CN107157966A - A kind of nano-encapsulated retinene blemish clearing gel and preparation method thereof - Google Patents
A kind of nano-encapsulated retinene blemish clearing gel and preparation method thereof Download PDFInfo
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Abstract
A kind of nano-encapsulated retinene blemish clearing gel and preparation method thereof, including following raw material by weight：The parts by weight of retinene 0.5 5；The parts by weight of vitamin C 13；The parts by weight of phosphatidase 1 20；The parts by weight of polyethylene glycol 20 20 40；Trivent OCG or the parts by weight of Triglyceride DDD 10 20%；The parts by weight of glycerine 10 30；The parts by weight of water 5 10.Nano-encapsulated retinene blemish clearing gel of the present invention and preparation method thereof, manufacture craft is simple, raw material meets cosmetics health specification；To various stage acne effects significantly, get married group invariably substantially.
Description
Technical field
The present invention relates to cosmetic composition or dermatological composition, more particularly to a kind of nano-encapsulated retinene anti-acne
Gel and preparation method thereof.
Background technology
Acne is pilosebaceous follicle chronic inflammatory skin caused by many factors.Basic reason is endocrinopathy,
3male hormone secretion is vigorous to be caused.The cause of disease of acne is also relevant with some pathogenic bacterial infections, it has already been proven that the generation of acne and third
Sour bacillus acnes infection is relevant.This bacillus acnes is parasitized in hebetic pilosebaceous follicle, passes through lipase
Effect, hydrolyzable triglyceride produces more free fatty, and these free fatties can occur hair follicle and perifollicolar
Nonspecific inflammation reacts.When inflammation is heavier, warts, tumour may occur in which.
Tretinoin medicines external application have the differentiation of regulation epidermal keratinocytes, improve pilosebaceous duct angling, it is molten
Solve micro mist thorn and acne and antiinflammatory action, also with control acne inflammation after pigmentation and improve Acne Scar the effects such as, and
Anti-inflammatory, antibacterial Drug combination can increase the percutaneous permeability of related drugs.
Skin irritation symptom may be caused in the use of Tretinoin, such as burn sense, erythema and furfur, skin damaged may be made brighter
It is aobvious, but show that medicine is the exacerbation of the state of an illness just in action, not simultaneously.Skin is suitable for and is resistant to mostly, stimulates phenomenon can be by
Step disappears.
Widely, but due to local excitation, its clinic is limited to a certain extent should for effect of the Tretinoin in skin disease
With.Tretinoin has a teratogenesis simultaneously, contraindication in pregnancy, therefore prohibits the use of in cosmetics (2015 cosmetics safety technical specifications
The upper limit of detection 0.0005% of middle regulation Tretinoin).
Retinene (Retinaldehyde, RAL) is also referred to as axerophthal, is the derivative after retinoic acid oxidation, be by β-
Oxidation scission generation occurs for carrotene, and reduction obtains retinol, and oxidation obtains retinoic acid.In the natural Tretinoin of retinene
Between metabolite, with the biological activity similar to Tretinoin, and skin is substantially better than Tretinoin to its tolerance.RAL
Need to be converted into after Tretinoin just playing a role by the enzyme in keratinocyte, so RAL has the biology similar to Tretinoin
Learn activity.One of index of Tretinoin activity is exactly inducing cell Tretinoin associated proteins (CRABP-2) expression, and external application RAL can be bright
It is aobvious to induce CRABP-2mRNA and protein expression.External natural Tretinoin also can induce the expression of core Retinoic acid receptor because.With dimension
A acid is the same, and RAL also has regulation cell propagation and the function of differentiation.It can increase epidermis DNA synthesis, increase epidermal thickness, lure
Lead 50kD keratin, the mRNA expression of reduction 7OkD keratin.Induce positivity angling, the mRNA expression of reduction 65kD keratin, increase
Filaggrin and loricrin (loricrin) mRNA expression.In addition, RAL also participates in adjusting the new vascular generation in skin,
Suppress keratinocyte and produce VEGF.Repair elastic fibers and the collagen damage of UVA inductions.Retinene mesh
Preceding application is mainly：Retinene can resist skin aging caused by ultrasound and fluid technique；Retinene can be effectively improved
Skin photoage symptom；The tolerance of retinol and retinene is good, and the larger retinene of retinoic acid excitant can effectively press down
Tabulation hull melanin；Anti-wrinkle：Promote collagen and hyaluronic acid synthesis, increase skin thickness and elasticity, anti-wrinkle Firm；Whitening
Nti-freckle：Suppress B16 cell, reduce pigment deposition, whitening spot-removing；Anti-aging：It is anti-oxidant, to resisting age of skin；Treat skin
Light aging.
But, it is not found the technology that retinene is applied directly to anti-acne and anti-acne India side face at present, because, anti-acne
It is a phasic course with anti-acne printed books body, is generally treated now using retinoic acid, its excitant is strong, and side effect is big.
Due to the unstability of retinene, retinene in application process it is oxidizable be retinoic acid, the oxidizable reduction of retinene simple substance, no
Easily storage.This also causes application of the retinene in anti-acne, anti-acne India side face to turn into a technical barrier.
The content of the invention
For defect of the prior art, a kind of anti-acne of present invention offer or anti-acne print effect are notable, safe and reliable, prepare
Easily, excitant, nano-encapsulated retinene blemish clearing gel of resistance to storage of Tretinoin and preparation method thereof are avoided.
A kind of nano-encapsulated retinene liposome, it is made up of following raw material by weight percentage：
Retinene 0.5-5 parts by weight；
Vitamin C 1-3 parts by weight；
The parts by weight of phosphatidase 1-20；
The 20-40 parts by weight of polyethylene glycol -20；
Trivent OCG or Triglyceride DDD 10-20 parts by weight；
Glycerine 10-30 parts by weight；
Water 5-10 parts by weight.
The preparation method of nano-encapsulated retinene liposome, is comprised the following steps that：
S1, weigh each component, into container add phosphatide (phosphoglyceride), polyethylene glycol -20, Trivent OCG or
Triglyceride DDD, glycerine, ultrasonically treated 5-7 minutes to being completely dissolved；Carry out heating water bath, heat 30-40 minutes, and to its
Middle addition ethanol, obtains solution；
S2, the retinene that the obtained solution of step S1 is slowly injected into 50-60 DEG C of constant temperature, keeping temperature is constant, and carries out
Magnetic agitation, mixing time is 50-70 minutes, then simultaneously adds water, vitamin C thereto；
S3, it is warming up to 60-75 DEG C, and continuing magnetic force is stirred 30-40 minutes, obtains retinene liposome turbid liquor, high pressure
Homogeneous makes particle diameter reach requirement, and freeze-drying prepares nano-encapsulated retinene liposome.
In the present invention, as a kind of perferred technical scheme, in step S1, the temperature of heating water bath is 75-85 DEG C.
In the present invention, as a kind of perferred technical scheme, in step S2, powder is made in retinene, and addition speed is 2-
8g/min。
In the present invention, as a kind of perferred technical scheme, in step S2, the speed of magnetic agitation is 100-150 revs/min
Clock.
In the present invention, as a kind of perferred technical scheme, in step S3, the pressure used when high-pressure homogeneous is 3.2-
3.7MPa。
A kind of gel, it is made up of following raw material by weight：
Nano-encapsulated retinene liposome 1-5 parts by weight；
Macromolecule thickener 1-3 parts by weight；
Glycerine 5-10 parts by weight；
Allantoin 0.05-0.5 parts by weight；
Hexamidine dihydroxy ethyl sulfonate 0.1-1 parts by weight；
Cetylpyridinium Chloride 0.2-0.8 parts by weight；
Deionized water 80.6-92.86 parts by weight.
In the present invention, as a kind of perferred technical scheme, the gel is made up of the raw material of following parts by weight：
The parts by weight of nano-encapsulated retinene liposome 3,
The parts by weight of macromolecule thickener 2,
The parts by weight of glycerine 7.5,
The parts by weight of allantoin 0.275,
The parts by weight of hexamidine dihydroxy ethyl sulfonate 0.075,
The parts by weight of Cetylpyridinium Chloride 0.5,
The parts by weight of deionized water 86.65.
In the present invention, as a kind of perferred technical scheme, macromolecule thickener uses polyvinylpyrrolidone, PVM/MA
The mixture of decadiene crosslinked polymer, both weight ratios are 3：1.
The preparation method of nano-encapsulated retinene blemish clearing gel, comprises the following steps：
(1) macromolecule thickener, glycerine, allantoin are sequentially added first and dissolves and stir in deionized water, it is quiet
Put and be cooled to normal temperature；
(2) hexamidine dihydroxy ethyl sulfonate, Cetylpyridinium Chloride, nano-encapsulated retinene liposome are added and stirred,
Nano-encapsulated retinene gel is made.
In the present invention, as a kind of perferred technical scheme, the speed of stirring is 50-60 revs/min in step (1).
In the present invention, as a kind of perferred technical scheme, the step (1) and step (2) it is sterile in anaerobic
Under the conditions of carry out.
The application of retinene, the nano-encapsulated retinene liposome, the gel in anti-acne or anti-acne India side face.
Due to using above technical scheme, the present invention has the advantages that：
Retinene (RAL) is the mesostate of natural Tretinoin, with the biological activity similar to Tretinoin, and
Skin is substantially better than Tretinoin to its tolerance.The heavy dose of the exogenous Tretinoin of non-physiological dose is acted on skin, meeting
Cause the excess load of Tretinoin Dependent in skin, so as to cause the adverse reactions such as skin irritatin.RAL is the natural of retinol
The direct precursor material of metabolite and Tretinoin, has similar biological activity to Tretinoin.It again can multidirectional generation simultaneously
Thanking --- the RAL of excess load can quickly be reduced into retinol, then storage, " inactivation " in the form of ester.A small amount of is oxidized to dimension A
Acid, plays significant biological action.It it also avoid the skin adverse reaction caused by heavy dose of Tretinoin.Sustained release is reached
Stable biological effectiveness, RAL also has dissolving acne and the direct bactericidal action to acne Propionibacterium, to related strain
Minimum inhibitory concentration is respectively 4mg/L and 8mg/L, and all-trans retinoic acid, without direct antibacterial activity, its minimum inhibitory concentration exceedes
128mg/L, it is by reducing sebum secretion and indirectly bacteria growing inhibiting.RAL and Tretinoin have to Rhino mouse models
The effect of significant dissolving acne.In addition, isotretinoin, all-trans retinoic acid and 9- may also suppress sebocyte cell along Tretinoin
Propagation, the effect is the selective dependence process of Retinoic acid receptor, and RAL is used as its precursor substance, it may have suppresses sebocyte cell and increases
The effect grown.In summary, RAL has expected treatment acne effect (particularly to first, mid-term acne), while to skin
The security of skin is much better than Tretinoin.Retinene after lecithin parcel substantially increases the stability and biological utilisation of retinene
Degree.Allantoin is a kind of amphoteric compound, many kinds of substance formation double salt can be combined, with lucifuge, sterilization and anticorrosion, analgesic, antioxygen
Change is acted on, and skin can be made to keep moisture content, is moistened and soft, allantoin have protective tissue, it is hydrophilic, absorb water and prevent moisture from distributing
Deng effect；Allantoin promotion organization grows, cell metabolism, cutin-softening layer albumen.Hexamidine dihydroxy ethyl sulphonate-base
This colorless and odorless, with slight convergence, no skin irritation, with broad-spectrum sterilization, also possesses UV absorption and antioxygen
The property changed, stability is good, safe, is easy to long term storage.Cetylpyridinium Chloride is cationic nitrogenous surfactant, primary to sterilize
Disinfectant.Biology is refined glycerine, except glycerine is contained, also the reduced sugar such as esters, glucose, belongs to polyalcohols glycerine；Remove
Outside with moisturizing, humectation function, also with the special efficacy such as high activity, anti-oxidant, rush alcoholization.
Anti-acne and anti-acne printed books body are a phasic courses, and are generally treated using retinoic acid, and its excitant is strong,
Side effect is big.Due to the unstability of retinene, it is retinoic acid that retinene is oxidizable in application process, causes current there is no to regard
Yellow aldehyde is difficult storage in the application in anti-acne and anti-acne India side face, the oxidizable reduction of retinene simple substance.With reference to the excellent of retinene simple substance
Good effect, prepares a kind of stable carrier containing retinene and just seems particularly necessary.And the present invention is a large amount of by inventor
Experiment repeatedly, eventually through rational proportioning, production technology, prepares nano-encapsulated retinene liposome and gel, its
Therapeutic effect is notable, stability is strong, and bioavilability is higher.In addition, anti-acne, anti-acne print and destratum corneum effect of dispelling spots mechanism phase
Difference is larger, and anti-acne, anti-acne print are interim process, and retinene is not sufficiently stable, and are reached for antibacterial, sterilization, acne print repairing effect
Less than optimal.
Nano-encapsulated retinene blemish clearing gel of the present invention and preparation method thereof, raw material meets cosmetics health specification, controls
Therapeutic effect is notable, safe and reliable, notable to various stage acne effects, and cure rate can reach 95%, the group that gets married invariably substantially, system
Standby technique is simple, avoid Tretinoin excitant, resistance to storage.
Embodiment
The following examples are only intended to illustrate the technical solution of the present invention more clearly, therefore is only used as example, and can not
Limited the scope of the invention with this.
Embodiment 1
A kind of nano-encapsulated retinene liposome, it is made up of following raw material by weight percentage：Retinene 0.5
Parts by weight；The parts by weight of vitamin C 1；Phosphatidase 1 parts by weight；The parts by weight of polyethylene glycol -20 20；Trivent OCG or capric acid are sweet
The oily parts by weight of three ester 10；The parts by weight of glycerine 10；The parts by weight of water 5.
The preparation method of the present embodiment is comprised the following steps that：
S1, weighing each component, phosphoglyceride, polyethylene glycol -20, Trivent OCG or capric acid are added into container sweet
Oily three esters, glycerine, ultrasonically treated 5 minutes to being completely dissolved；Heating water bath is carried out, the temperature of heating water bath is 75 DEG C, heating 30
Minute, and ethanol is added thereto, obtain solution；
Powder is made in S2, the retinene that the obtained solution of step S1 is slowly injected into 50 DEG C of constant temperature, retinene, adds speed
For 2g/min, keeping temperature is constant, and carries out magnetic agitation, and the speed of magnetic agitation is 100 revs/min, and mixing time is 50
Minute, then water, vitamin C are added thereto simultaneously；
S3, it is warming up to 60 DEG C, and continuing magnetic force is stirred 30 minutes, obtains retinene liposome turbid liquor, it is high-pressure homogeneous to make
Particle diameter reaches requirement, and the pressure used when high-pressure homogeneous is 3.2MPa, and freeze-drying prepares nano-encapsulated retinene fat
Plastid.
Embodiment 2
A kind of nano-encapsulated retinene liposome, it is made up of following raw material by weight percentage：The weight of retinene 5
Measure part；The parts by weight of vitamin C 3；The parts by weight of phosphatidase 20；The parts by weight of polyethylene glycol -20 40；Trivent OCG or capric acid glycerine
The parts by weight of three ester 20；The parts by weight of glycerine 30；The parts by weight of water 10.
The preparation method of the present embodiment is comprised the following steps that：
S1, weigh each component, into container add phosphatide (phosphoglyceride), polyethylene glycol -20, Trivent OCG or
Triglyceride DDD, glycerine, ultrasonically treated 7 minutes to being completely dissolved；Heating water bath is carried out, the temperature of heating water bath is 85 DEG C,
Heating 40 minutes, and ethanol is added thereto, obtain solution；
Powder is made in S2, the retinene that the obtained solution of step S1 is slowly injected into 60 DEG C of constant temperature, retinene, adds speed
For 8g/min, keeping temperature is constant, and carries out magnetic agitation, and the speed of magnetic agitation is 150 revs/min, and mixing time is 70
Minute, then water, vitamin C are added thereto simultaneously；
S3, it is warming up to 75 DEG C, and continuing magnetic force is stirred 40 minutes, obtains retinene liposome turbid liquor, it is high-pressure homogeneous to make
Particle diameter reaches requirement, and the pressure used when high-pressure homogeneous is 3.7MPa, and freeze-drying prepares nano-encapsulated retinene fat
Plastid.
Embodiment 3
A kind of nano-encapsulated retinene liposome, it is made up of following raw material by weight percentage：Retinene 2.5
Parts by weight；The parts by weight of vitamin C 2；The parts by weight of phosphatidase 10；The parts by weight of polyethylene glycol -20 30；Trivent OCG or capric acid are sweet
The oily parts by weight of three ester 15；The parts by weight of glycerine 20；The parts by weight of water 7.
The preparation method of the present embodiment is comprised the following steps that：
S1, weigh each component, into container add phosphatide (phosphoglyceride), polyethylene glycol -20, Trivent OCG or
Triglyceride DDD, glycerine, ultrasonically treated 6 minutes to being completely dissolved；Heating water bath is carried out, the temperature of heating water bath is 80 DEG C,
Heating 35 minutes, and ethanol is added thereto, obtain solution；
Powder is made in S2, the retinene that the obtained solution of step S1 is slowly injected into 55 DEG C of constant temperature, retinene, adds speed
For 5g/min, keeping temperature is constant, and carries out magnetic agitation, and the speed of magnetic agitation is 120 revs/min, and mixing time is 60
Minute, then water, vitamin C are added thereto simultaneously；
S3, it is warming up to 65 DEG C, and continuing magnetic force is stirred 35 minutes, obtains retinene liposome turbid liquor, it is high-pressure homogeneous to make
Particle diameter reaches requirement, and the pressure used when high-pressure homogeneous is 3.5MPa, and freeze-drying prepares nano-encapsulated retinene fat
Plastid.
Embodiment 4
A kind of nano-encapsulated retinene liposome, it is made up of following raw material by weight percentage：Retinene 0.5
Parts by weight；The parts by weight of vitamin C 3；Phosphatidase 1 parts by weight；The parts by weight of polyethylene glycol -20 40；Trivent OCG or capric acid are sweet
The oily parts by weight of three ester 10；The parts by weight of glycerine 30；The parts by weight of water 5.
The preparation method of the present embodiment is comprised the following steps that：
S1, weigh each component, into container add phosphatide (phosphoglyceride), polyethylene glycol -20, Trivent OCG or
Triglyceride DDD, glycerine, ultrasonically treated 7 minutes to being completely dissolved；Heating water bath is carried out, the temperature of heating water bath is 75 DEG C,
Heating 40 minutes, and ethanol is added thereto, obtain solution；
Powder is made in S2, the retinene that the obtained solution of step S1 is slowly injected into 50 DEG C of constant temperature, retinene, adds speed
For 8g/min, keeping temperature is constant, and carries out magnetic agitation, and the speed of magnetic agitation is 100 revs/min, and mixing time is 70
Minute, then water, vitamin C are added thereto simultaneously；
S3, it is warming up to 60 DEG C, and continuing magnetic force is stirred 40 minutes, obtains retinene liposome turbid liquor, it is high-pressure homogeneous to make
Particle diameter reaches requirement, and the pressure used when high-pressure homogeneous is 3.3MPa, and freeze-drying prepares nano-encapsulated retinene fat
Plastid.
Embodiment 5
A kind of nano-encapsulated retinene liposome, it is made up of following raw material by weight percentage：Retinene 4.5
Parts by weight；The parts by weight of vitamin C 1；The parts by weight of phosphatidase 15；The parts by weight of polyethylene glycol -20 21；Trivent OCG or capric acid are sweet
The oily parts by weight of three ester 20；The parts by weight of glycerine 12；The parts by weight of water 9.
The preparation method of the present embodiment is comprised the following steps that：
S1, weigh each component, into container add phosphatide (phosphoglyceride), polyethylene glycol -20, Trivent OCG or
Triglyceride DDD, glycerine, ultrasonically treated 6 minutes to being completely dissolved；Heating water bath is carried out, the temperature of heating water bath is 83 DEG C,
Heating 30 minutes, and ethanol is added thereto, obtain solution；
Powder is made in S2, the retinene that the obtained solution of step S1 is slowly injected into 60 DEG C of constant temperature, retinene, adds speed
For 3g/min, keeping temperature is constant, and carries out magnetic agitation, and the speed of magnetic agitation is 140 revs/min, and mixing time is 50
Minute, then water, vitamin C are added thereto simultaneously；
S3, it is warming up to 75 DEG C, and continuing magnetic force is stirred 30 minutes, obtains retinene liposome turbid liquor, it is high-pressure homogeneous to make
Particle diameter reaches requirement, and the pressure used when high-pressure homogeneous is 3.6MPa, and freeze-drying prepares nano-encapsulated retinene fat
Plastid.
Embodiment 6
A kind of gel, it is made up of following raw material by weight：The parts by weight of nano-encapsulated retinene liposome 1；It is high
The parts by weight of molecule thickener 1；The parts by weight of glycerine 5；The parts by weight of allantoin 0.05；The parts by weight of hexamidine dihydroxy ethyl sulfonate 0.1；
The parts by weight of Cetylpyridinium Chloride 0.2；The parts by weight of deionized water 80.6, wherein, macromolecule thickener uses polyvinylpyrrolidone, PVM/
The mixture of MA decadiene crosslinked polymers, both weight ratios are 3：1.
The preparation method of the present embodiment nano-encapsulated retinene blemish clearing gel, comprises the following steps：
(1) macromolecule thickener, glycerine, allantoin are sequentially added first and dissolves and stir in deionized water, stirred
The speed mixed is 50 revs/min, and standing is cooled to normal temperature；
(2) hexamidine dihydroxy ethyl sulfonate, Cetylpyridinium Chloride, nano-encapsulated retinene liposome are added and stirred,
Nano-encapsulated retinene gel is made.
Wherein, the progress under conditions of anaerobic is sterile of the step (1) and step (2).
Embodiment 7
A kind of gel, it is made up of following raw material by weight：The parts by weight of nano-encapsulated retinene liposome 5；It is high
The parts by weight of molecule thickener 3；The parts by weight of glycerine 10；The parts by weight of allantoin 0.5；The parts by weight of hexamidine dihydroxy ethyl sulfonate 1；West
The parts by weight of pyrrole oronain 0.8；The parts by weight of deionized water 92.86, wherein, macromolecule thickener uses polyvinylpyrrolidone, PVM/
The mixture of MA decadiene crosslinked polymers, both weight ratios are 3：1.
The preparation method of the present embodiment nano-encapsulated retinene blemish clearing gel, comprises the following steps：
(1) macromolecule thickener, glycerine, allantoin are sequentially added first and dissolves and stir in deionized water, stirred
The speed mixed is 60 revs/min, and standing is cooled to normal temperature；
(2) hexamidine dihydroxy ethyl sulfonate, Cetylpyridinium Chloride, nano-encapsulated retinene liposome are added and stirred,
Nano-encapsulated retinene gel is made.
Wherein, the progress under conditions of anaerobic is sterile of the step (1) and step (2).
Embodiment 8
A kind of gel, is made up of the raw material of following parts by weight：The parts by weight of nano-encapsulated retinene liposome 3, macromolecule increases
Thick dose of 2 parts by weight, the parts by weight of glycerine 7.5, the parts by weight of allantoin 0.275, the parts by weight of hexamidine dihydroxy ethyl sulfonate 0.075,
The parts by weight of Cetylpyridinium Chloride 0.5, the parts by weight of deionized water 86.65, wherein, macromolecule thickener using polyvinylpyrrolidone,
The mixture of PVM/MA decadiene crosslinked polymers, both weight ratios are 3：1.
The preparation method of the present embodiment nano-encapsulated retinene blemish clearing gel, comprises the following steps：
(1) macromolecule thickener, glycerine, allantoin are sequentially added first and dissolves and stir in deionized water, stirred
The speed mixed is 55 revs/min, and standing is cooled to normal temperature；
(2) hexamidine dihydroxy ethyl sulfonate, Cetylpyridinium Chloride, nano-encapsulated retinene liposome are added and stirred,
Nano-encapsulated retinene gel is made.
Wherein, the progress under conditions of anaerobic is sterile of the step (1) and step (2).
Embodiment 9
A kind of gel, it is made up of following raw material by weight：The parts by weight of nano-encapsulated retinene liposome 1；It is high
The parts by weight of molecule thickener 3；The parts by weight of glycerine 5；The parts by weight of allantoin 0.5；The parts by weight of hexamidine dihydroxy ethyl sulfonate 0.1；
The parts by weight of Cetylpyridinium Chloride 0.8；The parts by weight of deionized water 80.6, wherein, macromolecule thickener uses polyvinylpyrrolidone, PVM/
The mixture of MA decadiene crosslinked polymers, both weight ratios are 3：1.
The preparation method of the present embodiment nano-encapsulated retinene blemish clearing gel, comprises the following steps：
(1) macromolecule thickener, glycerine, allantoin are sequentially added first and dissolves and stir in deionized water, stirred
The speed mixed is 50 revs/min, and standing is cooled to normal temperature；
(2) hexamidine dihydroxy ethyl sulfonate, Cetylpyridinium Chloride, nano-encapsulated retinene liposome are added and stirred,
Nano-encapsulated retinene gel is made.
Wherein, the progress under conditions of anaerobic is sterile of the step (1) and step (2).
Embodiment 10
A kind of gel, it is made up of following raw material by weight：The parts by weight of nano-encapsulated retinene liposome 5；It is high
The parts by weight of molecule thickener 2；The parts by weight of glycerine 9；The parts by weight of allantoin 0.05；The parts by weight of hexamidine dihydroxy ethyl sulfonate 1；West
The parts by weight of pyrrole oronain 0.3；The parts by weight of deionized water 91, wherein, macromolecule thickener uses polyvinylpyrrolidone, the PVM/MA last of the ten Heavenly stems
The mixture of diene cross-linked polymer, both weight ratios are 3：1.
The preparation method of the present embodiment nano-encapsulated retinene blemish clearing gel, comprises the following steps：
(1) macromolecule thickener, glycerine, allantoin are sequentially added first and dissolves and stir in deionized water, stirred
The speed mixed is 58 revs/min, and standing is cooled to normal temperature；
(2) hexamidine dihydroxy ethyl sulfonate, Cetylpyridinium Chloride, nano-encapsulated retinene liposome are added and stirred,
Nano-encapsulated retinene gel is made.
Wherein, the progress under conditions of anaerobic is sterile of the step (1) and step (2).
Accept patients with acne 60 for medical treatment in the recent period, be equally divided into treatment group 30 and control group 30.Treatment group man 16, female 14
Example；The course of disease 1~9 year, it is average 5 years；It is 14~32 years old age, average 23 years old；Wherein acne type acne 3, papular type acne 14,
Papulopustular type acne 11, Acne conglobata 2.Control group man 13, female 17；The course of disease 1~8 year, it is average 4 years；Age
It is 13~32 years old, average 22 years old；Wherein acne type acne 5, papular type acne 13, papulopustular type acne 10, aggretion type
Acne 2.
Treatment method:Two groups after being dried with warm water cleaning face, treatment group give embodiment 8 preparation gel wipe in trouble
Place, control group is given 2% chloramphenicol tincture and embrocated in affected part, each 1 time sooner or later, adheres to using 1 month.All patients during observation
Disable other any medicines.
Curative effect judging standard:1. cure:Skin lesion is wholly absent, and occurs without new fash；2. it is effective:Skin lesion
Disappearance more than 70%；3. take a turn for the better:Skin lesion disappearance more than 30%；4. it is invalid:Skin lesion disappearance less than 30%.
As a result treatment group's total effective rate 93%, control group total effective rate 70%, two groups for the treatment of results compare, and tool difference has aobvious
All patients are showed no obvious adverse reaction in work property (P ＜ 0.05), whole therapeutic process.It see the table below.
| Group | n | Cure | Effectively | Take a turn for the better | It is invalid |
| Treatment group | 30 | 13 | 11 | 5 | 1 |
| Control group | 30 | 5 | 10 | 6 | 9 |
Various embodiments above is merely illustrative of the technical solution of the present invention, rather than its limitations；Although with reference to foregoing each reality
Example is applied the present invention is described in detail, it will be understood by those within the art that：It still can be to foregoing each
Technical scheme described in embodiment is modified, or carries out equivalent substitution to which part or all technical characteristic；And
These modifications are replaced, and the essence of appropriate technical solution is departed from the scope of various embodiments of the present invention technical scheme, its
It all should cover among the claim of the present invention and the scope of specification.
Claims (7)
1. a kind of nano-encapsulated retinene liposome, it is characterised in that including following raw material by weight：
Retinene 0.5-5 parts by weight；
Vitamin C 1-3 parts by weight；
The parts by weight of phosphatidase 1-20；
The 20-40 parts by weight of polyethylene glycol -20；
Trivent OCG or Triglyceride DDD 10-20% parts by weight；
Glycerine 10-30 parts by weight；
Water 5-10 parts by weight.
2. the preparation method of nano-encapsulated retinene liposome according to claim 1, it is characterised in that including following work
Skill step：
S1, weighing each component, phosphatide (phosphoglyceride), polyethylene glycol -20, Trivent OCG or capric acid are added into container
Triglycerides, glycerine, ultrasonically treated 5-7 minutes to being completely dissolved；Heating water bath is carried out, is heated 30-40 minutes, and is added thereto
Enter ethanol, obtain solution；
S2, the retinene that the obtained solution of step S1 is slowly injected into 50-60 DEG C of constant temperature, keeping temperature is constant, and carries out magnetic force
Stirring, mixing time is 50-70 minutes, then simultaneously adds water, vitamin C thereto；
S3, it is warming up to 60-75 DEG C, and continuing magnetic force is stirred 30-40 minutes, obtains retinene liposome turbid liquor, it is high-pressure homogeneous
Particle diameter is set to reach requirement, and freeze-drying prepares nano-encapsulated retinene liposome.
3. a kind of gel, it is characterised in that including following raw material by weight：
Nano-encapsulated retinene liposome 1-5 parts by weight；
Macromolecule thickener 1-3 parts by weight；
Glycerine 5-10 parts by weight；
Allantoin 0.05-0.5 parts by weight；
Hexamidine dihydroxy ethyl sulfonate 0.1-1 parts by weight；
Cetylpyridinium Chloride 0.2-0.8 parts by weight；
Deionized water 80.6-92.86 parts by weight.
4. nano-encapsulated retinene blemish clearing gel according to claim 3, it is characterised in that by the raw material of following parts by weight
It is prepared from：
The parts by weight of nano-encapsulated retinene liposome 3,
The parts by weight of macromolecule thickener 2,
The parts by weight of glycerine 7.5,
The parts by weight of allantoin 0.275,
The parts by weight of hexamidine dihydroxy ethyl sulfonate 0.075,
The parts by weight of Cetylpyridinium Chloride 0.5,
The parts by weight of deionized water 86.65.
5. the preparation method of the nano-encapsulated retinene blemish clearing gel according to claim 3 or 4, it is characterised in that
(1) macromolecule thickener, glycerine, allantoin are sequentially added first and dissolves and stir in deionized water, stand drop
Temperature is to normal temperature；
(2) hexamidine dihydroxy ethyl sulfonate, Cetylpyridinium Chloride, nano-encapsulated retinene liposome are added and stirred, be made
Nano-encapsulated retinene gel.
6. the preparation method of nano-encapsulated retinene blemish clearing gel according to claim 6, it is characterised in that the step
(1) carried out with step (2) under conditions of anaerobic is sterile.
7. retinene, the nano-encapsulated retinene liposome, the gel are in the application in anti-acne or anti-acne India side face.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108542848A (en) * | 2018-05-24 | 2018-09-18 | 广州銮滢化妆品有限公司 | A kind of crease-resistant topical composition and preparation method thereof containing nanometer retinene |
| CN110151603A (en) * | 2019-05-28 | 2019-08-23 | 广东萱嘉医品健康科技有限公司 | A kind of nano-encapsulated leonurine liposome and the preparation method and application thereof |
| CN112807268A (en) * | 2021-01-18 | 2021-05-18 | 宁波御坊堂生物科技有限公司 | Non-greasy make-up and food-homologous aloe gel derived from raw juice and preparation method thereof |
| WO2022014297A1 (en) * | 2020-07-15 | 2022-01-20 | ライオン株式会社 | Composition for external preparation for skin |
| CN116531275A (en) * | 2023-07-04 | 2023-08-04 | 北京青颜博识健康管理有限公司 | Microcapsule for relieving high-concentration vitamin C ethyl ether stimulation and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1874762A (en) * | 2003-11-03 | 2006-12-06 | 巴斯利尔药物股份公司 | New formulation for retinoid-containing soft gelatin capsules |
| CN105939704A (en) * | 2013-12-04 | 2016-09-14 | 盖尔德马研究及发展公司 | Lipid microcapsules preferably comprising a retinoid, and composition containing same, method for the production thereof, and use thereof in dermatology |
-
2017
- 2017-06-14 CN CN201710448812.6A patent/CN107157966B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1874762A (en) * | 2003-11-03 | 2006-12-06 | 巴斯利尔药物股份公司 | New formulation for retinoid-containing soft gelatin capsules |
| CN105939704A (en) * | 2013-12-04 | 2016-09-14 | 盖尔德马研究及发展公司 | Lipid microcapsules preferably comprising a retinoid, and composition containing same, method for the production thereof, and use thereof in dermatology |
Non-Patent Citations (3)
| Title |
|---|
| 李全林: "《新医药开发与研究（下）》", 31 December 2008, 北京：中国医药科技出版社 * |
| 苏强等: "新型杀菌剂——己脒定二羟乙基磺酸盐的特性及其应用", 《日用化妆品科学》 * |
| 蔡向红: "《生活中来的10000个窍门 下》", 31 March 2014, 天津：天津科学技术出版社 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108542848A (en) * | 2018-05-24 | 2018-09-18 | 广州銮滢化妆品有限公司 | A kind of crease-resistant topical composition and preparation method thereof containing nanometer retinene |
| CN110151603A (en) * | 2019-05-28 | 2019-08-23 | 广东萱嘉医品健康科技有限公司 | A kind of nano-encapsulated leonurine liposome and the preparation method and application thereof |
| WO2022014297A1 (en) * | 2020-07-15 | 2022-01-20 | ライオン株式会社 | Composition for external preparation for skin |
| CN115697295A (en) * | 2020-07-15 | 2023-02-03 | 狮王株式会社 | Composition for external application to skin |
| CN112807268A (en) * | 2021-01-18 | 2021-05-18 | 宁波御坊堂生物科技有限公司 | Non-greasy make-up and food-homologous aloe gel derived from raw juice and preparation method thereof |
| CN112807268B (en) * | 2021-01-18 | 2022-06-03 | 宁波御坊堂生物科技有限公司 | Non-greasy make-up and food-homologous aloe gel derived from raw juice and preparation method thereof |
| CN116531275A (en) * | 2023-07-04 | 2023-08-04 | 北京青颜博识健康管理有限公司 | Microcapsule for relieving high-concentration vitamin C ethyl ether stimulation and preparation method and application thereof |
| CN116531275B (en) * | 2023-07-04 | 2023-10-13 | 北京青颜博识健康管理有限公司 | Microcapsule for relieving high-concentration vitamin C ethyl ether stimulation and preparation method and application thereof |
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