Nitric oxide highly dispersible W / O cream

Abstract

The nitric oxide high-dispersity W / O emulsifiable paste is composed of an emulsifiable paste substrate, an emulsifier and a nitric oxide gas solution, the nitric oxide gas solution is uniformly dispersed in the emulsifiable paste substrate, and the volume ratio of the emulsifiable paste substrate to the emulsifier to the nitric oxide gas solution is 4: 1: 1-1: 1: 4. The emulsifiable paste substrate is composed of one or more of plant-derived vegetable oil or hydrogenated vegetable oil, saturated hydrocarbon, ester chemically synthesized or semi-synthesized by higher fatty acid and higher fatty alcohol and a mixture thereof; the emulsifier is composed of one or more of soap, higher fatty alcohol, polyol ester, fatty alcohol sulfate or sodium and polyoxyethylene ether derivatives, and the nitric oxide gas solution is formed by dispersing nitric oxide gas in a water-free and oxygen-free polyol solution which is in a liquid state at the temperature of 25 DEG C. The nitric oxide high-dispersity W / O cream overcomes the problems that nitric oxide molecules are poor in stability and prone to oxidation failure and the like, and is used for achieving the treatment effect of nitric oxide on body diseases, especially the treatment effect of nitric oxide on skin and mucosa inflammation.

Description

Technical Field

[0001] The invention relates to a nitric oxide pharmaceutical preparation, in particular to a nitric oxide highly dispersible W / O cream. Background Art

[0002] Studies have found that nitric oxide (NO) has a good therapeutic effect on many diseases of the body, especially inflammation of the skin and mucosa. Through animal experiments on inflammation models, it was found that in the early stage of inflammation, NO mainly plays an anti-inflammatory role, including: maintaining the integrity of microcirculation, relaxing vascular smooth muscle, increasing mucosal blood flow and inhibiting the adhesion and accumulation of platelets and leukocytes on the surface of endothelial cells, preventing thrombosis, inhibiting myeloperoxidase activity, protecting epithelial barriers and promoting epithelial tissue repair. However, in the late stage of inflammation, accompanied by the production of superoxide anion oxygen, NO can synthesize with anion oxygen to produce peroxynitrite, and its biological oxidizing property can cause damage to normal tissues.

[0003] It has been confirmed that NO can play an important role in the administration and treatment of body diseases. However, the methods of administering NO that have been reported are mostly the use of nitric oxide donor compounds. NO donor compounds are divided into two categories: non-enzymatic and enzymatic. Most of the non-enzymatic NO donor compounds come from nitro compounds, including nitroprusside, organic or inorganic nitrites and nitrates, nitrosamines, nitrogen mustard, hydrazine, etc., with small doses and large toxic side effects. Enzymatic NO donor compounds (such as arginine) need to be decomposed by biological enzymes in the body to produce NO molecules. Because the above NO donor compounds have to undergo degradation to produce NO molecules, they cannot take effect directly and promptly.

[0004] The NO molecule itself is in gaseous form and is slightly soluble in water. Its solubility in water at 20°C is only 5.6×10 -3 g / L (equivalent to 0.186μmol / L), but NO has very poor stability. It is very easy to generate brown-red NO2 when it encounters oxygen, and generates nitrous acid after dissolving in water, which not only loses the pharmacological effect of NO, but also produces serious toxic side effects. Therefore, how to overcome the problems of poor stability of NO gas molecules and easy oxidation failure, and prepare it into a drug delivery system for skin and mucous membranes, is the bottleneck restricting NO from exerting its pharmacological effect.

[0005] Creams refer to uniform semisolid preparations formed by dissolving or dispersing drugs in an emulsion-type matrix, which are divided into O / W or W / O creams. Creams are suitable for subacute, chronic, non-exudative skin lesions and pruritus, and are not suitable for erosion, ulcers, blisters and pustular diseases. Compared with O / W creams, W / O creams have better stability, and the water is in the internal phase, which is not easy to deteriorate and evaporate. Therefore, various physical and chemical parameters are good, and they are commonly used in skin and mucosal drug delivery applications. Although W / O creams have many advantages in skin and mucosal drug delivery, NO is a gas, and there is no research report that NO gas can be efficiently carried in W / O creams. Therefore, preparing a safe and stable W / O cream that efficiently carries NO gas is a limiting bottleneck for NO in the treatment of body diseases (especially the treatment of skin and mucosal inflammation). Summary of the invention

[0006] The purpose of the present invention is to overcome the shortcomings of the prior art - the lack of a safe, stable and efficient W / O cream for carrying nitric oxide (NO) gas, to provide a safe, stable and highly dispersible W / O cream for NO gas, to break through the restrictive bottleneck of NO in the treatment of body diseases (especially the treatment of skin and mucosal inflammation), and to meet the requirements of safety, effectiveness, convenience and economy of clinical treatment.

[0007] The inventors found that NO molecules have poor stability and are easily oxidized. When they encounter oxygen, they easily generate brown-red NO2, which generates nitrous acid after dissolving in water, which not only loses the pharmacological effects of NO, but also produces serious toxic side effects. To this end, the inventors have prepared a highly dispersed W / O cream with stable NO gas after a large number of experiments, achieving the purpose of safety, effectiveness, convenience and economy, breaking through the restrictive bottleneck of NO in the treatment of body diseases (especially the treatment of skin and mucosal inflammation), and giving full play to the NO therapeutic effect of body diseases, especially the NO therapeutic effect of skin and mucosal inflammation.

[0008] The highly dispersible nitric oxide W / O cream of the present invention is composed of a cream base, an emulsifier and a NO gas solution, wherein the NO gas solution is uniformly dispersed in the cream base;

[0009] The volume ratio of the above-mentioned cream base, emulsifier and NO gas solution is 4:1:1 to 1:1:4;

[0010] The above-mentioned cream base is composed of one or more combinations of vegetable oil or hydrogenated vegetable oil of plant origin, saturated hydrocarbons, chemically synthesized or semi-synthetic esters of higher fatty acids and higher fatty alcohols, and mixtures thereof;

[0011] The above-mentioned emulsifier is one or a combination of soaps, higher fatty alcohols, polyol esters, fatty alcohol sulfates or sodiums, and polyoxyethylene ether derivatives;

[0012] The above-mentioned NO gas solution is formed by dispersing NO gas in a polyol that is liquid at 25° C. without water or oxygen;

[0013] The W / O cream is used to achieve the therapeutic effect of NO on body diseases, especially the therapeutic effect of NO on skin and mucosal inflammation;

[0014] The above-mentioned NO gas solution is formed by saturating NO gas in a polyol solution without water or oxygen;

[0015] The volume ratio of the above-mentioned cream base, emulsifier and nitric oxide gas solution is 2:1:1 to 1:1:2;

[0016] The volume ratio of the above-mentioned cream base, emulsifier and nitric oxide gas solution is 1:1:1;

[0017] The saturated hydrocarbon is one or a combination of vaseline, solid paraffin, and liquid paraffin;

[0018] The chemically synthesized or semi-synthesized esters of higher fatty acids and higher fatty alcohols and mixtures thereof are one or a combination of stearic acid glyceryl ester, lanolin, beeswax and spermaceti;

[0019] The synthetic / semi-synthetic oils are one or a combination of squalane, lanolin derivatives, and silicones;

[0020] The above-mentioned polyol which is liquid at 25°C is one or a combination of polyethylene glycol 200-800, glycerol, and propylene glycol;

[0021] A method for preparing the above-mentioned NO highly dispersible W / O cream comprises the following steps:

[0022] a. Take 100 ml of polyol that is liquid at 25°C and heat it to 100°C to remove oxygen. Transfer it into a stoppered glass bottle. Saturate the inner space of the glass bottle with nitrogen. Cool it to 25°C and add NO gas to replace the nitrogen to form a NO gas solution.

[0023] b. Take the cream base and emulsifier in the prescribed volume ratio, first heat the cream base to melt, then add the emulsifier to the cream base and mix well, add the NO gas solution prepared in step a, mix well to form a NO highly dispersed W / O cream, and store it in a cool and sealed place.

[0024] One or a combination of antioxidants, antibacterial agents and pH regulators commonly used in pharmacy are added to the above-mentioned NO high-dispersibility W / O cream.

[0025] The NO highly dispersible W / O cream of the present invention has the following advantages: 1. converting gas molecules into semisolid preparations not only enhances the stability of NO but also facilitates application in local pharmaceutical treatment; 2. highly dispersing NO in a water-free W / O cream matrix to ensure compatibility with tissue fluids; 3. not using any nitric oxide donor compound, thus avoiding the adverse reactions and toxic side effects of NO donor compounds on body tissues; 4. the W / O cream is easy to prepare and easy to use, which is conducive to achieving the purpose of rapid and long-term treatment of local diseases (especially skin and mucosal inflammation). DETAILED DESCRIPTION

[0026] The specific embodiments of the present invention will be described in detail below. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be considered isolated, and they can be combined with each other to achieve better technical effects.

[0027] Example 1 Preparation of highly dispersible nitric oxide cream

[0028] According to the component ratios in Table 1, the cream sample was prepared using the following steps:

[0029] a. Take 100 ml of polyol that is liquid at 25°C, heat it to 100°C to remove oxygen, transfer it into a stoppered glass bottle, saturate the inner space of the glass bottle with nitrogen, cool it to 25°C, add NO gas to replace the nitrogen (saturated NO gas, or a mixture of NO gas and nitrogen in a specific ratio) to form a NO gas solution;

[0030] b. Take the cream base and emulsifier in the prescribed volume ratio, first heat the cream base to melt, then add the emulsifier to the cream base and mix well, add the NO gas solution prepared in step a, mix well, and seal to form a NO highly dispersed W / O cream.

[0031] The cream of the control group was prepared with reference to the experimental group according to the component ratios in Table 1. Each experimental group was configured according to the components and ratios within the protection scope of the claims of the present application, while each control group had a component replaced by another component or a component value exceeding the protection scope of the claims of the present application.

[0032] Table 1 Sample preparation of experimental group and control group

[0033]

[0034] Note: NO gas is nitric oxide gas; NO saturation state 100% means that the NO gas in the NO gas solution is in a saturated state at 25°C, that is, the volume ratio of NO is 100%; NO saturation state 60%-90% means that the NO gas and nitrogen in the NO gas solution are in a mixed state at 25°C, and the volume ratio of NO is 60%-90%; * represents that the component or value of this item is significantly different from that of the experimental group; / represents that the component of this item is 0; Control groups 1 and 2 are O / W creams.

[0035] Example 2 Application effect of highly dispersible nitric oxide cream

[0036] (1) Establishment of model animals

[0037] Reference: Establish a mouse auricle swelling model: Use phorbol ester (TPA) induction method to prepare mouse auricle swelling model: Take Kunming mice, male, weighing 18-22g, apply TPA acetone solution on the inside and outside of the ears, with a TPA dose of 2.5μg for each ear, and make a mouse auricle swelling model after 6 hours.

[0038] (2) Evaluation of the therapeutic effects of each group of preparations on model animals

[0039] The experiments were carried out according to the groups designed in Table 1, with 5 animals in each group. The preparations in each group were injected at 60 mg / cm2 at the swollen part of the auricle of the model animals. 2 The dosage was applied, and after administration, the same professional physician was asked to evaluate the disappearance of ear swelling, the degree of skin color recovery and the condition of the rat in a double-blind manner using a percentage system. A comprehensive score of the treatment effect was given based on the overall recovery of the rat. The higher the score, the better the treatment effect.

[0040] Experimental results: The therapeutic effects of the above preparations on local inflammation and swelling are shown in Table 2.

[0041] Table 2 Evaluation of the therapeutic effects of each group of preparations for local inflammation and swelling

[0042] Group Subsidence of inflammatory swelling Skin color restoration Rat status Overall Rating Experimental Group 1 73 67 70 70 Experimental Group 2 68 73 70 70 Experimental Group 3 80 81 82 81 Experimental Group 4 87 89 93 90 Experimental Group 5 87 89 92 89 Experimental Group 6 81 81 82 81 Experimental Group 7 69 71 74 71 Experimental Group 8 67 66 67 67 Experimental Group 9 57 53 55 55 Experimental Group 10 51 50 52 51 Control group 1 18 19 21 19 Control group 2 16 18 21 18 Control group 3 -6 -7 -10 -8 Control group 4 -5 -7 -9 -7 Control group 5 23 27 30 27 Control group 6 31 33 34 33 Control group 7 12 15 16 14 Control group 8 14 17 17 16 Control group 9 9 11 12 11

[0043] As can be seen from the experimental results in Table 2, the W / O cream in the experimental group has a good therapeutic effect on local inflammation and swelling, especially in experimental groups 4 and 5, where the inflammation and swelling subsided quickly, the skin color returned to normal, and the rats were in good condition without restlessness. Compared with the experimental group, the control group had a significantly poorer therapeutic effect on local inflammation and swelling, especially in control groups 3 and 4, where the inflammation and swelling not only did not subside, but stimulated the swelling to increase, the skin color could not return to normal, and the rats were restless and in a bad state. Analysis showed that the preparations in control groups 3 and 4 contained water, so NO easily generated nitrous acid, resulting in serious side effects.

[0044] The experimental results in Table 2 prove that any component and condition in the technical protection scheme of the present invention are mutually synergistic and indispensable, and the lack of any component and condition in the technical protection scheme of the present invention will have a significant impact on the therapeutic effect of nitric oxide on body diseases. The highly dispersible nitric oxide W / O cream of the present invention has good application prospects.

[0045] The above detailed description is a specific description of a feasible embodiment of the invention, and the embodiment is not intended to limit the scope of the invention. Any equivalent implementation or change that does not deviate from the invention should be included in the scope of the invention. In addition, those skilled in the art can also make various modifications, additions and substitutions in other forms and details within the scope and spirit disclosed in the claims of the invention. Of course, these various modifications, additions and substitutions made according to the spirit of the invention should be included in the scope of the invention.

Claims

1. A highly dispersible W / O cream of nitric oxide, characterized in that: the W / O cream is composed of a cream base, an emulsifier and a nitric oxide gas solution, and the nitric oxide gas solution is uniformly dispersed in the cream base; the volume ratio of the cream base, the emulsifier and the nitric oxide gas solution is 4:1:1 to 1:1:4; the cream base is composed of one or more combinations of plant oils or hydrogenated plant oils of plant origin, saturated hydrocarbons, chemically synthesized or semi-synthetic esters of higher fatty acids and higher fatty alcohols and mixtures thereof; the emulsifier is one or more combinations of soaps, higher fatty alcohols, polyol esters, fatty alcohol sulfates or sodiums, and polyoxyethylene ether derivatives; the nitric oxide gas solution is formed by dispersing nitric oxide gas in a polyol that is liquid at 25°C without water or oxygen; the W / O cream is used to achieve the therapeutic effect of nitric oxide on body diseases, especially the therapeutic effect of nitric oxide on skin and mucosal inflammation.

2. The highly dispersible W / O cream of nitric oxide according to claim 1, characterized in that: The nitric oxide gas solution is formed by saturating nitric oxide gas in a polyol solution without water or oxygen.

3. The highly dispersible W / O cream of nitric oxide according to claim 1, characterized in that: The volume ratio of the cream base, the emulsifier and the nitric oxide gas solution is 2:1:1 to 1:1:

2.

4. The highly dispersible W / O cream of nitric oxide according to claim 1, characterized in that: The volume ratio of the cream base, the emulsifier and the nitric oxide gas solution is 1:1:

1.

5. The highly dispersible W / O cream of nitric oxide according to claim 1, characterized in that: The saturated hydrocarbon is one or a combination of vaseline, solid paraffin and liquid paraffin.

6. The highly dispersible W / O cream of nitric oxide according to claim 1, characterized in that: The chemically synthesized or semi-synthesized esters of higher fatty acids and higher fatty alcohols and their mixtures are one or a combination of stearic acid glyceryl ester, lanolin, beeswax and spermaceti.

7. The highly dispersible W / O cream of nitric oxide according to claim 1, characterized in that: The synthetic or semi-synthetic oil is one or a combination of squalane, lanolin derivatives and silicone.

8. The highly dispersible W / O cream of nitric oxide according to claim 1, characterized in that: The polyol which is liquid at 25° C. is one or a combination of polyethylene glycol 200-800, glycerol and propylene glycol.

9. A method for preparing the highly dispersible W / O cream of nitric oxide according to claim 1, characterized in that: The steps include: a. Take 100 ml of polyol that is liquid at 25°C, heat it to 100°C to remove oxygen, transfer it into a stoppered glass bottle, saturate the inner space of the glass bottle with nitrogen, cool it to 25°C, add nitric oxide gas to replace the nitrogen, and form a nitric oxide gas solution; b. Take the cream base and emulsifier in the prescribed volume ratio, first heat the cream base to melt, then add the emulsifier to the cream base and mix well, add the nitric oxide gas solution prepared in step a, mix well to form a highly dispersed nitric oxide W / O cream, and store it in a cool and sealed place.

10. A highly dispersible W / O cream of nitric oxide according to claim 9, characterized in that: One or a combination of antioxidants, antibacterial agents and pH regulators commonly used in pharmacy are added to the highly dispersible W / O nitric oxide cream.

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