CN108135808A - Skin tissue regeneration comprising hollow porous micro sphere or skin histology volume increase composition for injection - Google Patents
Skin tissue regeneration comprising hollow porous micro sphere or skin histology volume increase composition for injection Download PDFInfo
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- CN108135808A CN108135808A CN201680060085.XA CN201680060085A CN108135808A CN 108135808 A CN108135808 A CN 108135808A CN 201680060085 A CN201680060085 A CN 201680060085A CN 108135808 A CN108135808 A CN 108135808A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/31—Hydrocarbons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
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Abstract
The present invention relates to a kind of skin tissue regeneration or skin histology volume increase composition for injection, and it includes hollow porous micro sphere, which includes being formed in the cavity in center and surround the partition wall for including fine pores in above-mentioned cavity.The hollow porous micro sphere included in composition according to the present invention is by the way that with small particle size, so as to be administered by injection into skin histology, the skin tissue cell of above-mentioned movement can be effectively proliferated in above-mentioned cavity.By after a certain period of time, for above-mentioned hollow porous micro sphere in skin after biodegradation, the skin tissue cell of above-mentioned new proliferation also maintains its volume, therefore can maintain skin tissue regeneration effect safely and muchly.
Description
Technical field
The present invention relates to a kind of for improving the skin tissue regeneration of wrinkle of skin and depressed area or skin histology volume
Increase composition for injection.
Background technology
In the beauty treatment medical instrument sold for the purpose of beauty treatment filler (filler) with to wrinkle and
The mode that depressed area skin histology is injected uses.
Most filler is to be injected into skin histology and increase skin histology by the volume of the substance in itself
The mode of volume improve wrinkle of skin or depressed area.Current most commonly used filler has hyaluronic acid and collagen
Isogel form without fixed shape substance, but be absorbed into over time in skin histology and there are its beauty treatment effects
The problem of fruit will not keep for a long time.
In addition, as beauty treatment medical instrument, in order to have wider use scope, need to pass by injecting
It passs, but there is the porous material of the filler ingredient as existing exploitation size can not possibly be moved for several ten more than ㎜ by injecting
It plants in skin histology, the shortcomings that in operation transplantation to skin histology that can only be by cutting skin histology.
[existing technical literature]
[patent document]
Korean Patent Laid the 2011-0075618th
Invention content
It is an object of the present invention to provide porous microsphere being injected into skin histology by injecting, above-mentioned
Make cell Proliferation in porous microsphere and the skin tissue regeneration of the volume of skin histology or the increase of skin histology volume can be increased
Composition for injection.
In order to solve purpose as described above, a viewpoint of the invention is provides a kind of skin tissue regeneration or skin histology
Volume increases composition for injection comprising hollow porous micro sphere, the hollow porous micro sphere include being formed in the cavity in center
With the partition wall for including fine pores for surrounding above-mentioned cavity.
The hollow porous micro sphere that includes is existing so as to solve due to small particle size in the composition of the present invention
Some porous materials need to cut the shortcomings that skin histology is transplanted due to big particle size.
Include being formed in huge cavity central in particle and comprising fine pores since above-mentioned hollow porous micro sphere has
Partition wall dual structure, therefore organism inner skin histocyte can be held by the use of the above-mentioned fine pores as channel
It changes places and is moved in above-mentioned hollow porous micro sphere, the skin tissue cell of above-mentioned movement can effectively increase in above-mentioned cavity
It grows.Moreover, the hollow porous micro sphere of the invention described above can be adapted for wrinkle of skin or depressed area by skin tissue regeneration
Improvement and bone tissue regeneration etc medicinal industry.
In addition, according to the present invention, after some period of time, above-mentioned hollow porous micro sphere is biodegradable in skin
Afterwards, the skin tissue cell of above-mentioned new proliferation also keeps its volume, therefore can expand skin histology volume increase effect, and
The effect can be kept safely and muchly.
Description of the drawings
Fig. 1 according to the type of pore-foaming agent and is contained when representing to manufacture the hollow porous micro sphere of an embodiment according to the present invention
The figure of the particle surface of amount and the electron scanning micrograph of slice.
Fig. 2 be represent to cultivate in the hollow porous micro sphere of an embodiment according to the present invention it is fibroblastic live/dead
(Live/dead) figure of Laser Scanning Confocal Microscope photo is dyed.
Fig. 3 is to be examined after cultivating fibroblast in the hollow porous micro sphere of an embodiment according to the present invention by MTT
Measure out the figure of cell growth rate.
Fig. 4 is to represent that the hollow porous micro sphere by an embodiment according to the present invention is transplanted to after the skin of white mouse to cell
Mobile and regeneration effect figure in porous microsphere.
Fig. 5 is to represent to carry out injectivity to the hollow porous micro sphere of an embodiment according to the present invention using tension tester
The figure of the metamorphosis of porous microsphere before and after measuring.
Specific embodiment
" skin " refers to the organ of the outside of covering biology in this specification, is made of epidermis, corium and subcutaneous layer of fat,
It is the concept of the most broad sense of the tissue of the outside not only comprising covering face or body whole also comprising scalp and hair.
" filler (filler) " refers to be injected into internal filler, reinforcing agent etc. in this specification, be in order to beauty,
Shaping, the broadest meaning for enhancing function and being injected into the substance in epidermis, corium, subcutaneous layer of fat or the joint of skin etc..
" average diameter " refers to the line segment at the both ends of the cross section of connecting object i.e. diameter being averaged in this specification
Value, such as the present invention cavity in the case of, can refer to when the cavity being formed in hollow porous micro sphere for it is aspherical when
The average value of diameter that above-mentioned cavity has itself.Or the diameter for being present in each cavity in multiple microballoons can also be referred to
Average value.In the case of fine pores, it can refer to above-mentioned fine pores when fine pores itself are aspherical and itself have
Diameter average value or multiple fine pores diameter average value.
In the following, the present invention is described in detail.
One embodiment of the invention provides skin tissue regeneration or skin histology volume increase composition for injection, wherein,
Comprising hollow porous micro sphere, which includes being formed in the cavity in center with the above-mentioned cavity of encirclement comprising fine gas
The partition wall in hole.
An embodiment according to the present invention can be provided for skin tissue regeneration or the increased injection of skin histology volume
Method, the above method include will include hollow porous micro sphere composition with effective quantity to object is needed to be administered the step of,
Above-mentioned hollow porous micro sphere includes the cavity for being formed in above-mentioned center and the partition wall for including fine pores for surrounding above-mentioned cavity.
Hollow porous micro sphere can be provided according to another embodiment of the present invention in skin tissue regeneration or skin tissue
Application in the manufacture of product increase composition for injection, above-mentioned hollow porous micro sphere include the cavity and the packet that are formed in above-mentioned center
Place the partition wall for including fine pores for stating cavity.
It can be provided according to another embodiment of the present invention for skin tissue regeneration or the increase injection of skin histology volume
Hollow porous micro sphere, above-mentioned hollow porous micro sphere include being formed in the cavity in above-mentioned center and surround above-mentioned cavity comprising micro-
The partition wall of thin stomata.
As an embodiment, being formed in the cavity in the center of above-mentioned hollow porous micro sphere can be averaged with 5 to 150 μm
Diameter.The growth of cell is difficult when the diameter in above-mentioned cavity is less than 5 μm, when more than 150 μm the intensity of microballoon it is excessively weak and
It may be destroyed when being injected into organism.Specifically, the average diameter in above-mentioned cavity can be 5 μm or more, 10 μm with
It is upper, 13 μm or more, 15 μm or more, 17 μm or more, 20 μm or more, 23 μm or more, 25 μm or more, 27 μm or more, 30 μm or more, 33
μm or more, 35 μm or more, 37 μm or more, 40 μm or more, 43 μm or more, 45 μm or more, 48 μm or more, 50 μm or more, 60 μm with
It is upper, 70 μm or more, 80 μm or more, 90 μm or more, 100 μm or more, 110 μm or more, 120 μm or more, 130 μm or more, 140 μm with
It is upper or 150 μm.In addition, the average diameter in above-mentioned cavity can be less than 150 μm, less than 140 μm, less than 130 μm, 120 μm with
Under, less than 110 μm, less than 100 μm, less than 90 μm, less than 80 μm, less than 70 μm, less than 60 μm, less than 50 μm, less than 47 μm,
Less than 45 μm, less than 43 μm, less than 40 μm, less than 37 μm, less than 35 μm, less than 33 μm, less than 30 μm, less than 28 μm, 25 μm
Below, less than 23 μm, less than 20 μm, less than 18 μm, less than 15 μm, less than 13 μm, less than 10 μm or 5 μm, can but as long as being
It realizes the size of the proliferation of skin tissue cell, is then not limited to above-mentioned size, can include.
As an embodiment, the particle of above-mentioned hollow porous micro sphere included in composition according to the present invention can have
50 to 200 μm of average diameter, but as long as it can be by being injected into skin histology, and can realize that skin histology is thin
The proliferation of born of the same parents is then not limited to above range, can include.Above-mentioned hollow porous micro sphere is by having range as described above
Small particle size, so as to by the way that there is the injection needle of less than 300 μm of internal diameter to being administered in skin histology, by
This can solve the disadvantage that existing porous material needs incision skin histology to be transplanted due to big particle size.When upper
The proliferation for stating skin tissue cell when the diameter of hollow porous micro sphere is less than 50 μm is difficult, is not easily accomplished when more than 200 μm
Utilize the transplanting into skin histology of injection needle.Specifically, the average diameter of above-mentioned hollow porous micro sphere particle can be
50 μm or more, 60 μm or more, 70 μm or more, 80 μm or more, 90 μm or more, 100 μm or more, 110 μm or more, 120 μm or more,
130 μm or more, 140 μm or more, 150 μm or more, 160 μm or more, 170 μm or more, 180 μm or more, 190 μm or more or 200 μm.
In addition, the average diameter of above-mentioned hollow porous micro sphere particle can be less than 200 μm, less than 190 μm, less than 180 μm, 170 μm
Below, less than 160 μm, less than 150 μm, less than 140 μm, less than 130 μm, less than 120 μm, less than 110 μm, less than 100 μm, 90
Below μm, less than 80 μm, less than 70 μm, less than 60 μm or 50 μm.
As an embodiment, the volume in the cavity of above-mentioned hollow porous micro sphere is relative to above-mentioned hollow porous micro sphere whole body
Product can be 20 to 80 volume %.When less than above-mentioned 20 volume %, skin tissue cell proliferation space it is insufficient, when more than
During 80 volume %, the thickness of partition wall becomes too thin, it is thus possible to can cannot keep the form of microballoon and collapse.Implement as one
Example, the thickness of above-mentioned partition wall can be the 1/5 to 1/2 of above-mentioned hollow porous micro sphere whole diameter.
Specifically, the fine pores that the partition wall of above-mentioned hollow porous micro sphere is included can have as an embodiment
5 to 50 μm of average diameter.When less than above-mentioned 5 μm, when above-mentioned hollow porous micro sphere is injected into subcutaneous tissue, skin histology
Cell can not be moved to inside microballoon, and when more than above-mentioned 50 μm, the volume shared by partition wall inner air vent increases and is difficult to keep
The form of microballoon.
For example, the preferred porosity of above-mentioned hollow porous micro sphere can be average 20 to 80%.
The above-mentioned hollow porous micro sphere of an embodiment according to the present invention can include hydrophobic biological as an embodiment
Degraded macromolecular.Specifically, above-mentioned hydrophobic biological degraded macromolecular can be included selected from polylactic acid (Poly-L-Lactic
Acid, PLLA), polyglycolic acid (polyglycolic acid, PGA), polylactic-co-glycolic acid (poly (lactic-
Co-glycolic acid), PLGA), poly-epsilon-caprolactone (Polycaprolactone, PCL), polyanhydride
(polyanhydrides), polyorthoester (polyorthoester), polyvinyl alcohol (polyviniyalcohol), polyethylene glycol
(polyethyleneglycol), polyurethanes (polyurethane), polyacrylic acid (polyacrylic acid),
Poly- n-isopropyl acrylamide (Poly-N-isopropyl acrylamide), poly- (ethylene oxide)-poly- (propylene oxide)-poly-
(ethylene oxide) copolymer (poly ethylene oxide)-poly propylene oxide-poly ethylene
Oxide copolymer), one or more of their copolymer and their mixture, but as long as being to be injected into skin
Safe and decomposable substance when in tissue, then it's not limited to that, can include.
In addition, an embodiment according to the present invention, the cavity of above-mentioned hollow porous micro sphere and fine pores are to pass through stomata
Formed inducing substance, that is, pore-foaming agent (porogen) formed, as long as above-mentioned pore-foaming agent with hydrophobic biological degraded macromolecular not
With intermiscibility and density is less than the hydrophobic fluid of water, then there is no limit can include.Specifically, it is above-mentioned cavity and
Fine pores formed inducing substance can be in the substances of 1atm, less than 250 DEG C with boiling point, 1atm, 30 to 150 DEG C can be with
Substance for liquid.Such as it can be selected from alkane (alkane) class, plant that above-mentioned cavity and fine pores, which form inducing substance,
Property one or more of oil and their mixture.As an embodiment, above-mentioned alkanes are selected from octane (Octane), 11
One or more of alkane (Undecane), tridecane (Tridecane), pentadecane (Pentadecane) and their mixture,
Above-mentioned plant oil can be included selected from soya-bean oil, corn oil, cottonseed oil, olive oil, grape seed oil, walnut oil, sesame oil, Perillaseed
One or more of oil and their mixture.The present invention can be applicable in other materials shape other than above-mentioned specific substance
Into stomata, as an embodiment, the present invention can be according to the pore-foaming agent for forming stomata when manufacturing above-mentioned hollow porous micro sphere
Concentration and type are adjusted hollow and fine pores sizes and form, and can increase the stomata uniformity.
According to an embodiment, in composition present invention as described above, above-mentioned skin tissue regeneration or skin histology
Volume increase can be included as an embodiment, and organism inner skin histocyte is by above-mentioned fine pores to above-mentioned hollow more
It is moved in the microballoon of hole, the skin tissue cell of above-mentioned movement is proliferated and makes skin tissue regeneration or increase body in the cavity in center
Product.That is, being present in the Premeabilisation of cells in bio-tissue to above-mentioned hollow porous micro sphere, growth is divided and can be formed new
Bio-tissue.An embodiment according to the present invention is high by degrading to above-mentioned stomatal limiting value inducing substance and hydrophobic biological
The mixing ratio of molecule is adjusted, so as to freely adjust the size in the cavity for being formed in microballoon center and form and divide
The size and form of the fine pores in next door, so as to assign be present in outside above-mentioned hollow porous micro sphere into fiber finer
Born of the same parents, adipocyte etc. can grow the space of division after penetrating into porous microsphere.
As an embodiment, the size of above-mentioned hollow porous micro sphere is formed in the cavity in center and the fine gas of partition wall
Hole can utilize microfluidic device or film emulsifier unit to be adjusted and manufacture.It, can be in the case of above-mentioned microfluidic device
By the way that the injection rate that discontinuous phase is injected into the conduit of conveying continuous phase with micro catheter is adjusted, so as to
To suitably sized controlling for microballoon.In the case that film emulsifies, instead of the micro catheter used in microfluidic device, pass through
Discontinuous phase is transported to the conduit of continuous phase flowing and controlled by the fixed-size film (membrane) of hole.
An embodiment according to the present invention, above-mentioned composition, which can be used for wrinkle of skin or skin depressions position, to be improved.More
Specifically, above-mentioned composition can be improved with the aging improvement comprising wrinkle of skin, skin complexion or skin elasticity improves use
Filler (filler) or promoted (lifting) the purpose of and use, it is but as long as being the regeneration based on skin, then and unlimited
Due to this, can include.For example, it can be used for artificial skin, artificial cartilage, bone filler, cosmetic prosthesis etc..On alternatively,
The composition of the present invention is stated as an embodiment, can also be used as pharmaceutical composition or cosmetic composition to provide.
In addition, skin tissue regeneration according to the present invention or skin histology volume increase composition for injection relative to combination
Object total weight can include the above-mentioned hollow porous micro sphere of 1 to 50 weight %.It is hollow porous micro- when less than above-mentioned 1 weight %
The content of ball is very few, is difficult to expect target effect when being injected into skin histology, can not pass through note when more than 50 weight %
It penetrates and is smoothly injecting into skin histology.More specifically, skin tissue regeneration or skin histology volume according to the present invention increases
Big composition for injection can include the above-mentioned hollow more of 5 to 20 weight % as an embodiment relative to composition total weight
Hole microballoon.
As an embodiment, above-mentioned composition is other than hollow porous micro sphere, in order to improve the group for including porous microsphere
It closes the sticky and stability of object and water soluble polymer can be included.As an embodiment, above-mentioned water soluble polymer can be with
Comprising selected from alginic acid (alginic acid), hyaluronic acid (hyaluronic acid), carboxymethyl cellulose
(carboxymethyl cellulose), glucan (dextran), collagen (collagen) and point as them
Solve the compound of one or more of gelatin (gelatin), the elastin laminin (elastin) of object.
In the following, the present invention is illustrated in more details by embodiment.These embodiments are used for the purpose of to the present invention
It is illustrated, and is not necessarily to be construed as the scope of the present invention and is defined in these embodiments, this is to those skilled in the art
It is obvious.
The manufacture 1 of [embodiment 1] hollow porous micro sphere
The hollow porous micro sphere of an embodiment according to the present invention has been manufactured by following methods.
Step 1：The making of microfluidic device (simple fluidic device)
It is put into pvc pipe and is bent No. 30 injection needles in 90 °, fine glass tube is inserted between injection needle and pvc pipe
And microfluidic device is made.The microfluidic device of making has blocked fine gap using epoxy adhesive.
Step 2：The manufacture of PLLA solution containing alkanes
Using PLLA (RESOMER the LR 704S, Evonik as hydrophobic biological degraded macromolecular of 0.1g
Industries AG), dichloromethane (34355-0350, Junsei), the alkanes as stomatal limiting value inducing substance of 10g
Substance, in particular octane (Octane, 412236, Sigma-aldrich) or hendecane (Undecane, U407, Sigma-
Aldrich) or tridecane (Tridecane, T57401, Sigma-aldrich) or pentadecane (Pentadecane, 76510,
Sigma-aldrich it is respectively) that 0.1g, 0.3g and 0.6g (1,3,6wt%) are mixed, so as to manufacture hydrophobic biological drop
Solve macromolecule (PLLA) solution.
Step 3：Manufacture uniform PLLA lotions
By the PLLA solution obtained in above-mentioned steps 2 using microfluidic device, using 2%PVA solution as continuous phase
Its flow velocity is set as 1.5ml per minute by (continuous phase), will contain the PLLA solution of alkanes as discontinuous phase
Flow velocity using No. 30 syringe needles, is set as 0.1ml per minute, so as to form a certain size by (discontinuous phase)
Lotion.
Step 4：The manufacture of uniform hollow porous micro sphere
The emulsion dispersion obtained in above-mentioned steps 3 is collected in 2%PVA in phase (collection phase), with
After 150rpm stirrings, dichloromethane is made fully to volatilize.
Step 5：It removes stomatal limiting value inducing substance and assigns porous
After the PLLA pearls obtained in above-mentioned steps 4 are washed for several times with distilled water (D.W.), made using freeze drier
Alkanes distil, so as to manufacture the porous PLLA pearls as evenly sized hollow porous micro sphere.
Each hollow porous micro sphere of above-mentioned manufacture is shown in Fig. 1.Containing with stomatal limiting value inducing substance can be confirmed
Amount increases or the length with carbochain, can more effectively manufacture cavity in microballoon center.
The manufacture 2 of [embodiment 2] hollow porous micro sphere
The hollow porous micro sphere of an embodiment according to the present invention has been manufactured by following methods.
Step 1：The making of microfluidic device (simple fluidic device)
It is put into pvc pipe and is bent No. 30 injection needles in 90 °, fine glass tube is inserted between injection needle and pvc pipe
And microfluidic device is made.The microfluidic device of making has blocked fine gap using epoxy adhesive.
Step 2：The manufacture of PLLA solution containing plant oil
Using PLLA (RESOMER the LR 704S, Evonik as hydrophobic biological degraded macromolecular of 0.1g
Industries AG), dichloromethane (34355-0350, Junsei), the cottonseed oil as stomatal limiting value inducing substance of 10g
Or each 0.5g of soya-bean oil is mixed, so as to make hydrophobic biological degraded macromolecular (PLLA) solution.
Step 3：Manufacture uniform PLLA lotions
By the PLLA solution obtained in step 2 above using microfluidic device, using 2%PVA solution as continuous phase
Its flow velocity is set as 1.5ml per minute by (continuous phase), will contain the PLLA solution of plant oil as discontinuous
Flow velocity using No. 30 syringe needles, is set as 0.1ml per minute by phase (discontinuous phase), certain big so as to be formed
Small lotion.
Step 4：The manufacture of uniform PLLA pearls
The emulsion dispersion obtained in above-mentioned steps 3 is collected in 2%PVA in phase (collection phase), with
After 150rpm is stirred, dichloromethane is made fully to volatilize.
Step 5：Removal internal porosity forms inducing substance and assigns porous
After the PLLA pearls obtained in above-mentioned steps 4 are washed for several times with distilled water (D.W.), gone using freeze drier
Except plant oil, so as to manufacture the porous PLLA pearls as evenly sized hollow porous micro sphere.
The manufacture of the composition for injection of [embodiment 3] containing hollow porous micro sphere
As one embodiment of the invention, by above-mentioned hollow porous micro sphere and for improving the composition for including porous microsphere
Viscosity and stability hyaluronic acid (hyaluronic acid), carboxymethyl cellulose (carboxymethyl
) etc. cellulose water soluble polymers are mixed and have manufactured composition for injection.
At this moment, shown in the following Tables 1 and 2 of the content of each composition, containing according to the content of each composition is also shown
There is the injection pressure measurement result of the composition for injection of hollow porous micro sphere.
[table 1]
[table 2]
The culture of [test example 1] skin tissue cell
As follows whether the hollow formation of the hollow porous micro sphere of an embodiment more according to the present invention cause
Cell mobility and proliferation effect experiment.
It, will be not comprising hollow porous microsphere (fine pore (small pores) as comparative example：Tridecane 3wt%) and
Above-described embodiment 1 includes hollow porous microsphere (macrovoid (Large pores)：The 13 of 6wt% are included as alkanes
Alkane) respectively in 70% ethyl alcohol after progress sterilization treatment, it is fully washed with PBS, transplants NIH3T3 fibroblasts and simultaneously observe
Cell Proliferation movement.By NIH3T3 fibroblasts with 1 × 103Cells/mL concentration is scattered in culture medium, utilizes revolving bottle
After (spinner flask) is stirred 6 hours, porous granule is moved on in culture vessel (culture Plate) and is cultivated.
Cell culture the 1st, 3,7,10 days, after each porous microsphere particle of above-mentioned culture is carried out LIVE/DEAD dyeing, pass through copolymerization
Focusing microscope and MTT detections, which adhere to cell and whether there is proliferation, to be confirmed.As shown in Figures 2 and 3, it can be confirmed in including
Empty hollow porous micro sphere (Large pores) is not with including porous microsphere (Small that is hollow and only including fine pores
Pores it) compares, internally the infiltration of stomata and proliferation carried out well to the 10th day NIH3T3 fibroblasts.This represents packet
Be contained in porous microsphere it is hollow to Premeabilisation of cells and proliferation have big effect.
The cell mobility for the hollow porous micro sphere that [test example 2] passes through zoopery and regeneration efficacy assessments
As follows whether the hollow formation of the hollow porous micro sphere of an embodiment more according to the present invention cause
Cell mobility and regeneration effect experiment.
It, will be not comprising hollow porous microsphere (fine pore (small pores) as comparative example：Tridecane 3wt%) and
Above-described embodiment 1 includes hollow porous microsphere (macrovoid (Large pores)：The 13 of 6wt% are included as alkanes
Alkane) sterilization treatment has been carried out in 70% ethyl alcohol respectively.It with PBS is fully washed, porous PLLA particles are scattered in PBS
Phase, and the subcutaneous of nude mice is injected into using No. 23 needles, whether through 8 weeks to Premeabilisation of cells and cell Proliferation in porous microsphere
It is observed.After injecting porous microsphere, the skin of nude mice was cut respectively at the 2nd, 4,6,8 week up to subcutaneous particle fraction, 4%
After formaldehyde fixes 3 hours, by the tissue impregnated of 12 hours in 30% sucrose (saccharose) solution.Then, by cold
Freeze histotome (cryo microtome) with 20 μm big little makings freezing microtome section (cryo section).By freezing microtome section
Tissue be attached on glass slide, dry 3 hours in 50 DEG C of heating plates (heating block), so that tissue is attached to load well
On slide.H＆E dyeing is carried out to the histotomy, the tissue reaction around porous PLLA microballoons is observed.
As a result, as shown in figure 4, the porous microsphere (fine pore (Small of fine pores is only included not comprising hollow
Pores in the case of)), until the 8th week, cell is mostly present in outside, but includes hollow hollow porous micro sphere
In the case of (macrovoid (Large pores)), Premeabilisation of cells to inside particles and show inducing new tissue generation state.
In addition, particle does not still decompose completely after 8 weeks, it is possible thereby to confirm that porous microsphere can be kept for a long time in vivo.
The injection property of the composition of [test example 3] comprising hollow porous micro sphere measures
Implement the performance test for determining whether to inject to be infused in the composition manufactured in above-mentioned Tables 1 and 2.
Tension tester is set as compression strength measurement pattern (mode) and determines injection property.Removal is equipped with comprising each hollow
Lid (cap) of the composition of porous microsphere as the syringe of content after installation has the injection needle of the specification of 23G, will be noted
Emitter is fixed in a manner that injection needle is downside perpendicular to tension tester assay plate.Start tension tester, on one side
The push rod (plunger) of installation on the injector was pushed away with the speed of 1mm/ seconds, the power according to compression is determined on one side, until being mounted in
Until content in syringe is completely emptying.
It the results are shown in above-mentioned table 1 and 2.From table 1 and 2 as can be seen that when hollow porous micro sphere is scattered in 2% respectively
Hyaluronic acid, 2% carboxymethyl cellulose and in the case of measuring injection property, as shown in comparison manufacturing example 1 and 2, in composition
In the case that the content of microballoon is more than 50 weight %, it can not inject.
Form compares before and after the injection injection of the composition of [test example 4] comprising hollow porous micro sphere
In order to confirm injection injection comprising hollow porous micro sphere according to an embodiment of the invention composition after whether
There is metamorphosis, for the Production Example 6 of above-mentioned table 1, collect the preceding sample with after experiment of injection property experiment, pass through laser capture microdissection
Mirror (3D measuring laser microscope, Olympus) observes the metamorphosis of hollow porous micro sphere.
It the results are shown in Fig. 5.From fig. 5, it can be seen that in the case of Production Example 6, even if can be confirmed under high injection pressure, with
It is compared before injection, the form of porous microsphere can be kept well.
The present invention can provide following embodiment as an embodiment.
1st embodiment can provide a kind of skin tissue regeneration or skin histology volume increase composition for injection,
In, comprising hollow porous micro sphere, which includes being formed in the cavity in center with the above-mentioned cavity of encirclement comprising micro-
The partition wall of thin stomata.
2nd embodiment can be provided according to the skin tissue regeneration described in the 1st embodiment or the increasing of skin histology volume
Big composition for injection, wherein, the average diameter in the cavity of above-mentioned hollow porous micro sphere is 5 to 150 μm.
3rd embodiment can be provided according to the above-described skin of any one of the 1st embodiment and the 2nd embodiment
Skin tissue regenerates or skin histology volume increase composition for injection, wherein, the average diameter of above-mentioned hollow porous micro sphere is 50
To 200 μm.
4th embodiment can be provided according to the 1st embodiment to the above-described skin of any one of the 3rd embodiment
Skin tissue regenerates or skin histology volume increase composition for injection, wherein, the volume phase in the cavity of above-mentioned hollow porous micro sphere
It is 20 to 80 volume % for above-mentioned hollow porous micro sphere whole volume.
5th embodiment can be provided according to the 1st embodiment to the above-described skin of any one of the 4th embodiment
Skin tissue regenerates or skin histology volume increase composition for injection, wherein, the fine pores of above-mentioned hollow porous micro sphere are put down
It is 5 to 50 μm a diameter of.
6th embodiment can be provided according to the 1st embodiment to the above-described skin of any one of the 5th embodiment
Skin tissue regenerates or skin histology volume increase composition for injection, wherein, the porosity of above-mentioned hollow porous micro sphere is average
20 to 80%.
7th embodiment can be provided according to the 1st embodiment to the above-described skin of any one of the 6th embodiment
Skin tissue regenerates or skin histology volume increase composition for injection, wherein, above-mentioned hollow porous micro sphere includes hydrophobic biological
Degraded macromolecular.
8th embodiment can be provided according to the skin tissue regeneration described in the 7th embodiment or the increasing of skin histology volume
Big composition for injection, wherein, above-mentioned hydrophobic biological degraded macromolecular be selected from polylactic acid (Poly-L-Lactic Acid,
PLLA), polyglycolic acid (polyglycolic acid, PGA), polylactic-co-glycolic acid (poly (lactic-co-
Glycolic acid), PLGA), it is poly-epsilon-caprolactone (Polycaprolactone, PCL), polyanhydride (polyanhydrides), poly-
Ortho esters (polyorthoe ster), polyvinyl alcohol (polyviniyalcohol), polyethylene glycol
(polyethyleneglycol), polyurethanes (polyurethane), polyacrylic acid (polyacrylic acid),
Poly- n-isopropyl acrylamide (Poly-N-isopropyl acrylamide), poly- (ethylene oxide)-poly- (propylene oxide)-poly-
(ethylene oxide) copolymer (poly ethylene oxide)-poly propylene oxide-poly ethylene
Oxide copolymer), one or more of their copolymer and their mixture.
9th embodiment can be provided according to the 1st embodiment to the above-described skin of any one of the 8th embodiment
Skin tissue regenerates or skin histology volume increase composition for injection, wherein, the cavity of above-mentioned hollow porous micro sphere and fine gas
It is the hydrophobic fluid for being less than water without intermiscibility and density with hydrophobic biological degraded macromolecular that hole, which forms inducing substance,.
10th embodiment can be provided according to the skin tissue regeneration described in the 9th embodiment or the increasing of skin histology volume
Big composition for injection, wherein, above-mentioned cavity and fine pores form inducing substance as selected from alkane (alkane) class, vegetalitas
One or more of oil and their mixture.
11st embodiment can be provided according to the skin tissue regeneration or skin histology volume described in the 10th embodiment
Increase composition for injection, wherein, above-mentioned alkanes are selected from octane (Octane), hendecane (Undecane), tridecane
(Tridecane), one or more of pentadecane (Pentadecane) and their mixture, above-mentioned plant oil be selected from
One kind in soya-bean oil, corn oil, cottonseed oil, olive oil, grape seed oil, walnut oil, sesame oil, perilla oil and their mixture
More than.
12nd embodiment can provide above-described to any one of the 11st embodiment according to the 1st embodiment
Skin tissue regeneration or skin histology volume increase composition for injection, wherein, above-mentioned composition is also included selected from alginic acid
(alginic acid), hyaluronic acid (hyaluronic acid), carboxymethyl cellulose (carboxymethyl
Cellulose), glucan (dextran), collagen (collagen), gelatin (gelatin) and elastin laminin
One or more of (elastin) water soluble polymer.
13rd embodiment can provide above-described to any one of the 12nd embodiment according to the 1st embodiment
Skin tissue regeneration or skin histology volume increase composition for injection, wherein, above-mentioned composition is relative to composition total weight
Include the above-mentioned hollow porous micro sphere of 1 to 50 weight %.
14th embodiment can provide above-described to any one of the 13rd embodiment according to the 1st embodiment
Skin tissue regeneration or skin histology volume increase composition for injection, wherein, above-mentioned skin tissue regeneration or skin tissue
Product increase is that organism inner skin histocyte is moved by above-mentioned fine pores into above-mentioned hollow porous micro sphere, in center
In cavity, the skin tissue cell of above-mentioned movement is proliferated and makes skin tissue regeneration or increase volume.
15th embodiment can provide above-described to any one of the 14th embodiment according to the 1st embodiment
Skin tissue regeneration or skin histology volume increase composition for injection, wherein, above-mentioned composition is recessed for wrinkle of skin or skin
Concave portion position improves filler composition.
The above embodiment be in order to the present invention will be described and it is disclosed, above description do not limit the present invention model
It encloses.Therefore, as long as no more than meaning of the present invention and range, then those skilled in the art various modifications can be carried out, deformation and
It replaces.
Claims (15)
1. a kind of skin tissue regeneration or skin histology volume increase composition for injection comprising hollow porous micro sphere, institute
Hollow porous micro sphere is stated to include being formed in the cavity in center and surround the partition wall for including fine pores in the cavity.
2. skin tissue regeneration according to claim 1 or skin histology volume increase composition for injection, wherein, it is described
The average diameter in the cavity of hollow porous micro sphere is 5 to 150 μm.
3. skin tissue regeneration according to claim 1 or skin histology volume increase composition for injection, wherein, it is described
The average diameter of hollow porous micro sphere is 50 to 200 μm.
4. skin tissue regeneration according to claim 1 or skin histology volume increase composition for injection, wherein, it is described
The volume in the cavity of hollow porous micro sphere is 20 to 80 volume % relative to the hollow porous micro sphere whole volume.
5. skin tissue regeneration according to claim 1 or skin histology volume increase composition for injection, wherein, it is described
The average diameter of the fine pores of hollow porous micro sphere is 5 to 50 μm.
6. skin tissue regeneration according to claim 1 or skin histology volume increase composition for injection, wherein, it is described
The porosity of hollow porous micro sphere is average 20 to 80%.
7. skin tissue regeneration according to claim 1 or skin histology volume increase composition for injection, wherein, it is described
Hollow porous micro sphere includes hydrophobic biological degraded macromolecular.
8. skin tissue regeneration according to claim 7 or skin histology volume increase composition for injection, wherein, it is described
Hydrophobic biological degraded macromolecular is selected from polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, poly-epsilon-caprolactone, gathers
Acid anhydride, polyorthoester, polyvinyl alcohol, polyethylene glycol, polyurethanes, polyacrylic acid, poly- n-isopropyl acrylamide, poly- (ring
Oxidative ethane)-poly- (propylene oxide)-poly- (ethylene oxide) copolymer, one kind in their copolymer and their mixture
More than.
9. skin tissue regeneration according to claim 1 or skin histology volume increase composition for injection, wherein, it is described
It is not have intermiscibility with hydrophobic biological degraded macromolecular that the cavity of hollow porous micro sphere and fine pores, which form inducing substance,
And density is less than the hydrophobic fluid of water.
10. skin tissue regeneration according to claim 9 or skin histology volume increase composition for injection, wherein, institute
It states cavity and fine pores forms inducing substance as selected from one or more of alkanes, plant oil and their mixture.
11. skin tissue regeneration according to claim 10 or skin histology volume increase composition for injection, wherein, institute
State alkanes be selected from one or more of octane, hendecane, tridecane, pentadecane and their mixture,
The plant oil is selected from soya-bean oil, corn oil, cottonseed oil, olive oil, grape seed oil, walnut oil, sesame oil, perilla oil
One or more of with their mixture.
12. skin tissue regeneration according to claim 1 or skin histology volume increase composition for injection, wherein, institute
Composition is stated also to include in alginic acid, hyaluronic acid, carboxymethyl cellulose, glucan, collagen, gelatin and elastin laminin
1 kind or more of water soluble polymer.
13. skin tissue regeneration according to claim 1 or skin histology volume increase composition for injection, wherein, institute
State the hollow porous micro sphere that composition includes 1 to 50 weight % relative to composition total weight.
14. skin tissue regeneration according to claim 1 or skin histology volume increase composition for injection, wherein, institute
It is that organism inner skin histocyte is moved to by the fine pores to state skin tissue regeneration or the increase of skin histology volume
In the hollow porous micro sphere, the skin tissue cell moved described in the cavity in center is proliferated and makes skin histology again
Life increases volume.
15. skin tissue regeneration or skin histology volume increase injection group according to any one of claim 1 to 14
Object is closed, wherein, the composition improves filler composition for wrinkle of skin or skin depressions position.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2015-0143524 | 2015-10-14 | ||
| KR1020150143524A KR102404093B1 (en) | 2015-10-14 | 2015-10-14 | Injectable composition for regenerating or enhancing volume of skin tissues comprising hollow porous microspheres |
| PCT/KR2016/010857 WO2017065429A1 (en) | 2015-10-14 | 2016-09-28 | Injectable composition for skin tissue regeneration or skin tissue volume increase comprising hollow porous microspheres |
Publications (1)
| Publication Number | Publication Date |
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| CN108135808A true CN108135808A (en) | 2018-06-08 |
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| CN201680060085.XA Pending CN108135808A (en) | 2015-10-14 | 2016-09-28 | Skin tissue regeneration comprising hollow porous micro sphere or skin histology volume increase composition for injection |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP6605722B2 (en) |
| KR (1) | KR102404093B1 (en) |
| CN (1) | CN108135808A (en) |
| WO (1) | WO2017065429A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111184909A (en) * | 2019-10-21 | 2020-05-22 | 湖北翎美生物科技有限公司 | Hyaluronic acid sustained-release filler and preparation method thereof |
| CN112438906A (en) * | 2020-11-02 | 2021-03-05 | 周军臣 | Preparation method of wrinkle-removing needle |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101967153B1 (en) * | 2018-04-04 | 2019-04-09 | 윤성준 | The material composition of the filler improving wrinkles, atrophic scars and other skin deficits |
| KR102094407B1 (en) * | 2020-01-21 | 2020-03-31 | 주식회사 울트라브이 | Fabrication method of hybrid hydrogel, Fabricaltion method of injection comprising the same, and Hybrid hydrogel |
| CN115850730A (en) * | 2021-09-23 | 2023-03-28 | 四川大学 | Use of photo-cured porous hydrogel material as hemostatic material |
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Also Published As
| Publication number | Publication date |
|---|---|
| JP6605722B2 (en) | 2019-11-13 |
| WO2017065429A1 (en) | 2017-04-20 |
| JP2018529454A (en) | 2018-10-11 |
| KR102404093B1 (en) | 2022-06-02 |
| KR20170043887A (en) | 2017-04-24 |
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Application publication date: 20180608 |