Controlled transdermal release of triprolidine using TPX membrane = TPX 막을 이용한 Triprolidine의 경피 제어 방출

국문 초록 (Abstract)

항히스타민제인 triprolidine을 경구투여하면 일시적인 혈중농도상승으로 인해 구갈, 졸음, 어지러움 등의 부작용이 발현될 수 있으므로 경피 흡수 시스템으로의 개발이 필요하다.
TPX(Poly(4-methyl-1-pentene))는 구조적 강도는 좋지만 너무 딱딱하여 부서지기 쉬우므로 가소제를 첨가하여 소성을 주변 경피 제어 방출 흡수 시스템에 이용될 수 있는 새로운 소재이다.
Triprolidine을 함유한 TPX 매트릭스를 casting법에 의해 제조하고 흰쥐 피부와 함께 또는 단독 TPX 막을 통한 triprolidine의 방출양상을 검토하였다. 또한 polyethylene glycol 400, 약물의 농도, 온도, 가소제, TPX의 분자량의 영향과 triprolidine의 흰쥐 피부를 통한 투과에 대한 흡수촉진제의 영향을 연구하였다.
난용성 약물인 triprolidine의 용해도 증가 및 boundary effect를 제거하기 위하여 친수성 PEG 400을 용해보조제로 첨가한 결과, PEG 400을 50%까지 증가시켜 보았을 때 지수적으로 증가하였으며 약물투과도 또한 증가하였다.
TPX 매트릭스에서 약물의 방출속도는 TPX의 분자량, 온도 및 약물농도가 증가함에 따라 증가하였다. 사용된 가소제 중 thethyl citrate가 가장 효과적이였으며 또한 흰쥐 피부를 통한 약물의 투과에 대한 흡수촉진제의 영향을 실험한 결과 diethylene glycol이 가장 우수하였다.
PSA(압력 감응성 부착제)의 농도가 증가함에 따라 생부착력은 증가되었으나 약물의 방출속도는 감소하였다. 약물의 방출속도와 생부착력을 모두 고려하였을 때 6% DURO-TAK^� 87-2169 이 가장 적절하였다. PSA와 흡수촉진제를 함유한 TPX 매트릭스에서 흰쥐 피부를 통한 약물의 투과는 흡수촉진제가 없는 것에 비해 투과도가 증가하였다.
이상의 연구에서 가소제와 흡수촉진제를 함유한 TPX 매트릭스가 triprolidine의 제어방출 경피 흡수를 위해 이용될 수 있다고 사료된다.

다국어 초록 (Multilingual Abstract)

Oral administration of triprolidine, antihistamines, may cause many adverse effects, such as dry mouth, sedation, dizziness and transdermal drug delivery was considered. TPX(Poly(4-methyl-1-pentene))membrane which has good mechanical strength was used in this transdermal drug delivery. TPX membranes was a little brittle and the plasticizers was added for preparig the membranes. The present study was carried out to develop a TPX matrix system for transdermal delivery of triprilidine.
The permeability of triprolidine through TPX and/or mouse skin was studied. The TPX matrix containing triprolidine was fabricated and the release patterns was observed. The effects of polyethylene glycol 400, drug concentration, temperature, plasticizers and molecular weights of TPX were studied. The effects of enhancer in the permeation of triprolidine through the excised mouse skin was also studied.
The solubility of triprolidine increased exponentially as the increased volume fraction of PEG 400 in saline, and the rate of permeation through TPX membrane was proportional to PEG 400 volume fraction.
The release rate of drug from TPX matrix increased with molecular weight of TPX, temperature and loading dose. Among the plasticizers used such as alkyl citrates, phthalates and sebacate. The best effective plasticizer for the release of triprolidine was the triethyl citrate. The permeation rate of drug through the excised mouse skin was also enhanced by an enhancer such as glycols and the best effective enhancer for the permeation of triprolidine was diethylene glycol.
Increasing concentration of pressure sensitive adhesive (PSA) showed the increased bioadhesive forces, but the reduced release rate. Considering the release rate and bioadhesiveness, 6% DURO-TAK^� 87-2196 was the proper adhesives.
The permeation of drug from TPX matrix containing enhancers and PSA through mouse skin showed enhancing effects comparing with that from TPX matrix without enhancer through mouse skin.
The transdermal controlled release of triprolidine system could be developed using the TPX matrix containing pernetration enhancer and plasticizer.

목차 (Table of Contents)

• 목차
• Abstract (in Englisg) = i
• Table of Contents = ii
• List of Notations = vii
• List of Figures = viii
• List of Tables = xii
• List of Schemes = xiii
• I. INTRODUCTION = 1
• II. EXPERIMENTAL = 8
• 1. Materials = 8
• 2. Instruments = 8
• 3. Extraction of the basic form of triprolidine = 9
• 4. Determination of Partition Coefficient = 9
• 5. Determination of Drug Solubility = 9
• 6. Permeation Studies = 10
• 6.1. Preparation of TPX copolymer membranes = 10
• 6.2. Drug permeation through TPX membranes = 12
• 6.3. Drug permeation through the mouse skin = 12
• 7. In vitro Release Studies from TPX Matrices = 14
• 7.1. Drug-containing TPX matrix preparation = 14
• 7.2. In vitro release studies = 16
• 7.3. In vitro release studies from plasticizer-containing TPX matrix = 18
• 8. In vitro Release Studies from TPX Matrices through Mouse skin = 20
• 8.1. HPLC dtermination of triprolidine = 20
• 8.2. Skin preparation = 22
• 8.3. In vitro release of triprolidine through the skin with TPX membrane = 22
• 8.4. Effect of enhancer on the permeation of triprolidine from TPX matrix through Mouse skin = 22
• 9. In vitro Release Studies from TPX Matrix Containing PSA = 23
• 9.1. TPX matrix containing PSA preparation = 23
• 9.2. In vitro release studied from TPX matrix containing PSA = 25
• 9.3. Effect of kinds and concentration of pressure sensitive adhesive, DURO-TAK^� on the bioadhesive forces = 25
• 10. In vitro Permeation Studies from TPX Matrix Contatining PSA through Mouse skin = 26
• 10.1. Skin preparation = 26
• 10.2. The permeation of triprolidine from TPX matrix containing PSA througs mouse skine = 26
• 10.3. Effect of enhancer on the permeation of triprolidine from the TPX matrix containing PSA through mouse skin = 26
• 11. Calculations = 26
• III. RESULTS AND DISCUSSION = 27
• 1. Solubilization of Triprolidine = 27
• 2. Partition Coefficent = 30
• 3. Permeation Studies through TPX Membranes = 31
• 3.1. Effect of solubilizer on the triprolidine permeation through TPX membrane = 31
• 3.2. Skin permeation profile of triprolidine across a stripped skin = 36
• 4. Release of Triprolidine from the TPX Matrix = 40
• 4.1. Effect of drug loading dose = 41
• 4.2. Effect of release media temperature = 48
• 4.3. Effect of molecular weight of the TPX on the drug release from TPX matrix = 58
• 4.4. Effect of plasticizers on the drug release from TPX matrix = 61
• 5. Permeation of Triprolidine from the TPX Matrix through Mouse Skin = 69
• 5.1. In vitro permeation of triprolidine through the skin with TPX membrane = 69
• 5.2. Effect of enhancers on the permeation of triprolidine across the mouse skin = 72
• 6. Release of Triprolidine from the TPX Matrix Containing PSA = 80
• 6.1. Effect of concentration of the PSA on the release of triprolidine from the TPX matrix containing PSA = 80
• 6.2. Effect of Kinds of the PSA on the release of triprolidine from the TPX matrix containing PSA = 87
• 7. Effect of Kinds and Concentration of Pressure Sensitive Adhesive, DURO-TAK^� on the Bioadhesive Forces = 91
• 8. Permeation of Triprolidine from the TPX Matrix through Mouse Skin = 94
• 8.1. In vitro permeation of triprolidine through the skin with TPX matrix containing PSA = 94
• 8.2. Effect of enhancers on the permeation of triprolidine across the mouse skin and TPX matrix containing PSA = 94
• IV. CONCLUSIONS = 97
• V. REFERENCES = 99
• Abstract(In Korean) = 108