WO2007014514A1 - Use of p-hydroxybenzoic acid and analogues for the manufacture of a mendicament for the prevention and treatment of skin mucosa virus infection - Google Patents

Abstract

The use of p-hydroxybenzoic acid and analogues for the manufacture of a medicament for the prevention and treatment of skin mucosa virus infection, especially Human infectious warts virus and herpesvirus infection is provided, wherein virus infection comprises condyloma acuminatum, vaginitis, cervicitis, and cervical erosion. Otherwise, the various kinds of medicament and personal nursing product which are prepared by p-hydroxybenzoic acid and analogues and adjuvant for skin administration are provided.

Description

 P-hydroxybenzoic acid and its analogues

 Application in preparing medicine for preventing and treating skin mucosal viral infection

 The present invention relates to the use of p-hydroxybenzoic acid and its analogs for the preparation of a medicament for the prevention and treatment of skin mucosal infections. More specifically, it relates to the use of p-hydroxybenzoic acid and its analogs for the preparation of a medicament for the prevention and treatment of human and animal skin mucosal human papillomavirus or herpesvirus infection. Background technique

 2-Hydroxybenzoic acid (salicylic acid) has been used to treat bacterial and fungal infectious diseases of the skin mucosa. Hydroxybenzoic acid and its esters are used as preservatives for foods and pharmaceuticals. Gallic acid (ie, 3,4,5-trihydroxybenzoic acid) is often used as an antioxidant, and has been shown to have an inhibitory effect on hepatitis B HBV virus (Journal of PLA Medical College of the People's Liberation Army, 1998, 26 ( 2 ) : 5-7 ). However, there is no literature on hydroxybenzoic acid and its analogues (except salicylic acid), including 3,4,5-trihydroxybenzoic acid, for the preparation of drugs for the treatment of skin mucosal virus infection. Although experiments have shown that gallic acid has an inhibitory effect on certain viruses, it does not mean that it is effective against all viruses, just like many antiviral drugs are known. The effect of a drug on a certain type of virus is not predictive until it is confirmed to be valid and pharmacological.

 The invention of Chinese Patent No. CN1411339A, U.S. Patent No. 6,294,186 describes an antimicrobial composition comprising a safe and effective amount of a benzoic acid analog comprising the following structure (Π):

其中 R₂、 R₄和 R₅独立地选自 H、 OH、 F、 I、 Br、 Cl、 SH、 NH2、 CN、 烷基、 烷氧基、 NR₂、 OR、 N0₂、 COR、 CONR₂、 C0₂R、 S0₃R; 其中 R独立地选自 H、 烷基和垸氧基。 R₃独立地选自 H、 OH、 F、 I、 Br、 Cl、 SH、 CN、 烷基、 垸氧基、 OR、 N0₂、 COR、 CONR₂、 C0₂R、 S0₃R; 其中 R独立 地选自 H、 烷基和烷氧基。 该专利还提出最优选的为水杨酸（即 2-羟基苯甲 酸）、 苯甲酸和它们的组合。

Wherein R ₂ , R ₄ and R _{5 are} independently selected from the group consisting of H, OH, F, I, Br, Cl, SH, NH 2, CN, alkyl, alkoxy, NR ₂ , OR, N0 ₂ , COR, CONR ₂ , C0 ₂ R, S0 ₃ R; R is independently selected from the group consisting of H, alkyl and decyloxy. R _{3 is} independently selected from the group consisting of H, OH, F, I, Br, Cl, SH, CN, alkyl, decyloxy, OR, NO ₂ , COR, CONR ₂ , C0 ₂ R, S0 ₃ R; wherein R is independent It is selected from the group consisting of H, alkyl and alkoxy. The patent also teaches that salicylic acid (i.e., 2-hydroxybenzoic acid), benzoic acid, and combinations thereof are most preferred.

 Although the virus is the smallest pathogenic microorganism, the virus spreads most widely. Currently, nearly three-quarters of the world's infectious diseases are caused by viruses. More clinically relevant diseases are associated with viral infections.

 Condyloma acuminata, also known as genital warts or sexually transmitted diseases, is a benign new skin skin mucosa caused by human papillomavirus (HPV). It is one of the most common sexually transmitted diseases, and is closely related to genital inflammation and cancer. At present, the drug for treating condyloma acuminata is podophyllotoxin. The advantage is that the course of treatment is short, but there are problems of irritating and toxic side effects. Specific manifestations are pain, edema, erosion and so on. Recombinant human interferon α - 2 β gel for the treatment of condyloma acuminata with topical drugs is currently recognized as an effective drug.

 Recent studies have shown that (Chen Fuqiang et al, Journal of Cancer Prevention and Treatment, 2001, 8 (4) 342-344; Xu Chengkang, Journal of Zhongshan Medical University, 1998, 19 (3): 223-226), 29.3% of patients with cervical erosion present HPV was positive, and the normal cervical positive rate was only 11.1%. According to reports (Ahn ws et al, J Cell Bioc em Suppl, 1997; 28-29: 133-139), high-risk HPV (human papillomavirus) type 16 and 18 expression rate in chronic cervicitis is 69%, high-risk HPV16 The detection rate of 18 showed an increasing trend with the increase of cervical erosion. The detection rate of HPV16, 18 of granular or mastoid erosion was significantly different from that of normal cervix. The positive rate of HPV16 and 18 in cervical cancer was 83.33%. The high-risk HPV DNA was integrated into the host cell chromosome, which produced E6 and E7 tumor proteins, which inhibited the tumor suppressor genes p53 and Rb, respectively, and enabled the cells to escape p53 and The control of Rb leads to abnormal cell cycle control, which makes the cells that are usually at rest active and tumors grow. If HPV16 persists, cervical lesions can develop. Unlike vulvar infection, cervical HPV infection is mainly HPV16/18 type, often without phlegm change, but long-term existence of recessive infection, first causing dysplasia, causing cancer when other factors are involved.

Herpes simplex virus (HSV) is a double-stranded DNA virus that invades the body through various routes such as the oral cavity, respiratory tract, genital tract mucosa, and damaged skin. Human infection is very common, and the infection rate is 80-90%. The common clinical manifestation is herpes accumulation in the mucous membrane or skin. Occasionally, serious systemic diseases can occur, involving the internal organs. Studies have shown that HSV-1 and HSV-2 may be associated with lip, vulvar and cervical cancer, respectively, and have received attention (Sun He et al., Chinese Journal of Practical Gynecology and Obstetrics, 2001, 17 ( 7 ): 407-409 ). The current treatments include herpes simplex, cytarabine, adenosine, vinyl bromide and acyclovir, but the treatment takes a long time and takes 5 to 7 days. Summary of the invention

 The object of the present invention is to provide a p-hydroxybenzoic acid and an analogue thereof for use in the preparation of a medicament for preventing and treating viral infections of the skin mucosa,

 The p-hydroxybenzoic acid and analogs thereof are selected from one or more of the compounds represented by the following formula (I).

其中 R₂、 R₃、 R₄独立地选自 OH或 H, 优选对羟基苯甲酸、 2,4-二 羟基苯甲酸、 3,4-二羟基苯甲酸、 2，3，4-三羟基苯甲酸、 3,4,5-三羟基苯甲酸、 2,4,5-三羟基苯甲酸； 更优选对羟基苯甲酸、 2，4-二羟基苯甲酸、 3,4，5-三羟基 苯甲酸； 最优选 3，4，5-三羟基苯甲酸即没食子酸。

Wherein R ₂ , R ₃ , R _{4 are} independently selected from OH or H, preferably p-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 2,3,4-trihydroxybenzene Formic acid, 3,4,5-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid; more preferred p-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid Most preferred is 3,4,5-trihydroxybenzoic acid, namely gallic acid.

 An effective dosage of the compound of the present invention and/or a composition containing the same as an active ingredient can be used for the preparation of a medicament for treating mucosal viral diseases of human and animal skin, in particular for treating human and animal skin mucosal human papilloma The use of viral (HPV), herpes virus-infected drugs, including condyloma acuminata, vaginitis, cervicitis and cervical erosion and adjuvant treatment of cervical cancer.

 The active ingredients of the compounds of the present invention are mostly known compounds, some have been used in the preparation of food additives, some are pharmaceutical excipients, and some are pharmaceutical intermediates which are commercially available or can be extracted from natural plants.

The compound of the present invention and/or a composition containing the same as an active ingredient, and various preparations for skin mucosa administration, can be prepared into various preparations, and can be a paste, a gel, a lotion, a tablet, a suppository, a film. Agents, sprays and other pharmaceutically acceptable preparations. The composition of the present invention as described in the present invention and/or or the composition of the composition comprising the active ingredient as an active ingredient, as Resistant to micro-biological organisms, personal care and nursing products, the described personal care products are washing soap, soap, soap, hand washing, washing Washing agent, Mumulol glue, washing Luoluo liquid, personal care and rubbing test objects, rubbing facial paper, nasal spray Spray aerosols are combined with their group. .

 When preparing the product described above, it may be possible to use a single chemical compound or a combination thereof, and when used in the preparation of a drug preparation When the preparation preparation is used, it may be combined with a different drug substance and a pharmaceutically acceptable carrier group to facilitate the preparation of the preparation. The shape of the carrier is such that: the starch powder, the paste essence, the spit temperature -80000, the kakapobom, the fiber fiber dimension Sucrose, sodium carboxymethylmethylcellulose fiber sodium sulphate, sodium sodium alginate, glycerol oil, propylene glycol alcohol, polyethylene glycol glycol, , month, month, laurel, oxazolone, isopropanol, triethylethanolamine, and tray 6,600, but not limited thereto. .

 In addition, as a single-integrated composition or a combination thereof, which is an active ingredient, it may also be added to the disinfecting venom solution. , hand soap soap, toilet hygiene hand washing agent, washing Luo Luo agent, Mu Mu Luo Luo glue, washing Luo Luo liquid, a personal care nursing wipe Try the object, rub the facial tissue paper, and spray the nasal spray into the nasal spray. Use the virus to kill the surface of the skin surface of the skin and mucous membrane. .

 The various kinds of preparation preparations described in the present invention and the anti-viral virus-resistant personal care and nursing products are cocoa and can be prepared by a method which is often used in the field of the present invention. Made up. .

 The invention expresses the change of the quantity of the HHPPVV virus by detecting the amount of the virus of the HHPPVV virus by the fluorescent fluorescence quantitative PPCCRR test, and observes the activity component and the effect of the product. The method of the party should be applied in the literatures published in several public publications ((Cai Cai has an age, etc., Chinese national sexually transmitted diseases, Ai Zizi Disease prevention and treatment, 22000022,, 88:: 22,, 110088;; Wu Wuyuan Yuan Shengsheng, Fan Fanrui Ruiqiang, etc., practical and practical Chinese and Western medicine combined with clinical clinical bed, 22000033, , 33:: 22,, 11 )). . The results showed that the FFQQ--PPOOVVRR could not be used when the tissue homogenate slurry of the sharp-edged wet and wet sputum was 2244 hours after the addition of the ginseng acid. The virus virus can be detected again, and p-hydroxyhydroxybenzoic acid, 22,33-dihydroxylhydroxybenzoic acid, 22, 44- After the di-dihydroxyhydroxybenzophenone acid, the reduction of HHPPVV1166//1188 is about one-half and a half less, and the 33,44-dihydroxylhydroxybenzophenone acid is slightly reduced. The reduction is small, and the empty blank is combined with the control tube and the control sample sample, such as benzoic acid, water salicylic acid, benzoic acid and the salicylic acid. However, the substance tube has a very high concentration of HHPPVV virus virulence, and it is said that the chemical compound of the invention has the ability to have energy outside the body and body. Fast and fast, the ability to effectively destroy the sharp and rickety virus. . And the Chinese patents CCNN11441111333399, the United States and the United States patents UUSS66229944118866, the invention of the invention is preferably selected benzoic acid, hydrated salicylic acid and benzoic acid The water salicylic acid group composition can not kill the HHPPVV virus, add benzoic acid, water, salicylic acid and benzoic acid with water After the salicylic acid group composition, the amount of the viral virulence was close to that of the empty blank group. . Implementing the implementation method

 The following examples are intended to be illustrative of the present invention, but are not intended to limit the scope of the invention. .

 The main main material materials used in the invention (both content content is greater than 9999%%) and its source source--..

 Material material source source

P-hydroxyhydroxybenzoic acid* 2,3-dihydroxybenzoic acid Taizhou Zhongda Chemical Co., Ltd.

 2,4-dihydroxybenzoic acid Taizhou Yuzhongda Chemical Co., Ltd.

 3,4-dihydroxybenzoic acid Taizhou Zhongda Chemical Co., Ltd.

 3,5-dihydroxybenzoic acid Haimen Best Fine Chemical Co., Ltd.

 2,3,4-trihydroxybenzoic acid Nanjing Longyuan Natural Polyphenol Synthetic Factory

 Gallic acid Zhejiang Bohai Chemical Reagent Factory

 2,4,5-trihydroxybenzoic acid Nanjing Longyuan Natural Polyphenol Synthetic Factory

 Salicylic acid Tianjin Benchmark Chemical Reagent Co., Ltd.

 Benzoic acid Guangzhou Panyuli Strengthening Factory

 Recombinant human interferon α - 2 P gel Hefei Zhaofeng Keda Pharmaceutical Co., Ltd.

 Poly muscle cell Guangdong Kaiping Biochemical Pharmaceutical Factory Example 1 Preparation of anti-HPV virus microemulsion disinfectant

 20 ml of 1,2-propanediol, 15 ml of Tween 80, and 5 ml of azone were mixed, and sterilized distilled water was added to a total volume of 100 ml to obtain a preparation solution for external use. Take 10 g of p-hydroxybenzoic acid, gallic acid, 2,4-dihydroxybenzoic acid, add 50 ml of the external preparation solution, adjust the pH to 5.5, and then add the external preparation solution to 100 ml to obtain 10% p-hydroxybenzoic acid, gallic acid. Acid, 2,4-dihydroxybenzoic acid microemulsion. Example 2 Preparation of Compound Gallic Acid Effervescent Tablets

 Take gallic acid 0.25g, polymyosin 0.01g, tartaric acid 0.45g through 80 mesh sieve, 95% ethanol made of soft material, 12 mesh sieve wet particles, dried at 50 ,, spare. Another sodium bicarbonate 0.65g, dextrin 0.02g and sterile distilled water to make a soft material, through 12 mesh sieve wet granules, dried at 50 ° C, and then mixed with the above dry granules, whole granules, add appropriate amount of sterilized distilled water, For a while, add 0.01g PEG6000. Mix, press, and get.

Example 3 Fluorescence quantitative PCR detection HPV virus screening drug experiment

 Drug sample preparation:

 Take 20 ml of 1,2-propanediol and 15 ml of Tween as solvent, respectively, benzoic acid, salicylic acid, p-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, gallic acid, 2,3-dihydroxybenzoic acid 2,4-dihydroxybenzoic acid was formulated into a 0.01 mol/L solution to adjust the pH to 5.5.

HPV virus source: Specimens of condyloma acuminata from clinical standards of multiple patients. After excision, wash the blood with physiological saline. Under sterile conditions, cut the specimen, add 3 times volume of physiological saline, mix and grind to homogenate and place at -40 °C. spare.

 experiment method:

 The homogenized condyloma acuminata tissue was homogenized 50 μ 1, grouped as shown in Table 1, and 50 μl each of the test drug solution was added. Incubate at 37 °C for 24 hours, then perform the assay according to the HPV6, 11 and 16, 18 FQ-PCR diagnostic kits purchased from Daan Gene Diagnostic Center: 0.2ml of DNA extracted by conventional alkaline lysis In the wall reaction tube, a certain concentration of primers, F-PROBE, DNTP, DNA polymerase and buffer were added at the same time, and then ABI PRISMTM 7700 real-time PCR amplification instrument was used to denature at 93 ° C for 2 min, followed by 93 ° C for 45 s. At 55 °C for 120 s, 40 cycles were repeated. The quantitative results were automatically analyzed by computer software to calculate the quantitative results of the initial copy number. The data is shown in Table 1.

 The results show:

 Tissue homogenate of condyloma acuminata 24 hours after the addition of gallic acid, FQ-POVR could not detect the virus again, after adding p-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, HPV16/ 18 reduction of about half, 3,4-dihydroxybenzoic acid slightly decreased, while the blank control tube and control samples of benzoic acid, salicylic acid and benzoic acid and salicylic acid combination tube have a very high concentration of HPV virus It is indicated that the compound of the present invention has the ability to rapidly and efficiently kill the sharp prion in vitro.

 Fluorescence quantitative PCR detection of HPV virus screening drug experiment

 Virus HPV 6/11 HPV16/18

Tube number (copy / ml) (copy / ml)

Blank control tube 1.45 X 10 ⁶ 1.40 X 10 ⁵

Benzoic acid 3.60 X 10 ⁵ 2.90 X 10 ⁴

Salicylic acid 5.50 X 10 ⁵ 2.60 X 10 ⁴

Benzoic acid + salicylic acid 2.90 X 10 ⁵ 4.50 X 10 ⁴

p-Hydroxybenzoic acid 7.00 X 10 ⁵ 1.30 X 10 ³

3,4-dihydroxybenzoic acid 1.90 X 10 ⁴ 8.50 X 10 ⁴

Gallic acid 0 0

2,3-dihydroxybenzoic acid 2.30 X 10 ⁴ 3.20 X 10 ³

2,4-dihydroxybenzoic acid 1.60 10 ⁴ 4.60 X 10 ³ Example 4 Clinical external treatment for condyloma acuminatum

 Diagnostic criteria:

 Refer to the "Sexually Transmitted Disease Prevention and Control Manual" edited by the Department of Health and Epidemiology of the Ministry of Health of the People's Republic of China for the second edition of 1994: Typical vulva (or perianal) skin mucosa, papillary, cauliflower or other shapes of soft growth, 5 % acetic acid white test was positive.

 Inclusion and exclusion criteria:

 In accordance with the above diagnostic criteria, a single lesion diameter < 0.5cm, patients who have not been treated 2 weeks before the visit were included in the clinical observation. Those with genital genital fungi, trichomoniasis, bacterial infections or other comorbidities, lactation, pregnant women or those with chronic systemic chronic disease, severe liver and kidney disease are not included in the observation. Female patients avoid menstrual periods during treatment.

 experimental method:

 Forty-eight patients with condyloma acuminata who met the observation conditions were randomly selected and divided into parahydroxybenzoic acid group, gallic acid group and recombinant human interferon α - 2 β gel control group.

 10 grams of gallic acid and p-hydroxybenzoic acid, 20 ml of 1,2-propanediol, Tween 80 15 ml, 5 ml of azone, respectively, mixed with sterile distilled water to a total volume of 100 ml, 10% external preparation solution .

 The patient is applied with gallic acid or hydroxybenzoic acid solution or recombinant human interferon α 2 β gel to the affected area, 3 times per sputum, divided into early, middle and late local application to cover the corpus callosum. The affected area and restricted activity for 20 minutes.

 Efficacy criteria:

 Observation time: 8 days, those who did not fall off continued to use, followed up for 12 weeks.

 Observation indicators: Carefully count and describe the location, shape, size and number of the carcass before treatment. Healing: All skin lesions disappeared; Significant effect: More than 70% of skin lesions disappeared; Progress: More than 30% of skin lesions disappeared; Invalid: Skin lesions subsided less than 30%, original skin lesions did not change or increase. The observation results are shown in Table 2.

The results showed that the recombinant human interferon α 2 β gel for external use of condyloma acuminatum is currently recognized as a drug, but the shortest course of treatment is also 4 weeks. After statistical treatment, the effect of p-hydroxybenzoic acid and gallic acid was significantly better than that of recombinant human interferon α 2 β gel, which was significantly different. Moreover, the compound of the present invention is not irritating to the skin mucosa, and only a few people feel a burning sensation. Clinical external treatment of condyloma acuminata observation results cured significantly improved

1-4 days 5-8 days 1-4 days 5-8 days

Gallic acid 2 3 1 4

P-hydroxybenzoic acid 5 2 3 recombinant human interferon α-2 β gel requires a minimum of 4 weeks. Example 5 Clinical topical treatment of herpes simplex virus (HSV) infection

 Example 1 Preparation of gallic acid microemulsion disinfectant, 22 patients with clinical diagnosis of herpes simplex virus (HSV) infection, randomly divided into gallic acid microemulsion disinfectant group and acyclovir ointment group, each group of 11 people, Apply three times per sputum and apply the affected area to the affected area. The results showed that the average recovery time was 3 days in the gallic acid disinfectant group and 5.5 days in the acyclovir ointment group. There was a significant difference between the two groups. The effect of the gallic acid disinfectant group was better than that of the acyclovir ointment group.

Example 6 Preparation of Liquid Hand Soap

 According to the ingredients listed in Table 4 and the proportions thereof, about 5% of water and materials other than p-hydroxybenzoic acid, NaOH or HCl were added to the mixing tank, heated to 8 CTC and stirred until dissolved. Cool to room temperature, add gallic acid, and stir until the material dissolves. Adjust the pH to 5.0 with NaOH or HC1 and add the remaining amount of water to make the product.

 Table 3 Preparation of liquid hand soap

Industrial applicability

The p-hydroxybenzoic acid and the analog thereof of the invention can be used for preparing a medicament for preventing and treating viral infection of skin mucosa, in particular for preparing a medicament for preventing and treating human papillomavirus and herpes virus infection, Such as genital warts, vaginitis, cervicitis or cervical erosion. The compounds of the invention have the ability to rapidly and efficiently kill sharp prions in vitro. P-hydroxybenzoic acid and its analogs are formulated into various pharmaceutical or personal care products in combination with various excipients for dermatological use. Although the present invention has been described in detail above with reference to the preferred embodiments of the present invention, it will be apparent to those skilled in the art. Therefore, such modifications or improvements made without departing from the spirit of the invention are intended to be within the scope of the invention.

Claims

Claim  1. General formula (I):

The use of p-hydroxybenzoic acid and analogs thereof for the preparation of a medicament for the prevention and treatment of viral infections of the skin, wherein R ₂ , R ₃ , R _{4 are} independently selected from OH or H.  2. The use according to claim 1 for the preparation of a medicament for the prevention and treatment of a viral infection of the skin mucosa, characterized in that said viral infection of the skin mucosa refers to human papillomavirus or herpes virus infection of human and animal skin mucosa.  3. The use of claim 1 or 2 in the preparation of a medicament for the prevention and treatment of a viral infection of the skin mucosa, characterized in that the viral infection of the skin mucosa refers to genital warts, vaginitis, cervicitis or cervical erosion.  The use according to Claim 1 or 2 for the preparation of a medicament for preventing and treating skin mucosal viral infection, characterized in that said skin mucosal viral infection drug is a medicament for adjuvant treatment of cervical cancer.  The use of any one of claims 1 to 4 for the preparation of a medicament for the prevention and treatment of viral infections of the skin, characterized in that the para-hydroxybenzoic acid and analogues thereof are selected from one of the following compounds: Benzoic acid, 2,4-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 2,3,4-trihydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid or 2,4,5-three Hydroxybenzoic acid.  6. The use according to any one of claims 1 to 5 for the preparation of a medicament for preventing and treating a viral infection of the skin mucosa, characterized in that the para-hydroxybenzoic acid and analogue thereof are selected from one of the following compounds: Benzoic acid, 2,4-dihydroxybenzoic acid or 3,4,5-trihydroxybenzoic acid.  7. The use of any one of claims 1-6 for the preparation of a medicament for the prevention and treatment of a viral infection of the skin mucosa, characterized in that the p-hydroxybenzoic acid and the analogue thereof are 3, 4, 5 - 3 Hydroxybenzoic acid. 8. The preparation of a medicament for preventing and treating skin mucosal viral infection according to any one of claims 1-7 Use in the preparation of the p-hydroxybenzoic acid and the like thereof in combination with various excipients for dermatological preparation to prepare a paste, a gel, a lotion, a tablet, a suppository, a film or a spray, and a pharmacy Other preparations that are acceptable.  9. The use of any one of claims 1 to 7 for the preparation of a medicament for the prevention and treatment of a viral infection of the skin mucosa, characterized in that the p-hydroxybenzoic acid and the analogue thereof are compatible with various excipients for dermatological administration. Prepared into a personal care product, which is a disinfectant, hand soap, hygienic hand lotion, catalyzed agent, mulocene, venom, personal care wipes, facial tissue, intranasal spray or them The combination.