합을 사용할 수 있고, 바람직하게는 디클로로메탄을 사용한다. 상기 약물과 계면활성 생분해성 고분자의 혼합물에 대하여 유기용매는 1:10 ~ 1:30 (w/v)의 혼합비로 혼합된다. 상기 범위에서 미립구에 원하는 홈 (딤플 구조)이 생성되어 있는 표면이 효과적으로 형성될 수 있도록 해준다. The organic solvent is not particularly limited, and dichloromethane, methanol, ethanol, chloroform, hexane, ethyl acetate, and mixtures thereof can be used, preferably dichloromethane. The organic solvent is mixed in a mixing ratio of 1:10 to 1:30 (w/v) with respect to the mixture of the drug and the surface-active biodegradable polymer. Within the above range, a surface in which desired grooves (dimple structures) are created in the microspheres can be effectively formed.
상기 단계 ii)에서 유상과 수상의 혼합을 포함한다. 수상은 용해된 수용성 고분자를 포함하고, 수용성 고분자는 에멀젼-용매 증발 제조 공정(단계 iii)) 중 에멀젼의 안정화를 위하여 첨가될 수 있다. Step ii) includes mixing the oil phase and the water phase. The aqueous phase contains dissolved water-soluble polymers, and the water-soluble polymers may be added to stabilize the emulsion during the emulsion-solvent evaporation manufacturing process (step iii)).
수용성 고분자 물질의 부재 시 공정 중 에멀젼끼리의 결합 혹은 섬유질의 형태와 같은 불균일한 형태의 결과를 얻을 수 있으며, 상기 첨가는 이를 방지하는데 기여할 수 있다. 상기 에멀젼-용매 증발 제조 공정 후 수용성 고분자는 세척 과정을 통하여 제거할 수 있다. 수용성 고분자로는 폴리비닐아세테이트(PVA), 폴리아크릴산(PAA), 폴리비닐피롤리돈(PVP), 폴리아크릴아마이드(PAM), 폴리에틸렌옥사이드(PEO), 폴리스베이트(Tween) 및 폴록사머(Poloxamer)등이 사용될 수 있다. 수용성 고분자는 중량평균분자량이 1,000 ~ 50,000,000 일 수 있다. 본 발명에서는 일례로서 PVA를 사용하였다. 수용성 고분자는 수상에서 0.01 내지 1 중량%, 바람직하게는 0.1 내지 0.5 중량%로 포함될 수 있다. 상기 조건의 농도로 사용할 때 에멀젼이 효과적으로 형성된다.In the absence of a water-soluble polymer material, a non-uniform form, such as a combination of emulsions or a fibrous form, may be obtained during the process, and the addition can contribute to preventing this. After the emulsion-solvent evaporation manufacturing process, water-soluble polymers can be removed through a washing process. Water-soluble polymers include polyvinylacetate (PVA), polyacrylic acid (PAA), polyvinylpyrrolidone (PVP), polyacrylamide (PAM), polyethylene oxide (PEO), polybait (Tween), and poloxamer. etc. may be used. Water-soluble polymers may have a weight average molecular weight of 1,000 to 50,000,000. In the present invention, PVA was used as an example. The water-soluble polymer may be included in an amount of 0.01 to 1% by weight in the water phase, preferably 0.1 to 0.5% by weight. Emulsions are effectively formed when used at concentrations under the above conditions.
상기 혼합은 호모게나이저 등의 기계적 교반수단 또는 초음파 등으로5,000 ~ 12,000rpm의 범위(1st shear)로, 가장 바람직하게는 12,000rpm으로 수행한다. 상기 범위에서의 혼합이 미립구에 원하는 홈 (딤플 구조)이 생성되어 있는 표면이 효과적으로 형성될 수 있도록 해준다. The mixing is performed in the range of 5,000 to 12,000 rpm (1st shear), most preferably at 12,000 rpm, using mechanical stirring means such as a homogenizer or ultrasonic waves. Mixing in the above range allows the microspheres to effectively form a surface with desired grooves (dimple structure).
상기 단계 iii)에서 증발은 연속상인 수상에 형성된 유상의 유기용매를 증발시키는 과정이다. 증발은 교반을 수반하여 이루어질 수 있으며, 교반은 기계적 교반을 포함할 수 있고, 이때 교반속도는 800 ~ 1,000rpm 범위(2nd shear)로, 가장 바람직하게는 1,000rpm로 수행한다. 상기 범위에서의 교반이 증발의 속도를 적절하게 조절하여 미립구 표면에 홈 (딤플 구조)을 잘 형성할 수 있도록 해준다. In step iii), evaporation is a process of evaporating the organic solvent of the oil phase formed in the aqueous phase, which is a continuous phase. Evaporation may be accompanied by stirring, and the stirring may include mechanical stirring, and the stirring speed is in the range of 800 to 1,000 rpm (2nd shear), most preferably 1,000 rpm. Stirring in the above range appropriately controls the rate of evaporation, allowing grooves (dimple structures) to be well formed on the surface of the microspheres.
증발을 통하여 미립구가 형성되며, 이는 연속상인 물에 분산되어 존재한다. 간단하게 필터링을 통하여 미립구를 수득할 수 있다. 필요에 따라서는 추가적으로 세척과 같은 불순물 제거 과정, 원심분리 과정, 건조 과정을 더 거칠 수 있다.Microspheres are formed through evaporation, which exist dispersed in continuous water. Microspheres can be obtained simply through filtering. If necessary, additional impurity removal processes such as washing, centrifugation, and drying may be performed.
본 발명에서 약물을 함유하는 표면개질 미립구를 피부 내로 전달하기 위해서는 마이크로니들의 재료가 피부 내의 수분에 의해 붕괴될 수 있는 용해성이어야 하고, 체내에 부작용 없이 흡수되거나 분해되는 생체적합성이야 하며, 마이크로니들로 제조된 후 피부를 뚫을 수 있는 강도의 재료로 제조되는 것이 바람직하다.In order to deliver drug-containing surface-modified microspheres into the skin in the present invention, the material of the microneedle must be soluble so that it can be disintegrated by moisture in the skin, be biocompatible to be absorbed or decomposed without side effects in the body, and be used as a microneedle. It is preferable that it is made of a material strong enough to pierce the skin after being manufactured.
본 발명의 마이크로니들은 용해성, 즉 피부 내에서 체액에 용해되는 수용해성이다.The microneedle of the present invention is soluble, that is, water-soluble, dissolving in body fluids within the skin.
본 발명의 마이크로니들을 형성하는 용해성 재료로는 알긴산, 키토산, 콜라겐, 젤라틴, 히알루론산, 콘드로이친(설페이트), 덱스트란(설페이트), 피브린, 아가로스, 풀루란, 셀룰로오스, 폴리비닐피롤리돈(PVP), 폴리에틸렌글리콜(PEG), 폴리비닐알코올(PVA), 비닐피롤리돈-비닐아세테이트 공중합체, 히드록시프로필 셀룰로오스, 히드록시에틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 나트륨 카르복시메틸셀룰로오스, 폴리알코올, 시클로덱스트린, 덱스트린, 트레할로스, 포도당, 과당, 녹말, 수크로스, 글루코스, 말토스, 락토스, 락툴로스, 프락토스, 투라노스, 멜리토스, 멜레지토스, 덱스트란, 솔비톨, 만니톨 및 크실리톨로 이루어진 군으로부터 선택되는 하나 이상의 생체적합성 재료; 상기 물질의 유도체; 또는 이들의 혼합물을 포함할 수 있다. 본 발명의 실시예에서는 일례로 알긴산 및 트레할로스를 혼합하여 사용하였다. Soluble materials forming the microneedle of the present invention include alginic acid, chitosan, collagen, gelatin, hyaluronic acid, chondroitin (sulfate), dextran (sulfate), fibrin, agarose, pullulan, cellulose, polyvinylpyrrolidone ( PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), vinylpyrrolidone-vinylacetate copolymer, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyalcohol, Cyclodextrin, dextrin, trehalose, glucose, fructose, starch, sucrose, glucose, maltose, lactose, lactulose, fructose, turranose, melitose, melegitose, dextran, sorbitol, mannitol and xylitol. One or more biocompatible materials selected from the group consisting of; Derivatives of the above substances; Or it may include a mixture thereof. In an example of the present invention, a mixture of alginic acid and trehalose was used.
본 발명의 마이크로니들은 가소제, 계면활성제, 보존제 등을 더 포함할 수 있다.The microneedle of the present invention may further contain a plasticizer, surfactant, preservative, etc.
가소제로서는, 예를 들어, 에틸렌글리콜, 프로필렌글리콜, 디프로필렌글리콜, 부틸렌글리콜, 글리세린 등의 폴리올을 단독으로 또는 혼합하여 사용할 수 있으나, 이에 한정되지는 않는다. 계면활성제로서는, 예를 들어, PEG-8 글리세릴 이소스테아레이트, PEG-10 글리세릴 이소스테아레이트, PEG-15 글리세릴 이소스테아레이트, PEG-20 수소첨가 캐스터 오일, PEG-30 수소첨가 캐스터 오일, PEG-40 수소첨가 캐스터 오일, PEG-60 수소첨가 캐스터 오일, PEG-80 수소첨가 캐스터 오일, 세테아레스-12 등을 단독으로 또는 혼합하여 사용할 수 있으나, 이에 한정되지는 않는다. 보존제로서는 예를 들어, 파라옥시안식향산메칠, 파라옥시안식향산에칠, 파라옥시안식향산, (이소)프로필파라옥시안식향산, (이소)부틸클로로부탄올(클로로부톨), 염화벤잘코늄, 염화벤젠토늄, 페놀(p체), 크레솔, 클로로크레솔, 디히드로초산, 디히드로초산나트륨, 소르빈산, 소르빈산칼륨, 소르빈산나트륨, 안식향산, 안식향산나트륨 등을 단독으로 또는 혼합하여 사용할 수 있으나, 이에 한정되지는 않는다. As a plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin can be used alone or in combination, but are not limited thereto. Surfactants include, for example, PEG-8 glyceryl isostearate, PEG-10 glyceryl isostearate, PEG-15 glyceryl isostearate, PEG-20 hydrogenated castor oil, and PEG-30 hydrogenated castor oil. , PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-80 hydrogenated castor oil, ceteareth-12, etc. can be used alone or in combination, but are not limited thereto. Preservatives include, for example, methyl parahydroxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid, (iso)propyl paraoxybenzoic acid, (iso)butylchlorobutanol (chlorobutol), benzalkonium chloride, benzenthonium chloride, phenol ( p form), cresol, chlorocresol, dihydroacetic acid, sodium dihydroacetate, sorbic acid, potassium sorbate, sodium sorbate, benzoic acid, sodium benzoate, etc. can be used singly or in combination, but are not limited thereto.
본 발명에 따른 마이크로니들의 니들부의 모양은 원뿔형, 피라미드형, 스피어형, 단두형 쐐기형, 칼날형 등일 수 있으며, 이들은 공통적으로 피부를 투과할 수 있는 형상이어야 한다. 본 발명의 일 실시예에서는 구조적으로 안정한 피라미드 형의 니들부를 갖는 마이크로니들을 채택하였다.The shape of the needle portion of the microneedle according to the present invention may be cone-shaped, pyramid-shaped, sphere-shaped, short-headed, wedge-shaped, blade-shaped, etc., and these must have a common shape that can penetrate the skin. In one embodiment of the present invention, a microneedle having a structurally stable pyramid-shaped needle portion was adopted.
본 발명에 따른 마이크로니들(10) 및 마이크로니들 패치(100)의 구조를 도 4a 및 도 4b에 예시하였다. 본 발명의 마이크로니들(10)은 니들부(11)와 매트리스층(12)을 포함할 수 있다. 상기 니들부(11)는 상기에서 정의된 바와 같은 피부에 침투하기 용이한 형상을 갖는다. 상기 니들부(11)의 길이는 500 내지 1000 ㎛이며, 바람직하게는 750 ㎛ 이다. 매트리스층(12)은 두께가 0.1 내지 1mm며, 바람직하게는 0.1 내지 0.3mm이다. 니들부와 매트리스층에는 약물을 포함하는 표면개질 미립구가 내입(함유)되어 있다. 본 발명의 마이크로니들 패치(100)는 매트리스층(12) 일측면에 위에 점착제층(20)을 적층하여 마이크로니들 패치를 피부에 부착하여 사용할 수 있도록 만들어진다. 마이크로니들 패치(100)에서 마이크로니들(10)가 점착제층(20)에 접하는 부분 외의 점착제층 부분은 점착제층 전체 면적의 50% 이하이다. 마이크로니들 패치(100)는 또한 점착제층 위에 보호필름(30)을 포함할 수 있다. The structures of the microneedle 10 and the microneedle patch 100 according to the present invention are illustrated in FIGS. 4A and 4B. The microneedle 10 of the present invention may include a needle portion 11 and a mattress layer 12. The needle portion 11 has a shape that facilitates penetration into the skin as defined above. The length of the needle portion 11 is 500 to 1000 ㎛, preferably 750 ㎛. The mattress layer 12 has a thickness of 0.1 to 1 mm, preferably 0.1 to 0.3 mm. The needle portion and the mattress layer are embedded with surface-modified microspheres containing a drug. The microneedle patch 100 of the present invention is made by laminating an adhesive layer 20 on one side of the mattress layer 12 so that the microneedle patch can be attached to the skin. In the microneedle patch 100, the portion of the adhesive layer other than the portion where the microneedle 10 is in contact with the adhesive layer 20 is less than 50% of the total area of the adhesive layer. The microneedle patch 100 may also include a protective film 30 on the adhesive layer.
본 발명에 또 다른 목적에 따라서 상기 마이크로니들의 제조방법을 제공한다.According to another object of the present invention, a method for manufacturing the microneedle is provided.
상기 제조방법은 The manufacturing method is
a) 용해성 재료를 물에 용해하여 제1 용액을 형성하는 단계,a) dissolving the soluble material in water to form a first solution,
b) 약물을 함유하는 표면개질 미립구를 제조하는 단계,b) preparing surface-modified microspheres containing a drug,
c) 제1 용액과 상기 표면개질 미립구를 혼합하고 균질화(homogenizing)시켜 혼합 용액을 만드는 단계,c) mixing the first solution and the surface-modified microspheres and homogenizing them to create a mixed solution,
d) 음각의 마이크로니들 몰드에 상기 혼합 용액을 채우는 단계, 및d) filling the mixed solution into an engraved microneedle mold, and
e) 채워진 혼합 용액을 건조시켜 몰드에서 분리하는 단계를 포함한다. e) Drying the filled mixed solution and separating it from the mold.
본 발명의 제조방법에서 용해성 재료, 약물, 표면개질, 미립구는 상기에서 정의된 바와 같다. In the production method of the present invention, the soluble material, drug, surface modification, and microspheres are as defined above.
단계 a)에서 제1 용액은 가소제, 계면활성제, 보존제 등을 추가로 포함할 수 있다. 가소제, 계면활성제, 보존제 등은 상기에서 정의된 바와 같다. In step a), the first solution may further include a plasticizer, surfactant, preservative, etc. Plasticizers, surfactants, preservatives, etc. are as defined above.
단계 b)의 표면개질 미립구를 제조하는 방법은 상기에서 정의된 바와 같다. The method for producing the surface-modified microspheres in step b) is as defined above.
단계 c)에서 제1 용액 100 중량부에 대하여 표면개질 미립구를 0.1 ~ 20 중량부로 혼합한다. In step c), 0.1 to 20 parts by weight of surface-modified microspheres are mixed with 100 parts by weight of the first solution.
혼합 용액을 만드는 단계는 마이크로니들 내에 약물을 포함하는 표면개질 미립구가 고르게 분포해야 하므로, 제1 용액과 표면개질 미립구를 혼합한 후 볼택싱 등으로 강하게 균질화시켜 혼합 용액 중의 미립구가 안정한 상태로 균일하게 분산되도록 한다. In the step of creating a mixed solution, the surface-modified microspheres containing the drug must be evenly distributed within the microneedles. Therefore, after mixing the first solution and the surface-modified microspheres, they are strongly homogenized by vortexing to ensure that the microspheres in the mixed solution are stable and uniform. Let it disperse.
상기 마이크로니들의 제조에 사용되는 온도 등의 조건은 용해성 재료나 표면개질 미립구를 분해되거나 변형되지 않고 충분히 용해하거나 혼합할 수 있는 한 특별히 제한되지 않는다.Conditions such as temperature used in the manufacture of the microneedle are not particularly limited as long as the soluble material or surface-modified microspheres can be sufficiently dissolved or mixed without being decomposed or deformed.
단계 d)에서 혼합 용액을 마이크로니들 몰드에 채우는 단계는 혼합 용액을 도포한 후 방치하는 방법, 원심분리기를 이용하여 혼합용액을 주입하는 방법, 진공을 이용해 내부의 공기를 빼내 혼합 용액을 주입하는 방법, 압력을 가하여 혼합 용액을 주입하는 방법 등을 사용할 수 있다In step d), the step of filling the microneedle mold with the mixed solution is a method of applying the mixed solution and leaving it to stand, a method of injecting the mixed solution using a centrifuge, or a method of injecting the mixed solution by removing the air inside using a vacuum. , a method of injecting a mixed solution by applying pressure can be used.
단계 e)에서 건조 상온에서는 건조시킬 수 있으며, 열풍건조기 등을 이용하여 실온 내지 80℃에서는 건조시킬 수 있으나, 이를 한정하지는 않는다. In step e), drying can be done at room temperature or at room temperature to 80°C using a hot air dryer, etc., but this is not limited.
본 발명의 또 다른 목적에 따라서, 상기 약물을 함유하는 표면개질 미립구를 포함하는 마이크로니들 또는 상기와 같은 제조방법에 의해 제조된 약물을 함유하는 표면개질 미립구를 포함하는 마이크로니들을 포함하는 마이크로니들 경피 패치를 제공한다. According to another object of the present invention, a transdermal microneedle comprising a microneedle containing surface-modified microspheres containing the drug or a microneedle containing surface-modified microspheres containing the drug prepared by the above manufacturing method. Provides patches.
상기 약물이 타크로무스일 경우, 상기 마이크로니들 경피 패치는 아토피성 피부염 치료 및 개선용, 여드름 치료 및 개선용으로 사용될 수 있다. When the drug is tacromus, the microneedle transdermal patch can be used for treating and improving atopic dermatitis and for treating and improving acne.
본 발명에 따른 약물을 함유하는 표면개질 미립구를 포함하는 마이크로니들은 체내 체류 지속성이 증진되어 서방성 효과가 우수하여 지속적인 약물 투여가 필요한 질환 치료에 사용하기에 유용하다. Microneedles containing surface-modified microspheres containing a drug according to the present invention have improved retention in the body and excellent sustained-release effect, making them useful for the treatment of diseases that require continuous drug administration.
도 1a 및 도 1b은 제조예 1에서 제조된 미립구들의 전자현미경 사진이다.
도 2는 재현성을 확인하기 위해 제조된 제형 7의 딤플 구조로 표면 개질된 타크로리무스를 함유한 미립구의 전자현미경 사진이다.
도 3a는 본 발명에 따른 딤플 구조로 표면 개질된 타크로리무스를 함유한 미립구의 분산 안정성을 LUMiSizer를 이용하여 측정한 결과이다.
도 3b는 종래의 매끄러운 표면 구조의 타크로리무스를 함유한 미립구의 분산 안정성을 LUMiSizer를 이용하여 측정한 결과이다.
도 4a 및 도 4b는 본 발명에 따른 마이크로니들 및 마이크로니들 패치의 일례의 모식도이다.
도 5는 본 발명에 따른 마이크로니들의 전자현미경사진이다.
도 6은 본 발명에 따른 마이크로니들 패치를 랫 피부 위에 부착한 후 시간 경과에 따른 피하 잔존 타크로리무스의 함량을 분석한 결과이다.Figures 1a and 1b are electron micrographs of microspheres prepared in Preparation Example 1.
Figure 2 is an electron micrograph of microspheres containing tacrolimus surface-modified with a dimple structure of Formulation 7, prepared to confirm reproducibility.
Figure 3a shows the results of measuring the dispersion stability of microspheres containing tacrolimus surface-modified with the dimple structure according to the present invention using LUMiSizer.
Figure 3b shows the results of measuring the dispersion stability of microspheres containing tacrolimus with a conventional smooth surface structure using LUMiSizer.
4A and 4B are schematic diagrams of an example of a microneedle and a microneedle patch according to the present invention.
Figure 5 is an electron micrograph of a microneedle according to the present invention.
Figure 6 shows the results of analyzing the content of remaining subcutaneous tacrolimus over time after attaching the microneedle patch according to the present invention to rat skin.
이하, 본 발명의 이해를 돕기 위하여 구체적인 실시예를 통하여 본 발명의 구성 및 효과를 보다 상세히 설명하기로 한다. 그러나 하기 실시예는 본 발명을 보다 명확하게 이해시키기 위하여 예시한 것일 뿐이며, 본 발명의 권리범위가 하기 실시예에 의해 한정되는 것은 아니다. Hereinafter, in order to facilitate understanding of the present invention, the configuration and effects of the present invention will be described in more detail through specific examples. However, the following examples are merely illustrative for a clearer understanding of the present invention, and the scope of the present invention is not limited by the following examples.
제조예 1: 타크로리무스를 함유한 표면개질 미립구 제조Preparation Example 1: Preparation of surface-modified microspheres containing tacrolimus
타크로리무스를 함유한 미립구를 수중유(O/W) 에멀젼 용매증발법을 통하여 제조하였다. 제형 조성, 유상, 수상, 용매 조성, 호모게나이져, 매커니칼 스터러에 대한 조건은 하기 표 1과 같이 하여 수행하였다. Microspheres containing tacrolimus were prepared through an oil-in-water (O/W) emulsion solvent evaporation method. Conditions for formulation composition, oil phase, water phase, solvent composition, homogenizer, and mechanical stirrer were performed as shown in Table 1 below.
구체적으로는 타크로리무스 120 mg과 PLGA 503H (Evonik Ltd., Germany) 300 mg에 디클로로메탄을 표 1 및 표 2와 같은 용량으로 첨가하여 용해하여 유상을 제조한 후, 0.5 ~ 1% 폴리비닐 알코올(PVA 500, OCI Company, Ltd., Korea) 용액의 수상과 호모게나이저로 표 1과 같은 조건으로 2분간 혼합하여 수중유 에멀젼을 형성하였다. 수중유 에멀젼을 매커니칼 스터러를 사용하여 표 1의 조건으로 3시간 이상 교반하면서 유기용매를 증발시켜 미립구를 형성하였다. 남아있는 PVA와 고분자에 포집되지 못한 약물입자를 제거하기 위해, 원심분리기 X 820g를 5분 진행하고 증류수로 3회 워싱하였고, 동결건조를 2일 진행하여 파우더 형태의 입자를 얻었다. Specifically, dichloromethane was added and dissolved in 120 mg of tacrolimus and 300 mg of PLGA 503H (Evonik Ltd., Germany) in the same amounts as Tables 1 and 2 to prepare an oil phase, and then dissolved in 0.5 to 1% polyvinyl alcohol (PVA). 500, OCI Company, Ltd., Korea) and the water phase of the solution were mixed with a homogenizer for 2 minutes under the conditions shown in Table 1 to form an oil-in-water emulsion. The oil-in-water emulsion was stirred using a mechanical stirrer under the conditions in Table 1 for more than 3 hours to evaporate the organic solvent to form microspheres. To remove the remaining PVA and drug particles that were not captured in the polymer, centrifuge x 820g was performed for 5 minutes, washed three times with distilled water, and freeze-dried for 2 days to obtain powder-type particles.
(Homogenizer)1 st Shear
(Homogenizer)
(Mechanical stirrer)2nd Shear
(Mechanical stirrer)
제조된 각각의 타크로리무스를 함유한 미립구의 입자크기 분포를 측정하여 표 2에 나타냈고, 각각의 미립구의 전자현미경 사진을 도 1a 및 도 1b에 나타냈다.The particle size distribution of each prepared microsphere containing tacrolimus was measured and shown in Table 2, and electron micrographs of each microsphere are shown in Figures 1A and 1B.
도 1a 및 도 1b에 의하면, 제형 4 및 7에서 딤플(dimple) 구조로 표면 개질된 타크로리무스를 함유한 미립구를 확인할 수 있었고, 제형 1, 2, 3, 5, 6, 8, 9에서는 대부분의 미립구가 종래의 매끄러운(smooth) 표면을 갖는다는 것을 확인할 수 있었다. According to Figures 1A and 1B, microspheres containing tacrolimus surface modified with a dimple structure were confirmed in formulations 4 and 7, and most of the microspheres were found in formulations 1, 2, 3, 5, 6, 8, and 9. It was confirmed that it had a conventional smooth surface.
제형 7에 대하여 재현성을 확인하였으며 도 2에 나타낸 바와 같이 총 4번 모두에서 균일한 딤플 구조로 표면 개질된 타크로리무스를 함유한 미립구를 얻었고, 총 4회의 제형 7을 취합하여 함량 및 크기를 분석한 결과를 표 3에 나타냈다. The reproducibility of Formulation 7 was confirmed, and as shown in Figure 2, microspheres containing tacrolimus surface-modified with a uniform dimple structure were obtained in all four cases, and the content and size were analyzed by collecting Formulation 7 from a total of four times. is shown in Table 3.
<표면개질 미립구 제조를 위한 최적 조건 도출><Derivative of optimal conditions for manufacturing surface-modified microspheres>
딤플 구조로 표면 개질된 타크로리무스를 함유한 미립구가 제조되는 최적 조건을 확립하고자, 표 1의 제형들의 제조 조건을 변경하여 추가 제조하여 보았다. 제형 1의 미립구 제조시에 수상에서 PVA 함량을 1.5%로 증가시켜 제조하여 보았으나 영향이 없었으며, 제형 2의 미립구 제조시에 증발시 교반속도(2nd Shear)를 1,000rpm으로 증가하여 제조해 보니 딤플 구조로 표면개질된 미립구가 제조되었으며, 제형 3의 미립구 제조시에 유상의 용매(DCM) 양을 10ml로 감소시켜 제조해 보니 딤플 구조로 표면개질된 미립구가 제조되었으며, 제형 5의 미립구 제조시에 증발단계에서 교반속도(2nd Shear)를 1,000rpm으로 증가시켜 제조해 보니 딤플 구조로 표면개질된 미립구가 제조되었으며, 제형 6의 미립구 제조시에 호모게나이저 혼합속도(1st Shear)를 12,000rpm으로 감소시켜 제조해 보니 딤플 구조로 표면개질된 미립구가 제조되었으며, 제형 8, 9의 미립구 제조시에 증발단계에서 교반속도(2nd Shear)를 800~1,000rpm으로 증가시켜 제조해 보니 딤플 구조로 표면개질된 미립구가 제조되었다. In order to establish the optimal conditions for manufacturing microspheres containing tacrolimus surface-modified with a dimple structure, the manufacturing conditions of the formulations in Table 1 were changed and additionally manufactured. When manufacturing the microspheres of Formulation 1, the PVA content in the water phase was increased to 1.5%, but there was no effect. When manufacturing the microspheres of Formulation 2, the stirring speed during evaporation (2nd shear) was increased to 1,000 rpm. Surface-modified microspheres with a dimple structure were manufactured. When manufacturing the microspheres of Formulation 3, the amount of oily solvent (DCM) was reduced to 10 ml. As a result, surface-modified microspheres with a dimple structure were manufactured. When manufacturing the microspheres of Formulation 5, In the evaporation step, the stirring speed (2nd shear) was increased to 1,000 rpm, and surface-modified microspheres with a dimple structure were produced. When manufacturing the microspheres of Formulation 6, the homogenizer mixing speed (1st shear) was increased to 12,000 rpm. When manufactured by reducing it, surface-modified microspheres with a dimple structure were produced. When manufacturing microspheres of formulations 8 and 9, the stirring speed (2nd shear) was increased to 800~1,000 rpm in the evaporation step, and the surface was modified with a dimple structure. Microspheres were prepared.
상기와 같은 제조 실험 결과를 종합해 볼 때, 딤플 구조로 표면개질된 미립구 제조를 위한 바람직한 조건은, 유상과 수상의 혼합은 5,000 ~ 15,000rpm의 범위(1st shear)로, 가장 바람직하게는 12,000rpm으로 수행하고, 용매 증발시 교반은 800 ~ 1,000rpm 범위(2nd shear)로, 가장 바람직하게는 1,000rpm으로 수행하고, 유상에서 약물과 계면활성 생분해성 고분자의 혼합물에 대하여 유기용매는 1:10 ~ 1:30 (w/v)로 첨가한다. Considering the results of the above manufacturing experiments, the preferred conditions for producing surface-modified microspheres with a dimple structure are mixing of the oil phase and the water phase in the range of 5,000 to 15,000 rpm (1st shear), most preferably 12,000 rpm. , and when the solvent evaporates, stirring is performed in the range of 800 to 1,000 rpm (2nd shear), most preferably 1,000 rpm, and the organic solvent is mixed at 1:10 to 1:10 for the mixture of drug and surface-active biodegradable polymer in the oil phase. Add at 1:30 (w/v).
시험예 1: 표면개질 미립구의 분산 안정성 분석 Test Example 1: Dispersion stability analysis of surface-modified microspheres
제조예 1에서 제조된 타크로리무스를 함유한 표면개질(딤플 구조) 미립구 (제형 7)와 매끄러운 표면의 미립구(제형 9) 각각의 분산 안정성을 LUMiSizer를 이용하여 측정하였으며 그 결과를 각각 도 3a 및 도 3b와 표 4에 나타냈다: The dispersion stability of the surface-modified (dimple structure) microspheres (formulation 7) and smooth surface microspheres (formulation 9) containing tacrolimus prepared in Preparation Example 1 were measured using LUMiSizer, and the results are shown in Figures 3a and 3b, respectively. and shown in Table 4:
본 발명에 따른 표면개질 미립구 (딤플 구조)가 Instability Index 결과값이 낮아서 분산 안정성이 높다는 것을 확인할 수 있다. It can be confirmed that the surface-modified microspheres (dimple structure) according to the present invention have a low Instability Index result and thus have high dispersion stability.
제조예 2: 표면개질 미립구를 포함하는 마이크로니들 제조Preparation Example 2: Preparation of microneedle containing surface-modified microspheres
제조예 1에서 제조된 타크로리무스를 함유한 표면개질(딤플 구조) 미립구 (제형 7)와 매끄러운 표면의 미립구(제형 9)를 포함하는 각각 실시예 1 및 비교예 1의 마이크로니들을 제조하였다. Microneedles of Example 1 and Comparative Example 1 were prepared, respectively, including surface-modified (dimple structure) microspheres (Formulation 7) containing tacrolimus prepared in Preparation Example 1 and microspheres with a smooth surface (Formulation 9).
구체적으로는 알긴산 나트륨(Sodium alginate, ㈜썬화인글로벌) 1.0g, 트레할로스(Trehalose, ㈜썬화인글로벌) 1.0g, H2O 33g으로 제1 용액을 제조한 후, 제1 용액 9.9g과 제조예 1에서 제조된 제형 7의 표면개질 미립구 0.1g 또는 제형 9의 매끄러운 표면의 미립구를 혼합하여 볼텍싱을 5분 이상하여 입자를 분산시켜 균질화한 후, 깊이 750㎛의 피라미드 형태의 음각 실리콘 몰드에 채운 후, 몰드를 데시케이터에 넣고 -0.04 Mpa로 감압하여 30분간 유지한 후, 열풍건조기에서 50℃로 1시간 30분 건조하였다. 건조 완료된 마이크로니들은 접착테이프를 사용하여 회수한 후, 패치 모양에 맞게 가장자리를 가위를 사용하여 둥글게 재단하였고 (도 4b), 완성된 마이크로니들의 전자현미경 사진을 촬영하여 도 5에 나타냈다.Specifically, after preparing a first solution with 1.0 g of sodium alginate (Sun Fine Global Co., Ltd.), 1.0 g of trehalose (Sun Fine Global Co., Ltd.), and 33 g of H 2 O, 9.9 g of the first solution and the preparation example Mix 0.1 g of surface-modified microspheres of Formulation 7 prepared in 1 or the smooth-surface microspheres of Formulation 9, disperse and homogenize the particles by vortexing for more than 5 minutes, and fill them into a pyramid-shaped engraved silicone mold with a depth of 750㎛. Afterwards, the mold was placed in a desiccator, reduced pressure to -0.04 Mpa, maintained for 30 minutes, and then dried in a hot air dryer at 50°C for 1 hour and 30 minutes. The dried microneedles were recovered using adhesive tape, and the edges were rounded using scissors to fit the shape of the patch (FIG. 4b). An electron microscope photo of the completed microneedles was taken and shown in FIG. 5.
도 5에 도시된 바와 같이, 마이크로니들이 잘 형성되어 있음을 확인할 수 있다. As shown in Figure 5, it can be confirmed that the microneedles are well formed.
또한 완성된 실시예 1의 마이크로니들의 강도를 Texture analysers로 표 5의 조건으로 평가하였고 그 결과를 표 6에 나타냈다: In addition, the strength of the completed microneedle of Example 1 was evaluated using texture analyzers under the conditions in Table 5, and the results are shown in Table 6:
표 6에 나타낸 바와 같이, 실시예 1의 마이크로니들의 강도는 평균 2.02로 피부 침투하기에 충분한 강도를 갖는다는 것을 확인할 수 있다. As shown in Table 6, the average strength of the microneedle of Example 1 was 2.02, which confirms that it has sufficient strength to penetrate the skin.
시험예 2: 약물의 피하 체내 체류 지속성 분석Test Example 2: Analysis of persistence of drug in subcutaneous body
6주령의 수컷 SD-랫의 제모한 등피부를 취하여 in-vitro Franz cell permeation test에 장착하고 제조예 2에서 제조된 실시예 1 및 비교예 1 각각의 마이크로니들 패치를 부착하여 0.5분이 경과한 후에 마이크로니들 패치를 제거한 후 각각 0, 1, 12, 24 시간의 샘플링 시간에 등피부를 취하여 표면을 알코올 솜으로 닦아내고, HPLC 이동상으로 진탕 혼합 추출하고 추출액의 상등액을 취하여 HPLC 정량 분석하여 그 결과를 표 7 및 도 6에 나타냈다. The shaved back skin of a 6-week-old male SD-rat was taken and mounted in an in-vitro Franz cell permeation test. Each microneedle patch of Example 1 and Comparative Example 1 prepared in Preparation Example 2 was attached, and after 0.5 minutes, the microneedle patch was applied. After removing the needle patch, the back skin was taken at sampling times of 0, 1, 12, and 24 hours, respectively, and the surface was wiped with an alcohol swab, shaken and extracted with an HPLC mobile phase, and the supernatant of the extract was taken and quantitatively analyzed by HPLC. The results are shown in Table 7 and It is shown in Figure 6.
도 6 및 표 7에 나타낸 바와 같이, 24시간까지 경과 후 실시예 1의 딤플 구조의 미립구를 포함하는 마이크로니들 패치를 사용한 경우, 피하 잔존 타크로리무스의 함량이 3.3 ㎍/cm2 로 높게 잔류되었으나, 비교예 1의 매끄러운 표면의 미립구를 포함하는 마이크로니들 패치를 사용한 경우는 피하 잔존 타크로리무스의 함량이 0.3 ㎍/cm2로 잔류량이 낮았다. As shown in Figure 6 and Table 7, when the microneedle patch containing the dimple-structured microspheres of Example 1 was used after 24 hours, the content of remaining subcutaneous tacrolimus remained as high as 3.3 ㎍/cm 2 , but compared When the microneedle patch containing microspheres with a smooth surface in Example 1 was used, the residual subcutaneous tacrolimus content was low at 0.3 ㎍/cm 2 .
삽입된 미립구는 피부 탄성으로 인해서 피하에서 제거될 수 있는데, 실시예 1의 딤플 구조의 미립구는 표면 거칠기로 인해서 비교예 1의 매끄러운 표면의 미립구에 비하여 피하에서 이탈하지 않아서 체내 체류 지속성이 높은 것으로 확인된다. 따라서 본 발명에 따른 표면개질 미립구를 포함하는 마이크로니들은 체내 체류 지속성이 증진되어 결과적으로 미립구 내의 약물의 지속효 (서방성 효과)가 달성됨을 알 수 있다. The inserted microspheres can be removed from the subcutaneous tissue due to skin elasticity, but the dimple-structured microspheres of Example 1 did not escape from the subcutaneous tissue compared to the smooth-surfaced microspheres of Comparative Example 1 due to the surface roughness, confirming that the persistence of stay in the body is high. do. Therefore, it can be seen that the microneedles containing the surface-modified microspheres according to the present invention have improved retention in the body, and as a result, the sustained effect (sustained release effect) of the drug in the microspheres is achieved.
10 : 마이크로니들
11: 니들부
12: 매트리스층
20: 점착제층
30: 보호필름
100: 마이크로니들 패치10: Microneedle
11: Needle part
12: Mattress layer
20: Adhesive layer
30: Protective film
100: Microneedle patch
Claims (18)
상기 표면개질 미립구는 딤플(dimple) 구조 또는 주름의 홈이 생성되어 있는 표면을 갖는 생분해성 미립구이며,
상기 표면개질 미립구는 i) 약물 및 계면활성 생분해성 고분자를 유기 용매에 용해하여 유상을 준비하는 단계; ii) 수용성 고분자가 용해된 수상에 상기 유상을 혼합하여 수중유 에멀젼을 형성하는 단계; 및 iii) 상기 수중유 에멀젼에서 용매를 증발시켜 표면이 개질된 미립구를 얻는 단계를 포함하는 방법에 의해 제조되고,
상기 계면활성 생분해성 고분자는 폴리락테이트-코-글라이클레이트(PLGA)이고,
상기 수용성 고분자는 폴리비닐아세테이트(PVA)이고,
상기 약물은 타크로리무스이고,
상기 마이크로니들을 형성하는 용해성 재료는 알긴산, 히알루론산, 덱스트란, 셀룰로오스, 폴리비닐피롤리돈(PVP), 폴리에틸렌글리콜(PEG), 폴리비닐알코올(PVA), 나트륨 카르복시메틸셀룰로오스, 폴리알코올, 시클로덱스트린, 덱스트린, 트레할로스, 수크로스, 락토스, 만니톨, 크실리톨 및 이들의 혼합물로 이루어진 군으로부터 선택되는 어느 하나이고,
상기 마이크로니들은 피부 내에서 용해성이고 증진된 체내 체류 지속성을 갖는 것인 마이크로니들.
A microneedle containing surface-modified microspheres encapsulated with a drug,
The surface-modified microspheres are biodegradable microspheres having a surface with a dimple structure or wrinkle grooves,
The surface-modified microspheres include the steps of i) dissolving a drug and a surface-active biodegradable polymer in an organic solvent to prepare an oil phase; ii) mixing the oil phase with an aqueous phase in which water-soluble polymers are dissolved to form an oil-in-water emulsion; and iii) evaporating the solvent in the oil-in-water emulsion to obtain surface-modified microspheres,
The surface-active biodegradable polymer is polylactate-co-glyclate (PLGA),
The water-soluble polymer is polyvinylacetate (PVA),
The drug is tacrolimus,
Soluble materials forming the microneedles include alginic acid, hyaluronic acid, dextran, cellulose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), sodium carboxymethylcellulose, polyalcohol, and cyclo Any one selected from the group consisting of dextrin, dextrin, trehalose, sucrose, lactose, mannitol, xylitol, and mixtures thereof,
The microneedles are soluble in the skin and have improved persistence in the body.
The microneedle according to claim 1, wherein the average size of the microspheres is 50㎛ or less.
The microneedle according to claim 1, wherein the mixing in step ii) is performed at 5,000 to 12,000 rpm, and the evaporation in step iii) is performed under stirring at 800 to 1,000 rpm.
The microneedle of claim 1, wherein the soluble material forming the microneedle is a mixture of alginic acid and trehalose.
The microneedle according to claim 1, wherein the needle portion of the microneedle is generally one of a cone shape, a pyramid shape, a sphere shape, a brachycephalic wedge shape, and a blade shape.
The microneedle according to claim 1, wherein the length of the needle portion of the microneedle is 500 to 1000 ㎛.
A microneedle transdermal patch comprising microneedles containing surface-modified microspheres encapsulated with the drug according to claim 1.
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|---|---|---|---|
| CN202280008593.9A CN116782887A (en) | 2021-12-31 | 2022-11-18 | Microneedle comprising surface modified microsphere and method for manufacturing same |
| US18/268,812 US20240198070A1 (en) | 2021-12-31 | 2022-11-18 | Microneedles comprising surface-modified microspheres and method of preparing the same |
| JP2023541116A JP2024504918A (en) | 2021-12-31 | 2022-11-18 | Microneedles containing surface-modified microspheres and their manufacturing method |
| EP22908812.5A EP4252740A4 (en) | 2021-12-31 | 2022-11-18 | Microneedle including surface-modified microspheres and manufacturing method therefor |
| PCT/KR2022/018353 WO2023128280A1 (en) | 2021-12-31 | 2022-11-18 | Microneedle including surface-modified microspheres and manufacturing method therefor |
| KR1020230089181A KR20230110465A (en) | 2021-12-31 | 2023-07-10 | Preparation method of mcroneedle comprising surface-modified microspheres |
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| KR1020230089181A Division KR20230110465A (en) | 2021-12-31 | 2023-07-10 | Preparation method of mcroneedle comprising surface-modified microspheres |
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| KR102652671B1 (en) * | 2023-12-26 | 2024-03-29 | 주식회사 스몰랩 | Microsphere composition for microneedles of contraception and microneedles of contraception prepared by using the same |
| CN117904764B (en) * | 2024-03-19 | 2024-06-25 | 德州华源生态科技有限公司 | Tiro compact spun yarn containing wool fibers and production method and application thereof |
| CN118416282B (en) * | 2024-07-04 | 2024-09-06 | 安徽皓元药业有限公司 | Sustained-release transdermal drug-absorbing dressing and preparation method thereof |
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| KR101549086B1 (en) * | 2014-11-10 | 2015-09-02 | 주식회사 스몰랩 | Micro-needle and micro-needle patch |
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| KR102509435B1 (en) * | 2015-09-15 | 2023-03-13 | 주식회사 엘지생활건강 | Soluble microneedle patch for delivery of atopic dermatitis drug |
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| KR101549086B1 (en) * | 2014-11-10 | 2015-09-02 | 주식회사 스몰랩 | Micro-needle and micro-needle patch |
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