CN113289003A - Stem cell factor composition and application thereof - Google Patents
Stem cell factor composition and application thereof Download PDFInfo
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Abstract
The invention relates to a stem cell factor composition and application thereof. In particular, the present invention provides a composition comprising basic fibroblast growth factor and nerve growth factor. The composition provided by the invention can improve diabetes and complications thereof such as pain, oxidative stress and AGEs content increase, and further prevent and treat other conditions of diabetes complications such as pain, oxidative stress and AGEs content increase.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a stem cell factor composition and application thereof.
Background
The prevalence of diabetes is rapidly increasing, and for diabetic patients, not only the blood sugar level is controlled, but also complications of the diabetes are prevented and treated. For example, due to various metabolic disorders of diabetic patients, the high sugar environment promotes the formation of advanced glycation end products (AGEs) which are products of non-enzymatic glycosylation reactions between carbohydrates and proteins, and the content of AGEs is increased to cause body aging, diabetic nephropathy, cardiovascular diseases and neuropathy diseases through a series of biochemical reactions. In addition, oxidative stress and pain are common complications of diabetes, for example, oxidative stress can accelerate skin aging and other diseases, and pain brings pain to patients. Thus, it can be seen that diabetes and its complications such as pain, oxidative stress, elevated levels of AGEs can further contribute to the development of other conditions due to the complexity of the body. Therefore, how to prevent and treat diabetes and its complications such as pain, oxidative stress, and increased AGEs content, and further prevent and treat diabetes complications such as pain, oxidative stress, and the occurrence of other diseases caused by increased AGEs content become a hot spot of research today.
Therefore, there is a need in the art to develop a drug that can improve diabetes and its complications and further prevent the occurrence of other disorders resulting from diabetic complications.
Disclosure of Invention
The invention aims to provide a composition capable of improving diabetes and complications thereof and further preventing and treating other diseases caused by diabetic complications.
In a first aspect of the invention, there is provided a composition comprising basic fibroblast growth factor and nerve growth factor.
Preferably, the weight ratio of the basic fibroblast growth factor to the nerve growth factor is 1: 0.1-15, preferably 1: 0.5 to 10, more preferably 1: 0.5 to 5, more preferably 1: 0.5 to 3, more preferably 1: 0.5-2.5, more preferably 1: 1-2, more preferably 1: 1.3-1.7.
Preferably, the basic fibroblast growth factor is present in an amount of 0.0005 to 0.005 wt%, preferably 0.001 to 0.005 wt%, more preferably 0.001 to 0.003 wt%, based on the total weight of the composition.
Preferably, the nerve growth factor is present in an amount of 0.0005 to 0.006 wt%, preferably 0.001 to 0.006 wt%, more preferably 0.002 to 0.004 wt%, based on the total weight of the composition.
Preferably, the composition is in the form of oral preparation, injection preparation or external preparation.
Preferably, the composition is a solid, liquid or semi-solid formulation.
Preferably, the composition is in the form of tablets, capsules, oral liquid, granules, powder or syrup.
Preferably, the composition is in the form of a skin external preparation.
Preferably, the composition is in the form of a skin application preparation.
Preferably, the composition comprises a pharmaceutical composition.
Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
Preferably, the composition is in the form of an emulsion.
Preferably, the composition is an emulsion comprising:
(A) an aqueous phase comprising basic fibroblast growth factor, nerve growth factor and water;
(B) an oil phase comprising sunflower oil and soybean oil; and
(C) an emulsifier, wherein the emulsifier comprises polysorbate-80.
Preferably, the emulsion is an oil-in-water emulsion.
Preferably, said water is selected from the group consisting of: distilled water, purified water, water for injection, or a combination thereof.
Preferably, the oil phase further comprises a vegetable oil selected from the group consisting of: soybean oil, olive oil, corn oil, fish oil, peanut oil, sesame oil, linseed oil, castor oil, rapeseed oil, walnut oil, sunflower oil, safflower oil, or combinations thereof.
Preferably, the emulsion further comprises a wetting agent selected from the group consisting of: glycerol, ethanol, propylene glycol, butylene glycol, polyethylene glycol, or combinations thereof.
Preferably, the emulsion further comprises a bacteriostatic agent selected from the group consisting of: methyl paraben, ethyl paraben, glacial paraben, or a combination thereof.
Preferably, the aqueous phase is present in an amount of 50 to 70 wt%, preferably 55 to 65 wt%, based on the total weight of the composition.
Preferably, the oil phase is present in an amount of from 25 to 40 wt%, preferably from 28 to 37 wt%, based on the total weight of the composition.
Preferably, the emulsifier is present in an amount of 4 to 12 wt%, preferably 6 to 10 wt%, based on the total weight of the composition.
Preferably, the formulation of said emulsion comprises:
preferably, the formulation of said emulsion comprises:
preferably, the formulation of said emulsion comprises:
preferably, the formulation of said emulsion comprises:
preferably, the unit of parts by weight is grams (g).
Preferably, the particle size of the emulsion is 110-130nm, more preferably 115-128 nm.
Preferably, the emulsion is prepared by the following method:
(1) mixing the components of the oil phase according to the prescription amount to obtain an oily phase A;
(2) mixing the components of the water phase in the prescription amount with the emulsifier component in the prescription amount to obtain a water-based phase B;
(3) adding the oily phase A into the aqueous phase B under the stirring condition, and stirring to obtain an emulsion.
Preferably, the emulsion is prepared by the following method:
(1) mixing the sunflower seed oil and the soybean oil according to the prescription amount to obtain an oily phase A;
(2) mixing a prescribed amount of basic fibroblast growth factor, nerve growth factor, water and polysorbate-80 to obtain an aqueous phase B;
(3) adding the oily phase A into the aqueous phase B under the stirring condition, and stirring to obtain an emulsion.
Preferably, in the step (1), the mixing is carried out under stirring at 35-45 deg.C (preferably 38-42 deg.C).
Preferably, in the step (2), the mixing is carried out under stirring at 35-45 deg.C (preferably 38-42 deg.C).
Preferably, said mixing comprises mixing with stirring.
A second aspect of the invention provides the use of a composition according to the first aspect of the invention for the manufacture of a medicament for one or more uses selected from the group consisting of: (a) preventing and/or treating diabetes and/or complications thereof; (b) prevention and/or treatment of pain; (c) preventing and/or treating oxidative stress; (d) preventing and/or treating diseases caused by oxidative stress; (e) reducing AGEs content; and/or (f) preventing and/or treating diseases caused by the increase of AGEs content.
Preferably, the diabetic complication is selected from the group consisting of: pain, oxidative stress, elevated AGEs, or combinations thereof.
Preferably, said (a) preventing and/or treating diabetes and/or its complications comprises one or more modes selected from the group consisting of: (b) prevention and/or treatment of pain; (c) preventing and/or treating oxidative stress; (d) preventing and/or treating diseases caused by oxidative stress; (e) reducing AGEs content; and/or (f) preventing and/or treating diseases caused by the increase of AGEs content.
Preferably, the pain comprises acute pain and/or inflammatory pain.
Preferably, said oxidative stress comprises oxidative stress due to an increase in ROS (reactive oxygen species).
Preferably, said oxidative stress comprises skin oxidative stress.
Preferably, said oxidative stress comprises oxidative stress of skin tissue.
Preferably, said ROS comprise cutaneous ROS.
Preferably, said ROS comprise ROS in skin tissue.
Preferably, the AGEs include skin AGEs.
Preferably, the AGEs include AGEs in skin tissue.
Preferably, the pain comprises pain associated with diabetes.
Preferably, the oxidative stress comprises oxidative stress associated with diabetes.
Preferably, the increase in AGEs comprises an increase in AGEs associated with diabetes.
Preferably, the disease caused by oxidative stress comprises diabetes and/or skin aging.
Preferably, the diseases caused by the increase of AGEs content comprise body aging, diabetic nephropathy, cardiovascular diseases and/or neuropathy.
A third aspect of the present invention provides a method of (a) preventing and/or treating diabetes and/or complications thereof; (b) prevention and/or treatment of pain; (c) preventing and/or treating oxidative stress; (b) preventing and/or treating diseases caused by oxidative stress; (e) reducing AGEs content; and/or (f) a method for preventing and/or treating diseases caused by elevated AGEs, administering a composition according to the first aspect of the invention to a subject in need thereof.
Preferably, the subject comprises a human or non-human mammal.
It should be understood that the above-mentioned technical features of the present invention can be combined with each other to form a new or preferred technical solution.
Detailed Description
The invention develops a composition comprising basic fibroblast growth factor and nerve growth factor, which can be used for preventing and treating diabetes and complications thereof such as pain, oxidative stress and increased AGEs content, and further preventing and treating diabetic complications such as pain, oxidative stress and other diseases caused by increased AGEs content.
Term(s) for
As used herein, the term "comprising" encompasses not only closed definitions, but also semi-closed, open definitions. In other words, the term includes "consisting of … …" and "consisting essentially of … …".
As used herein, the terms "parts by weight" and "parts by weight" are used interchangeably and can be any fixed weight expressed in milligrams, grams, or kilograms (e.g., 1mg, 1g, or 1kg, etc.). For example, a composition consisting of 1 part by weight of component a and 9 parts by weight of component b may be a composition consisting of 1g of component a +9 g of component b, or 10 g of component a +90 g of component b. In the composition, the percentage content of a certain component is (part by weight of the component/sum of parts by weight of all components) × 100%, and thus, in a composition composed of 1 part by weight of component a and 9 parts by weight of component b, the content of component a is 10% and the content of component b is 90%.
As used herein, the term "polysorbate-80" is used interchangeably with tween 80.
As used herein, the term "AGEs" is used interchangeably with "advanced glycation end products".
As used herein, the term "ROS" is used interchangeably with "reactive oxygen radicals.
Composition and preparation method thereof
The present invention provides a composition comprising stem cell factors, such as basic fibroblast growth factor (bFGF) and Nerve Growth Factor (NGF).
Basic fibroblast growth factor (bFGF), a type of stem cell factor, has an angiogenic effect, stimulates cell proliferation and migration in vitro, induces plasminogen activator and collagenase activity, and is a cell mitogen with high affinity for heparin.
Nerve Growth Factor (NGF) is one of stem cell factors, and can promote growth, development, differentiation and maturation of central and peripheral neurons, maintain normal functions of the nervous system, and accelerate repair of damaged nervous system.
In a preferred embodiment of the present invention, the weight ratio of the basic fibroblast growth factor to the nerve growth factor is 1: 0.1-15, preferably 1: 0.5 to 10, more preferably 1: 0.5 to 5, more preferably 1: 0.5 to 3, more preferably 1: 0.5-2.5, more preferably 1: 1-2, more preferably 1: 1.3-1.7.
Preferably, the basic fibroblast growth factor is present in an amount of 0.0005 to 0.005 wt%, preferably 0.001 to 0.005 wt%, more preferably 0.001 to 0.003 wt%, based on the total weight of the composition.
Preferably, the nerve growth factor is present in an amount of 0.0005 to 0.006 wt%, preferably 0.001 to 0.006 wt%, more preferably 0.002 to 0.004 wt%, based on the total weight of the composition.
The dosage form of the composition of the invention is preferably oral preparation, injection preparation or external preparation.
The dosage form of the composition of the present invention is preferably a solid preparation, a liquid preparation or a semisolid preparation.
Typically, the composition is in the form of tablets, capsules, oral liquid, granules, powder or syrup.
Typically, the composition is in the form of a skin external preparation.
Typically, the composition is in the form of a skin-applied preparation.
In a preferred embodiment of the present invention, the composition comprises a pharmaceutical composition.
Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
In a preferred embodiment of the present invention, the composition is in the form of an emulsion.
In a preferred embodiment of the present invention, the composition is an emulsion comprising:
(A) an aqueous phase comprising basic fibroblast growth factor, nerve growth factor and water;
(B) an oil phase comprising sunflower oil and soybean oil; and
(C) an emulsifier, wherein the emulsifier comprises polysorbate-80.
In a preferred embodiment of the invention the emulsion is an oil-in-water emulsion.
In a preferred embodiment of the present invention, the water is selected from the group consisting of: distilled water, purified water, water for injection, or a combination thereof.
In a preferred embodiment of the present invention, the oil phase further comprises a vegetable oil selected from the group consisting of: soybean oil, olive oil, corn oil, fish oil, peanut oil, sesame oil, linseed oil, castor oil, rapeseed oil, walnut oil, sunflower oil, safflower oil, or combinations thereof.
In a preferred embodiment of the present invention, the emulsion further comprises a wetting agent selected from the group consisting of: glycerol, ethanol, propylene glycol, butylene glycol, polyethylene glycol, or combinations thereof.
In a preferred embodiment of the present invention, the emulsion further comprises a bacteriostatic agent selected from the group consisting of: methyl paraben, ethyl paraben, glacial paraben, or a combination thereof.
In a preferred embodiment of the invention, said aqueous phase is present in an amount of 50 to 70 wt.%, preferably 55 to 65 wt.%, calculated on the total weight of the composition.
In a preferred embodiment of the invention, the oil phase is present in an amount of from 25 to 40 wt%, preferably from 28 to 37 wt%, based on the total weight of the composition.
In a preferred embodiment of the invention, the emulsifier is present in an amount of 4 to 12 wt.%, preferably 6 to 10 wt.%, based on the total weight of the composition.
Preferably, the formulation of said emulsion comprises:
preferably, the formulation of said emulsion comprises:
preferably, the formulation of said emulsion comprises:
preferably, the formulation of said emulsion comprises:
in a preferred embodiment of the present invention, the particle size of the emulsion is 110-130nm, more preferably 115-128 nm.
In a preferred embodiment of the present invention, the emulsion is prepared by the following method:
(1) mixing the components of the oil phase according to the prescription amount to obtain an oily phase A;
(2) mixing the components of the water phase in the prescription amount with the emulsifier component in the prescription amount to obtain a water-based phase B;
(3) adding the oily phase A into the aqueous phase B under the stirring condition, and stirring to obtain an emulsion.
Preferably, the emulsion is prepared by the following method:
(1) mixing the sunflower seed oil and the soybean oil according to the prescription amount to obtain an oily phase A;
(2) mixing a prescribed amount of basic fibroblast growth factor, nerve growth factor, water and polysorbate-80 to obtain an aqueous phase B;
(3) adding the oily phase A into the aqueous phase B under the stirring condition, and stirring to obtain an emulsion.
Preferably, in the step (1), the mixing is carried out under stirring at 35-45 deg.C (preferably 38-42 deg.C).
Preferably, in the step (2), the mixing is carried out under stirring at 35-45 deg.C (preferably 38-42 deg.C).
Preferably, in the step (1), the stirring is performed at 35 to 45 ℃ (preferably 38 to 42 ℃).
Preferably, in the step (2), the stirring is performed at 35 to 45 ℃ (preferably 38 to 42 ℃).
Use of
The present invention provides the use of a composition according to the invention for the preparation of a medicament for one or more uses selected from the group consisting of: (a) preventing and/or treating diabetes and/or complications thereof; (b) prevention and/or treatment of pain; (c) preventing and/or treating oxidative stress; (d) preventing and/or treating diseases caused by oxidative stress; (e) reducing AGEs content; and/or (f) preventing and/or treating diseases caused by the increase of AGEs content.
The present invention also provides a method for (a) preventing and/or treating diabetes and/or complications thereof; (b) prevention and/or treatment of pain; (c) preventing and/or treating oxidative stress; (d) preventing and/or treating diseases caused by oxidative stress; (e) reducing AGEs content; and/or (f) preventing and/or treating diseases caused by elevated AGEs levels by administering to a subject in need thereof a composition according to the present invention.
In the present invention, the term "prevention" refers to a method of preventing the onset of a disease and/or its attendant symptoms or protecting a subject from acquiring a disease. As used herein, "preventing" also includes delaying the onset of a disease and/or its attendant symptoms and reducing the risk of acquiring a disease in a subject.
"treating" as used herein includes delaying and stopping the progression of the disease, or eliminating the disease, and does not require 100% inhibition, elimination, or reversal, e.g., a composition of the invention comprising basic fibroblast growth factor and nerve growth factor reduces, inhibits, and/or reduces the levels of, e.g., at least about 10%, at least about 50%, or at least about 80% or completely eradicates, e.g., pain, oxidative stress, AGEs, associated with diabetes, as compared to the absence of the composition of the invention.
Preferably, the diabetic complication is selected from the group consisting of: pain, oxidative stress, elevated AGEs, or combinations thereof.
Preferably, said (a) preventing and/or treating diabetes and/or its complications comprises one or more modes selected from the group consisting of: (b) prevention and/or treatment of pain; (c) preventing and/or treating oxidative stress; (d) preventing and/or treating diseases caused by oxidative stress; (e) reducing AGEs content; and/or (f) preventing and/or treating diseases caused by the increase of AGEs content.
In a preferred embodiment of the invention, the pain comprises acute pain and/or inflammatory pain.
In a preferred embodiment of the invention, said oxidative stress comprises oxidative stress due to an increase in ROS (reactive oxygen species).
In a preferred embodiment of the invention, the oxidative stress comprises skin oxidative stress.
Preferably, said oxidative stress comprises oxidative stress of skin tissue.
Preferably, said ROS comprise cutaneous ROS.
Preferably, said ROS comprise ROS in skin tissue.
In a preferred embodiment of the present invention, the AGEs include skin AGEs.
Preferably, the AGEs include AGEs in skin tissue.
In a preferred embodiment of the present invention, the pain comprises pain associated with diabetes.
In a preferred embodiment of the present invention, the oxidative stress comprises oxidative stress concurrent with diabetes.
In a preferred embodiment of the present invention, the increase in AGEs content comprises an increase in AGEs content associated with diabetes.
In a preferred embodiment of the present invention, the diseases caused by oxidative stress include diabetes and/or skin aging.
In a preferred embodiment of the present invention, the diseases caused by the increase of AGEs content include body aging, diabetic nephropathy, cardiovascular diseases and/or neuropathy.
In the cream of the present invention, the amount of basic fibroblast growth factor and nerve growth factor administered is a therapeutically effective amount. In using the composition, a safe and effective amount of the drug is administered to a human or mammal, wherein the safe and effective amount is at least 10 micrograms/kg body weight, and in most cases does not exceed 10 mg/kg body weight, preferably 10 micrograms/kg body weight to 5 mg/kg body weight. The particular dosage will, of course, be determined by consideration of the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner. In addition, the cream of the present invention may also be used with other therapeutic agents such as transdermal agents (including before, during or after).
The excellent technical effects of the invention comprise:
the composition provided by the invention can improve diabetes and complications thereof such as pain, oxidative stress and AGEs content increase, and further prevent and treat other conditions of diabetes complications such as pain, oxidative stress and AGEs content increase.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1
This example 1 prepared an emulsion having the formula shown in Table 1:
TABLE 1 composition of the emulsion
The preparation method comprises the following steps:
(1) stirring and mixing the components of the oil phase according to the prescription amount at 40 ℃ to obtain an oily phase A;
(2) stirring and mixing the components of the water phase in the prescription amount and the emulsifier in the prescription amount at 40 ℃ to obtain a water-based phase B;
(3) adding the oily phase A into the aqueous phase B under stirring, and stirring to obtain an oil-in-water emulsion.
And (3) particle size measurement:
the average particle size of the emulsion was 123.8. + -. 5.7nm as measured using a Malvern laser particle sizer.
Example 2
This example 2 prepared an emulsion having the formula shown in Table 2:
TABLE 2 composition of the emulsion
The preparation method comprises the following steps:
(1) stirring and mixing the components of the oil phase according to the prescription amount at 40 ℃ to obtain an oily phase A;
(2) stirring and mixing the components of the water phase in the prescription amount and the emulsifier in the prescription amount at 40 ℃ to obtain a water-based phase B;
(3) adding the oily phase A into the aqueous phase B under stirring, and stirring to obtain an oil-in-water emulsion.
And (3) particle size measurement:
the average particle size of the emulsion was 117.9. + -. 6.2nm as measured using a Malvern laser particle sizer.
Example 3
Example 3 an emulsion was prepared, the emulsion being formulated as shown in table 3:
TABLE 3 composition of the emulsion
The preparation method comprises the following steps:
(1) stirring and mixing the components of the oil phase according to the prescription amount at 40 ℃ to obtain an oily phase A;
(2) stirring and mixing the components of the water phase in the prescription amount and the emulsifier in the prescription amount at 40 ℃ to obtain a water-based phase B;
(3) adding the oily phase A into the aqueous phase B under stirring, and stirring to obtain an oil-in-water emulsion.
And (3) particle size measurement:
the average particle size of the emulsion was 135.9. + -. 4.9nm as measured using a Malvern laser particle sizer.
Example 4
This example 4 prepared an emulsion having the formula shown in Table 4:
TABLE 4 composition of the emulsion
The preparation method comprises the following steps:
(1) stirring the oil phase components in the prescription amount at 40 ℃ to obtain an oily phase A;
(2) stirring and mixing the components of the water phase in the prescription amount and the emulsifier in the prescription amount at 40 ℃ to obtain a water-based phase B;
(3) adding the oily phase A into the aqueous phase B under stirring, and stirring to obtain an oil-in-water emulsion.
And (3) particle size measurement:
the average particle size of the emulsion was 109.3. + -. 5.2nm as determined using a Malvern laser particle sizer.
Example 5
This example 5 prepared an emulsion having the formula shown in Table 5:
TABLE 5 composition of the emulsions
The preparation method comprises the following steps:
(1) stirring the oil phase components in the prescription amount at 40 ℃ to obtain an oily phase A;
(2) stirring and mixing the components of the water phase in the prescription amount and the emulsifier in the prescription amount at 40 ℃ to obtain a water-based phase B;
(3) adding the oily phase A into the aqueous phase B under stirring, and stirring to obtain an oil-in-water emulsion.
And (3) particle size measurement:
the average particle size of the emulsion was 118.9. + -. 7.8nm as measured using a Malvern laser particle sizer.
Example 6
This example 6 prepared an emulsion having the formula shown in Table 6:
TABLE 6 composition of the emulsion
The preparation method comprises the following steps:
(1) stirring and mixing the components of the oil phase according to the prescription amount at 40 ℃ to obtain an oily phase A;
(2) stirring and mixing the components of the water phase in the prescription amount and the emulsifier in the prescription amount at 40 ℃ to obtain a water-based phase B;
(3) adding the oily phase A into the aqueous phase B under stirring, and stirring to obtain an oil-in-water emulsion.
And (3) particle size measurement:
the average particle size of the emulsion was 142.9. + -. 8.1nm as measured using a Malvern laser particle sizer.
Comparative example 1
Comparative example 1 a blank emulsion was prepared having a base formulation as shown in table 7:
TABLE 7 composition of blank emulsion base
The preparation method comprises the following steps:
(1) stirring and mixing the components of the oil phase according to the prescription amount at 40 ℃ to obtain an oily phase A;
(2) stirring and mixing the components of the water phase in the prescription amount and the emulsifier in the prescription amount at 40 ℃ to obtain a water-based phase B;
(3) adding the oily phase A into the aqueous phase B under stirring, and stirring to obtain an oil-in-water emulsion.
And (3) particle size measurement:
the average particle size of the emulsion was 128.2. + -. 6.7nm as measured using a Malvern laser particle sizer.
Examples of effects
1. Experimental methods
1.1 construction of diabetic rat model
A normal healthy male SD rat is induced into a diabetic rat model by injecting Streptozotocin (STZ), after 8 days of induction, the blood sugar value of the rat is maintained at 25.89 +/-1.25 mmol/L (p is less than 0.05), the blood sugar value is obviously higher than that of the normal rat by 7.4 +/-0.5 mmol/L, polydipsia, polyphagia and polyuria are realized, the body weight is obviously reduced compared with that of a normal healthy rat in the same period, the hair is withered and yellow, and the model construction of the diabetic rat model is successful.
1.2 animal grouping and administration
The method comprises the following steps of randomly dividing diabetic rats into a model group, an experimental group 1, an experimental group 2, an experimental group 3, an experimental group 4, an experimental group 5 and an experimental group 6, wherein each group comprises 5 rats, selecting 5 normal healthy male SD rats which are not induced by Streptozotocin (STZ) as blank control groups, feeding the rats in each group freely, keeping the temperature of an animal room at 24-26 ℃ and keeping the humidity at 40-60%.
The same back skin part of rats in each of the model group, experimental group 1, experimental group 2, experimental group 3, experimental group 4, experimental group 5 and experimental group 6 was coated with the same amount of different emulsions (the application part skin was depilated), the rats in the blank control group were coated with physiological saline in the same manner, and the rats in each group were administered as follows:
model group: the blank emulsion prepared in comparative example 1;
experimental group 1: the emulsion prepared in example 1;
experimental group 2: the emulsion prepared in example 2;
experimental group 3: the emulsion prepared in example 3;
experimental group 4: the emulsion prepared in example 4;
experimental group 5: the emulsion prepared in example 5;
experimental group 6: the emulsion prepared in example 6;
blank control group: physiological saline.
After administration for 6 weeks 1 time per day, the analgesic effect of each group of rats was examined, and then skin tissues of each group were taken and the AGEs and ROS (reactive oxygen species) content in the skin tissues was measured.
Examination of analgesic Effect: the rats are placed in a transparent and ventilated organic glass cylinder, 30 mu l of 4% formalin solution is injected into the left rear sole of each group of rats, the left foot licking time of each group of rats within 0-60min after the injection of the 4% formalin solution is recorded in real time by a miniature camera, and statistical analysis is carried out.
AGEs (advanced glycation end products) content determination: and after homogenizing the skin tissue, centrifuging to obtain supernatant, measuring the absorbance value of ultraviolet light at 280nm, and measuring the AGEs content in the skin tissue.
Method for determination of ROS (reactive oxygen species): after homogenizing skin tissue, centrifuging to obtain supernatant, treating a sample after protein quantification by using a commercially available Reactive Oxygen Species (ROS) detection kit, and detecting the absorbance of the sample to determine the expression content of ROS (reactive oxygen species).
2. Results of the experiment
2.1 therapeutic effects on pain
The left hind paw of each group of rats was injected with 4% formalin solution and left paw licking time within 0-60min was as shown in table 8;
TABLE 8 time to arm (M + -SD) for each group of rats
| Group of | Administration of drugs | Statistics of foot adding time(s) |
| Blank control group | Physiological saline | 327±18 |
| Model set | Blank emulsion of comparative example 1 | 586±26 |
| Experimental group 1 | Emulsion of example 1 | 348±16** |
| Experimental group 2 | Emulsion of example 2 | 482±23** |
| Experimental group 3 | Emulsion of example 3 | 511±19** |
| Experimental group 4 | Emulsion of example 4 | 387±24* |
| Experimental group 5 | Emulsion of example 5 | 392±30* |
| Experimental group 6 | Emulsion of example 6 | 432±22** |
Remarking: compared to the model group, "# is P <0.05," # is P < 0.01.
As can be seen from Table 8, the rats of the model group had significantly prolonged feeding time and significant difference (P <0.05) compared to the blank control group, indicating pain associated with diabetes. The formalin model is a classic model of acute pain and inflammatory pain, and compared with model group rats, the emulsion prepared in the embodiment has the advantages that the basic fibroblast growth factor and the nerve growth factor can synergistically and remarkably reduce pain, and the emulsion has an excellent synergistic treatment effect on pain (acute pain and inflammatory pain) complicated by diabetes.
2.2AGEs content determination
The AGEs content in the skin tissue of the rats in each group is shown in table 9:
TABLE 9 AGEs content (M + -SD) in skin tissues of each group
Remarking: compared to the model group, "# is P <0.05," # is P < 0.01.
As can be seen from Table 9, the AGEs content in the model group is significantly higher than that in the blank control group (P is less than 0.05, and has significant difference), which indicates that the AGEs are increased at the same time of diabetes, and the AGEs are increased to cause body aging, diabetic nephropathy, cardiovascular diseases, neuropathy and the like. Compared with model rats, in the emulsion prepared by the embodiment, the basic fibroblast growth factor and the nerve growth factor can obviously reduce the content of AGEs, so that the emulsion has an excellent improvement effect on the AGEs increase complicated by diabetes.
2.3 determination of ROS content
The ROS content in the skin tissue of each group of rats is shown in table 10:
TABLE 10 expression content of ROS (reactive oxygen free radical) (M. + -. SD)
| Group of | Administration of drugs | Amount of ROS (U/mug) |
| Blank control group | Physiological saline | 42.3±2.5 |
| Model set | Blank emulsion of comparative example 1 | 62.3±3.2 |
| Experimental group 1 | Emulsion of example 1 | 43.1±2.1** |
| Experimental group 2 | Emulsion of example 2 | 53.6±1.9** |
| Experimental group 3 | Emulsion of example 3 | 56.8±2.7** |
| Experimental group 4 | Emulsion of example 4 | 47.9±1.8* |
| Experimental group 5 | Emulsion of example 5 | 48.8±2.2** |
| Experimental group 6 | Emulsion of example 6 | 50.2±3.5* |
Remarking: compared to the model group, "# is P <0.05," # is P < 0.01.
As can be seen from Table 10, the ROS content in the model group was significantly higher than that in the blank control group (P <0.05, with significant differences), indicating diabetic concurrent oxidative stress. Compared with model rats, in the emulsion prepared by the embodiment, the basic fibroblast growth factor and the nerve growth factor can synergistically and remarkably reduce the ROS content, and the emulsion has an excellent synergistic treatment effect on oxidative stress complicated by diabetes.
While the invention has been described in terms of a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the spirit and scope of the invention.
Claims (10)
1. A composition comprising basic fibroblast growth factor and nerve growth factor.
2. The composition of claim 1, wherein the weight ratio of basic fibroblast growth factor to nerve growth factor is 1: 0.1-15, preferably 1: 0.5 to 10, more preferably 1: 0.5 to 5, more preferably 1: 0.5 to 3, more preferably 1: 0.5-2.5, more preferably 1: 1-2, more preferably 1: 1.3-1.7.
3. The composition of claim 1, wherein the composition is in the form of a skin preparation for external use.
4. The composition of claim 1, wherein the composition is an emulsion comprising:
(A) an aqueous phase comprising basic fibroblast growth factor, nerve growth factor and water;
(B) an oil phase comprising sunflower oil and soybean oil; and
(C) an emulsifier, said emulsifier comprising polysorbate-80;
preferably, the aqueous phase is present in an amount of 50 to 70 wt%, preferably 55 to 65 wt%, the oil phase is present in an amount of 25 to 40 wt%, preferably 28 to 37 wt%, and the emulsifier is present in an amount of 4 to 12 wt%, preferably 6 to 10 wt%, based on the total weight of the composition.
5. The composition of claim 4, wherein the emulsion is formulated by:
6. the composition of claim 4, wherein the emulsion is prepared by:
(1) mixing the components of the oil phase according to the prescription amount to obtain an oily phase A;
(2) mixing the components of the water phase in the prescription amount with the emulsifier component in the prescription amount to obtain a water-based phase B;
(3) adding the oily phase A into the aqueous phase B under the stirring condition, and stirring to obtain an emulsion.
7. Use of a composition according to claim 1 for the preparation of a medicament for one or more uses selected from the group consisting of: (a) preventing and/or treating diabetes and/or complications thereof; (b) prevention and/or treatment of pain; (c) preventing and/or treating oxidative stress; (d) preventing and/or treating diseases caused by oxidative stress; (e) reducing AGEs content; and/or (f) preventing and/or treating diseases caused by the increase of AGEs content.
8. The use of claim 7, wherein the diabetic complication is selected from the group consisting of: pain, oxidative stress, elevated AGEs content, or a combination thereof.
9. The use of claim 7, wherein said oxidative stress comprises oxidative stress due to an increase in Reactive Oxygen Species (ROS).
10. The use according to claim 7, wherein the pain comprises pain associated with diabetes;
the oxidative stress comprises oxidative stress complicated by diabetes; and/or
The increase of the AGEs content comprises the increase of the AGEs content complicated by diabetes.
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| CN101678035A (en) * | 2007-04-13 | 2010-03-24 | 田纳西大学研究基金会 | selective androgen receptor modulators for treating diabetes |
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