CN107961231A - A kind of creme for improving diabetic skin complication and preparation method thereof - Google Patents
A kind of creme for improving diabetic skin complication and preparation method thereof Download PDFInfo
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- CN107961231A CN107961231A CN201711396946.4A CN201711396946A CN107961231A CN 107961231 A CN107961231 A CN 107961231A CN 201711396946 A CN201711396946 A CN 201711396946A CN 107961231 A CN107961231 A CN 107961231A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- 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
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Abstract
The present invention provides a kind of creme for improving diabetic skin complication and preparation method thereof.Specifically, the present invention provides a kind of aminoguanidine hydrochloride pharmaceutical composition, and the pharmaceutical composition is creme, and the creme includes：(1) aminoguanidine hydrochloride of therapeutically effective amount；(2) pharmaceutically acceptable auxiliary material, auxiliary material composition cream carrier；The auxiliary material includes：(A) water phase；(B) oil phase, wherein the oil phase includes grape pip base oil and/or Sweet Almond Oil；(C) emulsifying agent；With optional component (D) wetting agent and/or (E) bacteriostatic agent.Creme in the present invention can substantially reduce inflammation and oxidative stress status in skin histology, hence it is evident that improve skin histology microenvironment, promote the healing of the surface of a wound.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to it is a kind of improve diabetic skin complication creme and its
Preparation method.
Background technology
Diabetes prevalence rises year by year, last decade, and diabetes mellitus in China patient's rapid development, number of patients is up to 9200
More than ten thousand, China becomes one of fastest-rising country of diabetes prevalence.For diabetic, not only to control
The blood sugar level of itself, will more control the generation of complication.Among many complication of diabetes, 15% diabetes are there are about
The ulcer of lower limb that patient can not recover for a long time concurrently, influences the live and work quality of patient, expends a large amount of health care resources.
The various metabolic disorders of diabetic's long-term existence, produce persistent pathologic hyperglycaemia, and high saccharide ring border promotes
Product --- the advanced glycation end products (advanced that nonenzymatic glycosylation reacts between carbohydrate and protein
Glycation end products, AGE) formation, AGE for the reproducibility carbohydrate containing aldehyde radical or ketone group in some oxidation bases
Under the action of group, non-enzymaticization reaction can occur with the amino of amino acid or nucleic acid, be known as Mailard reactions, generate invertibity
Simultaneously isomery is into more stable Amadori types early stage glycation product for Schiff base structure, and the latter is by a series of slow and complexity
Chemical reaction, ultimately forms a kind of irreversible i.e. AGE of glycation product.In human body the accumulation of AGE with advancing age and
Increase, accelerates to be formed, occurrence and development and organism aging process with diabetic complication etc. are closely related, are in diabetic's body
An important factor for causing diabetic nephropathy, angiocardiopathy, neuropathy etc..Meanwhile there is also substantial amounts of in skin histology
AGEs is deposited.
Dermatological complications are the common complication of diabetic, often show as skin infection, pruitus, dermal sensation
Exception, diabetes bullous disease, diabetic xanthoma, diabetes fash etc., very big pain is caused to patient.
Many researchs confirm that aminoguanidine hydrochloride can not only prevent the formation of AGE, and the aminoguanidine hydrochloride of low dosage has at the same time
There is suppression iNOS (inducible nitric oxide synthase, nitric oxide synthase type) activity, reduce nitrosation
Stress (nitrosative stress) and the effect of suppression hydrogen peroxide and the apoptosis of cell.One to diabetes lung tissue
Research prompting, as the inhibitor of AGE, aminoguanidine hydrochloride can not only improve the oxidative stress status of lung tissue, but also can be with
Improve the structural change of the lung tissue caused by diabetes.
Therefore, this area can improve diabetic skin complication medicine there is an urgent need for developing one kind, reduce diabetic's pain
Hardship, improves the quality of living.
The content of the invention
It is an object of the invention to provide one kind can be obviously improved skin histology microenvironment, promote the salt of the healing of the surface of a wound
Sour aminoguanidine pharmaceutical composition and preparation method thereof.
The first aspect of the present invention, there is provided a kind of aminoguanidine hydrochloride pharmaceutical composition, the pharmaceutical composition are creme,
And the creme includes：
(1) aminoguanidine hydrochloride of therapeutically effective amount；
(2) pharmaceutically acceptable auxiliary material, auxiliary material composition cream carrier；
The auxiliary material includes：
(A) water phase；
(B) oil phase, wherein the oil phase includes grape pip base oil and/or Sweet Almond Oil；
(C) emulsifying agent；
With optional component (D) wetting agent and/or (E) bacteriostatic agent.
In another preference, the emulsifying agent includes oleic acid.
In another preference, the creme includes：
(a) aminoguanidine hydrochloride of 35-65 parts by weight；
(b) the water phase of 350-700 parts by weight；
(c) oil phase of 200-400 parts by weight, including the grape pip base oil and/or 100-180 of 10-20 parts by weight
The Sweet Almond Oil of parts by weight；
(d) emulsifying agent of 10-30 parts by weight；
With it is optional
(e) wetting agent of 55-105 parts by weight；And/or
(f) bacteriostatic agent of 0.2-1 parts by weight.
In another preference, the dosage of the amino biguanide is 40-60 parts by weight.
In another preference, the dosage of the water phase is 400-600 parts by weight.
In another preference, the dosage of the oil phase is 250-350 parts by weight, including 10-20 parts by weight
The Sweet Almond Oil of grape pip base oil and/or 100-180 parts by weight.
In another preference, the dosage of the wetting agent is 60-100 parts by weight.
In another preference, the dosage of the bacteriostatic agent is 0.2-0.8 parts by weight.
In another preference, the dosage of the oleic acid is 15-25 parts by weight.
In another preference, the oil phase further include the aliphatic acid of straight or branched, straight or branched fatty alcohol,
One or more in aliphatic or aromatic mineral, fatty acid ester, natural oil.
In another preference, the aliphatic acid of the straight or branched is selected from the group：C1-C7 short chain fatty acids, C8-
C10 medium chain fatty acids, the long chain fatty acids of C11-C40, or its combination.
In another preference, the aliphatic acid of the straight or branched is selected from the group：Caproic acid, octanoic acid, capric acid, nutmeg beans
Acid, pentadecanoic acid, palmitic acid, Heptadecanoic acide, stearic acid, nonadecylic acid, arachidic acid, behenic acid, lignoceric acid, 20
Six alkanoic acids, octocosoic acid, melissic acid erucic acid, oleic acid, linoleic acid, laurate, and the aliphatic acid of substitution, or its combination.
In another preference, the fatty alcohol of the straight or branched is selected from the group：C1-C7 short chain fatty alcohols, C8-
C10 medium chain fatty acids, the long-chain fatty alcohol of C11-C40, or its combination.
In another preference, the fatty alcohol of the straight or branched is selected from the group：Tetradecanol, pentadecanol,
Hexadecanol, heptadecanol, octadecanol, isooctadecane alcohol, nonadecanol, eicosanol, tadenan, lignocerane
Alcohol, hexacosanol, triacontanol, oleyl alcohol, laruyl alcohol, octanol, certain herbaceous plants with big flowers alcohol, Palmitoleyl alcohol, substitute fatty alcohol, or its combination.
In another preference, the hydro carbons of the straight or branched is selected from the group：Vaseline, atoleine, or its group
Close.
In another preference, the fatty acid ester is selected from the group：Isopropyl myristate, tristerin, or
It is combined.
In another preference, the natural oil is selected from the group：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 its combination.
In another preference, the wetting agent is polyalcohol.
In another preference, the wetting agent is selected from the group：Glycerine, ethanol, propane diols, butanediol, polyethylene glycol,
Or its combination.
In another preference, the bacteriostatic agent is selected from the group：Nipalgin alcohol, nipalgin fat, or its combination.
In another preference, the bacteriostatic agent is selected from the group：Methyl hydroxybenzoate, ethylparaben, nipalgin ice ester,
Or its combination.
The second aspect of the present invention, there is provided a kind of preparation method of composition of the present invention, the method include
Step：
(I) by water phase, oil phase, emulsifying agent and optional component wetting agent and/or bacteriostatic agent heating mixing, stir, tentatively
Emulsification；
(II) it is fully emulsified；
(III) aminoguanidine hydrochloride is added, mixes, prepares creme.
In another preference, the heating-up temperature is 50-90 DEG C, preferable 60-80 DEG C.
In another preference, step (II) emulsifying under 10000-23000 revs/min of rotating speed.
In another preference, before aminoguanidine hydrochloride is added, the temperature of blank creme after the step (II) is emulsified
Degree control is at 30-50 DEG C.
Third aspect present invention, there is provided a kind of purposes of composition of the present invention, is used to prepare prevention and/or treatment
The medicine of diabetic skin complication.
In another preference, the diabetic skin complication is pruitus, subcutaneous fat is thinning, skin becomes
Thin, cacesthesia, bullosis diabeticorum, diabetic xanthoma, diabetic keratopathy fash, skin easily infect.
The fourth aspect of the present invention, there is provided a kind of method for preventing and/or treating diabetic skin complication, leads to
Cross object composition of the present invention needed for giving.
In another preference, the object is behaved or non-human mammal.
It is to be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, so as to form new or preferable technical solution.As space is limited, exist
This no longer tires out one by one states.
Brief description of the drawings
Fig. 1 is showing skin histology AGEs contents in the embodiment of the present invention and comparative example.
Fig. 2 shows in the embodiment of the present invention IL-1 β (interleukin-11 β), TNF-α (tumor necrosis factor in skin histology
α), the expression of IL-6 (interleukin 6), IFN-γ (gamma interferon) inflammatory factor.
Fig. 3 shows the expression of oxidative stress index in sample in the embodiment of the present invention, and detection index of correlation is as follows：
ROS (active oxygen radical), T-AOC (total antioxidant capacity), CAT (catalase), SOD (superoxide dismutase).
Fig. 4 shows the statistics of Wound healing rate in the embodiment of the present invention.
Fig. 5 shows the skin thickness of each intervention group in the embodiment of the present invention and comparative example.
Embodiment
The present invention passes through extensive and in-depth study, has had been surprisingly found that a kind of aminoguanidine hydrochloride pharmaceutical composition, described
Pharmaceutical composition be creme, and the creme includes：(1) aminoguanidine hydrochloride of therapeutically effective amount；(2) it is pharmaceutically acceptable
Auxiliary material, the auxiliary material composition cream carrier；The auxiliary material includes：(A) water phase；(B) oil phase, wherein the oil phase bag
Include grape pip base oil and/or Sweet Almond Oil；(C) emulsifying agent；With optional component (D) wetting agent and/or (E) bacteriostatic agent.Institute
The aminoguanidine hydrochloride pharmaceutical composition stated can substantially reduce inflammation and oxidative stress status in skin histology, hence it is evident that improve skin
Skin tissue microenvironment, promotes the healing of the surface of a wound.
Term
As used herein, term " therapeutically effective amount " refer to produce people and/or animal function or activity and can be by people
And/or the amount that animal is received.It will be apparent to an ordinarily skilled person in the art that " therapeutically effective amount " can be with administration
Approach, the auxiliary material of medicine used, the severity of disease and with difference situations such as other drugs drug combination and not
Together.
As used herein, term " comprising " not only includes closed definition, also comprising semiclosed, open definition.Change speech
It, the term include " by ... form ", " substantially by ... form ".
Aminoguanidine hydrochloride pharmaceutical composition
The present invention provides a kind of aminoguanidine hydrochloride pharmaceutical composition, and the pharmaceutical composition is creme, and the frost
Agent includes：
(1) aminoguanidine hydrochloride of therapeutically effective amount；
(2) pharmaceutically acceptable auxiliary material, auxiliary material composition cream carrier；
The auxiliary material includes：
(A) water phase；
(B) oil phase, wherein the oil phase includes grape pip base oil and/or Sweet Almond Oil；
(C) emulsifying agent；
With optional component (D) wetting agent and/or (E) bacteriostatic agent.
Water phase
In the present invention, water mutually refers to water, and water can form continuous water phase as solvent in creme.Available for this
The water of invention has no particular limits, and can be pure water, sterile water, distilled water, can also be physiological saline etc..
In the present invention, inventor mutually screens the water in creme, and in a preference, the dosage of the water phase is
350-700 parts by weight, preferable 400-600 parts by weight,.
Oil phase
The oil phase of aminoguanidine hydrochloride pharmaceutical composition includes grape pip base oil and/or Sweet Almond Oil in the present invention.One
In a preference, the oil phase further includes the aliphatic acid of straight or branched, the fatty alcohol of straight or branched, aliphatic or fragrance
One or more in the mineral of race, fatty acid ester, natural oil.
In another preference, the aliphatic acid of the straight or branched is selected from the group：C1-C7 short chain fatty acids, C8-
C10 medium chain fatty acids, the long chain fatty acids of C11-C40, or its combination.
In another preference, the aliphatic acid of the straight or branched is selected from the group：Nutmeg beans acid, pentadecanoic acid, palm fibre
Palmitic acid acid, Heptadecanoic acide, stearic acid, nonadecylic acid, arachidic acid, behenic acid, lignoceric acid, hexacosoic acid, melissane
Sour erucic acid, oleic acid, linoleic acid, laurate, and the aliphatic acid of substitution, or its combination.In another preference, the straight chain
Or the aliphatic acid of side chain is the aliphatic acid of substitution, such as hydroxy fatty acid, such as 12- hydroxy fatty acids and the acid amides of these aliphatic acid
And monoethanolamine.
In another preference, the fatty alcohol of the straight or branched is selected from the group：C1-C7 short chain fatty alcohols, C8-
C10 medium chain fatty acids, the long-chain fatty alcohol of C11-C40, or its combination.In another preference, the straight or branched
Fatty alcohol is selected from the group：Tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, isooctadecane alcohol, nonadecane
Alcohol, eicosanol, tadenan, tetracosanol, hexacosanol, triacontanol, oleyl alcohol, laruyl alcohol, octanol, certain herbaceous plants with big flowers alcohol,
Palmitoleyl alcohol, substitutes fatty alcohol, or its combination.In another preference, the fatty alcohol of the straight or branched is substitution
Fatty alcohol, such as hydroxy fatty alcohols, such as 12- hydroxy fatty alcohols.
In another preference, the fatty alcohol of the straight or branched is stearyl alcohol.
In another preference, during the aliphatic or aromatic mineral are selected from the group：Vaseline, atoleine,
Or its combination.
In another preference, the fatty acid ester is selected from the group：Isopropyl myristate, tristerin, or
It is combined.
In another preference, the natural oil is selected from the group：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 its combination.
In the present invention, inventor screens the oil phase in creme, and in a preference, the dosage of the oil phase is
200-400 parts by weight, the Sweet Almond Oil of grape pip base oil and/or 100-180 parts by weight including 10-20 parts by weight；
In another preference, the dosage of the oil phase is 250-350 parts by weight, including 10-20 parts by weight
The Sweet Almond Oil of grape pip base oil and/or 100-180 parts by weight.
Emulsifying agent
Emulsifying agent in the present invention plays emulsification.Emulsifying agent has hydrophilic lipophilic group at the same time, can be enclosed in point
Around scattered oil phase or water phase, to prevent the assembly again of oil phase or water phase, so as to prepare oil-in-water type creme or water-in-oil type
Creme.The foreign minister of the oil-in-water type creme is water phase, and interior phase is oil phase；The foreign minister of the water-in-oil type creme is oil
Phase, interior phase are water phase.
" hydrophilic lipophilic balance (HLB) " is used for representing the difference of its emulsifying capacity.If HLB is bigger, hydrophilic interaction is got over
Greatly, can stablize to form oil-in-water type creme；If HLB is smaller, lipophile is bigger, can stablize to form water-in-oil type creme.
Oil-in-water emulsifiers are selected in oil-in-water type creme.The hydrophilic group of the oil-in-water emulsifiers molecule compares oleophylic
Base is big and strong, belongs to a kind of hydrophilic emulsifier, is used to prepare oil-in-water type creme, the model of the HLB value of oil-in-water emulsifiers
Enclose for 8-18.The lipophilic group of the water-in-oil emulsifier molecule is bigger and strong than hydrophilic group, belongs to a kind of lipophilic emulsifier, uses
In preparing water-in-oil type creme, the scope of the HLB value of water-in-oil emulsifier is 3-6.
In a preferred embodiment of the invention, the emulsifying agent includes oleic acid.
In the present invention, inventor screens the dosage of emulsifying agent in creme.In a preferred embodiment, the breast
The dosage of agent is 10-30 parts by weight.In another preferred embodiment, the emulsifying agent includes oleic acid, and the dosage of oleic acid is
15-25 parts by weight.
Optional additive
Various additives commonly used in the art, such as wetting agent, bacteriostatic agent can also be added in the creme component of the present invention.
Wetting agent：Creme drying can be prevented to be hardened, keep the appearance and sophistication of creme light, and medicine can be promoted
Absorption, therefore, the dosage of wetting agent should be appropriate, and the creme having good stability can just be made.
In a preferred embodiment, the wetting agent in the present invention is polyalcohol, and representational, the wetting agent is selected from
The following group：Glycerine, ethanol, propane diols, butanediol, polyethylene glycol.
In the creme of the present invention, inventor screens the dosage of wetting agent, in a preference, the wetting
The dosage of agent is 55-105 parts by weight, is preferably 60-100 parts by weight.
Bacteriostatic agent：The growth of bacterium in creme is killed or suppressed, prevents bacteria breed excessive, is detrimental to health.At this
In invention, bacteriostatic agent is not particularly limited, and can be one or more combinations in nipalgin alcohol, nipagin esters.Represent
Property, the bacteriostatic agent in the present invention is selected from the group：Methyl hydroxybenzoate, ethylparaben, propylben, or its combination.
In the creme of the present invention, inventor screens the dosage of bacteriostatic agent, described antibacterial in a preference
The mass fraction of agent is 0.2-1 parts by weight 0.2-0.8 parts by weight.
Preparation method
The present invention provides a kind of preparation method of creme, the method includes step：
(I) by water phase, oil phase, emulsifying agent and optional component wetting agent and/or bacteriostatic agent heating mixing, stir, tentatively
Emulsification；
(II) it is fully emulsified；
(III) aminoguanidine hydrochloride is added, mixes, prepares creme.
In the creme preparation method of the present invention, in the step (I), the heating and temperature control of water phase and oil phase is suitable
When scope, preferably water phase is identical with the temperature of oil phase, the present invention a preference in, the heating-up temperature is 50-
90 DEG C, preferable 60-80 DEG C；
, it is necessary to which the step (II) described in carrying out is fully emulsified after the step (I) is primary emulsifying.In the example of the present invention
In, step (II) emulsifying under 10000-23000 revs/min of rotating speed, fully breast is carried out preferably using homogenizer
Change.
After step (II) is fully emulsified, aminoguanidine hydrochloride is added to the blank creme of step (II) fully emulsified preparation,
Mix, prepare external application aminoguanidine hydrochloride creme.In the preference of the present invention, before aminoguanidine hydrochloride is added, incite somebody to action
The temperature control of blank creme is at 30-50 DEG C after step (II) emulsification.
Application process and purposes
The creme of the present invention is external preparation, and typical application method is that creme is applied to the skin of diabetic simultaneously
At the beginning of sending out disease.
In the creme of the present invention, the dosage of active ingredient is therapeutically effective amount, such as about 1 micro- g kg body daily
The mg/kg weight of weight -20.When using pharmaceutical composition, the medicine of safe and effective amount is suitable for people or mammal, its
Middle safe and effective amount is at least 10 micrograms/kg body weight, and is in most cases no more than 10 mg/kg weight, compared with
It is good for 10 micrograms/mg/kg weight of kg body weight -5.Certainly specific dosage is also contemplated that method of administration, patient health shape
The factors such as condition, within the scope of these are all skilled practitioners technical ability.In addition creme of the present invention can also be together with other therapeutic agents
Using such as transdermal agent (including before, among or afterwards).
In the present invention, the creme is used to prepare prevention and/or treats the medicine of diabetic skin complication.Represent
Property, the diabetic skin complication is pruitus, subcutaneous fat is thinning, thinning of skin, cacesthesia, diabetic keratopathy
Bullous disease, diabetic xanthoma, diabetic keratopathy fash, skin easily infect.
Prevention and/or the method for the treatment of diabetic skin complication
The present invention provides a kind of method prevented and/or treat diabetic skin complication, by giving required object
The frost of the present invention.Representational, the object is behaved or non-human mammal.
Main advantages of the present invention include：
1st, creme of the present invention can substantially reduce the inflammation and oxidative stress status in skin histology, hence it is evident that improve skin group
Microenvironment is knitted, prevents or delay the generation of diabetic lower limb ulcer, even if ulcer occurs, the healing rate of ulcer is also significantly faster than that
The ulcer of this creme is not used.
2nd, this creme specific can reduce the harmful substance AGEs deposited in diabetic skin tissue, to skin histology
Play a protective role
With reference to specific embodiment, the present invention is further explained.It is to be understood that these embodiments are merely to illustrate the present invention
Rather than limit the scope of the invention.The experimental method of actual conditions is not specified in the following example, usually according to conventional strip
Part, or according to the condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Embodiment 1
The present invention provides a kind of aminoguanidine hydrochloride creme prescription, 1 prescription of the embodiment of the present invention is shown in Table 1.
Comparative example
Invention also provides a kind of comparative example prescription of aminoguanidine hydrochloride creme, the prescription of comparative example is shown in Table 1.
Composition in 1 aminoguanidine hydrochloride creme comparative example prescription of table and the embodiment of the present invention 1
The preparation of aminoguanidine hydrochloride creme
The embodiment of the present invention 1 is identical with the creme preparation method of comparative example, and step is as follows：
(1) A phases and B phases are mixed and heated to 70 degrees Celsius respectively, allow A phases to be completely dissolved with B phases.
(2) A phases are slowly injected into B phases under stirring, then proceed to uniform stirring.
(3) after stirring a few minutes, 23000 turns of homogeneous a few minutes, fully emulsified are gone to 10000 with homogenizer
(4) celite acid aminoguanidine is added when temperature drops to 40 degrees Celsius, mixes, prepares creme.
Investigate therapeutic effect of the aminoguanidine hydrochloride to diabetic skin complication
1. experimental design：
Experiment purpose：The aminoguanidine hydrochloride creme of embodiment 1 and comparative example is investigated to diabetes rat back skin tissues
After the influence of microenvironment, and external application aminoguanidine hydrochloride creme, the influence to skin histology ulcer healing.
Animal packet：
A. normal rat
B. diabetes rat
C. 1 creme of diabetes+embodiment (without hydrochloric acid aminoguanidine composition)
D. 1 creme of diabetes+embodiment (hydrochloric aminoguanidine composition)
E. diabetes+comparative example creme (without hydrochloric acid aminoguanidine composition)
F. diabetes+comparative example creme (hydrochloric aminoguanidine composition)
The creme prescription of C with D groups is compared, and for C groups in addition to without hydrochloric acid aminoguanidine component, other components are the same.
The creme prescription of E with F groups is compared, and for E groups in addition to without hydrochloric acid aminoguanidine component, other components are the same.
2. experiment flow：
B, C, D, E and F group rat inject Streptozotocin (STZ), induce as diabetes rat model, treat big after a week
Mouse blood glucose rise, blood glucose value, which maintains 16.7-30mmol/L and is considered as model, to be induced successfully.From second round, C, D, E and F group are big
Mouse starts external-application cream and is intervened, since inducing successfully to AGEs contents, inflammation in skin histology from the 12nd week materials
The expression of the factor and relevant growth factors is with the change with oxidative stress index.
Meanwhile at the 12nd week, A B C D E F groups make the shallow two degree scalding models of rat, observation the 7th, 14,21 day respectively
The healing state of the surface of a wound, using the surface of a wound at the initial stage of scalding as surface of a wound baseline area, with (the surface of a wound face of baseline surface of a wound area-at that time
Product) ÷ baseline surface of a wound cartographic represenation of area Wound healing rates.Healing speed is assessed with this
Meanwhile by observing influence to skin AGEs contents of 1 creme of the embodiment of the present invention and comparative example creme and right
The influence of skin histology thickness, to assess the good and bad of 1 creme of the embodiment of the present invention and comparative example creme
3. experimental result
3.1. diabetes rat model induction situation
After a week, diabetes rat nutrition condition starts to be deteriorated STZ induced diabetic rats, and hair is withered and yellow, tarnishes,
Irritability, more drinks, more foods, diuresis, weight is obvious compared with concurrent control to be mitigated.Blood glucose value is more apparent compared with control group to be increased
(normal group：7±0.2；Diabetes group：26.2±1.78；p<0.01).With the extension of the diabetes rat course of disease, rat body weight
Increase is slow, illustrates that model induces successfully.
3.2. the AGEs contents in skin histology are measured, after skin histology is homogenized, measure ultraviolet light 280nm absorbances
Value, assesses AGEs contents in skin histology, as a result such as Fig. 1：
From figure 1 it appears that the AGEs contents in D groups (aminoguanidine hydrochloride intervention group) rat skin tissue substantially drop
It is low, with B have notable difference (p≤0.01) compared with C groups, illustrate that external application aminoguanidine hydrochloride creme can be reduced in skin histology
The deposition of AGEs, meanwhile, compared with F groups, D groups AGEs is substantially reduced, and shows that AGEs reductions degree is substantially better than F groups, D in D groups
Group creme has excellent preventive and therapeutic action to diabetic skin complication.Numerous studies show, diabetic skin tissue
In a large amount of AGEs deposition infringement recessive with diabetes and chronic ulcer have direct relation.Aminoguanidine plays prevention effect
Key be to reduce skin histology in AGEs content, this experimental result display, in D group cremes, the decline of AGEs
Degree is notable.
3.3.ELSIA method detects the expression of inflammatory factor in skin histology, and the 12nd week skin of diabetic rats tissue is even
After slurry, supernatant tissue is taken after 1000g centrifugations, each sample carries out protein quantification, ELISA method (according to kit operating instruction) inspection
Survey the expression of inflammatory factor in skin histology, IL-1 β (interleukin-11 β), TNF-α (tumor necrosis factor α), IL-6 (interleukins
6), IFN-γ (gamma interferon)
From figure 2 it can be seen that diabetes model induce successfully after 12 weeks, tissue wound does not occur in the case of, sugar
Inflammatory factor in the sick rat skin tissue of urine just has expression, after preventive use aminoguanidine hydrochloride creme, can reduce skin
The expression of inflammatory factor in skin group, and indices are statistically significant (P≤0.05)
3.4. supernatant tissue will be taken after 1000g centrifugations after the homogenate of the 12nd week skin of diabetic rats tissue, each sample into
Row protein quantification, commodity in use kit processing sample, is aoxidized by detecting the absorbance of sample to measure in each sample
Stress index expression, detection index of correlation it is as follows：ROS (active oxygen radical), T-AOC (total antioxidant capacity), CAT (mistakes
Hydrogen oxide enzyme), SOD (superoxide dismutase)
From figure 3, it can be seen that diabetes model induce successfully after 12 weeks, tissue wound does not occur in the case of, sugar
High expression status is presented in oxidative stress index ROS in the sick rat skin tissue of urine, and total antioxidant capacity T-AOC substantially drops
It is low, in diabetic skin tissue the expression of relevant antioxidase substantially increase, illustrate that body is still in a kind of compensated state,
After preventive use aminoguanidine hydrochloride creme, the expression of the oxidative stress status in skin group can be reduced, and indices are equal
Statistically significant (P≤0.05)
3.5. the statistics of Wound healing rate, counts the wound healing situation of rat 7,14,21 respectively
Figure 4, it is seen that with the extension of observation number of days, healing trend, hydrochloric acid is presented in the intervention group rat surface of a wound
Although the healing rate of the aminoguanidine creme intervention group surface of a wound is significantly lower than normal rat, apparently higher than diabetes rats.
3.6. influence of each group creme to skin histology thickness is investigated,
Count the 12nd week, the numerical statistic of each group rat skin thickness is as shown in Figure 5：
It can be seen from the figure that for F groups, D groups can substantially increase skin of diabetic rats thickness, and thickness increases
About 0.3mm is added, it is well known that skin thickness often increases 0.1mm, the effect of skin histology ulcer healing and the resistance to environment
The enhancing of multiple is presented, therefore experiment shows that compared with comparative example creme, the creme in the embodiment of the present invention 1 can increase skin
Skin tissue thickness, improves the preventive and therapeutic action to diabetic complication.
4. summarize：
The above-mentioned experimental result of comprehensive assessment, in the aminoguanidine hydrochloride of the preventative external application present invention of diabetic animal rat back
Creme can significantly reduce inflammation and oxidative stress status in skin histology, skin histology microenvironment be improved obvious.One
Denier rat meets with wound, and the healing rate of the aminoguanidine hydrochloride intervention group rat surface of a wound is apparently higher than non-intervention group.Illustrate preventative
After intervening using aminoguanidine hydrochloride creme, the healing of the surface of a wound can be promoted.
Originally it is demonstrated experimentally that external application aminoguanidine hydrochloride creme can significantly improve skin microenvironment, the healing of the surface of a wound is promoted.
And 1 creme of the embodiment of the present invention is substantially better than comparative example creme in terms of AGEs contents and increase skin histology thickness is reduced.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To be made various changes or modifications to the present invention, such equivalent forms equally fall within the model that the application the appended claims are limited
Enclose.
Claims (10)
1. a kind of aminoguanidine hydrochloride pharmaceutical composition, it is characterised in that the pharmaceutical composition is creme, and the creme
Including：
(1) aminoguanidine hydrochloride of therapeutically effective amount；
(2) pharmaceutically acceptable auxiliary material, auxiliary material composition cream carrier；
The auxiliary material includes：
(A) water phase；
(B) oil phase, wherein the oil phase includes grape pip base oil and/or Sweet Almond Oil；
(C) emulsifying agent；
With optional component (D) wetting agent and/or (E) bacteriostatic agent.
2. composition as claimed in claim 1, it is characterised in that the emulsifying agent includes oleic acid.
3. composition as claimed in claim 1, it is characterised in that the creme includes：
(a) aminoguanidine hydrochloride of 35-65 parts by weight；
(b) the water phase of 350-700 parts by weight；
(c) oil phase of 200-400 parts by weight, including the grape pip base oil and/or 100-180 weight of 10-20 parts by weight
The Sweet Almond Oil of part；
(d) emulsifying agent of 10-30 parts by weight；
With it is optional
(e) wetting agent of 55-105 parts by weight；And/or
(f) bacteriostatic agent of 0.2-1 parts by weight.
4. composition as claimed in claim 2, it is characterised in that the dosage of the oleic acid is 15-25 parts by weight.
5. composition as claimed in claim 1, it is characterised in that the oil phase further include straight or branched aliphatic acid,
One or more in the fatty alcohol of straight or branched, aliphatic or aromatic mineral, fatty acid ester, natural oil.
6. composition as claimed in claim 1, it is characterised in that the wetting agent is polyalcohol.
7. composition as claimed in claim 1, it is characterised in that the bacteriostatic agent is selected from the group：Nipalgin alcohol, nipalgin
Fat, or its combination.
8. the preparation method of composition as claimed in claim 1, it is characterised in that the method includes step：
(I) it is water phase, oil phase, emulsifying agent and optional component wetting agent and/or bacteriostatic agent heating mixing, stirring is primary emulsifying；
(II) it is fully emulsified；
(III) aminoguanidine hydrochloride is added, mixes, prepares creme.
9. a kind of purposes of composition as claimed in claim 1, it is characterised in that be used to prepare prevention and/or treatment glycosuria
The medicine of sick dermatological complications.
A kind of 10. method for preventing and/or treating diabetic skin complication, it is characterised in that required right by giving
As composition as claimed in claim 1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113289003A (en) * | 2021-06-28 | 2021-08-24 | 北京清美联创干细胞科技有限公司 | Stem cell factor composition and application thereof |
| CN113768946A (en) * | 2020-05-25 | 2021-12-10 | 南京帝昌医药科技有限公司 | Ointment for treating diabetic skin complications and preparation method thereof |
| CN114848739A (en) * | 2022-02-09 | 2022-08-05 | 高一涵 | Chinese herbal medicine patch |
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| CN105411919A (en) * | 2015-12-01 | 2016-03-23 | 武汉光阴树生态科技有限公司 | Skin caring product made from roses and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113768946A (en) * | 2020-05-25 | 2021-12-10 | 南京帝昌医药科技有限公司 | Ointment for treating diabetic skin complications and preparation method thereof |
| CN113289003A (en) * | 2021-06-28 | 2021-08-24 | 北京清美联创干细胞科技有限公司 | Stem cell factor composition and application thereof |
| CN114848739A (en) * | 2022-02-09 | 2022-08-05 | 高一涵 | Chinese herbal medicine patch |
| CN114848739B (en) * | 2022-02-09 | 2024-03-15 | 高一涵 | Chinese herbal medicine patch |
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| CN107961231B (en) | 2020-06-05 |
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