TW201914584A - Supplies and system of microencapsulated powder based on spinach extract and acidic gel to prolong nitric oxide production characterized in that spinach extract is used as a nitric oxide donor, and the acidic gel has enough acidity to convert the spinach extract to nitric oxide - Google Patents

Abstract

The present invention relates to the supplies and systems of microencapsulated powder based on spinach extract and an acidic gel to prolong nitric oxide production, including microencapsulated spinach extract and acidic gel. The spinach extract is used as a nitric oxide supplier, and the acidic gel has enough acidity to convert the spinach extract to nitric oxide. The supplies and system of microencapsulated powder based on spinach extract and acidic gel to prolong nitric oxide production in the present invention can release nitric oxide for a long period of time and can continue to have effects on the affected site for a long period of time.

Description

基於菠菜萃取物的微膠囊化粉末和酸性凝膠延長產生一氧化氮的系統和用品Microencapsulated powder based on spinach extract and acid gel to prolong nitric oxide production system and supplies

本發明屬於醫藥領域，具體涉及一種含有菠菜萃取物作為活性成分的微囊化藥劑、含有該菠菜萃取物微囊化藥劑的系統和用品。The invention belongs to the field of medicine, and particularly relates to a microencapsulated medicament containing a spinach extract as an active ingredient, a system and a product containing the spinach extract microencapsulated medicament.

在哺乳動物中，NO在神經系統、免疫系統和心血管系統的很多生理過程中是一種內源性的生理調節物質，其作用包括血管平滑肌鬆弛，導致動脈的血管舒張和血流增加。NO是一種神經遞質，與神經元的活動和各種功能有關，從回避學習到男性和女性生殖器***(Kim et al., J. Nutrition 134 (2004) 2873S)。NO也具有部分調節巨噬細胞對微生物和腫瘤細胞的細胞毒性作用。NO 除了介導正常的生理功能外，還涉及感染性休克、高血壓、中風和神經退行性疾病等不同的病理生理狀態。In mammals, NO is an endogenous physiological regulator in many physiological processes of the nervous system, immune system, and cardiovascular system. Its effects include vascular smooth muscle relaxation, resulting in arterial vasodilation and increased blood flow. NO is a neurotransmitter that is involved in neuronal activity and various functions, from avoidance learning to male and female genital erections (Kim et al., J. Nutrition 134 (2004) 2873S). NO also partially modulates the cytotoxic effects of macrophages on microorganisms and tumor cells. In addition to mediating normal physiological functions, NO also involves different pathophysiological states such as septic shock, hypertension, stroke, and neurodegenerative diseases.

NO以各種形式應用在藥理學上，局部應用NO可以説明創傷和燒傷的傷口癒合、毛髮生長、陽痿、以及在需要的地方導致血管擴張（例如，促進由於糖尿病或其它條件受損的患者外周血流量的流通和在孕期子宮頸的成熟）。然而，雖然NO本身具有生理活性的，但是它在空氣中或在體內是化學不穩定的。因此，在現有技術中其藥理應用幾乎總是通過不同的各種單獨穩定的前體化合物的化學反應而產生。通常使用有機和無機硝酸鹽作為NO供體。在局部應用的範圍內，要求NO的劑量是低的、持久性的。NO作為一個強大的殺菌劑，對抗生素有抗藥性的細菌是有效的。在抗菌和其它的局部應用中，需要延長NO與皮膚接觸的時間。在抗菌應用中， NO有效治療劑量是很少的，只有百萬分之幾（ppm）（見 Ghaffari et al., Nitric Oxide Biology and Chemistry 14 (2006) 21-29)），但NO的有效性取決於維持與皮膚接觸的時間長短 (Ormerod et al., BMCResearch Notes 4 (2011) 458-465)。NO is applied in a variety of forms in pharmacology. Topical application of NO can demonstrate wound healing in wounds and burns, hair growth, impotence, and vasodilation where needed (eg, promotion of peripheral blood in patients with impaired diabetes or other conditions) Flow of circulation and maturation of the cervix during pregnancy). However, although NO itself is physiologically active, it is chemically unstable in the air or in the body. Thus, its pharmacological applications in the prior art are almost always produced by chemical reactions of different individual stable precursor compounds. Organic and inorganic nitrates are commonly used as NO donors. Within the scope of topical application, the dose of NO is required to be low and long lasting. As a powerful fungicide, NO is effective against antibiotic-resistant bacteria. In antibacterial and other topical applications, it is desirable to extend the time that NO is in contact with the skin. In antibacterial applications, the effective therapeutic dose of NO is very small, only parts per million (ppm) (see Ghaffari et al., Nitric Oxide Biology and Chemistry 14 (2006) 21-29), but the effectiveness of NO It depends on how long it takes to maintain contact with the skin (Ormerod et al., BMC Research Notes 4 (2011) 458-465).

儘管現有技術（專利申請CN201310355902.2、CN201310356220.3）中存在使用微囊化亞硝酸鹽和酸化水凝膠的延時產生一氧化氮的系統和方法，然而其使用的NO供體為亞硝酸鹽，而亞硝酸鹽一般存在一定毒性，特別是當劑量大時毒性很大。此外該延時系統和操作方法的應用依賴於一個或數個啟動體積的水，在具體操作中存在一定的限制。Although there are systems and methods for the delayed generation of nitric oxide using microencapsulated nitrites and acidified hydrogels in the prior art (patent application CN201310355902.2, CN201310356220.3), the NO donor used is nitrite. However, nitrite generally has some toxicity, especially when the dose is large. In addition, the application of the delay system and method of operation relies on one or several startup volumes of water, with certain limitations in the specific operation.

為解決現有技術的不足，本發明提供一種基於菠菜萃取物的微膠囊化粉末和酸性凝膠產生一氧化氮的系統，該系統採用菠菜萃取物作為NO供體，其來源於自然植物，成分天然，避免了亞硝酸鹽作為NO供體對機體的潛在危害。In order to solve the deficiencies of the prior art, the present invention provides a system for producing nitric oxide based on spinach extract microencapsulated powder and acid gel, which uses spinach extract as a NO donor, which is derived from natural plants and has natural ingredients. It avoids the potential hazard of nitrite as a NO donor to the body.

本發明還涉及基於菠菜萃取物的微膠囊化粉末和酸性凝膠產生一氧化氮的成套用品。The present invention also relates to a microencapsulated powder based on spinach extract and a kit for producing nitric oxide based on an acidic gel.

本發明提供了一種基於菠菜萃取物的微膠囊化粉末和酸性凝膠延長產生一氧化氮的系統和用品，本發明的延時產生一氧化氮的系統，能在較長時間條件下保證NO的持續釋放，且操作簡便，具有持續釋放的效果。The present invention provides a system and an article for prolonging the production of nitric oxide based on a microencapsulated powder of spinach extract and an acid gel, and the system for generating nitric oxide in a delayed manner according to the present invention can ensure the persistence of NO under a long time condition. It is easy to release and has a continuous release effect.

本發明還涉及延長產生一氧化氮的成套用品。The invention also relates to a kit for prolonging the production of nitric oxide.

本發明的系統和成套用品，製備過程簡單，且該系統具有較高的生物安全性，能長期發揮NO的生理活性。The system and the kit of the invention have simple preparation process, and the system has high biosafety and can exert the physiological activity of NO for a long time.

以下，對本發明的實施方式進行說明。Hereinafter, embodiments of the present invention will be described.

本發明公開了一種基於菠菜萃取物的微膠囊化粉末和酸性凝膠延長產生一氧化氮的系統和用品，亦即一種一氧化氮的延時釋放系統，包括微囊化的菠菜萃取物和酸性凝膠，所述酸性凝膠具有足夠的酸度將菠菜萃取物轉化為一氧化氮。The invention discloses a system and an article for prolonging the production of nitric oxide based on spinach extract microencapsulated powder and acid gel, that is, a delayed release system of nitric oxide, including microencapsulated spinach extract and acid coagulation A gel having sufficient acidity to convert the spinach extract to nitric oxide.

本發明採用菠菜萃取物作為產生藥學上可接受的NO的供體。本發明的反應原理根據下面的反應式（1）可見，通過亞硝酸鹽與酸（HA）反應產生亞硝酸。亞硝酸低溫時在水溶液中是穩定的，但在室溫下，它容易分解成NO和NO2，如反應式（2）所示。The present invention employs a spinach extract as a donor to produce pharmaceutically acceptable NO. The reaction principle of the present invention can be seen according to the following reaction formula (1), and nitrous acid is produced by reacting nitrite with an acid (HA). The nitrous acid is stable in an aqueous solution at a low temperature, but at room temperature, it is easily decomposed into NO and NO2 as shown in the reaction formula (2).

在還原劑（如抗壞血酸，二羥基抗壞血酸（Asc(OH) 2））的存在下，NO2很容易轉化為 NO，如下面的反應式（3）所示。In the presence of a reducing agent such as ascorbic acid, dihydroxyascorbic acid (Asc(OH) 2), NO2 is easily converted to NO as shown in the following reaction formula (3).

2HA+NaNO2→2HNO2+2NaA （1），2HA+NaNO2→2HNO2+2NaA (1),

HA 是一種可以是有機酸或無機酸HA is an organic or inorganic acid

2HNO2→NO+NO2+H2O （2），2HNO2→NO+NO2+H2O (2),

亞硝酸分解，生成二氧化氮Nitrous acid decomposes to form nitrogen dioxide

NO+NO2+H2O+ Asc(OH) 2→2NO+2H2O+ AscO2（3），NO+NO2+H2O+ Asc(OH) 2→2NO+2H2O+ AscO2(3),

抗壞血酸反應，生成一氧化氮Ascorbic acid reaction to form nitric oxide

本發明通過菠菜萃取物作為NO的供體，減少了亞硝酸鹽的毒性對人體的潛在危害。The present invention reduces the potential hazard of nitrite toxicity to the human body by using spinach extract as a donor of NO.

在一個實施方式中，所述菠菜萃取物中保留了菠菜中的維生素C，因此本發明的系統和成套用品可以在不添加還原性成分條件下，仍能持續長時間釋放NO。菠菜萃取物中的維生素C能夠防止或減慢一氧化氮氧化為二氧化氮的還原能力，並且還具有直接還原NO2為NO的能力，從而使由該組合物中釋放的氣體主要是NO。In one embodiment, the spinach extract retains vitamin C in the spinach, so the systems and kits of the present invention can continue to release NO for extended periods of time without the addition of reducing components. The vitamin C in the spinach extract can prevent or slow the reduction of nitric oxide to nitrogen dioxide, and also has the ability to directly reduce NO2 to NO, so that the gas released from the composition is mainly NO.

在一個實施方式中，所述菠菜萃取物在使用菠菜萃取過程中，用酸調節各萃取步驟溶液pH3~4，以保證源自菠菜的維C的提取和活性。In one embodiment, the spinach extract is adjusted with acid to adjust the pH of each extraction step solution 3 to 4 during the extraction using spinach to ensure the extraction and activity of vitamin C derived from spinach.

本發明的菠菜萃取物可以使用本領域的常規方法萃取，在萃取過程調節pH為3~4，以保證其中的維C的提取和活性。The spinach extract of the present invention can be extracted by a conventional method in the art, and the pH is adjusted to 3 to 4 during the extraction to ensure the extraction and activity of the vitamin C therein.

在一個實施方式中，所述菠菜萃取物在使用菠菜萃取過程中，所述調節溶液pH的酸為草酸。In one embodiment, the spinach extract is subjected to spinach extraction, and the acid that adjusts the pH of the solution is oxalic acid.

在一個實施方式中，所述菠菜萃取物中亞硝酸鹽含量為5.017×10-3mg/ml，硝酸鹽含量為0.236mg/ml，維C含量為1.21×10-2mg/ml。In one embodiment, the spinach extract has a nitrite content of 5.017 x 10-3 mg/ml, a nitrate content of 0.236 mg/ml, and a vitamin C content of 1.21 x 10-2 mg/ml.

在一個實施方式中，微囊化載體是一種聚合物基質。所述試劑和基質一起置於亞毫米級的結構內（至少有一個尺度規格不到1毫米）。這種結構可以是微粒、纖維或薄膜。In one embodiment, the microencapsulated carrier is a polymeric matrix. The reagent and matrix are placed together in a sub-millimeter structure (at least one dimension is less than 1 mm). This structure can be a particle, a fiber or a film.

本發明的一個實施方式中，利用微囊化的菠菜萃取物和足夠酸度的酸化水凝膠接觸，轉化亞硝酸鹽為一氧化氮。雖然無機酸如硼酸，也可能是合適的，但優選的酸化劑採用有機酸，如檸檬酸。其它酸化劑還可以包括乳酸、甘油酸、甲酸、抗壞血酸或那些在本技術領域的技術人員已知的其它的有機酸。也可以採用生物學上可接受的、有適當pKa 值的無機酸（例如上述的硼酸）。凝膠劑包括羥甲基纖維素、羥乙基纖維素、明膠、瓊脂、天然樹膠、澱粉和果膠等物質。In one embodiment of the invention, the microencapsulated spinach extract is contacted with an acidified hydrogel of sufficient acidity to convert the nitrite to nitric oxide. While inorganic acids such as boric acid may also be suitable, preferred acidifying agents employ organic acids such as citric acid. Other acidulants may also include lactic acid, glyceric acid, formic acid, ascorbic acid or other organic acids known to those skilled in the art. It is also possible to use a biologically acceptable inorganic acid having an appropriate pKa value (for example, boric acid as described above). Gelling agents include hydroxymethylcellulose, hydroxyethylcellulose, gelatin, agar, natural gums, starches, and pectins.

溶解酸的介質可以是水介質或非水介質。優選水介質，容易製備凝膠。酸凝膠組合物可另外含有一個或多個所使用的酸的共軛堿。雖然優選的堿是使用的酸的共軛堿，但也可以是那些本技術領域的技術人員已知的其它有機堿或無機堿。本發明的實施方式可直接應用於促進皮膚的迴圈、加快傷口癒合，在頭皮上保持一段時間作為一種治療以促進頭髮生長，並且可被應用在其它局部釋放NO有益的位置。The medium in which the acid is dissolved may be an aqueous medium or a non-aqueous medium. An aqueous medium is preferred, and the gel is easily prepared. The acid gel composition may additionally contain one or more conjugated oximes of the acid used. While the preferred hydrazine is the conjugate fluorene of the acid used, it can also be other organic hydrazine or inorganic hydrazine known to those skilled in the art. Embodiments of the present invention can be directly applied to promote skin loops, accelerate wound healing, remain on the scalp for a period of time as a treatment to promote hair growth, and can be applied to other locations where local release of NO is beneficial.

本發明的一個實施方式中，在凝膠中包含還原劑，以進一步幫助保持一氧化氮的生物活性。酸化劑也可以是還原劑，如抗壞血酸（維生素C）或抗壞血酸衍生物。所述抗壞血酸衍生物包括但不限於3-O-乙基抗壞血酸以及其它3-烷基抗壞血酸、6-O-辛醯基-抗壞血酸、6-O-十二烷醯基-抗壞血酸、6-O-十四烷醯基-抗壞血酸、6-O-十八烷醯基-抗壞血酸和6-O-癸二醯-抗壞血酸。優選的還原劑具有與菠菜萃取物中的維C一同防止或減慢一氧化氮氧化為二氧化氮的還原能力，並且還具有直接還原NO2為NO的能力，從而使由該組合物中釋放的氣體主要是NO。優選的還原劑包括抗壞血酸、抗壞血酸衍生物、抗壞血酸的鹽、生育酚，異抗壞血酸或α-生育酚。In one embodiment of the invention, a reducing agent is included in the gel to further help maintain the biological activity of nitric oxide. The acidulant may also be a reducing agent such as ascorbic acid (vitamin C) or an ascorbic acid derivative. The ascorbic acid derivatives include, but are not limited to, 3-O-ethyl ascorbic acid and other 3-alkylascorbic acid, 6-O-octyl-ascorbic acid, 6-O-dodecyldecyl-ascorbic acid, 6-O-tetradecene Alkyl-ascorbic acid, 6-O-octadecanoyl-ascorbic acid and 6-O-quinone dioxo-ascorbic acid. Preferred reducing agents have the ability to prevent or slow the oxidation of nitric oxide to nitrogen dioxide along with the vitamin C in the spinach extract, and also have the ability to directly reduce NO2 to NO, thereby allowing release from the composition. The gas is mainly NO. Preferred reducing agents include ascorbic acid, ascorbic acid derivatives, ascorbic acid salts, tocopherols, isoascorbic acid or alpha-tocopherol.

本發明的一個實施方式公開了一種套裝的酸化的凝膠和微囊化的菠菜萃取物。酸化的凝膠和微囊化的菠菜萃取物，都是單獨包裝在防潮包裝中，在應用混合物前，打開包裝，將它們的內容物立即混合在一起。在另一個可供選擇的實施方式中，微囊化的菠菜萃取物和酸化劑被一起或單獨包上防潮包裝。在應用前，打開包裝，用定量的水或中性 pH 的含水凝膠混合它們的內容物。One embodiment of the invention discloses a kit of acidified gel and microencapsulated spinach extract. The acidified gel and the microencapsulated spinach extract are individually packaged in a moisture barrier package, and the package is opened and the contents are immediately mixed together before applying the mixture. In another alternative embodiment, the microencapsulated spinach extract and acidulant are packaged together or separately in a moisture barrier package. Prior to application, the package is opened and their contents are mixed with a metered amount of water or a neutral pH aqueous gel.

微囊的一種製作方法：將一種試劑的溶解液或聚合物溶液噴霧乾燥，產生細小分散的單個微粒（內部包含分散在聚合物基質內的試劑）的粉末。也可以使用其它微囊的製作方法，如鍋包衣、空氣懸浮包衣、離心擠壓、纖維紡絲、纖維擠壓、噴嘴振動、離子型凝膠化、凝聚相分離、介面交聯、原位聚合法和基質聚合。A method of making a microcapsule: spray-drying a solution or a polymer solution of an agent to produce a powder of finely dispersed individual particles (containing a reagent dispersed inside the polymer matrix). Other microcapsules can also be used, such as pan coating, air suspension coating, centrifugal extrusion, fiber spinning, fiber extrusion, nozzle vibration, ionic gelation, condensed phase separation, interface crosslinking, original Polymerization and matrix polymerization.

本發明的微囊化的菠菜萃取物製備的一種實施方式，可以在菠菜萃取物中添加穩定劑，穩定劑能在微囊製備過程中，以及儲存中長時期維持其中的維生素C的活性，穩定劑可以為鹽酸-L-半胱氨酸和焦亞硫酸鈉。In one embodiment of the preparation of the microencapsulated spinach extract of the present invention, a stabilizer may be added to the spinach extract, and the stabilizer can maintain the activity of the vitamin C therein during the preparation of the microcapsule and during storage for a long period of time. The agent may be hydrochloric acid-L-cysteine and sodium metabisulfite.

為了適用於醫療適應症，本文公開的封裝聚合物是生物相容的聚合物。適合的聚合物包括乙基纖維素、天然聚合物如玉米蛋白（一種在某些禾本科植物如玉米和穀物中發現的醇溶種子儲存蛋白）、脫乙醯殼多糖、透明質酸、藻酸、可生物降解的聚酯、聚酐、聚乙烯（原酸酯）、聚磷腈或多糖（見Park et al., Molecules 10(2005)146-161）。To be suitable for medical indications, the encapsulating polymers disclosed herein are biocompatible polymers. Suitable polymers include ethyl cellulose, natural polymers such as zein (an alcohol-soluble seed storage protein found in certain grasses such as corn and cereals), acetaminophen, hyaluronic acid, alginic acid. Biodegradable polyester, polyanhydride, polyethylene (orthoester), polyphosphazene or polysaccharide (see Park et al., Molecules 10 (2005) 146-161).

上文所述的試劑微囊化的組合物用在藥物試劑輸送是眾所周知的。見Shalaby and Jamiolkowski, US Pat.No.4,130,639; Buchholz and Meduski, US Pat. No. 6,491,948。然而，在所有這些組合物中，微囊化的試劑是治療劑本身，治療劑不是通過微囊化的試劑的反應產生的。涉及一氧化氮加合物/供體的一氧化氮釋放聚合物在醫學文獻中已有描述，例如 Arnold, US Pat. No. 7,829,553 (二醇二氮烯翁碳基附著在疏水聚合物上); Knapp，US Pat. No. 7,135,189 (亞硝基硫醇的前體和一氧化氮供體)。The microencapsulated compositions of the reagents described above are well known for use in the delivery of pharmaceutical agents. See Shalaby and Jamiolkowski, US Pat. No. 4,130,639; Buchholz and Meduski, US Pat. No. 6,491,948. However, in all of these compositions, the microencapsulated agent is the therapeutic agent itself, and the therapeutic agent is not produced by the reaction of the microencapsulated agent. Nitric oxide-releasing polymers involving nitric oxide adducts/donors have been described in the medical literature, for example, Arnold, US Pat. No. 7,829,553 (diol diazirylene carbon groups attached to hydrophobic polymers) Knapp, US Pat. No. 7, 135, 189 (precursor of nitrosothiol and nitric oxide donor).

本發明實施方式的應用包括直接應用微膠囊化試劑到傷口、傷口敷料、外科敷料、褥瘡患者（或可能發展成患者）的床上護具、襪子、適合糖尿病和其它迴圈障礙患者的其他服裝、骨科石膏，以及用於血管擴張劑在治療性功能障礙時的NO局部遞送。本發明還能滿足與常規植入或***身體的醫療用品（如血管支架、導管、心臟起搏器、除顫器、心臟輔助裝置、人工閥、電極、以及骨科螺釘和引腳）相關的、對少量而持久的 NO 劑量的需要。Applications of embodiments of the present invention include direct application of microencapsulated reagents to wounds, wound dressings, surgical dressings, bed protectors for acne sufferers (or who may develop into patients), socks, other garments suitable for patients with diabetes and other circumflex disorders, Orthopaedic plaster, and local delivery of NO for vasodilators in the treatment of sexual dysfunction. The invention also provides for medical articles (such as vascular stents, catheters, pacemakers, defibrillators, cardiac assist devices, artificial valves, electrodes, and orthopedic screws and pins) that are conventionally implanted or inserted into the body, The need for a small but long-lasting NO dose.

本發明可以是一個傷口敷料包或繃帶包，所述傷口敷料的一部分包含微囊化試劑的顆粒。這部分敷料還結合了一種有保水性能的材料，以保持使顆粒處於潮濕環境時所需的適量的水分。潤濕敷料啟動試劑反應，敷料開始釋放NO。敷料經過設計使得在傷口附近釋放 NO。The invention may be a wound dressing pack or bandage pack, a portion of which comprises particles of a microencapsulated reagent. This part of the dressing also incorporates a water retaining material to maintain the proper amount of moisture required to keep the particles in a humid environment. The wet dressing initiates the reagent reaction and the dressing begins to release NO. The dressing is designed to release NO near the wound.

本發明的一個實施方式公開了一種多用途的、源於分層襯墊的延時釋放NO技術。如第1A圖所示的橫截面：微粒1包含在層2和層3之間，其中層2和層3中至少一個是面向身體層以傳輸氣態 NO，同時至少一個是面朝外的層，這個面朝外的層具有不滲透或有保留水分性能（允許應用的液體傳輸到微粒裡和/或維持微粒處於潮濕環境）。在希望襯墊的一側提供NO的應用中，層2或層3的其中之一是不滲透NO的。在亞毫米級的微粒包含微囊化的菠菜萃取物。在水溶液環境中，從微粒轉化形成的試劑相互結合產生 NO。當水被引入到該襯墊時，試劑開始釋放，NO開始產生。One embodiment of the present invention discloses a versatile time release release NO technology derived from a layered liner. Cross section as shown in Fig. 1A: Particles 1 are comprised between layer 2 and layer 3, wherein at least one of layer 2 and layer 3 is a body facing layer to transport gaseous NO while at least one is an outwardly facing layer, This outwardly facing layer has an impermeable or retained moisture property (allowing the applied liquid to be transported into the particulates and/or maintaining the particulates in a humid environment). In applications where NO is desired on one side of the liner, one of layer 2 or layer 3 is impermeable to NO. The sub-millimeter particles contain microencapsulated spinach extract. In an aqueous environment, reagents formed from the conversion of microparticles combine to produce NO. When water is introduced into the liner, the reagent begins to release and NO begins to form.

在如第1B圖所示的實施方式中，外層2和3被一個隔離層4所分離，層4用於維持外層之間距以及保持微粒層的適當位置。含有的試劑微粒可被嵌入或以其它方式固定在隔離層4上，或者外層2或3中任意一個的內表面上。In the embodiment as shown in Figure 1B, the outer layers 2 and 3 are separated by a barrier layer 4 which serves to maintain the spacing between the outer layers and to maintain the proper position of the layer of particles. The reagent particles contained may be embedded or otherwise affixed to the barrier layer 4, or to the inner surface of any of the outer layers 2 or 3.

如第1圖所示類型的襯墊可以製備成任何指定的尺寸和形狀。第1A-C圖中的垂直尺寸沒有比例，吸水材料5可以比含有試劑的襯墊厚很多。Pads of the type shown in Figure 1 can be prepared in any given size and shape. The vertical dimension in Figures 1A-C is not proportional, and the water absorbing material 5 can be much thicker than the liner containing the reagent.

這樣的襯墊有多種應用。它們可以通過放置在傷口上並覆蓋一個適宜的黏合醫用膠帶層而簡單地使用。它們也可以納入預先製成的繃帶或敷料。可選的，繃帶或敷料配有一個小包，小包含有能反應生成 NO 的微囊化試劑。此外，試劑可以被附著至不同的材料層，然後組裝在一起形成完整的繃帶或敷料。Such pads have a variety of applications. They can be used simply by placing them on the wound and covering a suitable layer of adhesive medical tape. They can also be incorporated into pre-formed bandages or dressings. Optionally, the bandage or dressing is provided with a small packet containing a microencapsulated reagent that reacts to form NO. In addition, the agents can be attached to different layers of material and then assembled together to form a complete bandage or dressing.

第1圖所示其它結構的襯墊可以作為長期持久的抗菌擦拭布。這種襯墊可以改編尺寸，***到迴圈障礙患者的服裝如襪子或緊身褲。通過對材料邊緣和包含顆粒的襯墊結構進行合適處理，襯墊本身也可以作為迴圈障礙患者的襪子、手套和其它服裝的織物。這些服裝可以通過來自患者皮膚的自然水分啟動或通過添加的水分啟動。The pad of the other structure shown in Fig. 1 can be used as a long-lasting antibacterial wipe. The pad can be resized to fit into a garment of a patient with a loopback disorder such as a sock or leggings. The pad itself can also be used as a fabric for socks, gloves and other garments for patients with circumflex disorders by appropriate treatment of the edges of the material and the padding structure comprising the particles. These garments can be activated by natural moisture from the patient's skin or by added moisture.

本發明的另一個實施方式是第1C圖所示的層墊，所述墊層由上述含有微粒的襯墊、吸收層或滲透層5和位於它下面的不透水層6組成。這種吸收層墊適合於已經或正在開始發展成褥瘡的患者。這類患者通過尿失禁和汗水，會產生適量的水分。水分將啟動產生NO的襯墊，並且多餘的水分會被襯墊下面的吸收層吸收。這樣的安排將褥瘡沐浴在NO中，一氧化氮刺激褥瘡癒合，防止潰瘍面積的進一步擴大。Another embodiment of the present invention is the layer mat shown in Fig. 1C, which is composed of the above-mentioned particle-containing pad, absorbent layer or permeation layer 5 and a water-impermeable layer 6 located therebelow. Such absorbent pad pads are suitable for patients who have or are beginning to develop acne. This type of patient produces moderate amounts of water through urinary incontinence and sweat. Moisture will initiate a liner that produces NO, and excess moisture will be absorbed by the absorbent layer beneath the liner. This arrangement bathes acne in NO, which stimulates the healing of acne and prevents further enlargement of the ulcer area.

在不同的應用中，小劑量的NO局部應用到陰莖從而快速刺激雄性大鼠陰莖***已被證明是非常有效的(Han et al., Journal of Sexual Medicine 7 (2010) 224)。本發明公開了用於人類的類似效果的NO的局部應用。目前性功能障礙的全身性藥物有多種副作用，而且需要一段時間才能生效。就可控制性和沒有發現的全身性副作用方面來說，需要這種速效、局部治療的藥物。產生NO的試劑可以放置在***組織的敷料上的乾燥塗層。一個實施方式是用作男用或女用避孕套的內部敷料。將應用到***組織的敷料潤濕從而啟動所述試劑，延時釋放NO。In different applications, small doses of NO applied locally to the penis to rapidly stimulate penile erection in male rats have proven to be very effective (Han et al., Journal of Sexual Medicine 7 (2010) 224). The present invention discloses a topical application of NO for similar effects in humans. Systemic drugs for sexual dysfunction currently have multiple side effects and take some time to take effect. Such fast-acting, topical treatments are needed in terms of controllability and systemic side effects not found. The NO-generating agent can be placed on a dry coating on the dressing of the erectile tissue. One embodiment is for use as an internal dressing for a male or female condom. The dressing applied to the erectile tissue is wetted to activate the reagent, releasing NO in a delayed manner.

本發明的另一個實施方式，避孕套內表面塗有塗層，所述塗層包含有微囊化的試劑，當在水溶液中時，微囊化試劑相互反應產生NO。本實施方式的微粒尺寸範圍可以是0.01到100微米，優選範圍為1〜10微米。較小的微粒尺寸有利於製備塗層時附著於避孕套內表面， NO釋放的時間尺度為分鐘，而不是小時。在採用這樣的實施方式中，用戶在戴上避孕套之前將一個含水化合物如K-Y膠狀物(由McNEIL-PPC, Inc., Ft. Washington，PA生產)應用到***組織上。當微粒接觸到含水化合物開始釋放NO。釋放的NO被限制在避孕套內直到其被***組織透皮吸收以刺激和延長***。In another embodiment of the invention, the inner surface of the condom is coated with a coating comprising microencapsulated reagents which, when in aqueous solution, react with each other to produce NO. The particle size of the present embodiment may range from 0.01 to 100 microns, preferably from 1 to 10 microns. The smaller particle size facilitates attachment to the inner surface of the condom when the coating is prepared, and the time scale for NO release is minutes rather than hours. In such an embodiment, the user applies an aqueous compound such as a K-Y gel (manufactured by McNEIL-PPC, Inc., Ft. Washington, PA) to the erectile tissue prior to wearing the condom. When the particles contact the aqueous compound, they begin to release NO. The released NO is confined within the condom until it is transdermally absorbed by the erectile tissue to stimulate and prolong the erection.

本發明的另一個實施方式，是一種性喚起的凝膠試劑套裝，包含一種類似 K-Y 膠狀物的含水凝膠化合物包裝和一種含微囊化試劑的防潮包裝，所述試劑在水溶液中一起反應產生NO。使用前，打開包裝混合含水凝膠，應用於男性/女性使用者的外生殖器，刺激其血液流動，從而促進陰莖和陰蒂***。這種套裝可用於治療性功能障礙，和提高男性和女性的性生活滿意度。Another embodiment of the present invention is a sexually aroused gel reagent kit comprising an aqueous gel compound package similar to a KY jelly and a moisture barrier package containing a microencapsulated reagent which reacts together in an aqueous solution. Produce NO. Before use, the packaged mixed aqueous gel is applied to the external genitalia of male/female users to stimulate blood flow, thereby promoting penis and clitoris erection. This kit can be used to treat sexual dysfunction and improve sexual life satisfaction for men and women.

雖然沒有人類的臨床研究，但是對大鼠的研究表明，Seitz 等（US Pat. No.6,103,275）所描述的凝膠組合物能夠刺激毛髮生長。眾所周知，局部血管擴張藥如米諾地爾可有效緩解人類的脫髮和刺激頭髮生長，因此持久的低劑量 NO（NO是一種有效的血管舒張劑）的局部應用很可能對脫髮有治療效果。因此，在這裡所公開了另一個延時釋放的應用在於緩解脫髮和刺激頭髮再生的設備和組合物。一個具體的實施方式是由如第1圖所示材料組成的頭形狀的帽子，用於治療脫髮。將帽子製作成適合於在病人頭部的禿頭區域應用，用水濕潤來啟動它。Although no human clinical studies have been conducted, studies in rats have shown that the gel compositions described by Seitz et al. (US Pat. No. 6, 103, 275) are capable of stimulating hair growth. It is well known that topical vasodilators such as minoxidil can effectively alleviate hair loss and stimulate hair growth in humans, so the topical application of long-lasting low-dose NO (NO is an effective vasodilator) is likely to have a therapeutic effect on hair loss. Accordingly, another application for delayed release disclosed herein is in devices and compositions that alleviate hair loss and stimulate hair regeneration. A specific embodiment is a head-shaped cap composed of a material as shown in Fig. 1 for treating hair loss. The cap is made to fit in the bald area of the patient's head and moistened with water to activate it.

下面結合具體實施例來進一步描述本發明，本發明的優點和特點將會隨著描述更為清楚。但這些實施例僅是範例性的，並不對本發明的範圍構成任何限制。本領域技術人員應該理解的是，在不偏離本發明的精神和範圍下可以對本發明技術方案的細節和形式進行修改或替換，但這些修改和替換均落入本發明的保護範圍內。The invention will be further described in conjunction with the specific embodiments, and the advantages and features of the invention will become more apparent. However, these examples are merely exemplary and do not constitute any limitation on the scope of the invention. It should be understood by those skilled in the art that the details and the details of the present invention may be modified or substituted without departing from the spirit and scope of the invention.

本發明實施例中所用到的化學試劑均為分析純，購自國藥集團。The chemical reagents used in the examples of the present invention are of analytical grade and are purchased from Sinopharm Group.

為使本發明更加容易理解，下面結合具體實施例，進一步闡述本發明。本發明所述的實驗方法，若無特殊說明，均為常規方法；所述的生物材料，若無特殊說明，均可從商業途徑獲得。In order to make the present invention easier to understand, the present invention will be further described below in conjunction with the specific embodiments. The experimental methods described in the present invention are conventional methods unless otherwise specified; the biological materials described above can be obtained commercially, unless otherwise specified.

實施例1 菠菜萃取物的製備Example 1 Preparation of spinach extract

1.1菠菜的萃取1.1 spinach extraction

將菠菜的可食用部分用自來水和去離子水清洗，晾乾，剁成小塊，取10g，放入大燒杯中，加50mL去離子水，用草酸調節提取液pH為3~4，研磨後，放到70℃水浴中孵育30min，萃取液過濾到100mL的容量瓶中，用去離子水定容至100mL，用草酸調節提取液pH為3~4，再濃縮至10mL左右，轉移到250mL的燒杯中，加入5mL飽和硼砂溶液和l00mL (70～80℃)熱水，用草酸調節提取液pH為3~4，置沸水浴中，加熱15min，並不斷搖動，取出後冷至室溫，再加入l0mL亞鐵氰化鉀溶液、l0mL乙酸鋅溶液和2g活性炭粉，每次加後，均充分混勻，然後轉移到250mL的容量容量瓶中，用草酸調節提取液pH為3~4，用水定容，過濾，得無色清亮的溶液。Wash the edible part of spinach with tap water and deionized water, dry it, knead it into small pieces, take 10g, put it into a large beaker, add 50mL of deionized water, adjust the pH of the extract with oxalic acid to 3~4, after grinding Incubate in a 70 ° C water bath for 30 min, filter the extract into a 100 mL volumetric flask, dilute to 100 mL with deionized water, adjust the pH of the extract to 3 to 4 with oxalic acid, concentrate to about 10 mL, and transfer to 250 mL. In the beaker, add 5mL of saturated borax solution and l00mL (70 ~ 80 °C) hot water, adjust the pH of the extract with oxalic acid to 3~4, put it in boiling water bath, heat for 15min, and shake continuously, take it out and then cool to room temperature, then Add 10 mL of potassium ferrocyanide solution, 10 mL of zinc acetate solution and 2 g of activated carbon powder. After each addition, mix thoroughly, then transfer to 250 mL volumetric flask, adjust the pH of the extract to 3~4 with oxalic acid. The volume is adjusted and filtered to obtain a colorless and clear solution.

在提取過程進一步添加鹽酸-L-半胱氨酸和焦亞硫酸鈉能保證在提取過程中維C的活性，選擇鹽酸-L-半胱氨酸含量為0.1%，焦亞硫酸鈉含量為0.2%。Further addition of hydrochloric acid-L-cysteine and sodium metabisulfite during the extraction process ensured the activity of vitamin C during the extraction process, and the content of hydrochloric acid-L-cysteine was 0.1%, and the content of sodium metabisulfite was 0.2%.

1.2 硝酸鹽的測定1.2 Determination of nitrate

用分光光度法測定菠菜萃取物中亞硝酸鹽和硝酸鹽的含量，結果表明，菠菜萃取物中亞硝酸鹽含量為5.017×10-3mg/ml; 硝酸鹽含量為0.236mg/ml。The content of nitrite and nitrate in spinach extract was determined by spectrophotometry. The results showed that the content of nitrite in spinach extract was 5.017×10-3 mg/ml; the content of nitrate was 0.236 mg/ml.

用分光光度法測定菠菜萃取物中維C的含量，結果表明，菠菜萃取物中維C含量為1.21×10-2mg/ml。The content of vitamin C in the spinach extract was determined by spectrophotometry. The results showed that the vitamin C content in the spinach extract was 1.21×10-2 mg/ml.

實施例2 微囊化菠菜萃取物的製備Example 2 Preparation of Microencapsulated Spinach Extract

濃縮實施例1製備的菠菜萃取物，通過噴霧乾燥由菠菜萃取物、鹽酸-L-半胱氨酸和焦亞硫酸鈉（維C穩定劑）、玉米醇溶蛋白和揮發性溶劑組成的溶液來製備以玉米醇溶蛋白為基質的菠菜萃取物的微粒，其含有相當於10%（重量百分比）的亞硝酸鹽。玉米醇溶蛋白是從玉米中獲得的富含脯氨酸的蛋白質，作為包衣和封裝的基質可用於加工食品和藥品。它由美國食品藥物管理局（FDA）列為一般公認安全（GRAS）。該溶液為10%的玉米醇溶蛋白(Flo Chemicals, 29 Puffer St., Ashburnham, MA 01430 (Lot F40000111C6))分散在由乙醇：水（90:10）組成的混合物中。溶液中還含有穩定劑鹽酸-L-半胱氨酸和焦亞硫酸鈉（維C穩定劑），鹽酸-L-半胱氨酸含量為0.1%，焦亞硫酸鈉含量為0.2%，將該溶液分散到使用旋轉盤霧化器的乾燥器中，以這種方式形成的微粒直徑範圍在10至100微米之間，這些微粒包含菠菜萃取物分散於其中的玉米醇溶蛋白基質。玉米醇溶蛋白是不溶于水的，當微粒暴露于水時，水慢慢地擴散到玉米醇溶蛋白基質中溶解菠菜萃取物中亞硝酸鈉和維C，含有亞硝酸鈉的溶液慢慢地從顆粒中擴散出來，從而產生了較長時間的亞硝酸鈉的持續釋放。The spinach extract prepared in Example 1 was concentrated and prepared by spray drying a solution consisting of spinach extract, hydrochloric acid-L-cysteine and sodium metabisulfite (vitamin C stabilizer), zein and volatile solvent. Granules of zein-based spinach extract containing 10% by weight of nitrite. Zein is a proline-rich protein obtained from corn and used as a substrate for coating and packaging for processing foods and pharmaceuticals. It is classified as generally recognized safety (GRAS) by the US Food and Drug Administration (FDA). The solution was 10% zein (Flo Chemicals, 29 Puffer St., Ashburnham, MA 01430 (Lot F40000111C6)) dispersed in a mixture consisting of ethanol:water (90:10). The solution also contains stabilizers hydrochloric acid-L-cysteine and sodium metabisulfite (vitamin C stabilizer), hydrochloric acid-L-cysteine content of 0.1%, sodium metabisulfite content of 0.2%, the solution is dispersed to use In a dryer for a rotary disk atomizer, the particles formed in this manner have a diameter ranging from 10 to 100 microns, and these particles comprise a zein matrix in which the spinach extract is dispersed. Zein is insoluble in water. When the particles are exposed to water, the water slowly diffuses into the zein matrix to dissolve the sodium nitrite and vitamin C in the spinach extract. The solution containing sodium nitrite slowly It diffuses out of the granules, resulting in a sustained release of sodium nitrite for a longer period of time.

實施例3 微囊化菠菜萃取物和酸性凝膠在溶液中NO的釋放Example 3 Release of NO in microencapsulated spinach extract and acid gel in solution

製備100毫升（100ml）的水溶液，其中含有5.6g檸檬酸和0.3g的PE9010（一種防腐劑，由Schü and Mayr生產, 30 Two Bridges Road Suite 225, Fairfield, NJ 07004, USA）。將40毫升（40ml）的該溶液放置於燒杯中，用配備 amiNO-700探針的inNO-T的一氧化氮測量系統(Innovative Instruments, Inc., Tampa, FL 33637)檢測溶液中的NO濃度。將10毫克(10mg)實施例2製備的包含玉米醇溶蛋白微囊化的菠菜萃取物的微粒，在指定的時間零時（0）加入到該溶液中，記錄溶液中的NO含量，NO的產生從加入微粒後產生，約20分鐘時，產生的NO從液體中形成，而後NO逐漸增加，大約在1小時達到峰值，然後逐漸減少。整個NO的釋放時間維持5小時，所述NO源於從微囊化顆粒中散發的亞硝酸鈉和溶液中的酸按照前述反應式（1）-（3）所發生的反應。NO的釋放過程見第2圖。A 100 ml (100 ml) aqueous solution containing 5.6 g citric acid and 0.3 g PE9010 (a preservative, manufactured by Schü and Mayr, 30 Two Bridges Road Suite 225, Fairfield, NJ 07004, USA) was prepared. 40 ml (40 ml) of this solution was placed in a beaker, and the concentration of NO in the solution was measured using a nitric oxide measuring system (Innovative Instruments, Inc., Tampa, FL 33637) equipped with an INONO-700 probe inno-T. 10 mg (10 mg) of the microparticles containing the zein microencapsulated spinach extract prepared in Example 2 was added to the solution at a specified time zero (0), and the NO content in the solution was recorded. The generation occurs after the addition of the microparticles. At about 20 minutes, the NO produced is formed from the liquid, and then the NO gradually increases, peaks at about 1 hour, and then gradually decreases. The release time of the entire NO was maintained for 5 hours, which originated from the reaction of the sodium nitrite and the acid in the solution which were emitted from the microencapsulated particles according to the above reaction formulas (1) to (3). See Figure 2 for the release process of NO.

實施例4 微囊化菠菜萃取物在溶液中NO的釋放Example 4 Release of NO by Microencapsulated Spinach Extract in Solution

將實施例2中製備的微粒10毫克（10mg）置於一個容器中。將該混合物加入到含有40毫升去離子水的燒杯中，攪拌均勻。10 mg (10 mg) of the microparticles prepared in Example 2 was placed in a container. The mixture was added to a beaker containing 40 ml of deionized water and stirred well.

用配備 amiNO-700探針的inNO-T 的一氧化氮測量系統(Innovative Instruments, Inc., Tampa, FL 33637)檢測溶液中的NO濃度，amino-700的探針針尖在指定的時間零時（0）加入到該溶液中，記錄溶液中的NO含量，接下來記錄NO信號，在前三個小時的監測中，能檢出微弱的NO。The concentration of NO in the solution was measured using a nitric oxide measurement system (Innovative Instruments, Inc., Tampa, FL 33637) equipped with an INONO-700 probe in Inno-T, and the probe tip of the amino-700 was at a specified time zero ( 0) Add to the solution, record the NO content in the solution, and then record the NO signal. During the first three hours of monitoring, weak NO can be detected.

實施例5微囊化菠菜萃取物和酸性凝膠在糊劑中NO的釋放Example 5 Release of NO by Microencapsulated Spinach Extract and Acidic Gel in Paste

本實施例意在模擬等量的微囊化菠菜萃取物和酸性凝膠直接應用到患者體表時，NO的釋放過程。This example is intended to simulate the release of NO when the same amount of microencapsulated spinach extract and acid gel are applied directly to the patient's body surface.

將實施例2中製備的10毫克微粒，放置於一個有小褶皺的稱量紙上。amino-700 的探針針尖***並完全由粉末混合物覆蓋。用等量的實施例3製備的酸性凝膠與微囊化菠菜萃取物混合均勻，接下來記錄NO信號，記錄過程中，可以根據糊狀系統乾燥狀態適時添加微量去離子水，在整個NO的釋放中，從開始記錄始，約1小時左右NO的釋放達到相對較高的水準，而整個釋放過程達10餘小時之久。而該過程中NO的水準一直處於穩定而平穩的狀態。NO的釋放過程見第3圖。The 10 mg of the microparticles prepared in Example 2 were placed on a weighing paper with small pleats. The probe tip of the amino-700 is inserted and completely covered by the powder mixture. The acid gel prepared in an equal amount of Example 3 was uniformly mixed with the microencapsulated spinach extract, and then the NO signal was recorded. During the recording process, a small amount of deionized water was added according to the dry state of the paste system, in the whole NO. During the release, from the beginning of the recording, the release of NO reached a relatively high level in about 1 hour, and the entire release process lasted for more than 10 hours. The level of NO in this process has been in a stable and stable state. See Figure 3 for the release process of NO.

實施例6微囊化亞硝酸鈉和酸性凝膠在糊劑中NO的釋放Example 6 Release of NO by Microencapsulated Sodium Nitrite and Acidic Gel in Paste

根據實施例2的微囊製備方法，通過噴霧乾燥由亞硝酸鈉、乙基纖維素和揮發性溶劑組成的溶液製備以乙基纖維素為基質的亞硝酸鈉的顆粒（亞硝酸鈉重量比 10%）。According to the microcapsule preparation method of Example 2, particles of sodium nitrite based on ethyl cellulose were prepared by spray drying a solution composed of sodium nitrite, ethyl cellulose and a volatile solvent (sodium nitrite weight ratio 10 %).

將上述製備的10毫克微囊化亞硝酸鈉微粒，放置於一個有小褶皺的稱量紙上。amino-700 的探針針尖***並完全由粉末混合物覆蓋。用等量的實施例3製備的酸性凝膠與微囊化亞硝酸鈉混合均勻，接下來記錄NO 信號，記錄過程中，可以根據糊狀系統乾燥狀態適時添加微量去離子水，在整個NO的釋放中，從開始記錄始，約1小時左右NO的釋放達到相對較高的水準，而整個釋放過程達8小時。而該過程中NO的水準一直處於穩定而平穩的狀態。整個NO釋放過程見第4圖。The 10 mg of microencapsulated sodium nitrite microparticles prepared above were placed on a weighing paper with small pleats. The probe tip of the amino-700 is inserted and completely covered by the powder mixture. The acid gel prepared in an equal amount of Example 3 was uniformly mixed with the microencapsulated sodium nitrite, and then the NO signal was recorded. During the recording process, a small amount of deionized water was added according to the dry state of the paste system, throughout the NO. In the release, from the beginning of the recording, the release of NO reaches a relatively high level in about 1 hour, and the entire release process reaches 8 hours. The level of NO in this process has been in a stable and stable state. See Figure 4 for the entire NO release process.

實施例7微囊化菠菜萃取物和酸性凝膠在糊劑中NO的釋放，酸性凝膠還含有還原劑Example 7 Release of NO by Microencapsulated Spinach Extract and Acidic Gel in Paste, Acid Gel Also Contains Reducing Agent

本實施例意在模擬等量的微囊化菠菜萃取物和酸性凝膠直接應用到患者體表時，NO的釋放過程。在製備的酸性凝膠中還額外添加有還原劑維C。This example is intended to simulate the release of NO when the same amount of microencapsulated spinach extract and acid gel are applied directly to the patient's body surface. A reducing agent dimension C is additionally added to the prepared acidic gel.

製備100毫升（100ml）的水溶液，其中含有5.6g檸檬酸、2.2g抗壞血酸和0.3g的PE9010（一種防腐劑，由Schü and Mayr生產, 30 Two Bridges Road Suite 225, Fairfield, NJ 07004, USA）。A 100 ml (100 ml) aqueous solution containing 5.6 g citric acid, 2.2 g ascorbic acid and 0.3 g PE9010 (a preservative, manufactured by Schü and Mayr, 30 Two Bridges Road Suite 225, Fairfield, NJ 07004, USA) was prepared.

將10毫克微粒，放置於一個有小褶皺的稱量紙上。amino-700的探針針尖***並完全由粉末混合物覆蓋。用等量的上述製備的含有額外還原劑的酸性凝膠與微囊化菠菜萃取物混合均勻，接下來記錄NO 信號，記錄過程中，可以根據糊狀系統乾燥狀態適時添加微量去離子水，在整個NO的釋放中，從開始記錄始，約40分鐘左右NO的釋放達到相對較高的水準，而整個釋放過程達10餘小時之久。而該過程中NO的水準一直處於穩定而平穩的狀態。整個NO釋放過程見第5圖。Place 10 mg of the particles on a weighing paper with small folds. The probe tip of the amino-700 was inserted and completely covered by the powder mixture. An equal amount of the above-prepared acid gel containing the additional reducing agent is mixed with the microencapsulated spinach extract uniformly, and then the NO signal is recorded. During the recording process, a small amount of deionized water can be added according to the dry state of the paste system. In the release of the entire NO, from the beginning of the recording, the release of NO reached a relatively high level in about 40 minutes, and the entire release process lasted for more than 10 hours. The level of NO in this process has been in a stable and stable state. See Figure 5 for the entire NO release process.

上述實驗結果表明，本發明的微囊化菠菜萃取物能夠較微囊化亞硝酸鹽（微囊化亞硝酸鹽能維持8個小時的NO的釋放）具有更長時間的NO釋放時間，即便不在系統中額外添加還原劑成分，其也能在長達10小時的過程中維持NO生理有效濃度的釋放，且該過程中NO的釋放速率恒定。The above experimental results show that the microencapsulated spinach extract of the present invention can have a longer NO release time than the microencapsulated nitrite (microencapsulated nitrite can maintain the release of NO for 8 hours), even if not An additional reducing agent component is added to the system which also maintains the release of the physiologically effective concentration of NO over a period of up to 10 hours, and the rate of NO release during the process is constant.

分析上述原因，可能是菠菜萃取物中的亞硝酸鹽和維C的特定形態或與存在其他物質形成複合結構能維持NO的長時間的釋放過程。Analysis of the above reasons may be due to the specific form of nitrite and vitamin C in the spinach extract or the formation of a composite structure with other substances to maintain the long-term release process of NO.

以上所述僅是本發明的優選實施例而已，並非對本發明做任何形式上的限制，雖然本發明已以優選實施例揭露如上，然而並非用以限定本發明，任何熟悉本專業的技術人員，在不脫離本發明技術方案的範圍內，當可利用上述揭示的技術內容作出些許更動或修飾為等同變化的等效實施例，但凡是未脫離本發明技術方案的內容，依據本發明的技術實質對以上實施例所作的任何簡單修改、等同變化與修飾，均仍屬於本發明技術方案的範圍內。The above is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. The present invention has been disclosed in the preferred embodiments, but is not intended to limit the present invention, and any person skilled in the art, In the scope of the technical solutions of the present invention, equivalent modifications may be made to the equivalents of the embodiments of the present invention without departing from the technical scope of the present invention. Any simple modifications, equivalent changes and modifications made to the above embodiments are still within the scope of the technical solutions of the present invention.

1‧‧‧微粒 1‧‧‧Particles

2‧‧‧層 2 layer

3‧‧‧層 3 ‧ ‧ layer

4‧‧‧隔離層 4‧‧‧Isolation layer

5‧‧‧吸水材料 5‧‧‧Water-absorbing materials

6‧‧‧不透水層 6‧‧‧impermeable layer

第1A圖是一個實施方式中含有微囊化試劑的混合物（反應生成NO）的墊的剖視圖； 第1B圖是一個包含保持微粒適當位置的內部元件的墊的剖視圖； 第1C圖是一個實施方式中吸收層包含微囊化試劑（反應產生NO）的墊的剖視圖； 第2圖為微囊化菠菜萃取物和酸性凝膠在溶液中NO的釋放過程，釋放時間持續5小時； 第3圖為微囊化菠菜萃取物和酸性凝膠在糊劑中NO的釋放過程，釋放時間持續10小時以上； 第4圖為微囊化亞硝酸鈉和酸性凝膠在糊劑中NO的釋放過程，釋放時間8小時； 第5圖為微囊化菠菜萃取物和酸性凝膠在糊劑中NO的釋放過程，酸性凝膠還含有還原劑，釋放時間持續10小時以上。1A is a cross-sectional view of a pad containing a mixture of microencapsulated reagents (reacted to form NO) in an embodiment; FIG. 1B is a cross-sectional view of a pad including internal components holding appropriate positions of the particles; FIG. 1C is an embodiment The middle absorbent layer comprises a cross-sectional view of the pad of the microencapsulated reagent (reacting to produce NO); Figure 2 is the release process of the microencapsulated spinach extract and the acidic gel in solution, the release time lasts 5 hours; The release process of NO in microencapsulated spinach extract and acid gel in paste, the release time lasts for more than 10 hours; Figure 4 shows the release process of NO in microencapsulated sodium nitrite and acid gel in paste, release The time is 8 hours; Figure 5 shows the release process of NO in microencapsulated spinach extract and acid gel in the paste. The acid gel also contains a reducing agent, and the release time lasts for more than 10 hours.

Claims (10)

一種一氧化氮的延時釋放系統，包括微囊化的菠菜萃取物和酸性凝膠，所述酸性凝膠具有足夠的酸度將菠菜萃取物轉化為一氧化氮。A delayed release system of nitric oxide comprising a microencapsulated spinach extract and an acidic gel having sufficient acidity to convert the spinach extract to nitric oxide. 依請求項1所述之一氧化氮的延時釋放系統，其中，所述菠菜萃取物中含有源自菠菜的維C。A delayed release system of nitrogen oxide according to claim 1, wherein the spinach extract contains vitamin C derived from spinach. 依請求項1所述之一氧化氮的延時釋放系統，其中，所述酸度由下列有機酸中的一種或多種提供：檸檬酸、乳酸、甘油酸、甲酸和抗壞血酸。A delayed release system of nitrogen oxide according to claim 1, wherein the acidity is provided by one or more of the following organic acids: citric acid, lactic acid, glyceric acid, formic acid, and ascorbic acid. 依請求項1所述之一氧化氮的延時釋放系統，其中，所述酸度由硼酸提供。A delayed release system of nitrogen oxide according to claim 1, wherein the acidity is provided by boric acid. 依請求項1所述之一氧化氮的延時釋放系統，其中，所述酸性凝膠包括下列聚合物的一種或多種：羥甲基纖維素、羥乙基纖維素、明膠、瓊脂、天然樹膠、澱粉和果膠。A delayed release system of nitrogen oxide according to claim 1, wherein the acidic gel comprises one or more of the following polymers: hydroxymethylcellulose, hydroxyethylcellulose, gelatin, agar, natural gum, Starch and pectin. 依請求項1所述之一氧化氮的延時釋放系統，其中，所述酸性凝膠包含一定量的聚合物，所述聚合物溶液的粘度為0.7-3.0%（w/v）的羥乙基纖維素水溶液的粘度。A delayed release system of nitrogen oxide according to claim 1, wherein the acidic gel comprises a certain amount of a polymer, and the viscosity of the polymer solution is 0.7-3.0% (w/v) of hydroxyethyl group. The viscosity of the aqueous cellulose solution. 依請求項1所述之一氧化氮的延時釋放系統，其中，所述酸性凝膠還包括還原劑，還原劑包括抗壞血酸（維生素C）或抗壞血酸衍生物；所述抗壞血酸衍生物包括3-O-乙基抗壞血酸以及3-烷基抗壞血酸、6-O-辛醯基-抗壞血酸、6-O-十二烷醯基-抗壞血酸、6-O-十四烷醯基-抗壞血酸、6-O-十八烷醯基-抗壞血酸和6-O-癸二醯-抗壞血酸。A delayed release system of nitrogen oxide according to claim 1, wherein the acidic gel further comprises a reducing agent, and the reducing agent comprises ascorbic acid (vitamin C) or an ascorbic acid derivative; and the ascorbic acid derivative comprises 3-O- Ethyl ascorbic acid and 3-alkylascorbic acid, 6-O-octyl-ascorbic acid, 6-O-dodecyldecyl-ascorbic acid, 6-O-tetradecylidene-ascorbic acid, 6-O-octadecane Base-ascorbic acid and 6-O-quinone dioxo-ascorbic acid. 依請求項1所述之一氧化氮的延時釋放系統，其中，所述微囊化的菠菜萃取物的囊材為乙基纖維素、玉米醇溶蛋白、脫乙醯殼多糖、透明質酸、藻酸、可生物降解的聚酯、聚酐、聚乙烯（原酸酯）、聚磷腈或多糖。The delayed release system of nitrogen oxide according to claim 1, wherein the capsule of the microencapsulated spinach extract is ethyl cellulose, zein, quercetin, hyaluronic acid, Alginic acid, biodegradable polyester, polyanhydride, polyethylene (orthoester), polyphosphazene or polysaccharide. 一種為患者提供延時釋放的治療性一氧化氮的成套用品，包括微囊化的菠菜萃取物和酸性凝膠，所述酸性凝膠具有足夠的酸度將菠菜萃取物轉化為一氧化氮；所述微囊化的菠菜萃取物和酸性凝膠分別放置。A kit for providing delayed release of therapeutic nitric oxide to a patient, comprising a microencapsulated spinach extract having an acidity sufficient to convert the spinach extract to nitric oxide; and said acid gel having sufficient acidity; The microencapsulated spinach extract and the acidic gel were placed separately. 依請求項9所述之為患者提供延時釋放的治療性一氧化氮的成套用品，其中，所述微囊化的菠菜萃取物置於傷口敷料或繃帶上，或塗布在安全套的內表面，所述酸性凝膠置於另外的容器。A kit for providing a delayed release therapeutic nitric oxide according to claim 9 wherein the microencapsulated spinach extract is placed on a wound dressing or bandage or coated on an inner surface of a condom, The acid gel is placed in an additional container.