Nitric oxide high-dispersity hydrophilic ointment

Abstract

The nitric oxide high-dispersity hydrophilic ointment is composed of an ointment substrate and a nitric oxide gas solution, the nitric oxide gas solution is uniformly dispersed in the ointment substrate, and the volume ratio of the ointment substrate to the nitric oxide gas solution is 3: 1-1: 3. The ointment substrate is composed of one or more of gelatin, collagen, poloxamer and a poloxamer derivative, chitosan and a chitosan derivative, alginic acid and an alginic acid derivative, povidone, polyethylene glycol which is in a solid state at 25 DEG C, and alkane alcohol with the carbon number of 16 or more; the nitric oxide gas solution is formed by dispersing nitric oxide gas in water-free and oxygen-free alkane alcohol which is in a liquid state at 25 DEG C. The nitric oxide high-dispersity hydrophilic ointment overcomes the problems that nitric oxide molecules are poor in stability and prone to oxidation failure and the like, and the treatment effect of nitric oxide on body diseases, especially the treatment effect of nitric oxide on skin and mucosa inflammations, is fully exerted.

Description

Technical Field

[0001] The invention relates to a nitric oxide pharmaceutical preparation, in particular to a nitric oxide highly dispersible hydrophilic ointment. 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] Ointment refers to a uniform semisolid topical preparation with a certain consistency made by mixing a drug with an oily or water-soluble matrix. Hydrophilic ointment is a washable ointment matrix, which is commonly used for drug administration to skin and mucous membranes, but the moisture in such a matrix evaporates easily and becomes moldy easily, so it is necessary to add a moisturizer and a preservative. Although hydrophilic ointment has a variety of advantages in terms of skin and mucous membrane administration, NO is a gas, and there is no research report that NO gas can be efficiently carried in a hydrophilic ointment. Therefore, the preparation of a safe and stable hydrophilic ointment that efficiently carries NO gas is a limiting bottleneck for the use of NO in the treatment of body diseases (especially the treatment of skin and mucous membrane 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 hydrophilic ointment for carrying nitric oxide (NO) gas, to provide a safe, stable and highly dispersible hydrophilic ointment 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 have 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 dispersible hydrophilic ointment 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 NO highly dispersible hydrophilic ointment of the present invention is composed of an ointment base and an NO gas solution, wherein the NO gas solution is uniformly dispersed in the ointment base;

[0009] The volume ratio of the above-mentioned ointment base to the NO gas solution is 3:1 to 1:3;

[0010] The above-mentioned ointment base is composed of one or a combination of gelatin, collagen, poloxamer and poloxamer derivatives, chitosan and chitosan derivatives, alginic acid and alginic acid derivatives, povidone, polyethylene glycol that is solid at 25°C, and alkane alcohols with 16 or more carbon atoms;

[0011] The above-mentioned NO gas solution is formed by dispersing NO gas in an alkane alcohol which is liquid at 25°C and is free of water and oxygen;

[0012] The above-mentioned hydrophilic ointment is used to achieve the therapeutic effect of NO on body diseases, especially the therapeutic effect of NO on skin and mucosal inflammation;

[0013] The above-mentioned NO gas solution is formed by saturating NO gas in an alkane alcohol solution without water or oxygen;

[0014] The volume ratio of the above-mentioned ointment base to the NO gas solution is 2:1 to 1:2;

[0015] The volume ratio of the above-mentioned ointment base to the NO gas solution is 1:1;

[0016] The chitosan derivative is carboxymethyl chitosan or chitosan quaternary ammonium salt;

[0017] The above-mentioned alginic acid derivative is the sodium salt of alginic acid;

[0018] The above-mentioned polyethylene glycol which is solid at 25°C is polyethylene glycol 1500-6000;

[0019] The above-mentioned alkane alcohol having 16 or more carbon atoms is one or a combination of hexadecanol, heptadecanol and octadecanol;

[0020] The above-mentioned alkane alcohol which is liquid at 25° C. is one or a combination of anhydrous ethanol, polyethylene glycol 200-800, glycerol, and propylene glycol.

[0021] A method for preparing the above-mentioned NO highly dispersible hydrophilic ointment is characterized by comprising the following steps:

[0022] a. Take 100 ml of alkane alcohol which is liquid at 25°C and heat it to boiling point 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, and form a NO gas solution;

[0023] b. Add the NO gas solution prepared in step a to the molten ointment base in the prescribed volume ratio, mix well to form a highly dispersible NO hydrophilic ointment, and store in a cool and sealed place.

[0024] One or a combination of antioxidants, emulsifiers, antibacterial agents and pH regulators commonly used in pharmacy are added to the above-mentioned NO highly dispersible hydrophilic ointment.

[0025] The NO highly dispersible hydrophilic ointment 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 to local pharmaceutical treatment; 2. highly dispersing NO in a water-free hydrophilic ointment matrix to ensure its compatibility with tissue fluids; 3. not using any NO donor compound to avoid adverse reactions and toxic side effects of NO donor compounds on body tissues; 4. the hydrophilic ointment is simple 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 hydrophilic nitric oxide ointment

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

[0029] a. Take 100 ml of alkane alcohol which is liquid at 25°C and heat it to boiling point 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 (saturated NO gas, or a mixture of NO gas and nitrogen in a specific ratio) to replace the nitrogen, and form a NO gas solution;

[0030] b. Add the NO gas solution prepared in step a to the molten ointment base in the prescribed volume ratio, mix well to form a highly dispersible NO hydrophilic ointment, and store in a cool and sealed place.

[0031] The ointment 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 proportion 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 proportion of NO is 60%~90%; * represents that the item has obvious differences in components or values ​​from the experimental group.

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

[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 74 68 71 71 Experimental Group 2 72 74 73 73 Experimental Group 3 81 83 84 83 Experimental Group 4 90 92 94 92 Experimental Group 5 91 92 94 92 Experimental Group 6 82 85 85 84 Experimental Group 7 73 75 76 75 Experimental Group 8 70 69 70 70 Experimental Group 9 65 61 62 63 Experimental Group 10 58 59 56 58 Control group 1 22 25 28 25 Control group 2 12 13 12 12 Control group 3 -6 -7 -10 -8 Control group 4 -3 -2 -3 -3 Control group 5 -13 -17 -20 -17 Control group 6 -11 -13 -14 -13 Control group 7 42 45 49 45 Control group 8 32 35 36 34

[0043] As shown in Table 2, the hydrophilic ointment 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 a good state 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, 5 and 6, 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. The control group 3, 5 and 6 preparations 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 hydrophilic ointment of nitric oxide 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 hydrophilic ointment of nitric oxide, the main characteristics of which are: the hydrophilic ointment is composed of an ointment base and a nitric oxide gas solution, and the nitric oxide gas solution is uniformly dispersed in the ointment base; the volume ratio of the ointment base to the nitric oxide gas solution is 3:1 to 1:3; the ointment base is composed of one or more combinations of gelatin, collagen, poloxamer and poloxamer derivatives, chitosan and chitosan derivatives, alginic acid and alginate derivatives, povidone, polyethylene glycol that is solid at 25°C, and alkane alcohols with 16 or more carbon atoms; the nitric oxide gas solution is formed by dispersing nitric oxide gas in anhydrous and oxygen-free alkane alcohols that are liquid at 25°C; the hydrophilic ointment 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 hydrophilic ointment of nitric oxide according to claim 1, characterized in that: The nitric oxide gas solution is formed by saturating the nitric oxide gas in an alkane alcohol solution without water or oxygen.

3. The highly dispersible hydrophilic ointment of nitric oxide according to claim 1, characterized in that: The volume ratio of the ointment base to the nitric oxide gas solution is 2:1 to 1:

2.

4. The highly dispersible hydrophilic ointment of nitric oxide according to claim 1, characterized in that: The volume ratio of the ointment base to the nitric oxide gas solution is 1:

1.

5. The highly dispersible hydrophilic ointment of nitric oxide according to claim 1, characterized in that: The chitosan derivative is carboxymethyl chitosan or chitosan quaternary ammonium salt, and the alginate derivative is sodium salt of alginate.

6. The highly dispersible hydrophilic ointment of nitric oxide according to claim 1, characterized in that: The polyethylene glycol which is solid at 25° C. is polyethylene glycol 1500-6000.

7. The highly dispersible hydrophilic ointment of nitric oxide according to claim 1, characterized in that: The alkane alcohol having 16 or more carbon atoms is one or a combination of hexadecanol, heptadecanol and octadecanol.

8. The highly dispersible hydrophilic ointment of nitric oxide according to claim 1, characterized in that: The alkane alcohol which is liquid at 25° C. is one or a combination of anhydrous ethanol, polyethylene glycol 200-800, glycerol and propylene glycol.

9. A method for preparing the highly dispersible hydrophilic nitric oxide ointment according to claim 1, characterized in that: The steps include: a. Take 100 ml of alkane alcohol which is liquid at 25°C and heat it in a water bath to boiling point 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. Add the NO gas solution prepared in step a to the molten ointment base in the prescribed volume ratio, mix well to form a highly dispersible NO hydrophilic ointment, and store in a cool and sealed place.

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

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