WO2019119668A1 - 一种具有强抗炎活性的组合物及其应用 - Google Patents
一种具有强抗炎活性的组合物及其应用 Download PDFInfo
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- WO2019119668A1 WO2019119668A1 PCT/CN2018/080606 CN2018080606W WO2019119668A1 WO 2019119668 A1 WO2019119668 A1 WO 2019119668A1 CN 2018080606 W CN2018080606 W CN 2018080606W WO 2019119668 A1 WO2019119668 A1 WO 2019119668A1
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- Prior art keywords
- hyaluronic acid
- surfactant
- inflammatory activity
- acid fragment
- gel
- Prior art date
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
- A23L33/12—Fatty acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention relates to a composition having strong anti-inflammatory activity and use thereof, in particular, a surfactant capable of enhancing the anti-inflammatory action of hyaluronic acid fragments having anti-inflammatory activity, and providing a surfactant having significant anti-inflammatory activity a composition comprising the hyaluronic acid fragment and a product and application comprising the combination.
- Hyaluronic acid also known as hyaluronic acid, uronic acid, hyaluronic acid, English name hyaluronic acid (referred to as HA), is a high-grade polysaccharide composed of D-glucuronic acid and N-acetylglucosamine. The disaccharide unit can reach 25,000 channels. Seoul. Tissues such as human subcutaneous tissue, epidermis and oropharyngeal mucosa contain a large amount of macromolecular hyaluronic acid. In other words, macromolecular hyaluronic acid is the basic building material for various tissues such as human skin, mucous membranes, and subcutaneous, and has water retention and moisturizing functions. The existing hyaluronic acid products in the market are mainly facial or facial beauty products with the addition of macromolecular hyaluronic acid as the main functional ingredient.
- small molecule hyaluronic acid and macromolecular hyaluronic acid which are differentiated according to molecular weight, show functional differences in small animal experiments, large animal, human and cell level studies. It indicates that small molecule hyaluronic acid is a degradation product of inflammation, which is consistent with the distribution of inflammation. Its function is to trigger and promote inflammatory response.
- the main references include:
- Hyaluronan stimulates ex vivo B lymphocyte chemotaxis and cytokine production in a murine model of fungal allergic asthma. Immunobiology.2015 Feb 7. PMID: 25698348.
- Campo GM1 Avenoso A, D'Ascola A, Prestipino V, Scuruchi M, Nastasi G, Calatroni A, Campo S. 4-mer hyaluronan oligosaccharides stimulate inflammation response in synovial fibroblasts in part via TAK-1and in part via p38-MAPK.Curr Med Chem.2013;20(9):1162-72.PMID:23298137.
- a small molecule hyaluronic acid having a molecular weight of 10-70 KD can be used in topical use in an in vitro preparation (such as daily necessities, hygiene products, cosmetics, skin care products, disinfecting products, etc.) to help alleviate or treat inflammation of the skin and mucous membranes.
- Small molecule hyaluronic acid of less than 10KD has substantially no such effect.
- the recent WODARS-SINAI MEDICAL CENTER patent WO/2014/165713 shows that the small molecule hyaluronic acid of less than 10KD produced by bacterial streptococci hyaluronidase cleavage does not cause an inflammatory reaction, but the bacterial Streptomyces hyaluronidase produces greater than 10KD.
- the small molecule hyaluronic acid causes an inflammatory response, suggesting that the function of the small molecule hyaluronic acid may also be related to the type of cleavage enzyme (ie, related to the steric structure or molecular arrangement of the chopped hyaluronic acid fragment).
- the invention is an unexpected discovery of the inventor in the application stage of the small molecule hyaluronic acid fragment, which makes us more familiar with the hyaluronic acid fragment, and manufactures more possible products for the subsequent development of the hyaluronic acid fragment. Provides the foundation and shows great market application value.
- hyaluronic acid for many years. After a series of studies, it has been found that small molecule hyaluronic acid fragments produced by a specific method have anti-inflammatory biological activity and can be used as an in vitro preparation for skin mucosa. In practical applications, it can be made into a variety of products for external use, including cosmetics, daily necessities, and skin external medicines. In the development stage of these products, due to the specific needs of different dosage forms or product types, it is necessary to add a series of conventional excipients for compatibility.
- the inventors unexpectedly found that as long as the compatibility of the substance contains oil and fat, the effect of skin mucosal inflammation treatment will be greatly reduced; as long as it contains a higher concentration of surfactant ingredients The therapeutic effect of skin mucosal inflammation is unexpectedly very good; further studies have found that the addition of higher concentrations of surfactant components to various products of such hyaluronic acid fragments does not cause significant side effects on the skin and mucous membranes.
- the object of the present invention is to provide a composition having strong anti-inflammatory activity and its use based on the discovered surfactant to enhance the anti-inflammatory action of the hyaluronic acid fragment having anti-inflammatory activity, and based on this
- the composition provides a composition comprising a surfactant and the hyaluronic acid fragment having significant anti-inflammatory activity and a product and application comprising the combination.
- the present invention adopts the following technical solutions:
- a composition having strong anti-inflammatory activity consisting of a hyaluronic acid fragment having anti-inflammatory activity and a surfactant for enhancing the anti-inflammatory action of the hyaluronic acid fragment.
- the surfactant is one or more of nonoxynol 9, sodium lauryl sulfate, soap, sucrose fatty acid ester or Tween 80.
- the weight ratio of the surfactant to the hyaluronic acid fragment having anti-inflammatory activity is 0.05 to 85: 0.2 to 6.0.
- the invention also protects the use of surfactants to enhance the anti-inflammatory effects of hyaluronic acid fragments having anti-inflammatory activity.
- the invention also protects the use of a combination of a surfactant and a hyaluronic acid fragment having anti-inflammatory activity as an active ingredient in the preparation of foods, pharmaceuticals, clinical special diets, daily necessities, hygiene products, cosmetics and medical devices.
- the present invention also protects the use of a composition of a surfactant and a hyaluronic acid fragment having anti-inflammatory activity as an active ingredient in the preparation of a medicament for treating acne.
- the present invention also provides a pharmaceutical composition for treating acne comprising a hyaluronic acid fragment having anti-inflammatory activity and nonoxynol ether 9 for enhancing the anti-inflammatory action of the hyaluronic acid fragment.
- a hyaluronic acid fragment having an anti-inflammatory activity of 1% by mass and a nonoxynol ether 9 having a mass fraction of 0.5% to 2% are included.
- the pharmaceutical composition is a gel preparation.
- the present invention has at least the following advantages:
- a composition of an anti-inflammatory active hyaluronic acid fragment and a surfactant will exert a greater than the use of the hyaluronic acid alone in the preparation of general foods, functional foods, clinical special diets, daily necessities, hygiene products, cosmetics, medical devices and pharmaceuticals. Better application of fragments.
- Figure 1 Schematic diagram of the B-HA toothpaste series.
- Figure 2 Schematic diagram of B-HA nasopharyngeal spray.
- Figure 3 Schematic diagram of B-HA nebulizer.
- Figure 4 Schematic diagram of B-HA eye serum (eye wash).
- Figure 5 (a) Schematic diagram of soap containing B-HA; (b) Schematic diagram of a 2-in-1 gel containing B-HA; (c) Schematic representation of a skin spray containing B-HA.
- Figure 6 Schematic diagram of a B-HA cream containing oil (without surfactant).
- Figure 7 (a) Schematic diagram of a B-HA contraceptive gel containing 2% surfactant nonoxynol ether 9; (b) Schematic diagram of a B-HA privacy gel containing no surfactant nonoxynol ether 9.
- Figure 8 (a) B-HA dietary supplement without food grade surfactant; (b) Schematic of B-HA beverage without food grade surfactant.
- Figure 9 Schematic diagram of surfactant-containing B-HA foot spray.
- the present invention is based on the results of research on the anti-inflammatory therapeutic effects of various products of the hyaluronic acid fragments having anti-inflammatory activity, which are produced by the present inventors, and found that various products of such hyaluronic acid fragments only contain The oil and fat component, the effect of the treatment of skin and mucous membrane inflammation is unexpectedly basically ineffective; further analysis found that the various products of the hyaluronic acid fragment are anti-inflammatory of the skin and mucous membrane inflammation as long as they contain the surfactant component or the site is easily absorbed. The treatment effect was unexpectedly very good.
- hyaluronic acid fragment product has the effect of treating a variety of subclinical and clinical skin mucosal diseases when it contains a higher concentration of surfactant components, and has no obvious side effects, and can be used to produce a variety of transparent Acidic acid fragment products, including skin products and intestinal mucosal products, in summary, this unexpected discovery has made the hyaluronic acid fragments of a variety of products have greater market applications and value, including not limited to the preparation of food, medicine, clinical Applications in special diets, daily necessities, hygiene products, cosmetics and medical devices.
- the surfactant types of the present invention relate to ionic surfactants (cationic and anionic surfactants) and nonionic surfactants, foaming and non-foaming surfactants, food grade surfactants.
- ionic surfactants cationic and anionic surfactants
- nonionic surfactants foaming and non-foaming surfactants
- food grade surfactants e.g., the following examples illustrate some of the surfactants commonly used in product applications for testing, not limited, such as the commonly used surfactant nonoxynol 9, sodium lauryl sulfate, soap, sucrose fat
- the weight ratio of the surfactant to the hyaluronic acid fragment having anti-inflammatory activity may range from 0.05 to 85: 0.2 to 6.0 in the product ratio.
- composition of the above surfactant and the hyaluronic acid fragment of the present invention has strong anti-inflammatory activity is mainly based on the results of large-scale research effects of various products based on specific hyaluronic acid fragments as raw materials.
- the invention is illustrated by the following examples, which are intended to illustrate and explain the invention.
- OBJECTIVE Production of engineered recombinant human hyaluronidase PH20 and preparation of raw materials containing hyaluronic acid fragments
- CHO-S cell line amplified and large-scale culture in a turbulent animal cell reactor; the harvested liquid containing PH20 was filtered through 0.22 um, separated by 2-3 steps using an ion column, and then inactivated by bacterial filtration and virus filtration. After the steps of ultrafiltration and concentration, a high-purity sterile saccharified recombinant human hyaluronidase PH20 is prepared.
- a hyaluronic acid raw material having a molecular weight of 800-1200 KD is purchased, placed in a stainless steel dry-baked bottle, dried at 105 degrees for 5-6 hours, and degraded into hyaluronic acid having a molecular weight of about 200-250 KD.
- OBJECTIVE To study the anti-inflammatory effects of skin and mucous membranes of various products or samples based on hyaluronic acid fragment (B-HA).
- the present invention is based on a variety of products or samples using hyaluronic acid fragments as raw materials, including B-HA toothpaste (Fig. 1), B-HA nasopharyngeal spray (Fig. 2), B-HA aerosol (Fig. 3 ), B-HA Eye Serum (Eyewashing Liquid) ( Figure 4), B-HA Mask, B-HA New and Old Skin Wound or Damage Spray, B-HA Skin Spray ( Figure 5(c)), without Surfactant B-HA skin cream ( Figure 6), surfactant-containing B-HA contraceptive gel (Figure 7 (a)), surfactant-free B-HA vaginal care gel (Fig. 8(a)) and B-HA foot spray (Fig. 9).
- B-HA toothpaste Fig. 1
- B-HA nasopharyngeal spray Fig. 2
- B-HA aerosol Fig. 3
- B-HA Eye Serum Eyewashing Liquid
- Figure 5(c) B-HA Mask, B-HA New and
- RESULTS The inventors analyzed large-scale anti-inflammatory effects (mainly including redness and itching of skin and mucous membranes, including gingivitis, pharyngitis, laryngitis, nasopharynx, dry eye disease, new and old skin wound inflammation, hemorrhoids, itchy itch and blisters, vaginitis Itching and secretions, scalp acne, drinking or eating pepper caused by intestinal mucosal inflammation, etc., anti-inflammatory effect is divided into very good, general, basically invalid three levels), found a variety of such hyaluronic acid fragments As long as the product contains oil and fat components, the effect of skin and mucous membrane inflammation treatment is unexpectedly poor (Table 1).
- the present inventors further analyzed that various products of such hyaluronic acid fragments were unexpectedly excellent in the treatment effect of skin mucosal inflammation as long as they contained a surfactant component or a hyaluronic acid fragment was easily absorbed (Table 1).
- the B-HA toothpaste in Fig. 1 is the first product of the present inventor to be most effectively reflected by the user (the customer continuously requests three batches), and is effective for treating gums and oral mucosal diseases.
- the user of B-HA nasopharyngeal spray in Figure 2 has obvious effects in treating nasopharyngitis, and the market sales are growing rapidly.
- the B-HA aerosol product in Figure 3 the user reflects the obvious effect of treating laryngitis and allergic asthma.
- the B-HA eye drops product in Figure 4 shows that the user has a significant effect in treating dry eye disease.
- Tables 1 and 2 show that the B-HA nasopharyngeal spray (Fig. 2) is very effective in treating nasopharyngitis. Further analysis revealed that the hyaluronic acid fragment B-HA is easily absorbed by the nasopharyngeal mucosa, so the effect is very good. .
- the B-HA aerosol product in Figure 3 is effective, suggesting that the absorption of B-HA by the laryngeal and tracheal mucosa is significantly better than the absorption of B-HA by the skin.
- the B-HA eye drop product in Figure 4 has a significant effect, suggesting that the conjunctival absorption of B-HA is better than the skin absorption of B-HA.
- B-HA toothpaste Fig. 1
- a sodium dilaurate sulfate containing 2% by mass of a mass fraction was a surfactant (detergent).
- the inventors have found that the hyaluronic acid fragment product B-HA cream (Fig. 6) contains oils and fats (without surfactants), and the effect of skin mucosal inflammation treatment is unexpectedly substantially ineffective (Table 1).
- the inventors added a general-purpose B-HA skin spray (Fig. 5(c)) to 16% or more of glycerin, and the effect was remarkably lowered to be substantially ineffective.
- the B-HA dietary supplement in Figure 8(a) requires 8 capsules per capsule (130 mg B-HA per capsule) or more to have a significant effect, or a large amount of fat in the diet of modern humans. relationship.
- the B-HA contraceptive gel (Fig. 7(a)) is far better (i.e., very good) in treating vaginal inflammatory itching than the B-HA protective gel (Fig. 7(b)), both The difference is that the B-HA contraceptive gel contains a 2% concentration of the spermicidal nonoxynol ether 9, but the nonoxynol ether 9 is also a nonionic surfactant (detergent). It is highly probable that nonoxynol 9 enhances the anti-inflammatory activity of bioactive hyaluronic acid.
- the inventors speculated that in addition to the effect of the easy absorption of the use site, there should be a component which enhances the anti-inflammatory activity of the hyaluronic acid component in the above-mentioned product compatibility, and the component is very This may be a surfactant, which was also verified in the inventors' subsequent comparative experiments.
- the inventors prepared a surfactant-containing 1% B-HA soap sample (Fig. 5(a)) and a scouring 2-in-1 gel sample (Fig. 5(b)) by means of the original production conditions, and found that surface activity was added.
- the anti-skin inflammation treatment effect of the 1% B-HA soap and the rinsing gel sample of the agent is far better than that of the B-HA spray without the surfactant (Fig. 5(c)).
- B-HA dietary supplements which do not contain food-grade surfactants, require larger doses to effectively treat intestinal mucosal inflammation, and beverage samples after the addition of food-grade surfactants (Figure In 8(b)), the effective dose of B-HA was significantly reduced by more than 4 times.
- Example 2 The results of the above Example 2 suggest that B-HA may increase the absorption of skin and mucous membranes by combining with surfactants, but further quantitative and repeated experimental studies are needed to prove that the products produced by B-HA fragments are contained.
- the high concentration of surfactant ingredients has the effect of treating a variety of subclinical and clinical skin and mucous membrane diseases, and can be used to produce a variety of hyaluronic acid fragment products and has greater market application and value.
- OBJECTIVE Quantitative experimental studies have shown that products made from B-HA fragments have the effect of treating a variety of subclinical and clinical skin and mucous membrane diseases when they contain higher concentrations of surfactant components.
- Table 3 shows a 1% B-HA wound gel containing 0.25% nonoxynol ether 9, a 1% B-HA wound gel group containing 0.05% nonoxynol ether 9, and a B-HA wound gel. Fresh skin wounds (but still visible redness) were compared with experimental findings.
- Table 4 shows the results of a comparative study of the 1% B-HA mosquito bite gel group and the 1% B-HA mosquito bite gel group containing 1% nonoxynol ether 9 in the treatment of itching symptoms and red or swelling signs.
- the 1% B-HA mosquito bite gel containing 1% nonoxynol ether 9 has a significantly lower onset time of itching on the mosquito bite than the start time of 1% B-HA mosquito bite gel;
- the 1% B-HA mosquito bite gel containing 1% nonoxynol ether 9 began to significantly improve the time required for red or swollen signs of mosquito bites to be significantly less than the time required for 1% B-HA mosquito bite gel;
- the 1% B-HA scalp spray group of nonoxynol ether 9 was treated once a day in the morning and evening, and the observation index was the improvement of itching or pain symptoms and red or swelling signs after treatment.
- Table 5 shows the results of a comparative study of 1% B-HA scalp spray group containing 1% nonoxynol ether 9 and 1% B-HA scalp spray group for treating itching or pain symptoms and red or swelling signs.
- METHODS Twenty subjects with mild athlete's foot were used in this study. Ten of them were 1% B-HA foot spray group containing 2.0% nonoxynol ether 9 and the other 10 cases were not containing 2.0% nonoxynol. The 1% B-HA foot spray group of ether 9 was treated once a day in the morning and evening. The observation index was the relief of itchy (symptoms) and the improvement of skin damage (signs) after the treatment.
- Table 6 shows the relief of itch (symptoms) and skin lesions (symptoms) in the athlete's foot area after treatment with 1% B-HA foot spray group containing 2.0% nonoxynol ether 9 and 1% B-HA foot spray group. ) improvement.
- the time required for the 1% B-HA foot spray group containing 2.0% nonoxynol 9 to effectively relieve the itching of the athlete's foot is significantly shorter than that required for the 1% B-HA foot spray group ( 0.5 to 2.0 hours); 2.
- the 1% B-HA foot spray group containing 2.0% nonoxynol ether 9 significantly improved the time of skin damage (signs) in the athlete's foot area compared with the 1% B-HA foot spray group. The time required is short (day 1 after treatment: day 2 after treatment).
- Table 7 shows a 1% B-HA 2-in-1 carbomer gel group containing 1% sodium lauryl sulfate and 2% nonoxynol ether 9 and 1% B-HA carbomer gel. The results of a comparative study of the gel group in the treatment of pruritus and signs of senile skin.
- Table 8 shows a 1% B-HA soap group containing 74% surfactant soap base and 13% glycerol and a 1% B-HA carbomer gel group containing 13% glycerol for 7 days of posterior acne and Improvements in skin discomfort and redness and heat signs caused by seborrheic dermatitis.
- Table 9 shows a 0.6% B-HA 2-in-1 carbomer gel group containing 0.6% sodium lauryl sulfate and 2% nonoxynol ether 9 and 0.6% B-HA carbomer gel. The results of a comparative study of the gel group in the treatment of pruritus and signs of senile skin.
- Table 10 shows 0.6% B-HA and 3% smectite powder soap group with 63% surfactant soap base and 13% glycerol and 0.6% B-HA and 3% montmorillonite powder Kappa with 13% glycerol.
- the gel group was treated with 7 days of acne and seborrheic dermatitis to improve the symptoms of skin discomfort and redness and swelling.
- Table 11 shows 0.2% B-HA and 3% smectite powder soap groups containing 69% surfactant soap base and 13% glycerol and 0.2% B-HA and 3% montmorillonite powder cards containing 13% glycerol.
- the Bom gel group was treated with 7 days of acne and seborrheic dermatitis to improve the symptoms of skin discomfort and redness and swelling.
- RESULTS Twenty patients with gingivitis were enrolled in this study. Ten of them were 1% B-HA brushing gel group containing 2% sodium lauryl sulfate and 2% nonoxynol ether 9, and the other 10 were 1% B-HA brushing gel group containing 2% sodium lauryl sulfate, both groups contain 2% large particles of hydrated silica to promote B-HA absorption, each morning and evening treatment for 7 days, the observation index is After treatment, the symptoms of itching and the improvement of signs of redness and swelling of the gums.
- Table 12 shows a 1% B-HA brushing gel containing 2% sodium lauryl sulfate and 2% nonoxynol-9 and 1% B-HA brushing gel containing 2% sodium lauryl sulfate. The symptoms of itching and the improvement of signs of redness and swelling of the gums.
- 1% B-HA brushing gel containing 2% sodium lauryl sulfate and 2% nonoxynol ether 9 has a surface containing more than 1% B-HA brushing gel containing 2% sodium lauryl sulfate.
- the active agent 2% nonoxynol ether 9 which relieves the symptoms of itching and improves the signs of gingival redness and swelling, is better than the 1% B-HA brushing gel containing 2% sodium lauryl sulfate, indicating that the surface is added to B-HA.
- the active agent 2% nonoxynol ether 9 has an effect of promoting the anti-inflammatory effect of B-HA; 2.3. B-HA does not lose anti-inflammatory activity in the case of a high concentration of surfactant.
- Method 1 This study used 14 patients with mild inflammatory bowel disease (no pus and bloody stools, 3 times of bowel movements/day, mild abdominal discomfort), and 7 of them had food-grade surfaces. Active agent 2% sucrose fatty acid ester and 0.15% Tween 80 (also known as polysorbate or Polysorbate) 1% B-HA lactic acid beverage group, the other 7 3% B-HA lactic acid beverage group, after eating chili diet Use a 1% B-HA lactic acid drink or a 3% B-HA lactic acid drink containing a food-grade surfactant 2% sucrose fatty acid ester and 0.15% Tween 80, and then eat a pepper diet, observe the indicators for stool frequency and mild abdomen Uncomfortable aggravation and improvement.
- Active agent 2% sucrose fatty acid ester and 0.15% Tween 80 also known as polysorbate or Polysorbate
- Results 1 Table 13 shows the 3% B-HA lactic acid beverage group and the 3% B-HA lactic acid beverage group containing food grade surfactant 2% sucrose fatty acid ester and 0.15% Tween 80 on the edible pepper diet and two groups. Comparative experimental study results of different treatment groups.
- Method 2 Inflammation of the intestinal mucosa may cause an increase in intestinal mucosal permeability, alcohol absorption after drinking, and easy drunk.
- B-HA is known to reduce intestinal mucosal permeability and reduce the incidence of intoxication.
- 10 subjects were used to drink alcohol easily, 5 of which were 6% B-HA lactic acid beverage group containing food grade surfactant 2% sucrose fatty acid ester and 0.15% Tween 80, and 5 cases were 6 %B-HA lactic acid beverage group, after drinking the known amount of drunken alcohol, use 6% B-HA lactic acid beverage or 1% B-HA lactic acid containing food grade surfactant 2% sucrose fatty acid ester and 0.15% Tween 80.
- Beverage treatment the two groups drink 100 ml of different beverages before drinking to prevent drunkenness.
- the observation index is drunkenness.
- the self-judgment standard of drunkenness is similar to the dizziness and headache of the subjects themselves and the previous drunkenness.
- the judging standard of drunkenness is onlookers. It is judged that the drinker is blushing, unstable and changing in a manner similar to drunkenness.
- Results 2 Table 14 shows the consumption of known drunken drinks by the 6% B-HA lactic acid beverage group and the 6% B-HA lactic acid beverage group containing food grade surfactant 2% sucrose fatty acid ester and 0.15% Tween 80. The results of the comparative experimental study.
- OBJECTIVE To study the effect of 1% B-HA protective gel containing no surfactant and nonoxynol-9 in the treatment of acne.
- the prepared different male and female private protective gels were inserted into the anus 1-5 mm after defecation, and each time 5 ml of gel was injected, 2 times a day in the morning and evening, and continuous treatment for 10 days.
- Table 15 used a large sample of patients to study the effects of a male and female private care gel with and without the surfactant nonoxynol 9 in the treatment of acne.
Abstract
一种具有强抗炎活性的组合物及应用,所述组合物由透明质酸片段和用于增强透明质酸片段的抗炎作用的表面活性剂组成。
Description
本发明涉及一种具有强抗炎活性的组合物及其应用,特别是基于表面活性剂能够增强具有抗炎活性的透明质酸片段的抗炎作用,提供具有显著抗炎活性的由表面活性剂和所述透明质酸片段组成的组合物及含有该组合组的产品及应用。
透明质酸,又称玻璃酸、糖醛酸、玻尿酸,英文名hyaluronic acid(简称HA),是由D-葡萄糖醛酸及N-乙酰葡糖胺组成的高级多糖,双糖单位可达25000道尔。人体皮下组织、表皮和口咽粘膜等组织含有大量的大分子透明质酸。换句话说,大分子透明质酸是人类皮肤、粘膜、皮下等各种组织的基本建筑材料,具有保水和保湿功能。市场现有的透明质酸产品主要是以添加大分子透明质酸为主要功效成分的面部护理或面部美容产品。
近年来一系列的研究表明,依据分子量的大小区分的小分子透明质酸与大分子透明质酸在小动物实验、大动物、人和细胞水平的研究中均显示出功能上的差异,主流文献表明小分子透明质酸是炎症的降解产物,和炎症分布一致,其功能是引发和促进炎症反应,主要参考文献包括:
[1].Jaime M.Cyphert,Carol S.Trempus,and Stavros Garantziotis,Size Matters:Molecular Weight Specificity of Hyaluronan Effects in Cell Biology(Review Article),International Journal of Cell Biology,Volume 2015(2015),Article ID 563818.
[2].Jiang D1,Liang J,Noble PW.Hyaluronan as an immune regulator in human diseases.Physiol Rev.2011 Jan;91(1):221-64.PMID:21248167.
[3].Zgheib C1,Xu J1,Liechty KW1.Targeting Inflammatory Cytokines and Extracellular Matrix Composition to Promote Wound Regeneration.Adv Wound Care(New Rochelle).2014 Apr 1;3(4):344-355.PMID:24757589.
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而发明人近年来的研究成果(专利申请号200780052196.7、201310325056.X、201310454955.X、201410153593.5、201510065499.9、201510065498.4、201510067326.0、201510333526.6)却还提示另一种可能性,即小分子透明质酸体外制剂具有抑制一些皮肤粘膜炎症的功能。这些文献提示小分子透明质酸的这种抑制炎症的功能可能与分子大小的程度有关,也可能与其生产方法有关。并且,小动物实验、大动物实验和人体实验的对比结果还提示小分子透明质酸的功能在小动物、大动物和人体中可能完全不同。例如,以上专利文献表明分子量10-70KD的小分子透明质酸可以制成体外制剂局部使用(如日用品、卫生用品、化妆品、护肤品、消毒用品等),有助于缓解或治疗皮肤和粘膜炎症,而小于10KD的小分子透明质酸基本没有上述功效。然而,最近CEDARS-SINAI MEDICAL CENTER的专利WO/2014/165713表明采用细菌streptococci透明质酸酶切割产生的小于10KD的小分子透明质酸不引起炎症反应,但细菌Streptomyces透明质酸酶产生的大于10KD的小分子透明质酸却引起炎症反应,提示小分子透明质酸的功能还可能与切割酶的种类有关(即与切割后的透明质酸片段的立体结构或分子排列有关)。
发明人对于小分子透明质酸片段的研究虽然已经多年,并初步取得了上述专利文献所记载的一些研究结果,但对于这种具有抗炎活性的小分子透明质酸片段的产品化应用仍然在不断开发和探索,关于小分子透明质酸 片段与其他物质之间的互作反应及相关机理,尚有很多仍未可知的空白。本发明即是发明人在小分子透明质酸片段产品化应用阶段的意外发现,使得我们对该种透明质酸片段的了解更近一步,为后续开发该透明质酸片段制造更多可能的产品提供了基础,显示了巨大的市场应用价值。
发明内容
发明人多年来一直研究透明质酸,经过一系列的研究发现,使用特定方法生产的小分子透明质酸片段具有抗炎的生物活性,可以制成皮肤黏膜的体外制剂使用。实际应用时,可以制成外用的多种产品,包括化妆品、日用品、皮肤外用药品等。在这些产品的开发阶段,由于不同的剂型或产品种类的特定需求,还需要添加一系列的常规辅料等进行配伍。而在大规模统计分析了多种产品的疗效之后,发明人意外地发现只要配伍物质中含有油脂成分,其皮肤粘膜炎症治疗的效果就会大打折扣;而只要含有较高浓度的表面活性剂成分,其皮肤粘膜炎症的治疗效果就出乎意料地非常好;进一步研究发现,在此种透明质酸片段的多种产品中添加较高浓度的表面活性剂成分对皮肤粘膜没有产生明显的副作用。因此,本发明的目的是基于发现的表面活性剂增强具有抗炎活性的透明质酸片段的抗炎作用的新用途,提供一种具有强抗炎活性的组合物及其应用,并基于这种应用提供了而具有显著抗炎活性的由表面活性剂和所述透明质酸片段组成的组合物及含有该组合组的产品及应用。
为实现上述目的,本发明采用如下技术方案:
一种具有强抗炎活性的组合物,由具有抗炎活性的透明质酸片段与用于增强该透明质酸片段的抗炎作用的表面活性剂组成。
进一步地,所述的具有抗炎活性的透明质酸片段是采用CHO细胞生产的有糖化的重组人透明质酸酶PH20切割大分子透明质酸获得的分子量为 10KD~70KD的透明质酸片段。
所述的表面活性剂为壬苯醇醚9、月桂醇硫酸酯钠、皂基、蔗糖脂肪酸酯或吐温80中的一种或多种。
所述的表面活性剂与具有抗炎活性的透明质酸片段的重量比为0.05~85:0.2~6.0。
本发明还保护表面活性剂在增强具有抗炎活性的透明质酸片段的抗炎作用上的应用。
本发明还保护表面活性剂与具有抗炎活性的透明质酸片段的组合物作为活性成分在制备食品、药品、临床特殊膳食、日用品、卫生产品、化妆品和医疗器械中的应用。
具体地,本发明还保护表面活性剂与具有抗炎活性的透明质酸片段的组合物作为活性成分在制备用于治疗痔疮的药物中的应用。
基于上述应用,本发明还提供一种用于治疗痔疮的药物组合物,包括具有抗炎活性的透明质酸片段与用于增强该透明质酸片段的抗炎作用的壬苯醇醚9。
进一步地,包括质量分数1%的具有抗炎活性的透明质酸片段与质量分数0.5%~2%的壬苯醇醚9。
进一步地,所述的药物组合物为凝胶制剂。
由于采用上述技术方案,本发明至少具有以下优点:
发明人意外发现的上述表面活性剂的新用途将使得涉及具有抗炎活性的透明质酸片段制造的多种产品有更加巨大的市场应用和价值。具有抗炎活性的透明质酸片段与表面活性剂的组合物在制备普通食品、功能食品、临床特殊膳食、日用品、卫生产品、化妆品、医疗器械和药品中将发挥比单独使用所述透明质酸片段更好的应用。
上述仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,以下结合附图与具体实施方式对本发明作进一步的详细说明。
图1:B-HA牙膏系列的示意图。
图2:B-HA鼻咽喷剂示意图。
图3:B-HA雾化剂示意图。
图4:B-HA眼部精华液(洗眼液)示意图。
图5:(a)含有B-HA的肥皂示意图;(b)含有B-HA的洗护二合一凝胶示意图;(c)含有B-HA的皮肤喷剂示意图。
图6:含有油脂(不含表面活性剂)的B-HA霜膏剂示意图。
图7:(a)含有2%表面活性剂壬苯醇醚9的B-HA避孕凝胶示意图;(b)不含表面活性剂壬苯醇醚9的B-HA私护凝胶示意图。
图8:(a)不含有食品级表面活性剂的B-HA膳食补充剂;(b)不含有食品级表面活性剂的B-HA饮料示意图。
图9:含表面活性剂的B-HA足喷剂示意图。
本发明基于对本发明人主持生产的以具有抗炎活性的透明质酸片段为原料的多种产品的说明书外抗炎治疗效果的研究结果,发现了此种透明质酸片段的多种产品只要含有油脂成分,其皮肤粘膜炎症治疗的效果出乎意料地基本无效;进一步分析发现此种透明质酸片段的多种产品只要含有表面活性剂成分或所在部位容易被吸收,其皮肤粘膜炎症的抗炎治疗效果就出乎意料地非常好。进一步的定量实验研究显示该透明质酸片段制造的产 品在含有较高浓度表面活性剂成分时具有治疗多种亚临床和临床皮肤黏膜疾病的效果,并且没有明显副作用,可以用来生产多种透明质酸片段产品,包括皮肤用品和肠道粘膜用品,总之,这个意外发现使得该透明质酸片段制造的多种产品有更大的市场应用和价值,包括并不限于在制备食品、药品、临床特殊膳食、日用品、卫生产品、化妆品和医疗器械等方面的应用。
具体地,本发明所述的表面活性剂种类涉及离子型表面活性剂(阳离子和阴离子表面活性剂)和非离子表面活性剂,起泡的及非起泡的表面活性剂,食品级表面活性剂等,以下的实施例中列举了一些产品应用中常用的表面活性剂进行试验说明,并不用于限定,例如常用的表面活性剂壬苯醇醚9、月桂醇硫酸酯钠、皂基、蔗糖脂肪酸酯或吐温80中的一种或多种,在产品配比中,表面活性剂与所述的具有抗炎活性的透明质酸片段的重量比范围可以是0.05~85:0.2~6.0。
本发明上述的表面活性剂与所述透明质酸片段的组合物具有强抗炎活性的发现主要是基于特定的透明质酸片段为原料的多种产品的大规模研究效果的结果进行分析。以下通过具体的实施例对本发明进行说明,应当理解,此处所描述的实施例仅用于说明和解释本发明,并不用于限定本发明。
实施例1
目的:工程酶重组人透明质酸酶PH20的生产及含有透明质酸片段原料的制备
方法:以公告号CN104342420A、CN103468662A、CN105018547A专利文献中记载的方法为基础,利用动物细胞(CHO细胞)生产有糖化的重组人透明质酸酶PH20。包括:将有糖化的重组人透明质酸酶PH20的基因cDNA人工合成,插入富含GC的pMH3、pMH4、pMH5空表达载体,建成pMH3-PH20、pMH4-PH20、pMH5-PH20表达载体(采用公告号为CN102124019A的专利文献记载的方法构建表达载体以便极高地表达重组 蛋白);再将pMH3-PH20、pMH4-PH20、pMH5-PH20的cDNA表达载体转入CHO-S细胞系,筛选高表达PH20的CHO-S细胞系,在激流式动物细胞反应器进行放大和大规模培养;将含有PH20的丰收液经0.22um过滤后采用离子柱等2-3步分离,再经细菌过滤和病毒过滤灭活、超滤浓缩等步骤后,制成高纯度无菌的有糖化的重组人透明质酸酶PH20。
购买分子量为800-1200KD的透明质酸原料,装入不锈钢干烤瓶,105度干烤5-6小时,降解成为分子量约为200-250KD的透明质酸。
使用工作体积500升的在位清洁在位灭菌的酶解混合罐,准备降解成为分子量约为200KD的透明质酸原料,一次或分多次加入纯水,再依次加入氯化钠80-90mM、镁离子1mM、重组人透明质酸酶3000-4000单位/每克大分子透明质酸,充分混合,在37度反应2-3小时,反复3次,共6小时,直至透明质酸的分子量达到10KD-70KD,成为具有抗炎生物活性的透明质酸片段,称为生物活性透明质酸片段(bioactive hyaluronic acid fragments,简写为B-HA)。
加氯化钠35-45mM将渗透压调至280-300毫渗量/升(mOsm/L),再经加热84-95度30-60分钟(重组人透明质酸酶热灭活、部分细菌灭活和降低pH病毒灭活),再经0.22um细菌过滤,得到6.5-7.5%透明质酸片段溶液原料。
结果:
1、获得高纯度的动物细胞(CHO细胞)生产的有糖化的重组人透明质酸酶;
2、制备出6.5-7.5%透明质酸片段溶液原料;
结论:结果表明成功生产了高纯度的动物细胞(CHO细胞)生产的有糖化的重组人透明质酸酶和制备出6.5-7.5%生物活性透明质酸片段(bioactive hyaluronic acid fragments或B-HA)溶液原料。
实施例2
目的:研究以透明质酸片段(B-HA)为原料的多种产品或样品的皮肤粘膜抗炎治疗效果。
方法:本发明基于以透明质酸片段为原料的多种产品或样品,包括B-HA牙膏(图1)、B-HA鼻咽喷剂(图2)、B-HA雾化剂(图3)、B-HA眼部精华液(洗眼液)(图4)、B-HA面膜、B-HA新旧皮肤创口或损伤喷剂、B-HA皮肤喷剂(图5(c))、不含表面活性剂的B-HA皮肤霜膏剂(图6)、含有表面活性剂的B-HA避孕凝胶(图7(a))、不含有表面活性剂的B-HA阴道护理凝胶(图7(b))、B-HA膳食补充剂(图8(a))和B-HA足喷剂(图9)等。本发明人对以上产品进行了大样本抗炎疗效结果分析,并对抗炎疗效好的产品进行了临床研究和文章发表。
结果:本发明人经过大规模抗炎疗效分析(主要包括皮肤粘膜红肿痛痒,治疗包括牙龈炎、咽炎、喉炎、鼻咽、干眼病、新旧皮肤创口炎症、痤疮、脚气痒和水泡、阴道炎痒和分泌物、头皮痤疮、饮酒或食辣椒引发的肠道粘膜炎症不适等,抗炎效果分为非常好、一般、基本无效三个等级表示),发现了此种透明质酸片段的多种产品只要含有油脂成分,其皮肤粘膜炎症治疗的效果出乎意料地差(表1)。本发明人进一步分析发现此种透明质酸片段的多种产品只要含有表面活性剂成分或透明质酸片段容易被吸收,其皮肤粘膜炎症的治疗效果就出乎意料地非常好(表1)。
结果出乎意料非常好的产品发表了学术文章三篇如下表2。
表1.不同产品的皮肤粘膜炎症的治疗效果。
表2.结果出乎意料好的B-HA牙膏、B-HA鼻咽喷剂和新鲜皮肤创口喷剂产品发表了学术文章。
其中,图1中的B-HA牙膏是本发明人的第一个被用户反映最有效的产品(客户连续要求生产了三批),有效治疗牙龈和口腔粘膜疾病。图2中的B-HA鼻咽喷剂用户反映治疗鼻咽炎效果明显,市场销售快速增长。图3中的B-HA雾化剂产品,用户反映治疗喉炎和过敏性哮喘效果明显。图4中的B-HA滴眼液产品,用户反映治疗干眼病有明显效果。
表1和表2显示了B-HA鼻咽喷剂(图2)治疗鼻咽喉炎的效果非常好,进一步分析发现,鼻咽喉粘膜对透明质酸片段B-HA容易被吸收,所以效果非常好。图3中的B-HA雾化剂产品效果明显,提示喉和气管粘膜吸收B-HA明显好于皮肤吸收B-HA。图4中的B-HA滴眼液产品有明显效果,提示眼结膜吸收B-HA好于皮肤吸收B-HA。本发明人发现由于B-HA牙膏(图1)抗炎效果出乎意料地非常好,但是牙龈组织对B-HA并不易吸 收,为什么B-HA牙膏抗炎效果出乎意料地好呢?研究这种B-HA牙膏的成分和含量,发明人发现其中含有质量分数2%浓度月桂醇硫酸酯钠是表面活性剂(洗涤剂)。
发明人发现了透明质酸片段产品B-HA霜膏剂(图6)含有油脂(不含表面活性剂),其皮肤粘膜炎症治疗的效果出乎意料地基本无效(表1)。发明人将效果一般的B-HA皮肤喷剂(图5(c))加入16%或以上的甘油,其效果明显下降为基本无效。图8(a)中的B-HA膳食补充剂需每次使用8个胶囊(每个胶囊含130毫克B-HA)或以上才有明显效果,或与现代人类的饮食中含有大量脂肪不无关系。
本发明人还发现B-HA避孕凝胶(图7(a))远比B-HA私护凝胶(图7(b))治疗阴道炎症性瘙痒的效果好(即非常好),两者不同之处是B-HA避孕凝胶含有2%浓度的杀精剂壬苯醇醚9,但壬苯醇醚9同时也是非离子表面活性剂(洗涤剂)。非常有可能壬苯醇醚9增强了生物活性透明质酸的抗炎活性。
因此,基于以上发现,发明人推测除了因使用部位的易于吸收所带来的效果影响外,上述效果很好的产品配伍中应该存在有增强透明质酸片段抗炎活性的成分,而该成分很可能就是表面活性剂,这在发明人后续的对比实验中也得到了验证。
发明人借助原有生产条件制备了含表面活性剂的1%B-HA肥皂样品(图5(a))和洗护二合一凝胶样品(图5(b)),发现添加了表面活性剂的1%B-HA肥皂和洗护二合一凝胶样品的抗皮肤炎症治疗效果远比不含表面活性剂的B-HA喷剂(图5(c))效果好。
如前所述,不含有食品级表面活性剂的B-HA膳食补充剂(图8(a))需较大剂量才能有效治疗肠道粘膜炎症,加入食品级表面活性剂后的饮料样品(图8(b))中,B-HA的有效剂量明显降低4倍以上。
同样地,发明人制备了含有2%表面活性剂壬苯醇醚9的B-HA足喷剂样品(图9),其治疗脚气的效果明显好于没有添加2%表面活性剂壬苯醇醚9的B-HA足喷剂的效果。
结论:
1、本研究结果提示透明质酸B-HA片段的产品或样品中只要含有油脂成分(其中不含表面活性剂),其皮肤粘膜炎症治疗的效果出乎意料地基本无效;
2、本研究结果提示透明质酸B-HA片段的产品或样品中只要含有表面活性剂成分或容易被皮肤粘膜或皮肤创口吸收,其皮肤粘膜炎症的治疗效果就出乎意料地非常好。
实施例3
研究背景:以上实施例2的研究结果提示B-HA有可能通过与表面活性剂合用,增加皮肤粘膜的吸收,但需进一步定量和重复的实验研究来证明B-HA片段制造的产品在含有较高浓度表面活性剂成分时具有治疗多种亚临床和临床皮肤粘膜疾病的效果,并且可以用来生产多种透明质酸片段产品和有更大的市场应用和价值。
目的:定量实验研究来表明B-HA片段制造的产品在含有较高浓度表面活性剂成分时具有治疗多种亚临床和临床皮肤粘膜疾病的效果。
3.1.含有壬苯醇醚9的B-HA创口凝胶和不含壬苯醇醚9的B-HA创口凝胶非新鲜创口对比实验研究。
方法:本实验使用有非新鲜皮肤创口但仍有可见红肿的受试者30例,其中10例为含有0.25%壬苯醇醚9的1%B-HA创口凝胶治疗组,另10例为含有0.05%壬苯醇醚9的1%B-HA创口凝胶治疗组,还有10例为不含有0.25%壬苯醇醚9的1%B-HA创口凝胶组,当场治疗1次,观察指标为治疗后痛症状和红或肿体征改善情况。
结果:表3显示了含有0.25%壬苯醇醚9的1%B-HA创口凝胶、含有0.05%壬苯醇醚9的1%B-HA创口凝胶组和B-HA创口凝胶非新鲜皮肤创口(但仍有可见红肿)对比实验研究结果。
表3.含有0.25%壬苯醇醚9的1%B-HA创口凝胶和1%B-HA创口凝胶非新鲜皮肤创口(但仍有可见红肿)对比实验研究结果。
结论:1.含有0.25%和0.05%壬苯醇醚9的1%B-HA创口凝胶对非新鲜皮肤创口(但仍有可见红肿)痛症状缓解开始时间明显少于不含有0.25%和0.05%壬苯醇醚9的1%B-HA创口凝胶的开始时间;2.含有0.25%和0.05%壬苯醇醚9的1%B-HA创口凝胶开始开始明显改善皮肤创口红或肿体征所需时间明显少于1%B-HA创口凝胶所需时间;
3.2.含有1%壬苯醇醚9的B-HA蚊虫叮咬凝胶和B-HA蚊虫叮咬凝胶治疗蚊虫叮咬的对比实验。
方法:本实验使用皮肤被蚊虫叮咬的受试者20例,其中10例为含有1%壬苯醇醚9的1%B-HA蚊虫叮咬凝胶组,另10例为不含有1%壬苯醇醚 9的1%B-HA蚊虫叮咬凝胶组,两组均含有2%大颗粒水合硅石以促进B-HA吸收,当场治疗1次,观察指标为治疗后痒症状和红或肿体征改善情况。
结果:表4显示了含有1%壬苯醇醚9的1%B-HA蚊虫叮咬凝胶组和1%B-HA蚊虫叮咬凝胶组治疗痒症状和红或肿体征的对比实验研究结果。
表4.含有1%壬苯醇醚9的1%B-HA蚊虫叮咬凝胶组和1%B-HA蚊虫叮咬凝胶组治疗痒症状和红或肿体征的对比实验研究结果。
结论:1.含有1%壬苯醇醚9的1%B-HA蚊虫叮咬凝胶对蚊虫叮咬处的痒症状缓解开始时间明显少于1%B-HA蚊虫叮咬凝胶的开始时间;2.含有1%壬苯醇醚9的1%B-HA蚊虫叮咬凝胶开始明显改善蚊虫叮咬处红或肿体征所需时间明显少于1%B-HA蚊虫叮咬凝胶所需时间;
3.3.含有0.5%壬苯醇醚9的1%B-HA头皮喷剂与1%B-HA头皮喷剂治疗头皮痤疮或脂溢性皮炎和控油对比实验。
方法:本实验使用头皮痤疮或脂溢性皮炎和控油的受试者30例,其中15例为含有0.5%壬苯醇醚91%B-HA头皮喷剂组,另15例为不含有0.5%壬苯醇醚9的1%B-HA头皮喷剂组,每天早晚各治疗一次,观察指标为治疗后痒或痛症状和红或肿体征改善情况。
结果:表5显示了含有1%壬苯醇醚9的1%B-HA头皮喷剂组和1%B-HA头皮喷剂组治疗痒或痛症状和红或肿体征的对比实验研究结果。
表5.含有1%壬苯醇醚9的1%B-HA头皮喷剂组和1%B-HA头皮喷剂组治疗头皮痒症状和头皮痤疮或脂溢性皮炎红色炎症区(体征)的对比实验研究结果。
结论:1.含有1%壬苯醇醚9的1%B-HA头皮喷剂组开始明显缓解头皮痒症状所需的时间(0.5小时)明显少于1%B-HA头皮喷剂组所需的时间(3.0小时);2.含有1%壬苯醇醚9的1%B-HA头皮喷剂组开始改善头皮痤疮或脂溢性皮炎红色炎症区域(体征)的开始时间明(0.5天)显少于1%B-HA头皮喷剂组的开始时间(2.0天);
3.4含有1%壬苯醇醚9的1%B-HA足喷剂和1%B-HA足喷剂治疗脚气对比实验。
方法:本实验使用有轻度脚气的受试者20例,其中10例为含有2.0%壬苯醇醚9的1%B-HA足喷剂组,另10例为不含有2.0%壬苯醇醚9的1%B-HA足喷剂组,每天早晚各治疗一次,观察指标为治疗后脚气部位痒 (症状)的缓解情况和皮肤破损(体征)的改善情况。
结果:表6显示了含有2.0%壬苯醇醚9的1%B-HA足喷剂组和1%B-HA足喷剂组治疗后脚气部位痒(症状)的缓解情况和皮肤破损(体征)的改善情况。
表6.含有2.0%壬苯醇醚9的1%B-HA足喷剂组和1%B-HA足喷剂组治疗后脚气部位痒(症状)的缓解情况和皮肤破损(体征)的改善情况。
结论:1.含有2.0%壬苯醇醚9的1%B-HA足喷剂组有效缓解脚气部位痒症状的所需的时间明显比1%B-HA足喷剂组所需的时间短(0.5比2.0小时);2.含有2.0%壬苯醇醚9的1%B-HA足喷剂组明显改善脚气部位皮肤破损(体征)所发生的时间明显比1%B-HA足喷剂组所需的时间短(治疗后第1天:治疗后第2天)。
3.5.含有表面活性剂的1%B-HA洗护二合一卡波姆凝胶与1%B-HA卡波姆凝胶治疗老年皮肤瘙痒对比研究实验。
方法:本实验使用皮肤瘙痒的老年受试者20例,其中10例为同时含有起泡的2%月桂醇硫酸酯钠和不起泡的2%壬苯醇醚9的1%B-HA洗护二合一卡波姆凝胶组,另10例为1%B-HA卡波姆凝胶组,每天早晚各治疗1次,观察指标为治疗后瘙痒症状和抓瘙伤引发的皮肤破损体征改善情况。1%
结果:表7显示了同时含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的1%B-HA洗护二合一凝卡波姆胶组和1%B-HA卡波姆凝胶组治疗老年皮肤瘙痒症状和体征的对比实验研究结果。
表7.同时含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的1%B-HA洗护二合一卡波姆凝胶组和1%B-HA卡波姆凝胶组治疗老年皮肤瘙痒症状和体征的对比实验研究结果。
结论:1.同时含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的1%B-HA洗护二合一卡波姆凝胶对老年皮肤瘙痒症状缓解程度好于1%B-HA卡波姆凝 胶组的缓解程度(瘙痒完全缓解:瘙痒大部分缓解);2.同时含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的1%B-HA洗护二合一卡波姆凝胶对老年皮肤瘙痒抓瘙伤引发的皮肤破损体征改善程度好于1%B-HA卡波姆凝胶组的改善程度(完全消失:大部分消失);
3.6含有74%表面活性剂皂基和13%甘油的1%B-HA肥皂与含有13%甘油的1%B-HA凝胶治疗面部痤疮和脂溢性皮炎对比研究实验。
方法:本实验使用面部痤疮和脂溢性皮炎的受试者20例,其中10例为含有74%表面活性剂皂基和13%甘油的1%B-HA肥皂组,另10例为含有13%甘油的1%B-HA卡波姆凝胶组,每天早晚各治疗1次,共治疗7天,观察指标为治疗后面部痤疮和脂溢性皮炎引发的皮肤不适症状和红肿热体征的改善情况。
结果:表8显示了含有74%表面活性剂皂基和13%甘油的1%B-HA肥皂组和含有13%甘油的1%B-HA卡波姆凝胶组组治疗7天后面部痤疮和脂溢性皮炎引发的皮肤不适症状和红肿热体征的改善情况。
表8.含有74%表面活性剂皂基和13%甘油的1%B-HA肥皂组和含有13%甘油的1%B-HA卡波姆凝胶组治疗7天后面部痤疮和脂溢性皮炎引发的皮肤不适症状和红肿热体征的改善情况。
结论:1.在含有13%甘油的1%B-HA卡波姆凝胶中,13%甘油使1%B-HA的皮肤抗炎效果基本消失;2.含有74%表面活性剂皂基和13%甘油的1%B-HA肥皂明显比含有13%甘油的1%B-HA卡波姆凝胶组治疗面部痤疮和脂溢性皮炎引发的皮肤不适症状和红肿热体征效果好;3.B-HA在高浓度皂基情况下和肥皂制造过程中没有失去抗炎活性。
3.7.含有表面活性剂的0.6%B-HA和3%蒙脱石粉洗护二合一卡波姆凝胶与0.6%B-HA和3%蒙脱石粉卡波姆凝胶治疗老年皮肤瘙痒对比研究实验。
方法:本实验使用皮肤瘙痒的老年受试者14例,其中7例为同时含有起泡的2%月桂醇硫酸酯钠和不起泡的2%壬苯醇醚9的0.6%B-HA和3%蒙脱石粉洗护二合一卡波姆凝胶组,另7例为0.6%B-HA和3%蒙脱石粉卡波姆凝胶组,每天早晚各治疗1次,观察指标为治疗后瘙痒症状和抓瘙伤引发的皮肤破损体征改善情况。
结果:表9显示了同时含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的0.6%B-HA洗护二合一凝卡波姆胶组和0.6%B-HA卡波姆凝胶组治疗老年皮肤瘙痒症状和体征的对比实验研究结果。
表9.同时含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的0.6%B-HA和3%蒙脱石粉洗护二合一卡波姆凝胶组和0.6%B-HA和3%蒙脱石粉卡波姆凝胶组治疗老年皮肤瘙痒症状和体征的对比实验研究结果。
结论:1.同时含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的0.6%B-HA和3%蒙脱石粉洗护二合一卡波姆凝胶对老年皮肤瘙痒症状缓解程度好于0.6%B-HA和3%蒙脱石粉卡波姆凝胶组的缓解程度(瘙痒完全缓解:瘙痒大部分缓解);2.含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的0.6%B-HA和3%蒙脱石粉洗护二合一卡波姆凝胶对老年皮肤瘙痒抓瘙伤引发的皮肤破损体征改善程度好于0.6%B-HA和3%蒙脱石粉卡波姆凝胶组的改善程度(完全消失:大部分消失);
3.8含有69%表面活性剂皂基和13%甘油的0.6%B-HA和含有13%甘油的0.6%B-HA和3%蒙脱石粉卡波姆凝胶治疗面部痤疮和脂溢性皮炎对比研究实验。
方法:本实验使用面部痤疮和脂溢性皮炎的受试者14例,其中7例为含有69%表面活性剂皂基和13%甘油的0.6%B-HA和3%蒙脱石粉肥皂组,另7例为含有13%甘油的0.6%B-HA和3%蒙脱石粉卡波姆凝胶组,每天早晚各治疗1次,共治疗7天,观察指标为治疗后面部痤疮和脂溢性皮炎引 发的皮肤不适症状和红肿热体征的改善情况。
结果:表10显示了含有69%表面活性剂皂基和13%甘油的0.6%B-HA和3%蒙脱石粉肥皂组和13%甘油的0.6%B-HA和3%蒙脱石粉卡波姆凝胶组治疗7天后面部痤疮和脂溢性皮炎引发的皮肤不适症状和红肿热体征的改善情况。
表10.含有69%表面活性剂皂基和13%甘油的0.6%B-HA和3%蒙脱石粉肥皂组和含有13%甘油的0.6%B-HA和3%蒙脱石粉卡波姆凝胶组治疗7天后面部痤疮和脂溢性皮炎引发的皮肤不适症状和红肿热体征的改善情况。
结论:1.在含有13%甘油的0.6%B-HA和3%蒙脱石粉卡波姆凝胶中,13%甘油使0.6%B-HA和3%蒙脱石粉的皮肤抗炎效果基本消失;2.含有69%表面活性剂皂基和13%甘油的0.6%B-HA和3%蒙脱石粉肥皂明显比含有13%甘油的0.6%B-HA和3%蒙脱石粉的卡波姆凝胶组治疗面部痤疮和脂溢性皮炎引发的皮肤不适症状和红肿热体征效果好;3.0.6%B-HA在高浓度 皂基情况下和肥皂制造过程中没有失去抗炎活性。
3.9含有69%表面活性剂皂基和13%甘油的0.2%B-HA和3%蒙脱石粉肥皂与含有13%甘油的0.2%B-HA和3%蒙脱石粉卡波姆凝胶治疗面部痤疮和脂溢性皮炎对比研究实验。
方法:本实验使用面部痤疮和脂溢性皮炎的受试者14例,其中7例为含有69%表面活性剂皂基和13%甘油的0.2%B-HA和3%蒙脱石粉肥皂组,另7例为含有13%甘油的0.2%B-HA和3%蒙脱石粉卡波姆凝胶组,每天早晚各治疗1次,共治疗7天,观察指标为治疗后面部痤疮和脂溢性皮炎引发的皮肤不适症状和红肿热体征的改善情况。
结果:表11显示了含有69%表面活性剂皂基和13%甘油的0.2%B-HA和3%蒙脱石粉肥皂组和含有13%甘油的0.2%B-HA和3%蒙脱石粉卡波姆凝胶组治疗7天后面部痤疮和脂溢性皮炎引发的皮肤不适症状和红肿热体征的改善情况。
表11.含有69%表面活性剂皂基和13%甘油的0.2%B-HA和3%蒙脱石粉肥皂组和含有13%甘油的0.2%B-HA和3%蒙脱石粉卡波姆凝胶组治疗7天后面部痤疮和脂溢性皮炎引发的皮肤不适症状和红肿热体征的改善情况。
结论:1.在含有13%甘油的0.2%B-HA和3%蒙脱石粉卡波姆凝胶中,13%甘油使0.2%B-HA的皮肤抗炎效果基本消失;2.含有69%表面活性剂皂基和13%甘油的0.2%B-HA和3%蒙脱石粉肥皂明显比含有13%甘油的0.2%B-HA和3%蒙脱石粉卡波姆凝胶组治疗面部痤疮和脂溢性皮炎引发的皮肤不适症状和红肿热体征效果好;3.0.2%B-HA在高浓度皂基情况下和肥皂制造过程中没有失去抗炎活性。
3.10.含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的1%B-HA刷牙凝胶和含有2%月桂醇硫酸酯钠的1%B-HA刷牙凝胶治疗牙龈炎的对比实验研究。
方法:本实验使用有牙龈炎的受试者20例,其中10例为含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的1%B-HA刷牙凝胶组,另10例为含有2%月桂醇硫酸酯钠的1%B-HA刷牙凝胶组,两组均含有2%大颗粒水合硅石以促进B-HA吸收,每天早晚各治疗1次,共7天,观察指标为治疗后牙龈痒症状和牙龈红肿体征改善情况。
结果:表12显示了含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的1%B-HA刷牙凝胶和含有2%月桂醇硫酸酯钠的1%B-HA刷牙凝胶治疗牙龈痒症状和牙龈红肿体征改善情况。
表12.含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的1%B-HA刷牙凝胶和含有2%月桂醇硫酸酯钠的1%B-HA刷牙凝胶治疗牙龈痒症状和牙龈红肿体征改善情况。
结论:1.含有2%月桂醇硫酸酯钠和2%壬苯醇醚9的1%B-HA刷牙凝胶比含有2%月桂醇硫酸酯钠的1%B-HA刷牙凝胶多含表面活性剂2%壬苯醇醚9,其缓解牙龈痒症状和改善牙龈红肿体征效果比含有2%月桂醇硫酸酯钠的1%B-HA刷牙凝胶好,表明多在B-HA中添加表面活性剂2%壬苯醇醚9有促进B-HA抗炎效果的作用;2.3.B-HA在高浓度表面活性剂情况下没有失去抗炎活性。
3.11.含有非起泡食品级表面活性剂的3%B-HA乳酸饮料和3%B-HA乳酸饮料治疗辣椒或喝酒引发的肠道粘膜炎症的对比实验研究。
方法1:本实验使用患有轻度炎症性肠病(无脓血便,大便次数3次/天,轻度腹部不适)的喜爱辣椒饮食的受试者14例,其中7例为含有食品级表面活性剂2%蔗糖脂肪酸酯和0.15%吐温80(又称聚山梨酯或Polysorbate)的1%B-HA乳酸饮料组,另7例为3%B-HA乳酸饮料组,食用辣椒饮食后使用含有食品级表面活性剂2%蔗糖脂肪酸酯和0.15%吐温80的1%B-HA乳酸饮料或3%B-HA乳酸饮料后再食用辣椒饮食,观察指标为大便次数和轻度腹部不适的加重和改善情况。
结果1:表13显示了含有食品级表面活性剂2%蔗糖脂肪酸酯和0.15%吐温80的3%B-HA乳酸饮料组和3%B-HA乳酸饮料组对食用辣椒饮食和两组不同治疗组的对比实验研究结果。
表13.含有食品级表面活性剂2%蔗糖脂肪酸酯和0.15%吐温80的3%B-HA乳酸饮料组和1%B-HA乳酸饮料组的对比治疗实验研究结果。注:两组均食用辣椒饮食,但治疗不同。
结论1:含有食品级表面活性剂2%蔗糖脂肪酸酯和0.15%吐温80的3%B-HA乳酸饮料组有效治疗了轻度炎症性肠病受试者食用辣椒饮食后引起的大便次数增加、轻度腹部不适的加重和少许血便。
方法2:肠道粘膜有炎症会引起肠道粘膜通透性增加,饮酒后酒精吸收快,容易醉酒。B-HA已知可以减少肠道粘膜通透性和减少醉酒发生。本实验使用饮酒容易醉的受试者10例,其中5例为含有食品级表面活性剂2%蔗糖脂肪酸酯和0.15%吐温80的6%B-HA乳酸饮料组,另5例为6%B-HA乳酸饮料组,饮用已知醉酒的酒量后,使用含有食品级表面活性剂2%蔗糖脂肪酸酯和0.15%吐温80的6%B-HA乳酸饮料或1%B-HA乳酸饮料治疗,两组饮酒前各饮用不同饮料100毫升预防醉酒,观察指标为醉酒情况,即 醉酒情况自我判断标准为受试者自己和以前醉酒时的头晕头痛无力类似;醉酒情况他人判断标准为旁观者判断饮酒人脸红、坐立不稳和说话方式改变类似醉酒状态。
结果2:表14显示了含有食品级表面活性剂2%蔗糖脂肪酸酯和0.15%吐温80的6%B-HA乳酸饮料组和6%B-HA乳酸饮料组对饮用已知醉酒的酒量的对比实验研究结果。
表14.含有食品级表面活性剂2%蔗糖脂肪酸酯和0.15%吐温80的6%B-HA乳酸饮料组和6%B-HA乳酸饮料组对饮用已知醉酒的酒量的对比实验研究结果。
结论2:含有食品级表面活性剂2%蔗糖脂肪酸酯和0.15%吐温80的6%B-HA乳酸饮料组有效预防了饮用已知醉酒的酒量后的醉酒情况发生,即控制了肠道粘膜炎症水平和减少了饮酒引起肠道粘膜通透性增加。
实施例4
研究背景:58岁男性混合痔患者1名,经常有内裤粪便黄色污染斑点、肛门瘙痒不适、肛门外观检查不呈典型菊花状和有小外痔突出。外出期间 因大便干燥,大便表面有少许鲜血,大便疼痛,有痔核脱出,不敢正常入食和大便。去当地医院就诊,建议手术治疗。试用1%B-HA女性阴道私护凝胶产品,0.5小时内开始止痛,当天脱出痔核开始回缩,连续3天后患者内裤粪便黄色污染斑点明显减少或基本消失、肛门瘙痒不适明显减轻或基本消失、肛门外观检查小外痔突出明显减轻或基本消失。以上结果提示1%B-HA凝胶有效治疗痔疮,需大样本患者进一步临床研究。
目的:研究不含有和含有表面活性剂壬苯醇醚9的1%B-HA私护凝胶治疗痔疮的效果。
方法:制造含有0.5%和2%表面活性剂壬苯醇醚9的1%B-HA男女两用私护凝胶和不含表面活性剂壬苯醇醚9的1%B-HA男女两用私护凝胶,5毫升每只。
混合痔患者60名,男34名,女26名,年龄28-68岁,随机分成3组,每组20名,分别为空白组(不含表面活性剂壬苯醇醚9的1%B-HA男女两用私护凝胶)、实验组1(含有0.5%表面活性剂壬苯醇醚9的1%B-HA男女两用私护凝胶)和实验组2(含有2%表面活性剂壬苯醇醚9的1%B-HA男女两用私护凝胶)。
将制备好的不同男女两用私护凝胶排便后插入肛门1-5毫米,每次注入5毫升凝胶,一天早晚共2次,连续治疗10天。
结果:表15使用大样本患者研究了含有和不含有表面活性剂壬苯醇醚9的男女两用私护凝胶治疗痔疮的效果。
表15.含有和不含有表面活性剂壬苯醇醚9的男女两用私护凝胶治疗痔疮的效果比较。
结论:表15结果经统计学综合处理后,表明:(1)1%B-HA男女两用私护凝胶出乎意料地有效治疗痔疮;(2)含有表面活性剂壬苯醇醚9的1%B-HA男女两用私护凝胶治疗痔疮效果更好。
以上所述,仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,本领域技术人员利用上述揭示的技术内容做出些许简单修改、等同变化或修饰,均落在本发明的保护范围内。
Claims (10)
- 一种具有强抗炎活性的组合物,其特征在于,由具有抗炎活性的透明质酸片段与用于增强该透明质酸片段的抗炎作用的表面活性剂组成。
- 根据权利要求1所述的具有强抗炎活性的组合物,其特征在于,所述的具有抗炎活性的透明质酸片段是采用CHO细胞生产的有糖化的重组人透明质酸酶PH20切割大分子透明质酸获得的分子量为10KD~70KD的透明质酸片段。
- 根据权利要求1所述的具有强抗炎活性的组合物,其特征在于,所述的表面活性剂为壬苯醇醚9、月桂醇硫酸酯钠、皂基、蔗糖脂肪酸酯或吐温80中的一种或多种。
- 根据权利要求1所述的具有强抗炎活性的组合物,其特征在于,所述的表面活性剂与具有抗炎活性的透明质酸片段的重量比为0.05~85:0.2~6.0。
- 表面活性剂在增强具有抗炎活性的透明质酸片段的抗炎作用上的应用。
- 表面活性剂与具有抗炎活性的透明质酸片段的组合物作为活性成分在制备食品、药品、临床特殊膳食、日用品、卫生产品、化妆品和医疗器械中的应用。
- 表面活性剂与具有抗炎活性的透明质酸片段的组合物作为活性成分在制备用于治疗痔疮的药物中的应用。
- 一种用于治疗痔疮的药物组合物,其特征在于,包括具有抗炎活性的透明质酸片段与用于增强该透明质酸片段的抗炎作用的壬苯醇醚9。
- 根据权利要求8所述的用于治疗痔疮的药物组合物,其特征在于, 包括质量分数1%的具有抗炎活性的透明质酸片段与质量分数0.5%~2%的壬苯醇醚9。
- 根据权利要求8所述的用于治疗痔疮的药物组合物,其特征在于,所述的药物组合物为凝胶制剂。
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