TWI530299B - Pharmaceutical composition for preparing drug delivery nano/micro bubbles - Google Patents
Pharmaceutical composition for preparing drug delivery nano/micro bubbles Download PDFInfo
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本發明係有關於一種醫藥組成物，尤其是一種用於製備藥物傳遞之奈/微米氣泡之醫藥組成物。The present invention relates to a pharmaceutical composition, and more particularly to a pharmaceutical composition for preparing a drug-delivered nano/micro bubble.
有別於藉由合成所獲得的小分子藥，生物製劑(例如蛋白質藥物、多醣類藥物等巨分子藥物)係以細菌或哺乳類動物的細胞當做平台，經由生物體內作用生成，雖然製備門檻相對較高，然其具有較高的人體相容性、高標靶性以及較低的毒性，因此已是近十年來逐漸嶄露頭角的熱門藥物，在全球占有極大的市場需求。Different from the small molecule drugs obtained by synthesis, biological agents (such as protein drugs, polysaccharide drugs and other macromolecular drugs) are generated by the action of organisms using bacteria or mammalian cells as a platform, although the threshold is relatively Higher, but with higher human compatibility, high target and low toxicity, it has become a popular drug in the past decade, and it has a huge market demand worldwide.
然而，親水性巨分子藥物如蛋白質、胜肽、多醣體、核酸類藥物因其結構特性以及在胃酸中的不穩定性，常必須被製備為針劑，而近年來為改善侵入性治療所帶來的不便，開發適合的藥物載體而用於製備口服劑型已為目前的趨勢。However, hydrophilic macromolecular drugs such as proteins, peptides, polysaccharides, and nucleic acid drugs often have to be prepared as injections due to their structural properties and instability in gastric acid, and in recent years have been improved to improve invasive treatment. The inconvenience of developing suitable pharmaceutical carriers for the preparation of oral dosage forms has been a current trend.
常見口服劑型藥物載體包含微脂體、以幾丁聚糖(Chitosan)與聚麩胺酸(γ-PGA)所構成之奈/微米微粒載體等。以後者為例，幾丁聚糖(Chitosan)與聚麩胺酸(γ-PGA)載體系統具有良好的胃酸耐受性，並可在小腸中溶解釋放包覆於其中的有效成分，然而其製程十分繁複，須先將前驅藥物以特殊製程進行混合乾燥後，再包覆於明膠膠囊中，此恐造成實務面上量產的困難；再者，膠囊在小腸中的溶解情況常不完全並難以控制，易影響藥效。因此，為提供長期施打該些藥物的病患更好的藥物劑型。 A common oral dosage form drug carrier comprises a liposome, a nano/micro particle carrier composed of chitosan and polyglutamic acid (γ-PGA), and the like. Taking the latter as an example, Chitosan and polyglutamic acid (γ-PGA) carrier systems have good gastric acid tolerance and can dissolve and release active ingredients coated in the small intestine, however, the process is Very complicated, the precursor drug must be mixed and dried in a special process, and then coated in gelatin capsules, which may cause difficulty in mass production on the practical surface; in addition, the dissolution of the capsule in the small intestine is often incomplete and difficult. Control, easy to affect the efficacy. Therefore, it is a better pharmaceutical dosage form for patients who have long-term exposure to these drugs.
綜合上述，開發合適的口服巨分子藥物係目前相關產業努力的目標。 In summary, the development of suitable oral macromolecular drugs is currently the goal of related industry efforts.
有鑑於上述習知技藝之問題，本發明之其中一目的就是在提供一種用於製備藥物傳遞之奈/微米氣泡之醫藥組成物，其可有效地應用藥物在人體中的傳遞、釋放、及吸收。 In view of the above problems of the prior art, one of the objects of the present invention is to provide a pharmaceutical composition for preparing a drug-transported nano/micro bubble, which can effectively utilize the drug to be delivered, released, and absorbed in the human body. .
根據本發明之目的，本發明之一實施例提供一種醫藥組成物，用以形成藥物傳遞之多個氣泡。醫藥組成物包括一藥物層，其包含一親水性活性成分、一界面活性劑、一酸性成分以及一起泡劑。親水性活性成分包含核酸、胜肽或蛋白質。藥物層之起泡劑與酸性成分在體內溶於水後反應產生二氧化碳進而形成氣泡。氣泡以界面活性劑包圍二氧化碳氣體核心並形成一雙層結構，其中雙層結構具有一內層及一外層，活性成分係包埋於雙層結構之內層及外層之間所形成的一間隙中。 In accordance with an aspect of the present invention, an embodiment of the present invention provides a pharmaceutical composition for forming a plurality of bubbles for drug delivery. The pharmaceutical composition includes a drug layer comprising a hydrophilic active ingredient, a surfactant, an acidic component, and a foaming agent. The hydrophilic active ingredient comprises a nucleic acid, a peptide or a protein. The foaming agent of the drug layer and the acidic component are dissolved in water in the body to react to generate carbon dioxide to form bubbles. The bubble surrounds the carbon dioxide gas core with a surfactant and forms a two-layer structure, wherein the double layer structure has an inner layer and an outer layer, and the active component is embedded in a gap formed between the inner layer and the outer layer of the double layer structure. .
以下藉由具體實施例配合所附的圖式詳加說明，當更容易瞭解本發明之目的、技術內容、特點及其所達成之功效。The purpose, technical contents, features, and effects achieved by the present invention will become more apparent from the detailed description of the appended claims.
本發明將藉由下述之較佳實施例及其配合之圖式，做進一步之詳細說明。需注意的是，以下各實施例所揭示之實驗數據，係為便於解釋本案技術特徵，並非用以限制其可實施之態樣。The invention will be further described in detail by the following preferred embodiments and the accompanying drawings. It should be noted that the experimental data disclosed in the following embodiments are for explaining the technical features of the present invention, and are not intended to limit the manner in which they can be implemented.
請參閱圖1，其係為根據本發明實施例之奈/微米氣泡1結構示意圖，其中多個界面活性劑12，包圍氣體核心11並形成一雙層結構，其中每一界面活性劑12具有一親水端122及一疏水端121，其中雙層結構具有一內層及一外層，其中內層之界面活性劑12係以其疏水端121面向氣體核心11以及外層之界面活性劑12係以其疏水端121朝向奈/微米氣泡1之外側，以及內層之界面活性劑12及雙層結構之外層之界面活性劑12以其親水端122彼此相對排列而形成雙層結構。活性成分13係包埋於雙層結構之內層及外層之間所形成的一間隙中。其中，界面活性劑12可包覆二氧化碳、空氣或其他氣體。Please refer to FIG. 1 , which is a schematic diagram of a nano/micro bubble 1 structure according to an embodiment of the present invention, in which a plurality of surfactants 12 surround the gas core 11 and form a two-layer structure, wherein each surfactant 12 has a a hydrophilic end 122 and a hydrophobic end 121, wherein the two-layer structure has an inner layer and an outer layer, wherein the inner layer of the surfactant 12 is hydrophobic with its hydrophobic end 121 facing the gas core 11 and the outer layer of the surfactant 12 The end 121 faces the outer side of the nano/micron bubble 1, and the surfactant 12 of the inner layer and the surfactant 12 of the outer layer of the two-layer structure are arranged with their hydrophilic ends 122 arranged opposite each other to form a two-layer structure. The active ingredient 13 is embedded in a gap formed between the inner layer and the outer layer of the two-layer structure. Among them, the surfactant 12 can coat carbon dioxide, air or other gases.
本發明之奈/微米氣泡的粒徑主要要取決於氣體核心之大小，因此粒徑範圍相當大。在一實施例中，奈/微米氣泡的粒徑之主要範圍可為50 nm~100 μm。The particle size of the nano/micro bubbles of the present invention is mainly determined by the size of the gas core, and thus the particle size range is rather large. In one embodiment, the particle size of the nano/micro bubbles may range from 50 nm to 100 μm.
應註明的是，本發明之奈/微米氣泡1中具有氣體核心11，而習知的微脂體或細胞膜之中心則為液態，因此本發明之奈/微米氣泡1可與習知的微脂體或細胞膜區隔。It should be noted that the nano/micro bubble 1 of the present invention has a gas core 11, and the center of the conventional liposome or cell membrane is liquid, so the nano/micro bubble 1 of the present invention can be combined with a conventional lipid. Body or cell membrane compartment.
再者，應註明的是在一較佳實施例中，本發明之奈/微米氣泡1中界面活性劑12所形成的雙層結構與習知的微脂體或細胞膜所具有的脂雙層(lipid bilayer)結構可為相反。詳言之，界面活性劑12係以疏水端121面向氣體核心11及朝向奈/微米氣泡1之外側，且以親水端122彼此相對排列而形成雙層結構。而習知的脂雙層結構則以親水端面向核心及朝向外側，且以疏水端彼此相對排列而形成雙層結構以維持氣體核心11之穩定。Furthermore, it should be noted that in a preferred embodiment, the two-layer structure formed by the surfactant 12 in the nano/microbubble 1 of the present invention is different from the lipid bilayer of the conventional liposome or cell membrane ( The lipid bilayer structure can be reversed. In detail, the surfactant 12 has a hydrophobic end 121 facing the gas core 11 and facing the outer side of the nano/micro bubble 1, and the hydrophilic ends 122 are arranged opposite each other to form a two-layer structure. The conventional lipid bilayer structure has a hydrophilic end facing the core and facing outward, and the hydrophobic ends are arranged opposite each other to form a two-layer structure to maintain the stability of the gas core 11.
一般而言，界面活性劑12可分類為陰離子界面活性劑、陽離子界面活性劑、兩性子界面活性劑或非離子界面活性劑。陰離子界面活性劑可包含但不限於烷基硫酸鹽、正十二苯磺酸鈉等；陽離子界面活性劑包含但不限於或聚氧乙烯十二甲胺鹽等；非離子界面活性劑包含但不限於月桂硫酸鈉、單油酸聚氧乙烯山梨糖醇酐等。In general, surfactant 12 can be classified as an anionic surfactant, a cationic surfactant, an amphoteric surfactant, or a nonionic surfactant. Anionic surfactants may include, but are not limited to, alkyl sulfates, sodium n-dodecylsulfonate, and the like; cationic surfactants include, but are not limited to, polyoxyethylene dodecylamine salts, etc.; nonionic surfactants include but not It is limited to sodium lauryl sulfate, polyoletoic acid polyoxyethylene sorbitan, and the like.
如圖1所示，活性成分可包埋於界面活性劑之親水端彼此相對排列所形成的間隙中，因此活性成分13之大小並未特別受限。活性成分13可為小分子藥物或是生物巨分子。在一較佳實施例中，活性成分13可包含核酸、胜肽或蛋白質。其中核酸包含去氧核醣核酸(DNA)、核醣核酸(RNA)；蛋白質可包含抗體或藥物蛋白質。藥物蛋白質例如胰島素、紅血球生成素(EPO)或干擾素等。As shown in Fig. 1, the active ingredient may be embedded in a gap formed by the opposite ends of the hydrophilic end of the surfactant, and thus the size of the active ingredient 13 is not particularly limited. The active ingredient 13 can be a small molecule drug or a biological macro molecule. In a preferred embodiment, the active ingredient 13 can comprise a nucleic acid, a peptide or a protein. Wherein the nucleic acid comprises deoxyribonucleic acid (DNA), ribonucleic acid (RNA); the protein may comprise an antibody or a pharmaceutical protein. Drug proteins such as insulin, erythropoietin (EPO) or interferon.
在一較佳實施例中，活性成分13可為親水性，以增加活性成分與界面活性劑之親水端之作用力。親水性的活性成分13例如但不限於胰島素及DNA等。In a preferred embodiment, the active ingredient 13 can be hydrophilic to increase the force of the active ingredient and the hydrophilic end of the surfactant. The hydrophilic active ingredient 13 is, for example but not limited to, insulin, DNA, and the like.
在一較佳實施例中，界面活性劑可視活性成分13所帶之電性決定以增加活性成分與界面活性劑的結合能力。舉例而言，在活性成分為DNA的情形中，因為DNA是帶負電，因此可以選擇具有正電的陽離子界面活性劑以增強活性成分與界面活性劑的結合能力。In a preferred embodiment, the surfactant can be determined by the electrical properties of the active ingredient 13 to increase the binding capacity of the active ingredient to the surfactant. For example, in the case where the active ingredient is DNA, since the DNA is negatively charged, a positively charged cationic surfactant can be selected to enhance the binding ability of the active ingredient to the surfactant.
請進一步參照本發明之圖6a及圖6b，其為分子模擬示意圖顯示本發明之奈/微米氣泡，其中圖6b為圖6a之局部放大圖。如圖所示之實例中，雙層結構之內層及外層之間所形成的間隙可為4.5 nm，而雙層結構之寬度可為7.5 nm。其中活性成分13可為胰島素六聚體而包埋於所形成的間隙中。Please refer to FIG. 6a and FIG. 6b of the present invention, which are schematic diagrams showing the nano/micro bubbles of the present invention, and FIG. 6b is a partial enlarged view of FIG. 6a. In the example shown, the gap formed between the inner and outer layers of the two-layer structure can be 4.5 nm, and the width of the two-layer structure can be 7.5 nm. The active ingredient 13 may be an insulin hexamer and embedded in the formed gap.
本發明之用於藥物傳遞的奈/微米氣泡可使用下列錠劑或膠囊醫藥組成物所製備，醫藥組成物包含界面活性劑、起泡劑以及活性成分。起泡劑較佳者為可遇酸之後產生二氧化碳之物質。起泡劑包含碳酸鹽或碳酸氫鹽，包含但不限於碳酸氫鈉、碳酸鈉或碳酸氫銨等。藉由將本發明之配方在含酸的酸性環境中，起泡劑遇酸之後產生二氧化碳，由於二氧化碳為爆裂(burst)產生，因此使配方中界面活性劑包覆二氧化碳而形成本發明之雙層結構並使活性成分位於間隙中，進而得到本發明之奈/微米氣泡。The nano/microbubbles for drug delivery of the present invention can be prepared using the following lozenge or capsule pharmaceutical compositions comprising a surfactant, a foaming agent, and an active ingredient. The foaming agent is preferably a substance which generates carbon dioxide after being exposed to an acid. The blowing agent comprises a carbonate or bicarbonate, including but not limited to sodium bicarbonate, sodium carbonate or ammonium bicarbonate. By formulating the formulation of the present invention in an acid-containing acidic environment, the foaming agent generates carbon dioxide after encountering the acid, and since the carbon dioxide is generated as a burst, the surfactant in the formulation is coated with carbon dioxide to form the double layer of the present invention. The structure is such that the active ingredient is placed in the gap to obtain the nano/micro bubbles of the present invention.
在一較佳實施例中，本發明之配方進一步包含酸性成分，酸性成分可在水中解離或水解為酸，進而使起泡劑產生二氧化碳。在這樣的實施例中，本發明之配方可在中性或鹼性環境中產生局部為酸性的環境進行，並進行如上述之反應，進而得到本發明之奈/微米氣泡。酸性成分包括有機酸或無機酸。舉例而言，酸性成分選自酒石酸、蘋果酸、馬來酸、富馬酸、琥珀酸、乳酸、抗壞血酸、氨基酸、羥基乙酸、己二酸、硼酸、酒石酸氫鉀以及它們的酸酐。有機酸可包含酸酐，包含但不限於檸檬酸酐、琥珀酸酐、枸櫞酸酐、其它適宜的有機酸酐。In a preferred embodiment, the formulation of the present invention further comprises an acidic component which can be dissociated or hydrolyzed to an acid in water to thereby produce carbon dioxide from the foaming agent. In such an embodiment, the formulation of the present invention can be carried out in a locally acidic environment in a neutral or alkaline environment, and subjected to the reaction as described above to provide the nano/micro bubbles of the present invention. The acidic component includes an organic acid or an inorganic acid. For example, the acidic component is selected from the group consisting of tartaric acid, malic acid, maleic acid, fumaric acid, succinic acid, lactic acid, ascorbic acid, amino acids, glycolic acid, adipic acid, boric acid, potassium hydrogen tartrate, and anhydrides thereof. The organic acid may comprise an acid anhydride including, but not limited to, citric anhydride, succinic anhydride, phthalic anhydride, and other suitable organic anhydrides.
本發明技術人士可知形成氣泡所需的酸性成分、起泡劑和界面活性劑比例。舉例而言，酸性成分、起泡劑和界面活性劑的莫爾比為5:21∶6，在有水存在時酸性成分和起泡劑反應產生二氧化碳，並與界面活性劑形成氣泡。Those skilled in the art will recognize the ratio of acidic components, blowing agents and surfactants required to form bubbles. For example, the molar ratio of the acidic component, the foaming agent, and the surfactant is 5:21:6, and the acidic component reacts with the foaming agent to generate carbon dioxide in the presence of water, and forms a bubble with the surfactant.
在一較佳實施例中，本發明之配方更包含一腸衣層，腸衣層包覆藥物層。腸衣層之成份包含但不限於(甲基)丙烯酸共聚物、羥丙基纖維素酞酸酯、羥丙基纖維素乙酸酯、羥丙基纖維素琥珀酸酯、羧甲基乙基纖維素或纖維素酮酞酸酯。In a preferred embodiment, the formulation of the present invention further comprises an enteric layer which coats the drug layer. The components of the casing layer include, but are not limited to, (meth)acrylic acid copolymer, hydroxypropyl cellulose phthalate, hydroxypropyl cellulose acetate, hydroxypropyl cellulose succinate, carboxymethyl ethyl cellulose. Or cellulose ketone phthalate.
舉例而言，在一實例中，可將藥物層進一步裝填於明膠膠囊內部，再利用塗佈的技術在膠囊外側塗佈EUDRAGIT® ，以躲過胃酸的破壞，一直到小腸才將藥品成分釋放出來，並使酸性成分為可在水中解離為酸，而使起泡劑產生二氧化碳。在這樣的實施例中，本發明之配方可在鹼性環境(例如小腸)中產生局部為酸性的環境進行，並進行如上述之反應，進而得到本發明之奈/微米氣泡。For example, in one example, the drug layer can be further filled into the gelatin capsule, and then coated with EUDRAGIT® on the outside of the capsule to avoid the destruction of gastric acid until the small intestine releases the drug component. And the acidic component is dissociable into acid in water, and the foaming agent produces carbon dioxide. In such an embodiment, the formulation of the present invention can be carried out in a locally acidic environment in an alkaline environment (e.g., the small intestine), and the reaction as described above can be carried out to obtain the nano/micro bubbles of the present invention.
在可接收之賦型劑方面，該藥學組成物可任擇地包括添加物，其諸如藥學可接受之載劑或稀釋液、香料、增甜劑、防腐劑、抗氧化劑、潤濕劑、緩衝劑、釋放控制成分、染料、黏著劑、懸浮劑、分散劑、著色劑、崩散劑、賦形劑、成膜劑、潤滑劑、塑化劑、食用油或上述之二或多種的任何組合。In the case of an acceptable excipient, the pharmaceutical composition may optionally include an additive such as a pharmaceutically acceptable carrier or diluent, a perfume, a sweetener, a preservative, an antioxidant, a wetting agent, a buffer. Agent, release controlling ingredient, dye, adhesive, suspending agent, dispersing agent, coloring agent, disintegrating agent, excipient, film former, lubricant, plasticizer, edible oil or any combination of two or more of the above.
適合的藥學上可接受之載劑或稀釋液包括，但不限於乙醇、水、甘油、丙二醇或甘油、二乙二醇單乙基醚、維生素A與E油、礦物油、PPG2十四醯丙酸鹽、磷酸鉀或二氧化矽。適合的潤滑劑係油酸鈉、硬脂酸鈉、月桂基反丁烯二酸鈉、硬脂酸鎂、苯甲酸鈉、醋酸鈉與氯化鈉。適合的懸浮劑係皂土、乙基化的異硬脂基醇、聚氧乙烯山梨糖醇與脫水山梨糖醇酯、微晶纖維素、偏氫氧化鋁(aluminum metahydroxide)、瓊脂與西黃蓍膠，或此等物質中之二或多種之混合物。適合的分散劑與懸浮劑係合成膠與天然膠，諸如植物膠、西黃蓍膠、金合歡膠、褐藻酸鹽、葡萄聚糖、羧甲基纖維素鈉鹽、甲基纖維素、聚乙烯－吡咯烷酮與明膠。適合的成膜劑係羥丙基甲基纖維素、乙基纖維素與聚甲基丙烯酸酯。適合的塑化劑包括具不同分子量(如200－8000 Da)之聚乙二醇、聚丙二醇與檸檬酸三乙酯。適合的著色劑係氧化鐵、二氧化鈦以及天然與合成色素。額外的添加劑之例子為山梨糖醇、滑石、硬三脂酸。Suitable pharmaceutically acceptable carriers or diluents include, but are not limited to, ethanol, water, glycerin, propylene glycol or glycerin, diethylene glycol monoethyl ether, vitamin A and E oils, mineral oil, PPG 2 Acid salt, potassium phosphate or cerium oxide. Suitable lubricants are sodium oleate, sodium stearate, sodium lauryl fumarate, magnesium stearate, sodium benzoate, sodium acetate and sodium chloride. Suitable suspending agents are bentonite, ethylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, agar and scutellaria Glue, or a mixture of two or more of these materials. Suitable dispersing and suspending agents are synthetic rubber and natural rubber, such as vegetable gum, tragacanth, acacia, alginate, dextran, sodium carboxymethyl cellulose, methyl cellulose, polyethylene Pyrrolidone and gelatin. Suitable film formers are hydroxypropyl methylcellulose, ethylcellulose and polymethacrylate. Suitable plasticizers include polyethylene glycols having different molecular weights (e.g., 200-8000 Da), polypropylene glycol, and triethyl citrate. Suitable color formers are iron oxide, titanium dioxide, and natural and synthetic pigments. Examples of additional additives are sorbitol, talc, and tristearic acid.
如上所述，在本發明之一實施例中，本發明之奈/微米氣泡係產生於腸道。在奈/微米氣泡產生後會與腸表皮上皮細胞相接觸，此使界面活性劑可促進胞旁通道(Paracellular pathway)及跨細胞通道(transcellular pathway)，並使本發明之活性成份可以送達更深層之體循環。As described above, in one embodiment of the present invention, the nano/micro bubble of the present invention is produced in the intestinal tract. After the na/microbubbles are produced, they are in contact with intestinal epithelial cells, which allows the surfactant to promote Paracellular pathways and transcellular pathways, and allows the active ingredients of the present invention to be delivered to deeper layers. The body cycle.
以下通過具體實施例配合附圖詳加說明，可更容易瞭解本發明的目的、技術內容、特點及所達成的功效，並據以實施，但不能以此限定本發明的保護範圍。The objects, technical contents, features and effects achieved by the present invention can be more easily understood from the following detailed description of the embodiments of the present invention, and are not intended to limit the scope of the present invention.
奈/微米氣泡配方之製備Preparation of nano/micro bubble formulation
界面活性劑為SDS，酸性成分為二乙烯三胺五乙酸二酐(diethylenetriaminepentaacetic dianhydride, DTPA dianhydride)，起泡劑為小蘇打(SBC)，活性成分為胰島素，腸衣層之成分為EUDRAGIT® L100-55，製備方式如下： 1. SDS (7 mg), DTPA dianhydride (14 mg), SBC (7 mg), insulin (5 IU/Kg) 均勻混合後填充於明膠膠囊(gelatin capsule)內。 2. 將上述製備的明膠膠囊外層塗佈EUDRAGIT® L100-55 (10 %)後風乾。The surfactant is SDS, the acidic component is diethylenetriaminepentaacetic dianhydride (DTPA dianhydride), the foaming agent is baking soda (SBC), the active ingredient is insulin, and the composition of the casing layer is EUDRAGIT® L100-55. The preparation was as follows: 1. SDS (7 mg), DTPA dianhydride (14 mg), SBC (7 mg), insulin (5 IU/Kg) were uniformly mixed and filled in gelatin capsules. 2. The outer layer of the gelatin capsule prepared above was coated with EUDRAGIT® L100-55 (10%) and air dried.
奈/微米氣泡之驗證Nai/micron bubble verification
請參照圖2，分別以FITC標示胰島素，以及螢光親脂性陽離子吲哚羰花青染料DII(1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate)對SDS之疏水端染色，所得到螢光影像，證明胰島素確實存在於本發明奈/微米氣泡之中，且位於界面活性劑所構成之雙層結構的間隙之中，顯示本發明之奈/微米氣泡係具有良好的活性成分包埋效果。Referring to Figure 2, the insulin is labeled with FITC and the hydrophobic end of the SDS with the fluorescent lipophilic cationic phthalocyanine dye DII (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate). Staining, the obtained fluorescent image, proves that insulin is indeed present in the nano/micro bubbles of the present invention, and is located in the gap of the two-layer structure composed of the surfactant, indicating that the nano/micro bubble system of the present invention has good Active ingredient embedding effect.
奈/微米氣泡與細胞結合之細胞影像Nano/micron bubble-cell-bound cell image
請參照圖3，其顯示各成份與細胞共同培養後顯微鏡下的影像，其中分別對細胞之緊密型連結(tight junction) Cld 4、黏著型連結(adherin junction) E-cadherin 以及細胞核(DAPI)染色。結果顯示DTPA dianhydride 可促使FITC-insulin經由胞旁通道傳輸；而SDS則可促使FITC-insulin同時經由胞旁通道及跨細胞通道兩種路徑傳輸。Referring to Figure 3, there is a microscopic image of each component co-cultured with cells, where the cells are tight junction Cld 4, adhesive junction E-cadherin, and nuclear (DAPI) staining. . The results show that DTPA dianhydride can promote FITC-insulin transmission through the paracellular pathway; while SDS can promote FITC-insulin transmission through both paracellular and transcellular pathways.
奈/微米氣泡於活體內之細胞影像Cell image of nai/micron bubbles in vivo
請參照圖4，其顯示奈/微米氣泡於腸道內作用的過程，其中在未加入起泡劑之組別，胰島素僅限於局部區域，而使用起泡劑之本發明組別，則可明顯看到經由起泡劑之作用，使奈/微米氣泡破裂而釋出胰島素，藉此將胰島素釋放至小腸中段及末段，相較於未加起泡劑的組別係具有較佳的釋放能力。Referring to Figure 4, there is shown a process in which the nano/micro bubbles act in the intestinal tract, wherein insulin is limited to a localized area in the group in which no foaming agent is added, and the present invention group using a foaming agent is apparent. It is seen that the action of the foaming agent causes the nano/micro bubble to rupture to release insulin, thereby releasing insulin to the middle and the end of the small intestine, which has better release ability than the group without the foaming agent. .
奈/微米氣泡之藥物動力試驗Pharmacodynamic test of nano/micro bubbles
動物實驗程序將依據農委會頒布之實驗室動物管理與使用指南來執行(採用約300~350克之公鼠(male Wistar rats))。本研究的動物實驗為探討載體系統包覆藥物Insulin以口服方式投藥後，在大鼠體內治療糖尿病的情形。實驗中將老鼠保定後，以餵食針以口服投藥(oral drug delivery, 30 IU/Kg)及皮下注射(Subcutaneous, 5 IU/Kg)的方式給藥，於不同時間下，將動物置於抽血保定架內，使其尾巴露出，再以碘酒消毒尾巴以防止細菌感染。接著以手術刀將其尾巴劃一切口，取其血液以觀察血糖隨時間之變化，同時以酵素免疫分析法測量藥物動力學。Animal testing procedures will be performed in accordance with the guidelines for the management and use of laboratory animals issued by the Council of Agriculture (using approximately 300-350 grams of male Wistar rats). The animal experiment in this study was to investigate the treatment of diabetes in rats after oral administration of the carrier system coated drug Insulin. After the rats were fixed in the experiment, the feeding needles were administered by oral drug delivery (30 IU/Kg) and subcutaneous (5 IU/Kg). At different times, the animals were placed in blood. Inside the Baoding rack, expose its tail and disinfect the tail with iodine to prevent bacterial infection. Then use a scalpel to draw a trail of his mouth, take blood to observe changes in blood sugar over time, and measure pharmacokinetics by enzyme immunoassay.
在本實施例中，將本發明之奈/微米氣泡(含30 IU/kg之胰島素)與口服胰島素(30 IU/kg)及皮下注射胰島素(5 IU/kg)的組別作比較，分別紀錄受試者服用或注射藥物0~10小時的血漿胰島素濃度及血糖變化率，其結果如圖5所示。而在血糖變化率的部分，皮下注射組別的血糖變化率快速下降又回升，顯示其無法長效穩定地控制血糖濃度，而服用奈/微米氣泡的組別則可使血糖緩降並穩定維持。上述實驗結果顯示本發明之奈/微米氣泡確實可達到緩釋且長效之效果，其具備良好的生物可利用性。In this example, the na/microbubbles (containing 30 IU/kg of insulin) of the present invention were compared with the groups of oral insulin (30 IU/kg) and subcutaneous insulin (5 IU/kg), respectively. The plasma insulin concentration and blood glucose change rate of the subjects taking or injecting the drug for 0 to 10 hours are shown in Fig. 5. In the part of blood glucose change rate, the blood glucose change rate of the subcutaneous injection group decreased rapidly and rebounded, indicating that it could not control the blood glucose concentration stably for a long time, and the group taking the nano/micro bubble could slow down the blood glucose and maintain it stably. . The above experimental results show that the nano/micro bubbles of the present invention can achieve a sustained release and long-lasting effect, and have good bioavailability.
綜上所述，本發明之用於藥物傳遞的奈/微米氣泡提供一種具有與傳統脂雙層載體排列相反的雙層結構，此奈/微米氣泡藉由遇酸產生氣體膨脹及與小腸表皮細胞作用使此奈/微米氣泡破裂，進而釋放活性成分於小腸中並被小腸表皮細胞吸收。本發明之奈/微米氣泡易於製備、具有優良的藥物包埋效率以及相較於傳統針劑具有更好的生物可利用性，因此可有效地應用於巨分子藥物劑型開發。In summary, the nano/microbubbles for drug delivery of the present invention provide a two-layer structure having an opposite arrangement to that of a conventional lipid bilayer carrier, which is caused by acid expansion by gas and interaction with intestinal epithelial cells. This nano/micro bubble is ruptured, thereby releasing the active ingredient in the small intestine and being absorbed by the intestinal epithelial cells. The nano/micro bubbles of the present invention are easy to prepare, have excellent drug embedding efficiency, and have better bioavailability than conventional injections, and thus can be effectively applied to the development of macromolecular pharmaceutical dosage forms.
以上所述之實施例僅係為說明本創作之技術思想及特點，其目的在使熟習此項技藝之人士能夠瞭解本創作之內容並據以實施，當不能以之限定本創作之專利範圍，即大凡依本創作所揭示之精神所作之均等變化或修飾，仍應涵蓋在本創作之專利範圍內。The embodiments described above are only for explaining the technical idea and characteristics of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement them according to the scope of the patent. That is, the equivalent changes or modifications made by the people in accordance with the spirit revealed by this creation should still be covered by the scope of the patent of this creation.
1 奈/微米氣泡 11 氣體核心 12 界面活性劑 121 疏水端 122 親水端 13 活性成分1 Nai/micron bubble 11 Gas core 12 Surfactant 121 Hydrophobic end 122 Hydrophilic end 13 Active ingredient
圖1為根據本發明實施例之奈/微米氣泡結構示意圖。 圖2至圖5為本發明一實施例之實驗數據。 圖6a為根據本發明實施例之奈/微米氣泡結構示意圖。 圖6b為圖6a之局部放大圖。1 is a schematic view of a nano/micro bubble structure in accordance with an embodiment of the present invention. 2 to 5 are experimental data according to an embodiment of the present invention. Figure 6a is a schematic diagram of a nano/micro bubble structure in accordance with an embodiment of the present invention. Figure 6b is a partial enlarged view of Figure 6a.
1 奈/微米氣泡 11 氣體核心 12 界面活性劑 121 疏水端 122 親水端 13 活性成分1 Nai/micron bubble 11 Gas core 12 Surfactant 121 Hydrophobic end 122 Hydrophilic end 13 Active ingredient
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