KR100332210B1 - Transdermal delivery matrix for anti-inflammatory agent - Google Patents
Transdermal delivery matrix for anti-inflammatory agent Download PDFInfo
- Publication number
- KR100332210B1 KR100332210B1 KR1019990054815A KR19990054815A KR100332210B1 KR 100332210 B1 KR100332210 B1 KR 100332210B1 KR 1019990054815 A KR1019990054815 A KR 1019990054815A KR 19990054815 A KR19990054815 A KR 19990054815A KR 100332210 B1 KR100332210 B1 KR 100332210B1
- Authority
- KR
- South Korea
- Prior art keywords
- inflammatory analgesic
- patch
- composition
- analgesic component
- layer
- Prior art date
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- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
Abstract
본 발명은 소염진통성분을 포함하는 경피투여 조성물 및 매트릭스형 경피투여 패취제에 관한 것으로서, 더욱 상세하게는 소염진통성분을 유효약물으로 함유하고 그 밖에도 통상의 조성성분으로서 용해제, 용해보조제, 흡수촉진제, 점착성 고분자 및 증점제가 함유되어 있으며, 특히 소염진통성분의 용해도를 높이기 위한 용해제로서 트로메타민을 그리고, 용해보조제로서 다가알콜, 극성 비양자성용매, 계면활성제를 함유시키며, 약물의 피부흡수를 촉진하기 위한 흡수촉진제로는 지방산, 지방산 유도체 또는 이들의 혼합물이 첨가되어 있어 이를 패취제로 제형화하게 되면 소염진통성분의 용해도를 크게 향상시키고 패취제를 적용하는 시간내내 소염진통성분을 효율적으로 경피전달하게되는 소염진통성분을 포함하는 경피투여 조성물과 매트릭스형 경피투여 패취제에 관한 것이다.The present invention relates to a transdermal administration composition comprising a anti-inflammatory analgesic component and a matrix transdermal patch, more specifically, an anti-inflammatory analgesic component as an effective drug, and in addition, as a conventional composition, solubilizers, dissolution aids, absorption accelerators, It contains cohesive polymer and thickener, especially Tromethamine as a dissolving agent to increase the solubility of anti-inflammatory analgesic ingredients, and polyhydric alcohol, polar aprotic solvent and surfactant as dissolution aid. As the absorption accelerator for the addition of fatty acids, fatty acid derivatives or mixtures thereof, when formulated as a patch, anti-inflammatory which greatly improves the solubility of the anti-inflammatory analgesic component and effectively transdermally transmits the anti-inflammatory analgesic component during the time of applying the patch. Percutaneous administration composition containing analgesic component and matrix type A transdermal patch.
Description
본 발명은 소염진통성분을 포함하는 경피투여 조성물 및 매트릭스형 경피투여 패취제에 관한 것으로서, 더욱 상세하게는 소염진통성분을 유효약물으로 함유하고 그 밖에도 통상의 조성성분으로서 용해제, 용해보조제, 흡수촉진제, 점착성 고분자 및 증점제가 함유되어 있으며, 특히 소염진통성분의 용해도를 높이기 위한 용해제로서 트로메타민을 그리고, 용해보조제로서 다가알콜, 극성 비양자성용매, 계면활성제를 함유시키며, 약물의 피부흡수를 촉진하기 위한 흡수촉진제로는 지방산, 지방산 유도체 또는 이들의 혼합물이 첨가되어 있어 이를 패취제로 제형화하게 되면 소염진통성분의 용해도를 크게 향상시키고 패취제를 적용하는 시간내내 소염진통성분을 효율적으로 경피전달하게되는 소염진통성분을 포함하는 경피투여 조성물과 매트릭스형 경피투여 패취제에 관한 것이다.The present invention relates to a transdermal administration composition comprising a anti-inflammatory analgesic component and a matrix transdermal patch, more specifically, an anti-inflammatory analgesic component as an effective drug, and in addition, as a conventional composition, solubilizers, dissolution aids, absorption accelerators, It contains cohesive polymer and thickener, especially Tromethamine as a dissolving agent to increase the solubility of anti-inflammatory analgesic ingredients, and polyhydric alcohol, polar aprotic solvent and surfactant as dissolution aid. As the absorption accelerator for the addition of fatty acids, fatty acid derivatives or mixtures thereof, when formulated as a patch, anti-inflammatory which greatly improves the solubility of the anti-inflammatory analgesic component and effectively transdermally transmits the anti-inflammatory analgesic component during the time of applying the patch. Percutaneous administration composition containing analgesic component and matrix type A transdermal patch.
일반적으로 패취에서 약물의 피부흡수를 증가시키기 위해서는 다음과 같은 조건이 충족되어야 한다.In general, the following conditions must be met to increase the skin absorption of drugs in patches.
첫째, 패취제내에 결정이 석출되지 않는 범위내에서 약물은 가능한한 고농도로 유지되어야 한다. 그 이유는 약물의 피부로의 분배는 패취내 약물의 농도에 비례하기 때문이다. 그러므로 패취제의 성상을 유지시키는 범위에서 가능하면 약물은 고농도로 유지되는 것이 유리하다.First, the drug should be kept as high as possible as long as crystals do not precipitate in the patch. This is because the distribution of the drug to the skin is proportional to the concentration of the drug in the patch. Therefore, it is advantageous to keep the drug as high as possible in the range of maintaining the appearance of the patch.
둘째, 대부분의 약물의 경우 그 자체로는 약효를 나타낸 정도로 흡수되기 어렵기 때문에 적절한 피부 흡수촉진제를 사용하여 약물이 각질층으로의 분배 및 확산되는 것을 증가시켜야 한다. 그러나, 패취제에서 흡수촉진제의 사용량은 한정되어 있고, 그 종류도 제한되어 있는 경우가 많다는 어려움이 있다.Second, since most drugs are not easily absorbed to the extent that they show efficacy, appropriate skin absorption promoters should be used to increase the distribution and diffusion of drugs into the stratum corneum. However, the amount of the use of the absorption accelerator in the patch is limited, and the kind is also difficult in many cases.
셋째, 패취제를 적용하는 시간동안 지속적으로 약물이 흡수될 수 있도록 적절한 점착력을 갖고 있어야 한다. 따라서, 적절한 점착제의 선정이 필요하다.Third, it must have a proper adhesive force so that the drug can be continuously absorbed during the time of applying the patch. Therefore, selection of an appropriate adhesive is necessary.
본 발명에 사용 가능한 소염진통성분은 이브프로펜(ibuprofen), 케토프로펜(ketoprofen), 플루르비프로펜(flurbiprofen), 페노프로펜(fenoprofen), 나프록센(naproxen) 등의 페닐프로피온산 유도체 계열, 피록시캄(piroxicam), 테녹시캄(tenoxicam), 이속시캄(isoxicam), 멜록시캄(meloxicam) 등의 옥시캄 유도체 계열, 그 외에도 인도메타신(indomethacin), 아세클로페낙(aceclofenac), 디클로페낙(diclofenac) 등이 있다. 이 중에서도 피록시캄은 케토프로펜, 인도메타신, 플루르프로펜, 디클로페낙 등의 다른 비스테로이드성 약물(NSAID)에 비해 약효가 강력하고 반감기가 길어 경피흡수제로 적용하기에 많은 장점을 갖고 있는 약물이다. 그러나, 상대적으로 큰 분자량(331.35)과 낮은 피부 투과성 그리고 수용액은 물론 대부분의 유기용매에 거의 녹지 않는 성질 때문에 경피흡수제로 개발하기에 단점도 많이 갖고 있다.Anti-inflammatory analgesic components that can be used in the present invention are phenylpropionic acid derivatives such as ibuprofen, ketoprofen, keruprofen, flurbiprofen, fenoprofen, and naproxen. , Oxycam derivatives such as piroxicam, tenoxicam, isoxxicam and meloxicam, as well as indomethacin, aceclofenac and diclofenac (diclofenac). Among these, pyroxycam has strong advantages over other nonsteroidal drugs (NSAIDs) such as ketoprofen, indomethacin, flurpropene, and diclofenac, and has a long half-life, which has many advantages for application as a transdermal absorbent. It is a drug. However, due to its relatively large molecular weight (331.35), low skin permeability, and insoluble in most organic solvents, there are many disadvantages in developing it as a transdermal absorbent.
따라서, 피록시캄의 낮은 용해도를 개선하여 경피흡수제제로 개발하기 위하여 미국특허 제4,678,666호에서는 저급 알콜, 물, 카복시비닐 폴리머, 알칸올아민 등을 사용하여 피록시캄의 용해성을 개선시키는 방법이 알려져 있고, 미국특허 제5,496,819호 및 제5,676,970호에서는 각각 트리아세틴 또는 트리에틸 시트레이트그리고 에틸렌 옥사이드와 폴리에틸렌 비이온성 계면활성제를 함유하는 플라스타제가 알려져 있으나, 이들의 실시예에는 단지 0.25%의 피록시캄이 포함되어 있어 피록시캄의 용해도를 크게 증가시키는 방법은 제시하지 않았다. 또한, 대한민국특허공개 제97-73591호에서는 고분자 전해질과 가속제를 사용하여 피록시캄의 용해성과 피부투과성을 획기적으로 증가시킬 수 있는 방법이 개시되어 있으나, 실시예에 제시된 경피투여 조성물은 반고체상으로 본 발명에서 제시하고자하는 매트릭스 타입의 패취형 조성물보다 실제 피부에 적용시 많은 제한이 따른다.Therefore, US Pat. No. 4,678,666 discloses a method for improving the solubility of pyroxicam by using lower alcohol, water, carboxyvinyl polymer, alkanolamine, etc. to improve the low solubility of pyroxicam. And U.S. Pat.Nos. 5,496,819 and 5,676,970, respectively, are known to have a platase containing triacetin or triethyl citrate and ethylene oxide and polyethylene nonionic surfactants, but in these examples only 0.25% of pyricampam It does not present a method for significantly increasing the solubility of pyroxicam. In addition, Korean Patent Publication No. 97-73591 discloses a method of dramatically increasing the solubility and skin permeability of pyroxicam using a polymer electrolyte and an accelerator, but the transdermal administration composition shown in the examples is semi-solid As applied to the actual skin than the patch-type composition of the matrix type to be presented in the present invention, there are many restrictions.
이상의 선행기술을 보면, 피록시캄의 용해성을 높이기 위해서 강력한 유기용매나 고분자 전해질 그리고 유기아민류 등의 염기성 물질을 가하는 방법을 많이 제시하고 있으나, 이러한 방법을 사용하여 패취제로 적용하는 데에는 무리가 따른다. 그 이유는 피록시캄을 잘 녹일 수 있는 대부분의 유기용매나 액상의 유기아민류 등을 피록시캄의 패취내 용해도를 증가시키기 위해 다량 사용할 경우, 본 발명에서 제시하고자 하는 매트릭스형 패취제의 성상을 유지하기가 힘들 뿐만 아니라 실제 피부에 적용시 패취내 액상성분의 증가로 급격한 점착력의 감소가 나타나기 때문이다. 이는 결국 약물의 피부투과력을 감소시키는 원인이 된다. 특히, 강염기성을 나타내는 유기아민을 패취내에 고농도로 함유시켜 피부에 장기간 적용할 경우에는 피부자극을 나타낼 우려가 있다.In view of the prior art, there are many methods of adding basic substances such as a strong organic solvent, a polymer electrolyte, and organic amines in order to increase the solubility of pyroxicam, but it is difficult to apply them as a patch using such a method. The reason for this is that when a large amount of organic solvents or liquid organic amines that can dissolve pyoxycham are used in a large amount to increase the solubility in pyrokoxy patch, the properties of the matrix patch proposed by the present invention are maintained. Not only is it hard to do, but when applied to the actual skin due to the increase in the liquid component in the patch is a sharp decrease in adhesion. This in turn causes a decrease in the skin penetration of the drug. In particular, when organic amines exhibiting strong basicity are contained in the patch at a high concentration and applied to the skin for a long time, there is a fear of showing skin irritation.
이에 본 발명자들은 패취내 유효약물의 고농도화 및 물리적인 안정성, 피부투과성 개선을 위한 흡수촉진제의 개발, 그리고 피부부작용이 없는 패취의 개발을 위하여 집중적으로 연구노력하였다. 그 결과 소염진통성분을 유효약물로 하는 조성물에 용해제로서 트로메타민을 함유시키고, 용해보조제로서 다가알콜, 극성 비양자성 용매 및 계면활성제 등을 첨가하고, 흡수촉진제로는 지방산, 지방산 유도체 또는 이들의 혼합물을 함유시키면 소정의 요건을 갖춘 패취제를 제조할 수 있음을 알게됨으로써 본 발명을 완성하게 되었다.Accordingly, the present inventors have intensively researched for the development of high concentration and effective physical stability of the effective drug in the patch, the absorption accelerator for improving skin permeability, and the development of the patch without skin side effects. As a result, tromethamine is contained as a dissolving agent in a composition having an anti-inflammatory analgesic ingredient, and polyhydric alcohol, a polar aprotic solvent and a surfactant are added as a dissolving aid. The present invention has been completed by knowing that the inclusion of a mixture allows the preparation of a patch with the required requirements.
따라서, 본 발명에서는 트로메타민을 이용하여 소염진통성분의 패취내 용해도를 효과적으로 극대화시키고 지방산과 지방산 유도체에 의한 유효약물의 경피흡수를 획기적으로 높일 수 있는 소염진통성분의 경피투여 조성물과 매트릭스형 경피투여 패취제를 제공하는데 그 목적이 있다.Therefore, the present invention effectively maximizes the solubility in the patch of anti-inflammatory analgesic components using tromethamine, and transdermal administration composition and matrix-dermal transdermal composition of anti-inflammatory analgesic components that can dramatically increase the percutaneous absorption of effective drugs by fatty acids and fatty acid derivatives. The purpose is to provide a dosage patch.
도 1은 본 발명에 따른 소염진통성분 패취제의 단면도이고,1 is a cross-sectional view of the anti-inflammatory analgesic patch according to the present invention,
도 2는 본 발명의 패취제와 종래의 패취제에 대한 혈장중 피록시캄 농도를 비교한 그래프이다.FIG. 2 is a graph comparing plasma concentrations of pyroxicam for the patch of the present invention and the conventional patch.
<도면의 주요 부분에 대한 부호의 설명><Explanation of symbols for main parts of the drawings>
1 : 외부배면층 2 : 점착제층1: outer back layer 2: adhesive layer
3 : 내부배면층 4 : 매트릭스층3: internal backing layer 4: matrix layer
5 : 박리층5: release layer
본 발명은 이브프로펜, 케토프로펜, 플루르비프로펜, 페노프로펜, 나프록센 등의 페닐프로피온산 유도체 계열, 피록시캄, 테녹시캄, 이속시캄, 멜록시캄 등의 옥시캄 유도체 계열, 그 외에도 인도메타신, 아세클로페낙, 디클로페낙 등의 소염진통성분을 유효약물으로 하고, 그 밖에도 통상의 조성성분으로서 용해제, 용해보조제, 흡수촉진제, 점착성 고분자 및 증점제가 함유되어 있는 경피투여 조성물에 있어서,The present invention relates to oxycamp derivatives such as phenylpropionic acid derivatives such as ibuprofen, ketoprofen, flurbiprofen, phenopropene, and naproxen, pyoxycamp, tenoxycamp, isoximecam, meloxycamp and the like. In the transdermal administration composition containing anti-inflammatory analgesic ingredients such as indomethacin, aceclofenac, diclofenac, etc., as an effective drug, and other common composition ingredients, such as solubilizers, dissolution aids, absorption accelerators, adhesive polymers, and thickeners. ,
상기 유효약물이 전체 조성물중에 0.1 ∼ 30 중량%; 상기 용해제로서 트로메타민이 전체 조성물중에 0.04 ∼ 12 중량%; 상기 용해보조제로서 다가알콜, 극성비양자성 용매 및 계면활성제 중에서 선택된 단독 또는 2종 이상의 혼합물이 전체 조성물중에 0.5 ∼ 30 중량%; 상기 흡수촉진제로서 지방산, 지방산 유도체 또는 이들의 혼합물이 전체 조성물중에 0.1 ∼ 20 중량%; 상기 점착성 고분자가 전체 조성물중에 30 ∼ 90 중량%; 그리고 상기 증점제가 전체 조성물중에 0.5 ∼ 30 중량% 함유되어 있는 경피투여 조성물을 그 특징으로 한다.The effective drug is 0.1-30% by weight of the total composition; Tromethamine is 0.04 to 12% by weight of the total composition as the solubilizer; 0.5-30% by weight of a single or a mixture of two or more selected from polyhydric alcohols, polar aprotic solvents and surfactants as the dissolution aids; 0.1-20% by weight of the fatty acid, fatty acid derivative or a mixture thereof as the absorption promoter in the total composition; 30 to 90% by weight of the adhesive polymer in the total composition; And a transdermal composition containing 0.5 to 30% by weight of the thickener in the total composition.
또한, 본 발명은 약물의 투과를 막아주는 외부배면층(1), 내부배면층과 피부의 점착을 도와주는 점착제층(2), 매트릭스층과 접하는 내부배면층(3), 상기한 소염진통성분의 경피투여 조성물이 단층 또는 다층구조를 이루고 있는 매트릭스층(4), 그리고 매트릭스층 하부에 박리가 가능토록 부착된 박리층으로 구성되어 있는 매트릭스형 경피투여 패취제를 또다른 특징으로 한다.In addition, the present invention is the outer back layer (1) to prevent the penetration of the drug, the inner back layer and the adhesive layer (2) to help the adhesion of the skin, the inner back layer (3) in contact with the matrix layer, the anti-inflammatory analgesic component described above The matrix transdermal patch is composed of a matrix layer (4) having a single or multi-layer structure, and a release layer adhered to the bottom of the matrix layer to enable peeling.
이와 같은 본 발명을 더욱 상세하게 설명하면 다음과 같다.The present invention will be described in more detail as follows.
본 발명에 따른 경피투여 조성물에는 소염진통성분의 유효약물, 용해제, 용해보조제, 흡수촉진제, 점착성 고분자 및 증점제가 함유되어 있으며, 이들 각 조성성분에 대하여 보다 구체적으로 설명하면 다음과 같다.The transdermal administration composition according to the present invention contains an effective drug of an anti-inflammatory analgesic component, a dissolving agent, a dissolving aid, an absorption accelerator, an adhesive polymer, and a thickening agent, which will be described in more detail with respect to each of these components.
먼저, 유효약물은 매트릭스층을 구성하는 전체 조성물중에 0.1 ∼ 30 중량% 함유시킨다. 만일, 유효약물의 함량이 0.1 중량% 미만이면 원하는 약물의 효과를 기대할 수 없고, 30 중량%를 초과하면 약물의 결정이 석출될 뿐만 아니라 점착력이 감소하는 문제가 있다.First, the effective drug is contained in an amount of 0.1 to 30% by weight in the total composition constituting the matrix layer. If the effective drug content is less than 0.1% by weight, the effect of the desired drug cannot be expected, and if it exceeds 30% by weight, the drug crystals are precipitated as well as the adhesive strength is reduced.
그리고, 용해제로서 함유되는 트로메타민은 매트릭스층을 구성하는 전체 조성물중에 0.04 ∼ 12 중량% 범위내에서 함유시킨다. 만일, 트로메타민의 함량이 0.04 중량% 미만이면 유효약물의 용해도 향상효과를 얻을 수 없고, 12 중량%를 초과하면 필요이상의 트로메타민 결정이 잔류하여 바람직하지 않다.And tromethamine contained as a solubilizer is contained in 0.04-12 weight% in the whole composition which comprises a matrix layer. If the content of tromethamine is less than 0.04% by weight, the effect of improving the solubility of the effective drug cannot be obtained, and if it exceeds 12% by weight, more than necessary tromethamine crystals remain undesirably.
본 발명이 용해제로서 특징적으로 사용하고 있는 트로메타민(Trometamine)은 종래의 용해제와는 커다란 차이가 있는 바, 종래의 약알칼리성을 나타내는 트리에탄올아민은 용해력이 매우 낮은 반면 트로메타민은 동일한 약알칼리성을 나타내지만 소염진통성분 특히 피록시캄을 비롯한 옥시캄계열의 소염진통성분에 대한 용해력이 현저하게 우수하다. 미국특허 제4,678,666호에서는 알칸올아민 등의 유기아민(디에탄올아민, 디이소프로판올아민)으로 피록시캄의 용해성을 향상시킬 수 있다고 하였으나, 이는 피록시캄 겔상 연고제로서 피록시캄의 함량은 0.3 ∼ 2 중량%에 불과하였고, 피록시캄을 녹이기 위해 사용된 유기아민의 함량이 1 ∼ 3 중량%이며, 실제로 실시예에 사용된 알칸올아민은 디에탄올아민, 디이소프로판올아민으로 모두 강염기성을 나타내는 것이다. 상기한 바와 같이 소염진통성분 유효약물의 용해도를 높이기 위해 종래에 사용되어온 대부분의 유기아민이 강염기성을 나타내기 때문에 패취내에 고농도로 유기아민이 존재할 경우에 피부자극을 나타낼 우려가 있을 뿐만 아니라 패취내에 존재하는 다른 성분들과의 반응으로 패취의 안정성에 악영향을 미칠 우려가 많다. 실제로 소염진통성분 유효약물을 피록시캄으로 하고 디에탄올아민, 디이소프로판올아민 등을 용해제로 사용하여 본 발명에서와 같은 패취를 제조할 경우, 조제액은 시간경과에 따라 짙은 갈색으로 변색되며 변색 전에 85℃에서 건조시켜도 마찬가지로 짙은 갈색으로 변색된다. 그러나, 트로메타민을 사용하여 제조하면 장시간에 걸쳐 처음 조제상태 그대로 존재하며, 건조후에도변색이 되지 않는다. 또한, 트로메타민은 약알칼리로서 소염진통성분 유효약물의 용해제로서 고농도로 사용되어도 피부부작용을 나타내지 않는다. 따라서, 본 발명에서는 필수적으로 트로메타민을 사용하는 것이 바람직하고, 필요에 따라서는 트리에탄올아민, 에틸렌디아민, 디이소프로필아민, 디에틸아민, 에탄올아민, 디에탄올아민, 이소프로필아민, 이소프로판올아민 등도 함께 사용할 수 있다.Tromethamine (Trometamine) which is characteristically used as a dissolving agent in the present invention has a great difference from conventional dissolving agents. The triethanolamine exhibiting the weak alkalinity has very low solubility while tromethamine has the same weak alkali property. Although the anti-inflammatory analgesic component, in particular, the solubility of the anti-inflammatory analgesic component of the oxycham series, including pyroxicam. In U.S. Patent No. 4,678,666, organic amines such as alkanolamines (diethanolamine, diisopropanolamine) can improve the solubility of pyrocampum, but the content of pyrocampam as a pyrocampam gel ointment is 0.3- Only 2% by weight, the content of the organic amine used to dissolve the pyricampam 1 to 3% by weight, in fact the alkanolamine used in the examples are both diethanolamine, diisopropanolamine showing strong basicity will be. As described above, since most organic amines conventionally used to increase the solubility of an anti-inflammatory analgesic active drug exhibit strong base properties, there is a risk of skin irritation when high concentrations of organic amines are present in the patch, Reaction with other components present is likely to adversely affect the stability of the patch. In fact, when an anti-inflammatory analgesic active drug is used as a hydroxycam and diethanolamine, diisopropanolamine, etc. as a dissolving agent to prepare a patch as in the present invention, the preparation is discolored to dark brown over time and before discoloration Drying at 85 DEG C also turns dark brown. However, when prepared using tromethamine, it is present as it is first prepared for a long time, and does not discolor after drying. In addition, tromethamine, as a weak alkali, does not show any side effects even when used in high concentrations as a dissolving agent for an anti-inflammatory analgesic active drug. Therefore, in the present invention, it is preferable to essentially use tromethamine, and if necessary, triethanolamine, ethylenediamine, diisopropylamine, diethylamine, ethanolamine, diethanolamine, isopropylamine, isopropanolamine, etc. Can be used together
또한, 소염진통성분 패취에서 소염진통성분의 피부투과성을 높이기 위해서는 패취내에 소염진통성분을 고농도로 용해시키는 것이 아주 중요하다. 그러기 위해서는 용해제의 패취내 농도도 높아지게 되는데, 상온에서 액체로 존재하는 대부분의 유기아민류 등은 패취내 고농도로 존재하면 패취의 고형분 함량을 낮추어 점착력을 감소시킴과 동시에 매트릭스층의 물성에 악영향을 주게 된다. 그러나, 트로메타민의 경우에는 다른 아민류와는 달리 상온에서는 고체상으로 존재하기 때문에 패취제 적용시 사용량에 큰 제한이 따르지 않아 소염진통성분의 패취내 농도를 효과적으로 높일 수 있을 뿐만 아니라 패취내의 고형분의 함량을 높여 패취의 점착성, 안정성 등의 성상에 많은 이점이 있다.In addition, in order to increase the skin permeability of the anti-inflammatory analgesic patch in an anti-inflammatory analgesic patch, it is very important to dissolve the anti-inflammatory analgesic component in a high concentration. To this end, the concentration in the patch of the solvent is also increased. Most organic amines present in the liquid at room temperature, when present in high concentrations in the patch, lower the solids content of the patch to reduce adhesion and adversely affect the physical properties of the matrix layer. . However, in the case of tromethamine, unlike other amines, since it exists in the solid phase at room temperature, the use of the patch does not have a large limit on the amount of anti-inflammatory analgesic, which effectively increases the concentration in the patch and increases the content of solids in the patch. There are many advantages in properties such as adhesiveness and stability of the patch.
한편, 본 발명에서는 소염진통성분의 유효약물을 고농도의 용해상태로 유지시키기 위한 용해보조제로서 용매가 함유되는 바, 예컨대 용해보조제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 디프로필렌글리콜, 디에틸렌글리콜, 디에틸렌글리콜 모노에틸에테르, 글리세롤 등을 포함하는 다가알콜; 디메틸설폭사이드, 디메틸아세트아미드, 디메틸포름아미드, N-알킬 피롤리딘 등을 포함하는 극성 비양자성 용매; 트윈 80, 라브라솔(Labrasol), 크레모포(Cremophor) 등을 포함하는 계면활성제 등이 사용될 수 있다. 이러한 용해보조제는 단독 또는 2종 이상의 혼합 사용이 가능하며, 매트릭스층을 구성하는 전체 조성물중에 0.5 ∼ 30 중량% 범위내에서 함유시키는 것이 바람직하다.On the other hand, the present invention contains a solvent as a dissolution aid for maintaining the effective drug of the anti-inflammatory analgesic in a high concentration of dissolution, for example, propylene glycol, polyethylene glycol, dipropylene glycol, diethylene glycol, diethylene Polyhydric alcohols including glycol monoethyl ether, glycerol and the like; Polar aprotic solvents including dimethylsulfoxide, dimethylacetamide, dimethylformamide, N-alkyl pyrrolidine and the like; Surfactants including Tween 80, Labrasol, Cremophor and the like can be used. These dissolution aids may be used alone or in combination of two or more, and are preferably contained within the range of 0.5 to 30% by weight in the total composition constituting the matrix layer.
한편, 본 발명에서는 소염진통성분 유효약물의 피부흡수를 더욱 촉진시키기 위해 약물을 패취내에서 고농도로 유지시키기 위한 용해제 및 용해보조제외에도 흡수촉진제로서 지방산, 지방산 유도체 또는 이들의 혼합물을 사용한다. 미국특허 제5,196,410호에서는 수용성 알콜 용매를 특징으로 하여 이것과 1-알킬아자시클로헵탄-2-온 및 올레인산이 흡수촉진제로 구성되는 피록시캄 등의 경피투여용 흡수증진 조성물을 제시되어 있으나, 이러한 방법은 저장고 형태(Reservoir type)의 패취제나, 겔, 에멀젼 및 연고 등의 제형에 적용이 가능하고 매트릭스형 패취를 조제하는데 직접적인 적용이 불가능하다.Meanwhile, in the present invention, in order to further promote skin absorption of an anti-inflammatory analgesic active drug, fatty acids, fatty acid derivatives, or mixtures thereof are used as absorption accelerators in addition to dissolving agents and dissolution aids for maintaining the drug in high concentrations in patches. U.S. Pat.No. 5,196,410 discloses a transdermal absorption enhancing composition such as pyroxicam, which is characterized by a water-soluble alcohol solvent and 1-alkylazacycloheptan-2-one and oleic acid composed of an absorption accelerator. The method is applicable to formulations such as reservoir type patches, gels, emulsions and ointments and is not directly applicable to the preparation of matrix patches.
본 발명이 흡수촉진제로 조성물중에 함유시키게 되는 지방산으로는 올레인산, 리놀레인산, 라우릴산, 팔미틴산, 스테아린산, 카프린산, 카르릴산, 미리스틴산 등을 사용할 수 있다. 그리고, 지방산 유도체로는 올레일알콜, 스테아릴알콜과 같은 지방산 알콜, 이소프로필 미리스테이트, 프로필렌글리콜 카프릴레이트, 프로필렌글리콜 라우레이트, 폴리에틸렌글리콜 라우레이트, 프로필렌글리콜 올레에이트 같은 지방산 에스테르, 1-도데실아자시클로헵탄-2-온, 라우릴 디메탄올아미드와 같은 지방산 알칸올아미드를 사용할 수 있다. 이러한 흡수촉진제는 단독 혹은 2종 이상을 혼합하여 사용하며, 그 총량은 매트릭스층을 구성하는 전체 조성물중에 0.1 ∼ 20 중량% 범위로 함유시키도록 한다.As the fatty acid to be contained in the composition as the absorption promoter of the present invention, oleic acid, linoleic acid, lauryl acid, palmitic acid, stearic acid, capric acid, carlylic acid, myristic acid and the like can be used. Fatty acid derivatives include fatty acid alcohols such as oleyl alcohol and stearyl alcohol, isopropyl myristate, propylene glycol caprylate, propylene glycol laurate, fatty acid esters such as polyethylene glycol laurate, propylene glycol oleate, 1-dode Fatty acid alkanolamides such as silacycloheptan-2-one, lauryl dimethanolamide can be used. These absorption accelerators are used alone or in combination of two or more, the total amount is to be contained in the range of 0.1 to 20% by weight in the total composition constituting the matrix layer.
그리고, 본 발명의 경피투여 조성물에는 점착성 고분자가 함유되는 바, 점착성 고분자로는 의약적으로 사용이 가능한 감압성 점착성 성분으로서 수계 또는 유기용매 물질들이 사용될 수 있다. 이런 점착성 고분자 물질로는 아크릴레이트 중합체, 비닐아세테이트-아크릴레이트 공중합체 등의 아크릴계 수지를 사용할 수 있고, 이 밖에도 로진계 수지, 폴리테르펜 수지, 석유계 수지, 테르펜 페놀 수지, 실리콘 중합체, 천연 또는 합성고무류 또는 이들의 혼합물을 사용할 수 있다. 상기한 점착성 고분자는 단독 혹은 2종 이상을 혼합하여 사용하며, 매트릭스층을 구성하는 전체 조성물중에 30 ∼ 90 중량% 범위로 함유시키도록 한다.In addition, the transdermal administration composition of the present invention may contain an adhesive polymer, and as the adhesive polymer, water-based or organic solvent materials may be used as the pressure-sensitive adhesive component that can be used pharmaceutically. As such a tacky polymer material, an acrylic resin such as an acrylate polymer or a vinyl acetate-acrylate copolymer may be used. In addition, a rosin resin, a polyterpene resin, a petroleum resin, a terpene phenol resin, a silicone polymer, natural or synthetic Rubbers or mixtures thereof can be used. Said adhesive polymer is used individually or in mixture of 2 or more types, It is made to contain in 30 to 90 weight% of the whole composition which comprises a matrix layer.
한편, 본 발명에서는 매트릭스층의 점착성, 내구성, 안정성 등의 물리적인 성질을 더욱 향상시킬 목적으로 증점제를 사용한다. 증점제로는 폴리비닐피롤리돈, 폴리비닐알콜, 하이드록시프로필셀룰로오스, 카르복시메틸셀룰로오스, 카보풀 등을 사용하며, 바람직하기로는 증점제로서 폴리비닐피롤리돈을 사용한다. 상기한 증점제는 단독 혹은 2종 이상을 혼합하여 사용하며, 매트릭스층을 구성하는 전체 조성물중에 0.5 ∼ 30 중량% 범위로 함유시키도록 한다.On the other hand, in the present invention, a thickener is used for the purpose of further improving physical properties such as adhesion, durability and stability of the matrix layer. As the thickener, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, carboxymethyl cellulose, carbofull, and the like are used. Preferably, polyvinylpyrrolidone is used as the thickener. Said thickener is used individually or in mixture of 2 or more types, It is made to contain in 0.5 to 30 weight% in the whole composition which comprises a matrix layer.
또한, 본 발명은 상기한 바와 같은 경피투여 조성물을 이용하여 제형화한 매트릭스형 경피투여 패취제를 포함하는 바, 본 발명에 따른 패취제의 구조는 첨부도면 도 1에 도시하였다.In addition, the present invention includes a matrix type transdermal patch prepared by using the transdermal composition as described above, the structure of the patch according to the present invention is shown in Figure 1 attached.
도 1에 나타낸 소염진통성분 패취는 신체 어느 부위의 피부에 적용하여도 효과적으로 약물을 경피투여시킬 수 있도록 5가지 구성물로 설계되어 있다. 즉, 약물의 투과를 막아주는 외부배면층(1), 외부배면층과 내부배면층 사이의 접착 및매트릭스층과 피부와의 점착을 도와주는 점착제층(2), 매트릭스층과 직접 접하는 내부배면층(3), 상기한 소염진통성분의 경피투여 조성물이 단층 또는 다층구조를 이루고 있는 매트릭스층(4), 그리고 매트릭스층 하부에 박리가 가능토록 부착된 박리층(5)으로 구성되어 있다.The anti-inflammatory analgesic patch shown in FIG. 1 is designed with five components so that the drug can be effectively transdermally applied to the skin of any part of the body. That is, the outer back layer (1) that prevents the drug permeation, the adhesive layer between the outer back layer and the inner back layer and the adhesive layer (2) to help the adhesion between the matrix layer and the skin, the inner back layer directly in contact with the matrix layer (3) The above-described anti-inflammatory analgesic composition is composed of a matrix layer 4 having a single layer or a multilayer structure, and a peeling layer 5 attached to the matrix layer so as to be peeled off.
외부배면층(1)은 매트릭스층(4)내의 약물이 투과되지 아니하며 투습성과 신축성이 좋은 재질로 이루어진 것으로서, 예컨대 폴리우레탄 또는 폴리에틸렌 필름 등이 사용될 수 있다.The outer back layer 1 is made of a material which is not permeable to the matrix layer 4 and has good moisture permeability and elasticity. For example, a polyurethane or polyethylene film may be used.
상기한 외부배면층의 안쪽면에 있는 점착제층(2)은 아크릴계 점착제로 구성된다.The pressure-sensitive adhesive layer 2 on the inner side of the outer back layer is composed of an acrylic pressure-sensitive adhesive.
내부배면층(3)은 외부배면층과 동일한 재질로 구성되며, 도 1에 나타낸 패취제를 용이하게 성형할 목적으로 형성된다. 본 발명에 따른 매트릭스형 경피투여 패취에 있어서, 상기 내부배면층이 형성되지 않는다 하더라도 본 발명의 목적에 어긋나는 것은 아니다.The inner back layer 3 is made of the same material as the outer back layer, and is formed for the purpose of easily molding the patch shown in FIG. In the matrix type transdermal administration patch according to the present invention, even if the inner back layer is not formed, it does not contradict the object of the present invention.
상기 외부배면층(1)과 내부배면층(3)의 두께는 각각 40 ∼ 300 ㎛, 10 ∼ 40 ㎛가 적당하다. 각각의 층 두께가 상기 범위를 벗어나는 경우 굴곡부위의 피부에 적용시 적절한 유연성을 잃어 점착력이 감소하기 때문에 바람직하지 않다.The thickness of the outer back layer 1 and the inner back layer 3 is preferably 40 to 300 µm and 10 to 40 µm, respectively. If the thickness of each layer is out of the above range, it is not preferable because it loses the proper flexibility when applied to the skin of the bent portion and the adhesion decreases.
매트릭스층(4)은 필요에 따라 단층 또는 다층으로 형성시킬 수 있다. 다층으로 형성시키는 경우에는 제조의 편의를 위하여 매트릭스층(4)을 구성하는 각 층의 조성을 같게 하거나, 아니면 조성을 서로 다르게 변화시켜서 내부배면층(3)에서 가장 먼곳에 위치하는 층이 가장 빠른 피부침투가 가능하게 하면서 차례로 중첩되게 층을 형성하여 활성성분의 확산 침투속도가 가장 낮은 경우를 내부배면층(3)에 가장 가깝게 위치되도록 할 수도 있다. 다층으로는 3층 정도가 가장 바람직하다.The matrix layer 4 can be formed in a single layer or multiple layers as necessary. In the case of forming a multilayer, the composition of each layer constituting the matrix layer 4 is made the same for the convenience of manufacturing, or the composition is changed differently so that the layer located farthest from the inner back layer 3 is the fastest skin penetration. In this case, the layers may be formed to overlap each other while enabling the case where the diffusion penetration rate of the active ingredient is lowest to be located closest to the inner back layer 3. As a multilayer, about 3 layers are the most preferable.
매트릭스층(4)과 외부배면층(1)은 원형, 사각형 또는 타원형 등의 다양한 형태로 만들 수 있다. 박리층(5)은 매트릭스층과 접하는 면이 실리콘으로 코팅된 폴리에틸렌 필름 또는 종이 등이 사용될 수 있다.The matrix layer 4 and the outer back layer 1 may be made in various shapes such as circular, square or elliptical. The release layer 5 may be a polyethylene film or paper coated with silicon on the surface contacting the matrix layer.
상술한 바와 같이 본 발명에 따른 소염진통성분 약물 함유 경피투여 조성물을 이용하여 통상의 방법으로 경피흡수제로 제형화한 패취는 약효가 강력하고 반감기가 길어 경피흡수제로 적절한 소염진통성분에 대한 용해도를 높이고, 흡수촉진제의 배합을 달리함으로써 약물의 피부투과도를 높일 수 있는 효과가 있다.As described above, the patch formulated as a transdermal absorbent by the conventional method using the anti-inflammatory analgesic drug-containing transdermal composition according to the present invention has a strong medicinal effect and a long half-life, so as to increase the solubility for the appropriate anti-inflammatory analgesic component as a transdermal absorbent. By varying the combination of absorption accelerators, there is an effect that can increase the skin permeability of the drug.
이와 같은 본 발명을 실시예에 의거하여 상세하게 설명하겠는 바, 본 발명이 실시예에 한정되는 것은 아니다.Although this invention is demonstrated in detail based on an Example, this invention is not limited to an Example.
실시예 1 ∼ 13Examples 1 to 13
먼저 에탄올과 용해보조제 혼합액에 폴리비닐피롤리돈(Kollidon 25)을 용해시키고, 피록시캄과 트로메타민을 차례로 가하여 완전히 용해될 때까지 교반한 다음, 흡수촉진제를 가하여 충분히 혼합하였다. 이 용액에 점착성 고분자 용액을 가하여 10여분간 충분히 교반한 다음, 기포를 제거하였다. 이 혼합물을 박리층에 원하는 약물 함량(㎎/㎠)이 되도록 적절한 두께(800 ∼ 1000 ㎛)로 도포한 후, 85℃에서 10분간 건조시켜 에탄올과 점착제의 휘발성 용매를 제거하였다. 건조후에는 내부배면층으로 노출된 매트릭스층면을 덮었다. 이와 같이 제조된 패취를 적절한 크기로 절단하였다. 1회 용량 단위는 1 ∼ 200 ㎠ 범위의 표면적을 가지며, 바람직하게는 5 ∼ 60 ㎠를 갖는다. 절단된 패취의 내부배면층을 외부배면층의 점착제층에 부착한 후, 박리층을 떼어내고 다시 큰 박리층으로 덮어서 피록시캄 패취를 제조하였다.First, polyvinylpyrrolidone (Kollidon 25) was dissolved in a mixture of ethanol and a dissolution aid, pyricam and tromethamine were added sequentially, followed by stirring until complete dissolution. Then, an absorption accelerator was added and mixed sufficiently. A viscous polymer solution was added to this solution, and the mixture was sufficiently stirred for 10 minutes to remove bubbles. The mixture was applied to the release layer in an appropriate thickness (800-1000 μm) so as to have a desired drug content (mg / cm 2), and then dried at 85 ° C. for 10 minutes to remove volatile solvents of ethanol and pressure-sensitive adhesive. After drying, the surface of the matrix layer exposed by the inner back layer was covered. The patch thus prepared was cut to an appropriate size. The single dose unit has a surface area in the range of 1 to 200 cm 2, preferably 5 to 60 cm 2. After attaching the inner back layer of the cut patch to the pressure-sensitive adhesive layer of the outer back layer, the peeling layer was removed and again covered with a large peeling layer to prepare a pyrocampal patch.
실험예 1 :피부흡수시험 Experimental Example 1: Skin Absorption Test
제조된 피록시캄 패취의 피부흡수도를 측정해보기 위하여 무모 마우스(hairless mouse) 피부를 이용한 피부흡수시험을 실시하였다. 무모 마우스(종:SKHI, female, 6∼8주령)의 피부를 실험 직전에 적출하여 프란쯔 타입의 확산기구(Franz-type diffusion cell)의 중간에 각질층 부분이 위로 향하도록 피부를 고정하였다. 리셉터에는 0.05M 등장인산염 완충용액(pH 7.4)을 넣고, 37℃로 유지시키며 마그네틱 교반기로 600 rpm의 교반속도로 일정하게 교반하였다. 각 실시예에서 제조한 패취를 피부에 부착시킨 후, 일정 시간마다 리셉터 부분의 용액을 채취하고 채취한 양만큼의 새로운 완충용액을 보충해 주었다. 채취한 시료중의 피록시캄 농도는 액체크로마토그래피(HPLC)로 측정하였다. 분석조건은 다음과 같다.In order to measure the skin absorbance of the prepared pyoxycamp patch, a skin absorption test using hairless mouse skin was performed. The skin of hairless mice (species: SKHI, female, 6-8 weeks old) was extracted immediately before the experiment, and the skin was fixed so that the stratum corneum layer faced up in the middle of a Franz-type diffusion cell. 0.05M isotonic phosphate buffer (pH 7.4) was added to the receptor, and maintained at 37 ° C., and stirred constantly at a stirring speed of 600 rpm with a magnetic stirrer. After attaching the patch prepared in each example to the skin, the solution of the receptor portion was taken at regular intervals and supplemented with fresh buffer solution in the amount of the collected amount. Pyroxycam concentration in the collected sample was measured by liquid chromatography (HPLC). The analysis conditions are as follows.
< 분석조건 ><Analysis condition>
·컬럼 : CAPCELL PAK C18(10μ, 4.6×150 ㎜)Column: CAPCELL PAK C18 (10μ, 4.6 × 150 mm)
·이동상 : 아세토니트릴/0.05M 인산염완충액(pH 3.3) = 60/40Mobile phase: Acetonitrile / 0.05 M phosphate buffer (pH 3.3) = 60/40
·유속 : 1.0 ㎖/분Flow rate: 1.0 ml / min
·검출기 : 자외선 358 ㎚Detector: UV 358 nm
다음 표 1은 경피투여 조성물중에 함유되는 유효약물을 피록시캄으로 하고, 용해제, 용해보조제 및 점착제의 종류와 함량을 변화시켰을때의 약물함량, 피부흡수정도 및 점착력에 대한 시험결과이다.Table 1 shows the test results for drug content, skin absorption and adhesive strength when the effective drug contained in the transdermal administration composition was pyroxicam, and the type and content of the dissolving agent, dissolving aid, and pressure-sensitive adhesive were changed.
상기 표 1의 결과에 따르면, 패취내 유효약물의 함량이 증가함에 따라 플럭스가 증가하는 바, 패취내 고농도의 피록시캄 유지가 패취제의 약효에 지대한 영향을 미침을 알 수 있다. 또한, 본 발명은 피록시캄의 용해제로서 특징적으로 사용하고 있는 트로메타민을 사용하여 피록시캄의 함유량을 높일 수 있었고, 많은 양(30 중량% 정도)의 피록시캄이 함유되어도 석출없이 고농도로 존재함을 보여준다.According to the results of Table 1, as the flux increases as the content of the effective drug in the patch, it can be seen that the high concentration of pyroxicam in the patch has a significant effect on the efficacy of the patch. In addition, the present invention was able to increase the content of pyroxicam by using tromethamine, which is characteristically used as a dissolving agent of pyroxicam, and high concentration without precipitation even when a large amount (about 30% by weight) of pyroxicam is contained. To be present.
이에 반하여 용해제로서 트리에탄올아민이 함유된 패취(비교예 1 ∼ 3)는 실시예 1 ∼ 5에 비해 훨씬 낮은 플럭스를 나타내는데, 이는 트리에탄올아민이 트로메타민을 용해제로 사용할 경우에 비해 패취내 존재하는 피록시캄에 대한 용해력이 매우 낮음을 보여주는 결과이다. 또한 점착력 시험 결과, 실시예 1 ∼ 5의 패취제가 비교예 1 ∼ 3의 패취제에 비해 매우 점착력이 우수함을 알 수 있다.In contrast, patches containing triethanolamine as a dissolving agent (Comparative Examples 1 to 3) show much lower fluxes than Examples 1 to 5, which indicates that the triethanolamine contained blood in the patch as compared to using tromethamine as a dissolving agent. The results show that the dissolving ability to roxycam is very low. Moreover, as a result of the adhesion test, it turns out that the patch of Examples 1-5 is very excellent compared with the patch of Comparative Examples 1-3.
다음 표 2는 약물을 피록시캄으로 하고 경피투여 조성물중에 함유되는 용해보조제, 흡수촉진제 및 점착제의 종류와 함량을 변화시켰을때의 약물함량, 피부흡수정도 및 점착력에 대한 시험결과이다.The following Table 2 shows the test results for drug content, skin absorption and adhesion when the type and content of the dissolution aid, absorption accelerator, and pressure-sensitive adhesive contained in the transdermal administration composition are defined as pyroxicam.
상기 표 2의 결과에 의하면, 동일양의 유효약물이 함유되어도 흡수촉진제의 함유 형태에 따라 피부흡수증진효과가 서로 다름을 알 수 있다.According to the results of Table 2, it can be seen that even if the same amount of effective drug is contained, the skin absorption promoting effect is different depending on the form of the absorption accelerator.
실시예 14 ∼ 19Examples 14-19
다음 표 3은 유효약물로서 여러 소염진통성분을 함유시켰을때의 약물함량에 대한 시험결과이다.Table 3 below shows the test results for drug content when various anti-inflammatory drugs were included as effective drugs.
실험예 2 :피록시캄-트로메타민 염의 용해도 Experimental Example 2: Solubility of the Pyroxycam-Trommethamine Salt
적절한 용해보조제 선택을 위하여, 여러 용매 및 계면활성제에 대한 피록시캄-트로메타민 염의 용해도를 측정하였다. 측정 방법은 피록시캄과 트로메타민을 당량으로 반응시켜 만든 염을 각각의 용매에 일정과량 넣은 후, 30℃에서 3시간 동안 초음파로 진탕시켜 용액의 피록시캄 농도를 스텍트로메타를 사용하여 정량하였다. 각 용매 또는 계면활성제에 대한 피록시캄의 용해도 측정 결과를 다음 표 4에 나타내었다.In order to select an appropriate solubilizer, the solubility of the pyroxicam-tromethamine salt in various solvents and surfactants was measured. The measuring method is to add a salt made by reacting pyoxycam and tromethamine in an equivalent amount to each solvent, and then shaken with ultrasonic waves at 30 ° C. for 3 hours to determine the concentration of phyroxicam in the solution using Strometrometh. Quantification by Table 4 shows the results of measuring solubility of pyroxycam in each solvent or surfactant.
실험예 3 :안정성 실험 Experimental Example 3: Stability Experiment
안정성 실험은 실시예 및 비교예에서 제조된 패취를 밀봉, 차광된 상태로 40℃, 상대습도 75%의 가속조건에서 실시하였으며 그 결과를 표 5에 나타내었다.Stability experiments were carried out under the acceleration conditions of 40 ℃, relative humidity 75% in a sealed and shielded state prepared in the Examples and Comparative Examples and the results are shown in Table 5.
상기 표 5의 안정성 실험결과에 따르면, 본 발명에 따른 실시예에서 제조된 패취는 비교예의 패취보다 안정이 매우 높다는 것을 알 수 있다.According to the stability test results of Table 5, it can be seen that the patch prepared in the Example according to the present invention is very stable than the patch of the comparative example.
실험예 4 :혈중농도측정 Experimental Example 4 Blood Level Measurement
상기 실시예 6 ∼ 13 에서 제조한 패취제와 현재 시판중인 패취제(SK제약, 트라스트)에 각각에 대하여 토끼(NZW, male, 2∼3㎏)를 대상으로 비교혈중농도를 실험하였다.Comparative blood concentrations were tested in rabbits (NZW, male, 2-3 kg) for the patch prepared in Examples 6 to 13 and the patch currently commercially available (SK Pharma, Trast).
실험 방법으로는 등부위의 피모를 실험 하루 전에 제거한 다음, 각각의 패취를 등부위에 부착하여 24시간동안 채혈하였다. 채혈한 혈액은 원심분리 후, 혈장을 취하였으며 분석은 고성능액체크로마토그래피(HPLC)로 측정하고 그 결과는 표 6 및 도 2에 나타내었다. 분석조건은 다음과 같다.In the experimental method, the hair on the back was removed one day before the experiment, and each patch was attached to the back to collect blood for 24 hours. The blood was collected after centrifugation and plasma was analyzed. The analysis was performed by high performance liquid chromatography (HPLC) and the results are shown in Table 6 and FIG. 2. The analysis conditions are as follows.
< 분석조건 ><Analysis condition>
·컬럼 : μBondapak CN (5μ, 3.9×150 ㎜)Column: μBondapak CN (5μ, 3.9 × 150 mm)
·이동상 : 아세토니트릴/0.05M 인산염완충액(pH 3.3) = 25/75Mobile phase: Acetonitrile / 0.05 M phosphate buffer (pH 3.3) = 25/75
·유속 : 1.0 ㎖/분Flow rate: 1.0 ml / min
·검출기 : 자외선 365 ㎚Detector: UV 365 nm
상기 표 6 및 도 2에 나타낸 바와 같이 본 발명의 패취제는 종래의 패취제에 비하여 혈장중 피록시캄의 농도가 현저히 높아 약물의 피부투과효과가 매우 개선되었음을 알 수 있다.As shown in Table 6 and Figure 2 it can be seen that the patch of the present invention has a significantly higher concentration of the plasma of the hydroxy hydroxycame compared to the conventional patch, the skin penetration effect of the drug.
상술한 바와 같이, 본 발명의 소염진통성분 유효약물의 경피투여 조성물을 매트릭스층에 함유한 패취는 소염진통성분의 용해도를 높일 수 있고, 소염진통성분을 효율적으로 일정시간이상 경피전달할 수 있는 효과가 있다.As described above, the patch containing the transdermal administration composition of the anti-inflammatory analgesic active ingredient of the present invention in the matrix layer can increase the solubility of the anti-inflammatory analgesic component, and can effectively transmit the anti-inflammatory analgesic component to transdermal delivery for a predetermined time or more. have.
Claims (8)
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| KR1019990054815A KR100332210B1 (en) | 1998-12-04 | 1999-12-03 | Transdermal delivery matrix for anti-inflammatory agent |
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| KR1019980053201 | 1998-12-04 | ||
| KR19980053201 | 1998-12-04 | ||
| KR1019990054815A KR100332210B1 (en) | 1998-12-04 | 1999-12-03 | Transdermal delivery matrix for anti-inflammatory agent |
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| KR20020066047A (en) * | 2001-02-08 | 2002-08-14 | 에스케이케미칼주식회사 | Compositions containing ketoprofen and Transdermal delivery matrix system for ketoprofen |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR100433614B1 (en) * | 2000-06-16 | 2004-05-31 | 주식회사 태평양 | Transdermal Preparation Containing Hydrophilic or Salt-form Drug |
| KR100363476B1 (en) * | 2000-06-27 | 2002-12-05 | 대신제약주식회사 | Transdermal plaster comprising diclofenac or its salt |
| CN100340237C (en) * | 2000-11-06 | 2007-10-03 | 株式会社三养社 | Transdermal drug delivery system with improved water absorbability and adhesion properties |
| KR100406576B1 (en) * | 2001-06-23 | 2003-11-20 | 최후균 | Transdermal delivery system for piroxicam |
| KR100439658B1 (en) * | 2001-06-23 | 2004-07-12 | 제일약품주식회사 | Transdermal Therapeutic System containing Isosorbide dinitrate |
| KR100397349B1 (en) * | 2002-11-23 | 2003-09-13 | Korea United Pharm Inc | Solubilized aceclofenac, soft capsule using the same and manufacturing method thereof |
| KR100835074B1 (en) * | 2006-09-27 | 2008-06-03 | 조선대학교산학협력단 | Preparation and composition of meloxicam transdermal drug delivery system |
| KR20210133821A (en) | 2020-04-29 | 2021-11-08 | 신신제약 주식회사 | Percutaneous absorption system comprising piroxicam |
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| KR20020066047A (en) * | 2001-02-08 | 2002-08-14 | 에스케이케미칼주식회사 | Compositions containing ketoprofen and Transdermal delivery matrix system for ketoprofen |
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