TW201605490A - Composition and uses thereof - Google Patents

Abstract

The invention relates to a composition, formulation, method of manufacture and means of manufacture of medical treatment preparations of ultrapure stabilised hypochlorous acid. More particularly, the invention relates to an ultrapure stablised hypochlorous acid-based composition which is low in contaminating chlorine gas and hypochlorite ions.

Description

組合物及其用途 Composition and use thereof

本發明係關於一種超純穩定化次氯酸之醫療製劑之組合物、調配物、製造方法及製造手段。更特定言之，本發明係關於一種基於超純穩定化次氯酸之組合物，其具有低含量污染氯氣及次氯酸根離子。因此，該組合物可用作具有次氯酸作為其活性藥劑之醫藥組合物。 The present invention relates to a composition, formulation, method of manufacture and method of manufacture of a medical preparation of ultrapure stabilized hypochlorous acid. More particularly, the present invention relates to a composition based on ultrapure stabilized hypochlorous acid having a low level of contaminating chlorine and hypochlorite ions. Therefore, the composition can be used as a pharmaceutical composition having hypochlorous acid as its active agent.

自次氯酸鈉(或液體漂白劑，如通常已知)產生次氯酸為此項技術中已知。直至最近方可主要以次氯酸鈉形式獲得次氯酸。當次氯酸鈉與水反應時，形成次氯酸(方程式1)：Na+(水性)+OCl^-(水性) → HOCl+OH^-：(方程式1) The production of hypochlorous acid from sodium hypochlorite (or liquid bleach, as is generally known) is known in the art. Until recently, hypochlorous acid was obtained mainly in the form of sodium hypochlorite. When sodium hypochlorite reacts with water, hypochlorous acid is formed (Equation 1): Na+ (aqueous) + OCl ^- (aqueous) → HOCl + OH ^- : (Equation 1)

當次氯酸在反應中以氣體形式形成時，其快速消散在空氣中且需要不斷自次氯酸鈉溶液補給。當其與溶液中之鹼分子反應時，其亦自發地恢復成漂白劑。就其自身而言，因此次氯酸為高度不穩定的。 When hypochlorous acid is formed as a gas in the reaction, it rapidly dissipates in the air and needs to be continuously replenished from the sodium hypochlorite solution. When it reacts with the base molecules in the solution, it also spontaneously returns to the bleach. For its part, hypochlorous acid is therefore highly unstable.

根據達金(Dakin)，增加次氯酸之含量可藉由將硼酸添加至混合物中達成。長期以來，此混合物(通常稱為達氏溶液(Dakin's solution))已在一般醫學應用中用作主要的基於次氯酸之消毒劑。混合物由於因硼酸反應造成溶液pH值降低而比先前調配物具有更高次氯酸組分，且具有更大的消毒能力。然而，由於混合物中存在次氯酸鹽(漂白劑)，其仍不適合作為用於患者之表面應用處理劑。(參考文獻9)。 According to Dakin, increasing the content of hypochlorous acid can be achieved by adding boric acid to the mixture. This mixture (commonly known as Dakin's solution) has long been used as a major hypochlorous acid-based disinfectant in general medical applications. The mixture has a higher hypochlorous acid component than the previous formulation due to a decrease in the pH of the solution due to the boric acid reaction and has greater disinfecting power. However, due to the presence of hypochlorite (bleach) in the mixture, it is still not suitable as a surface application treating agent for patients. (Reference 9).

另一種產生次氯酸溶液之方法包含在電解雙室(一個電解室含有正極(陽極)電極且另一個電解室含有負極(陰極)電極)中電解NaCl及水溶液之步驟。兩個電極通常由二氧化鈦製成。電極室藉由滲透膜分開。發生以下化學反應(方程式2)：2NaCl+2H₂O → 2NaOH+HOCl+H₂+Cl₂：方程式2 Another method of producing a hypochlorous acid solution comprises the steps of electrolyzing NaCl and an aqueous solution in an electrolysis dual chamber (one electrolysis chamber containing a positive (anode) electrode and the other electrolysis chamber containing a negative (cathode) electrode). The two electrodes are typically made of titanium dioxide. The electrode compartments are separated by a permeable membrane. The following chemical reaction occurs (Equation 2): 2NaCl + 2H ₂ O → ₂ NaOH + HOCl + H ₂ + Cl ₂ : Equation 2

含有藉由此方法獲得之次氯酸的混合物之穩定性可部分歸因於其酸性(pH值為約2.0至3.0)及部分歸因於次氯酸氣體分子周圍之水分子「簇」中之化學結構的變化。可能的解釋為電解過程引發氫鍵形成且部分質子自次氯酸轉移至水環結構(參考文獻10)。混合物(例如在達氏溶液中)中之所得含量增加之次氯酸使得進一步研究次氯酸成為可能，因為其不太容易消散成氣態形式。在此過程期間，保留次氯酸混合物(稱為陽極電解液)用於消毒劑用途，同時丟棄含NaOH混合物(稱為陰極電解液)。如上文所指示，次氯酸混合物為高度酸性，pH值為約2.0至3.0。因此，藉由次氯酸混合物中次氯酸之解離形成氯氣。氯氣(其為來自在電解過程期間於陽極發生之化學反應的殘餘物)與水反應(方程式3)。 The stability of the mixture containing hypochlorous acid obtained by this method can be attributed in part to its acidity (pH of about 2.0 to 3.0) and partly due to the "cluster" of water molecules surrounding the hypochlorous acid gas molecules. Changes in chemical structure. A possible explanation is that the electrolysis process initiates hydrogen bond formation and partial proton transfer from hypochlorous acid to the water ring structure (Reference 10). The resulting increase in the amount of hypochlorous acid in the mixture (e.g., in a solution of Dart's solution) makes further investigation of hypochlorous acid possible because it is less likely to dissipate into a gaseous form. During this process, a hypochlorous acid mixture (referred to as anolyte) is retained for disinfectant use while the NaOH containing mixture (referred to as catholyte) is discarded. As indicated above, the hypochlorous acid mixture is highly acidic with a pH of about 2.0 to 3.0. Therefore, chlorine gas is formed by the dissociation of hypochlorous acid in the hypochlorous acid mixture. Chlorine gas, which is a residue from a chemical reaction occurring at the anode during the electrolysis process, reacts with water (Equation 3).

Cl₂+H₂O → HOCl+HCl方程式3 Cl ₂ +H ₂ O → HOCl+HCl Equation 3

陽極電解液造成一些風險，因為當用於醫學治療中時，氯氣(其在反應期間存在且亦由次氯酸之解離(歸因於低pH值)形成)有毒且可產生副作用。亦已發現當與金屬表面接觸時，混合物引起生銹(歸因於低pH值)。可在氯氣存在下發生之副作用包括眼睛、嘴巴及鼻或上呼吸道刺激、肺刺激及過敏。當呼吸該等煙氣時，皮膚刺激以及皮膚過敏、噁心及嘔吐亦為常見的。 The anolyte poses some risks because when used in medical treatment, chlorine gas, which is present during the reaction and also formed by the dissociation of hypochlorous acid (due to low pH), is toxic and can cause side effects. It has also been found that when in contact with a metal surface, the mixture causes rust (due to low pH). Side effects that can occur in the presence of chlorine include eye, mouth and nose or upper respiratory tract irritation, lung irritation, and allergies. Skin irritation as well as skin irritation, nausea and vomiting are also common when breathing such fumes.

此項技術中亦已描述其他次氯酸溶液。 Other hypochlorous acid solutions have also been described in the art.

在Wang等人J.Burns Wounds 2007,6,65-79中，作者描述製備次氯酸於水中之穩定化溶液。研究溶液之殺菌特性。穩定化溶液係藉由將NaOCl添加至NaCl於無菌水中之溶液中，隨後添加稀鹽酸以形成活性組分來製備。所得溶液含有不同濃度之HOCl。已報導HOCl溶液顯示廣譜抗微生物活性。溶液需要漂白劑以用於產生且可含有漂白劑及次氯酸鹽作為污染物。其亦需要緩衝液以保持pH值。添加緩衝液亦可引起污染次氯酸鹽之產生。 In Wang et al., J. Burns Wounds 2007, 6 , 65-79 , the authors describe the preparation of a stabilizing solution of hypochlorous acid in water. Study the bactericidal properties of the solution. The stabilized solution is prepared by adding NaOCl to a solution of NaCl in sterile water followed by the addition of dilute hydrochloric acid to form the active component. The resulting solution contained varying concentrations of HOCl. HOCl solutions have been reported to exhibit broad spectrum antimicrobial activity. The solution requires a bleaching agent for production and may contain bleach and hypochlorite as contaminants. It also requires a buffer to maintain the pH. The addition of buffer can also cause the production of contaminated hypochlorite.

WO2010148004揭示次氯酸於水中之抗微生物溶液，其pH值為約4至6且包含緩衝劑。描述次氯酸濃度之若干範圍，且實例描述使用電解產生次氯酸溶液。又，溶液具有包含漂白劑分子且需要經緩衝以保持穩定性(可能導致進一步污染)之缺點。 WO2010148004 discloses an antimicrobial solution of hypochlorous acid in water having a pH of about 4 to 6 and comprising a buffer. Several ranges of hypochlorous acid concentrations are described, and the examples describe the use of electrolysis to produce a hypochlorous acid solution. Also, the solution has the disadvantage of containing bleach molecules and requiring buffering to maintain stability, which may lead to further contamination.

WO2001103926描述藉由電解製備次氯酸溶液。將生理鹽水水溶液傳送至鈦電極上之專用催化劑之混合物以產生氧化物質，尤其次氯酸之混合物。隨後使用磷酸鹽緩衝液調節溶液之pH位準。未提供所得溶液之濃度或純度的指示。 WO2001103926 describes the preparation of a hypochlorous acid solution by electrolysis. Aqueous saline solution is delivered to a mixture of dedicated catalysts on the titanium electrode to produce a mixture of oxidizing species, particularly hypochlorous acid. The pH level of the solution is then adjusted using phosphate buffer. No indication of the concentration or purity of the resulting solution is provided.

CN101223885揭示pH值為4.5至7且次氯酸濃度為10ppm至200ppm之次氯酸溶液，以及該溶液作為消毒劑之用途。一種藉由電解之製備方法報導於實施例1中。提供具有改良之濃度及純度之次氯酸溶液以用於特定用途及具有產生該等組合物之可控制方法為有用的。 CN101223885 discloses a hypochlorous acid solution having a pH of 4.5 to 7 and a hypochlorous acid concentration of 10 ppm to 200 ppm, and the use of the solution as a disinfectant. A preparation method by electrolysis is reported in Example 1. It is useful to provide a hypochlorous acid solution having improved concentrations and purity for a particular use and to have a controllable method of producing such compositions.

GB2488838描述維持活性達至少三個月之次氯酸溶液。亦報導該溶液穩定長達六個月。該溶液經緩衝，可能導致次氯酸鹽污染。宜提供無需緩衝之具有類似或改良之穩定性的次氯酸溶液。 GB 2488838 describes hypochlorous acid solutions that are active for at least three months. The solution was also reported to be stable for up to six months. This solution is buffered and may cause hypochlorite contamination. It is desirable to provide a hypochlorous acid solution having similar or improved stability without buffering.

Wood等人 Lett.Appl.Microbiol.2011,53,668-672中研究次氯酸溶液之pH值對使不同材料上之芽孢桿菌(Bacillus)孢子去污之影響。藉由將乙酸添加至漂白劑中製備具有不同pH值之一系列污次氯酸溶液。發現pH值低於6之漂白劑溶液之有效性及穩定性較高。據報導， 漂白劑中之游離有效氯(free available chlorine)含量在pH 4.5下最穩定。本發明溶液可經漂白劑污染。宜提供不基於漂白劑之溶液。 Wood et al . Lett. Appl. Microbiol. 2011, 53 , 668-672 studied the effect of the pH of a hypochlorous acid solution on the decontamination of Bacillus spores on different materials. A series of soiled hypochlorous acid solutions having different pH values are prepared by adding acetic acid to the bleach. A bleach solution having a pH below 6 was found to be highly effective and stable. It has been reported that the free available chlorine content of the bleach is most stable at pH 4.5. The solution of the invention can be contaminated with bleach. It is preferred to provide a solution that is not based on bleach.

發明人已研發另一種在溶液中獲得次氯酸之方法，其允許更純的形式製造次氯酸，次氯酸以該形式在水溶液中時更加穩定。該方法在某一pH值範圍內產生經定義及特定濃度之超純穩定化次氯酸，且因此為完全可控方法。溶液為穩定的，無需緩衝液且其生產過程不依賴於漂白劑。 The inventors have developed another method for obtaining hypochlorous acid in solution which allows the production of hypochlorous acid in a more pure form which is more stable in this form in aqueous solution. The method produces a defined and specific concentration of ultrapure stabilized hypochlorous acid over a range of pH values and is therefore a fully controllable method. The solution is stable, requires no buffer and is not dependent on the bleaching process.

本發明提供一種超純次氯酸溶液。該溶液較佳不含氯氣及次氯酸根離子。特定言之，溶液較佳包含小於20%，更佳小於15%，更佳小於10%，更佳小於5%，更佳小於1%，更佳小於0.5%，更佳小於0.01%氯氣。氯氣較佳量測為總游離有效氯(FAC)之百分比。 The present invention provides an ultrapure hypochlorous acid solution. The solution preferably contains no chlorine or hypochlorite ions. In particular, the solution preferably comprises less than 20%, more preferably less than 15%, more preferably less than 10%, more preferably less than 5%, more preferably less than 1%, still more preferably less than 0.5%, still more preferably less than 0.01% chlorine. Chlorine is preferably measured as a percentage of total free available chlorine (FAC).

FAC為水溶液中次氯酸、OCl^-(次氯酸根陰離子)及Cl₂(溶解氯氣)之組合形式。氯規格概況(該種類占主要地位)表示於圖1及表1中。可清楚發現較低pH值有利於氯氣(Cl₂)之存在，且較高pH值有利於次氯酸根離子(OCl^-)之存在。其中次氯酸占主要地位且純之pH值為4.5與5.5之間的pH位準。在表1中，亦可發現若溶液在4.5與5.5之間的pH值下製造且不變，則存在於混合物中之唯一FAC分子為次氯酸。不受任何理論束縛，本發明人咸信此製造之pH位準藉由所描述之製造次氯酸之方法更可能進行。經由NaCl電解製造次氯酸溶液產生極低pH值之溶液(pH 2-2.3)。若需要此溶液具有較高pH位準，則混合物之組成隨著次氯酸根(醫藥製劑及其他製劑中不需要的污染物)形成而變化。 FAC is a combination of hypochlorous acid, OCl ^- (hypochlorite anion) and Cl ₂ (dissolved chlorine gas) in an aqueous solution. The chlorine specification (this species is dominant) is shown in Figure 1 and Table 1. It can be clearly found that a lower pH favors the presence of chlorine (Cl ₂ ), and a higher pH favors the presence of hypochlorite ion (OCl ^- ). Among them, hypochlorous acid is dominant and the pH value of pure pH is between 4.5 and 5.5. In Table 1, it can also be found that if the solution is made at a pH between 4.5 and 5.5 and is unchanged, the only FAC molecule present in the mixture is hypochlorous acid. Without being bound by any theory, the inventors believe that the pH level of this fabrication is more likely to be carried out by the described method of making hypochlorous acid. A hypochlorous acid solution was produced via NaCl electrolysis to produce a very low pH solution (pH 2-2.3). If the solution is required to have a higher pH level, the composition of the mixture will vary with the formation of hypochlorite (unwanted contaminants in pharmaceutical preparations and other formulations).

組成中氯氣之百分比較佳為以氯氣形式存在之全部氯的百分比。其可藉由氯量測計(chlorinometer)(例如HI 96771 Hanna Instruments UHR光氯量測計)或藉由任何其他標準方法量測。 The percentage of chlorine in the composition is preferably the percentage of all chlorine present in the form of chlorine. It can be measured by a chlorinometer (e.g., HI 96771 Hanna Instruments UHR photochlorine meter) or by any other standard method.

本發明之組合物之pH值較佳在3.5與7之間，更佳在4與6之間，甚 至更佳在4.5與5.5之間。除次氯酸外，組合物較佳不含改變pH值之緩衝劑。 The pH of the composition of the invention is preferably between 3.5 and 7, more preferably between 4 and 6, even More preferably between 4.5 and 5.5. In addition to hypochlorous acid, the composition preferably does not contain a buffer which changes the pH.

組合物較佳包含濃度在約30毫克/公升與約120毫克/公升之間，更佳在約75毫克/公升至100毫克/公升之間，例如約80毫克/公升或100毫克/公升之次氯酸。 Preferably, the composition comprises a concentration of between about 30 mg/liter and about 120 mg/liter, more preferably between about 75 mg/liter and 100 mg/liter, such as about 80 mg/liter or 100 mg/liter. Chloric acid.

在一個實施例中，次氯酸濃度為約80毫克/公升且組合物之pH值為約5.4。在另一實施例中，次氯酸濃度為約100毫克/公升且組合物之pH值為約4.5。 In one embodiment, the hypochlorous acid concentration is about 80 mg/liter and the pH of the composition is about 5.4. In another embodiment, the hypochlorous acid concentration is about 100 mg/liter and the pH of the composition is about 4.5.

如所說明(表1B)，組合物較佳穩定達至少3個月，更佳至少6個月，更佳至少9個月，甚至更佳至少12個月，甚至更佳至少22個月。組合物較佳在保存於玻璃容器，尤其深色玻璃容器中時展示此穩定性。其亦可或替代性地在保存於高品質深色聚對苯二甲酸乙二醇酯(PET)或其他防潮塑膠容器中時展示此穩定性。其較佳在避免陽光照射保存時展示此穩定性。其較佳在保存於低於25℃之溫度下時展示此穩定性。 As illustrated (Table 1B), the composition is preferably stable for at least 3 months, more preferably at least 6 months, more preferably at least 9 months, even more preferably at least 12 months, and even more preferably at least 22 months. The composition preferably exhibits this stability when stored in a glass container, especially a dark glass container. It may also or alternatively exhibit this stability when stored in high quality dark polyethylene terephthalate (PET) or other moisture resistant plastic containers. It is preferred to exhibit this stability while avoiding the preservation of sunlight. It preferably exhibits this stability when stored at temperatures below 25 °C.

組合物亦較佳實質上不含漂白劑(次氯酸根)或次氯酸鹽。組合物較佳包含小於5%，更佳小於2%，更佳小於1%，更佳小於0.5%，更佳小於0.01%漂白劑及/或次氯酸鹽，尤其作為總FAC之百分比。 The composition is also preferably substantially free of bleach (hypochlorite) or hypochlorite. Preferably, the composition comprises less than 5%, more preferably less than 2%, more preferably less than 1%, more preferably less than 0.5%, more preferably less than 0.01% bleach and/or hypochlorite, especially as a percentage of total FAC.

亦提供一種製備根據本發明之超純、較佳穩定化次氯酸組合物的方法，其包含在電解室中電解鹽酸及水之步驟。電解室較佳含有鈦及二氧化銥電極。與使用此等金屬相關的一些優點包括高尺寸穩定性及耐負載性、低成本能量使用及低重量。 There is also provided a process for the preparation of an ultrapure, preferably stabilized hypochlorous acid composition according to the present invention comprising the step of electrolyzing hydrochloric acid and water in an electrolysis chamber. The electrolysis chamber preferably contains titanium and ruthenium dioxide electrodes. Some of the advantages associated with the use of such metals include high dimensional stability and load resistance, low cost energy usage, and low weight.

如上所提及，替代在習知方式中使用水及NaCl作為電解反應物，使用水及鹽酸。發生之化學反應由方程式4表示，其中產物為超純穩定化次氯酸水。 As mentioned above, instead of using water and NaCl as the electrolytic reactant in the conventional manner, water and hydrochloric acid are used. The chemical reaction that occurs is represented by Equation 4, where the product is ultrapure stabilized hypochlorous acid water.

2HCl+H₂O → HCl+HOCl+H₂(氣體) 方程式4 2HCl+H ₂ O → HCl+HOCl+H ₂ (gas) Equation 4

如上所述，在含有次氯酸之任何水溶液內，兩種其他游離氯物質(稱為游離有效氯或『FAC』)可能潛在地出現。此等物質包含氯氣(Cl₂)及離子型次氯酸根(OCl^-)。在FAC分子中，次氯酸作為治療製劑應用之潛力最顯著，且因此重要的是，在任何含有次氯酸之溶液中，化學環境使得與其他兩種FAC分子相比有利於次氯酸形成/濃縮。已發現此化學環境由混合物之pH值掌控。在此方面參考表1A及圖1。 As noted above, two other free chlorine species (referred to as free available chlorine or "FAC") may potentially be present in any aqueous solution containing hypochlorous acid. These materials include chlorine (Cl ₂ ) and ionic hypochlorite (OCl ^- ). Among the FAC molecules, hypochlorous acid has the greatest potential as a therapeutic formulation, and it is therefore important that in any solution containing hypochlorous acid, the chemical environment is advantageous for hypochlorous acid formation compared to the other two FAC molecules. /concentrate. This chemical environment has been found to be controlled by the pH of the mixture. Reference is made to Table 1A and Figure 1 in this regard.

*OCl*OCl ^-- 表示NaOCl(參考文獻12)。Represents NaOCl (Reference 12).

多種游離有效氯組分(Cl₂、HOCl及OCl^-)在水中平衡存在；主要形式視混合物之pH值而定。當pH值在2.0-7.0(尤其pH 4.5-5.5)之間時，平衡有利於次氯酸。當pH值降低至低於4時，存在增加量之Cl₂，其在大氣壓下自溶液釋出且不再屬於溶液。在pH值低於2.0時，主要形式為Cl₂。 A variety of free available chlorine components (Cl ₂ , HOCl and OCl ^- ) are present in equilibrium in water; the main form depends on the pH of the mixture. When the pH is between 2.0 and 7.0 (especially pH 4.5-5.5), the equilibrium favors hypochlorous acid. When the pH value is reduced to less than 4, the presence of increasing amounts of Cl _2, which is liberated from the solution at atmospheric pressure and no longer belongs to the solution. At pH values below 2.0, the predominant form is Cl ₂ .

在pH 7.4下，次氯酸及OCl^-大約相等，且當pH值大於7.4時，存在比例增加之OCl^-。在pH 4.5-5.5下獲得最大消毒功效，因為所有氯皆以次氯酸形式存在，次氯酸作為消毒劑之有效性比OCl^-高兩個數量級(參考文獻11)。電解步驟較佳在3.5與7之間，更佳4與6之間，甚至更佳4.5與5.5之間的pH值下進行。 At pH 7.4, hypochlorous acid and OCl ^- about equal, and when the pH is greater than 7.4, there is an increase of the proportion of OCl ^-. Maximum disinfection efficacy at pH 4.5-5.5, because all begin with the presence of chlorine in the form of hypochlorous acid, hypochlorous acid as disinfectant effectiveness ratio OCl ^- two orders of magnitude (Ref. 11). The electrolysis step is preferably carried out at a pH between 3.5 and 7, more preferably between 4 and 6, even more preferably between 4.5 and 5.5.

已發現使根據本發明之合成方法產生呈超純穩定化次氯酸形式之次氯酸的pH值為有利於次氯酸形成/濃縮之pH值。此方法在極小的次氯酸根離子及氯氣污染下產生穩定化次氯酸，其因此代表比迄今為止可能的更純及更穩定的次氯酸之水性調配方法。所定義之電解過程之產物較佳由以下定義2HCl+H₂O+電能 → HOCl+HCl+H₂(氣體)，不受理論束縛，本發明人理解准許進行二級電解反應，其中所得HCl進一步反應以形成HOCl及H₂O(下文)，使得產物內之HCl全面減少且溶液中之次氯酸比例更大。 It has been found that the pH of the hypochlorous acid in the form of ultrapure stabilized hypochlorous acid produced by the synthetic process according to the invention is a pH which facilitates the formation/concentration of hypochlorous acid. This process produces stabilized hypochlorous acid with minimal hypochlorite ion and chlorine contamination, which thus represents a more pure and stable aqueous formulation of hypochlorous acid than is possible to date. The product of the defined electrolysis process is preferably defined by 2HCl + H ₂ O + electric energy → HOCl + HCl + H ₂ (gas), which is not bound by theory. The inventors understand that it is permitted to carry out a secondary electrolysis reaction in which the obtained HCl is further reacted. To form HOCl and H ₂ O (below), the HCl in the product is reduced overall and the proportion of hypochlorous acid in the solution is greater.

2HCl+H₂O+電能 → HCl+HOCl+H₂(氣體)(二級電解) 2HCl+H ₂ O+ electric energy → HCl+HOCl+H ₂ (gas) (secondary electrolysis)

二級反應中消耗之HCl愈多，所保持之產物之pH值愈高。 The more HCl is consumed in the secondary reaction, the higher the pH of the product being maintained.

次氯酸為氣體，且一般經由在空氣中消散及經由分解成H⁺及OCl^-或恢復成HCl及O₂自水溶液損失。已發現用於製造本發明之組合物的方法可提供穩定溶液，其在製造之後具有長達(若不長於)一年之存放期，尤其當其在低於25℃下保存於深色玻璃瓶且避免直接陽光照射時。由於次氯酸之氫分子與混合物中之水分子之間的鍵，次氯酸在此水溶液中可保持穩定(參考文獻10)。此製造後穩定性例示於表1B中。 Hypochlorous acid is a gas and is generally lost from aqueous solution by dissipating in air and by decomposition into H ⁺ and OCl ⁻ or recovery to HCl and O ₂ . It has been found that the process for making the compositions of the present invention provides a stable solution which has a shelf life of up to, if not longer than, one year after manufacture, especially when it is stored in dark glass bottles below 25 °C. And avoid direct sunlight. Hypochlorous acid remains stable in this aqueous solution due to the bond between the hydrogen molecules of hypochlorous acid and the water molecules in the mixture (Reference 10). This post-manufacture stability is exemplified in Table 1B.

表1B Table 1B

80mg/l pH 5.5及100mg/l pH 4.5超純穩定化次氯酸在ICH條件下之穩定性 Stability of 80mg/l pH 5.5 and 100mg/l pH 4.5 ultra-pure stabilized hypochlorous acid under ICH conditions

(i)在25℃±2℃及60%±5%相對濕度(RH)，30℃±2℃及65%±5% RH以及40℃±2℃及75%±5% RH下將80mg/l超純HOCl(pH 5.4)儲存於具有玻璃滴管分配器之10ml未開口深色玻璃瓶中長達22個月(Batch 021012805.4)。(ii)在25℃±2℃及60%±5%相對濕度(RH)，30℃±2℃及65%±5% RH以及40℃±2℃及75%±5% RH下將100mg/l pH 4.5儲存於具有玻璃滴管分配器之10ml未開口深色玻璃瓶中 (Batch 0210121004.5.4)。 (i) 80 mg/at 25 °C ± 2 °C and 60% ± 5% relative humidity (RH), 30 °C ± 2 °C and 65% ± 5% RH and 40 °C ± 2 °C and 75% ± 5% RH. • Ultrapure HOCl (pH 5.4) was stored in a 10 ml unopened dark glass vial with a glass dropper dispenser for 22 months (Batch 021012805.4). (ii) 100 mg / 25 ° C ± 2 ° C and 60% ± 5% relative humidity (RH), 30 ° C ± 2 ° C and 65% ± 5% RH and 40 ° C ± 2 ° C and 75% ± 5% RH l pH 4.5 is stored in a 10ml unopened dark glass bottle with a glass dropper dispenser (Batch 0210121004.5.4).

(i) (i)

(ii) (ii)

如上所述，重要的是，在適當pH值下產生次氯酸溶液。此可使用諸如RECTIFY-240機器之標準電解室實現。使用此類機器，本發明人已發現可在pH 5.5(範圍5.4-5.6)下以每小時110公升製造80mg/l(範圍75mg/l至85mg/l)次氯酸。亦可產生與圖1中之值一致之所需範圍內之其他濃度及其他pH值。然而，除了產生與圖1中所引用一致之超純穩定化次氯酸溶液之能力、電極電流之獨特控制及反應物之流動速率(其調節電解室中之時間)以外，此創新生產方法可在不同pH值下產生相同濃度之超純穩定化次氯酸水溶液。類似的，可在例示方法內之控制之不同pH值下產生不同濃度。 As noted above, it is important to produce a hypochlorous acid solution at the appropriate pH. This can be achieved using a standard electrolysis chamber such as the RECTIFY-240 machine. Using such a machine, the inventors have discovered that 80 mg/l (ranging from 75 mg/l to 85 mg/l) hypochlorous acid can be produced at 110 liters per hour at pH 5.5 (range 5.4-5.6). Other concentrations and other pH values within the desired range consistent with the values in Figure 1 can also be produced. However, in addition to the ability to produce an ultrapure stabilized hypochlorous acid solution, the unique control of the electrode current, and the flow rate of the reactants (which regulates the time in the electrolysis chamber) consistent with that referenced in Figure 1, this innovative production method can The same concentration of ultrapure stabilized hypochlorous acid solution was produced at different pH values. Similarly, different concentrations can be produced at different pH values controlled within the exemplified methods.

表1C. 實現水反應物流動速率(psi，用於驅動流動之壓力)之條件變化及通過電極之電流允許完全控制過程且允許在特定pH值下產生 一系列超純穩定化次氯酸水溶液濃度。 Table 1C. Conditional changes in water reactant flow rate (psi, pressure used to drive the flow) and current through the electrode allow complete control of the process and allow for production at a specific pH A series of ultrapure stabilized hypochlorous acid aqueous solutions.

在不同pH值下產生相同濃度超純穩定化次氯酸水溶液之條件為粗體，在相同pH值下產生不同濃度超純穩定化次氯酸水溶液之條件標有下劃線。不同電流及反應物之流動速率(條件)產生相同濃度超純穩定化次氯酸水溶液之情況標有雙下劃線。 The conditions for producing the same concentration of ultrapure stabilized hypochlorous acid solution at different pH values are in bold, and the conditions for producing different concentrations of ultrapure stabilized hypochlorous acid aqueous solution at the same pH are underlined. The flow rates (conditions) of different currents and reactants produce the same concentration of ultrapure stabilized hypochlorous acid aqueous solution marked with double underlining.

使用先前技術之製造方法不可能產生具有適當pH值之次氯酸。 舉例而言，使用鹽水溶液(如氯化鈉)製造次氯酸之電解過程不可避免地引起產生高度酸性(pH 2.0-3.0)次氯酸，其對於治療用途而言酸性過高。在此低pH值下，溶液中存在大量(高達30%)氯氣，其在與人類組織接觸時可產生有毒副作用，如肺、皮膚及眼睛刺激。為了實現溶液中不存在氯氣之較有利pH值，需要以化學方式緩衝溶液。藉由緩衝次氯酸之高度酸性混合物，混合物中將存在作為緩衝過程之結果而形成的次氯酸鹽。最常見的次氯酸鹽(其由緩衝高度酸性次氯酸而產生)為次氯酸鈉(液體漂白劑)及次氯酸鈣(固體漂白劑)，兩者在用於治療人類皮膚且尤其人類眼睛之產品用之表面治療調配物中均為不合需要的。其存在與出現如眼睛或皮膚刺激、敏感性、過敏性反應及肺刺激 之副作用相關。 It is impossible to produce hypochlorous acid having an appropriate pH using the prior art manufacturing method. For example, the electrolysis process of making hypochlorous acid using a brine solution (such as sodium chloride) inevitably results in the production of highly acidic (pH 2.0-3.0) hypochlorous acid, which is too acidic for therapeutic use. At this low pH, a large amount (up to 30%) of chlorine is present in the solution, which can cause toxic side effects such as lung, skin and eye irritation when contacted with human tissue. In order to achieve a more favorable pH value in the absence of chlorine in the solution, it is necessary to chemically buffer the solution. By buffering the highly acidic mixture of hypochlorous acid, hypochlorite formed as a result of the buffering process will be present in the mixture. The most common hypochlorite, which is produced by buffering highly acidic hypochlorous acid, is sodium hypochlorite (liquid bleach) and calcium hypochlorite (solid bleach), both of which are used to treat human skin and especially human eyes. The surface treatment formulations used in the products are all undesirable. Its presence and appearance such as eye or skin irritation, sensitivity, allergic reactions and lung irritation The side effects are related.

亦應注意，最常見的使用氯化鈉之電解水方法不僅產生次氯酸與氯氣之高度酸性混合物(陽極電解液)，且亦產生一種其中次氯酸濃度通常較高(140mg/l至2500mg/l)之混合物。過高次氯酸濃度可刺激人類組織。僅稀釋所得的次氯酸與氯氣之混合物以降低濃度不會改變混合物之pH值。實際上，降低次氯酸濃度以避免毒性所需之稀釋(此可為約1：500稀釋)可使經稀釋混合物中之次氯酸濃度變得過低且無效。已發現此低濃度次氯酸溶液對治療細菌性結膜炎無效(參見圖5)。舉例而言，若以1：500因數稀釋1000mg/l次氯酸/Cl₂混合物之陽極電解液混合物，則次氯酸之濃度將僅為2mg/l之次氯酸/Cl₂混合物。混合物之pH值仍極低，混合物中將仍存氯氣，其(若使用)將引起組織刺激(參見圖5)。 It should also be noted that the most common method of electrolyzing water using sodium chloride not only produces a highly acidic mixture of hypochlorous acid and chlorine (anolyte), but also produces a medium in which the concentration of hypochlorous acid is usually high (140 mg/l to 2500 mg). / l) mixture. Excessive hypochlorous acid concentration can stimulate human tissue. Diluting only the resulting mixture of hypochlorous acid and chlorine to reduce the concentration does not change the pH of the mixture. In fact, the dilution required to reduce the concentration of hypochlorous acid to avoid toxicity (which can be about 1:500 dilution) can make the hypochlorous acid concentration in the diluted mixture too low and ineffective. This low concentration hypochlorous acid solution has been found to be ineffective for the treatment of bacterial conjunctivitis (see Figure 5). For example, if the anolyte mixture of 1000 mg/l hypochlorous acid/Cl ₂ mixture is diluted 1:500, the concentration of hypochlorous acid will be only 2 mg/l hypochlorous acid/Cl ₂ mixture. The pH of the mixture is still very low and chlorine will still be present in the mixture, which (if used) will cause tissue irritation (see Figure 5).

另一種常用的製造次氯酸之方法係藉由使用次氯酸鈉，且隨後使用鹽酸使pH值自極鹼性(約pH 10.0-12.0)位準降至pH 5.5。(方程式5)：NaOCl+2HCl → NaCl+HOCl，隨後 Another common method of making hypochlorous acid is to reduce the pH from a very basic (about pH 10.0-12.0) level to pH 5.5 by using sodium hypochlorite and then using hydrochloric acid. (Equation 5): NaOCl + 2HCl → NaCl + HOCl, followed by

HOCl+HCl → H₂O+Cl₂ 方程式5 HOCl+HCl → H ₂ O+Cl ₂ Equation 5

此過程之問題為不僅經由此化學反應形成且損失一定量氯氣，且最終產物為不穩定的且視混合物之pH值而在次氯酸、鹽(氯化鈉)、氯氣及未經轉化之漂白劑之間不斷變化。另一方面，純次氯酸，如使用本發明之方法製造，無需緩衝或以其他方式改變而達到所需濃度、pH值、純度及穩定性。 The problem with this process is that not only is this chemical reaction formed and a certain amount of chlorine is lost, but the final product is unstable and depending on the pH of the mixture, hypochlorous acid, salt (sodium chloride), chlorine and unconverted bleaching The agent is constantly changing. Pure hypochlorous acid, on the other hand, is produced using the method of the invention without buffering or otherwise altering to achieve the desired concentration, pH, purity and stability.

如方程式4中所展示，本發明之電解反應可在鹽酸與水之反應混合物中進行。特定言之，其可在陰極及陽極之存在下及操作輔助下進行，該等陰極及陽極至少部分浸沒於反應混合物中，且在其間傳送電流以驅動電解反應。反應混合物較佳僅包含作為反應物之鹽酸及水。 特定言之，陽極及陰極可具有鈦，且可塗佈有二氧化銥。 As shown in Equation 4, the electrolytic reaction of the present invention can be carried out in a reaction mixture of hydrochloric acid and water. In particular, it can be carried out in the presence of a cathode and an anode with the aid of an operation, the cathode and the anode being at least partially immersed in the reaction mixture, and an electric current is transmitted therebetween to drive the electrolysis reaction. The reaction mixture preferably contains only hydrochloric acid and water as reactants. In particular, the anode and cathode may have titanium and may be coated with cerium oxide.

驅動電解反應之電流可在約0.5安培與約3安培之間，更特定言之約1安培與約1.7安培之間之安培數，例如約1.40安培。在使用時，至少當電極至少部分浸沒於反應混合物中時，此類量值之電流可因此在其間傳送。 The current driving the electrolysis reaction can be between about 0.5 amps and about 3 amps, more specifically between about 1 amp and about 1.7 amps, for example about 1.40 amps. In use, at least when the electrode is at least partially immersed in the reaction mixture, such magnitude current can thus be transferred therebetween.

方程式4之電解反應可在電解反應階段中進行。該階段可包含電解反應容器。可互換使用『電解反應階段』及『電解反應容器』，鹽酸及水將較佳連續饋入反應容器以在穩定狀態下提供反應容器中之穩定體積之反應混合物，同時電流連續在陽極與陰極之間傳送以驅動電解反應且使其在反應容器中連續進行，且使得可自反應容器連續抽取經由電解反應形成之治療製劑。可因此藉由改變通過容器之流動速率來控制反應容器中之反應混合物之滯留時間及反應混合物之穩定體積之量值。因此，該反應可藉由水流動速率、鹽酸流動速率及所傳送電流來控制，且因此精確產物規格可藉由在預先指定電極安培數下電解容器內之反應時間來控制。 The electrolytic reaction of Equation 4 can be carried out in the electrolysis reaction stage. This stage can comprise an electrolytic reaction vessel. The "electrolysis reaction stage" and the "electrolytic reaction vessel" may be used interchangeably, and hydrochloric acid and water are preferably continuously fed into the reaction vessel to provide a stable volume of the reaction mixture in the reaction vessel under steady state, while the current is continuously at the anode and the cathode. The intermediate reaction is carried out to drive the electrolytic reaction and it is continuously carried out in the reaction vessel, and the therapeutic preparation formed by the electrolytic reaction can be continuously withdrawn from the reaction vessel. The residence time of the reaction mixture in the reaction vessel and the amount of stable volume of the reaction mixture can thus be controlled by varying the flow rate through the vessel. Thus, the reaction can be controlled by the water flow rate, the hydrochloric acid flow rate, and the delivered current, and thus the precise product specification can be controlled by the reaction time in the electrolysis vessel at a predetermined electrode amperage.

作為反應物之鹽酸可呈水溶液形式。通常在此情況下，鹽酸之濃度可在約4.5%至約9%之間，例如約4.5%、約6%或約9%，且更具體言之6%。此等濃度可藉由量測溶液之比重(SG)之比重計量測。習知地，此係使用不同濃度鹽酸之比重之標準表進行，該標準表提供不同溫度下之不同濃度鹽酸之比重。舉例而言，在攝氏20度下，4.5% HCl之SG為1.02055，6% HCl之SG為1.02790且9% HCl之SG為1.04250。 The hydrochloric acid as a reactant may be in the form of an aqueous solution. Typically, in this case, the concentration of hydrochloric acid can be between about 4.5% and about 9%, such as about 4.5%, about 6% or about 9%, and more specifically 6%. These concentrations can be measured by measuring the specific gravity (SG) of the solution. Conventionally, this is carried out using a standard table of the specific gravity of different concentrations of hydrochloric acid, which provides the specific gravity of different concentrations of hydrochloric acid at different temperatures. For example, at 20 degrees Celsius, the SG of 4.5% HCl is 1.02055, the SG of 6% HCl is 1.02790, and the SG of 9% HCl is 1.04250.

較佳地，鹽酸為化學純、食品級鹽酸。在此形式中，鹽酸可幾乎不含污染物，諸如金屬或基於金屬的物質及如砷之有毒物質。 Preferably, the hydrochloric acid is a chemically pure, food grade hydrochloric acid. In this form, hydrochloric acid can be almost free of contaminants such as metals or metal-based materials and toxic substances such as arsenic.

用作反應物之水可為自來水，例如可包含氯化物、鈣、氟化物及磷酸鹽。過程中使用之水之實例具有8mg/l氯化物、2.5mg/l溶解鈣、0.1mg/l氟化物、<0.1正磷酸鹽(pH 7.0)之組成。或者，水可為呈 現為蒸餾或經由逆滲透之純化水。水較佳包含小於2.5mg/l鈣及/或小於0.1mg/l磷酸鹽。由於反應之產物主要為具有少量HCl之次氯酸，因此次氯酸將為溶液內之主要緩衝劑。具有高溶解濃度鈣及磷酸之水將可能消耗次氯酸，引起次氯酸之有效濃度降低。使用具有低鈣(表1D(i))及正磷酸鹽含量之城市用水製備超純穩定化次氯酸產生在製造後45天穩定之產物(表1D(ii))，然而自具有較高濃度溶解鈣及正磷酸鹽之白雲質井孔源萃取的水(表1D(i))產生在製造後54天評估時具有減小穩定性之溶液(表1D(ii))。 The water used as the reactant may be tap water, and may include, for example, chloride, calcium, fluoride, and phosphate. An example of water used in the process has a composition of 8 mg/l chloride, 2.5 mg/l dissolved calcium, 0.1 mg/l fluoride, <0.1 orthophosphate (pH 7.0). Or water can be It is now distilled or purified water by reverse osmosis. The water preferably comprises less than 2.5 mg/l calcium and/or less than 0.1 mg/l phosphate. Since the product of the reaction is primarily hypochlorous acid with a small amount of HCl, hypochlorous acid will be the primary buffer in solution. Water with a high dissolved concentration of calcium and phosphoric acid will likely consume hypochlorous acid, causing a decrease in the effective concentration of hypochlorous acid. Preparation of ultrapure stabilized hypochlorous acid using municipal water with low calcium (Table 1D(i)) and orthophosphate content produced a product that was stable 45 days after manufacture (Table 1D(ii)), however, from higher concentrations Water extracted from the dolomitic pore source of dissolved calcium and orthophosphate (Table 1D(i)) produced a solution with reduced stability at 54 days after manufacture (Table 1D(ii)).

表1D. (i)來自城市及白雲質井孔源之水之組成及(ii)使用城市(低鈣及磷酸)或白雲質井孔衍生水(儲存於深色玻璃瓶中45天後含高鈣及磷酸鹽)製備之100mg/l超純次氯酸水溶液之穩定性 Table 1D. (i) Composition of water from urban and dolomitic boreholes and (ii) use of municipal (low calcium and phosphoric acid) or dolomitic borehole derived water (stored in dark glass bottles for 45 days high) Calcium and phosphate) Preparation of 100mg/l ultrapure hypochlorous acid aqueous solution stability

(i) (i)

(ii) (ii)

因此，待用於過程中之水之規格較佳具有<2.5mg/L溶解鈣濃度及<0.1mg/L正磷酸鹽，且pH值為中性。 Therefore, the specification of the water to be used in the process preferably has a dissolved calcium concentration of <2.5 mg/L and <0.1 mg/L orthophosphate, and the pH is neutral.

在製造根據本發明之具有上文所定義之治療製劑參數內之特定所需特性集合的次氯酸治療製劑時，以預定速率將鹽酸反應物(通常呈上文提供之水溶液形式)添加至水反應物中，藉此提供反應混合物。較佳地，鹽酸添加至水中為電腦控制的。隨後，預定量值電流在至少部分浸沒於反應混合物中之兩個電極之間傳送，且驅動方程式4 之電解反應。電流較佳為直流電。在電極之間傳送電流亦較佳為電腦控制的。由於在任何給定時刻，主體反應物混合物之導電率可由於電解室內之溶液中HCl的準確量而改變，電腦改變電流以便與輸入值一致。舉例而言，設定電流值可為1.4安培，但若HCl之流動速率在特定時刻略微較高或較低，則實際電流可在1.35安培與1.45安培之間改變。 In the manufacture of a hypochlorous acid treatment formulation according to the present invention having a particular desired set of characteristics within the therapeutic formulation parameters defined above, the hydrochloric acid reactant (usually in the form of an aqueous solution provided above) is added to the water at a predetermined rate. In the reaction, a reaction mixture is thereby provided. Preferably, the addition of hydrochloric acid to the water is computer controlled. Subsequently, a predetermined amount of current is transferred between the two electrodes at least partially immersed in the reaction mixture, and driving Equation 4 Electrolytic reaction. The current is preferably direct current. The current transfer between the electrodes is also preferably computer controlled. Since the conductivity of the bulk reactant mixture can change at any given time due to the exact amount of HCl in the solution in the electrolysis chamber, the computer changes the current to match the input value. For example, the set current value can be 1.4 amps, but if the flow rate of HCl is slightly higher or lower at a particular time, the actual current can vary between 1.35 amps and 1.45 amps.

在調節超純穩定化次氯酸溶液(亦即，產物)之特性時，可調節或改變電流量值、水流動速率及鹽酸流動速率中之任一者，使其維持恆定以獲得所需特性之特定集合。 When adjusting the characteristics of the ultrapure stabilized hypochlorous acid solution (ie, product), any one of current magnitude, water flow rate, and hydrochloric acid flow rate can be adjusted or changed to maintain a constant property to obtain desired characteristics. a specific collection.

如上文所暗指，改變通過反應容器之水之流動速率將通常改變任何離散體積水存在於電解室內部之滯留時間。儘管不希望受理論束縛，但本申請人咸信使離散體積水穿過電解室耗費的時間愈久，電解及二級電解反應可進行的時間愈長。因此，藉由降低通過電解室之水之流動速率同時保持通過電極之電流恆定，通常可在所得次氯酸溶液中獲得較高濃度次氯酸，其中產物中具有較低濃度之污染HCl。水流動速率愈快，則電解反應進行時間可能愈少，且因此所得次氯酸溶液中次氯酸濃度可愈低。咸信藉由改變水流動速率，次氯酸溶液中之次氯酸濃度通常可在約20mg/l與約120mg/l之間改變。 As implied above, varying the flow rate of water through the reaction vessel will generally change the residence time of any discrete volume of water present within the interior of the electrolysis chamber. While not wishing to be bound by theory, the applicant has been convinced that the longer it takes for the discrete volume of water to pass through the electrolysis chamber, the longer the electrolysis and secondary electrolysis reactions can be carried out. Thus, by reducing the flow rate of water through the electrolysis chamber while maintaining a constant current through the electrode, a higher concentration of hypochlorous acid can generally be obtained in the resulting hypochlorous acid solution, with a lower concentration of contaminated HCl in the product. The faster the water flow rate, the less time the electrolysis reaction may take place, and thus the lower the hypochlorous acid concentration in the resulting hypochlorous acid solution. By changing the water flow rate, the hypochlorous acid concentration in the hypochlorous acid solution can generally vary between about 20 mg/l and about 120 mg/l.

亦不希望受理論束縛，進一步表明藉由改變通過電解室之鹽酸流動，可改變最終次氯酸溶液之pH值。舉例而言，對於6%鹽酸饋料溶液、85公升/小時之水流動速率及5泵衝程/分鐘之酸流動速率(2毫升/分鐘6%鹽酸-一般在本說明書中，1泵衝程等於0.4毫升鹽酸溶液)，已發現溶液之pH值為約6.3。在此情況下，當鹽酸之流動速率增加至10衝程/分鐘時，已發現pH值減小至約5.9。因此，如將瞭解，對於特定電流量值、電壓差及水流動速率，藉由分別選擇性增加或降低鹽酸流動速率，可分別選擇性降低及增加所得次氯酸溶液之pH值。 Nor is it intended to be bound by theory, further indicating that the pH of the final hypochlorous acid solution can be varied by varying the flow of hydrochloric acid through the electrolysis chamber. For example, for a 6% hydrochloric acid feed solution, a water flow rate of 85 liters/hour and an acid flow rate of 5 pump strokes per minute (2 ml/min 6% hydrochloric acid - generally in this specification, 1 pump stroke equals 0.4 The pH of the solution was found to be about 6.3 in milliliters of hydrochloric acid. In this case, when the flow rate of hydrochloric acid was increased to 10 strokes/min, it was found that the pH was reduced to about 5.9. Thus, as will be appreciated, for a particular current magnitude, voltage differential, and water flow rate, the pH of the resulting hypochlorous acid solution can be selectively reduced and increased, respectively, by selectively increasing or decreasing the flow rate of hydrochloric acid, respectively.

仍不希望受理論束縛，進一步咸信次氯酸溶液中之次氯酸濃度亦可藉由增加或降低電極之間的安培數(亦即，電流)來改變。然而，認為使用此方法控制次氯酸濃度不太理想，因為安培數將因電解室之電源供應器可能過熱而受限制。 Without wishing to be bound by theory, it is further appreciated that the hypochlorous acid concentration in the hypochlorous acid solution can also be varied by increasing or decreasing the amperage (i.e., current) between the electrodes. However, it is considered less desirable to use this method to control the concentration of hypochlorous acid because the amperage will be limited by the possible overheating of the power supply to the electrolysis chamber.

電極之間的電位差(亦即，電壓)可通常高達約19伏。當需要約85公升/小時與約100公升/小時之間的速率之次氯酸溶液時，電壓可在約17伏與約19伏之間(例如約18伏)且電流為約1.4安培。 The potential difference (i.e., voltage) between the electrodes can typically be as high as about 19 volts. When a hypochlorous acid solution at a rate of between about 85 liters/hour and about 100 liters/hour is required, the voltage can be between about 17 volts and about 19 volts (e.g., about 18 volts) and the current is about 1.4 amps.

在連續製造中，流經反應容器之水可在約18psi至約26psi(例如約22psi)之預定水流動壓力下。對於約85公升/小時之治療製劑輸出體積，饋入電解室之HCl可在約1泵衝程/分鐘與約10泵衝程/分鐘之間，例如約5泵衝程/分鐘，各泵衝程為約0.4ml。泵衝程之脈衝寬度可在約50毫秒(ms)與約300ms之間，例如約170ms。 In continuous manufacturing, the water flowing through the reaction vessel can be at a predetermined water flow pressure of from about 18 psi to about 26 psi (e.g., about 22 psi). For a therapeutic preparation output volume of about 85 liters per hour, the HCl fed into the electrolysis chamber can be between about 1 pump stroke/minute and about 10 pump strokes/minute, for example about 5 pump strokes per minute, with each pump stroke being about 0.4. Ml. The pulse width of the pump stroke can be between about 50 milliseconds (ms) and about 300 ms, such as about 170 ms.

進一步提供一種包含本發明之次氯酸組合物之醫藥組合物。醫藥組合物可以用於向個體投與之任何適當形式提供。舉例而言，其可呈噴霧、滴眼劑形式或任何其他適當形式。亦提供包含本發明之次氯酸組合物之傷口敷料、紗布或其類似物。 Further provided is a pharmaceutical composition comprising the hypochlorous acid composition of the present invention. The pharmaceutical composition can be used in any suitable form for administration to an individual. For example, it can be in the form of a spray, eye drops, or any other suitable form. Wound dressings, gauze or the like comprising the hypochlorous acid composition of the present invention are also provided.

亦提供一種根據本發明之次氯酸組合物，其用於療法。組合物可用於治療多種不同不良病狀，如下文所論述。本發明進一步提供一種治療不良病狀之方法，其包含向有需要之個體投與本發明之次氯酸組合物。 A hypochlorous acid composition according to the present invention is also provided for use in therapy. The composition can be used to treat a variety of different undesirable conditions, as discussed below. The invention further provides a method of treating a poor condition comprising administering to a subject in need thereof a hypochlorous acid composition of the invention.

可用次氯酸治療之不良醫學病狀可包括不良眼部病狀、不良皮膚病狀、不良牙齒病狀、皮膚及/或皮肉傷口及灰髮。因此，個體之受影響區域可為眼部區域、皮膚區域、皮肉區域及其中存在灰髮之區域。 Adverse medical conditions that may be treated with hypochlorous acid may include adverse ocular conditions, undesirable skin conditions, poor dental conditions, skin and/or flesh wounds and gray hair. Thus, the affected area of the individual can be an eye area, a skin area, a flesh area, and an area in which gray hair is present.

不良眼部病狀或疾病可為眼損傷、眼感染、眼內壓升高病狀、視網膜及眼神經退化病狀及/或白內障中之至少一者。術語白內障意 謂在其範疇內包括眼睛晶狀體混濁。 The adverse ocular condition or disease may be at least one of an eye injury, an eye infection, an elevated intraocular pressure condition, a retinal and ocular neurodegenerative condition, and/or a cataract. The term cataract It is said to include opacity of the lens in the eye.

一般而言，「眼損傷」意謂眼睛結膜、角膜或鞏膜表面破裂。天然地，破裂可在角膜或鞏膜表面以不同深度出現。 In general, "eye damage" means rupture of the conjunctiva, cornea or sclera of the eye. Naturally, rupture can occur at different depths on the cornea or sclera surface.

一般而言，「眼感染」意謂結膜(包括眼皮)、角膜及/或鞏膜污染。此類污染可歸因於例如細菌及/或病毒及/或真菌感染。 In general, "eye infection" means conjunctival (including eyelids), cornea and/or sclera contamination. Such contamination can be attributed, for example, to bacterial and/or viral and/or fungal infections.

可用治療製劑治療之眼部區域可因此為受不良醫學病狀影響的眼睛之角膜、前房、晶狀體、後房、視網膜、脈絡膜(通常包括眼神經)及/或鞏膜。脈絡膜為視網膜與鞏膜之間眼球之色素血管層。 The area of the eye that can be treated with the therapeutic agent can thus be the cornea, anterior chamber, lens, posterior chamber, retina, choroid (usually including the ocular nerve) and/or the sclera of the eye affected by the adverse medical condition. The choroid is the pigmented vascular layer of the eyeball between the retina and the sclera.

在不良眼部病狀意義上，「投與」及「有效量」意謂約(較佳特定地)兩滴治療製劑溶液/眼睛，兩滴眼睛治療溶液等於0.1ml。實際上，典型的及較佳投與頻率可為首先在一小時內每隔5分鐘一次，隨後兩天每隔兩小時一次，隨後每天3次，例如07.00、17.00及睡覺之前。 In the sense of a bad eye condition, "administration" and "effective amount" mean about (preferably specifically) two drops of the therapeutic formulation solution/eye, and two drops of the eye treatment solution equals 0.1 ml. In practice, the typical and preferred frequency of administration may be once every 5 minutes for an hour, then every two hours for the next two days, followed by three times a day, such as 07.00, 17.00, and before going to bed.

儘管較佳以滴注施配產品形式施用治療製劑溶液，但通常在眼睛重度敏感性之情況下，治療製劑亦可以噴霧施配產品形式施用，其允許治療製劑溶液以精細薄霧噴霧形式施用。換言之，可藉由將治療製劑逐滴引入眼睛或藉由將治療製劑噴塗至眼睛中來投與。當治療製劑以噴霧形式施用時，應較佳保持噴霧瓶距離眼睛約10cm與約12cm之間，且兩次泵送噴霧應施配至睜開的眼睛上且遍及眼瞼。 While it is preferred to administer the therapeutic formulation solution in the form of a drip-administered product, the therapeutic formulation can also be administered in the form of a spray-dispensing product, typically in the case of severe eye sensitivity, which allows the therapeutic formulation solution to be applied as a fine mist spray. In other words, the therapeutic preparation can be administered by dripping into the eye or by spraying the therapeutic preparation into the eye. When the therapeutic formulation is applied as a spray, it is preferred to maintain the spray bottle between about 10 cm and about 12 cm from the eye, and two pump sprays should be applied to the open eye and throughout the eyelid.

較佳地，在眼感染之情況下，同時治療個體之雙眼，無論是否已知兩隻眼睛均受影響，藉此防止或限制不良眼睛病狀擴散至可能不受影響的眼睛。 Preferably, in the case of an eye infection, both eyes of the individual are treated simultaneously, whether or not both eyes are known to be affected, thereby preventing or limiting the spread of undesirable eye conditions to the eyes that may be unaffected.

調節正常細菌菌群促進牙周(牙齒植入顎骨位置之周圍區域)健康，且次氯酸在牙周炎期間似乎具有侵襲革蘭氏陰性病原體(Gram-negative pathogen)之能力。 Modulation of normal bacterial flora promotes the health of the periodontal (the area around which the teeth are implanted in the tibia), and hypochlorous acid appears to have the ability to invade the Gram-negative pathogen during periodontitis.

牙周炎為由牙菌斑生物膜引發之發炎過程，其導致根表面及相 鄰骨之牙周附著損害且最終導致牙齒損害。牙周病中之牙周組織損壞係由對某些細菌形成疾病之放大反應造成。因此，控制此等細菌及刺激癒合過程，以及毀壞生物膜及抑制發炎為控制牙周病之中心。 Periodontitis is an inflammatory process triggered by plaque biofilm, which leads to root surface and phase The periodontal attachment of the adjacent bone is damaged and eventually leads to tooth damage. Periodontal tissue damage in periodontal disease is caused by an amplified response to the formation of certain bacteria. Therefore, controlling these bacteria and stimulating the healing process, as well as destroying the biofilm and inhibiting inflammation are central to the control of periodontal disease.

口臭(口臭)係尤其由嘴中，尤其在舌頭上之成氣病原菌之積累造成。藉由根除此等細菌，可獲得顯著改良。 Bad breath (bad breath) is caused especially by the accumulation of gas-borne pathogens in the mouth, especially on the tongue. Significant improvements can be obtained by eradicating these bacteria.

使用方法：用30ml 80mg/l pH 5.4濃度次氯酸之次氯酸每天漱口三次。首先用30ml次氯酸清洗嘴巴以除去嘴巴中可中和次氯酸之過量(鹼性)唾液。緊接著漱口之後，使用重複劑量之30ml次氯酸澈底清洗嘴巴1分鐘。 Method of use: gargle three times a day with 30 ml of 80 mg/l hypochlorous acid of pH 5.4 concentration hypochlorous acid. The mouth was first rinsed with 30 ml of hypochlorous acid to remove excess (alkaline) saliva that could neutralize hypochlorous acid in the mouth. Immediately after the fistula, the mouth was rinsed with a repeating dose of 30 ml of hypochlorite for 1 minute.

不良皮膚病狀可包括痤瘡、紅斑痤瘡、膿皰、蜂窩組織炎、皮膚真菌感染(例如(但不限於)足癬、汗斑、花斑癬及念珠菌病)、皮膚病毒感染(例如(但不限於)疱疹熱疹及帶狀疱疹)、尿布疹、牛皮癬、濕疹及皮膚色素沉著病症，包括發炎後色素沉著(PIH)。尿布疹可包含特性組合，例如發炎、刺激皮膚、化學灼傷皮膚及感染。 Adverse skin conditions may include acne, rosacea, pustules, cellulitis, fungal skin infections (such as (but not limited to) athlete's foot, sweat stains, tinea versicolor and candidiasis), skin viral infections (eg (but not Limited to herpes zoster and herpes zoster, diaper rash, psoriasis, eczema and skin pigmentation disorders, including post-inflammatory pigmentation (PIH). Diaper rash can contain a combination of properties such as inflammation, skin irritation, chemical burns, and infections.

在治療痤瘡時，投與治療製劑(HOCl 100mg/l pH 4.5)可包括用治療製劑潤濕受影響皮膚區域。此類潤濕可通常藉由使用霧化器泵將治療製劑噴塗至皮膚上來進行。預期約10至15次噴塗將有效潤濕皮膚。投藥亦可包括用較佳不含肥皂之液體清潔劑每天兩次洗滌表面之先前步驟，因為其可因其鹼性性質而提高皮膚之pH值。皮膚上之鹼性表面pH值將中和次氯酸且使其無效，或在最不利情況下將次氯酸轉化成其鹽(次氯酸鈉(漂白劑))。此可能對皮膚造成過敏性反應、超敏反應或皮膚刺激形式之不良作用。較佳在施用治療製劑之前乾燥皮膚。在施用治療製劑之後，較佳允許皮膚自然乾燥。 In the treatment of acne, administration of a therapeutic formulation (HOCl 100 mg/l pH 4.5) can include wetting the affected area of the skin with a therapeutic formulation. Such wetting can typically be carried out by spraying a therapeutic formulation onto the skin using a nebulizer pump. It is expected that about 10 to 15 sprays will effectively wet the skin. Administration may also include the prior step of washing the surface twice a day with a preferably soap-free liquid cleanser because it may increase the pH of the skin due to its alkaline nature. The alkaline surface pH on the skin neutralizes and renders hypochlorous acid, or converts hypochlorous acid to its salt (sodium hypochlorite (bleach)) under the most unfavorable conditions. This may cause an allergic reaction to the skin, a hypersensitivity reaction, or an adverse effect on the form of skin irritation. Preferably, the skin is dried prior to administration of the therapeutic formulation. Preferably, the skin is allowed to dry naturally after administration of the therapeutic formulation.

關於其他不良皮膚病狀，投與治療製劑可包括用治療製劑潤濕受影響皮膚區域。此類潤濕亦可經由使用霧化器噴霧泵噴塗來實現。通常，可每天進行4次投藥。噴塗應較佳距離皮膚10cm至15cm且以 澈底潤濕皮膚之足夠量進行。隨後，應較佳保持皮膚自然乾燥。在尿布疹之情況下，投藥可在每次換尿布之後進行。 With regard to other undesirable skin conditions, administration of a therapeutic formulation can include wetting the affected area with a therapeutic formulation. Such wetting can also be achieved by spraying with an atomizer spray pump. Usually, it can be administered 4 times a day. Spraying should be preferably from 10cm to 15cm from the skin and A sufficient amount of moisturizing the skin is carried out. Subsequently, it should be better to keep the skin naturally dry. In the case of a diaper rash, administration can be carried out after each diaper change.

皮膚及/或皮肉傷口可包括皮膚內任何深度(例如表層、淺表真皮，達到且包括毛囊及其中灼傷傷口超過毛囊進一步延伸之深度皮膚)之灼傷。皮膚及/或皮肉傷口亦可包括壓瘡、慢性傷口、糖尿病性潰瘍、選擇性手術傷口，包括(但不限於)腹部手術傷口、開胸術傷口、婦科傷口、整形手術傷口、耳鼻及咽喉手術傷口、矯形外科手術傷口及造口療法傷口。慢性傷口分類為靜脈停滯或任何其他形式之血液供應不足。此等傷口傳統地但不僅出現在小腿且可存在多年。 Skin and/or flesh wounds can include burns at any depth within the skin (eg, superficial, superficial dermis, reaching and including the hair follicles and the deeper skin in which the burn wounds extend beyond the hair follicles). Skin and/or flesh wounds may also include pressure sores, chronic wounds, diabetic ulcers, and selective surgical wounds including, but not limited to, abdominal surgical wounds, thoracotomy wounds, gynecological wounds, plastic surgery wounds, ear, nose, and throat surgery. Wounds, orthopedic surgical wounds and ostomy wounds. Chronic wounds are classified as venous stasis or any other form of blood supply. These wounds are traditionally but not only found in the calf and can exist for many years.

向皮膚及/或皮肉傷口投與治療製劑可包括在術中將治療製劑施用於皮肉傷口，且在術後一旦移除手術敷料(若應用)，經由霧化器每天噴霧三次來噴塗傷口。此類投藥將通常在手術或傷口閉合後持續約三週，且隨後在下一個月內每天投與兩次。 Administration of a therapeutic formulation to the skin and/or flesh wound can include administering the therapeutic formulation to the skin wound intraoperatively, and once the surgical dressing is removed (if applied) after surgery, the wound is sprayed three times a day via a nebulizer. Such administration will typically last for about three weeks after surgery or wound closure, and then twice daily for the next month.

在選擇性手術傷口之情況下，投與治療製劑可包括用大量呈沖洗液體形式之治療製劑沖洗傷口，且隨後在封閉傷口之前使沖洗液體保留在傷口內約3與約5分鐘之間。若使用吸引引流法(suction drainage)，則投藥可包括***導管，但在約3至約5分鐘時間段內不啟用導管。因此，實現治療製劑與傷口之間的足夠接觸時間。 In the case of a selective surgical wound, administration of the therapeutic preparation can include rinsing the wound with a plurality of therapeutic agents in the form of a rinsing liquid, and then retaining the rinsing liquid within the wound for between about 3 and about 5 minutes prior to closing the wound. If suction drainage is used, administration can include insertion of the catheter, but the catheter is not activated for a period of about 3 to about 5 minutes. Thus, sufficient contact time between the therapeutic formulation and the wound is achieved.

組合物亦可為用於治療灰髮。投藥可包括將治療製劑施用於受影響區域，通常為頭皮。隨後亦可施用於頭髮。施用較佳涉及將治療製劑噴塗至受影響區域上。投藥可達到完全潤濕頭皮及頭髮之程度。隨後，可保持受影響區域自然乾燥。已描述灰髮由毛囊及髮幹中微分子量之H₂O₂(過氧化氫)之積聚引起。藉由將次氯酸施用於頭髮，假設(方程式6)：HOCl+H₂O₂ → H₂O+HCl+O₂：方程式6 The composition may also be used to treat gray hair. Administration can include administering a therapeutic formulation to the affected area, typically the scalp. It can then be applied to the hair. Administration preferably involves spraying the therapeutic formulation onto the affected area. It can be administered to the extent that it completely wets the scalp and hair. Subsequently, the affected area can be kept dry naturally. Gray hair has been described to be caused by the accumulation of micromolecular weight H ₂ O ₂ (hydrogen peroxide) in hair follicles and hair shafts. By applying hypochlorous acid to the hair, assume (Equation 6): HOCl + H ₂ O ₂ → H ₂ O + HCl + O ₂ : Equation 6

使過氧化氫被中和，因此防止灰髮形成。 The hydrogen peroxide is neutralized, thus preventing the formation of gray hair.

亦提供一種用於產生本發明之組合物之電解裝置。該裝置包含至少一個、較佳僅一個電解室。其進一步包含能夠將受控流動速率之反應物提供至電解室中之入口。流動速率可藉由任何適當構件(諸如閥門)控制。可較佳控制流動速率使得流動速率小於150l/h，較佳小於140l/h，更佳小於130l/h，甚至更佳小於125l/h。電解裝置可具備監測流動速率之感測器。電解裝置亦可具備監測通過電解室中電極之安培數的電流感測器。此外，裝置可具備改變電解室中電流之構件，以便控制所產生之次氯酸之濃度。 An electrolysis apparatus for producing the composition of the present invention is also provided. The device comprises at least one, preferably only one, electrolysis chamber. It further comprises an inlet capable of providing a reactant at a controlled flow rate to the electrolysis chamber. The flow rate can be controlled by any suitable means such as a valve. The flow rate can be preferably controlled such that the flow rate is less than 150 l/h, preferably less than 140 l/h, more preferably less than 130 l/h, even more preferably less than 125 l/h. The electrolysis unit can be provided with a sensor that monitors the flow rate. The electrolyzer can also be provided with a current sensor that monitors the amperage of the electrodes passing through the electrolysis chamber. Additionally, the apparatus can be provided with means for varying the current in the electrolysis chamber to control the concentration of hypochlorous acid produced.

現將參考隨附圖式藉由實例更詳細地描述本發明。 The invention will now be described in more detail by way of examples with reference to the accompanying drawings.

10‧‧‧裝備 10‧‧‧Equipment

12‧‧‧電解室 12‧‧‧Electrolytic chamber

13‧‧‧陰極 13‧‧‧ cathode

14‧‧‧饋料管線 14‧‧‧feeding pipeline

15‧‧‧陽極 15‧‧‧Anode

16‧‧‧饋料管線 16‧‧‧feeding pipeline

18‧‧‧產物管線 18‧‧‧Product pipeline

20‧‧‧輸送管線 20‧‧‧Transportation pipeline

圖1展示對於不同濃度之次氯酸溶液，呈次氯酸、次氯酸根離子及氯氣形式之有效氯百分比與溶液之pH值之間的關係。 Figure 1 shows the relationship between the percentage of available chlorine in the form of hypochlorous acid, hypochlorite ion and chlorine and the pH of the solution for different concentrations of hypochlorous acid solution.

圖2A圖解展示產生作為根據本發明之治療製劑之次氯酸溶液的典型製造設備裝備；裝備10包含適用於產生根據本發明之包含超純穩定化次氯酸於水中之穩定次氯酸溶液之治療製劑的習知電解室12，其中次氯酸作為活性醫藥成分。 2A illustrates a typical manufacturing equipment apparatus for producing a hypochlorous acid solution as a therapeutic preparation according to the present invention; the apparatus 10 comprises a stabilized hypochlorous acid solution suitable for producing an ultrapure stabilized hypochlorous acid in water according to the present invention. A conventional electrolysis chamber 12 for treating a preparation in which hypochlorous acid is used as an active pharmaceutical ingredient.

在產生根據本發明之治療製劑時，以預定速率將自來水或逆滲透純水(沿饋料管線14)及經稀釋化學純鹽酸(沿饋料管線16)連續饋入電解室12以在電解室12中形成其反應混合物。在穩定狀態操作中，混合物在電解室12內維持穩定體積，至少達到下文中所描述之電極至少部分浸沒於反應混合物中之程度。 In producing the therapeutic preparation according to the invention, tap water or reverse osmosis pure water (along feed line 14) and diluted chemically pure hydrochloric acid (along feed line 16) are continuously fed into the electrolysis chamber 12 at a predetermined rate for use in the electrolysis chamber The reaction mixture was formed in 12. In steady state operation, the mixture maintains a stable volume within the electrolysis chamber 12, at least to the extent that the electrodes described below are at least partially submerged in the reaction mixture.

電解室12中存在兩個電極。此等電極包含陰極13及陽極15。陰極13為帶負電電極且吸引陽離子，亦即帶正電離子。陽極15為帶正電電極且吸引陰離子，亦即帶負電離子。電極13、15由鈦製成且塗佈有二氧化銥，其中銅層***電極表面(亦即，鈦)與二氧化銥塗層之間。 銅層主要用以實現鈦與二氧化銥之間的連貫鍵。 There are two electrodes in the electrolysis chamber 12. These electrodes comprise a cathode 13 and an anode 15. The cathode 13 is a negatively charged electrode and attracts cations, that is, positively charged ions. The anode 15 is a positively charged electrode and attracts anions, that is, negatively charged ions. The electrodes 13, 15 are made of titanium and coated with cerium oxide, wherein a copper layer is interposed between the electrode surface (i.e., titanium) and the cerium oxide coating. The copper layer is mainly used to achieve a coherent bond between titanium and cerium oxide.

圖2B展示用於產生超純穩定化次氯酸之RECTIFY-240電解機器之組態及操作。 Figure 2B shows the configuration and operation of a RECTIFY-240 electrolysis machine for producing ultrapure stabilized hypochlorous acid.

圖2C展示Caleffi 536減壓閥門。 Figure 2C shows the Caleffi 536 pressure reducing valve.

圖3至圖15展示本發明之次氯酸組合物對多種病狀之治療作用。 3 to 15 show the therapeutic effects of the hypochlorous acid composition of the present invention on various conditions.

圖3 細菌性結膜炎之治療 Figure 3 treatment of bacterial conjunctivitis

(A)雙眼患有細菌性結膜炎之單個患者。用超純穩定化次氯酸治療(在白天期間，每隔2小時每隻眼睛2滴)。在治療4天之後，眼睛症狀消除且無症狀。(B)先前具有歷時3個月之托普黴素(Tobramax)(表面眼用抗生素)經驗之患者呈現引起眼皮顛倒之細菌性結膜炎，尤其在上眼皮上。托普黴素未消除症狀且未發現托普黴素治療具有疾病消除作用。在用超純穩定化次氯酸(在白天期間，每隔2小時每隻眼睛2滴)治療3天之後眼睛症狀消除，且患者報導在治療2天之後眼睛正常，症狀完全緩解。 (A) Individual patients with bacterial conjunctivitis in both eyes. Treatment with ultrapure stabilized hypochlorous acid (2 drops per eye every 2 hours during the day). After 4 days of treatment, the symptoms of the eyes were eliminated and asymptomatic. (B) Patients who previously had experience with Tobramax (surface ophthalmic antibiotics) for 3 months presented bacterial conjunctivitis causing reversal of the eyelids, especially on the upper eyelid. Topotemycin did not eliminate the symptoms and did not find that tobramycin treatment had a disease-eliminating effect. Eye symptoms were abolished after 3 days of treatment with ultrapure stabilized hypochlorous acid (2 drops per eye per day during the day), and the patient reported normal eyes after 2 days of treatment with complete relief of symptoms.

圖4 細菌性結膜炎之治療(額外資料) Figure 4 Treatment of bacterial conjunctivitis (additional information)

兩位患有細菌性結膜炎之患者(每位患者一隻眼睛)。用超純穩定化次氯酸治療(在白天期間，每隔2小時每隻眼睛2滴)。在治療4天之後，眼睛症狀消除且無症狀。 Two patients with bacterial conjunctivitis (one eye per patient). Treatment with ultrapure stabilized hypochlorous acid (2 drops per eye every 2 hours during the day). After 4 days of treatment, the symptoms of the eyes were eliminated and asymptomatic.

圖5 細菌性結膜炎患者中之劑量變化功效研究 Figure 5 : Study on the effect of dose change in patients with bacterial conjunctivitis

在細菌性結膜炎之情況下，使用超純穩定化次氯酸之劑量變化研究(在白天期間，每隔2小時每隻眼睛2滴)。在所有未觀測到功效之情況下，改為對患者使用臨床最佳耐受調配物(在白天期間，每隔2小時2滴)。 In the case of bacterial conjunctivitis, a dose change study of ultrapure stabilized hypochlorous acid was used (2 drops per eye every 2 hours during the day). In all cases where no efficacy was observed, the clinically best tolerant formulation was used instead (two drops every 2 hours during the day).

圖6 病毒性結膜炎之治療 Figure 6 treatment of viral conjunctivitis

患有病毒性結膜炎之單個患者(雙眼)。用超純穩定化次氯酸治療(在白天期間，每隔2小時每隻眼睛2滴)。在治療3天之後，眼睛展示 症狀顯著改善且在治療9天之後完全無症狀。 A single patient (both eyes) with viral conjunctivitis. Treatment with ultrapure stabilized hypochlorous acid (2 drops per eye every 2 hours during the day). After 3 days of treatment, the eyes show Symptoms were significantly improved and completely asymptomatic after 9 days of treatment.

圖7 病毒性結膜炎之治療(額外資料) Figure 7 Treatment of viral conjunctivitis (additional information)

兩位患有病毒性結膜炎之患者(每位患者一隻眼睛)。用超純穩定化次氯酸治療(在白天期間，每隔2小時每隻眼睛2滴)。患者VC01在7天之後展示結膜炎症狀消除且一致病毒性角膜炎症狀改善。患者VCO4之症狀展示治療3天之後完全消除。 Two patients with viral conjunctivitis (one eye per patient). Treatment with ultrapure stabilized hypochlorous acid (2 drops per eye every 2 hours during the day). Patient VC01 showed a reduction in conjunctival inflammatory symptoms after 7 days and a consistent improvement in viral keratitis. Symptoms of patient VCO4 showed complete elimination after 3 days of treatment.

圖8 瞼腺炎之治療 Figure 8 treatment of mumps

(A)兩位患有瞼腺炎之患者(每位患者一隻眼睛)。用超純穩定化次氯酸治療(在白天期間，每隔2小時每隻眼睛2滴)。患者M11呈現慢性病史及持續性疾病且在治療7天之後展示95%改善。患者M12呈現持續許多年之慢性疾病病史且在治療28天之後展示症狀消除。(B)患有雙側瞼腺炎，患有瞼緣炎(blepharitis)，具有持續性疾病病史之另一患者展示浮腫及紅眼。用每天2滴80mg/l次氯酸治療患者3天。在治療3天之後，眼皮症狀顯著清除。紅眼症狀消除且舒適性顯著改善。 (A) Two patients with mumps (one eye per patient). Treatment with ultrapure stabilized hypochlorous acid (2 drops per eye every 2 hours during the day). Patient M11 presented a chronic history and persistent disease and showed a 95% improvement after 7 days of treatment. Patient M12 presented a history of chronic disease that persisted for many years and demonstrated symptom relief after 28 days of treatment. (B) Another patient with bilateral mumps suffering from blepharitis with a history of persistent disease exhibits edema and red eyes. The patient was treated with 2 drops of 80 mg/l hypochlorous acid per day for 3 days. Eyelid symptoms were significantly cleared after 3 days of treatment. Red eye symptoms are eliminated and comfort is significantly improved.

圖9 角膜灼傷及角膜潰瘍之治療 Figure 9 treatment of corneal burns and corneal ulcers

具有單眼化學灼傷之單個患者。用超純穩定化次氯酸治療(在白天期間，每隔2小時每隻眼睛2滴)。灼傷展示較快癒合跡象且展示顯著改善且具有減少之症狀。在呈現角膜潰瘍之患者中發現類似作用。在治療之後，潰瘍展示顯著改善及顯著且快速癒合進程。 A single patient with a single eye chemical burn. Treatment with ultrapure stabilized hypochlorous acid (2 drops per eye every 2 hours during the day). Burns show signs of faster healing and show significant improvement with reduced symptoms. A similar effect was found in patients presenting corneal ulcers. After treatment, the ulcer shows a significant improvement and a significant and rapid healing process.

圖10 眼疱疹病毒感染之治療 Figure 10 treatment of herpes simplex virus infection

具有角膜眼疱疹感染跡象之單個患者。用超純穩定化次氯酸治療(在白天期間，每隔2小時每隻眼睛2滴)。感染症狀減少且角膜炎展示改善及較快癒合跡象。 A single patient with signs of corneal herpes infection. Treatment with ultrapure stabilized hypochlorous acid (2 drops per eye every 2 hours during the day). Symptoms of infection are reduced and keratitis is shown to show signs of improvement and faster healing.

圖11 角膜破裂及鞏膜翼狀胬肉之治療 Figure 11 Treatment of corneal rupture and scleral pterygium

患有單眼角膜破裂之單個患者。用超純穩定化次氯酸治療(在白天期間，每隔2小時每隻眼睛2滴)。治療之後，破裂展示改善跡象。 治療之後，患有鞏膜翼狀胬肉之患者亦展示疾病跡象。 A single patient with a single corneal rupture. Treatment with ultrapure stabilized hypochlorous acid (2 drops per eye every 2 hours during the day). After treatment, the rupture shows signs of improvement. After treatment, patients with scleral pterygium also showed signs of disease.

圖12 腹竇傷口及手術傷口之治療 Figure 12 treatment of sinus wounds and surgical wounds

用每日更換之經100mg/l次氯酸浸沒之紗布塞治療患者(上)，且用20ml之100mg/l次氯酸每隔2天沖洗傷口。在6天之後發現對傷口閉合之顯著作用。患者(下)罹患手術傷口之抗甲氧西林金黃色葡萄球菌(Methocillin resistant staphylococcus aureus；MRSA)感染，且藉由每三天投與100mg/l次氯酸治療30天。在30天時，傷口閉合顯著改善且在培養物上該傷口為MRSA陰性。 The patient (top) was treated with a daily replacement of 100 mg/l hypochlorite-impregnated gauze, and the wound was rinsed every 20 days with 20 ml of 100 mg/l hypochlorous acid. A significant effect on wound closure was found after 6 days. The patient (bottom) was infected with Methocillin resistant staphylococcus aureus (MRSA) and was treated with 100 mg/l hypochlorous acid for 30 days every three days. At 30 days, wound closure was significantly improved and the wound was MRSA negative on culture.

圖13 二度灼傷之治療 Figure 13 treatment of second degree burns

患者為罹患嚴重灼傷之2歲男孩，且用足以施用於全部病灶(除臍之外)之100mg/l次氯酸(8次施用)治療9天。傷口癒合比預期更快，且與良好癒合反應相關，無明顯感染跡象且發炎及疼痛皆顯著減少。 The patient was a 2-year-old boy with severe burns and was treated for 9 days with 100 mg/l hypochlorous acid (8 doses) sufficient to be administered to all lesions (except the umbilicus). Wound healing was faster than expected and was associated with a good healing response with no significant signs of infection and a significant reduction in inflammation and pain.

圖14 感染性手術傷口之治療 Figure 14 treatment of infectious surgical wounds

患者罹患顯著傷口感染(感染性)。藉由每隔三天施用2劑量之100mg/ml次氯酸治療患者。在治療後6天，傷口在腫脹及相關疼痛方面顯示顯著改善。 The patient developed a significant wound infection (infectivity). The patient was treated by administering 2 doses of 100 mg/ml hypochlorous acid every three days. At 6 days after treatment, the wound showed a significant improvement in swelling and related pain.

圖15 擦傷傷口 Figure 15 scratches the wound

用100mg/l次氯酸每天兩次治療患有面部擦傷傷口之患者5天(藉由噴塗以使得完全覆蓋傷口)。患者展示顯著改善，具有明顯及快速傷口癒合反應及面部疤痕消失。 Patients with facial abrasion wounds were treated twice daily with 100 mg/l hypochlorous acid for 5 days (by spraying to completely cover the wound). The patient showed significant improvement with significant and rapid wound healing response and facial scar disappearance.

圖16 熱油灼傷之治療 FIG 16 hot oil treatment of burns

因接觸熱食用油而遭受面部灼傷之9歲男孩。用100mg/l(噴霧)超純穩定化次氯酸pH 4.5治療患者6天(每天施用3次)。在第6天，感染及發炎皆受到控制且無「發紅」或明顯疤痕。 A 9-year-old boy who suffered facial burns due to exposure to hot cooking oil. Patients were treated with 100 mg/l (spray) of ultrapure stabilized hypochlorous acid pH 4.5 for 6 days (3 times per day). On day 6, infection and inflammation were controlled and there was no "redness" or significant scarring.

製造裝備Manufacturing equipment

在圖2A中，參考數字10一般指示用於製造本發明之治療製劑之製造裝備，且圖2B展示RECTIFY-240電解機器。為了建立滿足以下條件之機器(稱為RECTIFY-240)：其中可實現反應物之流動速率及電極電流之控制使得機器能夠產生超純次氯酸，調適現有電解製程。對來自Cosmic Round,Korea之Biocider BC 240機器進行調適，且該等調適為電子及機械調適。BC 240機器可最佳描述為混合合成設備。混合合成係指由軟體控制單元及機械區段(泵及電解室)組成之機器。此HOCl產生方法與使用雙室電解過程之其他電化學方法顯著不同。在典型雙室方法中，一個電解室含有正極(陽極)，另一個電解室含有負極(陰極)。兩個室由膜分開。此雙室方法電解鹽及水且產生兩種產物：酸性極高的HOCl形成於陽極電解室中且類似體積之鹼性物質(NaOH)形成於陰極電解室中。 In Figure 2A, reference numeral 10 generally indicates the manufacturing equipment used to make the therapeutic formulations of the present invention, and Figure 2B shows the RECTIFY-240 electrolysis machine. In order to establish a machine (referred to as RECTIFY-240) in which the flow rate of the reactants and the control of the electrode current are enabled to enable the machine to produce ultrapure hypochlorous acid, the existing electrolysis process is adapted. The Biocider BC 240 machine from Cosmic Round, Korea was adapted and adapted for electronic and mechanical adaptation. The BC 240 machine is best described as a hybrid synthesis unit. Hybrid synthesis refers to a machine consisting of a software control unit and a mechanical section (pump and electrolysis chamber). This HOCl production method is significantly different from other electrochemical methods using a two-chamber electrolysis process. In a typical two-chamber process, one electrolysis chamber contains a positive electrode (anode) and the other electrolysis chamber contains a negative electrode (cathode). The two chambers are separated by a membrane. This two-chamber method electrolyzes salt and water and produces two products: very acidic HOCl is formed in the anolyte chamber and a similar volume of alkaline material (NaOH) is formed in the cathodic electrolysis chamber.

在吾人之混合合成單室型機器情況下，軟體經設計以監測及控制電學及機械功能。此等功能包括： In the case of our hybrid synthesis single chamber machine, the software is designed to monitor and control electrical and mechanical functions. These features include:

1.控制HCl酸進入電解室之流動速率。當HCl流間斷或不為預定之6% HCl之濃度時，機器關閉。酸進入電解室之流動速率亦可根據必須製造之HOCl產物之濃度及pH值而變化且係藉由控制泵之脈衝速率及脈衝寬度來管理。 1. Control the flow rate of HCl acid into the electrolysis chamber. The machine shuts down when the HCl stream is intermittent or not at a predetermined concentration of 6% HCl. The flow rate of acid into the electrolysis chamber can also vary depending on the concentration and pH of the HOCl product that must be produced and is controlled by controlling the pulse rate and pulse width of the pump.

2.控制流向電解室內之電極的電流。電壓為恆定(18V)，但電流(安培數)可經調節。一般原理為安培數增加可引起形成更多的HOCl，以及產物之pH值因製品中之未水解鹽酸(HCl)之伴隨增加而降低。 2. Control the current flowing to the electrodes in the electrolysis chamber. The voltage is constant (18V), but the current (amperage) can be adjusted. The general principle is that an increase in amperage can result in the formation of more HOCl and the pH of the product is reduced by the concomitant increase in unhydrolyzed hydrochloric acid (HCl) in the product.

2HCl+H₂O+電能 → HOCl+HCl+H₂(氣體) 2HCl+H ₂ O+ electric energy → HOCl+HCl+H ₂ (gas)

3.監測電極所用之實際電流。視任何特定時間時電解室中之HCl量而定，電流可高於或低於設定電流。此幫助程式在電極之正極側與負極側之間傳遞適當平均電流。 3. Monitor the actual current used by the electrodes. Depending on the amount of HCl in the electrolysis chamber at any given time, the current can be above or below the set current. This helper program delivers the appropriate average current between the positive and negative sides of the electrode.

4.藉助於數位壓力感測器(Autonics PSA系列數位壓力感測器)監 測供水壓力。在未改變BC 240之情況下，水流應為240公升/小時。藉由電解室附近之孔閥門使水流保持此速率。需要至少150psi水壓力以維持以240公升流動速率通過孔閥門。此壓力藉助於自水儲料槽連接至BC 240之特殊供應泵來維持。若水壓降低或孔變得被阻塞，則結果將為供水流動速率降低。當此情況發生時，數位壓力感測器將與軟體通信以發出警報且關閉所有機器功能。 4. Monitor the water supply pressure by means of a digital pressure sensor ( Autonics PSA Series Digital Pressure Sensor). The water flow should be 240 liters/hour without changing the BC 240. The water flow is maintained at this rate by a orifice valve near the electrolysis chamber. At least 150 psi of water pressure is required to maintain the flow through the orifice valve at a flow rate of 240 liters. This pressure is maintained by means of a special supply pump connected to the BC 240 from a water hopper. If the water pressure drops or the pores become blocked, the result will be a decrease in the water supply flow rate. When this happens, the digital pressure sensor will communicate with the software to sound an alarm and turn off all machine functions.

吾人操控機器功能之目的為實現較高ppm之HOCl且產物之pH值不隨之降低。無此等變化時，機器可產生之HOCl之最大濃度為20ppm至30ppm，pH 5-6.5。主要變化為減小通過電解室之供水壓力(結果為流動速率降低)，以及阻止機器在此情況發生時關閉。一旦供水流動速率減小，可調節電流及HCl流動速率以精密調節成品達到80ppm至100ppm，pH 5.4至4.5。較高產率(80ppm至100ppm HOCl)係經由將HCl轉化成HOCl之二級水解實現。(2HCl+H₂O+電能 → HOCl+HCl+Hf(氣體))。此較長電解時間段允許更多HCl水解成HOCl。由於HOCl為比HCl弱很多的酸，因此實現HOCl之較高ppm值而pH值不降低。 The purpose of our machine function is to achieve a higher ppm of HOCl and the pH of the product does not decrease. Without such a change, the machine can produce a maximum concentration of HOCl of 20 ppm to 30 ppm, pH 5-6.5. The main change is to reduce the water supply pressure through the electrolysis chamber (resulting in a reduced flow rate) and to prevent the machine from shutting down when this occurs. Once the water supply flow rate is reduced, the current and HCl flow rate can be adjusted to fine tune the finished product to 80 ppm to 100 ppm, pH 5.4 to 4.5. Higher yields (80 ppm to 100 ppm HOCl) are achieved via secondary hydrolysis of HCl to HOCl. (2HCl + H ₂ O + electric energy → HOCl + HCl + Hf (gas)). This longer electrolysis period allows more HCl to be hydrolyzed to HOCl. Since HOCl is an acid that is much weaker than HCl, a higher ppm value of HOCl is achieved without a decrease in pH.

此機器操控為三重的： This machine is controlled as triple:

1.阻止數位壓力感測器起作用。此避免機器在水壓減小時關閉。將壓力感測器之上限及下限設定至0psi以避免軟體關閉機器。 1. Prevent the digital pressure sensor from functioning. This prevents the machine from shutting down when the water pressure is reduced. Set the upper and lower limits of the pressure sensor to 0 psi to prevent the software from shutting down the machine.

2.移除供應壓力泵，且將進水管線直接連接至水龍頭(在供水具有中性pH值之情況下)或RO水源。供應壓力應為至少30psi。此實現足夠壓力以允許使用者操控供水壓力及後續流動速率。 2. Remove the supply pressure pump and connect the inlet line directly to the faucet (if the water supply has a neutral pH) or RO water source. The supply pressure should be at least 30 psi. This achieves sufficient pressure to allow the user to manipulate the water supply pressure and subsequent flow rate.

3.在供水源與機器入口之間，安裝可變壓力控制閥門。可精密調節此閥門(Caleffi 536可變壓力減小閥門)以將15psi與25psi之間的流體傳遞至展示於(圖2C)中之電解室。 3. Install a variable pressure control valve between the water supply source and the machine inlet. This valve (Caleffi 536 Variable Pressure Reduction Valve) can be fine tuned to transfer fluid between 15 psi and 25 psi to the electrolysis chamber shown in (Fig. 2C).

裝備10包含適用於產生根據本發明之包含超純穩定化次氯酸於 水中之穩定次氯酸溶液之治療製劑(其中次氯酸作為活性醫藥成分)的習知電解室12。 Apparatus 10 comprising suitable for producing ultrapure stabilized hypochlorous acid according to the invention A known electrolysis chamber 12 for a therapeutic preparation of a stabilized hypochlorous acid solution in water, wherein hypochlorous acid is used as an active pharmaceutical ingredient.

在產生根據本發明之治療製劑時，以預定速率將自來水(沿饋料管線14)及經稀釋化學純鹽酸(沿饋料管線16)連續饋入電解室12以在電解室12中形成其反應混合物。在穩定狀態操作中，混合物在電解室12內維持穩定體積，至少達到下文中所描述之電極至少部分浸沒於反應混合物中之程度。 In producing the therapeutic preparation according to the present invention, tap water (along the feed line 14) and diluted chemically pure hydrochloric acid (along the feed line 16) are continuously fed into the electrolysis chamber 12 at a predetermined rate to form a reaction in the electrolysis chamber 12. mixture. In steady state operation, the mixture maintains a stable volume within the electrolysis chamber 12, at least to the extent that the electrodes described below are at least partially submerged in the reaction mixture.

電解室12中存在兩個電極。此等電極包含陰極13及陽極15。陰極13為帶負電電極且吸引陽離子，亦即帶正電離子。陽極15為帶正電電極且吸引陰離子，亦即帶負電離子。電極13、15由鈦製成且塗佈有二氧化銥，其中銅層***電極表面(亦即，鈦)與二氧化銥塗層之間。銅層主要用以實現鈦與二氧化銥之間的連貫鍵。 There are two electrodes in the electrolysis chamber 12. These electrodes comprise a cathode 13 and an anode 15. The cathode 13 is a negatively charged electrode and attracts cations, that is, positively charged ions. The anode 15 is a positively charged electrode and attracts anions, that is, negatively charged ions. The electrodes 13, 15 are made of titanium and coated with cerium oxide, wherein a copper layer is interposed between the electrode surface (i.e., titanium) and the cerium oxide coating. The copper layer is mainly used to achieve a coherent bond between titanium and cerium oxide.

在使用時，視所需超純穩定化次氯酸溶液之輸出速率及其特性且如下文更詳細描述而定，在約0.5安培與約3安培之間，更特定言之約1安培至約1.7安培之間的直流負載(例如約1.40安培)下，在電極13與15之間施加高達19伏之電位差。因此，驅動根據以上方程式4之電解反應(亦即，2HCl+H₂O→HCl+HOCl+H₂(氣體))之鹽酸與水的化學反應在水溶液中產生次氯酸，作為治療製劑。 In use, depending on the desired rate of output of the ultrapure stabilized hypochlorous acid solution and its characteristics and as described in more detail below, between about 0.5 amps and about 3 amps, more specifically about 1 amp to about A potential difference of up to 19 volts is applied between electrodes 13 and 15 at a DC load of between 1.7 amps (e.g., about 1.40 amps). Therefore, a chemical reaction of hydrochloric acid and water according to the above-described electrolytic reaction of Equation 4 (i.e., 2HCl + H ₂ O → HCl + HOCl + H ₂ (gas)) is driven to produce hypochlorous acid in an aqueous solution as a therapeutic preparation.

自電解室12沿著產物管線18抽取溶液。對於進一步稀釋，沿著產物管線18抽取之產物可視情況與沿著輸送管線20傳送之供應水組合。 The solution is withdrawn from the electrolysis chamber 12 along the product line 18. For further dilution, the product withdrawn along product line 18 may optionally be combined with the supply water conveyed along transfer line 20.

由此獲得之超純穩定化次氯酸產物水溶液(無論經稀釋與否)可隨後以根據本發明描述之方式直接用作本發明之治療製劑。 The ultrapure stabilized hypochlorous acid product aqueous solution thus obtained (whether diluted or not) can then be directly used as a therapeutic preparation of the present invention in the manner described in accordance with the present invention.

製造根據本發明之例示性超純穩定化次氯酸治療製劑：仍參考圖2A，描述本發明之治療製劑之一些實施例之製備：產生設置：110公升/小時次氯酸輸出，80mg/l，pH 5.4 Manufacture of an exemplary ultrapure stabilized hypochlorous acid therapeutic formulation in accordance with the present invention: Still with reference to Figure 2A, the preparation of some embodiments of the therapeutic formulations of the present invention is described: production setup: 110 liters per hour hypochlorous acid output, 80 mg/l , pH 5.4

(電壓18V)(voltage 18V)

產生設置：120公升/小時次氯酸輸出，80mg/l，pH 5.4Production setting: 120 liters/hour hypochlorous acid output, 80 mg/l, pH 5.4

(電壓18V) (voltage 18V)

產生設置：110公升/小時次氯酸輸出，100mg/l，pH 4.6Production setting: 110 liters/hour hypochlorous acid output, 100 mg/l, pH 4.6

(電壓18V) (voltage 18V)

產生設置：120公升/小時次氯酸輸出，100mg/l，pH 4.5Production setting: 120 liters / hour hypochlorous acid output, 100mg / l, pH 4.5

(電壓18V) (voltage 18V)

次氯酸溶液特性之調節Adjustment of the characteristics of hypochlorous acid solution

本申請人已發現方程式1之反應且因此超純穩定化次氯酸溶液之濃度(mg/l)及此溶液(亦即，產物溶液)之pH值可藉由調節以下參數來調節：1.通過電解室12中之電極的安培數；2.進入電解室12之鹽酸傳遞流動速率；及/或3.通過電解室12之水流動速率。 The Applicant has found that the concentration of the reaction of Equation 1 and thus the ultrapure stabilized hypochlorous acid solution (mg/l) and the pH of this solution (i.e., the product solution) can be adjusted by adjusting the following parameters: 1. The amperage of the electrode passing through the electrolysis chamber 12; 2. the hydrochloric acid transfer flow rate into the electrolysis chamber 12; and/or 3. the water flow rate through the electrolysis chamber 12.

應注意，次氯酸濃度升高不伴隨pH值顯著降低。不希望受理論束縛，本申請人咸信pH值不會更顯著降低之原因為在通過電解室之較長過渡時間內更多鹽酸經轉化，鑒於水之流動為滯留時間決定步驟。由於鹽酸為比次氯酸強更多的酸，因此當使用較低的通過電解室之酸流動速率作為增加次氯酸濃度之方法時，製品之pH值不顯著改變。 It should be noted that an increase in the concentration of hypochlorous acid is not accompanied by a significant decrease in pH. Without wishing to be bound by theory, the Applicant believes that the pH value will not decrease more significantly because more hydrochloric acid is converted during the longer transition period through the electrolysis chamber, and the residence time is determined in view of the flow of water. Since hydrochloric acid is a much stronger acid than hypochlorous acid, the pH of the product does not change significantly when a lower acid flow rate through the electrolysis chamber is used as a means of increasing the concentration of hypochlorous acid.

使用光氯量測計進行超純穩定化次氯酸濃度之量測，且用數位pH值量測計測試pH值。更特定言之，使用HI 96771 Hanna Instruments UHR光氯量測計及Hanna Instruments HI 98127防濺型pH測試儀。 The ultrapure stabilized hypochlorous acid concentration was measured using a photochlorinometer and the pH was measured using a digital pH meter. More specifically, a HI 96771 Hanna Instruments UHR photochlorine meter and a Hanna Instruments HI 98127 splash proof pH tester were used.

改變鹽酸流動速率、改變水流動速率及改變電流量值之影響分別在其他情況下測定，其中，(i)在170ms脈衝寬度下，水流壓力及鹽酸流動速率分別維持恆定在26psi及5×0.4ml泵衝程/分鐘，同時改變電流量值；(ii)在170ms脈衝寬度下，電流量值及鹽酸流動速率分別維持恆定在1.30安培及5×0.4ml泵衝程/分鐘，同時改變水流壓力；及(iii)電流量值及水流壓力分別維持恆定在1.30安培及24psi，同時改變鹽酸流動速率泵衝程，維持170ms恆定脈衝寬度。 The effects of changing the flow rate of hydrochloric acid, changing the flow rate of water and changing the magnitude of current were determined in other cases, respectively, (i) at 170 ms pulse width, the water flow pressure and the hydrochloric acid flow rate were kept constant at 26 psi and 5 x 0.4 ml, respectively. Pump stroke / minute, while changing the current value; (ii) at 170ms pulse width, the current magnitude and hydrochloric acid flow rate are maintained constant at 1.30 amps and 5 × 0.4ml pump stroke / minute, respectively, while changing the water flow pressure; and ( Iii) The current magnitude and water flow pressure were maintained constant at 1.30 amps and 24 psi, respectively, while changing the hydrochloric acid flow rate pump stroke to maintain a constant pulse width of 170 ms.

結果展示於表2至表4： The results are shown in Tables 2 to 4:

在眼用應用情況下之儲存及使用Storage and use in the case of ophthalmic applications

對於用作眼用應用中之治療試劑，溶液/治療製劑可藉由使用滴劑施配器或噴霧而保存於用於施用之深色玻璃瓶或高品質深色PET瓶中。 For use as a therapeutic agent in ophthalmic applications, the solution/therapeutic formulation can be stored in a dark glass vial or a high quality dark PET vial for application by using a drop dispenser or spray.

在眼治療之情況下，較佳治療方案為： In the case of eye treatment, the preferred treatment regimen is:

‧滴劑施配器：最初一小時內每隔5分鐘，隨後兩天內每隔兩小時，隨後每天3次，例如在07.00、17.00及睡覺之前。 ‧ Drop dispenser: every 5 minutes in the first hour, every 2 hours in the next two days, then 3 times a day, such as before 07.00, 17.00 and before going to bed.

‧噴霧：保持噴霧嘴距離眼睛10cm至12cm，且兩次噴霧應施配至睜開的眼睛及遍及眼瞼，其與滴劑施配器之治療時間段相同。理想地，0.05毫升/噴霧之噴霧體積等化成單眼滴劑劑量。當儲存於塑膠容器中時，超純穩定化次氯酸溶液呈現不穩定，且當儲存於塑膠中時濃度隨時間減小。當超純穩定化次氯酸儲存於深色玻璃瓶(包括藍色及棕色玻璃)中時，此為不明顯的。 ‧ Spray: Keep the spray nozzle 10 cm to 12 cm from the eye, and the two sprays should be applied to the open eyes and throughout the eyelids, which is the same as the treatment period of the drop dispenser. Ideally, a spray volume of 0.05 ml/spray is equalized to a single eye drop dose. The ultrapure stabilized hypochlorous acid solution appears to be unstable when stored in a plastic container and decreases in concentration as it is stored in the plastic. This is not apparent when ultrapure stabilized hypochlorous acid is stored in dark glass bottles, including blue and brown glass.

臨床研究Clinical research

在眼睛及其他傷口護理病例之不同病狀方面，研究經根據本發明之治療製劑治療之人類個體。此等個體中，204位為眼科患者，且用80mg/l次氯酸(pH 5.5)治療發現的改善展示於表5中： Human subjects treated with a therapeutic formulation according to the present invention are studied in terms of different conditions of the eye and other wound care cases. Of these individuals, 204 were ophthalmic patients, and the improvement found with 80 mg/l hypochlorous acid (pH 5.5) is shown in Table 5:

在治療患者之前及之後，進行以下檢查： Before and after treating the patient, the following checks are performed:

‧全部個人細節 ‧All personal details

‧完全同意 ‧totally agree

‧現用眼鏡Rx ‧Current glasses Rx

‧折射-最佳視力 ‧Refracting - Best Vision

‧眼內壓力讀取 ‧Intraocular pressure reading

‧角膜曲率讀取，「K」讀取 ‧Cornea curvature reading, "K" reading

‧照片 ‧photo

‧狹縫燈檢查以確定無副作用。 ‧ Slit lamp inspection to determine no side effects.

未在任一患者中發現副作用。最長觀測處於根據本發明之連續次氯酸治療之患者6個月。 No side effects were found in any of the patients. The longest observation was for 6 months of patients treated with continuous hypochlorous acid according to the present invention.

其他臨床評估之視覺觀測展示於圖3至圖15中，其各描述於下文中。在各情況下，治療之前之病狀展示於圖之左側，治療結果展示於圖之右側。 Visual observations of other clinical assessments are shown in Figures 3 through 15, each of which is described below. In each case, the condition before treatment is shown on the left side of the figure and the treatment results are shown on the right side of the figure.

圖3 細菌性結膜炎之治療 Figure 3 treatment of bacterial conjunctivitis

圖4 細菌性結膜炎之治療(額外資料) Figure 4 Treatment of bacterial conjunctivitis (additional information)

圖5 細菌性結膜炎患者中之劑量變化功效研究 Figure 5 : Study on the effect of dose change in patients with bacterial conjunctivitis

圖6 病毒性結膜炎之治療 Figure 6 treatment of viral conjunctivitis

圖7 病毒性結膜炎之治療(額外資料) Figure 7 Treatment of viral conjunctivitis (additional information)

圖8 瞼腺炎之治療 Figure 8 treatment of mumps

圖9 角膜灼傷及角膜潰瘍之治療 Treatment of corneal burns FIG. 9 and corneal ulcers

圖10 眼疱疹病毒感染之治療 Figure 10 treatment of herpes simplex virus infection

圖11 角膜破裂及鞏膜翼狀胬肉之治療 Figure 11 Treatment of corneal rupture and scleral pterygium

圖12 腹竇傷口及手術傷口之治療 Figure 12 treatment of sinus wounds and surgical wounds

圖13 二度灼傷之治療 Figure 13 treatment of second degree burns

圖14 感染性手術傷口之治療 Figure 14 treatment of infectious surgical wounds

圖15 擦傷傷口之治療 Figure 15 treatment of bruising wounds

圖16 熱油灼傷之治療 Figure 16 treatment of hot oil burns

其他例證(圖式中未展示)說明對於白內障逆轉、病毒性角膜炎、 過敏性結膜炎、病毒性上緣角膜結膜炎、黃斑變性及眼萎縮之治療作用。 Other examples (not shown in the figure) illustrate the reversal of cataracts, viral keratitis, Therapeutic effects of allergic conjunctivitis, viral upper keratoconjunctivitis, macular degeneration and atrophy of the eye.

超純穩定化次氯酸之臨床作用之論述Discussion on the clinical effect of ultra-pure stabilized hypochlorous acid

歸因於直至現在任存在的可產生次氯酸之多種形式中由於使用已知方法所產生之次氯酸中之污染氯氣及次氯酸根離子所引起之問題，直至現在，超純穩定化次氯酸之益處尚無法有效探知或受到限制。本發明人已發現有可製備極純次氯酸且此類次氯酸可用於多種醫藥應用。 Due to problems caused by the use of contaminated chlorine and hypochlorite ions in hypochlorous acid produced by known methods in various forms of hypochlorous acid that have existed until now, ultrapure stabilization times have been achieved until now The benefits of chloric acid are not yet fully detectable or restricted. The inventors have discovered that very pure hypochlorous acid can be prepared and such hypochlorous acid can be used in a variety of medical applications.

眼用應用Ophthalmic application

發明人已發現超純次氯酸在短至3天之時間段內完全消除絕大部分患者中之重度眼睛及傷口感染以及伴隨的發紅、腫脹及疼痛。當外部施用治療製劑時，此為明顯的。本發明人已發現使用抗生素消除一般感染所需之時間顯著較長：約一週至十天。在吾人之研究中，大量眼科患者(治療後3天再經檢查)顯示症狀顯著改善及患者舒適性。在至少一種情況下，超純穩定化次氯酸在患有重度細菌性結膜炎之患者中有效，該重度細菌性結膜炎對先前用眼科抗生素托普黴絲(tobramax)(托普黴素)、托普待絲(tobradex)(托普黴素及倍他米松(betamethasone))及馬克西醇(maxitrol)(新黴素(neomycin)、***(dexamethasone)及多黏菌素B(polymyxin B))進行之治療具有抗性(參見圖3B)。自然地，在眼部傷口及該物質之任何傷口之情況下，控制感染對於改善癒合速率極為重要(參見參考文獻7)。有趣的是，發現用含有70mg/l(濃度比吾人之眼研究中所用之超純穩定化次氯酸濃度低)陽極電解液治療之患者(細菌性結膜炎)，4/5患者展示耐受性問題(一位展示症狀完全消除)且眼睛保持發炎。(參見圖5、參考文獻7)。 The inventors have found that ultrapure hypochlorous acid completely eliminates severe eye and wound infections and concomitant redness, swelling and pain in the vast majority of patients over a period of as short as three days. This is evident when the therapeutic formulation is administered externally. The inventors have found that the time required to eliminate a general infection with an antibiotic is significantly longer: about one week to ten days. In our study, a large number of ophthalmic patients (rechecked 3 days after treatment) showed significant improvement in symptoms and patient comfort. In at least one case, ultrapure stabilized hypochlorous acid is effective in patients with severe bacterial conjunctivitis, which previously used ophthalmic antibiotics tobramax (topomycin), Tobradex (topomycin and betamethasone) and maxitrol (neomycin, dexamethasone, and polymyxin B) The treatment performed is resistant (see Figure 3B). Naturally, in the case of ocular wounds and any wounds of the substance, controlling infection is extremely important to improve the rate of healing (see reference 7). Interestingly, it was found that 4/5 patients showed tolerance in patients treated with anolyte containing 70 mg/l (concentration of ultrapure stabilized hypochlorous acid used in our eye study) (bacterial conjunctivitis). The problem (one shows that the symptoms are completely eliminated) and the eyes remain inflamed. (See Figure 5, Reference 7).

使用本發明之基於次氯酸之治療製劑在角膜及其他傷口中之另一優勢為當治療製劑外部施用於眼睛時發生加速癒合。皮膚病狀及一 般皮膚及/或皮肉傷口亦如此。已活體外及活體內證明作為活性劑之超純穩定化次氯酸在此方面呈現之輔助作用。加速癒合理解為歸因於較好控制受傷區域之細菌性負載及歸因於抗發炎反應之刺激，隨後不同基因序列為傷口中之正常情況。(參考文獻13)在次氯酸存在下加速癒合過程理解為如下：外部施用基於次氯酸之治療製劑具有誘導細胞增殖之作用，且刺激人類纖維母細胞中細胞外基質組分產生；細胞外基於次氯酸之治療製劑刺激膜受體且活化激酶級聯，引起細胞外基質及/或細胞激素之天然化合物(包括生長因子)產生(參見參考文獻12、13)。結果為皮膚傷口中傷口癒合較快，極少疤痕形成，且癒合眼角膜中幾乎無疤痕形成。 Another advantage of using hypochlorous acid-based therapeutic formulations of the present invention in corneas and other wounds is accelerated healing when the therapeutic formulation is applied externally to the eye. Skin condition and one The same is true for skin and/or flesh wounds. Ultrapurely stabilized hypochlorous acid as an active agent has been shown to be an auxiliary in this respect both in vitro and in vivo. Accelerated healing is understood to be due to better control of the bacterial load of the injured area and to the stimulation of the anti-inflammatory response, followed by different gene sequences as normal in the wound. (Ref. 13) Accelerated healing in the presence of hypochlorous acid is understood as follows: External application of hypochlorous acid-based therapeutic preparations has the effect of inducing cell proliferation and stimulates production of extracellular matrix components in human fibroblasts; Hypochlorous acid-based therapeutic formulations stimulate membrane receptors and activate the kinase cascade, resulting in the production of natural compounds (including growth factors) of extracellular matrices and/or cytokines (see references 12, 13). The result is a faster wound healing in the skin wound, minimal scar formation, and almost no scar formation in the healing cornea.

不受此理論限制，當使用基於次氯酸之治療製劑時，假設癒合角膜以及開放傷口中無疤痕形成可為出現在癒合角膜內之免疫調變結果。因此，可瞭解施用儘可能純且穩定形式之次氯酸(通常外部應用)在醫療行業中將為有利的，尤其在傷口治療方面，且具體言之在本發明情形下之眼睛治療。遺憾的是，至少直至現在，尚不能完全利用此所需優點。現在本發明使得此類應用成為可能，且已能夠有利地採用超純穩定化次氯酸之有益作用且說明於眼部及傷口護理病狀中。 Without being bound by this theory, when a hypochlorite-based therapeutic formulation is used, it is hypothesized that healing of the cornea and the absence of scar formation in the open wound may be the result of immunomodulation occurring within the healing cornea. Thus, it will be appreciated that the application of hypochlorous acid (usually external application) in as pure and stable form as possible would be advantageous in the medical industry, particularly in the treatment of wounds, and in particular in the context of the present invention. Unfortunately, at least until now, this advantage has not been fully utilized. The present invention now makes such applications possible, and has advantageously utilized the beneficial effects of ultrapure stabilized hypochlorous acid and is illustrated in ocular and wound care conditions.

由於患者之不良耐受性，先前不考慮次氯酸治療用於治療眼睛及皮膚病狀。由於本發明係關於使用特定純超之純穩定化次氯酸，因此其重要特徵之一為治療溶液中之次氯酸不伴隨有另一游離氯種類，尤其氯氣(Cl₂)及次氯酸根離子(OCl^-)。氯氣及次氯酸根兩者均與眼睛刺激、過敏及超敏反應相關。已發現此等副作用與本發明之治療製劑及/或治療製劑溶液無關。在用如所描述之優化臨床劑量治療之臨床病例中未發現任何副作用情況。當顯著更濃的超純穩定化次氯酸調配物用於相同臨床人群時，試劑引起刺激及發紅，其顯著降低患者順應性，且因此觀測到歸因於眼睛刺激之掩蔽作用的治療作用。濃度較低 之超純穩定化次氯酸樣品在消除經歷眼感染之患者症狀方面無效。應注意，當對來自兩個群體之患者改為使用臨床優化劑量超純穩定化次氯酸時，用臨床優化劑量7天後起始治療之所有患者經歷顯著治療作用(參見圖5)。 Due to the patient's poor tolerance, hypochlorous acid therapy has not previously been considered for the treatment of eye and skin conditions. Since the present invention relates to the use of a specific pure super pure stabilized hypochlorous acid, one of its important features is that hypochlorous acid in the therapeutic solution is not accompanied by another free chlorine species, especially chlorine (Cl ₂ ) and hypochlorite. Ion (OCl ^- ). Both chlorine and hypochlorite are associated with eye irritation, allergies and hypersensitivity reactions. These side effects have been found to be independent of the therapeutic formulations and/or therapeutic formulation solutions of the present invention. No side effects were found in clinical cases treated with optimized clinical doses as described. When a significantly more concentrated ultrapure stabilized hypochlorous acid formulation is used in the same clinical population, the agent causes irritation and redness, which significantly reduces patient compliance, and thus the therapeutic effect of masking due to eye irritation is observed . Ultra-lower stabilized hypochlorous acid samples with lower concentrations are ineffective in eliminating symptoms in patients experiencing eye infections. It should be noted that when patients from both populations were switched to clinically optimized doses of ultrapure stabilized hypochlorous acid, all patients who started treatment after 7 days of clinically optimized dose experienced significant therapeutic effects (see Figure 5).

皮膚及/或皮肉傷口Skin and/or skin wounds

需要特別提及作為次氯酸治療之指示的疤痕減少及瘢痕瘤預防。以下描述在次氯酸存在下皮膚傷口之修復(正常)癒合與再生癒合之間的差異。在修復癒合之情況下，存在明顯發炎反應，其中形成過量疤痕組織。在次氯酸存在下，已發現不存在此發炎反應且已發現存在顯著較小之疤痕形成，上文所提及之角膜損傷亦如此。假設無發炎反應直接擔負控制疤痕組織形成。正常疤痕、肥厚性疤痕及瘢痕瘤(其為異常及症狀性(癢，疼痛)疤痕組織生長超過初始疤痕之限制的病狀)亦極好對次氯酸治療作出反應。然而，應注意疤痕組織本身不對次氯酸作出較好反應。其指示防止疤痕組織形成。因此，理想的是：一旦有可能接近傷口(移除敷料之後)，即進行可能易於瘢痕瘤形成之傷口之次氯酸治療。 Special mention is needed of scar reduction and keloid prevention as an indication of hypochlorous acid therapy. The differences between repair (normal) healing and regenerative healing of skin wounds in the presence of hypochlorous acid are described below. In the case of repair healing, there is a significant inflammatory response in which excessive scar tissue is formed. In the presence of hypochlorous acid, this inflammatory response has been found to be absent and significant scar formation has been found to be present, as is the corneal damage mentioned above. It is assumed that no inflammatory reaction is directly responsible for controlling the formation of scar tissue. Normal scars, hypertrophic scars, and keloids (which are abnormal and symptomatic (itch, pain) scar tissue growth beyond the limits of the initial scar) are also excellent for response to hypochlorous acid therapy. However, it should be noted that the scar tissue itself does not respond well to hypochlorous acid. It is instructed to prevent the formation of scar tissue. Therefore, it is desirable to perform a hypochlorous acid treatment of a wound that may be susceptible to keloid formation, once it is possible to access the wound (after removal of the dressing).

由於多種重要原因，次氯酸對傷口有益。已注意就人類而論，純次氯酸具有卓越的安全分佈(參考文獻7及8)。對於能夠治癒之經感染傷口，控制任何細菌污染至關重要。基於可獲得的文獻，由次氯酸顯示之『殺菌』活性似乎極可能歸因於應用區域周圍之微環境的化學-物理改變(參考文獻4)。在傷口之情況下，控制感染對於改善癒合速率極為重要(參考文獻5)。 Hypochlorous acid is beneficial to the wound for a number of important reasons. It has been noted that pure hypochlorous acid has an excellent safety distribution in terms of humans (References 7 and 8). Controlling any bacterial contamination is critical for infected wounds that can be cured. Based on available literature, the "bactericidal" activity exhibited by hypochlorous acid appears to be highly likely due to chemical-physical changes in the microenvironment around the application area (Reference 4). In the case of wounds, controlling infection is extremely important to improve the rate of healing (Reference 5).

皮膚病狀Skin condition

痤瘡由油腺堵塞，隨後積聚腺內含物受細菌痤瘡丙酸桿菌(Propionibacterium acnes)感染而造成。病狀可能因雄性激素睪固酮之存在而變得更糟，雄性激素睪固酮稠化由油腺產生之皮脂次氯酸經由 多種路徑有益於痤瘡(參考文獻1)： The acne is blocked by the oil glands, and the accumulated glandular contents are subsequently infected by the bacteria Propionibacterium acnes. The condition may be worsened by the presence of androgen testosterone, which is thickened by sebum hypochlorous acid produced by the oil gland. Multiple pathways are beneficial for acne (Reference 1):

‧次氯酸針對痤瘡丙酸桿菌極為有效。 • Hypochlorous acid is extremely effective against P. acnes.

‧次氯酸有益減小與痤瘡相關的發炎病變(膿包)。 • Hypochloric acid is beneficial for reducing inflammatory lesions associated with acne (pustules).

‧發炎病變減小(伴隨發紅、疼痛及疤痕形成減少)，且在癒合痤瘡病變中呈現輔助。 ‧ Inflammatory lesions are reduced (with redness, pain, and reduced scar formation) and aid in healing acne lesions.

關於色素沉著病症(其可包括發炎後超色素沉著(PIH)：皮膚之重要功能為保護哺乳動物體不受環境條件侵襲。此保護包括尤其(但不限於)物理及化學刺激物。顯著物理刺激物為來自曝露於日光及曬黑床之紫外線光照射。化學刺激物包括肥皂(考慮到其pH值與正常皮膚大大不同)，及不同化妝品成分，例如對羥基苯甲酸酯防腐劑、香水及酒精衍生物。具有極高日光保護因子之防曬劑因來自活性成分之化學刺激亦可刺激皮膚。無論皮膚刺激之原因為何，皮膚將嘗試保護身體不受導致刺激之物質的不良效應。在此方面，皮膚之反應可能導致皮膚變色，如面頰及前額之一些區域比面部皮膚之其餘部分易於褪色較深。此通常被稱為黑斑。皮膚表面細胞(表層)亦常常變得較厚，且此給予皮膚粗糙感。 Regarding pigmentation disorders (which may include post-inflammatory hyperpigmentation (PIH): an important function of the skin is to protect the mammalian body from environmental conditions. This protection includes, inter alia, but not limited to physical and chemical stimuli. Significant physical stimulation The object is exposed to ultraviolet light from exposure to sunlight and tanning beds. Chemical irritants include soap (given that its pH is significantly different from normal skin), and different cosmetic ingredients such as paraben preservatives, perfumes and Alcohol derivatives. Sunscreens with extremely high sun protection factors can also irritate the skin due to chemical irritations from active ingredients. Regardless of the cause of skin irritation, the skin will attempt to protect the body from the undesirable effects of substances that cause irritation. Skin reactions may cause skin discoloration, such as areas on the cheeks and forehead that are more susceptible to fading than the rest of the facial skin. This is often referred to as dark spots. Skin surface cells (surface layers) also tend to become thicker, and This gives the skin a rough feel.

皮膚表面下方為稱為Grenz區之蛋白層。皮膚水合作用即存在於此區域中。當此層受損時，皮膚喪失水合作用，其導致皮膚感乾燥。 Below the surface of the skin is a protein layer called the Grenz region. Skin hydration is present in this area. When this layer is damaged, the skin loses its hydration, which causes the skin to feel dry.

次氯酸對皮膚具有不同積極益處。作為免疫調變物質，已觀察到其對於移除異常色素沉著標示之積極影響。當用次氯酸治療皮膚表面歷經12至16週時間段時，不僅色素沉著顯著減少，而且皮膚之可見及感知水合作用位準增加。同時，感覺皮膚更光滑。皮膚表面更光滑感覺可能歸因於較好水合作用以及導致異常聚合表面皮膚細胞排出之次氯酸。 Hypochlorous acid has different positive benefits to the skin. As an immunomodulatory substance, its positive effect on the removal of abnormal pigmentation markers has been observed. When the skin surface was treated with hypochlorous acid for a period of 12 to 16 weeks, not only was the pigmentation significantly reduced, but the visible and perceived hydration levels of the skin increased. At the same time, the skin feels smoother. A smoother sensation of the skin surface may be attributed to better hydration and hypochlorous acid which causes the skin cells of the abnormally polymerized surface to be excreted.

作為後雷射皮膚表面重修或皮膚脫皮治療，次氯酸應用可在確保經治療皮膚較快癒合、減少癒合皮膚中之發紅及疼痛及預防經治療 皮膚之感染中起重要作用。藉由預防通常由此類皮膚治療產生之發炎，次氯酸可在預防發炎後色素過多中起重要作用。 As a post-exposure skin resurfacing or skin peeling treatment, hypochlorous acid application can ensure faster healing of treated skin, reduce redness and pain in healing skin and prevent treatment It plays an important role in the infection of the skin. Hypochlorous acid plays an important role in preventing hyperpigmentation after inflammation by preventing inflammation that is usually caused by such skin treatment.

灰髮之治療Gray hair treatment

頭髮色度與反應性氧種類相關(參考文獻2)。特定言之，已展示過氧化氫(H₂O₂)擔負人類灰/白頭皮頭髮。髮幹及毛囊以毫莫耳濃度積聚過氧化氫(H₂O₂)。此藉由資料證明，且支持結論：整個人類毛囊(包括髮幹)中之H₂O₂誘發氧化損害為老年頭髮變灰之關鍵要素，其不僅僅影響毛囊黑素細胞(該等細胞擔負產生頭髮之色度色素)。 Hair color is related to the type of reactive oxygen species (Reference 2). In particular, hydrogen peroxide (H ₂ O ₂ ) has been shown to be responsible for human gray/white scalp hair. The hair shaft and hair follicles accumulate hydrogen peroxide (H ₂ O ₂ ) at a millimolar concentration. This is evidenced by the data, and supports the conclusion that H ₂ O ₂ induced oxidative damage in the entire human hair follicle (including hair shaft) is a key element in the graying of aged hair, which not only affects hair follicle melanocytes (the cells are responsible for production). The color of the hair pigment).

不希望受理論束縛，本申請人預期可經由將作為直接應用之超純穩定化次氯酸規則應用至頭髮及頭皮來防止過氧化氫在毛囊及髮幹中之積聚之逆轉。根據方程式6，次氯酸緊接著與H₂O₂反應：HOCl+H₂O₂= → H₂O+HCl+O₂ (方程式6) Without wishing to be bound by theory, the Applicant anticipates that the reversal of the accumulation of hydrogen peroxide in the hair follicles and hair shafts can be prevented by applying the ultrapure stabilized hypochlorous acid rule as a direct application to the hair and scalp. According to Equation 6, hypochlorous acid is then reacted with H ₂ O ₂ : HOCl + H ₂ O ₂ = → H ₂ O + HCl + O ₂ (Equation 6)

毛囊及髮幹中之過氧化氫之抵消可因此對灰髮逆轉具有影響。 The offset of hydrogen peroxide in the hair follicles and hair shaft can therefore have an effect on the gray hair reversal.

亦在灰髮逆轉之情形下，因此本發明預期獲得應用。 Also in the case of gray hair reversal, the invention is therefore expected to find application.

牙科應用Dental application

儘管具有高度酸性次氯酸水，但已在文獻中檢測牙科應用。在此方面參見參考文獻8。發現為強烈支持性的，用經電化學活化之溶液沖洗提供根管壁之高效清潔且可替代習知根管治療中之次氯酸鈉(NaOCl)。 Despite the presence of highly acidic hypochlorous acid water, dental applications have been tested in the literature. See reference 8 in this regard. Found to be strongly supportive, rinsing with an electrochemically activated solution provides efficient cleaning of the root canal wall and can replace sodium hypochlorite (NaOCl) in conventional root canal therapy.

用超純穩定化次氯酸代替牙科水線為可能的，因為其為無毒的。以此方式，自牙科水線根除細菌將變得可能，其通常經由城市用水系統及經由自患者嘴巴之逆行遷移定殖有細菌。次氯酸將不僅防止如根管膿腫之感染，而且自水線內移除生物膜。 It is possible to replace the dental water line with ultrapure stabilized hypochlorous acid because it is non-toxic. In this way, it will become possible to eradicate bacteria from the dental waterline, which normally colonizes bacteria via urban water systems and retrograde migration from the patient's mouth. Hypochlorous acid will not only prevent infections such as root canal abscesses, but also remove biofilm from the water line.

亦在牙科情形中，因此本發明預期獲得應用。在吾人之經驗中，在治療重症牙周病3個月之後獲得顯著改善。在診斷標記有牙齒 疏鬆、口臭及齒齦出血之長期慢性牙周炎之後，本申請人已每天兩次用100mg/l超純穩定化次氯酸之嘴巴沖洗液治療該病狀。病狀顯著改善，因為量測到牙齒更堅固，齒齦不再出血及口臭(口臭)消失。患者不再需要牙齒拔除以控制其疾病。 Also in dental situations, the invention is therefore expected to find application. In our experience, significant improvement was obtained after 3 months of treatment for severe periodontal disease. Have teeth in the diagnosis mark After long-term chronic periodontitis with loose, bad breath and gum bleeding, the Applicant has treated the condition twice daily with 100 mg/l ultrapure stabilized hypochlorous acid mouth rinse. The condition was significantly improved because the teeth were measured to be firmer, the gums no longer bleed and the bad breath (halitosis) disappeared. Patients no longer need tooth extraction to control their disease.

生物膜之控制Biofilm control

當固液界面中養分為可獲得的，水環境中之表面細菌定殖在本質上為正常過程。所得微生物菌落形成微菌落，其發展成生物膜。該等生物膜常常存在於眼睛表面且防止表面抗生素之使用穿透且使眼感染暴露於表面應用抗生素。次氯酸毀壞生物膜之能力將顯著輔助超純穩定化次氯酸有效治療眼及實際傷口感染之治療能力。另外，再次使用隱形眼鏡之不充分護理導致感染及生物膜存在於鏡片(其導致後續眼感染)，因此鏡片常常儲存於分解生物膜且一旦打開即具有較短儲存壽命且常常冷藏儲存之抗微生物液體中。超純穩定化次氯酸可用作無需防腐劑、自我殺菌且無需冷藏之隱形眼鏡儲存液體。 When the nutrients in the solid-liquid interface are available, the colonization of surface bacteria in the aqueous environment is essentially a normal process. The resulting microbial colonies form microcolonies that develop into biofilms. Such biofilms are often present on the surface of the eye and prevent the penetration of surface antibiotics and expose the eye infection to surface application of antibiotics. The ability of hypochlorous acid to destroy biofilms will significantly aid the therapeutic ability of ultrapure stabilized hypochlorous acid to effectively treat eye and actual wound infections. In addition, inadequate care of the contact lens again results in infection and biofilm present in the lens (which causes subsequent eye infections), so the lens is often stored in an antimicrobial system that decomposes the biofilm and, once opened, has a short shelf life and is often refrigerated for storage. In the liquid. Ultra-pure stabilized hypochlorous acid can be used as a contact lens storage liquid without preservatives, self-sterilizing, and without refrigeration.

細菌性生物膜在健康行業中具有消極後果。生物膜包含微生物，使難以控制經感染組織(包括傷口或眼睛感染及如慢性小腿傷口或經感染哆開傷口其他傷口)之生物負載。目前可根據多種方法防止及/或移除生物膜： Bacterial biofilms have negative consequences in the health industry. Biofilms contain microorganisms that make it difficult to control the bioburden of infected tissues, including wounds or eye infections and other wounds such as chronic calf wounds or infected with open wounds. Biofilms can now be prevented and/or removed according to a variety of methods:

(i)用除次氯酸外之殺菌化合物化學治療生物膜以殺死細菌。由於不同細胞壁特性，或由於其他抵抗性機制(固有的或誘導性的)，不同細菌對殺菌劑反應不同，此方法在哺乳動物中之應用存在限制，因為毀壞生物膜之化學物質亦對活組織之活力具有消極影響。 (i) Chemotherapy of biofilms with bactericidal compounds other than hypochlorous acid to kill bacteria. Due to different cell wall characteristics, or due to other resistance mechanisms (intrinsic or inducible), different bacteria react differently to fungicides, and this method has limitations in mammals because the chemical substances that destroy the biofilm are also resistant to living tissue. Vitality has a negative impact.

藉助於分散劑分散生物膜。 The biofilm is dispersed by means of a dispersing agent.

(iii)藉由多種程序物理移除生物膜，包括刮擦傷口或經由其他方法之清創術。此等方法亦負面影響身體治癒傷口之能力。 (iii) Physical removal of biofilms by a variety of procedures, including scraping wounds or debridement by other methods. These methods also negatively affect the body's ability to heal wounds.

(iv)藉由使用酶或螯合劑弱化生物膜結構。基於番木瓜之酶已用 於人類以移除生物膜，其中成效受限制。 (iv) weakening the biofilm structure by using an enzyme or a chelating agent. Papaya-based enzymes have been used For humans to remove biofilms, the effectiveness is limited.

已發現使用次氯酸不僅有效消除生物膜，而且快速消除且對傷口中之活組織不具任何消極影響(參考文獻6)。本發明人對應用本發明之治療製劑的大於100處傷口的經驗為即使在單次應用治療製劑之後亦可控制生物膜，其與在另一治療方法中及歸因於耐受性而使用不純次氯酸時觀察到的形成對比。 It has been found that the use of hypochlorous acid not only effectively eliminates the biofilm, but also eliminates it quickly and does not have any negative impact on the living tissue in the wound (Reference 6). The inventors' experience with more than 100 wounds in the application of the therapeutic formulations of the present invention is that the biofilm can be controlled even after a single application of the therapeutic formulation, which is impure in use in another therapeutic method and due to tolerance. A contrast was observed when hypochlorous acid was observed.

純及未經污染次氯酸具有快速控制傷口之生物負載的能力。快速控制感染不僅歸因於其極佳抗細菌性、抗真菌性及抗病毒性，而且因為次氯酸破壞生物膜(參考文獻7、8及11)。生物膜不僅包含疾病形成微生物，而且其之存在充當穿透任何消毒劑傷口應用之阻障。因此，移除生物膜極大輔助經感染傷口之治療。直至現在，除使用可用以處理傷口中生物膜之可獲得的非穩定高pH值形式次氯酸(次氯酸鈉)及低pH值形式(陽極電解液)外，無安全方法。 Pure and uncontaminated hypochlorous acid has the ability to rapidly control the biological load of the wound. Rapid control of infection is not only due to its excellent antibacterial, antifungal and antiviral properties, but also because hypochlorous acid destroys biofilms (References 7, 8 and 11). Biofilms not only contain disease-forming microorganisms, but their presence acts as a barrier to penetrating any disinfectant wound application. Therefore, removal of the biofilm greatly assists in the treatment of infected wounds. Until now, there has been no safe method other than the use of an unstably high pH form of hypochlorous acid (sodium hypochlorite) and a low pH form (anolyte) that can be used to treat biofilms in wounds.

然而，本發明在傷口中使用超純次氯酸的確具有顯著優勢，該等優勢為安全及有效可利用的。此等優勢為以下： However, the use of ultrapure hypochlorous acid in wounds of the present invention does have significant advantages that are safe and effective. These advantages are as follows:

1.純次氯酸為針對傷口中之感染性微生物之最有效試劑或其中之一。另外，其為已知安全及非毒性傷口之唯一消毒劑或其中之一。所有其他傷口消毒劑對哆開傷口中之細胞具有一定程度毒性。 1. Pure hypochlorous acid is one of the most effective agents for infectious microorganisms in wounds. In addition, it is the only disinfectant or one of the known safe and non-toxic wounds. All other wound disinfectants have a degree of toxicity to the cells in the wound.

2.其破壞生物膜。 2. It destroys the biofilm.

3.其免疫調變效應快速減少傷口中之疼痛、腫脹及發紅。 3. Its immune modulation effect rapidly reduces pain, swelling and redness in the wound.

4.其對傷口具有再生效應，其不同於迄今為止已知之常見修復傷口癒合。 4. It has a regenerative effect on the wound which is different from the healing of common repair wounds known to date.

在用本發明之治療製劑移除生物膜時，用已加熱至體溫(36.7℃至37.6℃)之治療製劑潤濕紗布拭子。隨後，用濕潤浸沒拭子(視傷口尺寸而定)覆蓋傷口，其保持在傷口上至少10分鐘但至多15分鐘。此時，用其他升溫治療製劑不斷潤濕拭子，以使得傷口保持濕潤且不允 許乾燥。在應用次氯酸濕潤拭子之後，用飽和有治療製劑之海綿覆蓋傷口，且隨後壓乾。較佳每隔兩天重複此程序。 Upon removal of the biofilm with the therapeutic formulation of the invention, the gauze swab is moistened with a therapeutic formulation that has been heated to body temperature (36.7 ° C to 37.6 ° C). Subsequently, the wound is covered with a wet immersion swab (depending on the size of the wound) which remains on the wound for at least 10 minutes but for up to 15 minutes. At this point, the swab is continuously moisturized with other warming treatments to keep the wound moist and unallowable. Dry. After applying the hypochlorous acid moisturizing swab, the wound is covered with a sponge saturated with the therapeutic preparation and then pressed dry. This procedure is preferably repeated every two days.

次氯酸Hypochlorous acid

次氯酸(化學符號HOCl，CAS編號770-92-3)為作為消毒劑具有已知功效之熟知化學物質。其在殺死微生物中之功效常常定量為大於其鹽(次氯酸鈉)在此方面功效之約100倍(參考文獻11)。 Hypochlorous acid (chemical symbol HOCl, CAS number 770-92-3) is a well-known chemical with known efficacy as a disinfectant. Its efficacy in killing microorganisms is often quantified to be about 100 times greater than its salt (sodium hypochlorite) in this respect (Ref. 11).

關於超純次氯酸之有用性(尤其在醫學領域中)亦為顯著的係在哺乳動物體內，次氯酸出現在白血球內且輔助控制感染及實現體內癒合。在眼睛之情形下，受傷角膜癒合之正常進展為小血管生長入受傷角膜之一部分，從而促進白血球(含有次氯酸)運輸至彼區域。發炎(發紅、腫脹及疼痛)為該過程之正常結果。血管之向內生長擔負角膜中之白色或不透光區域的發展，稱為角膜疤痕。此削弱視覺，因為現角膜之正常透明度減小。此癒合方法常常被稱為修復癒合(參考文獻3)。 The usefulness of ultrapure hypochlorous acid (especially in the medical field) is also significant in mammals, where hypochlorous acid is present in white blood cells and aids in the control of infection and healing in vivo. In the case of the eye, the normal progression of wounded corneal healing is the growth of small blood vessels into one part of the injured cornea, thereby promoting the transport of white blood cells (containing hypochlorous acid) to the area. Inflammation (redness, swelling, and pain) is a normal result of this process. The ingrowth of blood vessels bears the development of a white or opaque region of the cornea called a corneal scar. This weakens the vision because the normal transparency of the cornea is reduced. This healing method is often referred to as repair healing (Reference 3).

外部應用超純次氯酸導致發生不同情形癒合。本質上，研究已發現因此受刺激之癒合過程較快，伴隨發炎顯著減少及任何伴隨感染經快速控制。 External application of ultrapure hypochlorous acid causes healing in different situations. In essence, studies have found that the resulting healing process is faster, with a significant reduction in inflammation and rapid control of any concomitant infections.

使用超純次氯酸作為殺菌劑自先前技術未知，但已可獲得較粗糙型式含氯氣及次氯酸根離子之次氯酸的先前實證。次氯酸以物理方式破壞疾病形成微生物之細胞壁。次氯酸經由物理毀壞微生物之細菌壁將其殺死。細菌細胞膜向細胞提供滲透阻障，且促進養分活性運輸至彼細胞。次氯酸使得通過膜之電位改變，其由電子供體之作用或電子受體因子與次氯酸之氧化劑特性相關造成。結果為膜破裂及細菌細胞內含物流出。即使不出現細胞之瞬時死亡，膜中所有酶功能將受影響，且此亦將導致細胞活力喪失及隨後微生物死亡。 The use of ultrapure hypochlorous acid as a bactericide has not been known from the prior art, but previous evidence of a coarser type of hypochlorous acid containing chlorine and hypochlorite ions has been obtained. Hypochlorous acid physically destroys the cell wall of the disease-forming microorganism. Hypochlorous acid kills the bacteria by physically destroying the bacteria's walls. The bacterial cell membrane provides a osmotic barrier to the cell and promotes the transport of nutrient activity to the cell. Hypochlorous acid causes a change in the potential through the membrane, which is caused by the action of the electron donor or the electron acceptor factor and the oxidant properties of the hypochlorous acid. The result is membrane rupture and bacterial cell internals flow out. Even if there is no transient death of the cells, all enzyme functions in the membrane will be affected, and this will result in loss of cell viability and subsequent microbial death.

此不同於當使用抗生素時所產生之抵抗性。抗生素干擾微生物 之代謝，從而給予其經由其代謝過程之進化機制來調適且避開其影響之機會。此無法發生在直接作用於病原生物細胞壁之次氯酸上。 This is different from the resistance generated when antibiotics are used. Antibiotics interfere with microorganisms Metabolism, thereby giving it the opportunity to adapt and avoid its effects through the evolutionary mechanisms of its metabolic processes. This cannot occur on hypochlorous acid that acts directly on the cell wall of the pathogenic organism.

關於大量不同疾病形成微生物之測試揭示次氯酸針對所有疾病形成微生物極有效。其針對眼睛病毒感染以及針對皮膚或哆開傷口中之無數疾病形成微生物(包括醫院超級細菌)之效應具有重要意義。相比而言，針對病毒病痛之替代性治療極為昂貴且在鄉村區域無通常法獲得。當使用5分鐘接觸時間測試南非標準局(SABS)時，吾人之50mg/ml濃度超純次氯酸新穎調配物展示殺死鋪綠假單藏菌(P.aruginosa)、大腸桿菌(E.coli)及金黃色葡萄球菌(S.aureus)達99.9%。 Tests on the formation of microorganisms in a number of different diseases have revealed that hypochlorous acid is extremely effective in forming microorganisms for all diseases. It is important for the effects of ocular viral infections and the formation of microorganisms (including hospital superbugs) against numerous diseases in the skin or open wounds. In contrast, alternative treatments for viral ailments are extremely expensive and are not available in conventional areas in rural areas. When the South African Bureau of Standards (SABS) was tested using a 5 minute contact time, our 50 mg/ml concentration of ultrapure hypochlorous acid novel formulation showed the killing of P. aruginosa and E. coli. And S. aureus reached 99.9%.

另外，許多研究已證實作為消毒劑之次氯酸為疾病形成微生物之最強力殺手或其中之一。其藉由毀壞此等微生物之DNA及細胞壁將其殺死，使微生物無法產生針對次氯酸之防護。 In addition, many studies have confirmed that hypochlorite as a disinfectant is one of the most powerful killers of disease-forming microorganisms. It kills the DNA and cell walls of these microorganisms, preventing microbes from producing protection against hypochlorous acid.

次氯酸可描述為吾人免疫力之固有分子。當應用為外部應用時，不太可能預期針對其存在之過敏、超敏反應或有毒反應。此已經研究其經由許多研究證實。因此，其作為外部應用為安全的，且未描述由其使用產生之副作用，只要某些病狀符合，尤其涉及避免次氯酸分解成氯氣、次氯酸根離子及其他可能有害形式。次氯酸亦具有來自FDA(FDA 21聯邦法規彙編部分178.1010，發行編號00-03-13)之GRAS(普遍認為安全)認證。 Hypochlorous acid can be described as an intrinsic molecule of our immunity. When the application is an external application, it is unlikely to be expected to have an allergic, hypersensitivity or toxic reaction to its presence. This has been studied and confirmed by many studies. Therefore, it is safe as an external application and does not describe the side effects caused by its use, as long as certain conditions are met, especially involving avoiding the decomposition of hypochlorous acid into chlorine, hypochlorite ions and other potentially harmful forms. Hypochlorous acid also has GRAS (Generally Recognized As Security) certification from the FDA (FDA 21 Code of Federal Regulations 178.1010, issue number 00-03-13).

本發明具有優於現有基於次氯酸之治療製劑及相關方法顯著優勢。特定言之，經表明諸如陽極電解液之商業次氯酸之較粗糙形式具有不期望的較高濃度游離活性氯種類(諸如氯氣及次氯酸根離子)，且當以低於所製備之超純穩定化次氯酸可能濃度之濃度應用於人眼時為不耐受的(參見圖5：陽極電解液與超純穩定化次氯酸在治療細菌性結膜炎中治療比較)。 The present invention has significant advantages over existing hypochlorous acid-based therapeutic formulations and related methods. In particular, it has been shown that the coarser form of commercial hypochlorous acid, such as an anolyte, has an undesirably higher concentration of free active chlorine species (such as chlorine and hypochlorite ions), and when compared to the ultrapure prepared The concentration of the stabilized hypochlorous acid concentration is not tolerated when applied to the human eye (see Figure 5: Comparison of anolyte with ultrapure stabilized hypochlorous acid in the treatment of bacterial conjunctivitis).

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Claims (18)

一種次氯酸於水中之穩定溶液，其氯氣及次氯酸根離子含量較低。 A stable solution of hypochlorous acid in water with low chlorine and hypochlorite ion content. 如請求項1之溶液，其中該溶液包含小於30%，更佳小於25%，更佳小於20%氯氣。 The solution of claim 1, wherein the solution comprises less than 30%, more preferably less than 25%, more preferably less than 20% chlorine. 如請求項1或2之溶液，其中該溶液之pH值在3.5與7之間，更佳在3.5與6.3之間，更佳在4與6之間，甚至更佳在4.5與5.4之間。 A solution according to claim 1 or 2, wherein the pH of the solution is between 3.5 and 7, more preferably between 3.5 and 6.3, still more preferably between 4 and 6, and even more preferably between 4.5 and 5.4. 如請求項3之溶液，其中該溶液係在3.5與7之間，更佳在3.5與6.3之間，更佳在4與6之間，甚至更佳在4.5與5.4之間製備。 A solution according to claim 3, wherein the solution is prepared between 3.5 and 7, more preferably between 3.5 and 6.3, more preferably between 4 and 6, and even more preferably between 4.5 and 5.4. 如前述請求項中任一項之溶液，其中該溶液包含濃度在約30毫克/公升與約120毫克/公升之間，更佳在約33毫克/公升至109毫克/公升之間，更佳在約73毫克/公升至105毫克/公升之間，例如約80毫克/公升或100毫克/公升之次氯酸。 A solution according to any one of the preceding claims, wherein the solution comprises a concentration between about 30 mg/liter and about 120 mg/liter, more preferably between about 33 mg/liter and 109 mg/liter, more preferably About 73 mg/liter to 105 mg/liter, for example about 80 mg/liter or 100 mg/liter hypochlorous acid. 如請求項5之溶液，其中該次氯酸之濃度為約80毫克/公升且組合物之pH值為約5.4。 A solution according to claim 5, wherein the hypochlorous acid concentration is about 80 mg/liter and the composition has a pH of about 5.4. 如請求項5之溶液，其中該次氯酸之濃度為約100毫克/公升且該組合物之pH值為約4.5。 The solution of claim 5, wherein the hypochlorous acid concentration is about 100 mg/liter and the composition has a pH of about 4.5. 一種用於製備根據本發明之次氯酸溶液的方法，其包含在電解室中電解鹽酸及水之步驟。 A method for preparing a hypochlorous acid solution according to the present invention, comprising the step of electrolyzing hydrochloric acid and water in an electrolysis chamber. 如請求項8之方法，其中該電解室包含鈦及二氧化銥電極。 The method of claim 8, wherein the electrolysis chamber comprises a titanium and a cerium oxide electrode. 一種溶液，其係藉由如請求項8或請求項9之方法產生。 A solution produced by the method of claim 8 or claim 9. 一種醫藥組合物或敷料或消毒或清潔組合物，其例如用於隱形眼鏡及牙科線，其包含如請求項1至7或10中任一項之溶液。 A pharmaceutical composition or dressing or disinfecting or cleaning composition, for example, for contact lenses and dental lines, comprising a solution according to any one of claims 1 to 7 or 10. 如請求項1至7或10中任一項之溶液，其用於療法。 A solution according to any one of claims 1 to 7 or 10 for use in therapy. 如請求項1至7或10中任一項之溶液，其用於治療眼部病狀，諸 如選自眼損傷、眼感染、眼內壓升高病狀、視網膜及眼神經退化病狀、白內障之眼部病狀，諸如細菌性結膜炎、沙眼、病毒性結膜炎、眼睛真菌感染、瞼腺炎、過敏性結膜炎、角膜潰瘍、角膜化學灼傷、過敏性結膜炎、上緣角膜結膜炎(上鞏膜炎)、角膜病毒感染、眼疱疹病毒感染、角膜疤痕、鞏膜翼狀胬肉、瞼緣炎、鞏膜破裂、角膜血管生成、白內障逆轉、新生血管性黃斑變性、急性病毒性角膜內皮炎；牙科病狀，諸如選自牙周炎、牙齒疏鬆、口臭、齒齦出血之牙科病狀；皮膚病狀，諸如選自痤瘡、紅斑痤瘡、膿皰、蜂窩組織炎、皮膚真菌感染之皮膚病狀，例如足癬、汗斑、花斑癬及念珠菌病，皮膚病毒感染，例如疱疹熱疹及帶狀疱疹、尿布疹、牛皮癬、濕疹及皮膚色素沉著病症，包括發炎後超色素沉著(PIH)，或改善皮膚水合作用；傷口，包括皮膚及皮肉傷口，諸如灼傷、壓瘡、慢性傷口、糖尿病性潰瘍、選擇性手術傷口，例如腹部手術傷口、開胸術傷口、婦科傷口、整形手術傷口、耳鼻及咽喉手術傷口、矯形外科手術傷口及造口療法傷口，咬傷，尤其來自狗或人類，之後的傷口及該等傷口之感染；疤痕及結疤，包括治療諸如瘢痕瘤疤痕之疤痕組織，或預防或減少疤痕形成；或灰髮；或在提供眼治療之玻璃體內注射或眼治療之前房內、鞏膜內、角膜內、結膜下注射之前用作消毒劑。 A solution according to any one of claims 1 to 7 or 10 for use in the treatment of ocular conditions, Such as selected from eye damage, eye infection, elevated intraocular pressure, retinal and ocular neurodegenerative diseases, cataract eye conditions, such as bacterial conjunctivitis, trachoma, viral conjunctivitis, eye fungal infection, mumps , allergic conjunctivitis, corneal ulcer, corneal chemical burn, allergic conjunctivitis, upper keratoconjunctivitis (upper scleritis), corneal virus infection, herpes simplex virus infection, corneal scar, scleral pterygium, blepharitis, scleral rupture , corneal angiogenesis, cataract reversal, neovascular macular degeneration, acute viral corneal endotheliitis; dental conditions, such as dental conditions selected from the group consisting of periodontitis, loose teeth, bad breath, gum bleeding; skin conditions, such as selection From acne, rosacea, pustules, cellulitis, skin fungal infections, such as athlete's foot, sweat stains, tinea versicolor and candidiasis, skin viral infections such as herpes zoster and herpes zoster, diaper rash , psoriasis, eczema and skin pigmentation disorders, including post-inflammatory hyperpigmentation (PIH), or improving skin hydration; wounds, including skin And flesh wounds, such as burns, pressure sores, chronic wounds, diabetic ulcers, selective surgical wounds such as abdominal surgical wounds, thoracotomy wounds, gynecological wounds, plastic surgery wounds, ear and nose and throat surgical wounds, orthopedic surgical wounds and Ostomy for wounds, bites, especially from dogs or humans, subsequent wounds and infections of such wounds; scars and scarring, including treatment of scar tissue such as keloid scars, or prevention or reduction of scar formation; or gray hair; Used as a disinfectant before intravitreal, intrascleral, intracorneal, subconjunctival injection prior to intravitreal or ocular treatment for ophthalmic treatment. 一種治療選自以下病狀之方法：眼部病狀，諸如選自眼損傷、眼感染、眼內壓升高病狀、視網膜及眼神經退化病狀、白內障之眼部病狀，諸如細菌性結膜炎、沙眼、病毒性結膜炎、病毒性角膜炎、眼睛真菌感染、瞼腺炎、過敏性結膜炎、角膜潰瘍、角膜化學灼傷、過敏性結膜炎、上緣角膜結膜炎(上鞏膜 炎)、角膜病毒感染、眼疱疹病毒感染、角膜疤痕、鞏膜翼狀胬肉、瞼緣炎、鞏膜破裂、角膜血管生成、白內障逆轉、新生血管性黃斑變性；牙科病狀，諸如選自牙周炎、牙齒疏鬆、口臭、齒齦出血之牙科病狀；皮膚病狀，諸如選自痤瘡、紅斑痤瘡、膿皰、蜂窩組織炎、皮膚真菌感染之皮膚病狀，例如足癬、汗斑、花斑癬及念珠菌病，皮膚病毒感染，例如疱疹熱疹及帶狀疱疹、尿布疹、牛皮癬、濕疹及皮膚色素沉著病症，包括發炎後超色素沉著(PIH)，或改善皮膚水合作用；傷口，包括皮膚及皮肉傷口，諸如灼傷、壓瘡、慢性傷口、糖尿病性潰瘍、選擇性手術傷口，例如腹部手術傷口、開胸術傷口、婦科傷口、整形手術傷口、耳鼻及咽喉手術傷口、矯形外科手術傷口及造口療法傷口，咬傷，尤其來自狗或人類，之後的傷口及該等傷口之感染；疤痕及結疤，包括治療諸如瘢痕瘤疤痕之疤痕組織，或預防或減少疤痕形成；或灰髮；在提供眼治療之玻璃體內注射或眼治療之前房內、鞏膜內、角膜內、結膜下注射之前對某一區域進行消毒，其包含向有需要之個體投與有效量之如請求項1至7或10中任一項之溶液或如請求項11之組合物。 A method of treating a condition selected from the group consisting of an eye condition selected from the group consisting of an eye injury, an eye infection, an elevated intraocular pressure, a retinal and ocular neurodegenerative condition, an ocular condition of a cataract, such as a bacterial condition. Conjunctivitis, trachoma, viral conjunctivitis, viral keratitis, ocular fungal infection, mumps, allergic conjunctivitis, corneal ulcer, corneal chemical burn, allergic conjunctivitis, upper keratoconjunctivitis (upper sclera Inflammation, corneal virus infection, herpes simplex virus infection, corneal scar, scleral pterygium, blepharitis, scleral rupture, corneal angiogenesis, cataract reversal, neovascular macular degeneration; dental conditions, such as selected from periodontal Dental conditions of inflammation, loose teeth, bad breath, bleeding gums; skin conditions, such as skin conditions selected from acne, rosacea, pustules, cellulitis, skin fungal infections, such as athlete's foot, sweat stains, tinea versicolor And candidiasis, cutaneous viral infections such as herpes zoster and herpes zoster, diaper rash, psoriasis, eczema and skin pigmentation disorders, including post-inflammatory hyperpigmentation (PIH), or improving skin hydration; wounds, Includes skin and flesh wounds such as burns, pressure sores, chronic wounds, diabetic ulcers, selective surgical wounds such as abdominal surgical wounds, thoracotomy wounds, gynecological wounds, plastic surgery wounds, ear and nose and throat surgical wounds, orthopedic surgery Wounds and ostomy wounds, bites, especially from dogs or humans, subsequent wounds and infections of such wounds; scars and knots , including treatment of scar tissue such as keloid scars, or prevention or reduction of scar formation; or gray hair; before intravitreal, intrascleral, intracorneal, subconjunctival injection before intravitreal injection or ophthalmology for eye treatment The area is sterilized, which comprises administering to a subject in need thereof an effective amount of a solution according to any one of claims 1 to 7 or 10 or a composition as claimed in claim 11. 如請求項6之溶液，其用於治療皮膚病狀，或如請求項7之溶液，其用於治療眼部病狀。 A solution according to claim 6 for use in the treatment of a skin condition, or a solution according to claim 7, for use in the treatment of an ocular condition. 一種電解裝置，其用於產生如請求項1至7或10中任一項之溶液，該裝置包含電解室及能夠向該室中提供受控流動速率之反應物的入口，其中該流動速率可經控制使得該流動速率小於150l/h。 An electrolysis apparatus for producing a solution according to any one of claims 1 to 7 or 10, the apparatus comprising an electrolysis chamber and an inlet capable of providing a reactant at a controlled flow rate in the chamber, wherein the flow rate is It is controlled such that the flow rate is less than 150 l/h. 如請求項16之電解裝置，其進一步包含電流感測器以監測通過該室中之電極之電流。 The electrolysis device of claim 16, further comprising a current sensor to monitor current flow through the electrodes in the chamber. 如請求項16或17之電解裝置，其進一步包含用於回應於在該室中之電流變化而改變該反應物進入該室之流動速率的構件，以便控制所產生之次氯酸之濃度。 The electrolysis apparatus of claim 16 or 17, further comprising means for varying the flow rate of the reactant into the chamber in response to a change in current in the chamber to control the concentration of hypochlorous acid produced.