KR20020071407A - Novel composite of liquid suppository for rectal administration - Google Patents
Novel composite of liquid suppository for rectal administration Download PDFInfo
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- KR20020071407A KR20020071407A KR1020010011543A KR20010011543A KR20020071407A KR 20020071407 A KR20020071407 A KR 20020071407A KR 1020010011543 A KR1020010011543 A KR 1020010011543A KR 20010011543 A KR20010011543 A KR 20010011543A KR 20020071407 A KR20020071407 A KR 20020071407A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
- A61K9/025—Suppositories; Bougies; Bases therefor; Ovules characterised by shape or structure, e.g. hollow layered, coated
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- 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
- A61K47/02—Inorganic compounds
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- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Abstract
Description
본 발명은 신규한 직장투여용 액상좌제 조성물에 관한 것으로서, 더욱 상세하게는 액상좌제 조성물을 제조하는데 있어 종래의 생체부착성 고분자를 사용하는 대신에 염화나트륨을 사용하여 겔강도 및 생체부착력을 부여함으로써, 종래의 액상좌제 시스템에서 나타나는 상분리를 방지할 뿐만 아니라 약물의 체내투여의 편리성 및 우수한 약효성를 가지는 신규한 직장투여용 액상좌제 조성물에 관한 것이다.The present invention relates to a novel liquid suppository composition for rectal administration, and more particularly, in the preparation of the liquid suppository composition, by imparting gel strength and bioadhesive force using sodium chloride instead of using a conventional bioadhesive polymer, It relates to a novel liquid suppository composition for rectal administration that not only prevents phase separation seen in conventional liquid suppository systems, but also has the convenience and good drug efficacy of in vivo administration of drugs.
기존 좌제는 기제로 폴리에틸렌글리콜(polyethyleneglycol)이나위텝솔(witepsol)을 사용하였으며, 이들은 실온에서는 고형이고 체내에서 용융되거나 연화되어 유효성분을 방출하는 고형좌제이다. 이 고형좌제는 유효성분이 위장관 및 간에서의 초회통과효과를 받지 않고 흡수되고, 주사제 투여에 의한 동통 등 환자의 불편함을 해결할 수 있기 때문에 진통해열제, 마취제 및 치질치료제의 제형으로 사용되어 왔다. 그러나 상기 고형좌제는 실온에서 고형이기 때문에 투여시 환자들이 이물감 및 거부감을 느끼고, 직장 투여 후 직장에서 대장의 연동운동으로 인하여 대장 말단으로 이행되어 초회통과효과를 받을 우려가 있으며, 좌제 제조시 조성물을 용융시켜야 하는 등 제조의 어려움이 있기 때문에 약제학적 제제로의 개발에 많은 어려움이 있다(Huang et al.,Yakuzaigaku,47, 42-48 (1987)).Existing suppositories use polyethyleneglycol or witepsol as bases, which are solid at room temperature and are solid suppositories that melt or soften in the body to release active ingredients. This solid suppository has been used in the formulation of analgesic antipyretics, anesthetics, and hemorrhoids treatments because the active ingredient is absorbed without first-pass effect in the gastrointestinal tract and liver, and can solve the discomfort of the patient such as pain by injection. However, since the solid suppository is solid at room temperature, patients feel a foreign body and a feeling of rejection when administered, and there is a fear that the rectal transition to the end of the large intestine due to peristalsis of the large intestine after the rectal administration may receive a first pass effect. There are many difficulties in the development of pharmaceutical formulations because of difficulties in manufacturing, such as melting (Huang et al., Yakuzaigaku, 47, 42-48 (1987)).
따라서 이런 문제점을 해결하기 위하여 실온에서는 액상이고 체내에서는 겔을 형성하는 액상좌제라는 새로운 형태의 좌제 조성물이 개발되었다. 이 액상좌제는 기제로 폴록사머 2종 이상을 사용하여 겔화온도가 30 ∼ 36 ℃가 되도록 하고, 생체부착성 고분자인 카보폴, 폴리카보필 또는 알긴산나트륨을 첨가하여 적절한 겔강도 및 생체부착력을 가지도록 함으로써 체내투여가 용이하고 투여 후 직장점막에 부착하여 체외로 빠져나오지 않으며 대장말단으로 이행되지 않도록 하였다(Choi et al.,Int. J. Pharm.,165, 33-44 (1998); Choi et al.,Int. J. Pharm.,190, 13-19 (1999); Choi et al.,Int. J. Pharm.,165, 23-32 (1998)). 또한 상기 액상좌제는 제조시 용융단계를 거치지 않는 등 제조가 기존 좌제보다 용이하였으며, 이 액상좌제에 아세트아미노펜, 프로프라놀롤, 인슐린 및 프로스타글란딘 E1 등의 유효성분을 적용하여 이 유효성분들의 생체내이용율을 증가시켰다[대한민국 특허출원공개 제97-61240호, 제97-64596호, PCT/KR97/0032, PCT/KR97/0042].Therefore, to solve this problem, a new type of suppository composition called liquid suppository has been developed that is liquid at room temperature and forms gel in the body. This liquid suppository has gelation temperature of 30-36 ℃ using two or more poloxamers as a base, and it has proper gel strength and bioadhesive power by adding bioadhesive polymers such as carbopol, polycarbophil or sodium alginate. Intravitreal administration is facilitated and adhered to the rectal mucosa after administration, so that it does not escape out of the body and does not migrate to the end of the colon (Choi et al., Int. J. Pharm., 165, 33-44 (1998); Choi et. al., Int. J. Pharm., 190, 13-19 (1999); Choi et al., Int. J. Pharm., 165, 23-32 (1998). In addition, the liquid suppositories were easier to prepare than conventional suppositories, such as not undergoing a melting step during preparation, and the bioavailability of these active ingredients was increased by applying active ingredients such as acetaminophen, propranolol, insulin and prostaglandin E1 to the liquid suppositories. [Korean Patent Application Publication Nos. 97-61240, 97-64596, PCT / KR97 / 0032, PCT / KR97 / 0042].
그러나 상기 액상좌제는 겔강도 및 생체부착력 조정제로 사용한 생체부착성 고분자를 액상좌제 제조시 물에 팽윤시키는 데 많은 시간이 소요되며, 또한 물에는 녹지 않으나 폴록사머에 의해 물에서 녹는 성질을 가지고 있는 유효성분과 함께 첨가할 경우 상분리 현상을 일으켜 액상좌제 제조가 어려운 문제가 있다.However, the liquid suppository takes much time to swell the bioadhesive polymer used as a gel strength and bioadhesive modifier in water when preparing the liquid suppository, and is insoluble in water but has the property of dissolving in water by poloxamer. When added together with the powder causes a phase separation phenomenon it is difficult to manufacture a liquid suppository.
따라서, 기존 액상좌제의 투여의 편리성 및 약효성 뿐만 아니라 기존 액상좌제 시스템의 상분리를 방지하고 액상좌제 제조가 용이하도록 한 새로운 직장투여용 액상좌제의 개발이 절실히 요구되고 있는 실정이다.Therefore, there is an urgent need to develop a new rectal liquid suppository that prevents phase separation of the existing liquid suppository system and facilitates the preparation of the liquid suppository, as well as the convenience and drug efficacy of the administration of the existing liquid suppository.
이에, 본 발명은 상기와 같은 문제점을 개선하기 위하여, 폴록사머를 2종 이상 혼합하여 겔화온도가 30 ∼ 36 ℃가 되게 기제를 제조하고, 여기에 생체부착력 조정제로 염화나트륨을 첨가하여 겔강도 및 생체부착력을 적절히 조정하여 액상좌제를 제조함으로써, 실온에서 액체 상태이고 체내에서는 겔을 형성하여 직장점막에 부착하는 성질을 가져 투여가 용이하고 투여 후 직장점막에 부착하여 체외로 빠져나오지 않으며 대장말단으로 이행되지 않아 우수한 약효를 나타낼 뿐만 아니라 종래 액상좌제 시스템의 상분리를 방지하고 액상좌제 제조를 용이하도록 한 직장투여용 액상좌제 조성물을 제공하는 데 그 목적이 있다.Thus, the present invention, in order to improve the above problems, by mixing two or more kinds of poloxamers to prepare a base so that the gelation temperature is 30 ~ 36 ℃, and adding sodium chloride as a bioadhesive modifier to the gel strength and bio By preparing the liquid suppository by adjusting the adhesive force properly, it is liquid at room temperature and forms a gel in the body to attach to the rectal mucosa, so it is easy to administer and adheres to the rectal mucosa after administration, and does not escape out of the body and moves to the large intestine end. The purpose of the present invention is to provide a liquid suppository composition for rectal administration that prevents phase separation of a conventional liquid suppository system and facilitates the preparation of a liquid suppository.
도 1은 본 발명에 따른 직장투여용 액상좌제 조성물의 생체부착력을 측정하기위한 장치를 나타낸 것이다.Figure 1 shows an apparatus for measuring the bioadhesive power of the liquid suppository composition for rectal administration according to the present invention.
도 2는 본 발명에 따른 실시예 1의 액상좌제 조성물과 대조군의 쥐 직장투여 후의 요도점막 손상의 현미경 관찰도를 나타낸 것이다.Figure 2 shows the microscopic observation of the urethral mucosa damage after the rectal administration of the liquid suppository composition and the control group of Example 1 according to the present invention.
본 발명은 겔화온도가 30 ∼ 36 ℃인 폴록사머 기제 30 ∼ 45 중량부와 염화나트륨 0.2 ∼ 1 중량부 및 유효성분 0.1 ∼ 5 중량부 함유된 직장투여용 액상좌제 조성물을 그 특징으로 한다.The present invention features a liquid suppository composition for rectal administration containing 30 to 45 parts by weight of a poloxamer base having a gelation temperature of 30 to 36 ° C, 0.2 to 1 part by weight of sodium chloride, and 0.1 to 5 parts by weight of an active ingredient.
이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명에 따른 직장투여용 액상좌제 조성물에 함유되는 각 조성성분에 대하여 보다 구체적으로 설명하면 다음과 같다.When described in more detail with respect to each composition component contained in the liquid suppository composition for rectal administration according to the present invention.
본 발명에 따른 직장투여용 액상좌제 조성물 중에 기제로서 함유되는 폴록사머는 생체점막에 손상을 주지 않는 것으로 알려져 있다. 본 발명에서는 상업적으로 사용할 수 있는 폴록사머 중에서 선택하고, 바람직하게는 P 188, P 237, P 338 및 P 407 등에서 선택된 2종 이상의 혼합물을 사용한다. 상기한 폴록사머 기제는 전체 액상좌제 조성물 중에 30 ∼ 45 중량부 함유하는 것이 바람직하고, 또한 폴록사머 기제의 겔화온도는 30 ∼ 36 ℃범위를 유지하는 것이 바람직하다. 만일 폴록사머 기제의 겔화온도가 30 ℃ 미만일 경우 실온에서 직장투여용 액상좌제가 고상이 되어 직장투여가 어렵고, 36 ℃를 초과할 경우에는 체내에서 액상으로 되기 때문에 체외로 빠져나올 우려가 있다.Poloxamer contained as a base in the liquid suppository composition for rectal administration according to the present invention is known to not damage the mucosal membrane. In the present invention, it is selected from commercially available poloxamers, and preferably a mixture of two or more selected from P 188, P 237, P 338, P 407 and the like. It is preferable to contain 30-45 weight part of said poloxamer bases in the whole liquid suppository composition, and it is preferable to keep the gelation temperature of a poloxamer base 30-30 degreeC. If the gelation temperature of the poloxamer base is less than 30 ° C, the rectal liquid suppository becomes solid at room temperature, and rectal administration is difficult, and if it exceeds 36 ° C, it may be released into the body because it becomes liquid in the body.
그리고, 본 발명에 따른 직장투여용 액상좌제 조성물 중에서 겔강도 및 생체부착력 조정제로 사용한 염화나트륨은 전체 액상좌제 조성물 중에 0.2 ∼ 1 중량부 함유하는 것이 바람직하다. 만일, 염화나트륨의 함량이 0.2 중량부 미만이면본 발명에서 목적으로 하는 적절한 겔강도 및 생체부착력 효과가 유의성 있게 나타나지 않는 문제점이 있으며, 1 중량부를 초과하면 매우 강한 겔강도 및 생체부착력을 나타내는 등 강한 점도 때문에 액상좌제 제조의 어려움이 있으며 직장점막에 손상을 입힐 우려가 있다.In the liquid suppository composition for rectal administration according to the present invention, sodium chloride used as a gel strength and bioadhesive adjusting agent is preferably contained in an amount of 0.2 to 1 parts by weight in the total liquid suppository composition. If the content of sodium chloride is less than 0.2 parts by weight, there is a problem in that the appropriate gel strength and bioadhesive effect of the present invention does not appear significantly. Therefore, there is a difficulty in manufacturing a liquid suppository and there is a risk of damaging the rectal mucosa.
본 발명에 따른 유효성분으로는 물에는 잘 녹지 않으나 폴록사머에 의해 용해되는 성질을 가지고 있으며 카보폴, 폴리카보필 또는 알긴산나트륨 등 생체부착성 고분자 등과 함께 첨가하면 상분리 현상이 일어나는 물질을 사용하는 것이 바람직하며, 예컨대 나프록센나트륨(Sodium Naproxen), 디클로페낙나트륨(Sodium diclofenac), 케토프로펜(Ketoprofen) 또는 살리실산나트륨(Sodium salicylate) 등을 사용할 수 있다. 상기 유효성분은 전체 액상좌제 조성물 중에 0.1 ∼ 5 중량부 함유하는 것이 바람직하며, 만일 0.1 중량부 미만 함유하면 약효가 유의성있게 나타나지 않는 문제가 있으며, 5 중량부를 초과하면 본 발명에서 목적으로 하는 직장투여용 액상좌제 조성물에 적합한 겔화온도, 겔강도 및 생체부착력 등의 물리화학적 성질이 유의성 있게 나타나지 않는 문제점을 가지고 있다.As an active ingredient according to the present invention, it is insoluble in water but has a property of dissolving by poloxamer, and when used together with bioadhesive polymers such as carbopol, polycarbophil or sodium alginate, phase separation occurs. Preferably, for example, sodium naproxen, sodium diclofenac, ketoprofen or sodium salicylate may be used. The active ingredient is preferably contained in 0.1 to 5 parts by weight of the total liquid suppository composition, if less than 0.1 parts by weight of the drug does not appear to have a significant effect, if more than 5 parts by weight rectal administration for the present invention The physical and chemical properties such as gelling temperature, gel strength and bioadhesive force suitable for liquid suppository composition for a solution have a problem that does not appear significantly.
본 발명에 따른 직장투여용 액상좌제 조성물의 제제화 방법은 통상의 당업자들에게 잘 알려진 방법에 의하며, 통상의 부형제, 희석제 등을 포함하는 약제학적 형태로 제조할 수 있다.The method of formulating a liquid suppository composition for rectal administration according to the present invention is by methods well known to those skilled in the art, and may be prepared in a pharmaceutical form including conventional excipients, diluents, and the like.
상술한 바와 같이, 본 발명에 따른 직장투여용 액상좌제 조성물은 폴록사머 기제의 겔화온도가 30 ∼ 36 ℃이고, 생체부착력 조정제로 염화나트륨을 사용하여 적절한 겔강도 및 생체부착력을 가지므로 체내 투여가 용이하고 직장 투여 후 직장점막에 부착하여 체외로 빠져나오지 않으며 대장말단으로 이행되지 않으므로 투여의 편리성 및 우수한 약효를 나타낼 뿐만 아니라 기존 액상좌제 시스템의 상분리를 방지하여 액상좌제 제조를 용이하게 한다.As described above, the liquid suppository composition for rectal administration according to the present invention has a gelation temperature of 30 to 36 ° C. of the poloxamer base, and is easy to administer in the body since it has appropriate gel strength and bioadhesion power using sodium chloride as a bioadhesive modifier. It is attached to the rectal mucosa after rectal administration and does not escape to the outside of the colon and does not migrate to the end of the colon, thus showing convenience of administration and excellent efficacy, and preventing phase separation of the existing liquid suppository system to facilitate the preparation of liquid suppositories.
이하, 본 발명을 실시예에 의거 더욱 상세히 설명하겠는 바, 본 발명이 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by Examples.
실시예 1 ∼ 8 및 비교예 1 ∼ 5Examples 1-8 and Comparative Examples 1-5
다음 표 1에 나타낸 바와 같은 조성으로 실온에서 물에 염화나트륨 및 유효성분을 차례대로 녹이고 냉각시킨 후 4℃에서 폴록사머를 첨가하여 녹였다. 이 액을 냉장고에서 하루 방치하여 거품을 제거하여 직장투여용 액상좌제 조성물을 제조하였다.Next, as shown in Table 1, sodium chloride and the active ingredient were sequentially dissolved in water at room temperature, cooled, and dissolved by adding poloxamer at 4 ° C. This solution was left in the refrigerator for one day to remove bubbles to prepare a liquid suppository composition for rectal administration.
시험예 1: 상분리 시험Test Example 1: Phase Separation Test
상기에서 제조한 실시예 1 ∼ 8 및 비교예 1 ∼ 5를 4 ℃와 25 ℃에서 6개월간 보관하면서 성상을 관찰하여 그 결과를 표 2에 나타내었다.While keeping the Examples 1-8 and Comparative Examples 1-5 prepared above for 6 months at 4 ° C and 25 ° C, the properties were observed and the results are shown in Table 2.
상기 표 2에 나타난 바와 같이, 생체부착성 고분자를 사용하여 제조한 비교예 1 ∼ 5의 액상좌제 조성물은 제조후 상분리를 일으켰으나, 염화나트륨을 사용하여 제조한 실시예 1 ∼ 8의 액상좌제 조성물은 제조시나 6개월 경과 후 모두 상분리가 일어나지 않고 안정함을 확인할 수 있었다.As shown in Table 2, the liquid suppository compositions of Comparative Examples 1 to 5 prepared using bioadhesive polymers caused phase separation after preparation, but the liquid suppository compositions of Examples 1 to 8 prepared using sodium chloride were It was confirmed that the phase separation did not occur at all at the time of manufacture or after 6 months and was stable.
시험예 2: 겔화온도Test Example 2: Gelation Temperature
상기에서 제조한 실시예 1 ∼ 8의 액상좌제 조성물 약 10 g을 20 ml 용기에 마그넥틱바와 함께 넣고 4℃의 항온조에 장치한 다음, 마그네틱바와 접촉하지 않도록 디지탈 온도계를 시료에 꽂았다. 일정속도로 교반하면서 온도를 1℃/분의 속도로 상승시키면서 마그네틱바가 완전히 멈추는 온도를 겔화온도로 하였고, 그 결과를 표 3에 나타내었다.About 10 g of the liquid suppository composition of Examples 1 to 8 prepared above was placed together with a magnetic bar in a 20 ml container, placed in a thermostat at 4 ° C., and a digital thermometer was placed in the sample so as not to come into contact with the magnetic bar. The temperature at which the magnetic bar completely stops while increasing the temperature at a rate of 1 ° C./min while stirring at a constant speed was used as the gelling temperature, and the results are shown in Table 3.
상기 표 3에 나타난 바와 같이, 본 발명에 따른 실시예 1 ∼ 8의 액상 좌제 조성물은 겔화온도가 30 ∼ 36℃로서 실온에서 액상이고 체내에서는 겔상을 형성하여 제조 및 투여가 용이함을 확인할 수 있었다.As shown in Table 3, the liquid suppository composition of Examples 1 to 8 according to the present invention was confirmed that the gelation temperature is 30 to 36 ℃ liquid at room temperature and the gel form in the body to facilitate the preparation and administration.
시험예 3: 겔강도 역치(threshold) 생체내 실험Test Example 3: Gel Strength Threshold In Vivo Experiment
겔강도 역치를 측정하기 위하여 미리 겔강도를 측정한 직장투여용 액상좌제 조성물(실시예 1 ∼ 8)를 경구투여용 존데(stomach sonde for oral injection)를 이용하여 45°경사로 놓여진 토끼(New Zealand white rabbit)의 항문에 투여하였다(1.5 g/kg). 이 때 투여의 용이도 및 직장 투여 후 30분 동안 항문에서의 좌제 이탈여부를 조사하였다. 겔강도의 상위 역치는 어려움없이 토끼 항문으로 직장투여용 액상좌제가 투여되는 최대 겔강도의 수치로 정의하였다(어려움없이 투여되는 것은 투여시 존데와 주사기가 분리되지 않을 경우를 나타낸다). 하위역치는 직장 투여 후 30분 동안 항문에서 빠져나오지 않는 직장투여용 액상좌제의 최소 겔강도의 수치로 정의하였다.In order to measure the gel strength threshold, rabbits placed at 45 ° inclination using a stochastic sonde for oral injection of the liquid suppository composition (Examples 1 to 8), which previously measured gel strength, were used (New Zealand white). rabbit) into the anus (1.5 g / kg). At this time, the ease of administration and whether the suppository was released from the anus for 30 minutes after rectal administration were investigated. The upper threshold of gel strength was defined as the value of the maximum gel strength at which liquid suppositories for rectal administration were administered to the rabbit anus without difficulty (administration without difficulty indicates the absence of sonde and syringe at the time of administration). The lower threshold was defined as the value of the minimum gel strength of rectal liquid suppositories that did not escape from the anus for 30 minutes after rectal administration.
실시예 1 ∼ 8의 겔강도 역치는 10 ∼ 50 sec이었고, 이 액상좌제 조성물은항문에 어려움없이 투여되며 투여후 잘 빠져나오지 않았다.The gel strength thresholds of Examples 1-8 were 10-50 sec, and this liquid suppository composition was administered without difficulty to the anal and did not escape well after administration.
시험예 4: 겔강도Test Example 4: Gel Strength
100 ml 메스실린더에 상기에서 제조한 실시예 1 ∼ 8의 액상좌제 조성물 약 50 g을 넣고 36.5 ℃ 항온조에서 30분간 평형시킨 후, 겔강도 측정기구(무게: 35 g)를 메스실린더 위에 올려놓고 겔강도 측정기구가 5 cm 내려갈 때의 시간(sec)을 측정하였고, 그 결과를 표 4에 나타내었다.About 50 g of the liquid suppository composition of Examples 1 to 8 prepared above was added to a 100 ml measuring cylinder, equilibrated in a 36.5 ° C. thermostat for 30 minutes, and a gel strength measuring instrument (weight: 35 g) was placed on the measuring cylinder and the gel was The time (sec) when the intensity measuring instrument was 5 cm down was measured, and the results are shown in Table 4.
상기 표 4에 나타난 바와 같이, 본 발명에 따른 실시예 1 ∼ 8의 액상좌제 조성물은 겔강도가 10 ∼ 50 sec로서 직장 투여 후 체외로 빠져나오지 않는 것을 확인할 수 있었다.As shown in Table 4, the liquid suppository composition of Examples 1 to 8 according to the present invention was confirmed that the gel strength does not come out of the body after rectal administration as 10 ~ 50 sec.
시험예 5: 생체부착력 시험Test Example 5: Bioadhesion Test
도 1에 나타낸 생체부착력 측정장치에 두개의 바이알을 정착하고 양쪽 바이알 모두에 토끼의 직장점막을 부착하고 그 두 직장점막사이에 실시예 1 ∼ 8의 액상좌제 조성물 약 0.05 g을 넣은 다음, 분동을 차례로 올려놓았다. 두개의 바이알이 서로 분리되는 순간의 분동무게를 단위면적당 미치는 힘으로 환산하여 생체부착력을 측정하였고, 그 결과를 표 5에 나타내었다.Two vials were settled in the bioadhesion measuring apparatus shown in FIG. Put them in order. The bioadhesive force was measured by converting the weights of two vials from each other into the force per unit area, and the results are shown in Table 5.
상기 표 5에 나타난 바와 같이, 실시예 1 ∼ 8의 액상좌제 조성물은 생체부착력이 적절한 수치(10∼70 × 102dyne/cm2)이므로, 직장 투여후 직장점막에 달라붙어 체외로 빠져나오거나 대장말단으로 이행되지 않는 것을 확인할 수 있었다.As shown in Table 5, the liquid suppository composition of Examples 1 to 8 has an appropriate value of bioadhesive force (10 to 70 x 10 2 dyne / cm 2 ), so that it adheres to the rectal mucosa after rectal administration and exits out of the body. It was confirmed that the transition to the colon.
시험예 6 : 실온에서의 안정성 시험Test Example 6: Stability test at room temperature
실시예 1의 액상좌제 조성물을 25 ℃와 45 ℃에서 12개월간 보관하면서 디클로페낙 나트륨의 함량을 다음과 같은 방법으로 측정하였고, 그 결과를 표 6에 나타내었다. 실시예 1의 액상좌제 조성물 약 10 mg을 에탄올 20 ㎖에 넣고 5분간 교반하고 밀리포아여과기로 여과한 후 고성능액체크로마토그래피(HPLC)로 정량하였다.While storing the liquid suppository composition of Example 1 at 25 ° C. and 45 ° C. for 12 months, the content of diclofenac sodium was measured by the following method, and the results are shown in Table 6 below. About 10 mg of the liquid suppository composition of Example 1 was added to 20 ml of ethanol, stirred for 5 minutes, filtered through a Millipore filter, and quantified by high performance liquid chromatography (HPLC).
상기 표 6에 나타난 바와 같이, 실시예 1의 액상좌제 조성물의 함량은 12개월 동안 유의할 만한 차이가 없었고 디클로페낙 나트륨 함량은 25 ℃ 및 45 ℃에서 99 %이상을 유지하는 것으로 보아 이 제제는 45 ℃에서 적어도 1년간 안정함을 확인할 수 있었다.As shown in Table 6, the content of the liquid suppository composition of Example 1 was not significantly different for 12 months and the diclofenac sodium content was maintained at more than 99% at 25 ℃ and 45 ℃, the formulation at 45 ℃ It was confirmed that it was stable for at least one year.
시험예 7: 안전성 시험Test Example 7: Safety Test
실시예 1의 액상좌제 조성물을 사용하여 직장투여한 쥐의 직장을 분리하고 10 % 탄산완충-포르말린 용액에서 고정시켰다. 다시 임베딩 센터(embedding center)를 사용하여 파라핀안에 끼워 놓고 얇게 박편을 만들었다. 이 박편을헤마토실린-에오신(Haematoxylin-eosin)으로 염색하고 현미경으로 직장 점막세포를 관찰하였고, 그 결과를 도 2에 나타내었다.Using the liquid suppository composition of Example 1, the rectum of rectally administered rats was isolated and fixed in a 10% carbonated-formalin solution. Again embedding in paraffin using an embedding center to thin slices. The flakes were stained with Haematoxylin-eosin, and rectal mucosal cells were observed under a microscope, and the results are shown in FIG. 2.
도 2에 나타낸 바와 같이 실시예 1의 액상좌제 조성물(B)은 유효성분 처리를 하지 않은 대조군(A)과 같이 직장 점막세포가 손상을 나타내지 않으므로, 본 발명에 따른 액상좌제 조성물은 직장에 대한 안정성을 확보한 것을 알 수 있었다.As shown in Figure 2, the liquid suppository composition (B) of Example 1 does not show damage to the rectal mucosal cells as in the control (A) not treated with the active ingredient, the liquid suppository composition according to the present invention is stable to the rectum It was found that secured.
상술한 바와 같이, 본 발명에 따른 직장투여용 액상좌제는 겔강도 및 생체부착력 조절을 위하여 염화나트륨을 사용함으로써, 직장투여가 용이하고 투여 후 직장점막에 부착하여 체외로 빠져나오거나 대장말단으로 이행되는 것을 방지하여 우수한 약효를 나타낼 뿐만 아니라 액상좌제 시스템의 상분리를 방지하고 액상좌제 제조가 용이한 장점을 가지고 있다.As described above, the liquid suppository for rectal administration according to the present invention uses sodium chloride to control gel strength and bioadhesive power, so that rectal administration is easy and adheres to the rectal mucosa after administration, and exits to the outside of the colon or is transferred to the colon end. It has the advantage of preventing the phase separation of the liquid suppository system and preventing the preparation of the liquid suppository as well as showing excellent drug efficacy.
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| KR101010411B1 (en) * | 2008-07-31 | 2011-01-21 | 김종국 | Pharmaceutical preparation composition of ondansetron liquid suppository for rectal delivery |
| WO2011129627A2 (en) * | 2010-04-14 | 2011-10-20 | Industry-University Cooperation Foundation Hanyang University | Docetaxel-loaded thermosensitive liquid suppository composition for rectal administration |
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